One-pot synthesis of 6-(pyridyl)salicylates by formal [3+3] cyclizations of 1,3-bis(silyl enol ethers) with 3-pyridyl-3-silyloxy-2-en-1-ones

Article abstract of DOI:10.1055/s-2008-1042949

6-(Pyridyl)salicylates were regioselectively prepared by formal [3+3] cyclization of 1,3-bis(silyl enol ethers) with 3-(pyridyl)-3-silyloxy-2-en-1- ones. These reactions represent what are, to the best of our knowledge, the first [3+3] cyclizations of 1,3

Full text of DOI:10.1055/s-2008-1042949

1276
PAPER
One-Pot Synthesis of 6-(Pyridyl)salicylates by Formal [3+3] Cyclizations of
1,3-Bis(silyl enol ethers) with 3-Pyridyl-3-silyloxy-2-en-1-ones
One-Pot Synthesis of
6
i
-(Pyrid
r
yl)salicy
z
lates a A. Yawer,a Abdolmajid Riahi,a,b Muhammad Adeel,a Ibrar Hussain,a Christine Fischer,b Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert Einstein Str. 29a, 18059 Rostock, Germany
Received 29 November 2007; revised 17 January 2008
O
O
OH
Abstract: 6-(Pyridyl)salicylates were regioselectively prepared by
formal [3+3] cyclization of 1,3-bis(silyl enol ethers) with 3-(py-
ridyl)-3-silyloxy-2-en-1-ones. These reactions represent what are,
to the best of our knowledge, the first [3+3] cyclizations of 1,3-
bis(silyl enol ethers) with heterocyclic substrates.
O
i
N
N
EtO
+
R1
R1
1a–d
2a
3a–d
Key words: cyclizations, heterocycles, regioselectivity, pyridines,
silyl enol ethers
ii
Me3SiO
OSiMe3
OR3
O
OH
R2
R2
R1
OSiMe3
O
OR3
Pyridines are of considerable pharmacological relevance
and occur in a variety of natural products.1,2 (Pyrid-2-
yl)arenes are present in natural 4-azafluorenones (e.g.,
kinabaline, darienine, and onychine), which exhibit a
strong antimicrobial activity.3 In addition, they are present
in natural products containing the 1,6-diazabenzo[de]an-
thracen-7-one moiety, such as sampangin or eupomati-
dine.4 The latter were shown to induce apoptosis and are
active against human leukemia HL-60 cells.4 Hetaryl-
substituted arenes are available, for example, by palladi-
um(0)-catalyzed cross-coupling reactions.5 Despite their
great synthetic utility, the scope of all these methods is
limited by the availability of the starting materials. In fact,
the synthesis of more complex aryl halides or triflates by
regioselective functionalization of arenes is often rather
difficult. In addition, transition metal catalyzed reactions
of sterically encumbered substrates often proceed in low
yield or not at all. Some years ago, Chan and co-workers
presented6 an elegant approach to salicylates by cycliza-
tion of 1,3-bis(silyl enol ethers)7 with 3-(silyloxy)alk-2-
en-1-ones. Recently, we described the application of this
method to the synthesis of a variety of functionalized
arenes.8 Herein, we report a new synthesis of functional-
ized 3-(pyrid-2-yl)phenols based on formal [3+3] cycliza-
tions of 1,3-bis(silyl enol ethers). These reactions
represent what are, to the best of our knowledge, the first
[3+3] cyclizations of heterocyclic substrates. From a pre-
parative viewpoint, they offer a convenient and regio-
selective approach to functionalized and sterically
encumbered 6-(pyridyl)salicylates, which are not readily
available by other methods.
5a–f
N
R1
N
iii
4a–d
6a–l
TiCl4
O
O
R2
Me3SiO
R1
O
OR3
N
OTiCl3
N
R1
A
C
5a–d
– (Me3Si)2O
TiCl4
– Me3SiCl
O
Me3SiO
OR3
R2
OTiCl3
R1
N
Me3SiO
B
Scheme 1 Synthesis of 6a–l. Reagents and conditions: (i) LDA (1.5
equiv), THF; (ii) Et3N (1.6 equiv), Me3SiCl (3.6 equiv), C6H6, 20 °C,
3 d; (iii) TiCl4 (1.1 equiv), CH2Cl2, –78 → 20 °C.
the silyl enol ethers 4a–d. The TiCl4-mediated formal
[3+3] cyclization of 4a–d with 1,3-bis(silyl enol ethers)
5a–f – prepared from the corresponding 1,3-dicarbonyl
compounds in two steps9 – afforded the 6-(pyrid-2-yl)sal-
icylates 6a–l (Scheme 1, Table 1). All products were
formed with very good regioselectivity. During the opti-
mization of this reaction, the (high) concentration and the
temperature played an important role.
The 1-(pyrid-2-yl)-1,3-diones 3a–d were prepared by
LDA-mediated reaction of ketones 1a–d with ethyl (py-
rid-2-yl)carboxylate (2a). The silylation of 3a–d afforded
The cyclization of 4 with 5 can be explained by TiCl4-
mediated isomerization of 4 by shift of the silyl group (in-
termediate A), TiCl4-mediated attack of the terminal car-
bon atom of 5 onto the carbon located next to substituent
R1 to give intermediate B (conjugate addition), cyclization
SYNTHESIS 2008, No. 8, pp 1276–1282
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1042949; Art ID: T18707SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 6-(Pyridyl)salicylates
1277
O
Table 1 Compounds 6a–l Prepared
O
OH
O
4
5
6
R1
R2
R3
Yield of 6
(%)a
i
EtO
+
Me
N
N
1a
2b
7 (26%)
a
a
a
a
b
b
b
b
b
c
a
d
e
a
b
c
d
e
f
Me
Me
Me
Me
Et
H
Me
Me
Me
Et
31
30
30
33
40
44
38
30
30
33
31
26
n-C6H13
n-C8H17
Cl
ii
O
OH
Me3SiO
R1
OSiMe3
OR2
R1
OR2
f
OSiMe3
O
5a–c
a
b
c
H
Me
Me
Et
Me
Me
iii
Et
Me
N
N
9a–c
8 (61%)
g
h
i
Et
Et
Scheme 2 Synthesis of 9a–c. Reagents and conditions: (i) NaH (4.0
equiv), ethyl nicotinate (1.0 equiv), acetone (2.0 equiv), Et2O, reflux,
2 h; (ii) Et3N (1.6 equiv), Me3SiCl (3.6 equiv), C6H6, 20 °C, 3 d; (iii)
TiCl4 (1.1 equiv), CH2Cl2, –78 → 20 °C.
d
e
Et
n-C6H13
n-C8H17
H
Me
Me
Me
Et
Et
a
b
a
j
n-Pr
n-Pr
i-Pr
O
c
k
l
Et
O
OH
O
i
EtO
+
d
H
Me
n-Pr
n-Pr
1c
N
N
a Yields of isolated products.
2c
10 (63%)
Table 2 Compounds 9a–c Prepared
ii
Me3SiO
R
OSiMe3
OMe
O
OH
5
a
b
c
9
a
b
c
R1
H
R2
Yield of 9 (%)a
R
OSiMe3
O
OMe
N
Me
Me
Et
44
38
32
5a,b
n-Pr
n-Pr
Me
Et
N
iii
12a (R = H): 44%
12b (R = Me): 40%
11 (88%)
a Yields of isolated products.
Scheme 3 Synthesis of 12a,b Reagents and conditions: (i) LDA
(1.5 equiv), THF; (ii) Et3N (1.6 equiv), Me3SiCl (3.6 equiv), C6H6,
20 °C, 3 d; (iii) TiCl4 (1.1 equiv), CH2Cl2, –78 → 20 °C.
(intermediate C), and subsequent aromatization. This
mechanism has been previously proposed6 by Chan et al.
for the cyclization of 5a with 1-phenyl-1-(trimethylsilyl-
oxy)but-1-en-3-one. However, a TiCl4-mediated attack of
5a onto the carbonyl group of 4a and subsequent cycliza-
tion by an SN¢ mechanism with displacement of the
Cl3TiO group cannot be excluded. It is noteworthy, that
the lone pairs of the nitrogen atom of the pyridine moiety
did not hinder the [3+3] cyclization to proceed.
1,3-bis(silyl enol ethers) with 3-pyridyl-3-silyloxy-2-en-
1-ones. These reactions represent what are, to the best of
our knowledge, the first [3+3] cyclizations of 1,3-bis(silyl
enol ethers) with heterocyclic substrates.
All solvents were dried by standard methods and all reactions were
carried out under an inert atmosphere. For 1H and 13C NMR spectra,
the deuterated solvents indicated were used. Mass spectrometric
data (MS) were obtained by electron ionization (EI, 70 eV), chemi-
cal ionization (CI, H2O) or electrospray ionization (ESI). For pre-
parative scale chromatography, silica gel (60–200 mesh) was used.
Melting points are uncorrected. Compounds 1a–d and 2a–c are
commercially available.
The NaH-mediated reaction of acetone (1a) with ethyl
nicotinate (2b) afforded 1-(pyrid-3-yl)-1,3-dione 7. The
silylation of 7 afforded the silyl enol ether 8. The TiCl4-
mediated formal [3+3] cyclization of 8 with 1,3-bis(silyl
enol ethers) 5a–c afforded the 6-(pyrid-3-yl)salicylates
9a–c (Scheme 2, Table 2).
The 1-(pyrid-4-yl)-1,3-dione 10 was prepared by LDA-
mediated reaction of pentan-2-one (1c) with ethyl (pyrid-
4-yl)carboxylate (2c). The silylation of 10 gave the silyl
enol ether 11. The TiCl4-mediated cyclization of 11 with
1,3-bis(silyl enol ethers) 5a,b afforded the 6-(pyrid-4-
yl)salicylates 12a,b (Scheme 3).
1,3-Dicarbonyl Compounds 3a–d and 10; General Procedure
To a stirred solution of LDA (75.0 mmol) in THF (1.2 mL/1.0 mmol
of LDA) was added ketone 1 (50.0 mmol) at –78 °C. After stirring
the solution for 1 h, compound 2 or 8 (60.0 mmol) was added. The
temperature of the solution was allowed to rise to 20 °C over 12 h.
Aq sat. NH4Cl (100 mL) was added, the layers were separated, and
the aqueous layer was extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and the solvent
In conclusion, a variety of 6-(pyridyl)salicylates were re-
gioselectively prepared by formal [3+3] cyclizations of
Synthesis 2008, No. 8, 1276–1282 © Thieme Stuttgart · New York

1278
M. A. Yawer et al.
PAPER
was removed in vacuo. The residue was purified by chromatogra-
phy (silica gel, n-heptane–EtOAc, 30:1 → 20:1) to give 3.
1H NMR (300 MHz, CDCl3): d = 1.09 [m, 6 H, CH(CH3)2], 2.50–
2.56 [m, 1 H, CH(CH3)2], 6.73 (br s), 1 H, CH), 7.23–7.25 (m, 1 H,
ArH), 7.64–7.67 (m, 1 H, ArH), 7.92 (m, 1 H, ArH), 8.51 (m, 1 H,
ArH), 15.70 (s, 1 H, OH).
1-Hydroxy-1-(2-pyridyl)but-1-en-3-one (3a)
Starting from LDA (1.5 equiv) in THF (62 mL), acetone (3.7 mL,
50.0 mmol), and 2a (8.0 mL, 60.0 mmol), 3a was isolated as a yel-
lowish solid (8.53 g, 64%); mp 48–50 °C.
13C NMR (75 MHz, CDCl3): d = 19.5 [CH(CH3)2], 38.0
[CH(CH3)2], 95.0 (CH), 122.1, 125.9, 137.1, 149.1 (CHAr), 152.5
(CAr), 181.5 (COH), 202.5 (C=O).
IR (KBr): 3452 (s), 3117 (w), 3068 (w), 2916 (w), 1611 (s), 1581
(s), 1465 (m), 1431 (s), 1355 (m), 1288 (s), 1247 (m), 1185 (m),
1159 (w), 1080 (m), 1043 (w), 991 (s), 848 (m), 788 (s), 747 (m),
621 (m), 551 cm–1 (m).
GC-MS (EI, 70 eV): m/z (%) = 191 ([M+], 11), 148 (100), 121 (22),
106 (37), 93 (4), 78 (80), 43 (40).
HRMS (EI): m/z calcd for C11H13NO2: 191.09408; found:
191.09466.
1H NMR (300 MHz, CDCl3): d = 2.09 (s, 3 H, CH3), 6.70 (s, 1 H,
CH), 7.24–7.28 (m, 1 H, ArH), 7.65–7.71 (m, 1 H, ArH), 7.91 (d,
3J = 7.8 Hz, 1 H, ArH), 8.51 (m, 1 H, ArH), 15.58 (s, 1 H, OH).
1-Hydroxy-1-(pyrid-4-yl)hex-1-en-3-one (10)
Starting from LDA (1.5 equiv) in THF (62 mL), pentan-2-one (5.3
mL, 50.0 mmol), and 2c (5.3 mL, 35.0 mmol), 10 was isolated as a
yellow solid (4.208 g, 63%).
13C NMR (75 MHz, CDCl3): d = 26.2 (CH3), 97.5 (CH), 122.3,
126.5, 127.7, 137.2 (CHAr), 150.9 (CAr), 181.2 (COH), 195.1
(C=O).
1H NMR (250 MHz, CDCl3): d = 0.86 (t, 3J = 7.4 Hz, 3 H,
3
CH2CH2CH3), 1.55–1.64 (m, 2 H, CH2CH2CH3), 2.33 (t, J = 7.5
Hz, 2 H, CH2CH2CH3), 6.13 (s, 1 H, CH), 7.57 (d, 3J = 6.3 Hz, 2 H,
ArH), 8.61 (d, 3J = 5.3 Hz, 2 H, ArH), 15.06 (br s, 1 H, OH).
GC-MS (EI, 70 eV): m/z (%) = 163 (M+, 34), 148 (84), 134 (6), 121
(35), 106 (63), 85 (15), 78(100), 43(32).
HRMS (EI): m/z calcd for C9H9NO2: 163.06278; found:
163.063007.
13C NMR (75 MHz, CDCl3): d = 13.3 (CH2CH2CH3), 18.4
(CH2CH2CH3), 41.3 (CH2CH2CH3), 96.8 (CH), 120.1 (2 CHAr),
141.5 (CAr), 150.7 (2 CHAr), 178.2 (COH), 199.6 (C=O).
1-Hydroxy-1-(2-pyridyl)pent-1-en-3-one (3b)
Starting from LDA (1.5 equiv) in THF (62 mL), butan-2-one (4.4
mL, 50.0 mmol), and 2a (8.0 mL, 60.0 mmol), 3b was isolated as a
yellow oil (4.76 g, 54%).
GC-MS (EI, 70 eV): m/z (%) = 191 ([M+], 18), 163 (19), 148 (100),
121 (9), 106 (27), 93 (4), 78 (20), 51 (15), 43 (10).
HRMS (EI): m/z calcd for C11H13NO2: 191.09408; found:
191.09411.
IR (neat): 2976 (w), 2879 (w), 1600 (s), 1577 (s), 1563 (s), 1460
(m), 1311 (m), 1240 (m), 1048 (m), 781 (s), 742 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 1.19 (t, 3J = 7.4 Hz, 3 H,
4-Hydroxy-4-(pyrid-3-yl)but-3-en-2-one (7)
3
CH2CH3), 2.41 (q, J = 7.3 Hz, 2 H, CH2CH3), 6.73 (s, 1 H, CH),
To a stirred suspension of NaH (0.38 g, 15.9 mmol) in anhyd Et2O
(6 mL) at 0 °C, were added ethyl nicotinate (2b; 0.60 mL, 4.0
mmol) and acetone (1a; 0.59 mL, 8.0 mmol) at r.t. This mixture was
refluxed for 2 h, subsequently cooled to r.t., and aq 3 M HCl (100
mL) was added. The organic and the aqueous layer were separated
and the latter was extracted with Et2O (3 × 20 mL). The combined
organic layers were washed with brine (100 mL), dried (Na2SO4),
filtered, and the solvent was removed in vacuo. The residue was pu-
rified by chromatography (silica gel, n-heptane–EtOAc, 30:1 →
20:1) to give 7 as slightly red to yellow solid (0.34 g, 26%).
7.27–7.31 (m, 1 H, ArH), 7.68–7.74 (m, 1 H, ArH), 7.94–7.98 (m,
1 H, ArH), 8.54–8.56 (m, 1 H, ArH), 15.61 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 9.8 (CH2CH3), 33.0 (CH2CH3),
96.4 (CH), 122.3, 126.4, 137.2, 149.5 (CHAr), 152.4 (CAr), 180.6
(COH), 199.6 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 177 ([M+], 13), 162 (4), 148 (100),
106 (69), 78 (74), 51 (14).
HRMS (EI): m/z calcd for C10H11NO2: 177.07843; found:
177.07890.
IR (neat): 2952 (w), 2919 (w), 1926 (w), 1584 (s), 1411 (m), 1371
(s), 1204 (m), 1077 (s), 824 (m), 872 (s), 695 (s), 543 cm–1 (w).
1-Hydroxy-1-(2-pyridyl)hex-1-en-3-one (3c)
1H NMR (250 MHz, CDCl3): d = 2.17 (s, 3 H, CH3), 6.13 (s, 1 H,
CH), 7.32–7.37 (m, 1 H, ArH), 8.08–8.12 (m, 1 H, ArH), 8.67 (s, 1
H, ArH), 9.01 (s, 1 H, ArH), 15.92 (s, 1 H, OH).
Starting from LDA (1.5 equiv) in THF (62 mL), pentan-2-one (5.3
mL, 50.0 mmol), and 2a (8.0 mL, 60.0 mmol), 3c was isolated as a
yellow oil (5.32 g, 56%).
13C NMR (75 MHz, CDCl3): d = 26.0 (CH3), 97.2 (CH), 123.7,
128.5, 148.4, 152.7 (CHAr), 134.5 (CAr), 181.2 (COH), 194.6 (C=O).
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3J = 7.4 Hz, 3 H,
3
CH2CH2CH3), 1.59–1.67 (m, 2 H, CH2CH2CH3), 2.35 (t, J = 7.6
Hz, 2 H, CH2CH2CH3), 6.73 (s, 1 H, CH), 7.29–7.31 (m, 1 H, ArH),
7.71–7.72 (m, 1 H, ArH), 7.97 (d, 3J = 8.0 Hz, 1 H, ArH), 8.54 (m,
1 H, ArH), 15.68 (s, 1 H, OH).
GC-MS (EI, 70 eV): m/z (%) = 163 ([M+], 67), 162 (100), 148 (97),
106 (66), 104 (9), 85 (25), 79 (26), 78 (53), 69 (18), 65 (10), 51 (29),
50 (13), 43 (33), 39 (11).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH2CH2CH3), 19.3
(CH2CH2CH3), 41.6 (CH2CH2CH3), 97.0 (CH), 122.3, 126.4, 137.3,
149.5 (CHAr), 152.7 (CAr), 181.4 (COH), 198.3 (C=O).
HRMS (EI): m/z calcd for C9H9NO2: 163.06278; found:
163.062897.
Silyl Enol Ethers 4, 8, and 11; General Procedure
GC-MS (EI, 70 eV): m/z (%) = 191 ([M+], 10), 163 (14), 148 (100),
121 (21), 106 (77), 93 (14), 78.(83), 51 (15), 43 (14).
To a stirred solution of 3 (10.0 mmol) in benzene (2.5 mL/1.0 mmol
of 3) was added Et3N (16.0 mmol). After stirring the solution for 2
h, Me3SiCl (36.0 mmol) was added. After stirring the solution for
72 h, the solvent was removed in vacuo, and hexane (25 mL) was
added to the residue to give a suspension. The latter was filtered un-
der argon. The filtrate was concentrated in vacuo to give silyl enol
ethers 4a–d, 8, and 11. Due to the unstable nature of the silyl enol
ethers, they were characterized only by NMR spectroscopy.
HRMS (EI): m/z calcd for C11H13NO2: 191.09408; found:
191.09468.
1-Hydroxy-4-methyl-1-(pyrid-2-yl)pent-1-en-3-one (3d)
Starting from LDA (1.5 equiv) in THF (62 mL), 3-methylbutan-2-
one (5.3 mL, 50.0 mmol), and 2a (8.0 mL, 60.0 mmol), 3d was iso-
lated as a yellowish oil (5.653 g, 54%).
Synthesis 2008, No. 8, 1276–1282 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 6-(Pyridyl)salicylates
1279
4-(2-Pyridyl)-4-[(trimethylsilyl)oxy]but-3-en-2-one (4a)
Starting from benzene (38.0 mL), 3a (2.50 g, 15.3 mmol), Et3N (6.9
mL, 49.0 mmol), and Me3SiCl (6.96 mL, 55.1 mmol), 4a was iso-
lated as a reddish oil.
4-Methyl-1-(2-pyridyl)-1-[(trimethylsilyl)oxy]pent-1-en-3-one
(11)
Starting from benzene (65.0 mL), 10 (5.00 g, 26.1 mmol), Et3N (5.8
mL, 41.8 mmol), and Me3SiCl (11.9 mL, 94.1 mmol), 11 was iso-
lated as a reddish oil (6.05 g, 88%).
1H NMR (300 MHz, CDCl3): d = 0.29 [s, 9 H, OSi(CH3)3], 2.38 (s,
3 H, CH3), 7.10 (s, 1 H, CH), 7.52–7.33 (m, 1 H, ArH), 7.70–7.75
(m, 1 H, ArH), 7.99 (d, 3J = 8.8 Hz, 1 H, ArH), 8.56 (m, 1 H, ArH).
1H NMR (250 MHz, CDCl3): d = 0.04 [m, 9 H, OSi(CH3)3], 0.70–
0.73 (m, 3 H, CH2CH2CH3), 1.37–1.44 (m, 2 H, CH2CH2CH3), 2.19
(t, 3J = 7.4 Hz, 2 H, CH2CH2CH3), 5.90 (s, 1 H, CH), 7.36–7.42 (m,
2 H, ArH), 8.46–8.50 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 0.74 [OSi(CH3)3], 22.4 (CH3),
103.1 (CH), 121.5, 125.7, 136.4, 148.3 (CHAr), 155.3 (CAr), 172.3
(C), 189.3 (C=O).
13C NMR (75 MHz, CDCl3): d = 0.1 [OSi(CH3)3], 13.0
(CH2CH2CH3), 19.5 (CH2CH2CH3), 35.5 (CH2CH2CH3), 102.6
(CH), 120.1 (2 CHAr), 127.4 (CAr), 149.5 (2 CHAr), 176.8 (COH),
187.4 (C=O).
1-(2-Pyridyl)-1-[(trimethylsilyl)oxy]pent-1-en-3-one (4b)
Starting from benzene (38.0 mL), 3b (4.73 g, 15.3 mmol), Et3N (6.1
mL, 43.0 mmol), and Me3SiCl (10.51 mL, 83.2 mmol), 4b was iso-
lated as a reddish oil (5.10 g, 76%).
Salicylates 6a–l, 9a–c, and 12a,b; General Procedure
To a CH2Cl2 solution of 4 (10.0 mmol, 2 mL/1.0 mmol of 4) were
added 5 (11.0 mmol), and subsequently TiCl4 (11.0 mmol) at
–78 °C. The temperature of the solution was allowed to warm to
20 °C during 14 h with stirring. To the solution was added 10% aq
HCl (20 mL) and the organic and the aqueous layers were separated.
The latter was extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by chromatography
(silica gel, n-heptane–EtOAc) to give 6a–l, 9a–c, and 12a,b.
1H NMR (300 MHz, CDCl3): d = 0.25 [m, 9 H, OSi(CH3)3], 1.05–
1.08 (m, 3 H, CH2CH3), 2.80–2.88 (m, 2 H, CH2CH3), 7.07 (s, 1 H,
CH), 7.29–7.31 (m, 1 H, ArH), 7.68–7.72 (m, 1 H, ArH), 8.02–8.06
(m, 1 H, ArH), 8.54–8.56 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 0.12 [OSi(CH3)3], 11.1 (CH2CH3),
27.7 (CH2CH3), 102.0 (CH), 121.7, 125.9, 136.6, 148.5 (CHAr),
155.6 (CAr), 177.3 (C), 188.9 (C=O).
1-(2-Pyridyl)-1-[(trimethylsilyl)oxy]hex-1-en-3-one (4c)
Starting from benzene (69.5 mL), 3c (5.31 g, 27.8 mmol), Et3N
(6.23 mL, 44.5 mmol), and Me3SiCl (12.6 mL, 100.1 mmol), 4c was
isolated as a reddish oil (6.20 g, 86%).
Methyl 2-Hydroxy-4-methyl-6-(pyrid-2-yl)benzoate (6a)
Starting from 4a (0.47 g, 2.0 mmol), 5a (0.573 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 6a was isolated as a highly viscous red-
dish oil (0.148 g, 31%).
1H NMR (300 MHz, CDCl3): d = 0.24–0.29 [m, 9 H, OSi(CH3)3],
0.87–0.95 (m, 3 H, CH2CH2CH3), 1.56–1.66 (m, 2 H, CH2CH2CH3),
2.34–2.39 (m, 2 H, CH2CH2CH3), 7.26 (s, 1 H, CH), 7.32 (m, 1 H,
ArH), 7.26–7.36 (m, 1 H, ArH), 7.98–8.05 (m, 1 H, ArH), 8.54–8.58
(m, 1 H, ArH).
IR (neat): 3473 (m), 2918 (m), 2849 (m), 1731 (w), 1660 (m), 1605
(m), 1582 (s), 1494 (m), 1455 (m), 1409 (m), 1351 (s), 1294 (s),
1261 (m), 1158 (s), 1090 (m), 1015 (m), 980 (m), 850 (m), 823 (s),
755 (s), 602 cm–1 (s).
13C NMR (75 MHz, CDCl3): d = 0.09 [OSi(CH3)3], 13.6
(CH2CH2CH3), 20.2 (CH2CH2CH3), 30.0 (CH2CH2CH3), 102.0
(CH), 120.5, 125.8, 136.6, 148.4 (CHAr), 155.5 (CAr), 176.2 (C),
188.7 (C=O).
1H NMR (250 MHz, CDCl3): d = 2.29 (s, 3 H, CH3), 3.48 (s, 3 H,
OCH3), 6.67 (s, 1 H, ArH), 6.82 (s, 1 H, ArH), 7.29 (m, 1 H, ArH),
7.68 (m, 2 H, ArH), 8.58 (br s, 1 H, ArH), 10.61 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 20.6 (CH3), 50.8 (OCH3), 108.1
(CAr), 117.2 (2 C, CHAr), 122.3 (2 C, CHAr), 135.4 (2 C, CHAr),
140.5, 144.2, 159.3, 160.6 (CAr), 169.6 (C=O).
1-(2-Pyridyl)-1-[(trimethylsilyl)oxy]hex-1-en-3-one (4d)
Starting from benzene (38.0 mL), 3d (5.65 g, 29.5 mmol), Et3N
(6.58 mL, 47.0 mmol), and Me3SiCl (13.4 mL, 106.2 mmol), 4d
was isolated as a reddish oil.
GC-MS (EI, 70 eV): m/z (%) = 243 ([M+], 41), 211 (69), 182 (100),
154 (23), 127 (9), 91 (8), 77 (11).
1H NMR (300 MHz, CDCl3): d = 0.25 [OSi(CH3)3], 1.07–1.10 [m,
6 H, CH(CH3)2], 2.54–2.66 [m, 1 H, CH(CH3)2], 6.90 (s, 1 H, CH),
7.25–7.30 (m, 1 H, ArH), 7.70–7.72 (m, 1 H, ArH), 7.97–7.98 (m,
1 H, ArH), 8.52 (m, 1 H, ArH).
HRMS (EI): m/z calcd for C14H13NO3: 243.08899; found:
243.089361.
Methyl 3-Hexyl-2-hydroxy-4-methyl-6-(pyrid-2-yl)benzoate
(6b)
Starting from 4a (0.47 g, 2.0 mmol), 5d (0.756 g, 2.2 mmol), and
TiCl4 (0.241mL, 2.2 mmol), 6b was isolated as a highly viscous red-
dish oil (0.185 g, 30%).
13C NMR (75 MHz, CDCl3): d = 0.3 [OSi(CH3)3], 10.9 [CH(CH3)2],
32.2 [CH(CH3)2], 103.2 (CH), 127.5, 129.2, 129.8, 133.4 (CHAr),
147.2 (CAr), 176.5 (C), 185.9 (C=O).
4-(3-Pyridyl)-4-[(trimethylsilyl)oxy]but-3-en-2-one (8)
Starting from benzene (36.0 mL), 7 (2.01 g, 12.4 mmol), Et3N (2.75
mL, 19.7 mmol), and Me3SiCl (2.80 mL, 22.2 mmol), 8 was isolated
as a reddish oil (1.77 g, 61%).
IR (neat): 2952 (m), 2923 (s), 2854 (m), 1662 (s), 1608 (w), 1587
(m), 1561 (w), 1436 (s), 1391 (m), 1354 (m), 1269 (s), 1224 (s),
1148 (s), 1116 (m), 1049 (w), 991 (w), 863 (w), 810 (w), 784 (s),
745 cm–1 (m).
3
1H NMR (250 MHz, CDCl3): d = 2.17 [s, 9 H, OSi(CH3)3], 2.20 (s,
3 H, CH3), 6.02 (s, 1 H, CH), 7.13–7.19 (m, 1 H, ArH), 7.90–7.95
(m, 1 H, ArH), 8.50 (d, 3J = 7.5 Hz, 1 H, ArH), 8.83 (s, 1 H, ArH).
1H NMR (300 MHz, CDCl3): d = 0.82 (t, J = 7.2 Hz, 3 H, CH3),
1.27–1.60 (m, 8 H, CH2), 2.27 (s, 3 H, CH3), 2.63 (t, 3J = 7.8 Hz, 2
H, CH2), 3.39 (s, 3 H, OCH3), 6.65 (s, 1 H, ArH), 7.13–7.25 (m, 2
H, ArH), 7.63 (m, 1 H, ArH), 8.53 (br s, 1 H, ArH), 10.80 (s, 1 H,
OH).
13C NMR (75 MHz, CDCl3): d = 1.0 [OSi(CH3)3], 21.2 (CH3), 96.2
(CH), 122.5, 134.2, 148.0, 151.8 (CHAr), 134.4 (CAr), 172.2 (COH),
187.6 (C=O).
13C NMR (62 MHz, CDCl3): d = 14.0 (CH3), 19.8 (CH3), 22.6, 26.3,
28.6, 29.6, 31.7 (CH2), 51.6 (OCH3), 109.0 (CAr), 121.4 (CHAr),
123.6 (2 CHAr), 130.0 (CAr), 135.7 (2 CHAr), 142.6 (CAr), 148.4
(CHAr), 159.3, 160.6 (CAr), 171.4 (C=O).
Synthesis 2008, No. 8, 1276–1282 © Thieme Stuttgart · New York

1280
M. A. Yawer et al.
PAPER
GC-MS (EI, 70 eV): m/z (%) = 327 ([M+], 11), 294 (4), 280 (6), 257
(90), 238 (46), 225 (100), 196 (15), 167 (22).
13C NMR (75 MHz, CDCl3): d = 13.6 (CH2CH3), 27.8 (CH2CH3),
50.7 (OCH3), 108.4 (CAr), 115.6 (CHAr), 120.6 (CHAr), 121.9
(CHAr), 122.0, 134.7 (CHAr), 142.4 (CAr), 147.4 (CHAr), 151.1 (CAr),
159.4 (CAr), 160.5 (COH), 169.8 (C=O).
HRMS (EI): m/z calcd for C20H25NO3: 327.18290; found:
327.182616.
GC-MS (EI, 70 eV): m/z (%) = 257 ([M+], 32), 225 (61), 211 (8),
197 (11), 182 (100), 154 (10), 127 (8), 84 (9).
Methyl 2-Hydroxy-4-methyl-3-octyl-6-(pyrid-2-yl)benzoate
(6c)
Starting from 4a (0.47 g, 2.0 mmol), 5e (0.818 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 6c was isolated as a highly viscous red-
dish oil (0.195 g, 30%).
HRMS (EI): m/z calcd for C15H15NO3: 257.10464; found:
257.10461.
Methyl 4-Ethyl-2-hydroxy-3-methyl-6-(pyrid-2-yl)benzoate
(6f)
Starting from 4b (0.374 g, 1.5 mmol), 5b (0.448 g, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 6f was isolated as a highly viscous red-
dish oil (0.180, 44%).
IR (neat): 2952 (m), 2921 (s), 2852 (m), 1663 (s), 1608 (w), 1587
(m), 1561 (w), 1436 (s), 1391 (m), 1354 (m), 1272 (s), 1224 (s),
1195 (m), 1148 (s), 1118 (m), 1049 (w), 992 (w), 863 (w), 785 (m),
745 (s), 634 cm–1 (m).
3
1H NMR (300 MHz, CDCl3): d = 0.81 (t, J = 7.4 Hz, 3 H, CH3),
IR (neat): 2953 (w), 2870 (w), 1657 (m), 1364 (m), 1378 (m), 1378
(s), 1260 (m), 1195 (s), 1105 (s), 1009 cm–1 (m).
1.21–1.45 (m, 12 H, CH2), 2.27 (s, 3 H, CH3), 2.63 (t, 3J = 7.9 Hz,
2 H, CH2), 3.43 (s, 3 H, OCH3), 6.65 (s, 1 H, ArH), 7.31 (m, 2 H,
ArH), 7.77 (m, 1 H, ArH), 8.59 (br s , 1 H, ArH), 10.94 (s, 1 H, OH).
1H NMR (300 MHz, CDCl3): d = 1.12 (t, 3J = 7.7 Hz, 3 H,
CH2CH3), 2.18 (s, 3 H, CH3), 2.60 (d, 3J = 7.3 Hz, 2 H, CH2CH3),
3.39 (s, 3 H, OCH3), 6.67 (s, 1 H, ArH), 7.12–7.24 (m, 2 H, ArH),
7.59–7.65 (m, 1 H, ArH), 8.52 (m, 1 H, ArH), 10.80 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 14.0 (CH3), 19.8 (CH3), 22.6, 26.3,
28.6, 29.2, 29.5, 30.0, 31.9 (CH2), 51.9 (OCH3), 108.8 (CAr), 123.9
(2 C, CHAr), 130.9 (CAr), 137.0 (CAr), 137.5 (2 C, CHAr), 142.8
(CAr), 146.6 (CHAr), 159.3, 159.8 (CAr), 170.9 (C=O).
13C NMR (75 MHz, CDCl3): d = 11.4 (CH2CH3), 14.5 (CH3), 27.4
(CH2CH3), 52.1 (OCH3), 109.2 (CAr), 121.8, 122.2, 123.4 (CHAr),
124.7 (CAr), 136.1 (CHAr), 140.7 (CAr), 148.8 (CHAr), 149.1, 160.0
(CAr), 161.1 (COH), 171.8 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 355 ([M+], 9), 324 (8), 257 (100),
238 (30), 225 (90), 196 (10), 139 (25), 97 (19).
HRMS (EI): m/z calcd for C22H29NO3: 355.21420; found:
355.214056.
GC-MS (EI, 70 eV): m/z (%) = 271 ([M+], 35), 239 (100), 224 (23),
211 (20), 196 (20), 182 (10), 167 (17), 154 (7), 84 (7), 78 (5).
HRMS (EI): m/z calcd for C16H17NO3: 271.12029; found:
271.11995.
Ethyl 3-Chloro-2-hydroxy-4-methyl-6-(pyrid-2-yl)benzoate
(6d)
Starting from 4a (0.353 g, 1.5 mmol), 5f (0.508 g, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 6d was isolated as a highly viscous
reddish oil (0.141 g, 33%).
Ethyl 3,4-Diethyl-2-hydroxy-6-(pyrid-2-yl)benzoate (6g)
Starting from 4b (0.498 g, 2.0 mmol), 5c (0.659 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 6g was isolated as a highly viscous red-
dish oil (0.230 g, 38%).
IR (neat): 3058 (w), 2981 (m), 2924 (m), 1723 (m), 1655 (s), 1607
(m), 1584 (m), 1471 (m), 1447 (m), 1430 (m), 1380 (s), 1299 (s),
1269 (s), 1218 (s), 1166 (s), 1012 (s), 880 (m), 800 (s), 756 (s), 614
cm–1 (m).
IR (KBr): 2965 (w), 2873 (w), 1655 (s), 1587 (m), 1392 (m), 1371
(s), 1273 (s), 1183 (s), 1031 (s), 1031 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.83 (t, 3J = 7.3 Hz, 3 H,
OCH2CH3), 1.24–1.33 (m, 6 H, CH2CH3), 2.73–2.87 (m, 4 H,
CH2CH3), 4.05 (q, 3J = 7.2 Hz, 2 H, CO2CH2), 6.81 (s, 1 H, ArH),
7.29–7.33 (m, 1 H, ArH), 7.40 (d, 3J = 7.8 Hz, 1 H, ArH), 7.74–7.80
(m, 1 H, ArH), 8.66–8.68 (m, 1 H, ArH), 11.20 (s, 1 H, OH).
3
1H NMR (250 MHz, CDCl3): d = 0.70 (s, J = 7.1 Hz, 3 H, CH3),
2.37 (s, 3 H, CH3), 3.89 (q, 3J = 7.1 Hz, 2 H, OCH2), 6.74 (s, 1 H,
ArH), 7.18–7.24 (m, 2 H, ArH), 7.64 (m, 1 H, ArH), 8.52 (m, 1 H,
ArH), 11.41 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 12.1 (CH3), 19.7 (CH3), 60.38
(OCH2), 109.6 (CAr), 120.9 (CAr), 121.5 (CHAr), 122.0 (CHAr),
122.4 (CHAr), 134.8 (CHAr), 139.9 (CAr), 141.6 (CAr), 147.6 (CHAr),
156.3, 158.9 (CAr), 169.2 (C=O).
13C NMR (75 MHz, CDCl3): d = 13.5 (OCH2CH3), 14.2, 15.5
(CH2CH3), 19.4, 26.5 (CH2CH3), 61.1 (CO2CH2), 109.5 (CAr),
121.8, 122.3, 123.4 (CHAr), 130.8 (CAr), 136.0 (CHAr), 140.9 (CAr),
148.4 (CHAr), 148.8, 160.2 (CAr), 161.5 (COH), 171.4 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 293 ([M+], 37Cl, 10), 291 ([M+],
35Cl, 28), 245 (100), 216 (54), 210 (21), 182 (23), 154 (26), 127
(14).
GC-MS (EI, 70 eV): m/z (%) = 299 ([M+], 44), 253 (100), 238 (70),
224 (25), 210 (13), 167 (14), 117 (8), 78 (5).
HRMS (EI): m/z calcd for C18H21NO3: 299.15160; found:
299.15122.
HRMS (EI): m/z calcd for C15H14ClNO3 (M+, 35Cl): 291.06567;
found: 291.065867.
Methyl 4-Ethyl-3-hexyl-2-hydroxy-6-(pyrid-2-yl)benzoate (6h)
Starting from 4b (0.498 g, 2.0 mmol), 5d (0.751 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 6h was isolated as a highly viscous red-
dish oil (0.150 g, 30%).
Methyl 4-Ethyl-2-hydroxy-6-(pyrid-2-yl)benzoate (6e)
Starting from 4b (0.425 g, 1.67 mmol), 5a (0.627 g, 1.82 mmol),
and TiCl4 (0.20 mL, 1.67 mmol), 6e was isolated as a highly viscous
reddish oil (0.154 g, 40%).
IR (neat): 2952 (w), 2852 (w), 1663 (m), 1436 (m), 1397 (m), 1318
(m), 1271 (m), 1195 (s), 1119 (s), 745 cm–1 (m).
IR (neat): 2970 (w), 2930 (w), 1603 (s), 1578 (s), 1422 (s), 1239 (s),
1214 (s), 1158 (s), 1088 (m), 1056 (m), 818 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.86 [br t, 3J = 6.8 Hz, 3 H,
(CH2)5CH3], 1.12 (br t, 3J = 5.5 Hz, 3 H, CH2CH3), 1.22–1.28 (m, 8
H, CH2), 2.64 [t, 3J = 7.6 Hz, 2 H, CH2(C5H11)], 2.68 (q, 3J = 7.2 Hz,
2 H, CH2CH3), 3.44 (s, 3 H, OCH3), 6.72 (s, 1 H, ArH), 7.17–7.21
(m, 1 H, ArH), 7.28–7.31 (m, 1 H, ArH), 7.65–7.70 (m, 1 H, ArH),
8.56–8.58 (m, 1 H, ArH), 10.86 (s, 1 H, OH).
1H NMR (300 MHz, CDCl3): d = 1.17 (t, 3J = 7.6 Hz, 3 H,
CH2CH3), 2.60 (q, 3J = 7.6 Hz, 2 H, CH2CH3), 3.39 (s, 3 H, OCH3),
4
4
6.68 (d, J = 1.7 Hz, 1 H, ArH), 6.83 (d, J = 1.4 Hz, 1 H, ArH),
7.00 (ddd, 3J = 6.4 Hz, 3J = 6.0 Hz, 4J = 1.5 Hz, 1 H, ArH), 7.24 (d,
3J = 7.8 Hz, 1 H, ArH), 7.61–7.67 (m, 1 H, ArH), 8.53–8.54 (m, 1
H, ArH), 10.58 (s, 1 H, OH).
Synthesis 2008, No. 8, 1276–1282 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 6-(Pyridyl)salicylates
1281
13C NMR (75 MHz, CDCl3): d = 14.4 (C5H11CH3), 15.4 (CH2CH3),
23.0, 26.3, 26.6, 29.9, 30.1 [(CH2)5CH3], 33.1 (CH2CH3), 52.0
(OCH3), 109.4 (CAr), 121.8, 122.4, 123.3 (CHAr), 129.7 (CAr), 136.1
(CHAr), 140.7 (CAr), 148.7 (CHAr), 149.6, 160.0 (CAr), 161.1 (COH),
171.8 (C=O).
3.89 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 6.63 (s, 1 H, ArH), 6.63 (s, 1
H, ArH), 7.17–7.26 (m, 2 H, ArH), 7.60–7.65 (m, 1 H, ArH), 8.52
(m, 1 H, ArH), 11.04 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 12.1 (CH2CH2CH3), 12.8
(CH2CH3), 13.2 (OCH2CH3), 18.1 (CH2CH2CH3), 23.1
(CH2CH2CH3), 34.2 (CH2CH3), 59.7 (OCH2CH3), 108.0 (CAr),
121.7 (CHAr), 129.7 (2 CHAr), 134.7 (CAr), 145.6 (2 CHAr), 158.9 (2
CAr), 160.1 (2 CAr), 170.2 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 341 ([M+], 18), 308 (5), 271 (77),
239 (100), 167 (13), 117 (3), 78 (4), 57 (5), 43 (7).
HRMS (EI): m/z calcd for C21H27NO3: 341.19855; found:
341.19815.
GC-MS (EI, 70 eV): m/z (%) = 313 ([M+], 33), 267 (19), 252 (100),
238 (29), 210 (6), 195 (3), 167 (8), 154 (3), 78 (5).
Methyl 4-Ethyl-2-hydroxy-3-octyl-6-(pyrid-2-yl)benzoate (6i)
Starting from 4b (0.498 g, 2.0 mmol), 5e (0.812 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 6i was isolated as a dark highly viscous
reddish oil (0.220 g, 30%).
HRMS (EI): m/z calcd for C19H23NO3: 313.16725; found:
313.16693.
Methyl 2-Hydroxy-4-isopropyl-6-(pyrid-2-yl)benzoate (6l)
Starting from 4d (0.527 g, 2.0 mmol), 5a (0.565 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 6l was isolated as a highly viscous red-
dish oil (0.142 g, 26%).
IR (neat): 2953 (m), 2854 (w), 1663 (m), 1436 (m), 1397 (m), 1318
(m), 1270 (m), 1195 (s), 1149 (m), 1010 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.80–0.84 (m, 6 H, CH3), 1.12–
1.27 (m, 12 H, CH2), 2.59–2.65 (m, 4 H, CH2), 3.39 (s, 3 H, OCH3),
6.67 (s, 1 H, ArH), 7.13–7.17 (m, 1 H, ArH), 7.23–7.26 (m, 1 H,
ArH), 7.61–7.66 (m, 1 H, ArH), 8.51–8.54 (m, 1 H, ArH), 10.82 (s,
1 H, OH).
IR (neat): 3109 (w), 2868 (w), 1666 (m), 1601 (m), 1423 (m), 1353
(m), 1300 (s), 1270 (s), 1160 (s), 1058 (m), 809 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.17 [d, 3J = 7.1 Hz, 6 H,
CH(CH3)2], 2.75–2.89 [m, 1 H, CH(CH3)2], 3.41 (s, 3 H, CO2CH3),
13C NMR (75 MHz, CDCl3): d = 14.5 (C7H13CH3), 15.5 (CH2CH3),
22.9, 23.1, 26.3, 26.6, 29.9, 30.0, 30.1, 32.1 (CH2), 52.0 (OCH3),
109.3 (CAr), 121.9, 122.4, 123.4 (CHAr), 129.8 (2 CAr), 136.2
(CHAr), 140.7 (CAr), 148.7 (CHAr), 160.0 (CAr), 161.1 (COH), 171.8
(C=O).
6.71 (d, J = 1.3 Hz, 1 H, ArH), 6.86 (d, J = 1.3 Hz, 1 H, ArH),
7.17–7.18 (m, 1 H, ArH), 7.26 (d, 3J = 7.6 Hz, 1 H, ArH), 7.64 (ddd,
3J = 7.8 Hz, 3J = 7.7 Hz, 4J = 1.7 Hz, 1 H, ArH), 8.54 (m, 1 H, ArH),
10.57 (s, 1 H, OH).
4
4
13C NMR (75 MHz, CDCl3): d = 23.7 [CH(CH3)2], 34.6
[CH(CH3)2], 52.1 (CO2CH3), 109.9 (CAr), 115.6, 121.1, 122.1,
123.4, 136.2 (CHAr), 143.7 (CAr), 148.9 (CHAr), 156.2, 160.9 (CAr),
162.0 (COH), 177.2 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 369 ([M+], 11), 341 (30), 310 (5),
271 (94), 252 (60), 239 (100), 177 (13), 127 (4), 78 (4).
HRMS (EI): m/z calcd for C23H31NO3: 369.22985; found:
369.22968.
GC-MS (EI, 70 eV): m/z (%) = 271 ([M+], 33), 239 (69), 224 (16),
196 (100), 167 (23), 141 (5), 78 (4).
Methyl 2-Hydroxy-4-propyl-6-(pyrid-2-yl)benzoate (6j)
Starting from 4c (0.527 g, 2.0 mmol), 5a (0.565 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 6j was isolated as a highly viscous red-
dish oil (0.200 g, 33%).
HRMS (EI): m/z calcd for C16H17NO3: 271.12029; found:
271.12038.
Methyl 2-Hydroxy-4-methyl-6-(pyrid-3-yl)benzoate (9a)
Starting from 8 (0.353 g, 1.5 mmol), 5b (0.425 g, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 9a was isolated as a yellow gummy
solid (0.160 g, 44%).
IR (KBr): 3012 (w), 2844 (w), 1662 (s), 1499 (m), 1459 (s), 1378
(s), 1239 (s), 1106 (m), 1074 (m), 1025 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.87 (t, 3J = 7.2 Hz, 3 H,
3
CH2CH2CH3), 1.55–1.63 (m, 2 H, CH2CH2CH3), 2.51 (t, J = 7.2
Hz, 2 H, CH2CH2CH3), 3.40 (s, 3 H, OCH3), 6.67 (s, 1 H, ArH), 6.80
3
(s, 1 H, ArH), 7.14–7.17 (m, 1 H, ArH), 7.24 (d, J = 7.9 Hz, 1 H,
IR (neat): 2955 (w), 1658 (w), 1577 (w), 1434 (w), 1352 (w), 1334
(w), 1316 (w), 1261 (w), 1215 (w), 1189 (w), 1092 (w), 994 (w),
842 (w), 705 (w), 613 cm–1 (w).
ArH), 7.61–7.66 (m, 1 H, ArH), 8.53–8.54 (m, 1 H, ArH), 10.55 (s,
1 H, OH).
1H NMR (250 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 3.34 (s, 3 H,
OCH3), 6.50 (s, 1 H, ArH), 6.80 (s, 1 H, ArH), 7.20–7.51 (m, 3 H,
ArH), 8.64 (br s, 1 H, ArH), 10.79 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH2CH3), 24.1
(CH2CH2CH3), 38.3 (CH2CH2CH3), 52.1 (OCH3), 109.8 (CAr),
117.7, 122.1, 123.0, 123.3, 136.1 (CHAr), 143.6 (CAr), 148.9 (CHAr),
150.1, 160.8 (CAr), 161.1 (COH), 171.2 (C=O).
13C NMR (75 MHz, CDCl3): d = 20.7 (CH3), 50.8 (OCH3), 108.1
(CAr), 117.0 (3 CHAr), 123.2 (2 CHAr), 134.5 (CHAr), 139.8 (CAr),
144.4 (2 CAr), 161.3 (COH), 169.9 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 277 ([M+], 39), 239 (69), 211 (73),
182 (100), 167 (6), 154 (17), 127 (12), 78 (5).
GC-MS (EI, 70 eV): m/z (%) = 243 ([M+], 38), 211 (100), 183 (46),
154 (26), 127 (9), 77 (6).
HRMS (EI): m/z calcd for C16H17NO3: 271.12029; found:
271.12028.
HRMS (EI): m/z calcd for C14H13O3N: 243.08899; found:
243.08950.
Ethyl 3-Ethyl-2-hydroxy-4-propyl-6-(pyrid-2-yl)benzoate (6k)
Starting from 4c (0.527 g, 2.0 mmol), 5b (0.659 g, 2.2 mmol), and
TiCl4 (0.239 mL, 2.2 mmol), 6k was isolated as a highly viscous
reddish oil (0.200 g, 31%).
Methyl 2-Hydroxy-3,4-dimethyl-6-(pyrid-3-yl)benzoate (9b)
Starting from 8 (0.470 g, 2.0 mmol), 5b (0.598 g, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 9b was isolated as a yellow oil (0.158
g, 38%).
IR (neat): 2958 (w), 2871 (w), 1658 (m), 1464 (m), 1393 (m), 1371
(m), 1273 (m), 1183 (s), 1110 (s), 1027 cm–1 (m).
IR (neat): 2952 (w), 2923 (w), 1605 (w), 1656 (s), 1432 (m), 1383
(m), 1271 (s), 1191 (s), 1142 (m), 1094 (m), 919 (w), 832 (m), 768
(w), 615 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.67 (t, 3J = 7.0 Hz, 3 H,
CH2CH2CH3), 0.91 (t, 3J = 7.4 Hz, 3 H, CH2CH3), 1.10 (t, 3J = 8.5
Hz, 2 H, CH2CH3), 1.51–1.59 (m, 2 H, CH2CH2CH3), 2.53 (t,
3J = 7.8 Hz, 2 H, CH2CH2CH3), 2.67 (q, 3J = 7.4 Hz, 2 H, CH2CH3),
1H NMR (250 MHz, CDCl3): d = 2.10 (s, 3 H, CH3), 2.19 (s, 3 H,
CH3), 3.36 (s, 3 H, OCH3), 6.45 (s, 1 H, ArH), 7.15–7.30 (m, 1 H,
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ArH), 7.40 (d, J = 8.6 Hz, 1 H, ArH), 8.10–8.30 (m, 2 H, ArH),
11.22 (s, 1 H, OH).
IR (neat): 2956 (w), 2871 (w), 1699 (m), 1429 (m), 1398 (m), 1300
(m), 1267 (m), 1200 (s), 1114 (s), 753 cm–1 (m).
13C NMR (75 MHz, CDCl3): d = 11.6 (CH3), 20.5 (CH3), 51.8
(OCH3), 108.7 (CAr), 124.3 (1 C, 1 CHAr), 125.1 (CHAr), 135.4 (2
CAr,), 137.6 (CHAr), 143.5 (CAr), 147.7 (CHAr), 149.0 (CHAr), 160.4
(COH), 171.1 (C=O).
1H NMR (250 MHz, CDCl3): d = 0.90 (t, 3J = 6.5 Hz, 3 H,
CH2CH2CH3), 1.48–1.57 (m, 2 H, CH2CH2CH3), 2.21 (s, 3 H, CH3),
2.52 (t, 3J = 6.0 Hz, 2 H, CH2CH2CH3), 3.43 (s, 3 H, OCH3), 6.40
(s, 1 H, ArH), 7.11 (m, 1 H, ArH), 7.60–7.62 (m, 1 H, ArH), 8.69
(m, 2 H, ArH), 10.87 (br s, 1 H, OH).
GC-MS (EI, 70 eV): m/z (%) = 257 ([M+], 44), 225 (100), 197 (17),
182 (45), 168 (28), 154 (16), 115 (8).
13C NMR (62 MHz, CDCl3): d = 10.2 (CH2CH2CH3), 13.0 (CH3),
22.2 (CH2CH2CH3), 35.0 (CH2CH2CH3), 50.6 (OCH3), 106.7 (CAr),
121.3 (3 CHAr), 124.0, 137.7 (CAr), 146.7 (2 CAr), 149.6 (2 CHAr),
159.3 (COH), 170.2 (C=O).
HRMS (EI): m/z calcd for C15H15O3N: 257.10464; found:
257.10536.
Ethyl 3-Ethyl-2-hydroxy-4-methyl-6-(pyrid-3-yl)benzoate (9c)
Starting from 8 (0.470 g, 2.0 mmol), 5c (0.659 g, 2.2 mmol), and
TiCl4 (0.239 mL, 2.2 mmol), 9c was isolated as an orange oil (0.180
g, 32%).
GC-MS (EI, 70 eV): m/z (%) = 285 ([M+], 45), 238 (100), 225 (35),
210 (11), 196 (16), 182 (8), 167 (17), 154 (6), 139 (5), 84 (4), 78 (4).
HRMS (EI): m/z calcd for C17H19NO3: 285.13594; found:
285.13545.
IR (neat): 2917 (w), 1642 (s), 1613 (m), 1378 (s), 1283 (s), 1247
(m), 1227 (s), 1178 (s), 1103 (m), 1010 (m), 809 (s), 722 (s), 618
(m), 526 cm–1 (w).
References
1H NMR (250 MHz, CDCl3): d = 0.65 (t, 3J = 7.5 Hz, 3 H,
CH2CH3), 1.04 (t, 3J = 7.5 Hz, 3 H, OCH2CH3), 2.22 (s, 3 H, CH3),
2.62 (q, J = 7.5 Hz, 2 H, CH2CH3), 3.87 (q, J = 7.0 Hz, 2 H,
OCH2CH3), 6.43 (s, 1 H, ArH), 7.15–7.20 (m, 1 H, ArH), 7.41 (d,
3J = 7.9 Hz, 1 H, ArH), 7.74–9.24 (m, 2 H, ArH), 11.29 (s, 1 H,
OH).
(1) Römpp Lexikon Naturstoffe; Steglich, W.; Fugmann, B.;
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
(2) For recent pyridine syntheses, see: (a) Dash, J.; Lechel, T.;
Reissig, H.-U. Org. Lett. 2007, 9, 5541; and references cited
therein. (b) Andersson, H.; Almqvist, F.; Olsson, R. Org.
Lett. 2007, 9, 1335; and references cited therein.
3
3
(3) Kinabaline: (a) Tadic, D.; Cassels, B. K.; Leboeuf, M.;
Cave, A. Phytochemistry 1987, 26, 537. 6-Hydroxy-7-
methoxyonychine: (b) Chen, C.-Y.; Chang, F.-R.; Shih,
Y.-C.; Hsieh, T.-J.; Chia, Y.-C.; Tseng, H.-Y.; Chen, H.-C.;
Chen, S.-J.; Hsu, M.-C.; Wu, Y.-C. J. Nat. Prod. 2000, 63,
1475. 1-Methyl-4-azafluorenone: (c) Bracher, F. Arch.
Pharm. (Weinheim, Germany) 1992, 325, 645. (d) Chaves,
M. H.; de Santos, L. A.; Lago, J. H. G.; Roque, N. F. J. Nat.
Prod. 2001, 64, 240. (e) Koyama, J.; Morita, I.; Kobayashi,
N.; Osakai, T.; Usuki, Y.; Taniguchi, M. Bioorg. Med.
Chem. Lett. 2005, 15, 1079 . Darienine: (f) Arango, G. J.;
Cortes, D.; Cassels, B. K.; Cave, A.; Merienne, C.
Phytochemistry 1987, 26, 2093 . 5,6-Dimethoxyonychine:
(g) Koyama J., Ogura T., Tagahara K., Miyashita M., Irie H.;
Chem. Pharm. Bull.; 1993, 41: 1297.
(4) Sampangin: (a) Muhammad, I.; Dunbar, D. C.; Takamatsu,
S.; Walker, L. A.; Clark, A. M. J. Nat. Prod. 2001, 64, 559.
(b) Peterson, J. R.; Zjawiony, J. K.; Liu, S.; Hufford, C. D.;
Clark, A. M.; Rogers, R. D. J. Med. Chem. 1992, 35, 4069 .
Eupomatidine 1: (c) Kitahara, Y.; Onikura, H.; Shibano, Y.;
Watanabe, S.; Mikami, Y.; Kubo, A. Tetrahedron 1997, 53,
6001. (d) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991,
44, 1615 . Eupomatidin 2: (e) Peterson, J. R.; Zjawiony, J.
K.; Liu, S.; Hufford, C. D.; Clark, A. M.; Rogers, R. D.
J. Med. Chem. 1992, 35, 4069. (f) Kitahara, Y.; Mochii, M.;
Mori, M.; Kubo, A. Tetrahedron 2003, 59, 2885.
13C NMR (75 MHz, CDCl3): d = 13.1 (OCH2CH3), 13.2 (CH2CH3),
19.6 (CH2CH3), 19.7 (CH3), 61.1 (OCH2CH3), 109.1 (CAr), 124.5 (3
CHAr,), 131.0 (2 CAr,), 135.4 (2 CHAr), 137.8, 142.6 (CAr), 160.4
(COH), 171.1 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 285 ([M+], 60), 239 (100), 224 (40),
211 (78), 196 (63), 182 (13), 115 (8), 77 (5).
HRMS (EI): m/z calcd for C17H19O3N: 285.13594; found:
243.135775.
Methyl 2-Hydroxy-4-propyl-6-(pyrid-4-yl)benzoate (12a)
Starting from 11 (0.392 g, 1.5 mmol), 5a (0.429 g, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 12a was isolated as a highly viscous
reddish oil (0.180 g, 44%).
IR (neat): 2962 (w), 2873 (w), 1601 (m), 1577 (s), 1403 (m), 1283
(m), 1086 (m), 11042 (m), 993 (m), 742 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 0.87 (t, 3J = 7.2 Hz, 3 H,
3
CH2CH2CH3), 1.54–1.63 (m, 2 H, CH2CH2CH3), 2.50 (t, J = 7.2
Hz, 2 H, CH2CH2CH3), 3.42 (s, 3 H, OCH3), 6.48 (s, 1 H, ArH), 6.82
(s, 1 H, ArH), 7.09–7.12 (m, 2 H, ArH), 8.54–8.69 (m, 2 H, ArH),
10.87 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 13.7 (CH2CH2CH3), 23.6
(CH2CH2CH3), 37.9 (CH2CH2CH3), 51.6 (OCH3), 108.7 (CAr),
117.4 (2 CHAr), 122.7 (CHAr), 141.6 (CAr), 148.9 (CHAr), 150.2
(CAr), 150.7 (2 CHAr), 151.3 (CAr), 162.2 (COH), 170.5 (C=O).
(5) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
(6) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534.
(7) For a review on 1,3-bis(silyl enol ethers) in general, see:
Langer, P. Synthesis 2002, 441.
GC-MS (EI, 70 eV): m/z (%) = 271 ([M+], 48), 239 (100), 211 (99),
182 (30), 167 (5), 154 (4), 127 (16), 78 (4).
HRMS (EI): m/z calcd for C16H17NO3: 271.12029; found:
271.11994.
(8) For a review on the synthesis of carbacycles by [3+3]
cyclizations of 1,3-bis(silyl enol ethers) with 1,3-dielectro-
philes, see: Feist, H.; Langer, P. Synthesis 2007, 327.
(9) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830.
Methyl 2-Hydroxy-3-methyl-4-propyl-6-(pyrid-4-yl)benzoate
(12b)
Starting from 11 (0.395 g, 1.5 mmol), 5b (0.429 g, 1.65 mmol), and
TiCl4 (0.180 mL, 1.65 mmol), 12b was isolated as a highly viscous
reddish oil (0.170 g, 40%).
Synthesis 2008, No. 8, 1276–1282 © Thieme Stuttgart · New York