Iron-Catalyzed Mild and Selective Hydrogenative Cross-Coupling of Nitriles and Amines To Form Secondary Aldimines

Article abstract of DOI:10.1002/anie.201608537

The first example of a base-metal-catalyzed homogeneous hydrogenative coupling of nitriles and amines to selectively form secondary cross-imines is reported. The reaction is catalyzed under mild conditions by a well-defined (iPr-PNP)Fe(H)Br(CO) pincer pre-catalyst and catalytic tBuOK.

Full text of DOI:10.1002/anie.201608537

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201608537
German Edition: DOI: 10.1002/ange.201608537
Homogeneous Catalysis
Iron-Catalyzed Mild and Selective Hydrogenative Cross-Coupling of
Nitriles and Amines to Form Secondary Aldimines
Subrata Chakraborty, Gregory Leitus, and David Milstein*
Abstract: The first example of a base-metal-catalyzed homo-
geneous hydrogenative coupling of nitriles and amines to
selectively form secondary cross-imines is reported. The
reaction is catalyzed under mild conditions by a well-defined
(iPr-PNP)Fe(H)Br(CO) pincer pre-catalyst and catalytic
tBuOK.
Traditionally, stoichiometric amounts of metal hydrides or
hydrosilanes are required for the reduction of nitriles. This
approach is effective but not environmentally benign, gen-
erating stoichiometric amounts of waste.[8] Heterogeneous
catalysts based on Co, Ni, and Pd are commonly used for
nitrile hydrogenation in industry,[9] but they often suffer from
low selectivity and generally show low functional-group
tolerance. Homogeneous catalysts for the hydrogenation of
nitriles are mostly based on complexes of noble precious
metals such as Ru, Rh, Ir, and Re.[10–12] However, concerns
regarding the cost, limited availability, and toxicity of pre-
cious-metal catalysts have generated much interest in the
development of homogeneous catalysts based on earth-
abundant, low-toxicity base metals.[13,14]
In fact, selective homogeneous hydrogenation of nitriles
to primary amines was recently demonstrated with complexes
of the first-row transition metals Mn,[15] Fe,[16] and Co.[17]
Particularly attractive is catalysis based on iron since it is
the most earth-abundant metal and is less toxic.
Iron complexes have been successfully applied in the
hydrogenation of various substrates,[18] including esters[19] and
amides.[20] Recently, homogenous catalysis by iron complexes
in the selective hydrogenation of nitriles to form primary
amines was achieved using aliphatic PNP-pincer iron cata-
lysts[16a,b] and a dihalo iron PNP catalyst,[16c] as reported by
Beller et. al. and us, respectively (Figure 1). However, to our
knowledge, homogeneous hydrogenative cross-coupling of
nitriles with amines to selectively form secondary imines
catalyzed by complexes of base metals has not been
reported.[21]
I
mines and their derivatives are versatile intermediates and
precursors in the synthesis of various natural products,
agrochemicals, pharmaceuticals, dyes, pigments, and poly-
mers.[1] The conventional method for the preparation of
imines involves acid-catalyzed condensation of amines and
aldehydes. Several alternative methods have been published
in recent years, such as oxidation of secondary amines, self-
condensation of primary amines upon oxidation, hydroami-
nation of alkynes with amines, oxidative coupling of alcohols
and amines, acceptorless dehydrogenative coupling of alco-
hols and amines, transfer hydrogenative coupling of nitriles
and alcohols, and hydrosilylation of nitriles to give silylated
imines.[2–6] Routes based on nitrile partial hydrogenation offer
another attractive synthetic approach owing to the availabil-
ity of the starting materials and the fact that this approach is
more atom-economical.
Selectivity is a crucial issue in nitrile hydrogenation
catalyzed by transition metals; mixtures of primary, secon-
dary, and even tertiary amines are frequently formed via
intermediate imine formation (Scheme 1).[7] Driving the
selectivity towards a particular product through the design
of a suitable catalyst is a challenging task because of the high
reactivity of intermediate imines and amines.
Moreover, hydrogenative cross-coupling of nitriles with
amines to selectively form cross-imines has been sparsely
investigated, even with complexes of precious metals.[22] Our
group, and recently Prechtl and co-workers, have reported the
hydrogenation and hydrogenative coupling of nitriles and
amines to give secondary self-coupled imines and cross-
imines as major products using Ru-PNN[22a] and Ru-PNP[22b]
systems, respectively.
Scheme 1. General scheme for the hydrogenation of nitriles to form
primary and secondary amines via imine intermediates.
[*] Dr. S. Chakraborty, Dr. G. Leitus, Prof. D. Milstein
Department of Organic Chemistry, Weizmann Institute of Science
Rehovot, 76100 (Israel)
E-mail: david.milstein@weizmann.ac.il
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608537.
Figure 1. Fe-based catalysts for homogeneous nitrile hydrogenation/
hydrogenative cross-coupling with amines.
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Herein, we present the synthesis of a novel iron pre-
catalyst bearing an iPr-PNP pincer ligand, and the unprece-
dented base-metal-catalyzed hydrogenative cross-coupling of
nitriles with amines to selectively form cross-aldimines. The
reaction proceeds under remarkably mild conditions (608C,
10–20 bar H2). The iPr-PNP ligand 2-(diisopropylphosphino)-
N-(2-(diisopropylphosphino)benzyl)ethanamine (1) was pre-
pared starting from 2-(o-diisopropylphosphinophenyl)-1,3-
dioxolane, (see Scheme S1 in the Supporting Information) in
71% yield. Treatment of ligand 1 with one equivalent of FeBr2
at room temperature in THF led to formation of the off-white
complex Fe(iPr-PNP)Br2 (2) in 93% yield (Scheme 2).
amine, dibenzylamine or N-benzylbenzaldimine were
detected by GC-MS. Only the partially hydrogenated product
benzaldimine was detected by GC-MS, appearing as a broad
signal along with its trimerized product N,N-di(phenylmeth-
ylidene)phenylmethanediamine (hydrobenzamide).[23] This
observation prompted us to explore the possibility of coupling
of the imine intermediates, produced through partial hydro-
genation of the nitriles, with amines to obtain the cross-
coupled imines. Indeed, this turned out to be possible under
very mild conditions (10–20 bar H2, 608C). Upon stirring
equimolar amounts (1 mmol each) of benzonitrile and hexyl-
amine in benzene under 20 bar of hydrogen at 608C for 14 h
in the presence of 1 mol% complex 3 and 1 mol% tBuOK,
99% conversion of benzonitrile took place to selectively form
N-hexylbenzaldimine in 96% yield (Table 1, entry 1). Only
Table 1: Hydrogenative cross-coupling of nitriles and amines as cata-
lyzed by 3.[a]
Scheme 2. Synthesis of the FeII complexes.
Reaction of 2 with 1 bar CO followed by addition of
1 equiv of NaHBEt3 in THF at room temperature furnished
the monohydrido complex (iPr-PNP)Fe(H)(CO)Br (3) in
71% yield (Scheme 2; for spectral characterization, see the
Supporting Information).
Single crystals of the syn isomer of 3 suitable for X-ray
diffraction were obtained through slow diffusion of pentane
into a saturated solution of Et2O at À308C. The molecular
structure shown in Figure 2 exhibits an octahedral geometry
with a meridional occupation of the iPr-PNP ligand moiety,
with the trans H and Br ligands situated in apical positions,
and the N-H and Fe-H hydrogen atoms being mutually syn. It
is worth mentioning that while the syn and anti isomers of 3
are present in Et2O solution in a 4:3 ratio, the syn isomer of 3
crystallizes as the major product during initial crystallization,
probably due to its slightly lower solubility.
[a] Conditions: benzonitrile (1–0.125 mmol), amine (1–0.125 mmol), 3
(0.01 mmol), tBuOK (1 equiv relative to 3), 20 bar H2, and C6H6 (2 mL),
heated in an autoclave at 608C. Yields and conversions determined by
GC-MS and NMR analysis using m-xylene or toluene as internal
standards. [b] 10 bar H2. [c] 2 mol% catalyst used. [d] 8 mol% catalyst
used. [e] 24 mol% tBuOK, 30 bar H2, 908C. [f] 8 mol% 3, 8 mol% tBuOK
and 908C.
traces of the self-coupled product N-benzyl benzaldimine
1
were detected by GC-MS and H NMR analysis. Not even
traces of the hydrogenation product N-benzyl-hexane-1-
amine were detected. Interestingly, even lowering the hydro-
gen pressure to 10 bar under similar reaction conditions
resulted in complete conversion of benzonitrile, giving N-
hexylbenzaldimine in 95% yield after 12 h (Table S1, entry 1
in the Supporting Information).
Figure 2. Molecular structure of 3.[25] Thermal ellipsoids are drawn at
30% probability. Selected hydrogen atoms are omitted for clarity. For
bond lengths and angles, and experimental details, see the Supporting
Information.
We then studied the the scope of this new base-metal-
catalyzed reaction with respect to different nitriles and
amines. The reaction of hexylamine with electron donating
4-methoxy and 3-methylbenzonitrile in the presence of
complex 3 (1 mol%) and tBuOK (1 mol%) furnished N-(4-
methoxybenzylidene)hexan-1-amine and N-(3-methylbenzy-
lidene)hexan-1-amine in 96% and 98% yields, respectively,
At the outset of our catalytic studies, the syn and anti
isomeric mixture of 3 was examined in the hydrogenation of
nitriles in the presence of a catalytic amount of tBuOK. Using
tBuOK (1 mol%) and complex 3 (1 mol%) under 20 bar H2
at room temperature in C6H6, only 12% conversion of
benzonitrile was observed after 17 h. Surprisingly, no benzyl-
2
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after 12 h (entries 2 and 3). Likewise, the reaction between
the electron-poor nitrile 4-chlorobenzonitrile and hexylamine
gave 97% yield of N-(4-chlorobenzylidene)-hexan-1-amine
(entry 4). Traces of self-coupling products of the imine were
detected by GC-MS. Similarly, a 66% yield of N-(3-bromo-
benzylidene)hexan-1-amine was obtained after 18 h stirring
of equimolar amounts of 3-bromobenzonitrile and hexyl-
amine (entry 5) with 2 mol% of 3 and 2 mol% tBuOK.
To further explore the scope of the reaction, various
nitriles were reacted with cyclohexylamine, benzylic amines,
and substituted anilines, giving moderate to excellent yields
(56–99%) of the corresponding cross-products (entries 6–13).
The optimized reaction conditions were also applied to
heterocyclic nitriles. Reaction of 3- cyanopyridine with hexyl-
amine under 20 bar of hydrogen at 608C using 2 mol% pre-
catalyst 3 yielded 89% N-(pyridine-3-ylmethylene)hexan-1-
amine after 14 h (entry 14). Coupling of naphthalene-2-
carbonitrile with 1-hexylamine furnished N-(2-naphthalenyl-
methylene)hexane-1-amine in 96% yield under 20 bar H2 at
608C using 2 mol% pre-catalyst 3 and tBuOK (2 mol%) after
20 h (entry 15). However, cross-hydrogenative coupling of
alkyl nitriles and amines under these conditions progressed
slowly. Therefore, the catalyst loading, temperature, and
pressure were modified. The reaction of valeronitrile with
hexylamine gave N-pentylidenehexan-1-amine in 37% yield
after 30 h when using 8 mol% 3 and tBuOK at 608C under
20 bar H2 (Table 1, entry 16). On the other hand, the reaction
of the secondary alkyl nitrile cyclohexanecarbonitrile with
hexylamine gave N-cyclohexylidenehexane-1-amine with
a yield of only 10% (entry 18). However, coupling cyclo-
hexanecarbonitrile with cyclohexylamine resulted in the
formation of the cross-imine product in moderate yield
(52%) at 908C with 8 mol% pre-catalyst 3 and 8 mol%
tBuOK under 20 bar H2 (entry 19). Notably, hydrogenative
coupling of cinnamonitrile and hexylamine using 3 (8 mol%)
and tBuOK (8 mol%) at 908C under 20 bar H2 furnished the
secondary imine product in 58% yield without hydrogenating
Scheme 3. Reactivity of 3 with base and NaHBEt3.
exclusively form the cis-dihydridocarbonyl complex (iPr-
PNP)Fe(H)2(CO) (5), as supported by the appearance of
two multiplets in the 1H NMR at d = À21.38 (dt, JPH
=
2
2
2
52.4 Hz, JHH = 16 Hz, Fe-H) and À8.42 (dt, JPH = 63.6 Hz,
2JHH = 15.6 Hz, Fe-H) ppm (see the Supporting Information).
Analogous Fe-amido systems generate mainly the trans-
dihydride complex, along with a minor cis isomer when
reacted with H2.[16a,18i] Kirchner observed the cis-dihydrido-
carbonyl complex Fe(PNPMe-iPr)(H)2(CO) as the major
isomer when using his Fe-PNP system.[18h] Surprisingly,
formation of a trans-dihydride complex (iPr-PNP)Fe(H)2-
(CO) (5’) was not detected in our system. Complex 5 liberates
H2 upon exposure to vacuum, regenerating the precursor
amide 4. Complex 5 can be alternatively prepared through the
reaction of complex 3 with 1 equiv NaHBEt3 at room
temperature in THF (Scheme 3). However, in this case
a small amount of Fe0 dicarbonyl and free ligand were also
observed. It is likely that NaHBEt3 initially reacts with 3 to
give the (unobserved) trans-dihydride complex 5’, which
isomerizes rapidly to 5. Treatment of 4 with 3 equivalents of
benzonitrile at room temperature in C6D6 did not produce any
change in the 1H NMR or 31P NMR spectra, rendering
unlikely the possibility of an inner-sphere coordination
mechanism through substrate binding to the amide 4. How-
ever, when complex 5 was reacted with 4 equiv of benzonitrile
1
the olefinic C C bond (entry 20). It is thus possible to form
at room temperature, the 31P and H NMR spectra revealed
=
allylic imines through this procedure.
the regeneration of the amido complex 4 after several hours,
along with a minute quantity of (iPrPNP)Fe(CO)2 and free
iPrPNP ligand. In addition, characteristic benzaldimine peaks
To gain insight into the mechanism, stoichiometric
reactions were carried out. Initially complex 3 was treated
with 1 equiv of tBuOK in THF, or 1 equiv KHMDS in C6H6 at
=
=
at d = 8.1 (d, JHH = 17 Hz, HC ) and 10.3 (b, NH) ppm in the
1
room temperature. In both cases H NMR monitoring of the
1H NMR spectrum were also observed in THF and in C6D6
=
reaction mixture showed the appearance of a triplet hydride
the signals were observed at d = 8.0 (d, JHH = 17 Hz, HC )
[24]
signal at d = À15.4 (2JPH = 64.4 Hz), which correlates to
and 9.7 (b, NH) ppm. However, analysis of the organic
=
a
31P{1H} NMR doublet signal at d = 111.5 ppm as shown by
phase by GC-MS revealed the presence of excess benzonitrile
and benzaldehyde, which is most likely formed through
hydrolysis of the reactive benzaldimine during workup. This
2H transfer from the coordinatively saturated complex 5 to
benzonitrie, which takes place at room temperature, is
indicative of an outer-sphere mechanism. In addition, com-
plex 5 catalyzes the hydrogenative coupling reaction of
benzonitrile and hexylamine, giving N-hexylbenzaldimine in
89% yield after 13 h of reaction time at 608C in THF under
20 bar H2 (see the Supporting Information). Furthermore,
reaction of the amido species 4 with 1 bar D2 at room
temperature in C6D6 revealed the formation of the cis-(iPr-
PNDP)Fe(D)2(CO) (5-D3) complex as revealed by the
2H NMR spectra, thus indicating that H/D exchange took
31P-1H HMQC spectra. A nCO band at 1851 cmÀ1 was observed
in the IR spectrum. This complex is assignable as the
deprotonated amido complex (iPr-PNP)Fe(H)(CO) (4;
Scheme 3). Another minor triplet signal in the 1H NMR
spectra at d = À10.33 (2JPH = 57.5 Hz) correlated with two
doublet signals in the 31P NMR spectra at d = 103.5 (d, 2JPP
=
121 Hz), 122.3 (d, 2JPP = 121 Hz), and is attributed to an
isomer of 4. Formation of the free ligand and (iPr-PNP)Fe-
(CO)2 (see the Supporting Information) was observed in all
cases, which hindered the isolation and full characterization
of 4 in pure form.
The amido species 4, including its minor isomer, reacted
slowly with 1 bar H2 in C6D6 at room temperature to
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place, which is in line with the intermediacy of the trans-
Acknowledgements
dihydride intermediate 5’. In the IR spectrum, a weak band at
2380 cmÀ1 was assigned as the nN-D stretching frequency of 5-
D3 (based on nN-H = 3273 cmÀ1 of 5). When 5-D3 was reacted
with 4 equiv benzonitrile at room temperature in benzene in
the absence of an H2 atmosphere, regeneration of the
monodeuteride amido complex (iPr-PNP)Fe(D)(CO) (4-D)
This research was supported by the Israel Science Foundation,
by the MINERVA foundation and by the Kimmel Center for
Molecular Design. D.M. holds the Israel Matz Professorial
Chair of Organic Chemistry. S.C. is thankful to the Swiss
Friends of the Weizmann Institute of Science committee for
a generous postdoctoral fellowship.
2
was observed by H NMR and 31P NMR. The appearance of
two other signals in the 2H NMR at 8.0 and 9.7 ppm indicated
=
the formation of dideuterated benzaldimine (PhCD ND)
through 2D transfer from 5-D3. On the other hand, when 5-D3
was reacted with 4 equiv benzonitrile under 1 bar H2 at room
Conflict of interest
=
=
temperature, formation of PhCD ND, PhCH NH, and
complex 5 (but not 5-D3 or 4-D) were noticed, thus again
supporting H/D exchange and an outer-sphere mechanism
(see the Supporting Information).
The authors declare no conflict of interest.
Keywords: cross-coupling · hydrogenation · imines · iron ·
nitriles
Based on the aforementioned observations, and on
reported mechanistic investigations, including experimental
and theoretical support in the case of a related aliphatic iPr-
PNP-pincer iron system,[16a] a plausible outer-sphere mecha-
nism is illustrated in Scheme 4.
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Manuscript received: August 31, 2016
Revised: December 9, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Homogeneous Catalysis
S. Chakraborty, G. Leitus,
D. Milstein*
&&& — &&&
Iron-Catalyzed Mild and Selective
Hydrogenative Cross-Coupling of Nitriles
and Amines to Form Secondary
Aldimines
Ace of base: A base-metal-catalyzed
hydrogenative cross-coupling of nitriles
and amines to form secondary aldimines
is reported. The reaction is catalyzed
under mild conditions by a well-defined
(iPr-PNP)Fe(H)Br(CO) pincer pre-cata-
lyst and catalytic tBuOK.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!