Synthesis of functionalized acetophenones by formal [3+3] cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with 3-alkoxyand 3-silyloxy-2-acetyl-2-en-1-ones

Article abstract of DOI:10.5560/ZNB.2013-3123

The TiCl₄-mediated cyclization of 1,3-bis(silyloxy)-1,3- butadienes with 2-acetyl-1-silyloxybut-1-en-3-one and 3-acetyl-4-silyloxypent-3- en-2-one, readily available from 3-(formyl)acetylacetone and 3-(acetyl)acetylacetone (triacetylmethane), afforded a variety of functionalized acetophenones.

Full text of DOI:10.5560/ZNB.2013-3123

Synthesis of Functionalized Acetophenones by Formal [3 + 3]
Cyclocondensations of 1,3-Bis(silyloxy)-1,3-butadienes with 3-Alkoxy-
and 3-Silyloxy-2-acetyl-2-en-1-ones
Ru¨diger Dedea, Abdolmajid Riahia,b, Mohanad Shkoora, Mirza A. Yawera,
Ibrar Hussaina, Nazken Kelzhanovaa,c, Zharylkasyn A. Abilovc, Abiodun Faloduna,d
Helmar Go¨rlse, and Peter Langera,b
,
a
Institut fu¨r Chemie, Universita¨t Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut fu¨r Katalyse an der Universita¨t Rostock e.V., Albert Einstein Str. 29a, 18059
b
Rostock, Germany
c
Al-Farabi Kazakh National University, Al-Farabi ave. 71, 050040 Almaty, Kazakhstan
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin
City, Nigeria
Universita¨t Jena, Institut fu¨r Anorganische und Analytische Chemie, Humboldtstr. 8,
07743 Jena
d
e
Reprint requests to Prof. Peter Langer. E-mail: peter.langer@uni-rostock.de
Z. Naturforsch. 2013, 68b, 1021 – 1030 / DOI: 10.5560/ZNB.2013-3123
Received April 29, 2013
The TiCl4-mediated cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 2-acetyl-1-silyloxybut-1-
en-3-one and 3-acetyl-4-silyloxypent-3-en-2-one, readily available from 3-(formyl)acetylacetone and
3-(acetyl)acetylacetone (triacetylmethane), afforded a variety of functionalized acetophenones.
Key words: Cyclizations, Arenes, Regioselectivity, Acetophenones, Silyl Enol Ethers
Introduction
strategy. Examples include base-mediated cycliza-
tions of acetone-1,3-dicarboxylates [21, 22]. Har-
Highly functionalized benzene derivatives, such as ris et al. reported reactions of 1,3-dicarbonyl di-
hydroxylated benzoates, benzodioates and acetophe- anions with carboxylic acid derivatives and sub-
nones, are of considerable interest as lead structures sequent intramolecular cyclocondensations [23 – 27].
and synthetic building blocks in medicinal and agri- In addition, [4 + 2] cycloadditions have been re-
cultural chemistry [1 – 14]. Classical syntheses of such ported [28, 29]. Salicylates are available [30] by formal
compounds are based on electrophilic substitution and [3 + 3] cyclocondensations of 1,3-bis(silyloxy)-1,3-
oxidation reactions. Despite their great utility, elec- butadienes [31] with 1,3-dielectrophiles. This strat-
trophilic substitutions have several drawbacks (e. g., egy has been widely applied in recent years [32,
low regioselectivity and low reactivity of electron- 33]. We have reported preliminary results related
poor substrates). Oxidations of toluene to benzoic acid to the synthesis of acetophenones by formal [3 +
derivatives often require drastic conditions. Transi- 3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with
tion metal-catalyzed functionalizations of functional- 2-acetyl-1-(trimethylsilyloxy)but-1-en-3-one which is
ized benzene derivatives proceed under relatively mild derived from 3-formylacetylacetone [34]. Herein,
conditions [15 – 20]. However, the synthesis of the re- we report full details of this study and an ex-
quired starting materials, highly functionalized or ster- tension of the scope. In this context, we re-
ically encumbered benzene derivatives, can be a diffi- port the synthesis of related functionalized ben-
cult task.
zene derivatives based on cyclizations of 1,3-
Functionalized benzene derivatives have been pre- bis(silyloxy)-1,3-butadienes with a triacetylmethane
pared also by application of a ‘building block’ derivative.
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1022
R. Dede et al. · Synthesis of Functionalized Acetophenones
Me3SiO
R2
OSiMe3
R3
Me3SiOTf
NEt3, Et2O
O
Me
Me3SiO
O
O
O
)
1 TiCl4
Me
Me
−
+
3a m
OH
O
CH2Cl2
R2
R1
0 °C, 6 h
R3
Me
OH
1a
R1
O
−
78
20 °C
2a
2) H2O
Me
Me
Me
3SiO
Me
1) Ac2O, CH(OEt)3
O
Me
2a b
O
reflux
,
−
4a r
2) H2O
Scheme 2. Synthesis of 4a–r.
O
Me
Me
O
NaH, AcCl
Et2O
O
Me
Me
(Scheme 2). The reaction proceeded by regioselec-
tive attack of the more nucleophilic terminal carbon
atom of the diene onto the sterically less hindered car-
bon atom of 2a attached to the silyloxy group and
the hydrogen atom. Subsequently, the cyclization pro-
ceeded by attack of the central carbon atom of the di-
ene onto the acetyl group. The cyclization of 2a with
other 1,3-bis(silyloxy)-1,3-butadienes 3a–m followed
the same pattern of selectivity and afforded acetophe-
nones 4a–m (Scheme 2, Table 1). The cyclization of
dienes containing an alkyl group located at the termi-
nal carbon atom of the diene (3f–h and 3j, but not 3i)
tends to proceed in higher yields as compared to unsub-
stituted dienes. The yield of product 4a, prepared from
the acetylacetone-derived diene 3a, was, in many (but
not all) cases, lower as compared to the yields of prod-
0 °C, 3 h,
20 °C, 6 h
Me
OH
O
1b
Me3SiOTf
NEt3, Et2O
Me3SiO
Me
O
Me
Me
0 °C, 6 h
O
2b
Scheme 1. Synthesis of 2a and 2b.
Results and Discussion
3-Formylacetylacetone (1a) is available by reaction ucts derived from β-ketoesters, due to its lower nucle-
of acetylacetone with triethyl orthoformate and acetic ophilicity. Rather low yields were obtained for prod-
anhydride [35 – 37]. Its reactivity towards various nu- ucts 4d and 4e derived from dienes containing a ben-
cleophiles has been previously reported [38 – 47]. Al- zyloxy and 2-methoxethoxy group. This might be ex-
though the molecule is known for a long time, its de- plained by the low stability of these groups in the pres-
tailed structure in solution was not studied until re- ence of TiCl4.
cently [48].
The cyclization of dienes 3a–c, f, h with 2b af-
The reaction of an ether solution of 1a with forded products 4n–r. The yields of the reactions of di-
Me3SiOTf/NEt3 afforded 2-acetyl-1-silyloxybut-1- ene 3a were lower than those of the other dienes. This
en-3-one 2a in 85% yield (Scheme 1). The formyl can again be explained by the higher reactivity of β-
rather than the acetyl group was regioselectively sily- ketoester-derived dienes as compared to 1,3-diketone-
lated. Likewise, 2b [48] was prepared by silyla- derived dienes. In contrast to the situation for substrate
tion of 3-(acetyl)acetylacetone (1b) which is avail- 2a, the best yields were obtained for those products
able by reaction of acetylacetone with acetyl chloride. which are derived from dienes which contain no sub-
The known 1,3-bis(trimethylsilyloxy)-1,3-buatdienes stituent located at carbon C-4 of the diene, presumably
3a–m were prepared following literature proce- due to steric reasons.
dures [30, 50 – 52].
The structures of products 4a–e (R1 = R2 = H) were
The TiCl4-mediated formal [3 + 3] cyclization of elucidated simply by the neighborhood of two aromatic
2a with 1,3-bis(silyloxy)-1,3-butadiene 3a afforded protons which was established by the presence of cou-
3
acetophenone 4a with very good regioselectivity pling constants in the range of J = 8.7 – 8.8 Hz. For
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R. Dede et al. · Synthesis of Functionalized Acetophenones
1023
R1
R2
R3
Yield (%) (4) a
Table 1. Products and yields.
2
3
4
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
a
b
c
d
e
f
g
h
i
j
k
l
m
a
b
c
f
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
OMe
OEt
OBn
O(CH2)2OMe
OMe
OEt
OMe
OMe
OEt
OMe
OEt
OEt
Me
OMe
OEt
35
55
40
33
14
72
59
77
38
74
35
30
35
30
41
33
24
21
H
Me
Et
nBu
nHex
Allyl
OMe
OEt
O(4-Tol)
H
H
Me
Me
Me
Me
Me
H
H
Me
nBu
OMe
OMe
h
a
Yields of isolated products.
Table 2. Characteristic NOE effects.
H
O
O
H
O O
OMe
OEt
O
O
4f
4g
OH O
O
OH O
O
O
OMe
4h
4k
4i
OH O
Fig. 1 (color online). Molecular structure of 4j in the crystal
O
(ellipsoids at the 50% probability level).
OEt
group (δ = 2.53). In 4g the aromatic hydrogen atom
(δ = 7.46) correlates with the ethyl group attached to
the benzene moiety and with the acetyl group. In 4h
the aromatic hydrogen atom (δ = 7.45) correlates with
the acetyl group (δ = 2.53) and with the CH2 group
attached to the benzene moiety. In 4i the aromatic
O
4f–k, the structure elucidation was more difficult and hydrogen atom (δ = 7.47) correlates with the acetyl
had to rely on NOESY experiments (Table 2). In 4f the group (δ = 2.54) and with the CH2 group (δ = 3.42).
aromatic hydrogen atom (δ = 7.47) correlates with the In addition, the methyl group (δ = 2.60) was found to
aromatic methyl group (δ = 2.25) and with the acetyl correlate with the ethoxy group. In 4k the aromatic
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1024
R. Dede et al. · Synthesis of Functionalized Acetophenones
hydrogen atom (δ = 7.15) correlates with the acetyl wise at 0 ◦C. The reaction mixture was warmed to 20 ◦C
within 3 h. After stirring for further 12 h the reaction mix-
ture was filtered and the solid washed with ether. The pre-
cipitate was dissolved in water (100 mL) and extracted with
group (δ = 2.53) and with the ethoxy group (δ = 4.13).
For products 4l–p, no regioisomers are expected. The
structure of 4j was confirmed by X-ray crystal struc-
ture analysis (Fig. 1) [53].
ether (3 × 75 mL). The filtrate and organic extracts were
combined, dried (Na2SO4), and filtered. The filtrate was con-
In conclusion, we have reported the synthesis of var-
centrated in vacuo. A small amount of sodium tritylate was
ious functionalized acetophenones by formal [3 + 3]
added for stabilization and distillation yielded 1b as a clear
cyclization of 1,3-bis(silyloxy)-1,3-butadienes.
yellow liquid (25.6 g, 53%); b. p. 60 ◦C (0.1 mbar). – 1H
NMR (300 MHz, CDCl3): δ = 2.24 (s, 6H, CH3), 2.44 (s,
3H, CH3), 17.23 (s, 1H, OH). The spectroscopic data are in
Experimental Section
accordance with those presented in the literature [49].
General comments: All solvents were dried by stan-
dard methods, and all reactions were carried out under
3-(Trimethylsilyloxy-methylidene)-pentane-2,4-dione (2a)
an inert atmosphere. For 1H and 13C NMR spectra the
deuterated solvents indicated were used. Mass spectromet-
ric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, isobutane) or electrospray
ionization (ESI). For preparative scale chromatography sil-
ica gel 60 (0.063 – 0.200 mm, 70 – 230 mesh) was used. 1,3-
Bis(silyloxy)-1,3-butadienes 3a–m were prepared according
to the literature from the corresponding β-ketoesters in two
steps [30, 50 – 52].
To an ether solution (50 mL) of 1a (3.49 g, 27.2 mmol)
was added NEt3 (2.82 g, 27.9 mmol). The reaction mixture
was cooled to 0 ◦C, and Me3SiOTf (5.93 g, 26.7 mmol) was
added within 20 min. under vigorous stirring. The reaction
was stirred for 6 h at 0 ◦C. The ether phase was isolated,
and the residue was washed with ether (20 mL). The ether
phases were combined and concentrated in vacuo to yield
2a as a clear orange liquid (4.82 g, 88%). A detailed NMR
spectroscopic study has been reported [47].
3-Formyl-4-hydroxypent-3-en-2-one (1a)
3-(1-Trimethylsilyloxy-ethylidene)-pentane-2,4-dione (2b)
A mixture of acetylacetone (25.2 g, 252 mmol), triethyl
orthoformate (37.8 g, 255 mmol), and acetic acid anhydride
(43.2 g, 423 mmol) was refluxed for 3 h and then cooled
to 0 ◦C. Water (10 mL) was added, and the reaction mix-
ture was refluxed for 10 min. Volatile compounds were re-
moved in vacuo, and the residue was distilled to yield 1a as
a colorless solid quickly developing an oily surface (17.8 g,
55%, ratio of tautomers = 4 : 1 in CDCl3 at 25 ◦C); b. p.
To an ether solution (50 mL) of triacetylmethane 1b
(3.58 g, 25.2 mmol) NEt3 (2.61 g, 25.7 mmol) was added.
The reaction mixture was cooled to 0 ◦C, and Me3SiOTf
(5.49 g, 24.7 mmol) was added within 15 min. under vig-
orous stirring. The reaction mixture was stirred for 4.5 h
at 0 ◦C. The ether phase was isolated, and the residue was
washed with ether (20 mL). The ether phases were combined
and concentrated in vacuo to yield 2b as a clear yellow liq-
uid (4.52 g, 84%). – 1H NMR (300 MHz, CDCl3): δ = 0.26
(s, 9H, Si(CH3)3), 2.14 (s, 6H, CH3), 2.32 (s, 3H, CH3). –
13C NMR (75 MHz, CDCl3): δ = 0.6 (Si(CH3)3), 21.4, 30.5
(CH3), 127.2, 165.4 (C), 199.1 (CO). Due to the unstable na-
ture of this molecule, no further spectroscopic data were ob-
tained. The spectroscopic data are in accordance with those
reported in the literature [49].
1
57 ◦C (0.1 mbar). – H NMR (300 MHz, CDCl3): δ = 2.34
(s, 3H, CH3, minor), 2.54 (s, 6H, CH3, major), 2.57 (s, 3H,
CH3, minor), 8.98 (d, 3J = 7.0 Hz, 1H, CH, minor), 10.03
(s, 1H, CHO, major), 17.20 (d, 3J = 7.0 Hz, 1H, OH, minor),
18.36 (s, 1H, OH, major). – 13C NMR (150 MHz, CDCl3):
δ = 25.0 (CH3, major), 28.4 (CH3, minor), 114.8 (C, ma-
jor), 117.2 (C, minor), 184.5 (CHOH, minor), 187.2 (CO,
COH, major), 194.3 (CO, minor), 200.3 (CHO, major), 202.7
(CO, minor). – IR (neat, cm−1): ν = 3443 (br, w), 1787 (m),
˜
1771 (m), 1723 (m), 1674 (s), 1614 (s), 1568 (s), 1411 (s),
1363 (m), 1029 (m). MS (EI, 70 eV): m/z (%) = 128 (20)
[M]+, 100 (41), 72 (35), 68 (32), 43 (100). The spectroscopic
data (IR) are in accordance with those reported in the litera-
ture [35].
General procedure for the preparation of acetophenones
To a CH2Cl2 solution of 2a or 2b was added TiCl4 at
◦
˚
−78 C in the presence of molecular sieves (4 A). The ap-
propriate 1,3-bis(silyl enol ether) 3 was subsequently added.
The reaction mixture was allowed to warm to 20 ◦C in about
20 h and was stirred for another 4 h (in case of 2a) or for
Triacetylmethane (1b)
NaH (8.11 g, 338 mmol) was suspended in dry ether 2 – 7 d (in case of 2b). CH2Cl2 was added, the molecular
(300 mL), and the suspension was cooled to 0 ◦C. Acetylace- sieves were removed, and a saturated aqueous solution of
tone (33.7 g, 337 mmol) was added dropwise. Freshly des- NaHCO3 was added. The organic layer was separated, and
tilled acetyl chloride (26.4 g, 336 mmol) was added drop- the aqueous layer was repeatedly extracted with CH2Cl2 or
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R. Dede et al. · Synthesis of Functionalized Acetophenones
1025
CH2Cl2 and ether. The aqueous layer was acidified by hy- (n-hexane-EtOAc = 1 : 1). Reaction time: 23 h. – 1H NMR
drochloric acid (10%) and again extracted. All organic ex- (300 MHz, CDCl3): δ = 1.44 (t, 3J = 7.2 Hz, 3H, CH2CH3),
3
tracts were combined, dried (Na2SO4), and filtered. The fil- 2.54 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.47 (q, J = 7.2 Hz,
trate was concentrated in vacuo. The residue was purified by 2H, CH2), 6.88 (dd, 3J = 8.8 Hz, 4J = 0.3 Hz, 1H, Ar), 7.61
column chromatography (silica gel) to give salicylates 4.
1-(3-Acetyl-4-hydroxy-2-methylphenyl)-ethanone (4a)
Starting with 2a (212 mg, 1.06 mmol), CH2Cl2
(d, 3J = 8.8 Hz, 1H, Ar), 11.13 (s, 1H, OH). – 13C NMR
(150 MHz, CDCl3): δ = 14.2 (CH2CH3), 20.3 (ArCH3),
30.5 (COCH3), 62.3 (CH2), 115.1 (CHAr), 115.2, 133.1
(CAr), 134.1 (CHAr), 141.6 (CAr), 163.4, 171.3 (CArOH,
˚
COOEt), 201.9 (COCH3). – IR (KBr, cm−1): ν = 3173 (br,
˜
(4.5 mL), molecular sieves (4 A, 0.4 g), TiCl4 (0.13 mL,
s), 2992 (s), 1731 (s), 1650 (s), 1568 (s), 1445 (m), 1359
(m), 1293 (s), 1232 (s), 1098 (s), 822 (m). – MS (EI, 70 eV):
m/z (%) = 222 (33) [M]+, 207 (12), 177 (18), 176 (46), 161
(100). – Anal. for C12H14O4 (222.24): calcd. C 64.85; H,
6.35. Found: C, 64.91; H, 6.64.
1.2 mmol), and 3a (385 mg, 1.57 mmol), 4a was iso-
lated by column chromatography (silica gel; n-hexane-
EtOAc = 10 : 1 → 3 : 1) as an orange solid (71 mg, 35%).
M. p. 152 – 153 ◦C; Rf = 0.14 (n-hexane-EtOAc = 3 : 1). Re-
1
action time: 25 h. – H NMR (300 MHz, CDCl3): δ = 2.56
(s, 3H, CH3), 2.64 (s, 3H, CH3), 2.64 (s, 3H, CH3), 6.87 (dd,
3J = 8.8 Hz, 4J = 0.4 Hz, 1H, Ar), 7.71 (d, 3J = 8.8 Hz, 1H,
Ar), 10.75 (br, 1H, OH). – 13C NMR (150 MHz, CDCl3):
δ = 21.1 (ArCH3), 30.1, 33.1 (COCH3), 115.3 (CHAr),
126.3, 131.7 (CAr), 134.7 (CHAr), 140.4 (CAr), 161.2
Benzyl 3-acetyl-6-hydroxy-2-methylbenzoate (4d)
Starting with 2a (226 mg, 1.13 mmol), CH2Cl2 (4.5 mL),
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.12 mL, 1.1 mmol),
and 3d (532 mg, 1.58 mmol), 4d was isolated by col-
umn chromatography (silica gel; n-hexane-EtOAc = 8 : 1)
as a colorless solid (105 mg, 33%). M. p. 99 – 100 ◦C;
Rf = 0.35 (n-hexane-EtOAc = 3 : 1). Reaction time: 23 h. –
1H NMR (300 MHz, CDCl3): δ = 2.45 (s, 3H, CH3), 2.52
(s, 3H, CH3), 5.36 (s, 2H, CH2), 6.81 (dd, 3J = 8.7 Hz,
4J = 0.4 Hz, 1H, Ar), 7.28 – 7.40 (m, 5H, Ph), 7.53 (d,
3J = 8.7 Hz, 1H, Ar), 10.96 (s, 1H, OH). – 13C NMR
(75 MHz, CDCl3): δ = 20.4 (ArCH3), 30.4 (COCH3), 67.9
(CH2), 114.7 (CAr), 115.1, 128.6, 128.7, 128.7 (CHAr),
133.1 (CAr), 134.1 (CHAr), 134.6, 141.5 (CAr), 163.4, 171.0
(CArOH, COOCH2), 201.7 (COCH3). – IR (KBr, cm−1):
ν = 3065 (s), 3036 (s), 2929 (s), 2707 (m), 1732 (s), 1641
(m), 1559 (s), 1450 (m), 1288 (s), 1229 (s), 1102 (m), 820
(m). – MS (EI, 70 eV): m/z (%) = 284 (9) [M]+, 193 (19), 91
(100), 66 (7), 28 (6). – Anal. for C17H16O4 (284.31): calcd.
C 71.82, H 5.67; found C 71.64, H 5.86.
(CArOH), 200.9, 207.2 (CO). – IR (KBr, cm−1): ν = 3037
˜
(br, m), 2926 (m), 1695 (s), 1643 (m), 1557 (s), 1441 (m),
1364 (m), 1267 (m), 1215 (m), 818 (w). – MS (EI, 70 eV):
m/z (%) = 192 (65) [M]+, 177 (100), 159 (20), 103 (11),
77 (20). – Anal. for C11H12O3 (192.21): calcd. C 68.74, H
6.29; found C 68.56, H 6.54.
Methyl 3-acetyl-6-hydroxy-2-methylbenzoate (4b)
Starting with 2a (863 mg, 4.31 mmol), CH2Cl2 (20 mL),
˚
molecular sieves (4 A, 2.0 g), TiCl4 (0.47 mL, 4.3 mmol),
and 3b (1.56 g, 5.98 mmol), 4b was isolated by column chro-
matography (silica gel; n-hexane-EtOAc = 3 : 1) as a yel-
low solid (495 mg, 55%). M. p. 112 – 113 ◦C; Rf = 0.30
(n-hexane-EtOAc = 3 : 1). Reaction time: 22 h. – 1H NMR
(300 MHz, CDCl3): δ = 2.54 (s, 3H, CCH3), 2.61 (s, 3H,
3
CCH3), 3.99 (s, 3H, OCH3), 6.88 (d, J = 8.8 Hz, 1H, Ar),
7.62 (d, 3J = 8.8 Hz, 1H, Ar), 11.06 (s, 1H, OH). – 13C
NMR (75 MHz, CDCl3): δ = 19.9 (ArCH3), 30.2 (COCH3),
52.4 (COOCH3), 114.7 (CHAr), 114.9, 132.7 (CAr), 133.9
(CHAr), 141.2 (CAr), 162.9, 171.4 (CArOH, COOCH3),
201.6 (COCH3). – IR (KBr, cm−1): ν = 3068 (br, s), 2932
(s), 2852 (m), 2787 (m), 2712 (m), 1729 (s), 1643 (s), 1563
(s), 1437 (s), 1292 (s), 1235 (s), 1102 (s), 822 (m). – MS
(EI, 70 eV): m/z (%) = 208 (38) [M]+, 193 (19), 176 (36),
161 (100), 77 (13). – Anal. for C11H12O4 (208.21): calcd. C
63.45, H 5.81; found C 63.32; H 5.87.
2-Methoxy-ethyl 3-acetyl-6-hydroxy-2-methylbenzoate (4e)
Starting with 2a (205 mg, 1.02 mmol), CH2Cl2 (5.0 mL),
˚
molecular sieves (4 A, 0.5 g), TiCl4 (0.11 mL, 1.0 mmol),
and 3e (432 mg, 1.42 mmol), 4e was isolated by column
chromatography (silica gel; n-hexane-EtOAc = 5 : 1) as
a slightly yellow solid (36 mg, 14%). M. p. 113 – 115 ◦C;
Rf = 0.20 (n-hexane-EtOAc = 3 : 1). Reaction time: 22 h.
–
1H NMR (300 MHz, CDCl3): δ = 2.54 (s, 3H, CCH3),
2.63 (s, 3H, CCH3), 3.42 (s, 3H, OCH3), 3.73 (m,
2H, CH2OCH3), 4.54 (m, 2H, CH2CH2OCH3), 6.87 (dd,
3J = 8.8 Hz, 4J = 0.3 Hz, 1H, Ar), 7.62 (d, 3J = 8.8 Hz,
Ethyl 3-acetyl-6-hydroxy-2-methylbenzoate (4c)
Starting with 2a (195 mg, 0.97 mmol), CH2Cl2 (5.0 mL), 1H, Ar), 10.57 (br, 1H, OH). – 13C NMR (150 MHz,
˚
molecular sieves (4 A, 0.6 g), TiCl4 (0.11 mL, 1.0 mmol), CDCl3): δ = 20.0 (ArCH3), 30.6 (COCH3), 59.1 (OCH3),
and 3c (386 mg, 1.41 mmol), 4c was isolated by column 64.7, 70.0 (CH2), 115.2 (CHAr), 115.7, 133.1 (CAr), 134.2
chromatography (silica gel; n-hexane-EtOAc = 5 : 1) as an (CHAr), 141.7 (CAr), 162.8, 170.5 (CArOH, COOCH2),
orange solid (83 mg, 39%). M. p. 130 – 132 ◦C; Rf = 0.63 201.8 (COCH3). – IR (KBr, cm−1): ν = 3101 (br, s), 2934
˜
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1026
R. Dede et al. · Synthesis of Functionalized Acetophenones
(s), 1733 (s), 1645 (s), 1562 (s), 1356 (m), 1296 (s), 1243 (s), a colorless solid (200 mg, 77%). M. p. 54 – 55 ◦C; Rf = 0.42
1100 (m), 814 (m). – MS (EI, 70 eV): m/z (%) = 252 (42) (n-hexane-EtOAc = 5 : 1). Reaction time: 25 h. – 1H NMR
[M]+, 193 (12), 177 (31), 176 (70), 161 (100). – Anal. for (300 MHz, CDCl3): δ = 0.94 (t, 3J = 7.3 Hz, 3H, CH2CH3),
C13H16O5 (252.26): calcd. C 61.90, H 6.39; found C 61.86, 1.31 – 1.44 (m, 2H, CH2), 1.53 – 1.64 (m, 2H, CH2), 2.53 (s,
3
H 6.21.
3H, CCH3), 2.56 (s, 3H, ArCH3), 2.64 (t, J = 7.7 Hz, 2H,
ArCH2), 3.98 (s, 3H, OCH3), 7.45 (s, 1H, Ar), 11.27 (s, 1H,
OH). – 13C NMR (150 MHz, CDCl3): δ = 14.2 (CH2CH3),
20.2 (ArCH3), 22.8, 29.8 (CH2), 30.8 (COCH3), 31.7 (CH2),
52.7 (OCH3), 114.3, 128.7, 132.8 (CAr), 134.2 (CHAr), 138.6
(CAr), 161.8, 172.5 (CArOH, COOCH3), 202.5 (COCH3). –
Methyl 3-acetyl-6-hydroxy-2,5-dimethylbenzoate (4f)
Starting with 2a (206 mg, 1.03 mmol), CH2Cl2 (4.5 mL),
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.13 mL, 1.2 mmol),
and 3f (418 mg, 1.52 mmol), 4f was isolated by column chro-
matography (silica gel; n-hexane-EtOAc = 10 : 1) as a col-
orless solid (164 mg, 72%). M. p. 65 – 66 ◦C; Rf = 0.56 (n-
hexane-EtOAc = 3 : 1). Reaction time: 24 h. – 1H NMR
(300 MHz, CDCl3): δ = 2.25 (s, 3H, ArCH3), 2.53 (s, 3H,
CCH3), 2.57 (s, 3H, ArCH3), 3.98 (s, 3H, OCH3), 7.47 (s,
1H, Ar), 11.31 (s, 1H, OH). – 13C NMR (50 MHz, CDCl3):
δ = 15.7, 19.8 (ArCH3), 30.4 (COCH3), 52.4 (OCH3),
113.9, 123.8, 132.3 (CAr), 134.6 (CHAr), 138.4 (CAr), 161.7,
172.1 (CArOH, COOCH3), 201.9 (COCH3). – IR (KBr,
IR (nujol, cm−1): ν = 3193 (br, s), 1721 (s), 1648 (s), 1563
˜
(s), 1298 (s), 1254 (s), 1220 (s), 1145 (m), 1066 (m), 959 (m).
– MS (GC-EI, 70 eV): m/z (%) = 264 (61) [M]+, 217 (51),
204 (100), 190 (81), 189 (61), 175 (20), 162 (36). Anal. for
C15H20O4 (264.32): calcd. C 68.16, H 7.63; found: C 68.17,
H 7.72.
Methyl 3-acetyl-5-hexyl-6-hydroxy-2-methylbenzoate (4i)
Starting with 2a (0.400 g, 2.0 mmol), 3i (0.751 g,
2.18 mmol) and TiCl4 (0.238 mL, 2.18 mmol), 4i was iso-
lated as a colorless oil (0.221 g, 38%). – 1H NMR (250 MHz,
CDCl3): δ = 0.81 (t, 3J = 7.4 Hz, 3 H, CH2(CH2)4CH3),
1.18−1.27 (m, 8 H, CH2(CH2)4CH3), 2.45 (s, 3 H,
CH3), 2.48 (s, 3 H, CH3), 2.55 (t, 3J = 7.2 Hz, 2 H,
CH2(CH2)4CH3), 3.92 (s, 3 H, OCH3), 7.39 (s, 1 H, CHAr),
11.19 (s(br), 1 H, OH). – 13C NMR (62 MHz, CDCl3):
δ = 14.1, 19.9 (CH3), 22.5, 28.9, 29.1, 29.2 (CH2), 29.8
(CH3), 31.6 (CH2), 52.4 (OCH3), 114.0, 128.4, 132.4 (C),
133.9 (CHAr), 138.3 (C), 161.5 (COH), 172.2, 194.1 (CO).
– GC-MS (EI, 70 eV): m/z (%) = 292 (49) [M]+, 277 (12),
261 (11), 245 (37), 232 (100), 217 (26), 203 (18), 190 (74),
175 (18). – HRMS (EI): m/z = 292.16754 (calcd. 292.16691
for C17H24O4, [M]+).
cm−1): ν = 3222 (br, s), 2951 (m), 1733 (s), 1647 (s), 1561
˜
(s), 1439 (m), 1362 (m), 1303 (s), 1211 (s), 1149 (s), 1065
(m). – MS (EI, 70 eV): m/z (%) = 222 (49) [M]+, 191 (23),
190 (84), 175 (100), 162 (24), 91 (23). – Anal. for C12H14O4
(222.24): calcd. C 64.85, H 6.35; found: C 64.94, H 6.28.
Ethyl 3-acetyl-5-ethyl-6-hydroxy-2-methylbenzoate (4g)
Starting with 2a (113 mg, 0.56 mmol), CH2Cl2 (3.0 mL),
˚
molecular sieves (4 A, 0.2 g), TiCl4 (0.07 mL, 0.6 mmol),
and 3 g (229 mg, 0.76 mmol), dissolved in CH2Cl2 (0.5 mL)
4g was isolated by column chromatography (silica gel; n-
hexane-EtOAc = 10 : 1) as a colorless solid (83 mg, 59%).
M. p. 39 – 40 ◦C; Rf1= 0.40 (n-hexane-EtOAc = 10 : 1). Re-
action time: 27 h. – H NMR (300 MHz, CDCl3): δ = 1.22
(t, 3J = 7.5 Hz, 3H, ArCH2CH3), 1.43 (t, 3J = 7.1 Hz, 3H,
OCH2CH3), 2.53 (s, 3H, COCH3), 2.58 (s, 3H, ArCH3),
2.67 (q, 3J = 7.5 Hz, 2H, ArCH2CH3), 4.45 (q, 3J = 7.1 Hz,
2H, OCH2CH3), 7.46 (s, 1H, Ar), 11.35 (s, 1H, OH).
13C NMR (150 MHz, CDCl3): δ = 13.8, 14.3 (CH2CH3),
20.2 (ArCH3), 23.2 (ArCH2), 30.7 (COCH3), 62.2 (OCH2),
114.3, 129.9, 132.8 (CAr), 133.2 (CHAr), 138.5 (CAr), 161.7,
172.0 (CArOH, COOEt), 202.5 (COCH3). – IR (KBr, cm−1):
ν = 3168 (br, s), 2978 (s), 2937 (s), 1717 (s), 1652 (s), 1558
(s), 1458 (m), 1365 (m), 1298 (s), 1204 (s), 1066 (m), 1027
(m). – MS (EI, 70 eV): m/z (%) = 250 (53) [M]+, 205 (23),
204 (100), 189 (43), 176 (99), 28 (71). – Anal. for C14H18O4
(250.29): calcd. C 67.18, H 7.25; found C 67.18, H 7.21.
Ethyl 3-acetyl-5-allyl-6-hydroxy-2-methylbenzoate (4j)
Starting with 2a (218 mg, 1.09 mmol), CH2Cl2 (4.5 mL),
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.14 mL, 1.3 mmol),
and 3j (495 mg, 1.57 mmol), 4j was isolated by column chro-
matography (silica gel; n-hexane-EtOAc = 1 : 0 → 20 : 1)
as a yellow oil (209 mg, 74%); Rf = 0.38 (n-hexane-
EtOAc = 10 : 1). Reaction time: 25 h. – 1H NMR (300 MHz,
3
CDCl3): δ = 1.44 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.54 (s,
3H, COCH3), 2.60 (s, 3H, ArCH3), 3.42 (d, 3J = 6.5 Hz, 2H,
ArCH2), 4.47 (q, 3J = 7.1 Hz, 2H, OCH2CH3), 5.06 – 5.11
(m, 1H, CHCHAHB), 5.12 – 5.15 (m, 1H, CHCHAHB),
5.93 – 6.07 (m, 1H, CHCHAHB), 7.47 (s, 1H, Ar), 11.39
(s, 1H, OH). – 13C NMR (75 MHz, CDCl3): δ = 13.9
(CH2CH3), 19.9 (ArCH3), 30.3 (COCH3), 33.6 (ArCH2),
Methyl 3-acetyl-5-butyl-6-hydroxy-2-methylbenzoate (4h)
Starting with 2a (198 mg, 0.99 mmol), CH2Cl2 (4.5 mL), 62.0 (CH2CH3), 114.2 (CAr), 116.1 (CH2 Allyl), 125.7, 132.5
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.12 mL, 1.1 mmol), (CAr), 133.7, 135.6 (CH), 138.8 (CAr), 161.2, 171.5 (CArOH,
and 3h (469 mg, 1.48 mmol), 4h was isolated by column COOEt), 201.8 (COCH3). – IR (neat, cm−1): ν = 3334 (br,
chromatography (silica gel; n-hexane-EtOAc = 10 : 1) as w), 3079 (w), 2982 (m), 2939 (w), 1682 (s), 1658 (s), 1446
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R. Dede et al. · Synthesis of Functionalized Acetophenones
1027
(m), 1323 (s), 1230 (s), 1199 (s), 1150 (m), 1018 (m). – MS lated as a colorless oil (0.229 g, 35%). – 1H NMR (250 MHz,
(GC-EI, 70 eV): m/z (%) = 262 (70) [M]+, 216 (49), 201 CDCl3): δ = 1.31 (t, 3J = 7.5 Hz, 3 H, CH2CH3), 2.18 (s,
(67), 188 (89), 173 (100), 115 (30). – HRMS (EI, 70 eV): 3 H, CH3), 2.31 (s, 3 H, CH3), 2.44 (s, 3 H, OCH3), 4.34
m/z = 262.12000 (calcd. 262.11996 for C15H18O4, [M]+).
(q, 3J = 7.3 Hz, 2 H, OCH2CH3), 6.72 (d, 3J = 8.4 Hz, 2
H, CHAr), 6.98 (d, 3J = 8.3 Hz, 2 H, CHAr), 7.18 (s, 1
H, CHAr), 10.23 (s(br), 1 H, OH). – 13C NMR (62 MHz,
CDCl3): δ = 14.1 (CH2CH3), 19.3, 20.6, 30.2 (CH3), 62.2
(OCH2CH3), 117.1 (2CHAr), 118.1 (C), 123.7 (CHAr), 130.2
(2CHAr), 132.1, 132.8, 135.4, 141.9, 154.0 (C), 154.0 (C),
Methyl 3-acetyl-6-hydroxy-5-methoxy-
2-methylbenzoate (4k)
Starting with 2a (231 mg, 1.15 mmol), CH2Cl2
˚
(4.5 mL), molecular sieves (4 A, 0.4 g), TiCl4 (0.14 mL,
154.8 (COH), 170.2, 200.9 (CO). – IR (neat, cm−1): ν =
˜
1.3 mmol), and 3k (468 mg, 1.61 mmol), 4k was iso-
lated by column chromatography (silica gel; n-hexane-
3423 (w), 1654 (s), 1569 (m), 1442 (m), 1329 (m), 1271 (s),
1045 (w), 914 (w), 858 (w), 744 (m). – GC-MS (EI, 70 eV):
m/z (%) = 328 (51) [M]+, 282 (100), 267 (32), 239 (30),
211 (29), 119 (80), 91 (18), 65 (17), 43 (21). – HRMS (EI):
m/z = 328.13039 (calcd. 328.13053 for C19H20O5, [M]+).
EtOAc = 10 : 1 → 3 : 1) as
a
slightly yellow solid
(96 mg, 35%). M. p. 143 – 144 ◦C; Rf = 0.12 (n-hexane-
1
EtOAc = 3 : 1). Reaction time: 26 h. – H NMR (300 MHz,
CDCl3): δ = 2.47 (s, 3H, CH3), 2.54 (s, 3H, CH3), 3.91
(s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.13 (s, 1H, Ar),
9.77 (s, 1H, OH). – 13C NMR (75 MHz, CDCl3): δ = 18.8
(ArCH3), 30.4 (COCH3), 52.5, 56.3 (OCH3), 114.1 (CHAr),
117.3, 130.7, 131.9 (CAr), 145.4, 151.4 (CAr, CArOH),
1-(3-Acetyl-4-hydroxy-2,6-dimethyl)-ethanone (4n)
Starting with 2b (203 mg, 0.95 mmol), CH2Cl2 (4.5 mL),
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.12 mL, 1.1 mmol),
170.4 (COOCH3), 201.5 (COCH3). – IR (nujol, cm−1): ν =
˜
and 3a (323 mg, 1.32 mmol), 4n was isolated by col-
umn chromatography (silica gel; n-hexane-EtOAc = 3 :
1) as an orange-brown oil (56 mg, 29%); Rf = 0.23
3301 (br, m), 1732 (s), 1667 (s), 1573 (m), 1499 (m), 1291
(s), 1217 (s), 1196 (s), 1077 (s), 887 (w). – MS (GC-EI,
70 eV): m/z (%) = 238 (52) [M]+, 207 (46), 206 (100), 191
(51), 178 (64), 177 (46), 163 (24). – HRMS (EI, 70 eV):
m/z = 238.08392 (calcd. 238.08358 for C12H14O5, [M]+).
(n-hexane-EtOAc = 3 : 1). Reaction time: 3 d.
–
1H
NMR (250 MHz, CDCl3): δ = 2.18 (d, 4J = 0.7 Hz, 3H,
ArCH3), 2.39 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.60
(s, 3H, CH3), 6.66 (s, 1H, Ar), 11.56 (br, 1H, OH). –
13C NMR (150 MHz, CDCl3): δ = 19.8, 19.9 (ArCH3),
32.9, 33.3 (COCH3), 117.8 (CHAr), 121.5, 133.4, 136.3,
Ethyl 3-acetyl-5-ethoxy-6-hydroxy-2-methylbenzoate (4l)
Starting with 2a (207 mg, 1.03 mmol), CH2Cl2 (5.0 mL),
˚
139.9 (CAr), 160.9 (CArOH), 205.8, 207.9 (CO).
˜
–
molecular sieves (4 A, 0.5 g), TiCl4 (0.11 mL, 1.0 mmol),
IR (neat, cm−1): ν = 3293 (br, s), 2991 (m), 2927
(m), 1696 (s), 1597 (s), 1356 (s), 1307 (s), 1218 (s),
1188 (s), 1070 (m), 854 (m). – MS (EI, 70 eV): m/z
(%) = 206 (39) [M]+, 192 (11), 191 (100), 173 (22). –
HRMS (EI, 70 eV): m/z = 206.09367 (calcd. 206.09375
for C12H14O3, [M]+). It has been claimed that this com-
pound was prepared before, but no spectroscopic data were
given [53].
and 3l (454 mg, 1.43 mmol), 4l was isolated by col-
umn chromatography (silica gel; n-hexane-EtOAc = 5 :
1) as a yellow solid (80 mg, 29%). M. p. 82 – 83 ◦C;
Rf = 0.19 (n-hexane-EtOAc = 3 : 1). Reaction time: 24 h.
–
1H NMR (300 MHz, CDCl3): δ = 1.42 (t, 3J = 7.1 Hz,
3H, COOCH2CH3), 1.47 (t, 3J = 7.0 Hz, 3H, ArOCH2CH3),
2.49 (s, 3H, ArCH3), 2.53 (s, 3H, COCH3), 4.13 (q,
3J = 7.0 Hz, 2H, ArOCH2CH3), 4.45 (q, 3J = 7.1 Hz, 2H,
COOCH2CH3), 7.15 (s, 1H, Ar), 9.53 (s, 1H, OH). – 13C
NMR (150 MHz, CDCl3): δ = 14.3, 14.9 (CH2CH3), 19.0
(ArCH3), 30.6 (COCH3), 62.2, 65.3 (CH2), 115.6 (CHAr),
118.2, 131.0, 132.0 (CAr), 144.8, 151.5 (CAr, CArOH), 170.1
Methyl 3-acetyl-6-hydroxy-2,4-dimethylbenzoate (4o)
Starting with 2b (208 mg, 0.97 mmol), CH2Cl2 (4.5 mL),
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.12 mL, 1.1 mmol),
(COOEt), 201.7 (COCH3). – IR (KBr, cm−1): ν = 3223 (br,
˜
and 3b (411 mg, 1.58 mmol), 4o was isolated by column
chromatography (silica gel; n-hexane-EtOAc = 10 : 1) as
a slightly yellow solid (88 mg, 41%). M. p. 103 – 105 ◦C;
Rf = 0.31 (n-hexane-EtOAc = 5 : 1). Reaction time: 1 week.
w), 2983 (w), 1726 (s), 1658 (m), 1574 (s), 1295 (s), 1201
(s), 1161 (m), 1077 (m). – MS (EI, 70 eV): m/z (%) = 266
(69) [M]+, 221 (37), 220 (92), 205 (89), 192 (92), 177 (100),
148 (27). – Anal. for C14H18O5 (266.29): calcd. C 63.15, H
6.81; found C 63.07, H 7.04.
–
1H NMR (250 MHz, CDCl3): δ = 2.19 (d, 4J = 0.7 Hz,
3H, ArCH3), 2.39 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.95
(s, 3H, OCH3), 6.69 (s, 1H, Ar), 11.17 (s, 1H, OH). –
13C NMR (150 MHz, CDCl3): δ = 19.8, 20.0 (ArCH3), 33.0
(COCH3), 52.4 (OCH3), 110.7 (CAr), 117.4 (CHAr), 135.6,
Ethyl 3-acetyl-6-hydroxy-2,4-dimethyl-
5-(p-tolyloxy)benzoate (4m)
Starting with 2a (0.400 g, 2.0 mmol), 5b (0.829 g, 136.4, 140.0 (CAr), 162.4, 171.8 (CArOH, COOCH3), 207.9
2.18 mmol) and TiCl4 (0.238 mL, 2.18 mmol), 4m was iso- (COCH3). – IR (nujol, cm−1): ν = 1703 (s), 1662 (s), 1602
˜
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1028
R. Dede et al. · Synthesis of Functionalized Acetophenones
(m), 1586 (m), 1320 (s), 1252 (s), 1233 (s), 1178 (m), Methyl 3-acetyl-5-butyl-6-hydroxy-
1105 (m), 811 (m). – MS (GC-EI, 70 eV): m/z (%) = 222 2,4-dimethylbenzoate (4r)
(20) [M]+, 207 (18), 190 (21), 175 (100). – Anal. for
Starting with 2b (174 mg, 0.81 mmol), CH2Cl2 (4.5 mL),
molecular sieves (4 A, 0.4 g), TiCl4 (0.10 mL, 0.9 mmol),
C12H14O4 (222.24): calcd. C 64.85, H 6.35; found C 64.72,
H 6.53.
˚
and 3h (360 mg, 1.14 mmol), 4r was isolated by column
chromatography (silica gel; n-hexane-EtOAc = 10 : 1) as
a slightly yellow oil (47 mg, 21%); Rf = 0.25 (n-hexane-
Ethyl 3-acetyl-6-hydroxy-2,4-dimethylbenzoate (4p)
Starting with 2b (240 mg, 1.12 mmol), CH2Cl2 (4.5 mL),
1
EtOAc = 10 : 1). Reaction time: 4 d. – H NMR (300 MHz,
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.14 mL, 1.3 mmol),
CDCl3): δ = 0.94 (t, 3J = 7.1 Hz, 3H, CH2CH3), 1.33 – 1.52
(m, 4H, CH2CH2CH3), 2.17 (s, 3H, CH3), 2.36 (s, 3H, CH3),
2.45 (s, 3H, CH3), 2.66 (t, 3J = 7.6 Hz, 2H, ArCH2), 3.95
(s, 3H, OCH3), 11.49 (s, 1H, OH). – 13C NMR (150 MHz,
CDCl3): δ = 14.0, 16.5 (CH2CH3, ArCH3), 19.7 (ArCH3),
23.1, 25.8, 31.0 (CH2), 33.2 (COCH3), 52.2 (OCH3), 110.2,
128.4, 131.7, 136.3, 137.1 (CAr), 160.4, 172.4 (CArOH,
and 3c (369 mg, 1.34 mmol), 4p was isolated by col-
umn chromatography (silica gel; n-hexane-EtOAc = 15 : 2)
as a yellow solid (85 mg, 33%). M. p. 108 – 109 ◦C;
Rf = 0.35 (n-hexane-EtOAc = 5 : 1). Reaction time: 3 d.
–
1H NMR (300 MHz, CDCl3): δ = 1.43 (t, 3J = 7.1 Hz,
3H, OCH2CH3), 2.20 (d, 4J = 0.6 Hz, ArCH3), 2.42 (s,
3H, CH3), 2.45 (s, 3H, CH3), 4.44 (q, 3J = 7.1 Hz, 2H,
OCH2CH3), 6.71 (s, 1H, Ar), 11.30 (s, 1H, OH). – 13C
NMR (75 MHz, CDCl3): δ = 14.1 (CH2CH3), 19.5, 19.8
(ArCH3), 32.7 (COCH3), 61.7 (CH2), 110.6 (CAr), 117.1
(CHAr), 135.4, 136.1, 139.6 (CAr), 162.2, 171.2 (CArOH,
COOCH3), 208.9 (COCH3). – IR (Nujol, cm−1): ν = 1705
˜
(m), 1662 (s), 1598 (w), 1263 (w), 1215 (s), 1152 (m). – MS
(GC-EI, 70 eV): m/z (%) = 278 (48) [M]+, 263 (16), 231
(99), 218 (100), 204 (35), 203 (47), 176 (27). – Anal. for
C16H22O4 (278.34): calcd. C 69.04, H 7.97; found: C 69.01,
H 8.05.
COOEt), 207.7 (COCH3). – IR (Nujol, cm−1): ν = 1703 (s),
˜
1655 (s), 1602 (m), 1586 (m), 1355 (s), 1318 (s), 1234 (s),
1186 (s), 809 (m). – MS (GC-EI, 70 eV): m/z (%) = 236 (20)
[M]+, 221 (16), 191 (13), 190 (28), 175 (100). – Anal. for
C13H16O4 (236.26): calcd. C 66.09, H 6.83. found C 65.94,
H 6.87.
Crystal structure determination
The intensity data were collected on a Nonius Kap-
paCCD diffractometer, using graphite-monochromatized
MoKα radiation. Data were corrected for Lorentz and
polarization effects, but not for absorption [54, 55]. The
Methyl 3-acetyl-6-hydroxy-2,4,5-trimethylbenzoate (4q)
Starting with 2b (234 mg, 1.09 mmol), CH2Cl2 (4.5 mL), structure was solved by Direct Methods (SHELXS-97)
˚
molecular sieves (4 A, 0.4 g), TiCl4 (0.14 mL, 1.3 mmol), and refined by full-matrix least-squares techniques against
and 3f (406 mg, 1.48 mmol), 4q was isolated by col- Fo2 (SHELXL-97). The hydrogen atoms were located by
umn chromatography (silica gel; n-hexane-EtOAc = 20 : difference Fourier synthesis and refined isotropically [56].
1) as a colorless oil (63 mg, 24%); Rf = 0.25 (n-hexane- All non-hydrogen atoms were refined anisotropically [56].
EtOAc = 10 : 1). Reaction time: 5 d (Tmax = 13 ◦C). – 1H XP [57] was used for structure representations. Crystal Data
NMR (300 MHz, CDCl3): δ = 2.15 (s, 3H, CH3), 2.16 for 4j: C12H14O5, Mr = 238.23 g mol−1, colorless prism,
(s, 3H, CH3), 2.37 (s, 3H, CH3), 2.45 (s, 3H, CH3), size 0.05 × 0.05 × 0.04 mm3, monoclinic, space group
3.96 (s, 3H, OCH3), 11.57 (s, 1H, OH). – 13C NMR P21/n, a = 8.7850(7), b = 7.3091(10), c = 18.1530(18) A,
˚
(150 MHz, CDCl3): δ = 11.6, 17.3, 19.8 (ArCH3), 33.4 β = 94.624(6)◦, V = 1161.8(2) A , T = −90 ◦C, Z = 4,
3
˚
(COCH3), 52.4 (OCH3), 110.2, 123.7, 131.8, 136.3, 137.8 ρcalcd. = 1.36 g cm−3
,
µ(MoKα ) = 1.1 cm−1
,
F(000) =
(CAr), 160.5, 172.5 (CArOH, COOCH3), 208.8 COCH3). 504 e, 7822 reflections in hkl (−11→11; −9→8; −22→23),
– IR (nujol, cm−1): ν = 1700 (m), 1663 (s), 1595 (w), measured in the range 3.58◦ ≤ θ ≤ 27.48◦, completeness
˜
1325 (m), 1263 (m), 1213 (s), 1149 (m), 1099 (w), 806
θmax = 99.5%, 2648 independent reflections, Rint = 0.1095,
(w). – MS (GC-EI, 70 eV): m/z (%) = 236 (35) [M]+, 221 1234 reflections with Fo > 4σ(Fo), 210 parameters, 0
(9), 204 (52), 189 (100), 176 (35), 161 (11). – Anal. for restraints, R1obs = 0.0586, wR2obs = 0.1064, R1all = 0.1668,
C13H16O4 (236.26): calcd. C 66.09, H 6.83; found C 66.05, wR2all = 0.1409, GOOF = 0.961, largest difference peak /
−3
.
˚
H 6.95.
hole: 0.248 / −0.288 e A
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