Oxidant-free conversion of primary amines to nitriles

Article abstract of DOI:10.1021/ja409223a

An amide-derived NNN-Ru(II) hydride complex catalyzes oxidant-free, acceptorless, and chemoselective dehydrogenation of primary and secondary amines to the corresponding nitriles and imines with liberation of dihydrogen. The catalyst system tolerates oxidizable functionality and is selective for the dehydrogenation of primary amines (-CH₂NH₂) in the presence of amines without α-CH hydrogens.

Full text of DOI:10.1021/ja409223a

Communication
pubs.acs.org/JACS
Oxidant-Free Conversion of Primary Amines to Nitriles
Kuei-Nin T. Tseng, Andrew M. Rizzi, and Nathaniel K. Szymczak*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
(1, HRu(bmpi)(PPh3)2; bmpi =1,3-bis(6′methyl-2′-
pyridylimino)isoindoline).18 Because of the ability of 1 to
promote rapid H2 release from alcohol groups without product
inhibition, we surmised that 1 might also dehydrogenate other
polar substrates by a similar mechanistic pathway. Herein, we
report the application of 1 as a catalyst that efficiently promotes
dehydrogenation of primary and secondary amines to nitriles
and imines, respectively, without the requirement of exogenous
oxidant or hydrogen acceptor.
ABSTRACT: An amide-derived NNN-Ru(II) hydride
complex catalyzes oxidant-free, acceptorless, and chemo-
selective dehydrogenation of primary and secondary
amines to the corresponding nitriles and imines with
liberation of dihydrogen. The catalyst system tolerates
oxidizable functionality and is selective for the dehydro-
genation of primary amines (−CH2NH2) in the presence
of amines without α-CH hydrogens.
In contrast to the growing number of reports detailing
catalytic dehydrogenation of alcohols, analogous dehydrogen-
ative reactivity of amines is sparse15f,19 and even less reported
for the double dehydrogenation to afford the corresponding
nitrile.16,17 Moreover, one of the only well-defined examples of
direct amine dehydrogenation employed an olefin as a
hydrogen acceptor17a or excess base17b to drive the reaction
at high temperatures (160−200 °C).17 In light of this
precedent, we initiated investigations by examining transfer
dehydrogenation of n-octylamine with cyclohexene catalyzed by
1. When a toluene solution containing 0.5 mmol n-octylamine,
5 mmol (10 equiv) of cyclohexene and 1 mol % of 1 was heated
to 110 °C for 24 h in a sealed vessel, n-octanenitrile was
observed (40%) with concomitant formation of cyclohexane, as
determined by GC-MS analysis (eq 1).
itriles are a prominent class of organic molecules
N
included in a wide variety of natural products,1
biologically active compounds,2 and industrial processes
(polymers, agrochemicals, and dyes/pigments)3 and used as
synthons for further synthetic elaboration.4 Typical routes to
prepare nitriles proceed with low atom economy, require toxic
reagents, and/or have limited selectivity. Common laboratory-
scale syntheses include Sandmeyer-type reactivity,5 cyanation of
alkyl or aryl halides,6 dehydration of amides/aldoximes,7 and
metal-catalyzed cyanation/cyanomethylation,8 among others.9
In contrast, industrial syntheses typically rely on ammoxidation
protocols that operate at high temperatures (300−550 °C).3,10
All of the above synthetic methodologies require either the use
of hazardous/energy-intensive reagents, harsh reaction con-
ditions, and/or produce stoichiometric waste. Moreover,
reagents and conditions required for these transformations
often show limited compatibility with other functional groups.
Another methodology for nitrile synthesis that does not
introduce a carbon unit is the oxidation of primary amines,11
which can be mediated using stoichiometric inorganic12 or
iodine-based oxidants13 or a transition-metal catalyst and O2.14
Unfortunately, many transition-metal catalyzed oxidation
protocols require excess quantities of oxidant and/or basic
reagent for efficient catalysis, which decreases atom economy
by contributing to unwanted waste products.11b,13b,c,14a,b
Furthermore, the use of an external oxidant limits selectivity
and functional group tolerance, because oxidant-incompatible
functionality must then be protected prior to the nitrile
formation step.14
Under these conditions, the added hydrogen acceptor
(cyclohexene) was critical to promote the reaction, and in
the absence of a hydrogen acceptor (3.5 mL headspace), less
than 4% conversion to n-octanenitrile was observed. The
conversion efficiency was found to be sensitive to the overall
reaction volume (liquid plus headspace), consistent with a
reaction in which a gas is generated. In the limiting regime of an
infinitely large headspace (i.e., an open system), the efficiency
of 1 was further improved. For example, in the presence of 1 (1
mol %),20 n-octylamine was converted to n-octanenitrile in 76%
yield after heating for 24 h in refluxing toluene open to a N2
atmosphere (eq 2). H2 and n-octanenitrile were confirmed as
the sole reaction products by in situ examination of the reaction
mixture in a sealed NMR tube and control experiments showed
no reaction in the absence of 1 (Supporting Information).
An alternative procedure for amine oxidation is to use
transition-metal catalyzed dehydrogenation, which has been
widely exploited for alcohol oxidation.15 However, reports
detailing oxidant-free amine dehydrogenation are limited and
either proceed with low conversion16 or require exogenous
additives and harsh reaction conditions (160−200 °C).17 Our
laboratory recently reported base-free, acceptorless, and
chemoselective dehydrogenation and dehydrogenative coupling
reactions of secondary and primary alcohols/diols, respectively,
catalyzed by an amide-derived NNN-Ru(II) hydride complex
Received: September 5, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja409223a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
In order to evaluate the extent to which the release of H2
mediates the dehydrogenation reaction, we assessed the
product profile under elevated H2 pressures (Figure 1).
products that include aldehydes and alcohols in addition to
nitrogen-containing species.14e−h In contrast, a single product
was obtained from the dehydrogenation of secondary and
heterocyclic amines with −CH2NRH functionalities catalyzed
by 1. In the case of secondary amines, secondary aldimines
(10,11) were obtained in moderate yields, and indoline was
cleanly converted to indole (12) in high (81%) yield. Thus, in
addition to primary amine oxidation, 1 exhibits high selectivity
for the catalytic dehydrogenation of secondary and select
heterocyclic amines.
a
Table 1. Dehydrogenation of Amines Catalyzed by 1
Figure 1. Dependence of n-octylamine dehydrogenation catalyzed by
1 on the initial H2 pressure. Conditions: n-octylamine (0.5 mmol), 1
(1 mol %), and toluene (0.5 mL) were charged with H2 in a Fisher-
Porter tube (85 mL) and heated to 110 °C for 24 h.
Consistent with prior dehydrogenative alcohol oxidation
studies,18 the conversion efficiency of the reaction was found
to be highly sensitive to pressure and the dehydrogenation
reaction was significantly suppressed (33% yield) when
performed in a sealed Fischer−Porter tube (84.5 mL
headspace). The conversion decreased with increased H2
pressure: halving at 10, 20, 40, and 80 psig.
a
Reactions performed on 0.5 mmol scale. Yields were determined by
GC-MS using n-docosane as an internal standard. Isolated yields are
reported in parentheses.
Dehydrogenation of aliphatic amines was general to afford
the corresponding nitriles as the exclusive product (2−7). For
instance, when 1-cyclohexylmethanamine was used as a
substrate, cyclohexanecarbonitrile (4) was generated in 74%
yield. Furthermore, the dehydrogenation of 2-phenethylamine
to 2-phenylacetonitrile (8), an important precursor to several
pharmaceutical drugs,3 proceeded with 76% yield. When ortho-
and para-substituted phenethylamines were used as substrates,
conversions to the corresponding phenylacetonitriles depended
on the electron-donating and -withdrawing groups on the
benzene ring (8a−c). A modest (33%) yield was observed for
the ortho-substituted chlorophenethylamine, however, replacing
the chloro group for an electron-donating methoxy substituent
increased the yield to 53%. The proximity of the methoxy
substituent to the −CH2NH2 group had little effect on the
conversion efficiency, since both the ortho- and para-substituted
methoxyphenethylamines gave similar yields.
Dehydrogenation reactions of activated amines were
investigated with benzylic substrates, which were cleanly
converted to the corresponding benzonitriles. Substituent
effects were examined using a series of functionalized
benzylamines. While electron-donating groups were tolerated
(9a), electron-withdrawing groups decreased the yields,
regardless of the substitution pattern on the aromatic ring.
For instance, deactivating chloro groups at either the ortho-,
meta-, or para-positions led to decreased conversions (9b−d).
Because we observed high selectivity for primary amines, we
investigated whether 1 could also catalyze the selective
dehydrogenation of secondary amines. Oxidative protocols for
primary and secondary amines have been reported using O2;
however, selectivity is generally low with this methodology.14
For example, oxidation of secondary amines affords mixtures of
In contrast to (transfer) dehydrogenation reactivity of
alcohols,15h,21 reports of analogous reactivity with amines are
limited.16,17 Consistent with the lack of literature precedent, we
observed only trace (1−3%) nitrile formation from n-
octylamine using several common transfer hydrogenation
catalysts (Noyori’s HRuCl(PPh3)2(en) catalyst,22 Ru-
(H)2(PPh3)4,23 HRuCl(PPh3)3,24 and HRuCl(PPh3)3CO25).
Similar results (less than 1% n-octanenitrile) were obtained
when HRh(PiPr3)3 and n-octylamine were subjected to
identical condition as for the dehydrogenation by 1.26 Shvo’s
catalyst27 exhibited a reaction profile consistent with amine
coupling, affording dioctylamine in 22% yield after 24 h with no
conversion to n-octanenitrile.28 Based on known reports as well
as our own comparative experiments, the double dehydrogen-
ation reactivity mediated by 1 is atypical in terms of conversion
and product selectivity.
The oxidation of amines to nitriles without any required
additives allows our system to tolerate potentially oxidizable
functional groups; a limitation of traditional amine to nitrile
conversions. To highlight the utility of the amine oxidation
under the reducing conditions used by 1, we examined primary
amine dehydrogenation in the presence of a thioether
functionality, a motif typically susceptible to oxidation.29
Indeed, when 3-(methylthio)propylamine was subjected to 1,
only the amino moiety was oxidized under the standard
reaction conditions and 3-(methylthio)propanenitrile (7) was
obtained as the single product, produced in 66% yield. This
reactivity demonstrates the utility of 1 as an amine oxidation
catalyst that is compatible with an oxidant intolerant
functionality.
B
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Journal of the American Chemical Society
Communication
The preparation of aryl nitriles is typically achieved using
Sandmeyer-type5 or Rosenmund−von Braun6 methodologies,
but conditions necessary to promote these transformations also
limit chemoselectivity. Because α-CH hydrogens are required
to eliminate H2, an amine double dehydrogenative method-
ology allows the differentiation of a substrate containing two
chemically distinct amino functional groups (−CH2NH2 vs
−CR2NH2). To highlight this difference, complex 1 selectively
oxidized the benzyl amine moiety of 3-aminobenzylamine in
the presence of the aromatic amino group, which afforded 3-
aminobenzonitrile (13) as the sole product in 58% yield (54%
isolated yield), demonstrating the high chemoselectivity of 1
(eq 3). Furthermore, this illustrates the utility of dehydrogen-
ative oxidation reactions mediated by 1; instead of requiring an
oxidant, amine oxidation is achieved by H2 elimination.
octanenitrile (50 equiv).36 Under the standard reaction
conditions, 54% conversion was noted, consistent with
competitive binding of nitrile to the catalytically active Ru
species. This trend continued at 75 equiv n-octanenitrile, where
only 12% conversion was noted. These results are consistent
with catalyst inhibition at high concentrations of nitrile, where
competitive nitrile-coordination diverts the catalyst from a
productive dehydrogenation pathway. Hence, we propose that
following amine coordination, H2 loss affords an imine
intermediate that remains coordinated to Ru. This species
likely undergoes a further fast dehydrogenation reaction to
afford a Ru-nitrile adduct that is substitutionally labile at low
nitrile concentrations, but inert at high nitrile concentrations.
In conclusion, we have developed a selective dehydrogen-
ative amine oxidation protocol that requires no oxidant or
hydrogen acceptor additives, tolerates oxidizable functionality,
and liberates H2 as a product. Although, prior reports
demonstrated oxidative reactivity of primary amines to nitriles,
our system is the only reported homogeneous catalyst to
accomplish this without any additives and in good yields.
Additionally, the amine dehydrogenation methodology is
notable because 1 mediates the chemoselective oxidation of
primary amines with −CH2NH2 functionality in the presence of
primary amines without α-CH hydrogens. Further work is
ongoing to clearly elucidate the mechanism of amine
dehydrogenation and to examine its utility for energy-relevant
transformations, including the possibility of using amines as
reversible liquid H2 carriers,37 where selective amine dehydro-
genation is a required.
Catalytic dehydrogenation reactions can be mediated by
either heterogeneous or homogeneous pathways, and the
catalytically active form of 1 was initially probed using catalyst
poisoning studies.30 Consistent with an operative homogeneous
system, the catalytic activity of n-octanenitrile formation was
unaffected by the addition of Hg(0) (∼800 equiv) when added
during catalysis. A substoichiometric ligand poisoning experi-
ment was conducted to further interrogate the active catalytic
species.31 In the presence of 0.25 equiv 1,10-phenanthroline, no
change in the product distribution was noted, however,
complete poisoning was achieved using 1 equiv 1,10-
phenanthroline, inconsistent with a heterogeneous system,
where low surface area aggregates are typically poisoned by ≪1
equiv added ligand poison.32
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
Further investigations into the identity of catalytically active
species are currently underway, and preliminary analyses
suggest a catalytic cycle similar to alcohol dehydrogenation.15h
In situ analysis of the amine dehydrogenation reaction revealed
AUTHOR INFORMATION
Corresponding Author
*Corresponding Author nszym@umich.edu
■
the release of PPh3 from 1 during catalysis, as visualized by 31
P
Notes
NMR spectroscopy and GC-MS analysis. Furthermore, catalytic
reactions using Ru(bmpi)(PPh3)Cl (14) exhibited a similar
dehydrogenation profile to 1 in the presence of KOtBu (eq 4),
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by University of Michigan Depart-
ment of Chemistry. We are grateful to Professor John
Montgomery for helpful discussions.
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