A route to alkenyl-substituted 4-hydroxypyridine and pyrimidine derivatives via three-component access to β-alkoxy β-ketoenamides

Article abstract of DOI:10.1055/s-0029-1218787

β-Alkoxy β-ketoenamides with an alkenylated side arm were prepared by three-component reaction of lithiated methoxyallene, nitriles, and α,β-unsaturated carboxylic acids. Their subsequent treatment with trimethylsilyl triflate and base provided 6-alkenyl-4-hydroxypyridine derivatives that were converted into the corresponding nonaflates. Alternatively, condensation of β-alkoxy β- ketoenamides with an ammonium salt led to the smooth formation of alkenyl-substituted pyrimidine derivatives. The alkenyl group in pyridine or pyrimidine derivatives allows a wide scope of functional group modification. Moreover, the pyridin-4-yl nonaflates are excellent candidates for palladium-catalyzed coupling reactions and the 6-methyl group of the pyrimidine derivatives could also be employed for the introduction of functional groups and subsequent reactions. A variety of highly substituted pyridine and pyrimidine derivatives are available by this modular route to heterocycles. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218787

PAPER
2129
A Route to Alkenyl-Substituted 4-Hydroxypyridine and Pyrimidine
Derivatives via Three-Component Access to b-Alkoxy-b-ketoenamides
A
lkenyl-Substitute
d
Py
r
ridines
inimidines al K. Bera, 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 29 March 2010
Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday
Recently, we became interested in the synthesis of substi-
tuted pyridines and pyrimidines employing alkoxyallenes
as a crucial C3 building block.10 We have already accom-
plished the syntheses of numerous pyridine11 and
Abstract: b-Alkoxy-b-ketoenamides with an alkenylated side arm
were prepared by three-component reaction of lithiated methoxy-
allene, nitriles, and a,b-unsaturated carboxylic acids. Their subse-
quent treatment with trimethylsilyl triflate and base provided 6-
alkenyl-4-hydroxypyridine derivatives that were converted into the pyrimidine12 derivatives based upon the three-component
access to b-alkoxy-b-ketoenamides 4 (Scheme 1).11,12 The
corresponding nonaflates. Alternatively, condensation of b-alkoxy-
b-ketoenamides with an ammonium salt led to the smooth forma-
formation of these functionalized enamides occurs by a
tion of alkenyl-substituted pyrimidine derivatives. The alkenyl
novel and mechanistically intriguing reaction using lithi-
group in pyridine or pyrimidine derivatives allows a wide scope of
ated alkoxyallenes, such as lithiated methoxyallene 1, ni-
functional group modification. Moreover, the pyridin-4-yl nona-
flates are excellent candidates for palladium-catalyzed coupling
triles 2, and carboxylic acids 3 as precursors.11a The scope
of this transformation with respect to all three components
is remarkably broad. Subsequent Mukaiyama-type aldol
condensation using trimethylsilyl trifluoromethane-
sulfonate and an amine provided highly substituted 4-hy-
droxypyridine derivatives 5 in good yields (Scheme 1),
which were often converted into the corresponding pyri-
din-4-yl nonaflates (OSO2C4F9 instead of OH). On the
other hand, b-alkoxy-b-ketoenamides 4 could readily be
transformed into pyrimidine derivatives 6 by heating with
an ammonium salt in methanol (Scheme 1).12 The possi-
bility of synthesizing alkenyl-substituted pyridine and py-
rimidine derivatives has not been explored to date. In this
report we demonstrate that a,b-unsaturated carboxylic
acids, including even acrylic acid, are also tolerated in
these reactions and, thus, open a whole range of new op-
reactions and the 6-methyl group of the pyrimidine derivatives
could also be employed for the introduction of functional groups
and subsequent reactions. A variety of highly substituted pyridine
and pyrimidine derivatives are available by this modular route to
heterocycles.
Key words: alkoxyallenes, enamides, pyridines, nonaflates, pyrim-
idines, Suzuki couplings
Substituted pyridines are very common structural motifs
in naturally occurring substances with promising biologi-
cal properties and in the field of medicinal chemistry.1
Appropriately functionalized pyridines have also been
used as reagents in organic synthesis and for new materi-
als.2 For example, suitably substituted bipyridines and
terpyridines are used as ligands in organocatalysis and as
building blocks in supramolecular chemistry.3 Pyrimidine
derivatives are also a compound class with vast interest as
they are often biologically active.4 Compounds with a py-
rimidine core have shown antiviral, antibacterial, antimi-
crobial, antifungal, or anticancer activity.4 Therefore,
substituted pyrimidine derivatives frequently constitute a
crucial substructure in drug discovery. These heterocycles
have been attractive targets for synthetic organic chemists
for many years and as a consequence, various elegant
strategies for the preparation of specifically functional-
ized pyridines5 and pyrimidines6 are well documented in
the literature. Most of the routes towards pyrimidine de-
rivatives employ the condensation reaction of 1,3-dicar-
bonyl compounds with amidines (Pinner synthesis),7 or
with aldehydes and urea (Biginelli synthesis).8 Only a few
utilized enamides as precursors for the preparation of sub-
stituted pyridine and pyrimidine derivatives.9
OMe
•
Li
O
OH
1
+
R1C
OMe
R1
R2
NH
O
TMSOTf
base
N
R2
N
2
R1
+
5
OMe
R2CO2H
4
3
R
R
1 = alkyl, aryl, hetaryl
2 = CF3, alkyl, aryl, hetaryl
ammonium salt
R2
N
N
R1
OMe
6
Scheme 1 Preparation of 4-hydroxypyridine derivatives 5 and 5-
methoxypyrimidines 6 starting from lithiated methoxyallene 1,
nitriles 2, and carboxylic acids 3 via b-alkoxy-b-ketoenamides 4.
SYNTHESIS 2010, No. 13, pp 2129–2138
Advanced online publication: 20.05.2010
DOI: 10.1055/s-0029-1218787; Art ID: C01310SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

2130
M. K. Bera, H.-U. Reissig
PAPER
tions for subsequent synthetic elaboration of the two tives gave reasonably good NMR spectra, which is very
classes of heterocycles.
likely due to the equilibrium of the 4-hydroxypyridines
with their corresponding pyridin-4-one tautomers. There-
fore, in all cases, the purified 4-hydroxypyridine deriva-
tives 9a–g were treated with sodium hydride and
nonafluorobutanesulfonyl fluoride (NfF) to provide the
less polar, easily separable pyridin-4-yl nonaflates 10a–g
in good yields (Scheme 3, Table 2).
Reaction of lithiated methoxyallene 1 (in situ generated
by deprotonation of methoxyallene with n-BuLi in Et2O)
with pivalonitrile followed by addition of the correspond-
ing a,b-unsaturated carboxylic acids 7 provided the de-
sired enamides 8a–e in very good to excellent yields. As
carboxylic acids we used acrylic, crotonic, cinnamic, 3-
(thiophen-2-yl)acrylic, and 3-(furan-2-yl)acrylic acid
(Scheme 2, Table 1, entries 1–5). To demonstrate that the
formation of 8 is not restricted to tert-butyl-substituted de-
rivatives we also examined other combinations (Table 1,
entries 6–8). Benzonitrile or thiophene-2-carbonitrile also
provided the expected enamides 8f–h in moderate to good
yields.
O
OH
OMe
R1
R2
NH
O
a
R1
R2
N
9a–g
OMe
8a–g
b
O
R2
CO2H
R3
N
ONf
OMe
R2
NH
O
7
+
OMe
R1
•
R1
C
2
N
OMe
R1
coupling
reactions
a
R1
Li
1
R2
R2
N
OMe
8a–h
10a–g
Scheme 2 Synthesis of alkenyl-substituted enamides 8a–h (see
Table 1) (a) (i) Et2O, –50 °C, 4 h; (ii) carboxylic acid 7, –78 °C to r.t.,
12 h.
Scheme 3 Preparation of 6-alkenyl-substituted 4-hydroxypyridine
derivatives 9 and conversion into pyridin-4-yl nonaflates 10 (see
Table 2). Reagents and conditions: (a) TMSOTf, Et3N, DCE, sealed
tube, 90 °C, 3 d; (b) NaH, NfF, THF, r.t., 3–12 h.
Table 1 Synthesis of Enamides 8a–h Starting from Lithiated Meth-
oxyallene 1, Nitriles 2, and a,b-Unsaturated Carboxylic Acids 7
Table 2 Synthesis of 6-Alkenyl-Substituted 4-Hydroxypyridine
Derivatives 9a–g and Subsequent Conversion into Pyridin-4-yl
Nonaflates 10a–g
Entry
R1
R2
Product
8a
Yield (%)
1
2
3
4
5
6
7
8
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
H
91
93
87
80
89
51
68
45
Entry R1
R2
Product Yield
(%)
Product Yield
(%)
Me
8b
1
2
3
4
5
6
7
8
t-Bu
H
9a
9b
9c
63
67
63
55
53
82
68
–
10a
10b
10c
10d
10e
10f
80
79
76
72
70
66
81
–
Ph
8c
t-Bu
t-Bu
t-Bu
t-Bu
Ph
Me
Ph
2-thienyl
2-furyl
Ph
8d
8e
2-thienyl 9d
8f
2-furyl
Ph
9e
9f
2-thienyl
Ph
Ph
8g
H
8h
2-thienyl Ph
Ph
9g
9h
10g
10h
We also wanted to explore the possibility of achieving the
synthesis of dialkenyl-substituted pyridine and pyrimi-
dine derivatives. Towards this end, we employed alkeny-
lated carbonitriles such as acrylonitrile and cinnamonitrile
along with a,b-unsaturated carboxylic acids in the above
mentioned reaction, however, we have not, as yet, been
able to obtain the corresponding dialkenyl-substituted
enamides.
Following the standard cyclization protocol11a enamides
8a–g were readily converted into the desired 4-hydroxy-
pyridine derivatives 9a–g in moderate to good yields
(Scheme 3, Table 2); only phenyl-substituted derivative
8h containing the acrylamide moiety failed to undergo
this cyclization. None of these 4-hydroxypyridine deriva-
H
All nonaflates 10a–g have spectroscopic data that allow
unambiguous characterization. More importantly, these
nonaflates provide the option to perform different transi-
tion-metal-catalyzed cross-coupling reactions.13 In order
to test the feasibility of palladium-catalyzed coupling re-
actions we chose pyridin-4-yl nonaflate 10c as a model
substrate. Hence, this compound was treated with trans-
styrylboronic acid under typical Suzuki coupling
conditions14 to furnish compound 11 bearing two styryl
groups in 81% yield (Scheme 4).
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

PAPER
Alkenyl-Substituted Pyridines and Pyrimidines
2131
Ph
The presence of an alkenyl subunit at C2 position of the
prepared pyrimidine derivatives 12 is very advantageous,
since this group allows smooth subsequent functionaliza-
tions. Compound 12a was employed as a model com-
pound to demonstrate the versatility of these
intermediates. A standard osmium-promoted dihydroxy-
lation protocol15 converted 12a into diol 13 which was
subjected to oxidative cleavage by sodium periodate fur-
nishing aldehyde 14 in very good overall yield
(Scheme 6).
ONf
N
OMe
OMe
a
81%
Ph
Ph
N
10c
11
Scheme 4 Synthesis of 4,6-distyryl-substituted pyridine derivative
11. Reagents and conditions: (a) trans-styrylboronic acid, Pd(OAc)2
(cat.), Ph3P (cat.), K2CO3, DMF, 70 °C, 8 h.
OH
After the successful synthesis of 2-alkenyl-substituted 4-
hydroxypyridines 9 and their nonaflates 10, we turned our
attention to the preparation of the corresponding pyrimi-
dine derivatives using enamides 8a–h. First, ammonium
hydrogen carbonate (16 equiv) dissolved in methanol at
70 °C was used to convert 8a into 12a in moderate yield
(ca. 50%). By switching to ammonium acetate12 the yield
of pyrimidine derivative 12a increased remarkably. With
this modification lower amounts of ammonium salt (8
equiv) and shorter reaction times were sufficient. There-
fore, we employed this method for the transformation of
enamides 8a–h into pyrimidine derivatives 12a–h, which
were smoothly obtained in good to very good yields
(Scheme 5, Table 3). Here, enamide 8h with the acryl-
amide moiety undergoes the condensation reaction with-
out any problem, furnishing the desired pyrimidine
derivative 12h at least in moderate yield (entry 8).
HO
N
O
N
a
b
N
N
N
N
70%
(2 steps)
OMe
OMe
OMe
12a
13
14
Scheme 6 Synthesis of pyrimidine-2-carbaldehyde 14. Reagents
and conditions: (a) K2OsO4·2 H2O, NMO, acetone–H2O (5:1), r.t., 6
h; (b) NaIO4, THF–H2O (25:1), 0 °C, 1 h.
Moreover, the methyl group, which is present at C4 of all
prepared pyrimidine derivatives 12a–h, could also be a
useful tool for further functionalization. Oxidation of the
methyl group of 12c was carried out under standard Riley
conditions16 to provide aldehyde 15 in good yield. This in-
termediate was subsequently subjected to Wittig reaction
under standard conditions to give 2,6-distyryl-substituted
pyrimidine 16 in reasonable overall yield (Scheme 7). It
has to be mentioned here that in all compounds 12 it
should also be possible to convert the methoxy group into
a nonaflate group12b under fairly mild conditions, which
obviously will allow transition-metal-catalyzed coupling
reactions at C5 of the pyrimidine core.
R2
O
R2
NH
O
a
N
N
R1
8a–e
R1
OMe
OMe
12a–e
Ph
Ph
Ph
Scheme 5 Synthesis of alkenyl-substituted pyrimidine derivatives
12 starting from 8 (see Table 3). Reagents and conditions: (a)
NH4OAc, MeOH, sealed tube, 65 °C, 24 h.
a
b
N
N
N
N
N
N
80%
45%
Table 3 Synthesis of 2-Alkenyl-Substituted Pyrimidines 12a–h
Ph
OMe O
15
OMe
12c
OMe
16
Entry
R1
R2
Product
12a
Yield (%)
1
2
3
4
5
6
7
8
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
H
77
75
85
69
67
84
78
55
Scheme 7 Preparation of pyrimidine-4-carbaldehyde 15 and olefi-
nation to 16. Reagents and conditions: (a) SeO2, 1,4-dioxane, sealed
tube, 90 °C, 2 d; (b) Ph3PCH2PhBr, n-BuLi, Et2O, 0 °C, 1 h.
Me
12b
12c
Ph
2-thienyl
2-furyl
Ph
12d
12e
After the successful synthesis of a set of alkenyl-substitut-
ed pyridine and pyrimidine derivatives, our next objective
was to prepare the related allyl-substituted analogues. To
realize our target, the required allylated enamide 18 was
efficiently obtained by the three-component reaction in-
volving lithiated methoxyallene 1, pivalonitrile (2a), and
but-3-enoic acid (17) (Scheme 8). b-Alkoxy-b-ketoen-
amide 18 was smoothly converted into the corresponding
2-allyl-substituted pyrimidine 19 in the presence of am-
monium acetate in refluxing methanol. We expected that
12f
2-thienyl
Ph
Ph
12g
H
12h
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

2132
M. K. Bera, H.-U. Reissig
PAPER
the terminal double bond of enamide 18 or pyrimidine 19 The newly prepared pyridine and pyrimidine derivatives
might migrate to provide a conjugated system in the pres- contain a system with at least one alkenyl unit conjugated
ence of an amine. This was apparently not the case under with the heterocyclic core. Therefore, we were also inter-
the fairly mild conditions required for pyrimidine genera- ested in the physical properties of these compounds, in
tion. On the other hand, our expectation was found to be particular the optical properties.2 Hence, a series of UV-
correct when harsher conditions for pyridine synthesis Vis and fluorescence spectra were recorded and the results
were applied. Instead of an allyl-substituted pyridine de- are summarized in Table 4. The cross-conjugated pyri-
rivative the already known 4-hydroxypyridine derivative dine derivative 11 (Figure 1 and Table 4, entry 4) shows
9b was obtained (Scheme 8). It was routinely transformed the largest Stokes shift, but pyrimidines 12e and 16 have
into pyridin-4-yl nonaflate 10b whose spectroscopic data similar absorptions and emissions resulting in Stokes
undoubtedly agree with the compound already discussed shifts in the range of 110 nm.
(Scheme 2, Table 1). This observation was further con-
firmed by carrying out an attempted cyclization reaction
of enamide 18 at room temperature. After three days we
Table 4 UV-Vis and Fluorescence Spectra of Pyridine Derivatives
9d, 9e, 10d, and 11, and of Pyrimidine Derivatives 12e and 16
found that compound 18 was transformed into enamide 8b
Entry
Compound
l
Abs (nm)
lEm (nm) Stokes shift (nm)
containing a crotonic acid moiety. Since we did not ob-
serve any pyridine derivative, we conclude that under
these conditions allyl-substituted enamide 18 undergoes
double bond migration considerably faster than the cy-
clization reaction.
1
2
3
4
5
6
9d
9e
348
350
340
309
324
306
393
405
404
423
435
419
45
55
10d
11
64
114
111
113
OMe
•
12e
16
O
Li
1
NH
O
N
N
+
C
2a
+
b
a
t-Bu
N
68%
82%
In conclusion, a variety of new 2-alkenyl-substituted 4-
hydroxypyridine and pyrimidine derivatives have been
synthesized by a two-step procedure employing first the
three-component reaction of lithiated methoxyallene, ni-
triles, and a series of a,b-unsaturated carboxylic acids to
b-alkoxy-b-ketoenamides followed by the appropriate cy-
clization steps. It should be mentioned here, that the cru-
cial three-component reaction works with a broad range of
nitriles although frequently with lower yields.11 Instead of
tert-butyl groups as presented in this report in most of our
examples other alkyl or (hetero)aryl substituents are also
possible. First examples in this report demonstrate that the
enamide formation is smooth, however, that the cycliza-
tion to pyridine derivatives may require occasionally
milder conditions.
OMe
OMe
18
19
COOH
17
c
60%
OH
N
ONf
OMe
OMe
d
78%
N
9b
10b
Scheme 8 Conversion of allyl-substituted enamide 18 into 2-allyl-
pyrimidine 19 and pyridine derivatives 9b and 10b. Reagents and
conditions: (a) Et2O, –78 °C to r.t., 12 h; (b) NH4OAc, MeOH, sealed
tube, 65 °C, 24 h; (c) TMSOTf, Et3N, DCE, sealed tube, 90 °C, 3 d;
(d) NaH, NfF, THF, r.t., 12 h.
Figure 1 UV-Vis and fluorescence spectra of pyridine derivative 11
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

PAPER
Alkenyl-Substituted Pyridines and Pyrimidines
2133
mmol) in anhyd Et2O (50 mL) gave 8b (0.810 g, 93%) as pale yel-
low crystals; mp 145–148 °C.
The alkenyl group and the methyl group of the heterocy-
cles could be employed for further functionalizations. In
addition, the variety of highly substituted pyridine deriva- IR (KBr): 3335 (NH), 3020–2960 (=CH, C–H), 1685–1505 cm–1
(C=O, C=C).
tives accessible can further be increased by employing
1H NMR (400 MHz, CDCl3): d = 1.13 (s, 9 H, t-Bu), 1.75 (dd,
J = 3.7, 1.5 Hz, 3 H, =CHMe), 2.21 (s, 3 H, COMe), 3.44 (s, 3 H,
OMe), 5.82 (dd, J = 15.2, 1.5 Hz, 1 H, =CH), 6.73–6.78 (m, 1 H,
=CH), 7.47 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 17.8 (q, =CHMe), 27.8 (q, Me),
28.4, 36.5 (s, q, t-Bu), 58.8 (q, OMe), 124.7, 133.2, 141.4, 150.7 (2
d, 2 s, C1, C2, HC=CH), 165.6 (s, C1¢), 200.7 (s, C3).
palladium-catalyzed coupling reactions of the corre-
sponding pyridin-4-yl nonaflates. Therefore our modular
approach to specifically substituted pyridine and pyrimi-
dine derivates will considerably increase the availability
of these important heterocycles.
Reactions were generally performed under argon in flame-dried
flasks, and the components were added by syringe. Products were
purified by flash chromatography on silica gel (230–400 mesh,
Merck). Unless otherwise stated, yields refer to analytically pure
HRMS: m/z [M + Na]+ calcd for C13H21NNaO3: 262.1419; found:
262.1417.
Anal. Calcd for C13H21NO3 (239.3): C, 65.25; H, 8.84; N, 5.85.
Found: C, 65.05; H, 8.81; N, 5.84.
1
samples. H NMR [CHCl3 (d = 7.26), TMS (d = 0.00) as internal
standard] and 13C NMR spectra [CDCl3 (d = 77.0) as internal stan-
dard] were recorded with Joel ECX 400 instruments in CDCl3 solns.
Integrals are in accordance with assignments. IR spectra were mea-
sured with an FT-IR spectrophotometer Nicolet 5 SXC. HRMS
analyses were performed with Agilent 6210 (ESI-TOF, 4 mL/min,
1.0 bar, 4 kV) instrument. The elemental analyses were recorded
with Elemental-Analyzers (Perkin-Elmer or Carlo Erba). UV/Vis
spectra were measured with a UV-Vis spectrophotometer Scinco
S-3150 PDA. Fluorescence spectra were measured with a spectro-
fluorometer Jasco FP-6500.
N-[(E)-4-Methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl]cinnam-
amide (8c)
According to typical procedure 1, a mixture of methoxyallene (1.10
mL, 13.0 mmol), 2.5 M n-BuLi in hexanes (5.00 mL, 12.5 mmol),
pivalonitrile (0.70 mL, 6.33 mmol), and cinnamic acid (3.75 g, 25.3
mmol) in anhyd Et2O (75 mL) gave 8c (1.65 g, 87%) as a pale yel-
low solid; mp 125–128 °C.
IR (KBr): 3315 (NH), 3060–2835 (=CH, C–H), 1675–1575 cm–1
(C=O, C=C).
Methoxyallene was prepared according to the reported proce-
dure.10a All other chemicals are commercially available and were
used without further purification.
1H NMR (400 MHz, CDCl3): d = 1.20 (s, 9 H, t-Bu), 2.33 (s, 3 H,
COMe), 3.49 (s, 3 H, OMe), 6.50 (d, J = 15.7 Hz, 1 H, =CHCO),
7.19–7.28 (m, 5 H, Ph), 7.46 (d, J = 15.7 Hz, 1 H, =CHPh), 7.90 (s,
1 H, NH).
13C NMR (100 MHz, CDCl3): d = 27.6 (q, Me), 28.4, 36.4 (s, q, t-
Bu), 58.8 (q, OMe), 119.9, 134.5, 141.9, 150.5 (2 d, 2 s, C1, C2,
HC=CH), 127.7, 128.4, 129.4, 132.5 (3 d, s, Ph), 165.5 (s, C1¢),
201.0 (s, C3).
(E)-N-(4-Methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl)acryl-
amide (8a); Typical Procedure 1
To a soln of methoxyallene (0.83 mL, 9.86 mmol) in anhyd Et2O
(25 mL) was added 2.5 M n-BuLi in hexanes (3.60 mL, 9.00 mmol)
at –50 °C. The mixture was stirred at –50 °C for 30 min and then it
was cooled to –78 °C and pivalonitrile (0.33 mL, 3.0 mmol) in an-
hyd Et2O (5 mL) was added to the mixture, which was stirred at this
temperature for 4 h. A soln of acrylic acid (1.25 mL, 18.2 mmol) in
anhyd Et2O (10 mL) was added to the mixture and the temperature
was allowed to increase to r.t. and the mixture was stirred overnight.
The reaction was quenched with sat. aq NaHCO3 soln (20 mL) and
the product was extracted with Et2O (3 × 50 mL). The combined or-
ganic layers were washed with brine (25 mL) and finally dried
(Na2SO4). Solvent was removed on a rotary evaporator and the
crude product was purified by column chromatography (silica gel,
hexane–EtOAc, 1:1) to give 8a (0.615 g, 91%) as pale yellow crys-
tals; mp 140–144 °C.
IR (KBr): 3310 (NH), 3010–2835 (=CH, C–H), 1685–1510 cm–1
(C=O, C=C).
1H NMR (400 MHz, CDCl3): d = 1.16 (s, 9 H, t-Bu), 2.25 (s, 3 H,
COMe), 3.48 (s, 3 H, OMe), 5.59 (dd, J = 8.0, 1.8 Hz, 1 H, =CH2),
6.11–6.26 (m, 2 H, CH2=CH), 7.56 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 27.7 (q, Me), 28.5, 36.6 (s, q, t-
Bu), 58.9 (q, OMe), 127.7 (t, =CH2), 130.5, 132.9, 150.8 (2 s, d, C1,
C2, =CH), 165.3 (s, C1¢), 200.9 (s, C3).
HRMS: m/z [M + Na]+ calcd for C18H23NNaO3: 324.1576; found:
324.1574.
Anal. Calcd for C18H23NO3 (301.4): C, 71.73; H, 7.69; N, 4.65.
Found: C, 71.60; H, 7.75; N, 4.37.
(E)-N-[(E)-4-Methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl]-3-
(thiophen-2-yl)acrylamide (8d)
According to typical procedure 1, a mixture of methoxyallene (1.30
mL, 15.4 mmol), 2.5 M n-BuLi in hexanes (5.80 mL, 14.5 mmol),
pivalonitrile (0.80 mL, 7.24 mmol), and (E)-3-(thiophen-2-yl)acryl-
ic acid (4.45 g, 28.9 mmol) in anhyd Et2O (75 mL) gave 8d (1.77 g,
80%) as a pale yellow solid; mp 150–152 °C.
IR (KBr): 3290 (NH), 3100–2830 (=CH, C–H), 1700 (C=O), 1655–
1425 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.21 (s, 9 H, t-Bu), 2.32 (s, 3 H,
Me), 3.51 (s, 3 H, OMe), 6.26 (d, J = 15.2 Hz, 1 H, =CHCO), 6.91
(dd, J = 5.0, 3.5 Hz, 1 H, Hthienyl), 6.99 (d, J = 3.5 Hz, 1 H, Hthienyl),
7.23 (d, J = 5.0 Hz, 1 H, Hthienyl), 7.59 (d, J = 15.2 Hz, 1 H, =CH-
thienyl), 7.60 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 27.7 (q, Me), 28.6, 36.6 (s, q, t-
Bu), 59.1 (q, OMe), 119.1, 132.7, 134.8, 139.9, 150.6 (2 d, 3 s, C1,
C2, HC=CH, Cthienyl), 127.7, 127.9, 130.2 (3 d, Cthienyl), 165.4 (s,
C1¢), 201.2 (s, C3).
HRMS: m/z [M + Na]+ calcd for C12H19NNaO3: 248.1257; found:
248.1258.
Anal. Calcd for C12H19NO3 (225.1): C, 63.98; H, 8.50; N, 6.22.
Found: C, 63.85; H, 8.56; N, 6.23.
HRMS: m/z [M + Na]+ calcd for C16H21NNaO3S: 330.1140; found:
330.1138.
(E)-N-[(E)-4-Methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl]but-2-
enamide (8b)
According to typical procedure 1, a mixture of methoxyallene (1.00
mL, 11.9 mmol), 2.5 M n-BuLi in hexanes (4.32 mL, 10.8 mmol),
pivalonitrile (0.40 mL, 3.61 mmol), and crotonic acid (1.90 g, 22.1
(E)-3-(Furan-2-yl)-N-[(E)-4-methoxy-2,2-dimethyl-5-oxohex-3-
en-3-yl]acrylamide (8e)
According to typical procedure 1, a mixture of methoxyallene (1.10
mL, 13.0 mmol), 2.5 M n-BuLi in hexanes (5.00 mL, 12.5 mmol),
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

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M. K. Bera, H.-U. Reissig
PAPER
pivalonitrile (0.70 mL, 6.33 mmol), and (E)-3-(furan-2-yl)acrylic
acid (3.50 g, 25.4 mmol) in anhyd Et2O (75 mL) gave 8e (1.63 g,
89%) as a pale yellow solid; mp 134–137 °C.
1H NMR (400 MHz, CDCl3): d = 2.36 (s, 3 H, Me), 3.18 (s, 3 H,
OMe), 5.73 (dd, J = 9.8, 1.6 Hz, 1 H, =CH), 6.17–6.32 (m, 2 H,
=CH2, =CH), 7.37–7.43 (m, 5 H, Ph), 11.54 (br s, 1 H, NH).
IR (KBr): 3260 (NH), 3150–2835 (=CH, C–H), 1695–1495 cm–1
(C=O, C=C).
1H NMR (400 MHz, CDCl3): d = 1.19 (s, 9 H, t-Bu), 2.28 (s, 3 H,
Me), 3.49 (s, 3 H, OMe), 6.33–6.35 (m, 1 H, Hfuryl), 6.34 (d, J = 15.4
Hz, 1 H, =CHCO), 6.43–6.45 (m, 1 H, Hfuryl), 7.31 (d, J = 15.4 Hz,
1 H, =CH-furyl), 7.29–7.33 (m, 1 H, Hfuryl), 7.71 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 27.5 (q, Me), 60.7 (q, OMe),
127.9, 128.4, 128.9 (3 d, Ph), 128.7 (t, =CH2), 131.4, 132.1, 138.6,
142.8 (2 d, 2 s, C1, C2, =CH, Ph), 163.9 (s, C1¢), 202.3 (s, C3).
HRMS: m/z [M + Na]+ calcd for C14H15NNaO3: 268.0950; found:
268.0951.
2-tert-Butyl-3-methoxy-6-vinylpyridin-4-ol (9a) and 2-tert-Bu-
tyl-3-methoxy-6-vinylpyridin-4-yl Nonaflate (10a); Typical
Procedure 2
HRMS: m/z [M + Na]+ calcd for C16H21NNaO4: 314.1368; found:
314.1385.
Anal. Calcd for C16H21NO4 (291.3): C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.32; H, 7.23; N, 4.58.
Enamide 8a (0.225 g, 1.00 mmol) was dissolved in DCE (20 mL)
and placed in a sealed tube. Then Et3N (0.70 mL, 5.00 mmol) and
TMSOTf (0.90 mL, 5.00 mmol) were added at r.t. The resulting
mixture was heated at 90 °C for 3 d and quenched with sat. aq
NH4Cl soln (10 mL). After extraction with CH2Cl2 (3 × 25 mL), the
combined organic layers were dried (Na2SO4) and evaporated to
provide the crude product, which was purified by column chroma-
tography (silica gel, EtOAc) affording 9a (0.130 g, 63%) as a brown
liquid.
N-[(E)-2-Methoxy-3-oxo-1-phenylbut-1-enyl]cinnamamide (8f)
According to typical procedure 1, a mixture of methoxyallene (1.35
mL, 16.0 mmol), 2.5 M n-BuLi in hexanes (5.90 mL, 14.8 mmol),
benzonitrile (0.75 mL, 7.35 mmol), and cinnamic acid (4.30 g, 29.0
mmol) in anhyd Et2O (40 mL) gave 8f (1.21 g, 51%) as a pale yel-
low solid; mp 115–120 °C.
IR (KBr): 3310 (NH), 3095–2950 (=CH, C–H), 1705–1630 cm–1
(C=O, C=C).
1H NMR (400 MHz, CDCl3): d = 2.39 (s, 3 H, Me), 3.20 (s, 3 H,
OMe), 6.54 (d, J = 15.7 Hz, 1 H, =CHCO), 7.35–7.37 (m, 2 H, Ph),
7.39–7.42 (m, 3 H, Ph), 7.46–7.51 (m, 5 H, Ph), 7.61 (d, J = 15.7
Hz, 1 H, =CHPh), 11.65 (s, 1 H, NH).
Pyridinol 9a (0.130 g, 0.628 mmol) was dissolved in THF (10 mL)
and NaH (75 mg, 3.12 mmol) was added under an argon atmo-
sphere. Nonafluorobutanesulfonyl fluoride (0.55 mL, 3.04 mmol)
was added dropwise at r.t. The mixture was stirred at this tempera-
ture for 12 h and quenched by slow addition of H2O. The resulting
product was extracted with Et2O (3 × 25 mL), dried (Na2SO4), and
concentrated to dryness. The residue was purified by column chro-
matography (silica gel, 2–5% EtOAc–hexane) to give 10a (0.245 g,
80%) as a colorless oil.
13C NMR (100 MHz, CDCl3): d = 27.5 (q, Me), 60.7 (q, OMe),
120.9, 130.3, 132.3, 134.5, 138.5, 143.3 (2 d, 4 s, C1, C2, HC=CH,
Ph), 127.9, 128.2, 128.4, 128.9, 129.0 (5 d, Ph), 164.4 (s, C1¢),
202.7 (s, C3).
IR (neat): 2960–2870 (C–H), 1585–1430 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 9 H, t-Bu), 3.91 (s, 3 H,
OMe), 5.46 (dd, J = 10.5, 1.4 Hz, 1 H, =CH2), 6.23 (dd, J = 17.2,
1.5 Hz, 1 H, =CH2), 6.70 (dd, J = 17.2, 10.5 Hz, 1 H, =CH), 7.03 (s,
1 H, HPy).
13C NMR (100 MHz, CDCl3): d = 29.2, 38.9 (s, q, t-Bu), 61.8 (q,
OMe), 112.6 (d, C5), 118.9 (t, =CH2), 135.4 (d, =CH), 146.2, 149.9,
150.2, 164.3 (4 s, C2, C3, C4, C6).
HRMS: m/z [M + Na]+ calcd for C20H19NNaO3: 344.1263; found:
344.1251.
N-[(E)-2-Methoxy-3-oxo-1-(thiophen-2-yl)but-1-enyl]cinnam-
amide (8g)
According to typical procedure 1, a mixture of methoxyallene (1.00
mL, 12.1 mmol), 2.5 M n-BuLi in hexanes (4.40 mL, 11.0 mmol),
thiophene-2-carbonitrile (0.50 mL, 5.37 mmol), and cinnamic acid
(3.66 g, 24.7 mmol) in anhyd Et2O (50 mL) gave 8g (1.21 g, 68%)
as a deep brownish solid; mp 108–110 °C.
19F NMR (470 MHz, CDCl3): d = –80.6, –109.5, –120.6, –125.7.
HRMS: m/z [M + H]+ calcd for C16H17F9NO4S: 490.0735; found:
490.0737.
IR (KBr): 3280 (NH), 3015–2860 (=CH, C–H), 1685–1570 cm–1
(C=O, C=C).
1H NMR (400 MHz, CDCl3): d = 2.39 (s, 3 H, Me), 3.50 (s, 3 H,
OMe), 6.58 (d, J = 15.7 Hz, 1 H, =CHCO), 7.05–7.08 (m, 1 H,
Hthienyl), 7.35–7.40 (m, 4 H, Ph, Hthienyl), 7.49–7.52 (m, 3 H, Ph),
7.65 (d, J = 15.7 Hz, 1 H, =CHPh), 10.44 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 27.8 (q, Me), 60.2 (q, OMe),
120.7, 130.0, 130.3, 131.3, 133.1, 133.7, 134.4, 143.4 (5 d, 3 s, C1,
C2, HC=CH, Cthienyl), 126.8, 128.2, 128.9 (3 d, Ph), 165.7 (s, C1¢),
200.8 (s, C3).
Anal. Calcd for C16H16F9NO4S (489.4): C, 39.27; H, 3.30; N, 2.86;
S, 6.55. Found: C, 39.67; H, 2.89; N, 2.86; S, 6.61.
(E)-2-tert-Butyl-3-methoxy-6-(prop-1-enyl)pyridin-4-ol (9b)
and (E)-2-tert-Butyl-3-methoxy-6-(prop-1-enyl)pyridin-4-yl
Nonaflate (10b)
According to typical procedure 2, a mixture of enamide 8b (0.205
g, 0.858 mmol), Et3N (0.60 mL, 4.30 mmol), and TMSOTf (0.80
mL, 4.30 mmol) in DCE (20 mL) gave 9b (0.127 g, 67%) as a brown
oil.
HRMS: m/z [M + Na]+ calcd for C18H17NNaO3S: 350.0827; found:
350.0822.
A mixture of pyridinol 9b (0.127 g, 0.575 mmol), NaH (70 mg, 2.92
mmol), and NfF (0.500 mL, 2.78 mmol) in THF (10 mL) gave 10b
(0.228 g, 79%) as a colorless oil.
(E)-N-(2-Methoxy-3-oxo-1-phenylbut-1-enyl)acrylamide (8h)
According to typical procedure 1, a mixture of methoxyallene (1.30
mL, 15.8 mmol), 2.5 M n-BuLi in hexanes (5.80 mL, 14.5 mmol),
benzonitrile (0.50 mL, 4.90 mmol), and acrylic acid (2.00 mL, 29.1
mmol) in anhyd Et2O (25 mL) gave 8h (0.55 g, 45%) as a brownish
solid; mp 135–138 °C.
IR (neat): 2960–2870 (C–H), 1660–1400 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.41 (s, 9 H, t-Bu), 1.91 (dd,
J = 6.8, 1.6 Hz, 3 H, =CHMe), 3.88 (s, 3 H, OMe), 6.40 (dd,
J = 15.4, 1.6 Hz, 1 H, =CHMe), 6.77 (dd, J = 15.4, 6.8 Hz, 1 H,
=CH-Py), 6.92 (s, 1 H, HPy).
IR (KBr): 3295 (NH), 3070–2835 (=CH, C–H), 1705–1570 cm–1
(C=O, C=C).
13C NMR (100 MHz, CDCl3): d = 18.2 (q, Me), 29.3, 38.9 (s, q, t-
Bu), 61.8 (q, OMe), 111.8 (d, C5), 129.9, 131.7 (2 d, HC=CH),
145.4, 150.0, 150.8, 164.0 (4 s, C2, C3, C4, C6).
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

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Alkenyl-Substituted Pyridines and Pyrimidines
2135
HRMS: m/z [M + H]+ calcd for C17H19F9NO4S: 504.0891; found:
HRMS: m/z [M + H]+ calcd for C20H19F9NO5S: 556.0840; found:
504.0885.
556.0851.
(E)-2-tert-Butyl-3-methoxy-6-styrylpyridin-4-ol (9c) and (E)-2-
tert-Butyl-3-methoxy-6-styrylpyridin-4-yl Nonaflate (10c)
According to typical procedure 2, a mixture of enamide 8c (0.219 g,
0.727 mmol), Et3N (0.50 mL, 3.58 mmol), and TMSOTf (0.65 mL,
3.58 mmol) in DCE (14 mL) gave 9c (0.130 g, 63%) as a brown oil.
(E)-3-Methoxy-2-phenyl-6-styrylpyridin-4-ol (9f) and (E)-3-
Methoxy-2-phenyl-6-styrylpyridin-4-yl Nonaflate (10f)
According to typical procedure 2, a mixture of enamide 8f (0.195 g,
0.607 mmol), Et3N (0.425 mL, 3.04 mmol), and TMSOTf (0.55 mL,
3.04 mmol) in DCE (12 mL) gave 9f (0.152 g, 82%) as a brownish
foam.
A mixture of pyridinol 9c (0.130 g, 0.459 mmol), NaH (55 mg, 2.29
mmol), and NfF (0.40 mL, 2.22 mmol) in THF (10 mL) gave 10c
(0.197 g, 76%) as a colorless oil.
IR (neat): 2960–2870 (C–H), 1580–1200 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.48 (s, 9 H, t-Bu), 3.93 (s, 3 H,
OMe), 7.07 (d, J = 15.9 Hz, 1 H, =CH-Py), 7.11 (s, 1 H, HPy), 7.29–
7.40 (m, 3 H, Ph), 7.56–7.59 (m, 2 H, Ph), 7.64 (d, J = 15.9 Hz, 1
H, =CHPh).
13C NMR (100 MHz, CDCl3): d = 29.3, 39.1 (s, q, t-Bu), 61.9 (q,
OMe), 113.2 (d, C5), 126.7, 127.3, 128.5, 128.8, 133.6, 136.5 (5 d,
s, Ph, HC=CH), 145.8, 150.0, 150.3, 164.4 (4 s, C2, C3, C4, C6).
A mixture of pyridinol 9f (70 mg, 0.231 mmol), NaH (55 mg, 2.29
mmol), and NfF (0.40 mL, 2.22 mmol) in THF (5 mL) was stirred
at r.t. for 3 h to give 10f (90 mg, 66%) as a colorless oil.
IR (neat): 3010–2890 (C–H), 1575–1380 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 3.64 (s, 3 H, OMe), 7.16 (d,
J = 16.0 Hz, 1 H, =CH-Py), 7.22 (s, 1 H, HPy), 7.30–7.41 (m, 3 H,
Ph), 7.47–7.54 (m, 3 H, Ph), 7.57–7.59 (m, 2 H, Ph), 7.65 (d,
J = 16.0 Hz, 1 H, =CHPh), 8.00–8.03 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 61.6 (q, OMe), 113.3 (d, C5),
126.3, 127.3, 128.6, 128.8, 128.9, 129.1, 129.6, 134.3 (8 d, Ph,
HC=CH), 136.2, 136.6 (2 s, Ph), 145.1, 150.1, 152.6, 154.1 (4 s, C2,
C3, C4, C6).
19F NMR (470 MHz, CDCl3): d = –80.5, –109.4, –120.6, –125.7.
HRMS: m/z [M + H]+ calcd for C22H21F9NO4S: 566.1048; found:
19F NMR (470 MHz, CDCl3): d = –80.4, –109.2, –120.5, –125.6.
HRMS: m/z [M + H]+ calcd for C24H17F9NO4S: 586.0735; found:
566.1057.
(E)-2-tert-Butyl-3-methoxy-6-[2-(thiophen-2-yl)vinyl]pyridin-
4-ol (9d) and (E)-2-tert-Butyl-3-methoxy-6-[2-(thiophen-2-yl)vi-
nyl]pyridin-4-yl Nonaflate (10d)
According to typical procedure 2, a mixture of enamide 8d (0.220
g, 0.717 mmol), Et3N (0.50 mL, 3.58 mmol), and TMSOTf (0.650
mL, 3.59 mmol) in DCE (15 mL) gave 9d (0.115 g, 55%) as a brown
oil.
586.0743.
Anal. Calcd for C24H16F9NO4S (585.4): C, 49.24; H, 2.75; N, 2.39;
S, 5.48. Found: C, 49.67; H, 2.85; N, 2.43; S, 5.21.
(E)-3-Methoxy-6-styryl-2-(thiophen-2-yl)pyridin-4-ol (9g) and
(E)-3-Methoxy-6-styryl-2-(thiophen-2-yl)pyridin-4-yl Nona-
flate (10g)
A mixture of pyridinol 9d (0.115 g, 0.398 mmol), NaH (47 mg, 1.96
mmol), and NfF (0.350 mL, 1.96 mmol) in THF (10 mL) gave 10d
(0.165 g, 72%) as a colorless oil.
IR (neat): 3115–2870 (=CH, C–H), 1630–1290 cm–1 (C=C).
According to typical procedure 2, a mixture of enamide 8g (0.210
g, 0.642 mmol), Et3N (0.45 mL, 3.23 mmol), and TMSOTf (0.60
mL, 3.31 mmol) in DCE (10 mL) gave 9g (0.135 g, 68%) as a
brownish foam.
A mixture of pyridinol 9g (62 mg, 0.201 mmol), NaH (24 mg, 1.00
mmol), and NfF (0.20 mL, 1.11 mmol) in THF (5 mL) was stirred
at r.t. for 3 h to give 10g (95 mg, 81%) as a pale yellow oil.
IR (neat): 3060–2945 (C–H), 1550–1425 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.46 (s, 9 H, t-Bu), 3.92 (s, 3 H,
OMe), 6.86 (d, J = 15.5 Hz, 1 H, =CH-Py), 7.02–7.04 (m, 1 H,
Hthienyl), 7.03 (s, 1 H, HPy), 7.18 (d, J = 3.7 Hz, 1 H, Hthienyl), 7.26 (d,
J = 3.7 Hz, 1 H, Hthienyl), 7.77 (d, J = 15.5 Hz, 1 H, =CH-thienyl).
13C NMR (100 MHz, CDCl3): d = 29.3, 39.1 (s, q, t-Bu), 61.9 (q,
OMe), 113.1, 125.7, 125.9, 126.6, 127.9, 128.0, 142.0 (6 d, s, C5,
HC=CH, Cthienyl), 145.8, 149.8, 149.9, 164.5 (4 s, C2, C3, C4, C6).
1H NMR (400 MHz, CDCl3): d = 3.94 (s, 3 H, OMe), 7.09 (d,
J = 16.0 Hz, 1 H, =CH-Py), 7.12 (s, 1 H, HPy), 7.17–7.19 (m, 1 H,
Hthienyl), 7.31–7.42 (m, 3 H, Ph), 7.51 (dd, J = 5.0, 1.0 Hz, 1 H,
H
thienyl), 7.59–7.61 (m, 2 H, Ph), 7.68 (d, J = 16.0 Hz, 1 H, =CHPh),
HRMS: m/z [M + H]+ calcd for C20H19F9NO4S2: 572.0612; found:
572.0612.
8.06–8.07 (m, 1 H, Hthienyl).
13C NMR (100 MHz, CDCl3): d = 61.2 (q, OMe), 112.9 (d, C5),
126.0, 127.4, 128.2, 128.9, 129.1, 129.4, 134.6, 134.7, 136.2, 140.2
(8 d, 2 s, Ph, Cthienyl, HC=CH), 142.8, 148.5, 150.4, 152.6 (4 s, C2,
C3, C4, C6).
(E)-2-tert-Butyl-6-[2-(furan-2-yl)vinyl]-3-methoxypyridin-4-ol
(9e) and (E)-2-tert-Butyl-6-[2-(furan-2-yl)vinyl]-3-methoxypy-
ridin-4-yl Nonaflate (10e)
According to typical procedure 2, a mixture of enamide 8e (0.185 g,
0.635 mmol), Et3N (0.45 mL, 3.23 mmol), and TMSOTf (0.60 mL,
3.24 mmol) in DCE (13 mL) gave 9e (92 mg, 53%) as a brownish
oil.
19F NMR (470 MHz, CDCl3): d = –80.4, –109.2, –120.5, –125.6.
HRMS: m/z [M + H]+ calcd for C22H15F9NO4S2: 592.0298; found:
592.0324.
Anal. Calcd for C22H14F9NO4S2 (591.5): C, 44.67; H, 2.39; N, 2.37;
S, 10.84. Found: C, 44.94; H, 2.39; N, 2.39; S, 10.51.
A mixture of pyridinol 9e (92 mg, 0.337 mmol), NaH (40 mg, 1.67
mmol), and NfF (0.30 mL, 1.67 mmol) in THF (8 mL) gave 10e
(0.130 g, 70%) as a colorless oil.
IR (neat): 2955–2855 (C–H), 1620–1350 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.45 (s, 9 H, t-Bu), 3.91 (s, 3 H,
OMe), 6.44–6.48 (m, 2 H, Hfuryl), 6.95 (d, J = 15.5 Hz, 1 H, =CH-
Py), 7.00 (s, 1 H, HPy), 7.43 (s, 1 H, Hfuryl), 7.45 (d, J = 15.5 Hz, 1
H, =CH-furyl).
13C NMR (100 MHz, CDCl3): d = 29.3, 39.1 (s, q, t-Bu), 61.9 (q,
OMe), 111.0, 111.9, 113.4, 120.9, 124.6, 142.9, 145.7 (6 d, s, C5,
HC=CH, Cfuryl), 149.8, 149.9, 152.8, 164.4 (4 s, C2, C3, C4, C6).
2-tert-Butyl-3-methoxy-4,6-distyrylpyridine (11)
A mixture of pyridinyl nonaflate 10c (85 mg, 0.150 mmol),
Pd(OAc)2 (4 mg, 0.020 mmol), Ph3P (8 mg, 0.032 mmol), K2CO3
(25 mg, 0.181 mmol), and trans-styrylboronic acid (27 mg, 0.183
mmol) in DMF (5 mL) was heated at 70 °C for 8 h under an argon
atmosphere. The mixture was cooled to r.t., diluted with brine (5
mL), and extracted with Et2O (3 × 10 mL). The combined organic
phases were dried (Na2SO4) and concentrated to dryness. The resi-
due was purified by column chromatography (silica gel, 2%
EtOAc–hexane) to give 11 (45 mg, 81%) as a colorless oil.
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

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M. K. Bera, H.-U. Reissig
PAPER
IR (neat): 3080–2865 (=CH, C–H), 1635–1355 cm–1 (C=C).
HRMS: m/z [M + H]+ calcd for C18H23N2O: 283.1810; found:
283.1766.
1H NMR (400 MHz, CDCl3): d = 1.49 (s, 9 H, t-Bu), 3.80 (s, 3 H,
OMe), 7.16 (d, J = 16.0 Hz, 1 H, =CH-Py), 7.26–7.43 (m, 10 H, Ph),
7.57–7.59 (m, 3 H, Ph, HPy), 7.64 (d, J = 16.0 Hz, 1 H, =CHPh).
13C NMR (100 MHz, CDCl3): d = 29.8, 38.4 (s, q, t-Bu), 62.5 (q,
OMe), 117.6 (d, C5), 122.6, 126.9, 127.1, 127.9, 128.3, 128.6,
128.7, 128.8, 128.9, 131.5, 132.5, 136.9, 137.3, 138.5, 148.7, 152.4,
161.5 (10 d, 6 s, Ph, HC=CH, C2, C3, C4, C6).
(E)-4-tert-Butyl-5-methoxy-6-methyl-2-[2-(thiophen-2-yl)vi-
nyl]pyrimidine (12d)
According to typical procedure 3, a mixture of enamide 8d (0.225
g, 0.733 mmol) and NH4OAc (0.450 g, 5.84 mmol) in MeOH (5
mL) gave 12d (0.145 g, 69%) as a colorless oil.
IR (neat): 2955–2865 (C–H), 1630–1360 cm–1 (C=C, C=N).
HRMS: m/z [M + H]+ calcd for C26H28NO: 370.2165; found:
370.2183.
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 9 H, t-Bu), 2.49 (s, 3 H,
Me), 3.76 (s, 3 H, OMe), 6.97 (d, J = 16.1 Hz, 1 H, =CH-Pyr), 6.96–
7.02 (m, 1 H, Hthienyl), 7.18 (d, J = 3.6 Hz, 1 H, Hthienyl), 7.24 (d,
J = 5.8 Hz, 1 H, Hthienyl), 7.94 (d, J = 16.1 Hz, 1 H, =CH-thienyl).
Anal. Calcd for C26H27NO (369.5): C, 84.51; H, 7.37; N, 3.79.
Found: C, 83.70; H, 7.57; N, 3.63.
13C NMR (100 MHz, CDCl3): d = 19.8 (q, Me), 29.2, 38.1 (s, q, t-
Bu), 61.1 (q, OMe), 126.0, 127.3, 127.8 128.1, 129.1, 142.1 (5 d, s,
Cthienyl, HC=CH), 150.4, 157.6, 159.9, 168.0 (4 s, C2, C4, C5, C6).
HRMS: m/z [M + H]+ calcd for C16H21N2OS: 289.1358; found:
289.1363.
4-tert-Butyl-5-methoxy-6-methyl-2-vinylpyrimidine (12a); Typ-
ical Procedure 3
Enamide 8a (0.285 g, 1.27 mmol) and NH4OAc (0.780 g, 10.1
mmol) were placed in an ACE-sealed tube. The mixture was dis-
solved in MeOH (5 mL) and stirred at 65 °C for 1 d. After addition
of H2O and Et2O (10 mL) the layers were separated and the aqueous
layer was extracted with Et2O (2 × 20 mL). The combined organic
layers were dried (Na2SO4), filtered, and evaporated to dryness.
Column chromatography (silica gel, hexane–EtOAc, 10:1) provid-
ed 12a (0.200 g, 77%) as a colorless oil.
(E)-4-tert-Butyl-2-[2-(furan-2-yl)vinyl]-5-methoxy-6-methylpy-
rimidine (12e)
According to typical procedure 3, a mixture of enamide 8e (0.205 g,
0.704 mmol) and NH4OAc (0.435 g, 5.64 mmol) in MeOH (5 mL)
gave 12e (0.128 g, 67%) as a colorless oil.
IR (neat): 2955–2885 (C–H), 1555–1365 cm–1 (C=C, C=N).
IR (neat): 3115–2870 (=CH, C–H), 1640–1360 cm–1 (C=C, C=N).
1H NMR (400 MHz, CDCl3): d = 1.39 (s, 9 H, t-Bu), 2.48 (s, 3 H,
Me), 3.76 (s, 3 H, OMe), 5.58 (dd, J = 10.5, 2.1 Hz, 1 H, =CH2),
6.49 (dd, J = 17.3, 2.1 Hz, 1 H, =CH2), 6.78 (dd, J = 17.3, 10.5 Hz,
1 H, =CH).
13C NMR (100 MHz, CDCl3): d = 19.7 (q, Me), 29.2, 38.0 (s, q, t-
Bu), 61.1 (q, OMe), 121.9 (t, =CH2), 136.6 (d, =CH), 150.9, 157.5,
159.9, 167.9 (4 s, C2, C4, C5, C6).
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 9 H, t-Bu), 2.48 (s, 3 H,
Me), 3.75 (s, 3 H, OMe), 6.41 (dd, J = 3.4, 1.8 Hz, 1 H, Hfuryl), 6.48
(d, J = 3.4 Hz, 1 H, Hfuryl), 7.05 (d, J = 15.8 Hz, 1 H, =CH-Pyr), 7.42
(d, J = 1.8 Hz, 1 H, Hfuryl), 7.61 (d, J = 15.8 Hz, 1 H, =CH-furyl).
13C NMR (100 MHz, CDCl3): d = 19.8 (q, Me), 29.2, 38.0 (s, q, t-
Bu), 61.1 (q, OMe), 111.0 111.9, 123.6, 126.2, 143.2, 152.9 (5 d, s,
Fu, HC=CH), 150.3, 157.8, 159.9, 167.9 (4 s, C2, C4, C5, C6).
HRMS: m/z [M + H]+ calcd for C12H19N2O: 207.1497; found:
207.1496.
HRMS: m/z [M + H]+ calcd for C16H21N2O2: 273.1603; found:
273.1599.
(E)-4-tert-Butyl-5-methoxy-6-methyl-2-(prop-1-enyl)pyrimi-
dine (12b)
According to typical procedure 3, a mixture of enamide 8b (0.210
g, 0.879 mmol) and NH4OAc (0.540 g, 7.01 mmol) in MeOH (5
mL) gave 12b (0.145 g, 75%) as a colorless oil.
(E)-5-Methoxy-4-methyl-6-phenyl-2-styrylpyrimidine (12f)
According to typical procedure 3, a mixture of enamide 8f (0.124 g,
0.386 mmol) and NH4OAc (0.237 g, 3.08 mmol) in MeOH (4 mL)
gave 12f (98 mg, 84%) as a colorless oil.
IR (neat): 2955–2855 (C–H), 1660–1385 cm–1 (C=C, C=N).
IR (neat): 3080–2845 (=CH, C–H), 1635–1390 cm–1 (C=C, C=N).
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 9 H, t-Bu), 1.92 (dd,
J = 5.2, 1.7 Hz, 3 H, =CHMe), 2.46 (s, 3 H, Me), 3.74 (s, 3 H, OMe),
6.46–6.51 (m, 1 H, =CHMe), 6.97–7.07 (m, 1 H, =CH-Pyr).
13C NMR (100 MHz, CDCl3): d = 18.0 (q, Me), 19.7 (q, =CHMe),
29.2, 37.9 (s, q, t-Bu), 61.0 (q, OMe), 131.0, 134.9 (2 d, HC=CH),
150.3, 157.92, 159.8, 167.8 (4 s, C2, C4, C5, C6).
1H NMR (400 MHz, CDCl3): d = 2.59 (s, 3 H, Me), 3.53 (s, 3 H,
OMe), 7.28 (d, J = 16.0 Hz, 1 H, =CHPh), 7.33–7.40 (m, 3 H, Ph),
7.47–7.53 (m, 3 H, Ph), 7.62–7.64 (m, 2 H, Ph), 7.96 (d, J = 16.0
Hz, 1 H, =CH-Pyr), 8.10–8.13 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 19.3 (q, Me), 60.4 (q, OMe),
127.6, 128.6, 128.7, 128.8, 129.2, 130.0, 136.0, 136.5, 136.9, 137.0
(8 d, 2 s, Ph, HC=CH), 149.0, 156.6, 159.5, 161.9 (4 s, C2, C4, C5,
C6).
HRMS: m/z [M + H]+ calcd for C13H21N2O: 221.1654; found:
221.1680.
HRMS: m/z [M + H]+ calcd for C20H19N2O: 303.1497; found:
(E)-4-tert-Butyl-5-methoxy-6-methyl-2-styrylpyrimidine (12c)
According to typical procedure 3, a mixture of enamide 8c (0.510 g,
1.69 mmol) and NH4OAc (1.04 g, 13.5 mmol) in MeOH (10 mL)
gave 12c (0.405 g, 85%) as a colorless oil.
303.1499.
(E)-5-Methoxy-4-methyl-2-styryl-6-(thiophen-2-yl)pyrimidine
(12g)
According to typical procedure 3, a mixture of enamide 8g (0.104
g, 0.318 mmol) and NH4OAc (0.196 g, 2.54 mmol) in MeOH (3
mL) gave 12g (76 mg, 78%) as a colorless oil.
IR (neat): 3080–2865 (=CH, C–H), 1640–1380 cm–1 (C=C, C=N).
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 9 H, t-Bu), 2.52 (s, 3 H,
Me), 3.77 (s, 3 H, OMe), 7.17 (d, J = 16.0 Hz, 1 H, =CHPh), 7.25–
7.31 (m, 1 H, Ph), 7.34–7.38 (m, 2 H, Ph), 7.59–7.61 (m, 2 H, Ph),
7.85 (d, J = 16.0 Hz, 1 H, =CH-Pyr).
13C NMR (100 MHz, CDCl3): d = 19.8 (q, Me), 29.2, 38.1 (s, q, t-
Bu), 61.1 (q, OMe), 127.5, 127.9, 128.6, 128.7 136.3, 136.7 (6 d, s,
Ph, HC=CH), 150.5, 157.9, 159.9, 168.0 (4 s, C2, C4, C5, C6).
IR (neat): 3100–2855 (=CH, C–H), 1636–1380 cm–1 (C=C, C=N).
1H NMR (400 MHz, CDCl3): d = 2.58 (s, 3 H, Me), 3.81 (s, 3 H,
OMe), 7.21 (d, J = 16.0 Hz, 1 H, =CHPh), 7.18–7.23 (m, 1 H, Ph),
7.29–7.40 (m, 3 H, Ph), 7.55 (dd, J = 5.0, 1.0 Hz, 1 H, Hthienyl), 7.62–
7.65 (m, 2 H, Ph, Hthienyl), 7.93 (d, J = 16.0 Hz, 1 H, =CH-Pyr),
8.15–8.16 (m, 1 H, Hthienyl).
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

PAPER
Alkenyl-Substituted Pyridines and Pyrimidines
2137
13C NMR (100 MHz, CDCl3): d = 19.2 (q, Me), 60.2 (q, OMe),
127.3, 127.6, 128.3, 128.8, 130.4, 130.5, 136.4, 137.1, 137.2, 139.1
(8 d, 2 s, Ph, Cthienyl, HC=CH), 146.4, 150.9, 159.4, 161.8 (4 s, C2,
C4, C5, C6).
HRMS: m/z [M + H]+ calcd for C18H17N2OS: 309.1062; found:
309.1062.
1H NMR (400 MHz, CDCl3): d = 1.47 (s, 9 H, t-Bu), 3.94 (s, 3 H,
OMe), 7.24–7.39 (m, 4 H, Ph), 7.60–7.62 (m, 2 H, Ph, =CH), 7.93
(d, J = 16.0 Hz, 1 H, =CH), 10.14 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 28.9, 38.9 (s, q, t-Bu), 67.1 (q,
OMe), 126.8, 127.6, 128.8, 129.0, 136.2, 137.7 (5 d, s, Ph,
HC=CH), 148.4, 151.7, 158.4, 172.8 (4 s, C2, C4, C5, C6), 192.1
(d, CHO).
5-Methoxy-4-methyl-6-phenyl-2-vinylpyrimidine (12h)
According to typical procedure 3, a mixture of enamide 8h (90 mg,
0.367 mmol), NH4OAc (0.225 g, 2.92 mmol) in MeOH (3 mL)
gave 12h (45 mg, 55%) as a colorless oil.
HRMS: m/z [M + Na]+ calcd for C18H20N2NaO2: 319.1422; found:
319.1434.
4-tert-Butyl-5-methoxy-2,6-distyrylpyrimidine (16)
IR (neat): 3060–2935 (=CH, C–H), 1560–1380 cm–1 (C=C, C=N).
To a suspension of benzyl(triphenyl)phosphonium bromide (0.780
g, 1.88 mmol) in anhyd Et2O (10 mL) was added 2.5 M n-BuLi in
hexanes (0.65 mL, 1.64 mmol) at r.t. The mixture was stirred for 30
min and then the solid residue was allowed to precipitate. The or-
ange-colored ylide soln was then transferred to a soln of aldehyde
15 (97 mg, 0.328 mmol) in anhyd Et2O (5 mL) kept at 0 °C. The
mixture was stirred at 0 °C for 1 h and then the reaction was
quenched by addition of sat. aq NH4Cl soln (5 mL). The aqueous
phase was extracted with Et2O (3 × 20 mL). The combined ether
layers were washed with brine (15 mL), dried (Na2SO4), and evap-
orated to dryness. The crude product was subjected to column chro-
matography (silica gel, 5% EtOAc–hexane) to afford 16 (54 mg,
45%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 2.56 (s, 3 H, Me), 3.52 (s, 3 H,
OMe), 5.65 (dd, J = 10.6, 1.8 Hz, 1 H, =CH2), 6.56 (dd, J = 17.3,
1.8 Hz, 1 H, =CH2), 6.87 (dd, J = 17.3, 10.6 Hz, 1 H, =CH), 7.46–
7.48 (m, 3 H, Ph), 8.06–8.08 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 19.2 (q, Me), 60.3 (q, OMe),
122.6 (t, =CH2), 128.6, 129.1, 129.9, 135.9, 136.4 (4 d, s, Ph, =CH),
149.4, 156.4, 159.0, 161.9 (4 s, C2, C4, C5, C6).
HRMS: m/z [M + H]+ calcd for C14H15N2O: 227.1184; found:
227.1199.
4-tert-Butyl-2-(1,2-dihydroxyethyl)-5-methoxy-6-methylpyrim-
idine (13) and 4-tert-Butyl-5-methoxy-6-methylpyrimidine-2-
carbaldehyde (14)
IR (neat): 3060–2850 (=CH, C–H), 1600–1355 cm–1 (C=C, C=N).
1H NMR (400 MHz, CDCl3): d = 1.48 (s, 9 H, t-Bu), 3.84 (s, 3 H,
OMe), 7.25–7.43 (m, 8 H, Ph, =CHPh, =CH-Pyr), 7.64–7.69 (m, 4
H, Ph), 7.95 (d, J = 16.0 Hz, 1 H, =CHPh), 8.06 (d, J = 16.0 Hz, 1
H, =CH-Pyr).
13C NMR (100 MHz, CDCl3): d = 29.3, 38.3 (s, q, t-Bu), 62.9 (q,
OMe), 120.9, 127.6, 127.8, 128.2, 128.6, 128.8, 128.9, 129.1,
136.5, 136.5, 136.5, 136.7 (10 d, 2 s, Ph, HC=CH), 149.3, 155.2,
158.2, 169.4 (4 s, C2, C4, C5, C6).
To a soln of pyrimidine 12a (92 mg, 0.447 mmol) in acetone–H2O
(6 mL, 5:1) was added K2OsO4·2 H2O (16 mg, 0.043 mmol) and sol-
id NMO (0.180 g, 1.54 mmol) at r.t. and the resulting mixture was
stirred at r.t. for 6 h. The reaction was quenched by addition of solid
Na2SO3 (11 mg). Acetone was removed and the resulting product
was extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were washed with brine (10 mL) and dried (Na2SO4) and evap-
orated to dryness to give crude diol 13 (69 mg).
Crude diol 13 (69 mg, 0.291 mmol) was dissolved in moist THF (4
mL) and NaIO4 (99 mg, 0.463 mmol) was added at 0 °C; the mixture
was stirred for 1 h. The product was extracted with Et2O (3 × 10
mL) and the combined ether layers were washed with brine (10 mL)
and dried (Na2SO4). Evaporation of solvent gave the crude product
which was purified by column chromatography (silica gel, 10%
EtOAc–hexane) to provide 14 (65 mg, 70% after 2 steps) as a pale
yellow oil.
HRMS: m/z [M + H]+ calcd for C25H27N2O: 371.2118; found:
371.2170.
(E)-N-(4-Methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl)but-3-en-
amide (18)
According to typical procedure 1, a mixture of methoxyallene (2.60
mL, 30.8 mmol), 2.5 M n-BuLi in hexanes (11.6 mL, 29.0 mmol),
pivalonitrile (1.60 mL, 14.5 mmol), and but-3-enoic acid 17 (4.90
mL, 57.5 mmol) in anhyd Et2O (50 mL) gave 18 (2.83 g, 82%) as a
pale yellow solid; mp 82–85 °C.
IR (neat): 2955–2870 (C–H), 1725 (CHO), 1555–1355 cm–1 (C=C,
C=N).
IR (KBr): 3320 (NH), 3010–2830 (=CH, C–H), 1685 (C=O), 1550–
1380 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.18 (s, 9 H, t-Bu), 2.26 (s, 3 H,
Me), 2.97–2.99 (m, 2 H, COCH2), 3.49 (s, 3 H, OMe), 5.22–5.27
(m, 2 H, =CH2), 5.86–5.96 (m, 1 H, =CH), 6.88 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 27.5 (q, Me), 28.5, 36.5 (s, q, t-
Bu), 42.1 (t, COCH2), 59.1 (q, OMe), 120.5 (t, CH2=CH), 130.9 (d,
=CH), 132.6, 150.5 (2 s, C1, C2), 169.9 (s, C1¢), 200.7 (s, C3).
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 9 H, t-Bu), 2.58 (s, 3 H,
Me), 3.83 (s, 3 H, OMe), 9.96 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 20.2 (q, Me), 28.9, 38.2 (s, q, t-
Bu), 61.2 (q, OMe), 153.0, 154.0, 161.6, 169.2 (4 s, C2, C4, C5,
C6), 191.3 (d, CHO).
HRMS: m/z [M + Na]+ calcd for C11H16N2NaO2: 231.1109; found:
231.1097.
(E)-6-tert-Butyl-5-methoxy-2-styrylpyrimidine-4-carbalde-
hyde (15)
HRMS: m/z [M + Na]+ calcd for C13H21NNaO3: 262.1414; found:
262.1416.
Pyrimidine 12c (0.205 g, 0.727 mmol) and SeO2 (0.240 g, 2.16
mmol) were placed in an ACE-sealed tube. The mixture was dis-
solved in 1,4-dioxane (5 mL) and stirred at 90 °C for 2 d. The black
metal residue was filtered of by a small Celite pad and the solvent
was removed under reduced pressure. The crude product was puri-
fied by column chromatography (silica gel, 15% EtOAc–hexane) to
afford 15 (0.174 g, 80%) as a pale yellow oil.
2-Allyl-4-tert-butyl-5-methoxy-6-methylpyrimidine (19)
According to typical procedure 3, a mixture of enamide 18 (0.425
g, 1.78 mmol) and NH4OAc (1.10 g, 14.3 mmol) in MeOH (10 mL)
gave 19 (0.266 g, 68%) as a colorless oil.
IR (neat): 3080–2865 (=CH, C–H), 1550–1380 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 1.35 (s, 9 H, t-Bu), 2.45 (s, 3 H,
Me), 3.59–3.61 (m, 2 H, COCH2), 3.72 (s, 3 H, OMe), 5.05–5.16
(m, 2 H, =CH2), 6.12–6.23 (m, 1 H, =CH).
IR (neat): 3080–2830 (=CH, C–H), 1715 (C=O), 1635–1365 cm–1
(C=C, C=N).
Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York

2138
M. K. Bera, H.-U. Reissig
PAPER
13C NMR (100 MHz, CDCl3): d = 19.6 (q, Me), 29.3, 37.9 (s, q, t-
Bu), 43.4 (t, CH2-Pyr), 60.9 (q, OMe), 116.1, 135.6 (t, d, CH2=CH),
150.3, 160.2, 162.0, 168.1 (4 s, C2, C4, C5, C6).
HRMS: m/z [M + H]+ calcd for C13H21N2O: 221.1654; found:
221.1668.
A. Synthesis 2010, 1000.
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Acknowledgment
Generous support of this work by the Alexander von Humboldt
Foundation (postdoctoral research fellowship for M.K.B.), the
Fonds der Chemischen Industrie and the Bayer Schering Pharma
AG are most gratefully acknowledged. We also thank Dr. R.
Zimmer and Dr. T. Lechel for their help during the preparation of
this manuscript.
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Synthesis 2010, No. 13, 2129–2138 © Thieme Stuttgart · New York