Preparation of pyrimidine-N-oxides by condensation of functionalized enamides with hydroxylamine hydrochloride

Article abstract of DOI:10.1055/s-0030-1258088

β-Alkoxy β- ketoenamides and hydroxylamine hydrochloride smoothly provide pyrimidine-N-oxides under very mild conditions. Alkyl, aryl, and heteroaryl substituents are compatible with this new method. By treatment with acetic acid anhydride these pyrimidine-N-oxides undergo a rearrangement furnishing highly functionalized 6-acetoxymethyl-substituted pyrimidine derivatives in good yields. Our method, which is based on a three-component reaction of alkoxyallenes, nitriles, and carboxylic acids, therefore constitutes a highly flexible route to densely substituted pyrimidine derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258088

LETTER
1793
Preparation of Pyrimidine-N-oxides by Condensation of Functionalized
Enamides with Hydroxylamine Hydrochloride
Preparation of
P
y
e
rimidine-
N
i
-oxidesnhold Zimmer, Tilman Lechel, Giaime Rancan, Mrinal K. Bera, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 8 April 2010
Dedicated to Professor Helmut Vorbrüggen on the occasion of his 80th birthday
The pyrimidines are formed when enamides 1 were treat-
ed with ammonium acetate under appropriate conditions
(ca. 65 °C for several hours). In this letter we report the
extremely smooth preparation of pyrimidine-N-oxides 2
Abstract: b-Alkoxy-b-ketoenamides and hydroxylamine hydro-
chloride smoothly provide pyrimidine-N-oxides under very mild
conditions. Alkyl, aryl, and heteroaryl substituents are compatible
with this new method. By treatment with acetic acid anhydride these
pyrimidine-N-oxides undergo a rearrangement furnishing highly when enamides 1 were mixed with hydroxylamine hydro-
functionalized 6-acetoxymethyl-substituted pyrimidine derivatives
chloride at room temperature (Scheme 2). Furthermore,
in good yields. Our method, which is based on a three-component
reaction of alkoxyallenes, nitriles, and carboxylic acids, therefore
pyrimidines with an acetoxymethyl side chain by treat-
constitutes a highly flexible route to densely substituted pyrimidine
we describe the rearrangement of these N-oxides into
ment of 2 with acetic acid anhydride.
derivatives.
O
R1
Key words: pyrimidines, N-oxides, enamides, hydroxylamine,
condensation, 3,3-sigmatropic rearrangement
R1
NH
O
O
N
N
a
R2
R2
OR3
We recently discovered and subsequently exploited a nov-
el three-component reaction, which employs lithiated
alkoxyallenes1 [(R3O)LiC=C=CH2], nitriles (R2CN), and
carboxylic acids (R1CO2H) and furnishes synthetically
highly versatile b-alkoxy-b-ketoenamides 1. These served
as flexible building blocks for the synthesis of specifically
functionalized heterocycles such as pyridine,2 pyrimi-
dine,3 and oxazole4 derivatives (Scheme 1).
OR3
2
1
Scheme 2 Preparation of pyrimidine-N-oxides 2. Reagents and
conditions: a) NH2OH·HCl, MeOH, r.t., 1–3 d.
Combination of a range of differently substituted enam-
ides 1 bearing alkyl, aryl, or heteroaryl substituents R1 and
R2 with hydroxylamine hydrochloride in methanol at
room temperature provided the desired pyrimidine-N-
oxides 2 in good to excellent yields (Table 1). The condi-
tions are very mild and the products are easily purified by
column chromatography. The spectroscopic data fully
confirm the existence of the pyrimidine ring, excluding
the conceivable formation of 1,2,6-oxadiazepine deriva-
tives.
OR3
R2
C N
R1 CO2H
+
+
•
Li
R1
R1
O
R1
NH
O
N
NH3
N
N
TMSOTf
base
The treatment of enamide 1j, containing an acryl amide
substructure, with hydroxylamine hydrochloride not only
delivered the expected vinyl-substituted pyrimidine-N-
oxide 2k (Scheme 3) but as major component 2j. This
product arises from an addition of methanol to the double
bond (probably occurring at the stage of 1j). For precursor
1k with the unconjugated double bond the formation of
pyrimidine-N-oxides proceeded smoothly and we isolated
a 2:1 mixture of compound 2l with an isomerized double
bond together with the primary cyclization product 2m
bearing an allyl substituent.
R2
R2
OH
R2
OR3
OR3
OR3
1
R3 = (CH2)2SiMe3
TFA
R1
N
O
R2
O
The mechanism of the pyrimidine-N-oxide formation is
fairly straightforward and briefly illustrated in Scheme 4.
After oxime generation its nitrogen intramolecularly at-
tacks the amide carbon and after water displacement the
final product with the N-oxide moiety is formed. Very
likely all steps proceed under acid catalysis.
Scheme 1 b-Alkoxy-b-ketoenamides 1 as key building blocks for
the synthesis of pyridine, oxazole, and pyrimidine derivatives
SYNLETT 2010, No. 12, pp 1793–1796
x
x
.x
x
.2
0
1
0
Advanced online publication: 11.06.2010
DOI: 10.1055/s-0030-1258088; Art ID: G11610ST
© Georg Thieme Verlag Stuttgart · New York

1794
R. Zimmer et al.
LETTER
Table 1 Preparation of Pyrimidine-N-oxides 2 from Enamides 1
Enamide
1a
R1
R2
R3
Product
2a
Yield (%)
Ph
i-Pr
Me
61
97
72
85
74
59
67
65
84
1b
Ph
t-Bu
Me
2b
1c
PhHC=CH
2-thienyl-HC=CH
2-furanyl-HC=CH
2-thienyl
c-Pr
t-Bu
Me
2c
1d
t-Bu
Me
2d
1e
t-Bu
Me
2e
1f
2-thienyl
1-adamantyl
c-Pr
Me
2f
1g
Me
2g
1h
c-Pr
TMSEa
TMSEa
2h
1i
c-Pr
1-adamantyl
2i
a TMSE = 2-(trimethylsilyl)ethyl.
3 hours afforded the acetoxymethyl-substituted pyrimi-
dine derivatives 3 in fair yields. This method allows a very
elegant functionalization of the methyl group of pyrimi-
dine derivatives obtained via enamides 1, which usually
contain this alkyl group. The rearrangement probably oc-
curs by a 3,3-sigmatropic reaction of the intermediate O-
acetylated species.6 Table 2 collects the examples demon-
strating that the efficacy of this step is generally good to
excellent.
OMe
N
O
O
O
NH
O
a
N
N
N
+
36%
OMe
OMe
OMe
1j
2j
(2:1)
2k
O
R1
R1
O
O
NH
O
a
N
N
N
N
O
a
+
N
N
N
N
72%
OAc
R2
R2
OMe
OMe
2l
OMe
2m
OR3
OR3
1k
(2:1)
2
3
Scheme 3 Formation of pyrimidine-N-oxides 2j–m. Reagents and
conditions: a) NH2OH·HCl, MeOH, r.t., 1 d.
Scheme 5 Rearrangement of pyrimidine-N-oxides 2 into functiona-
lized pyrimidines 3. Reagents and conditions: a) Ac2O, 120 °C, 3 h.
O
O
Table 2 Conversion of Pyrimidine-N-oxides 2 into Acetoxymethyl-
Substituted Pyrimidines 3
R1
NH
O
R1
NH
NOH
NH2OH⋅HCl
R2
R2
Precursor R1
R2
R3
Product Yield
(%)
OR3
OR3
+ H
1
2b
2c
2d
2f
Ph
t-Bu
t-Bu
Me
Me
Me
Me
3a
3b
3c
3d
69
70
81
67
91
76
R1
R1
PhHC=CH
OH
– H
– H2O
O
OH
N
N
HN
R2
N
2-thienyl-HC=CH t-Bu
R2
2-thienyl
c-Pr
2-thienyl
c-Pr
1-adamantyl TMSE 3f
OR3
OR3
2h
2i
TMSE 3e
2
Scheme 4 Proposed mechanism for the condensation of b-alkoxy-
b-ketoenamides 1 and hydroxylamine hydrochloride to pyrimidine-
N-oxides
c-Pr
The 2-(trimethylsilyl)ethoxy-substituted pyrimidine de-
rivatives allow O-deprotection under fairly mild condi-
tions. Example 2h demonstrates that a quantitative
transformation into 4 is possible with trifluoroacetic acid
(Equation 1). Compounds of type 4 should be excellent
An interesting and synthetically useful subsequent reac-
tion employs the known rearrangement of heterocyclic N-
oxides into side-chain-functionalized products.5 Heating
of compounds 2 with acetic acid anhydride to 120 °C for
Synlett 2010, No. 12, 1793–1796 © Thieme Stuttgart · New York

LETTER
Preparation of Pyrimidine-N-oxides
1795
149.1, 150.0, 151.8 (3 s, C-4, C-5, C-6), 156.4 (s, C-2) ppm. IR
(ATR): 3050–2880 (=CH, CH), 1605, 1465 (C=C, C=N) cm–1.
Anal. Calcd for C16H21N2O2 (272.3): C, 70.56; H, 7.40; N, 10.29.
Found: C, 69.93; H, 7.54; N, 9.92. HRMS (ESI-TOF): m/z calcd for
C16H22N2O2 [M + H]+: 273.1603; found: 273.1610. HRMS (ESI-
TOF): m/z calcd for C16H21N2O2Na [M + Na]+: 295.1422; found:
295.1431.
candidates for transition-metal-catalyzed coupling reac-
tions after their conversion into pyrimidinyl triflates or
nonaflates.7
O
O
a
N
N
N
N
Typical Procedure for the Synthesis of 4-tert-Butyl-5-methoxy-
6-(acetoxymethyl)-2-phenylpyrimidine (3a)
quant.
In an ACE sealed tube, pyrimidine-N-oxide 2b (878 mg, 3.22
mmol) was dissolved in Ac2O (10 mL), and the solution was re-
fluxed at 120 °C for 3 h. After cooling to r.t. the excess of Ac2O was
removed under reduced pressure. The residue was purified by col-
umn chromatography (silica gel, hexane–EtOAc = 8:1) to afford
699 mg (69%) 3a as colorless oil.
OTMSE
2h
OH
4
Equation 1 Acid-induced deprotection of pyrimidine-N-oxide 2h
providing 4. Reagents and conditions: a) TFA, CH2Cl2, r.t., overnight.
1H NMR (400 MHz, CDCl3): d = 1.49 (s, 9 H, t-Bu), 2.21 (s, 3 H,
OAc), 3.86 (s, 3 H, OMe), 5.33 (s, 2 H, CH2O), 7.40–7.48, 8.35–
8.53 (2 m, 3 H, 2 H, Ph) ppm. 13C NMR (100.6 MHz, CDCl3):
d = 20.9 (q, O2CMe), 29.2, 38.4 (q, s, t-Bu), 61.7 (t, 6-CH2), 62.6 (q,
OMe), 128.0, 128.3, 129.9, 137.7 (3 d, s, Ph), 150.4, 156.6, 157.8 (3
s, C-4, C-5, C-6), 169.2 (s, C-2), 170.8 (s, O2CMe) ppm. IR (ATR):
3050–2865 (=CH, CH), 1750 (C=O), 1550, 1450 (C=C, C=N) cm–1.
HRMS (ESI-TOF): m/z calcd for C18H22N2O3Na [M + Na]+:
337.1528; found: 337.1540.
In this letter we have disclosed a new application of the
easily available enamides 1. Their conversion into pyri-
midine-N-oxides occurs under very mild conditions and in
very good yields. The N-oxide moiety allows a very sim-
ple transformation of the 6-methyl group into an ace-
toxymethyl group. Our methods should be of value for the
synthesis of highly substituted pyrimidine derivatives,
which are important for many applications.8
Typical Procedure for the Synthesis of N-[(1E)-1-tert-Butyl-2-
methoxy-3-oxobut-1-enyl]phenylcarboxamide (1b)
Acknowledgment
Generous support of this work by the Deutsche Forschungsgemein-
schaft, the Alexander von Humboldt Foundation (fellowship for
M.K.B.), the Fonds der Chemischen Industrie, and the Bayer
Schering Pharma AG is most gratefully acknowledged.
Methoxyallene (2.00 g, 28.5 mmol) was dissolved in Et2O (60 mL)
and n-BuLi (12.5 mL, 31.3 mmol, 2.5 M in hexanes) was added at
–40 °C. After 25 min at –50 °C to –40 °C pivaloylnitrile (4.69 mL,
42.8 mmol) was added. The solution was stirred at –40 °C for 30
min and then cooled to –78 °C. After stirring for 4 h at this temper-
ature benzoic acid (10.4 g, 85.5 mmol) was added, and the mixture
was warmed up overnight to r.t. The mixture was quenched with sat.
aq NaHCO3 solution (50 mL) and extracted with CH2Cl2 (3 × 50
mL). The combined organic layers were dried with Na2SO4, filtered,
and concentrated. Column chromatography (silica gel, hexane–
EtOAc = 4:1, 1:1 to 1:3) provided 2.55 g (33%) 1b as colorless sol-
id, mp 117–119 °C.
1H NMR (400 MHz, CDCl3): d = 1.29 (s, 9 H, t-Bu), 2.36 (s, 3 H,
Me), 3.55 (s, 3 H, OMe), 7.35–7.46, 7.75–7.90 (2 m, 3 H, 2 H, Ph)
ppm, NH signal could not be detected. 13C NMR (100.6 MHz,
CDCl3): d = 27.6 (q, Me), 28.6, 36.8 (q, s, t-Bu), 59.2 (q, OMe),
127.1, 128.6, 131.8 (3 d, Ph), 134.4, 135.4, 150.2 (3 s, Ph, C=C),
167.4 (s, CONH), 200.7 (s, C=O) ppm. IR (ATR): 3390 (NH),
3030–2830 (=CH, CH), 1700 (C=O), 1650, 1630 (C=C, C=O) cm–1.
Anal. Calcd for C16H21NO3 (275.4): C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.51; H, 7.43; N, 5.11. HRMS (ESI-TOF): m/z calcd for
C16H21NO3 [M + Na]+: 298.1414; found: 298.1416.
References
(1) Reviews dealing with various aspects of lithiated
alkoxyallene chemistry: (a) Zimmer, R. Synthesis 1993,
165. (b) Zimmer, R.; Khan, F. A. J. Prakt. Chem. 1996, 338,
92. (c) Reissig, H.-U.; Schade, W.; Okala Amombo, M. G.;
Pulz, R.; Hausherr, A. Pure Appl. Chem. 2002, 74, 175.
(d) Zimmer, R.; Reissig, H.-U. In Modern Allene Chemistry,
Vol. 1; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004, Chap. 8, 425–492. (e) Brasholz, M.;
Reissig, H.-U.; Zimmer, R. Acc. Chem. Res. 2009, 42, 45.
(f) Pfrengle, F.; Reissig, H.-U. Chem. Soc. Rev. 2010, 39,
549. (g) Lechel, T.; Reissig, H.-U. Pure Appl. Chem. 2010,
82, No. 9.
(2) (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 10336497, 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. (e) Lechel,
T.; Dash, J.; Hommes, P.; Lentz, D.; Reissig, H.-U. J. Org.
Chem. 2010, 75, 726. (f) Lechel, T.; Dash, J.; Eidamshaus,
C.; Brüdgam, I.; Lentz, D.; Reissig, H.-U. Org. Biomol.
Chem. 2010, in press; DOI: 10.1039/B925468D.
(g) Synthesis of chiral pyridine derivatives: Eidamshaus, C.;
Reissig, H.-U. Adv. Synth. Catal. 2009, 351, 1162.
(3) (a) Lechel, T.; Möhl, S.; Reissig, H.-U. Synlett 2009, 1059.
(b) Lechel, T.; Reissig, H.-U. Eur. J. Org. Chem. 2010,
2555.
Typical Procedure for the Synthesis of 4-tert-Butyl-5-methoxy-
6-methyl-2-phenylpyrimidine-1-oxide (2b)
Enamide 1b (1.40 g, 5.08 mmol) was dissolved in MeOH (16 mL)
and NH2OH⋅HCl (1.10 g, 15.9 mmol) was added. The solution was
stirred at r.t. for 1 d. After addition of H2O (15 mL), the mixture was
extracted with CH2Cl2 (5 × 20 mL). The combined organic layers
were dried with Na2SO4, filtered, and concentrated. Column chro-
matography (silica gel, hexane–EtOAc = 2:1 to 1:2) provided 1.34
g (97%) 2b as colorless viscous oil.
1H NMR (400 MHz, CDCl3): d = 1.45 (s, 9 H, t-Bu), 2.58 (s, 3 H,
Me), 3.85 (s, 3 H, OMe), 7.34–7.53, 8.55–8.63 (2 m, 3 H, 2 H, Ph)
ppm. 13C NMR (100.6 MHz, CDCl3): d = 12.6 (q, Me), 29.0, 38.0
(q, s, t-Bu), 61.8 (q, OMe), 127.3, 128.2, 130.3, 132.5 (3 d, s, Ph),
(4) (a) Lechel, T.; Reissig, H.-U. DE 10 049 431.3, 2008.
(b) Lechel, T.; Lentz, D.; Reissig, H.-U. Chem. Eur. J. 2009,
15, 5432.
Synlett 2010, No. 12, 1793–1796 © Thieme Stuttgart · New York

1796
R. Zimmer et al.
LETTER
A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984,
(5) Pyrimidine-N-oxide chemistry, review: (a) Yamanaka, H.;
Sakamoto, T.; Niitsuma, S. Heterocycles 1990, 31, 923.
Acetoxylations: (b) Sakamoto, T.; Yoshizawa, H.; Kaneda,
S.; Yamanaka, H. Chem. Pharm. Bull. 1984, 32, 728.
Chlorination to chloromethylpyrimidines: (c) Sakamoto, T.;
Kaneda, S.; Hama, Y.; Yamanaka, H. Heterocycles 1983,
20, 991. Conversion to isoxazoles: (d) Kato, T.; Yamanaka,
H.; Yasuda, N. J. Org. Chem. 1967, 32, 3593. Reactions
with electrophiles: (e) Tikhonov, A. Ya.; Volodarskii, L. B.;
Vakolova, O. A.; Podgornaya, M. I. Chem. Heterocycl.
Compd. 1981, 17, 89.
(6) Review on hetero-Cope rearrangements, see: Blechert, S.
Synthesis 1989, 71.
(7) For a recent review on perfluoroalkylsulfonates, see:
Högermeier, J.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351,
2747.
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) Von
Angerer, S. Sci. Synth., Vol. 16; Yamamoto, Y., Ed.;
Thieme: Stuttgart, 2004, 379. (f) Lamberth, C. Heterocycles
2006, 68, 561. (g) Radi, M.; Schenone, S.; Botta, M. Org.
Biomol. Chem. 2009, 7, 2841. For recent publications on
pyrimidine synthesis, see: (h) Nara, S. J.; Jha, M.;
Brinkhorst, J.; Zemanek, T. J.; Pratt, D. A. J. Org. Chem.
2008, 73, 9326. (i) Hill, M. D.; Movassaghi, M. Chem. Eur.
J. 2008, 14, 6836. (j) Bannwarth, P.; Grée, D.; Grée, R.
Tetrahedron Lett. 2010, 51, 2413.
(8) Reviews on pyrimidine chemistry: (a) Brown, D. J. In
Comprehensive Heterocyclic Chemistry, Vol. 3; Katritzky,
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