Ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides

Article abstract of DOI:10.1016/j.jorganchem.2011.08.026

A ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides was found to afford corresponding amides in good to high yields. A simple RuCl ₃/Zn-Cu/alcohol system, without the addition of any other ligands, exhibited a high catalytic activity, and therefore the present reaction does not require a stoichiometric amount of metals or metal complexes as reductants. When β-substituted-α,β-unsaturated N-methoxyamides were employed as substrates, concurrent hydrogenation of the olefin moiety proceeded slowly with deprotection of the methoxy group. In the reduction of N-hydroxyamides, the alcoholic solvent was found to function as a hydrogen donor.

Full text of DOI:10.1016/j.jorganchem.2011.08.026

Journal of Organometallic Chemistry 696 (2011) 3643e3648
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides
*
Hiroko Fukuzawa, Yasuyuki Ura , Yasutaka Kataoka
Department of Chemistry, Faculty of Science, Nara Women’s University, Kitauoyanishi-machi, Nara 630-8506, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides was found to afford corresponding
amides in good to high yields. A simple RuCl3/ZneCu/alcohol system, without the addition of any other
ligands, exhibited a high catalytic activity, and therefore the present reaction does not require a stoi-
Received 10 June 2011
Received in revised form
11 August 2011
chiometric amount of metals or metal complexes as reductants. When b-substituted-a,b-unsaturated
Accepted 18 August 2011
N-methoxyamides were employed as substrates, concurrent hydrogenation of the olefin moiety pro-
ceeded slowly with deprotection of the methoxy group. In the reduction of N-hydroxyamides, the
alcoholic solvent was found to function as a hydrogen donor.
Keywords:
Reduction
Ó 2011 Elsevier B.V. All rights reserved.
Deprotection
N-Alkoxyamides
N-Hydroxyamides
Hydroxamic acids
Ruthenium
1. Introduction
2. Results and discussion
N-Alkoxy- and N-hydroxyamides (hydroxamic acids and their
derivatives) have been widely used as biologically active
compounds [1e3] as well as versatile synthetic intermediates [4].
2.1. Optimization of reaction conditions
Initially, N-methyl-N-methoxybutyramide (1a), which is known
as a Weinreb amide [4a], was treated with 5 mol% of RuCl3$3H2O and
30 mol% of ZneCu couple in MeOH at 80 ꢀC under an argon atmo-
sphere. The reduction proceeded to give the deprotected product, N-
methylbutyramide (2a), in 76% NMR yield after 24 h (Eq. (1)).
In the synthesis of b-lactams [5] and compounds derived from O-
alkyl oximes [6], the alkoxy groups of the alkoxyamide moieties are
utilized as protecting groups, and Li [5a,7], Cp2TiCl2/Zn (or Mn)
[5d], H2ePd/C and TiCl3 [5b,c], TiCl3 only [8] and SmI2 [6] have been
employed as reductants in conventional methods for deprotection.
N-Hydroxyamides can be reduced by titanium complexes as well
[5bed]. As non-metal reductants, tert-butyldimethylsilyl triflate/
triethylamine [9] and an organic neutral super-electron donor [10]
have also been reported. These reactions occur via single-electron
transfer and require a stoichiometric amount of metals, metal
complexes or organic reductants.
During the course of our investigation on the reactions of
Weinreb amides in the presence of ruthenium complexes, we found
that the NeO bond cleavage occurred efficiently to afford the cor-
responding deprotected amides. We report here a novel catalytic
reduction of N-alkoxyamides using a simple RuCl3/ZneCu/alcohol
system, which was also found to be effective for the reduction of N-
hydroxyamides.
The catalytic activity of other ruthenium complexes such as
[RuCl2(CO)3]2, RuCl2(PPh3)3, [RuCl2(1,5-cyclooctadiene)]n, [RuCl2(2,5-
norbornadiene)]n, [Cp*RuCl2]2 (Cp*¼ pentamethylcyclopentadienyl),
RuCl4(2,20-bipyridine), [RuCl2(C6H6)]2, and [RuCl2(p-cymene)]2 was
examinedinthepresenceofZneCuinMeOH. In mostcases, theyields
were less than 30% and none were comparable to RuCl3. In the
absence of ZneCu, Ru(C6H6)(methyl acrylate)2 [11], a zerovalent
complex, was employed for the reaction in toluene at 130 ꢀC for 24 h.
However, this resulted in a low yield (21%). We also attempted the
reactions with additives such as monodentate/bidentate nitrogen or
phosphorous ligands (5e10 mol%) under the same reaction condi-
tions as in Eq. (1); however, lower yields of the product (12e46%)
were obtained in all cases.
* Corresponding author. Tel.: þ81 742 20 3403; fax: þ81 742 20 3979.
E-mail address: ura@cc.nara-wu.ac.jp (Y. Ura).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.08.026

3644
H. Fukuzawa et al. / Journal of Organometallic Chemistry 696 (2011) 3643e3648
Table 1
proceeded smoothly to give butyramide (2d) (entry 6). A benzyloxy
protected amide, N-methyl-N-benzyloxybutyramide (1e), also
afforded 2a (entry 7) with the formation of benzyl alcohol (65%)
and benzaldehyde (21%), whereas the reaction of N-methyl-N-iso-
propoxybutyramide (1f) was sluggish, probably because of steric
hindrance (entry 8). The reduction was also found to be applicable
to N-hydroxyamides 1gei, resulting in 2a, N-phenylbutyramide
(2e), and 2d, respectively (entries 9e11). Although all the substrates
converted in these cases, the yields varied from moderate to high
depending on the substituents on the nitrogen atoms.
Effects of various solvents and reaction temperatures.a
Entry Solvent
Temp. (ꢀC)b Conversion of 1a (%)c Yield of 2a (%)c
1
2
3
4
5
6
MeOH
EtOH
EtOH
2-PrOH
2-BuOH
EtOH/H2O ¼ 10:1 100
80
80
100
100
110
76
83
97
90
78
50
76
83
97
90
73
43
The present method was applied to
b-substituted-a,b-unsatu-
rated N-methoxyamides (Table 4) [12]. The deprotection proceeded
as well, but hydrogenation of the olefin moiety occurred simulta-
neously. When N-methyl-N-methoxycrotonamide (3a) was
employed, there was a low yield of N-methylcrotonamide (4a),
whereas in the case of N-methyl-N-methoxycinnamamide (3b), the
yield of deprotected product 4b was up to 93% after 6 h and that of
deprotected/hydrogenated product 2f was 6% (entry 2) [13]. In the
both cases, the formation ratios of 4/2 were high at the early stage
(3 h), and the highest yields of 4 were observed after 6 h. The yields
of 4 decreased after 24 h along with the further formation of 2.
Whereas the conversions of the substrate 3b and the total yields of
the products 4b and 2f are well balanced (entry 2), the conversions
of 3a are approximately 15e30% higher than the total yields of 4a
and 2a (entry 1). The imbalance may be attributable to the strong
a
Reaction conditions: amide 1a (0.50 mmol), RuCl3$3H2O (0.025 mmol), ZneCu
(0.15 mmol), and solvent (1.0 mL) for 24 h.
b
Bath temperature.
c
Determined by 1H NMR. Dibenzyl ether was used as an internal standard.
Next we examined the effects of various solvents and reaction
temperatures (Table 1). The use of EtOH instead of MeOH gave
a slightly higher yield of 2a (entry 2) and raising the bath
temperature to 100 ꢀC gave the best result of 97% (entry 3).
Secondary alcohols such as 2-PrOH and 2-BuOH were also effective;
however, these lowered the yield as compared to that of EtOH
(entries 4 and 5). The presence of a certain amount of water (EtOH/
H2O ¼ 10:1) considerably inhibited the reduction (entry 6).
The effects of reductants were also examined (Table 2). Even in
the absence of a reductant, the reaction proceeded to give 13% of 2a
(entry 1). Although 5 mol% of ZneCu did not operate well (entry 2),
both conversion and yield were critically improved by using more
than 15 mol% (entries 3 and 4). Either Zn or Mg did not compare
with ZneCu (entries 5 and 6).
coordination of
p-acidic a,b-unsaturated amides 3a and/or 4a to
ruthenium, by which they cannot be detected as free amides. The
aforementioned changes in the yields of the products 4 and 2 with
time, and the fact that hydrogenated products of 3 without
deprotection were not formed during the course of the reactions,
indicate that the deprotection rather than the hydrogenation from
3 proceeds preferentially to afford 4, and then the hydrogenation of
4 would follow.
2.3. Possible reaction mechanisms
2.2. Scope of substrates
To elucidate the role of the solvent molecule in the catalytic
cycle, the reduction of 1h was performed in 2-octanol at 100 ꢀC for
6 h (Eq. (2)). As a result, 2-octanone was formed in 45% NMR yield
along with the formation of deprotected amide 2e in 86% NMR
yield. Although a small amount of 2-octanone (9%) was detected
even in the absence of 1h under the same reaction conditions as in
Eq. (2), these results imply the participation of the solvent as
a hydrogen donor in the catalytic cycle of the reduction.
The optimized reaction conditions found above were applied to
several N-alkoxyamides (Table 3). Decreasing the precatalyst
loading to 2 mol% slightly lowered the yield (entry 2), whereas
decreasing to 1 mol% resulted in substantially low conversion (54%)
and yield (34%) (entry 3). Relatively bulky N-methyl-N-methox-
ypivalamide (1b) was converted to N-methylpivalamide (2b) in
24 h (entry 4). N-Methyl-N-methoxybenzamide (1c) afforded N-
methylbenzamide (2c) in high yield (entry 5). In addition, the
reaction of N-methoxybutyramide (1d) having an amide proton
Table 2
Effects of reductants.a
Taking these observations into consideration, three possible
reaction mechanisms are proposed as shown in Scheme 1. In each
mechanism, either a zerovalent ruthenium complex or a divalent
ruthenium hydride complex is supposed to be involved as a cata-
lytically active species. Zerovalent ruthenium complexes such as
Entry Reductant Amount (mol%) Conversion of 1a (%)b Yield of 2a (%)b
1
2
3
4
5
6
None
ZneCu
ZneCu
ZneCu
Zn
16
33
91
97
100
50
13
13
91
97
86
34
5
15
30
30
30
Ru(1,5-cyclooctadiene)(1,3,5-cyclooctatriene),
Ru(benzene)(1,3-
cyclohexadiene) [14] and Ru{P(OMe)3}(dimethyl muconate)2 [15]
are known to be formed from RuCl3$3H2O in the presence of Zn
and appropriate ligands in an alcoholic solvent, and divalent
ruthenium hydride species can be generated under the similar
reaction conditions as well [15]. In Path A, N-alkoxy- or N-
hydroxyamide 1 coordinates to zerovalent ruthenium species 5 to
Mg
a
Reaction conditions: amide 1a (0.50 mmol), RuCl3$3H2O (0.025 mmol), reduc-
tant (0e0.15 mmol), and EtOH (1.0 mL) at 100 ꢀC for 24 h.
b
Determined by 1H NMR. Dibenzyl ether was used as an internal standard.

H. Fukuzawa et al. / Journal of Organometallic Chemistry 696 (2011) 3643e3648
3645
Table 3
Reduction of several N-alkoxy- and N-hydroxyamides.a
Entry
1
Substrate
Product
Ru Catalyst (mol%)
Time (h)
Conversion of 1 (%)b
Yield of 2 (%)b,c
6
24
94
97
94
97 (93)
1a
2a
5
2
3
2
1
24
24
96
54
90
34
6
24
64
100
64
>99 (95)
4
5
1b
1c
2b
2c
5
5
6
24
91
96
91 (85)
96
6
7
1d
1e
2d
2a
5
3
3
100
100
89 (81)
10
>99 (92)
6
24
41
74
41
74 (60)
8
1f
2a
2a
10
3
20
100
100
65
74 (72)
9
1g
5
10
1h
1i
2e
2d
5
5
4
3
100
100
98 (89)
66 (62)
11
a
Reaction conditions: amide 1 (0.50 mmol), RuCl3$3H2O (0.005e0.05 mmol), ZneCu (0.03e0.3 mmol, 6 equiv. relative to RuCl3$3H2O), and EtOH (1.0 mL) at 100 ꢀC.
Determined by 1H NMR. Dibenzyl ether was used as an internal standard.
Isolated yields are shown in parentheses.
b
c
form 6, and oxidative addition of the NeO bond occurs to give
deprotected product 2 is dissociated to regenerate 5. The result
using zerovalent complex, Ru(C6H6)(methyl acrylate)2,
mentioned in Section 2.1 may support Path A, while the yield of the
product was low.
divalent ruthenium species 7 having amidato and alkoxo (or
hydroxo) ligands [16]. At this stage, the alkoxo (or hydroxo) ligand
may exchange with an external alcohol used as a solvent. The
a
subsequent
date hydride species 9 along with an aldehyde (or ketone), and
reductive elimination from affords 10, from which the
b
-hydrogen elimination from 8 gives ruthenium ami-
On the other hand, both Paths B and C involve only divalent
ruthenium species. In Path B, divalent ruthenium hydride species
11 is formed initially, and subsequent coordination of 1 to
9

3646
H. Fukuzawa et al. / Journal of Organometallic Chemistry 696 (2011) 3643e3648
Table 4
ruthenium gives 12. Elimination of alcohol (or water) via weak NeO
bond cleavage, followed by the reaction with EtOH, liberates 2
along with the formation of 14, from which -hydrogen elimination
Reduction of a,b
-unsaturated N-methoxyamides.a
b
proceeds to regenerate 11. In Path C, another type of NeO bond
cleavage occurs from 12, where the hydride ligand migrates to
nitrogen to form 2 and 15. To evaluate the validity of Paths B and C,
the reactions of 1a using ruthenium hydride complexes,
RuHCl(PPh3)3 and RuHCl(CO)(PPh3)3, as a precatalyst (5 mol%) in
the absence of ZneCu in MeOH at 80 ꢀC for 24 h were performed. As
a result, the yields of the deprotected product 2a were low (10% and
9%, respectively); however, since the presence of phosphorous
ligands tends to lower the yield as mentioned in Section 2.1, these
results may be still reasonable even if the reaction proceeds via
Path B or C.
Although all of these mechanisms can explain most of the ob-
tained experimental results, the relativelylow yield of 2-octanone as
compared to that of 2e in Eq. (2) is unexpected, because the yields of
these compounds should be nearly equal according to the mecha-
nisms proposed above. This fact indicates that other mechanisms
may be concurrently involved in the present reaction. In any case, it
appears to be difficult to elucidate the mechanism at this stage.
Entry
1
R
Substrate Products Time (h) Conversion Yield
Yield
of 3 (%)b
of 4 (%)b,c of 2 (%)b,c
Me 3a
4a, 2a
4b, 2f
3
6
24
3
86
99
100
82
48
56 (52)
47
6
13 (13)
38
4
6
18
2
Ph 3b
76
6
24
99
100
93 (79)
81
a
Amide 3 (0.50 mmol), RuCl3$3H2O (0.025 mmol), ZneCu (0.15 mmol) and EtOH
(1.0 mL) at 100 ꢀC.
b
Determined by 1H NMR. Dibenzyl ether was used as an internal standard.
Isolated yields are shown in parentheses.
3. Conclusions
c
We have developed a novel ruthenium-catalyzed reduction of
N-alkoxy- and N-hydroxyamides to give corresponding amides. A
simple RuCl3/ZneCu/alcohol system, without the addition of
ligands, exhibited a high catalytic activity. In the reduction of N-
hydroxyamides, the alcoholic solvent was found to function as
a hydrogen donor. The present method does not require a stoi-
chiometric amount of metals or metal complexes as reductants, and
may complement the reported procedures which proceed via
single-electron transfer.
4. Experimental section
4.1. General
RuCl3$3H2O was purchased from Furuya Metal. [RuCl2(CO)3]2
and [RuCl2(p-cymene)]2 were obtained from Strem and
SigmaeAldrich, respectively. Other ruthenium catalysts,
RuCl2(PPh3)3 [17], [RuCl2(1,5-cyclooctadiene)]n [18], [RuCl2(2,5-
norbornadiene)]n [19], [Cp*RuCl2]2 [20], RuCl4(2,20-bipyridine)
[21], [RuCl2(C6H6)]2 [22], Ru(C6H6)(methyl acrylate)2 [11], and
ZneCu [23] were prepared as described in the literature. N-Alkoxy-
and N-hydroxyamides were prepared by the similar procedure re-
ported previously [24,25]. Dehydrated EtOH was purchased from
Wako Pure Chemical Industries. Other dehydrated solvents were
obtained from Wako, Nacalai Tesque and SigmaeAldrich. Other
chemicals were also commercially available and were used without
further purification. All reactions were performed under an argon
atmosphere. Flash column chromatography was performed using
silica gel SILICYCLE SiliaFlash F60 (40e63 mm, 230e400 mesh). NMR
spectra were recorded on either a JEOL AL-400 (400 MHz (1H),
100 MHz (13C)) or a Bruker AV-300N (300 MHz (1H), 75 MHz (13C))
spectrometer. Chemical shift values (d) were expressed relative to
SiMe4. IR measurements (ATR) were carried out using a JASCO FT/IR-
6100 spectrometer. Elemental analysis was obtained using a J-
SCIENCE LAB JM-10 analyzer. Mass spectra were recorded on either
a JEOL JMS-T100LC or a SHIMADZU GCMS-QP5050 spectrometer.
4.2. Preparation of N-methoxyamides 1aed, 3aeb
A
procedure for N-methyl-N-methoxybutyramide (1a) is
Scheme 1. Possible reaction mechanisms.
representative. Dry pyridine (8.90 mL, 110 mmol) was added

H. Fukuzawa et al. / Journal of Organometallic Chemistry 696 (2011) 3643e3648
3647
dropwise to a mixture of N,O-dimethylhydroxylamine hydrochlo-
ride (5.36 g, 55 mmol) and butyryl chloride (5.19 mL, 50 mmol) in
CH2Cl2 (150 mL) at 0 ꢀC under argon. The reaction mixture was
warmed up to room temperature and stirred for 2 h. The solvent
was evaporated to give a white solid, to which a saturated brine and
a 1:1 mixture of Et2O/CH2Cl2 were added for extraction. The
aqueous layer was further extracted by a 1:1 mixture of Et2O/
CH2Cl2 three times. The combined organic layer was dried over
MgSO4, filtered, and the solvent was evaporated to dry. Purification
by flash column chromatography (eluent: hexane/ethyl
acetate ¼ 1:1) afforded 1a (3.89 g, 29.7 mmol) as a colorless oil in
59% yield. Spectral data were consistent with those reported
previously [26].
mixture of NaHCO3 (1.26 g, 15 mmol) and N-methylhydroxylamine
hydrochloride (0.42 g, 5.0 mmol) and the solution was vigorously
stirred. Butyryl chloride (0.52 mL, 5.0 mmol) was added dropwise
to the reaction mixture at 0 ꢀC, and then the mixture was stirred at
room temperature for 3 h. The organic layer was separated, and the
aqueous layer was acidified with AcOH and was extracted with
Et2O three times. The combined organic layer was dried over
MgSO4, filtered, and the solvent was evaporated to dry. Purification
by flash column chromatography (eluent: hexane/ethyl
acetate ¼ 2:1) afforded 1g (0.35 g, 3.0 mmol) as a colorless oil in
60% yield. Spectral data were consistent with those reported
previously [31]. Compounds 1h and 1i were prepared in the same
manner.
Compounds 1bed and 3a,b were prepared in the same manner,
and the spectral data for N-methyl-N-methoxypivalamide (1b) [27],
N-methyl-N-methoxybenzamide (1c) [28], N-methyl-N-methox-
ycrotonamide (3a) [29] and N-methyl-N-methoxycinnamamide
(3b) [30] were in accordance with those in the literature.
4.4.1. N-Phenyl-N-hydroxybutyramide (1h)
Colorless plate crystal. IR spectrum (ATR): 3171, 2958,
1626 cmꢁ1 1H NMR (CDCl3, 400 MHz):
. d 8.95 (br s, 1H, OH),
7.47e7.32 (m, 5H, arom.), 2.28 (br s, 2H, CH2CO), 1.72e1.61 (m, 2H,
CH2), 0.89 (t, J ¼ 7.6 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 168.5
4.2.1. N-Methoxybutyramide (1d)
(C]O), 138.4 (ipso-C of Ph), 129.2 (Ph), 126.7 (Ph), 126.6 (Ph), 34.2
(CH2CO), 18.7 (CH2), 13.7 (CH3). Anal. Calcd for C10H13NO: C, 67.02;
H, 7.31; N, 7.82. Found: C, 66.67; H, 7.27; N, 7.71.
Colorless oil. IR spectrum (ATR): 3195, 2967, 1661, 1519,
1057 cmꢁ1. 1H NMR (CDCl3, 300 MHz):
d 9.98 (br s, 1H, NH), 3.67 (s,
3H, OCH3), 2.04 (br t, J ¼ 6.9 Hz, 2H, CH2CO), 1.66e1.54 (m, 2H, CH2),
0.88 (t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 75 MHz):
d
171.0 (C]
4.4.2. N-Hydroxybutyramide (1i)
O), 63.9 (NOCH3), 34.8 (eCH2COe),18.8 (CH2),13.5 (CH3). MS (EI) m/
Pale yellow oil. IR spectrum (ATR): 3224, 2967, 1645 cmꢁ1
.
1H
z 117 (Mþ).
NMR (CDCl3, 300 MHz):
d 8.34 (br s, 1H), 3.49 (s, 1H), 2.13 (t,
J ¼ 7.3 Hz, 2H, CH2CO),1.71e1.64 (m, 2H, CH2), 0.95 (t, J ¼ 7.3 Hz, 3H,
4.3. Preparation of N-benzyloxyamide 1e and N-isopropoxyamide
1f
CH3). 13C NMR (CDCl3, 75 MHz):
(CH2), 13.5 (CH3).
d 171.8 (C]O), 34.8 (CH2CO), 18.8
A
procedure for N-methyl-N-benzyloxybutyramide (1e) is
4.5. General procedure for ruthenium-catalyzed reduction of
N-alkoxy- and N-hydroxyamides
representative. solution of N-methyl-N-hydroxybutyramide
A
(1.00 mL, 8.3 mmol), anhydrous K2CO3 (1.52 g, 11 mmol) and benzyl
bromide (1.31 mL, 11 mmol) in dry acetone (25 mL) was stirred for
12 h at 75 ꢀC under argon. The solvent was evaporated and the
residue was dissolved in CH2Cl2 and washed with a 1 M solution of
NaOH. The two layers were separated and the aqueous layer was
extracted three times with CH2Cl2. The combined organic layer was
dried over MgSO4, filtered and the solvent was evaporated to dry.
Purification by flash column chromatography (eluent: hexane/ethyl
acetate ¼ 10:1) afforded 1e (1.35 g, 6.51 mmol) as a colorless oil in
79% yield. Compound 1f was prepared in the same manner.
RuCl3$3H2O (6.5 mg, 0.025 mmol) and ZneCu couple (9.8 mg,
0.15 mmol) were placed in a glass Schlenk tube which was filled
with argon. Dibenzyl ether (90 mL, 0.47 mmol, internal standard), an
N-alkoxy- or N-hydroxyamide (0.50 mmol), and dehydrated EtOH
(1.0 mL) were added to the mixture in this order, and the reaction
mixture was refluxed at 100 ꢀC (bath temperature). The reaction
was followed by 1H NMR spectroscopy. NMR sample solutions were
prepared by sampling the reaction mixture (0.2 mL) which was
quenched under air and was mixed with CDCl3 (0.5 mL). Conver-
sions of substrates and yields of products were calculated based on
the ratio of integral areas for substrates and products relative to
that for the internal standard.
4.3.1. N-Methyl-N-benzyloxybutyramide (1e)
Colorless oil. IR spectrum (ATR): 2963, 1667, 1456, 1386 cmꢁ1. 1H
NMR (CDCl3, 300 MHz):
d
7.38e7.34 (m, 5H, arom.), 4.81 (s, 2H,
For isolation of the products, the reaction mixture was filtered to
remove insoluble materials. After removal of the solvent under
vacuum, the residue was extracted with ethyl acetate, and the
extract was filtered again to remove insoluble materials. The filtrate
was evaporated to dry, and purification by flash column chroma-
tography (eluent: hexane/ethyl acetate) afforded the products.
Spectral data for N-methylbutyramide (2a) [32], N-methyl-
pivalamide (2b) [32,33], N-methylbenzamide (2c) [34], butyramide
(2d) [35], N-phenylbutyramide (2e) [36], N-methyl-3-phenyl-
propanamide (2f) [37] and N-methylcinnamamide (4b) [38] were
consistent with those reported previously.
NOCH2Ph), 3.18 (s, 3H, NCH3), 2.35 (t, J ¼ 7.5 Hz, 2H, CH2CO),
1.67e1.54 (m, 2H, CH2), 0.90 (t, J ¼ 7.5 Hz, 3H, CH3). 13C NMR (CDCl3,
75 MHz):
d 175.1 (C]O), 134.6 (Ph), 129.2 (Ph), 128.9 (Ph), 128.7
(Ph), 76.2 (NOCH2Ph), 34.1 (eCH2COe), 34.0 (NCH3), 18.0 (CH2), 13.9
(CH3). MS (ESI) m/z 230.1 (M þ Naþ).
4.3.2. N-Methyl-N-isopropoxybutyramide (1f)
Colorless oil. IR spectrum (ATR): 2974, 1669, 1383, 1112 cmꢁ1
.
1H NMR (CDCl3, 300 MHz):
d 4.14e4.06 (m, 1H, NOCH(CH3)2), 3.16
(s, 3H, NCH3), 2.38 (t, J ¼ 7.2 Hz, 2H, CH2CO), 1.67e1.58 (m, 2H,
CH2), 1.22 (d, J ¼ 6.4 Hz, 6H, NOCH(CH3)2), 0.92 (t, J ¼ 7.2 Hz, 3H,
CH3). 13C NMR (CDCl3, 75 MHz):
d
176.3 (C]O), 75.6 (NOCH(CH3)2),
4.5.1. N-Methylcrotonamide (4a)
35.1 (NCH3), 34.2 (CH2CO), 20.8 (NOCH(CH3)2), 18.0 (CH2), 14.0
(CH3).
Colorless oil. IR spectrum (KBr, tablet): 3286, 3096, 2962,
1626 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
6.80 (dq, J ¼ 15.2, 6.8 Hz,
1H, CH3CH]CHe), 5.76 (dq, J ¼ 15.2, 1.6 Hz, 1H, CH3CH]CHe), 5.52
(br s, NH, 1H), 2.79 (d, J ¼ 4.8 Hz, 3H, NCH3), 1.82 (dd, J ¼ 6.8, 1.6 Hz,
4.4. Preparation of N-hydroxyamides 1gei
3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 166.7 (C]O), 139.6
A procedure for N-methyl-N-hydroxybutyramide (1g) is repre-
sentative. Et2O (12 mL) and water (6 mL) were added to the
(CH3CH]CHe), 124.9 (CH3CH]CHe), 26.2 (NCH3), 17.6 (CH3). MS
(EI) m/z 99 (Mþ).

3648
H. Fukuzawa et al. / Journal of Organometallic Chemistry 696 (2011) 3643e3648
[11] R.J. McKinney, Organometallics 5 (1986) 1752.
[12] The present method was also applied to N-methoxy-N-methylacrylamide,
Acknowledgment
which has no substituent at
b-position; however, polymerization of the amide
appeared to occur and no deprotected compounds were detected by 1H NMR
analysis.
The authors thank Nara Women’s University (Intramural Grant
for Project Research) for financial support.
[13] In these reactions, the hydrogen source would be EtOH used as a solvent, and
therefore, we performed the reduction of 3a with a small amount of EtOH
(30 mol%) and DMA as a solvent at 100 ꢀC for 24 h, in order to circumvent the
hydrogenation. Although these reaction conditions suppressed the formation
of deprotected/hydrogenated product 2a (7%), the conversion of 3a and the
yield of 4a were low as well (69% and 33% respectively).
References
[1] (a) M.J. Miller, Chem. Rev. 89 (1989) 1563;
(b) M.J. Miller, Acc. Chem. Res. 19 (1986) 49;
[14] P. Pertici, G. Vitulli, M. Paci, L. Porri, J. Chem. Soc., Dalton Trans. (1980) 1961.
[15] R.J. McKinney, M.C. Colton, Organometallics 5 (1986) 1080.
[16] For examples of isolated mononuclear ruthenium amidate complexes, see: (a)
J. Zhang, T.B. Gunnoe, J.L. Petersen, Inorg. Chem. 44 (2005) 2895;
(b) J.P. Lee, K.A. Pittard, N.J. DeYonker, T.R. Cundari, T.B. Gunnoe, J.L. Petersen,
Organometallics 25 (2006) 1500.
[17] P.S. Hallman, T.A. Stephenson, G. Wilkinson, Inorg. Synth. 12 (1970) 238.
[18] M.O. Albers, E. Singleton, J.E. Yates, Inorg. Synth. 26 (1989) 253.
[19] E.W. Abel, M.A. Bennett, G. Wilkinson, J. Chem. Soc. (1959) 3178.
[20] N. Oshima, H. Suzuki, Y. Moro-oka, Chem. Lett. (1984) 1161.
[21] S.J. Stoessel, C.M. Elliott, J.K. Stille, Chem. Mater. 2 (1989) 259.
[22] M.A. Bennett, A.K. Smith, J. Chem. Soc., Dalton Trans. (1974) 233.
[23] G.F. Hennion, J.J. Sheehan, J. Am. Chem. Soc. 71 (1949) 1964.
[24] O. Corminboeuf, P. Renaud, Org. Lett. 4 (2002) 1731.
(c) H.C.J. Ottenheijm, J.D.M. Herscheid, Chem. Rev. 86 (1986) 697.
[2] (a) M. Whittaker, C.D. Floyd, P. Brown, A.J.H. Gearing, Chem. Rev. 99 (1999)
2735;
(b) M. Cheng, B. De, S. Pikul, N.G. Almstead, M.G. Natchus, M.V. Anastasio,
S.J. McPhail, C.E. Snider, Y.O. Taiwo, L. Chen, C.M. Dunaway, F. Gu, M.E. Dowty,
G.E. Mieling, M.J. Janusz, S. Wang-Weigand, J. Med. Chem. 43 (2000) 369.
[3] (a) B. Kurzak, H. Kozlowski, E. Farkas, Coord. Chem. Rev. 114 (1992) 169;
(b) S. Boukhris, A. Souizi, A. Robert, Tetrahedron Lett. 37 (1996) 179.
[4] (a) S. Nahm, S.M. Weinreb, Tetrahedron Lett. 22 (1981) 3815;
(b) M.P. Sibi, Org. Prep. Proced. Int. 25 (1993) 15;
(c) M. Mentzel, H.M.R. Hoffmann, J. Prakt. Chem. 339 (1997) 517;
(d) J. Singh, N. Satyamurthi, I.S. Aidhen, J. Prakt. Chem. 342 (2000) 340;
(e) V.K. Khlestkin, D.G. Mazhukin, Curr. Org. Chem. 7 (2003) 967;
(f) L. Bauer, O. Exner, Angew. Chem. 86 (1974) 419;
[25] O. Corminboeuf, P. Renaud, Org. Lett. 4 (2002) 1735.
Angew. Chem., Int. Ed. Engl. 13 (1974) 376.
[26] M. Wolberg, W. Hummel, M. Müller, Chem. Eur. J. 7 (2001) 4562.
[27] J.C.S. Woo, E. Fenster, G.R. Dake, J. Org. Chem. 69 (2004) 8984.
[28] D.K. Friel, M.L. Snapper, A.H. Hoveyda, J. Am. Chem. Soc. 130 (2008) 9942.
[29] D.A. Evans, K.R. Fandrick, H.-J. Song, J. Am. Chem. Soc. 127 (2005) 8942.
[30] R. Krishnamoorthy, S.Q. Lam, C.M. Manley, R.J. Herr, J. Org. Chem. 75 (2010)
1251.
[5] (a) F. Shirai, T. Nakai, Tetrahedron Lett. 29 (1988) 6461;
(b) P.G. Mattingly, M.J. Miller, J. Org. Chem. 45 (1980) 410;
(c) M.J. Miller, P.G. Mattingly, M.A. Morrison, J.F. Kerwin Jr., J. Am. Chem. Soc.
102 (1980) 7026;
(d) C. Cesario, L.P. Tardibono Jr., M.J. Miller, J. Org. Chem. 74 (2009) 448.
[6] (a) J.L. Chiara, C. Destabel, P. Gallego, J. Marco-Contelles, J. Org. Chem. 61
(1996) 359;
ꢀ
[31] W. Przychodzen, Heteroatom Chem. 17 (2006) 676.
[32] G.V. Zyryanov, D.M. Rudkevich, Org. Lett. 5 (2003) 1253.
[33] E. Alonso, D.J. Ramon, M. Yus, Tetrahedron 53 (1997) 14355.
[34] Y. Jo, J. Ju, S. Lee, J. Choe, H.S. Kwang, J. Org. Chem. 74 (2009) 6358.
[35] N.A. Owston, A.J. Parker, J.M.J. Williams, Org. Lett. 9 (2007) 73.
[36] C. Arkaitz, E. Simon, B. Carsten, Chem. Eur. J. 14 (2008) 3527.
[37] S. Hanada, T. Ishida, Y. Motoyama, H. Nagashima, J. Org. Chem. 72 (2007)
7551.
(b) G.E. Keck, S.F. McHardy, J.A. Murry, J. Am. Chem. Soc. 117 (1995) 7289;
(c) G.E. Keck, S.F. McHardy, T.T. Wager, Tetrahedron Lett. 36 (1995) 7419.
[7] M. Yus, G. Radivoy, F. Alonso, Synthesis (2001) 914.
[8] L.E. Fisher, J.M. Caroon, J.S. Russell Stabler, S. Lundberg, J.M. Muchowski, J. Org.
Chem. 58 (1993) 3643.
[9] G.E. Keck, S.F. McHardy, J.A. Murry, Tetrahedron Lett. 34 (1993) 6215.
[10] S.P.Y. Cutulic, J.A. Murphy, H. Farwaha, S.-Z. Zhou, E. Chrystal, Synlett (2008)
2132.
[38] R.V. Hoffman, S. Madan, J. Org. Chem. 68 (2003) 4876.