A sustainable multicomponent pyrimidine synthesis

Article abstract of DOI:10.1021/jacs.5b09510

Since alcohols are accessible from indigestible biomass (lignocellulose), the development of novel preferentially catalytic reactions in which alcohols are converted into important classes of fine chemicals is a central topic of sustainable synthesis. Multicomponent reactions are especially attractive in organic chemistry as they allow the synthesis of large libraries of diversely functionalized products in a short time when run in a combinatorial fashion. Herein, we report a novel, regioselective, iridium-catalyzed multicomponent synthesis of pyrimidines from amidines and up to three (different) alcohols. This reaction proceeds via a sequence of condensation and dehydrogenation steps which give rise to selective C-C and C-N bond formations. While the condensation steps deoxygenate the alcohol components, the dehydrogenations lead to aromatization. Two equiv of hydrogen and water are liberated in the course of the reactions. PN₅P-Ir-pincer complexes, recently developed in our laboratory, catalyze this sustainable multicomponent process most efficiently. A total of 38 different pyrimidines were synthesized in isolated yields of up to 93%. Strong points of the new protocol are its regioselectivity and thus the immediate access to pyrimidines that are highly and unsymmetrically decorated with alkyl or aryl substituents. The combination of this novel protocol with established methods for converting alcohols to nitriles now allows to selectively assemble pyrimidines from four alcohol building blocks and 2 equiv of ammonia.

Full text of DOI:10.1021/jacs.5b09510

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A Sustainable Multi-Component Pyrimidine Synthesis
Nicklas Deibl, Kevin Ament, and Rhett Kempe
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Sep 2015
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A Sustainable Multi-Component Pyrimidine Synthesis
Nicklas Deibl, Kevin Ament, and Rhett Kempe*
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Anorganische Chemie II—Katalysatordesign, Universität Bayreuth, 95440 Bayreuth, Germany
Supporting Information Placeholder
multiple bonds.9 Condensation steps deoxygenate the alco-
ABSTRACT: Since alcohols are accessible from indigestible
hols and dehydrogenation allows aromatization. Multi-
component reactions10 are especially attractive among the
transition metal mediated or catalyzed syntheses of aromatic
N-heterocycles.11 Large libraries of diversely substituted
products can be synthesized without constructing sophisti-
cated educts. We became interested in developing a 4-
component reaction in which amidines and three (different)
alcohol components are selectively connected to pyrimidines
(Scheme 1, bottom). Based on the already known catalytic
methodology to synthesize nitriles from alcohols,12 the selec-
tive assembly of pyrimidines just from alcohols and ammonia
(Scheme 1, bottom) becomes feasible.
biomass (lignocellulose), the development of novel preferen-
tially catalytic reactions in which alcohols are converted into
important classes of fine chemicals is a central topic of sus-
tainable synthesis. Multi-component reactions are especially
attractive in organic chemistry as they allow the synthesis of
large libraries of diversely functionalized products in a short
time when run in a combinatorial fashion. Herein, we report
a novel, regioselective, iridium catalyzed multi-component
synthesis of pyrimidines from amidines and up to three (dif-
ferent) alcohols. This reaction proceeds via a sequence of
condensation and dehydrogenation steps which give rise to
selective C-C and C-N bond formations. While the condensa-
tion steps deoxygenate the alcohol components, the dehy-
drogenations lead to aromatization. Two equivalents of hy-
drogen and water are liberated in the course of the reactions.
PN5P-Ir-pincer complexes, recently developed in our labora-
tory, catalyze this sustainable multi-component process most
efficiently. 38 different pyrimidines were synthesized in iso-
lated yields of up to 93%. Strong points of the new protocol
are its regioselectivity and thus the immediate access to
pyrimidines that are highly and unsymmetrically decorated
with alkyl or aryl substituents. The combination of this novel
protocol with established methods for converting alcohols to
nitriles now even allows to selectively assemble pyrimidines
from four alcohol building blocks and two equivalents of
ammonia.
Scheme 1. Recently introduced syntheses of aromatic N-
heterocycles from alcohols (top and middle) and the
pyrimidine synthesis described here (bottom)
Dwindling fossil carbon resources and environmental con-
cerns associated with their use call for alternative ways to
produce fine chemicals. Out of the available biomass, ligno-
cellulose is especially attractive since it is abundantly availa-
ble1 and food chain competition is negligible. Since lignocel-
lulose can be catalytically processed to alcohols,2 the devel-
opment of novel catalytic reactions converting alcohols into
important classes of compounds is highly desirable.3 Aro-
matic N-heterocyclic compounds have a wide range of appli-
cations and also feature prominently in medicinal chemis-
try.4 Recently, a sustainable 2-component synthesis of pyr-
roles from alcohols has been reported by the groups of Mil-
stein, Saito and us (Scheme 1, top).3,5,6 Diversely functional-
ized pyridines have been synthesized similarly.7 In parallel,
Beller and co-workers disclosed a 3-component pyrrole syn-
thesis using the same conceptual approach (Scheme 1, mid-
dle).8 These alcohol-to-heterocycle reactions proceed via a
combination of dehydrogenation and condensation: Accep-
tor-less Dehydrogenative Condensation and represent a
novel and sustainable approach to construct C-C and C-N
Herein, we report on a novel iridium catalyzed multi-
component pyrimidine synthesis. Alcohols and one equiva-
lent of an amidine are selectively linked via C-C and C-N
bond formation steps. Two equivalents of hydrogen and
water are liberated in the course of this sustainable reaction.
The synthesis protocol is especially useful with regard to the
formation of diversely and selectively arylated and/or alkyl-
ated pyrimidines.
Initially, we investigated the 3-component reaction of 1-
substituted ethanol derivatives with primary alcohols (Table
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1, top). The two alcohols get oxidized by the Ir-catalyst with
ketone. However, the amidine reacts preferably with a less-
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release of dihydrogen. A subsequent base-mediated aldol
condensation may afford an α,β-unsaturated ketone inter-
mediate, which in turn could react with the amidine.4 The C-
alkylation by alcohols13 (borrowing hydrogen or hydrogen
auto-transfer concept) represents a frequently used C-C bond
formation strategy employing alcohols, but to date there are
only a few reactions described where the unsaturated prima-
ry product is directly used as a reaction intermediate (e.g. for
1,4-addition of a nucleophile).14 We recently extended the β-
alkylation concept to methyl-N-heteroarenes.15 The optimal
conditions (solvent, base, temperature, and catalyst) for the
3-component reaction were identified by thoroughly investi-
gating the reaction of 1-phenylethanol, benzyl alcohol, and
benzamidine (Table 1). For instance, we found that the reac-
tion should be run with KOH or t-BuOK as the base in tert-
amyl alcohol under reflux [for details of the screenings cf.
Supporting Information (SI)]. Precatalysts A and B (Table 1,
entries 1, 2) gave the highest yield of 2,3,5-
triphenylpyrimidine (4a) in the screening reaction. Based on
the convenience of 19F NMR spectroscopy, catalyst A was
selected.
substituted α,β-unsaturated ketone compared to an unsatu-
rated ketone which is derived from multiple alkylations.
When the reaction was run with 0.5 equiv KOH (w/r to the
amidine), complete conversion of the alcohols was observed
for the screening reaction. A catalyst loading of 1 mol% with
respect to the amidine (0.25 mol% with respect to alcohols)
was chosen to allow for a broad range of alcohols. Having
pinpointed these optimal conditions, we then addressed the
scope of possible substrates for this 3-component reaction
(Table 2, compounds 4a-p). Variation of the secondary alco-
hol led to compounds 4a-g (Table 2). Aryl chlorides, hetero-
cycles like pyridine and thiophene, as well as olefins were
tolerated. Very good isolated yield were obtained for most
pyrimidine products. Compound 4g (olefinic functional
group) was isolated in lower yield since alkylation can occur
on the primary and secondary carbon atom. No reduction of
the double bond was observed (GC-MS analysis). The prima-
ry alcohol was then varied to introduce branched (4h, Cy =
cyclohexyl) or linear aliphatic moieties (4i,j) in again very
good isolated yields.
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Table 2. Synthesis of tri-substituted pyrimidines via
3-component reactiona
Table 1. Catalyst Screeninga
Entry
Precatalyst
Yield [%]b
1
A
83
79
75
64
45
43
37
2
3
4
5
6
7
B
C
D
E
0.5 [IrCl(COD)]2
0.5 [Ir(OMe)(COD)]2
R3
N
N
4o: R3 = NH2, 63 %c,d
4p: R3 = NHMe, 55 %c,d
F
aReaction conditions: 1-Phenyl ethanol (2 mmol), benzyl
alcohol (2 mmol), benzamidine (1 mmol), t-BuOK (1.1 mmol),
tert-amyl alcohol (3 mL), catalyst (0.005 mmol), 20 h reflux
a Reaction conditions: Secondary alcohol (2 mmol), prima-
ry alcohol (2 mmol), amidine (1 mmol), KOH (0.7 mmol),
catalyst A (0.01 mmol), tert-amyl alcohol (3 mL), 24 h reflux
under inert atmosphere. PMP = para-methoxyphenyl; bYields
b
under inert atmosphere. Yield was determined by GC with
dodecane as internal standard. COD = 1,5-Cyclooctadiene,
Me = methyl, Ph = phenyl, i-Pr = iso-propyl, Bu = butyl.
c
of isolated products. additional 1.0 equiv KOH to trap HCl
from guanidine hydrochloride. d 1.1 equiv of secondary alco-
hol.
A substrate ratio of 2 equiv of each alcohol with respect to
the amidine was found to give the highest yield of pyrimi-
dine. Noticed side-reactions were self-condensation of the
secondary alcohol (upon oxidation) and irreversible reduc-
tion of the conjugated C=C double bond of the unsaturated
Last, the amidine moiety was varied. The use of guanidine (as
the hydrochloride along with an additional equivalent of
KOH) gave the pyrimidine 4k and gratifyingly no
N-alkylation of the amino function was observed under the
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reaction conditions used. Substituents (n-butyl, methoxy,
of the methyl group of 1-substituted ethanol derivatives (Ta-
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3
4
5
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7
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chloride) at the phenyl ring of benzamidine gave rise to the
products 4l-n. The application of 1-(4-fluorophenyl)-ethanol,
isobutanol and guanidine or methyl guanidine hydrochloride
afforded the core pyrimidines 4o and 4p of the drug rosuvas-
tatin which acts as a HMG-CoA reductase inhibitor and is
used to treat high cholesterol levels. In this case, the amount
of secondary alcohol could be lowered to 1.1 equiv since no
saturated β-alkylation product was observed. After having
addressed the 2,4,6-substitution, we became interested in
employing secondary alcohols carrying a substituent at the β-
position. The significantly more challenging alkylation of a
secondary carbon atom gives access to fully substituted py-
rimidines. An optimization of the substrate ratio in the reac-
tion between cycloheptanol, para-methoxybenzyl alcohol
and benzamidine, which afforded pyrimidine 5b (Table 3),
indicated that the amount of primary alcohol can be lowered
from 2.0 to 1.1 equivalents. When a secondary carbon atom is
alkylated, reduction of the α,β-unsaturated ketone is signifi-
cantly slower as the C=C bond is less accessible for the Ir
catalyst. With these optimal conditions established, we pre-
pared pyrimidines with a fused carbocycle (Table 3, 5a-c)
from cyclic alcohols and 5d from nonan-5-ol. 2,4,5-
substituted pyrimidines (5e-h) were obtained by employing
two primary alcohols of which one contributes the C-2 frag-
ment to the pyrimidine core. For this reaction, the use of
KOH was found to be superior compared to t-BuOK and
most of the examples were isolated in very good yields.
ble 4, top, left). Addition of a third alcohol and the amidine
building block can give rise to fully substituted pyrimidines.
Since this synthesis features four starting materials and four
catalyst operations (three oxidations, one reduction) suitable
reaction conditions had to be found. The reaction between 1-
phenylethanol, 1-propanol and the later addition of ben-
zamidine and benzyl alcohol was chosen as the model reac-
tion. We found that the β-alkylation reaction proceeds with-
in less than four hours if 1,4-dioxane and t-BuOK were used
as solvent and base, respectively.
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Table 4. Synthesis of tetra-substituted pyrimidines
by a consecutive 4-component reactiona
add t-AmOH
reflux, open
system, 24h
R4
2
1,4-dioxane
t-BuOK (2.0 eq.)
OH
OH
R2
OH
+
N
4
N
+ 3 H2O
+ 2 H2
A
catalyst
125 °C, 4 h
R1
R1
R1
R3
6
5
R2
1
2
R2
OH
R3
R4
+
H2N
NH
, yieldb (mol% cat.)
6
2
3
Table 3. Synthesis of pyrimidines via alkylation of
methylene groupsa
aReaction conditions: Secondary alcohol (2 mmol), primary
alcohol (2.2 mmol), t-BuOK (2.0 mmol), catalyst A (0.01-0.02
mmol), 1,4-dioxane (1-2 mL), 4 h at 125 °C (oil bath). Then
addition of remaining starting materials: primary alcohol (1.1
mmol), amidine (1.0 mmol) in tert-amyl alcohol (2 mL), 24 h
aReaction conditions: Secondary alcohol (2 mmol), prima-
ry alcohol (1.1 mmol), amidine (1 mmol,), t-BuOK (1.5 mmol),
catalyst A (0.007-0.010 mmol), tert-amyl alcohol (3 mL), 24 h
reflux under inert atmosphere. KOH (1.5 mmol) was used for
2,4,5-substituted pyrimidines. bYields of isolated products.
PMP = para-methoxyphenyl.
b
reflux under inert atmosphere. Yields of isolated products.
PMP = para-methoxyphenyl, Cy = cyclohexyl. c Correspond-
ing amidine or guanidine hydrochloride (respectively) along
with 1 additional equiv of t-BuOK was used.
The optimal ratio for the β-alkylation reaction was 1 equiv of
secondary alcohol and 1.1 equiv of primary alcohol. The com-
plete conversion of the secondary alcohol is important, be-
cause its reaction with the later added third alcohol compo-
nent would lead to 5-unsubstituted pyrimidines and thus to a
Based on the efficient and selective alkylation of a secondary
carbon atoms (synthesis of 5a-h, Table 3), a consecutive 4-
component reaction becomes feasible. In the first step, the
“secondary carbon atom” is formed by selective β-alkylation
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product mixture. It should be noted, that the β-alkylation
Thomas Dietel for X-ray crystal structure analysis and Rainer
1
2
3
4
5
6
7
8
reaction can either be run in a pressurized tube or in an open
system (reflux condenser). In no case, a product with a C=C
bond was observed (GC-MS monitoring). Next, the addition
of a solution of benzamidine and benzyl alcohol was investi-
gated and tert-amyl alcohol (2 mL/mmol amidine) turned
out to be optimal as the solvent. A base screening indicated,
that t-BuOK is most efficient, as is catalyst A in 1-2 mol%
loading. With these reaction conditions in hand, we started
exploring the substrate scope of the consecutive 4-
component reaction (Table 4). First, the “N-C-N” substituent
was varied. Aryl (6a), alkyl (6b) and an amino function (6c,
from guanidine) can be introduced in this position. Second,
the substituent at the 4-position was varied by employing
different 1-substituted ethanol derivatives which, in addition
to this substituent, contribute two carbon atoms to the py-
rimidine ring (for numbering, see Table 4, top right). Aro-
matic (6d,e) as well as aliphatic substituents (6f) were toler-
ated. Third, different primary alcohols were used in the first
reaction as a source of the respective residues at the 5-
position (6g-j). Notably, the use of methanol gave rise to a
primary quasi-benzylic functional group at the pyrimidine in
5-position which is interesting for further functionalization
reactions. Fourth, the remaining substituent at C-6, which is
introduced with the primary alcohol added last, was varied.
Aliphatic (Cy = cyclohexyl, 6k) and (hetero)aromatic (6l-n)
substituents can be introduced. Based on the examples listed
in Table 4, and the modular synthesis concept of the consec-
utive 4-component reaction, a virtual library of more than
300 compounds (5x4x4x4-doublings) has been created.
Schobert for helpful discussions.
REFERENCES
(1) Tuck, C. O.; Perez, E.; Horvath, I. T.; Sheldon, R. A.; Poliakoff, M.
Science 2012, 337, 695-699.
(2) (a) Vispute, T. P.; Zhang, H.; Sanna, A.; Xiao, R.; Huber, G. W.
Science 2010, 330, 1222-1227. (b) Besson, M.; Gallezot, P.; Pinel, C.
Chem. Rev. 2014, 114, 1827-1870.
(3) Michlick, S.; Kempe R. Nat. Chem. 2013, 5, 140-144.
(4) Joule, J. A., Mills, K. in Heterocyclic Chemistry, 5th ed. (Wiley,
Chichester, UK, 2010).
(5) (a) Srimani, D.; Ben-David, Y.; Milstein, D. Angew. Chem. Int. Ed.
2013, 52, 4012-4015. (b) Iida, K.; Miura, T.; Ando, J.; Saito, S. Org. Lett.
2013, 15, 1436-1439.
(6) The reported pyrrole synthesis is based on contributions by Ishii
and Crabtree: (a) Taguchi, K.; Sakaguchi, S.; Ishii, Y. Tetrahedron
Lett. 2005, 46, 4539-4542. (b) Schley, N. D.; Dobereiner, G. E.;
Crabtree, R. H. Organometallics 2011, 30, 4174-4179.
(7) (a) Michlik, S.; Kempe, R. Angew. Chem. Int. Ed. 2013, 52, 6326-
6329. (b) Srimani, D.; Ben-David, Y.; Milstein, D. Chem. Commun.
2013, 49, 6632-6634. (c) Ruch, S.; Irrgang, T.; Kempe, R. Chem. Eur. J.
2014, 20, 13279-13285.
(8) (a) Zhang, M.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed.
2013, 52, 597-601. (b) Zhang, M.; Fang, X.; Neumann, H.; Beller, M. J.
Am. Chem. Soc. 2013, 135, 11384-11388.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Schranck, J.; Tlili, A.; Beller, M. Angew. Chem. Int. Ed. 2013, 52,
7642-7644.
(10) For recent reviews on multicomponent synthesis of heterocycles,
see: (a) D'Souza, D. M.; Müller, T. J. Chem. Soc. Rev. 2007, 36, 1095-
1108. (b) Balme, G.; Bouyssi, D.; Monteiro, N. Heterocycles 2007, 73,
87-124. (c) Arndtsen, B. A. Chem. Eur. J. 2009, 15, 302-313. (d) Estevez,
V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402-
4421. (e) Jiang, B.; Rajale, T.; Wever, W.; Tu, S. J.; Li, G. Chem. Asian.
J. 2010, 5, 2318-2335. (f) Estevez, V.; Villacampa, M.; Menendez, J. C.
Chem. Soc. Rev. 2014, 43, 4633-4657. (g) Allais, C.; Grassot, J.-M.;
Rodriguez, J.; Constantieux, T. Chem. Rev. 2014, 114, 10829-10868.
(11) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Chem. Rev. 2013, 113, 3084-3213.
(12) For selected examples please see: (a) Oishi, T.; Yamaguchi, K.;
Mizuno, N. Angew. Chem. Int. Ed. 2009, 48, 6286-6288. (b) Yamagu-
chi, K.; He, J.; Oishi, T.; Mizuno, N. Chem. Eur. J. 2010, 16, 7199-7207.
(c) Dornan, L. M.; Cao, Q.; Flanagan, J. C. A.; Crawford, J. J.; Cook,
M. J.; Muldoon, M. J. Chem. Commun. 2013, 49, 6030-6032. (d) Kim,
J.; Stahl, S. S. ACS Catal. 2013, 3, 1652-1656. (e) Yin, W.; Wang, C.;
Huang, Y. Org. Lett. 2013, 15, 1850-1853. (f) Dighe, S. U.; Chowdhury,
D.; Batra, S. Adv. Synth. Catal. 2014, 356, 3892-3896. (g) Jagadeesh, R.
V.; Junge, H.; Beller, M. Nat. Commun. 2014, 5, 1-8.
(13) For selected reviews on C-alkylation by alcohols, see: (a) Guille-
na, G.; Ramon, D. J.; Yus, M. Angew. Chem. Int. Ed. 2007, 46, 2358-
2364. (b) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv.
Synth. Catal. 2007, 349, 1555-1575. (c) Nixon, T. D.; Whittlesey, M. K.;
Williams, J. M. Dalton Trans. 2009, 753-762. (d) Dobereiner, G. E.;
Crabtree, R. H. Chem. Rev. 2010, 110, 681-703. (e) Yamaguchi, R.;
Fujita, K.-i.; Zhu, M. Heterocycles 2010, 81, 1093-1140. (f) Ishii, Y.;
Obora, Y. Synlett 2010, 2011, 30-51. (g) Alonso, F.; Riente, P.; Yus, M.
Acc. Chem. Res. 2011, 44, 379-391. (h) Suzuki, T. Chem. Rev. 2011, 111,
1825-1845. (i) Obora, Y. ACS Catal. 2014, 4, 3972-3981. (j) Shimizu, K.-
I. Catal. Sci. Technol. 2015, 5, 1412-1427. (k) Gunanathan, C.; Milstein,
D. Science 2013, 341, 1229712.
In summary, we introduced a novel sustainable multi-
component pyrimidine synthesis. Alcohols and amidines can
be assembled in 3- or consecutive 4-component reactions.
The selective C-C and C-N bond formations proceed with the
liberation of two equivalents of dihydrogen (acceptor-less
dehydrogenation) and the elimination of water (condensa-
tion). Unsymmetrically and fully substituted pyrimidines are
accessible. The synthesis protocol is especially useful in
forming selectively alkylated and/or arylated pyrimidines.
The synthesis of 4-(4-fluorophenyl)-6-isopropylpyrimidin-2-
amine underlines the applicability of the novel reactions to
the synthesis of important pharmaceuticals. The Ir catalyst
used and the optimized reaction conditions allow the pres-
ence of a wide range of typical organic functional groups.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectroscopic and crystallographic
data. This material is available free of charge via the Internet
at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
(14) Shen, D.; Poole, D. L.; Shotton, C. C.; Kornahrens, A. F.; Healy,
M. P.; Donohoe, T. J. Angew. Chem. Int. Ed. 2015, 54, 1642-1645.
(15) Blank, B.; Kempe, R. J. Am. Chem. Soc. 2010, 132, 924-925.
*kempe@uni-bayreuth.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the Deutsche Forschungsgemeinschaft, DFG, KE
756/23-2, for financial support, Mikhail Butovskii as well as
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