A concise synthesis of alkoxy-substituted pyrimidine derivatives based upon a three-component access to functionalized enamides

Article abstract of DOI:10.1055/s-0028-1088220

Substituted enamides were prepared by a three-component reaction of lithiated alkoxyallenes, nitriles, and carboxylic acids. Their subsequent condensation with ammonium salts provided alkoxy-substituted pyrimidine derivatives. This two-step method is high

Full text of DOI:10.1055/s-0028-1088220

LETTER
1059
A Concise Synthesis of Alkoxy-Substituted Pyrimidine Derivatives Based
upon a Three-Component Access to Functionalized Enamides
Synthesis of
A
lk
i
oxy-S
l
ubstitu
m
avatives n Lechel, Sophia Möhl, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 16 January 2009
In our previous work we demonstrated that alkoxyallenes
are versatile C-3 building blocks for a variety of hetero-
cyclic compounds being intermediates of natural or inter-
esting unnatural products.4 We recently described an
Abstract: Substituted enamides were prepared by a three-compo-
nent reaction of lithiated alkoxyallenes, nitriles, and carboxylic
acids. Their subsequent condensation with ammonium salts provid-
ed alkoxy-substituted pyrimidine derivatives. This two-step method
is highly flexible with respect to the substitution pattern at C-2 and interesting formation of enamides such as 4 that were gen-
C-6. The C-4 and C-5 positions can smoothly be functionalized em-
erated by a novel and mechanistically intriguing three-
ploying either Pd-catalyzed couplings or oxidation methods.
component synthesis using lithiated alkoxyallenes, ni-
triles, and carboxylic acids as precursors.5 The scope of
Key words: allenes, enamides, pyrimidines, ammonium salts,
nonaflates, Pd catalysis
the reaction with respect to the alkoxyallenes, nitriles, and
carboxylic acids is fairly broad. Subsequent Mukaiyama-
type aldol condensation using trimethylsilyl triflate and
The pyrimidine substructure is important in functional base provided highly substituted 4-hydroxypyridine de-
materials and many biologically active natural products.1 rivatives 5 in good yield (Scheme 1).
Compounds including this heterocyclic core have shown
In general, enamides 4a–e could be obtained by following
antiviral, antibacterial, antimicrobial, antifungal, or anti-
the reported procedure6 in reasonable to good yields (the
cancer activity.1 This broad range of application makes
mechanism of this reaction has been discussed in ref. 5).
the development of new and efficient pyrimidine synthe-
In case of benzonitrile, benzoic acid (R2 = R3 = Ph), and
ses very valuable. As a consequence, a variety of pyrimi-
different alkoxyallenes (R1 = Me, Bn, or TMSE) the
dine syntheses have been reported in the literature.2 Most
yields were between 36% and 54%. Changing the nitrile
of them start from 1,3-dicarbonyl compounds or
to 2-thiophenenitrile (R1 = TMSE, R2 = 2-thienyl,
amidines. Only a few deal with enamides as precursors for
R3 = Ph) the expected product was formed in 74% yield.
pyrimidine derivatives.3 In this communication we de-
The best result was obtained with methoxyallene, cyclo-
scribe a mild and efficient route towards alkoxy-substitut-
propylnitrile, and cyclopropane carboxylic acid (R1 = Me,
ed pyrimidines 6 by treatment of enamides of type 4 with
R2 = R3 = c-Pr, 75%) as precursors (Table 1).
ammonium salts (Scheme 1).
Table 1 Three-Component Synthesis of Enamides 4a–e Starting
OR1
from Alkoxyallenesa
⋅
R2C
2
OR1
Li
R3
1
O
O
⋅
+
R3
NH
O
TMSOTf
base
N
+
R2C
R3
NH
O
a–c
N
N
R2
OH
R2
R2
+
OR1
+
OR1
OR1
4a–e
R3CO2H
R3CO2H
4
5
3
R1 = Me, Bn, TMSE
R1
R2
R3
Yield (%)
R
R
2 = alkyl, aryl
3 = alkyl, aryl
ammonium salt
R3
Me
Ph
Ph
Ph
Ph
Ph
c-Pr
4a
45
54
36
74
75
Bn
Ph
4b
4c
4d
4e
N
N
TMSEb
TMSE
Me
Ph
R2
OR1
2-thienyl
c-Prc
6
Scheme 1 4-Hydroxypyridine and pyrimidine syntheses starting
from lithiated alkoxyallenes 1, nitriles 2, and carboxylic acids 3
a Reagents and conditions: (a) alkoxyallene (1.0 or 3.0 equiv), n-BuLi
(1.1 or 2.7 equiv), Et2O, –40 °C, 20 min; (b) nitrile (1.5 or 1.0 equiv),
30 min at –40 °C; –78 °C, 4 h; (c) carboxylic acid (3.0 or 6.0 equiv),
warm up to r.t. overnight.
SYNLETT 2009, No. 7, pp 1059–1062
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088220; Art ID: G00709ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9
b TMSE = trimethylsilylethyl.
c c-Pr = cyclopropyl.

1060
T. Lechel et al.
LETTER
Pyrimidine derivative 7a (R1 = Me, R2 = R3 = Ph) was with TFA and a subsequent nonaflation led to compound
prepared employing two different methods. We first ap- 10 in 60% yield over two steps.9
plied modified conditions as described by Taddei for the
synthesis of 2,4-disubstituted quinazolines.7 In method A,
16 equivalents of ammonium bicarbonate dissolved in
methanol at 70 °C were necessary to obtain pyrimidine 7a
in 65% yield. By employing other solvents like toluene,
1,2-dichloroethane, or water no conversion or only poor
yields were observed. With method B the yield of 7a in-
creased to 73% by changing the ammonia source to am-
monium acetate. With this modification less ammonium
salt (8.0 equiv) and lower temperature are sufficient.8 It
should be noted here that experiments employing other
ammonia sources like ammonium chloride or aqueous
ammonia (25%) were not successful or gave only traces of
7a.
O
O
NH3
method A or B
R3
NH
O
R3
NH
NH
R2
R2
OR1
OR1
8
4
H+
R3
R3 OH
HN
N
N
N
– H2O
R2
R2
OR1
OR1
Pyrimidine derivatives 7b–e could be obtained in the
same manner using either method A or B. The corre-
sponding benzyl- or trimethylsilylethyl-protected pyrimi-
dine derivatives 7b–d (R2 = Ph or 2-thienyl, R3 = Ph)
could be isolated in higher yields (74–86%) whereas the
cyclopropyl-substituted pyrimidine 7e was obtained in
56% yield (Table 2).
6
Scheme 2 Proposed mechanism of the pyrimidine formation
Ph
Ph
Ph
b
a
N
N
N
N
N
N
66%
92%
Ph
Ph
Ph
Table 2 Synthesis of Alkoxy-Substituted Pyrimidine Derivatives
7a–e
OPG
PG = Bn
OH
ONf
9
10
7b,c
R3
O
c, then b
PG = TMSE 60%
R3
NH
O
N
N
method A or B
R2
R2
Scheme 3 Cleavage and nonaflation of different alkoxypyrimi-
dines. Reagents and conditions: (a) H2 (1.0 bar), Pd/C (10 mol%),
MeOH, r.t., 1 d; Nonaflation: (b) NaH (3.0 equiv), NfF (3.0 equiv),
THF, r.t., 1 d; (c) TFA–CH2Cl2 (1:3), r.t., 2 h.
OR1
4a–e
OR1
7a–e
R1
R2
Ph
Ph
Ph
R3
Ph
Ph
Ph
Yield (%) Methoda
Me
7a
7b
7c
7d
7e
65, 73
75
A, B
A
We have earlier shown that nonaflates represent ideal pre-
cursors for Pd-catalyzed coupling reactions.10 Here we
demonstrate a first coupling of pyrimidyl nonaflate 10
with phenylacetylene carried out under standard Sonoga-
shira conditions. The expected product 11 was provided in
73% yield (Scheme 4).
Bn
TMSE
TMSE
Me
86
B
2-thienyl
Ph
74
A
c-Pr
c-Pr
56
B
Moreover, the methyl group which is present in all of the
synthesized pyrimidine derivatives could easily be func-
tionalized. The oxidation of pyrimidine 7a to aldehyde 12
was performed under Riley conditions in very good yield
(90%). Further Pinnick oxidation afforded the carboxylic
acid 13 in 66% yield (Scheme 5).
a Method A: NH4HCO3 (16 equiv), MeOH, sealed tube, 65 °C, 1 d;
method B: NH4OAc (8.0 equiv), MeOH, sealed tube, 60–65 °C, 1 d.
The formation of pyrimidine derivatives 7a–e can be ra-
tionalized by the mechanism depicted in Scheme 2. Upon
heating of enamide 4 with the ammonium salt an imine 8
is formed. Acid-catalyzed cyclization of the imine fol-
lowed by dehydration furnishes pyrimidine derivative 6.
In conclusion, a variety of substituted pyrimidine deriva-
tives are available by a two-step procedure employing a-
lithiated alkoxyallenes, nitriles, and carboxylic acids as
suitable precursors. We could demonstrate that function-
alizations in two different positions are possible by using
standard Pd-coupling reactions or oxidation methods.
The presence of protecting groups like benzyl or tri-
methylsilylethyl allows an easy and mild deprotection to
5-hydroxypyrimidine derivatives such as 9 (Scheme 3).
The benzyl group of 7b was smoothly cleaved by hydro-
gen in presence of Pd/C catalyst, which furnished 9 in
very good yield (92%). The hydroxy function could sub-
sequently be converted into a nonaflyl group using nona-
fluorobutanesulfonyl fluoride in presence of a base.
Acknowledgment
Support by the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie, and the Bayer Schering Pharma AG is most
Pyrimidyl nonaflate 10 was isolated in 66% yield. The tri- gratefully acknowledged.
methylsilylethyl-protected pyrimidine 7c was first treated
Synlett 2009, No. 7, 1059–1062 © Thieme Stuttgart · New York

LETTER
Synthesis of Alkoxy-Substituted Pyrimidine Derivatives
1061
M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007, 46, 1634;
Angew. Chem. 2007, 119, 1659. (k) Gwiazda, M.; Reissig,
H.-U. Synthesis 2008, 990.
Ph
Ph
N
N
a
N
N
(5) (a) Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reissig,
H.-U. Chem. Eur. J. 2004, 10, 4283. (b) Flögel, O.; Reissig,
H.-U. DE 103 36 497.8 A1, 2005. (c) Dash, J.; Lechel, T.;
Reissig, H.-U. Org. Lett. 2007, 9, 5541. (d) Lechel, T.;
Dash, J.; Reissig, H.-U. Eur. J. Org. Chem. 2008, 3647.
(6) Typical Procedure for the Synthesis of Enamide 4c
Trimethylsilylethoxyallene (2.45 g, 15.7 mmol) was
dissolved in Et2O (32 mL) and n-BuLi (6.90 mL, 17.2 mmol,
2.5 M in hexanes) was added at –40 °C. After 25 min at
–50 °C to –40 °C benzonitrile (2.40 mL, 23.5 mmol) was
added. After stirring for 4 h at this temperature benzoic acid
(5.74 g, 47.0 mmol, dissolved in 15 mL Et2O) was added,
and the mixture was warmed up over night to r.t. The
mixture was quenched with sat. aq NaHCO3 soln and
extracted three times with Et2O (30 mL). The combined
organic layers were dried with Na2SO4, filtered, and
concentrated. Column chromatography (SiO2, EtOAc–
hexane, 1:10) and subsequent recrystallization in hexane
provided 4c (2.14 g, 36%) as colorless solid (mp 65 °C).
Analytical Data for (E)-N-{3-Oxo-1-phenyl-2-[2-
(trimethylsilyl)ethoxy]but-1-enyl}benzamide (4c)
1H NMR (400 MHz, CDCl3): d = –0.15 (s, 9 H, SiMe3),
0.66–0.71 (m, 2 H, CH2Si), 2.40 (s, 3 H, CH3), 3.33–3.38 (m,
2 H, OCH2), 7.36–7.55, 7.95–7.98 (2 m, 10 H, Ph), 12.40 (br
s, 1 H, NH) ppm. 13C NMR (101 MHz, CDCl3): d = –1.7 (q,
SiMe3), 18.6 (t, CH2Si), 27.5 (q, CH3), 71.5 (t, OCH2), 127.8,
128.4, 128.68, 128.73, 132.3, 132.6, 133.7 (5 d, 2 s, Ph)*,
137.6, 143.3 (2 s, C=C), 165.2, 202.9 (2 s, C=O) ppm;
*overlapping Ph signals. IR (KBr): n = 3400 (NH), 3110–
2995 (=CH), 2960–2895 (CH), 1730–1580 (C=O, C=C)
cm–1. Anal. Calcd for C22H27NO3Si (381.5): C, 69.25; H,
7.13; N, 3.67. Found: C, 69.05; H, 7.08; N, 3.69.
73%
Ph
Ph
ONf
10
Ph
11
Scheme 4 Pd-catalyzed coupling reactions with pyrimidyl nonaflate
10. Reagents and conditions: a) Sonogashira reaction: Pd(OAc)2 (5
mol%), Ph3P (20 mol%), CuI (5 mol%), phenylacetylene, i-Pr2NH–
DMF (1:2), 70 °C, 3 h.
Ph
Ph
Ph
b
a
N
N
N
N
N
N
90%
66%
O
Ph
Ph
Ph
CO2H
OMe
OMe
H
OMe
7a
12
13
Scheme 5 Oxidation of pyrimidine derivative 7a. Reagents and
conditions: (a) SeO2 (2.0 equiv), dioxane, sealed tube, 80 °C, 2 d; (b)
NaClO2 (1.3 equiv), aq NaH2PO4–t-BuOH (1:1).
References and Notes
(1) (a) Karpov, A. S.; Müller, T. J. J. Synthesis 2003, 2815.
(b) Bevk, D.; Grošelj, U.; Meden, A.; Svete, J.; Stanovnik,
B. Helv. Chim. Acta 2007, 90, 1737. (c) Sagar, R.; Kim,
M.-J.; Park, S. B. Tetrahedron Lett. 2008, 49, 5080.
(d) Xie, F.; Zhao, H.; Zhao, L.; Lou, L.; Hu, L. Bioorg. Med.
Chem. Lett. 2009, 19, 275.
(2) (a) Brown, D. J. In Comprehensive Heterocyclic Chemistry,
Vol. 3; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984, Chap. 2.13. (b) Eicher, T.; Hauptmann, S.
Chemie der Heterocyclen; Thieme: Stuttgart, 1994, 398.
(c) Gilchrist, T. L. Heterocyclenchemie; Neunhoeffer, H.,
Ed.; Wiley-VCH: Weinheim, 1995, 270. (d) Hoffmann,
M. G. In Houben-Weyl, Methoden der Organischen Chemie,
Vol. E9; Schaumann, E., Ed.; Thieme: Stuttgart, 1996.
(e) Angerer, S. Science of Synthesis, Vol. 16; Yamamoto, Y.,
Ed.; Thieme: Stuttgart, 2004, 379.
(7) Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9, 69.
(8) Typical Procedure for the Synthesis of Pyrimidine 7c
Enamide 4c (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 H2O and CH2Cl2 (5.0 mL) the layers were
separated, and the aqueous layer was extracted twice with
CH2Cl2 (5.0 mL). The combined organic layers were dried
with Na2SO4, filtered, and concentrated. Column
chromatography (SiO2, EtOAc–hexane, 1:10) provided 7c
(285 mg, 86%) as colorless oil.
Analytical Data for 4-Methyl-2,6-diphenyl-5-[2-
(trimethylsilyl)ethoxy]pyrimidine (7c)
(3) Recent pyrimidine derivative syntheses starting from
enamides: (a) Barthakur, M. G.; Borthakur, M.; Devi, P.;
Saikia, C. J.; Saikia, A.; Bora, U.; Chetia, A.; Boruah, R. C.
Synlett 2007, 223. (b) Hill, M. D.; Movassaghi, M. Chem.
Eur. J. 2008, 14, 6836.
1H NMR (500 MHz, CDCl3): d = –0.08 (s, 9 H, SiMe3),
0.97–1.06 (m, 2 H, CH2Si), 2.64 (s, 3 H, CH3), 3.66–3.71 (m,
2 H, OCH2), 7.41–7.53, 8.16–8.19, 8.47–8.50 (3 m, 10 H,
Ph) ppm. 13C NMR (101 MHz, CDCl3): d = –1.6 (q, SiMe3),
18.9 (t, CH2Si), 19.6 (q, CH3), 71.1 (t, OCH2), 128.0, 128.3,
128.4, 129.1, 129.77, 129.84, 136.4, 137.8 (6 d, 2 s, Ph),
148.2 (s, C-5), 156.6, 158.7, 162.4 (3 s, C-2, C-4, C-6) ppm.
IR (film): n = 3090–2870 (=CH, CH), 1680–1540 (C=C,
C=N) cm–1. Anal. Calcd for C22H26N2OSi (362.5): C, 72.88;
H, 7.23; N, 7.73. Found: C, 72.63; H, 7.12; N, 7.78.
(9) Typical Procedure for the Synthesis of Pyrimidyl
Nonaflate 10
(4) For reviews on alkoxyallenes, see: (a) Zimmer, R. Synthesis
1993, 165. (b) Zimmer, R.; Khan, F. A. J. Prakt. Chem.
1996, 338, 92. (c) Reissig, H.-U.; Hormuth, S.; Schade, W.;
Okala Amombo, M. G.; Watanabe, T.; Pulz, R.; Hausherr,
A.; Zimmer, R. J. Heterocycl. Chem. 2000, 37, 597.
(d) Zimmer, R.; Reissig, H.-U. In Modern Allene Chemistry,
Vol. 2; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004, 425. (e) Reissig, H.-U.; Zimmer, R.
Science of Synthesis, Vol. 44; Krause, N., Ed.; Thieme:
Stuttgart, 2007, 301. (f) Brasholz, M.; Reissig, H.-U.;
Zimmer, R. Acc. Chem. Res. 2009, 42, 45. For selected
recent applications developed by our group, see: (g) Al-
Harrasi, A.; Reissig, H.-U. Angew. Chem. Int. Ed. 2005, 44,
6227; Angew. Chem. 2005, 117, 6383. (h) Kaden, S.;
Reissig, H.-U. Org. Lett. 2006, 8, 4763. (i) Sörgel, S.;Azap,
C.; Reissig, H.-U. Org. Lett. 2006, 8, 4875. (j) Brasholz,
Pyrimidine 7c (285 mg, 0.786 mmol) was dissolved in a 1:2
mixture of TFA and CH2Cl2 (3.0 mL) and stirred for 30 min
at r.t. After addition of H2O and CH2Cl2 (5.0 mL) the layers
were separated, and the aqueous layer was extracted twice
with CH2Cl2 (8.0 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
Synlett 2009, No. 7, 1059–1062 © Thieme Stuttgart · New York

1062
T. Lechel et al.
LETTER
2.36 mmol) was added. After 5 min NfF (0.42 mL, 2.36
mmol) was added, and the reaction mixture was stirred over
night at r.t. After slowly addition of H2O and EtOAc (5.0
mL) the layers were separated, and the aqueous layer was
extracted twice with EtOAc (8.0 mL). The combined organic
layers were dried with Na2SO4, filtered, and concentrated.
Column chromatography (SiO2, EtOAc–hexane, 1:10)
provided 10 (257 mg, 60%) as colorless oil.
Analytical Data for 4-Methyl-2,6-diphenylpyrimidin-5-
yl 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonate (10)
1H NMR (500 MHz, CDCl3): d = 2.77 (s, 3 H, CH3), 7.49–
7.56, 7.89–7.91, 8.52–8.55 (3 m, 10 H, Ph) ppm. 13C NMR
(101 MHz, CDCl3): d = 20.5 (q, CH3), 128.56, 128.58,
128.7, 129.5, 130.8, 129.9, 134.3, 136.3 (6 d, 2 s, Ph), 140.7
(s, C-5), 159.0, 162.0, 162.3 (3 s, C-2, C-4, C-6) ppm. 19
NMR (470 MHz, CDCl3): d = –80.6, –109.8, –120.6, –125.8
(4 m, Nf) ppm. IR (film): n = 3095–2855 (=CH, CH), 1605–
1560 (C=C, C=N) cm–1. ESI-TOF: m/z calcd for [M + H]+:
545.0576; found: 545.0607. Anal. Calcd for C21H13F9N2O3S
(544.4): C, 46.33; H, 2.41; N, 5.15. Found: C, 46.93; H, 2.18;
N, 5.06.
F
(10) For recent applications of the particularly useful alkenyl and
aryl nonaflates, see: Högermeier, J.; Reissig, H.-U. Chem.
Eur. J. 2007, 13, 2410; and references cited therein.
Synlett 2009, No. 7, 1059–1062 © Thieme Stuttgart · New York

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