First synthesis of 5-cyanosalicylates by formal [3+3] Cyclocondensations of 1,3-Bis(silyloxy)-1,3-butadienes

Article abstract of DOI:10.1055/s-0028-1088043

A variety of functionalized benzonitriles were regioselectively prepared by formal [3+3] cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 3-ethoxy- and 3-silyloxy-2-cyano-2-en-1-ones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088043

PAPER
1623
First Synthesis of 5-Cyanosalicylates by Formal [3+3] Cyclocondensations of
1,3-Bis(silyloxy)-1,3-butadienes
S
ynthesis of 5-Cya
b
nosalicylatesdolmajid Riahi,a,b Olumide Fatunsin,a Mohanad Shkoor,a Rüdiger Dede,a Helmut Reinke,a Christine Fischer,a,b
Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse, Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Received 28 November 2008; revised 19 January 2009
catalyzed reaction of aryl halides with zinc or potassium
Abstract: A variety of functionalized benzonitriles were regiose-
lectively prepared by formal [3+3] cyclocondensation of 1,3-bis(si-
lyloxy)-1,3-butadienes with 3-ethoxy- and 3-silyloxy-2-cyano-2-
en-1-ones.
cyanide,17 and by Grignard reaction of 4-hydroxy-3,5-di-
iodobenzonitrile with carbon dioxide.18
Despite their great synthetic utility, catalytic cyanations
Key words: arenes, benzonitriles, cyclizations, regioselectivity, si- can suffer from several drawbacks, such as low turnover
lyl enol ethers
numbers. In addition, reactions of ortho-substituted aryl
halides are often problematic or not possible at all or re-
quire the use of toxic thallium reagents.19 It is important to
note that the synthesis of the required starting materials –
functionalized or highly substituted aryl halides or tri-
flates – can be a difficult and tedious task due to the low
ortho/para regioselectivity of electrophilic substitutions,
harsh reaction conditions, and several other drawbacks.
Functionalized benzonitriles represent important building
blocks for fine chemical synthesis. In addition, they are
important substructures of various dyes, pharmaceuticals,
agrochemicals, herbicides, and pesticides.1 The present
paper is focussed on the synthesis of functionalized 5-cy-
anosalicylates, which can be regarded as functionalized 4-
cyanophenols. This substructure is present in a great vari-
ety of pharmacologically active compounds; in fact, a
Beilstein database search reveals more than 900 4-cy-
anophenols which show a broad spectrum of pharmaco-
logical activities. 5-Cyanosalicylates and 2-acyl-4-
cyanophenols are the specific derivatives studied in the
present report. Their pharmacological properties include,
for example, antiallergic activity,2 inhibition of HIV-1,3
anti-dopaminergic activity,4 vasorelaxing activity,5 inhi-
bition of LTD4-induced contraction of lung membranes,6
leukotriene D4 inhibitory activity,7 antibacterial activity,8
binding to CHO cell membranes,9 antagonistic activity
against bTC3 cells,10 inhibition of recombinant human al-
dehyde reductase,11 or inhibition of catechol O-methyl-
transferase.12
An interesting alternative approach to the synthesis of
benzonitriles is based on the application of a ‘building-
block strategy’. Examples include the base-mediated cy-
clocondensation of ethoxymethylene-malononitrile with
b-keto esters,20 the cyclization of diethyl acetone-1,3-di-
carboxylate with 3-oxopentanedioic acid diethyl ester,21
and the reaction of malodinitrile with methyl 2-acetyl-3-
methoxyacrylate.22 Another building-block approach to
the synthesis of benzonitriles relies on [4+2] cycloaddi-
tion reactions of cyano-substituted dienes or dieno-
philes.23 This includes, for example, the [4+2]
cycloaddition of 3-cyano-2,4-bis(silyloxy)penta-1,3-di-
ene with methyl propynoate.24 Recently, we have
reported25 the synthesis of functionalized 5-cyanosalicy-
lates by formal [3+3] cyclocondensations26,27 of 1,3-
bis(silyloxy)-1,3-butadienes28 with cyano-substituted 3-
ethoxy- and 3-silyloxy-2-en-1-ones. These reactions pro-
vide a convenient and regioselective approach to a variety
of 5-cyanosalicylates which are not readily available by
other methods. Herein, we report a comprehensive study
on the preparative scope of this approach.
Simple benzonitriles are prepared on industrial scales by
ammoxidation of toluenes. In addition, ‘classical’ reac-
tions of copper(I) cyanide with aryl halides or aryl diazo-
nium salts using, for example, the Rosenmund-von-Braun
or the Sandmeyer reaction, are often used. In recent years,
various catalytic variants have been developed.13,14 Sub-
stituted 5-cyanosalicylates represent highly functional-
ized arenes containing a nitrile, ester and hydroxy group.
Due to their polyfunctional nature, they represent versatile
synthetic building blocks. 5-Cyanosalicylates have been
previously prepared by transformation of oximes into ni-
triles,15 by cyanation of aryl halides,16 by palladium(0)-
2-Cyano-3-ethoxy-2-en-1-ones 2a–e were prepared, fol-
lowing a known procedure,29 by reaction of ketonitriles
1a–e with ethyl orthoformate and acetic anhydride
(Table 1). 1,3-Bis(silyloxy)-1,3-butadienes 3a–k were
prepared from the corresponding b-keto esters in two
steps.16 The titanium tetrachloride mediated cyclization of
2a with 3a afforded the 5-cyanosalicylate 4a (Scheme 1).
The cyclization proceeded with excellent regioselectivity.
The formation of product 4a might be explained by titani-
um tetrachloride mediated conjugate addition of the ter-
minal carbon atom of 3a to 2a, to give intermediate A,
SYNTHESIS 2009, No. 10, pp 1623–1634
x
x.
x
x
.
2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088043; Art ID: T20808SS
© Georg Thieme Verlag Stuttgart · New York

1624
A. Riahi et al.
PAPER
Table 2 Synthesis of 4a–ac
cyclization via the central carbon of 3a to give intermedi-
ate B (SN¢ reaction), and subsequent aromatization. The
formal [3+3] cyclization of 2-cyano-3-ethoxy-2-en-1-
ones 2a–e with 1,3-bis(silyloxy)-1,3-butadienes 3a–k af-
forded the 5-cyanosalicylates 4a–ac in 33–64% yields
(Table 2). The substituent R1, located next to the carbonyl
group of 2a–e, has some influence on the yields. Better
yields were generally obtained for the products 4h–ac de-
rived from 2b–e, containing an aryl group, compared to
products 4a–g, derived from 2a, which contains a methyl
group. The best yields were observed for the products de-
rived from chloro- or bromo-substituted enones 2c and
2d. This might be explained by the fact that the electron-
withdrawing halogen atoms increase the reactivity of the
enone. The substitution pattern of the diene had no signif-
icant influence on the yield.
Me3SiO
R2
OSiMe3
OR3
O
OH
CN
TiCl4
CH2Cl2
R2
OR3
3a–i
EtO
–78 to 20 °C
14 h
O
R1
+
R1
CN
2a–e
4a–ac
2
3
4
R1
R2
R3
Yield
(%)a
a
a
a
a
a
a
a
b
b
b
b
b
b
b
c
a
b
c
d
e
f
a
b
c
d
e
f
Me
H
Me
Et
34
33
35
34
35
42
34
45
43
42
41
42
40
44
61
62
64
59
62
58
60
55
55
57
50
51
49
52
50
Me
H
Me
Me
Et
Me
Et
Me
Table 1 Synthesis of 2a–e
Me
n-Bu
n-Hex
n-Hept
H
Me
Me
Me
Et
O
EtO
O
HC(OEt)3
i
R1
R1
Me
CN
1a
CN
2a
g
b
c
d
e
g
h
k
c
d
f
g
h
i
Me
–e
–
e
Ph
2
a
b
c
R1
Yield (%)a
Ph
Me
Me
Et
Me
Ph
100
88
j
Ph
Et
k
l
Ph
n-Bu
n-Hept
n-Oct
Me
Me
Me
4-ClC6H4
4-BrC6H4
4-(MeO)C6H4
98
96
95
Ph
d
e
m
Ph
n
o
Ph
4-ClC6H4 Me
a Reaction conditions: 1a–e (1.0 equiv), HC(OEt)3 (3.0 equiv), Ac2O,
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
Me
Me
Et
reflux, 2 h.
a Yield of isolated products.
c
p
q
r
Et
c
n-Hex
n-Oct
i-Pent
Me
Me
Me
Me
Me
Et
Me3SiO
OSiMe3
O
OH
c
h
j
TiCl4
CH2Cl2
OEt
O
OEt
3a
c
s
EtO
+
–78 to 20 °C
14 h
d
d
d
d
d
e
c
d
f
t
CN
u
v
Et
CN
2a
4a
n-Hex
n-Oct
n-Non
H
Me
Me
Me
Et
h
i
w
x
– Me3SiOEt
H2O
O
O
b
c
d
f
y
O
Me3SiO
OEt
e
z
Me
Me
Et
TiCl4
O
OEt
OTiCl3
– Me3SiCl
e
aa
ab
ac
Et
Me
CN
CN
e
n-Hex
n-Oct
Me
Me
A
B
e
h
Scheme 1 Possible mechanism for formation of 4a
a Yield of isolated products.
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Cyanosalicylates
1625
An optimization study was carried out for the synthesis of 3a,b,d,l–n afforded the 5-cyanosalicylates 6a–f in moder-
4e (Table 3). The best yields were obtained when the re- ate yields (except for 6d) (Table 4). The best yields were
action was carried out in a highly concentrated solution, again obtained when the reactions were carried out in a
however, the stoichiometry (2a–3e–TiCl4 = 1:1.1:1.1), highly concentrated solution. The low yield of 6d can be
the temperature (slow warming from –78 to 20 °C), and explained by TiCl4-mediated cleavage of the tert-butyl es-
the reaction time also played important roles. The use of ter.
TMSOTf, BF3·OEt2, and SnCl4 resulted in the formation
of complex mixtures. The moderate yields might be ex-
Table 4 Synthesis of 6a–f
plained by TiCl4-mediated oxidative dimerization of the
Me3SiO
R1
OSiMe3
diene; this type of reaction has been previously reported.30
In addition, some hydrolysis of the enone was observed.
O
OH
OR2
TiCl4
CH2Cl2
R1
3a,b,d,l–n
OR2
+
–78 to 20 °C,
20 h
Table 3 Optimization of the Synthesis of 4e
Me3SiO
O
Entry 2a:3e:TiCl4 Concn of 2a Temp ( °C) Time (h) 4e (%)b
CN
20 °C, 4 h
4 Å MS
Me
(mol/L)a
6a–f
CN
5
1
2
3
4
5
6
7
8
1:1.1:1.1
1:1:2
0.5
0.5
0.5
0.5
0.2
0.1
0.5
0.5
–78→20
–78→20
–78→20
–78→20
–78→20
0→20
14
14
14
14
14
14
14
5
35
20
15
29
10
trace
0
3
6
R1
H
R2
6 (%)a
34
1:2:1
a
b
l
a
b
c
d
e
f
Me
Et
1:2:2
H
41
1:1.1:1.1
1:1.1:1.1
1:1.1:1.1
1:1.1:1.1
H
i-Bu
t-Bu
Me
Et
40
m
n
d
H
8
0→20
Et
Et
44
–78→20
15
58
a All experiments were carried out on a 1.0 mmol scale.
b Isolated yields.
a Yields of isolated products.
In conclusion, we have reported a convenient and regiose-
lective synthesis of functionalized benzonitriles by what
are, to the best of our knowledge, the first formal [3+3]
cyclizations of 1,3-bis(silyloxy)-1,3-butadienes with
cyano-substituted enones. The products are not readily
available by other methods. The reactions are easy to per-
form and the starting materials are readily available. We
are currently studying the preparative scope of the meth-
odology and applications to the synthesis of pharmacolog-
ically active products.
The configuration of all products was established by spec-
troscopic methods (2D NMR). The structures of benzoni-
triles 4b–d,i,o,t were independently confirmed by X-ray
crystal structure analyses – one of which is exemplarily
depicted in Figure 1.31
All solvents were dried by standard methods and all reactions were
carried out under an Argon atmosphere. For 1H and 13C NMR spec-
tra, the deuterated solvents indicated were used. Mass spectrometric
data (MS) were obtained by electron ionization (EI, 70 eV), chemi-
cal ionization (CI, i-Bu) or electrospray ionization (ESI). For pre-
parative scale chromatography, silica gel 60 (0.063–0.200 mm, 70–
230 mesh) was used.
2-Cyano-3-ethoxy-2-en-1-ones 2a–e; General Procedure
To a flask containing Ac2O (2.5 mL/10.0 mmol of 1), was added ke-
tonitrile 1a–e (1.0 equiv) and CH(OEt)3 (3.0 equiv). The mixture
was stirred under reflux for 2 h, then Ac2O was removed in vacuo
and the solid residue was purified by crystallization from EtOH to
give 2a–e.
Figure 1 Ortep plot of 4c (hydrogen at O3 found in the difference
map and refined freely)
2-(Ethoxymethylene)-3-oxobutane-nitrile (2a)
Starting with 1a (2.00 g, 24.4 mmol) and CH(OEt)3 (12.17 mL, 73.1
mmol), 2a was isolated after recrystallization from EtOH.
3-Cyano-4-(trimethylsilyloxy)pent-3-en-2-one (5) was
prepared by silylation of known32 3-cyano-acetylacetone.
The TiCl4-mediated [3+3] cyclocondensation of 5 with
Yield: 3.387 g (100%); brown crystals; mp 70–71 °C.
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

1626
A. Riahi et al.
PAPER
IR (KBr): 2958 (w), 2922 (m), 2852 (w), 2253 (w), 2226 (w), 1693
(m), 1671 (m), 1612 (s), 1612 (s), 1590 (m), 1469 (w), 1445 (w),
1394 (w), 1383 (w), 1309 (m), 1294 (m), 1232 (s), 1153 (m), 1094
(m), 1075 (m), 999 (m), 957 (m), 908 (m), 877 (m), 784 (w), 728
(m), 648 (w), 638 (m), 624 (m), 608 (m), 537 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.44 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.38 (s, 3 H, CH3), 4.36 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 8.0 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 15.3, 28.2 (CH3), 74.1 (OCH2),
94.4 (CCN), 114.4 (CN), 171.8 (CH), 191.8 (CO).
GC–MS (EI, 70 eV): m/z (%) = 139 (50) [M+], 124 (8), 111 (21), 96
Yield: 2.40 g (96%); pink crystals; mp 99–102 °C.
IR (KBr): 3073 (w), 3042 (w), 2920 (w), 2852 (w), 2221 (m), 1921
(w), 1621 (m), 1586 (m), 1537 (m), 1504 (m), 1483 (m), 1384 (m),
1317 (m), 1245 (m), 1184 (m), 1166 (m), 1116 (m), 1071 (m), 1021
(m), 1010 (m), 980 (m), 906 (m), 827 (s), 749 (s), 689 (m), 626 (m),
604 (m), 576 (m), 559 (m), 533 (m) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.42 (t, 3J = 7.1 Hz, 3 H,
3
OCH2CH3), 4.36 (q, J = 7.4 Hz, 2 H, OCH2CH3), 7.53–7.58 (m,
2 H, CHAr), 7.67–7.72 (m, 2 H, CHAr), 8.05 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 15.2 (CH3), 74.4 (OCH2), 93.5
(CCN), 114.4 (CN), 128.1 (CAr), 130.2 (2 × CHAr), 131.9
(2 × CHAr), 135.5 (CAr), 174.7 (CH), 186.5 (CO).
(100), 83 (81), 68 (93), 52 (10).
HRMS (EI): m/z [M+] calcd for C7H9O2N: 139.06278; found:
139.063030.
GC–MS (EI, 70 eV): m/z (%) = 281 (16) [81Br; M+], 279 (16) [79Br;
M+], 278 (11), 252 (15), 238 (4), 225 (6), 200 (10), 185 (97), 183
(100), 172 (12), 157 (29), 155 (29), 143 (8), 115 (5), 96 (4), 76 (21),
68 (6), 50 (12), 29 (12).
2-Benzoyl-3-ethoxyacrylonitrile (2b)
Starting with 1b (2.00 g, 13.8 mmol) and CH(OEt)3 (6.9 mL, 41.3
mmol), 2b was isolated after recrystallization from EtOH.
HRMS (EI): m/z [M+] calcd for C12H10O2NBr: 278.98894; found:
278.988999.
Yield: 2.43 g (88%); brown solid; mp 70–71 °C.
3-Ethoxy-2-(4-methoxybenzoyl)acrylonitrile (2e)
Starting with 1e (2.00 g, 11.4 mmol) and CH(OEt)3 (5.70 mL, 34.3
mmol), 2e was isolated after recrystallization from EtOH.
IR (KBr): 3060 (w), 2985 (w), 2937 (w), 2219 (w), 1645 (m), 1598
(s), 1577 (s), 1492 (w), 1472 (w), 1446 (m), 1393 (m), 1376 (m),
1352 (m), 1301 (m), 1288 (m), 1231 (s), 1180 (m), 1153 (m), 1104
(m), 1004 (m), 922 (m), 909 (m), 870 (w), 796 (w), 716 (m), 698
(m), 670 (m), 611 (w), 555 (w) cm–1.
Yield: 2.50 g (95%); reddish-brown solid; mp 45–50 °C.
IR (KBr): 3066 (w), 2929 (w), 2844 (w), 2215 (m), 1911 (w), 1738
(w), 1682 (w), 1631 (m), 1597 (m), 1574 (m), 1556 (m), 1504 (m),
1462 (m), 1450 (m), 1423 (m), 1377 (m), 1308 (m), 1255 (s), 1167
(s), 1125 (m), 1022 (s), 974 (m), 960 (m), 838 (s), 812 (m), 800 (m),
751 (m), 700 (m), 632 (m), 605 (m), 541 (m), 531 (m) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.41 (t, 3J = 7.1 Hz, 3 H,
OCH2CH3), 3.80 (s, 3 H, OCH3), 4.33 (q, 3J = 7.0 Hz, 2 H,
OCH2CH3), 6.87–6.90 (m, 2 H, CHAr), 7.86–7.89 (m, 2 H, CHAr),
8.02 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 15.3 (CH3), 55.6 (OCH3), 74.0
(OCH2), 93.6 (CCN), 113.8 (2 × CHAr), 115.1 (CN), 131.3
(2 × CHAr), 161.2, 163.7 (CAr), 174.0 (CH), 185.8 (CO).
GC–MS (EI, 70 eV): m/z (%) = 231 (23) [M+], 216 (2), 202 (6), 188
(4), 174 (3), 160 (2), 136 (9), 135 (100), 107 (6), 92 (11), 77 (13),
64 (5), 50 (2).
1H NMR (250 MHz, CDCl3): d = 1.41 (t, 3J = 7.2 Hz, 3 H,
3
OCH2CH3), 4.34 (q, J = 7.2 Hz, 2 H, OCH2CH3), 7.40–7.52 (m,
3 H, CHAr), 7.77–7.82 (m, 2 H, CHAr), 8.03 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 15.4 (CH3), 74.3 (OCH2), 94.1
(CCN), 114.7 (CN), 128.5 (2 × CHAr), 128.7 (2 × CHAr), 133.1
(CHAr), 136.9 (CAr), 174.4 (CH), 187.9 (CO).
GC–MS (EI, 70 eV): m/z (%) = 201 (13) [M+], 200 (14), 183 (2),
172 (19), 158 (2), 145 (3), 116 (3), 105 (100), 89 (5), 77 (43), 51
(13), 29 (7).
HRMS (EI): m/z [M+] calcd for C12H11O2N: 201.07843; found:
201.078326.
2-(4-Chlorobenzoyl)-3-ethoxyacrylonitrile (2c)
Starting with 1c (2.00 g, 11.1 mmol) and CH(OEt)3 (5.56 mL, 33.4
mmol), 2c was isolated after recrystallization from EtOH.
HRMS (EI): m/z [M+] calcd for C13H13O3N: 231.08899; found:
Yield: 2.57 g (98%); pink crystals; mp 95–97 °C.
231.089338.
IR (KBr): 3026 (w), 2982 (w), 2937 (w), 2227 (m), 1921 (w), 1642
(m), 1594 (m), 1487 (m), 1394 (m), 1373 (w), 1354 (m), 1308 (m),
1258 (s), 1180 (m), 1157 (m), 1106 (m), 1090 (m), 1005 (m), 965
(w), 955 (m), 914 (m), 867 (m), 836 (m), 785 (m), 753 (s), 730 (m),
694 (m), 628 (w), 585 (m), 563 (m) cm–1.
Cyanosalicylates 4a–ac; General Procedure
To a stirred solution of 2a–e in CH2Cl2 (2.0 mL/1.0 mmol of 2), was
added 3a–k (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol) at
–78 °C under an argon atmosphere. The temperature of the reaction
mixture was allowed to rise to 20 °C during 14 h with stirring. To
the solution was added HCl (10%, 20 mL) and the organic and the
aqueous layer were separated. The latter was extracted with CH2Cl2
(3 × 20 mL) and the combined organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel; heptanes–EtOAc)
to give 4a–ac.
1H NMR (250 MHz, CDCl3): d = 1.42 (t, 3J = 7.2 Hz, 3 H,
3
OCH2CH3), 4.36 (q, J = 7.2 Hz, 2 H, OCH2CH3), 7.37–7.41 (m,
2 H, CHAr), 7.75–7.79 (m, 2 H, CHAr), 8.05 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 14.4 (CH3), 73.6 (OCH2), 92.7
(CCN), 113.6 (CN), 128.0 (2 × CHAr), 129.2 (2 × CHAr), 134.1,
138.5 (CAr), 173.8 (CH), 185.4 (CO).
GC–MS (EI, 70 eV): m/z (%) = 235 (13) [35Cl; M+], 234 (8) [37Cl;
M+], 206 (14), 172 (8), 139 (100), 123 (3), 111 (31), 75 (17), 50 (5),
29 (8).
HRMS (EI): m/z [M+] calcd for C12H10O2NCl: 235.03946; found:
235.039090.
Methyl 3-Cyano-6-hydroxy-2-methylbenzoate (4a)
Starting with 2a (0.209 g, 1.5 mmol) and 3a (0.430 g, 1.7 mmol), 4a
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.097 g (34%); yellow solid; mp 84–85 °C.
IR (KBr): 2957 (w), 2927 (w), 2854 (w), 2252 (w), 2222 (w), 1737
(w), 1669 (m), 1590 (m), 1469 (m), 1442 (m), 1385 (w), 1352 (m),
1323 (m), 1303 (m), 1224 (m), 1172 (w), 1135 (w), 1057 (w), 1019
(w), 940 (w), 910 (m), 835 (w), 811 (w), 773 (w), 731 (s), 649 (w),
606 (w), 562 (w) cm–1.
2-(4-Bromobenzoyl)-3-ethoxyacrylonitrile (2d)
Starting with 1d (2.00 g, 8.9 mmol) and CH(OEt)3 (4.46 mL, 26.8
mmol), 2d was isolated after crystallization from EtOH.
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Cyanosalicylates
1627
3
1H NMR (250 MHz, CDCl3): d = 2.71 (s, 3 H, CH3), 3.95 (s, 3 H,
OCH3), 6.85 (d, 3J = 8.9 Hz, 1 H, CHAr), 7.54 (d, 3J = 8.9 Hz, 1 H,
CHAr), 11.69 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 21.9 (CH3), 52.9 (OCH3), 105.9
(CCN), 113.4 (CCOOCH3), 117.0 (CHAr), 118.4 (CN), 137.8
(CHAr), 146.5 (CAr), 165.7 (COH), 171.1 (CO).
GC–MS (EI, 70 eV): m/z (%) = 191 (76) [M+], 160 (68), 159 (100),
131 (55), 130 (48), 103 (21), 77 (21), 76 (15), 63 (4), 51 (11).
HRMS (EI): m/z [M+] calcd for C10H9O3N: 191.05769; found:
191.057322.
1H NMR (250 MHz, CDCl3): d = 1.14 (t, J = 8.1 Hz, 3 H, CH3),
3
3
1.38 (t, J = 6.9 Hz, 3 H, OCH2CH3), 3.43 (q, J = 8.1 Hz, 2 H,
CH2), 2.68 (s, 3 H, CH3), 4.41 (q, 3J = 6.3 Hz, 2 H, OCH2CH3), 7.40
(s, 1 H, CHAr), 12.10 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 12.1, 13.2, 20.5 (CH3), 21.6 (CH2),
61.6 (OCH2), 104.0 (CCN), 111.9 (CCOOCH2CH3), 118.0 (CN),
130.9 (CAr), 135.4 (CHAr), 142.7 (CAr), 163.1 (COH), 170.3 (CO).
GC–MS (EI, 70 eV): m/z (%) = 233 (28) [M+], 187 (60), 172 (9),
159 (100), 144 (7), 130 (7), 116 (8), 103 (7), 89 (9), 77 (8), 51 (3),
29 (5).
HRMS (EI): m/z [M+] calcd for C13H15O3N: 233.10464; found:
Ethyl 3-Cyano-6-hydroxy-2-methylbenzoate (4b)
233.104263.
Starting with 2a (0.209 g, 1.5 mmol) and 3b (0.446 g, 1.7 mmol),
4b was isolated after chromatography (silica gel; heptanes–EtOAc).
Methyl 3-Butyl-5-cyano-2-hydroxy-6-methylbenzoate (4e)
Starting with 2a (0.209 g, 1.5 mmol) and 3e (0.522 g, 1.7 mmol), 4e
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.101 g (33%); white solid; mp 86–87 °C.
IR (KBr): 3072 (w), 2991 (w), 2923 (w), 2851 (w), 2777 (w), 2692
(w), 2589 (w), 2224 (w), 1660 (s), 1588 (m), 1570 (w), 1476 (m),
1450 (w), 1398 (m), 1375 (s), 1348 (m), 1318(m), 1302 (m), 1231
(s), 1182 (w), 1146 (m), 1108 (w), 1057 (w), 1021 (m), 996 (w), 909
(w), 856 (m), 831 (m), 723 (w), 632 (w), 609 (w), 558 (w) cm–1.
Yield: 0.130 g (35%); slightly yellowish oil.
IR (KBr): 2957 (m), 2931 (m), 2862 (w), 2222 (m), 1717 (w), 1666
(s), 1609 (w), 1577 (w), 1559 (w), 1541 (w), 1507 (w), 1456 (m),
1438 (m), 1384 (w), 1354 (m), 1338 (m), 1299 (m), 1262 (w), 1234
(w), 1203 (m), 1171 (m), 1105 (w), 1077 (w), 988 (w), 911 (w), 812
(m), 772 (w), 733 (m), 695 (w), 649 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.39 (t, 3J = 7.0 Hz, 3 H,
OCH2CH3), 2.72 (s, 3 H, CH3), 4.42 (q, 3J = 7.3 Hz, 2 H,
3
3
OCH2CH3), 6.84 (d, J = 8.8 Hz, 1 H, CH), 7.53 (d, J = 8.9 Hz,
1H NMR (250 MHz, CDCl3): d = 0.86 [t, 3J = 7.3 Hz, 3 H,
(CH2)3CH3], 1.24–1.33 (m, 2 H, CH2), 1.45–1.52 (m, 2 H, CH2),
1 H, CH), 11.78 (s, 1 H, OH).
3
2.54 (t, J = 7.3 Hz, 2 H, CH2), 2.65 (s, 3 H, CH3), 3.93 (s, 3 H,
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 20.8 (OCH2CH3), 61.7
(OCH2), 104.8 (CCN), 112.6 (CCOOCH2CH3), 116.0 (CH), 117.4
(CN), 136.7 (CH), 145.5 (CCH3), 164.8 (COH), 169.62 (CO).
GC–MS (70 eV): m/z (%) = 205 (26) [M+], 159 (100), 130 (22), 103
(8), 77 (12), 51 (6).
HRMS (EI): m/z [M+] calcd for C11H11O3N: 205.07334; found:
205.073572.
OCH3), 7.38 (s, 1 H, CHAr), 11.98 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 13.1, 20.6 (CH3), 21.6, 28.3, 30.2
(CH2), 52.0 (OCH3), 104.1 (CCN), 112.0 (CCOOCH3), 118.0 (CN),
129.9 (CAr), 136.3 (CHAr), 143.0 (CAr), 163.2 (COH), 170.9 (CO).
GC–MS (EI, 70 eV): m/z (%) = 247 (32) [M+], 215 (29), 198 (16),
186 (19), 173 (100), 159 (3), 145 (36), 130 (5), 116 (11), 103 (6), 89
(19), 77 (6), 63 (4), 51 (3), 39 (5), 29 (3).
Methyl 3-Cyano-6-hydroxy-2,5-dimethylbenzoate (4c)
Starting with 2a (0.208 g, 1.5 mmol) and 3c (0.457 g, 1.7 mmol), 4c
was isolated after chromatography (silica gel; heptanes–EtOAc).
HRMS (EI): m/z [M+] calcd for C14H17O3N: 247.12029; found:
247.119876.
Methyl 3-Cyano-5-hexyl-6-hydroxy-2-methylbenzoate (4f)
Starting with 2a (0.208 g, 1.5 mmol) and 3f (0.568 g, 1.7 mmol), 4f
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.107 g (35%); white solid; mp 134–136 °C.
IR (KBr): 2990 (w), 2956 (w), 2926 (w), 2851 (w), 2217 (m), 1667
(s), 1605 (m), 1592 (m), 1580 (m), 1444 (s), 1413 (m), 1377 (m),
1334 (s), 1264 (s), 1199 (s), 1166 (s), 1077 (m), 1019 (m), 979 (m),
910 (m), 889 (m), 803 (s), 770 (m), 688 (m), 659 (m).
1H NMR (250 MHz, CDCl3): d = 2.15 (s, 3 H, CH3), 2.66 (s, 3 H,
CH3), 3.93 (s, 3 H, OCH3), 7.40 (s, 1 H, CHAr), 11.99 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 15.6, 21.6 (CH3), 52.6 (OCH3),
104.9 (CCN), 112.7 (CCOOCH3), 118.7 (CN), 126.5 (CAr), 138.2
(CHAr), 143.7 (CAr), 164.5 (COH), 171.6 (CO).
GC–MS (EI, 70 eV): m/z (%) = 205 (37) [M+], 174 (25), 173 (100),
145 (90), 144 (20), 116 (19), 91 (11), 90 (14), 89 (19).
Yield: 0.173 g (42%); yellowish oil.
IR (KBr): 2955 (m), 2927 (m), 2856 (w), 2221 (w), 1665 (m), 1608
(w), 1579 (w), 1438 (m), 1334 (m), 1245 (w), 1201 (m), 1170 (m),
1077 (w), 989 (w), 908 (m), 812 (w), 731 (s), 649 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.67 [t, 3J = 7.4 Hz, 3 H,
(CH2)5CH3], 1.06–1.13 (m, 6 H, 3 × CH2), 1.31–1.42 (m, 2 H,
3
CH2), 2.39 (t, J = 7.5 Hz, 2 H, CH2), 2.52 (s, 3 H, CH3), 3.79 (s,
3 H, OCH3), 7.25 (s, 1 H, CHAr), 11.83 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 13.9, 21.6 (CH3), 22.6, 28.7, 29.0,
29.4, 31.6 (CH2), 52.8 (OCH3), 104.9 (CCN), 112.7 (CCOOCH3),
118.7 (CN), 130.7 (CAr), 137.2 (CHAr), 143.5 (CAr), 164.0 (COH),
171.6 (CO).
HRMS (EI): m/z [M+] calcd for C11H11O3N: 205.07334; found:
205.073468.
GC–MS (EI, 70 eV): m/z (%) = 275 (37) [M+], 244 (12), 243 (29),
226 (13), 215 (15), 214 (33), 200 (13), 187 (13), 186 (22), 174 (20),
173 (100), 145 (36), 144 (15), 116 (11), 89 (19) cm–1.
HRMS (EI): m/z [M+] calcd for C16H21NO3: 275.15160; found:
275.151528.
Ethyl 3-Cyano-5-ethyl-6-hydroxy-2-methylbenzoate (4d)
Starting with 2a (0.209 g, 1.5 mmol) and 3d (0.498 g, 1.7 mmol),
4d was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.119 g (34%); white solid; mp 72–73 °C.
IR (KBr): 2975 (w), 2933 (w), 2221 (w), 1658 (m), 1610 (w), 1577
(w), 1559 (w), 1541 (w), 1507 (w), 1437 (m), 1398 (w), 1376 (m),
1352 (w), 1325 (m), 1293 (w), 1265 (w), 1244 (m), 1188 (s), 1086
(w), 1019 (w), 909 (m), 874 (w), 811 (w), 733 (s), 686 (w), 667 (w),
649 (w) cm–1.
Methyl 3-Cyano-5-heptyl-6-hydroxy-2-methylbenzoate (4g)
Starting with 2a (0.209 g, 1.5 mmol) and 3g (0.420 g, 1.7 mmol), 4g
was isolated after chromatography (silica gel; heptane–EtOAc).
Yield: 0.148 g (34%); yellow oil.
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

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A. Riahi et al.
PAPER
Ethyl 6-Cyano-4-ethyl-3-hydroxybiphenyl-2-carboxylate (4j)
Starting with 2b (0.302 g, 1.5 mmol) and 3d (0.498 g, 1.7 mmol), 4j
was isolated after chromatography (silica gel; heptanes–EtOAc).
IR (KBr): 2955 (m), 2926 (m), 2855 (m), 2222 (w), 1665 (m), 1609
(w), 1579 (w), 1438 (m), 1384 (w), 1354 (m), 1335 (m), 1262 (w),
1238 (w), 1202 (m), 1171 (m), 1122 (w), 1077 (w), 988 (w), 908
(m), 812 (w), 772 (w), 732 (m), 696 (w), 649 (w) cm–1.
Yield: 0.186 g (42%); yellow crystalline solid; mp 47–48 °C.
1H NMR (250 MHz, CDCl3): d = 0.81 [t, 3J = 6.7 Hz, 3 H,
(CH2)6CH3], 1.21–1.25 (m, 8 H, 4 × CH2), 1.48–1.55 (m, 2 H,
IR (KBr): 3061 (w), 2972 (w), 2937 (w), 2877 (w), 2252 (w), 2226
(w), 1663 (s), 1601 (w), 1567 (w), 1445 (m), 1424 (m), 1401 (m),
1376 (m), 1329 (m), 1306 (m), 1269 (w), 1242 (m), 1196 (s), 1147
(m), 1113 (w), 1096 (w), 1067 (w), 1021 (w), 909 (m), 841 (w), 819
(m), 762 (m), 732 (s), 701 (m), 649 (w), 549 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.58 (t, 3J = 7.4 Hz, 3 H,
CH2CH3), 1.15 (t, 3J = 7.4 Hz, 3 H, OCH2CH3), 2.61 (q, 3J = 7.2 Hz,
2 H, CH2CH3), 3.83 (q, 3J = 6.9 Hz, 2 H, OCH2CH3), 7.08–7.11 (m,
2 H, CHPh), 7.25–7.29 (m, 3 H, CHPh), 7.46 (s, 1 H, CHAr), 11.65 (s,
1 H, OH).
13C NMR (75 MHz, CDCl3): d = 12.8, 13.1 (CH3), 22.7 (CH2), 61.6
(OCH2), 105.1 (CCN), 112.8 (CCOOEt), 118.2 (CN), 127.9
(2 × CHPh), 128.0 (CHPh), 128.2 (2 × CHPh), 133.4 (CAr), 136.1
(CHAr), 139.2, 146.9 (CAr), 162.9 (COH), 170.2 (CO).
3
CH2), 2.54 (t, J = 7.4 Hz, 2 H, CH2), 2.67 (s, 3 H, CH3), 3.94 (s,
3 H, OCH3), 7.39 (s, 1 H, CHAr), 11.98 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 14.1, 21.6 (CH3), 22.7, 28.9, 29.1,
29.3, 29.5, 31.8 (CH2), 52.9 (OCH3), 104.9 (CCN), 112.8
(CCOOCH3), 118.8 (CN), 130.7 (CAr), 137.1 (CHAr), 143.6 (CAr),
164.0 (COH), 171.7 (CO).
GC–MS (EI, 70 eV): m/z (%) = 289 (38) [M+], 257 (29), 240 (12),
214 (33), 200 (11), 186 (21), 173 (100), 159 (9), 145 (34), 130 (5),
116 (12), 103 (6), 89 (19), 77 (6), 55 (4), 41 (11).
HRMS (EI): m/z [M+] calcd for C17H23O3N: 289.17507; found:
289.17512.
Ethyl 6-Cyano-3-hydroxybiphenyl-2-carboxylate (4h)
Starting with 2b (0.302 g, 1.5 mmol) and 3b (0.446 g, 1.7 mmol),
4h was isolated after chromatography (silica gel; heptanes–EtOAc).
GC–MS (EI, 70 eV): m/z (%) = 295 (48) [M+], 249 (59), 231 (100),
220 (12), 203 (21), 190 (9), 177 (14), 165 (12), 151 (13), 139 (4),
102 (2), 77 (3), 51 (2).
Yield: 0.180 g (45%); yellow solid; mp 122–124 °C.
HRMS (EI): m/z [M+] calcd for C18H17O3N: 295.12029; found:
IR (KBr): 3061 (w), 2984 (w), 2939 (w), 2227 (w), 1730 (w), 1668
(m), 1584 (m), 1548 (w), 1462 (m), 1444 (m), 1400 (w), 1376 (m),
1324 (m), 1222 (s), 1140 (w), 1097 (w), 1075 (w), 1013 (w), 910
(w), 836 (w), 759 (m), 731 (m), 716 (m), 699 (m), 645 (w), 598 (w),
550 (w) cm–1.
295.120225.
Methyl 4-Butyl-6-cyano-3-hydroxybiphenyl-2-carboxylate (4k)
Starting with 2b (0.302 g, 1.5 mmol) and 3e (0.522 g, 1.7 mmol), 4k
was isolated after chromatography (silica gel; heptanes–EtOAc).
1H NMR (250 MHz, CDCl3): d = 0.64 (t, 3J = 8.3 Hz, 3 H,
OCH2CH3), 3.89 (q, 3J = 7.0 Hz, 2 H, OCH2CH3), 7.01 (d, 3J = 8.2
Hz, 1 H, CHAr), 7.14–7.19 (m, 2 H, CHPh), 7.34–7.37 (m, 3 H,
CHPh), 7.64 (d, 3J = 8.6 Hz, 1 H, CHAr), 11.47 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 12.8 (CH3), 61.9 (OCH2), 105.7
(CCN), 113.5 (CCOOEt), 117.7 (CN), 118.1 (CHAr), 128.0
(3 × CHPh), 128.3 (2 × CHPh), 137.4 (CHAr), 138.9, 149.6 (CAr),
164.7 (COH), 169.9 (CO).
Yield: 0.190 g (41%); slightly yellow viscous oil.
IR (KBr): 2954 (w), 2920 (w), 2223 (w), 1742 (w), 1663 (m), 1593
(w), 1565 (w), 1494 (w), 1435 (s), 1333 (m), 1314 (m), 1261 (m),
1205 (s), 1170 (m), 1074 (w), 1029 (w), 985 (w), 856 (w), 815 (m),
759 (s), 699 (s), 658 (m), 549 (m) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.86 [t, 3J = 7.5 Hz, 3 H,
(CH2)3CH3], 1.26–1.35 (m, 2 H, CH2), 1.46–1.55 (m, 2 H, CH2),
2.59 (t, 3J = 7.9 Hz, 2 H, CH2), 3.33 (s, 3 H, OCH3), 7.08–7.13 (m,
2 H, CHPh), 7.27–7.31 (m, 3 H, CHPh), 8.46 (s, 1 H, CHAr), 11.45 (s,
1 H, OH).
GC–MS (EI, 70 eV): m/z (%) = 267 (34) [M+], 221 (100), 193 (41),
164 (21), 139 (11), 114 (3), 88 (2), 63 (3).
HRMS (EI): m/z [M+] calcd for C16H13O3N: 267.08899; found:
267.088732.
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 22.5, 29.2, 31.2 (CH2),
52.2 (OCH3), 105.2 (CCN), 112.7 (CCOOCH3), 118.1 (CN), 127.9
(2 × CHPh), 128.1 (3 × CHPh), 132.1 (CAr), 137.0 (CHAr), 139.1,
146.6 (CAr), 163.0 (COH), 170.9 (CO).
Methyl 6-Cyano-3-hydroxy-4-methylbiphenyl-2-carboxylate
(4i)
GC–MS (EI, 70 eV): m/z (%) = 309 (40) [M+], 277 (27), 259 (18),
244 (10), 236 (17), 235 (100), 234 (35), 221 (8), 206 (10), 178 (11),
177 (15), 151 (18).
HRMS (EI): m/z [M+] calcd for C19H19O3N: 309.13594; found:
309.135859.
Starting with 2b (0.302 g, 1.5 mmol) and 3c (0.457 g, 1.65 mmol),
the product was isolated after chromatography (silica gel; heptanes–
EtOAc).
Yield: 0.172 g (43%); light-yellowish solid; mp 105–107 °C.
IR (KBr): 3071 (w), 3027 (w), 2954 (w), 2924 (w), 2217 (w), 1722
(m), 1673 (m), 1594 (w), 1566 (w), 1461 (m), 1434 (s), 1377 (m),
1322 (s), 1259 (m), 1241 (m), 1162 (m), 1076 (m), 1022 (m), 983
(m), 848 (m), 809 (s), 757 (s), 702 (s), 677 (m), 552 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H, CH3), 3.37 (s, 3 H,
OCH3), 7.12–7.17 (m, 2 H, CHPh), 7.30–7.35 (m, 3 H, CHPh), 7.51
(s, 1 H, CHAr), 11.53 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 15.7 (CH3), 52.2 (OCH3), 104.9
(CCN), 112.6 (CCOOCH3), 118.2 (CN), 127.6 (CAr), 127.9
(2 × CHPh), 128.1 (3 × CHPh), 137.9 (CHAr), 138.9, 147.2 (CAr),
163.1 (COH), 170.6 (CO).
Methyl 6-Cyano-4-heptyl-3-hydroxybiphenyl-2-carboxylate
(4l)
Starting with 2b (0.302 g, 1.5 mmol) and 3g (0.591 g, 1.7 mmol), 4l
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.221 g (42%); light yellowish oil.
IR (neat): 2952 (w), 2924 (m), 2854 (w), 2223 (w), 1745 (w), 1664
(m), 1599 (w), 1566 (w), 1439 (m), 1335 (m), 1234 (m), 1204 (s),
1146 (m), 1074 (w), 990 (w), 897 (w), 815 (m), 760 (s), 724 (w),
699 (s), 549 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.82 [t, 3J = 7.6 Hz, 3 H,
(CH2)6CH3], 1.26–1.35 (m, 8 H, 4 × CH2), 1.51–1.61 (m, 2 H,
GC–MS (EI, 70 eV): m/z (%) = 267 (32) [M+], 236 (19), 235 (100),
234 (15), 207 (12), 206 (16), 179 (10), 178 (14), 151 (10), 76 (7).
3
CH2), 2.62 (t, J = 7.6 Hz, 2 H, CH2), 3.37 (s, 3 H, OCH3), 7.12–
7.17 (m, 2 H, CHPh), 7.30–7.36 (m, 3 H, CHPh), 7.49 (s, 1 H, CHAr),
11.49 (s, 1 H, OH).
HRMS (EI): m/z [M+] calcd for C16H13O3N: 267.08899; found:
267.088902.
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Cyanosalicylates
1629
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6, 28.9, 29.1, 29.4,
29.5, 31.8 (CH2), 52.2 (OCH3), 104.9 (CCN), 112.7 (CCOOCH3),
118.1 (CN), 127.9 (2 × CHPh), 128.1 (3 × CHPh), 132.1 (CAr), 137.1
(CHAr), 139.1, 147.0 (CAr), 162.9 (COH), 170.8 (CO).
Methyl 4¢-Chloro-6-cyano-3-hydroxy-4-methylbiphenyl-2-car-
boxylate (4o)
Starting with 2c (0.353 g, 1.5 mmol) and 3c (0.457 g, 1.7 mmol), 4o
was isolated after chromatography (silica gel; heptanes–EtOAc).
GC–MS (EI, 70 eV): m/z (%) = 351 (39) [M+], 320 (9), 319 (32),
236 (23), 235 (100), 234 (45), 231 (9), 219 (13), 206 (10), 178 (10),
177 (13), 151 (15), 41 (7).
HRMS (EI): m/z [M+] calcd for C22H25O3N: 351.18290; found:
351.183058.
Yield: 0.275 g (61%); white solid; mp 167–169 °C.
IR (KBr): 3034 (w), 2958 (w), 2848 (w), 2227 (w), 1932 (w), 1837
(w), 1667 (m), 1597 (m), 1557 (w), 1500 (w), 1435 (m), 1353 (m),
1332 (s), 1268 (m), 1203 (m), 1169 (m), 1147 (m), 1042 (w), 1017
(m), 981 (m), 902 (w), 868 (w), 809 (s), 771 (m), 659 (w), 613 (m),
548 (m) cm–1.
Methyl 6-Cyano-3-hydroxy-4-octylbiphenyl-2-carboxylate
(4m)
Starting with 2b (0.302 g, 1.5 mmol) and 3h (0.614 g, 1.7 mmol),
4m was isolated after chromatography (silica gel; heptanes–
EtOAc).
1H NMR (250 MHz, CDCl3): d = 2.24 (s, 3 H, CH3), 3.42 (s, 3 H,
OCH3), 7.06–7.10 (m, 2 H, CHClPh), 7.31–7.35 (m, 2 H, CHClPh),
7.51 (s, 1 H, CHAr), 11.61 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 51.4 (OCH3), 103.9
(CCN), 111.3 (CCOOCH3), 116.8 (CN), 127.2 (CAr), 127.9
(2 × CHClPh), 128.5 (2 × CHClPh), 133.2, 136.3 (CAr), 136.6 (CHAr),
144.7 (CAr), 162.4 (COH), 169.4 (CO).
GC–MS (EI, 70 eV): m/z (%) = 303 (11) [37Cl; M+], 301 (31) [35Cl;
M+], 271 (21), 270 (13), 269 (61), 235 (17), 234 (100), 178 (9), 177
(14), 151 (11).
Yield: 0.219 g (40%); yellowish oil.
IR (neat): 2952 (w), 2923 (m), 2853 (m), 2224 (w), 1749 (w), 1665
(m), 1600 (w), 1567 (w), 1436 (m), 1335 (m), 1234 (m), 1205 (s),
1146 (m), 1074 (w), 999 (w), 907 (w), 816 (m), 760 (s), 727 (w),
700 (s), 549 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.83 [t, 3J = 7.5 Hz, 3 H,
(CH2)7CH3], 1.06–1.08 (m, 10 H, 5 × CH2), 1.52–1.62 (m, 2 H,
HRMS (EI): m/z [M+] calcd for C16H12O3ClN: 301.5002; found:
301.050144.
3
CH2), 2.50 (t, J = 7.3 Hz, 2 H, CH2), 3.46 (s, 3 H, OCH3), 7.13–
7.18 (m, 2 H, CHPh), 7.31–7.37 (m, 3 H, CHPh), 7.50 (s, 1 H, CHAr),
11.50 (s, 1 H, OH).
Ethyl 4¢-Chloro-6-cyano-4-ethyl-3-hydroxybiphenyl-2-carbox-
ylate (4p)
Starting with 2c (0.353 g, 1.5 mmol) and 3d (0.499 g, 1.7 mmol), 4p
was isolated after chromatography (silica gel; heptanes–EtOAc).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6, 28.8, 29.2, 29.3,
29.4, 29.5, 31.8 (CH2), 52.2 (OCH3), 105.0 (CCN), 112.7
(CCOOCH3), 118.1 (CN), 127.9 (2 × CHPh), 128.1 (3 × CHPh),
132.1 (CAr), 137.0 (CHAr), 139.0, 147.0 (CAr), 162.9 (COH), 170.9
(CO).
GC–MS (EI, 70 eV): m/z (%) = 365 (21) [M+], 333 (29), 236 (26),
235 (100), 234 (47), 231 (13), 222 (11), 221 (10), 219 (24), 218
(12), 207 (15), 206 (18), 190 (11), 179 (11), 178 (17), 177 (18), 152
(12), 151 (25), 129 (20), 116 (39), 101 (12), 98 (10), 97 (11), 85
(11), 81 (9), 71 (20), 69 (32), 57 (42), 55 (34).
Yield: 0.306 g (62%); light-yellow solid; mp 165–167 °C.
IR (KBr): 2978 (w), 2876 (w), 2227 (w), 1910 (w), 1654 (m), 1568
(w), 1498 (m), 1444 (m), 1420 (m), 1374 (m), 1326 (s), 1274 (w),
1223 (m), 1194 (s), 1142 (m), 1111 (w), 1006 (m), 948 (w), 906 (w),
808 (s), 775 (m), 665 (w), 605 (m), 547 (m) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.71 (t, 3J = 6.7 Hz, 3 H,
CH2CH3), 1.19 (t, 3J = 7.4 Hz, 3 H, OCH2CH3), 2.65 (q, 3J = 7.4 Hz,
2 H, CH2CH3), 3.92 (q, 3J = 7.4 Hz, 2 H, OCH2CH3), 7.07–7.11 (m,
2 H, CHClPh), 7.31–7.34 (m, 2 H, CHClPh), 7.50 (s, 1 H, CHAr), 11.77
(s, 1 H, OH).
HRMS (EI): m/z [M+] calcd for C23H27O3N: 365.19885; found:
365.198427.
13C NMR (75 MHz, CDCl3): d = 12.9, 13.1 (CH3), 22.7, 62.0 (CH2),
104.9 (CCN), 112.5 (CCOOEt), 117.9 (CN), 128.2 (2 × CHClPh),
129.6 (2 × CHClPh), 133.8, 134.2 (CAr), 136.1 (CHAr), 137.7, 145.7
(CAr), 163.0 (COH), 170.0 (CO).
Methyl 6-Cyano-3-hydroxy-4-(4-chlorophenyl)biphenyl-2-car-
boxylate (4n)
Starting with 2b (0.302 g, 1.5 mmol) and 3k (0.612 g, 1.7 mmol),
4n was isolated after chromatography (silica gel; heptanes–EtOAc).
GC–MS (EI, 70 eV): m/z (%) = 331 (9) [37Cl; M+], 329 (26) [35Cl;
Yield: 0.240 g (44%); yellow solid; mp 149–151 °C.
M+], 285 (12), 283 (35), 249 (18), 248 (100), 177 (11).
IR (KBr): 3086 (w), 3061 (w), 3027 (w), 2954 (w), 2929 (w), 2852
(w), 2252 (w), 2226 (w), 1737 (w), 1667 (m), 1593 (w), 1553 (w),
1493 (w), 1437 (m), 1393 (m), 1330 (m), 1249 (w), 1208 (m), 1182
(m), 1094 (m), 1081 (w), 1031 (w), 1015 (w), 987 (w), 909 (m), 834
(m), 764 (m), 732 (s), 704 (m), 661 (w), 650 (w), 544 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 3.40 (s, 3 H, OCH3), 7.17–7.23
(m, 2 H, CHPh), 7.28–7.47 (m, 7 H, CHClPh,Ph), 7.67 (s, 1 H, CHAr),
11.73 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 53.6 (OCH3), 106.9 (CCN), 114.9
(CCOOCH3), 118.6 (CN), 128.9 (2 × CHPh), 129.0 (2 × CHPh),
129.3 (CHPh), 129.6 (2 × CHClPh), 130.7 (CAr), 131.5 (2 × CHClPh),
134.4, 135.3 (CAr), 138.7 (CHAr), 139.4, 149.5 (CAr), 162.7 (COH),
171.7 (CO).
HRMS (EI): m/z [M+] calcd for C18H16O3ClN: 329.08183; found:
329.081140.
Methyl 4¢-Chloro-6-cyano-4-hexyl-3-hydroxybiphenyl-2-car-
boxylate (4q)
Starting with 2c (0.353 g, 1.5 mmol) and 3f (0.568 g, 1.7 mmol), 4q
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.357 g (64%); white solid; mp 45–46 °C.
IR (KBr): 2955 (w), 2929 (w), 2857 (w), 2225 (w), 1668 (m), 1601
(w), 1575 (w), 1496 (w), 1439 (m), 1397 (w), 1345 (m), 1207 (m),
1171 (w), 1148 (w), 1091 (w), 908 (m), 825 (w), 732 (s), 649 (w)
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 [t, 3J = 7.5 Hz, 3 H,
(CH2)5CH3], 1.18–1.32 (m, 6 H, 3 × CH2), 1.50–1.57 (m, 2 H,
MS (ESI+): m/z [M + H]+ calcd for C21H15ClNO3: 364.0735; found:
364.07353.
MS (ESI+): m/z [M + Na]+ calcd for C21H14ClNNaO3: 386.05544;
found: 386.05531.
3
CH2), 2.62 (t, J = 7.6 Hz, 2 H, CH2), 3.42 (s, 3 H, OCH3), 7.07–
7.10 (m, 2 H, 2 × CHPh), 7.31–7.35 (m, 2 H, 2 × CHPh), 7.49 (s, 1 H,
CHAr), 11.59 (s, 1 H, OH).
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

1630
A. Riahi et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 21.6, 27.8, 28.1, 28.6,
30.7 (CH2), 51.5 (OCH3), 103.9 (CCN), 111.5 (CCOOCH3), 116.9
(CN), 127.3 (2 × CHPh), 128.6 (2 × CHPh), 131.7, 133.3 (CAr), 136.0
(CHAr), 136.4, 144.5 (CAr), 162.0 (COH), 169.5 (CO).
Methyl 4¢-Bromo-6-cyano-3-hydroxy-4-methylbiphenyl-2-car-
boxylate (4t)
Starting with 2d (0.420 g, 1.5 mmol) and 3c (0.457 g, 1.7 mmol),
the product was isolated after chromatography (silica gel; heptanes–
EtOAc).
GC–MS (EI, 70 eV): m/z (%) = 371 (23) [M+], 304 (39), 268 (18),
235 (18), 234 (100), 177 (16).
Yield: 0.301 g (58%); white crystalline solid; mp 199–200 °C.
HRMS (EI): m/z [M+] calcd for C21H22O3NCl: 371.12827; found:
371.127801.
IR (KBr): 3082 (w), 2957 (w), 2852 (w), 2227 (m), 1933 (w), 1667
(m), 1591 (w), 1555 (w), 1496 (w), 1435 (m), 1353 (m), 1331 (m),
1267 (m), 1201 (m), 1167 (m), 1146 (m), 1042 (w), 1012 (m), 987
(m), 902 (m), 861 (w), 807 (s), 770 (m), 659 (w), 600 (m), 548 (m)
cm–1.
Methyl 4¢-Chloro-6-cyano-3-hydroxy-4-octylbiphenyl-2-car-
boxylate (4r)
Starting with 2c (0.353 g, 1.5 mmol) and 3h (0.614 g, 1.7 mmol), 4r
was isolated after chromatography (silica gel; heptanes–EtOAc).
1H NMR (250 MHz, CDCl3): d = 2.24 (s, 3 H, CH3), 3.42 (s, 3 H,
OCH3), 7.00–7.04 (m, 2 H, CHBrPh), 7.47 (s, 1 H, CHAr), 7.50–7.52
(m, 2 H, CHBrPh), 11.61 (s, 1 H, OH).
Yield: 0.354 g (59%); pale-yellow solid; mp 68–71 °C.
IR (KBr): 2953 (w), 2925 (m), 2854 (w), 2224 (w), 1666 (m), 1600
(w), 1576 (w), 1496 (w), 1438 (m), 1397 (m), 1342 (m), 1341 (m),
1259 (w), 1206 (m), 1172 (m), 1091 (m), 1016 (w), 990 (w), 906
(m), 816 (w), 730 (s), 649 (w) cm–1.
13C NMR (75 MHz, CDCl3): d = 15.8 (CH3), 52.6 (OCH3), 104.9
(CCN), 112.2 (CCOOCH3), 117.8 (CN), 122.5, 128.3 (CAr), 129.9
(2 × CHBrPh), 131.5 (2 × CHBrPh), 137.7 (CHAr), 137.8, 145.4 (CAr),
163.2 (COH), 170.4 (CO).
1H NMR (300 MHz, CDCl3): d = 0.81 [t, 3J = 7.4 Hz, 3 H,
(CH2)7CH3], 1.17–1.34 (m, 10 H, 5 × CH2), 1.49–1.58 (m, 2 H,
GC–MS (EI, 70 eV): m/z (%) = 347 (29) [81Br; M+], 345 (29) [79Br;
M+], 316 (10), 315 (60), 314 (12), 313 (60), 235 (20), 234 (100), 206
(12), 178 (10), 177 (19), 151 (17).
3
CH2), 2.61 (t, J = 7.4 Hz, 2 H, CH2), 3.42 (s, 3 H, OCH3), 7.06–
7.12 (m, 2 H, 2 × CHPh), 7.31–7.35 (m, 2 H, 2 × CHPh), 7.51 (s, 1 H,
HRMS (EI): m/z [79Br; M+] calcd for C16H12O3BrN: 344.99951;
found: 344.999038.
HRMS (EI): m/z [81Br; M+] calcd for C16H12O3BrN: 346.99746;
found: 346.997318.
CHAr), 11.59 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.6, 28.8, 29.2, 29.3,
29.4, 29.6, 31.9 (CH2), 52.5 (OCH3), 104.9 (CCN), 112.5
(CCOOCH3), 117.9 (CN), 128.3 (2 × CHPh), 129.5 (2 × CHPh),
132.7, 134.1 (CAr), 137.0 (CHAr), 137.4, 145.5 (CAr), 163.2 (COH),
170.6 (CO).
Ethyl 4¢-Bromo-6-cyano-4-ethyl-3-hydroxybiphenyl-2-carbox-
ylate (4u)
Starting with 2d (0.420 g, 1.5 mmol) and 3d (0.499 g, 1.7 mmol),
GC–MS (EI, 70 eV): m/z (%) = 399 (22) [M+], 332 (38), 270 (10),
268 (21), 235 (18), 234 (100), 177 (15).
4u was isolated after chromatography (silica gel; heptanes–EtOAc).
HRMS (EI): m/z [M+] calcd for C23H26O3NCl: 399.15957; found:
Yield: 0.453 g (60%); yellowish oil; mp 197–199 °C.
399.159574.
IR (KBr): 2970 (w), 2874 (w), 2224 (w), 1898 (w), 1659 (s), 1573
(w), 1492 (w), 1421 (m), 1393 (m), 1327 (s), 1268 (m), 1239 (m),
1190 (s), 1146 (m), 1100 (w), 1004 (m), 906 (w), 809 (s), 727 (m),
652 (w), 599 (m), 547 (m) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.71 (t, 3J = 7.5 Hz, 3 H,
CH2CH3), 1.19 (t, 3J = 7.0 Hz, 3 H, OCH2CH3), 2.65 (q, 3J = 7.5 Hz,
2 H, CH2CH3), 3.93 (q, 3J = 7.5 Hz, 2 H, OCH2CH3), 7.01–7.05 (m,
2 H, CHBrPh), 7.47 (s, 1 H, CHAr), 7.50–7.52 (m, 2 H, CHBrPh), 11.78
(s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 12.9, 13.0 (CH3), 22.7, 62.0 (CH2),
104.8 (CCN), 112.4 (CCOOCH3), 117.9 (CN), 122.3 (CAr), 129.5
(2 × CHBrPh), 131.2 (2 × CHBrPh), 133.8 (CAr), 136.0 (CHAr), 138.2,
145.5 (CAr), 163.2 (COH), 170.0 (CO).
Methyl 4¢-Chloro-6-cyano-3-hydroxy-4-isopentylbiphenyl-2-
carboxylate (4s)
Starting with 2c (0.353 g, 1.5 mmol) and 3j (0.522 g, 1.7 mmol), 4s
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.319 g (62%); light-yellow solid; mp 74–76 °C.
IR (KBr): 2955 (m), 2928 (m), 2868 (w), 2224 (w), 1741 (w), 1665
(s), 1599 (m), 1575 (w), 1496 (m), 1436 (s), 1397 (m), 1385 (w),
1345 (m), 1325 (m), 1314 (m), 1263 (m), 1204 (s), 1169 (m), 1148
(m), 1089 (s), 1016 (m), 1000 (m), 981 (m), 945 (w), 904 (w), 888
(w), 861 (w), 820 (m), 771 (m), 738 (m), 660 (m), 634 (m), 545 (m)
cm–1.
1H NMR (250 MHz, CDCl3): d = 0.89 (d, 3J = 6.7 Hz, 6 H,
2 × CH3), 1.90–1.99 [m, 1 H, CH(CH3)2], 2.51 (d, 3J = 7.2 Hz, 2 H,
CH2), 3.43 (s, 3 H, OCH3), 7.08–7.13 (m, 2 H, CHClPh), 7.32–7.36
(m, 2 H, CHClPh), 7.47 (s, 1 H, CHAr), 11.57 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 21.4 (2 × CH3), 27.0 [CH(CH3)2],
37.8 (CH2), 51.5 (OCH3), 103.8 (CCN), 111.6 (CCOOCH3), 116.9
(CN), 127.3 (2 × CHClPh), 128.6 (2 × CHClPh), 130.5, 133.3, 136.4
(CAr), 137.0 (CHAr), 144.6 (CAr), 162.2 (COH), 169.6 (CO).
GC–MS (EI, 70 eV): m/z (%) = 375 (20) [81Br; M+], 373 (21) [79Br;
M+], 329 (32), 327 (32), 249 (19), 248 (100), 190 (10), 177 (12).
HRMS (EI): m/z [79Br; M+] calcd for C18H16O3BrN: 373.03081;
found: 373.030467.
HRMS (EI): m/z [81Br; M+] calcd for C18H16O3BrN: 375.02876;
found: 375.028656.
Methyl 4¢-Bromo-6-cyano-4-hexyl-3-hydroxybiphenyl-2-car-
boxylate (4v)
Starting with 2d (0.420 g, 1.5 mmol) and 3f (0.568 g, 1.7 mmol), the
product was isolated after chromatography (silica gel; n-heptane–
EtOAc).
GC–MS (EI, 70 eV): m/z (%) = 343 (29) [M+], 277 (20), 276 (100),
270 (16), 268 (44), 234 (39), 177 (24), 151 (5), 130 (2), 88 (2), 43
(5).
HRMS (EI): m/z [M+] calcd for C19H18O3NCl: 343.09697; found:
343.096981.
Yield: 0.343 g (55%); yellowish oil.
IR (KBr): 2954 (w), 2927 (m), 2856 (w), 2224 (w), 1666 (m), 1601
(w), 1573 (w), 1493 (w), 1438 (m), 1392 (w), 1340 (m), 1262 (w),
1206 (m), 1171 (w), 1101 (w), 1071 (w), 1013 (w), 908 (m), 817
(w), 770 (w), 730 (s), 649 (w), 621 (w) cm–1.
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Cyanosalicylates
1631
1H NMR (300 MHz, CDCl3): d = 0.73 [t, 3J = 7.5 Hz, 3 H,
(CH2)7CH3], 1.07–1.20 (m, 6 H, 3 × CH2), 1.42–1.50 (m, 2 H,
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 21.7, 27.8, 28.3, 28.4,
28.5, 28.6, 29.9, 30.9 (CH2), 51.5 (OCH3), 103.8 (CCN), 111.4
(CCOOCH3), 116.9 (CN), 121.4 (CAr), 128.8 (2 × CHBrPh), 130.2
(2 × CHBrPh), 131.7 (CAr), 136.0 (CHAr), 136.9, 144.5 (CAr), 162.1
(COH), 169.5 (CO).
3
CH2), 2.51 (t, J = 7.5 Hz, 2 H, CH2), 3.42 (s, 3 H, OCH3), 6.90–
6.95 (m, 2 H, 2 × CHPh), 7.36–7.39 (m, 3 H, 3 × CHAr), 11.49 (s,
1 H, OH).
13C NMR (75 MHz, CDCl3): d = 15.3 (CH3), 23.8, 30.0, 30.3, 30.8,
32.9 (CH2), 53.7 (OCH3), 106.0 (CCN), 113.6 (CCOOCH3), 119.1
(CN), 123.6 (CAr), 131.1, 132.4 (4 × CHPh), 133.9 (CAr), 138.2
(CHAr), 139.0, 146.6 (CAr), 164.2 (COH), 171.7 (CO).
GC–MS (EI, 70 eV): m/z (%) = 459 (41) [81Br; M+], 457 (41) [79Br;
M+], 427 (9), 390 (5), 368 (4), 346 (90), 330 (7), 314 (22), 288 (14),
235 (73), 224 (11), 205 (22), 177 (22), 158 (13), 129 (42), 116
(100), 97 (21), 85 (34), 71 (48), 57 (74).
GC–MS (EI, 70 eV): m/z (%) = 417 (17), 415 (17) [M+], 304 (26),
HRMS (EI): m/z [M+] calcd for C24H28O3NBr: 457.12471; found:
235 (17), 234 (100), 205 (11), 177 (12).
457.124229.
HRMS (EI): m/z [79Br; M+] calcd for C21H22O3NBr: 415.07776;
found: 415.077792.
HRMS (EI): m/z [81Br; M+] calcd for C23H26O3NBr: 417.07571;
found: 417.076005.
Ethyl 4¢-Methoxy-6-cyano-3-hydroxy-biphenyl-2-carboxylate
(4y)
Starting with 2e (0.347 g, 1.5 mmol) and 3b (0.453 g, 1.7 mmol), 4y
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.223 g (50%); yellow solid; mp 116–117 °C.
Methyl 4¢-Bromo-6-cyano-3-hydroxy-4-octylbiphenyl-2-car-
boxylate (4w)
Starting with 2d (0.420 g, 1.5 mmol) and 3h (0.614 g, 1.7 mmol),
4w was isolated after chromatography (silica gel; heptanes–
EtOAc).
IR (KBr): 3306 (w, br), 3070 (w), 2987 (w), 2959 (w), 2921 (m),
2838 (w), 2537 (w), 2351 (w), 2225 (m), 2175 (w), 2050 (w), 1931
(w), 1682 (m), 1651 (w), 1609 (m), 1570 (m), 1517 (m), 1464 (m),
1455 (m), 1395 (m), 1372 (m), 1311 (m), 1294 (m), 1251 (m), 1174
(s), 1138 (m), 1112 (m), 1096 (m), 1028 (m), 1016 (m), 948 (m),
929 (w), 908 (w), 872 (w), 848 (m), 835 (s), 806 (m), 795 (m), 778
(m), 742 (m), 723 (m), 706 (m), 675 (m), 646 (m), 621 (m), 579 (m),
558 (m), 532 (m) cm–1.
Yield: 0.367 g (55%); yellowish solid; mp 73–75 °C.
IR (KBr): 2953 (w), 2924 (m), 2854 (w), 2224 (w), 1667 (m), 1602
(w), 1574 (w), 1493 (w), 1438 (m), 1392 (w), 1339 (m), 1259 (w),
1205 (m), 1172 (m), 1103 (w), 1071 (w), 1012 (w), 906 (m), 817
(w), 770 (w), 728 (s), 649 (w), 548 (w) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.73 (t, 3J = 7.0 Hz, 3 H,
OCH2CH3), 3.79 (s, 3 H, OCH3), 3.93 (q, 3J = 7.0 Hz, 2 H,
OCH2CH3), 6.86–6.91 (m, 2 H, CHOMePh), 6.99 (d, 3J = 8.7 Hz, 1 H,
1H NMR (300 MHz, CDCl3): d = 0.83 [t, 3J = 7.4 Hz, 3 H,
(CH2)7CH3], 1.16–1.32 (m, 10 H, 5 × CH2), 1.49–1.61 (m, 2 H,
3
CHAr), 7.07–7.12 (m, 2 H, CHOMePh), 7.62 (d, J = 9.0 Hz, 1 H,
3
CH2), 2.61 (t, J = 7.6 Hz, 2 H, CH2), 3.43 (s, 3 H, OCH3), 7.01–
CHAr), 11.36 (s, 1 H, OH).
7.05 (m, 2 H, 2 × CHPh), 7.47–7.51 (m, 3 H, 3 × CHAr), 11.59 (s,
1 H, OH).
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 55.4 (OCH3), 61.9
(OCH2), 106.1 (CCN), 113.5 (2 × CHOMePh), 113.9
(CCOOCH2CH3), 117.9 (CHAr), 118.0 (CN), 129.4 (2 × CHOMePh),
131.2 (CAr), 137.4 CHAr), 149.5, 159.8 (CAr), 164.7 (COH), 170.0
(CO).
GC–MS (EI, 70 eV): m/z (%) = 297 (44) [M+], 251 (100), 236 (5),
223 (16), 208 (9), 180 (9), 152 (7), 126 (5), 101 (1), 75 (2), 63 (2).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.6, 28.8, 29.2, 29.4,
29.5, 29.6, 31.8 (CH2), 52.5 (OCH3), 104.8 (CCN), 112.4
(CCOOCH3), 117.9 (CN), 122.3 (CAr), 129.8, 131.3 (4 × HPh),
132.7 (CAr), 137.0 (CHAr), 137.8, 145.5 (CAr), 163.1 (COH), 170.6
(CO).
GC–MS (EI, 70 eV): m/z (%) = 445 (15), 443 (15), 332 (29), 235
(20), 234 (100).
HRMS (EI): m/z [79Br; M+] calcd for C23H26O3NBr: 443.10906;
HRMS (EI): m/z [M+] calcd for C17H15O4N: 297.09956; found:
297.099391.
found: 443.109033.
HRMS (EI): m/z [81Br; M+] calcd for C23H26O3NBr: 445.10701;
found: 445.107259.
Methyl 6-Cyano-3-hydroxy-4¢-methoxy-4-methylbiphenyl-2-
carboxylate (4z)
Starting with 2e (0.346 g, 1.5 mmol) and 3c (0.457 g, 1.7 mmol), 4z
was isolated after chromatography (silica gel; heptanes–EtOAc).
Methyl 4¢-Bromo-6-cyano-3-hydroxy-4-nonylbiphenyl-2-car-
boxylate (4x)
Starting with 2d (0.420 g, 1.5 mmol) and 3i (0.638 g, 1.7 mmol), 4x
was isolated after chromatography (silica gel; heptanes–EtOAc).
Yield: 0.266 g (51%); yellowish solid; mp 85–87 °C.
IR (KBr): 2958 (w), 2843 (w), 2219 (w), 1659 (m), 1608 (m), 1555
(w), 1515 (m), 1427 (m), 1331 (m), 1308 (s), 1260 (m), 1202 (m),
1176 (m), 1145 (m), 1033 (m), 1019 (m), 983 (m), 902 (m), 862 (w),
808 (s), 767 (m), 661 (w), 648 (m), 535 (m) cm–1.
Yield: 0.392 g (57%); yellow solid; mp 65–67 °C.
1H NMR (250 MHz, CDCl3): d = 2.23 (s, 3 H, CH3), 3.42 (s, 3 H,
OCH3), 3.78 (s, 3 H, OCH3), 6.85–6.89 (m, 2 H, CHOMePh), 7.05–
7.09 (m, 2 H, CHOMePh), 7.49 (s, 1 H, CHAr), 11.43 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 15.6 (CH3), 52.4, 55.3 (OCH3),
105.2 (CCN), 112.8 (CCOOCH3), 113.5 (2 × CHOMePh), 118.3
(CN), 127.4 (CAr), 129.2 (2 × CHOMePh), 131.1 (CAr), 137.7 (CHAr),
146.9, 159.5 (CAr), 162.9 (COH), 170.9 (CO).
GC–MS (EI, 70 eV): m/z (%) = 297 (45) [M+], 266 (19), 265 (100),
264 (12), 250 (11), 222 (9), 166 (9), 140 (8), 39 (8).
HRMS (EI): m/z [M+] calcd for C17H15O4N: 297.09956; found:
IR (KBr): 3333 (w), 2949 (m), 2921 (m), 2871 (m), 2847 (m), 2226
(w), 1911 (w), 1736 (m), 1714 (m), 1639 (w), 1599 (m), 1568 (m),
1493 (w), 1458 (m), 1428 (m), 1403 (m), 1392 (m), 1374 (w), 1356
(w), 1334 (w), 1301 (m), 1257 (m), 1237 (m), 1207 (m), 1187 (m),
1176 (m), 1148 (s), 1125 (m), 1072 (m), 1055 (w), 1038 (w), 1028
(w), 1012 (m) cm–1.
1H NMR (250 MHz, CDCl3): d = 0.82 [t, 3J = 6.8 Hz, 3 H,
(CH2)8CH3], 1.18–1.24 (m, 12 H, 6 × CH2), 1.51–1.59 (m, 2 H,
3
CH2), 2.62 (t, J = 7.4 Hz, 2 H, CH2), 3.43 (s, 3 H, OCH3), 7.01–
7.05 (m, 2 H, CHBrPh), 7.48 (s, 1 H, CHAr), 7.49–7.51 (m, 2 H,
CHBrPh), 11.60 (s, 1 H, OH).
297.099657.
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Ethyl 6-Cyano-4-ethyl-3-hydroxy-4¢-methoxybiphenyl-2-car-
boxylate (4aa)
Starting with 2e (0.346 g, 1.5 mmol) and 3d (0.499 g, 1.7 mmol),
4aa was isolated after chromatography (silica gel; heptanes–
EtOAc).
CH2), 2.61 (t, 3J = 7.5 Hz, 2 H, CH2), 3.42 (s, 3 H, OCH3), 3.78 (s,
3 H, OCH3), 6.84–6.90 (m, 2 H, 2 × CHPh), 7.05–7.11 (m, 2 H,
2 × CHPh), 7.48 (s, 1 H, CHAr), 11.49 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 21.6, 27.9, 28.2, 28.3,
28.4, 28.6, 30.9 (CH2), 51.3, 54.3 (OCH3), 104.1 (CCN), 111.9
(CCOOCH3), 112.4 (2 × CHPh), 117.4 (CN), 128.4 (2 × CHPh),
130.1, 130.8 (CAr), 136.1 (CHAr), 145.5, 158.4 (CAr), 161.7 (COH),
170.0 (CO).
Yield: 0.237 g (49%); yellowish solid; mp 54–56 °C.
IR (neat): 2968 (w), 2875 (w), 2223 (w), 1658 (m), 1608 (m), 1566
(w), 1515(s), 1434 (m), 1399 (m), 1373 (m), 1326 (m), 1302 (m),
1268 (m), 1239 (s), 1189 (s), 1145 (s), 1109 (m), 1065 (w), 1030
(m), 906 (w), 808 (s), 770 (m), 643 (w), 534 (m).
GC–MS (EI, 70 eV): m/z (%) = 396 (21), 395 (97) [M+], 364 (14),
363 (56), 266 (17), 265 (100), 264 (50), 234 (21).
1H NMR (250 MHz, CDCl3): d = 0.71 (t, 3J = 7.2 Hz, 3 H,
CH2CH3), 1.19 (t, 3J = 7.2 Hz, 3 H, OCH2CH3), 2.65 (q, 3J = 7.2 Hz,
2 H, CH2CH3), 3.92 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 3.77 (s, 3 H,
OCH3), 6.85–6.88 (m, 2 H, CHOMePh), 7.06–7.09 (m, 2 H, CHOMePh),
7.49 (s, 1 H, CHAr), 11.60 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 12.9, 13.2 (CH3), 22.7 (CH2), 55.3
(OCH3), 62.0 (OCH2), 105.2 (CCN), 112.9 (CCOOCH3), 113.5
(2 × CHOMePh), 118.3 (CN), 129.2 (2 × CHOMePh), 132.5 (CAr), 133.8
(CAr), 136.9 (CHAr), 146.9, 159.8 (CAr), 163.0 (COH), 170.5 (CO).
GC–MS (EI, 70 eV): m/z (%) = 325 (84) [M+], 280 (23), 279 (100),
264 (29), 262 (12), 261 (52), 251 (10), 250 (10), 249 (12), 248 (60),
247 (12), 246 (30), 236 (15), 208 (9), 193 (8), 177 (8), 165 (9), 152
(8), 29 (9).
HRMS (EI): m/z [M+] calcd for C24H29NO4: 395.20911; found:
395.209162.
Benzonitriles 6a–f; General Procedure
To a solution of 5 in CH2Cl2, was added TiCl4 at –78 °C in the pres-
ence of molecular sieves (4 Å). The appropriate bis(silyl enol ether)
3 was subsequently added and the reaction mixture was allowed to
warm to 20 °C during 20 h then stirred for a further 4 h. To this so-
lution was added CH2Cl2, the molecular sieves were removed by fil-
tration and sat. aq NaHCO3 was added. The organic layer was
separated and the aqueous layer was repeatedly extracted with
CH2Cl2 (3 × 100 mL). The combined organic layers were dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (silica gel; hep-
tanes–EtOAc) to give salicylates 6.
HRMS (EI): m/z [M+] calcd for C19H19O4N: 325.13086; found:
325.130617.
Methyl 3-Cyano-6-hydroxy-2,4-dimethylbenzoate (6a)
Starting with 5 (188 mg, 1.0 mmol), CH2Cl2 (3.0 mL), molecular
sieves (4 Å, 0.4 g), TiCl4 (0.11 mL, 1.0 mmol), and 3a (356 mg, 1.4
mmol), 6a was obtained after 21 h and isolated by column chroma-
tography (silica gel; heptanes–EtOAc, 10:1).
Methyl 6-Cyano-4-hexyl-3-hydroxy-4¢-methoxybiphenyl-2-car-
boxylate (4ab)
Starting with 2e (0.346 g, 1.5 mmol) and 3f (0.568 g, 1.7 mmol),
4ab was isolated after chromatography (silica gel; heptanes–
EtOAc).
Yield: 67 mg (34%); colourless solid; mp 109–110 °C; Rf = 0.21
(heptanes–EtOAc, 10:1).
Yield: 0.286 g (52%); yellowish solid; mp 43–44 °C.
IR (KBr): 3431 (br, m), 2957 (m), 2217 (s), 1668 (s), 1601 (s), 1581
(s), 1442 (s), 1368 (s), 1358 (s), 1319 (s), 1241 (s), 810 (s) cm–1.
1H NMR (250 MHz, CDCl3): d = 2.48 (d, 4J = 0.9 Hz, 3 H, ArCH3),
2.75 (s, 3 H, ArCH3), 3.98 (s, 3 H, OCH3), 6.76 (s, 1 H, CHAr),
11.72 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 21.4, 21.8 (ArCH3), 52.7 (OCH3),
107.0, 111.0, 117.3 (2 × CAr, CN), 117.4 (CHAr), 146.6, 148.4 (CAr),
165.1, 171.0 (CArOH, CO).
IR (KBr): 2954 (w), 2927 (m), 2856 (w), 2223 (w), 1746 (w), 1665
(m), 1609 (m), 1579 (w), 1516 (m), 1436 (m), 1337 (m), 1289 (m),
1247 (s), 1205 (m), 1176 (m), 1147 (m), 1110 (w), 1034 (w), 906
(m), 830 (m), 768 (w), 728 (s), 649 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 [t, 3J = 7.5 Hz, 3 H,
(CH2)5CH3], 1.18–1.32 (m, 6 H, 3 × CH2), 1.50–1.59 (m, 2 H,
CH2), 2.61 (t, 3J = 7.5 Hz, 2 H, CH2), 3.40 (s, 3 H, OCH3), 3.77 (s,
3 H, OCH3), 6.83–6.88 (m, 2 H, 2 × CHPh), 7.04–7.09 (m, 2 H,
2 × CHPh), 7.46 (s, 1 H, CHAr), 11.39 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.6, 28.8, 29.1, 29.5,
31.6 (CH2), 52.4, 55.2 (OCH3), 105.6 (CCN), 113.0 (CCOOCH3),
113.5 (2 × CHPh), 118.4 (CN), 129.4 (2 × CHPh), 131.1, 131.8 (CAr),
137.0 (CHAr), 146.6, 159.4 (CAr), 162.7 (COH), 170.9 (CO).
MS (EI, 70 eV): m/z (%) = 205 (83) [M+], 174 (76), 173 (100), 145
(66), 144 (37), 116 (20), 91 (14).
Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C,
64.64; H, 5.52; N, 6.65.
GC–MS (EI, 70 eV): m/z (%) = 368 (17), 367 (85) [M+], 336 (13),
335 (54), 266 (17), 265 (100), 264 (44), 234 (22).
HRMS (EI): m/z [M+] calcd for C22H25O4N: 367.17781; found:
367.177574.
Ethyl 3-Cyano-6-hydroxy-2,4-dimethylbenzoate (6b)
Starting with 5 (196 mg, 1.0 mmol), CH2Cl2 (3.0 mL), molecular
sieves (4 Å, 0.4 g), TiCl4 (0.11 mL, 1.0 mmol), and 3b (390 mg, 1.4
mmol), 6b was obtained after 25 h and isolated by column chroma-
tography (silica gel; heptanes–EtOAc, 10:1→7:1).
Methyl 6-Cyano-3-hydroxy-4¢-methoxy-4-octylbiphenyl-2-car-
boxylate (4ac)
Starting with 2e (0.346 g, 1.5 mmol) and 3h (0.614 g, 1.7 mmol),
4ac was isolated after chromatography (silica gel; heptanes–
EtOAc).
Yield: 90 mg (41%); colourless solid; mp 114–115 °C; Rf = 0.22 (n-
heptane–EtOAc, 10:1).
IR (KBr): 3426 (br, w), 2995 (m), 2213 (s), 1662 (s), 1373 (s), 1315
(s), 1239 (s), 809 (m) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.45 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.49 (s, 3 H, ArCH3), 2.78 (s, 3 H, ArCH3), 4.46 (q,
3J = 7.2 Hz, 2 H, OCH2CH3), 6.77 (s, 1 H, Ar), 11.83 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 14.1 (OCH2CH3), 21.4, 21.9
(ArCH3), 62.4 (OCH2CH3), 106.9, 111.2, 117.3 (2 × CAr, CN),
117.4 (CHAr), 146.7, 148.3 (CAr), 165.2, 170.6 (CArOH, CO).
Yield: 0.297 g (50%); yellowish oil.
IR (KBr): 2953 (w), 2924 (m), 2854 (w), 2223 (w), 1665 (m), 1609
(m), 1516 (m), 1436 (s), 1339 (m), 1290 (m), 1247 (s), 1205 (m),
1175 (m), 1034 (m), 991 (w), 906 (m), 829 (m), 767 (w), 729 (s),
649 (m), 536 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.81 [t, 3J = 7.4 Hz, 3 H,
(CH2)7CH3], 1.17–1.32 (m, 10 H, 5 × CH2), 1.50–1.59 (m, 2 H,
Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Cyanosalicylates
1633
MS (EI, 70 eV): m/z (%) = 219 (64) [M+], 174 (63), 173 (100), 145
(42), 144 (17).
13C NMR (75 MHz, CDCl3): d = 12.8 (CH2CH3), 18.2 (ArCH3),
19.5 (CH2), 21.7 (ArCH3), 52.6 (OCH3), 107.0, 110.6, 118.0
(2 × CAr, CN), 130.1, 143.4, 145.3 (CAr), 163.1, 171.6 (CArOH, CO).
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.92; H, 6.01; N, 6.17.
MS (EI, 70 eV): m/z (%) = 233 (87) [M+], 202 (73), 201 (100), 186
(62), 174 (49), 173 (97), 158 (34), 130 (17).
Isobutyl 3-Cyano-6-hydroxy-2,4-dimethylbenzoate (6c)
Starting with 5 (188 mg, 1.0 mmol), CH2Cl2 (3.0 mL), molecular
sieves (4 Å, 0.4 g), TiCl4 (0.11 mL, 1.0 mmol), and 3l (394 mg, 1.3
mmol), 6c was obtained after 22 h and isolated by column chroma-
tography (silica gel; heptanes–EtOAc, 10:1).
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C,
66.99; H, 6.64; N, 5.80.
Ethyl 3-Cyano-5-ethyl-6-hydroxy-2,4-dimethylbenzoate (6f)
Starting with 5 (189 mg, 1.0 mmol), CH2Cl2 (3.0 mL), molecular
sieves (4 Å, 0.4 g), TiCl4 (0.11 mL, 1.0 mmol), and 3d (400 mg, 1.3
mmol), 6f was obtained after 26 h and isolated by column chroma-
tography (silica gel; n-heptane–EtOAc, 10:1).
Yield: 91 mg (39%); colourless solid; mp 51–52 °C; Rf = 0.29 (hep-
tanes–EtOAc, 10:1).
IR (KBr): 3427 (br, w), 2960 (s), 2930 (m), 2875 (m), 2216 (m),
1656 (s), 1318 (s), 1242 (s), 1080 (s), 814 (m) cm–1.
Yield: 138 mg (58%); colourless solid; mp 48–49 °C; Rf = 0.33
(heptanes–EtOAc, 10:1).
1H NMR (250 MHz, CDCl3): d = 1.04 [d, 3J = 6.9 Hz, 6 H,
CH(CH3)2], 2.12 (m, 1 H, OCH2CH), 2.48 (s, 3 H, ArCH3), 2.79 (s,
3 H, ArCH3), 4.19 (d, 3J = 6.4 Hz, 2 H, OCH2CH), 6.77 (s, 1 H, Ar),
11.88 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 19.3 [CH(CH3)2], 21.4, 22.1
(ArCH3), 27.6 (OCH2CH), 72.7 (OCH2CH), 106.9, 111.2, 117.3
(2 × CAr, CN), 117.5 (CHAr), 146.5, 148.3 (CAr), 165.3, 170.8
(CArOH, CO).
IR (KBr): 3441 (br, m), 2978 (s), 2943 (m), 2879 (m), 2218 (s),
1654 (s), 1399 (s), 1377 (s), 1208 (s), 824 (m).
1H NMR (250 MHz, CDCl3): d = 1.07 (t, 3J = 7.4 Hz, 3 H,
3
ArCH2CH3), 1.44 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.49 (s, 3 H,
ArCH3), 2.68 (q, 3J = 7.4 Hz, 2 H, ArCH2CH3), 2.73 (s, 3 H,
ArCH3), 4.45 (q, 3J = 7.1 Hz, 2 H, OCH2CH3), 12.14 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 12.8, 14.0 (CH2CH3), 18.2
(ArCH3), 19.5 (ArCH2), 21.8 (ArCH3), 62.3 (OCH2), 107.0, 110.7,
118.1 (2 × CAr, CN), 130.1, 143.4, 145.2 (CAr), 163.2, 171.2
(CArOH, CO).
MS (EI, 70 eV): m/z (%) = 247 (64) [M+], 191 (55), 174 (81), 173
(100), 145 (26), 91 (14), 57 (23).
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
67.95; H, 7.04; N, 5.36.
MS (EI, 70 eV): m/z (%) = 247 (40) [M+], 202 (29), 201 (100), 186
(14), 173 (99), 158 (10).
tert-Butyl 3-Cyano-6-hydroxy-2,4-dimethylbenzoate (6d)
Starting with 5 (300 mg, 1.52 mmol), CH2Cl2 (4.5 mL), molecular
sieves (4 Å, 0.6 g), TiCl4 (0.17 mL, 1.5 mmol), and 3m (634 mg,
2.10 mmol), 6d was obtained after 26 h and isolated by column
chromatography (silica gel; n-heptane–EtOAc, 1:0→20:1).
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
68.34; H, 7.07; N, 5.49.
Acknowledgment
Yield: 29 mg (8%); yellow solid; mp 92–94 °C; Rf 0.43 (n-heptane–
EtOAc, 5:1).
Financial support by the State of Mecklenburg-Vorpommern (scho-
larship for M.S.) is gratefully acknowledged.
IR (KBr): 2987 (m), 2928 (m), 2212 (m), 1661 (s), 1601 (m), 1575
(m), 1466 (m), 1377 (s), 1327 (s), 1245 (s), 1153 (s), 1080 (m), 839
(m), 813 (m) cm–1.
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1H NMR (250 MHz, CDCl3): d = 1.63 [s, 9 H, C(CH3)3], 2.48 (d,
4J = 0.7 Hz, 3 H, ArCH3), 2.75 (s, 3 H, ArCH3), 6.75 (s, 1 H, CHAr),
11.93 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 21.4, 22.1 (ArCH3), 28.3
[OC(CH3)3], 85.0 [OC(CH3)3], 106.8, 112.5 (C), 117.4 (CHAr),
117.5 (C), 146.4, 147.9 (CAr), 165.2, 170.0 (CArOH, CO).
MS (GC-EI, 70 eV): m/z (%) = 247 (4) [M+], 191 (34), 174 (40),
173 (100), 57 (29).
HRMS (EI, 70 eV): m/z [M+] calcd for C14H17NO3: 247.12029;
found: 247.12041.
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Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York

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Synthesis 2009, No. 10, 1623–1634 © Thieme Stuttgart · New York