Cooperative ruthenium complex catalyzed multicomponent synthesis of pyrimidines

Article abstract of DOI:10.1039/c9dt04040d

A new set of 2-(2-benzimidazolyl) pyridine ligand based air and moisture stable ruthenium complexes were synthesized and characterized. The catalytic behaviors of these complexes were evaluated towards the multicomponent synthesis of highly substituted py

Full text of DOI:10.1039/c9dt04040d

Dalton
Transactions
View Article Online
View Journal | View Issue
PAPER
Cooperative ruthenium complex catalyzed
multicomponent synthesis of pyrimidines†
Cite this: Dalton Trans., 2019, 48,
17479
Milan Maji and Sabuj Kundu
*
A new set of 2-(2-benzimidazolyl) pyridine ligand based air and moisture stable ruthenium complexes
were synthesized and characterized. The catalytic behaviors of these complexes were evaluated towards
the multicomponent synthesis of highly substituted pyrimidines directly from various amidines, primary
alcohols, and secondary alcohols. Among all the metal complexes, 2-hydroxypyridine and benzimidazole
fragments containing complex A showed the best reactivity in this reaction. In addition, it was observed
that the N–H proton of benzimidazole and the hydroxyl group of pyridine played a critical role in enhan-
cing catalytic activity. Several control experiments and mechanistic studies were carried out to understand
this multicomponent synthesis of pyrimidines using complex A.
Received 15th October 2019,
Accepted 2nd November 2019
DOI: 10.1039/c9dt04040d
rsc.li/dalton
will be exciting to explore for the synthesis of pyrimidines
from amidines and alcohols.
Introduction
Pyrimidines constitute an important class of N-heterocycles
Based on the metal–ligand cooperation in homogeneous
with diverse applications in pharmaceuticals, agrochemicals, catalysis, various chemical transformations were extensively
dyes, molecular devices and functional materials.1–10 Thus, studied.41–46 With these catalysts generally higher reaction
the development of a sustainable and atom economical meth- rates were observed due to the simultaneous participation of
odology is highly desirable for the synthesis of pyrimidine both metals and ligands. Among the various cooperative
derivatives from easily available substrates. Alcohols are cheap ligands, 2-hydroxypyridine and benzimidazole fragment-based
precursors which can be easily accessed by various industrial bifunctional ligands received considerable attention.47–52
processes and the catalytic conversion of lignocellulose Apart from the –O–H fragment in 2-hydroxypyridine ligands,
biomass or fermentation processes.11,12 Hence, efficient and the benzimidazole –N–H unit also plays an important role in
sustainable methodologies for the catalytic transformation of enhancing catalytic activity.53–56
alcohols to valuable N-heterocycles have become vital
We hypothesized that a combination of 2-hydroxypyridine
nowadays.13–16 Acceptorless dehydrogenative coupling strategy and benzimidazole fragments in a same ligand platform
has become a promising tool for eco-friendly C–C and would deliver more efficient catalysts where the unique charac-
C–N bond formation reactions using alcohols.14,17–30 teristics of each fragment of this hybrid ligand will enhance
Multicomponent reactions are also a highly attractive strategy the catalytic performance. Previously, we found that a similar
to construct structurally diverse and complex molecules start- hybrid ligand based iridium catalyst exhibited higher catalytic
ing from simple precursors.31–34 The first multicomponent activity in the synthesis of various N-heterocycles in water.28
synthesis of pyrimidines from amidines and alcohols was Herein, we report the synthesis of various benzimidazole con-
reported by Kempe and co-workers using the (PNP)Ir catalyst.35 taining functionalized pyridine-based ruthenium complexes
Later, for a similar transformation, a few other reports and compare their catalytic activity in the multicomponent
emerged in the literature.36–40 However, most of the homo- synthesis of pyrimidines. To the best of our knowledge, a
geneous catalytic systems were based on either expensive air similar ruthenium catalyzed transformation has not been
and moisture sensitive alkyl phosphine based ligand systems reported yet (Scheme 1).
or required an excess amount of base as an additive. Hence,
air and moisture stable alkyl phosphine free catalytic systems
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016,
Uttar Pradesh (U.P.), India. E-mail: sabuj@iitk.ac.in
†Electronic supplementary information (ESI) available. CCDC 1937945, 1954543,
1953620 and 1953618 for complex A, C, D and E respectively. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/C9DT04040D
Scheme 1 Multicomponent synthesis of pyrimidines.
This journal is © The Royal Society of Chemistry 2019
Dalton Trans., 2019, 48, 17479–17487 | 17479

View Article Online
Paper
Dalton Transactions
Results and discussion
Various substituted 2-(2-benzimidazolyl) pyridine ligands were
synthesized in good yields by following the reported literature,
and their corresponding Ru(II) complexes were synthesized by
the reaction with RuHCl(CO)(PPh3)3 in dichloromethane at
room temperature (Scheme 2). All these new Ru(II) complexes
were characterized by NMR spectroscopy, ESI-MS and elemen-
tal analysis. Complexes A, C, D and E were also characterized
by X-ray diffraction study (Fig. 1 and 2).
In the 1H-NMR spectrum, the hydride signal of the com-
plexes A, B, C, D, E and F appeared as a triplet at δ =
−12.15 ppm (JH,P = 20.0 Hz), −12.05 ppm (JH,P = 19.2 Hz),
−12.05 ppm (JH,P = 20.4 Hz), −12.17 ppm (JH,P = 19.3 Hz),
−11.63 ppm (JH,P = 19.3 Hz) and −12.14 ppm (JH,P = 18.4 Hz),
respectively. 31P{1H}-NMR resonances of the complexes A, B, C,
D, E and F appeared as a singlet at δ = 46.54 ppm, 44.57 ppm,
45.77 ppm, 43.91 ppm, 44.58 ppm and 44.26 ppm respectively.
The appearance of the singlet peak in 31P-NMR indicated the
Fig. 2 (a) Solid state structure of complex D with 30% thermal ellip-
soids. Selective bond distances (Å) and angles (°): Ru–N1 2.117(3), Ru–
N3 2.304(3), Ru–P1 2.366(11), Ru–P2 2.358(11), C–O 1.154(4), P1–Ru–P2
170.53(4), N1–Ru–N3 75.43(12), N1–Ru–P1 86.49(8), N3–Ru–P1
91.66(8), and N3–Ru–P2 97.09(8). (b) Solid state structure of complex E
with 30% thermal ellipsoids. Selective bond distances (Å) and angles (°):
Ru–N1 2.112(3), Ru–N3 2.233(3), Ru–P1 2.361(11), Ru–P2 2.355(11), C–O
1.157(5), P1–Ru–P2 171.45(4), N1–Ru–N3 75.31(12), N1–Ru–P1 92.12(9),
N3–Ru–P1 94.67(8), and N3–Ru–P2 93.57(8). The counter anion and
solvent molecules were omitted for clarity.
Table 1 Carbonyl IR stretching frequencies of Ru(II) complexes
Complex
A
B
C
D
E
F
IR [νCvO (cm−1)]
1957
1941
1937
1930
1934
1917
presence of one type of phosphorus environment around the
Ru(II) centre, which suggested that two PPh3 molecules were
trans to each other. The IR spectra of all these complexes were
recorded and complex F displayed the lowest IR stretching fre-
quency of carbonyl (νCO) which specified that L5 was the most
electron rich ligand compared to the other ligands (Table 1).
The solid state structure of the complexes A, C, D, and E
showed a distorted octahedral coordination around the Ru(II)
center. Each Ru(II) was coordinated to two trans PPh3 mole-
cules, one bidentate NN ligand, one hydride and one CO
ligand which was trans to benzimidazole nitrogen (N1). The
P1–Ru–P2 bond angles of complexes A, C, D, and E were
166.91°, 177.17°, 170.55°, and 171.45° respectively, indicating
that two PPh3 molecules were present in an axial arrangement.
The Ru–PPh3 bond length was slightly longer compared with
the other adjacent Ru–N1, Ru–N3, Ru–CO and Ru–H bonds.
The Ru–N1 bond length was relatively shorter (∼0.1–0.2 Å)
compared to Ru–N3 in all these complexes, which revealed
that the binding of the benzimidazole nitrogen was stronger
than that of the pyridine nitrogen with the Ru-center. A chlor-
ide ion was present outside the primary coordination sphere
of all the complexes.
Scheme 2 Synthesis of Ru(II) metal complexes.
Fig. 1 (a) Solid state structure of complex
A with 30% thermal
ellipsoids. Selective bond distances (Å) and angles (°): Ru–N1 2.113(2),
Ru–N3 2.253(2), Ru–P1 2.363(9), Ru–P2 2.367(9), C–O1 1.165(4), P1–
Ru–P2 166.91(3), N1–Ru–N3 75.19(19), N1–Ru–P1 88.30(7), N3–Ru–P1
96.07(7), and N3–Ru–P2 96.09(7). (b) Solid state structure of complex C
with 30% thermal ellipsoids. Selective bond distances (Å) and angles (°):
Ru–N1 2.102(3), Ru–N3 2.216(3), Ru–P1 2.359(7), Ru–P2 2.359(7), C–O1
1.136(5), P1–Ru–P2 177.17(4), N1–Ru–N3 75.48(13), N1–Ru–P1 90.32(2),
N3–Ru–P1 91.413(19), and N3–Ru–P2 91.412(19). The counter anion
and solvent molecules were omitted for clarity.
To obtain the most suitable reaction conditions, the
coupling of benzamidine (1), 1-phenylethanol (2) and benzyl
alcohol (3) was picked as the model reaction (Table 2).
Initially, 1 (0.25 mmol), 2 (0.32 mmol) and 3 (0.32 mmol) were
allowed to react in presence of 1 mol% of cat. A and KOtBu
(0.13 mmol) in toluene for 24 h, which afforded 61% yield of
17480 | Dalton Trans., 2019, 48, 17479–17487
This journal is © The Royal Society of Chemistry 2019

View Article Online
Dalton Transactions
Paper
Table 2 Optimization of reaction conditionsa
ity compared to complex D (Table 2, entry 9). This established
the importance of the benzimidazole N–H proton in this cata-
lytic reaction. Next, the effect of various bases was tested and
KOtBu delivered the best result (Table 2, entries 12–15), while
with only base, a lower yield of 4 was observed (entry 11).
When the amount of base was increased to 1 equiv., the yield
of 4 increased to 95% whereas, decreasing the amount of the
catalyst as well as the reaction time led to a lower yield of the
desired product (Table 1, entries 16–18). Moreover, decreasing
the amount of both the alcohols to 1 equiv. afforded lower
yields (Table 2, entry 19).
Inspired by the promising result (Table 2, entry 16), next,
we investigated the scope of this protocol towards the synthesis
of several pyrimidines as shown in Table 3. First, the compat-
ibility of this methodology with respect to various secondary
alcohols in reaction with benzamidine and benzyl alcohol was
tested which produced several tri-substituted pyrimidine
derivatives in good to excellent yields (69–95%). Apart from
1-phenylethanol, substituted secondary alcohols having both
electron donating substituents like 4-methoxy and electron
withdrawing groups like 4-fluoro afforded good to excellent
yields of the desired products (Table 3, entries 4–6). meta-
Substituted secondary alcohol also delivered excellent yield
(Table 3, entry 7). Sterically bulky 1-(2-naphthyl)ethanol and
Amidine : 1° Base
Yielda
(%)
Entry Alc : 2° Alc
(equiv.)
Ru(II) cat
Solvent
1
2
1 : 1.3 : 1.3
1 : 1.3 : 1.3
KOtBu (0.5) Cat. A
KOtBu (0.5) Cat. A
Toluene
tert-Amyl
alcohol
Diglyme
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
61
42
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1.3 : 1.3
1 : 1 : 1
KOtBu (0.5) Cat. A
KOtBu (0.5) Cat. A
KOtBu (0.5) Cat. B
KOtBu (0.5) Cat. C
KOtBu (0.5) Cat. D
KOtBu (0.5) Cat. E
KOtBu (0.5) Cat. F
21
79
31
43
51
28
37
39
<10
41
heteroatom
substituted
alcohols
e.g.
1-(3,4-methyl-
enedioxyphenyl)ethanol and 1-(3-pyridyl)ethanol were also
converted successfully (Table 3, entries 8–10). A slightly lower
KOtBu (0.5) RuHClCO(PPh3)3 Dioxane
KOtBu (0.5)
KOH (0.5)
—
Cat. A
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
NaOH (0.5) Cat. A
Cs2CO3 (0.5) Cat. A
K2CO3 (0.5) Cat. A
KOtBu (1.0) Cat. A
KOtBu (1.0) Cat. A
KOtBu (1.0) Cat. A
KOtBu (1.0) Cat. A
28
<10
<10
95
Table 3 Synthesis of pyrimidines from various secondary alcohols and
benzyl alcohola
61b
41c
71
a Reaction conditions: Benzamidine (0.25 mmol), 1-phenylethanol
(0.325 mmol), benzyl alcohol (0.325 mmol), and cat A (1.0 mol%). The
amount (equiv.) of KOtBu was given with respect to the benzamidine
substrate. Yields were determined by 1H-NMR spectroscopy using 1,3,5-
trimethoxy benzene as the internal standard. b Heated for 12 h. c Using
0.5 mol% cat. A.
the desired product 4 (Table 2, entry 1). To improve the
yields, different solvents were screened and among them
dioxane was found to be the most effective (Table 2, entries
2–4). Next, the effect of ligand substituents and the counter
anion of the complex on the catalytic activity was screened
(Table 2, entries 5–9). Upon changing the counter anion of
catalyst A from chloride to hexafluorophosphate, the yield of 4
decreased considerably (Table 2, entry 5). Afterward, other Ru-
complexes in which the substituents were varied from –OMe,
–Me and –H to a ligand framework were tested (Table 2,
entries 6–8). Notably, with these metal complexes, the yield of
the desired product 4 was lower compared to that of cat. A.
This suggested that the 2-hydroxypyridine moiety played a sig-
nificant role in this catalytic process. Complex F bearing the
ligand in which the N–H proton of benzimidazole was substi-
tuted with the methyl group showed considerably lower reactiv-
a Reaction conditions: benzamidine (0.5 mmol), secondary alcohol
(0.65 mmol), benzyl alcohol (0.65 mmol), KOtBu (0.5 mmol), dioxane
(2 mL), isolated yield.
This journal is © The Royal Society of Chemistry 2019
Dalton Trans., 2019, 48, 17479–17487 | 17481

View Article Online
Paper
Dalton Transactions
Table 5 Preparative scale synthesis of a few challenging substrates
yield was obtained with less reactive aliphatic alcohols like
1-cyclopropylethanol and 1,2-dimethylpropanol compared to
the aromatic alcohols (Table 3, entries 11–12). Notably, several
tetra-substituted pyrimidine derivatives were also synthesized
in excellent yields following this protocol (Table 3, entries
13–15).
Next, the scope of primary alcohols was tested (Table 4).
Mono, di- and tri-substituted primary alcohols with electron
donating groups either in para- or meta- positions, afforded
good to excellent yields of the desired products (Table 4,
entries 16–19). A relatively lower yield was obtained for
primary alcohols having electron withdrawing groups (Table 4,
entries 20–22). With the halide substituted primary alcohols,
lower yields of the desired products were observed due to the
dehalogenation reaction. Along with the expected products,
the dehalogenated final products were also isolated after the
reaction. A comparatively lower yield was detected with ortho-
substituted primary alcohol probably due to steric reasons
(Table 4, entry 23). Moreover, the reaction with bulky
1-naphthalenemethanol, heteroatom containing 2-thiophene-
methanol, 3-pyridinemethanol and cyclic aliphatic alcohols
like cyclohexylmethanol delivered good to excellent yields
(59–91%) (Table 4, entries 24–27). The scope of a few amidines
was also investigated. Aryl amidines bearing electron with-
drawing groups, and aliphatic amidines like acetamidine and
guanidine could also be utilized under the optimized reaction
conditions (Table 4, entries 28–31).
The synthetic competence of this methodology was
further extrapolated by the gram scale synthesis of various sub-
stituted pyrimidines and 2-alkylaminopyrimidines (Table 5).
These results demonstrated the practical applicability of this
protocol.
Table 4 Synthesis of pyrimidines from various primary alcohols and
amidines in reaction with 1-phenylethanola
Reaction mechanism
To gain insight into the reaction mechanism, several control
experiments were performed. First, the cross coupling of
benzyl alcohol and 1-phenylethanol was carried out under the
standard reaction conditions (Scheme 3A). Within 2 h, 84%
conversion of benzyl alcohol was achieved with the formation
of β-alkylated alcohol as the major product, whereas in the
absence of cat. A, both alcohols remained unreacted
(Scheme 3B). This result suggested that the dehydrogenation
of alcohols was catalyzed by cat. A. Notably, the coupling of
benzamidine with either 1,3-diphenylpropan-1-one (M) or
β-alkylated alcohol (N) produced a significantly lower amount
of the desired pyrimidine product (Scheme 3C and D).
However, when benzamidine was reacted with chalcone (O) in
the presence and absence of cat. A, the pyrimidine product
was obtained in 55% and 26% yields, respectively, within 2 h
(Scheme 3E and F). Notably, when benzamidine, benzyl
alcohol and 1-phenylethanol were reacted for 4 h, none of the
potential intermediates (M, N and O) were observed and sig-
nificant amounts of benzamidine and alcohols remained
unreacted (Scheme 3G). The dehydrogenation of 1-pheny-
lethaol under reaction conditions was much faster in the
absence of benzamidine; 51% of acetophenone was produced
after 2 h, whereas in the presence of benzamidine, only 11%
of acetophenone was observed (Scheme 3H and I). These
experiments revealed that for the synthesis of pyrimidine in
this multicomponent reaction, chalcone was the plausible
intermediate, and in the presence of benzamidine, the hydro-
genation of chalcone and the dehydrogenation of alcohols
a Reaction conditions: benzamidine (0.5 mmol), primary alcohol
(0.65 mmol), 1-phenylethanol (0.65 mmol), KOtBu (0.5 mmol), dioxane
(3 mL), isolated yield. b Amidine hydrochloride salts were used as the
substrate and an additional 1.0 equiv. of KOH (0.5 mmol) was used to
trap the HCl of amidine hydrochlorides. c Using 1.5 mol% Cat. A.
17482 | Dalton Trans., 2019, 48, 17479–17487
This journal is © The Royal Society of Chemistry 2019

View Article Online
Dalton Transactions
Paper
Scheme 4 A) Synthesis of intermediate A’; (B) reactivity of intermediate A’.
compared to that of A also confirmed that this complex con-
tains a dearomatized pyridonate core. When, complex A′ was
used as the catalyst, under the standard reaction conditions,
88% yield of the desired product was obtained (Scheme 4B).
This clearly indicated that complex A′ was the active catalyst in
this reaction. Next, a complex A′ mediated dehydrogenation of
alcohols through an outer-sphere pathway would give the
corresponding aldehydes/ketones and Ru-hydride species
(A″).62,63 Our experimental findings (Table 2, entries 4 and 6)
and previous reports suggested that for the dehydrogenation
of alcohols with this system, the outer-sphere pathway was
more favoured over the inner-sphere pathway.62,64–66 However,
all attempts to isolate the Ru-dihydride species (A″) were
unsuccessful. Afterward, the ligand assisted hydrogen elimin-
ation from (A″) would regenerate the active catalyst A′
(Scheme 5). Next, a base mediated aldol condensation between
the aldehyde and ketone would produce the α,β-unsaturated
ketone which subsequently would react with benzamidine to
Scheme 3 Verifying experiments for the multicomponent synthesis of
pyrimidines.
were inhibited. Also, it was evident that cat. A not only facili-
tated the dehydrogenation of alcohols but also played a signifi-
cant role in the dehydrogenation of dihydropyrimidine deriva-
tive (P) for the production of pyrimidine (Scheme 3E and F).36
Based on the control experiments and the previous litera-
ture reports on 2-hydroxypyridine based bifunctional catalysts,
a probable mechanism for the synthesis of pyrimidines was
proposed (Scheme 5).49,57–59 Initially, base mediated activation
of pre-catalyst A would generate catalytically active species A′,
having a pyridonate ligand fragment,48,50,58,60 although the
deprotonation of the N–H proton in the benzimidazole ring
cannot be ruled out. To confirm the participation of ruthe-
nium-pyridonate species (A′), they were synthesized indepen-
dently by treating cat. A with 5 equiv. of KOtBu in dichloro-
methane (Scheme 4A).
Complex A′ was characterized by NMR spectroscopy and
elemental analysis. In the 1H-NMR spectrum, it showed a
sharp triplet at δ = −11.38 ppm (JH–P = 22.0 Hz) which was
different from the parent complex A (δ = −12.15 ppm, JH–P
=
20.0 Hz) and in the 13C{1H} NMR spectrum it presented a new
peak at δ = 170.2 ppm (pyridonate CvO) which further confirmed
the formation of complex A′.61 In the 1H-NMR spectrum of
Scheme 5 Proposed catalytic cycle for the multicomponent synthesis
complex A′, the slight upfield shift of pyridine proton peaks of pyrimidines.
This journal is © The Royal Society of Chemistry 2019
Dalton Trans., 2019, 48, 17479–17487 | 17483

View Article Online
Paper
Dalton Transactions
give the dihydropyrimidine derivative (P). Finally, a complex A′ ing solution was filtered and the precipitate was washed with
mediated dehydrogenation of P would deliver the final pyrimi- diethyl ether to afford pure complex A (156 mg, yield: 72%) as
dine product.36
a yellow solid. Single crystals suitable for X-ray diffraction were
grown in CH2Cl2/diethyl ether by a slow evaporation process at
ambient temperature.1H NMR (500 MHz, DMSO-d6): δ = 13.81
(s, 1H), 7.54 (t, JH,H = 7.8 Hz, 1H), 7.25 (d, JH,H = 7.3 Hz, 1H),
7.15 (d, JH,H = 8.2 Hz, 1H), 7.12–7.0 (m, 30H), 6.95 (t, JH,H = 7.7
Hz, 1H), 6.79 (d, JH,H = 8.3 Hz, 1H), 6.72 (d, JH,H = 8.3 Hz, 1H),
6.62 (d, JH,H = 7.6 Hz, 1H), −12.15 (t, JH,H = 20 Hz, 1H). Due to
the poor solubility of this complex in common NMR solvents,
we were unable to record the 13C-NMR spectrum of this
complex. 31P{1H} NMR (160 MHz, DMSO-d6): δ = 46.54 ppm.
Conclusions
In summary, various 2-(2-benzimidazolyl) pyridine ligand
based new ruthenium complexes were synthesized. Among
them, cat. A exhibited the highest catalytic activity in the three
component synthesis of substituted pyrimidines. A wide range
of multi-substituted pyrimidine derivatives were synthesized in
excellent yields from various alcohols and amidines. Several
kinetic experiments were carried out to understand the mecha-
nism of this reaction. Control experiments revealed that for
the synthesis of pyrimidines, chalcone was the plausible inter-
mediate. Notably, the Ru-pyridonate intermediate was success-
fully characterized and it was found to be the active catalyst in
this multicomponent reaction. The synthetic competence of
this methodology was also extended toward the gram scale syn-
thesis of various pyrimidine derivatives. To the best of our
knowledge, this is the first report of the ruthenium catalyzed
multicomponent synthesis of pyrimidines from amidines and
alcohols.
IR (νCvO
,
KBr, cm−1): 1957; HRMS (ESI): calcd for
C49H40N3O2P2Ru, [M − Cl]+: 866.1639; found: 866.1621. Anal.
calculated (C49H40N3O2P2RuCl): C, 65.30; H, 4.47; N, 4.66;
found: C, 65.46; H, 4.32; N, 4.55.
Synthesis of complex B
In a Schlenk flask, complex A (50 mg, 0.055 mmol) and
NH4PF6 (0.825 mmol) were taken and dry methanol (15 mL)
was added to it and stirred at room temperature for 12 h under
an argon atmosphere. The resulting solution was filtered and
the insoluble part was removed. The filtrate was evaporated to
dryness under reduced pressure and washed with diethyl ether
to afford complex B (45 mg, yield: 81%) as a light yellow solid.
1H NMR (500 MHz, DMSO-d6): δ = 7.98–7.91 (m, 2H), 7.37 (d,
JH,H = 7.5 Hz, 2H), 7.24–7.12 (m, 31H), 6.94 (t, JH,H = 7.5 Hz,
2H), −12.05 (t, JH,H = 19.2 Hz, 1H). 13C{1H} NMR (125 MHz,
DMSO-d6): δ = 151.15, 144.45, 139.43, 134.07, 133.29, 132.68,
132.52, 132.35, 130.38, 128.49, 125.35, 123.16, 119.12,
Experimental section
General procedure and materials
All reactions were performed under an inert atmosphere using
standard Schlenk line techniques unless otherwise stated.
Glassware was flame-dried under vacuum prior to use. Dry sol-
vents were prepared according to literature methods, distilled
under argon and deoxygenated prior to use. Chemicals were
purchased from Sigma-Aldrich, Alfa Aesar, Avra, SDFCL, and
Spectrochem and used without further purification. The
ligands were synthesized according to the reported
procedures.67–69 The synthesis of complexes C and D was pre-
viously reported by our group.70 1H and 13C NMR spectra were
recorded on a JEOL 400 and a 500 MHz spectrometer. ESI-MS
were recorded on a Waters Micromass Quattro Micro triple-
quadrupole mass spectrometer. GC analysis was done using
an Agilent 7890 B gas chromatograph; GC-MS were recorded
using an Agilent 7890 A gas chromatograph equipped with an
Agilent 5890 triple-quadrupole mass system.
112.96, 112.75. 31P{1H} NMR (160 MHz, CDCl3):
δ =
44.57 ppm. IR (νCvO, KBr, cm−1): 1941; HRMS (ESI): calcd for
C49H40N3O2P2Ru, [M − PF6]+: 866.1639; found: 866.1639. Anal.
calculated (C49H40F6N3O2P2RuPF6): C, 58.22; H, 3.99; N, 4.16;
found: C, 58.09; H, 3.81; N, 3.98.
Synthesis of complex E
Synthesis of complex A
In a Schlenk flask, ligand L4 (50 mg, 0.26 mmol) and [RuHCl
(CO)(PPh3)3] (248 mg, 0.26 mmol) were taken. Then dry di-
chloromethane (15 mL) was added to it and stirred at room
temperature for 24 h under an argon atmosphere. The result-
In a Schlenk flask, ligand L1 (50 mg, 0.24 mmol) and ing solution was filtered and the insoluble part was removed.
[RuHCl(CO)(PPh3)3] (228 mg, 0.24 mmol) were taken. Then dry The filtrate was evaporated to dryness under reduced pressure
dichloromethane (15 mL) was added to it and stirred at room and washed with diethyl ether to afford complex E (180 mg,
temperature for 24 h under an argon atmosphere. The result- yield: 78%) as a yellow solid. Single crystals suitable for X-ray
17484 | Dalton Trans., 2019, 48, 17479–17487
This journal is © The Royal Society of Chemistry 2019

View Article Online
Dalton Transactions
Paper
diffraction were grown in CH2Cl2/benzene by the slow evapor- (t, JH,H = 7.8 Hz, 1H), 6.27–6.26 (m, 2H), 6.14 (d, JH,H = 6.6 Hz,
ation process at ambient temperature. 1H NMR (400 MHz, 1H), 5.93 (t, JH,H = 7.6 Hz, 1H), 5.65 (d, JH,H = 8.4 Hz, 1H),
DMSO-d6): δ = 9.20 (d, JH,H = 5.1 Hz, 1H), 8.03 (d, JH,H = 7.1 Hz, −11.38 (d, JH,P = 20.0 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-
1H), 7.90 (t, JH,H = 7.7 Hz, 1H), 7.59–7.50 (m, 1H), 7.36–7.27 d6): δ = 206.90, 170.29, 163.54, 150.89, 147.11, 134.51, 134.36,
(m, 3H), 7.24–7.11 (m, 30H), 6.88 (d, JH,H = 8.6 Hz, 1H), 6.81 (t, 134.20, 133.67, 128.60, 127.08, 117.23, 116.94, 116.13, 115.65,
JH,H = 7.4 Hz, 1H), −11.63 (t, JH,H = 19.3 Hz, 1H). 13C{1H} NMR 113.07, 102.02. 31P{1H} NMR (160 MHz, CDCl3): δ = 48.84 ppm.
(125 MHz, DMSO-d6): δ = 210.95, 155.81, 150.09, 146.14, Anal. calculated (C49H39N3O2P2Ru): C, 68.05; H, 4.55; N, 4.86;
139.16, 138.59, 133.14, 132.17, 131.95, 130.56, 128.77, 126.77, found: C, 67.89; H, 4.47; N, 4.76.
125.48, 123.42, 122.93, 118.83, 113.32. 31P{1H} NMR (160 MHz,
CDCl3): δ = 44.58 ppm. IR (νCvO, KBr, cm−1): 1934; HRMS
General procedure for the synthesis of pyrimidines
(ESI): calcd for C49H40N3OP2Ru, [M − Cl]+: 851.1768; found:
In a Schlenk tube, amidine (0.5 mmol), primary alcohol
867.1741. Anal. calculated (C49H40N3OP2RuCl): C, 66.48;
H, 4.55; N, 4.75; found: C, 66.32; H, 4.39; N, 4.61.
(0.65 mmol), secondary alcohol (0.65 mmol), cat.
A
(1.0 mol%), KOtBu (0.5 mmol) and dioxane (3.0 mL) were
taken. The tube was sealed and the reaction mixture was
heated to 120 °C in a preheated oil bath for 24 h. After the
reaction, it was cooled to room temperature and then 1,3,5-tri-
methoxy benzene was added as the internal standard. Then
the reaction mixture was filtered through a small plug of
neutral alumina and a small portion was taken for the deter-
mination of yield. The yield was determined by the analysis of
the 1H-NMR spectra of the crude reaction mixture using CDCl3
as the NMR solvent. The final products were purified by silica-
gel column chromatography using hexane/ethyl acetate as the
eluent. (Caution: All the catalytic reactions were carried out
inside the fume hood and after the reactions Schlenk tubes were
carefully opened under proper ventilation to release the hydrogen
gas produced in the reactions.)
Synthesis of complex F
In a Schlenk flask, ligand L5 (50 mg, 0.22 mmol) and [RuHCl
(CO)(PPh3)3] (213 mg, 0.22 mmol) were taken. Then dry di-
chloromethane (15 mL) was added to it and stirred at room
temperature for 24 h under an argon atmosphere. The result-
ing solution was filtered and the insoluble part was removed.
The filtrate was evaporated to dryness under reduced pressure
and washed with diethyl ether to afford complex F (139 mg,
yield: 69%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6):
δ = 8.13 (d, JH,H = 7.7 Hz, 1H), 8.0 (t, JH,H = 8.1 Hz, 1H), 7.46 (d,
JH,H = 7.5 Hz, 1H), 7.33 (d, JH,H = 7.8 Hz, 1H), 7.25–7.22 (m,
7H), 7.17–7.10 (m, 25H), 6.94 (t, JH,H = 7.7 Hz, 1H), 3.93 (s,
3H), 2.12 (s, 3H), −12.14 (t, JH,H = 18.4 Hz, 1H). 13C{1H} NMR
(125 MHz, DMSO-d6): δ = 207.16, 149.88, 146.42, 138.88,
137.65, 135.95, 134.16, 133.01, 132.75, 132.58, 130.57, 128.69,
125.64, 123.87, 122.81, 119.42, 112.03, 33.85, 28.79. 31P{1H}
NMR (160 MHz, CDCl3): δ = 44.26 ppm. IR (νCvO, KBr, cm−1):
1917; HRMS (ESI): calcd for C51H44N3OP2Ru, [M − Cl]+:
879.2081; found: 879.2076. Anal. calculated (C51H44N3OP2RuCl):
C, 67.06; H, 4.86; N, 4.60; found: C, 66.89; H, 4.78; N, 4.49.
Procedure for gram scale reaction
In a Schlenk tube, amidine (5.0 mmol), primary alcohol
(6.5 mmol), secondary alcohol (6.5 mmol), cat. A (1.0 mol%),
KOtBu (5.0 mmol) and dioxane (3.0 mL) were taken. The tube
was sealed and the reaction mixture was heated at 120 °C in a
preheated oil bath for 24 h. After the reaction, it was cooled to
room temperature and the final products were purified by
silica-gel column chromatography using hexane/ethyl acetate
as the eluent.
Conflicts of interest
Synthesis of pyridonate intermediate (A′)
There are no conflicts to declare.
Acknowledgements
We are grateful to the Department of Science and Technology,
International Cooperation (INT/RUS/RFBR/P-326), India and
the Science and Engineering Research Board (SERB/CHM/
2018-565), India for funding. M. M. thanks the CSIR, India for
a fellowship.
In a J-Young NMR tube, complex A (20 mg, 0.022 mmol) and
KOtBu (12.5 mg, 0.11 mmol) were taken and dry dichloro-
methane (1 mL) was added to it and stirred at room tempera-
ture for 10 min under an argon atmosphere. The resulting
solution was filtered and the insoluble part was removed. The
filtrate was evaporated to dryness under reduced pressure and
washed with diethyl ether to afford complex A′ (45 mg, yield:
Notes and references
1
81%) as a yellow solid. H NMR (500 MHz, DMSO-d6): δ = 7.01
(brs, 12H), 6.94–6.88 (m, 7H), 6.82 (t, JH,H = 7.5 Hz, 12H), 6.48
1 Y. Kubota, Y. Ozaki, K. Funabiki and M. Matsui, J. Org.
Chem., 2013, 78, 7058–7067.
This journal is © The Royal Society of Chemistry 2019
Dalton Trans., 2019, 48, 17479–17487 | 17485

View Article Online
Paper
Dalton Transactions
2 G. R. Humphrey, P. J. Pye, Y.-L. Zhong, R. Angelaud, 24 W. Zhao, P. Liu and F. Li, ChemCatChem, 2016, 8, 1523–
D. Askin, K. M. Belyk, P. E. Maligres, D. E. Mancheno, 1530.
R. A. Miller, R. A. Reamer and S. A. Weissman, Org. Process 25 R. H. Crabtree, Chem. Rev., 2017, 117, 9228–9246.
Res. Dev., 2011, 15, 73–83.
3 A. Agarwal, K. Srivastava, S. K. Puri and P. M. S. Chauhan,
Bioorg. Med. Chem., 2005, 13, 4645–4650.
26 M. Maji, K. Chakrabarti, B. Paul, B. C. Roy and S. Kundu,
Adv. Synth. Catal., 2018, 360, 722–729.
27 D. Srimani, Y. Ben-David and D. Milstein, Angew. Chem.,
Int. Ed., 2013, 52, 4012–4015.
4 K.-T. Wong, T. S. Hung, Y. Lin, C.-C. Wu, G.-H. Lee,
S.-M. Peng, C. H. Chou and Y. O. Su, Org. Lett., 2002, 4, 28 M. Maji, K. Chakrabarti, D. Panja and S. Kundu, J. Catal.,
513–516. 2019, 373, 93–102.
5 K. A. Eliazyan, F. V. Avetisyan, T. L. Jivanshiryan, 29 S. Musa, L. Ackermann and D. Gelman, Adv. Synth. Catal.,
V. A. Pivazyan, E. A. Ghazaryan, L. V. Shahbazyan, 2013, 355, 3077–3080.
S. V. Harutyunyan and A. P. Yengoyan, J. Heterocycl. Chem., 30 S. Shee, K. Ganguli, K. Jana and S. Kundu, Chem. Commun.,
2011, 48, 118–123. 2018, 54, 6883–6886.
6 J. Tang, K. Maddali, C. D. Dreis, Y. Y. Sham, R. Vince, 31 V. Estévez, M. Villacampa and J. C. Menéndez, Chem. Soc.
Y. Pommier and Z. Wang, ACS Med. Chem. Lett., 2011, 2,
63–67.
Rev., 2014, 43, 4633–4657.
32 P. Dang, W. Zeng and Y. Liang, Org. Lett., 2015, 17, 34–37.
7 S. Lee, D. Lim, E. Lee, N. Lee, H.-g. Lee, J. Cechetto, 33 D. B. Ramachary and S. Jain, Org. Biomol. Chem., 2011, 9,
M. Liuzzi, L. H. Freitas-Junior, J. S. Song, M. A. Bae, S. Oh, 1277–1300.
L. Ayong and S. B. Park, J. Med. Chem., 2014, 57, 7425– 34 D. M. D’Souza and T. J. J. Müller, Chem. Soc. Rev., 2007, 36,
7434. 1095–1108.
8 C. D. Jones, D. M. Andrews, A. J. Barker, K. Blades, 35 N. Deibl, K. Ament and R. Kempe, J. Am. Chem. Soc., 2015,
P. Daunt, S. East, C. Geh, M. A. Graham, K. M. Johnson, 137, 12804–12807.
S. A. Loddick, H. M. McFarland, A. McGregor, L. Moss, 36 S. Sultana Poly, S. M. A. H. Siddiki, A. S. Touchy,
D. A. Rudge, P. B. Simpson, M. L. Swain, K. Y. Tam,
J. A. Tucker and M. Walker, Bioorg. Med. Chem. Lett., 2008,
18, 6369–6373.
9 R. W. Fischer and M. Misun, Org. Process Res. Dev., 2001, 5,
581–586.
K. W. Ting, T. Toyao, Z. Maeno, Y. Kanda and K.-i. Shimizu,
ACS Catal., 2018, 8, 11330–11341.
37 T. Shi, F. Qin, Q. Li and W. Zhang, Org. Biomol. Chem.,
2018, 16, 9487–9491.
38 M. Mastalir, M. Glatz, E. Pittenauer, G. Allmaier and
K. Kirchner, J. Am. Chem. Soc., 2016, 138, 15543–15546.
10 F. Varano, D. Catarzi, F. Vincenzi, M. Betti, M. Falsini,
A. Ravani, P. A. Borea, V. Colotta and K. Varani, J. Med. 39 N. Deibl and R. Kempe, Angew. Chem., Int. Ed., 2017, 56,
Chem., 2016, 59, 10564–10576. 1663–1666.
11 T. P. Vispute, H. Zhang, A. Sanna, R. Xiao and G. W. Huber, 40 M. Mastalir, M. Glatz, E. Pittenauer, G. Allmaier and
Science, 2010, 330, 1222–1227. K. Kirchner, Org. Lett., 2019, 21, 1116–1120.
12 M. Besson, P. Gallezot and C. Pinel, Chem. Rev., 2014, 114, 41 J. R. Khusnutdinova and D. Milstein, Angew. Chem., Int.
1827–1870. Ed., 2015, 54, 12236–12273.
13 S. Michlik and R. Kempe, Angew. Chem., Int. Ed., 2013, 52, 42 R. Noyori and S. Hashiguchi, Acc. Chem. Res., 1997, 30, 97–102.
6326–6329.
43 R. H. Morris, Acc. Chem. Res., 2015, 48, 1494–1502.
44 B. L. Conley, M. K. Pennington-Boggio, E. Boz and
T. J. Williams, Chem. Rev., 2010, 110, 2294–2312.
14 S. Michlik and R. Kempe, Nat. Chem., 2013, 5, 140.
15 G. E. Dobereiner and R. H. Crabtree, Chem. Rev., 2010, 110,
681–703.
45 M. D. Wodrich and X. Hu, Nat. Rev. Chem., 2017, 2, 0099.
16 T. Hille, T. Irrgang and R. Kempe, Angew. Chem., Int. Ed., 46 Y. Shvo, D. Czarkie, Y. Rahamim and D. F. Chodosh, J. Am.
2017, 56, 371–374. Chem. Soc., 1986, 108, 7400–7402.
17 M. Zhang, H. Neumann and M. Beller, Angew. Chem., Int. 47 J. Frank and A. R. Katritzky, J. Chem. Soc., Perkin Trans. 2,
Ed., 2013, 52, 597–601. 1976, 1428–1431.
18 S. Ruch, T. Irrgang and R. Kempe, Chem. – Eur. J., 2014, 20, 48 K.-i. Fujita, Y. Tanaka, M. Kobayashi and R. Yamaguchi,
13279–13285. J. Am. Chem. Soc., 2014, 136, 4829–4832.
19 C. Gunanathan and D. Milstein, Science, 2013, 341, 49 R. Kawahara, K.-i. Fujita and R. Yamaguchi, J. Am. Chem.
1229712. Soc., 2012, 134, 3643–3646.
20 B. Pandey, S. Xu and K. Ding, Org. Lett., 2019, 21, 7420– 50 A. M. Royer, T. B. Rauchfuss and D. L. Gray,
7423. Organometallics, 2010, 29, 6763–6768.
21 N. D. Schley, G. E. Dobereiner and R. H. Crabtree, 51 C. M. Moore and N. K. Szymczak, Chem. Commun., 2013,
Organometallics, 2011, 30, 4174–4179. 49, 400–402.
22 P. Daw, S. Chakraborty, J. A. Garg, Y. Ben-David and 52 R. Kawahara, K.-i. Fujita and R. Yamaguchi, Angew. Chem.,
D. Milstein, Angew. Chem., Int. Ed., 2016, 55, 14373–14377. Int. Ed., 2012, 51, 12790–12794.
23 S. P. Midya, V. G. Landge, M. K. Sahoo, J. Rana and 53 Y. Li, K. Ding and C. A. Sandoval, Org. Lett., 2009, 11,
E. Balaraman, Chem. Commun., 2018, 54, 90–93.
907–910.
17486 | Dalton Trans., 2019, 48, 17479–17487
This journal is © The Royal Society of Chemistry 2019

View Article Online
Dalton Transactions
Paper
54 R. Liang, S. Li, R. Wang, L. Lu and F. Li, Org. Lett., 2017, 62 H. Li, G. Lu, J. Jiang, F. Huang and Z.-X. Wang,
19, 5790–5793. Organometallics, 2011, 30, 2349–2363.
55 Y. Manaka, W.-H. Wang, Y. Suna, H. Kambayashi, 63 K.-i. Fujita, R. Tamura, Y. Tanaka, M. Yoshida, M. Onoda
J. T. Muckerman, E. Fujita and Y. Himeda, Catal. Sci.
Technol., 2014, 4, 34–37.
56 A. O. Ogweno, S. O. Ojwach and M. P. Akerman, Dalton
Trans., 2014, 43, 1228–1237.
and R. Yamaguchi, ACS Catal., 2017, 7, 7226–7230.
64 K.-N. T. Tseng, J. W. Kampf and N. K. Szymczak, ACS
Catal., 2015, 5, 5468–5485.
65 P. A. Dub and J. C. Gordon, ACS Catal., 2017, 7, 6635–6655.
57 B. C. Roy, K. Chakrabarti, S. Shee, S. Paul and S. Kundu, 66 G. Zeng, S. Sakaki, K.-i. Fujita, H. Sano and R. Yamaguchi,
Chem. – Eur. J., 2016, 22, 18147–18155. ACS Catal., 2014, 4, 1010–1020.
58 C. Zhang, J.-P. Zhao, B. Hu, J. Shi and D. Chen, 67 R. Schiffmann, A. Neugebauer and C. D. Klein, J. Med.
Organometallics, 2019, 38, 654–664. Chem., 2006, 49, 511–522.
59 R. Wang, H. Fan, W. Zhao and F. Li, Org. Lett., 2016, 18, 68 W.-H. Sun, P. Hao, S. Zhang, Q. Shi, W. Zuo, X. Tang and
3558–3561. X. Lu, Organometallics, 2007, 26, 2720–2734.
60 K. Chakrabarti, B. Paul, M. Maji, B. C. Roy, S. Shee and 69 S. Chen, R.-Q. Fan, X.-M. Wang and Y.-L. Yang,
S. Kundu, Org. Biomol. Chem., 2016, 14, 10988–10997. CrystEngComm, 2014, 16, 6114–6125.
61 K.-i. Fujita, N. Tanino and R. Yamaguchi, Org. Lett., 2007, 70 B. Paul, M. Maji, D. Panja and S. Kundu, Adv. Synth. Catal.,
9, 109–111.
2019, DOI: 10.1002/adsc.201900962.
This journal is © The Royal Society of Chemistry 2019
Dalton Trans., 2019, 48, 17479–17487 | 17487