Synthesis of Pyridines, Quinolines, and Pyrimidines via Acceptorless Dehydrogenative Coupling Catalyzed by a Simple Bidentate P^ N Ligand Supported Ru Complex

Article abstract of DOI:10.1021/acs.organomet.0c00058

A ruthenium hydrido chloride complex (1) supported by a simple, heteroleptic bidentate P^N ligand (L1) containing a diarylphosphine and a benzannulated phenanthridine donor arm is reported. In the presence of base, complex 1 catalyzes multicomponent reactions using alcohol precursors to produce structurally diverse molecules including pyridines, quinolines, and pyrimidines via acceptorless dehydrogenative coupling pathways. Notably, L1 does not bear readily (de)protonated Br?nsted acidic or basic groups common to transition metal catalysts capable of these sorts of transformations, suggesting metal-ligand cooperativity does not play a significant role in the catalytic reactivity of 1. A rare example of an η2-aldehyde adduct of ruthenium was isolated and structurally characterized, and its role in acceptorless dehydrogenative coupling reactions is discussed.

Full text of DOI:10.1021/acs.organomet.0c00058

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Article
Synthesis of Pyridines, Quinolines, and Pyrimidines via Acceptorless
Dehydrogenative Coupling Catalyzed by a Simple Bidentate P^N
Ligand Supported Ru Complex
Rajarshi Mondal and David E. Herbert*
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ABSTRACT: A ruthenium hydrido chloride complex (1) sup-
ported by a simple, heteroleptic bidentate P^N ligand (L1)
containing a diarylphosphine and a benzannulated phenanthridine
donor arm is reported. In the presence of base, complex 1 catalyzes
multicomponent reactions using alcohol precursors to produce
structurally diverse molecules including pyridines, quinolines, and
pyrimidines via acceptorless dehydrogenative coupling pathways.
Notably, L1 does not bear readily (de)protonated Brønsted acidic
or basic groups common to transition metal catalysts capable of
these sorts of transformations, suggesting metal−ligand coopera-
tivity does not play a significant role in the catalytic reactivity of 1. A
rare example of an η2-aldehyde adduct of ruthenium was isolated
and structurally characterized, and its role in acceptorless dehydrogenative coupling reactions is discussed.
and reports that commercially available cis-(dimethyl sulfox-
INTRODUCTION
■
2,27
28
ide)4RuCl2
and (PPh3)3RuCl2 can catalyze the dehydro-
̈
The Friedlander annulation reaction, in which 2-aminophenyl
ketones or aldehydes are coupled with carbonyl compounds
possessing acidic α-hydrogens, is a straightforward approach to
the preparation of substituted quinolines.1 This atom-efficient
reaction was made even more so with the discovery that the
corresponding saturated alcohols could be used, provided they
could be efficiently dehydrogenated in situ. The resulting
genative/dehydrative formation of polysubstituted quinolines
from 2-aminobenzyl alcohol and primary or secondary alcohols
in respectable yields in the presence of a significant excess of a
sacrificial hydrogen acceptor, we were curious as to the
capability of complexes supported by simpler ligand frame-
works lacking reactive E−H groups or obvious Brønsted basic
̈
sites to carry out complex, multicomponent Friedlander-type
̈
“indirect” Friedlander annulation employs a single catalyst for
ADC reactions. Catalyst platforms based on simple, bidentate
ligands that can facilitate ADC reactions with a wide product
scope would expand the chemical space available for ligand
design for these useful reactions.
both the oxidation of alcohols and their catalytic condensa-
tion.2 The combination of the acceptorless dehydrogenation of
alcohols with C−N bond-forming condensation reactions can
in fact enable atom-efficient, one-pot, acceptorless dehydrogen-
ative coupling (ADC) syntheses of a range of value-added
organic molecules including N-heterocyclic pyridines, quino-
lines, pyrroles, and pyrimidines.3 These can be mediated by a
wide variety of mid to late transition metal complexes based on
Ru,4−10 Mn,11−14 Ir,15−17 Co,18−20 and Ni.21,22 With respect to
catalytic efficiency, Ru precatalysts at present enable the
highest reported yields at the lowest catalyst loadings. For
example, Liu and Sun and co-workers reported efficient
catalysis using loadings of 0.025 mol %, though relatively
long reaction times (72 h) were required for high conversion.6
In general, the most highly active Ru catalysts are comprised of
tridentate, pincer-type ligands (Figure 1) typically bearing N−
H4−6 or O−H7,23 moieties that lead to invocations of metal−
ligand cooperativity (MLC).24
We have been exploring the utility of bidentate P^N
coordinating ligands combining phosphine and phenanthridine
(3,4-benzoquinoline) donors,29 that are benzannulated ana-
logues of (8-diphenylphosphino)quinoline.30 Using phenan-
thridine in place of quinoline opens up a more easily accessed
range of N-heterocycle substituted P^N proligands as 2-
substituted phenanthridines can be assembled using one-pot
cross-coupling/condensation reactions31,32 that are more
convenient compared with less tractable Skraup conditions
Received: January 27, 2020
Given the recent debate over the activation of ligand-based
N−H groups in related dehydrogenative amide synthesis25,26
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Figure 1. Representative structures of highly active Ru catalysts for ADC reactions.
Figure 2. Synthesis of precatalyst 1 and accompanying minor isomers.
required for synthesis of 6-substituted quinolines.33 Here, we
report that a simple octahedral Ru complex (1) supported by
this type of ligand framework can catalyze ADC reactions in
the presence of base to form substituted pyridines, quinolines,
and pyrimidines at low loadings. While a number of systems
for formation of polysubstituted pyridines and quinolines via
ADC have been reported, the literature contains comparably
fewer examples of the construction of pyrimidines, which find
use in antibacterials, as pharmaceutical building blocks, and as
photoemissive materials.11,16,34,35 Importantly, L1 does not
contain obvious Brønsted acidic or basic sites, precluding MLC
pathways.
slight upfield shift of δ(H) = −13.52 (L = pyridine; t, JHP
=
2
19.5 Hz),37 −13.39 (L = isoquinoline; t, 2JHP = 19.5 Hz),38 and
2
−13.20 (1; pseudo t, JHP = 21.8 Hz).
Also present in solution are two minor isomers, which could
not be separated by crystallization. The hydride resonances of
the minor isomers are instructive as to their structures. In the
2
more prominent minor isomer (1-B: −12.27 ppm; dd, JPH
=
26.0, 15.0 Hz), the hydride couples differently to each
phosphorus but with the magnitude of the coupling constants
consistent with a similar cis orientation of the hydride and two
phosphines to the major isomer. In the 31P{1H} NMR
spectrum, signals attributed to 1-B appear as a set of doublets
2
(46.92 and 40.64 ppm; JPP = 310.7 Hz) with similarly large
2JPP as seen for the major isomer, suggestive of a trans
orientation to the phosphorus nuclei. These similarities lead us
to favor a structural assignment for 1-B where the two ligands
of strongest trans influence (hydride and carbonyl) switch
positions with respect to being trans to either the chloride or
the phenanthridinyl nitrogen. The other minor isomer (1-C)
does not show strong P−P coupling (signals at 78.0 and 28.8
ppm) and so likely has a cis orientation of the two phosphorus
nuclei, with the PPh3 trans-disposed to the hydride (1-C:
−6.54 ppm; dd, 2JPH = 121.6, 27.0 Hz). The large change in δP
observed for the diphenylphosphino unit of the P^N ligand is
attributed to twisting of the ligand arm due to changes in the
coordination sphere around the metal.39 As it is not part of a
chelate, the geometry of the PPh3 ligand, and therefore δP, is
not impacted as significantly by changes in molecular structure.
High-resolution mass spectrometry (HR-MS) and elemental
analysis both indicate a pure mixture of isomers, so we refer
here on in to this mixture in terms of the major isomer (1).
Reactivity Studies. To investigate the activity of 1 with
respect to dehydrogenation of saturated alcohols, a toluene
solution containing an excess of benzyl alcohol was combined
with 1 and a base (KOtBu) at ambient temperature and stirred
for 2 h, forming a deep red solution. Neither liberated H2 gas
nor significant consumption of benzaldehyde were detected in
1H NMR spectra of aliquots taken from the reaction mixture;
however, dark red crystals of a benzaldehyde adduct (2) were
isolated in substantial yield (64%) by layering the reaction
RESULTS AND DISCUSSION
■
Catalyst Synthesis. 4-(Diphenylphosphino)-2-methylphe-
nanthridine (L1) was assembled from 4-bromo-2-methylphe-
nanthridine and Ph2PCl, as previously described.32 The
proligand L1 was then reacted with (PPh3)3RuH(CO)Cl36
in toluene at 100 °C for 16 h to give the target complex
(L1)(PPh3)RuH(CO)Cl (1; Figure 2). Complex 1 precipitates
from the reaction mixture as a fine yellow crystalline powder
that is sparingly soluble in toluene but readily soluble in
chlorinated and more polar solvents. 31P{1H} NMR spectros-
copy confirmed installation of 1 equiv of the bidentate ligand
and retention of a PPh3 donor trans to the phosphorus arm of
L1 through the appearance of two doublets with a large
2
coupling constant (δP = 57.71, 37.38; JPP = 285.5 Hz). The
carbonyl and hydride ligands are also retained, with IR
signatures of νCO = 1919 cm−1 (vs) and νRuH = 1992 cm−1
(w). The observed ν(RuH) absorption fits into a trend with
(L)(PPh3)2RuH(CO)Cl (L = pyridine, isoquinoline), whereby
benzannulation of the heterocyclic donor leads to a shift of
ν(RuH) to lower wavenumbers from 2008 cm−1 for
(pyridine)(PPh3)2RuH(CO)Cl37 to 2000 cm−1 for
(isoquinoline)(PPh3)2RuH(CO)Cl38 to 1992 cm−1 for 1.
1
The hydride ligand is also visible in the H NMR spectrum
as an upfield-shifted pseudo triplet with similar coupling to
both phosphine nuclei, suggesting a cis orientation. The NMR
data again fits into a series with (L)(PPh3)2RuH(CO)Cl (L =
pyridine, isoquinoline); benzannulation is accompanied by a
B
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mixture with pentane. Thus, while 1 appears to dehydrogenate
benzyl alcohol, the resultant adduct does not easily liberate
benzaldehyde, preventing turnover. Complex 2 is also formed,
albeit in lower yields, by reaction of 1 with stoichiometric
amounts of benzyl alcohol and base (Figure 3). Crystalline 2 is
Figure 4. Solid-state structures of 1 and 2 with ellipsoids shown at
50% probability levels. With the exception of the hydride in 1 and
aldehyde proton in 2, hydrogen atoms and select atom labels are
omitted for clarity. Selected bond distances (Å) and angles (deg): 1:
Ru1−P1 2.2812(6), Ru1−P2 2.4116(6), Ru1−N1 2.1966(19), Ru1−
Cl1 2.5455(6), Ru1−C45 1.831(3), C45−O1 1.161(3); P1−Ru1−P2
169.51(2), P1−Ru1−Cl1 96.17(2), P2−Ru1−C1l 93.94(2), P1−
Ru1−C45 89.23(8), P2−Ru1−C45 91.87(8), C45−Ru1−Cl1
99.32(8). 2: Ru1−P1 2.2668(11), Ru1−P2 2.3899(11), Ru1−N1
2.164(3), Ru1−O1 2.104(3), Ru1−C45 2.136(4), Ru1−C52
1.822(4), C45−O1 1.344(5), C52−O2 1.175(5); P1−Ru1−P2
102.95(4), P1−Ru1−C52 91.40(13), P2−Ru1−C52 95.47(14),
N1−Ru1−P1 81.28(9), C45−Ru1−P1 118.58(13), C45−Ru1−N1
85.80(15), C45−O1−Ru1 72.8(2), O1−Ru1−C45 36.94(14), C52−
Ru1−N1 171.43(16), C52−Ru1−O1 100.29(16).
Figure 3. Dehydrogenation of benzyl alcohol and formation of 2.
only sparingly soluble in toluene or benzene and does appear
to liberate benzaldehyde upon heating or sonication, instead
decomposing to unidentified metal-containing products.
Despite the numerous reports of Ru-based alcohol
dehydrogenation catalysis, isolated Ru η2-adducts of benzalde-
hyde turned out to be quite rare. To our knowledge, only two
such complexes have been crystallographically characterized
and solution characterization data was not delineated.40,41
Complex 2 proved stable/soluble enough to obtain both
solution and solid-state structural information. In solution, the
metal-bound aldehyde CH resonates considerably upfield and
shows coupling to both phosphines (δH: 4.52 ppm; virtual
triplet, JPH = 5 Hz) consistent with significant back-bonding
from the metal. The 31P{1H} resonances of 2 appeared as a set
of doublets (68.12 and 37.50 ppm; JPP = 38.38 Hz) with a
smaller JPP coupling constant indicating a cis arrangement of
the two phosphorus nuclei. Both the carbonyl and
benzaldehyde group frequencies are observed by FT-IR
spectroscopy, with absorptions assigned to νCO = 1896
cm−1 (vs) and νRubenzaldehyde = 1584 cm−1 (m). The carbonyl
stretching frequency is only slightly lower than that in 1, while
the η2-benzaldehyde stretch is significantly lower than that of
the free organic molecule.
Single crystals suitable for crystallographic analysis could be
grown for both 1 and 2 (Figure 4). For 1, this enabled
confirmation of the geometry of the major isomer as assigned
by multinuclear NMR, with a hydride trans to a chloride. The
solid-state structure of 2 is best described as having a Ru(0)
sitting within a distorted trigonal bipyramid, with an η2-
aldehyde and two phosphines occupying the equatorial plane,
and a carbonyl and phenanthridinyl nitrogen in axial positions.
The elongation of the aldehyde CO bond [C45−O1
1.344(5) Å] is consistent with stabilization of the low valent
Ru center through significant π back-bonding; the CO
distance is longer than that in the most closely related
structurally characterized Ru−η2-aldehyde complex, [Ru(η2-
OCHPh)(trop2dae), trop2dae = N,N′-bis(5H-dibenzo[a,d]-
cyclohepten(5-yl)-1,4-diaminoethane); d(η2-CO): 1.310(9)
Å], which furthermore lacks an additional π-acidic CO ligand
and whose precursor K[Ru(H)(trop2dae)] is a potent
precatalyst for the production of H2 from alcohols in the
presence of water.41 The enhanced back-bonding and
accompanying stability may speak to the reluctance of 2 to
turn over following dehydrogenation of 1 equiv of primary
alcohol.
Considering that 1 can mediate the dehydrogenation of
benzyl alcohol in the presence of exogenous base but is
reluctant to dissociate the generated benzaldehyde, we
proceeded to investigate the dehydrogenation of a secondary
alcohol to see if increased steric bulk could promote
dissociation of the oxidized product. Complex 1 proved still
sluggish in the acceptorless dehydrogenation of cyclohexanol.
1
Only ∼5% conversion to cyclohexanone was observed by H
NMR after 24 h reaction time in a capped vial at room
temperature using 0.33 mol % catalyst loading. In an open
reflux, activity is moderately boosted to 18% conversion. The
fate of 1 proved more interesting. Isolation and recrystalliza-
tion of the organometallic product (3) from the reaction
mixtures gave orange crystals in ∼20% yield based on Ru, on
average. The 31P{1H} NMR spectrum contained three coupled
resonances. Two of these resonances are consistent with
retention of a P^N ligand (64.9 ppm; d, JPP = 258 Hz) and a
PPh3 (32.4 ppm; d, JPP = 160 Hz), though the coupling
constants make it clear these two nuclei do not couple to each
other. The third resonance appeared considerably downfield,
with a chemical shift more consistent with a bridging
phosphide (111.5 ppm; dd, JPP = 258, 160 Hz). In the
hydride region of the 1H NMR spectrum, the hydride
resonances of 1 have been replaced with a triplet of doublets
2
(−8.24 ppm; JHP = 18.5, 6.8 Hz). X-ray crystallographic
analysis of 3 (Figure 5) revealed the formation of a binuclear
dimer, where two Ru centers are bridged by a hydride, a
phosphide, and an imide derived from P−C and C−H
activation of two P^N ligands.
Activation of a diphenylphosphino P−C unit with insertion
of Ru into a P−Ph bond appears to have led to phenyl group
transfer, while C−H activation at the 6-position of a
phenanthridine ligand arm forms an unusual κ2-Ru1, μ2-
Ru1,Ru2 arrangement supporting the Ru−Ru unit (Figure 6).
Formation of a related dimer via P−C bond cleavage and
C
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consumption of alcohol. We note moderate conversion (34%)
when the simple (PPh3)3Ru(CO)(Cl)H is used in place of 1
(run 4). Under the same conditions using complex 1, the yield
of product is boosted to 54% (run 3). A decrease in isolated
yield is observed when the reaction is performed in a more
polar solvent such as dioxane or THF (runs 5 and 6). Using
KOH in place of an alkoxide base did not substantially affect
the observed yield (runs 7 and 13). We were able to decrease
the catalyst loading to 0.1 mol % with 0.5 equiv of base without
impacting the yield (run 8), while decreasing the excess of
secondary alcohol led to a drop in yield (run 9). In fact, higher
yields could be obtained at 0.025 mol % catalyst loading,
provided an excess (2 equiv) of KOtBu base and secondary
alcohol was used (run 10). No significant improvement was
observed on extending the reaction time from 24 to 48 h (run
11). While even lower catalyst loadings of 0.01 mol % (run 12)
led to respectable isolated yields, run 10 (bold in Table 1)
represents our optimized reaction conditions. Interestingly,
both the η2-aldehyde adduct 2 and hydride-bridged dimer 3
are competent precatalysts for this ADC reaction as well (runs
14−17). The presence of an exogenous nucleophile, in this
case aminobenzyl alcohol, therefore appears to be sufficient to
turn over 2. In addition, formation of 3 is not a catalytic dead-
end.
The scope of catalytic ADC of γ-amino alcohols and
secondary alcohols was then explored, and the results are
shown in Table 2. Isolated yields >80% were obtained for a
range of substrate combinations. Overall, catalytic coupling
using 1 is tolerant of a variety of chloro, methoxy, and aryl
substituents, and a range of aliphatic ring sizes, with highest
yields observed for the highest boiling point secondary
alcohols presumably as a result of minimal losses during
open reflux. In some cases where low yields were observed
(4b), increasing the amount of base used led to a significant
boost in yield. In this way, we were able to prepare a variety of
substituted pyridines and quinolines, including novel com-
pounds such as 2-(8-methoxynaphthyl)-6-phenylpyridine (4k).
Catalyst loadings as low as 0.025 mol % still allowed for
isolation of appreciable amounts of product, in some cases with
yields exceeding 80% (4f, 4n, and 4t). In comparison, Ru
complexes of tridentate amido ligands can reach similar yields
for this reaction only with extended reaction times of 72 h at
comparable catalyst loadings.6 To probe the mechanism of
ADC, an aliquot of the reaction mixture from the synthesis of
2-methyl-5,6,7,8-tetrahydroquinoline (4r) from cyclohexanol
and 3-amino-1-butanol was analyzed midway through the
reaction at the 12 h mark (see the Supporting Information,
Figures S18 and S98). In addition to cyclohexanone (observed
by 1H NMR) and the product (4r), a number of peaks
consistent with chemical species that plausibly form as
intermediates could be discerned by mass spectrometry
including the direct product of dehydrative coupling of 3-
amino-1-butanol and cyclohexanone, 2,3,5,6,7,8-hexahydro-2-
methyl-4(1H)-quinolinone, and 2,3,5,6,7,8-hexahydroquino-
line (Figure S18). Formation of these species is consistent
with the mechanism proposed by Pan et al. based on DFT-
calculated relative free energies of the likely organic
intermediates.6
Figure 5. Solid-state structure of 3 with ellipsoids shown at 50%
probability levels. Select hydrogen atoms and atom labels omitted for
clarity. Selected bond distances (Å) and angles (deg): C(1)−Ru(2)
2.075(6), C(27)−Ru(1) 2.127(6), C(86)−Ru(2) 1.859(8), C(87)−
Ru(1) 1.835(7), N(1)−Ru(1) 2.115(5), N(2)−Ru(2) 2.216(5),
P(1)−Ru(2) 2.2749(18), P(1)−Ru(1) 2.3350(19), P(2)−Ru(1)
2.3115(19), P(3)−Ru(2) 2.408(2), Ru(1)−Ru(2) 2.9570(13),
Ru(1)−H(1) 1.83(5), Ru(2)−H(1) 1.79(5); N(1)−C(1)−Ru(2)
109.0(4), C(2)−C(1)−Ru(2) 133.2(5), C(32)−C(27)−Ru(1)
121.9(5), C(28)−C(27)−Ru(1) 123.0(5), O(1)−C(86)−Ru(2)
175.0(5), O(2)−C(87)−Ru(1) 175.8(6), C(1)−N(1)−Ru(1)
116.5(4), C(9)−N(1)−Ru(1) 120.9(4), C(33)−N(2)−Ru(2)
123.8(4), C(41)−N(2)−Ru(2) 118.7(4), Ru(2)−P(1)−Ru(1)
79.79(6), C(15)−P(2)−Ru(1) 117.3(2), C(10)−P(2)−Ru(1)
101.0(2), N(1)−Ru(1)−P(1) 86.50(14), P(2)−Ru(1)−P(1)
164.46(6), P(2)−Ru(1)−Ru(2) 128.80(5), P(1)−Ru(1)−Ru(2)
49.21(5), N(1)−Ru(1)−Ru(2) 64.66(14), Ru(2)−Ru(1)−H(1)
34.6(16), P(1)−Ru(1)−H(1) 80.9(16), N(1)−Ru(1)−H(1)
74.4(15), Ru(1)−Ru(2)−H(1) 35.5(16), P(1)−Ru(2)−H(1)
83.4(16).
Figure 6. Decomposition of 1 leading to formation of 3.
phenyl group transfer was observed on treatment of the
commercially available precatalyst Ru(HN(CH2CH2PPh2)2)-
H(Cl)(CO) with base at room temperature, along with a
number of other products.42
The finding that 1 can mediate alcohol dehydrogenation but
is reluctant to liberate the resulting aldehyde leading to a stable
aldehyde adduct (2) or decomposition (formation of 3) led us
to investigate if the unsaturated organic fragment could be
intercepted by an incoming nucleophile. Optimization of ADC
catalysis conditions was carried out using the reaction of 2-
aminobenzyl alcohol and 1-phenylethanol (Table 1). We first
confirmed that no reaction was observed when either catalyst
or base is absent (runs 1 and 2); an unidentified side product
was observed in the presence of base alone but with no
The utility of 1 in catalytic ADC coupling reactions of γ-
amino alcohols and secondary alcohols led us to next explore
one-pot, three-component pyrimidine syntheses from benza-
midines, a primary alcohol, and a secondary alcohol (Table 3).
In these reactions, an extra equivalent of base was introduced
D
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Table 1. Optimization of Reaction Conditions for 2-Phenylquinoline Synthesis Using 1
a
c
run
A:B
equiv. base
[Ru] (mol %)
solvent
T
(°C)
t (h)
yield (%)
1
2
3
4
5
6
7
8
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
0.5 (KOtBu)
toluene
toluene
toluene
toluene
dioxane
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
110
24
24
24
24
24
24
24
24
24
24
48
24
24
24
24
24
24
0
0
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.1)
1 (0.1)
1 (0.025)
1 (0.025)
1 (0.01)
1 (0.025)
2 (1.0)
2 (0.5)
3 (0.5)
3 (0.25)
110
110
110
101
66
110
110
110
110
110
110
110
110
110
110
110
0.5 (KOtBu)
0.5 (KOtBu)
0.5 (KOtBu)
0.5 (KOtBu)
0.5 (KOH)
0.5 (KOtBu)
0.5 (KOtBu)
2 (KOtBu)
2 (KOtBu)
2 (KOtBu)
2 (KOH)
54
34
45
14
38
36
46
61
66
43
60
74
50
77
65
b
9
10
11
12
13
14
15
16
17
2 (KOtBu)
2 (KOtBu)
2 (KOtBu)
2 (KOtBu)
a
b
Conditions: open system under an Ar atmosphere, in a heating bath set to 20 °C above the solvent boiling point. (PPh3)3Ru(CO)HCl used in
c
place of 1. Isolated yield.
a
Table 2. Catalytic ADC of γ-Amino Alcohols and Secondary Alcohols
a
Reaction conditions: γ-amino alcohol (2 mmol), secondary alcohol (4 mmol), KOtBu (1 mmol), 1 (0.5 mol %), toluene reflux, Ar atmosphere,
b
c
d
open system, 24 h. Isolated yields following column chromatography, average of two trials. KOtBu (4 mmol), 1 (0.025 mol %). KOtBu (4
mmol), 1 (0.5 mol %).
E
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5a formed in a 45% yield, with a mixture of the β-alkylated
secondary alcohol (1,3-diphenylpropan-1-ol) and unreacted
phenyl ethanol comprising the remainder of the isolated
product. Under similar conditions but omitting the benzami-
dine, complete conversion to a 3:1 mixture of coupled
products, 1,3-diphenylpropan-1-ol and the corresponding
ketone 1,3-diphenylpropan-1-one, was found after 2.5 h. The
unsaturated chalcone, proposed as a key intermediate in
catalytic pyrimidine synthesis from alcohols,23,35 was not
observed. Subsequent addition of an equivalent of benzamidine
to this reaction mixture and resubmission to the reaction
conditions led to moderate conversion to 5a (12%). The
hydrogenation of chalcone and 1,3-diphenylpropan-1-one
appears responsible for the diminished conversion to 5a, likely
a result of less efficient dehydrogenation of the coupled
alcohols compared to the parent starting materials. In
comparison, related Mn-based catalysts have been demon-
strated to efficiently catalyze four-component reactions, where
initial β-alkylation of secondary alcohols by primary alcohols
can be followed by addition of another primary alcohol and an
amidine to produce even more complex pyrimidines in a one-
pot process.34
Table 3. Catalytic ADC Synthesis of Pyrimidines Using
Various Alcohols and Benzamidines
a
CONCLUSION
■
In summary, a Ru complex (1) supported by a simple P^N
ligand comprised of a benzannulated pyridine and a phosphine
donor has proved efficient in a range of ADC-type reactions,
enabling the catalytic synthesis of pyridines, quinolines, and
pyrimidines at some of the lowest catalyst loadings
reported.6,23 With respect to ligand design, we note that the
participation of the ligand (L1) in an active, cooperative
fashion as proposed for a range of dehydrogenation-type
reactivity24 is unlikely in the case of 1. As has been previously
suggested for quinoline-derived N^N^P ligands,6 the benzo-
fused π-extended phenanthridine ring may provide added
stability enabling the observed high catalytic efficiency. The
sluggish turnover in dehydrogenation of alcohols in the
absence of exogenous amines and the subsequent isolation of
a rare Ru η2-benzaldehyde adduct likely boosts the reactivity of
1 in multicomponent reactions as well. Efforts to exploit this
bonding motif in alternate catalytic transformations43 are
underway.
a
Conditions unless otherwise specified: benzamidine·HCl (1 mmol),
primary alcohol (1.1 mmol), secondary alcohol (2 mmol), KOtBu
(2.5 mmol), 1 (0.5 mol %), and 8 mL of toluene under an Ar
atmosphere at open reflux. Isolated yields following column
chromatography are shown in parentheses. Benzamidine·HCl (1
mmol), primary alcohol (1.1 mmol), secondary alcohol (1.1 mmol),
b
KOtBu (3.5 mmol), 1 (0.025 mol %).
to enable use of the more easily handled hydrochloride salt of
the benzamidine precursors. Pyrimidines 5a−n could be
obtained in respectable yields following column chromatog-
raphy (40−73%) using a catalyst loading of 0.5 mol % (see the
Supporting Information for optimization). In comparison,
similar yields using Mn-based catalysts require higher catalyst
loadings of 234 or 5 mol %,11 as do supported Pt
nanoparticles.35 We also note that supported Ru nanoparticles
are much less efficient at this transformation, with much lower
conversions (∼25%) reported at higher catalyst loadings.35
This supports homogeneous reactivity mediated by 1. To our
knowledge, only one other report of efficient, Ru-mediated
homogeneous catalysis of pyrimidine formation from alcohols
has appeared in the literature, and again invokes a key role for
metal−ligand cooperativity.23
Lowering the catalyst loading to 0.025 mol % led to a
reduction in the isolated yields, though appreciable conversion
could still be observed in the presence of added base (Table 3,
conditions b). The reaction conditions are similarly tolerant of
electron-releasing or -withdrawing groups, alkane-derived
primary alcohols, heteroatom-containing moieties such as
furan (5l) and thiophene (5m), and the formation of fully
substituted pyrimidines (5g−i) through the use of β-
substituted secondary alcohols. Varying the electronics of the
benzamidine by including an electron-releasing methyl group
(5e,f,h) did not appreciably impact product yields.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00058.
Multinuclear NMR spectra and HR-MS spectra of all
new compounds; details of optimization experiments
and intermediate identification; crystallographic infor-
mation file containing X-ray data with embedded
structure factors and .res file (PDF)
Accession Codes
CCDC 1978730−1978732 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Using a stoichiometric mixture of benzamidine (as hydro-
chloride salt), phenyl ethanol, and benzyl alcohol, pyrimidine
F
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Organometallics XXXX, XXX, XXX−XXX

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Article
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AUTHOR INFORMATION
Corresponding Author
David E. Herbert − Department of Chemistry and the
Manitoba Institute for Materials, University of Manitoba,
Winnipeg, Manitoba R3T 2N2, Canada; orcid.org/0000-
0001-8190-2468; Email: david.herbert@umanitoba.ca
■
Author
Rajarshi Mondal − Department of Chemistry and the Manitoba
Institute for Materials, University of Manitoba, Winnipeg,
Manitoba R3T 2N2, Canada
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00058
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The following sources of funding are gratefully acknowledged:
Natural Sciences Engineering Research Council of Canada for
a Discovery Grant to D.E.H. (RGPIN-2014-03733); the
Canadian Foundation for Innovation and Research Manitoba
for an award in support of an X-ray diffractometer (CFI
#32146); and the University of Manitoba for GETS support
(R.M.).
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