New 5-alkoxypyrimidine derivatives from β-alkoxy β-keto enamides and ammonium salts

Article abstract of DOI:10.1002/ejoc.201000056

A series of highly substituted β-alkoxy β-keto enamides were prepared by a multi-component reaction combining lithiated alkoxyallenes, nitriles and carboxylic acids. Apt conditions were developed for their conversion into 5-alkoxypyrimidine derivatives. This synthesis is highly flexible with respect to the substitution pattern at C-2 and C-4 of the pyrimidine core. The corresponding pyrimidin-5-yl nonaflates allowed subsequent transformations at C-5 by palladium-catalyzed couplings such as Sonogashira and Suzuki reactions. The Sonogashira coupling of a pyrimidinyl alkyne with a pyrid-inyl nonaflate and a subsequent cyclization led to an efficient access to pyrimidinyl-substituted furo[2, 3-c]pyridine deriva-tives. The C-6 methyl group which is present in all of the prepared pyrimidines can easily be converted into formyl, carboxylic or alkynyl moieties which allow the synthesis of additional pyrimidine derivatives.

Full text of DOI:10.1002/ejoc.201000056

FULL PAPER
DOI: 10.1002/ejoc.201000056
New 5-Alkoxypyrimidine Derivatives from β-Alkoxy β-Keto Enamides and
Ammonium Salts
Tilman Lechel[a] and Hans-Ulrich Reissig*[a]
Keywords: Nitrogen heterocycles / Allenes / Enamides / Palladium / Pyrimidines
A series of highly substituted β-alkoxy β-keto enamides were
prepared by a multi-component reaction combining lithiated
alkoxyallenes, nitriles and carboxylic acids. Apt conditions
were developed for their conversion into 5-alkoxypyrimidine
derivatives. This synthesis is highly flexible with respect to
the substitution pattern at C-2 and C-4 of the pyrimidine
core. The corresponding pyrimidin-5-yl nonaflates allowed
subsequent transformations at C-5 by palladium-catalyzed
couplings such as Sonogashira and Suzuki reactions. The
Sonogashira coupling of a pyrimidinyl alkyne with a pyrid-
inyl nonaflate and a subsequent cyclization led to an efficient
access to pyrimidinyl-substituted furo[2,3-c]pyridine deriva-
tives. The C-6 methyl group which is present in all of the
prepared pyrimidines can easily be converted into formyl,
carboxylic or alkynyl moieties which allow the synthesis of
additional pyrimidine derivatives.
Introduction
In recent reports we described the remarkable versatility
of lithiated alkoxyallenes 1 as crucial C3-building blocks for
the synthesis of several classes of heterocycles.[1] As an en-
tirely unexpected result we discovered the three-component
reaction of 1 with nitriles 2 and carboxylic acids 3 to highly
substituted β-alkoxy β-keto enamides 5. The unique mecha-
nism of this transformation has been disclosed in earlier
publications.[2] These enamides 5 have so far served as
highly flexible precursor for the cyclization to heteroarom-
atic compounds such as 3-alkoxypyridinols and their nona-
flates 4 or 5-acetyloxazoles 6 (Scheme 1).[2–3] Moreover,
preliminary results have shown that enamides 5 can also be
employed for the synthesis of highly substituted 5-alkoxy-
pyrimidines 7 when appropriate ammonia sources are
used.[4] Due to the permanent interest in highly substituted
pyrimidine derivatives[5] for applications in medicinal chem-
istry and material science we investigated the preparation
of this class of heterocycles more closely. In this article, we
describe in full detail our efforts aimed at the synthesis of
5-alkoxypyrimidine derivatives 7 by cyclization of β-alkoxy
β-keto enamides 5.[6] We also demonstrate the high flexibil-
ity with respect to the substitution pattern at the pyrimidine
core and show that subsequent functionalizations such as
palladium-catalyzed couplings at C-5 and oxidation reac-
tions of the methyl group at C-6 are easily achieved leading
to a broad range of new pyrimidine derivatives.
Scheme 1. Three-component reaction of lithiated alkoxyallenes 1,
nitriles 2 and carboxylic acids 3 leading to enamides 5 and their
subsequent conversion into highly substituted 3-alkoxy-4-pyridinyl
nonaflates 4, 5-acetyloxazoles 6 and 5-alkoxypyrimidines 7.
Results and Discussion
Three-Component Reaction to Enamides and Investigation
of the Pyrimidine Formation
The required β-alkoxy β-keto enamides were prepared by
the previously described three-component reaction starting
with the lithiation of the corresponding alkoxyallene by n-
butyllithium at –40 °C. Then, the required nitrile was added
at –78 °C, followed by quenching with an excess of the carb-
[a] Institut für Chemie und Biochemie, Freie Universität Berlin
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-55367
E-mail: Hans.Reissig@chemie.fu-berlin.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000056.
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T. Lechel, H.-U. Reissig
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oxylic acid. As depicted in Scheme 2 enamide 5a is a first formed by condensation of the carbonyl group with ammo-
example that has been synthesized from methoxyallene 8, nia, which is then converted by cyclization to intermediate
benzonitrile and benzoic acid in 45% yield.
10 followed by dehydration to the corresponding product 7.
It is likely that all steps are proton catalyzed.
Scheme 2. Synthesis of enamide 5a starting from methoxyallene 8,
benzonitrile and benzoic acid.
Compound 5a was chosen as a model substrate for the
subsequent optimization of the pyrimidine preparation
since the phenyl substituents should not interfere with any
of the involved steps. Two methods A and B with different
ammonia sources have been developed. For the cyclization
of 5a to pyrimidine derivative 7a we first applied modified
conditions as described by Taddei for the synthesis of 2,4-
disubstituted quinazolines (Table 1).[7] Initially, 16 equiv. of
ammonium bicarbonate were necessary for a complete con-
version and different solvents like toluene, 1,2-dichloro-
ethane, water or methanol have been tested (Entries 1–5,
Table 1). In entries 1–4 only traces or low amounts of pyr-
imidine 7a were observed, whereas the use of methanol
strongly increased the efficacy providing a yield of 65%
(Entry 5, method A). A change of the ammonia source to
ammonium acetate (8.0 equiv.) led to a slight increase to
73% (Entry 6, method B). Experiments with ammonium
chloride or microwave reactions to shorten the reaction
time failed to provide the product in good yield (Entries 7–
8).
Scheme 3. Proposed mechanism of the formation of pyrimidines 7
from enamides 5 and ammonia.
Conversion of Enamides into 5-Alkoxypyrimidine
Derivatives – Scope and Limitations
A variety of differently substituted enamides 5 have been
prepared (Table 2) in order to examine the applicability of
methods A and B for the synthesis of pyrimidines. In gene-
ral, enamides 5b–l could be obtained by following the pro-
cedure as briefly described above in fair to good yields. The
three-component reaction allows the use of a vast number
of nitriles (aliphatic, functionalized aliphatic, aromatic or
heteroaromatic) as well as carboxylic acids. The aromatic
and heteroaromatic carboxylic acids had to be dissolved in
diethyl ether, THF or DMF prior addition to the reaction
mixture. With respect to the alkoxyallenes 11, methoxy-,
benzyloxy- or even the acid labile 2-(trimethylsilyl)ethoxy-
substituted allenes were successfully employed in the first
step. In principle, the reaction can be performed either with
2.7 equiv. of allene and 1.0 equiv. of nitrile (method C in
Table 2) or with an excess of nitrile (method D) with com-
parable yields. However, it should be noted that for α-acidic
nitriles only method C furnishes no side products.[2f] In case
of a perfluorinated carboxylic acid such as TFA, pyridinol
derivatives like 12 were isolated as main product (Entry 9).
This subsequent reaction proceeds via a rapid intramolecu-
lar acid catalyzed aldol condensation, which has already
been discussed in detail in our previous publications de-
scribing the route to pyridine derivatives.[2]
Table 1. Optimization of the conversion of enamide 5a into pyrim-
idine derivative 7a.
Entry
Solvent T [°C] Ammonia
7a, % yield
(method)
source
[a]
1
2
3
4
5
6
7
8
PhMe
C2H4Cl2 80
H2O
H2O
MeOH
MeOH
MeOH
MeOH
90
NH4HCO3[a]
6
NH4HCO3[a]
NH4HCO3
NH3 (25%)
traces
traces
26
65 (A)
73 (B)
traces
60% conv.
80
90
65
65
65
60
[a]
NH4HCO3
NH4OAc[b]
NH4Cl[a]
NH4OAc[b,c]
[a] Method A: 16 equiv. of NH4HCO3. [b] Method B: 8.0 equiv.
NH4OAc. [c] Reaction was carried out in a microwave reactor for
5 h.
By means of methods A and B enamides 5b–l were then
cyclized to furnish 5-alkoxypyrimidine derivatives 7b–l in
38–86% yield hence demonstrating the impressive flexibility
The reaction of enamide 5 with an ammonium salt to with respect to substituents at C-2, C-4 and C-5 of the pyr-
pyrimidine derivative 7 is supposed to proceed by the simple imidine core. According to our experience the initial three-
mechanism depicted in Scheme 3. Initially, imine 9 is component reaction to enamides 5 is the bottle neck of the
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New 5-Alkoxypyrimidine Derivatives
Table 2. Synthesis of β-alkoxy β-keto enamides 5b–l starting from alkoxyallenes 11, nitriles and carboxylic acids followed by their conver-
sion into 5-alkoxypyrimidines 7b–l.
Entry
R1
R2
R3
5
% yield (method[a]
)
7
% yield (method[b]
)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Bn
Bn
Me
iPr
cPr
tBu
Ph
Ph
Ph
2-thienyl
tBu
Ph[c]
5b
5c
5d
5e
5f
5g
5h
5i
13 (C)[3b]
53 (D)[3b]
79 (C)[3b]
72 (D)[3b]
43 (C)[3b]
42 (C)
7b
7c
7d
7e
7f
7g
7h
7i
40 (B)
54 (B)
56 (B)
55 (B)
65 (A)
38 (B)
75 (A)
68 (B)
66 (A)
86 (B)
75 (A)
Ph[c]
cPr
CϵCH
2-thienyl[c]
2-Py[d]
Ph[c]
54 (C)[3b]
32 (D)[3b]
14 (D)[e]
36 (D)
2-thienyl[c]
CF3
9
10
11
TMSE
TMSE
TMSE
5j
7j
Ph
2-thienyl
Ph[c]
5k
5l
7k
7l
Ph[c]
74 (C)[3b]
[a] Method C: 2.7 equiv. lithiated alkoxyallene, 1.0 equiv. nitrile, 5.4 equiv. carboxylic acid; Method D: 1.0 equiv. lithiated alkoxyallene,
1.5–3.0 equiv. nitrile, 3.0–6.0 equiv. carboxylic acid. [b] Method A: 16 equiv. NH4HCO3, MeOH, sealed tube, 65 °C, 1 d; Method B:
8.0 equiv. NH4OAc, MeOH, sealed tube, 60–65 °C, 1 d. [c] Dissolved in Et2O or THF. [d] Dissolved in DMF. [e] 28% of pyridinol 12[2f]
was isolated.
two stage preparation of pyrimidines 7, whereas the con- ture of TFA and dichloromethane followed by the nona-
densation with ammonia did never make trouble in one of flation reaction. Without purification of the intermediate
the examples investigated.
product 16 was isolated in 60% yield after two steps. On
The methyl group at C-6, which is present in all pyrimid- the other hand, methyl ether 7c could only be cleaved under
ines synthesized above, could be replaced by other substitu- fairly harsh conditions (Scheme 5). Deprotection with tri-
ents when suitable precursors of γ-substituted alkoxyallenes methylsilyl iodide as reagent and subsequent nonaflation
are employed in the first step of the sequence.[2f] Enamide afforded the desired product 17 in 59% yield after two steps.
13 shows a benzyl group in this position (Scheme 4) and
its cyclization to pyrimidine 14 was achieved in 31% yield
applying method B.
Scheme 4. Cyclization of enamide 13 to 6-benzyl-substituted pyr-
imidine derivative 14.
Synthesis of Pyrimidin-5-yl Nonaflates, Subsequent
Palladium-Catalyzed Coupling Reactions and other
Transformations
Scheme 5. Cleavage and nonaflation of different alkoxypyrimidines
leading to pyrimidin-5-yl nonaflates 16 and 17.
The cleavage of the benzyloxy group at C-5 of compound
7h could be achieved under very mild conditions. The reac-
Alkenyl, aryl and heteroaryl nonaflates have been proven
tion was performed with catalytic amounts of palladium to be excellent substrates in palladium-catalyzed coupling
on charcoal under a hydrogen atmosphere and 5-hydroxy- reactions.[2,8–9] We therefore expected that pyrimidin-5-yl
pyrimidine 15 was obtained in very good yield (Scheme 5). nonaflates will also behave well in C–C couplings. The reac-
The hydroxy group was then easily converted into a nona- tion of 16 with trans-2-styrylboronic acid under Suzuki con-
flate group by use of a suspension of sodium hydride in ditions led to the desired product 18 in moderate yield
THF and nonafluorobutanesulfonyl fluoride (NfF) as rea- whereas the Sonogashira reaction with phenylacetylene as
gent that provided pyrimidin-5-yl nonaflate 16. 2-(Trimeth- coupling partner furnished alkyne 19 in 73% yield
ylsilyl)ethyl protected pyrimidine 7k was subjected to a mix- (Scheme 6).
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T. Lechel, H.-U. Reissig
FULL PAPER
verted 22 into dibromoolefin 25 in 87% yield, whereas the
subsequent (not optimized) n-butyllithium promoted elimi-
nation yielded only 19% of the expected alkyne 26. These
examples clearly demonstrate the potential of compounds 7
to rapidly lead to a variety of other functionalized pyridim-
ine derivatives.
Scheme 6. Palladium-catalyzed couplings. [a] Suzuki reaction condi-
tions: 5 mol-% Pd(OAc)2, 20 mol-% PPh3, 2.0 equiv. K2CO3,
1.2 equiv. trans-2-styrylboronic acid, 70 °C; Sonogashira reaction
conditions: 5 mol-% Pd(OAc)2, 20 mol-% PPh3, 5 mol-% CuI,
DMF, 1.2 equiv. phenylacetylene, 70 °C.
Furo-pyridine derivatives have remarkable photophysical
features[2d,3b] that might be useful for the development of
novel organic light emitting materials or optoelectron-
ics.[10–12] Thus, a three-step method[2d] to a highly substi-
tuted furo[2,3-c]pyridine derivative was achieved by a Sono-
gashira reaction of pyrimidinyl alkyne 7e with pyridinyl
nonaflate 20[2f] as coupling partner (Scheme 7). The depro-
tection of the 2-(trimethylsilyl)ethyl ether function at C-5
and a subsequent treatment with potassium carbonate pro-
vided the cyclized product 21 in good overall yield (71%
after three steps).
Scheme 8. Use of the C-6 methyl group of pyrimidine 7a for func-
tionalizations leading to aldehyde 22, oxime 23, carboxylic acid 24,
dibromoalkene 25, and alkyne 26.
Conclusions
Scheme 7. Three-step conversion of pyrimidine derivative 7e and
pyridinyl nonaflate 20 into the highly substituted furo-pyridine 21.
We demonstrated that enamides of type 5 are ideal sub-
strates for the synthesis of highly substituted 5-alkoxypyr-
imidine derivatives 7. Simple reaction conditions with am-
monia sources allow this transformation with good efficacy
and all compounds 5 examined could be converted into 7.
This new method allows high flexibility with respect to sub-
stituents at C-2, C-4 and C-5 of the pyrimidine core. Con-
version of the alkoxy group at C-5 of the prepared pyrimid-
ine derivatives into nonaflates provided the option to per-
form palladium-catalyzed C–C cross couplings at this posi-
tion. Furthermore, an alkynyl-substituted pyrimidine could
be easily coupled with a pyridin-4-yl nonaflate and cyclized
to a furo-pyridine derivative. Several functionalizations at
C-6 of pyrimidines also show the broad variability at this
position opening further options to many new heterocycles.
It should be noted here that compound 21 nicely demon-
strates the high versatility of alkoxyallenes as C-3 building
blocks for the synthesis of various functionalized heterocy-
cles. In this example two alkoxyallene units are incorpo-
rated into the heterocyclic cores and hence we have high-
lighted the two allene-derived units in Scheme 7 to emphas-
ize this fact.
The methyl group at C-6 of the pyrimidine derivatives
prepared by our route might be regarded as limitation of
the method (for an exception see Scheme 4). However, this
substituent also offers interesting options to install new
functional groups at C-6. As an example, the oxidation of
the methyl group of pyrimidine 7a to a formyl substituent
was smoothly achieved by using the Riley method. An ex-
cess of selenium dioxide as oxidizing agent provided alde-
hyde 22 in very good yield, which was converted under stan-
dard conditions into the corresponding aldoxime 23 as a
singular isomer (Scheme 8). Aldehyde 22 could also be oxi-
dized (Pinnick protocol) to furnish the corresponding carb-
Experimental Section
General Methods: Reactions were generally performed under argon
in flame-dried flasks. Solvents and reagents were added by syringes.
Solvents were dried using standard procedures. Reagents were pur-
oxylic acid 24 in 66% yield. The Corey–Fuchs reaction con- chased and were used as received without further purification un-
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New 5-Alkoxypyrimidine Derivatives
less otherwise stated. Unless otherwise stated, products were puri-
residue was purified by chromatography on silica gel (hexane/ethyl
fied by flash chromatography on silica gel (230–400 mesh, Merck
acetate, 10:1) to afford 2.14 g (36%) of (E)-N-{3-oxo-1-phenyl-2-[2-
or Fluka) or HPLC (Nucleosil 50–5). Unless otherwise stated, (trimethylsilyl)ethoxy]but-1-enyl}benzamide (5k) as a colourless so-
yields refer to analytically pure samples. NMR spectra were re-
corded on Bruker (AC 500) and JOEL (Eclipse 500 and ECX 400)
instruments. Chemical shifts are reported relative to TMS (1H: δ =
0.00 ppm), CDCl3 (1H: δ = 7.25 ppm, 13C: δ = 77.0 ppm). Integrals
are in accordance with assignments; coupling constants are given
in Hz. All 13C-NMR spectra are proton-decoupled. Multiplicity is
indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet),
hept (heptet), m (multiplet), mc (centered multiplet), dd (doublet of
doublet), br. s (broad singlet). For detailed peak assignments 2D
spectra were measured (COSY, HMBC and HMQC). IR spectra
were measured with an FT-IRD spectrometer Nicolet 5 SXC. MS
and HRMS analyses were performed with Finnigan MAT 711 (EI,
80 eV, 8 kV), MAT CH7A (EI, 80 eV, 3 kV), CH5DF (FAB, 3 kV),
Varian Ionspec QFT-7 (ESI-FT ICRMS) and Agilent 6210 (ESI-
TOF) instruments. Elemental analyses were carried out with Per-
kin–Elmer CHN-Analyzer 2400 or Vario EL Elemental Analyzer.
Melting points were measured with a Reichert apparatus Thermo-
var and are uncorrected. The preparations of enamide derivatives
5b–f, 5h–i, 5l,[3b] 13[2f] and pyridinol 12[2f] were published in pre-
vious reports.
lid; m.p. 65 °C. 1H NMR (CDCl3, 400 MHz): δ = –0.15 (s, 9 H,
SiMe3), 0.69 (mc, 2 H, CH2Si), 2.40 (s, 3 H, Me), 3.36 (mc, 2 H,
OCH2), 7.36–7.55, 7.95–7.98 (2m, 8 H, 2 H, Ph), 12.40 (br. s, 1 H,
NH) ppm. 13C NMR (CDCl3, 101 MHz): δ = –1.7 (q, SiMe3), 18.6
(t, CH2Si), 27.5 (q, C-4), 71.5 (t, OCH2), 127.8, 128.4, 128.68,
128.73, 132.3, 132.6, 133.7 (5d, 2s, Ph)*, 137.6, 143.4 (2s, C-1, C-
2), 165.2 (s, C-1ЈЈ), 202.9 (s, C-3) ppm; * overlap of Ph signals. IR
(KBr): ν = 3400 (N–H), 3110–2995 (=C–H), 2960–2895 (C–H),
˜
1730–1580 (C=O, C=C) cm–1. C22H27NO3Si (381.5): calcd. C
69.25, H 7.13, N 3.67; found C 69.05, H 7.08, N 3.69.
(E)-N-{1-tert-Butyl-3-oxo-2-[2-(trimethylsilyl)ethoxy]-1-butenyl}-
2,2,2-trifluoroacetamide (5j): According to typical procedure
(method D), [2-(trimethylsilyl)ethoxy]allene (501 mg, 3.21 mmol) in
Et2O (7.0 mL), n-butyllithium (1.41 mL, 3.53 mmol, 2.5  in hex-
anes), pivalonitrile (1.06 mL, 9.63 mmol) and TFA (1.48 mL,
19.3 mmol) provided the crude product. The residue was purified
by chromatography on silica gel (hexane/ethyl acetate, 10:1) to af-
ford 159 mg (14%) of 5j as a colourless solid and 302 mg (28%) of
2-tert-butyl-6-(trifluoromethyl)-3-[2-(trimethylsilyl)ethoxy]-4-pyrid-
inol (12) as a pale yellow oil. Characterization of enamide 5j: M.p.
147–149 °C. 1H NMR (CDCl3, 500 MHz): δ = 0.04 (s, 9 H, SiMe3),
1.11 (mc, 2 H, CH2Si), 1.23 (s, 9 H, tBu), 2.28 (s, 3 H, Me), 3.67
(mc, 2 H, OCH2), 7.56 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3,
126 MHz): δ = –1.5 (q, SiMe3), 18.7 (t, CH2Si), 27.4 (q, Me), 28.4,
Typical Procedure for the Enamide Synthesis (Method C): Meth-
oxyallene 8 (1.65 mL, 19.8 mmol) was dissolved in Et2O (40 mL)
and n-butyllithium (6.60 mL, 16.5 mmol, 2.5  in hexanes) was
added at –40 °C. After 25 min at –50 to –40 °C the solution was
cooled to –78 °C and benzonitrile (0.61 mL, 5.97 mmol) was added.
After stirring for 4 h at this temperature picolinic acid (4.80 g,
39.0 mmol, dissolved in 20 mL of DMF) was added and the mix-
ture was warmed up to room temperature overnight. The reaction
mixture was quenched with satd. aq. NaHCO3 solution (60 mL)
and extracted with Et2O (3ϫ50 mL). The combined organic phases
were dried with Na2SO4 and then evaporated. The residue was
purified by chromatography on silica gel (hexane/ethyl acetate, 2:1)
to afford 743 mg (42%) of (E)-N-(2-methoxy-3-oxo-1-phenylbut-1-
enyl)picolinamide (5g) as a colourless solid; m.p. 139–140 °C. 1H
NMR (CDCl3, 500 MHz): δ = 2.40 (s, 3 H, CH3), 3.22 (s, 3 H,
OMe), 7.40–7.43, 7.49–7.79 (m, 5 H, Ph), 7.44 (ddd, J = 7.6, 4.8,
1.1 Hz, 1 H, 5Ј-H), 7.79 (td, J = 7.8, 1.6 Hz, 1 H, 4Ј-H), 8.04 (dt,
J = 7.8, 0.7 Hz, 1 H, 3Ј-H), 8.74 (ddd, J = 4.8, 1.6, 1.1 Hz, 1 H,
6Ј-H), 10.03 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3, 126 MHz):
δ = 27.5 (q, Me), 60.7 (q, OMe), 123.0, 126.7 (2d, C-3Ј, C-5Ј),
128.0, 128.5, 128.9, 132.6 (3d, s, Ph), 137.4 (s, C-1), 139.6 (d, C-
4Ј), 141.1, (s, C-2), 148.7 (d, C-6Ј), 149.9 (s, C-2Ј), 163.3 (s, C-1ЈЈ),
1
26.3 (q, s, tBu) 69.9 (t, OCH2), 115.9 (q, JCF = 288 Hz, CF3),
2
129.1, 151.2 (2s, C-1, C-2), 156.7 (q, JCF = 36.5 Hz, C-1Ј), 200.7
(s, C-3) ppm. IR (KBr): ν = 3280 (N–H), 3050–2880 (C–H), 1725–
˜
1630 (C=O, C=C) cm–1. C15H26F3NO3Si (353.5): calcd. C 50.97,
H 7.41, N 3.96; found C 51.02, H 7.31, N 3.87.
Characterization of 12 has been reported previously.[2f]
Typical Procedure for the Pyrimidine Synthesis (Method A): En-
amide 5f (211 mg, 0.700 mmol) and NH4HCO3 (885 mg,
11.2 mmol) were placed in an ACE-sealed tube. The mixture was
dissolved in MeOH (7.0 mL) and stirred for 1 d at 65 °C. After
addition of water and CH2Cl2 (7 mL) the layers were separated and
the aqueous layer was extracted twice with CH2Cl2 (7 mL). The
combined organic layers were dried with Na2SO4, filtered and con-
centrated. Column chromatography (silica gel, hexane/ethyl acetate
= 10:1) provided 129 mg (65%) 5-methoxy-4-methyl-6-phenyl-2-
1
(thiophen-2-yl)pyrimidine (7f) as a colourless solid; m.p. 39 °C. H
NMR (CDCl3, 500 MHz): δ = 2.59 (s, 3 H, Me), 3.54 (s, 3 H,
OMe), 7.12 (dd, J = 5.0, 3.7 Hz, 1 H, 4Ј-H), 7.45–7.52, 8.15–8.17
(2 m, 3 H, 2 H, Ph), 7.42 (dd, J = 5.0, 1.3 Hz, 1 H, 3Ј-H), 7.77 (dd,
J = 3.7, 1.3 Hz, 1 H, 5Ј-H) ppm. 13C NMR (CDCl3, 101 MHz): δ
= 19.1 (q, Me), 60.3 (q, OMe), 128.0, 128.2, 128.5, 129.0, 129.2,
130.0, 135.6 (6d, s, Ph, C-3Ј, C-4Ј, C-5Ј), 143.5 (s, C-2Ј), 148.9 (s,
201.5 (s, C-3) ppm. IR (KBr): ν = 3460 (N–H), 3060–2030 (=C–
˜
H), 2930–2830 (C–H), 1700–1580 (C=O, C=C) cm–1. MS (EI): m/z
(%) = 296 (10) [M]+, 253 (100) [M – C2H3O]+, 107 (23)
[C6H6NO]+, 78 (48) [C5H5N]+, 43 (29) [C2H3O]+. HRMS (EI):
calcd. for C17H16N2O3: 296.1161; found 296.1153. C17H16N2O3
(296.3): calcd. C 68.91, H 5.44, N 9.45; found C 69.00, H 4.95, N
9.69.
C-5), 156.18, 156.20, 162.4 (3s, C-2, C-4, C-6) ppm. IR (KBr): ν =
˜
3095–3025 (=C–H), 3000–2845 (C–H), 1715–1580 (C=C, C=N)
cm–1. C16H14N2OS (282.4): calcd. C 68.06, H 5.00, N 9.92; found
C 68.02, H 4.91, N 9.87.
Typical Procedure for the Enamide Synthesis (Method D): [2-(Tri-
methylsilyl)ethoxy]allene (2.45 g, 15.7 mmol) was dissolved in Et2O
(32 mL) and n-butyllithium (6.91 mL, 17.3 mmol, 2.5  in hexanes)
was added at –40 °C. After 25 min at –50 to –40 °C the solution
was cooled to –78 °C and benzonitrile (2.40 mL, 23.6 mmol) was
added. After stirring for 4 h at this temperature benzoic acid
Typical Procedure for the Pyrimidine Synthesis (Method B): En-
amide 5k (350 mg, 0.917 mmol) and NH4OAc (566 mg, 7.34 mmol)
were placed in an ACE-sealed tube. The mixture was dissolved in
MeOH (5.0 mL) and stirred for 1 d at 65 °C. After addition of
(5.74 g, 47.1 mmol, dissolved in 15 mL of Et2O) was added and the water and CH2Cl2 (5 mL) the layers were separated and the aque-
mixture was warmed up overnight to room temperature. Then the
reaction mixture was quenched with satd. aq. NaHCO3 solution
(30 mL) and extracted with Et2O (3ϫ25 mL). The combined or-
ganic phases were dried with Na2SO4 and then evaporated. The
ous layer was extracted twice with CH2Cl2 (5 mL). The combined
organic layers were dried with Na2SO4, filtered and concentrated.
Column chromatography (silica gel, hexane/ethyl acetate = 10:1)
provided 285 mg (86%) 4-methyl-2,6-diphenyl-5-[2-(trimethylsilyl)-
Eur. J. Org. Chem. 2010, 2555–2564
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2559

T. Lechel, H.-U. Reissig
ethoxy]pyrimidine (7k) as a colourless oil. 1H NMR (CDCl3, ppm. IR (film): ν = 3050–2830 (C–H), 1720–1560 (C=C, C=N)
FULL PAPER
˜
500 MHz): δ = –0.08 (s, 9 H, SiMe3), 1.04 (mc, 2 H, CH2Si), 2.64
cm–1. HRMS (ESI-TOF): calcd. for C12H17N2O [M + H]+:
(s, 3 H, Me), 3.70 (mc, 2 H, OCH2), 7.41–7.53, 8.16–8.19, 8.47– 205.1335; found 205.1351.
8.50 (3m, 10 H, Ph) ppm. 13C NMR (CDCl3, 101 MHz): δ = –1.6
(q, SiMe3), 18.9 (t, CH2Si), 19.6 (q, Me), 71.1 (t, OCH2), 128.0,
128.3, 128.4, 129.1, 129.77, 129.84, 136.4, 137.8 (6d, 2s, Ph), 148.2
4-tert-Butyl-2-ethynyl-5-methoxy-6-methylpyrimidine (7e): Accord-
ing to typical procedure (method B), enamide 5e (600 mg,
2.69 mmol) and NH4OAc (1.66 g, 21.5 mmol) in MeOH (6.0 mL)
provided the crude product. The residue was purified by
chromatography on silica gel (hexane/ethyl acetate, 10:1) to afford
302 mg (55%) of 7e as a colourless solid; m.p. 103 °C. 1H NMR
(CDCl3, 500 MHz): δ = 1.37 (s, 9 H, tBu), 2.48 (s, 3 H, Me), 2.98
(s, 1 H, ϵC-H), 3.78 (s, 3 H, OMe) ppm. 13C NMR (CDCl3,
126 MHz): δ = 9.7 (q, Me), 29.0, 37.9 (q, s, tBu), 61.1 (q, OMe),
(s, C-5), 156.6, 158.7, 162.4 (3s, C-2, C-4, C-6) ppm. IR (film): ν =
˜
3090–2870 (=C–H, C–H), 1680–1540 (C=C, C=N) cm–1.
C22H26N2OSi (362.5): calcd. C 72.88, H 7.23, N 7.73; found C
72.63, H 7.12, N 7.78.
5-Methoxy-4-methyl-2,6-diphenylpyrimidine (7a): According to typ-
ical procedure (method B), enamide 5a (1.17 g, 3.97 mmol) and
NH4OAc (2.45 g, 31.8 mmol) in MeOH (5.0 mL) provided the 73.6, 82.3 (s, d, CϵC), 144.9 (s, C-2), 152.0 (s, C-5), 160.7 (s, C-6),
crude product. The residue was purified by chromatography on sil-
169.0 (s, C-4) ppm. IR (KBr): ν = 3190 (ϵC–H), 3020–2860 (C–
˜
ica gel (hexane/ethyl acetate, 12:1) to afford 795 mg (73%) of 7a as
H), 2110 (CϵC), 1545–1525 (C=C, C=N) cm–1. C12H16N2O
(204.3): calcd. C 70.56, H 7.90, N 13.71; found C 70.38, H 7.96, N
13.63.
1
a colourless solid; m.p. 91–92 °C. H NMR (CDCl3, 500 MHz): δ
= 2.64 (s, 3 H, Me), 3.57 (s, 3 H, OMe), 7.41–7.53, 8.18–8.21, 8.46–
8.50 (3m, 6 H, 2 H, 2 H, Ph) ppm. 13C NMR (CDCl3, 101 MHz):
δ = 19.3 (q, Me), 60.3 (q, OMe), 128.1, 128.4, 128.5, 129.2, 129.9,
136.1, 137.8 (5d, 2s, Ph)*, 149.4 (s, C-5), 156.2, 159.0, 162.2 (3s, C-
5-Methoxy-4-methyl-6-phenyl-2-(pyridin-2-yl)pyrimidine (7 g): Ac-
cording to typical procedure (method B), enamide 5g (175 mg,
0.591 mmol) and NH4OAc (729 mg, 9.46 mmol) in MeOH
(3.0 mL) provided the crude product. The residue was purified by
chromatography on silica gel (hexane/ethyl acetate, 2:1) to afford
62 mg (38%) of 7g as a colourless solid; m.p. 101 °C. 1H NMR
(CDCl3, 500 MHz): δ = 2.69 (s, 3 H, Me), 3.55 (s, 3 H, OMe), 7.31
(ddt, J = 7.4, 4.9, 0.5 Hz, 1 H, 5Ј-H), 7.43–7.49, 8.14–8.16 (2m, 3
H, 2 H, Ph), 7.79 (tdd, J = 7.4, 1.8, 0.5 Hz, 1 H, 4Ј-H), 8.52 (dt, J
2, C-4, C-6) ppm; * overlap of Ph signals. IR (KBr): ν = 3090–3010
˜
(=C–H), 2900–2800 (C–H), 1640–1545 (C=C, C=N) cm–1. HRMS
(ESI-TOF): calcd. for C18H17N2O [M + H]+: 277.1335; found
277.1315.
5-Methoxy-4,6-dimethyl-2-phenylpyrimidine (7b): According to typ-
ical procedure (method B), enamide 5b (80 mg, 0.343 mmol) and
NH4OAc (423 mg, 5.49 mmol) in MeOH (2.0 mL) provided the = 7.4, 1.8 Hz, 1 H, 3Ј-H), 8.80 (dt, J = 4.9, 0.5 Hz, 1 H, 6Ј-H) ppm.
crude product. The residue was purified by chromatography on sil-
ica gel (hexane/ethyl acetate, 10:1) to afford 29 mg (40%) of 7b as
a colourless solid; m.p. 53 °C. 1H NMR (CDCl3, 500 MHz): δ =
2.54 (s, 6 H, Me), 3.78 (s, 3 H, OMe), 7.39–7.46, 8.33–8.36 (2m, 3
13C NMR (CDCl3, 101 MHz): δ = 19.4 (q, Me), 60.2 (q, OMe),
123.5 (d, C-5Ј), 124.1 (d, C-3Ј), 128.4, 129.1, 130.0, 135.6 (3d, s,
Ph), 136.6 (d, C-4Ј), 149.9 (d, C-6Ј), 150.3 (s, C-5), 154.9 (s, C-2Ј),
156.4, 158.0, 163.1 (3s, C-2, C-4, C-6) ppm. IR (KBr): ν = 3090–
˜
H, 2 H, Ph) ppm. 13C NMR (CDCl3, 101 MHz): δ = 19.0 (q, Me), 3005 (=C–H), 2945–2850 (C–H), 1595–1545 (C=C, C=N) cm–1.
60.4 (q, OMe), 127.9, 128.4, 130.0, 137.7 (3d, s, Ph), 150.1 (s, C-
C17H15N3O (277.3): calcd. C 73.63, H 5.45, N 15.15; found C
2), 159.0, 159.8 (2s, C-5, C-4) ppm. IR (KBr): ν = 3065–2765 (=C– 73.30, H 5.56, N 14.94.
˜
H, C–H), 1625–1555 (C=C, C=N) cm–1. HRMS (ESI-TOF): calcd.
5-(Benzyloxy)-4-methyl-2,6-diphenylpyrimidine (7h): According to
for C13H15N2O [M + H]+: 215.1179; found 215.1182. C13H14N2O
(214.3): calcd. C 72.87, H 6.59, N 13.07; found C 72.75, H 6.51, N
12.61.
typical procedure (method A), enamide 5h (210 mg, 0.565 mmol)
and NH4HCO3 (536 mg, 6.78 mmol) in MeOH (6.0 mL) provided
the crude product. The residue was purified by chromatography on
4-Isopropyl-5-methoxy-6-methyl-2-phenylpyrimidine (7c): According silica gel (hexane/ethyl acetate, 10:1) to afford 149 mg (75%) of 7h
1
to typical procedure (method B), enamide 5c (100 mg, 0.383 mmol)
and NH4OAc (471 mg, 6.12 mmol) in MeOH (2.0 mL) provided
the crude product. The residue was purified by chromatography on
as a colourless oil. H NMR (CDCl3, 500 MHz): δ = 2.58 (s, 3 H,
Me), 4.62 (s, 2 H, CH2Ph), 7.23–7.55, 8.19–8.22, 8.49–8.52 (3m, 11
H, 2 H, 2 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 19.6 (q,
silica gel (hexane/ethyl acetate, 10:1) to afford 50 mg (54%) of 7c Me), 75.0 (t, CH2Ph), 128.11, 128.13, 128.39, 128.44, 128.5, 129.3,
1
as a colourless oil. H NMR (CDCl3, 400 MHz): δ = 1.32 (d, J = 130.0, 136.1, 137.7 (6d, 3s, Ph)*, 147.9 (s, C-5), 156.8, 159.1, 162.6
6.8 Hz, 6 H, iPr), 2.55 (s, 3 H, Me), 3.43 (hept, J = 6.8 Hz, 1 H,
(3s, C-2, C-4, C-6) ppm; * overlap of Ph signals. IR (film): ν =
˜
iPr), 3.78 (s, 3 H, OMe), 7.39–7.47, 8.40–8.44 (2m, 3 H, 2 H, Ph) 3090–3030 (=C–H), 2955–2845 (C–H), 1720–1550 (C=C, C=N)
ppm. 13C NMR (CDCl3, 101 MHz): δ = 19.2 (q, Me), 21.6, 28.7
(q, d, iPr), 61.3 (q, OMe), 128.0, 128.3, 129.7, 138.1 (3d, s, Ph),
148.7 (s, C-5), 159.0, 159.9, 167.4 (3s, C-2, C-4, C-6) ppm. IR
cm–1. HRMS (ESI-TOF): calcd. for C24H21N2O [M + H]+:
353.1648; found 353.1665.
5-(Benzyloxy)-4-methyl-2,6-bis(thiophen-2-yl)pyrimidine (7i): Ac-
cording to typical procedure (method B), enamide 5i (100 mg,
0.261 mmol) and NH4OAc (322 mg, 4.18 mmol) in MeOH
(2.0 mL) provided the crude product. The residue was purified by
(film): ν = 3095–3850 (=C–H, C–H), 1590–1550 (C=C, C=N) cm–1.
˜
HRMS (ESI-TOF): calcd. for C15H19N2O [M + H]+: 243.1492;
found 243.1506.
2,4-Dicyclopropyl-5-methoxy-6-methylpyrimidine (7d): According to chromatography on silica gel (hexane/ethyl acetate, 10:1) to afford
typical procedure (method B), enamide 5d (450 mg, 2.02 mmol)
and NH4OAc (1.25 mg, 16.2 mmol) in MeOH (8.0 mL) provided
the crude product. The residue was purified by chromatography on
65 mg (68%) of 7i as a colourless oil. 1H NMR (CDCl3, 500 MHz):
δ = 2.53 (s, 3 H, Me), 4.90 (s, 2 H, CH2Ph), 7.13, 7.15 (2dd, J =
5.0, 3.7 Hz, 1 H each, 4Ј-H, 4ЈЈ-H), 7.37–7.48 (m, 5 H, Ph), 7.44,
silica gel (hexane/ethyl acetate, 10:1) to afford 232 mg (56%) of 7d 7.54 (2dd, J = 5.0, 1.0 Hz, 1 H each, 3Ј-H, 3ЈЈ-H), 7.98, 8.15 (2dd,
as a colourless oil. 1H NMR (CDCl3, 500 MHz): δ = 0.82–1.09 (m, J = 3.7, 1.0 Hz, 1 H each, 5Ј-H, 5ЈЈ-H) ppm. 13C NMR (CDCl3,
8 H, cPr), 2.03 (mc, 1 H, cPr), 2.25 (mc, 1 H, cPr), 2.38 (s, 3 H,
Me), 3.74 (s, 3 H, OMe) ppm. 13C NMR (CDCl3, 126 MHz): δ =
101 MHz): δ = 19.4 (q, Me), 76.7 (t, CH2Ph), 128.1, 128.2, 128.4,
128.5, 128.7, 129.2, 130.5, 130.7, 136.1 (9d, s, C-3Ј, C-4Ј, C-5Ј, C-
9.8, 10.1 (2t, cPr), 10.3 (d, cPr), 17.4 (d, cPr), 18.4 (q, Me), 60.9 3ЈЈ, C-4ЈЈ, C-5ЈЈ, Ph)*, 139.1, 143.2, (2s, C-2Ј, C-2ЈЈ), 144.9 (s, C-
(q, OMe), 148.8 (s, C-5), 157.8, 163.2, 165.7 (3s, C-6, C-2, C-4) 5), 151.2 (s, C-6), 156.1, 162.6 (2s, C-2, C-4) ppm; * overlap of Ph
2560
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2555–2564

New 5-Alkoxypyrimidine Derivatives
signals. IR (film): ν = 3090–3030 (=C–H), 3000–2865 (C–H), 1710– 1605–1550 (C=C, C=N) cm–1. HRMS (ESI-TOF): calcd. for
˜
1610 (C=C, C=N) cm–1. HRMS (ESI-TOF): calcd. for C17H15N2O [M + H]+: 263.1179; found 263.1184.
C20H17N2OS2 [M + H]+: 365.0777; found 365.0796.
4-Methyl-2,6-diphenylpyrimidin-5-yl Nonaflate (16): Pyrimidine 15
was dissolved in THF (5.0 mL) and NaH (87 mg, 2.17 mmol) was
added. After 5 min NfF (0.39 mL, 2.36 mmol) was added and the
reaction mixture was stirred overnight at room temperature. After
4-tert-Butyl-6-methyl-2-(trifluoromethyl)-5-[2-(trimethylsilyl)ethoxy]-
pyrimidine (7j): According to typical procedure (method A), en-
amide 5j (156 mg, 0.441 mmol) and NH4HCO3 (558 mg,
slow addition of water and ethyl acetate (5 mL) the layers were
7.06 mmol) in MeOH (4.0 mL) provided the crude product. The
separated and the aqueous layer was extracted with EtOAc
residue was purified by chromatography on silica gel (hexane/ethyl
(2ϫ8 mL). The combined organic layers were dried with Na2SO4,
acetate, 20:1) to afford 97 mg (66%) of 7j as a colourless oil. 1H
filtered and concentrated. Column chromatography (silica gel, hex-
NMR (CDCl3, 500 MHz): δ = 0.06 (s, 9 H, SiMe3), 1.25 (mc, 2 H,
ane/ethyl acetate = 40:1) provided 260 mg (66%) of 16 as a colour-
CH2Si), 1.40 (s, 9 H, tBu), 2.54 (s, 3 H, Me), 3.92 (mc, 2 H, OCH2)
1
less oil. H NMR (CDCl3, 500 MHz): δ = 2.77 (s, 3 H, Me), 7.49–
ppm. 13C NMR (CDCl3, 101 MHz): δ = –1.5 (q, SiMe3), 18.6 (t,
7.56, 7.89–7.91, 8.52–8.55 (3m, 10 H, Ph) ppm. 13C NMR (CDCl3,
CH2Si), 20.0 (q, Me), 29.0, 38.3 (q, s, tBu), 71.8 (t, OCH2), 119.8
101 MHz): δ = 20.5 (q, Me), 128.56, 128.58, 128.7, 129.5, 130.8,
(q, 1JCF = 276 Hz, CF3), 152.4 (s, C-5), 149.2 (q, 2JCF = 36.1 Hz, C-
129.9, 134.3, 136.3 (6d, 2s, Ph), 140.7 (s, C-5), 159.0, 162.0, 162.3
2), 161.9, 169.7 (2s, C-4, C-6) ppm. 19F NMR (CDCl3, 470 MHz): δ
(3s, C-2, C-4, C-6) ppm. 19F NMR (CDCl3, 470 MHz): δ = –80.6,
= –69.4 (s, CF ) ppm. IR (film): ν = 2960–2870 (C–H), 1740–1570
˜
3
–109.8, –120.6, –125.8 (4 m , ONf) ppm. IR (film): ν = 3095–2855
˜
c
(C=C, C=N) cm–1. HRMS (ESI-TOF): calcd. for C15H26F3N2OSi
(=C–H, C–H), 1605–1560 (C=C, C=N) cm–1. HRMS (ESI-TOF):
calcd. for C21H14F9N2O3S [M + H]+: 545.0576; found 545.0607.
C21H13F9N2O3S (544.4): calcd. C 46.33, H 2.41, N 5.15; found C
46.93, H 2.18, N 5.06.
[M + H]+: 335.1761; found 335.1772.
4-Methyl-2-phenyl-6-(thiophen-2-yl)-5-[2-(trimethylsilyl)ethoxy]pyr-
imidine (7l): According to typical procedure (method A), enamide
5l (200 mg, 0.511 mmol) and NH4HCO3 (333 mg, 4.22 mmol) in
MeOH (4.0 mL) provided the crude product. The residue was puri-
fied by chromatography on silica gel (hexane/ethyl acetate, 8:1) to
afford 141 mg (75%) of 7l as a colourless oil. 1H NMR (CDCl3,
500 MHz): δ = 0.06 (s, 9 H, SiMe3), 1.31 (mc, 2 H, CH2Si), 2.62 (s,
3 H, Me), 3.99 (mc, 2 H, OCH2), 7.20 (dd, J = 5.1, 3.7 Hz, 1 H,
4Ј-H), 7.55 (dd, J = 5.1, 1.1 Hz, 1 H, 5Ј-H), 8.23 (dd, J = 3.7,
1.1 Hz, 1 H, 3Ј-H), 7.43–7.52, 8.48–8.51 (2m, 3 H, 2 H, Ph) ppm.
13C NMR (CDCl3, 101 MHz): δ = –1.5 (q, SiMe3), 19.2 (t, CH2Si),
19.6 (q, Me), 70.9 (t, OCH2), 127.97, 128.0, 128.4, 129.9, 130.08,
130.12, 137.5 (6d, s, Ph, C-3Ј, C-4Ј, C-5Ј), 139.7 (s, C-2Ј), 145.5 (s,
Synthesis of 4-Methyl-2,6-diphenylpyrimidin-5-yl Nonaflate (16)
Starting from 7k: Pyrimidine 7k (285 mg, 0.786 mmol) was dis-
solved in a 1:2 mixture of TFA and CH2Cl2 (3.0 mL) and stirred
for 30 min at room temperature. After addition of water and
CH2Cl2 (5 mL) the layers were separated and the aqueous layer
was extracted twice with CH2Cl2 (8 mL). The combined organic
layers were dried with Na2SO4, filtered and concentrated. The
crude product was dissolved in THF (5.0 mL) and NaH (94 mg,
2.36 mmol) was added. After 5 min NfF (0.42 mL, 2.36 mmol) was
added and the reaction mixture was stirred overnight at room tem-
perature. After slow addition of water and ethyl acetate (5 mL) the
layers were separated and the aqueous layer was extracted with
ethyl acetate (2ϫ8 mL). The combined organic layers were dried
with Na2SO4, filtered and concentrated. Column chromatography
(silica gel, hexane/ethyl acetate = 40:1) provided 257 mg (60%) of
16.
C-5), 151.1 (s, C-6), 158.6 (s, C-2), 162.2 (s, C-4) ppm. IR (film): ν
˜
= 3090–3030 (=C–H), 2955–2895 (C–H), 1590–1545 (C=C, C=N)
cm–1. C20H24N2OSSi (368.6): calcd. C 65.17, H 6.56, N 7.60; found
C 64.95, H 6.84, N 7.42.
4-Benzyl-6-tert-butyl-5-methoxy-2-(trifluoromethyl)pyrimidine (14):
According to typical procedure (method B), enamide 13 (442 mg,
1.29 mmol) and NH4OAc (794 mg, 10.3 mmol) in MeOH (6.0 mL)
provided the crude product. The residue was purified by
chromatography on silica gel (hexane/ethyl acetate, 10:1) to afford
128 mg (31%) of 14 as a colourless oil. 1H NMR (CDCl3,
500 MHz): δ = 1.41 (s, 9 H, tBu), 3.78 (s, 3 H, OMe), 4.22 (s, 2 H,
CH2Ph), 7.20–7.33 (m, 5 H, Ph) ppm. 13C NMR (CDCl3,
101 MHz): δ = 29.0, 38.5 (q, s, tBu), 38.3 (t, CH2Ph), 62.7 (q,
Synthesis of 4-Isopropyl-6-methyl-2-phenylpyrimidin-5-yl Nonaflate
(17) Starting from 7c: Pyrimidine 7c (200 mg, 0.825 mmol) and tri-
methylsilyl iodide (2.4 mL, 2.40 mmol, 1  in CH2Cl2) were placed
in an ACE-sealed tube. The mixture was dissolved in 1,2-dichloro-
ethane (4.0 mL) and stirred for 1 d at 80 °C. The mixture was al-
lowed to cool to room temperature, diluted with satd. aq. Na2S2O3
solution (8 mL) and extracted with CH2Cl2 (3ϫ8 mL). The com-
bined organic layers were dried with Na2SO4, filtered and concen-
trated. The crude product was dissolved in THF (10 mL) and NaH
(99 mg, 2.48 mmol) was added. After 5 min NfF (0.45 mL,
2.48 mmol) was added and the reaction mixture was stirred over-
night at room temperature. After slow addition of water and ethyl
acetate (10 mL) the layers were separated and the aqueous layer
was extracted twice with ethyl acetate (10 mL). The combined or-
ganic phases were dried with Na2SO4 and concentrated to dryness.
The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate = 10:1) to give 249 mg (59%) of 17 as a
colourless oil. 1H NMR (CDCl3, 400 MHz): δ = 1.35 (d, J =
6.7 Hz, 6 H, iPr), 2.65 (s, 3 H, Me), 3.44 (hept, J = 6.7 Hz, 1 H,
iPr), 7.47–7.49, 8.46–8.48 (2m, 3 H, 2 H, Ph) ppm. 13C NMR
(CDCl3, 101 MHz): δ = 20.4, 21.3 (q, d, iPr), 29.6 (q, Me), 128.5,
128.6, 131.0, 136.6 (3d, s, Ph), 139.7 (s, C-5), 160.6, 162.4, 168.1
1
OMe), 119.8 (q, JCF = 276 Hz, CF3), 126.8, 128.6, 129.8, 137.1
2
(3d, s, Ph), 149.7 (q, JCF = 36.2 Hz, C-2), 153.3, (s, C-4), 163.2 (s,
C-5), 170.8 (s, C-6) ppm. 19F NMR (CDCl3, 470 MHz): δ = –69.4
(s, CF ) ppm. IR (film): ν = 3110–2870 (=C–H, C–H), 1605–1560
˜
3
(C=C, C=N) cm–1. C17H19F3N2O (324.3): calcd. C 62.95, H 5.90,
N 8.64; found C 63.32, H 5.99, N 8.48.
4-Methyl-2,6-diphenylpyrimidin-5-ol (15): A mixture of pyrimidine
7h (212 mg, 0.602 mmol) and palladium (61 mg, 10% on charcoal)
in MeOH (2.0 mL) was stirred for one day under an atmosphere
of hydrogen. Filtration of the reaction mixture through celite with
MeOH afforded 145 mg (92%) of 15 as a colourless solid; m.p.
1
142–144 °C. H NMR (CDCl3, 500 MHz): δ = 2.60 (s, 3 H, Me),
5.44 (br. s, 1 H, OH), 7.38–7.56, 7.84–7.87, 8.38–8.41 (3m, 6 H, 2
H, 2 H, Ph) ppm. 13C NMR (CDCl3, 101 MHz): δ = 19.1 (q, Me), (3s, C-2, C-4, C-6) ppm. 19F NMR (CDCl3, 470 MHz): δ = –80.4,
127.7, 128.4, 128.6, 129.3, 129.5, 129.9, 135.0, 137.8 (6d, 2s, Ph),
144.4 (s, C-5), 150.1, 155.5, 156.8 (3s, C-2, C-4, C-6) ppm. IR
–108.9, –120.4, –125.6 (4 m , ONf) ppm. IR (film): ν = 3005–2880
˜
c
(C–H), 1610–1580 (C=C, C=N) cm–1. C18H15F9N2O3S (510.4):
(KBr): ν = 3170 (O–H), 3090–3030 (=C–H), 2965–2900 (C–H),
calcd. C 42.36, H 2.96, N 5.49; found C 42.84, H 3.12, N 5.53.
˜
Eur. J. Org. Chem. 2010, 2555–2564
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2561

T. Lechel, H.-U. Reissig
Suzuki Coupling of Pyrimidinyl Nonaflate 16 to (E)-4-Methyl-2,6- 1H NMR (CDCl3, 500 MHz): δ = 1.47, 1.62 (2s, 9 H each, tBu),
FULL PAPER
diphenyl-5-styrylpyrimidine (18): A mixture of pyrimidinyl nona-
flate 16 (190 mg, 0.349 mmol), Pd(OAc)2 (3.8 mg, 0.017 mmol),
2.60 (s, 3 H, Me), 3.84 (s, 3 H, OMe), 7.54 (s, 1 H, 3-H), 7.82 (s, 1
H, 4-H) ppm. 13C NMR (CDCl3, 126 MHz): δ = 20.0 (q, Me),
PPh3 (18 mg, 0.070 mmol), K2CO3 (96 mg, 0.689 mmol), trans-2- 28.8, 29.0, 37.7, 38.2 (2q, 2s, tBu), 61.1 (q, OMe), 106.4 (d, C-3),
styrylboronic acid (67 mg, 0.454 mmol) in DMF (1.5 mL) was
heated to 70 °C for 2 h under an argon atmosphere. The mixture
was allowed to cool to room temperature, diluted with brine (5 mL)
112.3 (dq, 3JCF = 3.0 Hz, C-4), 122.3 (q, 1JCF = 273 Hz, CF3), 135.5
2
(s, C-2), 140.0 (q, JCF = 34.0 Hz, C-5), 150.3 (s, C-2Ј), 151.0 (q,
4JCF = 1.0 Hz, C-3a), 151.8 (s, C-5Ј), 154.6, 157.0 (2s, C-7, C-7a),
and extracted with Et2O (3ϫ5 mL). The combined organic phases 161.1 (s, C-6Ј), 168.7 (s, C-4Ј) ppm. 19F NMR (CDCl3, 470 MHz):
were dried with Na2SO4 and concentrated to dryness. The residue
was purified by column chromatography on silica gel (hexane/ethyl
acetate = 20:1) to give 57 mg (47%) of 18 as a colourless solid;
m.p. 91–93 °C. 1H NMR (CDCl3, 500 MHz): δ = 2.79 (s, 3 H, Me),
6.68 (d, J = 16.7 Hz, 1 H, C=CH), 7.03 (d, J = 16.7 Hz, 1 H,
C=CH), 7.27–7.51, 7.78–7.80, 8.53–8.56 (3m, 11 H, 2 H, 2 H, Ph)
ppm. 13C NMR (CDCl3, 101 MHz): δ = 24.3 (q, Me), 123.6 (d,
C=CH), 126.0 (s, C-5), 126.4, 128.1, 128.16, 128.2, 128.4, 128.8,
129.2, 130.0, 130.4, 136.9, 137.8, 138.9 (9d, 3s, Ph), 135.8 (d,
δ = –67.1 (s, CF ) ppm. IR (KBr): ν = 2965–2870 (=C–H, C–H),
˜
3
1605–1540 (C=C) cm–1. C22H26F3N3O2 (421.5): calcd. C 62.70, H
6.22, N 9.97; found C 62.69, H 6.19, N 9.90.
Oxidation of 7a to 5-Methoxy-2,6-diphenylpyrimidine-4-carbal-
dehyde (22): Pyrimidine 7a (800 mg, 2.90 mmol) and SeO2 (995 mg,
8.97 mmol) were placed in an ACE-sealed tube. The mixture was
dissolved in 1,4-dioxane (22 mL) and stirred for 2 d at 80 °C. The
mixture was allowed to cool to room temperature, diluted with
satd. aq. NaHCO3 solution (20 mL) and extracted with ethyl ace-
tate (3ϫ20 mL). The combined organic phases were dried with
Na2SO4 and concentrated to dryness. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate = 6:1)
to give 760 mg (90%) of 22 as a colourless solid; m.p. 98 °C. 1H
NMR (CDCl3, 500 MHz): δ = 3.76 (s, 3 H, OMe), 7.48–7.56, 8.22–
8.24, 8.54–8.56 (3m, 6 H, 2 H, 2 H, Ph), 10.32 (s, 1 H, CHO) ppm.
13C NMR (CDCl3, 101 MHz): δ = 62.6 (q, OMe), 128.2, 128.6,
129.5, 130.7, 130.8, 134.9, 136.5 (5d, 2s, Ph)*, 150.4, 150.7 (2s, C-
5, C-4), 159.7, 161.3 (2s, C-2, C-6), 191.5 (d, CHO) ppm; * overlap
C=CH), 161.5, 163.9, 165.5 (3s, C-2, C-4, C-6) ppm. IR (KBr): ν
˜
= 3100–3025 (=C–H), 2995–2845 (C–H), 1695–1580 (C=C, C=N)
cm–1. HRMS (ESI-TOF): calcd. for C25H21N2 [M + H]+: 349.1699;
found 349.1720.
Sonogashira Coupling of Pyrimidinyl Nonaflate 16 to 4-Methyl-2,6-
diphenyl-5-(phenylethynyl)pyrimidine (19): A mixture of pyrimidinyl
nonaflate 16 (114 mg, 0.209 mmol), Pd(OAc)2 (2.3 mg,
0.010 mmol), PPh3 (11 mg, 0.041 mmol), CuI (1.9 mg,
0.011 mmol), phenylacetylene (26 mg, 0.251 mmol) in DMF
(1.0 mL) and diisopropylamine (0.5 mL) was heated to 70 °C for
3 h under an argon atmosphere. The mixture was allowed to cool
to room temperature, diluted with brine (5 mL) and extracted with
Et2O (3ϫ5 mL). The combined organic phases were dried with
Na2SO4 and concentrated to dryness. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate = 40:1)
to give 53 mg (73%) of 19 as a colourless solid; m.p. 109–110 °C.
1H NMR (CDCl3, 500 MHz): δ = 2.88 (s, 3 H, Me), 7.34–7.38,
7.43–7.56, 8.25–8.28, 8.57–8.59 (4m, 3 H, 8 H, 2 H, 2 H, Ph) ppm.
13C NMR (CDCl3, 101 MHz): δ = 24.2 (q, Me), 85.2, 100.8 (2s,
CϵC), 112.8 (s, C-5), 122.9, 128.0, 128.48, 128.49, 128.51, 128.8,
129.6, 130.1, 130.7, 131.2, 137.5, 137.9 (s, 9d, 2s, Ph), 161.2, 165.1,
of Ph signals. IR (KBr): ν = 3110–3005 (=C–H), 2955–2830 (C–
˜
H), 1710–1580 (C=O, C=C, C=N) cm–1. HRMS (ESI-TOF): calcd.
for C18H15N2O2 [M + H]+: 291.1128; found 291.1130.
5-Methoxy-2,6-diphenylpyrimidine-4-carbaldehyde Oxime (23): Al-
dehyde 22 (160 mg, 0.551 mmol) and NH2OH·HCl (115 mg,
1.65 mmol) were dissolved in MeOH (3.0 mL). The mixture was
stirred for 1 d at room temperature, then diluted with H2O (5 mL)
and extracted with CH2Cl2 (3ϫ5 mL). The combined organic
phases were dried with Na2SO4 and concentrated to dryness. The
residue was purified by column chromatography on silica gel (hex-
ane/ethyl acetate = 4:1) to give 117 mg (70%) of 23 as a colourless
1
solid; m.p. 187 °C. H NMR (CDCl3, 500 MHz): δ = 3.64 (s, 3 H,
170.1 (3s, C-2, C-4, C-6) ppm. IR (KBr): ν = 3060–3030 (=C–
˜
H), 2955–2845 (C–H), 2205 (CϵC), 1600–1565 (C=C, C=N) cm–1.
C25H18N2 (346.4): calcd. C 86.68, H 5.24, N 8.09; found C 86.44,
H 5.15, N 8.00.
OMe), 7.46–7.56, 8.22–8.25, 8.52–8.55 (3m, 6 H, 2 H, 2 H, Ph),
8.62 (s, 1 H, CHN), 10.50 (br. s, 1 H, OH) ppm. 13C NMR (CDCl3,
126 MHz): δ = 61.7 (q, OMe), 128.3, 128.5, 128.6, 129.3, 130.4,
130.5, 135.5, 137.1 (6d, 2s, Ph), 144.8 (d, CHN), 149.1, 152.1 (2s,
7-tert-Butyl-2-(4-tert-butyl-5-methoxy-6-methylpyrimidin-2-yl)-5-(tri-
fluoromethyl)furo[2,3-c]pyridine (21): A mixture of pyridine-4-yl
nonaflate 20 (403 mg, 0.653 mmol), Pd(OAc)2 (7.3 mg,
0.033 mmol), PPh3 (34 mg, 0.131 mmol), CuI (6.2 mg,
0.033 mmol), pyrimidine 7e (267 mg, 1.31 mmol) in DMF (2.7 mL)
and diisopropylamine (1.3 mL) was heated to 70 °C for 3 h under
an argon atmosphere. The mixture was allowed to cool to room
temperature, diluted with brine (10 mL) and extracted with Et2O
(3ϫ10 mL). The combined organic phases were dried with Na2SO4
and concentrated to dryness. The crude product was dissolved in a
1:2 mixture of TFA and CH2Cl2 (4 mL). After stirring for 2 h at
room temperature the reaction mixture was quenched with H2O
(10 mL) and extracted with CH2Cl2 (3ϫ10 mL). The combined or-
ganic phases were dried with Na2SO4 and concentrated to dryness.
The resulting crude product was dissolved in DMF (2.7 mL) and
K2CO3 (271 mg, 1.96 mmol) was added. After heating for 3 h at
80 °C, the mixture was quenched at room temperature with H2O
(10 mL) and extracted with Et2O (3ϫ10 mL). The combined or-
ganic phases were dried with Na2SO4 and concentrated to dryness.
Column chromatography on silica gel (hexane/ethyl acetate = 10:1)
afforded 195 mg (71%) of 21 as a colourless solid; m.p. 92–94 °C.
C-5, C-4), 159.2, 159.8 (2s, C-2, C-6) ppm. IR (KBr): ν = 3375
˜
(O–H), 3080–2850 (=C–H, C–H), 1600–1545 (C=C, C=N) cm–1.
C18H15N3O2 (305.3): calcd. C 70.81, H 4.95, N 13.76; found C
70.60, H 4.99, N 13.74.
Oxidation of 22 to 5-Methoxy-2,6-diphenylpyrimidine-4-carboxylic
Acid (24): NaClO2 (75 mg, 0.828 mmol) was dissolved in a satd.
aq. NaH2PO4 solution (2.0 mL) and stirred for 5 min at room tem-
perature. The solution was added to a mixture of aldehyde 22
(185 mg, 0.637 mmol) in tBuOH (2.0 mL) and stirred for 1 d at
room temperature. The mixture was diluted with HCl (4 mL, 1 )
and extracted with ethyl acetate (3ϫ5 mL). The combined organic
phases were dried with Na2SO4 and concentrated to dryness. The
residue was purified by column chromatography on silica gel (hex-
ane/ethyl acetate = 2:1) to give 128 mg (66%) of 24 as a colourless
1
solid; m.p. 111 °C. H NMR (CDCl3, 500 MHz): δ = 3.82 (s, 3 H,
OMe), 7.49–7.58, 8.23–8.26, 8.41–8.46 (3m, 6 H, 2 H, 2 H, Ph)
ppm; the CO2H signal could not be detected. 13C NMR (CDCl3,
101 MHz): δ = 62.5 (q, OMe), 128.1, 128.6, 128.8, 129.7, 131.15,
131.23, 134.6, 135.5 (6d, 2s, Ph), 145.3, 151.1 (2s, C-5, C-4), 158.0,
163.2 (2s, C-2, C-6), 161.7 (s, CO H) ppm. IR (KBr): ν = 3515–
˜
2
2562
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2555–2564

New 5-Alkoxypyrimidine Derivatives
45–56; g) F. Pfrengle, H.-U. Reissig, Chem. Soc. Rev. 2010, 39,
549–557; h) T. Lechel, H.-U. Reissig, Pure Appl. Chem. 2010, in
press. For most recent applications of alkoxyallenes as building
blocks from our group, see: i) M. Brasholz, H.-U. Reissig, Eur.
J. Org. Chem. 2009, 3595–3604; j) F. Pfrengle, D. Lentz, H.-U.
Reissig, Angew. Chem. 2009, 121, 3211–3215; Angew. Chem.
Int. Ed. 2009, 48, 3165–3169; k) B. Bressel, H.-U. Reissig, Org.
Lett. 2009, 11, 527–530; l) F. Pfrengle, A. Al-Harrasi, I.
Brüdgam, H.-U. Reissig, Eur. J. Org. Chem. 2009, 282–291; m)
V. Prisyazhnyuk, M. Jachan, I. Brüdgam, R. Zimmer, H.-U.
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n) V. Dekaris, H.-U. Reissig, Synlett 2010, 42–46; o) V. Dekaris,
B. Bressel, H.-U. Reissig, Synlett 2010, 47–50; p) A. Al-Har-
rasi, S. Fischer, R. Zimmer, H.-U. Reissig, Synthesis 2010, 304–
314.
a) O. Flögel, J. Dash, I. Brüdgam, H. Hartl, H.-U. Reissig,
Chem. Eur. J. 2004, 10, 4283–4290; b) O. Flögel, H.-U. Reissig,
German Patent Nr. 103 36 497.8. A1 (March 03, 2005); c) J.
Dash, T. Lechel, H.-U. Reissig, Org. Lett. 2007, 9, 5541–5544;
d) T. Lechel, J. Dash, H.-U. Reissig, Eur. J. Org. Chem. 2008,
3647–3655; e) C. Eidamshaus, H.-U. Reissig, Adv. Synth. Catal.
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For recent applications of β-alkoxy β-keto enamides in the syn-
thesis of highly functionalized oxazoles or pyridines, see: a) T.
Lechel, H.-U. Reissig, Chem. Eur. J. 2009, 15, 5432–5435; b) T.
Lechel, J. Dash, C. Eidamshaus, I. Brüdgam, H.-U. Reissig,
Org. Biomol. Chem. 2010, in press.
3110 (O–H), 3065–2825 (=C–H, C–H), 1765–1555 (C=O, C=C,
C=N) cm–1. C18H14N2O3 (306.3): calcd. C 70.58, H 4.61, N 9.15;
found C 70.20, H 4.76, N 9.18.
4-(2,2-Dibromovinyl)-5-methoxy-2,6-diphenylpyrimidine (25): Alde-
hyde 22 (151 mg, 0.520 mmol) was dissolved in CH2Cl2 (10 mL)
and added at 0 °C to a mixture of PPh3 (542 mg, 2.02 mmol) and
CBr4 (345 mg, 1.04 mmol). After 5 min at this temperature the mix-
ture was warmed up to room temperature and stirred for 2 h. After
filtration with pentane the filtrate was concentrated to dryness. The
residue was purified by column chromatography on silica gel (hex-
ane/ethyl acetate = 10:1) to give 201 mg (87%) of 25 as a colourless
oil. 1H NMR (CDCl3, 500 MHz): δ = 3.60 (s, 3 H, OMe), 7.45–
7.56, 8.19–8.21, 8.56–8.58 (3m, 6 H, 2 H, 2 H, Ph), 7.91 (s, 1 H,
CH=C) ppm. 13C NMR (CDCl3, 101 MHz): δ = 61.5 (q, OMe),
98.3 (s, CH=C), 128.3, 128.4, 128.5, 129.1, 130.30, 130.31, 135.7,
137.4 (6d, 2s, Ph), 129.4 (d, CH=C), 148.2 (s, C-5), 154.9, 158.0,
[2]
[3]
158.9 (3s, C-2, C-4, C-6) ppm. IR (film): ν = 3085–3000 (=C–H),
˜
2955–2845 (C–H), 1600–1565 (C=C, C=N) cm–1. HRMS (ESI-
TOF): calcd. for C19H15Br2N2O [M + H]+: 444.9546; found
444.9559. C19H14Br2N2O (446.1): calcd. C 51.15, H 3.16, N 6.28;
found C 51.49, H 3.58, N 5.95.
4-Ethynyl-5-methoxy-2,6-diphenylpyrimidine (26): The dibromoole-
fin 25 (338 mg, 0.758 mmol) was dissolved in THF (4.6 mL) and
cooled to –78 °C. n-Butyllithium (0.64 mL, 1.59 mmol, 2.5  in
hexanes) was slowly added to this solution and stirred for 1 h. The
reaction mixture was warmed up to room temperature and stirred
for 1 h, then diluted with H2O (10 mL) and extracted with ethyl
acetate (3ϫ10 mL). The combined organic phases were dried with
Na2SO4 and concentrated to dryness. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate = 20:1)
[4]
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1
to give 41 mg (19%) of 26 as a colourless oil. H NMR (CDCl3,
400 MHz): δ = 3.59 (s, 1 H, CϵCH), 3.83 (s, 3 H, OMe), 7.44–
7.53, 8.21–8.23, 8.47–8.50 (3m, 6 H, 2 H, 2 H, Ph) ppm. 13C NMR
(CDCl3, 101 MHz): δ = 61.4 (q, OMe), 78.9, 84.6 (s, d, CϵCH),
128.3, 128.46, 128.53, 129.4, 130.4, 130.5, 135.2, 136.9 (6d, 2s, Ph),
144.6 (s, C-5), 152.3 (s, C-4), 158.0, 159.6 (2s, C-2, C-6) ppm. IR
(film): ν = 3280 (ϵC–H), 3095–3000 (=C–H), 2960–2850 (C–H),
˜
2115 (CϵC), 1600–1525 (C=C, C=N) cm–1. MS (EI): m/z (%) = 286
(100) [M]+, 77 (21) [C6H5]+. HRMS (EI): calcd. for C19H14N2O:
286.1090; found 286.1106.
Supporting Information (see also the footnote on the first page of
this article): Copies of all NMR spectra of compounds described
here.
Acknowledgments
Generous support of this work by the Deutsche Forschungsgemein-
schaft (DFG), the Fonds der Chemischen Industrie and the Bayer
Schering Pharma AG is most gratefully acknowledged. We also
thank S. Möhl for experimental contributions and Dr. R. Zimmer
for his help during the preparation of this manuscript.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2563

T. Lechel, H.-U. Reissig
FULL PAPER
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Received: January 16, 2010
Published Online: March 19, 2010
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