Iron Catalyzed Synthesis of Pyrimidines Under Air

Article abstract of DOI:10.1002/adsc.201901172

Herein we report an iron-catalyzed multicomponent dehydrogenative functionalization of alcohols to pyrimidines under atmospheric conditions. Using a well-defined Fe(II)-complex featuring redox noninnocent 2-phenylazo-(1,10-phenanthroline) ligand, as a cat

Full text of DOI:10.1002/adsc.201901172

Title: Iron Catalyzed Synthesis of Pyrimidines Under Air
Authors: Rakesh Mondal, suman sinha, Siuli Das, Gargi Chakraborty,
and Nanda Paul
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10.1002/adsc.201901172
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iron Catalyzed Synthesis of Pyrimidines Under Air
Rakesh Mondal, Suman Sinha, Siuli Das, Gargi Chakraborty, and Nanda D. Paul*
Department of Chemistry, Indian Institute of Engineering Science and Technology,
Shibpur, Botanic Garden, Howrah 711103, India, E-mail: ndpaul@gmail.com;
ndpaul2014@chem.iiests.ac.in
Received :((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Herein we report an iron-catalyzed and secondary alcohols with amidines under air at 100°C.
multicomponent dehydrogenative functionalization of A few control experiments were carried out to understand
alcohols to pyrimidines under atmospheric conditions. and unveil the plausible reaction mechanism.
Using
a well-defined Fe(II)-complex featuring redox
noninnocent 2-phenylazo-(1,10-phenanthroline) ligand, as a Keywords: redox-active ligands; iron catalysis; metal-
catalyst, a wide array of 2,4,6-trisubstituted pyrimidines ligand cooperativity; multicomponent dehydrogenative
were prepared via dehydrogenative coupling of primary,
coupling; pyrimidines
living systems as well as due to its wide application in
medicinal chemistry.[11] Besides, they also function as
photoactive materials in light-emitting devices.[12]
Traditionally pyrimidines are prepared via transition
metal-catalyzed condensation/cyclization reactions,
which require expensive noble metals as catalysts,
stoichiometric, or excess amounts of strong oxidants
and the reactions are carried out at high temperature.[13]
Therefore, sustainable and economically affordable
mild synthesis of pyrimidines from inexpensive and
readily available starting materials is desirable.
Introduction
Alcohols have been an environmentally benign and
sustainable starting material for synthesis chemistry.[1]
Lignocellulose biomass, which is prevalent in nature,
can easily serve as the raw material for alcohol
production. This, in turn, reduces the dependence on
the decreasing fossil fuel resources. Functionalization
of alcohol to different important products thus
continues to be an active area of research.[1-10]
Over the last decade, several research groups have
been working on the functionalization of alcohols to
various complex organic molecules, including organo-
heterocycles. The groups of Milstein,[2,3] Kempe,[4,5]
Kirchner,[6,7] Sun,[8] and a few others[9,10] have made a
significant contribution on the synthesis of various N-
heterocycles like quinoline, quinazoline, pyrrole,
pyrimidine, pyridine, etc. using alcohol as the primary
feedstock. Most of these reactions reported till now are
mostly based on expensive and scarce late transition
metal catalysts such as ruthenium,[2,9f] iridium,[5,9c-e]
palladium,[9a] rhenium,[6] etc. However, reports with
inexpensive and earth-abundant base metal catalysts
are limited.[3,5,7,10] Therefore, to make the sustainable
dehydrogenative alcohol functionalization reactions
more environmentally benign and economically
affordable, the expensive and scarce noble metals need
to be substituted by comparatively less costly and
environmentally benign base metals such as
manganese,[3a-b,5,7,10a-c]
nickel,[10g-i] etc.
iron,[10d]
cobalt,[3c-d,10e-f]
Pyrimidine(s), among the various N-heterocycles,
possess a strong identity because of its presence in
Scheme 1. Synthesis of pyrimidines via three-component
dehydrogenative coupling using alcohols as key feedstock.
1
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10.1002/adsc.201901172
Advanced Synthesis & Catalysis
In 2015, Kempe and co-workers reported an iridium- Table 1. Optimization of the reaction conditions for 2,4,6-
trisubstituted pyrimidine synthesis.[a-g]
catalyzed sustainable synthesis of pyrimidines via a
multicomponent dehydrogenative coupling reaction of
alcohols with amidines.[4c] Later on, Kempe[5] and
Kirchner[7] independently improvised this strategy
using abundantly available manganese-based catalysts.
However, the tedious multistep synthesis of air-
sensitive phosphine ligands and the requirement of
high temperature (≥130°C) may limit its large scale
industrial application. Very recently, Siddiki and
Shimizu reported a heterogeneous catalytic approach
for the synthesis of pyrimidines using platinum
nanoparticles as a catalyst.[9a] Therefore, it would be
worth to achieve these reactions using abundantly
available 3d-base metal catalysts under relatively less
demanding conditions.
Entry
Catalyst
(mol%)
Solvent
Base
Yield
(%)
52
1b (3.0 mol%)
toluene
t-BuOK
1[b]
2
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (3.0 mol%)
1b (2.0 mol%)
1a (3.0 mol%)
xylene
1,4-dioxane
acetonitrile
tert-amyl alcohol
THF
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
NaOH
58
35
3
4
NR
trace
NR
NR
71
5
6
Recently, we reported catalytic dehydrogenation of
alcohols at 75°C under aerial conditions using well
defined iron(II)-complexes, [FeLa/bCl2] (1a, 1b)
featuring redox-active 2-arylazo-(1,10-phenanthroline)
7
DMF
8
toluene
9
toluene
63
ligands, La/b (La
=
2-(phenyldiazenyl)-1,10-
10
11
12
13
14[c]
15
16[d]
17[e]
18[f]
19
20
21
toluene
KOH
59
phenanthroline; Lb = 2-((4-chlorophenyl)diazenyl)-
1,10-phenanthroline) as catalysts (Scheme 1).[14]
Mechanistic investigations revealed that iron and the
2-arylazo-(1,10-phenanthroline) moiety participate
synergistically during dehydrogenation of alcohols. In
the presence of reducing agents or excess t-BuOK, the
iron(II)-catalyst, 1b undergoes one-electron ligand-
centered reduction to form azo-anion radical species
[1a]- which then acts as the active catalyst. The iron-
stabilized azo-anion radical abstracts hydrogen atom of
the alcohol via a one-electron hydrogen atom transfer
(HAT) process to form a ketyl radical intermediate,
which on subsequent rapid one-electron oxidation
produce the desired carbonyls.[14a] Active participation
of azo-anion radical ligand allows avoiding the
energetically demanding iron-centered two-electron
Fe(II)/Fe(IV) redox events, which in turn made it
possible to achieve the dehydrogenation reaction at
75°C. To further expand the scope of the iron-
catalyzed dehydrogenation of alcohols, we decided to
explore the multicomponent dehydrogenative coupling
of primary and secondary alcohols with amidines to
construct pyrimidines.[4c,5,7,9a] The catalyst 1b showed
promising activity and yielded a variety of 2,4,6-
trisubstituted pyrimidines in moderate to good isolated
yields at 100°C under air.
toluene
K3PO4
trace
NR
NR
82
toluene
Na2CO3
DBU
toluene
toluene
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
toluene
82
toluene
60
toluene
80
toluene
72
toluene
63
toluene
68
FeCl2.6H2O
(10.0 mol%)
L1b+
FeCl2.6H2O
1b (3.0 mol%)
toluene
trace
22
23
toluene
toluene
t-BuOK
57
-
NR
24
25
26
-
toluene
toluene
toluene
t-BuOK
t-BuOK
t-BuOK
trace
39
L1a (5.0 mol%)
L1b (5.0 mol%)
41
[a] Reaction conditions: Stoichiometry: 1-phenyl ethanol (2a) (2.0
mmol), benzyl alcohol (3a) (2.0 mmol), guanidine (4a) (1.0 mmol);
Temperature: 100°C; Base: 0.5 equiv.; Time 16h. [b] Temperature: 75°C;
Base: t-BuOK (10.0 mol%). [c] Temperature: 120ºC. [d] Temperature:
90ºC [e] Time: 24h. [f] Time: 12h. [g] Isolated yields after column
chromatography.
of 10.0 mol% of t-BuOK.[14a] Among the two
complexes, 1a and 1b, since the catalyst 1b exhibited
better activity during alcohol dehydrogenation
reactions, we began our present work using 1b as the
catalyst.
Initially, using benzyl alcohol (3a), 1-phenyl ethanol
(2a), and guanidine (4a) as model substrates, we
explored the possibility of pyrimidine synthesis under
the pre-optimized conditions (Table 1, entry 1).[14a] At
75°C in toluene, in presence of 10.0 mol% t-BuOK
and 3.0 mol% of catalyst 1b, 52% of 4,6-
diphenylpyrimidin-2-amine (5a) was isolated under air
(Table 1, entry 1). To further improve the yield of 5a,
Result and Discussion
Two penta-coordinated iron(II)-complexes [FeLaCl2]
(1a) and [FeLbCl2] (1b), differing in respect of
substitution on the aryl ring of the 2-arylazo-(1,10-
phenanthroline) ligand was used as catalyst for the
present multicomponent dehydrogenative coupling
reaction (Scheme 1).[14] In our previous work, we
observed that both the complexes 1a and 1b showed
the best activity towards dehydrogenation of alcohols
when the reaction was performed in toluene at 75°C
for 5 h with 3.0 mol% catalyst loading in the presence
2
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10.1002/adsc.201901172
Advanced Synthesis & Catalysis
the reaction was performed in different organic present iron-catalyzed multicomponent synthesis of
solvents such as xylene, 1,4-dioxane, acetonitrile, tert- pyrimidines under air. Initial efforts were given to
amyl alcohol, THF, DMF (Table 1, entries 2-7). The explore the substrate scope for alcohols (Tables 2, 3).
reaction proceeds well in non-polar solvents like The reaction proceeds well with a variety of electron-
toluene, xylene; however, traces or no product was donating, -withdrawing, and heteroaryl functionalities
isolated from polar solvents like THF, 1,4-dioxane, present both on primary (Table 2) and secondary
acetonitrile, tert-amyl alcohol, DMF. Other than t- (Table 3) alcohols. Pyrimidines were obtained in
BuOK, the reaction conditions were also screened for higher yields in the presence of electron-donating
bases like t-BuONa, NaOH, KOH, K3PO4, Na2CO3, methyl, or methoxy groups at ortho-, meta- or para-
DBU (Table 1, entries 8-13). As observed previously positions (Table 2, entries 2-7; Table 3, entries 1-4).
during the dehydrogenation of alcohols,[14a] the t- Pyrimidines were obtained in slightly higher yields
BuOK was found to be most effective. The pyrimidine starting from secondary alcohols containing the
5a was isolated at the highest yield of 82% when the electron-donating groups than the benzyl alcohols
coupling of 2a, 3a, and 4a was carried out at 100°C bearing the same functionalities. For example, 4-
for 16 h in the presence of 0.5 equiv. of t-BuOK and phenyl-6-(o-tolyl)pyrimidine-2-amine
(5b)
was
3.0 mol% of 1b. Increasing the temperature, time, obtained in 83% yield from the reaction of 2a and 2-
catalyst, or base loading beyond optimized conditions methylbenzyl alcohol (3b) with 4a (Table 2, entry 2)
did not produce any notable improvement of yield of while the same pyrimidine, 5b was obtained in slightly
5a (Table 1, entries 16-19). However, lowering these higher yield, 86% from the reaction of 3a and 1-(o-
parameters leads to a significant lowering in yields of tolyl)ethan-1-ol (2b) with 4a (Table 3, entry 1). The
5a.
reaction was also well tolerant towards strong electron-
withdrawing -NO2, -CF3 groups producing the
Table 2. Synthesis of 2,4,6-trisubstituted pyrimidines from respective pyrimidines 5i in 65%, 5n in 63% (Table 2,
various primary alcohols, 1-phenyl ethanol, and guanidine.[a- entries 9, 14) and 5n in 69% (Table 3, entry 9) yields,
d]
respectively. With heteroaryl substitution, the yield
varied in the range of 63 to 70% (Table 3, entries 10-
12). Reaction also proceeds with aliphatic alcohols.
Cyclopropanemethanol yielded the desired pyrimidine
5o in 62% yield (Table 2, entry 15).
Table 3. Synthesis of 2,4,6-trisubstituted pyrimidines from
various secondary alcohols, benzyl alcohol, and guanidine.[a-
d]
[a] Stoichiometry: 1-phenyl ethanol (2a) (2.0 mmol),
primary alcohol (3a-3o) (2.0 mmol), guanidine (4a) (1.0
mmol). [b] toluene (4.0 mL). [c] Isolated yields after column
chromatography. [d] Under air.
[a] Stoichiometry: secondary alcohol (2b-2m) (2.0 mmol),
benzyl alcohol (3a) (2.0 mmol), guanidine (4a) (1.0 mmol).
[b] toluene (4.0 mL). [c] Isolated yields after column
chromatography. [d] Under air.
Substrate scope was also explored varying
substitution on both primary and secondary alcohols
(Table 4). In the presence of electron-donating groups
in both primary and secondary alcohols, the respective
pyrimidines were obtained in good yields (Table 4,
entries 1-3). In the presence of methyl or methoxy
groups on both primary and secondary alcohols, the
Control
experiments using iron-salts like
FeCl2.6H2O, Fe(ClO4)2.6H2O, FeCl3 as catalysts
afforded 5a only in trace amounts under the optimized
conditions (Table 1, entries 21, 22). The reaction did
not proceed in the absence of t-BuOK and in the
presence of only t-BuOK or t-BuOK and ligand (L1a,1b
)
the desired pyrimidine 5a was obtained in trace, 39,
and 41% yields respectively (Table 1, entries 23-26).
Having optimized conditions at hand, we screened a
wide variety of substrates under the optimal conditions
using 1b as the catalyst to investigate the scope of the
3
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10.1002/adsc.201901172
Advanced Synthesis & Catalysis
desired pyrimidines 5u, 5v, 5w were obtained in 74- entry 3). Amidines containing methyl or cyclopropyl
83% yields, respectively. The presence of electron- groups were also found to be compatible. The
withdrawing halogens on both alcohols were also well corresponding pyrimidines 5zd and 5zg were obtained
tolerated under our optimal conditions. The respective in 83 and 81% yields from the reaction of 2a, and 3a,
pyrimidines 5x, 5y, 5z, 5za, 5zb, 5zc were obtained in with acetamidine (4b) and cyclopropylcarboxamidine
61-75% yields, respectively (Table 4, entries 4-8,10). (4e), respectively (Table 5, entries 1 and 4).
Pyrimidines were also isolated in good yields with
Finally, we performed a few control experiments to
primary alcohols containing electron-donating and explore the plausible steps involved behind the
secondary alcohols bearing an electron-withdrawing formation of 2,4,6-trisubstituted pyrimidines via
group or vice versa (Table 4, entry 9).
selective C−C and C−N bond formation reaction
catalyzed by 1b (Scheme 2).[9a] We have chosen 1-
phenyl ethanol (2a), 3-methoxybenzyl alcohol (3c),
and guanidine (4a) as the model substrates. In the
presence of t-BuOK, coupling of 2a and 3c yielded
trace amount of the intermolecular condensation
product, 1-(3-methoxyphenyl)-3-phenylprop-2-en-1-
one (7ac), after refluxing in toluene at 100˚C for 5h
under atmospheric conditions in the absence of 1b. On
the other hand, under optimized catalytic conditions, in
the presence of both 1b and t-BuOK, 2a and 3c
undergoes condensation to produce the α,β-unsaturated
ketone 7ac in 80% yield. The compound 7ac was also
obtained in 78% yield under identical reaction
conditions starting from the pre-formed acetophenone
(6a) and 3-methoxy benzaldehyde (6c). However, in
the absence of t-BuOK, the coupling of 6a and 6c did
not produce any 7ac. These experimental results
indicate the involvement of the iron-catalyst 1b during
the dehydrogenation of alcohols as well as the
necessity of the t-BuOK during the selective C−C
bond formation between two in-situ formed carbonyls.
Table 4. Synthesis of 2,4,6-trisubstituted pyrimidines from
various primary alcohols, secondary alcohols, and
guanidine.[a-d]
[a] Stoichiometry: secondary alcohol (2c,2e,2h,2i,2n,2o)
(2.0 mmol), benzyl alcohol (3d,3f,3k,3l) (2.0 mmol),
guanidine (4a) (1.0 mmol). [b] toluene (4.0 mL). [c] Isolated
yields after column chromatography. [d] Under air.
Table 5. Synthesis of 2,4,6-trisubstituted pyrimidines from
various amidines, 1-phenyl ethanol, and benzyl alcohol.[a-d]
[a] Stoichiometry: secondary alcohol (2a) (2.0 mmol),
benzyl alcohol (3a) (2.0 mmol), guanidine (4b-e) (1.0
mmol). [b] toluene (4.0 mL). [c] Isolated yields after column
chromatography. [d] Under air.
Scheme 2. Control experiments for mechanistic
investigations.
To further expand the substrate scope and check the
versatility, reactions were carried out with various
substituted amidines (Table 5). Reaction of 2a and 3a
with benzamidine (4c) afforded the desired pyrimidine,
5ze in 88% yield (Table 5, entry 2). With 4-
The reaction of guanidine (4a) with the preformed
intermediate 7ac under the optimized conditions in the
presence
of
catalyst
1b,
afforded
4-(3-
methoxyphenyl)-6-phenylpyrimidine-2-amine (5c) in
89% yield. Interestingly, the coupling of 4a and 7ac
yielded 5c in almost identical yield under the optimal
conditions, even in the absence of the catalyst 1b. On
chlorobenzimidamide
(4d),
the
corresponding
pyrimidine, 5zf was isolated in 65% yield (Table 5,
4
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10.1002/adsc.201901172
Advanced Synthesis & Catalysis
the other hand, the intermediates obtained from the prepared in moderate to good yields under air using
coupling of 4a with 6a or 6c did not produce 5c when alcohol as the primary feedstock. Mechanistic
reacted with the second molecule of the carbonyl investigation reveals that both the arylazo ligand and
compound.
iron
participate
cooperatively
during
the
dehydrogenation of alcohols.[14a] In the presence of
excess t-BuOK, the iron(II)-catalyst, 1b undergoes
one-electron ligand-centered reduction to form the
active azo-anion radical catalyst [1a]-.[14a] The iron-
stabilized azo-anion radical abstracts hydrogen atom of
the alcohol via a one-electron hydrogen atom transfer
(HAT) process to form a ketyl radical intermediate,
which on subsequent rapid one-electron oxidation
produce
the
desired
carbonyls.
Synergistic
participation of iron and the arylazo ligand allowed to
avoid the energetically demanding iron centered two-
electron redox events and made it possible to achieve
this multicomponent reaction at 100°C in the presence
of air. Successful development of such metal-ligand
cooperative approaches would possibly enable us to
achieve the dehydrogenative functionalization
reactions under mild conditions using 3d-base metal
catalysts.
Experimental Section
General Information. THF, xylene, 1,4-dioxane, toluene,
and other solvents used in this work were distilled and dried
following the standard procedures. All other chemicals were
used as received from the commercial suppliers without
further purification. Analytical TLC and column
chromatography were performed by using Merck 60 F254
silica gel plate (0.25 mm thickness) and Merck 60 silica gel
1
(60−120 mesh). H and 13C spectra were recorded on a
Bruker Avance 400/500 MHz and JEOL 400 MHz
spectrometers, and SiMe4 was used as the internal standard.
Scheme 3. Plausible mechanism.
Catalyst Synthesis. Catalyst 1a and 1b were synthesized
following the literature procedure.[14]
A plausible mechanism is depicted in Scheme 2. The
reaction begins with the 1b-catalyzed dehydrogenation
of primary and secondary alcohols. In our previous
work, we observed that in the presence of t-BuOK, the
catalyst 1b undergoes one-electron reduction to form
the mono-anionic species [1b]- containing an azo-
anion radical ligand.[14] The complex [1b]- then acts as
the active catalyst.[14] The iron-stabilized azo-anion
radical abstracts hydrogen atom of the alcohol via a
one-electron hydrogen atom transfer (HAT) process to
form a ketyl radical intermediate, which on subsequent
rapid one-electron oxidation produce the respective
carbonyls.[14a] The carbonyls formed in-situ undergo
base promoted condensation to form the α,β-
unsaturated ketone, which upon subsequent base
General Procedure for the Synthesis of Pyrimidine
Derivatives. In a 50 mL oven-dried round bottom flask, 2.0
mmol of respective secondary and primary alcohols
dissolved in 4.0 mL toluene was taken. To it, the iron
catalyst 1b (3.0 mol%) and t-BuOK (0.5 equiv.) were added
under atmospheric conditions. The whole reaction mixture
was then placed in an oil bath preheated at 100°C. The
reaction was continued for 16h. Once the reaction was
complete, the residue was concentrated under reduced
pressure and purified by silica gel column chromatography
using 7:3 (petroleum ether: diethyl ether) as eluent.
Acknowledgments
mediated condensation with amidine followed by The research was supported by DST, Govt. of India (Project:
YSS/2015/001552). R.M. thanks CSIR, S.S. thanks IIESTS, S. D.
intramolecular cyclization produce the desired
pyrimidines.
and G. C. thanks UGC for fellowship support. Financial assistance
from IIESTS is duly acknowledged.
Conclusion
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10.1002/adsc.201901172
Advanced Synthesis & Catalysis
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Iron Catalyzed Synthesis of Pyrimidines
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Rakesh Mondal, Suman Sinha, Siuli Das,
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