Ruthenium(ii)-catalysed direct synthesis of ketazines using secondary alcohols

Article abstract of DOI:10.1039/c9cc01383k

Direct one-pot synthesis of ketazines from secondary alcohols and hydrazine hydrate catalyzed by a ruthenium pincer complex is reported, which proceeds through O-H bond activation of secondary alcohols via amine-amide metal-ligand cooperation in the catalyst. Remarkably, liberated molecular hydrogen and water are the only byproducts.

Full text of DOI:10.1039/c9cc01383k

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Ruthenium(II)-catalysed direct synthesis
of ketazines using secondary alcohols†
Cite this:DOI: 10.1039/c9cc01383k
Jugal Kishore, Subramanian Thiyagarajan and Chidambaram Gunanathan
*
Received 18th February 2019,
Accepted 21st March 2019
DOI: 10.1039/c9cc01383k
rsc.li/chemcomm
Direct one-pot synthesis of ketazines from secondary alcohols and be oxidized to the carbonyl compounds, which involves the
hydrazine hydrate catalyzed by a ruthenium pincer complex is excess use of toxic inorganic salts, and further reaction with
reported, which proceeds through O–H bond activation of secondary hydrazine hydrate provides azine products. This multistep
alcohols via amine–amide metal–ligand cooperation in the catalyst. synthesis of azines produces waste and requires workup methods
Remarkably, liberated molecular hydrogen and water are the only and isolation procedures. Thus, developing a direct one-pot
byproducts.
synthesis of azines from alcohols can be valuable in organic
synthesis. Catalytic dehydrogenation of feedstock chemicals
Azines (R2CQN–NQCR2) are versatile building blocks for the such as alcohols to value-added products with the concomitant
synthesis of various nitrogen containing natural products and generation of dihydrogen is of much interest in the context of
molecules of pharmacological relevance.1,2 They are a class of the hydrogen economy and is an effective alternative to the
compounds with interesting chemical properties and undergo classical oxidation reactions. In this direction, acceptorless
a wide variety of chemical transformations.3 Azines have dehydrogenation of alcohols has become an important para-
attracted considerable attention in cycloaddition reactions due digm to afford atom-economical and sustainable chemical
to the presence of two conjugated double bonds. For example, transformations17 as the oxidation of alcohols is achieved
azines can be used for the synthesis of N-heterocyclic compounds without using toxic oxidizing reagents and sacrificial hydrogen
via cycloaddition reactions.4 Azines display interesting physical acceptors. Recently, Milstein and Goswami reported the cata-
properties and are used as ion-selective optical sensors,5 conduc- lytic one-pot direct synthesis of azines using primary alcohols
tive materials,6 NLO materials,7 dye lasers, and image recording and hydrazine hydrate (Scheme 1a and b).18 However, reactions
materials.8 The reducing tendency of azines makes them suitable remain applicable to the synthesis of aldazines using primary
for application as hole-transport materials in optoelectronic and benzylic primary alcohols. Direct synthesis of ketazines
devices.9 Additionally, azines can be used in the construction using secondary alcohols is unknown and challenging due to the
of covalent organic frameworks (COFs)10 and chemosensing lower reactivity and higher steric hindrance of secondary alcohols
detectors11 and as building blocks in supramolecular chemistry.12 in comparison to primary alcohols. Recently, using ruthenium
Recently, azines have also been utilized in the synthesis of PNP pincer complex 1 we have developed the a-alkylation and
isoquinoline derivatives.13
Conventional methods for the synthesis of azines involve the
treatment of carbonyl compounds with hydrazine hydrate or
hydrazones.1a,14 Alternative methods have been developed to
synthesize azines from diazo compounds, alkynes, isocyanates
and azides.15,16 Synthesis of azines directly from alcohols by the
traditional method is not known. In general, alcohols have to
School of Chemical Sciences, National Institute of Science Education
and Research (NISER), HBNI, Bhubaneswar, Khurda-752050, India.
E-mail: gunanathan@niser.ac.in
† Electronic supplementary information (ESI) available: Experimental procedures,
NMR spectra of ketazines and their spectral data; and X-ray data for 2d, 2n, and 3m.
CCDC 1889888–1889890. For ESI and crystallographic data in CIF or other
Scheme 1 Direct catalytic synthesis of azines using alcohols.
electronic format see DOI: 10.1039/c9cc01383k
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a-olefination of nitriles19a,b using primary and secondary conversions and the corresponding ketazine products were
alcohols, respectively, and also the cross-coupling of secondary obtained in good to excellent yields (Table 1).
alcohols.19c Facile activation of the O–H bonds of alcohols and
In general, simple cyclic and benzylic secondary alcohols
water through amine–amide metal–ligand cooperation was with methyl substituents provided the corresponding products
established from our previous studies.19,20 Herein, we report in good yields. The reaction of 4-methyl tetralin-1-ol, 1-phenyl-
a new catalytic protocol for the synthesis of ketazines directly 1-ethanol and 1-(p-tolyl)ethanol substrates provided the ketazine
from secondary alcohols and hydrazine hydrate (Scheme 1c).
products 2b, 2d and 2e, respectively, in more than 90% isolated
Using tetralin-1-ol as a benchmark substrate along with yields. Further, the reaction of 6-methoxytetralin-1-ol, 1-(2-methoxy-
hydrazine hydrate, the optimization studies were carried out to phenyl)ethanol, and 1-(4-methoxyphenyl)ethanol provided the
find the suitable experimental conditions for ketazine synthesis ketazine products 2c, 2f and 2g in 81–86% yields, indicating
(see Table S1, ESI†). When the reaction between tetralin-1-ol that the catalytic azine formation is sensitive to steric hindrance
(0.5 mmol), hydrazine hydrate (0.75 mmol), catalyst 1 (1 mol%) in the proximity as well as electronic factors. Notably, azine
and base (5 mol%, KOtBu) in toluene with molecular sieves product 2f can be used in the synthesis of aphrodisiac drugs22a
(4 Å) was performed at 125 1C, the quantitative conversion of and is also used as dielectric and photosemiconductor
the secondary alcohol occurred to provide an azine product 2a materials.22b In addition, 1-(pyridin-3-yl)ethanol reacted with
in 97% yield (Table 1). Notably, no desired azine (2a) formation hydrazine hydrate to form an azine in good yield (2h, Table 1).
was observed upon reaction of the Milstein PNP-Ru catalyst Interestingly, electron withdrawing groups containing benzylic
with tetralin-1-ol under reported conditions.18b Using the optimal alcohols are well tolerated and afforded the symmetrical azines
reaction conditions for the synthesis of ketazine, we examined 2i, 2j and 2k in 89–91% yields. The reaction also proceeded
the scope of different benzylic secondary alcohols in catalysis. smoothly with 1-phenylpropan-1-ol and 1-phenylbutan-1-ol to
Remarkably, in all cases, we observed almost quantitative afford the azine products 2l and 2m in 58% and 90% yields,
respectively (Table 1). 1-(Naphthalen-2-yl)ethanol exhibited
499% conversion and provided product 2n in 89% yield.
Single-crystal X-ray analyses of compounds 2d (see the ESI†)
and 2n (Table 1) confirmed their ketazine structures.
Table 1 Ruthenium catalysed synthesis of ketazines using benzylic secondary
alcoholsa
The scope of aliphatic secondary alcohols was explored in
direct catalytic ketazine synthesis. A variety of cyclic as well as
acyclic aliphatic secondary alcohols afforded good to excellent
yields (Table 2). When cyclohexanol was examined under the
optimized reaction conditions, 70% conversion was observed
and product 3b was isolated in 65% yield. Thus, increased
loadings of catalyst 1 (2 mol%) and base KOtBu (10 mol%) were
used, which resulted in the complete conversion of cyclo-
hexanol and product 3b in 84% isolated yield (Table 2). A wide
variety of cyclic alcohols such as cyclopentanol, 4-methyl cyclo-
hexanol, cycloheptanol and cyclooctanol were reacted with
hydrazine hydrate, which provided the quantitative conversion
of alcohols to afford symmetrical ketazine products 3a–3e in
very good yields (entries 1–5, Table 2). A sterically hindered
substrate such as 2-adamantanol also afforded ketazine product
3f in 78% yield (entry 6, Table 2). Further, acyclic symmetrical
as well as unsymmetrical aliphatic secondary alcohols were
explored in this catalytic transformation. When low boiling
point secondary alcohols such as isopropanol and 2-butanol
were subjected to the reaction, ketazine products 3g and 3h were
obtained in 50% and 73% yields, respectively (entries 7 and 8,
Table 2). Further, higher order acyclic secondary alcohols were
used, leading to the formation of ketazine products 3i–3l in
excellent yields (entries 9–12, Table 2). Unsymmetrical acyclic
secondary alcohols provided E/Z mixtures of ketazine products.
Notably, ketazines from natural products can also be synthe-
sized using this methodology. Catalytic reaction of cholesterol
a
Catalytic conditions: catalyst 1 (1 mol%), base (5 mol%), secondary
alcohol (0.5 mmol), N2H4ÁH2O (0.75 mmol) and toluene (2 mL) with
molecular sieves (4 Å) were heated at 125 1C in a Schlenk flask for 12 h. with hydrazine hydrate under the standard conditions used in
Conversion of alcohols was determined by GC analysis and are given
Table 2 provided the ketazine product 3m in 45% yield in which
isomerization of the homoallylic double bond was observed
within parentheses. Yields correspond to isolated products after
column chromatography. b Reaction was conducted with 2 mol% catalyst 1
and 10 mol% base.
(Scheme 2). The diminished yield of 3m may be attributable to
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Table 2 Ruthenium catalyzed synthesis of ketazines using aliphatic secondary
alcohols by catalyst 1a
Scheme 2 Direct synthesis and single crystal X-ray structure of ketazine
3m using cholesterol.
Product
Entry
1
Conv.b (%)
Yieldc (%)
74
3a
3b
499
2
3
4
499
499
499
84
92
89
3c
3d
5
3e
3f
499
87
78
Fig. 1 GC monitoring of ketazine formation using tetralin-1-ol and hydra-
zine hydrate using ruthenium pincer catalyst 1. The concentrations of
tetralin-1-ol (black line), intermediate hydrazone (red line) and product 2a
(green line) are plotted for direct catalytic synthesis of ketazines from
secondary alcohols.
6d
90
7e
3g
3h
n.d.
50
73
(see the ESI†). 1H NMR analysis of the reaction mixture showed
a broad singlet at d 5.20 ppm, indicating the formation
of a hydrazone intermediate (Scheme S1, ESI†). Rapid reaction
progress was observed at the outset of the reaction, then it
slowed down gradually and exhibited complete conversion
within 12 h (Fig. 1).
8e, f
499
9e, f
10
3i
3j
499
499
90
83
Based on these experimental studies and our previous
work,19–21 the catalytic cycle for the synthesis of ketazines using
secondary alcohols catalyzed by 1 is proposed in Scheme 3.
On treatment of catalyst 1 with KOtBu, a 16-electron unsaturated
amide-ligated intermediate (I) is obtained. Reaction of unsaturated
intermediate I with a secondary alcohol leads to the formation of
an alkoxy ligand-coordinated intermediate (II) via O–H bond
activation20c in which the central amide donor of I is converted
into an amine donor in intermediate II. Further, b-hydride
elimination in II provides the corresponding ketone compound
and a ruthenium dihydride complex (III) via amine–amide
metal–ligand cooperation. Complex III can liberate dihydrogen
and regenerate the catalytically active intermediate I, thus
closing one loop in a catalytic cycle. Finally, the in situ formed
ketone undergoes a condensation reaction with hydrazine hydrate
to provide a hydrazone intermediate, which upon subsequent
11
3k
3l
499
499
84
90
12 f
a
Catalytic conditions: catalyst 1 (2 mol%), base (10 mol%), secondary
alcohol (0.5 mmol), hydrazine hydrate (1.5 mmol) and toluene (2 mL)
with molecular sieves (4 Å) were heated at 125 1C in a Schlenk flask for 12 h.
b
c
The conversion of alcohols was determined by GC analysis. The yields
d
correspond to isolated products after column chromatography. The
e
reaction was carried out for 18 h. The yield of the product was calculated
from 1H NMR analyses using mesitylene as an internal standard. f The
product isolated as a mixture of E/Z isomers. n.d.: not determined.
the low solubility of cholesterol in the reaction medium. The condensation with another molecule of ketone provided the
structure of ketazine 3m is unequivocally corroborated by desired symmetrical ketazine products.
single-crystal X-Ray analyses.
In summary, we have developed an efficient protocol for
To understand the reaction pathways, kinetic analysis was ruthenium(II)-catalyzed direct synthesis of ketazines using
carried out. GC monitoring of the reaction progress for secondary alcohols. Several aromatic as well as aliphatic secondary
tetraline-1-ol with hydrazine hydrate catalyzed by 1 (1 mol%) alcohols underwent facile reaction to provide the corresponding
confirmed that the reaction followed first-order kinetics with ketazine products in good to excellent yields. Using this strategy,
respect to the consumption of tetraline-1-ol. The formation we have synthesized the cholesterol azine product directly from
of the corresponding 1-tetralone and hydrazone intermediates cholesterol. Kinetic and NMR studies strongly suggest that the
was observed in GC and 1H NMR of the reaction mixture reaction follows first order kinetics and proceeds via hydrazone
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genation of secondary alcohols via amine–amide metal–ligand
cooperation in catalyst 1 to provide ketones followed by a con-
secutive condensation reaction with hydrazine hydrate to provide
the corresponding ketazine products. Remarkably, H2O and H2 are
the only byproducts in this environmentally benign catalytic
transformation.
We thank SERB New Delhi (EMR/2016/002517), DAE and
NISER for financial support. J. K. thanks DST for an INSPIRE
fellowship. S. T. thanks UGC for a research fellowship. We are
thankful to Prof. Basker Sundararaju for his kind support and
fruitful discussions. We thank P. Kalita for his kind help.
Conflicts of interest
There are no conflicts to declare.
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