Regioselective synthesis of salicylates and acetophenones by formal [3+3]-cyclocondensations of 3-oxoorthoesters with 1,3-bis(trimethylsilyloxy)-1,3-butadienes

Z. Naturforsch. 2021; 76(1)b: 1–26

Jörg-Peter Gütlein, Mathias Lubbe, Holger Feist, Alexander Villinger and Peter Langer*

Regioselective synthesis of salicylates and

acetophenones by formal [3+3]-

cyclocondensations of 3-oxoorthoesters with

1,3-bis(trimethylsilyloxy)-1,3-butadienes

https://doi.org/10.1515/znb-2020-0114

Received June 30, 2020; accepted October 15, 2020;

published online December 10, 2020

Phenols, naphthols and salicylates were prepared by a

biomimetic approach developed by Harris and coworkers

[25 –31]. The condensation of 1,3-dicarbonyl dianions or

1,3,5-tricarbonyl trianions with carboxylic acid derivatives

result in the formation of unstable 1,3,5,7-tetracarbonyl

compounds which are rapidly converted to poly-

hydroxylated arenes by intramolecular aldol condensation

reactions.

Abstract: A variety of 4-methoxysalicylates and related

polyketide-type phenols are regioselectively prepared by

formal [3+3] cyclocondensations of 1,3-bis(trimethylsilyloxy)-

1,3-butadienes with 3-oxo-orthoesters. Cycloalkyl-substituted

salicylates were prepared for the ﬁrst time.

1,3-Bis(silyloxy)-1,3-butadienes can be regarded as

masked 1,3-dicarbonyl dianions [32, 33]. Chan and Brown-

bridge were the ﬁrst to report formal [3+3] cyclocondensation

reactions of 1,3-bis(silyloxy)-1,3-butadienes with 3-silyloxy-

2-en-1-ones [32]. These reactions provide a convenient

approach to salicylates. In recent years, we have devel-

oped new types of [3+3] cyclocondensation reactions of

1,3-bis(silyloxy)-1,3-butadienes using a variety of different

1,3-dielectrophiles [34, 35]. Chan and Stössel reported the

synthesis of 4-hydroxysalicylates by TiCl₄-mediated formal

[5+1] cyclization of 1-methoxy-1,3,5-tris(trimethylsiloxy)-

1,3,5-hexatriene with acid chlorides or imidazolides [36, 37].

Disadvantages of this method are the limited availability of

the used 1-methoxy-1,3,5-tris(trimethylsilyloxy)-1,3,5-hexatriene

and their low stability.

We were able to synthesize highly functionalized 4-ethyl-

6-hydroxysalicylates and 6-ethyl-4-hydroxysalicylates by

TiCl₄-activated cyclization of 1,3-bis(silyloxy)-1,3-butadienes

with 3,3-dimethoxypentanoyl chloride [38]. Later, we reported

the cyclization of 1,3-bis(silyloxy)-1,3-butadienes with tetra-

methoxymethane yielding 4-alkoxy-6-(alkoycarbonylethyl)sa-

licylates [39]. Furthermore, TiCl₄-mediated 2:1 reaction of

1-methoxy-1,3-bis(trimethylsiloxy)buta-1,3-diene with trimetyl

orthoformiate or trimethyl orthoacetate, respectively, was

reported to give hydroxyhomophthalates [40].

Keywords: cyclizations; phenols; regioselectivity; salicy-

lates; silyl enol ethers.

1 Introduction

Phenolic compounds are widely distributed in higher

plants [1 –4]. At least eight thousand naturally occurring

phenolic compounds are known [5]. As secondary metab-

olites they play multiple essential roles in plant physi-

ology. In addition to their functions in plants, phenolic

compounds are important for a healthy human diet.

Moreover, they can act as antioxidants [4, 6 –8], showing

anti-inﬂammatory [9 –11], anti-microbial [2, 12, 13], enzyme

inhibiting [14, 15], anti-cancer [16, 17] and other activities.

With regard to their structure, the most important

groups of natural phenolic compounds are flavonoids,

phenolic acids and tannins. Naturally occurring phenolic

acids [18 –21] are present in the organisms in the form of

their esters, glycosides or amides, but rarely in free form.

Highly substituted phenols are often biosynthetically

derived from poly(β-oxo)carboxylic acids (polyketides)

[22 –24].

Some years ago, we described our preliminary results

related to the cyclocondensation of 1,3-bis(silyloxy)-

1,3-butadienes with 3-oxoorthoesters [41]. This trans-

formation is, to the best of our knowledge, a new type of

[3+3] cyclocondensation reaction which facilitates the

synthesis of a series of 4-methoxysalicylates containing an

alkyl or cycloalkyl group in position 6 which are not readily

available by other methods. In a number of cases, these

*Corresponding author: Peter Langer, Institut für Chemie, Universität

Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany; and

Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-

Einstein-Str. 29a, 18059 Rostock, Germany, E-mail: peter.langer@uni-

rostock.de. https://www.langer.chemie.uni-rostock.de/

Jörg-Peter Gütlein, Mathias Lubbe, Holger Feist and Alexander

Villinger, Institut für Chemie, Universität Rostock, Albert-Einstein-Str.

3a, 18059 Rostock, Germany

2

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

Table : Synthesis of a–n.

salicylates carry an additional substituent in the 2 position.

This reaction, thus, represents an extension of our meth-

odology to synthesize a broad set of highly functionalized

protected or non-protected 4-hydroxysalicylates as many

natural occurring salicylates contain a free or masked

hydroxyl group at this position. Herein, we report a

comprehensive study which includes a great extension of

the scope with regard to our short communication. For

example, salicylates containing cycloalkyl substituents

were prepared for the ﬁrst time by [3+3] cyclizations.

, , 

R

Yields (%)^a







a

b

c

d

e

f

Me

Et

nPr

iPr

cPr

cBu















































g

h

i

cPent

cHex

(CH_)_(cPent)

C_H_

j











2 Results and discussion

k

l

C_H_

Ph

The 3-oxoorthoesters 5, required as starting material for the

synthesis of the desired 4-methoxysalicylates 7, are pre-

pared in two steps according to known literature proced-

ures (Scheme 1, Table 1). In a ﬁrst AlCl₃-mediated step,

1,1-dichloroethylene (2) is reacted with various acid chlo-

rides 1 yielding either a 3,3,3-trichloroketone 3 or a

3,3-dichloroenon 4 [42 –44]. During the following reaction

of compounds 3 or 4 with methanol the corresponding

3-oxo-trimethyl orthoesters 5 are formed in good over-

all yields (except for 5e) [45]. According to the literature it is

known [42 –44, 46, 47] that the reaction of

1,1-dichloroethylene (2) with acid chlorides provides an

access to 3,3,3-trichloroketones or 3,3-dichloroenones,

whereby the dichloroenones are formed from the initially

formed trichloroketones by elimination of HCl. Due to this

reaction behaviour and the possibility to form two prod-

ucts, problems appeared regarding the puriﬁcation of

compounds 3 and 4. Furthermore, it was difﬁcult to get the

3-oxoorthoesters 5 in an analytically pure form. So we

decided to use the chlorinated compounds 3 and 4 as well

as orthoesters 5 in crude form for the following reactions

without further puriﬁcation. The synthesis of 5a [45, 46]

and 5c [45] has been previously reported.

m

n

-ClC_H_

-Furfuryl

^aYields of isolated products.

one step from the corresponding 1,3-diketones [48],

respectively.

At the beginning, we studied the employment of

3-oxoorthoester 5a, derived from acetyl chloride (1a), in

the TiCl₄-mediated [3+3] cyclization reactions with simple

1,3-bis(trimethylsilyloxy)-1,3-butadiens 6a–d. These re-

actions resulted in regioselective formation of acetophenone

7a and of 4-methoxy-6-methylsalicylates 7b–d. The forma-

tion of the regioisomeric 6-methoxy-4-methylsalicylates was

not observed. The most efﬁcient reaction conditions were

determined in optimization experiments (Scheme 3),

whereby 5, 6 and TiCl₄were employed in a stoichiometric

ratio of 1:2:1 and the reactions were carried out in relatively

concentrated solutions (c(5) = 0.5 M).

A possible mechanistic course is illustrated by the re-

action of 5a with 6a (Scheme 2). Intermediate A is formed by

TiCl₄-mediated attackoftheterminal carbonatomof6aonto

the orthoester functionality of5a. Asa result of the following

cyclization, by attack of the central carbon atom of the

dicarbonyl moiety to the TiCl₄-activated keto function of the

former 3-ketoorthoester, 1,4-cyclohexadien B is generated

under extrusion of methoxytrimethylsilane. Finally,

aromatization provides intermediate C from which 7a is

liberated by hydrolysis upon aqueous work up. Alterna-

tively, the cyclocondensation may proceed by TiCl₄-medi-

ated transformation of 5a into 4,4-dimethoxybut-3-en-

2-one, conjugate addition of the terminal carbon atom of

6a onto the latter and subsequent cyclization. The conjugate

addition follows the mechanism earlier suggested for the

cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with

3-alkoxy- and 3-silyloxy-2-en-1-ones [32, 34].

According to known literature procedures,

1,3-bis(trimethylsilyloxy)-1,3-butadiens 6 were prepared

from the corresponding ß-ketoesters [32] in two steps or in

Scheme 1: Synthesis of 5a–n; i: AlCl₃, CH₂Cl₂, 20 °C, 2–14 h;

ii: MeOH, 20 °C, 2–14 h.

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

3

Table : Synthesis of a–bt.







R^

R^

R^

Yield  (%)^a

a

b

c

d

e

f

a

b

c

d

a

e

c

f

g

h

e

i

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

ab

ac

ad

ae

af

ag

ah

ai

aj

ak

al

Me

Et

nPr

iPr

H

Me

OMe

OEt

OBn

Me

OMe

OEt

OMe

Ph

O(CH_)_OMe

OMe

OiPr

Me

















































































































Et

Cl

H

Cl

OMe

H

Me

nOctyl OEt

OMe

H

OMe

H

OMe

H

a

j

k

l

Et

OMe

iPr

f

OMe

Me

OMe

O(CH_)_OMe

Me

OMe

OiPr

OiBu

Me

a

e

f

h

a

e

f

nNonyl

nTridecyl

cPr

Scheme 2: Possible mechanism of the formation of 7a; i: (1) TiCl₄

(1.0 equiv.), CH₂Cl₂, –78 → 20 °C, 14 h; (2) HCl (10%).

f

Starting with orthoesters 5 and 1,3-butadienes 6 a great

variety of functionalized 4-methoxysalicylates and aceto-

phenones 6 (72 examples) could be successfully synthe-

sized in moderate to good yields and with very good

regioselectivity (Scheme 3, Table 2). Compounds 6 exhibit a

distinct substitution pattern. Diverse structural variations

could be realized at position 3 and 6 of the aromatic core

structure as well as within the ester function (salicylates) or

in case of the ketones. Substiuents R¹attached to the aro-

matic system include different alkyl and aryl group, a

2-furyl and various cycloalkyl grups. It is noteworthy, that

the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl

groups proved to be compatible with the reaction condi-

tions. No decrease of the yield was observed despite the

steric hindrance of these groups. The cyclopropyl group

g

h

i

e

i

m

a

k

n

l

e

a

k

n

l

f

e

i

m

a

j

k

n

l

f

e

i

m

a

k

n

l

H

Me

nPr

nOctyl OEt

H

Me

nPr

nOctyl OEt

OMe

H

Me

nPr

nOctyl OEt

OMe

H

OMe

cPr

cBu

OMe

Me

OMe

OiPr

OiBu

Me

Et

OMe

am cPent

an

ao

ap

aq

ar

cPent

cHex

as

at

au

av

aw

ax

ay

az

ba

bb

bc

bd

OMe

OiPr

OiBu

Me

j

H

Me

nPr

nOctyl OEt

OMe

Cl

OMe

f

c

OMe

OEt

Scheme 3: Synthesis of 7a–bt; i: (1) TiCl₄(1.0 equiv.),

CH₂Cl₂, –78 → 20 °C, 14 h; (2) HCl (10%).

j

4

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

Table : (continued)

11–13 ppm for the proton of the OH group which suggests

that the proton is involved in an intramolecular hydrogen

bond with the neighbouring ester function. In case of ke-

tones 7, this signal appears more downﬁeld in the range of

13–14 ppm and, therefore, the hydrogen bond seems to be

stronger.

Later, it was possible to grow single crystals of com-

pounds 7ai and 7bo which were used for X-ray crystal

structure analyses. They independently conﬁrm the regio-

selectivity of the cyclization (Figure 2). Again hydrogen

bonds between the OH group and the ester function could

be detected.







R^

R^

R^

Yield  (%)^a

k

l

m

n

e

i

be

bf

bg

bh

bi

bj

bk

bl

(CH_)_cPent

(CH_)_cPent Me

(CH_)_cPent nPr

(CH_)_cPent nOctyl OEt

H

OMe

OiPr

OiBu

Me

Ph

OMe

































m

a

g

k

n

l

f

bm (CH_)_cPent OMe

OMe

Me

OMe

OEt

OMe

OEt

Me

a

e

o

e

o

a

e

bn

bo

bp

bq

br

Ph

-ClC_H_

-Furyl

H

3 Conclusion

bs

bt

OMe

In conclusion, a great variety of 4-methoxysalicylates and

acetophenones were regioselectively prepared by [3+3]

cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes

with 3-oxo-orthoesters. Several functional groups and

substituents were tolerated. Salicylates containing cyclo-

alkyl substituents were prepared for the ﬁrst time by [3+3]

cyclizations.

^aYields of isolated products.

was not cleaved during the reaction, despite the presence

of Lewis acid. To the best of our knowledge, cycloalkyl-

substituted arenes have previously not been synthesized

by formal [3+3] cyclizations. With regard to substituents

R², besides hydrogen alkyl groups, chlorine and the

methoxy group were tolerated without problems. Substit-

uent R³is mainly characterised by aliphatic alkoxy groups

(salicylates) or by different alkyl groups and the phenyl

group (synthesis of phenolic ketones).

4 Experimental section

4.1 General

The structure of all products was established by NMR

measurements and mass spectrometry supplemented by

HRMS and elemental analysis data. The regioselectivity of

If not otherwise indicated, chemicals used in this study

were obtained from commercial sources. No further puri-

fications were done. Solvents, which were employed for

work-up and purification processes, were distilled ac-

cording to standard procedures. Yields refer to isolated

products. ¹H NMR spectra (250.13, 300.13 and 500.13 MHz)

and ¹³C NMR spectra (62.9, 75.5 and 125.8 MHz) were

recorded on Bruker spectrometers AV 250, AV 300 and AV

500 in CDCl₃as solvents. The calibration of spectra was

carried out on solvent signals (CDCl₃: δ (¹H) = 7.25,

δ (¹³C) = 77.0 ppm). IR spectra were detected with Bruker

IFS 66 (FT-IR), Nicolet 205 FT-IR and Nicolet Protégé 460

FT-IR. Mass spectrometric data (MS) were obtained

by electron ionization (EI, 70 eV), chemical ionization

(CI, isobutane) or electrospray ionization (ESI). The mass

spectra and high-resolution mass spectra (HRMS) were

recorded on the following MS instruments: Time-of-Flight

LC/MS 6210 (Agilent Technologies), AMD 402 (AMD

Intectra), Varian MAT CH 7, Varian MAT 311 and Finnigan

MAT 95 XP (Thermo Electron Corporation). Elemental an-

alyses were performed on a C, H, N, S analyser (LECO

CHNS-932, Thermo Quest Flash EA 1112). The melting

1

cyclization was confirmed by H,¹H-NOESY experiments.

For 7a, correlations between the methoxy protons at C-4

with protons H-3 and H-5 of the aromatic ring were

observed. Only one interaction between the methyl protons

at C-6 with the aromatic proton H-5 was detected (Figure 1).

In contrast, for regioisomer 1a′, which was not formed, only

one correlation between the methoxy protons with protons

H-5 and two couplings between the methyl protons and

1

protons H-3 and H-5 would be expected. In the H NMR

spectra, salicylates 7 show a singlet in the range of

Figure 1: NOESY-correlations in compound 1a.

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

5

Figure 2: ORTEP plots of the molecular

structures of 7ai and 7bo in the crystal.

Displacement ellipsoids at the 50%

probability level, hydrogen atoms as

spheres with arbitrary radius.

points were measured with a polarizing microscope (Leitz (³⁷Cl³⁵Cl, 9), 152 [M-HCl]⁺(³⁵Cl³⁵Cl, 14), 127 (11), 125 (67), 123

Laborlux 12 Pol-S) equipped with a hot stage (Mettler FP (100), 60 (11).

90). Thin layer chromatography was performed on silica-

gel foil (Merck DC-foil, silica gel 60, F₂₅₄). Detection was

carried out via UV absorbance at 254 nm or 366 nm and/or

development by treatment with anisaldehyde-methanol-

acetic acid-sulfuric acid (1 mL anisaldehyde in 100 mL of a

solution of 85 mL methanol, 14 mL acetic acid, 1 mL sulfuric

acid) and subsequent heat treatment. Column chroma-

tography was performed on Merck silica gel 60 (particle

size 63–200 nm, 70–230 mesh).

4.2.2 1,1,1-Trichlorododecan-3-one (3j)

Starting with 1j (1.908 g, 10.0 mmol), AlCl₃(1.334 g,

10.0 mmol) and 1,1-dichloroethylene (2, 1.261 g, 13.0 mmol)

in CH₂Cl₂(10 mL) product 3j was isolated as a light-green oil

(2.454 g, 86%). – ¹H NMR (CDCl₃, 300 MHz): δ = 3.80 (s, 2H,

3

CH₂CCl₃), 2.54 (t, J = 7.4 Hz, 2H, COCH₂), 1.26 (br s, 14H,

3

7 × CH₂), 0.88 (t, J = 6.7 Hz, 3H, CH₃). – ¹³C NMR (CDCl₃,

63 MHz): δ = 201.1 (C=O), 92.8 (CCl₃), 63.5, 43.9, 31.8, 29.4,

29.3, 29.2, 29.0, 23.4, 22.6 (CH₂), 14.1 (CH₃). – MS (EI, 70 eV):

m/z (%) = 286 [M]⁺(³⁵Cl³⁵Cl³⁵Cl, 2), 253 [M-HCl]⁺(³⁷Cl³⁵Cl,

23), 251 [M-HCl]⁺(³⁵Cl³⁵Cl, 36), 215 (14), 174 (30), 155 (89),

140 (67), 138 (100), 125 (52). – HRMS (EI, 70 eV): m/z calcd.

for C₁₂H₂₁Cl₃O [M]⁺(3 × ³⁵Cl): 286.06525; found 286.065757.

4.2 General procedure for the synthesis of

3b, j–n

To a suspension of anhydrous AlCl₃(1.0 equiv.) inmp dry

CH₂Cl₂(1.0 mL mmol⁻¹) 1b, j–n were added dropwise under

stirring and stirring was continued for another 10–20 min.

Then, also under stirring 1,1-dichloroethylene (2, 1.3

equiv.) was added at 20 °C to the reaction mixture and the

stirring was maintained for 2–14 h (DC control). The reac-

tion was quenched by adding water. The organic layer was

separated, washed with a saturated NaHCO₃solution and

with water, dried (Na₂SO₄) and concentrated in vacuo. The

remaining oil of the 3,3,3-trichloroketones can be con-

verted into the 3-oxoorthoesters 5b, j–n without further

puriﬁcation.

4.2.3 1,1,1-Trichlorohexadecan-3-one (3k)

Starting with 1k (2.469 g, 10.0 mmol), AlCl₃(1.334 g,

10.0 mmol) and 1,1-dichloroethylene (2, 1.261 g, 13.0 mmol)

in CH₂Cl₂(10 mL) product 3k was isolated as a light-green

1

oil (2.793 g, 82%). – H NMR (CDCl₃, 300 MHz): δ = 3.80

(s, 2H, CH₂CCl₃), 2.54 (t, ³J = 7.4 Hz, 2H, COCH₂), 1.25 (br s,

3

22H, 11 × CH₂), 0.88 (t, J = 6.7 Hz, 3H, CH₃). – ¹³C NMR

(CDCl₃, 63 MHz): δ = 201.1 (C=O), 92.8 (CCl₃), 63.5,

43.9, 31.9, 29.6, 29.6, 29.4, 29.3, 29.0, 23.4, 22.7 (CH₂), 14.1

(CH₃). – HRMS (ESI): m/z calcd. for C₁₆H₃₀Cl₃O [M+H]⁺

(3 × ³⁵Cl): 343.13568; found 343.13554.

4.2.1 1,1,1-Trichloropentan-3-one (3b)

4.2.4 1-Phenyl-3,3,3-trichlorpropan-1-one (3l)

Starting with 1b (0.926 g, 10.0 mmol), AlCl₃(1.334 g,

10.0 mmol) and 1,1-dichloroethylene (2, 1.261 g, 13.0 mmol) Starting with 1l (1.406 g, 10.0 mmol), AlCl₃(1.334 g,

in CH₂Cl₂(10 mL) product 3b was isolated as a light-green 10.0 mmol) and 1,1-dichloroethylene (2, 1.261 g, 13.0 mmol)

1

oil (1.734 g, 92%). – H NMR (CDCl₃, 300 MHz): δ = 3.82 in CH₂Cl₂(10 mL) product 3l was isolated as a light-green oil

3

(s, 2H, CH₂CCl₃), 2.59 (q, J = 7.3 Hz, 2H, CH₂CH₃), 1.11 (2.707 g, 97%). – ¹H NMR (CDCl₃, 250 MHz): δ = 7.99–7.96

(t, ³J = 7.3 Hz, 3H, CH₃). – ¹³C NMR (CDCl₃, 63 MHz): δ = 201.5 (m, 2H, 2 × CH), 7.66–7.61 (m, 1H, CH), 7.54–7.48 (m, 2H,

(C=O), 92.7 (CCl₃), 63.3, 37.2 (CH₂), 7.3 (CH₃). – MS 2× CH), 4.40 (s, 2H, CH₂). – ¹³C NMR (CDCl₃, 75 MHz):

(EI, 70 eV): m/z (%) = 156 [M-HCl]⁺(³⁷Cl³⁷Cl, 2), 154 [M-HCl]⁺δ = 190.6 (C=O), 136.1 (C), 134.0, 128.9, 128.2 (CH), 93.3

6

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

(CCl₃), 59.2 (CH₂). – MS (EI, 70 eV): m/z (%) = 240 [M]⁺oil of the compounds 3e and 4d, f–i can be converted into

(³⁷Cl³⁷Cl³⁵Cl, 3), 238 [M]⁺(³⁷Cl³⁵Cl³⁵Cl, 11), 236 [M]⁺(3 × ³⁵Cl, the 3-oxoorthoesters 5d–i without further puriﬁcation.

12), 105 (100), 77 (37), 51 (12). – HRMS (EI, 70 eV): m/z calcd.

for C₉H₇Cl₃O [M]⁺(3 × ³⁵Cl): 235.95570; found 235.955755.

4.3.1 1,1-Dichloro-4-methyl-pent-1-en-3-one (4d)

Starting with 1d (5.327 g, 50.0 mmol), AlCl₃(6.667 g,

50.0 mmol) and 1,1-dichloroethylene (2, 6.301 g,

65.0 mmol) in CH₂Cl₂(10 mL) product 4d was isolated as a

4.2.5 1-(4-Chlorphenyl)-3,3,3-trichlorpropan-1-one (3m)

Starting with 1m (2.101 g, 12.0 mmol), AlCl₃(1.601 g,

12.0 mmol) and 1,1-dichloroethylene (2, 1.552 g, 16.0 mmol)

in CH₂Cl₂(12 mL) product 3m was isolated as a light-green

1

brown oil (8.187 g, 98%). – H NMR (250 MHz, CDCl₃):

δ = 1.10 (d, ³J = 7.0 Hz, 6H, CH(CH₃)₂), 2.64 (hept, ³J = 6.8 Hz,

1H, CH(CH₃)₂), 6.70 (s, 1H, CH=CCl₂). – ¹³C NMR (63 MHz,

1

oil (2.997 g, 92%). – H NMR (CDCl₃, 250 MHz): δ = 7.91

CDCl₃): δ = 17.7 (CH₃), 41.7 (CHCH₃), 124.9 (CH=CCl₂), 135.2

(d, ³J = 8.8 Hz, 1H, 2 × CH), 7.48 (d, ³J = 8.8 Hz, 1H, 2 × CH),

4.36 (s, 1H, CH₂). – ¹³C NMR (CDCl₃, 75 MHz): δ = 189.4

(C=O), 140.6, 134.4 (C), 129.6, 129.2 (CH), 93.0 (CCl₃), 59.1

(CH₂). – MS (ESI): m/z calcd. for C₉H₆Cl₃O [M-HCl+H]⁺:

234.94783; found 234.94787. – Analysis calcd. for C₉H₆Cl₄O

(271.96): C 39.75, H 2.22; found C 40.04, H 2.05.

−1

˜

(CCl₂), 199.1(C=O). – IR (ATR, cm ): ν ꢀ 2972 (w), 2934 (w),

2874 (w), 1698 (s), 1565 (s), 1465 (m), 1385 (w), 1295 (w), 1177

(w), 1052 (s), 999 (w), 942 (s), 884 (m), 838 (m), 799 (s), 724

(w), 659 (w), 632 (m), 543 (w). – MS (EI): m/z (%) = 168 [M]⁺

(³⁷Cl³⁵Cl, 2), 166 [M]⁺(³⁵Cl³⁵Cl, 3) 138 (13), 127 (11), 125 (67),

123 (100), 60 (12). – Analysis calcd. for C₆H₈Cl₂O (167.03): C

43.14, H 4.83; found C 42.86, H 4.80.

4.2.6 3,3,3-Trichloro-1-(furan-2-yl)propan-1-one (3n)

4.3.2 3,3,3-Trichloro-1-cyclopropylpropan-1-one (3e)

Starting with 1n (1.306 g, 10.0 mmol), AlCl₃(1.334 g,

10.0 mmol) and 1,1-dichloroethylene (2, 1.261 g, 13.0 mmol)

in CH₂Cl₂(10 mL) product 3n was isolated as a brown oil

Starting with 1e (5.227 g, 50.0 mmol), AlCl₃(6.667 g,

50.0 mmol) and 1,1-dichloroethylene (2, 6.301 g,

65.0 mmol) in CH₂Cl₂(10 mL) product 3e was isolated as a

1

(1.944 g, 86%). – H NMR (CDCl₃, 250 MHz): δ = 7.64

(dd, ³J = 1.7 Hz, ⁴J = 0.8 Hz, 1H, CH), 7.33 (dd, ³J = 3.6 Hz,

⁴J = 0.8 Hz, 1H, CH), 6.61 (dd, ³J = 3.6 Hz, ³J = 1.7 Hz, 1H, H-4),

4.25 (s, 2H, CH₂). – ¹³C NMR (CDCl₃, 63 MHz): δ = 179.5

(C=O), 152.1 (C–O), 147.1 (HC–O), 118.6, 112.9 (CH), 92.9

(CCl₃), 59.1 (CH₂). – MS (EI, 70 eV): m/z (%) = 194 [M-HCl]⁺

(³⁷Cl³⁷Cl, 6), 192 [M-HCl]⁺(³⁷Cl³⁵Cl, 31), 190 [M-HCl]⁺

(³⁵Cl³⁵Cl, 48), 164 (27), 162 (42), 125 (15), 123 (23), 95

(100). – HRMS (EI, 70 eV): m/z calcd. for C₇H₄Cl₂O₂[M-HCl]⁺

(2 × ³⁵Cl): 189.95829; found 189.958570.

1

brown oil (8.273 g, 82%). – H NMR (250 MHz, CDCl₃):

δ = 0.87–1.08 (m, 4H, cyclopropyl-CH₂), 2.01–2.16 (m, 1H,

cyclopropyl-CH), 3.96 (s, 2H, CH₂CCl₃). – ¹³C NMR (63 MHz,

CDCl₃): δ = 9.2 (CH₂), 12.8 (CH), 64.4 (CH₂), 92.7 (CCl₃), 181.5

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 3017 (w), 2960 (w), 2667 (w),

2564 (w), 1689 (s), 1571 (s), 1437 (m), 1350 (m), 1295 (m), 1234

(s), 1192 (m), 1066 (m), 930 (s), 894 (m), 821 (m), 693 (m),

645 (m), 541 (w). – MS (EI): m/z (%) = 167 [M–Cl]⁺(³⁷Cl³⁵Cl,

2), 165 [M–Cl]⁺(³⁵Cl³⁵Cl, 3), 138 (32), 125 (64), 123 (100).

4.3.3 3,3-Dichloro-1-cyclobutylprop-2-en-1-one (4f)

4.3 General procedure for the synthesis of

3e and 4d, f–i

Starting with 1f (5.925 g, 50.0 mmol), AlCl₃(6.667 g,

50.0 mmol) and 1,1-dichloroethylene (2, 6.301 g,

To a suspension of anhydrous AlCl₃(1.0 equiv.) in dry 65.0 mmol) in CH₂Cl₂(10 mL) product 4f was isolated as a

1

CH₂Cl₂(1 mL per 5 mmol) cooled in an ice bath acid chlo- brown oil (8.673 g, 97%). – H NMR (250 MHz, CDCl₃):

rides 3d–i were added dropwise under stirring, whereby δ = 1.75–2.30 (m, 6H, cyclobutyl-CH₂), 3.33 (quint,

the temperature should not exceed 20 °C. As soon as a clear ³J = 8.2 Hz, 1H, cyclobutyl-CH), 6.56 (s, 1H, CH=CCl₂). – ¹³

C

solution is obtained 1,1-dichloroethylene (2, 1.3 equiv.) was NMR (75 MHz, CDCl₃): δ = 17.5, 23.9 (CH₂), 46.3 (CH),

added dropwise, again avoiding heating above 20 °C. 125.0 (CH=CCl₂), 135.2 (CCl₂), 196.6 (C=O). – IR (ATR, cm¹):

˜

Stirring was continued for 1 h at 0 °C. The reaction mixture ν ꢀ 2985 (w), 2944 (w), 2866 (w), 1695 (s), 1664 (m), 1569 (s),

was poured on ice (2 g ice per 1 mmol of AlCl₃used) and 1435 (w), 1343 (w), 1288 (m), 1244 (m), 1170 (m), 1123 (m),

extracted with CH₂Cl₂(3 × 1 mL of CH₂Cl₂per 1 mmol of AlCl₃1002 (m), 946 (m), 905 (m), 834 (m), 778 (m), 631 (s). – MS

used). The combined organic phases were washed with (EI): m/z (%) = 180 [M]⁺(³⁷Cl³⁵Cl, 0.10), 178 [M]⁺(³⁵Cl³⁵Cl,

brine (2 × 2 mL per 1 mmol of AlCl₃used), dried over 0.17), 145 [M–Cl]⁺(³⁷Cl, 7), 143 [M–Cl]⁺(³⁵Cl, 23), 125 (68), 123

Na₂SO₄, ﬁltered and concentrated in vacuo. The remaining (100), 55 (64).

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

7

4.3.4 3,3-Dichloro-1-cyclopentylprop-2-en-1-one (4g)

(³⁵Cl³⁵Cl, 0.14), 185 (17), 140 (65), 138 (100), 125 (50), 123

(76). – Analysis calcd. for C₁₀H₁₄Cl₂O (221.12): C 54.32, H

Starting with 1g (5.000 g, 37.70 mmol), AlCl₃(5.027 g, 6.38; found C 53.70, H 6.51.

37.70 mmol) and 1,1-dichloroethylene (2, 4.751 g,

49.0 mmol) in CH₂Cl₂(8 mL) product 4g was isolated as a

1

4.4 General procedure for the synthesis of

brown oil (6.848 g, 94%). – H NMR (250 MHz, CDCl₃):

δ = 1.52–1.89 (m, 8H, cyclopentyl-CH₂), 2.92 (quint,

³J = 7.7 Hz, 1H, cyclopentyl-CH), 6.68 (s, 1H, CH=CCl₂). – ¹³C

NMR (63 MHz, CDCl₃): δ = 25.9, 28.5 (CH₂), 52.4 (CH),

125.7 (CH=CCl₂), 134.8 (CCl₂), 197.8 (C=O). – IR (ATR, cm⁻¹):

5a–n

To a freshly prepared sodium methoxide solution (3.0

equiv. Na) in methanol (0.5 mL mmol⁻¹Natrium) com-

pounds 3 or 4 were added and the resulting reaction

mixture was stirred at 20 °C for 2–4 h (DC control). The

solution was poured on ice and extracted with CH₂Cl₂

(3 × 1 mL mmol⁻¹starting material). The combined organic

phases were washed with water (2 × 1 mL mmol⁻¹starting

material), dried (Na₂SO₄), ﬁltered and concentrated under

reduced pressure. The remaining 3-keto-orthoesters 5a–n

can be used for [3+3] cyclocondensations without further

puriﬁcation.

˜

ν ꢀ 2953 (m), 2869 (w), 1698 (s), 1667 (s), 1450 (w), 1353 (w),

1289 (m), 1233 (w), 1142 (w), 1103 (m), 1050 (m), 965 (m), 935

(m), 908 (m), 835 (m), 796 (m), 633 (m). – MS (EI): m/z

(%) = 194 [M]⁺(³⁷Cl³⁵Cl, 12), 192 [M]⁺(³⁵Cl³⁵Cl, 19), 153 (34),

151 (54), 125 (65), 123 (100), 69 (81). – HRMS (EI): m/z

calcd. for C₈H₁₀Cl₂O [M]⁺(2 × ³⁵Cl): 192.01032; found

192.01104. – Analysis calcd. for C₈H₁₀Cl₂O (193.07): C 49.77,

H 5.22; found C 49.55, H 5.45.

4.3.5 3,3-Dichloro-1-cyclohexylprop-2-en-1-one (4h)

4.4.1 1,1,1-Trimethoxypentan-3-one (5b)

Starting with 1h (7.331 g, 50.00 mmol), AlCl₃(6.667 g,

50.00 mmol) and 1,1-dichloroethylene (2, 6.301 g,

65.0 mmol) in CH₂Cl₂(10 mL) product 4h was isolated as a

Starting with 3b (0.948 g, 5.0 mmol), Na (0.345 g,

15.0 mmol) in methanol (8 mL) product 5b was isolated as a

brown oil (0.821 g, 94%). – H NMR (CDCl₃, 300 MHz):

1

brown oil (9.861 g, 95%). – H NMR (250 MHz, CDCl₃):

δ = 1.20–1.86 (m, 10H, cyclohexyl-CH₂), 2.40 (tt, ³J = 8.6 Hz,

³J = 5.7 Hz, 1H, cyclohexyl-CH), 6.69 (s, 1H, CH=CCl₂). – ¹³C

NMR (63 MHz, CDCl₃): δ = 25.4, 25.7, 28.0 (CH₂), 51.4 (CH),

125.3 (CH=CCl₂), 134.9 (CCl₂), 198.5 (C=O). – IR (ATR, cm⁻¹):

δ = 3.30 (s, 9H, 3 × OCH₃), 2.85 (s, 2H, CH₂COCH₃), 2.59

(q, ³J = 7.3 Hz, 2H, CH₂CH₃), 1.01 (t, ³J = 7.3 Hz, 3H,

CH₂CH₃). – ¹³C NMR (CDCl₃, 63 MHz): δ = 207.2 (C=O), 113.5

(C(OCH₃)₃), 49.9 (OCH₃), 45.5, 36.1 (CH₂), 7.5 (CH₂CH₃).

˜

ν ꢀ 2928 (m), 2853 (m), 1694 (s), 1565 (s), 1449 (m), 1370 (w),

4.4.2 1,1,1-Trimethoxy-4-methylpentan-3-on (5d)

1311 (w), 1288 (m), 1235 (w), 1183 (w), 1143 (m), 1084 (w),

1069 (m), 1009 (m), 947 (s), 877 (m), 835 (m), 790 (m), 737

(m), 636 (m). – MS (EI): m/z (%) = 208 [M]⁺(³⁷Cl³⁵Cl, 5),

206 [M]⁺(³⁵Cl³⁵Cl, 7), 171 (41), 123 (44), 83 (78), 55 (100), 41

(35). – MS (ESI): m/z calcd. for C₉H₁₃Cl₂O [M+H]⁺(2 × ³⁵Cl):

207.03380; found 207.03381.

Starting with 4d (8.161 g, 48.87 mmol), Na (3.450 g,

150.0 mmol) in methanol (50 mL) product 5d was isolated

as a yellow oil (8.051 g, 87%). – ¹H NMR (250 MHz, CDCl₃):

δ = 1.04 (d, ³J = 6.9 Hz, 6H, CH(CH₃)₂), 2.88 (s, 2H, CH₂), 2.92

(hept, ³J = 6.9 Hz, 1H, CH(CH₃)₂), 3.28 (s, 9H, 3 × OCH₃). – ¹³C

NMR (75 MHz, CDCl₃): δ = 18.2 (CH₃), 40.1 (CH), 43.5 (CH₂),

4.3.6 1,1-Dichloro-5-cyclopentylpent-1-en-3-one (4i)

50.0 (OCH₃), 113.6 (C(OCH₃)₃), 210.6 (C=O). – IR (ATR,

−1

˜

cm ): ν ꢀ 2970 (m), 2949 (w), 2839 (w), 1708 (s), 1467 (w),

Starting with 1i (6.426 g, 40.00 mmol), AlCl₃(5.330 g,

40.00 mmol) and 1,1-dichloroethylene (2, 5.040 g,

52.0 mmol) in CH₂Cl₂(10 mL) product 4i was isolated as a

red brown oil (8.497 g, 96%). – ¹H NMR (250 MHz, CDCl₃):

δ = 1.04–1.73 (m, 11H, cyclopentyl-CH₂, cyclopentyl-CH),

1443 (w), 1382 (w), 1352 (w), 1301 (w), 1228 (m), 1185 (m),

1152 (m), 1128 (s), 1097 (s), 1059 (s), 1038 (s), 1008 (s), 877

(w), 748 (w), 641 (w).

2.52 (t, ³J = 7.5 Hz, 2H, CH₂C=O), 6.64 (s, 1H, CH=CCl₂). – ¹³C 4.4.3 1-Cyclopropyl-3,3,3-trimethoxypropan-1-on (5e)

NMR (63 MHz, CDCl₃): δ = 25.1, 29.8, 32.4 (CH₂), 39.5 (CH),

43.5 (CH₂), 126.4 (CH=CCl₂), 134.8 (CCl₂), 196.0 (C=O). – IR Starting with 3e (8.219 g, 40.79 mmol), Na (2.874 g,

−1

˜

(ATR, cm ): ν ꢀ 2945 (m), 2864 (m), 1701 (s), 1568 (s), 1451 125.0 mmol) in methanol (40 mL) product 5e was isolated

(w), 1406 (w), 1352 (w), 1300 (w), 1169 (w), 1075 (m), as a brown oil (1.912 g, 25%). – ¹H NMR (250 MHz, CDCl₃):

945 (m), 888 (m), 828 (m), 705 (m), 646 (m), 570 (w), 549 δ = 0.76–0.98 (m, 4H, cyclopropyl-CH₂), 2.23 (tt, ³J = 7.8 Hz,

(m). – MS (EI): m/z (%) = 222 [M]⁺(³⁷Cl³⁵Cl, 0.10), 220 [M]⁺³J = 4.6 Hz, 1H, cyclopropyl-CH), 2.91 (s, 2H, CH₂C(OCH₃)₃),

8

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

3.25 (s, 9H, 3 × OCH₃). – ¹³C NMR (63 MHz, CDCl₃): δ = 11.3 4.4.7 5-Cyclopentyl-1,1,1-trimethoxypentan-3-on (5i)

(CH₂), 20.4 (CH), 46.3 (CH₂), 49.8 (OCH₃), 113.6 (C(OCH₃)₃),

−1

˜

206.5 (C=O). – IR (ATR, cm ): ν ꢀ 2947 (w), 2839 (w), 1692 Starting with 4i (8.457 g, 38.25 mmol), Na (2.759 g,

(s), 1606 (w), 1569 (w), 1442 (w), 1382 (m), 1294 (m), 1229 120.0 mmol) in methanol (40 mL) product 5i was isolated

(m), 1195 (m), 1137 (s), 1069 (s), 1038 (s), 900 (s), 819 (w), as a brown oil (8.875 g, 95%). – ¹H NMR (250 MHz, CDCl₃):

710 (w), 640 (m). – HRMS (ESI): m/z calcd. for C₉H₁₆NaO₄δ = 1.40–1.80 (m, 11H, Cyclopentyl-CH₂, cyclopentyl-CH),

[M + Na]⁺: 211.09408; found 211.09396.

2.56 (t, ³J = 7.6 Hz, 2H, CH₂CH₂C=O), 2.84 (s, 2H,

CH₂C(OCH₃)₃), 3.29 (s, 9H, 3 × OCH₃). – ¹³C NMR (63 MHz,

CDCl₃): δ = 25.1, 29.6, 32.5 (CH₂), 39.5 (CH), 42.1, 45.6 (CH₂),

50.0 (OCH₃), 113.6 (C(OCH₃)₃), 207.1 (C=O). – IR (ATR, cm⁻¹):

˜

4.4.4 1-Cyclobutyl-3,3,3-trimethoxypropan-1-on (5f)

Starting with 4f (8.642 g, 48.28 mmol), Na (3.450 g, ν ꢀ 2945 (m), 2865 (m), 1709 (m), 1609 (w), 1572 (w), 1451

150.0 mmol) in methanol (50 mL) product 5f was isolated (m), 1410 (w), 1354 (w), 1300 (m), 1229 (s), 1192 (m), 1166

as a brown oil (8.913 g, 91%). – ¹H NMR (250 MHz, CDCl₃): (m), 1132 (s), 1064 (s), 1038 (s), 880 (w), 774 (w), 735 (w), 642

δ = 1.76–2.24 (m, 6H, cyclobutyl-CH₂), 2.79 (s, 2H, (w), 567 (w). – Analysis calcd. for C₁₃H₂₄O₄(244.33): C 63.91,

CH₂C(OCH₃)₃), 3.27 (s, 9H, 3 × OCH₃), 3.52 (quint, ³J = 8.9 Hz, H 9.90; found C 64.13, H 9.90.

1H, cyclobutyl-CH). – ¹³C NMR (63 MHz, CDCl₃): δ = 17.4,

24.4, 43.1 (CH₂), 45.3 (CH), 49.9 (OCH₃), 113.6 (C(OCH₃)₃), 4.4.8 1,1,1-Trimethoxydodecan-3-one (5j)

−1

˜

207.5 (C=O). – IR (ATR, cm ): ν ꢀ 2946 (m), 2867 (w), 2839

(w), 1746 (m), 1700 (s), 1601 (w), 1438 (m), 1352 (m), 1294 Starting with 3j (2.424 g, 8.4 mmol), Na (0.582 g, 25.3 mmol)

(m), 1229 (s), 1194 (m), 1136 (s), 1072 (s), 1039 (s), 998 (s), 919 in methanol (13 mL) product 5j was isolated as a brown oil

(w), 875 (w), 800 (w), 715 (w), 648 (m). – Analysis calcd. for (1.684 g, 73%). – ¹H NMR (CDCl₃, 250 MHz): δ = 3.30 (s, 9H,

C₁₀H₁₈O₄(202.25): C 59.39, H 8.97; found C 59.57, H 9.04.

3 × OCH₃), 2.84 (s, 2H, CH₂C(OCH₃)₃), 2.55 (t, ³J = 7.4 Hz, 2H,

3

COCH₂), 1.25 (br s, 14H, 7 × CH₂), 0.87 (t, J = 6.5 Hz, 3H,

4.4.5 1-Cyclopentyl-3,3,3-trimethoxypropan-1-on (5g)

CH₃). – ¹³C NMR (CDCl₃, 75 MHz): δ = 206.9 (C=O), 113.6

(C(OCH₃)₃), 49.9 (OCH₃), 45.7, 42.9, 31.8, 29.4, 29.2, 29.1,

Starting with 4g (6.812 g, 35.28 mmol), Na (2.482 g, 23.4, 22.6 (CH₂), 14.1 (CH₃). – MS (EI, 70 eV): m/z (%) = 242

108.0 mmol) in methanol (40 mL) product 5g was isolated [M]⁺(1), 143 (8), 130 (33), 115 (100). – HRMS (EI, 70 eV): m/z

1

as a brown oil Öl (6.434 g, 84%). – H NMR (250 MHz, calcd. for C₁₄H₂₆O₃[M]⁺: 242.18765; found 242.187913.

CDCl₃): δ = 1.59–1.82 (m, 8H, cyclopentyl-CH₂), 2.89 (s, 2H,

CH₂C(OCH₃)₃), 3.10–3.23 (m, 1H, cyclopentyl-CH), 3.29 (s, 4.4.9 1,1,1-Trimethoxyhexadecan-3-one (5k)

9H, 3 × OCH₃). – ¹³C NMR (63 MHz, CDCl₃): δ = 26.0, 29.1,

44.7 (CH₂), 50.0 (OCH₃), 51.1 (CH), 113.7 (C(OCH₃)₃), 209.2 Starting with 3k (2.763 g, 8.0 mmol), Na (0.553 g,

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 2948 (m), 2868 (w), 2839 (w), 24.0 mmol) in methanol (13 mL) product 5k was isolated as

1

1747 (w), 1703 (s), 1605 (w), 1568 (w), 1442 (m), 1361 (w), a brown oil (2.295 g, 87%). – H NMR (CDCl₃, 250 MHz):

1298 (m), 1228 (s), 1192 (m), 1133 (s), 1076 (s), 1037 (s), 1003 δ = 3.30 (s, 9H, 3 × OCH₃), 2.83 (s, 2H, CH₂C(OCH₃)₃), 2.55

3

(s), 948 (w), 877 (w), 816 (w), 718 (w), 650 (w).

(t, J = 7.4 Hz, 2H, COCH₂), 1.24 (br s, 22H, 11 × CH₂), 0.87

(t, ³J = 6.5 Hz, 3H, CH₃). – ¹³C NMR (CDCl₃, 75 MHz): δ = 206.9

(C=O), 113.6 (C(OCH₃)₃), 49.9 (OCH₃), 45.6, 42.9, 31.9, 29.6,

29.6, 29.5, 29.4, 29.3, 29.1, 23.4, 22.7 (CH₂), 14.1 (CH₃). – MS

4.4.6 1-Cyclohexyl-3,3,3-trimethoxypropan-1-on (5h)

Starting with 4h (9.820 g, 47.42 mmol), Na (3.450 g, (EI, 70 eV): m/z (%) = 298 [M]⁺(1), 143 (11), 130 (54), 115

150.0 mmol) in methanol (50 mL) product 5h was isolated (100). – HRMS (EI, 70 eV): m/z calcd. for C₁₈H₃₄O₃[M]⁺:

as a brown oil (10.153 g, 93%). – ¹H NMR (250 MHz, CDCl₃): 298.25025; found 298.250818.

δ = 1.18–1.84 (m, 10H, cyclohexyl-CH₂), 2.64 (tt, ³J = 11.4 Hz,

³J = 3.2 Hz, 1H, cyclohexyl-CH), 2.86 (s, 2H, CH₂C(OCH₃)₃), 4.4.10 1-(Furan-2-yl)-3,3,3-trimethoxypropan-1-one (5n)

3.28 (s, 9H, 3 × OCH₃). – ¹³C NMR (63 MHz, CDCl₃): δ = 25.7,

25.9, 28.4, 43.6 (CH₂), 50.0 (OCH₃), 50.3 (CH), 113.7 Starting with 3n (1.138 g, 5.0 mmol), Na (0.345 g,

−1

˜

(C(OCH₃)₃), 209.9 (C=O). – IR (ATR, cm ): ν ꢀ 2927 (m), 15.0 mmol) in methanol (8 mL) product 5n was isolated as a

1

2852 (m), 1703 (m), 1605 (w), 1566 (w), 1448 (m), 1371 (w), brown oil (0.712 g, 67%). – H NMR (CDCl₃, 300 MHz):

3

4

1316 (m), 1296 (w), 1226 (s), 1191 (m), 1164 (m), 1142 (s), 1126 δ = 7.57 (dd, J = 1.7 Hz, J = 0.8 Hz, 1H, CH), 7.23 (dd,

4

3

(s), 1065 (s), 1037 (s), 1003 (s), 921 (w), 895 (m), 868 (m), 794 ³J = 3.6 Hz, J = 0.8 Hz, 1H, CH), 6.52 (dd, J = 3.6 Hz,

(w), 717 (w), 653 (m).

³J = 1.7 Hz, 1H, H-4), 3.33 (s, 9H, 3 × OCH₃), 3.28 (s, 2H,

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

9

CH₂). – ¹³C NMR (CDCl₃, 63 MHz): δ = 183.9 (C=O), 154.9 24.6 (COCH₃), 16.0 (CH₂), 13.3 (CH₂CH₃). – IR (ATR, cm⁻¹):

˜

(C–O), 146.3 (HC–O), 118.0, 112.4 (CH), 50.2 (CH₃), 40.0 ν ꢀ 3007 (w), 2967 (m), 2937 (m), 2973 (w), 1726 (w), 1641(s),

(CH₂). – MS (ESI): m/z calcd. for C₉H₁₁O₄[M-MeOH+H]⁺: 1608 (s), 1573 (s), 1520 (m), 1456 (m), 1439 (s), 1402

183.06519; found 183.06496.

(m). – MS (EI, 70 eV): m/z (%) = 224 [M]⁺(46), 193 (21), 192

(69), 177 (47), 164 (100), 149 (16), 147 (10). – HRMS (EI,

70 eV): m/z calcd. for C₁₂H₁₆O₄[M]⁺: 224.10431; found

224.104539.

4.5 General procedure for the synthesis of

7a–bt

4.5.3 Ethyl 3-chloro-2-hydroxy-4-methoxy-

6-methylbenzoate (7c)

To a solution of 5a–n and 6a–o (1.5 or 2.0 equiv.) in CH₂Cl₂

TiCl₄(1.0 equiv.) was added under an argon atmosphere

and stirring at −78 °C. The reaction mixture was allowed to

warm up to 20 °C slowly and stirring was continued for

further 12 h. Then aqueous hydrochloric acid (10%,

4 mL mmol⁻¹5) was added and the solution was stirred for

10 min. The organic and the aqueous layer were separated

and the latter was extracted with CH₂Cl₂(3 × 8 mL mmol⁻¹

5). The combined organic phases were dried (Na₂SO₄), ﬁl-

trated and the ﬁltrate was concentrated in vacuo. Puriﬁ-

cation was performed by column chromatography (silica

gel, heptane-EtOAc).

Starting with 5a (163 mg, 1.0 mmol), 6c (618 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product

7c was isolated as a colourless solid (80 mg, 33%);

1

m.p. = 91–92 °C; R_f= 0.74 (heptane-EtOAc 1:1). – H NMR

(CDCl₃, 250 MHz): δ = 12.32 (s, 1H, OH), 6.34 (s, 1H, CH), 4.43

3

(q, J = 7.1 Hz, 2H, OCH₂), 3.94 (s, 3H, OCH₃), 2.56 (s, 3H,

3

ArCH₃), 1.43 (t, J = 7.1 Hz, 3H, OCH₂CH₃). – ¹³C NMR

(63 MHz, CDCl₃): δ = 171.5 (C=O), 160.0, 158.8 (C–O), 141.3,

107.3, 106.7 (C), 106.5 (CH), 61.8 (OCH₂), 56.1 (OCH₃), 24.7

−1

˜

(ArCH₃), 14.1 (CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2985 (m), 2945

(m), 2906 (m), 2847 (m), 2747 (m), 1731 (s), 1647 (s), 1597 (s),

1557 (s), 1467 (s), 1398 (s), 1377 (s). – MS (EI, 70 eV): m/z

(%) = 245 [M–H]⁺(³⁷Cl, 3), 244 [M]⁺(³⁵Cl, 20), 200 (34), 199

(22), 198 (100), 155 (14). – Analysis calcd. for C₁₁H₁₃ClO₄

(244.67): C 54.00, H 5.36; found C 53.99, H 5.50.

4.5.1 1-(2-Hydroxy-4-methoxy-6-methylphenyl)ethan-

1-one (7a)

Starting with 5a (163 mg, 1.0 mmol), 6a (489 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7a

was isolated as a colourless oil (105 mg, 59 %); R_f= 0.79

(heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 250 MHz): δ = 13.56

(s, 1H, OH), 6.31–6.27 (m, 2H, 2 × CH), 3.81 (s, 3H, OCH₃),

2.62 (s, 3H, CH₃), 2.56 (s, 3H, CH₃). – ¹³C NMR (75 MHz,

CDCl₃): δ = 203.9 (C=O), 167.1, 164.3 (C–O), 141.8, 115.1 (C),

4.5.4 Benzyl 2-hydroxy-4-methoxy-6-methylbenzoate

(7d)

Starting with 5a (163 mg, 1.0 mmol), 6d (674 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7d

was isolated as a light-green solid (120 mg, 44%);

m.p. = 66–67 °C; R_f= 0.71 (heptane-EtOAc 1:1). – ¹H NMR

(CDCl₃, 300 MHz): δ = 11.78 (s, 1H, OH), 7.46–7.35 (m, 5H,

Ph), 6.34 (d, ⁴J = 2.6 Hz, 1H, CH), 6.27 (d, ⁴J = 2.6 Hz, 1H, CH),

5.83 (s, 2H, OCH₂), 3.79 (s, 3H, OCH₃), 2.49 (s, 3H,

ArCH₃). – ¹³C NMR (63 MHz, CDCl₃): δ = 171.5 (C=O), 165.7,

164.0 (C–O), 143.2, 135.4 (C), 128.6, 128.4, 111.2 (CH), 105.1

111.8, 99.0 (CH), 55.3 (OCH₃), 33.0, 25.1 (CH₃). – IR (ATR,

−1

˜

cm ): ν ꢀ 2924 (m), 2846 (m), 2727 (m), 1588 (s), 1578 (s),

1558 (s), 1494 (m), 1426 (m), 1405 (m), 1349 (s). – MS

(EI, 70 eV): m/z (%) = 180 [M]⁺(28), 165 (100), 109 (6), 94

(4). – Analysis calcd. for C₁₀H₁₂O₃(180.20): C 66.65, H 6.71;

found C 66.47, H 6.95.

4.5.2 Methyl 3-ethyl-2-hydroxy-4-methoxy-

6-methylbenzoate (7b)

(C), 98.7 (CH), 67.0 (OCH₂), 55.3 (OCH₃), 24.6 (ArCH₃). – IR

−1

˜

(ATR, cm ): ν ꢀ 2986 (m), 2952 (m), 2931 (w), 2901 (m), 2867

(m), 1651 (s), 1607 (s), 1586 (s), 1511 (s), 1450 (m), 1434 (s),

Starting with 5a (163 mg, 1.0 mmol), 6b (578 mg, 2.0 mmol) 1422 (m). – MS (EI, 70 eV): m/z (%) = 272 [M]⁺(29), 254 (9),

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 165 (8), 164 (25), 91 (100). – HRMS (EI, 70 eV): m/z calcd. for

7b was isolated as a colourless solid (104 mg, 47%); C₁₆H₁₆O₄[M]⁺: 272.10431; found 272.104343.

m.p. = 76–78 °C; R_f= 0.79 (heptane-EtOAc 1:1). – ¹H NMR

(CDCl₃, 250 MHz): δ = 11.77 (s, 1H, OH), 6.28 (s, 1H, CH), 3.92 4.5.5 1-(6-Ethyl-2-hydroxy-4-methoxyphenyl)ethan-

3

(s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 2.65 (q, J = 7.4 Hz, 2H,

1-one (7e)

CH₂), 2.52 (s, 3H, ArCH₃), 1.08 (t, ³J = 7.4 Hz, CH₂CH₃). – ¹³C

NMR (63 MHz, CDCl₃): δ = 172.5 (C=O), 161.9, 161.1 (C–O), Starting with 5b (177 mg, 1.0 mmol), 6a (489 mg, 2.0 mmol)

140.3, 117.2 (C), 106.0 (CH), 105.6 (C), 55.4, 51.7 (OCH₃), and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7e

10

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

was isolated as a colourless oil (58 mg, 30%); R_f= 0.88 4.5.8 Ethyl 3-chloro-2-hydroxy-4-methoxy-

(heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 250 MHz): δ = 13.23

(s, 1H, OH), 6.33 (d, ⁴J = 2.5 Hz, 1H, CH), 6.30 (d, ⁴J = 2.5 Hz,

6-propylbenzoate (7h)

1H, CH), 3.82 (s, 3H, OCH₃), 2.90 (q, ³J = 7.4 Hz, 2H, ArCH₂), Starting with 5c (191 mg, 1.0 mmol), 6c (618 mg, 2.0 mmol)

2.66 (s, 3H, COCH₃), 1.27 (t, ³J = 7.4 Hz, 3H, CH₂CH₃). – ¹³

C

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product

NMR (63 MHz, CDCl₃): δ = 203.9 (C=O), 166.5, 164.5 (C–O), 7h was isolated as a colourless solid (199 mg, 73%);

1

148.0, 114.8 (C), 109.9, 98.8 (CH), 55.3 (OCH₃), 32.3 (CH₃), m.p. = 71–73 °C; R_f= 0.78 (heptane-EtOAc 1:1). – H NMR

−1

˜

29.1 (CH₂), 16.0 (CH₃). – IR (ATR, cm ): ν ꢀ 2972 (m), 2948 (CDCl₃, 250 MHz): δ = 12.28 (s, 1H, OH), 6.39 (s, 1H, CH), 4.43

(m), 2883 (w), 2851 (w), 1587 (s), 1447 (m), 1426 (m), 1406 (q, ³J = 7.1 Hz, 2H, OCH₂), 3.94 (s, 3H, OCH₃), 2.88

3

(m), 1388 (m), 1359 (s). – MS (EI, 70 eV): m/z (%) = 194 [M]⁺(t, J = 7.7 Hz, 2H, ArCH₂), 1.66–1.51 (m, 2H, CH₂), 1.43

(26), 179 (100), 164 (4), 151 (3), 133 (6), 121 (3). – Analysis (t, ³J = 7.1 Hz, 3H, OCH₂CH₃), 0.98 (t, ³J = 7.3 Hz,

calcd. for C₁₁H₁₄O₃(194.23): C 68.02, H 7.27; found C (CH₂)₂CH₃). – ¹³C NMR (75 MHz, CDCl₃): δ = 171.3 (C=O),

68.00, H 7.51.

159.9, 158.8 (C–O), 146.0, 107.4, 106.1 (C), 106.0 (CH), 61.8

(OCH₂), 56.1 (OCH₃), 39.2, 25.2 (CH₂), 14.1, 14.0 (CH₃). – IR

−1

˜

4.5.6 1-(2-hydroxy-4-methoxy-6-propylphenyl)ethan-

1-one (7f)

(ATR, cm ): ν ꢀ 2979 (m), 2965 (m), 2932 (m), 2972 (m),

2868 (m), 1651 (s), 1599 (s), 1557 (s), 1466 (s), 1439 (w), 1398

(s), 1375 (m). – MS (EI, 70 eV): m/z (%) = 274 [M]⁺(³⁷Cl, 6),

Starting with 5c (191 mg, 1.0 mmol), 6a (489 mg, 2.0 mmol) 272 [M]⁺(³⁵Cl, 17), 228 (35), 226 (100), 211 (5), 198 (10), 169

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7f (17). – Analysis calcd. for C₁₃H₁₇ClO₄(272.72): C 57.25, H

was isolated as a colourless oil (102 mg, 49 %); R_f= 0.66 6.28; found C 57.32, H 6.31.

(heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 300 MHz): δ = 13.14

(s, 1H, OH), 6.30 (s, 2H, 2 × CH), 3.81 (s, 3H, OCH₃), 2.83 (t, 4.5.9 Methyl 2-hydroxy-3,4-dimethoxy-

³J = 7.9 Hz, 2H, ArCH₂), 2.94 (s, 3H, COCH₃), 1.71–1.59 (m,

2H, CH₂CH₂CH₃), 0.99 (t, ³J = 7.4 Hz, 3H, CH₂CH₃). – ¹³C NMR

6-propylbenzoate (7i)

(75 MHz, CDCl₃): δ = 204.1 (C=O), 166.4, 164.3 (C–O), 146.6, Starting with 5c (191 mg, 1.0 mmol), 6f (581 mg, 2.0 mmol)

114.9 (C), 110.7, 98.9 (CH), 55.3 (OCH₃), 38.3 (CH₂), 32.1 and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product

−1

˜

(CH₃), 25.4 (CH₂), 14.1 (CH₃). – IR (ATR, cm ): ν ꢀ 2960 (m), 7i was isolated as a colourless solid (134 mg, 53%);

2933 (m), 2872 (w), 2846 (w), 1605 (s), 1480 (m), 1461 (m), m.p. = 53–54 °C; R_f= 0.66 (heptane-EtOAc 1:1). – ¹H NMR

1424 (m), 1378 (m), 1358 (s). – MS (EI, 70 eV): m/z (CDCl₃, 250 MHz): δ = 11.40 (s, 1H, OH), 6.31 (s, 2H, 2 × CH),

(%) = 208 [M]⁺(22), 193 (100), 190 (30), 175 (23), 165 (6), 147 3.94 (s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃),

(5). – HRMS (EI, 70 eV): m/z calcd. for C₁₂H₁₆O₃[M]⁺: 2.83 (t, ³J = 7.7 Hz, 2H, ArCH₂), 1.71–1.59 (m, 2H,

3

208.1094; found 208.109667.

CH₂CH₂CH₃), 0.97 (t, J = 7.4 Hz, 3H, CH₂CH₃). – ¹³C NMR

(63 MHz, CDCl₃): δ = 171.8 (C=O), 156.9, 156.2 (C–O), 142.1,

4.5.7 Methyl 2-hydroxy-4-methoxy-6-propylbenzoate

(7g)

134.7 (C), 106.2 (CH), 60.6, 55.8, 52.0 (OCH₃), 38.1 (CH₂), 25.2

−1

˜

(CH₂), 14.3 (CH₃). – IR (ATR, cm ): ν ꢀ 2956 (m), 2933 (m),

2871 (w), 1727 (m), 1651 (s), 1607 (m), 1571 (s), 1508 (m), 1434

Starting with 5c (191 mg, 1.0 mmol), 6e (521 mg, 2.0 mmol) (s), 1405 (s), 1272 (s). – MS (EI, 70 eV): m/z (%) = 254 [M]⁺

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7g (44), 222 (100), 207 (14), 193 (24), 179 (57), 166 (86). – HRMS

was isolated as a colourless oil (92 mg, 42%); R_f= 0.88 (EI, 70 eV): m/z calcd. for C₁₃H₁₈O₅[M]⁺: 254.11488; found

(heptane-EtOAc 1:1). – ¹H NMR (250 MHz, CDCl₃): δ = 11.73 254.114784.

(s, 1H, OH), 6.34 (d, ⁴J = 2.7 Hz, 1H, CH), 6.29 (d, ⁴J = 2.7 Hz,

1H, CH), 3.93 (s, 3H, OCH₃), 3.38 (s, 3H, OCH₃), 2.83 4.5.10 (2-Hydroxy-4-methoxy-6-propylphenyl)(phenyl)

(t, ³J = 7.7 Hz, 2H, ArCH₂), 1.63–1.49 (m, 2H, CH₂CH₃), 0.95

methanone (7j)

3

(t, J = 7.4 Hz, 3H, CH₂CH₃). – ¹³C NMR (63 MHz, CDCl₃):

δ = 172.0 (C=O), 165.5, 163.9 (C–O), 147.7 (C), 110.7 (CH), Starting with 5c (191 mg, 1.0 mmol), 6g (614 mg, 2.0 mmol)

104.6 (C), 98.7 (CH), 55.3, 51.8 (OCH₃), 38.9 (ArCH₂), 24.9 and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7j

−1

˜

(CH₂CH₃), 14.2 (CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2956 (br m), was isolated as a colourless solid (171 mg, 48%);

2871 (w), 2846 (w), 1649 (s), 1611 (s), 1575 (s). – MS (EI, m.p. = 112–113 °C; R_f= 0.38 (heptane-EtOAc 1:1). – ¹H NMR

70 eV): m/z (%) = 224 [M]⁺(33), 192 (100), 164 (34), 135 (CDCl₃, 250 MHz): δ = 10.23 (s, 1H, OH), 7.63–7.40 (m, 5H,

(45). – Analysis calcd. for C₁₂H₁₆O₄(224.25): C 64.27, H 7.19; Ph), 6.40 (d, ⁴J = 2.5 Hz, 1H, CH), 6.34 (d, ⁴J = 2.5 Hz, 1H, CH),

found C 64.27, H 7.39.

3.77 (s, 3H, OCH₃), 2.10 (t, ³J = 7.6 Hz, 2H, ArCH₂), 1.40–1.25

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

11

3

(m, 2H, CH₂), 0.50 (t, J = 7.3 Hz, CH₂CH₃). – ¹³C NMR (100), 191 (10), 177 (12), 149 (43). – HRMS (EI): m/z calcd. for

(75 MHz, CDCl₃): δ = 200.9 (C=O), 164.0, 162.7 (C–O), 146.5, C₁₂H₁₆O₄[M]⁺: 224.10431; found 224.10416. – Analysis

140.9 (C), 132.2, 128.6, 128.4 (CH), 115.3 (C), 109.7, 98.8 (CH), calcd. for C₁₂H₁₆O₄(224.25): C 64.27, H 7.19; found C

55.3 (OCH₃), 37.4, 25.0 (CH₂), 13.6 (CH₂CH₃). – IR 64.30, H 7.22.

−1

˜

(ATR, cm ): ν ꢀ 3233 (br, m), 2953 (m), 2937 (m), 2967 (w),

2842 (m), 1638 (s), 1604 (s), 1593 (s), 1577 (s), 1504 (w), 1451 4.5.13 Isopropyl 2-hydroxy-6-isopropyl-

(m), 1436 (m). – MS (EI, 70 eV): m/z (%) = 270 [M]⁺(74), 269

(91), 251 (26), 241 (100), 240 (50), 224 (11), 223 (41). – Anal-

4-methoxybenzoate (7m)

ysis calcd. for C₁₇H₁₈O₃(270.32): C 75.53, H 6.71; found C Starting with 5d (285 mg, 1.50 mmol), 6i (650 mg,

75.20, H 6.72.

2.25 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7m was isolated as a yellow oil (147 mg, 39%);

column chromatography: heptane → heptane-EtOAc

10:1. – ¹H NMR (500 MHz, CDCl₃): δ = 1.22 (d, ³J = 6.8 Hz, 6H,

4.5.11 2-Methoxyethyl 2-hydroxy-4-methoxy-

6-propylbenzoate (7k)

CH(CH₃)₂), 1.40 (d, ³J = 6.2 Hz, 6H, OCH(CH₃)₂), 3.82 (s, 3H,

3

Starting with 5c (191 mg, 1.0 mmol), 6h (609 mg, 2.0 mmol) OCH₃), 3.84 (hept, J = 6.8 Hz, 1H, CH(CH₃)₂), 5.31 (hept,

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product ³J = 6.3 Hz, 1H, OCH(CH₃)₂), 6.32 (d, ⁴J = 2.6 Hz, 1H, CH_Ar),

7k was isolated as a colourless solid (167 mg, 63%); 6.45 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.65 (s, 1H, OH). – ¹³C NMR

m.p. = 39–40 °C; R_f= 0.62 (heptane-EtOAc 1:1). – ¹H NMR (125 MHz, CDCl₃): δ = 21.8, 24.1 (CH₃), 30.5 (CH(CH₃)₂), 55.2

(CDCl₃, 300 MHz): δ = 11.61 (s, 1H, OH), 6.33 (d, ⁴J = 2.6 Hz, (OCH₃), 69.3 (OCH), 98.3 (CH), 105.3 (C), 106.2 (CH), 153.7

1H, CH), 6.29 (d, ⁴J = 2.6 Hz, 1H, CH), 4.70 (t, ³J = 4.7 Hz, 2H, (C), 164.0, 164.8 (CO), 171.0 (C=O). – IR (ATR, cm ): ν ꢀ

−1

˜

OCH₂), 3.79 (s, 3H, OCH₃), 3.70 (t, ³J = 4.7 Hz, 2H, OCH₂), 3.41 2977 (m), 2938 (w), 2872 (w), 2844 (w), 1721 (w), 1640 (m),

(s, 3H, OCH₃), 2.86 (t, ³J = 7.8 Hz, 2H, ArCH₂), 1.65–1.52 (m, 1610 (s), 1579 (m), 1464 (m), 1439 (m), 1424 (m), 1374 (m),

2H, CH₂CH₃), 0.96 (t, J = 7.4 Hz, 3H, CH₂CH₃). – ¹³C NMR 1350 (m), 1310 (s), 1268 (m), 1247 (s), 1214 (s), 1202 (s), 1152

3

(63 MHz, CDCl₃): δ = 171.3 (C=O), 165.4, 163.9 (C–O), 148.0 (s), 1098 (s), 1036 (s), 1004 (s), 911 (m), 846 (m), 829 (m),

(C), 110.7 (CH), 104.7 (C), 98.8 (CH), 70.1, 63.9 (OCH₂), 58.8, 808 (m), 769 (br m), 714 (m), 618 (m), 555 (m), 536 (m). – MS

55.2 (OCH₃), 38.9, 25.0 (CH₂), 14.2 (CH₂CH₃). – IR (ATR, (EI): m/z (%) = 252 [M]⁺(20), 193 (20), 192 (100), 191 (11), 149

−1

cm ): ν ꢀ 2949 (s), 2927 (m), 2881 (m), 2846 (m), 1637 (s), (25). – HRMS (EI): m/z calcd. for C₁₄H₂₀O₄[M]⁺: 252.13561;

˜

1613 (s), 1574 (s), 1458 (m), 1438 (m), 1379 (m), 1363 (s). – MS found 252.13568. – Analysis calcd. for C₁₄H₂₀O₄(252.31): C

(EI, 70 eV): m/z (%) = 268 [M]⁺(22), 193 (23), 192 (100), 177 66.65, H 7.99; found C 66.71, H 7.94.

(13), 164 (23), 135 (23). – Analysis calcd. for C₁₄H₂₀O₅

(268.31): C 62.67, H 7.51; found C 62.40, H 7.57.

4.5.14 1-(2-hydroxy-6-isopropyl-4-methoxyphenyl)

ethan-1-one (7n)

4.5.12 Methyl 2-hydroxy-6-isopropyl-

4-methoxybenzoate (7l)

Starting with 5d (190 mg, 1.0 mmol), 6a (366 mg,

1.50 mmol) and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL)

Starting with 5d (285 mg, 1.50 mmol), 6e (585 mg, product 7n was isolated as a orange oil (129 mg, 62%);

2.0 mmol) and TiCl₄(285 mg, 1.5 mmol) in CH₂Cl₂(3 mL) column chromatography: heptane → heptane-EtOAc

product 7l was isolated as a light-yellow oil (221 mg, 66%); 10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 1.27 (d, ³J = 6.7 Hz, 6H,

column chromatography: heptane → heptane-EtOAc CH(CH₃)₂), 2.63 (s, 3H, C=OCH₃), 3.43 (hept, ³J = 6.7 Hz, 1H,

10:1. – ¹H NMR (500 MHz, CDCl₃): δ = 1.19 (d, ³J = 6.8 Hz, 6H, CH(CH₃)₂), 3.80 (s, 3H, OCH₃), 6.28 (d, ⁴J = 2.6 Hz, 1H, CH_Ar),

CH(CH₃)₂), 3.78 (hept, ³J = 6.8 Hz, 1H, CH(CH₃)₂), 3.80 (s, 3H, 6.43 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 12.29 (s, 1H, OH). – ¹³C NMR

OCH₃), 3.9 (s, 3H, CO₂CH₃), 6.32 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), (75 MHz, CDCl₃): δ = 24.5 (CH₃), 30.9 (CH), 32.3 (CH₃), 55.3

6.45 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.48 (s, 1H, OH). – ¹³C NMR (OCH₃), 98.4, 106.6 (CH), 115.7, 152.9 (C), 164.4, 164.5 (CO),

−1

˜

(125 MHz, CDCl₃): δ = 24.1 (CH(CH₃)₂), 30.5 (CH(CH₃)₂), 52.0, 204.4 (C=O). – IR (ATR, cm ): ν ꢀ 2962 (m), 2931 (w), 2871

55.3 (OCH₃), 98.3 (CH), 104.8 (C), 106.4 (CH), 153.9 (C), (w), 2844 (w), 1681 (w), 1607 (s), 1581 (s), 1461 (m), 1434 (m),

−1

˜

164.2, 164.8 (CO), 172.0 (C=O). – IR (ATR, cm ): ν ꢀ 2954 1358 (m), 1339 (m), 1248 (s), 1200 (s), 1148 (s), 1092 (m), 1055

(m), 2872 (w), 2845 (w), 1725 (w), 1648 (s), 1612 (s), 1578 (s), (m), 1031 (m), 1011 (m), 989 (m), 964 (m), 939 (m), 843 (m),

1459 (m), 1431 (s), 1376 (m), 1363 (m), 1319 (s), 1247 (s), 1202 829 (m), 752 (m), 698 (m), 651 (m), 585 (m), 567 (m), 535

(s), 1149 (s), 1110 (s), 1086 (m), 1035 (s), 1007 (s), 953 (m), (m). – MS (EI): m/z (%) = 208 [M]⁺(39), 194 (12), 193 (100),

846 (m), 829 (m), 805 (m), 758 (br m), 714 (s), 619 (m), 557 190 (16), 175 (40). – HRMS (EI): m/z calcd. for C₁₂H₁₆O₃[M]⁺:

(m), 535 (m). – MS (EI): m/z (%) = 224 [M]⁺(28), 193 (17), 192 208.10940; found 208.10911.

12

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

4.5.15 1-(2-hydroxy-6-isopropyl-4-methoxy-

3-methylphenyl)propan-1-one (7o)

column chromatography: heptane → heptane-EtOAc

10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 0.87 (t, ³J = 6.7 Hz, 3H,

(CH₂)₇CH₃), 1.23 (d, J = 6.8 Hz, 6H, CH(CH₃)₂), 1.24–1.53

3

Starting with 5d (285 mg, 1.50 mmol), 6j (613 mg, (m, 12H, 6 × CH₂), 1.40 (t, ³J = 7.1 Hz, 3H, CO₂CH₂CH₃), 2.59

2.25 mmol) and TiCl₄(285 mg, 1.5 mmol) in CH₂Cl₂(3 mL) (t, J = 7.6 Hz, 2H, Ar-CH₂), 3.82 (hept, J = 6.8 Hz, 1H,

3

product 7o was isolated as a yellow oil (107 mg, 30%); CH(CH₃)₂), 3.85 (s, 3H, OCH₃), 4.40 (q, J = 7.1 Hz, 2H,

column chromatography: heptane → heptane-EtOAc CO₂CH₂), 6.44 (s, 1H, CH_Ar), 11.35 (s, 1H, OH). – ¹³C NMR

10:1. – ¹H NMR (300 MHz, CDCl₃): δ = 1.22 (t, ³J = 7.3 Hz, 3H, (75 MHz, CDCl₃): δ = 14.1, 14.1 (CH₃), 22.7 22.8 (CH₂), 24.3

CH₂CH₃), 1.28 (d, ³J = 6.8 Hz, 6H, CH(CH₃)₂), 2.05 (s, 3H, Ar- (CH₃), 28.9, 29.3, 29.6, 29.9 (CH₂), 30.7 (CH), 32.0 (CH₂), 55.3

CH₃), 2.86 (q, ³J = 7.3 Hz, 2H, CH₂CH₃), 3.28 (hept, ³J = 6.7 Hz, (OCH₃), 61.2 (OCH₂), 100.4 (CH), 105.6, 115.9, 150.9 (C),

−1

˜

1H, CH(CH₃)₂), 3.86 (s, 3H, OCH₃), 6.41 (s, 1H, CH_Ar), 10.83 160.9, 161.5 (CO), 171.9 (C=O). – IR (ATR, cm ): ν ꢀ 2955

(s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 7.8, 9.9, 24.7 (m), 2924 (m), 2853 (m), 1646 (m), 1609 (m), 1573 (m), 1463

(CH₃), 31.4 (CH), 37.5 (CH₂), 55.4 (OCH₃), 100.3 (CH), 110.8, (m), 1406 (m), 1394 (m), 1372 (m), 1270 (s), 1231 (s), 1190 (m),

117.1, 148.8 (C), 158.3, 161.3 (CO), 209.6 (C=O). – IR (ATR, 1172 (s), 1150 (s), 1131 (s), 1100 (m), 1077 (m), 1023 (m), 992

−1

˜

cm ): ν ꢀ 2963 (m), 2937 (m), 2874 (w), 1693 (w), 1608 (s), (w), 895 (w), 866 (w), 830 (m), 808 (m), 752 (br w), 722 (w),

1575 (m), 1490 (w), 1461 (m), 1395 (m), 1324 (m), 1228 (s), 669 (w), 636 (w), 614 (w), 586 (w). – MS (EI): m/z (%) = 350

1139 (s), 1100 (m), 1082 (m), 1049 (m), 1009 (m), 919 (w), [M]⁺(29), 304 (22), 287 (31), 273 (48), 206 (100), 205

831 (s), 794 (s), 678 (m), 642 (m), 583 (m), 571 (m). – MS (EI): (85). – HRMS (EI): m/z calcd. for C₂₁H₃₄O₄[M]⁺: 350.24516;

m/z (%) = 236 [M]⁺(18), 208 (14), 207 (100), 189 (15). – HRMS found 350.24483.

(EI): m/z calcd. for C₁₄H₂₀O₃[M]⁺: 236.14070;

found 236.14073.

4.5.18 Methyl 2-hydroxy-6-isopropyl-

3,4-dimethoxybenzoate (7r)

4.5.16 Methyl 2-hydroxy-6-isopropyl-4-methoxy-

3-methylbenzoate (7p)

Starting with 5d (190 mg, 1.0 mmol), 6f (435 mg, 1.50 mmol)

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) product 7r

Starting with 5d (190 mg, 1.0 mmol), 6k (411 mg, was isolated as a yellow oil (180 mg, 71%); column chro-

1

1.50 mmol) and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) matography: heptane → heptane-EtOAc 10:1. – H NMR

3

product 7p was isolated as a white solid (0.147 g, 62%); (250 MHz, CDCl₃): δ = 1.20 (d, J = 6.8 Hz, 6H, CH(CH₃)₂),

3

m.p. = 77–78 °C; column chromatography: heptane → hep- 3.68 (hept, J = 6.8 Hz, 1H, CH(CH₃)₂), 3.84 (s, 3H, OCH₃),

1

tane-EtOAc 10:1. – H NMR (250 MHz, CDCl₃): δ = 1.22 (d, 3.90 (s, 3H, OCH₃), 3.93 (s, 3H, OCH₃), 6.45 (s, 1H, CH_Ar),

³J = 6.8 Hz, 6H, CH(CH₃)₂), 2.07 (s, 3H, Ar-CH₃), 3.79 (hept, 10.60 (s, 1H, OH). – ¹³C NMR (75 MHz, CDCl₃): δ = 24.1 (CH₃),

³J = 6.8 Hz, 1H, CH(CH₃)₂), 3.87 (s, 3H, OCH₃), 3.92 (s, 3H, 30.6 (CH), 52.1, 55.8, 60.6 (OCH₃), 101.4 (CH), 107.3 (C),

CO₂CH₃), 6.46 (s, 1H, CH_Ar), 11.37 (s, 1H, OH). – ¹³C NMR 134.4 (CO), 147.5 (C), 155.1, 156.1 (CO), 171.4 (C=O). – IR

−1

˜

(75 MHz, CDCl₃): δ = 7.9, 24.2 (CH₃), 30.7 (CH), 51.9, 55.3 (ATR, cm ): ν ꢀ 2955 (m), 2872 (w), 2844 (w), 1726 (m), 1650

(OCH₃), 100.3 (CH), 105.3, 110.8, 150.8 (C), 160.9, 161.6 (CO), (m), 1608 (m), 1574 (m), 1503 (m), 1460 (m), 1432 (m), 1406

−1

˜

172.3 (C=O). – IR (ATR, cm ): ν ꢀ 3001 (w), 2954 (m), 2929 (m), 1384 (m), 1364 (m), 1340 (m), 1300 (s), 1270 (s), 1195 (s),

(m), 2872 (w), 1726 (m), 1644 (m), 1607 (m), 1574 (m), 1462 1146 (s), 1118 (s), 1079 (m), 1033 (s), 978 (s), 945 (m), 877 (w),

(m), 1428 (m), 1402 (m), 1360 (m), 1311 (m), 1269 (s), 1233 (s), 831 (m), 807 (m), 778 (m), 756 (m), 708 (m), 677 (m), 620

1192 (m), 1171 (m), 1128 (s), 1085 (m), 1072 (s), 1040 (m), 1017 (m), 582 (m). – MS (EI): m/z (%) = 254 [M]⁺(35), 223 (24), 222

(m), 1001 (s), 980 (m), 927 (m), 831 (s), 804 (s), 742 (s), 680 (86), 207 (16), 193 (16), 179 (100). – HRMS (EI): m/z calcd. for

(m), 664 (m), 636 (m), 614 (m), 581 (m). – MS (EI): m/z C₁₃H₁₈O₅[M]⁺: 254.11488; found 254.11473.

(%) = 238 [M]⁺(47), 207 (23), 206 (100), 205 (16), 163 (52), 159

(16), 91 (21). – HRMS (EI): m/z calcd. for C₁₃H₁₈O₄[M]⁺: 4.5.19 1-(2-Hydroxy-4-methoxy-6-nonylphenyl)ethan-

238.11996; found 238.12011.

1-one (7s)

4.5.17 Ethyl 2-hydroxy-6-isopropyl-4-methoxy-

3-octylbenzoate (7q)

Starting with 5e (275 mg, 1.0 mmol), 6a (489 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7s

was isolated as a colourless oil (159 mg, 54%); R_f= 0.62

Starting with 5d (285 mg, 1.50 mmol), 6l (870 mg, (heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 250 MHz): δ = 13.15

2.25 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) (s, 1H, OH), 6.30 (s, 2H, 2 × CH), 3.81 (s, 3H, OCH₃), 2.84

3

product 7q was isolated as a yellow oil (413 mg, 79%); (t, J = 7.7 Hz, 2H, ArCH₂), 2.64 (s, 3H, COCH₃), 1.56–1.26

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

13

3

(m, 14H, 7 × CH₂), 0.88 (t, J = 6.9 Hz, 3H, CH₂CH₃). – ¹³C 4.5.22 2-Methoxyethyl 2-hydroxy-4-methoxy-

NMR (63 MHz, CDCl₃): δ = 204.0 (C=O), 166.4, 164.3 (C–O),

6-nonylbenzoate (7v)

146.9, 114.9 (C), 110.7, 98.8 (CH), 55.3 (OCH₃), 36.4, 32.3, 32.1

(CH₂), 31.8 (COCH₃), 29.7, 29.5, 29.4, 29.2, 22.6, (CH₂), 14.1 Starting with 5e (275 mg, 1.0 mmol), 6h (609 mg, 2.0 mmol)

−1

˜

(CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2923 (s), 2852 (m), 1607 (s), and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product

1463 (m), 1441 (m), 1424 (m), 1358 (s). – MS (EI, 70 eV): m/z 7v was isolated as a colourless solid (250 mg, 71%);

(%) = 292 [M]⁺(40), 278 (20), 277 (100), 274 (10), 207 (10), 193 m.p. = 45–46 °C; R_f= 0.67 (heptane-EtOAc 1:1). – ¹H NMR

(35), 190 (36), 180 (48), 176 (88). – Analysis calcd. for (CDCl₃, 300 MHz): δ = 11.61 (s, 1H, OH), 6.33 (d, ⁴J = 2.6 Hz,

C₁₈H₂₈O₃(292.41): C 73.93, H 9.65; found C 74.19, H 9.57.

1H, CH), 6.29 (d, ⁴J = 2.6 Hz, 1H, CH), 4.47 (t, ³J = 4.7 Hz, 2H,

3

OCH₂), 3.79 (s, 3H, OCH₃), 3.70 (t, J = 4.7 Hz, 2H, OCH₂),

3.40 (s, 3H, OCH₃), 2.88 (t, ³J = 7.8 Hz, 2H, ArCH₂), 1.39–1.27

3

4.5.20 Methyl 2-hydroxy-4-methoxy-6-nonylbenzoate

(7t)

(m, 14H, CH₂CH₃), 0.88 (t, J = 6.7 Hz, 3H, CH₂CH₃). – ¹³C

NMR (63 MHz, CDCl₃): δ = 171.3 (C=O), 165.4, 163.9 (C–O),

148.3 (C), 110.6 (CH), 104.7 (C), 98.7 (CH), 70.1, 63.9 (OCH₂),

Starting with 5e (275 mg, 1.0 mmol), 6e (521 mg, 2.0 mmol) 58.8, 55.2 (OCH₃), 36.9, 32.0, 31.9, 29.8, 29.7, 29.6, 29.3, 22.6

−1

˜

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product (CH₂), 14.1 (CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2954 (m), 2921

7t was isolated as a colourless solid (279 mg, 77%); (s), 2882 (m), 2848 (m), 1634 (s), 1609 (s), 1579 (s), 1461 (m),

m.p. = 40–41 °C; R_f= 0.91 (heptane-EtOAc 1:1). – ¹H NMR 1435 (m), 1385 (m), 1366 (s). – HRMS (ESI): berechnet für

(CDCl₃, 250 MHz): δ = 11.73 (s, 1H, OH), 6.33 (d, ⁴J = 2.5 Hz, C₂₀H₃₃O₅[M+H]⁺: 353.23225, gefunden 353.23269. – Anal-

1H, CH), 6.29 (d, ⁴J = 2.5 Hz, 1H, CH), 3.92 (s, 3H, OCH₃), 3.80 ysis calcd. for C₂₀H₃₂O₅(352.47): C 68.15, H 9.15; found C

(s, 3H, OCH₃), 2.84 (t, ³J = 7.6 Hz, 2H, ArCH₂), 1.52–1.27 (m, 67.98, H 9.42.

14H, 7 × CH₂), 0.88 (t, ³J = 6.9 Hz, 3H, CH₂CH₃). – ¹³C NMR

(75 MHz, CDCl₃): δ = 172.0 (C=O), 165.5, 163.9 (C–O), 148.1 4.5.23 1-(2-Hydroxy-4-methoxy-6-tridecylphenyl)

(C), 110.6 (CH), 104.6 (C), 98.7 (CH), 55.2, 51.8 (OCH₃), 36.9,

ethan-1-one (7w)

31.9, 31.8, 29.8, 29.6, 29.5, 29.3, 22.7, (CH₂), 14.1 (CH₃). – IR

−1

˜

(ATR, cm ): ν ꢀ 2956 (m), 2919 (m), 2848 (m), 1746 (w), 1722 Starting with 5f (331 mg, 1.0 mmol), 6a (489 mg, 2.0 mmol)

(w), 1640 (s), 1613 (s), 1574 (s), 1462 (s), 1435 (s), 1382 (m), and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7w

1326 (s). – MS (EI, 70 eV): m/z (%) = 308 [M]⁺(25), 206 was isolated as a colourless oil (201 mg, 58%); R_f= 0.62

(9), 197 (11), 196 (100), 192 (16), 191 (18), 178 (16), 177 (heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 250 MHz): δ = 13.15

(35). – Analysis calcd. for C₁₈H₂₈O₄(308.41): C 70.10, H 9.15; (s, 1H, OH), 6.30 (s, 2H, 2 × CH), 3.81 (s, 3H, OCH₃), 2.84

found C 69.99, H 9.42.

(t, ³J = 7.7 Hz, 2H, ArCH₂), 2.64 (s, 3H, COCH₃), 1.39–1.25 (m,

22H, 11 × CH₂), 0.88 (t, ³J = 6.9 Hz, 3H, CH₂CH₃). – ¹³C NMR

(63 MHz, CDCl₃): δ = 204.0 (C=O), 166.4, 164.3 (C–O), 146.9,

114.9 (C), 110.7, 98.8 (CH), 55.3 (OCH₃), 36.4, 32.3, 32.1 (CH₂),

4.5.21 Methyl 2-hydroxy-3,4-dimethoxy-

6-nonylbenzoate (7u)

31.9 (COCH₃), 29.7, 29.6, 29.6, 29.5, 29.4, 29.2, 22.7, (CH₂),

−1

˜

14.1 (CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2916 (s), 2846 (m), 1605

Starting with 5e (275 mg, 1.0 mmol), 6f (581 mg, 2.0 mmol) (s), 1579 (s), 1464 (m), 1445 (m), 1426 (m), 1386 (s), 1359

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7u (s). – MS (EI, 70 eV): m/z (%) = 348 [M]⁺(34), 334 (19), 333

was isolated as a colourless oil (233 mg, 69%); R_f= 0.64 (100), 305 (7), 193 (25), 190 (34), 189 (36), 180 (65), 176

(heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 300 MHz): δ = 11.41 (80). – Analysis calcd. for C₂₂H₃₆O₃(348.52): C 75.82, H

(s, 1H, OH), 6.30 (s, 1H, CH), 3.93 (s, 3H, OCH₃), 3.90 (s, 3H, 10.41; found C 75.94, H 10.40.

OCH₃), 3.85 (s, 3H, OCH₃), 2.83 (t, ³J = 7.6 Hz, 2H, ArCH₂),

1.51–1.27 (m, 14H, 7 × CH₂), 0.88 (t, ³J = 7.0 Hz, 3H, 4.5.24 Methyl 2-hydroxy-4-methoxy-

CH₂CH₃). – ¹³C NMR (75 MHz, CDCl₃): δ = 171.8 (C=O), 156.9,

156.2 (C–O), 142.4, 134.7, 106.1 (C), 106.1 (CH), 60.5, 55.8,

6-tridecylbenzoate (7x)

52.0 (OCH₃), 37.0, 32.1, 31.9, 29.9, 29.6, 29.5, 29.3, 22.6, Starting with 5f (331 mg, 1.0 mmol), 6e (521 mg, 2.0 mmol)

−1

˜

(CH₂), 14.1 (CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2923 (s), 2852 and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product

(m), 1651 (s), 1608 (m), 1571 (s), 1446 (m), 1435 (m), 1406 7x was isolated as a colourless solid (279 mg, 77%);

1

(s). – MS (EI, 70 eV): m/z (%) = 338 [M]⁺(420), 307 (26), 306 m.p. = 5–55 °C; R_f= 0.91 (heptane-EtOAc 1:1). – H NMR

(100), 179 (11), 166 (37). – Analysis calcd. for C₁₉H₃₀O₅(CDCl₃, 250 MHz): δ = 11.73 (s, 1H, OH), 6.33 (d, ⁴J = 2.7 Hz,

(338.44): C 67.43, H 8.93; found C 67.47, H 8.96.

1H, CH), 6.29 (d, ⁴J = 2.7 Hz, 1H, CH), 3.92 (s, 3H, OCH₃), 3.80

14

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

3

(s, 3H, OCH₃), 2.84 (t, J = 7.6 Hz, 2H, ArCH₂), 1.52–1.26 (s). – MS (EI): m/z (%) = 222 [M]⁺(23), 194 (100), 190 (30), 179

(m, 22H, 11 × CH₂), 0.88 (t, ³J = 6.9 Hz, 3H, CH₂CH₃). – ¹³

C

(88), 119 (22), 91 (20). – Analysis calcd. for C₁₂H₁₄O₄(222.24):

NMR (75 MHz, CDCl₃): δ = 172.0 (C=O), 165.5, 163.9 (C–O), C 64.85, H 6.35; found C 64.47, H 6.47.

148.0 (C), 110.6 (CH), 104.5 (C), 98.7 (CH), 55.2, 51.8 (OCH₃),

36.9, 31.9, 31.8, 29.8, 29.7, 29.6, 29.6, 29.6, 29.5, 29.4, 29.3,

−1

4.5.27 Isopropyl 6-cyclopropyl-2-hydroxy-

4-methoxybenzoate (7aa)

˜

22.7, (CH₂), 14.1 (CH₃). – IR (ATR, cm ): ν ꢀ 2955 (m), 2916

(m), 2847 (m), 1746 (w), 1711 (w), 1640 (s), 1613 (s), 1574 (s),

1464 (s), 1435 (s), 1383 (m), 1327 (s). – MS (EI, 70 eV): m/z

(%) = 364 [M]⁺(14), 196 (100), 177 (18), 164 (19), 138

(8). – HRMS (EI, 70 eV): m/z calcd. for für C₂₂H₃₆O₄[M]⁺:

364.26081; found 364.260403.

Starting with 5g (282 mg, 1.50 mmol), 6i (866 mg, 3.0 mmol)

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7aa

was isolated as a colourless oil (179 mg, 48%); column

1

chromatography: heptane → heptane-EtOAc 10:1. – H

NMR (250 MHz, CDCl₃): δ = 0.61–0.67 (m, 2H, cyclopropyl-

CH₂), 0.84–0.92 (m, 2H, cyclopropyl-CH₂), 1.38 (d,

³J = 6.3 Hz, 6H, CH(CH₃)₂), 2.40 (tt, ³J = 8.6 Hz, ³J = 5.7 Hz, 1H,

cyclopropyl-CH), 3.78 (s, 3H, OCH₃), 5.32 (hept, ³J = 6.3 Hz,

1H, CH(CH₃)₂), 6.23 (dd, ⁴J = 2.6 Hz, ⁵J = 0.7 Hz, 1H, CH_Ar),

6.31 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.89 (s, 1H, OH). – ¹³C NMR

(75 MHz, CDCl₃): δ = 8.1 (CH₂), 17.1 (cyclopropyl-CH), 21.9

(CH₃), 55.2 (OCH₃), 69.0 (CH(CH₃)₂), 98.7 (CH), 106.8 (C),

4.5.25 Methyl 2-hydroxy-3,4-dimethoxy-

6-tridecylbenzoate (7y)

Starting with 5f (331 mg, 1.0 mmol), 6f (581 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7y

was isolated as a colourless oil (313 mg, 79%); R_f= 0.54

(heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 250 MHz): δ = 11.41

(s, 1H, OH), 6.30 (s, 1H, CH), 3.93 (s, 3H, OCH₃), 3.90 (s, 3H,

OCH₃), 3.85 (s, 3H, OCH₃), 2.83 (t, ³J = 7.6 Hz, 2H, ArCH₂),

107.8 (CH), 147.5 (C), 163.9, 165.3 (CO), 171.3 (C=O). – IR

−1

3

˜

(ATR, cm ): ν ꢀ 3083 (w), 2980 (w), 2938 (w), 1639 (s), 1608

1.31–1.26 (m, 22H, 11 × CH₂), 0.88 (t, J = 7.0 Hz, 3H,

CH₂CH₃). – ¹³C NMR (75 MHz, CDCl₃): δ = 171.8 (C=O), 156.9,

156.2 (C–O), 142.5, 134.7, 106.1 (C), 106.1 (CH), 60.6, 55.8,

(s), 1575 (s), 1465 (m), 1424 (m), 1386 (m), 1352 (s), 1313 (s),

1251 (s), 1218 (s), 1202 (s), 1155 (s), 1099 (s), 1039 (s), 1009 (s),

948 (m), 911 (m), 855 (m), 809 (br s), 780 (br m), 707 (s), 617

(m). – MS (EI): m/z (%) = 250 [M]⁺(12), 190 (23), 180 (100),

151 (10), 119 (9), 91 (9). – Analysis calcd. for C₁₄H₁₈O₄

(250.29): C 67.18, H 7.25; found C 67.08, H 7.32.

52.0 (OCH₃), 37.0, 32.2, 31.9, 29.9, 29.6, 29.6, 29.5, 29.4, 29.3,

−1

˜

22.7, (CH₂), 14.1 (CH₃). – IR (ATR, cm ): ν ꢀ 2922 (s), 2851

(s), 1725 (w), 1653 (s), 1609 (m), 1572 (s), 1513 (w), 1446 (s),

1435 (s), 1407 (s). – MS (EI, 70 eV): m/z (%) = 394 [M]⁺(27),

363 (41), 362 (100), 333 (4), 207 (7), 166 (16). – Analysis

calcd. for C₂₃H₃₈O₅(394.54): C 70.02, H 9.71; found C 70.13, 4.5.28 Isobutyl 6-cyclopropyl-2-hydroxy-

H 9.70.

4-methoxybenzoate (7ab)

4.5.26 Methyl 6-cyclopropyl-2-hydroxy-

4-methoxybenzoate (7z)

Starting with 5g (282 mg, 1.50 mmol), 6m (909 mg,

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7ab was isolated as a white solid (180 mg, 45%);

Starting with 5g (282 mg, 1.50 mmol), 6e (780 mg, m.p.

=

59–60 °C; column chromatography: hep-

1

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) tane → heptane-EtOAc 10:1. – H NMR (250 MHz, CDCl₃):

product 7z was isolated as a white solid (99 mg, 30%); δ = 0.65–0.68 (m, 2H, cyclopropyl-CH₂), 0.86–0.95 (m, 2H,

m.p. = 42–43 °C; column chromatography: heptane → hep- cyclopropyl-CH₂), 1.00 (d, ³J = 6.7 Hz, 6H, CH(CH₃)₂), 2.08

tane-EtOAc 10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 0.59–0.65 (hept, J = 6.7 Hz, 1H, CH(CH₃)₂), 2.47 (tt, J = 8.5 Hz,

(m, 2H, Cyclopropyl-CH₂), 0.8–0.93 (m, 2H, cyclopropyl- ³J = 5.7 Hz, 1H, cyclopropyl-CH), 3.78 (s, 3H, OCH₃), 4.15 (d,

CH₂), 2.40 (tt, ³J = 8.6 Hz, ³J = 5.7 Hz, 1H, cyclopropyl-CH), ³J = 6.7 Hz, 2H, OCH₂), 6.19 (dd, ⁴J = 2.6 Hz, ⁵J = 0.5 Hz, 1H,

3.78 (s, 3H, OCH₃), 3.93 (s, 3H, CO₂CH₃), 6.20 (dd, ⁴J = 2.6 Hz, CH_Ar), 6.31 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.83 (s, 1H, OH). – ¹³C

⁵J = 0.6 Hz, 1H, CH_Ar), 6.31 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.68 (s, NMR (75 MHz, CDCl₃): δ = 8.2 (CH₂), 16.6 (cyclopropyl-CH),

1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 8.0 (CH₂), 16.6 19.3 (CH₃), 27.8 (CH(CH₃)₂), 55.3 (OCH₃), 71.7 (OCH₂), 98.6

3

(cyclopropyl-CH), 51.9, 55.3 (OCH₃), 98.6 (CH), 106.3 (C), (CH), 106.5 (C), 107.2 (CH), 147.7 (C), 164.1, 165.4 (CO), 172.0

−1

˜

107.5 (CH), 147.8 (C), 164.1, 165.2 (CO), 172.2 (C=O). – IR (C=O). – IR (ATR, cm ): ν ꢀ 3082 (w), 2958 (m), 2872 (w),

−1

˜

(ATR, cm ): ν ꢀ 3011 (w), 2954 (w), 2851 (w), 1637 (s), 1608 1634 (s), 1613 (s), 1578 (s), 1468 (m), 1428 (m), 1398 (m), 1386

(s), 1571 (s), 1438 (s), 1371 (m), 1317 (s), 1255 (s), 1224 (s), 1203 (m), 1375 (m), 1364 (m), 1341 (m), 1323 (s), 1279 (m), 1254 (s),

(s), 1158 (s), 1117 (s), 1040 (m), 1024 (m), 1005 (s), 953 (s), 1248 (s), 1221 (s), 1207 (s), 1161 (s), 1094 (m), 1057 (m),

839 (s), 805 (s), 779 (s), 703 (s), 660 (m), 640 (m), 619 1041 (m), 1010 (s), 972 (s), 945 (m), 905 (m), 849 (s), 815

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

15

(br s), 789 (s), 707 (s), 619 (m). – MS (EI): m/z (%) = 264 [M]⁺4.5.31 Methyl 6-cyclopropyl-2-hydroxy-4-methoxy-

(12), 190 (24), 180 (100), 151 (7), 119 (8), 91 (8). – Analysis

calcd. for C₁₅H₂₀O₄(264.32): C 68.16, H 7.63; found C

68.12, H 7.92.

3-propylbenzoate (7ae)

Starting with 5g (188 mg, 1.0 mmol), 6n (605 mg, 2.0 mmol)

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) prod-

uct 7ae was isolated as a white solid (136 mg, 52%);

m.p. = 53–54 °C; column chromatography: heptane → hep-

tane-EtOAc 10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 0.59–0.65

(m, 2H, cyclopropyl-CH₂), 0.85–0.92 (m, 2H, cyclopropyl-

4.5.29 1-(6-Cyclopropyl-2-hydroxy-4-methoxyphenyl)

ethan-1-one (7ac)

3

CH₂), 0.92 (t, J = 7.4 Hz, 3H, CH₂CH₃), 1.42–1.57 (m, 2H,

Starting with 5g (282 mg, 1.50 mmol), 6a (733 mg, 3.0 mmol)

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7ac

was isolated as a yellow oil (155 mg, 50%); column chro-

CH₂CH₃), 2.40 (tt, ³J = 8.6 Hz, ³J = 5.8 Hz, 1H, cyclopropyl-

CH), 2.58 (t, ³J = 7.7 Hz, 2H, Ar-CH₂), 3.82 (s, 3H, OCH₃), 3.93

(s, 3H, CO₂CH₃), 6.25 (s, 1H, CH_Ar), 11.59 (s, 1H, OH). – ¹³

C

1

matography: heptane → heptane-EtOAc 10:1. – H NMR

NMR (63 MHz, CDCl₃): δ = 7.7 (CH₂), 14.2 (CH₂CH₃) 17.2

(cyclopropyl-CH), 22.0, 24.7 (CH₂), 51.9, 55.3 (OCH₃), 102.5

(250 MHz, CDCl₃): δ = 0.76–0.82 (m, 2H, cyclopropyl-CH₂),

3

0.99–1.07 (m, 2H, cyclopropyl-CH₂), 2.10 (tt, J = 8.3 Hz,

³J = 5.5 Hz, 1H, cyclopropyl-CH), 2.80 (s, 3H, C=OCH₃), 3.78

(s, 3H, OCH₃), 6.26–6.29 (m, 2H, CH_Ar), 12.39 (s, 1H,

OH). – ¹³C NMR (75 MHz, CDCl₃): δ = 9.3 (CH₂), 17.8

(cyclopropyl-CH), 32.5 (C=OCH₃), 53.3 (OCH₃), 99.0, 109.0

(CH), 106.9, 116.0, 144.8 (C), 161.5, 161.6 (CO), 172.6

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 3003 (w), 2955 (m), 2869 (w),

1649 (s), 1609 (m), 1570 (m), 1436 (m), 1402 (m), 1371 (m),

1360 (m), 1272 (s), 1232 (s), 1222 (s), 1194 (m), 1156 (s), 1131

(s), 1004 (m), 950 (w), 841 (m), 810 (m), 747 (m), 675 (m),

663 (m), 635 (w), 614 (m), 572 (m). – MS (EI): m/z

(%) = 264 [M]⁺(58), 236 (92), 232 (59), 231 (34), 221 (65), 217

(23), 204 (27), 203 (100), 115 (21). – HRMS (EI): m/z calcd. for

C₁₅H₂₀O₄[M]⁺: 264.13561; found 264.13564.

(CH), 116.1, 146.7 (C), 164.4, 166.5 (CO), 204.6 (C=O). – IR

−1

˜

(ATR, cm ): ν ꢀ 3004 (w), 2967 (w), 2941 (w), 2849 (w),

1603 (br s), 1462 (m), 1425 (s), 1384 (m), 1358 (s), 1301 (m),

1249 (s), 1221 (s), 1203 (s), 1155 (s), 1066 (m), 1013 (s), 959 (s),

828 (br s), 746 (m), 703 (m), 653 (m), 595 (s). – MS (EI): m/z

(%) = 206 [M]⁺(3), 179 (11), 178 (100), 135 (10). – HRMS (EI):

m/z calcd. for C₁₂H₁₄O₃[M]⁺: 206.09375; found 206.09351.

4.5.32 Ethyl 6-cyclopropyl-2-hydroxy-4-methoxy-

3-octylbenzoate (7af)

4.5.30 Methyl 6-cyclopropyl-2-hydroxy-4-methoxy-

3-methylbenzoate (7ad)

Starting with 5g (282 mg, 1.50 mmol), 6l (870 mg,

2.25 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7af was isolated as a light-yellow oil (369 mg,

71%); column chromatography: heptane → heptane-EtOAc

Starting with 5g (282 mg, 1.50 mmol), 6k (824 mg,

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7ad was isolated as a white solid (220 mg, 62%);

m.p. = 62–63 °C; column chromatography: heptane → hep-

tane-EtOAc 10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 0.58–0.64

(m, 2H, cyclopropyl-CH₂), 0.86–0.94 (m, 2H, cyclopropyl-

CH₂), 2.06 (s, 3H, Ar–CH₃), 2.41 (tt, ³J = 8.5 Hz, ³J = 5.7 Hz, 1H,

cyclopropyl-CH), 3.83 (s, 3H, OCH₃), 3.94 (s, 3H, CO₂CH₃),

6.26 (s, 1H, CH_Ar), 11.66 (s, 1H, OH). – ¹³C NMR (63 MHz,

CDCl₃): δ = 7.7 (CH₂), 7.8 (Ar–CH₃) 17.2 (cyclopropyl-CH),

1

10:1. – H NMR (300 MHz, CDCl₃): δ = 0.61–0.66 (m, 2H,

cyclopropyl-CH₂), 0.84–0.90 (m, 5H, cyclopropyl-CH₂,

Octyl-CH₃), 1.21–1.55 (m, 12H, 6 × CH₂), 1.40 (t, ³J = 7.1 Hz,

3

3H, CO₂CH₂CH₃), 2.41 (tt, J = 8.5 Hz, J = 5.9 Hz, 1H,

cyclopropyl-CH), 2.56–2.61 (m, 2H, Ar–CH₂), 3.82 (s, 3H,

3

OCH₃), 4.41 (q, J = 7.2 Hz, 2H, CO₂CH₂CH₃), 6.26 (s, 1H,

CH_Ar), 11.70 (s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 7.9

(CH₂), 14.1, 14.2 (CH₂CH₃) 17.5 (cyclopropyl-CH), 22.7, 22.7,

28.8, 29.3, 29.6, 29.8, 32.0 (CH₂), 55.3 (OCH₃), 61.1 (CO₂CH₂),

51.9, 55.4 (OCH₃), 102.3 (CH), 106.8, 111.2, 144.6 (C), 161.4,

−1

102.7 (ArCH), 107.0, 116.3, 144.6 (C), 161.3, 161.7 (CO), 172.1

˜

161.6 (CO), 172.5 (C=O). – IR (ATR, cm ): ν ꢀ 3001 (m), 2951

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 2955 (m), 2923 (m), 2853 (m),

(m), 2852 (w), 1649 (s), 1611 (s), 1573 (s), 1433 (s), 1401 (s),

1364 (m), 1312 (m), 1277 (s), 1232 (s), 1193 (s), 1160 (s), 1131

(s), 1057 (m), 1029 (s), 1005 (s), 990 (s), 934 (m), 904 (m),

877 (m), 842 (s), 806 (s), 763 (br s), 679 (m), 657 (s), 637 (m),

613 (m), 562 (s). – MS (EI): m/z (%) = 236 [M]⁺(60), 208 (94),

204 (59), 203 (26), 193 (100), 189 (34), 173 (24), 161 (23), 77

(21). – Analysis calcd. for C₁₃H₁₆O₄(236.26): C 66.09, H 6.83;

found C 65.78, H 6.90.

1713 (w), 1646 (s), 1610 (m), 1571 (m), 1463 (m), 1405 (m),

1395 (m), 1366 (m), 1274 (s), 1229 (s), 1199 (m), 1167 (s), 1156

(s), 1133 (s), 1024 (s), 899 (w), 839 (m), 811 (m), 778 (m),

722 (m), 676 (w), 663 (w), 635 (w), 614 (w), 573 (w). – MS (EI):

m/z (%) = 348 [M]⁺(36), 321 (20), 320 (100), 292 (20), 291

(84), 271 (22), 204 (80), 203 (89). – HRMS (EI): m/z calcd. for

C₂₁H₃₂O₄[M]⁺: 348.22951; gefunden: 348.22918.

16

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

4.5.33 Methyl 6-cyclobutyl-2-hydroxy-

4-methoxybenzoate (7ag)

cyclobutyl-CH₂), 2.08 (s, 3H, Ar-CH₃), 2.25–2.36 (m, 2H,

cyclobutyl-CH₂), 3.88 (s, 3H, OCH₃), 3.91 (s, 3H, CO₂CH₃),

4.05–4.12 (m, 1H, cyclobutyl-CH), 6.41 (s, 1H, CH_Ar), 11.49 (s,

Starting with 5h (303 mg, 1.50 mmol), 6e (780 mg, 3.0 mmol) 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 7.8 (Ar-CH₃), 17.9,

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) prod- 29.6 (CH₂), 40.5 (cyclobutyl-CH), 51.9, 55.4 (OCH₃), 101.6

uct 7ag was isolated as a white solid (140 mg, 40%); (CH), 104.3, 110.8, 147.2 (C), 161.5, 161.5 (CO), 172.1

−1

˜

m.p. = 44–45 °C; column chromatography: heptane → hep- (C=O). – IR (ATR, cm ): ν ꢀ 2983 (m), 2947 (m), 2918 (m),

tane-EtOAc 10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 1.70–2.33 2867 (m), 1644 (s), 1620 (m), 1610 (s), 1575 (s), 1505 (m), 1453

(m, 6H, cyclobutyl-CH₂), 3.81 (s, 3H, OCH₃), 3.91 (s, 3H, (m), 1435 (s), 1403 (s), 1364 (m), 1314 (s), 1282 (s), 1263 (s),

CO₂CH₃), 3.94–4.08 (m, 1H, cyclobutyl-CH), 6.32 1223 (m), 1195 (s), 1159 (s), 1126 (s), 1080 (m), 1006 (s), 970

(d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.42 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.54 (m), 916 (m), 827 (s), 804 (s), 741 (s), 678 (s), 647 (m), 629 (m),

(s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 17.9, 29.5 (CH₂), 613 (m), 543 (m). – MS (EI): m/z (%) = 250 [M]⁺(36), 222

40.2 (cyclobutyl-CH), 51.9, 55.3 (OCH₃), 98.2 (CH), 104.0 (C), (15), 218 (25), 191 (19), 190 (100), 172 (21), 147 (15). – HRMS

107.5 (CH), 150.1 (C), 164.2, 165.2 (CO), 171.8 (C=O). – IR (ATR, (EI): m/z calcd. for C₁₄H₁₈O₄[M]⁺: 250.11996;

−1

˜

cm ): ν ꢀ 2946 (m), 2866 (w), 1648 (s), 1611 (s), 1575 (s), 1428 found 250.11953.

(m), 1378 (m), 1323 (s), 1259 (s), 1239 (s), 1201 (s), 1154 (s), 1114

(s), 1049 (m), 1010 (m), 988 (m), 950 (m), 845 (m), 829 (m), 4.5.36 Methyl 6-cyclobutyl-2-hydroxy-4-methoxy-

806 (s), 760 (br m), 714 (m), 641 (m), 616 (m), 539 (m). – MS

(EI): m/z (%) = 236 [M]⁺(34), 208 (24), 204 (33), 177 (20), 176

3-propylbenzoate (7aj)

(100), 148 (31). – HRMS (EI): m/z calcd. for C₁₃H₁₆O₄[M]⁺: Starting with 5h (202 mg, 1.0 mmol), 6n (605 mg, 2.0 mmol)

236.10431; found 236.10441.

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) product

7aj was isolated as a light-yellow solid (147 mg, 53%);

m.p. = 55–56 °C; column chromatography: heptane → hep-

4.5.34 1-(6-Cyclobutyl-2-hydroxy-4-methoxyphenyl)

ethan-1-one (7ah)

tane-EtOAc 10:1.

–

¹H NMR (250 MHz, CDCl₃):

δ = 0.93 (t, ³J = 7.4 Hz, 3H, CH₃), 1.43–1.58 (m, 2H, CH₂CH₃),

Starting with 5h (303 mg, 1.50 mmol), 6a (733 mg, 3.0 mmol) 1.70–2.10 (m, 4H, cyclobutyl-CH₂), 2.25–2.35 (m, 2H, cyclo-

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7ah butyl-CH₂), 2.56–2.62(m, 2H, Ar-CH₂), 3.87(s, 3H, OCH₃), 3.91

was isolated as a yellow oil (170 mg, 51%); column chro- (s, 3H, CO₂CH₃), 3.98–4.11 (m, 1H, cyclobutyl-CH), 6.41 (s,

1

matography: heptane → heptane-EtOAc 10:1. – H NMR 1H, CH_Ar), 11.42 (s, 1H, OH). – ¹³C NMR (75 MHz, CDCl₃):

(250 MHz, CDCl₃):δ =1.84–2.44(m, 6H, cyclobutyl-CH₂), 2.59 δ = 14.2 (CH₃), 17.9, 22.0, 24.7, 39.6 (CH₂), 40.5 (cyclobutyl-

(s, 3H, C=OCH₃), 3.81 (s, 3H, OCH₃), 3.90 (quint, ³J = 8.3 Hz, CH), 51.9, 55.3 (OCH₃), 101.7 (CH), 104.5, 115.6, 147.4 (C),

−1

1H, cyclobutyl-CH), 6.27 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.48 (d, 161.5, 161.5 (CO), 172.2 (C=O). – IR (ATR, cm ): ν ꢀ 2956 (m),

˜

⁴J = 2.6 Hz, 1H, CH_Ar), 12.47 (s, 1H, OH). – ¹³C NMR (63 MHz, 2868 (w), 1650 (s), 1609 (m), 1571 (m), 1436 (m), 1401 (m),

CDCl₃): δ = 17.9, 30.4 (CH₂), 31.3 (C=OCH₃), 39.5 (cyclobutyl- 1375 (w), 1316 (m), 1276 (s), 1248 (s), 1223 (m), 1195 (m), 1157

CH), 55.3 (OCH₃), 98.3, 108.0 (CH), 115.1, 149.4 (C), 164.4, (s), 1131 (s), 1061 (m), 1004 (m), 946 (m), 829 (s), 809 (m), 745

−1

˜

164.8 (CO), 204.3 (C=O). – IR (ATR, cm ): ν ꢀ 2966 (m), 2941 (m), 673 (m), 630 (m), 613 (m), 563 (m). – MS (EI): m/z

(m), 2866 (w), 1746 (w), 1684 (w), 1604 (s), 1581 (s), 1463 (m), (%) = 278 [M]⁺(48), 250 (21), 246 (29), 219 (22), 218 (100), 217

1432 (m), 1357 (m), 1297 (m), 1242 (s), 1201 (s), 1155 (s), 1062 (37), 190 (22), 189 (71). – HRMS (EI): m/z calcd. for C₁₆H₂₂O₄

(m), 1014 (m), 991 (m), 964 (m), 843 (s), 828 (s), 747 (m), 703 [M]⁺: 278.15126; found 278.15144.

(m), 651 (m), 581 (m). – MS (EI): m/z (%) = 220 [M]⁺(31), 192

(28), 191 (100), 177 (62), 149 (16). – HRMS (EI): m/z calcd. for 4.5.37 Ethyl 6-cyclobutyl-2-hydroxy-4-methoxy-

C₁₃H₁₆O₃[M]⁺: 220.10940; found 220.10980.

3-octylbenzoate (7ak)

4.5.35 Methyl 6-cyclobutyl-2-hydroxy-4-methoxy-

3-methylbenzoate (7ai)

Startingwith 5h(303 mg, 1.50 mmol), 6l(870 mg, 2.25 mmol)

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(2 mL) product 7ak

was isolated as a light-yellow oil (211 mg, 37%); column

Startingwith 5h(303 mg, 1.50 mmol), 6k(780mg, 3.0 mmol) chromatography: heptane → heptane-EtOAc 10:1. – ¹H

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7ai NMR (300 MHz, CDCl₃): δ = 0.84–0.89 (m, 3H, octyl-CH₃),

was isolated as a white solid (178 mg, 71%); m.p. = 59–60 °C; 1.21–1.49 (m, 12H, 6 × CH₂), 1.42 (t, ³J = 7.2 Hz, 3H,

column chromatography: heptane

10:1. – H NMR (250 MHz, CDCl₃): δ = 1.71–2.05 (m, 4H, (m, 2H, Ar-CH₂), 3.87 (s, 3H, OCH₃), 4.04–4.19 (m, 1H,

→ heptane-EtOAc CO₂CH₂CH₃), 1.76–2.36 (m, 6H, cyclobutyl-CH₂), 2.57–2.62

1

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

17

cyclobutyl-CH), 4.38 (q, ³J = 7.1 Hz, 2H, CO₂CH₂CH₃), 6.42 (s, 105.6 (C), 106.8 (CH), 151.4 (C), 164.0, 164.7 (CO), 172.0

−1

1H, CH_Ar), 11.50 (s, 1H, OH). – ¹³C NMR (75 MHz, CDCl₃): (C=O). – IR (ATR, cm ): ν ꢀ 2950 (m), 2868 (w), 1725 (w),

˜

δ = 14.1, 14.1 (CH₂CH₃) 18.0, 22.7, 22.7, 28.9, 29.3, 29.6, 29.7, 1647 (s), 1611 (s), 1574 (s), 1431 (s), 1377 (m), 1320 (s), 1248

29.9, 32.0 (CH₂), 40.5 (cyclobutyl-CH), 55.3 (OCH₃), 61.2 (s), 1201 (s), 1154 (s), 1108 (m), 1039 (s), 1016 (m), 954 (m),

(CO₂CH₂), 101.6 (ArCH), 104.7, 115.9, 147.1 (C), 161.4, 161.5 843 (m), 828 (m), 804 (m), 758 (br m), 713 (m), 634 (m), 618

−1

(CO), 171.8 (C=O). – IR (ATR, cm ): ν ꢀ 2976 (m), 2951 (m), (m), 538 (m). – MS (EI): m/z (%) = 250 [M]⁺(29), 219 (18), 218

˜

2919 (m), 2849 (m), 1713 (w), 1633 (s), 1609 (s), 1572 (m), 1520 (100), 190 (19), 177 (16). – Analysis calcd. for C₁₄H₁₈O₄

(m), 1463 (m), 1445 (m), 1403 (m), 1391 (m), 1374 (m), 1359 (250.29): C 67.18, H 7.25; found C 67.14, H 7.22.

(m), 1345(w), 1325(m), 1291(s), 1278(s), 1257 (s), 1216(s), 1165

(s), 1133 (s), 1091 (m), 1067 (m), 1029 (s), 979 (m), 955 (w), 921 4.5.40 Isopropyl 6-cyclopentyl-2-hydroxy-

(m), 871 (w), 832 (m), 804 (s), 781 (m), 748 (m), 722 (m), 694

4-methoxybenzoate (7an)

(w), 676 (m), 657 (w), 634 (w), 613 (m), 563 (m). – MS

(ESI): m/z calcd. for C₂₂H₃₅O₄[M+H]⁺: 363.25299; found Starting with 5i (324 mg, 1.50 mmol), 6i (866 mg, 3.0 mmol)

363.25353; m/z calcd. for C₂₂H₃₄NaO₄[M+Na]⁺: 385.23493; and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7an

found 385.23520.

was isolated as a colourless oil (279 mg, 67%); column

1

chromatography: heptane → heptane-EtOAc 10:1. – H

4.5.38 Methyl 6-cyclobutyl-2-hydroxy-

3,4-dimethoxybenzoate (7al)

NMR (250 MHz, CDCl₃): δ = 1.38 (d, ³J = 6.3 Hz, 6H,

CH(CH₃)₂), 1.46–1.85 (m, 6H, cyclopentyl-CH₂), 1.95–2.05

(m, 2H, cyclopentyl-CH₂), 3.73–3.86 (m, 1H, cyclopentyl-

Starting with 5h (202 mg, 1.0 mmol), 6f (435 mg, 1.50 mmol) CH), 3.79 (s, 3H, OCH₃), 5.30 (hept, ³J = 6.3 Hz, 1H,

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) product 7al CH(CH₃)₂), 6.31 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.45 (d, ⁴J = 2.6 Hz,

was isolated as a light-yellow oil (140 mg, 53%); column 1H, CH_Ar), 11.58 (s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃):

1

chromatography: heptane → heptane-EtOAc 10:1. – H δ = 21.8 (CH₃), 25.0, 34.5 (CH₂), 43.2 (cyclopentyl-CH), 55.2

NMR (250 MHz, CDCl₃): δ = 1.73–2.34 (m, 6H, cyclobutyl- (OCH₃), 69.2 (CH(CH₃)₂), 98.3 (CH), 106.1 (C), 106.6 (CH),

CH₂), 3.84 (s, 3H, OCH₃), 3.92 (s, 6H, 2 × OCH₃), 3.97–4.08 151.0 (C), 163.9, 164.8 (CO), 171.1 (C=O). – IR (ATR, cm⁻¹):

˜

(m, 1H, cyclobutyl-CH), 6.43 (s, 1H, CH_Ar), 11.06 (s, 1H, ν ꢀ 2952 (m), 2868 (w), 1639 (s), 1610 (s), 1575 (s), 1464 (m),

OH). – ¹³C NMR (75 MHz, CDCl₃): δ = 17.9, 29.6 (CH₂), 40.1 1454 (m), 1424 (m), 1374 (m), 1350 (m), 1310 (s), 1248 (s),

(cyclobutyl-CH), 52.0, 55.8, 60.6 (OCH₃), 102.7 (CH), 105.9 1202 (s), 1155 (s), 1097 (s), 1038 (s), 1016 (m), 966 (m), 912

(C), 134.5 (CO), 144.3 (C), 156.1, 156.2 (CO), 171.5 (C=O). – IR (m), 844 (m), 807 (m), 767 (br m), 713 (m), 617 (m), 538

−1

(ATR, cm ): ν ꢀ 2938 (m), 2860 (w), 1727 (w), 1650 (s), 1606 (m). – MS (EI): m/z (%) = 278 [M]⁺(22), 219 (20), 218 (100),

˜

(m), 1571 (s), 1505 (w), 1437 (m), 1403 (s), 1303 (s), 1272 (s), 190 (15), 177 (13). – HRMS (EI): m/z calcd. for C₁₆H₂₂O₄[M]⁺:

1199 (s), 1163 (m), 1119 (s), 1076 (m), 1030 (s), 987 (m), 975 278.15126; found 278.15201. – Analysis calcd. for C₁₆H₂₂O₄

(m), 947 (m), 828 (m), 807 (m), 770 (br m), 692 (m), 616 (278.34): C 69.04, H 7.97; found C 69.46, H 7.78.

(m). – MS (EI): m/z (%) = 266 [M]⁺(42), 238 (15), 235 (16), 234

(29), 207 (19), 206 (100), 191 (17), 177 (17), 176 (15), 175 (20), 4.5.41 Isobutyl 6-cyclopentyl-2-hydroxy-

163 (28). – HRMS (EI): m/z calcd. for C₁₄H₁₈O₅[M]⁺:

4-methoxybenzoate (7ao)

266.11488; found 266.11505.

Starting with 5i (324 mg, 1.50 mmol), 6m (909 mg,

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7ao was isolated as a light-yellow oil (236 mg,

4.5.39 Methyl 6-cyclopentyl-2-hydroxy-

4-methoxybenzoate (7am)

54%); column chromatography: heptane → heptane-

1

Starting with 5i (324 mg, 1.50 mmol), 6e (780 mg, 3.0 mmol) EtOAc 10:1. – H NMR (250 MHz, CDCl₃): δ = 1.02 (d,

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7am ³J = 6.7 Hz, 6H, CH(CH₃)₂), 1.46–2.18 (m, 9H, cyclopentyl-

was isolated as a colourless oil (137 mg, 37%); column CH₂, CH(CH₃)₂), 3.79 (s, 3H, OCH₃), 3.82–3.93 (m, 1H,

1

chromatography: heptane → heptane-EtOAc 10:1. – H cyclopentyl-CH), 4.13 (d, ³J = 6.3 Hz, 2H, CO₂CH₂), 6.32 (d,

NMR (250 MHz, CDCl₃): δ = 1.46–1.83 (m, 6H, cyclopentyl- ⁴J = 2.6 Hz, 1H, CH_Ar), 6.46 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.54 (s,

CH₂), 1.94–2.04 (m, 2H, cyclopentyl-CH₂), 3.70–3.83 (m, 1H, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 19.4 (CH₃), 25.3

cyclopentyl-CH), 3.79 (s, 3H, OCH₃), 3.92 (s, 3H, CO₂CH₃), (CH₂), 27.7 (CH(CH₃)₂), 34.7 (CH₂), 42.9 (cyclopentyl-CH),

6.32 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.46 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 55.2 (OCH₃), 72.0 (OCH₂), 98.3 (CH), 105.8 (C), 106.7 (CH),

11.40 (s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 25.4, 34.5 151.2 (C), 163.9, 164.8 (CO), 171.9 (C=O). – IR (ATR, cm⁻¹):

˜

(CH₂), 43.0 (cyclopentyl-CH), 52.0, 55.2 (OCH₃), 98.2 (CH), ν ꢀ 2957 (m), 2870 (m), 1713 (w), 1643 (s), 1610 (s), 1575 (s),

18

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

1464 (m), 1424 (m), 1397 (m), 1369 (m), 1343 (m), 1315 (s), 4.5.44 Methyl 6-cyclopentyl-2-hydroxy-4-methoxy-

1245 (s), 1202 (s), 1155 (s), 1105 (s), 1039 (m), 1017 (m), 970

(s), 944 (m), 844 (m), 828 (m), 805 (m), 767 (br m), 713 (m),

3-methylbenzoate (7ar)

617 (m), 538 (m). – MS (EI): m/z (%) = 292 [M]⁺(21), 219 (23), Starting with 5i (324 mg, 1.50 mmol), 6k (824 mg, 3.0 mmol)

218 (100), 190 (14), 177 (11). – Analysis calcd. for C₁₇H₂₄O₄and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7ar

(292.37): C 69.84, H 8.27; found C 69.62, H 8.36.

was isolated as a light-yellow oil (203 mg, 51%); column

chromatography: heptane → heptane-EtOAc 10:1. – H

1

4.5.42 1-(6-Cyclopentyl-2-hydroxy-4-methoxyphenyl)

ethan-1-one (7ap)

NMR (250 MHz, CDCl₃): δ = 1.48–1.86 (m, 6H, cyclopentyl-

CH₂), 1.96–2.06 (m, 2H, cyclopentyl-CH₂), 2.07 (s, 3H, Ar-

CH₃), 3.71–3.81 (m, 1H, cyclopentyl-CH), 3.85 (s, 3H, OCH₃),

Starting with 5i (324 mg, 1.50 mmol), 6a (733 mg, 3.0 mmol) 3.92 (s, 3H, CO₂CH₃), 6.46 (s, 1H, CH_Ar), 11.28 (s, 1H,

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7ap OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 7.9 (Ar-CH₃), 25.4, 34.7

was isolated as a yellow oil (184 mg, 52%); column chro- (CH₂), 43.3 (cyclopentyl-CH), 51.9, 55.3 (OCH₃), 100.8 (CH),

1

matography: heptane → heptane-EtOAc 10:1. – H NMR 106.2, 110.8, 148.2 (C), 160.8, 161.5 (CO), 172.3 (C=O). – IR

−1

˜

(250 MHz, CDCl₃): δ = 1.58–1.87 (m, 6H, cyclopentyl-CH₂), (ATR, cm ): ν ꢀ 2950 (m), 2867 (w), 1724 (w), 1647 (s), 1608

2.01–2.11 (m, 2H, cyclopentyl-CH₂), 2.62 (s, 3H, C=OCH₃), (m), 1577 (s), 1435 (m), 1398 (m), 1367 (m), 1305 (m), 1268 (s),

3.33–3.46 (m, 1H, cyclopentyl-CH), 3.80 (s, 3H, OCH₃), 6.27 1234 (s), 1193 (s), 1155 (s), 1127 (s), 1057 (m), 1003 (s), 931 (w),

(d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.42 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 12.14 825 (m), 805 (m), 736 (br m), 673 (m), 629 (m), 609 (m). – MS

(s, 1H, OH). – ¹³C NMR (75 MHz, CDCl₃): δ = 25.8 (CH₂), 32.1 (EI): m/z (%) = 264 [M]⁺(44), 233 (24), 232 (100), 214 (15), 163

(C=OCH₃), 36.0 (CH₂), 43.3 (cyclopentyl-CH), 55.3 (OCH₃), (25). – Analysis calcd. for C₁₅H₂₀O₄(264.32): C 68.16, H 7.63;

98.3, 107.3 (CH), 116.8, 151.1 (C), 163.9, 164.3 (CO), 204.6 found C 67.93, H 7.70.

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 2949 (m), 2868 (m), 1746 (w),

1687 (w), 1606 (s), 1583 (s), 1434 (m), 1350 (m), 1248 (s), 1201 4.5.45 Methyl 6-cyclopentyl-2-hydroxy-4-methoxy-

(s), 1155 (s), 1072 (m), 1034 (m), 1016 (m), 961 (m), 840 (s),

3-propylbenzoate (7as)

829 (s), 750 (m), 692 (m), 651 (m), 577 (m). – MS (EI): m/z

(%) = 234 [M]⁺(50), 219 (100), 216 (57), 201 (35) 191 (25), 188 Starting with 5i (324 mg, 1.50 mmol), 6n (908 mg,

(52), 187 (30), 175 (30), 43 (20). – HRMS (EI): m/z calcd. for 3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

C₁₄H₁₈O₃[M]⁺: 234.12505; found 234.12513.

product 7as was isolated as a colourless oil (312 mg, 71%);

column chromatography: heptane → heptane-EtOAc

10:1. – H NMR (250 MHz, CDCl₃): δ = 0.93 (t, J = 7.3 Hz,

3H, CH₃), 1.43–1.85 (m, 8H, 3 × cyclopentyl-CH₂, CH₂CH₃),

1.96–2.07 (m, 2H, cyclopentyl-CH₂), 2.56–2.62 (m, 2H, Ar-

1

3

4.5.43 1-(6-Cyclopentyl-2-hydroxy-4-methoxy-

3-methylphenyl)propan-1-one (7aq)

Starting with 5i (324 mg, 1.50 mmol), 6j (613 mg, 2.25 mmol) CH₂), 3.6 –3.79 (m, 1H, cyclopentyl-CH), 3.83 (s, 3H, OCH₃),

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7aq 3.91 (s, 3H, CO₂CH₃), 6.46 (s, 1H, CH_Ar), 11.20 (s, 1H,

was isolated as a white solid (130 mg, 33%); m.p. = 76– OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 14.3 (CH₃), 22.0, 24.8,

77 °C; column chromatography: heptane → heptane-EtOAc 25.4, 34.7 (CH₂), 43.3 (cyclopentyl-CH), 51.9, 55.3 (OCH₃),

10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 1.21 (t, ³J = 7.3 Hz, 3H, 101.0 (CH), 106.3, 115.6, 148.3 (C), 160.8, 161.5 (CO), 172.4

−1

˜

CH₂CH₃), 1.58–1.89 (m, 6H, cyclopentyl-CH₂), 2.02–2.15 (m, (C=O). – IR (ATR, cm ): ν ꢀ 2953 (m), 2868 (m), 1725 (w),

2H, cyclopentyl-CH₂), 2.05 (s, 3H, Ar-CH₃), 2.86 (q, 1649 (s), 1608 (m), 1573 (m), 1435 (m), 1403 (m), 1375 (m),

3J = 7.3 Hz, 2H, CH₂CH₃), 3.19–3.32 (m, 1H, cyclopentyl-CH), 1270 (s), 1233 (s), 1221 (s), 1193 (m), 1154 (s), 1129 (s), 1047

3.85 (s, 3H, OCH₃), 6.41 (s, 1H, CH_Ar), 10.79 (s, 1H, OH). – ¹³C (m), 1002 (m), 952 (m), 827 (m), 808 (m), 750 (br m), 674 (m),

NMR (75 MHz, CDCl₃): δ = 9.8, 9.9 (CH₃), 25.9, 36.3, 37.3 629 (m), 610 (m). – MS (EI): m/z (%) = 292 [M]⁺(36), 261 (15),

(CH₂), 43.9 (cyclopentyl-CH), 55.4 (OCH₃), 101.0 (CH), 110.7, 260 (63), 232 (45), 231 (100). – HRMS (EI): m/z calcd. for

118.2, 146.8 (C), 158.1, 161.2 (CO), 209.8 (C=O). – IR (ATR, C₁₇H₂₄O₄[M]⁺: 292.16691; found 292.16702.

−1

˜

cm ): ν ꢀ 2962 (m), 2816 (m), 2873 (w), 1676 (s), 1605 (m),

1569 (s), 1464 (m), 1451 (m), 1405 (m), 1346 (m), 1321 (m), 4.5.46 Ethyl 6-cyclopentyl-2-hydroxy-4-methoxy-

1254 (m), 1223 (s), 1180 (m), 1127 (s), 1107 (s), 1062 (m), 1037

(m), 1001 (m), 978 (m), 961 (m), 927 (m), 826 (m), 799 (m),

3-octylbenzoate (7at)

758 (w), 698 (w), 661 (m). – MS (EI): m/z (%) = 262 [M]⁺(16), Starting with 5i (324 mg, 1.50 mmol), 6l (870 mg,

234 (15), 233 (100), 215 (12). – HRMS (EI): m/z calcd. for 2.25 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

C₁₆H₂₂O₃[M]⁺: 262.15635; found 262.15638.

product 7at was isolated as a yellow oil (346 mg, 61%);

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

19

column chromatography: heptane → heptane-EtOAc cyclohexyl-CH), 3.79 (s, 3H, OCH₃), 3.93 (s, 3H, CO₂CH₃),

1

10:1. – H NMR (300 MHz, CDCl₃): δ = 0.84–0.89 (m, 3H, 6.32 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.42 (d, ⁴J = 2.6 Hz, 1H, CH_Ar),

octyl-CH₃), 1.18–1.82 (m, 18H, 3 × cyclopentyl-CH₂, 11.48 (s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 26.3, 27.3,

(CH₂)₆CH₃), 1.39 (t, ³J = 7.1 Hz, 3H, CO₂CH₂CH₃), 1.98–2.07 34.7 (CH₂), 41.6 (cyclohexyl-CH), 52.0, 55.2 (OCH₃), 98.3

(m, 2H, cyclopentyl-CH₂), 2.57–2.62 (m, 2H, Ar-CH₂), 3.67– (CH), 104.8 (C), 107.0 (CH), 152.7 (C), 164.1, 164.9 (CO), 172.0

−1

˜

3.84 (m, 1H, cyclopentyl-CH), 3.83 (s, 3H, OCH₃), 4.39 (q, (C=O). – IR (ATR, cm ): ν ꢀ 3001 (w), 2922 (m), 2849 (m),

³J = 7.1 Hz, 2H, CO₂CH₂), 6.45 (s, 1H, CH_Ar), 11.27 (s, 1H, 1647 (s), 1611 (s), 1577 (s), 1431 (s), 1379 (m), 1323 (s), 1310

OH). – ¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 14.1 (CH₃), 22.7, (s), 1247 (s), 1201 (s), 1154 (s), 1108 (m), 1048 (m), 993 (s), 953

22.8, 25.2, 28.9, 29.3, 29.6, 29.9, 32.0, 34.7 (CH₂), 43.4 (m), 894 (w), 843 (m), 828 (m), 805 (m), 759 (br m), 715 (m),

(cyclopentyl-CH), 55.3 (OCH₃), 61.2 (CO₂CH₂), 100.9 (CH), 620 (m). – MS (EI): m/z (%) = 264 [M]⁺(29), 232 (100), 203

106.4, 115.9, 148.0 (C), 160.8, 161.3 (CO), 172.0 (C=O). – IR (9), 177 (10), 164 (8), 91 (6). – Analysis calcd. for C₁₅H₂₀O₄

−1

˜

(ATR, cm ): ν ꢀ 2954 (m), 2923 (m), 2854 (m), 1714 (w), 1646 (264.32): C 68.16, H 7.63; found C 67.95, H 7.71.

(s), 1609 (m), 1573 (m), 1462 (m), 1455 (m), 1405 (m), 1394

(m), 1372 (m), 1272 (s), 1231 (s), 1165 (s), 1156 (s), 1132 (s), 4.5.49 Isopropyl 6-cyclohexyl-2-hydroxy-

1094 (m), 1024 (s), 845 (w), 827 (m), 807 (m), 763 (br m), 722

(m) 674 (w), 629 (w), 610 (w). – MS (EI): m/z (%) = 376 [M]⁺

4-methoxybenzoate (7aw)

(20), 330 (17), 313 (15), 299 (25), 232 (100), 231 (76), 170 (21), Starting with 5j (345 mg, 1.50 mmol), 6i (866 mg, 3.0 mmol)

130 (28), 71 (28), 69 (31), 57 (34), 55 (28), 43 (83), 41 and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7aw

(43). – HRMS (EI): m/z calcd. for C₂₃H₃₆O₄[M]⁺: 376.26081; was isolated as a colourless oil (295 mg, 67%); column

1

found 376.26049.

chromatography: heptane → heptane-EtOAc 10:1. – H

NMR (250 MHz, CDCl₃): δ = 1.25–1.36 (m, 5H, cyclohexyl-

CH₂), 1.40 (d, ³J = 6.3 Hz, 6H, CH(CH₃)₂), 1.73–1.86 (m, 5H,

cyclohexyl-CH₂), 3.38–3.47 (m, 1H, cyclohexyl-CH), 3.79 (s,

4.5.47 Methyl 6-cyclopentyl-2-hydroxy-

3,4-dimethoxybenzoate (7au)

3

3H, OCH₃), 5.33 (hept, J = 6.3 Hz, 1H, CH(CH₃)₂), 6.31 (d,

Starting with 5i (216 mg, 1.0 mmol), 6f (435 mg, 1.50 mmol) ⁴J = 2.6 Hz, 1H, CH_Ar), 6.42 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.65 (s,

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(3 mL) product 7au 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 22.0 (CH₃), 26.3,

was isolated as a yellow oil (185 mg, 66%); column chro- 27.2, 34.6 (CH₂), 41.2 (cyclohexyl-CH), 55.2 (OCH₃), 69.2

1

matography: heptane → heptane-EtOAc 10:1. – H NMR (CH(CH₃)₂), 98.3 (CH), 105.3 (C), 106.9 (CH), 152.6 (C), 163.9,

−1

˜

(250 MHz, CDCl₃): δ = 1.49–2.07 (m, 8H, cyclopentyl-CH₂), 164.8 (CO), 171.2 (C=O). – IR (ATR, cm ): ν ꢀ 2980 (w), 2923

3.59–3.74 (m, 1H, cyclopentyl-CH), 3.85 (s, 3H, OCH₃), 3.89 (m), 2850 (m), 1639 (s), 1609 (s), 1577 (s), 1464 (m), 1449 (m),

(s, 3H, OCH₃), 3.93 (s, 3H, OCH₃), 6.47 (s, 1H, CH_Ar), 10.59 (s, 1423 (m), 1374 (m), 1351 (m), 1305 (s), 1247 (s), 1201 (s), 1156

1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 25.4, 34.7 (CH₂), (s), 1097 (s), 1049 (m), 1031 (m), 992 (s), 948 (w), 911 (m),

43.0 (cyclopentyl-CH), 52.1, 55.8, 60.6 (OCH₃), 101.9 (CH), 843 (m), 807 (br m), 714 (m), 619 (m). – MS (EI): m/z

108.2 (C), 134.4 (CO), 144.9 (C), 154.9, 155.9 (CO), 171.4 (%) = 292 [M]⁺(24), 233 (21), 232 (100), 203 (9), 177 (7). –

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 2949 (m), 2867 (w), 1726 (m), Analysis calcd. for C₁₇H₂₄O₄(292.37): C 69.84, H 8.27; found

1650 (m), 1607 (m), 1573 (m), 1504 (m), 1433 (m), 1405 (m), C 69.99, H 8.43.

1269 (s), 1194 (s), 1151 (s), 1115 (s), 1051 (m), 1031 (s), 984 (m),

953 (m), 825 (m), 806 (m), 777 (m), 688 (m), 612 (m). – MS 4.5.50 Isobutyl 6-cyclohexyl-2-hydroxy-

(EI): m/z (%) = 280 [M]⁺(36), 249 (25), 248 (100), 234 (30),

219 (10), 179 (34). – HRMS (EI): m/z calcd. for C₁₅H₂₀O₅[M]⁺:

280.13053; found 280.13072.

4-methoxybenzoate (7ax)

Starting with 5j (345 mg, 1.50 mmol), 6m (909 mg,

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7ax was isolated as a colourless solid (258 mg,

56%); m.p. = 55–56 °C; column chromatography: hep-

4.5.48 Methyl 6-cyclohexyl-2-hydroxy-

4-methoxybenzoate (7av)

1

tane → heptane-EtOAc 10:1. – H NMR (250 MHz, CDCl₃):

3

Starting with 5j (345 mg, 1.50 mmol), 6e (780 mg, 3.0 mmol) δ = 1.03 (d, J = 6.7 Hz, 6H, CH(CH₃)₂), 1.2–1.44 (m, 5H,

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7av cyclohexyl-CH₂), 1.72–1.85 (m, 5H, cyclohexyl-CH₂), 2.11

was isolated as a colourless oil (231 mg, 58%); column (hept, ³J = 6.7 Hz, 1H, CH(CH₃)₂), 3.4 –3.53 (m, 1H,

1

chromatography: heptane →Фheptane-EtOAc 10:1. – H cyclohexyl-CH), 3.79 (s, 3H, OCH₃), 4.13 (d, ³J = 6.7 Hz, 2H,

NMR (250 MHz, CDCl₃): δ = 1.25–1.41 (m, 5H, cyclohexyl- OCH₂), 6.32 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.44 (d, ⁴J = 2.6 Hz, 1H,

CH₂), 1.73–1.85 (m, 5H, cyclohexyl-CH₂), 3.31–3.40 (m, 1H, CH_Ar), 11.60 (s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 19.5

20

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

(CH₃), 26.3, 27.1 (CH₂), 27.7 (CH(CH₃)₂), 34.8 (CH₂), 41.0 (s), 777 (m), 764 (m), 676 (m), 628 (m), 607 (m). – MS (EI): m/

(cyclohexyl-CH), 55.2 (OCH₃), 71.9 (OCH₂), 98.4 (CH), 105.0 z (%) = 278 [M]⁺(31), 247 (20), 246 (100), 228 (12), 211 (9), 197

(C), 107.1 (CH), 152.8 (C), 164.0, 164.9 (CO), 171.9 (C=O). – IR (19). – HRMS (EI): m/z calcd. for C₁₆H₂₂O₄[M]⁺: 278.15126;

−1

˜

(ATR, cm ): ν ꢀ 2924 (m), 2850 (m), 1642 (s), 1610 (s), 1577 found 278.15105. – Analysis calcd. for für C₁₆H₂₂O₄(278.34):

(s), 1464 (m), 1448 (m), 1423 (m), 1397 (m), 1370 (m), 1342 C 69.04, H 7.97; found C 68.93, H 8.13.

(w), 1309 (s), 1244 (s), 1202 (s), 1155 (s), 1006 (s), 1048 (m),

993 (s), 972 (m), 943 (m), 919 (w), 893 (w), 844 (m), 828 (m), 4.5.53 Methyl 6-cyclohexyl-2-hydroxy-4-methoxy-

805 (m), 714 (m), 620 (m). – MS (EI): m/z (%) = 306 [M]⁺(21),

233 (23), 232 (100), 203 (7), 177 (6). – Analysis calcd. for

C₁₈H₂₆O₄(306.40): C 70.56, H 8.55; found C 70.23, H 8.76.

3-propylbenzoate (7ba)

Starting with 5j (230 mg, 1.0 mmol), 6n (605 mg, 2.0 mmol)

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) product 7ba

was isolated as a light-yellow oil (269 mg, 88%); column

4.5.51 1-(6-Cyclohexyl-2-hydroxy-4-methoxyphenyl)

ethan-1-one (7ay)

1

chromatography: heptane → heptane-EtOAc 10:1. – H

NMR (250 MHz, CDCl₃): δ = 0.93 (t, ³J = 7.4 Hz, 3H, CH₂CH₃),

Starting with 5j (345 mg, 1.50 mmol), 6a (733 mg, 3.0 mmol) 1.23–1.39 (m, 5H, cyclohexyl-CH₂), 1.43–1.58 (m, 2H,

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7ay CH₂CH₃), 1.75–1.86 (m, 5H, cyclohexyl-CH₂), 2.55–2.62 (m,

was isolated as a light-yellow oil (236 mg, 63%); column 2H, Ar-CH₂), 3.30–3.36 (m, 1H, cyclohexyl-CH), 3.84 (s, 3H,

1

chromatography: heptane → heptane-EtOAc 10:1. – H OCH₃), 3.92 (s, 3H, CO₂CH₃), 6.42 (s, 1H, CH_Ar), 11.30 (s, 1H,

NMR (250 MHz, CDCl₃): δ = 1.24–1.47 (m, 5H, cyclohexyl- OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 14.3 (CH₃) 22.0, 24.8,

CH₂), 1.75–1.87 (m, 5H, cyclohexyl-CH₂), 2.61 (s, 3H, 26.4, 27.3, 34.9 (CH₂), 41.8 (cyclohexyl-CH), 51.9, 55.3

C=OCH₃), 2.93–3.01 (m, 1H, cyclohexyl-CH), 3.79 (s, 3H, (OCH₃), 101.2 (CH), 105.4, 115.6, 149.8 (C), 161.0, 161.6 (CO),

−1

OCH₃), 6.27 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 6.40 (d, ⁴J = 2.6 Hz, 1H, 172.4 (C=O). – IR (ATR, cm ): ν ꢀ 2952 (m), 2925 (m), 2850

˜

CH_Ar), 12.27 (s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 26.0, (m), 1648 (s), 1608 (m), 1573 (m), 1435 (m), 1403 (m), 1373

27.0 (CH₂), 32.2 (C=OCH₃), 35.1 (CH₂), 41.9 (cyclohexyl-CH), (m), 1276 (s), 1263 (s), 1232 (m), 1219 (s), 1192 (m), 1154 (s),

55.3 (OCH₃), 98.4, 107.4 (CH), 115.8, 151.6 (C), 164.3, 164.4 1130 (s), 1040 (m), 1003 (m), 978 (m), 950 (w), 840 (s), 826

−1

˜

(CO), 204.5 (C=O). – IR (ATR, cm ): ν ꢀ 2924 (m), 2851 (m), (s), 806 (s), 750 (m), 676 (m), 628 (m), 609 (m). – MS (EI): m/

1748 (w), 1687 (w), 1608 (s), 1586 (s), 1439 (m), 1353 (m), z (%) = 306 [M]⁺(34), 275 (18), 274 (73), 256 (16), 246 (38), 245

1330 (m), 1288 (m), 1248 (s), 1201 (s), 1155 (s), 1078 (m), 1030 (100). – HRMS (EI): m/z calcd. for C₁₈H₂₆O₄[M]⁺: 306.18256;

(m), 995 (m), 960 (m), 841 (s), 750 (m), 713 (m), 690 (m), 651 found 306.18310.

(m). – MS (EI): m/z (%) = 248 [M]⁺(70), 233 (74), 230 (54), 215

(59), 189 (100), 187 (40). – HRMS (EI): m/z calcd. for 4.5.54 Ethyl 6-cyclohexyl-2-hydroxy-4-methoxy-

C₁₅H₂₀O₃[M]⁺: 248.14070; found 248.14038.

3-octylbenzoate (7bb)

4.5.52 Methyl 6-cyclohexyl-2-hydroxy-4-methoxy-

3-methylbenzoate (7az)

Starting with 5j (345 mg, 1.50 mmol), 6l (870 mg,

2.25 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7bb was isolated as a light-yellow oil (470 mg,

Starting with 5j (345 mg, 1.50 mmol), 6k (824 mg, 3.0 mmol) 80%); column chromatography: heptane → heptane-

1

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7az EtOAc 10:1. – H NMR (300 MHz, CDCl₃): δ = 0.86 (t,

was isolated as a white solid (256 mg, 61%); m.p. = 62– ³J = 6.7 Hz, 3H, octyl-CH₃), 1.26–1.52 (m, 17H, cyclohexyl-

63 °C; column chromatography: heptane → heptane-EtOAc CH₂, (CH₂)₆CH₃), 1.42 (t, ³J = 7.2 Hz, 3H, CO₂CH₂CH₃), 1.73–

1

10:1. – H NMR (250 MHz, CDCl₃): δ = 1.24–1.43 (m, 5H, 1.89 (m, 5H, cyclohexyl-CH₂), 2.56–2.61 (m, 2H, Ar-CH₂),

cyclohexyl-CH₂), 1.74–1.86 (m, 5H, cyclohexyl-CH₂), 2.07 3.37–3.44 (m, 1H, cyclohexyl-CH), 3.84 (s, 3H, OCH₃), 4.39

(s, 3H, Ar-CH₃), 3.32–3.40 (m, 1H, cyclohexyl-CH), 3.86 (s, (q, ³J = 7.2 Hz, 2H, CO₂CH₂), 6.42 (s, 1H, CH_Ar), 11.37 (s, 1H,

3H, OCH₃), 3.93 (s, 3H, CO₂CH₃), 6.43 (s, 1H, CH_Ar), 11.38 (s, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 14.1, 14.2 (CH₃) 22.7,

1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 7.9 (Ar-CH₃), 26.4, 22.8, 26.4, 27.2, 28.9, 29.3, 29.6, 29.9, 32.0, 34.8 (CH₂), 41.6

27.3, 34.9 (CH₂), 41.8 (cyclohexyl-CH), 51.9, 55.3 (OCH₃), (cyclohexyl-CH), 55.3 (OCH₃), 61.3 (CO₂CH₂), 101.2 (CH),

101.0 (CH), 105.3, 110.8, 149.7 (C), 161.0, 161.6 (CO), 172.4 105.6, 115.8, 149.7 (C), 160.9, 161.4 (CO), 172.1 (C=O). – IR

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 3005 (w), 2937 (m), 2919 (m), (ATR, cm ): ν ꢀ 2921 (m), 2851 (m), 1644 (m), 1608 (m), 1573

2851 (m), 1640 (s), 1608 (m), 1578 (s), 1455 (m), 1431 (s), 1397 (m), 1448 (m), 1405 (m), 1393 (m), 1371 (m), 1276 (s), 1261 (s),

(s), 1371 (m), 1305 (s), 1275 (s), 1266 (s), 1238 (s), 1193 (m), 1225 (m), 1154 (s), 1131 (s), 1094 (m), 1023 (m), 979 (m), 895

1155 (s), 1126 (s), 1048 (m), 1001 (s), 970 (m), 895 (m), 807 (w), 866 (w), 826 (m), 806 (m), 753 (w), 722 (w), 674 (w), 629

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

21

(w), 609 (w). – MS (EI): m/z (%) = 390 [M]⁺(25), 344 (24), 327 4.5.57 Methyl 6-(2-cyclopentylethyl)-2-hydroxy-

(20), 313 (32), 246 (100), 245 (77). – HRMS (EI): m/z calcd. for

4-methoxybenzoate (7be)

C₂₄H₃₈O₄[M]⁺: 390.27646; found 390.27567.

Starting with 5k (366 mg, 1.50 mmol), 6e (780 mg,

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

product 7be was isolated as a yellow oil (204 mg, 49%);

column chromatography: heptane → heptane-EtOAc

10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 1.09–1.18 (m, 2H, CH₂),

1.47–1.83 (m, 9H, 4 × CH₂, cyclopentyl-CH), 2.82–2.89 (m,

2H, Ar-CH₂), 3.79 (s, 3H, OCH₃), 3.91 (s, 3H, CO₂CH₃), 6.28 (d,

⁴J = 2.6 Hz, 1H, CH_Ar), 6.32 (d, ⁴J = 2.6 Hz, 1H, CH_Ar), 11.72 (s,

1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 25.2, 32.6, 36.2, 38.5

(CH₂), 40.4 (cyclopentyl-CH), 51.8, 55.3 (OCH₃), 98.7 (CH),

4.5.55 Methyl 6-cyclohexyl-2-hydroxy-

3,4-dimethoxybenzoate (7bc)

Starting with 5j (230 mg, 1.0 mmol), 6f (435 mg, 1.50 mmol)

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bc

was isolated as a yellow solid (198 mg, 67%); m.p. = 63–

64 °C; column chromatography: heptane → heptane-EtOAc

1

10:1. – H NMR (250 MHz, CDCl₃): δ = 1.27–1.42 (m, 5H,

cyclohexyl-CH₂), 1.74–1.85 (m, 5H, cyclohexyl-CH₂), 3.22–

3.28 (m, 1H, cyclohexyl-CH), 3.85 (s, 3H, OCH₃), 3.90 (s, 3H,

OCH₃), 3.94 (s, 3H, OCH₃), 6.44 (s, 1H, CH_Ar), 10.65 (s, 1H,

OH). – ¹³C NMR (75 MHz, CDCl₃): δ = 26.3, 27.2, 34.8 (CH₂),

41.6 (cyclohexyl-CH), 52.1, 55.8, 60.6 (OCH₃), 102.1 (CH),

104.6 (C), 110.6 (CH), 148.2 (C), 164.0, 165.5 (CO), 172.0

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 2945 (m), 2863 (w), 1649 (s),

1612 (s), 1574 (s), 1433 (s), 1378 (m), 1324 (s), 1304 (m), 1252

(s), 1201 (s), 1155 (s), 1110 (m), 1045 (s), 956 (m), 845 (m), 829

(m), 806 (m), 762 (br m), 712 (m), 638 (m), 598 (m), 536

(m). – MS (EI): m/z (%) = 278 [M]⁺(9), 197 (12), 196 (100), 165

(10), 164 (69). – Analysis calcd. for C₁₆H₂₂O₄(278.34): C

69.04, H 7.97; found C 68.81, H 8.06.

107.2 (C), 134.4 (CO), 146.5 (C), 155.3, 156.0 (CO), 171.5

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 2927 (m), 2851 (m), 1721 (s), 1651

(m), 1612 (m), 1583 (m), 1501 (m), 1447 (s), 1427 (s), 1340 (m),

1297 (s), 1273 (s), 1240 (s), 1193 (s), 1183 (s), 1146 (s), 1101 (s),

1058 (m), 1043 (m), 1017 (s), 971 (s), 940 (s), 891 (m), 867

(m), 835 (m), 827 (m), 804 (m), 779 (m), 758 (m), 643 (s), 595

(s). – MS (EI): m/z (%) = 294 [M]⁺(25), 263 (24), 262 (100), 179

(12). – HRMS (EI): m/z calcd. for C₁₆H₂₂O₅[M]⁺: 294.14618;

found 294.14578.

4.5.58 Isopropyl 6-(2-cyclopentylethyl)-2-hydroxy-

4-methoxybenzoate (7bf)

Starting with 5k (366 mg, 1.50 mmol), 6i (866 mg, 3.0 mmol)

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7bf

was isolated as a yellow oil (307 mg, 67%); column chro-

1

4.5.56 Ethyl 3-chloro-6-cyclohexyl-2-hydroxy-

4-methoxybenzoate (7bd)

matography: heptane → heptane-EtOAc 10:1. – H NMR

(250 MHz, CDCl₃): δ = 1.06–1.20 (m, 2H, CH₂), 1.39 (d,

³J = 6.3 Hz, 6H, CH(CH₃)₂), 1.47–1.84 (m, 9H, 4 × CH₂,

cyclopentyl-CH), 2.85–2.91 (m, 2H, Ar-CH₂), 3.79 (s, 3H,

OCH₃), 5.32 (hept, ³J = 6.3 Hz, 1H, CH(CH₃)₂), 6.27 (d,

⁴J = 2.7 Hz, 1H, CH_Ar), 6.31 (d, ⁴J = 2.7 Hz, 1H, CH_Ar), 11.92 (s,

1H, OH). – ¹³C NMR (75 MHz, CDCl₃): δ = 21.9 (CH₃), 25.2, 32.7,

36.1, 38.4 (CH₂), 40.3 (cyclopentyl-CH), 55.2 (OCH₃), 69.1

Starting with 5j (345 mg, 1.50 mmol), 6c (927 mg, 3.0 mmol)

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(2 mL) product 7bd

was isolated as a yellow solid (238 mg, 51%); m.p. = 104–

105 °C; column chromatography: heptane → heptane-

EtOAc 10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 1.33–1.40 (m,

5H, cyclohexyl-CH₂), 1.43 (t, ³J = 7.1 Hz, 3H, CH₂CH₃), 1.74–

1.86 (m, 5H, cyclohexyl-CH₂), 3.39–3.47 (m, 1H, cyclohexyl-

(OCH), 98.7 (CH), 105.1 (C), 110.5 (CH), 148.1 (C), 163.8, 165.6

−1

˜

(CO), 171.1 (C=O). – IR (ATR, cm ): ν ꢀ 2942 (m), 2865 (w),

3

CH), 3.93 (s, 3H, OCH₃), 4.42 (q, J = 7.1 Hz, 2H, CH₂CH₃),

1644 (s), 1610 (s), 1574 (s), 1464 (m), 1453 (m), 1441 (m), 1421

(w), 1374 (m), 1351 (m), 1314 (m), 1302 (m), 1252 (s), 1216 (m),

1202 (s), 1157 (s), 1098 (s), 1044 (s), 958 (m), 912 (m), 845 (m),

829 (m), 808 (m), 771 (br m), 711 (m), 634 (m), 601 (m), 536

(m). – MS (EI): m/z (%) = 306 [M]⁺(19), 225 (12), 224 (90), 205

(20), 182 (74) 165 (13), 164 (100). – Analysis calcd. for

C₁₈H₂₆O₄(306.40): C 70.56, H 8.55; found C 70.45, H 8.67.

6.49 (s, 1H, CH_Ar), 11.83 (s, 1H, OH). – ¹³C NMR (75 MHz,

CDCl₃): δ = 14.1 (CH₃), 26.2, 27.1, 34.7 (CH₂), 41.5 (cyclo-

hexyl-CH), 56.0 (OCH₃), 61.9 (OCH₂), 101.8 (CH), 106.8,

107.2, 150.7 (C), 158.9, 158.9 (CO), 171.3 (C=O). – IR (ATR,

−1

˜

cm ): ν ꢀ 2970 (w), 2928 (m), 2850 (m), 1643 (m), 1602 (m),

1558 (m), 1467 (m), 1443 (m), 1401 (s), 1378 (m), 1360 (m),

1300 (s), 1291 (s), 1264 (s), 1218 (s), 1190 (s), 1136 (s), 1103 (s),

1017 (s), 966 (m), 896 (m), 883 (m), 868 (m), 848 (m), 815 (br

s), 728 (m), 675 (s) 639 (m), 598 (m). – MS (EI): m/z (%) = 314

[M]⁺(³⁷Cl, 5), 312 [M]⁺(³⁵Cl, 15), 268 (36), 267 (22), 266

(100). – HRMS (EI): m/z calcd. for C₁₆H₂₁ClO₃[M]⁺(³⁵Cl):

312.11229; found 312.11192.

4.5.59 Isobutyl 6-(2-cyclopentylethyl)-2-hydroxy-

4-methoxybenzoate (7bg)

Starting with 5k (366 mg, 1.50 mmol), 6m (909 mg,

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL)

22

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

product 7bg was isolated as a yellow oil (313 mg, 65%); 83%); column chromatography: heptane → heptane-

column chromatography: heptane → heptane-EtOAc EtOAc 10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 0.72–0.79 (m,

10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 1.01 (d, ³J = 6.7 Hz, 6H, 2H, CH₂), 1.24–1.74 (m, 9H, 4 × CH₂, cyclopentyl-CH), 2.18–

CH(CH₃)₂), 1.07– 1.15 (m, 2H, CH₂), 1.50 –1.82 (m, 9H, 2.24 (m, 2H, Ar-CH₂), 3.83 (s, 3H, OCH₃), 6.34 (d, ⁴J = 2.5 Hz,

4 × CH₂, cyclopentyl-CH), 2.09 (hept, ³J = 6.7 Hz, 1H, 1H, CH_Ar), 6.39 (d, ⁴J = 2.5 Hz, 1H, CH_Ar), 7.39–7.64 (m, 5H,

CH(CH₃)₂), 2.89–2.94 (m, 2H, Ar-CH₂), 3.79 (s, 3H, OCH₃), CH_Ar) 10.29 (s, 1H, OH). – ¹³C NMR (63 MHz, CDCl₃): δ = 25.0,

4.14 (d, ³J = 6.7 Hz, 2H, OCH₂), 6.29 (d, ⁴J = 2.7 Hz, 1H, CH_Ar), 32.1, 34.8, 38.4 (CH₂), 39.6 (cyclopentyl-CH), 55.4 (OCH₃),

6.32 (d, ⁴J = 2.7 Hz, 1H, CH_Ar), 11.84 (s, 1H, OH). – ¹³C NMR 98.7, 109.6 (CH), 115.2 (C), 128.4, 128.8, 132.3 (CH), 140.9,

(75 MHz, CDCl₃): δ = 19.4 (CH₃), 25.2 (CH₂), 27.7 (CHCH₃), 147.0 (C), 162.7, 164.1 (CO), 200.9 (C=O). – IR (ATR, cm⁻¹):

˜

32.7, 35.8, 38.2 (CH₂), 40.1 (cyclopentyl-CH), 55.3 (OCH₃), ν ꢀ 2935 (m), 2857 (m), 1745 (w), 1714 (w), 1641 (s), 1615 (s),

71.8 (OCH), 98.7 (CH), 104.9 (C), 110.3 (CH), 148.0 (C), 163.9, 1579 (s), 1504 (m), 1450 (m), 1433 (m), 1361 (m), 1323 (s),

−1

˜

165.6 (CO), 171.8 (C=O). – IR (ATR, cm ): ν ꢀ 2945 (m), 2869 1266 (s), 1259 (s), 1195 (s), 1162 (s), 1133 (s), 1041 (s), 1033 (s),

(w), 1715 (w), 1644 (s), 1611 (s), 1575 (s), 1463 (m), 1441 (m), 1004 (m), 999 (m), 956 (s), 939 (m), 915 (s), 843 (s), 821 (s),

1420 (w), 1397 (m), 1370 (m), 1342 (w), 1319 (s), 1304 (m), 804 (s), 768 (m), 758 (m), 719 (s), 696 (s), 683 (s), 642 (m),

1248 (s), 1202 (s), 1156 (s), 1107 (s), 1045 (s), 973 (m), 959 (m), 602 (s), 584 (m), 560 (m). – MS (EI): m/z (%) = 324 [M]⁺(28),

944 (m), 845 (m), 829 (m), 807 (m), 770 (br m), 712 (m), 640 323 (23), 242 (39), 241 (100), 224 (19), 105 (25). – HRMS (EI):

(m), 599 (m), 536 (m). – MS (EI): m/z (%) = 320 [M]⁺(14), 239 m/z calcd. for C₂₁H₂₄O₃[M]⁺: 324.17200; found 324.17118.

(18), 238 (100), 205 (20), 182 (39) 165 (18), 164 (94), 138

(17). – HRMS (EI): m/z calcd. for C₁₉H₂₈O₄[M]⁺: 320.19821; 4.5.62 Methyl 6-(2-cyclopentylethyl)-2-hydroxy-

found 320.19839.

4-methoxy-3-methylbenzoate (7bj)

4.5.60 1-[6-(2-Cyclopentylethyl)-2-hydroxy-

4-methoxyphenyl)]ethan-1-one (7bh)

Starting with 5k (244 mg, 1.0 mmol), 6k (549 mg, 2.0 mmol)

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bj

was isolated as a light-yellow oil (196 mg, 67%); column

1

Starting with 5k (366 mg, 1.50 mmol), 6a (733 mg, chromatography: heptane → heptane-EtOAc 10:1. – H

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) NMR (250 MHz, CDCl₃): δ = 1.14 (br s, 2H, CH₂), 1.48–1.84

product 7bh was isolated as a yellow oil (224 mg, 57%); (m, 9H, 4 × CH₂, cyclopentyl-CH), 2.06 (s, 3H, Ar-CH₃),

column chromatography: heptane → heptane-EtOAc 2.84–2.91 (m, 2H, Ar-CH₂), 3.85 (s, 3H, OCH₃), 3.91 (s, 3H,

10:1. – ¹H NMR (250 MHz, CDCl₃): δ = 1.03–1.18 (m, 2H, CH₂), CO₂CH₃), 6.27 (s, 1H, CH_Ar), 11.75 (s, 1H, OH). – ¹³C NMR

1.51–1.64 (m, 6H, 3 × CH₂), 1.72–1.83 (m, 3H, CH₂, (63 MHz, CDCl₃): δ = 7.8 (Ar-CH₃), 25.2, 32.6, 36.6, 38.8

cyclopentyl-CH), 2.64 (s, 3H, C=OCH₃), 2.82–2.88 (m, 2H, (CH₂), 40.5 (cyclopentyl-CH), 51.7, 55.4 (OCH₃), 104.8 (C),

Ar-CH₂), 3.79 (s, 3H, OCH₃), 6.28 (d, ⁴J = 2.7 Hz, 1H, CH_Ar), 105.2 (CH), 110.9, 145.3 (C), 161.4, 161.9 (CO), 172.3 (C=O). –

−1

6.30 (d, ⁴J = 2.7 Hz, 1H, CH_Ar), 13.01 (s, 1H, OH). – ¹³C NMR IR (ATR, cm ): ν ꢀ 2945 (m), 2864 (m), 1648 (s), 1611 (m),

˜

(75 MHz, CDCl₃): δ = 25.1 (CH₂), 32.2 (C=OCH₃), 32.6, 35.6, 1575 (s), 1506 (w), 1434 (m), 1400 (m), 1366 (m), 1274 (s),

38.6 (CH₂), 40.2 (cyclopentyl-CH), 55.3 (OCH₃), 98.8, 110.6 1229 (s), 1193 (m), 1157 (s), 1129 (s), 1049 (m), 1006 (m), 933

(CH), 114.9, 147.0 (C), 164.3, 166.3 (CO), 204.0 (C=O). – IR (w), 827 (m), 807 (m), 764 (br m), 680 (m), 661 (w), 605

−1

(ATR, cm ): ν ꢀ 2944 (m), 2914 (m), 2862 (w), 1740 (w), 1607 (m). – MS (EI): m/z (%) = 292 [M]⁺(45), 261 (20), 260 (100),

˜

(s), 1441 (m), 1424 (m), 1379 (m), 1359 (s), 1252 (s), 1203 (s), 210 (85), 178 (74), 150 (24), 149 (31). – HRMS (EI): m/z calcd.

1156 (s), 1069 (m), 1037 (m), 1020 (m), 1006 (m), 957 (m), for C₁₇H₂₄O₄[M]⁺: 292.16691; found 292.16680.

840 (s), 829 (s), 747 (m), 701 (m), 652 (m), 593 (m). – MS (EI):

m/z (%) = 262 [M]⁺(28), 247 (23), 193 (29), 180 (100), 179 4.5.63 Methyl 6-(2-cyclopentylethyl)-2-hydroxy-

(61), 176 (38), 165 (55), 149 (28), 138 (26), 137 (31), 43

(23). – HRMS (EI): m/z calcd. for C₁₆H₂₂O₃[M]⁺: 262.15635;

found 262.15605.

4-methoxy-3-propylbenzoate (7bk)

Starting with 5k (244 mg, 1.0 mmol), 6n (454 mg,

2.25 mmol) and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(2 mL)

product 7bk was isolated as a light-yellow waxy solid

(217 mg, 68%); column chromatography: heptane → hep-

4.5.61 [6-(2-Cyclopentylethyl)-2-hydroxy-

4-methoxyphenyl](phenyl)methanone (7bi)

1

tane-EtOAc 10:1. – H NMR (250 MHz, CDCl₃): δ = 0.93 (t,

Starting with 5k (366 mg, 1.50 mmol), 6g (920 mg, ³J = 7.4 Hz, 3H, CH₃), 1.08–1.20 (m, 2H, CH₂), 1.46–1.85 (m,

3.0 mmol) and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) 11H, 5 × CH₂, cyclopentyl-CH), 2.55–2.61 (m, 2H, Ar-CH₂),

product 7bi was isolated as a light-yellow oil (403 mg, 2.8 –2.90 (m, 2H, Ar–CH₂), 3.83 (s, 3H, OCH₃), 3.91 (s, 3H,

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

23

CO₂CH₃), 6.27 (s, 1H, CH_Ar), 11.68 (s, 1H, OH). – ¹³C NMR (cyclopentyl-CH), 52.0, 55.8, 60.6 (OCH₃), 106.1 (CH), 106.2

(75 MHz, CDCl₃): δ = 14.2 (CH₃), 22.0, 24.7, 25.2, 32.6, 36.7, (C), 134.6 (CO), 142.6(C), 156.3, 156.9 (CO), 171.8 (C=O). – IR

−1

˜

38.8 (CH₂), 40.5 (cyclopentyl-CH), 51.7, 55.4 (OCH₃), 105.0 (ATR, cm ): ν ꢀ 2943 (m), 2862 (w), 1726 (w), 1651 (s), 1608

(C), 105.4 (CH), 115.8, 145.5 (C), 161.5, 162.0 (CO), 172.4 (m), 1571 (m), 1511 (m), 1444 (m), 1433 (m), 1406 (s), 1298 (s),

−1

˜

(C=O). – IR (ATR, cm ): ν ꢀ 2949 (m), 2867 (m), 1649 (s), 1273 (s), 1201 (s), 1165 (m), 1117 (s), 1046 (s), 1026 (s), 987 (s),

1610 (m), 1572 (m), 1505 (w), 1462 (m), 1435 (m), 1403 (m), 952 (m), 827 (m), 807 (m), 786 (m), 763 (m), 695 (m), 607

1366 (w), 1273 (s), 1221 (s), 1194 (m), 1156 (s), 1132 (s), 1038 (m). – MS (EI): m/z (%) = 308 [M]⁺(36), 277 (30), 276 (100),

(m), 1005 (m), 951 (w), 829 (m), 810 (m), 763 (m), 751 (m), 193 (10), 179 (15), 166 (41). – HRMS (EI): m/z calcd.

680 (m), 607 (m). – MS (EI): m/z (%) = 320 [M]⁺(41), for C₁₇H₂₄O₅[M]⁺: 308.16183; found 308.16093. – Analysis

288 (59), 260 (29), 259 (100), 238 (71), 206 (24), 178 calcd. for C₁₇H₂₄O₅(308.37): C 66.21, H 7.84; found

(31). – HRMS (EI): m/z calcd. for C₁₉H₂₈O₄[M]⁺: 320.19821; C 65.74, H 7.83.

found 320.19817.

4.5.66 1-(3-Hydroxy-5-methoxy-[1,1′-biphenyl]-2-yl)

4.5.64 Ethyl 6-(2-cyclopentylethyl)-2-hydroxy-

4-methoxy-3-octylbenzoate (7bl)

ethan-1-one (7bn)

Starting with 5l (225 mg, 1.0 mmol), 6a (489 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bn

was isolated as a colourless solid (140 mg, 58%); m.p. = 96–

Starting with 5k (366 mg, 1.50 mmol), 6l(870 mg, 2.25 mmol)

and TiCl₄(285 mg, 1.50 mmol) in CH₂Cl₂(3 mL) product 7bl

was isolated as a light-yellow oil (293 mg, 48%); column

chromatography: heptane → heptane-EtOAc 10:1. – ¹H NMR

(300 MHz, CDCl₃): δ = 0.84–0.89 (m, 3H, octyl-CH₃), 1.06–

1.84 (m, 23H, 11 × CH₂, cyclopentyl-CH), 1.40 (t, ³J = 7.1 Hz,

3H, CO₂CH₂CH₃), 2.56–2.61 (m, 2H, Ar-CH₂), 2.87–2.92 (m, 2H,

Ar-CH₂), 3.83 (s, 3H, OCH₃), 4.40 (q, ³J = 7.1 Hz, 2H, CO₂CH₂),

6.25 (s, 1H, CH_Ar), 11.75 (s, 1H, OH). – ¹³C NMR (75 MHz,

CDCl₃): δ = 14.1, 14.3 (CH₃), 22.7, 22.8, 25.2, 28.9, 29.3, 29.6,

29.9, 32.0, 32.7, 36.6, 38.7 (CH₂), 40.4 (cyclopentyl-CH), 55.4

1

97 °C; R_f= 0.76 (heptane-EtOAc 1:1). – H NMR (CDCl₃,

300 MHz): δ = 12.74 (s, 1H, OH), 7.37–7.19 (m, 5H, Ph), 6.38

(d, ⁴J = 2.7 Hz, 1H, CH), 6.29 (d, ⁴J = 2.7 Hz, 1H, CH), 3.77 (s,

3H, OCH₃), 1.71 (s, 3H, COCH₃). – ¹³C NMR (63 MHz, CDCl₃):

δ = 204.1 (C=O), 164.2, 162.7 (C–O), 146.0, 141.2 (C), 127.8,

127.6, 127.2 (CH), 113.8 (C), 110.0, 99.0 (CH), 54.5 (OCH₃),

−1

˜

30.4 (COCH₃). – IR (ATR, cm ): ν ꢀ 2961 (m), 2927 (m), 2855

(w), 1731 (w), 1594 (s), 1495 (m), 1468 (m), 1422 (m), 1378

(m), 1358 (m). – MS (EI, 70 eV): m/z (%) = 242 [M]⁺(67), 241

(83), 227 (100), 212 (6), 195 (6), 184 (10), 139 (17). – HRMS

(EI, 70 eV): m/z calcd. for C₁₅H₁₄O₃[M]⁺: 242.09240; found

242.092875.

(OCH₃), 61.1 (OCH₂), 105.2 (C), 105.3 (CH), 116.0, 145.3 (C),

−1

˜

161.3, 161.9 (CO), 172.0 (C=O). – IR (ATR, cm ): ν ꢀ 2923 (s),

2853 (m), 1744 (w), 1716 (w), 1646 (s), 1610 (m), 1573 (m), 1463

(m), 1405 (m), 1393 (m), 1372 (m), 1274 (s), 1226 (s), 1167 (s),

1155 (s), 1133 (s), 1094 (m), 1024 (m), 828 (m), 808 (m), 771 (br

w), 722 (w), 684 (w), 658 (w), 608 (w). – MS (EI): m/z

(%) = 404 [M]⁺(7), 171 (15), 170 (75), 155 (16), 130 (21), 127 (18),

110 (38), 96 (16), 85 (29), 71 (71), 69 (24), 58 (21), 57 (45), 55

(33), 43 (100), 41 (35). – HRMS (EI): m/z calcd. for C₂₅H₄₀O₄

[M]⁺: 404.29211; found 404.29260.

4.5.67 Methyl 3-hydroxy-5-methoxy-[1,1′-biphenyl]-

2-carboxylate (7bo)

Starting with 5l (225 mg, 1.0 mmol), 6e (521 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bo

was isolated as a colourless solid (81 mg, 31%); m.p. = 110–

1

4.5.65 Methyl 6-(2-cyclopentylethyl)-2-hydroxy-

3,4-dimethoxybenzoate (7bm)

111 °C; R_f= 0.83 (heptane-EtOAc 1:1). – H NMR (CDCl₃,

250 MHz): δ = 11.27 (s, 1H, OH), 7.37–7.19 (m, 5H, Phenyl),

6.49 (d, ⁴J = 2.6 Hz, 1H, CH), 6.35 (d, ⁴J = 2.6 Hz, 1H, CH), 3.83

Starting with 5k (244 mg, 1.0 mmol), 6f (435 mg, 1.50 mmol) (s, 3H, OCH₃), 3.45 (s, 3H, OCH₃). – ¹³C NMR (75 MHz,

and TiCl₄(190 mg, 1.0 mmol) in CH₂Cl₂(3 mL) product 7bm CDCl₃): δ = 171.3 (C=O), 164.2, 163.5 (C–O), 146.7, 142.8 (C),

was isolated as a light-yellow oil (264 mg, 86%); column 127.9, 127.4, 126.8, 110.9 (CH), 104.9 (C), 100.0 (CH), 55.5,

1

−1

˜

chromatography: heptane → heptane-EtOAc 10:1. – H 51.4 (OCH₃). – IR (ATR, cm ): ν ꢀ 2978 (m), 2951 (m), 2925

NMR (250 MHz, CDCl₃): δ = 1.07–1.18 (m, 2H, CH₂), 1.48– (w), 2851 (m), 1645 (s), 1610 (s), 1599 (m), 1570 (m), 1498 (w),

1.84 (m, 9H, 4 × CH₂, cyclopentyl-CH), 2.81–2.88 (m, 2H, Ar- 1437 (m), 1437 (m). – MS (EI, 70 eV): m/z (%) = 258 [M]⁺(43),

CH₂), 3.84 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 3.93 (s, 3H, 227 (21), 226 (100), 198 (32), 183 (12), 169 (9), 155 (17). –

OCH₃), 6.29 (s, 1H, CH_Ar), 11.42 (s, 1H, OH). – ¹³C NMR Analysis calcd. for C₁₅H₁₄O₄(258.27): C 69.67, H 5.46; found

(63 MHz, CDCl₃): δ = 25.2, 32.6, 36.3, 38.7 (CH₂), 40.4 C 69.97, H 5.66.

24

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

4.5.68 Ethyl 3-hydroxy-5-methoxy-[1,1′-biphenyl]-

(q, ³J = 7.1 Hz, 2H, CH₂), 3.83 (s, 3H, OCH₃), 0.80 (t,

³J = 7.1 Hz, 3H, CH₂CH₃). – ¹³C NMR (63 MHz, CDCl₃):

δ = 170.6 (C=O), 164.6, 163.5 (C–O), 145.3, 141.6, 132.8 (C),

2-carboxylate (7bp)

Starting with 5l (225 mg, 1.0 mmol), 6o (549 mg, 2.0 mmol) 129.4, 127.6, 110.8 (CH), 104.8 (C), 100.2 (CH), 60.8 (CH₂),

−1

˜

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bp 55.5 (OCH₃), 13.1 (CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2983 (m),

was isolated as a colourless solid (126 mg, 47%); m.p. = 83– 2938 (m), 2899 (w), 2849 (m), 1644 (s), 1614 (s), 1568 (m),

1

84 °C; R_f= 0.83 (heptane-EtOAc 1:1). – H NMR (CDCl₃, 1556 (w), 1486 (s), 1469 (m). – MS (EI, 70 eV): m/z (%) = 308

300 MHz): δ = 11.41 (s, 1H, OH), 7.35–7.19 (m, 5H, Ph), 6.49 [M]⁺(³⁷Cl, 10), 306 [M]⁺(³⁵Cl, 33), 262 (36), 261 (19), 260

(d, ⁴J = 2.6 Hz, 1H, CH), 6.34 (d, ⁴J = 2.6 Hz, 1H, CH), 3.94 (q, (100), 232 (18), 197 (10). – Analysis calcd. for C₁₆H₁₅ClO₄

³J = 7.2 Hz, 2H, OCH₂), 3.83 (s, 3H, OCH₃), 0.73 (t, ³J = 7.2 Hz, (306.74): C 62.65, H 4.93; found C 62.71, H 5.05.

CH₂CH₃). – ¹³C NMR (75 MHz, CDCl₃): δ = 170.9 (C=O), 164.3,

163.4 (C–O), 146.8, 143.1 (C), 128.0, 127.4, 126.7, 110.7 (CH),

4.5.71 1-[6-(Furan-2-yl)-2-hydroxy-4-methoxyphenyl]

ethan-1-one (7bs)

105.0 (C), 100.0 (CH), 60.6 (CH₂), 55.4 (OCH₃), 12.9

−1

˜

(CH₂CH₃). – IR (ATR, cm ): ν ꢀ 2983 (m), 2901 (m), 2855 (w),

1644 (s), 1608 (s), 1582 (m), 1569 (m), 1497 (w), 1442 (m), 1362

(s). – MS (EI, 70 eV): m/z (%) = 272 [M]⁺(34), 227 (20), 226

(100), 198 (27), 183 (10), 169 (6), 155 (14). – Analysis calcd. for

C₁₆H₁₆O₄(272.30): C 70.57, H 5.92; found C 70.53, H 6.05.

Starting with 5n (215 mg, 1.0 mmol), 6a (489 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bs

was isolated as a light-yellow oil (107 mg, 46%); R_f= 0.84

(heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 250 MHz): δ = 12.55

(s, 1H, OH), 7.55 (d, ³J = 2.7 Hz, 1H, CH-Furyl), 6.55–6.52 (m,

3H, 3 × CH), 6.47 (d, ⁴J = 2.5 Hz, 1H, CH), 3.85 (s, 3H, OCH₃),

1.94 (s, 3H, COCH₃). – ¹³C NMR (63 MHz, CDCl₃): δ = 204.5

(C=O), 164.7, 163.9, 153.1 (C–O), 143.0 (OCH), 134.6 (C),

4.5.69 Methyl 4′-chloro-3-hydroxy-5-methoxy-

[1,1′-biphenyl]-2-carboxylate (7bq)

Starting with 5m (259 mg, 1.0 mmol), 6e (521 mg, 2.0 mmol) 112.1, 110.3, 108.8 (CH), 101.8 (C), 101.1 (CH), 55.6(OCH₃),

−1

˜

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bq 28.2 (COCH₃). – IR (ATR, cm ): ν ꢀ 3118 (w), 3011 (m), 2979

was isolated as a colourless solid (100 mg, 34%); m.p. = 81– (m), 2926 (m), 2850 (m), 1604 (s), 1574 (s), 1503 (s), 1469 (s),

1

82 °C; R_f= 0.70 (heptane-EtOAc 1:1). – H NMR (CDCl₃, 1429 (m), 1385 (m), 1361 (s). – MS (EI, 70 eV): m/z (%) = 232

3

250 MHz): δ = 11.34 (s, 1H, OH), 7.32 (d, J = 8.7 Hz, 2H, [M]⁺(100), 217 (45), 191 (12), 190 (87), 189 (24), 178 (41), 161

2 × CH), 7.14 (d, ³J = 8.7 Hz, 2H, 2 × CH), 6.49 (d, ⁴J = 2.6 Hz, (38), 147 (11). – HRMS (EI, 70 eV): m/z calcd. for C₁₃H₁₂O₄

1H, CH), 6.30 (d, ⁴J = 2.6 Hz, 1H, CH), 3.83 (s, 3H, OCH₃), 3.49 [M]⁺: 232.07301; found 232.072815.

(s, 3H, OCH₃). – ¹³C NMR (63 MHz, CDCl₃): δ = 171.1 (C=O),

164.5, 163.6 (C–O), 145.3, 141.3, 132.8 (C), 129.3, 127.6, 111.1

4.5.72 Methyl 6-(furan-2-yl)-2-hydroxy-

4-methoxybenzoate (7bt)

(CH), 104.6 (C), 100.2 (CH), 55.5, 51.5 (OCH₃). – IR (ATR,

−1

˜

cm ): ν ꢀ 2978 (m), 2956 (m), 2943 (w), 2847 (m), 1657 (s),

1607 (s), 1582 (m), 1567 (m), 1494 (w), 1434 (m). – MS (EI,

70 eV): m/z (%) = 294 [M]⁺(³⁷Cl, 13), 292 [M]⁺(³⁵Cl, 36), 263

(7), 262 (35), 261 (19), 260 (100), 232 (16). – HRMS (EI, 70 eV):

m/z calcd. for C₁₅H₁₃ClO₃[M]⁺(³⁵Cl): 292.04969; found

292.049738.

Starting with 5n (215 mg, 1.0 mmol), 6e (521 mg, 2.0 mmol)

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7bt

was isolated as a light-yellow oil (135 mg, 55%); R_f= 0.86

(heptane-EtOAc 1:1). – ¹H NMR (CDCl₃, 250 MHz): δ = 10.98

3

(s, 1H, OH), 7.45 (d, J = 1.9 Hz, 1H, CH-Furyl), 6.53 (d,

⁴J = 2.6 Hz, 1H, CH), 6.50 (d, ⁴J = 2.6 Hz, 1H, CH), 6.45 (dd,

³J = 1.9 Hz, ³J = 3.3 Hz, 1H, CH-Furyl), 6.38 (d, ³J = 3.3 Hz, 1H,

CH-Furyl), 3.84 (s, 3H, OCH₃), 3.70 (s, 3H, OCH₃). – ¹³C NMR

(75 MHz, CDCl₃): δ = 170.9 (C=O), 163.8, 163.7, 153.8 (C–O),

4.5.70 Ethyl 4′-chloro-3-hydroxy-5-methoxy-

[1,1′-biphenyl]-2-carboxylate (7br)

Starting with 5m (259 mg, 1.0 mmol), 6o (549 mg, 2.0 mmol) 142.1 (OCH), 134.3 (C), 111.0, 110.5, 107.4 (CH), 104.7 (C),

−1

˜

and TiCl₄(0.11 mL, 1.0 mmol) in CH₂Cl₂(2 mL) product 7br 101.1 (CH), 55.5, 55.3 (OCH₃). – IR (ATR, cm ): ν ꢀ 3117 (m),

was isolated as a colourless solid (118 mg, 39%); 3004 (m), 2950 (m), 2845 (m), 1655 (s), 1610 (s), 1567 (s),

m.p. = 142–143 °C; R_f= 0.74 (heptane-EtOAc 1:1). – ¹H NMR 1430 (s), 1379 (m), 1331 (s). – MS (EI, 70 eV): m/z (%) = 248

(CDCl₃, 250 MHz): δ = 11.47 (s, 1H, OH), 7.32 (d, ³J = 8.6 Hz, [M]⁺(49), 217 (18), 216 (100), 188 (36), 173 (3), 145

3

2H, 2 × CH), 7.14 (d, J = 8.6 Hz, 2H, 2 × CH), 6.49 (d, (32). – HRMS (EI, 70 eV): m/z calcd. for C₁₃H₁₂O₅[M]⁺:

4

⁴J = 2.5 Hz, 1H, CH), 6.29 (d, J = 2.5 Hz, 1H, CH), 3.98 248.06792; found 248.067867.

J.-P. Gütlein et al.: Regioselective synthesis of salicylates and acetophenones

25

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4.6 Crystal structure determinations

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and graphite monochromator, λ = 0.71073 Å). The space

group was determined with the program XPREP and the

structure was solved and reﬁned with the SHELXS/L-97

program package [49 –51]. The reﬁnement was carried out

by full-matrix least squares procedures on F².

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Details of the structure determination of 7bo have been

described in ref. [41].

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CCDC 2014935 (7ai) and 690564 (7bo) contain the

supplementary crystallographic 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.

Acknowledgements: Financial support by the State of

Mecklenburg-Vorpommern is gratefully acknowledged.

Author contributions: All the authors have accepted

responsibility for the entire content of this submitted

manuscript and approved submission.

Research funding: State of Mecklenburg-Vorpommern.

Conﬂict of interest statement: The authors declare no

conﬂicts of interest regarding this article.

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Article Doi

Regioselective synthesis of salicylates and acetophenones by formal [3+3]-cyclocondensations of 3-oxoorthoesters with 1,3-bis(trimethylsilyloxy)-1,3-butadienes

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