Operationally Simple and Selective One-Pot Synthesis of Hydroxyphenones: A Facile Access to SNARF Dyes

Article abstract of DOI:10.1055/s-0035-1561370

High selectivity is observed during a Friedel-Crafts acylation/demethylation cascade. In contrast to this cascade, oxygen-containing acylating reagents do not undergo the demethylation step. By the methodology elaborated here, an access is provided to important intermediates for the total synthesis of seminaphthorhodafluor (SNARF) dyes.

Full text of DOI:10.1055/s-0035-1561370

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
C. Richter et al.
Paper
Synthesis
Operationally Simple and Selective One-Pot Synthesis of Hydroxy-
phenones: A Facile Access to SNARF Dyes
Celin Richter
O
O
O
O
Nikolaus P. Ernsting
Rainer Mahrwald*
OMe
OMe
O
OMe
Cl
CO2Et
CO2H
Department of Chemistry, Humboldt Universität zu Berlin,
Brook-Taylor Str. 2, 12484 Berlin, Germany
rainer.mahrwald@rz.hu-berlin.de
AlCl3 (1.5 equiv)
AlCl3 (1.5 equiv)
O
CO2Et
92%
AlCl3 (2 equiv)
AlCl3 (2 equiv)
decomposition
OH
CO2H
O
78%
Received: 28.11.2015
Accepted after revision: 15.01.2016
Published online: 16.02.2016
Unfortunately, the conditions for the common Friedel–
Crafts acylation of unprotected phenols are not compatible
with a simple and direct acylation of 3-dimethylaminophe-
nol (5).4 The formation of the acylated products 3 or 4 was
not observed when 3-dimethylaminophenol (5) was used
under these conditions.
Acyl chlorides or anhydrides often react with phenols to
the corresponding phenyl esters to a more or less extent
under the conditions of a Friedel–Crafts acylation.5 To avoid
this yield-diminishing side reaction several different multi-
step approaches have been developed to isolate the re-
quired acylated target molecule in high yields.6
DOI: 10.1055/s-0035-1561370; Art ID: ss-2015-t0689-op
Abstract High selectivity is observed during a Friedel–Crafts acyla-
tion/demethylation cascade. In contrast to this cascade, oxygen-con-
taining acylating reagents do not undergo the demethylation step. By
the methodology elaborated here, an access is provided to important
intermediates for the total synthesis of seminaphthorhodafluor
(SNARF) dyes.
Key words Friedel–Crafts acylation, demethylation cascade, alumi-
num chloride, selectivity
In general, a three-step sequence is used: protection of
the hydroxyl group as the methyl ether, Friedel–Crafts acy-
lation, and subsequent final deprotection. This stepwise
strategy is exemplified by the synthesis of several cytospo-
rones,7 chromanones,8 and flavonoides.9 In addition, some
authors have described a one-pot acylation/deprotection
procedure of protected phenols in the presence of alumi-
num and boron halides. This approach was mostly accom-
plished by acetylation of methoxybenzenes as a starting se-
quence in a great many total syntheses of flavones, benzo-
phenones, chalcones, or catechols.10 This phenomenon –
the concomitant deprotection during the acylation step – is
a very old one and goes probably back to an observation
made by Karl von Auwers in 1909.11 A systematic study of
substrates used in this simplified procedure does not exist
so far.
Xanthene-based ratiometric pH-probes are often uti-
lized for imaging pH changes in cells and biofilms.1 Investi-
gation on a time-resolved picosecond scale demands a dual
emission band, reflecting the protonated as well as the
deprotonated state of the fluorophore. Seminaphthorhoda-
fluor (SNARF) homologues offer this property together
with a wide excitation range and a pKa in the physiological
range.2 In a previous article, two SNARF-derivatives for
measurements in cells or linked to protein surfaces have
been reported.3
To construct the SNARF-dyes 1 and 2 we followed the
classic synthetic route to unsymmetric benzoxanthenes
(Scheme 1).1 For this approach the well-defined, highly
substituted 3-chloro-1-[4-(dimethylamino)-2-hydroxyphe-
nyl]propan-1-one (3) and 4-[4-(dimethylamino)-2-hy-
droxyphenyl]-4-oxobutanoic acid (4) are needed. By ret-
rosynthetic evaluation, the 3-aminophenols 3 and 4 should
be accessible by Friedel–Crafts acylation of the correspond-
ing 3-dimethylaminophenol (5) (Scheme 1).
Following this simplified synthetic route we tested 3-di-
methylaminoanisole (8) and 3-chloropropionyl chloride (6)
as substrates. The expected Friedel–Crafts product 9 was
isolated from the reaction of 3-dimethylaminoanisole (8)
with 3-chloropropionyl chloride (6) in the presence of 1.5
equivalents of aluminum chloride in 11% yield. In addition
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
C. Richter et al.
Paper
Synthesis
O
Me2N
O
Me2N
OH
OH
+
O
HO
R
R
3: R = Cl
4: R = CO2H
1: R = NH-CO-CH2I
2: R = CO2H
O
Me2N
OH
Cl
Cl
6
+
O
O
O
5
7
Scheme 1 Retrosynthetic map of SNARF-derivatives
to the methyl ether 9 the formation of small amounts of the
acylated unprotected phenol 3 was observed (yield: 3%,
Scheme 2).
reactions of unprotected 3-dimethylaminophenol 5 with
chloropropionic acid. A Fries rearrangement did not occur.
The optimization of these results ends up in the following
one-pot procedure. Only the acylated phenol 3 was detect-
ed when an excess of 3.5 equivalents of aluminum chloride
was used, although in low yields (18%). Approximately 30%
of the starting 3-dimethylaminoanisole (8) was recovered.
By-products could not be detected by thin layer chromatog-
raphy in the organic phase.
In a first series of experiments, further substrates were
tested under the conditions as they were elaborated for the
reaction of 3-dimethylaminoanisole (8) and chloropropi-
onyl chloride (6) (Scheme 2).
This systematic optimization process appeared neces-
sary because many different protocols exist (reaction time,
reaction temperature, substrates, equivalents of Lewis ac-
ids).13 Even conflicting results have been reported for this
reaction.14 A set of different aryl methyl ethers, 8 and 10–12
were reacted with different acyl halides 6, 13, and succinic
anhydride (7) under the described conditions (Scheme 3).
The yields of these reactions strongly depend on the sub-
strates employed. These results were obtained inde-
pendently of the performance of the experiments. Similar
yields were obtained by successive addition of 1.5 equiva-
lents followed by a further addition of 2 equivalents of alu-
This operationally simple and direct access to the de-
methylated Friedel–Crafts product 3 was subjected to fur-
ther investigation, since the acylated phenol 3 represents a
valuable intermediate in the total synthesis of SNARF dye 1
(Scheme 1). It has been demonstrated, that the demethyla-
tion occurs only via the acylated methyl ether 9.12 A de-
methylation of the starting aminoanisole 8 was not ob-
served under these conditions. Also, a direct acylation of
the unprotected 3-dimethylaminophenol (5) could not be
accomplished under the described reaction conditions or
by Fries rearrangement. In a further series, several different
Lewis acids were tested in these reactions. A clear forma-
tion of the ortho-acylated phenol 3 was observed only by
the deployment of aluminum chloride. Use of aluminum
bromide, boron halides, or titanium(IV) chloride led only to
the formation of the methyl ether 9 or decomposition prod-
ucts. Both 1.5 and 3.5 equivalents of the corresponding
Lewis acids were tested in these experiments. No reactions
were observed by using boron trifluoride etherate and the
starting material was recovered quantitatively. The forma-
tion of the corresponding and undesired ester was detected
by application of trifluoromethanesulfonic acid in acylation
AlCl3 (1.5 equiv)
0 °C to r.t.
Me2N
OMe
O
Me2N
OH
Me2N
OMe
O
+
+
O
Cl
Cl
8
6
9: 11%
3: 3%
Cl
Cl
Scheme 2 Acylation of 3-dimethylaminoanisole
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
C. Richter et al.
Paper
Synthesis
minum chloride or by a singular addition of 3.5 equivalents
of aluminum chloride. The addition of aluminum chloride
to the reactants was performed at 0 °C, whereas the reac-
tions themselves were carried out at room temperature.
The corresponding methyl ethers were not detected when
3.5 equivalents of aluminum chloride were used. By-prod-
ucts or doubly demethylated products were not observed.
In a second series of experiments, we tested oxygen-
containing acyl halides as substrates in these reactions.
There is a strong difference between the use of oxygen-con-
taining halides and simple, unfunctionalized halides as
shown in Scheme 3. In contrast to the results of Scheme 3, a
demethylation was not observed when the acyl halides 23–
25 were used (Scheme 4). The corresponding acylated aryl
methyl ethers 26–37 can easily be accessed in good to high
yields. Even when used with an additional excess of alumi-
num chloride (3.5 equiv) a demethylation does not occur.
By further addition of aluminum chloride only decomposi-
tion of products was observed. Comparison of results from
the second series to reactions described in the literature
cannot be made, since the latter were carried out in the
presence of equimolar amounts of aluminum chloride or
other Lewis acids.15
A first explanation for this high chemoselectivity is giv-
en by comparison of the corresponding complexation
states. By acylation of anisoles with succinic anhydride (7)
the complexation of aluminum chloride can occur within
the succinic moiety (7-membered ring system A – unfa-
vored) or via a 6-membered ring system, which includes the
methyl ether B (Scheme 5)
Result of this kind of complexation is the demethylation.
In contrast, by carrying out the acylation of anisoles with
methyl malonyl chloride (23), a preferred complexation of
aluminum chloride via a 6-membered ring system C can be
assumed (Scheme 5). A demethylation is not observed un-
der these conditions.
Note that high regio- and chemoselectivity were ob-
served in all transformations. The acylation occurs only at
the ortho-position to the methoxy groups. Moreover, a sec-
ond Friedel–Crafts acylation was not observed in all the re-
actions carried out, even when an excess of 10 equivalents
of aluminum chloride or acyl chloride was used. Several
products of our investigations are rarely described in the lit-
O
AlCl3 (3.5 equiv)
OH
OMe
0 °C to r.t.
R1
R1
+
Cl
R2
O
R2
8: R1 = 3-Me2N
10: R1 = 3-MeO
11: R1 = 3,5-(MeO)2
12: R1 = 4-Me
6: R2 = (CH)2Cl
13: R2 = Tol
7:
3, 4, 14–22
O
O
O
Me2N
OH
Me2N
OH
MeO
OH
MeO
OH
Tol
O
O
O
O
CO2H
Cl
Cl
3: 18%
4: 45%
14: 15%
15: 51%
MeO
OH
MeO
OH
MeO
OH
MeO
OH
O
O
O
O
OMe
OMe
OMe Tol
Cl
CO2H
CO2H
16: 70%
17: 70%
18: 38%
19: 64%
OH
OH
OH
O
O
O
Tol
CO2H
Cl
20: 80%
21: 68%
22:78%
Scheme 3 One-pot Friedel–Crafts acylation/demethylation reactions
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
C. Richter et al.
Paper
Synthesis
AlCl3 (1.5 equiv)
0 °C to r.t.
O
OMe
O
OMe
+
R1
R1
Cl
R2
R2
8: R1 = 3-Me2N
23: R2 = CH2CO2Me
24: R2 = CO2Et
25: R2 = CH2OMe
10: R1 = 3-MeO
11: R1 = 3,5-(MeO)2
12: R1 = 4-Me
26–37
Me2N
OMe
O
Me2N
OMe
O
MeO
MeO
OMe
O
Me2N
OMe
O
CO2Et
OMe
CO2Me
CO2Me
27: 50%
26: 8%
28: 7%
29: 89%
MeO
OMe
O
OMe
O
MeO
OMe
O
MeO
OMe
O
OMe
OMe CO2Et
CO2Et
CO2Me
OMe
30: 93%
31: 90%
32: 48%
33: 68%
OMe
O
MeO
OMe
O
OMe
O
OMe
O
OMe
CO2Et
OMe
CO2Me
OMe
36: 92%
34: 62%
35: 90%
37:84%
Scheme 4 Friedel–Crafts acylation with oxygen-containing acyl halides
In conclusion, we have investigated an operationally
H
Me
simple one-pot procedure for a Friedel–Crafts acylation/de-
methylation cascade. By an optimization process of the sub-
strates employed, high selectivity was obtained. Using sim-
ple acyl halides or anhydrides a simultaneous demethyla-
tion process is observed. However, this demethylation failed
to appear in the cases of oxygen-containing acyl halides.
Using 3-dimethylaminoanisole (8) as aromatic substrate in
these transformations, important intermediates for the to-
tal synthesis of several SNARF-dyes are accessible.
O
OMe
O
O
AlCl3
O
AlCl3
O
AlCl3
O
OH
O
OH
O
OH
A
B
Me
O
OMe
AlCl3
O
O
AlCl3
O
1H NMR, 13C NMR, DEPT, and correlation experiments 1H, 1H-1H-COSY,
HSQC, NOESY, and JRES were carried out at 500 MHz or 300 MHz for
1H and 125 MHz or 75 MHz for 13C, respectively, using a Bruker
Avance-300 or Bruker-500 spectrometer. Chemical shifts are given in
ppm, coupling constants in Hz. High-resolution mass spectroscopy
was performed on a LTQ-FT-ICR spectrometer (Finnigan) (ESI). Purifi-
cation of products was accomplished by flash chromatography
(Merck silica gel 60, particle size 0.04–0.063 mm). The solvent mix-
ture of hexane and EtOAc in ratio 90:10 to 1:1 was used as eluent.
Yields were determined after column chromatography. TLC was per-
formed with Merck Silica Gel 60 F254 TLC plates. Development was
performed with cerium(IV) sulfate/phosphormolybdic acid. Solvents
were purchased from Sigma-Aldrich and used, unless otherwise men-
tioned, without further purification or drying.
O
OMe
OMe
C
Scheme 5 Different aluminum chloride complexation states
erature, or they are described with insufficient characteri-
zation. To this end a complete set of analytic data is given in
the experimental section.
Based on these results we successfully completed the
synthesis of the SNARF dyes 1 and 2.3 These reaction se-
quences are depicted in Scheme 6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
C. Richter et al.
Paper
Synthesis
Cl
O
Me2N
OH
O
O
O
Me2N
OH
Me2N
OMe
Me2N
OH
O
Cl
O
O
i
i
ii
N
O
O
4
3
CO2H
Cl
OH
OH
iii
iii
OH
O
OH
O
Me2N
O
Me2N
O
CO2H
2
Pht
iv
O
O
Me2N
O
Me2N
O
v–vii
HN
O
1
NH3Cl
I
Scheme 6 Syntheses of SNARF-dyes 1 and 2. Reagents and conditions: i. AlCl3, CH2Cl2 0 °C → r.t.; ii. potassium phthalimide, DMF; iii. H3PO4, 145 °C, 6 h;
iv. HCl/AcOH; v. chloroacetyl chloride; vi. NaOH, MeOH; vii. NaI, acetone.
Friedel–Crafts Reactions of Aryl Methyl Ethers 8, 10–12 with Acyl
Chlorides 6, 7, and 13; General Procedure A
at 0 °C. After 5 min, the corresponding acyl chloride 23–25 (1.5
mmol) was added dropwise and the resulting mixture was stirred at
r.t. The progress of the reaction was monitored by TLC (hexane/EtOAc,
8:2). At the end of the reaction (5–10 h), the mixture was poured into
aq 1 N HCl and extracted with CH2Cl2 (4 ×). The combined organic
phases were washed with aq 1 N HCl, aq NaHCO3 and H2O, and dried
over MgSO4. The solvents were evaporated under reduced pressure
and the remaining residue was purified by column chromatography.
AlCl3 (467 mg, 3.5 mmol) was suspended in CH2Cl2 (10 mL) in a
round-bottom flask. The corresponding aryl methyl ether 8 or 10–12
(1.0 mmol) was added to this suspension and the mixture was cooled
down to 0 °C. After stirring for 5 min, the corresponding acyl chloride
6, 7, or 13 (1.5 mmol) was added dropwise and the resulting mixture
was stirred at r.t. The progress of the reaction was monitored by TLC
(hexane/EtOAc, 8:2). At the end of the reaction (5–10 h), the mixture
was poured into aq 1 N HCl and extracted with CH2Cl2 (4 ×). The com-
bined organic phases were washed with aq 1 N HCl, aq NaHCO3 (with
the exception of reactions with 7) and H2O, and dried over MgSO4.
The solvents were evaporated under reduced pressure and the re-
maining residue was purified by column chromatography.
3-Chloro-1-[4-(dimethylamino)-2-hydroxyphenyl]propan-1-one
(3)
Yield: 40 mg (18%); white solid.
1H NMR (300 MHz, CDCl3): δ = 12.68 (s, 1 H), 7.52 (d, J = 9.1 Hz, 1 H),
6.22 (dd, J = 9.1, 2.6 Hz, 1 H), 6.09 (d, J = 2.6 Hz, 1 H), 3.90 (t, J = 6.9 Hz,
2 H), 3.33 (t, J = 6.9 Hz, 2 H), 3.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 198.6, 165.1, 156.2, 131.6, 109.8, 104.3,
97.9, 40.1, 39.9, 39.4.
Friedel–Crafts Reactions of Aryl Methyl Ethers 8, 10–12 with Acyl
Chlorides 23–25; General Procedure B
AlCl3 (200 mg, 1.5 mmol) was suspended in CH2Cl2 (10 mL) in a
round-bottom flask. The corresponding aryl methyl ether 8 or 10–12
(1.0 mmol) was added to this suspension and the mixture was stirred
HRMS (ESI): m/z [M + H]+ calcd for C11H15ClNO2: 228.0786; found:
228.0787.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
C. Richter et al.
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Synthesis
4-[4-(Dimethylamino)-2-hydroxyphenyl]-4-oxobutanoic Acid (4)
13C NMR (126 MHz, CDCl3): δ = 198.8, 166.2, 165.7, 161.9, 141.7,
138.8, 128.4, 128.3, 105.8, 93.7, 91.4, 55.6, 55.2, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H17O4: 273.1121; found:
273.1122.
Yield: 105 mg (45%); white solid.
1H NMR (300 MHz, DMSO-d6): δ = 12.68 (s, 1 H), 12.14 (s, 1 H), 7.69
(d, J = 9.2 Hz, 1 H), 6.31 (dd, J = 9.2, 2.5 Hz, 1 H), 6.02 (d, J = 2.5 Hz, 1
H), 3.13 (t, J = 6.4 Hz, 2 H), 3.00 (s, 6 H) 2.54 (t, J = 6.4 Hz, 2 H).
4-(2-Hydroxy-4,6-dimethoxyphenyl)-4-oxobutanoic Acid (19)
13C NMR (75 MHz, DMSO-d6): δ = 201.1, 173.9, 163.9, 155.7, 131.9,
Yield: 162 mg (64%); white solid.
109.0, 104.3, 97.0, 39.6, 31.8, 27.9.
1H NMR (500 MHz, DMSO-d6): δ = 13.60 (s, 1 H), 6.09 (d, J = 2.4 Hz, 1
H), 6.06 (d, J = 2.4 Hz, 1 H), 3.85 (s, 3 H), 3.79 (s, 3 H), 3.18 (t, J = 6.2 Hz,
2 H), 2.51 (t, J = 6.2 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO4: 238.1074; found:
238.1074.
3-Chloro-1-(2-hydroxy-4-methoxyphenyl)propan-1-one (14)16
13C NMR (125 MHz, DMSO-d6): δ = 203.6, 174.1, 166.1, 165.9, 162.9,
105.3, 93.8, 90.9, 56.1, 55.8, 38.8, 28.1.
Yield: 31 mg (15%); yellow oil.
HRMS (ESI): m/z [M + H]+ calcd for C12H15O6: 255.0863; found:
255.0864.
1H NMR (300 MHz, CDCl3): δ = 12.42 (s, 1 H), 7.79 (d, J = 8.8 Hz, 1 H),
6.76 (d, J = 2.2 Hz, 1 H), 6.70 (dd, J = 8.8, 2.2 Hz, 1 H), 3.81 (t, J = 6.3 Hz,
2 H), 3.38 (s, 3 H), 3.23 (t, J = 6.3 Hz, 2 H).
3-Chloro-1-(2-hydroxy-5-methylphenyl)propan-1-one (20)21
13C NMR (75 MHz, CDCl3): δ = 202.1, 145.8, 144.3, 131.7, 114.8, 112.9,
Yield: 158 mg (80%); white solid.
111.3, 59.2, 38.8, 38.6.
1H NMR (300 MHz, CDCl3): δ = 11.85 (s, 1 H), 7.49 (d, J = 2.0 Hz, 1 H),
7.30 (dd, J = 8.5, 2.0 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 3.91 (t, J = 6.7 Hz,
2 H), 3.47 (t, J = 6.7 Hz, 2 H), 2.31 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C10H12ClO3: 215.0469; found:
215.0470.
(2-Hydroxy-4-methoxyphenyl)(p-tolyl)methanone (15)17
13C NMR (75 MHz, CDCl3): δ = 202.4, 160.5, 138.0, 129.5, 128.4, 118.9,
118.5, 40.9, 38.3, 20.6.
Yield: 122 mg (51%); white solid.
HRMS (ESI): m/z [M + H]+ calcd for C10H12ClO2: 199.0520; found:
199.0520.
1H NMR (500 MHz, CDCl3): δ = 12.73 (s, 1 H), 7.55 (d, J = 8.1 Hz, 2 H),
7.53 (d, J = 9.0 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 2 H), 6.52 (d, J = 2.5 Hz, 1 H),
6.41 (dd, J = 9.0, 2.5 Hz, 1 H), 3.86 (s, 3 H), 2.44 (s, 3 H).
(2-Hydroxy-5-methylphenyl)(p-tolyl)methanone (21)22
13C NMR (126 MHz, CDCl3): δ = 200.0, 166.4, 166.2, 142.3, 135.6,
Yield: 152 mg (68%); yellow solid.
135.3, 129.2, 129.1, 113.4, 107.3, 101.2, 55.7, 21.7.
1H NMR (500 MHz, CDCl3): δ = 11.73 (s, 1 H), 7.47 (d, J = 8.0 Hz, 2 H),
7.28–7.25 (m, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.5 Hz, 1 H),
6.85 (d, J = 8.5 Hz, 1 H), 2.33 (s, 3 H), 2.13 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H15O3: 243.1016; found:
243.1017.
4-(2-Hydroxy-4-methoxyphenyl)-4-oxobutanoic Acid (16)18
13C NMR (126 MHz, CDCl3): δ = 201.4, 161.1, 142.7, 137.2, 135.5,
133.3, 129.5, 129.1, 127.8, 119.1, 118.2, 21.7, 20.6.
HRMS (ESI): m/z [M + H]+ calcd for C15H15O2: 227.1067; found:
227.1068.
Yield: 156 mg (70%); white solid.
1H NMR (300 MHz, DMSO-d6): δ = 12.40 (s, 1 H), 12.18 (s, 1 H), 7.89
(d, J = 9.0 Hz, 1 H), 6.54 (dd, J = 9.0, 2.5 Hz, 1 H), 6.48 (d, J = 2.5 Hz, 1
H), 3.82 (s, 3 H), 3.26 (t, J = 6.2 Hz, 2 H), 2.58 (t, J = 6.2 Hz, 2 H).
4-(2-Hydroxy-5-methylphenyl)-4-oxobutanoic Acid (22)23
13C NMR (75 MHz, DMSO-d6): δ = 203.0, 173.8, 165.6, 163.8, 132.4,
Yield: 161 mg (78%); white solid.
113.5, 107.3, 100.8, 55.7, 32.9, 27.6.
1H NMR (300 MHz, DMSO-d6): δ = 12.17 (s, 1 H), 11.55 (s, 1 H), 7.71
(d, J = 1.7 Hz, 1 H), 7.33 (dd, J = 8.4, 1.7 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1
H), 3.47–3.10 (t, J = 6.3 Hz, 2 H), 2.58 (t, J = 6.3 Hz, 2 H), 2.27 (s, 3 H).
HRMS (ESI): m/z [M – H]+ calcd for C11H11O5: 223.0612; found:
223.0612.
3-Chloro-1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (17)19
13C NMR (75 MHz, DMSO-d6): δ = 204.2, 173.8, 158.4, 136.8, 130.1,
127.9, 119.9, 117.5, 34.1, 27.7, 20.0.
Yield: 170 mg (70%); yellow solid.
HRMS (ESI): m/z [M – H]– calcd for C11H11O4: 207.0663; found:
207.0663.
1H NMR (300 MHz, CDCl3): δ = 13.70 (s, 1 H), 6.06 (d, J = 2.4 Hz, 1 H),
5.92 (d, J = 2.4 Hz, 1 H), 3.87 (s, 3 H), 3.86 (t, J = 6.9 Hz, 2 H), 3.82 (s, 3
H), 3.48 (t, J = 6.8 Hz, 2 H).
Methyl 3-[4-(Dimethylamino)-2-methoxyphenyl]-3-oxopropa-
noate (26)
13C NMR (75 MHz, CDCl3): δ = 201.3, 167.8, 166.5, 162.8, 105.7, 93.8,
91.0, 55.8, 55.7, 46.7, 39.2.
Yield: 19 mg (8%); yellow oil.
HRMS (ESI): m/z [M + H]+ calcd for C11H14ClO4: 245.0575; found:
1H NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 9.0 Hz, 1 H), 6.31 (dd, J = 9.0,
2.4 Hz, 1 H), 6.02 (d, J = 2.4 Hz, 1 H), 3.90 (s, 2 H), 3.86 (s, 3 H), 3.70 (s,
3 H), 3.06 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 190.1, 169.7, 161.8, 155.5, 134.4, 133.2,
104.8, 93.3, 67.9, 55.0, 52.0, 40.2.
245.0574.
(2-Hydroxy-4,6-dimethoxyphenyl)(p-tolyl)methanone (18)20
Yield: 102 mg (38%); yellow solid.
1H NMR (500 MHz, CDCl3): δ = 12.11 (s, 1 H), 7.46 (d, J = 8.2 Hz, 2 H),
7.18 (d, J = 8.2 Hz, 2 H), 6.16 (d, J = 2.3 Hz, 1 H), 5.94 (d, J = 2.3 Hz, 1 H),
3.83 (s, 3 H), 3.47 (s, 3 H), 2.40 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO4: 252.1230; found:
252.1231.
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Ethyl 2-[4-(Dimethylamino)-2-methoxyphenyl]-2-oxoacetate (27)
13C NMR (126 MHz, CDCl3): δ = 194.1, 168.2, 163.3, 159.4, 111.7, 90.6,
55.9, 55.5, 52.0, 50.6.
Yield: 124 mg (50%); yellow oil.
HRMS (ESI): m/z [M + H]+ calcd for C13H17O6: 269.1020; found:
269.1021.
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 9.0 Hz, 1 H), 6.33 (dd, J = 9.0,
2.3 Hz, 1 H), 5.98 (d, J = 2.3 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 3.83 (s, 3
H), 3.07 (s, 6 H), 1.37 (t, J = 7.2 Hz, 3 H).
Ethyl 2-(2,4,6-Trimethoxyphenyl)-2-oxoacetate (33)
13C NMR (75 MHz, CDCl3): δ = 184.0, 167.0, 162.7, 156.5, 132.5, 110.5,
Yield: 181 mg (68%); white solid.
105.4, 93.1, 61.2, 55.6, 40.2, 14.2.
1H NMR (300 MHz, CDCl3): δ = 6.00 (s, 2 H), 4.20 (q, J = 7.1 Hz, 2 H),
3.74 (s, 3 H), 3.70 (s, 6 H), 1.24 (t, J = 7.1 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO4: 252.1230; found:
252.1231.
13C NMR (75 MHz, CDCl3): δ = 184.2, 165.7, 164.5, 162.4, 106.6, 90.6,
2-Methoxy-1-[4-(dimethylamino)-2-methoxyphenyl]ethanone
(28)
61.4, 55.9, 55.4, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C13H17O6: 269.1020; found:
Yield: 15 mg (7%); yellow oil.
269.1020.
1H NMR (300 MHz, CDCl3): δ = 7.95 (d, J = 9.0 Hz, 1 H), 6.33 (dd, J = 9.0,
2.3 Hz, 1 H), 6.05 (d, J = 2.3 Hz, 1 H), 4.60 (s, 2 H), 3.92 (s, 3 H), 3.50 (s,
3 H), 3.06 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 194.4, 161.6, 155.1, 134.2, 132.6, 104.7,
93.2, 78.8, 59.2, 55.0, 40.1.
Methoxy-1-(2,4,6-trimethoxyphenyl)ethanone (34)
Yield: 148 mg (62%); yellow solid.
1H NMR (500 MHz, CDCl3): δ = 6.01 (s, 2 H), 3.73 (s, 3 H), 3.73 (s, 2 H),
3.70 (s, 6 H), 3.62 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 194.0, 163.2, 159.3, 111.6, 90.5, 55.7,
HRMS (ESI): m/z [M + H]+ calcd for C12H18NO3: 224.1281; found:
224.1280.
55.4, 51.9, 50.8.
HRMS (ESI): m/z [M + H]+ calcd for C12H17O5: 241.1071; found:
241.1070.
Methyl 3-(2,4-Dimethoxyphenyl)-3-oxopropanoate (29)24
Yield: 211 mg (89%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 8.8 Hz, 1 H), 6.52 (dd, J = 8.8,
2.3 Hz, 1 H), 6.41 (d, J = 2.3 Hz, 1 H), 3.90 (s, 2 H), 3.83 (s, 3 H), 3.83 (s,
3 H), 3.68 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 191.3, 169.2, 165.5, 161.3, 133.3, 119.4,
105.8, 98.1, 55.7, 55.4, 52.1, 40.7.
Methyl 3-(2-Methoxy-5-methylphenyl)-3-oxopropanoate (35)23
Yield: 199 mg (90%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 2.4 Hz, 1 H), 7.28 (dd, J = 8.4,
2.4 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 3.94 (s, 2 H), 3.83 (s, 3 H), 3.69 (s,
3 H), 2.27 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 193.1, 168.7, 157.3, 135.4, 131.2, 130.2,
125.8, 111.7, 55.5, 52.0, 50.4, 20.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H15O5: 239.0914; found:
239.0914.
HRMS (ESI): m/z [M + H]+ calcd for C12H15O4: 223.0965; found:
223.0966.
Ethyl 2-(2,4-Dimethoxyphenyl)-2-oxoacetate (30)25
Yield: 220 mg (93%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 8.8 Hz, 1 H), 6.59 (dd, J = 8.8,
2.3 Hz, 1 H), 6.43 (d, J = 2.3 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 3.88 (s, 3
H), 3.84 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 185.2, 166.9, 166.0, 133.1, 116.1, 106.8,
98.3, 61.7, 56.1, 55.9, 14.3.
Ethyl 2-(2-Methoxy-5-methylphenyl)-2-oxoacetate (36)
Yield: 203 mg (92%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.58 (d, J = 2.1 Hz, 1 H), 7.29 (ddd, J =
8.5, 2.4, 0.6 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H),
3.74 (s, 3 H), 2.22 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 186.59, 165.30, 158.33, 137.04, 130.54,
130.28, 122.09, 112.04, 61.54, 55.91, 19.98, 13.94.
HRMS (ESI): m/z [M + H]+ calcd for C12H15O5: 239.0914; found:
239.0914.
HRMS (ESI): m/z [M + H]+ calcd for C12H15O4: 223.0965; found:
223.0964.
2-Methoxy-1-(2,4-dimethoxyphenyl)ethanone (31)
Yield: 188 mg (90%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 8.8 Hz, 1 H), 6.54 (dd, J = 8.8,
2.3 Hz, 1 H), 6.43 (d, J = 2.3 Hz, 1 H), 4.58 (s, 2 H), 3.89 (s, 3 H), 3.84 (s,
3 H), 3.48 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 195.6, 165.1, 161.3, 133.0, 118.6, 105.7,
98.2, 79.1, 59.4, 55.7, 55.6.
2-Methoxy-1-(2-methoxy-5-methylphenyl)ethanone (37)
Yield: 162 mg (84%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 2.2 Hz, 1 H), 7.27 (dd, J = 8.6,
2.2 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 4.62 (s, 2 H), 3.87 (s, 3 H), 3.47 (s,
3 H), 2.28 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 197.6, 157.3, 135.0, 130.8, 130.3, 124.9,
111.5, 79.2, 59.3, 55.6, 20.3.
HRMS (ESI): m/z [M + H]+ calcd for C11H15O4: 211.0965; found:
211.0966.
HRMS (ESI): m/z [M + H]+ calcd for C11H15O3: 195.1016; found:
195.1015.
Methyl 3-(2,4,6-Trimethoxyphenyl)-3-oxopropanoate (32)26
Yield: 128 mg (48%); white solid.
1H NMR (500 MHz, CDCl3): δ = 6.06 (s, 2 H), 3.79 (s, 3 H), 3.78 (s, 2 H),
3.76 (s, 6 H), 3.67 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
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Paper
Synthesis
Acknowledgment
6033. (g) Liu, G.; Ge, Z.; Zhao, M.; Zhou, Y. Molecules 2013, 18,
14070. (h) Belloa, M. L.; Chiaradiac, L. D.; Dias, L. R. S.; Pachecod,
L. K.; Stumpf, T. R.; Mascarelloc, A.; Steindeld, M.; Yunesc, R. A.;
Castroe, H. C.; Nunesc, R. J.; Rodrigues, C. R. Bioorg. Med. Chem.
2011, 19, 5046. For multistep construction of the required
target molecule by the use of commercially available 4-
dimethylamino-2-hydroxybenzaldehyde, see: (i) Chou, P.-T.;
Huang, C.-H.; Pu, S.-C.; Cheng, Y.-M.; Liu, Y.-H.; Wang, Y.; Chen,
C.-T. J. Phys. Chem. A 2004, 108, 6452. For access to the corre-
sponding substituted acylated intermediate by Fries rearrange-
ment, see: (j) Poronik, Y. M.; Shandura, M. P.; Kovtun, Y. P. Dyes
Pigments 2007, 72, 199. (k) Cheng, Y.-M.; Pu, S.-C.; Yu, Y.-C.;
Chou, P.-T.; Huang, C.; Chen, C.-T.; Li, T.-H.; Hu, W.-P. J. Phys.
Chem. A 2005, 109, 11696. (l) Poronik, Y. M.; Shandura, M. P.;
Kovtun, Y. P. Chem. Heterocycl. Compd. 2005, 41, 546.
(m) Sauers, R. R.; Husain, S. N.; Piechowski, A. P.; Bird, G. R. Dyes
Pigments 1987, 8, 35.
This project was supported by the Deutsche Forschungsgemeinschaft
through a grant to N.P.E. (Collaborative Research Center 1078 ‘Proton-
ation Dynamics in Protein Function’).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561370.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I