Microwave-assisted diversity-oriented domino synthesis of functionalized nicotinic acid derivatives

Article abstract of DOI:10.1002/ejoc.201001067

The microwave-assisted diversity-oriented domino synthesis of functionalized alkyl nicotinates from propargyl vinyl ethers is described. The domino manifold comprises a complex network of reactions involving at least five distinct chemical steps. The obtained alkyl nicotinates incorporate two diversity points at the ring and one ester functionality as convenient handles for further elaboration. Copyright

Full text of DOI:10.1002/ejoc.201001067

FULL PAPER
DOI: 10.1002/ejoc.201001067
Microwave-Assisted Diversity-Oriented Domino Synthesis of Functionalized
Nicotinic Acid Derivatives
David Tejedor,*[a,b] Gabriela Méndez-Abt,[a,b] and Fernando García-Tellado*[a,b]
Dedicated to Professor Carmen Nájera on the occasion of her 60th birthday
Keywords: Domino reactions / Electrocyclic reactions / Microwave chemistry / Nitrogen heterocycles / Nicotinic acid
The microwave-assisted diversity-oriented domino synthesis
of functionalized alkyl nicotinates from propargyl vinyl
ethers is described. The domino manifold comprises a com-
plex network of reactions involving at least five distinct
chemical steps. The obtained alkyl nicotinates incorporate
two diversity points at the ring and one ester functionality as
convenient handles for further elaboration.
bench-friendly and environmentally benign reaction condi-
tions are important factors that should be taken into ac-
count in these strategies.[8]
Introduction
Functionalized pyridines with one carboxylic acid de-
rived function (e.g., amide, ester, oxazoline) at the C-3 posi-
tion (nicotinic acid derivatives), constitute an important
group of biologically and pharmaceutically relevant mole-
cules.[1] A survey of the methodologies for general access to
functionalized pyridine rings has been published.[2] Among
the approaches described, modern (catalyzed) versions of
the Bohlmann–Rahtz heteroannulation reaction[3] with
combinatorial[4] and multicomponent[4a,5] extensions, in-
volving β-amino acrylates (conjugated enamines) and con-
jugated alkynes, have proven to be synthetically convenient
and general processes for the construction of substituted
nicotinic derivatives.[2c] Recently, Rodriguez and co-workers
have reported a regioselective, multicomponent synthesis of
functionalized nicotinic acid derivatives through the H+-
catalyzed reaction of 1,3-dicarbonyl compounds with β,γ-
unsaturated α-oxo carbonyl compounds and ammonium
acetate under oxidative conditions.[6] In spite of these ad-
vances, there is still a need for synthetic methodologies that
enable controlled access to these heterocycles with struc-
tural (functional) diversity and a wide range of ring substi-
tution patterns.[7] The use of commercially available or
readily accessible, simple starting materials, together with
In a recent communication,[9] we reported the formation
of substituted alkyl 1,2-dihydropyridine-3-carboxylates 5
from propargyl enol ethers 1 and primary amines through
a microwave-assisted domino reaction (Scheme 1). Therein,
we proposed that azatrienes 4 could be conveniently trans-
formed into substituted alkyl nicotinates 6 if a primary
amine armed with a good leaving group was used in this
[a] Instituto de Productos Naturales y Agrobiología, Consejo
Superior de Investigaciones Científicas,
Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife,
Canary Islands, Spain
Scheme 1. Microwave-assisted diversity-oriented domino synthesis
(DODS) of 1,2-dihydropyridines 5 and nicotinic acid derivatives 6
from propargyl vinyl ethers 1. Domino sequence: (i) [3,3] propargyl
enol ether rearrangement; (ii) 1,3-protropic isomerization; (iii) con-
densation; (iv) 6π-aza-electrocyclization; (v) elimination. Z =
CO2R; LG = leaving group.
Fax: +34-922-260135
E-mail: fgarcia@ipna.csic.es
dtejedor@ipna.csic.es
http://www.ipna.csic.es/departamentos/qbb/qb/
[b] Instituto Canario de Investigación del Cáncer,
Canary Islands, Spain
6582
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Nicotinic Acid Derivatives
manifold [R4 = leaving group (LG); Scheme 1]. In this sce- are commercially available) (Table 1).[12] Because libraries of
nario, the 1,2-dihydropyridine intermediate 5, which would these scaffolds can be prepared in a very simple and direct
be formed from the corresponding azatriene 4 through a way with a certain degree of functional (structural) diver-
thermally allowed 6π-aza electrocyclization reaction,[10] sity, they constitute versatile building blocks for use in
would generate the corresponding pyridine derivative 6 by DODS. We started our study by optimizing the previously
elimination of a neutral molecule (H-LG). As a proof of reported reaction of propargyl vinyl ether 1a and meth-
concept, we reported therein the microwave-assisted dom- oxyamine hydrochloride to generate ethyl nicotinate 6a
ino synthesis of ethyl 6-phenylnicotinate (6a) from the pro- [Equation (1)]; the reaction was assessed by careful varia-
pargyl derivative 1a and methoxyamine hydrochloride tion of the reaction conditions (microwave potency, tem-
[Equation (1)]. In this paper, we have extended this protocol perature, time, solvent, stoichiometry, and buffer). It was
to the diversity-oriented domino synthesis (DODS) of func- found that performing the reaction in ethanol, in the pres-
tionalized alkyl nicotinates 6 from propargyl vinyl ethers 1 ence of sodium acetate (0.55 equiv.), under microwave irra-
and methoxyamine hydrochloride under microwave irradia- diation (200 W, 100 °C, closed vessel)[13] for 60 min, in-
tion. Nicotinates 6 are obtained in good yields, incorporat- creased the initially reported 55% yield for product 6a[9] to
ing three points for diversity and a wide range of aryl-based 65%. The use of 2-propanol instead of ethanol as the reac-
substitution patterns on the ring.[11]
tion solvent allowed the yield to be further increased to
77% (Table 1, Entry 1). Once a set of optimized conditions
was established, we next studied the scope of this process
by using the set of propargyl vinyl ethers 1a–n outlined in
Table 1. Under the standardized conditions, the majority of
propargyl vinyl ethers assayed afforded the corresponding
alkyl nicotinates 6 in good yields, although we observed
that changing the solvent from ethanol to 2-propanol was
not beneficial in all cases (small differences were observed).
Therefore, we routinely performed the reactions in both sol-
vents to determine the optimal solvent for each entry.
With regard to the functionalities decorating the propar-
Results and Discussion
Propargyl vinyl ethers 1 (Scheme 1) constitute densely gylic platform 1, the reaction tolerated a diverse range of
functionalized platforms with three diversity points and a alkyl/aryl substitution patterns. As a general tendency, aro-
reactivity-directing carboxylic ester group.[9] These scaffolds matic substituents at the propargylic sp3-position (R2) and
can be conveniently assembled from commercial sources the sp3-alkyne position (R1) were more productive than
(aldehydes, alkynes, and alkyl propiolates) in one or two alkyl substituents (compare Table 1, Entries 1 and 9 with
straightforward synthetic steps (some propargyl alcohols Entries 2–4). A bulky tert-butyl group located at the pro-
Table 1. Microwave-assisted diversity-oriented domino synthesis of functionalized alkyl nicotinates 6 from propargyl vinyl ethers 1.[a]
Entry
R1
R2
1 (yield [%])[b] Solvent Microwave power [W][c] Temperature [°C] Time [min]
6
Yield [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
Ph
nPent
Me
Ph
Ph
Ph
Ph
Ph
Ph
1a (95)
1b (87)
1c (98)[e]
1d (96)
1e (78)[f]
1f (79)
1g (84)
1h (81)[f]
1i (89)
iPrOH
EtOH
EtOH
EtOH
iPrOH
EtOH
EtOH
EtOH
EtOH
iPrOH
EtOH
iPrOH
iPrOH
iPrOH
200
300
300
200
200
200
200
200
200
300
200
200
200
200
100
150
150
100
100
100
100
100
100
150
100
100
100
100
60
180
180
60
60
60
60
60
60
180
60
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
77
54
14
45
78
61
60
61
67
13
62
72
60
35
nBu
p-MeOC6H4
3,4-Cl2C6H3
p-ClC6H4
p-MeC6H4
Ph
Ph
Ph
Ph
Ph
tBu
1j (99)
p-ClC6H4
p-MeOC6H4
2-furyl
Ph
1k (79)[f]
1l (76)[f]
1m (48)
1n (77)
60
60
60
Me3Si
[a] Reagents and conditions: (i) BuLi, THF, –78 °C (30 min), then –30 °C (30 min), then –78 °C, R2CHO, 1 h; (ii) Et3N (10 mol-%),
CH2Cl2, room temp., 2 h; (iii) propargyl vinyl ether 1 (1 mmol), MeONH2·HCl (1.1 mmol), NaOAc (0.55 mmol), EtOH or iPrOH (5 mL),
microwave irradiation. [b] Yields of isolated compounds 1 from the corresponding propargyl alcohols. [c] Microwave irradiation of
specialized closed vessels. [d] Yield of isolated compounds 6. [e] Methyl propiolate was used as alkynoate. [f] These substrates spontane-
ously rearranged partially to the corresponding dienals 3 (combined yield of 1 and 3).
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6583

D. Tejedor, G. Méndez-Abt, F. García-Tellado
FULL PAPER
pargylic sp3-position (1j; R2 = tBu) reduced the efficiency
of the reaction significantly (Table 1, Entry 10). Release of
steric congestion at this position (1b; R2 = nPent) increased
the yield to 54% (Table 1, Entry 2). Intriguingly, methyl-
substituted 1c (R2 = Me) afforded nicotinate 6c in very low
yield (14%; Table 1, Entry 3). Remarkably, when no substit-
uents were present in the propargylic scaffold (R1 = R2 =
H), none of the desired product was formed (data not
shown). These results could point to the existence of a cer-
500 and 125 MHz (Bruker AC200 or AMX2-500), respectively. Mi-
crowave reactions were conducted in sealed glass vessels (capacity
10 mL) with a CEM Discover microwave reactor. FTIR spectra
were measured in chloroform solutions with a Perkin–Elmer FTIR
Spectrum BX spectrophotometer. Mass spectra (low-resolution)
(EI/CI) were obtained with a Hewlett–Packard 5995 gas chromato-
graph/mass spectrometer. High-resolution mass spectra (HRMS)
were recorded with a Micromass Autospec mass spectrometer.
Microanalyses were performed with a Fisons Instruments EA 1108
carbon, hydrogen, and nitrogen analyzer. Analytical thin-layer
tain degree of conformational control (a substituent-biased chromatography (TLC) plates used were E. Merck Brinkman UV-
active silica gel (Kieselgel 60 F254) on aluminum. Flash column
chromatography was carried out with E. Merck silica gel 60 (par-
ticle size less than 0.020 mm) by using appropriate mixtures of ethyl
acetate and hexanes as eluent. All reactions were performed in
oven-dried glassware under nitrogen unless otherwise stated.
Dichloromethane was distilled from CaH2. All other materials were
obtained from commercial suppliers and used as received. Products
1a,[9] 6a,[14] and 6c[15] have been previously reported, and all data
are in accordance with those reported in the literature.
conformational control) in the intermediate azatriene 4,
which drives the process toward pyridine ring formation.
Substitution at the sp3-propargylic position (R2) was found
to be dependent on the nature of substituent R1.[9] Whereas
R2 could be aliphatic or aromatic for terminal alkynes (R1
= H) (Table 1, Entries 1, 2, and 3) and aromatic for internal
alkynes (R1 = nBu, Ar, or Me3Si) (Entries 4–9 and En-
tries 11–14), the combination of R2 = alkyl and an internal
alkyne, was detrimental for the transformation of these pro-
pargyl derivatives into the corresponding functionalized
pyridines (data not shown). The electronic nature of the
aryl substituents at either the propargylic sp3-position or at
the alkyne sp-position did not significantly influence the
global efficiency of the reaction (compare Table 1, En-
tries 5–8 and 11–13 with Entry 9), although the para-meth-
oxy group proved to be the most convenient (compare
Table 1, Entries 5 and 12 with Entries 6–8 and 11). Propar-
gylic scaffold 1m, bearing a furan ring at the propargylic
Representative Procedure for the Synthesis of Propargyl Vinyl Ethers
1a–n: Triethylamine (0.30 mmol) was added to a solution of ethyl
propiolate (3.0 mmol) and 1-phenylprop-2-yn-1-ol (3.0 mmol) in
anhydrous CH2Cl2 (10 mL). The reaction mixture was stirred for
2 h; then, after removing the solvent under reduced pressure, the
products were purified by flash column chromatography (silica gel;
n-hexane/EtOAc, 90:10) to yield 1a (656 mg, 95%).[9]
(؎)-Ethyl (E)-3-(Oct-1-yn-3-yloxy)acrylate (1b): Yield: 584.6 mg
(2.61 mmol, 87%). 1H NMR (CDCl3, 400 MHz): δ = 0.89 (t, 3JH,H
3
= 6.9 Hz, 3 H, Me), 1.26 (t, JH,H = 6.9 Hz, 3 H, Me), 1.29–1.33
sp3-position, was efficiently converted into the correspond- (m, 4 H, 2ϫ5Ј-H and 2ϫ6Ј-H), 1.42–1.50 (m, 2 H, 2ϫ7Ј-H), 1.76–
3
1.90 (m, 2 H, 2ϫ4Ј-H), 2.57 (d, JH,H = 2.1 Hz, 1 H, 1Ј-H), 4.12–
ing nicotinate derivative 6m, which is a very interesting bi-
heterocyclic scaffold (Table 1, Entry 13). Remarkably, even
the silyl-containing propargylic vinyl ether 1n was able to
give, in reasonable yield (35%), the corresponding alkyl nic-
otinate 6n, which bears an important trimethylsilyl group
at the ring.
3
3
4.20 (q, JH,H = 6.9 Hz, 2 H, OCH2Me), 4.52 (dt, JH,H = 6.6,
3
2.1 Hz, 1 H, 3Ј-H), 5.37 (d, JH,H = 12.5 Hz, 1 H, 2-H), 7.59 (d,
3JH,H = 12.5 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
13.9, 14.3, 22.4, 24.4, 31.2, 35.1, 59.8, 71.2, 75.9, 80.2, 99.0, 160.1,
167.5 ppm. IR (CHCl ): ν = 3305.6, 2957.8, 2122.7, 1701.0, 1640.3,
˜
3
1464.7, 1371.3, 1289.6, 1222.8, 1191.7, 1136.5 cm–1. MS (70 eV):
m/z (%) = 225 (22) [M+ + 1], 195 (12.7), 179 (22), 151 (9.4), 139
(9.1), 125 (8.5), 117 (40), 109 (35), 93 (49), 89 (22), 81 (54), 79 (56),
71 (66), 67 (100), 55 (75). C13H20O3 (224.14): calcd. C 69.61, H
8.99; found C 69.52, H 8.69.
Conclusions
We have described the microwave-assisted diversity-ori-
ented synthesis of functionalized alkyl nicotinates 6 from
propargyl vinyl ethers 1 through a complex and efficient
domino manifold involving at least five discrete chemical
steps. The propargylic platforms 1 are rapidly and easily
assembled from commercially available or readily available
materials. The obtained alkyl nicotinates 6 feature a maxi-
mum of two diversity points at the ring and one appended
chemical handle for further elaboration (ester function-
ality). The reaction is fast, economical, bench-friendly (it
(؎)-Methyl (E)-3-(But-3-yn-2-yloxy)acrylate (1c): Yield: 452.8 mg
(2.94 mmol, 98%). 1H NMR (CDCl3, 400 MHz): δ = 1.56 (d, 3JH,H
3
= 6.6 Hz, 3 H, Me), 2.57 (d, JH,H = 2.1 Hz, 1 H, 4Ј-H), 3.69 (s, 3
3
3
H, OMe), 4.66 (dq, JH,H = 6.6, 2.1 Hz, 1 H, 2Ј-H), 5.37 (d, JH,H
3
= 12.5 Hz, 1 H, 2-H), 7.59 (d, JH,H = 12.5 Hz, 1 H, 3-H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 21.6, 51.2, 67.0, 75.4, 80.9, 98.8,
160.0, 167.9 ppm. IR (CHCl ): ν = 3306.9, 3024.2, 2952.9, 2122.0,
˜
3
1706.4, 1645.7, 1625.6, 1438.4, 1333.4, 1293.9, 1224.5, 1194.1,
1145.3, 1120.8, 1035.2 cm–1. MS (70 eV): m/z (%) = 154 (3.8)
does not require special care with solvent and protective [M]+, 123 (20), 111 (16), 102 (13), 95 (30), 71 (76), 53 (100).
C8H10O3 (154.06): calcd. C 62.33, H 6.54; found C 62.20, H 6.56.
reaction atmospheres) and environmentally benign. These
practical advantages make this approach a good alternative
to other well-known methods, and can be used to rapidly
generate libraries of functionalized nicotinate derivatives 6
for use in drug discovery programs.[11]
(؎)-Ethyl (E)-3-(1-Phenylhept-2-ynyloxy)acrylate (1d): Yield:
823.7 mg (2.88 mmol, 96%). 1H NMR (CDCl3, 400 MHz): δ = 0.91
3
3
(t, JH,H = 7.2 Hz, 3 H, Me), 1.26 (t, JH,H = 7.2 Hz, 3 H, Me),
1.37–1.46 (m, 2 H, 2ϫ6Ј-H), 1.50–1.57 (m, 2 H, 2ϫ5Ј-H), 2.30
3
3
(dt, JH,H = 6.9, 2.1 Hz, 2 H, 2ϫ4Ј-H), 4.16 (q, JH,H = 7.2 Hz, 2
3
3
H, OCH2Me), 5.43 (d, JH,H = 12.5 Hz, 1 H, 2-H), 5.62 (t, JH,H
= 2.1 Hz, 1 H, 1Ј-H), 7.35–7.41 (m, 3 H, Ph), 7.48–7.51 (m, 2 H,
Experimental Section
General Remarks: 1H and 13C NMR spectra of the samples as
Ph), 7.69 (d, JH,H = 12.5 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3,
3
CDCl3 solutions were recorded either at 400 and 100 MHz or at
100 MHz): δ = 13.5, 14.3, 18.5, 21.9, 30.4, 59.7, 73.7, 75.7, 91.4,
6584
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Eur. J. Org. Chem. 2010, 6582–6587

Nicotinic Acid Derivatives
99.4, 127.4, 128.7, 129.0, 137.0, 159.9, 167.6 ppm. IR (CHCl ): ν =
84.3, 89.8, 99.7, 121.7, 127.5, 128.4, 128.8, 129.1, 129.3, 131.9,
136.5, 159.9, 167.5 ppm. IR (CHCl ): ν = 3020.2, 2228.4, 1701.8,
˜
3
3018.8, 2936.1, 2871.1, 2232.5, 1701.2, 1641.4, 1324.4, 1289.0,
˜
3
1216.8, 1179.0, 1131.5 cm–1. MS (70 eV): m/z (%) = 286 (1.4) 1642.4, 1323.7, 1289.5, 1177.1, 1132.3 cm–1. MS (70 eV): m/z (%)
[M]+, 257 (1.7), 229 (2.9), 213 (4.8), 171 (100), 141 (9.9), 128 (30),
= 306 (2.9) [M]+, 260 (3.9), 231 (4.4), 202 (4.5), 191 (100), 189
115 (23), 91 (36), 77 (10). C18H22O3 (286.16): calcd. C 75.50, H (14.7), 165 (5.4), 129 (3.0), 105 (5.2), 89 (2.7), 77 (4.8). C20H18O3
7.74; found C 75.15, H 7.39.
(306.13): calcd. C 78.41, H 5.92; found C 78.23, H 6.00.
Ethyl (2Z,4E)-2-Formyl-3-(4-methoxyphenyl)-5-phenylpenta-2,4-di-
(؎)-Ethyl (E)-3-(4,4-Dimethyl-1-phenylpent-1-yn-3-yloxy)acrylate
1
enoate (1e): Yield: 786.2 mg (2.34 mmol, 78%). H NMR (CDCl3, (1j): Yield: 849.4 mg (2.97 mmol, 99%). 1H NMR (CDCl3,
3
400 MHz): δ = 1.42 (t, JH,H = 7.2 Hz, 3 H, Me), 3.88 (s, 3 H,
400 MHz): δ = 1.08 (s, 9 H, tBu), 1.26 (t, 3JH,H = 7.2 Hz, 3 H, Me),
3
3
3
OMe), 4.44 (q, JH,H = 7.2 Hz, 2 H, OCH2Me), 6.68 (d, JH,H
=
4.16 (q, JH,H = 7.2 Hz, 2 H, OCH2Me), 4.38 (s, 1 H, 3Ј-H), 5.42
15.9 Hz, 1 H, 5-H), 6.98–7.02 (m, 2 H, ArH), 7.26–7.41 (m, 8 H,
4-H and ArH), 9.33 (s, 1 H, CHO) ppm. 13C NMR (CDCl3,
100 MHz): δ = 14.3, 55.3, 61.6, 113.9, 125.6, 127.2, 127.8, 128.8,
129.9, 131.8, 132.8, 135.6, 143.3, 157.7, 160.7, 166.4, 189.6 ppm.
(d, 3JH,H = 12.5 Hz, 1 H, 2-H), 7.28–7.34 (m, 3 H, PhH), 7.42–7.45
(m, 2 H, PhH), 7.69 (d, 3JH,H = 12.5 Hz, 1 H, 3-H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 14.3, 25.6, 36.0, 59.7, 80.8, 84.3, 88.5, 98.4,
122.1, 128.3, 128.7, 131.8, 161.2, 167.8 ppm. IR (CHCl ): ν =
˜
3
MS (70 eV): m/z (%) = 336 (32) [M]+, 318 (25), 290 (100), 262 (81), 3017.7, 2976.7, 2226.7, 1699.4, 1626.0, 1323.4, 1221.9, 1186.5,
247 (33), 234 (29), 231 (32), 219 (42), 202 (32), 191 (37), 165 (22),
1135.6 cm–1. MS (70 eV): m/z (%) = 286 (0.8) [M]+, 229 (6.4), 213
159 (11), 135 (17), 115 (19), 105 (16), 91 (28), 77 (20). HRMS: (8.7), 171 (100), 156 (54), 143 (25), 129 (21), 115 (26), 102 (3.6), 91
calcd. for C21H20O4 [M]+ 336.1362; found 336.1354.
(18), 77 (8.6), 57 (12). C18H22O3 (286.16): calcd. C 75.50, H 7.74;
found C 75.66, H 7.45.
(؎)-Ethyl (E)-3-[3-(3,4-Dichlorophenyl)-1-phenylprop-2-ynyloxy]-
acrylate (1f): Yield: 886.4 mg (2.37 mmol, 79% yield). 1H NMR
(؎)-Ethyl (E)-3-[1-(4-Chlorophenyl)-3-phenylprop-2-ynyloxy]acryl-
(CDCl3, 400 MHz): δ = 1.23–1.28 (m, 3 H, Me), 4.08–4.19 (m, 2 ate (1k): Yield: 805.8 mg (2.37 mmol, 79%). 1H NMR (CDCl3,
3
3
3
H, OCH2Me), 5.48 (d, JH,H = 12.7 Hz, 1 H, 2-H), 5.82 (s, 1 H,
400 MHz): δ = 1.26 (t, JH,H = 7.2 Hz, 3 H, Me), 4.16 (q, JH,H =
3
3
1Ј-H), 7.29 (dd, JH,H = 8.5 and 2.1 Hz, 1 H, ArH), 7.38–7.43 (m,
7.2 Hz, 2 H, OCH2Me), 5.49 (d, JH,H = 12.5 Hz, 1 H, 2-H), 5.82
(s, 1 H, 1Ј-H), 7.30–7.36 (m, 3 H, ArH), 7.37–7.40 (m, 2 H, ArH),
3
4 H, ArH), 7.53–7.55 (m, 3 H, ArH), 7.69 (d, JH,H = 12.7 Hz, 3-
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.3, 59.9, 73.4, 86.4,
7.46–7.48 (m, 2 H, ArH), 7.49–7.52 (m, 2 H, ArH), 7.72 (d, JH,H
3
87.2, 99.9, 121.5, 127.4, 128.9, 129.4, 130.4, 131.0, 132.7, 133.5,
= 12.5 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.3,
133.7, 136.0, 159.6, 167.3 ppm. IR (CHCl ): ν = 3025.1, 2231.8,
59.9, 72.9, 83.8, 90.1, 99.9, 121.4, 128.4, 128.8, 129.0, 129.2, 131.9,
135.0, 135.2, 159.6, 167.4 ppm. IR (CHCl ): ν = 3017.6, 2228.9,
˜
3
˜
3
1703.3, 1653.0, 1466.9, 1288.3, 1177.1, 1131.9 cm–1. MS (70 eV):
m/z (%) = 374 (8.0) [M]+, 328 (16), 301 (13), 259 (100), 236 (10), 1703.8, 1643.6, 1491.3, 1131.8, 1044.6 cm–1. MS (70 eV): m/z (%)
202 (26), 189 (20), 105 (13), 91 (13), 77 (11). C20H16O3Cl2 (374.05): = 294 (11) [M+ – EtOH], 240 (11), 225 (100), 202 (15), 139 (13),
calcd. C 64.02, H 4.30; found C 63.90, H 4.51.
129 (19), 105 (19), 77 (12). C20H17ClO3 (340.09): calcd. C 70.49, H
5.03; found C 70.25, H 5.00.
(؎)-Ethyl (E)-3-[3-(4-Chlorophenyl)-1-phenylprop-2-ynyloxy]acryl-
ate (1g): Yield: 856.8 mg (2.52 mmol, 84%). 1H NMR (CDCl3, Ethyl (2Z,4E)-2-Formyl-5-(4-methoxyphenyl)-3-phenylpenta-2,4-di-
3
3
1
400 MHz): δ = 1.26 (t, JH,H = 7.2 Hz, 3 H, Me), 4.16 (q, JH,H
=
enoate (3l): Yield: 766.1 mg (2.28 mmol, 76%). H NMR (CDCl3,
3
3
7.2 Hz, 2 H, OCH2Me), 5.51 (d, JH,H = 12.5 Hz, 1 H, 2-H), 5.84
400 MHz): δ = 1.42 (t, JH,H = 7.2 Hz, 3 H, Me), 3.81 (s, 3 H,
3
3
(s, 1 H, 1Ј-H), 7.28–7.31 (m, 2 H, ArH), 7.39–7.45 (m, 5 H, ArH), OMe), 4.44 (q, JH,H = 7.2 Hz, 2 H, OCH2Me), 6.55 (d, JH,H
=
=
7.55–7.58 (m, 2 H, ArH), 7.74 (d, 3JH,H = 12.5 Hz, 1 H, 3-H) ppm. 15.6 Hz, 1 H, 5-H), 6.83–6.87 (m, 2 H, ArH), 7.21 (d, JH,H
3
13C NMR (CDCl3, 100 MHz): δ = 14.3, 59.8, 73.5, 85.3, 88.5, 99.7,
15.6 Hz, 1 H, 4-H), 7.33–7.35 (m, 4 H, ArH), 7.46–7.48 (m, 3 H,
120.1, 127.4, 128.7, 128.8, 129.3, 133.1, 135.2, 136.2, 159.7, ArH), 9.25 (s, 1 H, CHO) ppm. 13C NMR (CDCl3, 100 MHz): δ =
167.6 ppm. MS (70 eV): m/z (%) = 340 (3.0) [M]+, 225 (56), 188
(4.9), 138 (9.2), 105 (13), 91 (100), 65 (9.2). HRMS: calcd. for
C20H17ClO3 [M]+ 340.0866; found 340.0854.
14.3, 55.4, 61.6, 114.4, 124.7, 128.0, 128.4, 129.2, 129.6, 130.1,
132.1, 133.8, 143.5, 158.4, 161.3, 166.4, 189.6 ppm. MS (70 eV):
m/z (%) = 336 (48) [M]+, 290 (100), 245 (12), 234 (68), 219 (24),
202 (21), 191 (46), 165 (17), 135 (22), 121 (20), 105 (11), 77 (15).
HRMS: calcd. for C21H20O4 [M]+ 336.1362; found 336.1358.
(؎)-Ethyl (E)-3-[1-Phenyl-3-(p-tolyl)prop-2-ynyloxy]acrylate (1h):
1
Yield: 777.6 mg (2.43 mmol, 81%). H NMR (CDCl3, 400 MHz):
3
δ = 1.27 (t, JH,H = 7.2 Hz, 3 H, Me), 2.35 (s, 3 H, Me), 4.17 (q,
Ethyl (2Z,4E)-2-Formyl-5-(furan-2-yl)-3-phenylpenta-2,4-dienoate
3
3JH,H = 7.2 Hz, 2 H, OCH2Me), 5.50 (d, JH,H = 12.5 Hz, 1 H, 2- (3m): Yield: 426.2 mg (1.44 mmol, 48%). 1H NMR (CDCl3,
3
3
3
H), 5.86 (s, 1 H, 1Ј-H), 7.13 (d, JH,H = 7.9 Hz, 2 H, ArH), 7.36–
400 MHz): δ = 1.42 (t, JH,H = 7.2 Hz, 3 H, Me), 4.44 (q, JH,H =
3
3
7.45 (m, 5 H, ArH), 7.57–7.60 (m, 2 H, ArH), 7.76 (d, JH,H
=
7.2 Hz, 2 H, OCH2Me), 6.33 (d, JH,H = 15.4 Hz, 1 H, 5-H), 6.42
12.5 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.3, (m, 2 H, furan 3-H and 4-H), 7.22 (d, JH,H = 15.4 Hz, 1 H, 4-H),
3
21.5, 59.9, 73.8, 83.6, 90.0, 99.6, 118.6, 127.5, 128.8, 129.1, 129.2,
7.31–7.33 (m, 2 H, PhH), 7.46–7.48 (m, 4 H, PhH and furan 5-H),
9.20 (s, 1 H, CHO) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.2,
61.6, 112.5, 114.5, 124.9, 128.1, 128.4, 129.3, 129.5, 130.0, 133.3,
131.8, 136.6, 139.4, 159.9, 167.6 ppm. IR (CHCl ): ν = 3027.0,
˜
3
2227.6, 1701.9, 1642.7, 1511.6, 1287.8, 1177.8, 1131.6 cm–1. MS
(70 eV): m/z (%) = 320 (3.5) [M]+, 247 (7.7), 205 (100), 143 (6.8),
119 (8.1), 77 (5.1). C21H20O3 (320.38): calcd. C 78.73, H 6.29; found
C 78.83, H 6.25.
144.8, 152.0, 157.4, 166.1, 189.4 ppm. IR (CHCl ): ν = 3019.7,
˜
3
1724.7, 1661.8, 1567.1, 1333.0, 1266.8, 1146.4, 1019.3 cm–1. MS
(70 eV): m/z (%) = 296 (32) [M]+, 250 (65), 221 (28), 194 (83), 165
(100), 152 (27), 139 (16), 115 (27), 105 (14), 94 (12), 77 (19), 63
(14). C18H16O4 (296.10): calcd. C 72.96, H 5.44; found C 73.09, H
5.48.
(؎)-Ethyl (E)-3-(1,3-Diphenylprop-2-ynyloxy)acrylate (1i): Yield:
817.0 mg (2.67 mmol, 89%). 1H NMR (CDCl3, 400 MHz): δ = 1.27
3
3
(t, JH,H = 7.2 Hz, 3 H, Me), 4.17 (q, JH,H = 7.2 Hz, 2 H,
3
OCH2Me), 5.51 (d, JH,H = 12.5 Hz, 1 H, 2-H), 5.86 (s, 1 H, 1Ј- (؎)-Ethyl (E)-3-[1-Phenyl-3-(trimethylsilyl)prop-2-ynyloxy]acrylate
H), 7.30–7.38 (m, 3 H, PhH), 7.39–7.45 (m, 3 H, PhH), 7.48–7.50
(1n): Yield: 697.6 mg (2.31 mmol, 77%). 1H NMR (CDCl3,
3
3
(m, 2 H, PhH), 7.57–7.59 (m, 2 H, PhH), 7.75 (d, JH,H = 12.5 Hz, 400 MHz): δ = 0.09 (s, 9 H, SiMe3), 1.13 (t, JH,H = 7.2 Hz, 3 H,
1 H, 3-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.3, 59.9, 73.7,
Me), 4.03 (q, JH,H = 7.2 Hz, 2 H, OCH2Me), 5.33 (d, JH,H
=
3
3
Eur. J. Org. Chem. 2010, 6582–6587
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6585

D. Tejedor, G. Méndez-Abt, F. García-Tellado
FULL PAPER
12.5 Hz, 1 H, 2-H), 5.50 (s, 1 H, 1Ј-H), 7.23–7.29 (m, 3 H, PhH),
PhH), 9.18 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
7.36–7.39 (m, 2 H, PhH), 7.57 (d, 3JH,H = 12.5 Hz, 1 H, 3-H) ppm. 13.9, 61.4, 121.3, 123.9, 127.3, 127.5, 128.9, 130.0, 130.1, 130.2,
13C NMR (CDCl3, 100 MHz): δ = –0.45, 14.2, 59.7, 73.5, 95.7, 132.5, 132.7, 137.8, 139.1, 148.8, 151.6, 159.9, 165.9 ppm. IR
99.6, 100.0, 127.4, 128.7, 129.1, 136.1, 159.6, 167.3 ppm. IR
(CHCl ): ν = 2986.7, 1717.2, 1591.7, 1466.4, 1290.3, 1120.1,
˜
3
(CHCl ): ν = 3019.7, 2178.5, 1701.7, 1642.0, 1454.0, 1248.9, 1176.8,
1038.2 cm–1. MS (70 eV): m/z (%) = 371 (100) [M]+, 342 (65), 326
˜
3
1133.0, 849.9 cm–1. MS (70 eV): m/z (%) = 302 (0.5) [M]+, 213 (12),
(99), 273 (20), 236 (35), 200 (15), 160 (8.9), 77 (12). C20H15Cl2NO2
187 (100), 172 (11), 83 (15). C17H22O3Si (302.13): calcd. C 67.51, (371.05): calcd. C 64.53, H 4.06, N 3.76; found C 64.47, H 4.18, N
H 7.33; found C 67.70, H 7.15.
3.51.
Representative Procedure for the Microwave-Assisted Synthesis of
Pyridines 6a–n: A solution of propargyl vinyl ether 1a (1.0 mmol),
methoxyamine hydrochloride (1.1 mmol), and NaOAc (0.55 mmol)
in 2-propanol (5 mL) was placed in a microwave-specific closed
vial, and the solution was irradiated in a single-mode microwave
oven (200 W, 100 °C) for 60 min. The reaction mixture was filtered
through Celite by using dichloromethane as solvent. After remov-
ing the solvent under reduced pressure, the products were purified
by flash column chromatography (silica gel; n-hexane/EtOAc,
90:10, 1% Et3N) to yield 6a (175.0 mg, 77%).[14]
Ethyl 4-(4-Chlorophenyl)-6-phenylnicotinate (6g): Yield: 202.2 mg
(0.60 mmol, 60%). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3JH,H
= 7.2 Hz, 3 H, Me), 4.20 (q, 3JH,H = 7.2 Hz, 2 H, OCH2Me), 7.29–
7.31 (m, 2 H, p-ClC6H4, 3-H and 5-H), 7.41–7.44 (m, 2 H, ArH),
3
7.45–7.50 (m, 3 H, ArH), 7.66 (d, JH,H = 0.8 Hz, 1 H, 5-H), 8.04–
3
8.07 (m, 2 H, PhH), 9.15 (d, JH,H = 0.8 Hz, 1 H, 2-H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 13.8, 61.3, 121.5, 124.3, 127.3, 128.4,
128.9, 129.4, 129.9, 134.6, 137.6, 138.0, 150.1, 151.4, 159.7,
166.3 ppm. IR (CHCl ): ν = 3021.2, 2084.1, 1715.6, 1641.2, 1473.0,
˜
3
1285.0, 1218.7, 1115.3 cm–1. MS (70 eV): m/z (%) = 337 (100)
[M]+, 308 (57), 292 (94), 237 (31), 202 (39), 126 (9.1), 77 (11).
HRMS: calcd. for C20H16ClNO2 [M]+ 337.0870; found 337.0859.
Ethyl 6-Pentylnicotinate (6b): Yield: 119.34 mg (0.54 mmol, 54%).
3
1H NMR (CDCl3, 400 MHz): δ = 0.86 (t, JH,H = 7.2 Hz, 3 H,
3
Me), 1.22–1.33 (m, 4 H, 2ϫ3Ј-H and 2ϫ4Ј-H), 1.37 (t, JH,H
=
Ethyl 6-Phenyl-4-p-tolylnicotinate (6h): Yield: 193.4 mg (0.61 mmol,
1
3
7.2 Hz, 3 H, Me), 1.69–1.73 (m, 2 H, 2ϫ2Ј-H), 2.82 (pseudo t,
61%). H NMR (CDCl3, 400 MHz): δ = 0.99 (t, JH,H = 7.2 Hz, 3
H, Me), 2.28 (s, 3 H, Me), 4.06 (q, 3JH,H = 7.2 Hz, 2 H, OCH2Me),
7.10–7.15 (m, 4 H, tolyl), 7.29–7.36 (m, 3 H, PhH), 7.56 (s, 1 H, 5-
H), 7.90–7.93 (m, 2 H, PhH), 8.97 (s, 1 H, 2-H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.8, 21.2, 61.2, 121.7, 124.9, 127.3, 128.0,
128.8, 129.0, 129.8, 136.1, 138.2, 138.4, 150.9, 151.2, 159.3,
3
3JH,H = 7.7 Hz, 2 H, 2ϫ1Ј-H), 4.36 (q, JH,H = 7.2 Hz, 2 H,
3
3
OCH2Me), 7.20 (d, JH,H = 8.0 Hz, 1 H, 5-H), 8.16 (dd, JH,H
=
C
8.0, 2.4 Hz, 1 H, 4-H), 9.10 (d, 3JH,H = 2.4 Hz, 1 H, 2-H) ppm. 13
NMR (CDCl3, 100 MHz): δ = 13.9, 14.2, 22.4, 29.3, 31.5, 38.4,
61.1, 122.3, 123.8, 137.3, 150.3, 165.4, 167.0 ppm. IR (CHCl ): ν
˜
3
= 2933.2, 1715.8, 1600.8, 1377.7, 1289.9, 1121.9, 1030.7 cm–1. MS
(70 eV): m/z (%) = 221 (7.4) [M]+, 192 (56), 178 (65), 165 (100),
150 (27), 137 (90), 92 (15), 65 (16). C13H19NO2 (221.14): calcd. C
70.56, H 8.65, N 6.33; found C 70.19, H 8.61, N 5.92.
166.8 ppm. IR (CHCl ): ν = 2985.8, 1716.2, 1593.6, 1472.5, 1292.6,
˜
3
1222.5, 1113.0 cm–1. MS (70 eV): m/z (%) = 317 (90) [M]+, 272
(100), 244 (15), 217 (16), 202 (18), 115 (10), 59 (17). C21H19NO2
(317.14): calcd. C 79.47, H 6.03, N 4.41; found C 79.39, H 6.06, N
4.34.
Ethyl 4-Butyl-6-phenylnicotinate (6d): Yield: 127.4 mg (0.45 mmol,
1
3
45%). H NMR (CDCl3, 400 MHz): δ = 0.95 (t, JH,H = 7.4 Hz, 3 Ethyl 4,6-Diphenylnicotinate (6i): Yield: 203.0 mg (0.67 mmol,
3
1
3
H, Me), 1.41 (t, JH,H = 7.2 Hz, 3 H, Me), 1.38–1.48 (m, 2 H,
2ϫ3Ј-H), 1.59–1.67 (m, 2 H, 2ϫ2Ј-H), 3.03 (pseudo t, JH,H
8.0 Hz, 2 H, 2ϫ1Ј-H), 4.40 (q, JH,H = 7.2 Hz, 2 H, OCH2Me),
67%). H NMR (CDCl3, 400 MHz): δ = 1.07 (t, JH,H = 7.2 Hz, 3
3
3
=
H, Me), 4.17 (q, JH,H = 7.2 Hz, 2 H, OCH2Me), 7.36–7.51 (m, 8
3
3
H, PhH), 7.71 (d, JH,H = 0.5 Hz, 1 H, 5-H), 8.05–8.07 (m, 2 H,
7.41–7.50 (m, 3 H, PhH), 7.58 (s, 1 H, 5-H), 8.01–8.03 (m, 2 H,
PhH), 9.13 (d, 3JH,H = 0.5 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3,
PhH), 9.12 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 100 MHz): δ = 13.7, 61.2, 121.7, 124.8, 127.3, 128.1, 128.2, 128.3,
13.9, 14.2, 22.8, 33.1, 33.9, 61.0, 121.9, 124.1, 127.2, 128.8, 129.6,
128.9, 129.8, 138.3, 139.2, 151.13, 151.16, 159.5, 166.8 ppm. IR
138.5, 152.0, 154.4, 159.6, 166.2 ppm. IR (CHCl ): ν = 2964.3,
(CHCl ): ν = 2987.6, 1716.1, 1590.7, 1296.3, 1221.3, 1115.8 cm–1.
˜
˜
3
3
1713.2, 1596.9, 1371.6, 1282.4, 1102.4 cm–1. MS (70 eV): m/z (%)
= 283 (100) [M]+, 241 (33), 28 (72), 226 (45), 208 (36), 194 (13),
167 (17), 153 (14), 115 (10), 77 (13). C18H21NO2 (283.16): calcd. C
76.29, H 7.47, N 4.94; found C 76.24, H 7.42, N 5.00.
MS (70 eV): m/z (%) = 303 (90) [M]+, 274 (58), 258 (100), 230 (18),
202 (41), 77 (15). HRMS: calcd. for C20H17NO2 [M]+ 303.1260;
found 303.1259.
Ethyl 6-tert-Butyl-4-phenylnicotinate (6j): Yield: 36.8 mg
Ethyl 4-(4-Methoxyphenyl)-6-phenylnicotinate (6e): Yield: 259.7 mg
(0.13 mmol, 13%). 1H NMR (CDCl3, 400 MHz): δ = 1.04 (t, 3JH,H
(0.78 mmol, 78%). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3JH,H = 7.2 Hz, 3 H, Me), 1.40 (s, 9 H, tBu), 4.13 (q, JH,H = 7.2 Hz, 2
3
3
= 7.2 Hz, 3 H, Me), 3.84 (s, 3 H, OMe), 4.21 (q, JH,H = 7.2 Hz, 2
H, OCH2Me), 6.95–6.99 (m, 2 H, p-MeOC6H4, 3-H and 5 H),
H, OCH2Me), 7.30–7.33 (m, 3 H, PhH), 7.41–7.44 (m, 3 H, PhH
and 5-H), 9.00 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3, 100 MHz):
7.31–7.33 (m, 2 H, p-MeOC6H4, 2-H and 6 H), 7.41–7.50 (m, 3 H, δ = 13.7, 30.0, 37.8, 61.1, 120.6, 123.9, 128.1, 128.2, 128.3, 131.9,
PhH), 7.69 (d, 3JH,H = 0.8 Hz, 1 H, 5-H), 8.04–8.07 (m, 2 H, PhH),
139.4, 149.7, 149.8, 166.8 ppm. IR (CHCl ): ν = 2970.4, 1717.2,
˜
3
3
9.08 (d, JH,H = 0.8 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3, 1592.4, 1370.2, 1294.3, 1142.1 cm–1. MS (70 eV): m/z (%) = 283
100 MHz): δ = 13.8, 55.2, 61.1, 113.7, 121.5, 124.7, 127.2, 128.7,
129.4, 129.6, 131.2, 138.2, 150.6, 151.0, 159.3, 159.9, 166.9 ppm.
(69) [M]+, 268 (100), 254 (17), 241 (62), 238 (18), 227 (13), 194 (14),
154 (12), 127 (12), 86 (15), 84 (21), 57 (23). HRMS: calcd. for
C18H21NO2 [M]+ 283.1572; found 283.1570.
IR (CHCl ): ν = 2984.6, 2840.6, 1715.9, 1598.1, 1513.7, 1291.7,
˜
3
1246.1, 1111.6 cm–1. MS (70 eV): m/z (%) = 333 (100) [M]+, 304
(29), 288 (75), 233 (15), 189 (13), 77 (4.2). C21H19NO3 (333.14):
calcd. C 75.66, H 5.74, N 4.20; found C 75.62, H 5.80, N 3.92.
Ethyl 6-(4-Chlorophenyl)-4-phenylnicotinate (6k): Yield: 208.9 mg
(0.62 mmol, 62%). 1H NMR (CDCl3, 400 MHz): δ = 1.06 (t, 3JH,H
= 7.2 Hz, 3 H, Me), 4.16 (q, 3JH,H = 7.2 Hz, 2 H, OCH2Me), 7.34–
7.37 (m, 2 H, PhH), 7.36–7.46 (m, 5 H, ArH), 7.67 (s, 1 H, 5-H),
8.00–8.02 (m, 2 H, p-ClC6H4, 2-H and 6-H), 9.10 (s, 1 H, 2-H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.7, 61.3, 121.4, 125.1,
128.0, 128.3, 128.5, 128.6, 129.1, 136.1, 136.6, 139.0, 151.1, 151.3,
Ethyl
4-(3,4-Dichlorophenyl)-6-phenylnicotinate
(6f):
Yield:
226.3 mg (0.61 mmol, 61%). 1H NMR (CDCl3, 400 MHz): δ = 1.17
3
3
(t, JH,H = 7.2 Hz, 3 H, Me), 4.22 (q, JH,H = 7.2 Hz, 2 H,
3
OCH2Me), 7.19 (dd, JH,H = 8.2, 2.1 Hz, 1 H, 3,4-Cl2Ph 5-H),
7.46–7.52 (m, 5 H, ArH), 7.64 (s, 1 H, 5-H), 8.04–8.06 (m, 2 H,
158.2, 166.6 ppm. IR (CHCl ): ν = 2979.8, 1717.8, 1592.9, 1469.7,
˜
3
6586
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6582–6587

Nicotinic Acid Derivatives
1296.5, 1220.6, 1100.1 cm–1. MS (70 eV): m/z (%) = 337 (100)
[M]+, 292 (99), 265 (25), 237 (28), 202 (41), 127 (10), 105 (13), 77 [1] For selected reviews, see: a) H. Vosper, Br. J. Pharmacol. 2009,
158, 429–441; b) J. A. Farmer, Curr. Atheroscler. Rep. 2009, 11,
87–92; c) E. T. Bodor, S. Offermanns, Br. J. Pharmacol. 2008,
153, S68–S75; d) R. Raja, J. M. Thomas, M. Greenhill-Hooper,
S. V. Ley, A. A. F. Paz, Chem. Eur. J. 2008, 14, 2340–2348; e)
V. M. Kopelevich, V. I. Gunar, Pharm. Chem. J. 1999, 33, 177–
187.
(17). C20H16ClNO2 (337.09): calcd. C 71.11, H 4.77, N 4.15; found
C 71.00, H 5.09, N 4.11.
Ethyl 6-(4-Methoxyphenyl)-4-phenylnicotinate (6l): Yield: 239.8 mg
(0.72 mmol, 72%). 1H NMR (CDCl3, 400 MHz): δ = 1.06 (t, 3JH,H
3
= 7.2 Hz, 3 H, Me), 3.87 (s, 3 H, OMe), 4.15 (q, JH,H = 7.2 Hz, 2
[2] For selected reviews, see: a) P. A. Keller, “Pyridines and their
Benzo Derivatives: Synthesis” in Comprehensive Heterocyclic
Chemistry III (Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V.
Scriven, R. J. K. Taylor), Elsevier Science, Ltd., Oxford, 2008,
vol. 7, pp. 217–308; b) J. A. Varela, C. Saa, Synlett 2008, 2571–
2578; c) M. C. Bagley, C. Glover, E. A. Merritt, Synlett 2007,
2459–2482; d) B. Heller, M. Hapke, Chem. Soc. Rev. 2007, 36,
1085–1094; e) G. D. Henry, Tetrahedron 2004, 60, 6043–6061;
f) J. A. Varela, C. Saa, Chem. Rev. 2003, 103, 3787–3801; g)
T. L. Gilchrist, J. Chem. Soc. Perkin Trans. 1 2001, 2491–2515.
[3] F. Bohlmann, D. Rahtz, Chem. Ber. 1957, 90, 2265–2272.
[4] For selected examples, see: a) A.-L. Blayo, S. L. Meur, D. Grée,
R. Grée, Adv. Synth. Catal. 2008, 350, 471–476; b) M. C. Bag-
ley, J. W. Dale, M. Ohnesorge, X. Xiong, J. Bower, J. Comb.
Chem. 2003, 5, 41–44.
H, OCH2Me), 6.98–7.02 (m, 2 H, p-MeOC6H4, 3-H and 5-H),
7.35–7.37 (m, 2 H, PhH), 7.43–7.45 (m, 3 H, PhH), 7.64 (s, 1 H,
5-H), 8.02–8.06 (m, 2 H, p-MeOC6H4, 2-H and 6-H), 9.09 (s, 1 H,
2-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.7, 55.4, 61.1,
114.3, 120.9, 124.0, 128.0, 128.2, 128.3, 128.5, 128.8, 139.4, 151.0 (2
signals), 159.0, 161.3, 166.7 ppm. IR (CHCl ): ν = 2978.9, 2841.7,
˜
3
1714.0, 1590.9, 1470.1, 1369.3, 1228.7, 1176.6, 1113.8 cm–1. MS
(70 eV): m/z (%) = 333 (100) [M]+, 304 (16), 288 (43), 233 (15), 189
(11). C21H19NO3 (333.14): calcd. C 75.66, H 5.74, N 4.20; found C
75.82, H 5.93, N 3.86.
Ethyl 6-(Furan-2-yl)-4-phenylnicotinate (6m): Yield: 175.8 mg
(0.60 mmol, 60%). 1H NMR (CDCl3, 400 MHz): δ = 1.04 (t, 3JH,H
3
= 7.2 Hz, 3 H, Me), 4.14 (q, JH,H = 7.2 Hz, 2 H, OCH2Me), 6.55
[5] M. C. Bagley, J. W. Dale, J. Bower, Chem. Commun. 2002,
3
3
(dd, JH,H = 3.5, 1.9 Hz, 1 H, furan 4-H), 7.19 (dd, JH,H = 3.5,
1682–1683.
0.8 Hz, 1 H, furan 3-H), 7.33–7.35 (m, 2 H, PhH), 7.40–7.44 (m, 3
[6] a) C. Allais, T. Constantieux, J. Rodriguez, Chem. Eur. J. 2009,
15, 12945–12948;b) F. Liéby-Muller, C. Allais, T. Constantieux,
J. Rodriguez, Chem. Commun. 2008, 4207–4209.
3
H, Ph and furan 5-H), 7.54 (dd, JH,H = 1.9, 0.8 Hz, 1 H, 5-H),
3
7.65 (d, JH,H = 0.8 Hz, 1 H, 2-H), 9.02 (s, 1 H, 2-H) ppm. 13C
[7] For selected recent examples of controlled ring substitution of
simple nicotinic acid derivatives, see: a) M. Wasa, B. T. Worrell,
J.-Q. Yu, Angew. Chem. 2010, 122, 1297–1299; Angew. Chem.
Int. Ed. 2010, 49, 1275–1277; b) N. Robert, A.-L. Bonneau, C.
Hoarau, F. Marsais, Org. Lett. 2006, 8, 6071–6074; for an excel-
lent review on this topic, see: c) M. Schlosser, F. Mongin,
Chem. Soc. Rev. 2007, 36, 1161–1172.
NMR (CDCl3, 100 MHz): δ = 13.6, 61.1, 110.9, 112.4, 119.5, 124.3,
128.0, 128.2, 128.3, 139.0, 144.3, 151.0, 151.2, 151.3, 152.8,
166.5 ppm. IR (CHCl ): ν = 2979.0, 1713.7, 1602.6, 1493.1, 1372.1,
˜
3
1290.1, 1224.6, 1162.8, 1113.3, 1044.7 cm–1. MS (70 eV): m/z (%)
= 293 (96) [M]+, 248 (100), 193 (15), 165 (36), 139 (10), 77 (5.0).
C18H15NO3 (293.11): calcd. C 73.71, H 5.15, N 4.78; found C
73.86, H 5.33, N 4.35.
[8] For a review, see: T. E. Nielsen, S. L. Schreiber, Angew. Chem.
2008, 120, 52–61; Angew. Chem. Int. Ed. 2008, 47, 48–56.
[9] D. Tejedor, G. Méndez-Abt, F. García-Tellado, Chem. Eur. J.
2010, 16, 428–431.
Ethyl 4-(Trimethylsilyl)-6-phenylnicotinate (6n): Yield: 104.7 mg
1
(0.35 mmol, 35%). H NMR (CDCl3, 400 MHz): δ = 0.39 (s, 9 H,
[10] For a mechanistic discussion of this process, see ref.[9] and ref-
erences cited therein.
3
3
SiMe3), 1.42 (t, JH,H = 7.2 Hz, 3 H, Me), 4.42 (q, JH,H = 7.2 Hz,
2 H, OCH2Me), 7.43–7.52 (m, 3 H, PhH), 7.98 (d, 3JH,H = 0.8 Hz,
3
[11] Arylated derivatives of nicotinic acids are widely used as build-
ing blocks for pharmaceuticals, see: a) Y. S. Babu, R. S. Row-
land, P. Chand, P. L. Kotian, Y. El-Kattan, S. Niwas, U. S.
Patent No. 6699994, 2004; b) K. H. Donaldson, B. G. Shearer,
D. E. Uehling, WO Patent No. 01/42217, 2001; c) R. C.
Bernotas, R. R. Singhaus, J. W. Ullrich, D. H. Kaufman, R. L.
Morris, J. E. Wrobel, B. Hu, J. W. Jetter, M. D. Collini, J. M.
Travins, R. L. Magolda, WO Patent No. 2008/049047, 2008.
[12] a) Propargylic alcohols were either commercially available or
prepared from the corresponding aldehydes and lithiated
acetylenes according to a standard procedure, see: T. E. Niel-
sen, D. Tanner, J. Org. Chem. 2002, 67, 6366–6371; b) propar-
gyl vinyl ethers 1 were assembled from alkyl propiolates and
the corresponding propargylic alcohols according to published
protocols, see: D. Tejedor, A. Santos-Expósito, G. Méndez-
Abt, C. Ruiz-Pérez, F. García-Tellado, Synlett 2009, 1223–1226
and references cited therein.
1 H, 5-H), 8.02–8.04 (m, 2 H, PhH), 9.24 (d, JH,H = 0.8 Hz, 1 H,
2-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = –0.37, 14.3, 61.3,
126.4, 127.4, 128.9, 129.5, 129.7, 138.7, 150.5, 153.3, 158.8,
167.0 ppm. IR (CHCl ): ν = 2984.9, 1714.9, 1513.9, 1286.1,
˜
3
1137.7 cm–1. MS (70 eV): m/z (%) = 284 (18) [M+ – CH3], 256 (61),
203 (19), 187 (27), 159 (33), 128 (17), 115 (13), 99 (28), 77 (18), 73
(100), 59 (11). HRMS: calcd. for C17H21NO2Si [M – 15]+ 284.1107;
found 284.1111.
Acknowledgments
This research was supported by the Spanish Ministerio de Ciencia
e Innovación (MICINN), the European Regional Development
Fund (CTQ2008-06806-C02-02), the Spanish Ministerio de Sani-
dad y Consumo, Instituto de Salud Carlos III (MSC ISCIII) (RE-
TICS RD06/0020/1046), the Fundación Canaria de Investigación
y Salud (FUNCIS) (REDESFAC PI01/06) and the Fundación In-
stituto Canario de Investigación del Cancer (FICI-G.I.N808/2007).
G. M.-A. thanks the Spanish Ministerio de Educación y Ciencia
(MEC) for a Beca del Programa de Formación del Profesorado
Universitario (FPU) grant. The authors thank technician Ms.
Anna Jurado Varona for her assistance with the experiments.
[13] Microwave reactions were conducted in microwave-specific
closed vials (capacity 10 mL) by using a CEM Discover micro-
wave reactor.
[14] P. Molina, A. Pastor, M. J. Vilaplana, J. Org. Chem. 1996, 61,
8094–8098.
[15] F. Palacios, E. Herran, G. Rubiales, C. Alonso, Tetrahedron
2007, 63, 5669–5676.
Received: July 27, 2010
Published Online: October 22, 2010
Eur. J. Org. Chem. 2010, 6582–6587
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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