Direct synthesis of symmetrical azines from alcohols and hydrazine catalyzed by a ruthenium pincer complex: Effect of hydrogen bonding

Article abstract of DOI:10.1021/acscatal.6b02946

Azines (2,3-diazabuta-1,3-dienes) are a widely used class of compounds with conjugated CN double bonds. Herein, we present a direct synthesis of azines from alcohols and hydrazine hydrate. The reaction, catalyzed by a ruthenium pincer complex, evolves dihydrogen and can be run in a base-free version The deh dro enative cou lin of benz lic and aliphatic alcohols led to good conversions and yields. Spectroscopic evidence for a hydrazine-coordinated dearomatized ruthenium pincer complex was obtained. Isolation of a supramolecular crystalline compound provided evidence for the important role of hydrogen bonding networks under the reaction conditions.

Full text of DOI:10.1021/acscatal.6b02946

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Letter
Direct Synthesis of Symmetrical Azines from Alcohols and Hydrazine
Catalyzed by a Ruthenium Pincer Complex. Effect of Hydrogen Bonding
Jonathan O. Bauer, Gregory Leitus, Yehoshoa Ben-David, and David Milstein
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02946 • Publication Date (Web): 17 Nov 2016
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ACS Catalysis
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Direct Synthesis of Symmetrical Azines from Alcohols and
Hydrazine Catalyzed by a Ruthenium Pincer Complex. Effect
of Hydrogen Bonding
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Jonathan O. Bauer,† Gregory Leitus,‡ Yehoshoa Ben-David,† and David Milstein∗,†
Departments of †Organic Chemistry and ‡Chemical Research Support, The Weizmann Institute of Science, 76100
Rehovot, Israel
ABSTRACT: Azines (2,3-diazabuta-1,3-dienes) are a widely used class of compounds with conjugated C=N double bonds. Here-
in, we present a direct synthesis of azines from alcohols and hydrazine hydrate. The reaction, catalyzed by a ruthenium pincer
complex, evolves dihydrogen and can be run in a base-free version. The dehydrogenative coupling of benzylic and aliphatic
alcohols led to good conversions and yields. Spectroscopic evidence for a hydrazine-coordinated dearomatized ruthenium pincer
complex was obtained. Isolation of a supramolecular crystalline compound provided evidence for the important role of hydrogen
bonding networks under the reaction conditions.
KEYWORDS: azines, homogeneous catalysis, hydrogen bonds, pincer complexes, ruthenium, supramolecular compounds
Azines (R2C=N–N=CR2), namely 2,3-diazabuta-1,3-dienes,
are an important class of compounds that display diverse
reactivity and are useful for many applications, such as the
synthesis of N-heterocycles and functional polymers.1,2 Met-
al-promoted transformations of azines have led to new syn-
thetic applications.3 Azine formation has also proven benefi-
cial in studying metal-mediated N2 activation.4 Recently,
azines have generated much interest in the construction of
covalent organic frameworks (COFs) having photocatalytic
activity5 or serving as chemosensing detectors.6 Due to their
unique electronic structure and stereochemical versatility,7
azine units give also rise to remarkable chromophoric prop-
erties8 and are interesting as nonlinear optical materials.9
Applications as ferroelectric liquid crystals were also de-
scribed.10 The biological activity of azine derivatives holds
promise for pharmacological applications.11
mation of waste and excessive use of costly or toxic rea-
gents.18
The dehydrogenative coupling of alcohols and amines cat-
alyzed by pyridine-based pincer ruthenium complexes has
led to the synthesis of amides,19 imines,20 peptides, pyra-
zines,21 and pyrroles.22 Lately, our group reported the devel-
opment of hydrogen storage systems based on amide bond
formation.23 Ruthenium and iridium-catalyzed dehydro-
genative coupling of alcohols with substituted hydrazines are
known as well,24 but the direct use of N2H4 in catalysis is very
challenging. Very recently, Ru-catalyzed reaction of primary
alcohols with hydrazine resulted in alcohol deoxygenation.25
Azines are generally synthesized by reaction of carbonyl
compounds with hydrazine hydrate or hydrazones,12 even
though some effort in enhancing this general method was
undertaken in recent years.13 Aside from that, only a small
number of alternative routes were reported,3b,14-16 such as the
reaction of diazoalkanes with carbenes or carbenoids3b,14b,c,15
or the transformation of a tetrazole with cyclooctyne.14d
However, all of these methods lack generality and are limited
to a few very specific substrates. Recently, Chiba reported the
conversion of vinyl azides to α-trifluoromethyl azines which
are precursors to various fluorinated compounds.16
Figure 1. Ruthenium PNP pincer complexes studied for azine syn-
thesis. [P] = P(tBu)2. Molecular structure of [(tBuPNP)Ru(CO)H]
[PF6] (3) (hydrogen atoms at carbon are omitted for clarity).
One of the major challenges in the field of catalysis is the
development of environmentally benign transformations of
widely accessible starting materials into synthetically valua-
ble products. In recent years, our group reported on new
catalytic procedures based on the concept of metal-ligand
cooperation17 involving reversible aromatization/dearomati-
zation within the ligand backbone. Using pincer-type com-
plexes, this concept has become an important paradigm in
the development of unprecedented one-step reactions to-
wards fundamental building blocks, while avoiding the for-
Herein, we present the first direct synthesis of azines from
alcohols. The reaction is based on acceptorless dehydrogen-
ative coupling of alcohols and hydrazine catalyzed by a ru-
thenium pincer complex (Figure 1). This one-step strategy is
atom-economical and environmentally benign, forming
azines directly from readily available, sustainable starting
materials while producing H2. Mechanistic insight, including
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Page 2 of 5
involvement of hydrogen bonding in this process, which has
(78%) and the formation of 66% azine. Even when using the
chloride-free cationic complex [(tBuPNP)Ru(CO)H]+[PF6]–
(3) (Figure 1) in the presence of molecular sieves, the reaction
proceeded smoothly, albeit the yield of the desired azine was
only 48% (entry 9). However, no conversion was observed
with 3 in the absence of molecular sieves (entry 10). These
findings lead to the conclusion that the presence of molecu-
lar sieves or γ-alumina is crucial, and that the hydrazine-
containing reaction conditions are capable of forming an
active catalyst species directly from complex 1 without the
need of added base. Significantly, complexes 1 and 3 were
completely inactive towards dehydrogenation of 4-methoxy-
benzyl alcohol, whereas the dearomatized complex 2 led to
full conversion after 50 h heating at toluene reflux and gave
both aldehyde (45%) and ester (54%). These findings suggest
that under the reaction conditions complex 1 is converted to
an active dearomatized catalyst with assistance of excess
hydrazine, prior to the actual catalytic cycle, since dehydro-
genation of the alcohol to form the aldehyde is required for
condensation with hydrazine to form an azine.
1
2
3
4
5
6
7
8
led to the isolation of a supramolecular crystalline com-
pound, and an unexpected role of molecular sieves, is pro-
vided.
Exploring the best reaction conditions for the coupling re-
action, 4-methoxybenzyl alcohol was chosen as a model
system (Table 1). Heating a solution of 4-methoxybenzyl
alcohol and hydrazine hydrate in the presence of 0.5 mol%
120 and 1.5 mol% KOtBu in toluene at reflux for 50 h resulted
in only 32% of 4-methoxybenzaldazine along with 34% alde-
hyde and 25% ester (Table 1, entry 1). Using the isolated
dearomatized complex 220 instead of in situ deprotonation of
1 with base, the conversion was lower (50%) but the relative
amounts of azine (15%), aldehyde (18%), and ester (10%)
remained the same (Table 1, entry 2). Significantly, upon
addition of molecular sieves (3 Å) to the reaction catalyzed
by 1 and base, full conversion was obtained, the desired azine
being obtained as the only product under otherwise identical
conditions (entry 3). Carrying out the reaction with complex
2 (0.5 mol%) in the presence of molecular sieves but without
base, the azine was also selectively obtained, although in
lower conversion (62%) and yield (58%, entry 4). Unexpect-
edly, in a base-free variant, starting directly from the aro-
matic complex 1 (0.5 mol%), the coupling reaction of the
alcohol and hydrazine proceeded smoothly (91% conversion)
with high yield (91%) and without formation of any side
products (entry 5). Performing the same reaction with no
molecular sieves and no base using 1 (0.5 mol%), the conver-
sion was negligible (9%), the azine being formed in only 6%
yield (entry 6). As shown in entries 7 and 8 of Table 1, we also
studied Na2SO4 and γ-Al2O3 as water-capturing additives in
the azine synthesis. Whereas the reaction was totally inhibit-
ed by Na2SO4, the use of γ-alumina led to good conversion
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It was of interest to us to get more information regarding
the role of molecular sieves. Normally it is assumed that they
act just as a water scavenger. Surprisingly, addition of excess
water to an experiment under the normal conditions, using
molecular sieves, had little effect on the reaction (compare
entries 5 and 11, Table 1). Next, a mixture of hydrazine hy-
drate, complex 1, and molecular sieves in toluene, in absence
of alcohol, was heated at reflux for 17 h. Then, the sieves were
removed and 4-methoxybenzyl alcohol was added to the
supernatant solution and the solution was refluxed for 29 h;
to our surprise, no azine was formed, although 25% aldehyde
was still obtained. 4-Methoxybenzyl alcohol was then added
to the removed molecular sieves in fresh toluene and the
mixture refluxed for 50 h, leading to high conversion
(85%) of the alcohol to form the azine (58%) along with
the aldehyde (23%). Hence it is obvious that hydrazine
remains attached to the molecular sieves, ready for the
reaction with an aldehyde, with the catalyst also being
partly bound to the molecular sieves, probably by rever-
sible coordination of hydrazine to the ruthenium center.
Table 1. Optimization of the reaction conditions for azine formation.a
Complex 1-3
KOtBu
Conv. of
alcohol [%]b
Azine
[%]b
Aldehyde
[%]b
Ester
[%]b
Entry
[0.5 mol%]
[mol%]
To get more insight into possible intermediates, we in-
vestigated the interaction between hydrazine and the
dearomatized, unsaturated complex 2 (Scheme 1), the
latter being considered a key intermediate in the alcohol
dehydrogenation process. Addition of hydrazine hydrate
(1 equiv.) to a freshly prepared solution of 2 in [D6]-
benzene led to a color change from dark-blue to yellow.
1H NMR spectroscopy showed a dramatic downfield shift
of the metal-hydride triplet signal from –25.76 to
–16.16 ppm, indicative of coordination trans to the hy-
dride ligand of 2. Since water addition to dearomatized
ruthenium pincer complexes is likely reversible,20,26 it is
plausible that hydrazine coordinates to the metal center
of 2. Such a complex derived from 2 and an amine was
previously observed for ammonia, and is in line with the
general preference of electron-rich amines to coordinate
via the lone electron pair rather than undergo N–H bond
activation.27 Broad 1H NMR signals that overlap the
chemical shift regions from 2.8 to 3.8 (CH2P and =CHP)
and from 5.3 to 6.4 ppm (Py-H3,5) but the presence of a
sharp triplet at 6.51 ppm (Py-H4) indicate an equilibrium
1
1
2
1
2
1
1
1
1
3
3
1
1.5
–
94
50
99
62
91
9
32
15
99
58
91
6
34
18
–
25
10
–
2
3c
4c
5c
6
1.5
–
–
–
–
–
–
–
–
–
7d
8e
9c
10
11c,f
–
–
–
–
–
–
78
62
–
66
48
–
5
–
–
2
5
–
–
–
–
89
85
3
–
aReaction conditions: Complex 1-3, alcohol (2.5 mmol), hydrazine hydrate
(0.7 equiv., 1.75 mmol), KOtBu (0-1.5 mol%), and toluene (5 ml) were heated
at reflux in a Schlenk flask (oil bath temperature: 130 °C) for 50 h. bConver-
sion of alcohol and yields of products were determined by 1H NMR spec-
troscopy using N,N-dimethylformamide as internal standard, supported by
GC/MS analysis. cIn the presence of molecular sieves (3 Å) (1 g). dIn the pre-
sence of Na2SO4 (1 g). eIn the presence of γ-Al2O3 (0.6 g). fAddition of excess
water (0.2 ml).
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ACS Catalysis
Scheme 1. Formation of a coordination complex from 2 and
hydrazine hydrate in solution. [P] = P(tBu)2.
with imine formation by coupling of amines with alcohols,
which generates water as well, but does not require the use
of molecular sieves.20
1
2
3
4
5
6
7
8
9
Table 2 shows the substrate scope of the new dehydro-
genative coupling reaction of alcohols and hydrazine under
slightly basic conditions or in base-free versions using com-
plex 1. The reaction tolerates a variety of substituent patterns
of benzylic alcohols. The base-free method can be performed
with low catalyst loading (0.5 mol%) to obtain good to high
yields (Table 2, entries 1-8). For 3-(dimethylamino)benzyl
(75% isolated yield) and 4-methylbenzyl alcohol (70% isolat-
ed yield) the base-free version led to significantly better
results with lower amounts of the catalyst (entries 3 and 5).
The base-free variant led also to good results for benz-
aldazine (78% yield; entry 6) and can be expanded to halogen
substituted benzyl alcohols as well, as shown for the chloro
derivative (entry 7), although in lower yield. The presence of
between the vinylic and benzylic protons via a symmetric
cationic intermediate like [2-N2H4]H+ OH– in which the PNP
ligand underwent protonation by water (Scheme 1). The
appearance of sharp 13C{1H} NMR signals for carbon atoms
which are only marginally affected by such an equilibrium,
like Py-C4 (132.6 ppm) and Ru-CO (triplet at 209.2 ppm) is in
line with this equilibrium. The 31P{1H} NMR spectrum
showed a broad unsymmetrical splitting pattern at 78.4 and
81.8 ppm that also supports the existence of a dearomatized
coordination complex (for details, see SI).28 Such an equilib-
rium might also take place under the catalytic conditions,
the coordinated hydrazine being eventually displaced by an
alcohol, enabling the catalytic cycle.
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Table 2. Direct synthesis of azines from alcohols and hydrazine
hydrate using the ruthenium complex 1.a [P] = P(tBu)2.
Surprisingly, treating a solution of complex 2 and hydra-
zine hydrate in benzene with molecular sieves (3 Å) resulted
in formation of single-crystals of a unique supramolecular
compound.
The
unit
cell
consists
of
eight
[(tBuPNP)Ru(CO)H(N2H4)]+ cations (Figure 2) of the type [2-
N2H4]H+ having an aromatized PNP ligand and coordinated
hydrazine. The coordinated hydrazine is part of a sophisti-
cated hydrogen bonding network together with water mole-
cules and a [Si8O20]8– cluster which undoubtedly originated
from the molecular sieves (for structural details including
hydrogen bond analysis, see SI). Most likely, the acidity of
silanol groups led to protonation of the dearomatized PNP
complex [2-N2H4] resulting in stabilization of the cationic [2-
N2H4]H+ in the equilibrium of Scheme 1.29 The interesting
crystal structure sheds more light on the molecular condi-
tions during the ruthenium-catalyzed azine synthesis and
allows for the conclusion that breaking hydrogen-bonded
networks between the highly protic reactants, most likely
with surface siloxide groups of molecular sieves being in-
volved in hydrogen bonding, might be crucial for releasing
the catalyst and enabling the catalytic cycle. This contrasts
Conv. of
t
1
KOtBu
Yield
[%]b
Entry
R
alcohol
[%]b
[h]
[mol%]
[mol%]
50
50
0.5
0.5
1.5
–
99
91
99 (91)
91
1
2
3
4
5
6
7
8
4-(MeO)C6H4
3,4-(MeO)2C6H3
3-(Me2N)C6H4
3-(MeO)C6H4
4-(Me)C6H4
Ph
66
66
0.5
0.5
1.5
–
69
88
66 (56)
69 (59)
65
65
1
2
–
79
86
77 (57)
86 (75)
0.5
67
0.5
–
67
50 (36)
67
67
1
2
–
68
88
61 (46)
82 (70)
0.5
67
69
65
0.5
0.5
0.5
–
–
–
88
58
79
78 (59)
35 (27)
70 (58)
4-(Cl)C6H4
Me(CH2)4
aReaction conditions: Complex 1, alcohol (2.5 mmol), hydrazine hydrate
(0.7 equiv., 1.75 mmol), KOtBu (0-2 mol%), and toluene (5 ml) were
heated at reflux in the presence of molecular sieves (3 Å) (1 g) in a
Schlenk flask (oil bath temperature: 130 °C). bConversion of alcohols
and yields of products were determined by 1H NMR spectroscopy using
N,N-dimethylformamide as internal standard, supported by GC/MS
analysis. Yields of isolated products in parentheses.
strong electron withdrawing substituents like CF3 or F in
para position resulted in very little, conversion, forming (for
CF3) a mixture of products. Hexanaldazine was synthesized
in good yield (70%), demonstrating the applicability for
aliphatic alcohols (entry 8).
Figure
2.
Part
of
the
crystal
structure
of
{[(tBuPNP)Ru(CO)H(N2H4)]+}8[Si8O20]8–(C6H6)9(H2O)37 (4): Cationic
complex [2-N2H4]H+ hydrogen-bonded to a [Si8O20]8– cluster (some
of the hydrogen atoms are omitted for clarity).
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(8) (a) Caballero, A.; Martínez, R.; Lloveras, V.; Ratera, I.; Vidal-
In summary, we have developed a general synthetic meth-
od for the preparation of symmetrical azines from alcohols
and hydrazine hydrate catalyzed by a ruthenium PNP com-
plex in the presence of molecular sieves, which can be per-
formed without base. This dehydrogenative coupling reac-
tion is an efficient way of forming N–N-linked building
blocks that can be used for a variety of subsequent transfor-
mations. The use of molecular sieves (or γ-alumina) is essen-
tial. Hydrazine is strongly bound to the molecular sieves, and
an unusual ruthenium complex bearing hydrazine H-bonded
to a siloxane cluster was isolated. Studies aimed at further
mechanistic insight, and synthetic applications of the hydra-
zine-based catalytic methodology are in progress.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, crystallographic and spectroscopic
details. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
david.milstein@weizmann.ac.il
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was supported by the European Research
Council (ERC AdG 692775). D.M. holds the Israel Matz Prof-
essorial Chair. J.O.B. thanks the Alexander von Humboldt
Foundation for the award of a Feodor Lynen Postdoctoral
Fellowship.
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