Diversity-oriented synthesis of chlorinated arenes by one-pot cyclizations of 4-chloro-1,3-bis(trimethylsilyloxy)buta-1,3-dienes

Article abstract of DOI:10.1002/ejoc.200900816

A variety of 3-chlorosalicylates were prepared by one-pot cyclizations of the first reported 4-chloro-1,3-bis(trimethylsilyloxy)buta-1,3-dienes with various 1,3-dielectrophiles, These include cyclizations with 3-silyloxy-2-en-1-ones, 3-aryl-3-silyloxy-2-en-1-ones, 1-methoxy-1-en-3-ones, 1,1-bis-(methylthio)-1-en-3-ones, 3-oxo orthoesters, 1,1,3,3- tetraethoxypropanes, 1,1-diacetylcyclopropane, and 3-formylchromones.

Full text of DOI:10.1002/ejoc.200900816

FULL PAPER
DOI: 10.1002/ejoc.200900816
Diversity-Oriented Synthesis of Chlorinated Arenes by One-Pot Cyclizations of
4-Chloro-1,3-bis(trimethylsilyloxy)buta-1,3-dienes
Verena Wolf,[a] Muhammad Adeel,[a,b] Stefanie Reim,[a] Alexander Villinger,[a]
Christine Fischer,[c] and Peter Langer*[a,c]
Keywords: Arenes / Cyclization / Organochlorine compounds / Regioselectivity / Silyl enol ethers
A variety of 3-chlorosalicylates were prepared by one-pot
cyclizations of the first reported 4-chloro-1,3-bis(trimethyl-
silyloxy)buta-1,3-dienes with various 1,3-dielectrophiles.
These include cyclizations with 3-silyloxy-2-en-1-ones, 3-
aryl-3-silyloxy-2-en-1-ones, 1-methoxy-1-en-3-ones, 1,1-bis-
(methylthio)-1-en-3-ones, 3-oxo orthoesters, 1,1,3,3-tetra-
ethoxypropanes, 1,1-diacetylcyclopropane, and 3-formyl-
chromones.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
compounds are also present in simple arenes, acetophe-
nones (longissiminone B), benzophenones (chloroisosul-
ochrin, pestalone) and diaryl ethers (methyl chloroas-
terrate),[18] falconensin B,[19] natural chromones[20] and 7-
chloro-8-hydroxy-6-methoxy-3-methylisochroman-1-one.[21]
Introduction
Chlorinated benzene derivatives represent important core
structures in medicinal chemistry and are present in a vari-
ety of natural products, including dibenzo[b,e][1,4]dioxepin-
11-ones,[1] spirocycles (e.g., the clastogenic, cytotoxic and
antifungal aspirochlorins, grisandions, griseofulvins and
epigriseofulvin),[2] xanthones (austocystin A),[3] tetracy-
clins,[4] isochromanones (ochratoxin A, Scheme 1),[5] ter-
penes (ascofuranol, ascochlorin),[6] macrocycles (radicicol,
bazzanin K),[7]
dibenzo[b,d]pyran-6-one
(graphislac-
tone G),[8] oligosaccharides (flambamycin),[9] benzophen-
ones,[10] polycycles,[11] arenes[12] and biaryls (ambigol A).[13]
They have found many technical and medicinal applications
and represent important synthetic building blocks. 2-Acyl-
4-chlorophenols are found, for example, in the natural
product chloratranorin (Scheme 2);[1] other natural prod-
ucts include dihydronidulin.[14] Geodin[15] and geodinhydr-
ate methyl ester[16] show antibacterial and antifungal ac-
tivity, and 7-chloro-1-O-methylemodin has been reported to
exhibit antiviral activity.[17] 3-Chlorosalicylates and related
Scheme 2. Chloratranorin.
With the development of new and efficient catalysts,
chloroarenes are attracting more and more interest as sub-
strates for transition-metal-catalysed cross-coupling reac-
tions.[22,23] Classic syntheses of functionalized chlorophe-
nols, based on chlorination of phenols, often suffer from
low regioselectivities and yields. An alternative strategy re-
lies on the use of suitable chlorinated substrates in cycliza-
tion reactions, although examples of this building block
strategy have so far been reported only rarely. Syntheses of
4-chlorophenols based on [4+2] cycloadditions of chloro-
substituted buta-1,3-dienes have been reported: Brassard
and co-workers, for example, reported the synthesis of a
chlorinated anthraquinone through a [4+2] cycloaddition
between 2-chloro-1-methoxy-1,3-bis(trimethylsilyloxy)buta-
1,3-diene and a 2-chloronaphthoquinone,[24] and 4-chloro-
phenol was also prepared through a [4+2] cycloaddition be-
tween a chlorinated thiophene and dimethyl acetylenedicar-
boxylate.[25]
Scheme 1. Ochratoxin A.
[a] Institut für Chemie der Universität Rostock,
Albert-Einstein-Straße 3a, 18059 Rostock
Fax: +49-381-498-6411
1,3-Bis(trimethylsilyloxy)buta-1,3-dienes (e.g., Chan’s
diene[26]) represent important synthetic building blocks that
have been used in formal [3+2], [3+3], [4+2] and [4+3] cycli-
zations and various other transformations.[27,28] We have re-
E-mail: peter.langer@uni-rostock.de
[b] Department of Chemistry, Gomal University,
Dera Ismail Khan, N.W.F.P, Pakistan
[c] Leibniz Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Straße 29a, 18059 Rostock
5854
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5854–5867

Diversity-Oriented Synthesis of Chlorinated Arenes
cently reported the synthesis of 4-chlorophenols by cycliza-
tion of 1,3-bis(silyloxy)buta-1,3-dienes with 2-chloro-3-silyl-
oxy-2-en-1-ones[29] and the synthesis of chlorinated hetero-
and carbacycles through cyclization reactions of 2-chloro-
1,3-bis(silyloxy)buta-1,3-dienes.[30] Recently we have re-
ported[31] the synthesis of the first 4-chloro-1,3-bis(silyloxy)-
buta-1,3-dienes and their application to the synthesis of
chlorinated arenes and hetarenes. Here we report full details
and a significant extension of the scope. A variety of 3-
chlorosalicylates were prepared through formal [3+3]
cyclocondensations with various 1,3-dielectrophiles. The
products are not readily available by other methods.
Scheme 4. Synthesis of 5a–g. Conditions: i. TiCl4, CH2Cl2, –78° to
20 °C, 20 h.
Table 1. Synthesis of 3-chlorosalicylates 5a–g.
4,5
R1
R2
R3
5 (%)[a]
a
b
c
d
e
f
Me
Me
Me
Me
Et
Me
Me
Me
H
Me
Me
38
36
Results and Discussion
(CH2)4
42[b]
44
Et
H
Cl
Me
Et
Me
Me
The silylation of commercially available methyl and ethyl
4-chloroacetoacetate (1a and 1b) gave the 4-chloro-3-
(silylox)ycrotonates 2a and 2b (Scheme 3). The 1-alkoxy-4-
chloro-1,3-bis(silyloxy)buta-1,3-dienes 3a and 3b were pre-
pared by deprotonation (LDA) of 2a and 2b at –78 °C and
subsequent addition of chlorotrimethylsilane. Notably, the
chloro group proved to be compatible with the reaction
conditions. Dienes 3a and 3b can be stored at –20 °C under
inert atmosphere for several weeks.
38
36
30
g
CO2Et
[a] Yields of isolated products. [b] 1:1 mixture of regioisomers.
7a–f (Scheme 5, Table 2). During the optimization it again
proved to be important to carry out the reactions in highly
concentrated solutions. As in the case of the syntheses of
5a–g, the use of other Lewis acids was not successful. The
products containing the aryl group located ortho to the es-
ter group were formed with very good regioselectivity. The
formation of the regioisomers with the aryl group para to
the ester group could not be detected by chromatography
or NMR spectroscopy. However, the yields of 7a–f were
only moderate, which can be explained by practical prob-
lems during the chromatographic purification. The regiose-
lectivity can be interpreted in terms of a mechanism first
suggested by Chan et al.,[26] proceeding through TiCl4-me-
diated isomerization of 6a–f, conjugate addition by attack
of carbon atom C-4 of the diene onto 6 and subsequent
cyclization and aromatization. The structures of all prod-
ucts were confirmed spectroscopically. The structure of 7b
was independently confirmed by an X-ray crystal structure
analysis (Figure 1).[32]
Scheme 3. Synthesis of 3a and 3b. Conditions: i. Me3SiCl, NEt3,
C6H6, 20 °C, 72 h; ii. 1) LDA, THF, –78 °C, 1 h, 2) Me3SiCl, –78
Ǟ 20 °C.
TiCl4-mediated [3+3] cyclizations between diene 3a and
the 3-silyloxy-2-en-1-ones 4a–g, prepared by silylation of
the corresponding 1,3-diketones, afforded the 3-chlorosali-
cylates 5a–g (Scheme 4, Table 1). During the optimization,
it proved to be important to carry out the reactions in
highly concentrated solutions. The employment of other
Lewis acids, such as Me3SiOTf, BF3·OEt2, Et2AlCl or
Sc(OTf)3, proved unsuccessful (low levels of conversion or
formation of complex mixtures). It has previously been re-
ported[26] that the cycloaddition between 1-methoxy-1,3-
bis(silyloxy)buta-1,3-diene and enone 4c proceeds with ex-
cellent regioselectivity. In contrast, product 5c, derived from
diene 3a, was isolated as an inseparable mixture of regioiso-
mers. Derivative 5f contains two chlorine atoms (R2 = Cl).
TiCl4-mediated [3+3] cyclizations between the 4-chloro-
Scheme 5. Synthesis of 7a–f. Conditions: i. TiCl4, CH2Cl2, –78°Ǟ
20 °C, 20 h.
TiCl4-mediated reactions between 3a or 3b and the 1-
1,3-bis(silyloxy)-1,3-dienes 3a or 3b and the 3-aryl-3-silyl- methoxy-1-en-3-ones 8a–c resulted in the regioselective for-
oxy-2-en-1-ones 6a–f, prepared by silylation of the corre- mation of the 3-chlorosalicylates 9a–c (Scheme 6, Table 3).
sponding benzoylacetones, afforded the chlorinated biaryls The R3 substituent in each product is located ortho to the
Eur. J. Org. Chem. 2009, 5854–5867
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5855

V. Wolf, M. Adeel, S. Reim, A. Villinger, C. Fischer, P. Langer
FULL PAPER
Table 2. Synthesis of 4-chlorobiphenyls 7a–e.
6,7
R1
R2
R3
7 (%)[a]
a
b
c
d
e
f
H
H
H
Cl
Me
F
H
H
F
H
H
H
Me
Et
Et
Et
Et
Et
42
41
48
50
45
40
[a] Yields of isolated products.
Figure 2. Ortep plot of 9c (50% probability level).
the novel 3-chloro-6-(methylthio)salicylates 11a–i in moder-
ate to excellent yields (Scheme 7, Table 4). In each case the
product containing the methylthio group located ortho to
the ester group was formed with very good regioselectivity.
The formation of other regioisomers, with the methylthio
group located para to the ester group, again could not be
detected by chromatography or NMR spectroscopy. The cy-
clizations proceed by attack of the terminal carbon atom of
the diene on the carbonyl group and subsequent cyclization.
The structure of 11a was independently confirmed by X-
ray crystal structure analysis (Figure 3).[32]
Figure 1. Ortep plot of 7b (50% probability level).
ester group. The formation of the other regioisomer could
not be detected by chromatography or NMR spectroscopy.
The moderate yields can again be explained by practical
problems during chromatography. The employment of Me3-
SiOTf resulted in low levels of conversion and the use of
BF3·OEt2, Et2AlCl or Sc(OTf)3 resulted in the formation of
complex mixtures. The yields could not be improved when
the reactions were carried out in more dilute solutions. The
regioselectivity can be explained in terms of a mechanism
related to that discussed for the formation of salicylates 7a–
f. The structure of 9c was independently confirmed by X-
ray crystal structure analysis (Figure 2).[32]
Scheme 7. Synthesis of 3-chloro-6-(methylthio)salicylates 11a–i.
Conditions: i. 1) TiCl4, –78 Ǟ 20 °C, 14 h; 2) HCl (10%).
Table 4. Synthesis of 3-chloro-6-(methylthio)salicylates 11a–i.
10,11
R
11 (%)[a]
a
b
c
d
e
f
g
h
i
Ph
96
89
83
44
51
59
54
67
91
4-MeC6H4
4-FC6H4
4-MeOC6H4
4-PhC6H4
4-EtC6H4
4-ClC6H4
4-BrC6H4
Me
Scheme 6. Synthesis of 9a–c. Conditions: i. TiCl4, CH2Cl2, –78 Ǟ
20 °C, 20 h, 25%.
[a] Yields of isolated products.
Table 3. Synthesis of 3-chlorosalicylates 9a–c.
Cyclizations between the 4-chloro-1,3-bis(trimethylsil-
yloxy)buta-1,3-diene 3b and the 3-oxo orthoesters 12a–j,
by our recently reported procedure,[34] afforded the novel 3-
chloro-4-methoxysalicylates 13a–j in moderate to good
yields (Scheme 8, Table 5). In each case the product con-
taining the methoxy group located para to the ester group
8,9
R1
R2
R3
9 (%)[a]
a
b
c
Me
Et
Et
H
CN
CN
Me
4-ClC6H4
Me
25
40
38
[a] Yields of isolated products.
Cyclizations between the 4-chloro-1,3-bis(trimethylsilyl- was regioselectively formed. The formation of the regioiso-
oxy)buta-1,3-diene 3b and the 1,1-bis(methylthio)-1-en-3- mers, with the methoxy group located ortho to the ester
ones 10a–i, by our recently reported procedure,[33] afforded group, could not be detected by chromatography or NMR
5856
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5854–5867

Diversity-Oriented Synthesis of Chlorinated Arenes
Scheme 9. Diagnostic NOESY interactions in products 13a, 13f
and 13h.
Figure 3. ORTEP plot of 11a (50% probability level).
spectroscopy. The cyclizations proceed by attack of the ter-
minal carbon atom of the diene onto the orthoester group
and subsequent cyclization.
Figure 4. Ortep plot of 13a (50% probability level).
Scheme 8. Synthesis of 3-chloro-4-methoxysalicylates 13a–j. Condi-
tions: i. 1) TiCl4, –78 Ǟ 20 °C, 14 h; 2) HCl (10%).
The cyclization between 3a and 14a in the presence of cata-
lytic amounts of Me3SiOTf (0.1 equiv.), by a protocol re-
cently developed by us,[37] gave 15a, but in very low yield.
Table 5. Synthesis of 3-chloro-4-methoxysalicylates 13a–j.
12,13
R
13 (%)[a]
a
b
c
d
e
f
iPr
nPr
Ph
60
65
65
52
56
61
59
63
36
47
4-ClC6H4
cPr
cBu
g
h
i
cPent
nPent
cPent(CH2)2
cHex
Scheme 10. Synthesis of 3-chlorosalicylates 15a–e. Conditions:
i. TiCl4, CH2Cl2, –78 Ǟ 20 °C.
j
[a] Yields of isolated products.
Table 6. Synthesis of 3-chlorosalicylates 15a–e.
14,15
R
R1
15 (%)[a]
The structures were established by NOESY experiments
(Scheme 9). The structure of 13a was independently con-
firmed by X-ray crystal structure analysis (Figure 4).[32]
Chan et al. were the first to report TiCl4-mediated cycli-
zations between 1,3-bis(silyloxy)buta-1,3-dienes and
1,1,3,3-tetramethoxypropane (14a),[26] whereas we have re-
ported[35] TiCl4-mediated cyclizations between 1,3-bis(sil-
yloxy)buta-1,3-dienes and the 1,1,3,3-tetraethoxypropanes
a
b
c
d
e
Me
Et
Et
Et
Et
H
Me
iPr
nPent
nHept
26
35
36
52
30
[a] Yields of isolated products.
The TiCl4-mediated reaction between the 4-chloro-1,3-
14b–e, which are available in three steps by a known proto- bis(silyloxy)-1,3-diene 3a and 1,1-diacetylcyclopropane
col.[36] TiCl4-mediated cyclizations between the chlorinated (16), by our recently reported protocol,[38] afforded the 3-
diene 3a and 14a–e afforded the 3-chlorosalicylates 15a–e chlorosalicylate 17 in 30% yield (Scheme 11). The forma-
(Scheme 10, Table 6). During the optimization of the reac- tion of the product can be explained in terms of a domino
tions, the stoichiometry proved to be important (Table 7). “[3+3] cyclization/homo-Michael” reaction.
Eur. J. Org. Chem. 2009, 5854–5867
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5857

V. Wolf, M. Adeel, S. Reim, A. Villinger, C. Fischer, P. Langer
FULL PAPER
Table 7. Optimization of the yield of 15a.
Conclusions
Entry
Stoichiometry
3a/14a/Me3SiOTf/TiCl4
CH2Cl2
15a (% )[a]
A variety of highly substituted 3-chlorosalicylates were
regioselectively prepared through one-pot cyclizations be-
[mLmmol–1]
1
2
3
1.0:1.1:0.1:0
1.0:1.1:0:1.0
2.0:1.0:0:2.0
10
10
2
19
25
26
tween
4-chloro-1,3-bis(trimethylsilyloxy)buta-1,3-dienes
and various 1,3-dielectrophiles. The products are not read-
ily available by other methods.
[a] Yields of isolated product.
Experimental Section
General Comments: All solvents were dried by standard methods
and all reactions were carried out under argon. For 1H and 13C
NMR spectra the deuterated solvents indicated were used. Mass
spectrometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, isobutane) or electrospray ioniza-
tion (ESI). For preparative scale chromatography silica gel 60
(0.063–0.200 mm, 70–230 mesh) was used.
Scheme 11. Synthesis of 17; i. TiCl4, CH2Cl2, –78 Ǟ 20 °C, 20 h;
30%.
General Procedure for the Synthesis of 2a and 2b: A solution of
methyl or ethyl 4-chloroacetoacetate (1a or 1b, 1.0 equiv.) and tri-
ethylamine (1.3 equiv.) in benzene (2 mL per 1 mmol of 1) was
stirred at 20 °C for 30 min. Chlorotrimethylsilane (1.5 equiv.) was
added and the solution was stirred at 20 °C for 3 d. The solvent
was removed in vacuo, and n-hexane (50 mL) was added to the
residue. The mixture was filtered under argon and the filtrate was
concentrated in vacuo. n-Hexane (50 mL) was again added to the
residue, the mixture was filtered, and the filtrate was concentrated
in vacuo. Because of the unstable natures of 2a and 2b, only NMR
spectra could be obtained.
The Me3SiOTf-catalysed reactions between the 1,3-bis-
(silyloxy)-1,3-dienes 3a or 3b and the 3-formylchromones
18a–i afforded the chlorinated 2,4Ј-dihydroxybenzophen-
ones 19a–i (Scheme 12, Table 8). The products are formed
by domino “Michael/retro-Michael/Mukaiyama/aldol” re-
actions.[39] The employment of the Lewis acid TiCl4, as un-
der the conditions reported for the synthesis of 5a–g, re-
sulted in the formation of complex mixtures. The structures
of all products were confirmed spectroscopically.
Methyl 4-Chloro-3-(trimethylsilyloxy)but-2-enoate (2a): Compound
2a was isolated as a light brown oil (8.925 g, 93%) from methyl 4-
chloroacetoacetate (1a, 5.1 mL, 43.0 mmol), triethylamine (7.7 mL,
55.9 mmol) and chlorotrimethylsilane (8.1 mL, 64.5 mmol) in ben-
zene (86 mL). 1H NMR (250 MHz, CDCl3): δ = 0.20 (s, 9 H, CH3),
3.59 (s, 3 H, OCH3), 4.48 (s, 2 H, CH2), 5.09 (s, 1 H, CH) ppm.
13C NMR (63 MHz, CDCl3): δ = 0.002 (CH3), 41.1 (CH2), 51.2
(OCH3), 101.2 (CH), 147.5 (COOCH3), 166.9 [COSi(CH3)3] ppm.
Methyl 4-Chloro-3-(trimethylsilyloxy)but-2-enoate (2b): Compound
2b was isolated as a light brown oil (9.711 g, 95%) from ethyl 4-
chloroacetoacetate (1b, 5.6 mL, 43.0 mmol), triethylamine (7.7 mL,
55.9 mmol) and chlorotrimethylsilane (8.1 mL, 64.5 mmol) in ben-
zene (86 mL). 1H NMR (250 MHz, CDCl3): δ = 0.30 (s, 9 H, CH3),
1.27 (t, 3J = 7.1 Hz 3 H, OCH2CH3), 4.15 (q, 3J = 7.1 Hz, 2 H,
OCH2CH3), 4.58 (s, 2 H, CH2), 5.18 (s, 1 H, CH) ppm.
General Procedure for the Synthesis of 3a and 3b: A THF solution
of LDA was prepared from diisopropylamine (1.3 equiv.), nBuLi
(1.3 equiv.) and THF (1.5 mL per 1 mmol of nBuLi), and 2a or 2b
(1.0 equiv.) was added at –78 °C. After the system had been stirred
for 1 h at –78 °C chlorotrimethylsilane (1.5 equiv.) was added at
–78 °C. The solution was allowed to warm to ambient temperature
over 20 h with stirring. The solvent was removed in vacuo and n-
hexane (50 mL) was added to the residue. The mixture was filtered
under argon and the filtrate was concentrated in vacuo. n-Hexane
(50 mL) was again added to the residue, the mixture was filtered,
and the filtrate was concentrated in vacuo. Because of the unstable
natures of 3a and 3b, only NMR spectra could be obtained.
Scheme 12. Synthesis of 19a–i. Reagents and conditions: i) 18a–i,
Me3SiOTf (0.3 equiv.), 20 °C, 10 min; ii) 1) 3a or 3b (1.3 equiv.),
CH2Cl2, 0Ǟ20 °C, 12 h; 2) HCl (10%).
Table 8. Synthesis of chlorinated benzophenones 19a–i.
18,19
R1
R2
R3
19 (%)[a]
a
b
c
d
e
f
g
h
i
H
Me
Et
iPr
NO2
F
Cl
Br
Br
H
H
H
H
H
H
H
H
Br
Et
Et
Et
Et
Et
Et
Me
Et
Et
42
40
40
44
40
34
33
42
75
4-Chloro-1-methoxy-1,3-bis-(trimethylsilyloxy)buta-1,3-diene (3a):
Compound 3a was isolated as a light brown oil (1.910 g, 65%) from
diisopropylamine
(1.8 mL,
13.0 mmol),
nBuLi
(5.1 mL,
13.0 mmol), THF (15 mL), 2a (2.227 g, 10.0 mmol) and chlorotri-
1
[a] Yields of isolated products.
methylsilane (1.9 mL, 15.0 mmol). H NMR (250 MHz, CDCl3): δ
5858
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5854–5867

Diversity-Oriented Synthesis of Chlorinated Arenes
= 0.23 (s, 9 H, CH3), 0.24 (s, 9 H, CH3), 3.55 (s, 3 H, OCH3), 5.40 128.3, 129.1, 136.5, 137.3, 141.4, 141.7 (C), 153.4, 155.0 (COH),
(s, 1 H, CH), 5.61 (s, 1 H, CH) ppm. 13C NMR (63 MHz, CDCl3): 171.6, 171.9 (COOCH ) ppm. IR (ATR): ν = 3014 (w), 2928 (w),
˜
3
δ = 1.9 (CH3), 55.1 (OCH3), 75.8, 97.2 (CH), 147.4, 158.4 [CO- 2861 (w), 1652 (m), 1590 (w), 1558 (w), 1427 (m), 1406 (m), 1356
Si(CH3)3] ppm.
(m), 1315 (m) 1279 (m), 1223 (s), 1195 (m), 1165 (m), 1091 (m),
1079 (m), 1029 (m) cm–1. MS (GC-MS, 70 eV): m/z (%) = 256
[M]+ ([37Cl], 7), 254 [M]+ ([35Cl], 20), 224 (35), 223 (23), 222 (100).
HRMS (EI): calcd. for C13H15ClO3 [M]+ ([35Cl]): 254.07042; found
254.070276.
4-Chloro-1-ethoxy-1,3-bis-(trimethylsilyloxy)buta-1,3-diene
(3b):
Compound 3b was isolated as a brown oil (10.309 g, 97%) from
diisopropylamine (6.3 mL, 45.0 mmol), nBuLi (17.6 mL,
45.0 mmol), THF (53 mL), 2b (8.150 g, 34.4 mmol) and chlorotri-
methylsilane (6.5 mL, 51.0 mmol). H NMR (250 MHz, CDCl3): δ
= 0.14 (s, 9 H, CH3), 0.17 (s, 9 H, CH3), 1.22 (t, J = 7.1 Hz, 3 H,
1
Methyl 3-Chloro-5-ethyl-2-hydroxy-4,6-dimethylbenzoate (5d):
Compound 5d was isolated as a yellow solid (0.161 g, 44%) from
3a (0.442 g, 1.5 mmol), 4d (0.301 g, 1.5 mmol) and TiCl4 (0.16 mL,
3
OCH2CH3), 3.61–3.78 (m, 2 H, OCH2CH3), 4.50 (s, 1 H, CH), 5.52
(s, 1 H, CH) ppm.
1
1.5 mmol) in CH2Cl2 (3 mL); m.p. 49–51 °C. H NMR (300 MHz,
3
CDCl3): δ = 1.06 (t, J = 7.5 Hz, 3 H, CH3), 2.41 (s, 6 H, CH3),
General Procedure for the Synthesis of 3-Chlorosalicylates 5a–g:
TiCl4 (1.0 equiv.) was added at –78 °C to an enone (4a–g,
1.0 equiv.) and diene 3a (1.0 equiv.) in dichloromethane (2.5 mL
per 1 mmol of 4). The solution was allowed to warm slowly to
20 °C with stirring. Hydrochloric acid (10%) was added to the solu-
tion and the organic and the aqueous layers were separated. The
latter was extracted with dichloromethane. The combined organic
layers were dried (sodium sulfate) and filtered and the filtrate was
concentrated in vacuo. The residue was purified by chromatog-
raphy (silica gel, heptanes/EtOAc 20:1).
3
2.65 (q, J = 7.5 Hz, 2 H, CH2), 3.95 (s, 3 H, OCH3), 10.58 (s, 1
H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.6, 17.3, 18.0
(CH3), 23.2 (CH2), 52.4 (OCH3), 113.4, 120.3, 133.9, 135.4, 140.4
(C), 153.9 (COH), 171.6 (COOCH ) ppm. IR (KBr): ν = 3422 (br.,
˜
3
w), 3016 (w), 2972 (m), 2956 (w), 2937 (w), 2875 (w), 1656 (s), 1592
(w), 1552 (w), 1496 (w), 1442 (s), 1406 (w), 1377 (w), 1352 (s), 1321
(m), 1310 (m), 1255 (s), 1226 (s), 1195 (m), 1165 (w), 1081 (m),
1049 (w) cm–1. MS (GC-MS, 70 eV): m/z (%) = 244 [M]+ ([37Cl],
9), 242 [M]+ ([35Cl], 26), 212 (35), 210 (100), 197 (29), 195 (88).
C12H15ClO3 (242.70): calcd. C 59.39, H 6.23; found C 59.09, H
6.40.
Methyl 3-Chloro-2-hydroxy-4,5,6-trimethylbenzoate (5a): Com-
pound 5a was isolated as a yellow oil (0.129 g, 38%) from 3a
(0.442 g, 1.5 mmol), 4a (0.279 g, 1.5 mmol) and TiCl4 (0.16 mL,
1.5 mmol) in CH2Cl2 (3 mL). 1H NMR (300 MHz, CDCl3): δ =
2.17 (s, 3 H, CH3), 2.38 (s, 6 H, CH3), 3.95 (s, 3 H, OCH3), 10.58
(s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.4, 18.0,
18.9 (CH3), 52.3 (OCH3), 113.0, 119.9, 128.0, 135.8, 140.7 (C),
Methyl 3-Chloro-4,6-diethyl-2-hydroxybenzoate (5e): Compound 5e
was isolated as a yellow oil (0.139 g, 38%) from 3a (0.442 g,
1.5 mmol), 4e (0.301 g, 1.5 mmol) and TiCl4 (0.16 mL, 1.5 mmol)
1
3
in CH2Cl2 (3 mL). H NMR (300 MHz, CDCl3): δ = 1.17 (t, J =
3
3
7.4 Hz, 3 H, CH3), 1.22 (t, J = 7.4 Hz, 3 H, CH3), 2.74 (q, J =
3
7.4 Hz, 2 H, CH2), 2.88 (q, J = 7.4 Hz, 2 H, CH2), 3.97 (s, 3 H,
153.9 (COH), 171.5 (COOCH ) ppm. IR (ATR): ν = 2957 (w),
˜
3
OCH3), 6.65 (s, 1 H, CH), 11.81 (s, 1 H, OH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.5, 16.0 (CH3), 27.3, 29.4 (CH2), 52.4
(OCH3), 110.5, 119.5 (C), 121.9 (CH), 145.2, 148.4 (C), 158.1
2922 (w), 2851 (w), 1732 (m), 1660 (m), 1593 (w), 1496 (w), 1439
(m), 1333 (m), 1314 (m), 1257 (s), 1232 (s), 1198 (s), 1160 (s), 1077
(s), 1010 (s) cm–1. MS (GC-MS, 70 eV): m/z (%) = 230 [M]+ ([37Cl],
8), 228 [M]+ ([35Cl], 24), 198 (35), 197 (28), 196 (100). HRMS (EI):
calcd. for C11H13ClO3 [M]+ ([35Cl]): 228.05477; found 228.054628.
(COH), 171.8 (COOCH ) ppm. IR (ATR): ν = 2968 (w), 2935 (w),
˜
3
2874 (w), 1734 (w), 1658 (s), 1606 (w), 1547 (w), 1435 (m), 1398
(m), 1359 (m), 1310 (m), 1291 (m), 1254 (s), 1202 (s), 1116 (w),
1094 (w), 1068 (m), 1032 (w), 1017 (w) cm–1. MS (GC/MS, 70 eV):
m/z (%) = 244 [M]+ ([37Cl], 6), 242 [M]+ ([35Cl], 17), 212 (33), 210
(100). HRMS (EI): calcd. for C12H15ClO3 [M]+ ([35Cl]): 242.07042;
found 242.070864.
Methyl 3-Chloro-2-hydroxy-4,6-dimethylbenzoate (5b): Compound
5b was isolated as a yellow solid (0.077 g, 36%) from 3a (0.295 g,
1.0 mmol), 4b (0.172 g, 1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol)
1
in CH2Cl2 (2 mL); m.p. 89–91 °C. H NMR (300 MHz, CDCl3): δ
= 2.35 (s, 3 H, CH3), 2.47 (s, 3 H, CH3), 3.96 (s, 3 H, OCH3), 6.62
(s, 1 H, CH), 11.99 (s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 20.5, 23.6 (CH3), 52.3 (OCH3), 110.8 (C), 119.9 (CH), 124.6,
138.7, 142.9 (C), 158.3 (COH), 172.0 (COOCH3) ppm. IR (KBr):
Methyl 3,5-Dichloro-2-hydroxy-4,6-dimethylbenzoate (5f): Com-
pound 5f was isolated as a colourless solid (0.133 g, 36%) from
3a (0.442 g, 1.5 mmol), 4f (0.310 g, 1.5 mmol) and TiCl4 (0.16 mL,
1
1.5 mmol) in CH2Cl2 (3 mL); m.p. 67–69 °C. H NMR (300 MHz,
ν = 2976 (w), 2955 (m), 2937 (w), 2854 (w), 1662 (s), 1608 (m),
˜
CDCl3): δ = 2.54 (s, 3 H, CH3), 2.57 (s, 3 H, CH3), 3.98 (s, 3 H,
OCH3), 11.16 (s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ =
19.4, 19.9 (CH3), 52.8 (OCH3), 112.9, 121.0, 127.1, 136.0, 141.0
1556 (w), 1452 (s), 1430 (s), 1394 (s), 1366 (s), 1294 (s), 1266 (s),
1219 (s), 1117 (w), 1075 (w), 1008 (s) cm–1. MS (GC-MS, 70 eV):
m/z (%) = 216 [M]+ ([37Cl], 9), 214 [M]+ ([35Cl], 25), 184 (34), 183
(21), 182 (100). HRMS (EI): calcd. for C10H11ClO3 [M]+ ([35Cl]):
214.03912; found 214.039137. Elemental analysis calcd. (%) for
C10H11ClO3 (214.65): C 55.96, H 5.17; found C 55.81, H 5.27.
(C), 155.4 (COH), 171.1 (COOCH ) ppm. IR (KBr): ν = 2957 (w),
˜
3
2930 (w), 1704 (s), 1665 (s), 1591 (w), 1439 (s), 1379 (s), 1358 (m),
1283 (s), 1228 (s), 1130 (w), 1070 (w), 1010 (m) cm–1. MS (EI,
70 eV): m/z (%) = 250 [M]+ ([37Cl], 15), 248 [M]+ ([35Cl], 23), 218
(66), 216 (100). HRMS (EI): calcd. for C10H10Cl2O3 [M]+ ([35Cl]):
248.00015; found 247.999925.
Methyl 4-Chloro-3-hydroxy-1-methyl-4a,5,6,7,8,8a-hexahydronaph-
thalene-2-carboxylate (5c, Together with Methyl 3-Chloro-2-hy-
droxy-4-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxylate): Com-
pound 5c was isolated as a yellow solid (0.160 g, 42%) from 3a
(0.442 g, 1.5 mmol) in CH2Cl2 (3 mL), 4c (0.319 g, 1.5 mmol) and
TiCl4 (0.16 mL, 1.5 mmol); m.p. 50–52 °C. 1H NMR (300 MHz,
1-Ethyl 3-Methyl 5-Chloro-4-hydroxy-2,6-dimethylisophthalate (5g):
Compound 5g was isolated as a light red, viscous oil (0.180 g, 30%)
from 4g (0.150 g, 2.0 mmol), 3a (0.600 g, 2.26 mmol) and TiCl4
CDCl3): δ = 1.64–1.80 (m, 8 H, CH2), 2.33 (s, 3 H, CH3), 2.34 (s, (0.240 mL, 2.2 mmol). 1H NMR (250 MHz, CDCl3): δ = 1.31 (t,
3 H, CH3), 2.54–2.62 (m, 4 H, CH2), 2.78–2.82 (m, 2 H, CH2),
3J = 7.4 Hz, 3 H, OCH2CH3), 1.36 (t, 3J = 7.6 Hz, 3 H,
3
2.91–2.95 (m, 2 H, CH2), 3.95 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3), OCH2CH3), 2.29 (s, 3 H, CH3), 2.39 (s, 3 H, CH3), 4.31 (q, J =
10.52 (s, 1 H, OH), 11.19 (s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 16.9, 17.7 (CH3), 22.1, 22.5, 22.8, 22.9, 27.5, 28.2,
28.8, 29.9 (CH2), 52.3, 52.4 (OCH3), 111.8, 113.1, 119.6, 120.4,
7.6 Hz, 2 H, OCH2CH3), 4.38 (q, 3J = 7.6 Hz, 2 H, OCH2CH3),
11.84 (s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0,
14.1 (OCH2CH3), 18.1, 20.8 (CH3), 61.5, 62.3 (OCH2CH3), 111.7,
Eur. J. Org. Chem. 2009, 5854–5867
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5859

V. Wolf, M. Adeel, S. Reim, A. Villinger, C. Fischer, P. Langer
FULL PAPER
116.9, 129.1, 135.1, 139.0 (C), 158.2 (COH), 169.1, 171.0
49%) from 6d (140 mg, 0.53 mmol), 1,3-bis(silyl enol ether) 3b
(CO) ppm. GC-MS (EI, 70 eV): m/z (%) = 300 [M]+ (23), 254 (100), (179 mg, 0.58 mmol) and TiCl4 (0.06 mL, 0.58 mmol); m.p. 85–
1
226 (7), 208 (34), 197 (4), 182 (4), 153 (4), 125 (4), 89 (7). HRMS 88 °C. H NMR (250 MHz, CDCl3): δ = 0.69 (t, J = 7.4 Hz, 3 H,
(EI): calcd. for C14H17ClO5: 300.07590; found 300.07615.
CH3), 2.35 (s, 3 H, CH3), 3.92 (q, J = 7.4 Hz, 2 H, OCH2), 6.54 (s,
1 H, ArH), 7.07–7.11 (m, 1 H, ArH), 7.18–7.20 (m, 2 H, ArH),
7.21–7.32 (m, 1 H, ArH), 11.90 (s, 1 H, OH) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 12.8 (CH3), 20.7 (CH3), 61.5 (OCH2),
110.8, 112.2 (C), 123.8, 126.2,128.3, 128.6, 129.6 (CH), 132.3,
General Procedure for the Synthesis of Chlorinated Biaryls 7a–f:
TiCl4 (1.0 equiv.) was added dropwise at –78 °C under argon to a
CH2Cl2 solution of a 3-silyloxy-2-en-1-one (6a–f, 1.0 equiv.) and a
4-chloro-1,3-bis(silyl enol ether) (3a or 3b, 1.0 equiv.). The solution
was stirred for 30 min at –78 °C and was then allowed to warm to
20 °C over 18 h. An aqueous solution of HCl (10%) was added to
the reaction mixture. The organic layer was separated and the aque-
ous layer was repeatedly extracted with CH2Cl2. The combined or-
ganic extracts were dried (Na2SO4) and filtered. The filtrate was
concentrated in vacuo and the residue was purified by chromatog-
raphy (silica gel, n-heptane/EtOAc) to gave a biaryl (7a–f).
139.1, 141.3, 142.9, 157.7 (C), 170.3 (C=O) ppm. IR (neat): ν =
˜
3305 (br), 2986 (m), 2855 (w), 1731 (w), 1651 (s), 1435 (w), 1374
(s), 1214 (s), 1011 (m), 753 (s) cm–1. MS (GC = 70 eV): m/z (%) =
326 [M]+ ([37Cl], 2), 324 [M]+ (4), 289 (98), 280 (65), 278 (100), 261
(67). HRMS (EI): calcd. for C16H14Cl2O3 [M]+ ([35Cl]): 324.03145;
found 324.030996.
Ethyl 4-Chloro-3-hydroxy-2Ј,5-dimethyl[1,1Ј-biphenyl]-2-carboxyl-
ate (7e): Compound 7e was isolated as a crystalline solid (120 mg,
40%) from 6e (248 mg, 1 mmol), 1,3-bis(silyl enol ether) 3b
(339 mg, 1.1 mmol) and TiCl4 (0.12 mL, 1.1 mmol); m.p. 77–79 °C.
1H NMR (250 MHz, CDCl3): δ = 0.69 (t, J = 7.4 Hz, 3 H, CH3),
1.95 (s, 3 H, CH3), 2.34 (s, 3 H, CH3), 3.87 (q, J = 7.4 Hz, 2 H,
OCH2), 6.53 (s, 1 H, ArH), 6.90–6.94 (m, 1 H, ArH), 7.07–7.10
(m, 2 H, ArH), 7.15–7.21 (m, 1 H, ArH), 11.85 (s, 1 H, OH) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 12.8 (CH3), 19.9 (CH3), 20.7
(CH3), 61.3 (OCH2), 110.7, 121.3 (C), 123.7, 125.0, 127.0, 128.4,
129.1 (CH), 134.9, 141.9, 142.2, 142.8, 157.7 (C), 170.7
Methyl 4-Chloro-3-hydroxy-5-methylbiphenyl-2-carboxylate (7a):
Compound 7a was isolated as a white solid (119 mg, 42%) from 6a
(234 mg, 1 mmol), 1,3-bis(silyl enol ether) 3a (324 mg, 1.1 mmol)
and TiCl4 (208 mg, 0.12 mL, 0.58 mmol); m.p. 94–96 °C. 1H NMR
(250 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3), 3.49 (s, 3 H, OCH3),
6.75 (s, 1 H, ArH), 7.18–7.21 (m, 2 H, ArH), 7.31–7.37 (m, 3 H,
ArH), 11.32 (s, 1 H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
20.7 (CH3), 51.9 (OCH3), 110.8, 121.4 (C), 124.2, 127.0 (CH),
127.4, 128.0 (2 C, CH), 142.0, 142.38, 142.47, 157.0 (C), 171.1
(C=O) ppm. IR (neat): ν = 3369 (w), 2951 (w), 2918 (w), 1664 (s),
˜
1596 (w), 1435 (s), 1347 (m), 1050 (m), 771 (s) cm–1. MS (GC =
70 eV): m/z (%) = 278 [M]+ ([37Cl], 7), 276 [M]+ (20), 244 (100),
216 (9), 181 (9), 152 (24). HRMS (EI): calcd. for C15H13ClO3
[M]+ ([35Cl]): 276.05477; found 276.054965.
(C=O) ppm. IR (neat): ν = 2985 (w), 2922 (m), 2853 (w), 1650 (s),
˜
1600 (m), 1373 (s), 1294 (s), 1213 (m), 727 (s) cm–1. MS (GC =
70 eV): m/z (%) = 306 [M]+ ([37Cl], 4), 304 [M]+ (13), 260 (35), 258
(100), 195 (21), 165 (24). HRMS (EI): calcd. for C17H17ClO3 [M]+
([35Cl]): 304.08607; found 304.0086736.
Ethyl 4-Chloro-3-hydroxy-5-methylbiphenyl-2-carboxylate (7b):
Compound 7b was isolated as a crystalline solid (112 mg, 41%)
from 6b (234 mg, 1 mmol), 1,3-bis(silyl enol ether) 3b (330 mg,
1.1 mmol) and TiCl4 (208 mg, 0.12 mL, 0.58 mmol); m.p. 94–96 °C.
1H NMR (300 MHz, CDCl3): δ = 0.74 (t, J = 7.4 Hz, 3 H, CH3),
2.42 (s, 3 H, CH3), 3.95 (q, J = 7.4 Hz, 2 H, OCH2), 6.71 (s, 1 H,
ArH), 7.17–7.20 (m, 2 H, ArH), 7.31–7.36 (m, 3 H, ArH), 11.53 (s,
1 H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 12.9 (CH3),
20.7 (CH3), 61.3 (OCH2), 110.8, 121.4 (C), 124.1, 126.8 (CH),
127.6, 128.0 (2 C, CH), 142.32, 142.36, 142.5, 157.2 (C), 170.7
Ethyl 4-Chloro-2Ј-fluoro-3-hydroxy-5-methyl[1,1Ј-biphenyl]-2-carb-
oxylate (7f): Compound 7f was isolated as a crystalline solid
(390 mg, 45%) from 6f (720 mg, 2.85 mmol), 1,3-bis(silyl enol
ether) 3b (970 mg, 3.14 mmol) and TiCl4 (0.34 mL, 3.14 mmol);
m.p. 76–79 °C. 1H NMR (250 MHz, CDCl3): δ = 0.75 (t, J =
6.5 Hz, 3 H, CH3), 2.34 (s, 3 H, CH3), 3.96 (q, J = 7.0 Hz, 2 H,
OCH2), 6.60 (s, 1 H, ArH), 6.91–6.98 (m, 1 H, ArH), 7.06–7.11
(m, 2 H, ArH), 7.22 (m, 1 H, ArH), 11.53 (s, 1 H, OH) ppm. 13C
NMR (62.9 MHz, CDCl3): δ = 13.0 (CH3), 20.7 (CH3), 61.5
(OCH2), 111.0 (C), 114.4, 114.8 (CH), 122.3 (C), 123.7, 124.4, 129.0
(CH), 135.4, 142.9, 142.4, 157.7, 161.0 (C), 170.5 (C=O) ppm. IR
(C=O) ppm. IR (neat): ν = 3063 (s), 2988 (m), 2921 (m), 2881 (w),
˜
1651 (m), 1599 (m), 1440 (m), 1375 (s), 1266 (s), 1216 (s) cm–1. MS
(GC = 70 eV): m/z (%) = 292 [M]+ ([37Cl], 7), 290 [M]+ ([37Cl],
18), 244 (100), 216 (7), 181 (9), 152 (21). HRMS (EI): calcd. for
C16H15ClO3 [M]+ ([35Cl]): 290.07042; found 290.070573.
(neat): ν = 3040 (w), 2979 (m), 1657 (m), 1604 (m), 1495 (m), 1440
˜
(m), 1374 (s), 1260 (s), 1215 (s), 759 (s) cm–1. MS (GC = 70 eV):
m/z (%) = 310 [M]+ ([37Cl], 8), 308 [M]+ (24), 262 (100), 234 (12),
199 (11), 170 (24). HRMS (EI): calcd. for C16H14ClFO3 [M]+
([35Cl]): 308.06100; found 308.060555.
Ethyl 4-Chloro-4Ј-fluoro-3-hydroxy-5-methyl[1,1Ј-biphenyl]-2-carb-
oxylate (7c): Compound 7c was isolated as a crystalline solid
(59 mg, 48%) from 6c (101 mg, 0.4 mmol), 1,3-bis(silyl enol ether)
3b (135 mg, 0.44 mmol) and TiCl4 (0.05 mL, 0.44 mmol); m.p. 140–
142 °C. 1H NMR (250 MHz, CDCl3): δ = 0.75 (t, J = 7.1 Hz, 3 H,
CH3), 2.35 (s, 3 H, CH3), 3.94 (q, J = 7.0 Hz, 2 H, OCH2), 6.60 (s,
1 H, ArH), 6.94–7.01 (m, 2 H, ArH), 7.06–7.12 (m, 2 H, ArH),
11.53 (s, 1 H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 13.06
(CH3), 20.6 (CH3), 61.4 (OCH2), 110.7 (C), 114.2, 114.6 (CH),
121.7 (C), 124.2, 129.6, 129.7 (CH), 138.3, 141.3, 142.4, 157.4,
General Procedure for the Synthesis of 3-Chlorosalicylates 9a–c:
TiCl4 (1.0 equiv.) was added at –78 °C to a 1-methoxy-1-en-3-one
(8a–c, 1.0 equiv.) and a diene (3a or 3b, 1.0 equiv.) in dichlorometh-
ane (2.5 mL per 1 mmol of 8). The solution was allowed to warm
slowly to 20 °C with stirring. Hydrochloric acid (10%) was added
to the solution and the organic and the aqueous layers were sepa-
rated. The latter was extracted with dichloromethane. The com-
bined organic layers were dried (sodium sulfate) and filtered, and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes/EtOAc 20:1).
160.1 (C), 170.5 (C=O) ppm. IR (neat): ν = 3076 (w), 2917 (s), 2837
˜
(m), 1656 (m), 1602 (s), 1504 (m), 1453 (m), 1375 (s), 1221 (m),
1155 (s), 777 (m) cm–1. MS (GC = 70 eV): m/z (%) = 310 [M]+
([37Cl], 6), 308 [M]+ (19), 262 (100), 234 (9), 199 (9), 170 (22).
HRMS (EI): calcd. for C16H14ClFO3 [M]+ ([35Cl]): 308.06100;
found 308.060716.
Methyl 3-Chloro-2-hydroxy-6-methylbenzoate (9a): Compound 9a
was isolated as an orange oil (0.050 g, 25%) from 3a (0.295 g,
1.0 mmol) in CH2Cl2 (2 mL), 8a (0.100 g, 1.0 mmol) and TiCl4
1
(0.11 mL, 1.0 mmol). H NMR (300 MHz, CDCl3): δ = 2.50 (s, 3
2
3
Ethyl 2Ј,4-Dichloro-3-hydroxy-5-methyl[1,1Ј-biphenyl]-2-carboxyl-
ate (7d): Compound 7d was isolated as a crystalline solid (85 mg,
H, CH3), 3.98 (s, 3 H, OCH3), 6.66 (dd, J = 0.8, J = 8.2 Hz, 1
4
H, CH), 7.36 (d, J = 8.2 Hz, 1 H, CH), 11.83 (d, J = 0.5 Hz, 1 H,
5860
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5854–5867

Diversity-Oriented Synthesis of Chlorinated Arenes
OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.7 (CH3), 52.5 (SCH3), 62.7 (CH2CH3), 110.1 (C), 116.9 (CH), 117.1 (C), 128.2,
(OCH3), 113.5, 120.0 (C), 122.8, 134.2 (CH), 140.0 (C), 158.1 128.3, 129.0 (CH), 138.7, 142.1, 145.8 (C), 159.3 (COH), 170.4
(COH), 171.9 (COOCH ) ppm. IR (KBr): ν = 3018 (w), 2957 (m), (C=O) ppm. IR (ATR): ν = 3057 (w), 2980 (w), 2918 (w), 1653 (s),
˜
˜
3
2928 (m), 2852 (w), 1665 (s), 1601 (m), 1567 (w), 1453 (s), 1417 (s),
1587 (m), 1529 (m), 1495 (m), 1473 (w), 1443 (m), 1373 (s), 1342
1350 (s), 1299 (s), 1256 (s), 1205 (s), 1156 (m), 1122 (w) cm–1. MS (m), 1309 (m), 1278 (s), 1242 (s), 1187 (s), 1145 (s), 1111 (w), 1055
(GC/MS, 70 eV): m/z (%) = 202 [M]+ ([37Cl], 9), 200 [M]+ ([35Cl],
28), 170 (34), 169 (23), 168 (100). HRMS (EI): calcd. for C9H9ClO3
[M]+ ([35Cl]): 200.02347; found 200.023426.
(m), 1011 (s) cm–1. MS (EI, 70 eV): m/z (%) = 324 [M]+ ([37Cl], 13),
322 [M]+ ([35Cl], 32), 278 (39), 277 (23), 276 (100), 233 (15). HRMS
(EI): calcd. for C16H15O3ClS ([M]+, 35Cl) 322.04249; found
322.042502.
Ethyl 3-Chloro-6-(4-chlorophenyl)-5-cyano-2-hydroxybenzoate (9b):
Compound 9b was isolated as a yellow solid (0.134 g, 40%) from
3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 8b (0.235 g, 1.0 mmol)
and TiCl4 (0.11 mL, 1.0 mmol); m.p. 116–118 °C. 1H NMR
(CDCl3, 300 MHz): δ = 0.80 (t, 3J = 7.2 Hz, 3 H, OCH2CH3), 4.03
(q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.15–7.17, 7.41–7.44 (m, 4 H,
CH), 7.83 (s, 1 H, CH), 12.16 (s, 1 H, OH) ppm. 13C NMR (CDCl3,
75 MHz): δ = 12.9 (OCH2CH3) 62.7 (OCH2CH3), 105.9, 114.3 (C),
123.4 (CϵN), 128.5, 129.5 (CH), 134.8, 136.5 (C), 136.9, 146.3,
Ethyl 3-Chloro-2-hydroxy-4-(4-methylphenyl)-6-(methylthio)benzo-
ate (11b): Compound 11b was isolated as a yellow solid (0.211 g,
89%) from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10b (0.283 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 103–105 °C. 1H
NMR (CDCl3, 250 MHz): δ = 1.50 (t, 3J = 7.1 Hz, 3 H,
3
OCH2CH3), 2.39 (s, 3 H, CH3), 2.41 (s, 3 H, SCH3), 4.53 (q, J =
7.1 Hz, 2 H, OCH2CH3), 6.62 (s, 1 H, CH), 7.28–7.36 (m, 4 H,
CH), 12.29 (s, 1 H, OH) ppm. 13C NMR (CDCl3, 63 MHz): δ =
14.2 (OCH2CH3), 16.4 (SCH3), 21.3 (CH3), 62.7 (OCH2CH3),
109.9, 116.9 (C), 117.1, 128.2, 128.3. 129.0 (CH), 135.8, 138.3,
(CH), 160.9 (COH), 169.3 (C=O) ppm. IR (ATR): ν = 3074 (w),
˜
2995 (w), 2977 (w), 2935 (w), 2227 (s), 1731 (w), 1658 (s), 1651 (s),
1598 (w), 1574 (w), 1556 (w), 1495 (s), 1471 (w), 1442 (m), 1397
(s), 1373 (s), 1326 (w), 1306 (w), 1245 (w), 1220 (m), 1195 (m), 1114
(w), 1091 (s), 1013 (s) cm–1. MS (EI, 70 eV): m/z (%) = 339 [M]+
([37Cl] [37Cl], 3), 337 [M]+ ([37Cl] [35Cl], [35Cl] [37Cl], 16), 335 [M]+
([35Cl] [35Cl], 25), 293 (13), 292 (13), 291 (68), 290 (20), 289 (100),
198 (22). HRMS (EI): calcd. for C16H11O3NCl2 ([M]+, 35Cl)
335.01105; found 335.011032.
142.0, 145.8 (C), 159.3 (COH), 170.4 (C=O) ppm. IR (ATR): ν =
˜
3296 (w), 2992 (w), 2967 (w), 2916 (w), 2866 (w), 1648 (s), 1609
(w), 1584 (m), 1546 (w), 1473 (m), 1447 (m), 1407 (w), 1395 (m),
1372 (s), 1341 (m), 1307 (m), 1279 (s), 1241 (s), 1202 (w), 1188 (m),
1147 (m), 1106 (m), 1040 (w), 1008 (s) cm–1. MS (EI, 70 eV): m/z
(%) = 338 [M]+ ([37Cl], 13), 336 [M]+ ([35Cl], 32), 292 (39), 291 (23),
290 (100), 247 (12). HRMS (EI): calcd. for C17H17O3ClS ([M]+,
35Cl) 336.057884; found 336.05814. Elemental analysis calcd. (%)
for C17H17ClO3S (336.83): C 60.62, H 5.09, S 9.52; found C 60.69,
H 5.43, S 9.62.
Ethyl 3-Chloro-5-cyano-2-hydroxy-6-methylbenzoate (9c): Com-
pound 9c was isolated as a yellow crystalline solid (0.092 g, 38%)
from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 8c (0.139 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 111–113 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.46 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.76 (s, 3 H, CH3), 4.51 (q, 3J = 7.0 Hz, 2 H,
OCH2CH3), 7.73 (s, 1 H, CH), 12.43 (s, 1 H, OH) ppm. 13C NMR
Ethyl 3-Chloro-4-(4-fluorophenyl)-2-hydroxy-6-(methylthio)benzoate
(11c): Compound 11c was isolated as a yellow solid (0.201 g, 83%)
from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10c (0.242 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 94–96 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.44 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.34 (s, 3 H, SCH3), 4.47 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 6.54 (s, 1 H, CH), 7.05–7.11, 7.33–7.38 (m, 4 H, CH),
12.24 (s, 1 H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.2
(OCH2CH3), 16.5 (SCH3), 62.8 (CH2CH3), 110.2 (C), 115.1, 115.4,
117.0, 130.8, 130.9 (CH), 134.7 (d, JC,F = 3.3 Hz, 1 C), 142.3, 144.7
(C), 159.4 (COH), 161.1, 164.4 (C), 170.3 (C=O) ppm. 19F NMR
(CDCl3, 75 MHz):
δ = 14.0 (OCH2CH3) 21.6 (CH3), 62.3
(OCH2CH3), 106.0, 114.6, 117.2 (C), 121.5 (CϵN), 137.1 (CH),
144.6 (C), 161.6 (COH), 170.4 (C=O) ppm. IR (ATR): ν = 3060
˜
(m), 2984 (w), 2941 (w), 2742 (w), 2560 (w), 2226 (s), 1861 (w),
1731 (w), 1652 (s), 1591 (w), 1562 (m), 1474 (w), 1434 (s), 1398
(m), 1374 (s), 1336 (w), 1313 (w), 1301 (w), 1232 (s), 1205 (m), 1182
(w), 1112 (w), 1098 (w), 1060 (w), 1033 (w), 1003 (s) cm–1. MS (EI,
70 eV): m/z (%) = 241 [M]+ ([37Cl], 6), 239 [M]+ ([35Cl], 17), 195
(31), 194 (21), 193 (100). HRMS (EI): calcd. for C11H10O3NCl
([M]+, 35Cl) 239.03437; found 239.034019.
(CDCl , 235 MHz): δ = –113.13 (CF) ppm. IR (ATR): ν = 3075
˜
3
(w), 3042 (w), 2993 (w), 2916 (w), 2656 (w), 2622 (w), 1892 (w),
1645 (s), 1589 (s), 1531 (m), 1505 (s), 1481 (w), 1449 (m), 1412 (m),
1397 (m), 1372 (s), 1340 (m), 1307 (w), 1298 (w), 1278 (s), 1246
(m), 1228 (w), 1215 (w), 1196 (w), 1160 (w), 1151 (m), 1110 (w),
1101 (m), 1012 (s) cm–1. MS (EI, 70 eV): m/z (%) = 342 [M]+ ([37Cl],
12), 340 [M]+ ([35Cl], 31), 296 (39), 295 (22), 294 (100), 251 (16).
HRMS (EI): calcd. for C16H14O3ClFS ([M]+, 35Cl) 340.032595;
found 340.03307.
General Procedure for the Synthesis of 3-Chloro-6-(methylthio)sali-
cylates 11a–i: TiCl4 (1.0 equiv.) was added at –78 °C to a 1,1-bis-
(methylthio)-1-en-3-one 10 (1.0 equiv.) and the 4-chloro-1,3-bis-
(trimethylsilyloxy)buta-1,3-diene 3b (1.3 equiv.) in dichloromethane
(2.5 mL per 1 mmol of 10). The solution was allowed to warm
slowly to 20 °C with stirring. Hydrochloric acid (10%) was added
to the solution and the organic and the aqueous layers were sepa-
rated. The latter was extracted with dichloromethane. The com-
bined organic layers were dried (sodium sulfate) and filtered, and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes/EtOAc 10:1).
Ethyl 3-Chloro-2-hydroxy-4-(4-methoxyphenyl)-6-(methylthio)ben-
zoate (11d): Compound 11d was isolated as a yellow solid (0.156 g,
44%) from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10d (0.254 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 97–98 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.49 (t, 3J = 7.1 Hz, 3 H,
3
Ethyl 3-Chloro-2-hydroxy-6-(methylthio)-4-phenylbenzoate (11a): OCH2CH3), 2.40 (s, 3 H, SCH3), 3.86 (s, 3 H, OCH3), 4.53 (q, J
Compound 11a was isolated as a yellow crystalline solid (0.308 g,
= 7.1 Hz, 2 H, OCH2CH3), 6.62 (s, 1 H, CH), 6.96–7.00, 7.39–7.41
96%) from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10a (0.224 g, (m, 4 H, CH), 12.29 (s, 1 H, OH) ppm. 13C NMR (CDCl3,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 76–77 °C. 1H 75 MHz): δ = 14.2 (OCH2CH3), 16.4 (SCH3), 55.3 (OCH3), 62.7
NMR (CDCl3, 250 MHz): δ = 1.50 (t, 3J = 7.1 Hz, 3 H,
(CH2CH3), 109.8 (C), 113.6 (CH), 113.9 (C), 117.1, 128.3, 130.4
(CH), 131.0 (C), 131.2 (CH), 142.0, 145.4 (C), 159.4 (COH), 159.7
OCH2CH3), 2.40 (s, 3 H, SCH3), 4.53 (q, 3J = 7.1 Hz, 2 H,
OCH2CH3), 6.63 (s, 1 H, CH), 7.44 (s, 5 H, CH), 12.29 (s, 1 H, (C), 170.4 (C=O) ppm. IR (ATR): ν = 3076 (w), 3039 (w), 2999
˜
OH) ppm. 13C NMR (CDCl3, 63 MHz): δ = 14.2 (OCH2CH3), 16.4
(w), 2982 (w), 2938 (w), 2921 (w), 2842 (w), 2050 (w), 2023 (w),
Eur. J. Org. Chem. 2009, 5854–5867
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5861

V. Wolf, M. Adeel, S. Reim, A. Villinger, C. Fischer, P. Langer
FULL PAPER
1873 (w), 1731 (w), 1694 (w), 1646 (s), 1591 (s), 1508 (s), 1484 (w), 1247 (m), 1201 (w), 1188 (w), 1152 (m), 1126 (w), 1086 (m), 1048
1463 (w), 1454 (w), 1440 (w), 1416 (w), 1401 (w), 1385 (w), 1369
(m), 1012 (s) cm–1. MS (EI, 70 eV): m/z (%) = 360 [M]+ ([37Cl]
(s), 1347 (m), 1306 (m), 1286 (s), 1244 (s), 1201 (w), 1180 (m), 1151 [37Cl], 5), 358 [M]+ ([37Cl] [35Cl],[35Cl] [37Cl], 22), 356 [M]+ ([35Cl]
(w), 1124 (w), 1104 (m), 1054 (w), 1026 (w), 1015 (w) cm–1. MS [35Cl], 30), 314 (16), 313 (15), 312 (72), 311 (22), 310 (100), 267
(EI, 70 eV): m/z (%) = 354 [M]+ ([37Cl], 27), 352 [M]+ ([35Cl], 74), (15). HRMS (EI): calcd. for C16H14O3Cl2S ([M]+, 35Cl) 356.00352;
318 (17), 309 (17), 308 (80), 307 (53), 306 (100). HRMS (EI): calcd. found 356.002785. Elemental analysis calcd. (%) for C16H14O3Cl2S
for C17H17O4ClS ([M]+, 35Cl) 352.05306; found 352.052915. Ele-
mental analysis calcd. (%) for C17H17ClO4S (352.05): C 57.87, H
4.86, S 9.09; found C 58.17, H 5.10, S 9.36.
(357.25): C 53.79, H 3.95; found C 53.14, H 4.13.
Ethyl 4-(4-Bromophenyl)-3-chloro-2-hydroxy-6-(methylthio)benzoate
(11h): Compound 11h was isolated as a yellow solid (0.202 g, 67%)
from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10h (0.302 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 159–161 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.50 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.39 (s, 3 H, SCH3), 4.53 (q, 3J = 7.0 Hz, 2 H,
OCH2CH3), 6.60 (s, 1 H, CH), 7.29–7.33, 7.56–7.60 (m, 4 H, CH),
12.29 (s, 1 H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.2
(OCH2CH3), 16.4 (SCH3), 62.8 (OCH2CH3), 110.3 (C), 116.7,
122.7, 127.8, 130.3, 130.7 (CH), 131.4, 132.0, 137.5, 142.4, 144.5
Ethyl 4-Biphenylyl-3-chloro-2-hydroxy-6-(methylthio)benzoate (11e):
Compound 11e was isolated as a yellow solid (0.203 g, 51%) from
3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10e (0.300 g, 1.0 mmol)
and TiCl4 (0.11 mL, 1.0 mmol); m.p. 155–157 °C. 1H NMR
(CDCl3, 300 MHz): δ = 1.51 (t, 3J = 7.0 Hz, 3 H, OCH2CH3), 2.42
(s, 3 H, SCH3), 4.54 (q, 3J = 7.0 Hz, 2 H, OCH2CH3), 6.68 (s, 1
H, CH), 7.34–7.40, 7.44–7.49, 7.52–7.55, 7.63–7.77 (m, 9 H, CH),
12.32 (s, 1 H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.2
(OCH2CH3), 16.5 (SCH3), 62.8 (CH2CH3), 110.1, 116.9 (C), 117.1,
126.9, 127.1, 127.6, 128.8, 129.5 (CH), 137.6, 140.5, 141.3, 142.2,
(C), 159.4 (COH), 170.3 (C=O) ppm. IR (ATR): ν = 2990 (w), 2923
˜
(w), 2863 (w), 1731 (w), 1704 (w), 1646 (s), 1587 (s), 1520 (w), 1486
(s), 1435 (w), 1417 (w), 1397 (s), 1370 (s), 1341 (m), 1309 (m), 1281
(m), 1247 (m), 1201 (w), 1187 (w), 1150 (m), 1126 (w), 1098 (m),
1068 (w), 1047 (m), 1008 (s) cm–1. MS (EI, 70 eV): m/z (%) = 404
[M]+ ([37Cl] [81Br], 14), 402 [M]+ ([37Cl] [79Br], [35Cl] [81Br], 59), 400
[M]+ ([35Cl] [79Br], 40), 358 (54), 357 (34), 356 (100), 255 (25), 354
(91), 313 (18) 311 (14). HRMS (EI): calcd. for C16H14O3BrClS
([M]+, 35Cl, 79Br) 399.95301; found 399.953090. Elemental analysis
calcd. (%) for C16H14O3ClBrS (401.70): C 47.84, H 3.51; found C
47.54, H 3.57.
145.4 (C), 159.4 (COH), 170.4 (C=O) ppm. IR (ATR): ν = 3031
˜
(w), 2981 (w), 2961 (w), 2920 (w), 2853 (w), 1731 (w), 1705 (w),
1650 (s), 1583 (m), 1557 (w), 1516 (m), 1488 (s), 1471 (w), 1452
(w), 1434 (w), 1398 (m), 1373 (s), 1341 (m), 1306 (m), 1275 (m),
1245 (m), 1197 (w), 1181 (m), 1149 (m), 1108 (w), 1006 (s) cm–1.
MS (EI, 70 eV): m/z (%) = 400 [M]+ ([37Cl], 27), 398 [M]+ ([35Cl],
77), 355 (17), 354 (80), 353 (50), 352 (100), 309 (13). HRMS (EI):
calcd. for C22H19O3ClS ([M]+, 35Cl) 398.07379; found 398.072845.
Elemental analysis calcd. (%) for C22H19O3ClS (398.90): C 66.24,
H 4.80; found C 65.87, H 5.16.
Ethyl 3-Chloro-2-hydroxy-4-methyl-6-(methylthio)benzoate (11i):
Compound 11i was isolated as a yellow solid (0.148 g, 91%) from
3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10i (0.162 g, 1.0 mmol)
Ethyl 3-Chloro-4-(4-ethylphenyl)-2-hydroxy-6-(methylthio)benzoate
(11f): Compound 11f was isolated as a yellow solid (0.132 g, 53%)
from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10f (0.252 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 94–96 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.29 (t, 3J = 7.6 Hz, 3 H, CH2CH3),
1
and TiCl4 (0.11 mL, 1.0 mmol); m.p. 78–80 °C. H NMR (CDCl3,
3
300 MHz): δ = 1.46 (t, J = 7.2 Hz, 3 H, OCH2CH3), 2.40 (s, 3 H,
3
CH3), 2.41 (s, 3 H, SCH3), 4.47 (q, J = 7.2 Hz, 2 H, OCH2CH3),
6.54 (s, 1 H, CH), 12.17 (s, 1 H, OH) ppm. 13C NMR (CDCl3,
75 MHz): δ = 14.2 (OCH2CH3) 16.4 (SCH3), 21.1 (CH3), 62.5
(OCH2CH3), 109.1 (C), 116.7 (CH), 118.3, 141.6, 142.7 (C), 158.9
3
1.50 (t, J = 7.2 Hz, 3 H, OCH2CH3), 2.39 (s, 3 H, SCH3), 2.67–
2.75 (m, 2 H, CH2CH3), 4.53 (q, 3J = 7.2 Hz, 2 H, OCH2CH3),
6.63 (s, 1 H, CH), 7.27–7.30, 7.36–7.39 (m, 4 H, CH), 12.29 (s, 1
H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.2 (OCH2CH3)
15.4 (CH2CH3), 16.5 (SCH3), 28.6 (CH2CH3), 62.7 (OCH2CH3),
109.9 (C), 117.2 (CH), 126.5 (C), 127.7, 129.0 (CH), 136.1, 142.0,
(COH), 170.4 (C=O) ppm. IR (ATR): ν = 2984 (w), 2960 (w), 2919
˜
(w), 2859 (w), 1731 (w), 1709 (w), 1650 (s), 1591 (s), 1537 (w), 1463
(w), 1443 (w), 1426 (w), 1395 (m), 1371 (s), 1341 (m), 1314 (m),
1286 (m), 1241 (s), 1190 (s), 1131 (w), 1105 (w), 1055 (m), 1017 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 262 [M]+ ([37Cl], 11), 260 [M]+
([35Cl], 29), 216 (40), 215 (18), 214 (100), 171 (19). HRMS (EI):
calcd. for C11H13O3ClS ([M]+, 35Cl) 260.02684; found 260.026278.
144.6, 145.8 (C), 159.3 (COH), 170.4 (C=O) ppm. IR (ATR): ν =
˜
3049 (w), 2997 (w), 2960 (w), 2926 (w), 2874 (w), 1902 (w), 1645
(s), 1609 (w), 1587 (w), 1565 (w), 1526 (w), 1509 (s), 1469 (w), 1437
(w), 1421 (m), 1396 (m), 1371 (s), 1342 (m), 1311 (m), 1284 (s),
1246 (s), 1187 (s), 1152 (m), 1123 (w), 1096 (m), 1052 (m), 1016
(s) cm–1. MS (EI, 70 eV): m/z (%) = 352 [M]+ ([37Cl], 21), 350
[M]+ ([35Cl], 65), 307 (13), 306 (74), 305 (39), 304 (100), 276 (11),
261 (16), 44 (20). HRMS (EI): calcd. for C18H19O3ClS ([M]+, 35Cl)
350.07379; found 350.073428.
General Procedure for the Synthesis of 3-Chloro-4-methoxysalicyl-
ates 13a–j: TiCl4 (1.0 equiv.) was added at –78 °C to a 3-oxo ortho-
ester 12 (1.0 equiv.) and diene 3b (1.3 equiv.) in dichloromethane
(2.5 mL per 1 mmol of 12). The solution was allowed to warm
slowly to 20 °C with stirring. Hydrochloric acid (10%) was added
to the solution and the organic and the aqueous layers were sepa-
rated. The latter was extracted with dichloromethane. The com-
bined organic layers were dried (sodium sulfate) and filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes/EtOAc, 10:1).
Ethyl 3-Chloro-4-(4-chlorophenyl)-2-hydroxy-6-(methylthio)benzo-
ate (11g): Compound 11g was isolated as a yellow solid (0.139 g,
54%) from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 10g (0.258 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 150–153 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.50 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.39 (s, 3 H, SCH3), 4.53 (q, 3J = 7.2 Hz, 2 H,
Ethyl 3-Chloro-2-hydroxy-6-isopropyl-4-methoxybenzoate (13a):
OCH2CH3), 6.58 (s, 1 H, CH), 7.36–7.44 (m, 4 H, CH), 12.29 (s, 1 Compound 13a was isolated as a yellow crystalline solid (0.163 g,
H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.2 (OCH2CH3),
60%) from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12a (0.190 g,
16.4 (SCH3), 62.8 (OCH2CH3), 110.3 (C), 116.8, 128.5, 130.4 (CH), 1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 84–86 °C. 1H
134.5, 137.5, 142.4, 144.5 (C), 159.4 (COH), 170.3 (C=O) ppm. IR
NMR (CDCl3, 300 MHz): δ = 1.23 [d, 3J = 6.6 Hz, 6 H, CH-
3
(ATR): ν = 2995 (w), 2924 (w), 2850 (w), 1900 (w), 1699 (w), 1640 (CH3)2], 1.42 (t, J = 7.2 Hz, 3 H, OCH2CH3), 3.79–3.88 [m, 1 H,
˜
(s), 1613 (w), 1591 (m), 1564 (w), 1557 (w), 1524 (w), 1488 (s), 1437
(w), 1417(w), 1398 (m), 1372 (s), 1342 (m), 1310 (m), 1281 (m),
CH(CH3)2], 3.95 (s, 3 H, OCH3), 4.43 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 6.51 (s, 1 H, CH), 11.74 (s, 1 H, OH) ppm. 13C NMR
5862
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5854–5867

Diversity-Oriented Synthesis of Chlorinated Arenes
(CDCl3, 63 MHz):
14.0 (OCH2CH3), 24.1 (CH3), 30.7 ([37Cl] [37Cl], 2), 342 [M]+ ([37Cl] [35Cl], [35Cl] [37Cl], 11), 340 [M]+
δ
=
[CH(CH3)2], 56.0 (OCH3), 61.9 (OCH2CH3), 101.1 (CH), 106.8, ([35Cl] [35Cl], 17), 298 (12), 297 (12), 296 (66), 295 (19), 294 (100).
107.2, 151.8 (C), 158.7 (COMe), 159.0 (COH), 171.1 (C=O) ppm.
HRMS (EI): calcd. for C16H14O4Cl2 ([M]+, 35Cl) 340.02637; found
340.026469.
IR (ATR): ν = 3003 (w), 2981 (w), 2943 (w), 2911 (w), 2861 (w),
˜
2714 (w), 2628 (w), 1650 (s), 1582 (w), 1556 (w), 1489 (w), 1471
(w), 1461 (w), 1441 (w), 1398 (s), 1379 (m), 1362 (w), 1346 (w),
1306 (w), 1296 (w), 1285 (w), 1265 (s), 1217 (s), 1186 (m), 1140 (s),
1103 (s), 1076 (s), 1018 (s) cm–1. MS (EI, 70 eV): m/z (%) = 274
[M]+ ([37Cl], 6), 272 [M]+ ([35Cl], 18), 228 (36), 227 (27), 226 (100),
225 (14), 211 (17), 183 (11). HRMS (EI): calcd. for C13H17O4Cl
([M]+, 35Cl) 272.08099; found 272.080737.
Ethyl
3-Chloro-6-cyclopropanyl-2-hydroxy-4-methoxybenzoate
(13e): Compound 13e was isolated as a yellow solid (0.152 g, 56%)
from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12e (0.188 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 89–92 °C. 1H
NMR (CDCl3, 300 MHz): δ = 0.63–0.69 (m, 2 H, CH2), 0.91–0.98
(m, 2 H, CH2), 1.41 (t, 3J = 7.2 Hz, 3 H, OCH2CH3), 2.38–2.48
(m, 1 H, CH), 3.92 (s, 3 H, OCH3), 4.44 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 6.33 (s, 1 H, CH), 12.18 (s, 1 H, OH) ppm. 13C NMR
Ethyl 3-Chloro-2-hydroxy-4-methoxy-6-propylbenzoate (13b): Com-
pound 13b was isolated as a yellow crystalline solid (0.178 g, 65%) (CDCl3, 75 MHz): δ = 8.2 (CH2), 11.7 (CH), 14.1 (OCH2CH3) 56.1
from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12b (0.190 g, (OCH3), 61.8 (OCH2CH3), 103.2 (CH), 107.6, 108.1, 145.7 (C),
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 74–76 °C. 1H 158.9 (COMe), 159.6 (COH), 171.5 (C=O) ppm. IR (ATR): ν =
˜
NMR (CDCl3, 250 MHz): δ = 0.97 (t, 3J = 7.3 Hz, 3 H, CH3), 1.42
3068 (w), 2985 (w), 2970 (m), 2941 (w), 2854 (w), 1743 (w), 1652
(t, J = 7.3 Hz, 3 H, OCH2CH3), 1.54–1.66 (m, 2 H, CH2), 2.84– (s), 1602 (m), 1558 (m), 1468 (m), 1404 (m), 1386 (w), 1369 (m),
3
3
2.91 (m, 2 H, CH2), 3.93 (s, 3 H, OCH3), 4.42 (q, J = 7.3 Hz, 2
H, OCH2CH3), 6.33 (s, 1 H, CH), 12.26 (s, 1 H, OH) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 14.0 (CH3), 14.1 (OCH2CH3), 25.2,
39.3 (CH2), 56.2 (OCH3), 61.8 (OCH2CH3), 106.1 (CH), 107.5,
117.7, 146.0 (C), 158.8 (COMe), 160.0 (COH), 171.3 (C=O) ppm.
1296 (w), 1270 (m), 1229 (m), 1191 (m), 1158 (w), 1140 (m), 1113
(w), 1096 (m), 1055 (w), 1022 (s) cm–1. MS (EI, 70 eV): m/z (%) =
272 [M]+ ([37Cl], 15), 270 [M]+ ([35Cl], 44), 244 (27), 242 (86), 226
(34), 225 (22), 224 (91), 216 (18), 215 (37), 214 (57), 213 (100), 181
(18), 161 (23), 89 (20). HRMS (EI): calcd. for C13H15O4Cl ([M]+,
35Cl) 270.06534; found 270.065689.
IR (ATR): ν = 3271 (w), 2979 (w), 2962 (w), 2930 (w), 2872 (w),
˜
2669 (w), 1726 (w), 1651 (s), 1599 (w), 1557 (w), 1494 (w), 1468
(m), 1439 (w), 1398 (m), 1373 (m), 1304 (m), 1263 (m), 1223 (w),
1208 (w), 1190 (w), 1135 (w), 1108 (w), 1095 (w), 1080 (w), 1013
(m) cm–1. MS (EI, 70 eV): m/z (%) = 274 [M]+ ([37Cl], 6), 272
[M]+ ([35Cl], 17), 228 (35), 227 (19), 226 (100), 169 (14). HRMS
(EI): calcd. for C13H17O4Cl ([M]+, 35Cl) 272.080644; found
272.08099.
Ethyl 3-Chloro-6-cyclobutanyl-2-hydroxy-4-methoxybenzoate (13f):
Compound 13f was isolated as a yellow solid (0.174 g, 61%) from
3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12f (0.202 g, 1.0 mmol)
1
and TiCl4 (0.11 mL, 1.0 mmol); m.p. 78–80 °C. H NMR (CDCl3,
300 MHz): δ = 1.44 (t, 3J = 7.2 Hz, 3 H, OCH2CH3), 1.75–1.84 (m,
2 H, CH2), 1.91–2.12 (m, 2 H, CH2), 2.29–2.38 (m, 2 H, CH2), 3.97
(s, 3 H, OCH3), 4.09 (q, 3J = 8.7 Hz, 1 H, CH), 4.42 (q, 3J = 7.2 Hz,
2 H, OCH2CH3), 6.49 (s, 1 H, CH), 11.97 (s, 1 H, OH) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 14.0 (OCH2CH3) 17.9, 29.6 (CH2),
40.3 (CH), 56.1 (OCH3), 61.9 (OCH2CH3), 102.3 (CH), 105.8,
Ethyl 3-Chloro-2-hydroxy-4-methoxy-6-phenylbenzoate (13c): Com-
pound 13c was isolated as a yellow oil (0.199 g, 65%) from 3b
(0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12c (0.244 g, 1.0 mmol) and
1
TiCl4 (0.11 mL, 1.0 mmol). H NMR (CDCl3, 300 MHz): δ = 0.73 107.2, 148.1 (C), 158.9 (COMe), 159.4 (COH), 171.1 (C=O) ppm.
3
3
(t, J = 7.2 Hz, 3 H, OCH2CH3), 3.92 (s, 3 H, OCH3), 3.96 (q, J
IR (ATR): ν = 3013 (w), 2978 (w), 2947 (w), 2866 (w), 1645 (s),
˜
= 7.2 Hz, 2 H, OCH2CH3), 6.39 (s, 1 H, CH), 7.19–7.22, 7.33–7.36 1603 (m), 1574 (w), 1556 (s), 1467 (m), 1454 (m), 1399 (s), 1380
(m, 5 H, CH), 11.87 (s, 1 H, OH) ppm. 13C NMR (CDCl3, (w), 1361 (w), 1305 (w), 1292 (w), 1278 (m), 1250 (m), 1220 (w),
75 MHz): δ = 12.9 (OCH2CH3) 56.4 (OCH3), 61.2 (OCH2CH3), 1207 (s), 1186 (m), 1160 (w), 1133 (m), 1107 (w), 1091 (s), 1018 (s)
106.3 (CH), 106.4 (C), 127.1, 127.6, 128.0 (CH), 142.7, 144.7 (C), cm–1. MS (EI, 70 eV): m/z (%) = 286 [M]+ ([37Cl], 19), 284 [M]+
158.4 (COMe), 159.0 (COH), 170.4 (C=O) ppm. IR (ATR): ν =
([35Cl], 52), 240 (33), 239 (18), 238 (100), 235 (39), 210 (16), 207
˜
3057 (w), 2925 (w), 2853 (w), 1727 (w), 1652 (s), 1596 (s), 1554 (s), (18), 203 (30), 176 (13), 175 (53), 161 (15), 147 (16), 115 (15).
1503 (w), 1486 (w), 1463 (w), 1444 (w), 1395 (s), 1376 (w), 1360
HRMS (EI): calcd. for C14H17O4Cl ([M]+, 35Cl) 284.08099; found
(w), 1321 (w), 1298 (m), 1266 (s), 1227 (s), 1185 (m), 1152 (w), 1137 284.080896. Elemental analysis calcd. (%) for C14H17ClO4 (284.74):
(m), 1097 (s), 1072 (w), 1015 (s) cm–1. MS (EI, 70 eV): m/z (%) =
308 [M]+ ([37Cl], 7), 307 (3), 306 [M]+ ([35Cl], 20), 262 (38), 261
(21), 260 (100). HRMS (EI): calcd. for C16H15O4Cl ([M]+, 35Cl)
306.06534; found 306.065304.
C 59.05, H 6.02; found C 59.18, H 6.08.
Ethyl 3-Chloro-6-cyclopentyl-2-hydroxy-4-methoxybenzoate (13g):
Compound 13g was isolated as a yellow solid (0.177 g, 59%) from
3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12g (0.216 g, 1.0 mmol)
1
Ethyl
3-Chloro-6-(4-chlorophenyl)-2-hydroxy-4-methoxybenzoate
and TiCl4 (0.11 mL, 1.0 mmol); m.p. 54–55 °C. H NMR (CDCl3,
(13d): Compound 13d was isolated as a yellow crystalline solid
300 MHz): δ = 1.41 (t, 3J = 7.2 Hz, 3 H, OCH2CH3), 1.54–1.84 (m,
(0.178 g, 52%) from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12d 6 H, CH2), 1.99–2.09 (m, 2 H, CH2), 3.75–3.86 (m, 1 H, CH), 3.93
3
(0.258 g, 1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 126–
(s, 3 H, OCH3), 4.42 (q, J = 7.2 Hz, 2 H, OCH2CH3), 6.52 (s, 1
127 °C. 1H NMR (CDCl3, 300 MHz): δ = 0.81 (t, 3J = 7.2 Hz, 3
H, CH), 11.68 (s, 1 H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ
H, OCH2CH3), 3.92 (s, 3 H, OCH3), 4.00 (q, 3J = 7.0 Hz, 2 H, = 14.0 (OCH2CH3) 25.2, 34.6 (CH2), 43.3 (CH), 56.0 (OCH3), 61.9
OCH2CH3), 6.33 (s, 1 H, CH), 7.12–7.17, 7.32–7.36 (m, 4 H, CH), (OCH2CH3), 101.6 (CH), 107.2, 107.6, 149.1 (C), 158.7 (COMe),
11.91 (s, 1 H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.0 158.8 (COH), 171.2 (C=O) ppm. IR (ATR): ν = 3010 (w), 2975
˜
(OCH2CH3), 56.4 (OCH3), 61.4 (OCH2CH3), 106.2 (CH), 109.2,
117.7 (C), 127.8, 129.4 (CH), 133.2, 141.2, 142.3 (C), 158.5
(w), 2948 (m), 2868 (m), 2744 (w), 2663 (w), 1644 (s), 1603 (m),
1556 (s), 1504 (w), 1495 (w), 1471 (w), 1456 (w), 1442 (w), 1402
(COMe), 159.2 (COH), 170.4 (C=O) ppm. IR (ATR): ν = 3063 (w), (s), 1383 (w), 1362 (m), 1312 (w), 1293 (s), 1264 (s), 1221 (m), 1193
˜
3054 (w), 2979 (w), 2931 (w), 2853 (w), 1653 (s), 1596 (m), 1556 (w), 1162 (w), 1137 (s), 1099 (s), 1080 (w), 1017 (s) cm–1. MS (EI,
(m), 1491 (m), 1462 (m), 1442 (w), 1393 (w), 1359 (m), 1319 (w), 70 eV): m/z (%) = 300 [M]+ ([37Cl], 5), 298 [M]+ ([35Cl], 15), 254
1304 (m), 1264 (s), 1227 (s), 1183 (m), 1151 (w), 1134 (m), 1096 (34), 253 (21), 252 (100). HRMS (EI): calcd. for C15H19O4Cl
(w), 1086 (w), 1015 (s) cm–1. MS (EI, 70 eV): m/z (%) = 344 [M]+
([M]+, 35Cl) 298.09664; found 298.096028. Elemental analysis
Eur. J. Org. Chem. 2009, 5854–5867
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5863

V. Wolf, M. Adeel, S. Reim, A. Villinger, C. Fischer, P. Langer
FULL PAPER
calcd. (%) for C15H19O4Cl (298.76): C 60.30, H 6.41; found C
60.45, H 6.34.
General Procedure for the Synthesis of 3-Chlorosalicylates 15a–e:
TiCl4 (2.0 equiv.) was added at –78 °C under argon to a solution
of 3a (2.0 equiv.) and
a 1,1,3,3-tetraalkoxypropane (14a–e,
Ethyl 3-Chloro-2-hydroxy-4-methoxy-6-pentylbenzoate (13h): Com-
pound 13h was isolated as a yellow solid (0.181 g, 63%) from 3b
(0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12h (0.218 g, 1.0 mmol) and
TiCl4 (0.11 mL, 1.0 mmol); m.p. 49–50 °C. 1H NMR (CDCl3,
1.0 equiv.) in dichloromethane (2.0 mL per 1 mmol of 14). The
solution was allowed to warm slowly to 20 °C with stirring. Hydro-
chloric acid (10%) was added to the solution and the organic and
the aqueous layers were separated. The latter was extracted with
dichloromethane. The combined organic layers were dried (sodium
sulfate) and filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (silica gel, heptanes/EtOAc
20:1).
3
300 MHz): δ = 0.90 (t, J = 7.2 Hz, 3 H, CH3), 1.31–1.37 (m, 4 H,
CH2), 1.42 (t, 3J = 7.2 Hz, 3 H, OCH2CH3), 1.50–1.60 (m, 2 H,
3
CH2), 2.86–2.91 (m, 2 H, CH2), 3.93 (s, 3 H, OCH3), 4.43 (q, J =
7.2 Hz, 2 H, OCH2CH3), 6.33 (s, 1 H, CH), 12.25 (s, 1 H,
OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0 (CH3), 14.0
(OCH2CH3), 22.6, 31.8, 32.0, 37.3 (CH2), 56.2 (OCH3), 61.8
(OCH2CH3), 105.9 (CH), 107.4, 108.7, 146.2 (C), 158.8 (COMe),
Methyl 3-Chloro-2-hydroxybenzoate (15a): Compound 15a was iso-
lated as a yellow oil (0.054 g, 26%) from 3a (0.590 g, 2.0 mmol),
1,1,3,3-tetramethoxypropane (14a, 0.164 g, 1.0 mmol) and TiCl4
(0.22 mL, 2.0 mmol) in CH2Cl2 (2 mL). 1H NMR (300 MHz,
159.9 (COH), 171.3 (C=O) ppm. IR (ATR): ν = 3014 (w), 2976
˜
(w), 2955 (w), 2931 (w), 2853 (w), 1647 (s), 1604 (s), 1559 (s), 1537
(w), 1495 (w), 1465 (m), 1442 (w), 1425 (w), 1401 (s), 1376 (m),
1300 (w), 1286 (w), 1266 (m), 1242 (w), 1222 (m), 1189 (w), 1159
(w), 1138 (m), 1121 (w), 1094 (s), 1043 (w), 1017 (s) cm–1. MS (EI,
70 eV): m/z (%) = 302 [M]+ ([37Cl], 7), 300 [M]+ ([35Cl], 19), 285
(1), 256 (35), 255 (20), 254 (100), 198 (29), 169 (10). HRMS (EI):
calcd. for C15H21O4Cl ([M]+, 35Cl) 300.11229; found 300.111609.
Elemental analysis calcd. (%) for C15H21ClO4 (300.78): C 59.90, H
7.04; found C 60.07, H 7.13.
3
CDCl3): δ = 3.96 (s, 3 H, OCH3), 6.83 (t, J = 8.0 Hz, 1 H, CH),
2
3
2
3
7.54 (dd, J = 1.7, J = 6.3 Hz, 1 H, CH), 7.76 (dd, J = 1.7, J =
6.3 Hz, 1 H, CH), 11.33 (s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 52.7 (OCH3), 113.6 (C), 119.2 (CH), 122.2 (C), 128.4,
135.8 (CH), 157.3 (COH), 170.3 (COOCH ) ppm. IR (ATR): ν =
˜
3
3090 (w), 2955 (w), 2926 (w), 2853 (w), 1732 (w), 1675 (s), 1607
(m), 1438 (s), 1322 (s), 1282 (m), 1252 (s), 1197 (s), 1176 (s), 1151
(s), 1073 (m) cm–1. MS (GC-MS, 70 eV): m/z (%) = 188 [M]+
([37Cl], 11), 186 [M]+ ([35Cl], 33), 156 (34), 154 (100). HRMS (EI):
calcd. for C8H7ClO3 [M]+ ([35Cl]): 186.00782; found 186.007530.
Ethyl
3-Chloro-6-cyclopentylethyl-2-hydroxy-4-methoxybenzoate
(13i): Compound 13i was isolated as a yellow solid (0.118 g, 36%)
from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12i (0.244 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 50–53 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.42 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 1.49–1.64 (m, 8 H, CH2), 1.76–1.81 (m, 2 H, CH2),
Methyl 3-Chloro-2-hydroxy-5-methylbenzoate (15b): Compound
15b was isolated as a yellow solid (0.070 g, 35%) from 3a (0.590 g,
2.0 mmol), 1,1,3,3-tetraethoxy-2-methylpropane (14b, 0.234 g,
1.0 mmol) and TiCl4 (0.22 mL, 2.0 mmol) in CH2Cl2 (2 mL); m.p.
1
104–107 °C. H NMR (250 MHz, CDCl3): δ = 2.26 (s, 3 H, CH3),
3
2.89–2.94 (m, 2 H, CH2), 3.73 (t, J = 22.5 Hz, 1 H, CH), 3.93 (s,
3.94 (s, 3 H, OCH3), 7.35–7.37 (m, 1 H, CH), 7.54–7.56 (m, 1 H,
CH), 11.09 (d, 4J = 0.5 Hz, 1 H, OH) ppm. 13C NMR (63 MHz,
CDCl3): δ = 20.2 (CH3), 52.6 (OCH3), 113.1, 121.6 (C), 128.3 (CH),
128.8 (C), 136.5 (CH), 155.1 (COH), 170.2 (COOCH3) ppm. IR
3
3 H, OCH3), 4.44 (q, J = 7.2 Hz, 2 H, OCH2CH3), 6.33 (s, 1 H,
CH), 12.23 (s, 1 H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ =
14.2 (OCH2CH3) 25.2, 32.6, 36.5, 38.5 (CH2), 40.3 (CH), 56.2
(OCH3), 61.8 (OCH2CH3), 105.8 (CH), 106.2, 107.4, 146.4 (C),
(ATR): ν = 3092 (w), 3070 (w), 3013 (w), 2960 (w), 2922 (w), 2855
˜
158.8 (COCH ), 158.9 (COH), 171.3 (C=O) ppm. IR (ATR): ν =
˜
3
(w), 1659 (s), 1608 (m), 1469 (w), 1437 (s), 1396 (w), 1384 (w), 1329
(s), 1250 (s), 1216 (s), 1193 (s), 1175 (s), 1100 (s), 1047 (m), 1010
(m) cm–1. MS (GC/MS, 70 eV): m/z (%) = 202 [M]+ ([37Cl], 10),
200 [M]+ ([35Cl], 30), 170 (34), 169 (19), 168 (100). C9H9ClO3
(200.62): calcd. C 53.88, H 4.52; found C 53.87, H 4.45.
2943 (w), 2914 (w), 2866 (w), 1748 (w), 1717 (w), 1643 (s), 1602
(m), 1557 (m), 1519 (w), 1463 (w), 1443 (w), 1422 (m), 1395 (s),
1375 (s), 1355 (w), 1296 (s), 1266 (m), 1218 (s), 1190 (m), 1160 (w),
1139 (m), 1100 (s), 1018 (s) cm–1. MS (EI, 70 eV): m/z (%) = 328
[M]+ ([37Cl], 11), 326 [M]+ ([35Cl], 31), 282 (34), 281 (22), 280 (100),
272 (15), 246 (20), 244 (62), 239 (21), 200 (27), 198 (73). HRMS
(ESI-TOF/MS): calcd. for C17H22O4Cl3 [M – H]+ (35Cl) 325.12121;
found 325.12149.
Methyl 3-Chloro-2-hydroxy-5-isopropylbenzoate (15c): Compound
15c was isolated as a yellow oil (0.082 g, 36%) from 3a (0.590 g,
2.0 mmol), 2-diethoxymethyl-1,1-diethoxy-3-methylbutane (14c,
0.262 g, 1.0 mmol) and TiCl4 (0.22 mL, 2.0 mmol) in CH2Cl2
Ethyl 3-Chloro-6-cyclohexyl-2-hydroxy-4-methoxybenzoate (13j):
Compound 13j was isolated as a yellow crystalline solid (0.147 g,
47%) from 3b (0.400 g, 1.3 mmol) in CH2Cl2 (2 mL), 12j (0.230 g,
1.0 mmol) and TiCl4 (0.11 mL, 1.0 mmol); m.p. 80–82 °C. 1H
1
(2 mL). H NMR (250 MHz, CDCl3): δ = 1.20 (s, 3 H, CH3), 1.23
(s, 3 H, CH3), 2.83 (quint, 3J = 6.9 Hz, 1 H, CH), 3.96 (s, 3 H,
OCH3), 7.42 (d, 4J = 2.2 Hz, 1 H, CH), 7.60 (dd, J = 0.5, 4J =
2.2 Hz, 1 H, CH), 11.13 (d, 4J = 0.5 Hz, 1 H, OH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.8 (CH3), 33.2 (CH), 52.6 (OCH3), 113.2,
121.8 (C), 125.8, 134.2 (CH), 140.0 (C), 155.3 (COH), 170.3 (CO-
3
NMR (CDCl3, 300 MHz): δ = 1.28–1.39 (m, 4 H, CH2), 1.44 (t, J
3
= 7.2 Hz, 3 H, OCH2CH3), 1.76–1.87 (m, 6 H, CH2), 3.60 (d, J =
3
72.3 Hz, 1 H, CH), 3.94 (s, 3 H, OCH3), 4.43 (q, J = 7.2 Hz, 2 H,
OCH ) ppm. IR (ATR): ν = 3107 (br., w), 3006 (w), 2958 (m), 2929
˜
3
OCH2CH3), 6.50 (s, 1 H, CH), 11.80 (s, 1 H, OH) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 14.2 (OCH2CH3) 26.2, 27.1, 34.7 (CH2),
41.5 (CH), 56.0 (OCH3), 61.9 (OCH2CH3), 101.8 (CH), 106.8,
107.2, 150.7, 158.8 (COCH3), 158.9 (COH), 171.3 (C=O) ppm. IR
(w), 2871 (w), 1676 (s), 1609 (w), 1468 (m), 1440 (s), 1384 (w), 1363
(w), 1334 (s), 1306 (m), 1278 (m), 1243 (s), 1196 (s), 1176 (s), 1150
(m), 1102 (m), 1067 (w) cm–1. MS (GC-MS, 70 eV): m/z (%) = 230
[M]+ ([37Cl], 10), 228 [M]+ ([35Cl], 32), 198 (28), 196 (84), 183 (33),
181 (100). HRMS (EI): calcd. for C11H13ClO3 [M]+ ([35Cl]):
228.05477; found 228.054789.
(ATR): ν = 2970 (w), 2927 (m), 2850 (m), 1712 (w), 1643 (s), 1602
˜
(m), 1561 (m), 1494 (w), 1467 (w), 1443 (m), 1400 (s), 1378 (w),
1360 (w), 1330 (w), 1300 (w), 1291 (w), 1263 (s), 1218 (s), 1189 (w),
1136 (s), 1102 (s), 1076 (w), 1017 (s) cm–1. MS (EI, 70 eV): m/z (%)
Methyl 3-Chloro-2-hydroxy-5-pentylbenzoate (15d): Compound 15d
= 314 [M]+ ([37Cl], 5), 312 [M]+ ([35Cl], 16), 268 (35), 267 (22), 266 was isolated as a yellow oil (0.133 g, 52%) from 3a (0.590 g,
(100). HRMS (ESI-TOF/MS): calcd. for C16H20O4Cl [M – H]+
(35Cl) 311.10556; found 311.1058. Elemental analysis calcd. (%) for
C16H21O4Cl (312.79): C 61.44, H 6.77; found C 61.43, H 6.83.
2.0 mmol), 2-diethoxymethyl-1,1-diethoxyheptane (14d, 0.290 g,
1.0 mmol) and TiCl4 (0.22 mL, 2.0 mmol) in CH2Cl2 (2 mL). 1H
NMR (250 MHz, CDCl3): δ = 0.88 (t, J = 6.9 Hz, 3 H, CH3), 1.24–
5864
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5854–5867

Diversity-Oriented Synthesis of Chlorinated Arenes
1.32 (m, 4 H, CH2), 1.51–1.63 (m, 2 H, CH2), 2.48–2.54 (m, 2 H,
and the organic and the aqueous layers were separated. The latter
CH2), 3.96 (s, 3 H, OCH3), 7.37 (d, 4J = 2.2 Hz, 1 H, CH), 7.55 was extracted with dichloromethane. The combined organic layers
4
4
(d, J = 2.2 Hz, 1 H, CH), 11.12 (d, J = 0.5 Hz, 1 H, OH) ppm.
were dried (sodium sulfate) and filtered and the filtrate was concen-
trated in vacuo. The residue was purified by chromatography (silica
13C NMR (63 MHz, CDCl3): δ = 14.0 (CH3), 22.4, 31.0, 31.2, 34.7
(CH2), 52.6 (OCH3), 113.2, 121.7 (C), 127.7 (CH), 134.0 (C), 135.9 gel, heptanes/EtOAc 20:1).
(CH), 155.2 (COH), 170.3 (COOCH ) ppm. IR (ATR): ν = 3111
˜
3
Ethyl 3-Chloro-2-hydroxy-5-(2-hydroxybenzoyl)benzoate (19a):
Compound 19a was isolated as a colourless solid (200 mg, 42%)
from 18a (261 mg, 1.5 mmol), 3b (602 mg, 2.0 mmol) and Me3-
SiOTf (0.08 mL, 0.5 mmol); m.p. 117–118 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.33 (t, J = 7.1 Hz, 3 H, CH3), 4.36 (q, J = 7.0,
14.2 Hz, 2 H, OCH2), 6.83 (m, 1 H, ArH), 6.96 (d, J = 8.3 Hz, 1
H, ArH), 7.40–7.47 (m, 2 H, ArH), 7.82 (d, J = 2.25 Hz, 1 H,
ArH), 7.68 (d, J = 2.3 Hz, 1 H, ArH), 8.08 (d, J = 2.43 Hz, 1 H,
ArH), 11.60 (s, 1 H, OH), 11.80 (s, 1 H, OH) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 14.0 (CH3), 62.6 (OCH2), 113.4, 118.6 (C),
118.6, 118.9 (CH), 122.7, 129.0 (C), 130.2, 132.7, 136.2, 136.5
(br., w), 2955 (w), 2927 (w), 2857 (w), 1676 (s), 1610 (w), 1440 (s),
1377 (w), 1325 (m), 1279 (m), 1247 (s), 1215 (m), 1196 (s), 1172 (s),
1102 (w) cm–1. MS (GC-MS, 70 eV): m/z (%) = 258 [M]+ ([37Cl],
9), 256 [M]+ ([35Cl], 29), 226 (34), 224 (100), 169 (30), 167 (87).
HRMS (EI): calcd. for C13H17ClO3 [M]+ ([35Cl]): 256.08607; found
256.086570.
Methyl 3-Chloro-5-heptyl-2-hydroxybenzoate (15e): Compound 15e
was isolated as a yellow oil (0.082 g, 30%) from 3a (0.590 g,
2.0 mmol), 2-diethoxymethyl-1,1-diethoxynonane (14e, 0.318 g,
1.0 mmol) and TiCl4 (0.22 mL, 2.0 mmol) in CH2Cl2 (2 mL). 1H
NMR (250 MHz, CDCl3): δ = 0.87 (t, 3J = 6.9 Hz, 3 H, CH3), (CH), 160.3, 163.0 (C-OH), 169.3, 197.8 (C=O) ppm. IR (neat): ν
˜
3
1.24–1.28 (m, 10 H, CH2), 2.51 (t, J = 7.7 Hz, 2 H, CH2), 3.96 (s, = 3086 (w), 2991 (m), 2962 (w), 1720 (w), 1680 (s), 1622 (s), 1567
3 H, OCH3), 7.37 (d, 4J = 2.2 Hz, 1 H, CH), 7.55 (d, 4J = 2.2 Hz, 1
(m), 1444 (m), 1374 (m), 1337 (s), 1239 (s), 1014 (m) cm–1. MS (GC
H, CH), 11.12 (d, 4J = 0.5 Hz, 1 H, OH) ppm. 13C NMR (63 MHz, = 70 eV): m/z (%): 322 [M]+ ([37Cl], 26), 320 [M]+ (75), 274 (34),
CDCl3): δ = 14.1 (CH3), 22.6, 29.0, 29.1, 31.3, 31.7, 34.7 (CH2), 181 (21), 154 (39), 121 (100). HRMS (EI) calcd. for C16H13ClO5
52.6 (OCH3), 113.2, 121.7 (C), 127.7 (CH), 134.0 (C), 135.9 (CH),
[M]+ ([35Cl]): 320.04460; found 320.044647.
155.2 (COH), 170.3 (COOCH ) ppm. IR (ATR): ν = 3114 (br., w),
˜
3
Ethyl 3-Chloro-2-hydroxy-5-(2-hydroxy-5-methylbenzoyl)benzoate
(19b): Compound 19b was isolated as a colourless solid (201 mg,
40%) from 18b (282 mg, 1.5 mmol), 3b (602 mg, 2.0 mmol) and
Me3SiOTf (0.08 mL, 0.5 mmol); m.p. 142–144 °C. 1H NMR
(250 MHz, CDCl3): δ = 1.35 (t, J = 7.1 Hz, 3 H, CH3), 2.21 (s, 3
H, CH3), 4.36 (q, J = 7.0, 14.2 Hz, 2 H, OCH2), 6.89 (d, J = 8.3 Hz,
1 H, ArH), 6.96 (d, J = 8.3 Hz, 1 H, ArH), 7.24–7.29 (m, 2 H,
ArH), 7.85 (d, J = 2.1 Hz, 1 H, ArH), 8.10 (d, J = 2.1 Hz, 1 H,
ArH), 11.43 (s, 1 H, OH), 11.81 (s, 1 H, OH) ppm. 13C NMR
(62 MHz, CDCl3): δ = 14.0 (CH3), 20.5 (CH3), 62.6 (OCH2), 113.4,
118.0 (C), 118.4 (CH), 122.7, 128.0, 129.2 (C), 130.2, 132.3, 136.1,
137.5 (CH), 160.2, 160.9 (C–OH), 169.3, 197.7 (C=O) ppm. IR
2954 (w), 2924 (m), 2854 (w), 1678 (s), 1610 (w), 1587 (w), 1440
(s), 1326 (m), 1280 (m), 1252 (s), 1215 (m), 1196 (s), 1172 (s), 1102
(w), 1022 (w) cm–1. MS (GC/MS, 70 eV): m/z (%) = 286 [M]+
([37Cl], 9), 284 [M]+ ([35Cl], 27), 254 (34), 252 (100), 169 (27), 167
(78). HRMS (EI): calcd. for C15H21ClO3 [M]+ ([35Cl]): 284.11737;
found 284.117164.
General Procedure for the Synthesis of 3-Chloro-5-(2-chloroethyl)-
salicylate 17: TiCl4 (1.8 equiv.) was added at –78 °C under argon
to a solution of 1,1-diacetylcyclopropane (16, 1.0 equiv.) and 3a
(1.5 equiv.) in dichloromethane (90 mL per 1 mmol of 16). The
solution was allowed to warm slowly to 20 °C with stirring. Hydro-
chloric acid (10%) was added to the solution and the organic and
the aqueous layer were separated. The latter was extracted with
dichloromethane. The combined organic layers were dried (sodium
sulfate) and filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (silica gel, heptanes/EtOAc
20:1).
(neat): ν = 3065 (w), 2993 (w), 2856 (w), 1679 (s), 1627 (s), 1581
˜
(s), 1482 (m), 1375 (m), 1338 (s), 1288 (s), 1210 (s), 786 (s) cm–1.
MS (GC = 70 eV): m/z (%): 336 [M]+ ([37Cl], 13), 334 [M]+ (37),
288 (11), 181 (9), 134 (100), 77 (11). HRMS (EI): calcd. for
C17H15ClO5 [M]+ ([35Cl]): 334.06025; found 334.060293.
Ethyl
Methyl 3-Chloro-5-(2-chloroethyl)-2-hydroxy-4,6-dimethylbenzoate (19c): Compound 19c was isolated as a yellow oil (0.140 g, 40%)
(17): Compound 17 (0.081 g, 30%) was isolated as a colourless so- from 18c (0.202 g, 1.0 mmol), Me3SiOTf (0.05 mL, 0.3 mmol) and
3-Chloro-5-(5-ethyl-2-hydroxybenzoyl)-2-hydroxybenzoate
lid from 3a (0.472 g, 1.6 mmol), 16 (0.139 g, 1.10 mmol) and TiCl4 3b (0.402 g, 1.3 mmol) in CH2Cl2 (15 mL); m.p. 69–72 °C. 1H
(0.22 mL, 2.0 mmol) in CH2Cl2 (100 mL); m.p. 80–82 °C. 1H NMR
(250 MHz, CDCl3): δ = 2.46 (s, 6 H, CH3), 3.12–3.18 (m, 2 H,
CH2), 3.46–3.53 (m, 2 H, CH2), 3.97 (s, 3 H, OCH3), 10.69 (s, 1 H,
NMR (CDCl3, 250 MHz): δ = 1.19 (t, 3J = 7.6 Hz, 3 H, CH2CH3),
3
1.40 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 2.57 (q, J = 7.6 Hz, 2 H,
CH2CH3), 4.46 (q, 3J = 7.1 Hz, 2 H, OCH2CH3), 7.01 (dd, 3J =
OH) ppm. 13C NMR (63 MHz, CDCl3): δ = 17.8, 18.5 (CH3), 33.7, 8.2 Hz, 1 H, CH), 7.35–7.40 (m, 2 H, CH), 7.97 (dd, J = 2.2 Hz,
42.0 (CH2), 52.6 (OCH3), 113.7, 120.9, 127.8, 136.5, 141.2 (C), 1 H, CH), 8.20 (d, 4J = 2.0 Hz, 1 H, CH), 11.50 (s, 1 H, OH), 11.90
4
155.0 (COH), 171.3 (COOCH ) ppm. IR (ATR): ν = 3017 (w),
(s, 1 H, OH) ppm. 13C NMR (63 MHz, CDCl3): δ = 14.1 (CH3),
15.8 (OCH2CH3), 27.9 (CH2), 62.6 (OCH2CH3), 113.3 (C), 118.5
(CH), 122.9 (C), 129.1, 130.4 (CH), 131.3, 134.6 (C), 136.3, 136.5
˜
3
2980 (w), 2954 (w), 2929 (w), 2873 (w), 2851 (w), 1661 (s), 1584
(w), 1548 (w), 1439 (s), 1408 (m), 1377 (m), 1337 (s), 1311 (s), 1265
(m), 1245 (m), 1200 (s), 1161 (s), 1144 (s), 1077 (s), 1041 (m), 1011 (CH), 160.4, 161.1 (COH), 169.4, 197.7 (C=O) ppm. IR (ATR): ν
˜
(m) cm–1. MS (GC-MS, 70 eV): m/z (%) = 278 [M]+ ([37Cl], 12), = 3271 (w), 3068 (w), 2967 (w), 2930 (w), 2871 (w), 1731 (w), 1675
276 [M]+ ([35Cl], 18), 246 (48), 244 (71), 197 (35), 195 (100).
C12H14Cl2O3 (277.14): calcd. C 52.00, H 5.09; found C 52.09, H
4.84.
(s), 1626 (s), 1600 (m), 1572 (m), 1479 (w), 1465 (w), 1454 (w), 1401
(w), 1373 (m), 1341 (w), 1324 (w), 1287 (w), 1258 (m), 1184 (m),
1146 (w), 1114 (w), 1096 (m), 1017 (s) cm–1. MS (GC-MS, 70 eV):
m/z (%) = 348 [M]+ (38), 149 (42), 148 (100), 133 (38). HRMS (EI):
calcd. for C18H17O5Cl [M]+ 348.07590; found 348.07127.
Procedure for the Synthesis of Benzophenones 19a–i: TMSOTf
(0.3 equiv.) was added at 0 °C to a formylchromone (18a–i,
1.0 equiv.). After the system had been stirred for 5 min, dichloro-
methane (15 mL) and diene 3a or 3b (1.3 equiv.) were added. The
solution was allowed to warm to ambient temperature over 12 h
with stirring. Hydrochloric acid (10%) was added to the mixture
Ethyl 3-Chloro-2-hydroxy-5-(2-hydroxy-5-isopropylbenzoyl)benzoate
(19d): Compound 19d was isolated as a white solid (0.158 g, 44%)
from 18d (0.216 g, 1.0 mmol), Me3SiOTf (0.05 mL, 0.3 mmol) and
3b (0.402 g, 1.3 mmol) in CH2Cl2 (15 mL); m.p. 62–63 °C. 1H
Eur. J. Org. Chem. 2009, 5854–5867
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5865

V. Wolf, M. Adeel, S. Reim, A. Villinger, C. Fischer, P. Langer
FULL PAPER
NMR (250 MHz, [D6]DMSO): δ = 3.68 (s, 3 H, OCH3), 5.44 (s, 1 42%) from 18h (253 mg, 1.0 mmol), 3b (401 mg, 1.3 mmol) and
H, CH) ppm. 13C NMR (63 MHz, [D6]DMSO): δ = 51.7 (OCH3), Me3SiOTf (0.05 mL, 0.3 mmol); m.p. 133–135 °C. 1H NMR
93.5 (CH), 111.4 (C–Cl), 144.7 (C), 154.4 (COH), 162.1, 163.1 (250 MHz, CDCl3): δ = 1.36 (t, J = 7.2 Hz, 3 H, CH3), 4.37 (q, J
(C=O) ppm. IR (ATR): ν = 2983 (w), 2943 (w), 2909 (w), 2883 (w),
= 7.2, 14.2 Hz, 2 H, OCH2), 6.90 (d, J = 8.8 Hz, 1 H, ArH), 7.51–
˜
1724 (s), 1643 (w), 1608 (w), 1461 (w), 1405 (w), 1369 (m), 1348 7.60 (m, 2 H, ArH), 7.8 (d, J = 2.1 Hz, 1 H, ArH), 8.09 (d, J =
(w), 1299 (m), 1258 (s), 1176 (s), 1098 (m), 1067 (w), 1020 (s) cm–1. 2.1 Hz, 1 H, ArH), 11.50 (s, 1 H, OH), 11.88 (s, 1 H, OH) ppm.
MS (GC-MS, 70 eV): m/z (%) = 178 [M]+ (2), 94 (11), 57 (100). 13C NMR (62 MHz, CDCl3): δ = 14.0 (CH3), 62.7 (OCH2), 110.4,
HRMS (EI): calcd. for C11H13O3Cl [M]+ 228.05477; found
228.054628.
113.5, 119.8, (C), 120.7 (CH), 123.2, 128.3 (C), 130.4, 134.5, 136.0,
139.1 (CH), 160.8, 161.9 (C–OH), 169.2, 196.6 (C=O) ppm. IR
(neat): ν = 3068 (w), 2917 (w), 1686 (s), 1625 (s), 1595 (s), 1567 (s),
˜
Ethyl
3-Chloro-2-hydroxy-5-(2-hydroxy-5-nitrobenzoyl)benzoate
1343 (s), 1164 (s), 681 (s) cm–1. MS (GC = 70 eV): m/z (%): 401
[M]+ ([37Cl], 12), 399 [M]+ (77), 354 (33), 200 (100), 198 (75), 154
(67). HRMS (EI): calcd. for C16H12BrClO5 [M]+ (35Cl, 81Br):
399.95307; found 399.952332.
(19e): Compound 19e was isolated as a light yellow solid (141 mg,
40%) from 18e (219 mg, 1.0 mmol), 3b (401 mg, 1.3 mmol) and
Me3SiOTf (0.05 mL, 0.3 mmol); m.p. 159–161 °C. 1H NMR
(250 MHz, CDCl3): δ = 1.34 (t, J = 7.1 Hz, 3 H, CH3), 4.36 (q, J
= 7.2, 14.2 Hz, 2 H, OCH2), 7.12 (d, J = 9.3 Hz, 1 H, ArH), 7.93
(d, J = 2.62 Hz, 1 H, ArH), 8.14 (d, J = 2.35 Hz, 1 H, ArH), 8.32
(dd, J = 3.0, 9.3 Hz, 1 H, ArH), 8.50 (d, J = 2.5 Hz, 1 H, ArH),
11.99 (s, 1 H, OH), 12.29 (s, 1 H, OH) ppm. 13C NMR (62 MHz,
CDCl3): δ = 14.0 (CH3), 62.9 (OCH2), 113.6, 117.5 (C), 119.7 (CH),
123.8, 127.4 (C), 128.7, 130.5, 131.0, 136.0 (CH), 139.5 (C), 161.3,
Ethyl 3-Chloro-5-(3,5-dibromo-2-hydroxybenzoyl)-2-hydroxybenzo-
ate (19i): Compound 19i was isolated as a yellow solid (0.360 g,
75%) from 19i (0.332 g, 1.0 mmol), Me3SiOTf (0.05 mL, 0.3 mmol)
and 3b (0.402 g, 1.3 mmol) in CH2Cl2 (15 mL); m.p. 166–169 °C.
1H NMR (250 MHz, CDCl3): δ = 1.43 (t, 3J = 7.1 Hz, 3 H,
OCH2CH3), 4.48 (q, 3J = 7.1 Hz, 2 H, OCH2CH3), 7.64 (d, 4J =
167.7 (C-OH), 169.1, 196.6 (C=O) ppm. IR (neat): ν = 2919 (m),
˜
4
4
2.2 Hz, 1 H, CH), 7.91 (d, J = 2.2 Hz, 1 H, CH), 7.95 (dd, J =
2850 (w), 1682 (m), 1632 (m), 1460 (m), 1336 (s) cm–1. MS (GC =
70 eV): m/z (%): 367 [M]+ ([37Cl], 21), 365 [M]+ (77), 329 (7), 319
(100), 283 (16), 154 (58). HRMS (EI): calcd. for C16H12NClO7
[M]+ ([35Cl]): 365.02919; found 365.029150.
4
4
2.2 Hz, 1 H, CH), 8.16 (d, J = 2.2 Hz, 1 H, CH), 11.99 (d, J =
0.5 Hz, 1 H, OH), 12.13 (d, 4J = 0.5 Hz, 1 H, OH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1 (OCH2CH3), 62.8 (OCH2CH3), 110.4,
113.5, 120.4, 123.5, 127.7 (C), 130.6, 133.8, 136.0, 141.4 (CH),
Ethyl
3-Chloro-5-(5-fluoro-2-hydroxybenzoyl)-2-hydroxybenzoate
158.4, 161.1 (COH), 169.1, 196.2 (C=O) ppm. IR (ATR): ν = 3070
˜
(19f): Compound 19f was isolated as a yellow solid (0.116 g, 34%)
from 18f (0.192 g, 1.0 mmol), Me3SiOTf (0.05 mL, 0.3 mmol) and
3b (0.402 g, 1.3 mmol) in CH2Cl2 (15 mL); m.p. 104–108 °C. 1H
NMR (250 MHz, CDCl3): δ = 1.42 (t, 3J = 7.1 Hz, 3 H,
(w), 2979 (w), 2930 (w), 2872 (w), 1723 (w), 1714 (w), 1681 (w),
1651 (w), 1651 (w), 1626 (s), 1590 (m), 1566 (m), 1552 (m), 1444
(m), 1405 (w), 1377 (s), 1339 (s), 1300 (s), 1256 (m), 1227 (s), 1174
(m), 1096 (w), 1016 (w), 1001 (w) cm–1. MS (GC-MS, 70 eV): m/z
(%) = 476 [M]+ (23), 280 (56), 279 (53), 278 (100), 276 (47), 200
(40), 181 (60), 154 (92). HRMS (EI): calcd. for C16H11O5Br2Cl
[M]+ 475.86563; found 475.864230.
3
OCH2CH3), 4.48 (q, J = 7.1 Hz, 2 H, OCH2CH3), 7.03–7.09 (m,
1 H, CH), 7.21–7.24 (m, 1 H, CH), 7.26–7.32 (m, 1 H, CH), 7.94
4
4
(d, J = 2.2 Hz, 1 H, CH), 8.17 (d, J = 2.2 Hz, 1 H, CH), 11.41
(s, 1 H, OH), 11.95 (s, 1 H, OH) ppm. 13C NMR (63 MHz, CDCl3):
δ = 14.1 (OCH2CH3), 62.8 (OCH2CH3), 113.6 (C), 117.2, 117.6
(CH), 120.0, 120.1 (CH), 123.2 (C), 123.9, 124.3 (CH), 128.5 (C),
130.2 136.0 (CH), 159.2, 160.7 (COH), 169.3, 196.9 (C=O) ppm.
19F NMR (CDCl3, 235 MHz): δ = –123.5 (CF3) ppm. IR (ATR):
Acknowledgments
Financial support from the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
ν = 3074 (w), 3001 (w), 2986 (w), 2929 (w), 1678 (m), 1638 (m),
˜
1617 (m), 1581 (m), 1475 (s), 1412 (m), 1376 (m), 1347 (s), 1336
(s), 1317 (m), 1285 (s), 1261 (s), 1240 (m), 1210 (s), 1194 (s), 1144
(s), 1099 (s), 1016 (m) cm–1. MS (GC-MS, 70 eV): m/z (%) = 340
[M]+ ([37Cl], 30), 338 [M]+ ([35Cl], 87), 292 (43), 154 (90), 139 (100).
HRMS (EI): calcd. for C16H12ClFO5 [M]+ 338.03518; found
338.035409.
[1] a) T. Sala, M. V. Sargent, J. Chem. Soc., Perkin Trans. 1 1981,
849; b) A. A. Birkbeck, M. V. Sargent, J. A. Elix, Aust. J.
Chem. 1990, 43, 419; c) M. M. Mahandru, A. Tajbakhsh, J.
Chem. Soc., Perkin Trans. 1 1983, 413; d) J. A. Elix, U. A. Jenie,
L. Arvidsson, P. M. Joergensen, P. W. James, Aust. J. Chem.
1986, 39, 719; e) J. Nielsen, P. H. Nielsen, J. C. Frisvad, Phyto-
chemistry 1999, 50, 263.
Methyl 3-Chloro-5-(5-chloro-2-hydroxybenzoyl)-2-hydroxybenzoate
(19g): Compound 19g was isolated as a yellow solid (0.112 g, 33%)
from 18g (0.209 g, 1.0 mmol), Me3SiOTf (0.05 mL, 0.3 mmol) and
3a (0.383 g, 1.3 mmol) in CH2Cl2 (15 mL); m.p. 151–154 °C. 1H
[2] a) K. Sakata, H. Masago, A. Sakurai, N. Takahashi, Tetrahe-
dron Lett. 1982, 23, 2095; b) H. Tomozane, Y. Takeuchi, T.
Choshi, S. Kishida, M. Yamato, Chem. Pharm. Bull. 1990, 38,
925; c) T. Oda, Y. Yamaguchi, Y. Sato, Chem. Pharm. Bull.
1986, 34, 858; d) G. N. Belofsky, K. B. Gloer, J. B. Gloer, D. T.
Wicklow, P. F. Dowd, J. Nat. Prod. 1998, 61, 1115. Griseoful-
vin: e) C. S. Osborne, I. Leitner, B. Hofbauer, C. A. Fielding,
B. Favre, N. S. Ryder, Antimicrob. Agents Chemother. 2006, 50,
2234; f) R. Takano, K. Sugano, A. Higashida, Y. Hayashi, M.
Machida, Y. Aso, S. Yamashita, Pharm. Res. 2006, 23, 1144;
g) C. Xue, T. Li, Z. Deng, H. Fu, W. Lin, Pharmazie 2006, 61,
1041; h) J. B. Phelps, W. P. Hoffman, C. Lee, G. P. Murphy,
M. L. Garriott, Mutat. Res. 2004, 561, 153; i) C. Rosefort, E.
Fauth, H. Zankl, Mutagenesis 2004, 19, 277; j) R. T. Kinobe,
R. A. Dercho, J. Z. Vlahakis, J. F. Brien, W. A. Szarek, K. Nak-
atsu, J. Pharmacol. Exp. Ther. 2006, 319, 277; k) D. Albaugh,
G. Albert, P. Bradford, V. Cotter, J. Froyd, J. Antibiot. 1998,
51, 317. Epigriseofulvin: l) M. Namikoshi, H. Kobayashi, T.
3
NMR (250 MHz, CDCl3): δ = 4.02 (s, 3 H, OCH3), 7.05 (dd, J =
5
4
8.5, J = 0.6 Hz, 1 H, CH), 7.45–7.51 (m, 2 H, CH), 7.94 (d, J =
4
2.2 Hz, 1 H, CH), 8.15 (d, J = 2.2 Hz, 1 H, CH), 11.54 (s, 1 H,
OH), 11.85 (s, 1 H, OH) ppm. 13C NMR (63 MHz, CDCl3): δ =
53.3 (OCH3), 113.2, 119.4 (C), 120.3 (CH), 123.3, 123.7, 128.5 (C),
130.2, 131.5, 136.2, 136.4 (CH), 160.7, 161.5 (COH), 169.7, 196.8
(C=O) ppm. IR (ATR): ν = 3077 (w), 2959 (w), 2920 (w), 2851 (w),
˜
1697 (m), 1629 (m), 1600 (m), 1568 (m), 1464 (m), 1436 (m), 1353
(s), 1322 (m), 1286 (m), 1258 (m), 1223 (s), 1192 (s), 1160 (s), 1104
(m) cm–1. MS (GC-MS, 70 eV): m/z (%) = 342 [M]+ ([37Cl], 30),
340 [M]+ ([35Cl], 44), 308 (16), 155 (50), 154 (100). C15H10Cl2O5
(341.14): calcd. C 52.81, H 2.95; found C 52.66, H 3.13.
Ethyl
5-(5-Bromo-2-hydroxybenzoyl)-3-chloro-2-hydroxybenzoate
(19h): Compound 19h was isolated as a light yellow solid (170 mg,
5866
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5854–5867

Diversity-Oriented Synthesis of Chlorinated Arenes
Yoshimoto, S. Meguro, K. Akano, Chem. Pharm. Bull. 2000,
48, 1452.
[3] a) P. Steyn, G. Vleggaar, J. Chem. Soc., Perkin Trans. 1 1974,
2250; b) G. N. Belofsky, K. B. Gloer, J. B. Gloer, D. T. Wick-
low, P. F. Dowd, J. Nat. Prod. 1998, 61, 1115.
[4] See, for example, 6-demethylchlortetracyclin: G. Olack, H.
Morrison, J. Org. Chem. 1991, 56, 4969.
[5] K. Nozawa, S. Nakajima, M. Yamada, K.-i. Kawai, Chem.
Pharm. Bull. 1980, 28, 1622.
Kawano, Y. Kimura, Z. Naturforsch., Teil B 2001, 56, 797. Pes-
talone: e) M. Cueto, P. R. Jensen, C. Kauffman, W. Fenical, E.
Lobkovsky, J. Clardy, J. Nat. Prod. 2001, 64, 1444; f) D. Iijima,
D. Tanaka, M. Hamada, T. Ogamino, Y. Ishikawa, S. Nishi-
yama, Tetrahedron Lett. 2004, 45, 5469. Methyl chloroas-
terrate: g) J. Hargreaves, J.-o. Park, E. L. Ghisalberti, K. Sivasi-
thamparam, B. W. Skelton, A. H. White, J. Nat. Prod. 2002,
65, 7; h) H. J. Lee, J. H. Lee, B. Y. Hwang, H. S. Kim, J. J. Lee,
J. Antibiot. 2002, 55, 552.
[6] a) S. Wei, J. Chu, Experientia 1974, 30, 174; b) H. Sasaki, T.
Hosokawa, M. Sawada, K. Ando, J. Antibiot. 1973, 26, 676; c)
R. Hunter, G. Mellows, Tetrahedron Lett. 1978, 19, 5051.
[7] a) H. J. Kwon, M. Yoshida, K. Abe, S. Horinouchi, T. Beppu,
Biosci. Biotechnol. Biochem. 1992, 56, 538; b) M. Lampilas, R.
Lett, Tetrahedron Lett. 1992, 33, 777; c) A. J. Elix, C. E. Bar-
clay, H. T. Lumbsch, J. H. Wardlaw, Aust. J. Chem. 1997, 50,
971. Bazzanin: d) U. Martin, J. Zapp, H. Becker, Phytochemis-
try 1998, 47, 89.
[8] H.-W. Zhang, W.-Y. Huang, Y.-C. Song, J.-R. Chen, R.-X. Tan,
Helv. Chim. Acta 2005, 88, 2861.
[9] Flambamycin: a) W. D. Ollis, C. Smith, D. E. Wright, Tetrahe-
dron 1979, 35, 105. Everninomicin: b) Schering Co., Kenil-
worth, N. J. (USA); US 3920629, 1975; Chem. Abstr. 1975, 84,
90526.
[19] Falconensin B: T. Itabashi, K. Nozawa, M. Miyaji, S.-i. Uda-
gawa, S. Nakajima, K.-i. Kawai, Chem. Pharm. Bull. 1992, 40,
3142.
[20] Chromones: N. Kawamura, R. Sawa, Y. Takahashi, K. Issiki,
T. Sawa, J. Antibiot. 1995, 48, 435.
[21] U. Hoeller, G. Koening, A. D. Wright, J. Nat. Prod. 1999, 62,
114.
[22] a) S. Harkal, K. Kumar, D. Michalik, A. Zapf, R. Jackstell, F.
Rataboul, T. Riermeier, A. Monsees, M. Beller, Tetrahedron
Lett. 2005, 46, 3237, and references cited therein; b) S. Harkal,
F. Rataboul, A. Zapf, C. Fuhrmann, T. H. Riermeier, A. Mon-
sees, M. Beller, Adv. Synth. Catal. 2004, 346, 1742.
[23] Metal-Catalyzed Cross-Coupling Reactions (Eds: A. de Meijere,
F. Diederich), Wiley-VCH, Weinheim, 2004.
[24] J. Savard, P. Brassard, Tetrahedron Lett. 1979, 20, 4911.
[25] C. Corral, J. Lissavetzky, I. Manzanares, Synthesis 1997, 29.
[26] a) T.-H. Chan, P. Brownbridge, J. Am. Chem. Soc. 1980, 102,
3534; b) P. Brownbridge, T.-H. Chan, M. A. Brook, G. J. Kang,
Can. J. Chem. 1983, 61, 688.
[10] T. Oda, Y. Yamaguchi, Y. Sato, Chem. Pharm. Bull. 1986, 34,
858.
[11] 4-O-Methylarmillaridin: a) D. M. X. Donnelly, R. M. Hutchin-
son, Phytochemistry 1990, 29, 179. Melledonal B: b) A. Ar-
none, R. Cardillo, G. Nasini, S. V. J. Meille, J. Chem. Soc., Per-
kin Trans. 1 1988, 503.
[27] For a review of 1,3-bis(trimethylsilyloxy)-1,3-dienes in general,
see: P. Langer, Synthesis 2002, 441.
[12] a) S. Jinno, K. Hata, N. Shimidzu, T. Okita, J. Antibiot. 1998, [28] For a review of [3+3] cyclizations, see: H. Feist, P. Langer, Syn-
51, 508; b) S. Jinno, T. Okita, Chem. Pharm. Bull. 1998, 46,
1688; c) O. Papendorf, G. M. Koenig, A. D. Wright, Phyto-
chemistry 1998, 49, 2383; d) F. Bohlmann, W. Knauf, L. N.
Misra, Tetrahedron 1984, 40, 4987. Methoxymicareic acid: e)
J. A. Elix, A. J. Jones, L. Lajide, B. J. Coppins, P. W. James,
Aust. J. Chem. 1984, 37, 2349.
thesis 2007, 327.
[29] M. A. Yawer, I. Hussain, S. Reim, Z. Ahmed, E. Ullah, I.
Iqbal, C. Fischer, H. Reinke, H. Görls, P. Langer, Tetrahedron
2007, 63, 12562.
[30] S. Reim, I. Hussain, M. Adeel, M. A. Yawer, A. Villinger, P.
Langer, Tetrahedron Lett. 2008, 49, 4901.
[13] B. S. Falch, G. M. Koenig, A. D. Wright, O. Sticher, J. Org.
Chem. 1993, 58, 6570.
[14] Dihydronidulin: P. F. Finlay-Jones, T. Sala, M. V. Sargent, J.
Chem. Soc., Perkin Trans. 1 1981, 874.
[31] S. Reim, P. Langer, Tetrahedron Lett. 2008, 49, 2329.
[32] CCDC-745592 to -745595 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[33] M. Lubbe, R. Klassen, T. Trabhardt, A. Villinger, P. Langer,
Synlett 2008, 2331.
[15] Geodin: a) T. Katoh, O. Ohmori, Tetrahedron Lett. 2000, 41,
465; b) I. Fujii, H. Iijima, Y. Ebizuka, U. Sankawa, Chem.
Pharm. Bull. 1983, 31, 337; c) T. Katoh, O. Ohmori, K. Iwa-
saki, M. Inoue, Tetrahedron 2002, 58, 1289.
[34] M. Lubbe, J.-P. Gütlein, H. Reinke, P. Langer, Synlett 2008,
2671.
[16] Geodinhydrate methyl ester: a) J. Hargreaves, J.-o. Park, E. L.
Ghisalberti, K. Sivasithamparam, B. W. Skelton, A. H. White, [35] C. Mamat, S. Büttner, T. Trabhardt, C. Fischer, P. Langer, J.
J. Nat. Prod. 2002, 65, 7.
Org. Chem. 2007, 72, 6273.
[17] 7-Chloro-1-O-methylemodin: a) P. A. Cohen, G. H. N. Towers,
Phytochemistry 1996, 42, 1325; b) Y.-Z. Shu, M. Arcuri, M. R.
Kozlowski, R. R. Wang, K. S. Lam, J. Antibiot. 1994, 47, 1328;
c) P. A. Cohen, J. B. Hudson, G. H. N. Towers, Experientia
1996, 52, 180.
[36] a) R. Ruegg, H. Lindlar, M. Montavon, G. Savey, S. T. Scha-
eren, U. Schwieter, O. Isler, Helv. Chim. Acta 1959, 42, 844; b)
R. Ruegg, H. Lindlar, M. Montavon, G. Savey, S. T. Schaeren,
U. Schwieter, O. Isler, Helv. Chim. Acta 1959, 42, 859.
[37] M. Sher, Z. Ahmed, M. A. Rashid, C. Fischer, P. Langer, J.
Org. Chem. 2007, 72, 6284.
[18] a) A. M. Ahad, Y. Goto, F. Kiuchi, Y. Tsuda, K. Kondo, T.
Sato, Chem. Pharm. Bull. 1991, 39, 1043; b) Y.-J. Kim, H. Nish-
ida, C.-H. Pang, T. Saito, S. Shinichi, H. Tonai-Kachi, N.
Yoshikawa, M. A. Vanvolkenburg, J. C. Parkerf, Y. Kojima, J.
Antibiot. 2002, 55, 121. Longissiminone B: c) M. I. Choudhary,
M. Azizuddin, S. Jalil, Atta-ur-Rahman, Phytochemistry 2005,
66, 2346. Chloroisosulochrin: d) A. Shimada, I. Takahashi, T.
[38] G. Bose, V. T. H. Nguyen, E. Ullah, S. Lahiri, H. Görls, P.
Langer, J. Org. Chem. 2004, 69, 9128.
[39] B. Appel, S. Rotzoll, H. Reinke, P. Langer, Eur. J. Org. Chem.
2006, 3638.
Received: July 20, 2009
Published Online: September 29, 2009
Eur. J. Org. Chem. 2009, 5854–5867
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5867