Tetrahedron Letters 54 (2013) 2674–2678

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Tetrahedron Letters
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Catalytic hydrogenation of unactivated amides enabled by hydrogenation

of catalyst precursor
Takashi Miura a, Ingmar E. Held b, Shunsuke Oishi a, Masayuki Naruto a, Susumu Saito a,b,c,⇑
a
Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
b
Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
c
Institute for Advanced Research, Nagoya University, Chikusa, Nagoya 464-8601, Japan

a r t i c l e i n f o a b s t r a c t

Article history: A general method for catalytic hydrogenation of unactivated amides was achieved. During the catalyst
Received 16 January 2013 induction period, a novel structural change was observed involving full hydrogenation of the interior
Revised 6 March 2013 unsaturated bonds of the pyridines of the Ru-containing catalyst precursor. Based on this observation,
Accepted 11 March 2013
the mechanism of amide hydrogenation may involve a two-step pathway, wherein the Ru catalyst having
Available online 20 March 2013
an H–Ru–N–H functionality is generated in the first step, followed by the amide carbonyl group interact-
ing with the outer, rather than the inner, sphere of the Ru catalyst.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Hydrogenation
Amide
Ruthenium complex
Alcohol
Amine

Amides1a are abundant functional groups which can be found, more inert amides, whereby dehydrative cleavage of the C@O
for example, in the repeating units of polypeptide macromolecules bonds affords higher amines, albeit with accompanying dearomat-
and artificial polymeric materials (e.g., polyacrylamide), nylons, ic hydrogenation.9 As part of our research on the catalytic transfor-
Kevlar), and their respective monomers (e.g., a,b-unsaturated car- mation of amides,10 herein is reported a more general and selective
boxamides, caprolactams), which can be produced on an enormous method for the hydrogenation of unactivated amides, affording
scale via existing industrial processes. They also exist as potent selective C–N or C@O bond cleavage using a new Ru complex 1a
pharmacophores,1d,e,g–i which are useful building blocks accessible (Scheme 1).
via many synthetic methods.1b,c,f,j,k Were it possible to develop cat- Since the need for harsh reaction conditions was anticipated for
alytic transformations of amide resources without the salt-con- this otherwise difficult unactivated amide hydrogenation, the
taining wastes formed in stoichiometric amounts with respect to ‘structural robustness’ of the catalyst precursor was the foremost
the amide, such chemical processes would provide a shortcut or consideration in the initial molecular design of a Ru complex cata-
alternative route to presently known and/or unknown materials lyst. Such robustness may obviate the facile detachment of the li-
or chemicals. However, the salt-free transformation of amides2 is gands from the Ru center during the induction period of the
a significant challenge, as there is a lack of basic knowledge con- catalyst. Accordingly, the emphasis was placed on imposing a
cerning the catalytic activation. Such activation is frequently ham- ‘coordinatively saturated Ru center’ on a catalyst precursor with
pered by high thermodynamic stability3 and kinetic inertness due sterically demanding and strongly coordinative ligand(s), with
to the low electrophilicity of the amide carbonyl carbon among the additional expectation that only an H2 molecule could make
carbon(x)yl functionalities.1a In particular, the catalytic hydrogena- easy access to the narrow space (though large enough to accept
tion of unactivated amides has rarely been accomplished using an H2) around the metal center of an intermediate active species
existing homogeneous catalysis methods. Recently, Cole-Hamil- that subsequently forms a metal hydride. Indeed, the derivation
ton,4 Ikariya,5 Milstein,6a and Bergens7 reported different ruthe- of a metal hydride species from H2 is frequently rate-determin-
nium (Ru) complexes, which hydrogenate a range of strongly or ing.11 To satisfy such primary criteria for catalyst design, a biden-
moderately activated amides, including N-phenyl-, N-acyl-, a-alk- tate (P,N)-ligand12,13 as in 1a was chosen first. Additional Ru
oxy8 amides, morpholino ketones, and relatively small unactivated complexes 1b and 1c were also prepared for control experiments.14
amides. Heterobimetallic clusters are able to hydrogenate larger, Since N-benzylbenzamide (3a) was hydrogenated previously in
moderate yield [4a: 57%; ruthenium complex (1 mol %), H2 pres-
⇑ Corresponding author. Tel./fax: +81 51 789 5945. sure (PH2) = 1 MPa, 110 °C, 48 h],6a examination of 3a is thought
E-mail address: [email protected] (S. Saito). to be a good starting point for analysis.

0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.047
 T. Miura et al. / Tetrahedron Letters 54 (2013) 2674–2678 2675

H2 (2–8 MPa) (entry 14). Hydrogenation was rather sluggish with 3m derived
O 1a (2 mol %) by N-methylation of 3l (entry 15). Products 4l and 4m could be a
2 (4–20 mol %) OH R1
R1 + HN synthetic precursor of N,N-dimethyl-6-amino-1-hexanol, a poly-
R N solvent R
120–160 °C merization initiator.17 In contrast, C@O bond cleavage predomi-
R2 R2
nated with five- and six-membered lactams 3n,o (entries 16 and
R = aromatic or aliphatic; R1 = alkyl or H; R2 = alkyl or H
17). This apparent C@O bond scission can be explained by a multi-
t
R2 R2 Bu step reaction sequence consisting of hydrogenative C–N bond
P Cl P ONa ONa
1a : R = Cy (= c-hexyl) cleavage of the amides giving NH2(CH2)nOH, followed by oxidation
Ru 1b : R = iPr of the HOCH2 group giving NH2(CH2)n1CHO, then intramolecular
N N 1c : R = Ph t
Bu t
Bu
Cl imine formation, and finally, imine hydrogenation. In fact, when 4n
2a 2b
was used as the starting material in the absence of H2 or with
Scheme 1. Hydrogenation of unactivated amides using 1 and 2. PH2 = 8 MPa under otherwise identical conditions (160 °C, 24 h),
amide 3n and piperidine (5n) were obtained in 53% and 25%, and
Treatment of a toluene solution of 3a and 1a (2 mol %) with ste- 28% and 48% yields, respectively. Primary and tertiary amides 3c
rically bulky base 2a (20 mol %) under PH2 = 8 MPa at 160 °C for and 3b, and simple aliphatic amides 3i and 3j, were also applicable
24 h gave both 4a and 5a in 92% yield (Table 1, entry 1). The steric substrates, but marginal hydrogenation took place with more
bulkiness of the base was more important than its basicity under bulky 3k (entry 13). Hydrogenation of urea6c 3p (entry 18) is
similar conditions ([1a]0 = 6.7 mM; PH2 = 6 MPa, 160 °C, 24 h): use important with respect to the methanol economy,6b,18 since ureas
of phenoxide 2b in place of 2a gave 4a with similar effectiveness are excellent chemical reservoirs and carriers of CO2. However, a
(entry 2), while either NaOtBu, KOtBu, NaOMe, or NaOH was less larger amount of base (20 mol %) only ensured a reasonable reac-
satisfactory (4a: 43%, 27%, 2%, and 31%, respectively; 5a: 44%, tion rate for the more inert aliphatic amides. In addition, hydroge-
26%, 1%, and 26%, respectively). Although toluene was the best nation was sluggish and required harsh reaction conditions
solvent of those tested in terms of enabling smooth conversion of (entries 3, 4, 17, and 18), so additional optimized conditions for
3a, a sterically more demanding alcohol solvent was better than generating catalytic species were evaluated.
a smaller one [4a: <1% (MeOH); 4% (EtOH); 45% (iPrOH); 61% Such a catalytic species could be generated following a deproto-
(tBuOH). [1a]0 = 6.7 mM; PH2 = 8 MPa, 160 °C, 24 h]. Ru complex nation pathway similar to those disclosed by Milstein (Fig. 1),6,19 in
1b showed a similar effectiveness but with formation of a byprod- which a base deprotonates the methylene group vicinal to the
uct (entry 3), while the reaction using 1c15 led to the formation of a phosphorous atom (PyCH2P) of 1a. However, the primary (3c)
fine, black powder precipitate, and almost full recovery of 3a (entry and secondary (3a, 3d–l, and 3n,o) amides used here have acidic
4). Obviously, the combined use of 1a and a base additive such as hydrogens in excess quantity relative to 1a. Thus, deprotonation
2a or 2b, both being sterically demanding, is crucial for selective of the NH hydrogen of those 3 would prevail over that of 1a. Due
hydrogenation. The preference for formation of Ru–OR with alkox- to the less basic nature of the deprotonated form (the conjugate
ides of 1° alcohols [or partial formation of the Ru–O bond as in base) of 3, deprotonation of 1a might be sluggish, and thus, a high
Ru+(HOR)] was recently explained as being due to their higher temperature and a high PH2 may be required either to produce a
acidity and lower steric congestion,16 and this preference may be catalytic species from 1a, or for the hydrogenation of 3.
detrimental to the initiation of a catalytically active RuH species To probe this speculation, 2a (4 mol %) was exposed to a toluene
in the present system. In contrast, 4 mol % instead of 20 mol % of solution of 1a (2 mol %) in the absence of amide 3 (160 °C, 5 h,
2a was satisfactory to obtain a high conversion of 3a by prolonging PH2 = 8 MPa) for preactivation of the catalyst, and the resulting ma-
the reaction time to 36 h (4a: 88%; 5a: 88%) under regular tured catalyst was used for the hydrogenation of 3a under milder
conditions. conditions with a shortened reaction time (140 °C, PH2 = 4 MPa,
This hydrogenation method was more selective (i.e., negligible 12 h). Indeed, 4a and 5a were produced in 89% and 89% yields,
dearomatization) and showed a wider substrate scope with respect respectively. Another important aspect is that both 2a and H2 are
to unactivated amides (Table 2) than the established methods. critical to inducing the catalyst. When preactivation was carried
Selective C–N bond cleavage of linear amides was uniformly ob- out in the absence of H2 (toluene, 160 °C, 5 h), 1a was recovered al-
served.5–7 The active species maintained its catalytic integrity even most unchanged. This feature, namely the structural robustness of
after a lengthy reaction time (entries 3, 4, 17, and 18). The hydro- 1a toward bulky base 2a, is in contrast to previous observation,6,19
genation of e-caprolactam (3l), a cyclic amide, which serves as the in which the PyCH2P moiety was deprotonated below 0 °C without
monomer of nylon-6, showed a similar pattern of bond cleavage H2, giving, for example, 1d.19

Table 1
Different Ru complexes 1a–c for hydrogenation of 3aa

O 1 (2 mol %) OH
2a (20 mol %)
N + 2 H2 + H 2N
H toluene
8 MPa 160 °C, t h
3a 4a 5a

Entry Ru complex t (h) Conversionb (%) Yieldb (%) 4a, 5a

1 1a 24 92 92, 92
2c 1a 24 75 (94)d 74 (94)d,75 (86)d
3 1b 24 98e 84, 92
4 1c 24 <5 0, 0
a
Reaction was carried out in toluene at 160 °C using 1a:2a:3a = 2:20:100; [1a]0 = 6.7 mM; PH2 = 8 MPa.
b
Determined by 1H NMR.
c
2b instead of 2a; PH2 = 6 MPa.
d
t = 48.
e
PhCH2NH(CH2)Ph (6%) was obtained.
2676 T. Miura et al. / Tetrahedron Letters 54 (2013) 2674–2678

Table 2
Hydrogenation of 3 using 1a and 2aa

Entry Amide 3 Conditions Products 4 and 5 (yieldb%) [conversionb% of 3]

1 A 4a (83) [84]

2 3b B 4a (85) [92]

3 Ac 4a (74) [87]

4 3c Bd 4a (71) [96]

5 A 5a (95) [95]

6 3d B 5a (87) [99]

7 Ae
4e (99), 5a (99) [99]
3e (X = CF3)
8 3f (X = Ph) Ae 4f (83), 5a (76) [83]
9 3g (X = Me) Ae 4g (73), 5a (70) [74]
10 3h (X = OMe) A 4h (62), 5a (67) [67]

Me(CH2)7OH (4i (88))

11 Af
Me(CH2)7NH2 (5i (94)) [94]

(C6H11)CH2OH (4j (66)),

12 Af
5i (59) [66]

13 A

14 Ae HO(CH2)6NH2 (4l (92)) [94]

15 A HO(CH2)6NHMe (4m (64)) [64]

16 Af

17 Ac

18 B 5a (74)i [97]; (97)d [99]

a
Unless otherwise specified, reaction was carried out at 160 °C, PH2 = 8 MPa with: conditions A: 1a:2a:3 = 2:20:100, t = 24 (h); or conditions B: 1a:2a:3 = 2:4:100, t = 36 (h).
b
Determined by 1H NMR.
c
t = 216 (h).
d
t = 168 (h).
e
PH2 = 6 MPa.
f
t = 48 (h).
g
HO(CH2)5NH2 (4n) (4%) was obtained.
h
HO(CH2)4NH2 (5%) was obtained.
i
(CHO)NHCH2Ph (13% based on 3p) was obtained.

The mercury test20 was also employed, in which Hg(0) was added (160 °C, 30 h), respectively, with shorter reaction times
during the hydrogenation step to probe the possibility of catalysis by (PH2 = 8 MPa). When even milder conditions were used for the
a Ru nanoparticle. The catalytic activity was not perturbed during hydrogenation of 3a (120 °C, PH2 = 2 MPa), a high yield of 4a (93%)
the course of the reaction (4a: 94%; 5a: 92%).14 This preactivation and 5a (92%) was still obtained by prolonging the reaction time to
procedure using 4 mol % of 2a also improved the yields of 4h and 60 h. Preactivation of 1a over a shorter time (1 h, 160 °C,
4i obtained previously using 20 mol % of 2a (Table 2, entries 10 PH2 = 8 MPa) or keeping the induction period at 5 h but at a lower
and 11, 62% and 88%, respectively) to 80% (160 °C, 19 h) and 92% temperature and PH2 (140 °C, 4 MPa) was found to be less promising
 T. Miura et al. / Tetrahedron Letters 54 (2013) 2674–2678 2677

H R2 H PCy2 Acknowledgments
R2
P CO KOtBu P CO
H Ru
Ru < 0 °C
N L N L N This work was supported by Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Molecular Activation Directed toward
KCl, tBuOH
Cl 1d 6a Straightforward Synthesis’, MEXT. T.M. and S.O. acknowledge IGER
in chemistry at Nagoya University (NU) and JSPS for financial sup-
Figure 1. Milstein’s mechanism for pyridine dearomatization (L = Et2N or iPr2P) and port. The authors wish to thank Dr. K. Oyama and Y. Maeda (Chem-
the ligand used here, 6a.
ical Instrument Facility of RCMS) for NMR and ESI-MS
measurements and Professor R. Noyori (NU & RIKEN) for fruitful
discussions.

Supplementary data
H2 H H H
2a P 7 H2 P
1a
N Ru P H Ru P Supplementary data associated with this article can be found, in
Milstein's N
mechanism the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
N H N
H 047.
IA H catA
References and notes

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2678 T. Miura et al. / Tetrahedron Letters 54 (2013) 2674–2678

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