Ruthenium-catalyzed redox-neutral and single-step amide synthesis from alcohol and nitrile with complete atom economy

Article abstract of DOI:10.1021/ja404695t

A completely atom-economical and redox-neutral catalytic amide synthesis from an alcohol and a nitrile is realized. The amide C-N bond is efficiently formed between the nitrogen atom of nitrile and the α-carbon of alcohol, with the help of an N-heterocyclic carbene-based ruthenium catalyst, without a single byproduct. A utility of the reaction was demonstrated by synthesizing ¹³C or ¹⁵N isotope-labeled amides without involvement of any separate reduction and oxidation step.

Full text of DOI:10.1021/ja404695t

Communication
pubs.acs.org/JACS
Ruthenium-Catalyzed Redox-Neutral and Single-Step Amide
Synthesis from Alcohol and Nitrile with Complete Atom Economy
Byungjoon Kang,†,‡,§ Zhenqian Fu,‡,§ and Soon Hyeok Hong*,†,‡
†Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 151-742, Republic of Korea
‡Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea
S
* Supporting Information
Scheme 1. Redox-Neutral Amide Synthesis Directly from
Alcohols and Nitriles
ABSTRACT: A completely atom-economical and redox-
neutral catalytic amide synthesis from an alcohol and a
nitrile is realized. The amide C−N bond is efficiently
formed between the nitrogen atom of nitrile and the α-
carbon of alcohol, with the help of an N-heterocyclic
carbene-based ruthenium catalyst, without a single by-
product. A utility of the reaction was demonstrated by
synthesizing 13C or 15N isotope-labeled amides without
involvement of any separate reduction and oxidation step.
tom-economical amide synthesis1 is one of the top
A
challenges in green organic synthesis and process
chemistry as discussed in the round table of global
pharmaceutical corporations and the ACS Green Chemistry
Institute in 2005.2 Many approaches such as oxidative amide
synthesis directly from alcohols and amines by liberating
hydrogen gas as the byproduct have been extensively studied to
realize the highly atom-economical and environmentally benign
amide synthesis.3,4
Catalytic methods to utilize nitriles as primary amine
surrogates have been less explored in organic synthesis,
although it can offer efficient and versatile synthetic strategies
with high atom economy and waste prevention.5 Recently, Ru-
catalyzed selective hydrogenation of nitriles into primary
amines, suppressing the formation of side products such as
imines and secondary amines, has been reported.6 Inspired by
the recent advances in the selective catalytic nitrile reductions,
we envisioned that a completely atom-economical and redox-
neutral amide synthesis could be realized through hydrogen
transfer from alcohol to nitrile with the subsequent C−N bond
formation between the nitrogen of a nitrile and the α-carbon of
a primary alcohol without generation of any byproduct
(Scheme 1). Herein, we report the first catalytic, single-step,
and redox-neutral transformation of alcohols and nitriles into
amide with 100% atom economy. To the best of our
knowledge, it is the first completely atom-economical amide
synthesis. This method also provides a distinctive way of amide
syntheses directly from nitriles, compared with other well-
known methods using C of nitriles as a carbonyl source as in
the Ritter reaction7 and hydration of nitriles (Scheme 1).8
Initially, the reaction between 2-phenylethanol and 3-
phenylpropionitrile was chosen as a model reaction to
investigate the catalytic conditions to realize the goal (Table
1). We first tried several catalytic systems that have been known
as active for the direct amidation between alcohols and amines.
Various Ru(II)- and Ru(III)-chloride precatalysts accompanied
with an NHC precursor, 1,3-diisopropylimidazolium bromide
(4), and a base, however, showed no activity (entries 1−4). It
has been suggested that the role of the base is not only to
generate the NHC by deprotonation of the imidazolium salt
but also to activate a Ru precatalyst from the reaction between
the precatalyst and alkoxide formed by deprotonation of an
alcohol substrate.4h−l Also, a Milstein catalyst gave only 18%
product yield (entry 5). Then we found that a RuH2(PPh3)4-
based catalytic system, reported as active for the synthesis of
amides and cyclic imides,4e,h,9 showed significant activity (entry
6). After screening experiments with other Ru hydride
complexes, RuH2(CO)(PPh3)3 was identified as an efficient
precatalyst for this reaction (entry 7).
With the optimal conditions in hand, substrate scope was
investigated. First, different nitriles were tested with 2-
phenylethanol (Table 2). Various aliphatic nitriles including
acetonitrile afforded the corresponding amides in moderate to
Received: May 10, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja404695t | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
excellent yields (entries 1−4). Acetonitrile afforded a moderate
yield of 3da presumably due to its low boiling point. Secondary
cyanides showed good activity for the reaction (entries 5−8). In
the case of cyclopropanecarbonitrile (1f), no ring opening with
C−C bond cleavage was observed, affording the desired amide
(3fa) in 84% yield (entry 6). To our delight, even a sterically
bulky tertiary cyanide worked well for the amidation (entry 9).
Benzonitrile was also transformed to the corresponding amide
in a good yield (entry 10). Aryl chloride exhibited reduced
activity (entry 11). Aryl bromide, alkyl halides, and esters were
not tolerant in the reaction, presumably due to the basic
reaction conditions with the involvement of hydrogen transfer.
Next, the reactions between 3-phenylpropionitrile and
various alcohols were investigated (Table 3). A range of
aliphatic alcohols generated the corresponding amides in
moderate to excellent yields (entries 1−5). In the case of
substituted benzyl alcohols, electron-donating methoxy-group-
substituted benzyl alcohols gave good yields regardless of the
substituted positions (entry 7). An electron-withdrawing
fluoride-substituted benzyl alcohol 2k exhibited reduced activity
Table 1. Catalyst Screening
time
(h)
yield
b
entry
Ru complex
ligand
base
NaH
(%)
1
2
3
4
[Ru(benzene)Cl2]2
[Ru(n-cymene)Cl2]2
Ru(COD)Cl2
RuCl3
CH3CN
pyridine
PCy3
24
24
24
24
24
48
48
0
0
NaH
t-BuOK
NaH
5
CH3CN
0
c
d
5
Milstein catalyst
18
82
90
6
7
RuH2(PPh3)4
NaH
NaH
RuH2(CO)(PPh3)3
a
Reaction conditions: 1a (0.5 mmol, 1.0 equiv), 2a (0.55 mmol, 1.1
equiv), Ru complex (5 mol %), 4 (5 mol %), ligand (5 mol %), base
(20 mol %), toluene (0.6 mL), 110 °C. Determined by GC. Without
NHC precursor 4. Milstein catalyst = carbonylhydrido[6-(di-tert-
b
c
d
butylphosphinomethylene)-2-(N,N-diethyl aminomethyl)-1,6-dihydro-
pyridine]ruthenium(II).
Table 2. Amide Synthesis from 2-Phenylethanol and
Nitriles
Table 3. Amide Synthesis from 3-Phenylpropionitrile and
Alcohols
a
a
a
Reaction conditions: nitrile (0.5 mmol, 1.0 equiv), 2a (0.55 mmol,
a
1.1 equiv), RuH2(CO)(PPh3)3 (10 mol %), NHC precursor 4 (10 mol
%), NaH (20 mol %), toluene (0.6 mL), 110 °C, 48 h. Isolated yield.
Reaction conditions: 2a (0.5 mmol, 1.0 equiv), alcohol (0.55 mmol,
b
1.1 equiv), RuH2(CO)(PPh3)3 (10 mol %), NHC precursor 4 (10 mol
%), NaH (20 mol %), toluene (0.6 mL), 110 °C, 48 h. Isolated yield.
b
B
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Journal of the American Chemical Society
Communication
(entry 8). Furan ring (entry 9) or tertiary amine group (entry
10) were tolerant to the catalytic conditions.
complex could be bis-NHC complex, RuH2(CO)(PPh3)(IiPr)2,
because its chemical shifts and coupling constants of hydrides
are almost identical with the reported complex RuH2(CO)-
(PPh3)(ICy)2 (ICy = 1,2-dicyclohexylimidazol-2-ylidene).13,14
As previously proposed,4i,l an NHC-bound ruthenium dihy-
dride complex is considered a major catalytic species in this
process.
Encouraged by the results, we applied newly developed
methodology into synthesizing specific isotope-labeled amides.
A site-specific labeled amide is used as an important tool for a
spectroscopy-based protein-structure-defining process10 and
metabolic pathway tracking.11 By using our method, specific
labeled amide was easily synthesized within two steps from
alkyl halide and labeled potassium cyanide. First, simple SN2
reaction between 2-bromoethylbenzene and three commercially
available isotope-labeled potassium cyanide (K13CN, KC15N,
and K13C15N) afforded the corresponding isotope-substituted
3-phenylpropionitriles. Then they were reacted with 2-phenyl-
ethanol to make the labeled amides in good yields with
complete incorporation of isotopes (Scheme 2).
Interestingly, we could observe an unusual doublet peak
around δ = 10.2 ppm with a large coupling constant of 23 Hz
1
by H NMR spectroscopy during the experiment. To confirm
its identity, another reaction of benzonitrile and 0.5 equiv of the
precatalyst mixture was performed at 90 °C in benzene-d6 in a
sealed NMR tube. Two sets of doublets appeared with almost
identical coupling constant of ∼23 Hz (Figure 1A). Based on
a
Scheme 2. Selective Isotope Labeling
a
Reaction conditions: nitrile (0.5 mmol), 2-phenylethanol (0.55
mmol), RuH2(CO)(PPh3)3 (10 mol %), NHC precursor 4 (10 mol
%), NaH (20 mol %) in toluene (0.6 mL), 110 °C, 48 h.
Figure 1. Observation of benzaldimine intermediates by 1H NMR
spectroscopy.
To gain insight on the mechanism, several experiments were
performed. First, to investigate overall hydrogen transfer during
the catalysis, the reaction between 4-tert-butylbenzylalcohol-
the recent reports on the synthesis and characterization of N-
unsubstituted imine, either free15 or Ru-bound,6h one doublet
peak at 10.2 ppm was identified as the N−H proton from trans-
benzaldimine. The other peak at 9.2 ppm was assigned as its
ruthenium coordinated form. It was further confirmed by two
experimental results. First, when alcohol was added to the in
situ generated imine system and stirred at 90 °C for a while,
two peaks disappeared with concurrent generation of the
corresponding amide. Second, when triethylborane was added
to the solution, the reported immediate coordination of BEt3 to
trans-benzaldimine was observed,15 while the other peak
remains intact, which suggested that the other species is a
Ru-bound imine complex (Figure 1). Although we confirmed
the involvement of imine intermediates, neither free aldehyde
nor amine was detected during the reaction (Figure S5).
Based on the experimental observations, an innersphere
mechanism is proposed (Scheme 4). At the initiation stage,
nitrile is hydrogenated to trans-imine, generating a Ru-imine
complex A. We think that steric hindrance from the Ru
complex induces the trans selectivity of N-unsubstituted imine,
as in the reported case of BEt3-coordination-derived cis to trans
isomerization of benzaldimine.15 After oxidative addition of
alcohol to the Ru complex, dehydrogenation of alcohol to
aldehyde occurs, followed by addition of imine to acyl carbon16
and further reduction. Finally, one more dehydrogenation
reaction of the resulting hemiaminal intermediate D gives the
corresponding amide with regeneration of dihydrido ruthenium
species.
2
1,1-d2 (2n) and 3-phenylpropionitrile was monitored with D
NMR spectroscopy (Scheme 3). Deuteration at α-CH2 of the
a
Scheme 3. Deuterium Labeling Study
a
Reaction conditions: 3-phenylpropionitrile (0.5 mmol), 2-phenyl-
ethanol (0.55 mmol), RuH2(CO)(PPh3)3 (5 mol %), NHC precursor
4 (5 mol %), NaH (20 mol %), benzene-d6 (10 μL) in toluene (0.6
mL), 110 °C, 48 h.
nitrogen of the amide, originated from nitrile carbon, was
observed during the reaction, while the deuterium peak of
alcohol diminished. This result is concrete evidence that
hydrogen generated from oxidation of alcohol is used for
reduction of nitrile. In addition, deuteration at the acidic C2
carbon of 3-phenylpropionitrile, resulting in deuteration at β-
CH2 of the nitrogen of the amide, presumably mediated by
sodium hydride, was observed.
To investigate real catalytic species, the reaction between 2-
phenylethanol and 3-phenylpropionitrile in benzene-d6 was
1
monitored with H and 31P NMR spectroscopy. Two sets of
new Ru hydride complexes, in addition to RuH2(CO)(PPh3)3
precatalyst, were observed (Figure S2). One is identified as
RuH2(CO)(PPh3)2(IiPr) (IiPr = 1,2-diisopropylimidazol-2-
ylidene) complex reported by Whittlesey and Williams.12
Independently synthesized RuH2(CO)(PPh3)2(IiPr) was active
for the reaction between 1a and 2a, generating the amide 3aa in
90% GC yield with 5 mol % catalyst loading. The other hydride
In summary, a completely atom-economical catalytic amide
synthesis from an alcohol and a nitrile is achieved by an NHC-
based Ru hydride catalyst. The reaction is an overall redox-
neutral process involving hydrogen transfer from alcohol to
nitrile. Facile syntheses of isotope-labeled amides were
C
dx.doi.org/10.1021/ja404695t | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
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Experimental procedure and characterization data. This ma-
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AUTHOR INFORMATION
Corresponding Author
soonhong@snu.ac.kr
■
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Science, ICT & Future
Planning (2012004077), and the Research Center Program of
IBS (Institute for Basic Science) in Korea. We thank Prof. Y.K.
Chung and Dr. S. Muthaiah for helpful discussions. We also
thank the Korean Basic Science Institute (Daegu) for mass
analysis. This paper is dedicated to Professor Young Keun
Chung on the occasion of his 60th birthday.
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