Convenient and efficient method for the obtainment of ketones from highly hindered aromatic N,N-dimethyl-amides

Article abstract of DOI:10.1080/00397910701411077

A simple and efficient procedure to synthesize highly hindered alkyl aryl ketones that involves the coupling of N,N-dimethyl-3,5-di-tert-butylsalicylamide with organolithium compounds is described. Mild reaction conditions and good to excellent yields of the products are the noteworthy advantages of the procedure. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701411077

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Convenient and Efficient Method for the
Obtainment of Ketones from Highly Hindered
Aromatic N,N‐Dimethyl‐amides
Claudio A. Jiménez a & Julio B. Belmar a
a Faculty of Chemical Sciences, Department of Organic Chemistry ,
University of Concepción , Concepción, Chile
Published online: 11 Jul 2007.
To cite this article: Claudio A. Jiménez & Julio B. Belmar (2007) Convenient and Efficient Method for the
Obtainment of Ketones from Highly Hindered Aromatic N,N‐Dimethyl‐amides, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:14, 2391-2397, DOI:
10.1080/00397910701411077
To link to this article: http://dx.doi.org/10.1080/00397910701411077
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Synthetic Communicationsw, 37: 2391–2397, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701411077
Convenient and Efficient Method for the
Obtainment of Ketones from Highly
Hindered Aromatic N,N-Dimethyl-amides
´
Claudio A. Jimenez and Julio B. Belmar
Faculty of Chemical Sciences, Department of Organic Chemistry,
´ ´
University of Concepcion, Concepcion, Chile
Abstract: A simple and efficient procedure to synthesize highly hindered alkyl aryl
ketones that involves the coupling of N,N-dimethyl-3,5-di-tert-butylsalicylamide
with organolithium compounds is described. Mild reaction conditions and good to
excellent yields of the products are the noteworthy advantages of the procedure.
Keywords: acylphenols, coupling reactions, organolithium compound
During the past three decades, thousands of ligands have been synthesized and
assayed in many different reactions.[1] A class of chelating ligands that would
be very interesting to study are 2,4-di-tert-butyl-6-acylphenols. Excellent enan-
tioselectivities have been achieved with related ligands because of the sterically
restrictive tert-butyl groups.[2] However, these compounds are scarce in litera-
ture because their synthesis features several problems. Therefore, no convenient
nor general syntheses to obtain these highly substituted acylphenols are reported.
Friedel–Crafts acylation, for instance, cannot be used because the Lewis acid
catalyst promotes secondary unwanted reactions that yield complex mixtures
of degradation compounds.[3] Nevertheless, some alkylacylphenols have been
described in very particular situations.[4] Larrow and Jacobsen’s procedure for
Received in the USA December 8, 2006
Address correspondence to Julio B. Belmar, Faculty of Chemical Sciences,
´ ´
Department of Organic Chemistry, University of Concepcion, Concepcion, Chile.
E-mail: jbelmar@udec.cl
2391

´
C. A. Jimenez and J. B. Belmar
2392
2,4-di-tert-butyl-6-formylphenol does not exceed 40% yield, and the workup is
very awkward.[5] Hayasi et al. described the synthesis of 6-acetyl and 6-benzoyl-
2,4-ditert-butylphenol with overall yields not higher than 20%.[6] Better results
¨
have been achieved by Pietikaien and Haikarainen, who obtained the ethyl
and phenyl ketones using the Fries rearrangement: the yields were close to
55%.[7] The development of new synthetic routes for highly substituted acylphe-
nols is still a challenge as they may find application in many processes where the
ability to chelate metal ions is to be exploited.
Previously we reported the synthesis of 2,4-di-tert-butyl-6-pivaloylphe-
nol following a route where the key step was the preparation of an aryllithium
precursor.[8] However, the generality of the procedure was not studied. Herein
the synthesis and characterization of acylphenols using N,N-dimethyl-3,5-di-
tert-butylsalicylamide and an alkyllithium reagent is presented.
RESULTS AND DISCUSSION
In the first approaches to obtain 2,4-di-tert-butyl-6-acylphenols, the coupling
between a carboxylic acid derivative and an organometallic compound was
considered. Thus, the reaction of salicyloyl chloride with organomanganese
reagents following the method described by Cahiez et al.,[9] and then the
coupling between acid chlorides and Grignard reagents in the presence of
Fe(acac)3 were tried.[10] Regardless of the procedure, no ketones were
isolated from the reaction mixtures, with secondary reactions being favored
in both cases. Fortunately, the reaction between N,N-dimethyl-3,5-di-tert-
butylsalicylamide and three commercially available alkyllithium reagents
affords the corresponding ketones. Scheme 1 outlines the synthesis of N,N-
dimethyl-3,5-di-tert-butylsalicylamide (4). Starting from methyl salicylate
Scheme 1. Synthesis of N,N-di-methyl-3,5-di-tert-butylsalicylamide (4).

Highly Hindered Ketones
2393
(1) and tert-butyl alcohol, methyl 3,5-di-tert-butylsalicylate is obtained (2).
The procedure can be scaled up to obtain several grams of this product
without significant decrease of the yield (84 to 94%). Keeping good control
of the reaction temperature is key in this step. Alkaline hydrolysis of 2
yields 3,5-di-tert-butylsalicylic acid (3). The acid chloride is obtained by
reaction of 3 with thionyl chloride and DMF as catalyst without purification
in the reaction with an excess of dimethylamine. In this way, the amide (4)
is obtained with an overall yield of 73%.
Scheme 2 shows the coupling between compound 4 and the alkyllithium
compounds. The reaction is carried out at 08C under a nitrogen atmosphere.
Because in this case the tetrahedral intermediate is stable under the reaction
conditions and the ketones are formed only after decomposing it with acid,
the reaction works quite well. The yields are 61, 75, and 83% for the tert-
butyl, n-butyl, and methyl ketones, respectively. The yield diminution as
the chain volume increases may be correlated with increasing steric hindrance.
The NMR spectra of the three acylphenols 5a–c obtained show the
signals expected for this kind of compound.
Summary, it was possible to obtain 6-ethanoyl-, 6-pentanoyl-, and 6-(2,2-
dimethylpropanoyl)-2,4-di-tert-butyl-phenol (5a–c) with good yields starting
from a very convenient precursor. These compounds represent an important
advance in the design and synthesis of ligands with high steric hindrance as
precursors of catalysts in asymmetric synthesis.
EXPERIMENTAL
The synthesized compounds were characterized using FTIR (Nicolet, Magna
1
550, KBr discs). 13C and H NMR (Bruker AC 250P; 62.9 and 250 MHz,
1
respectively, TMS as internal standard). The solvent was CDCl3. H-13C
correlation spectra and distortionless enhancement by polarization
transfer (DEPT) were also used for signal assignment. Melting points (in
Celsius degrees) were obtained using a Kofler microscope and are uncor-
rected. Mass spectra were obtained by gas chromatography-mass spectrometry
(CG-MS) (gas chromatographs HP 5890 Serie II, coupling to MS HP 5972
Scheme 2. Coupling reaction between N,N-di-methyl-3,5-di-tert-butylsalicylamide
and alkyllithium.

´
C. A. Jimenez and J. B. Belmar
2394
MSD with quadrupolar detector). Elemental analyses were obtained in a
Fison EA 1108 analyzer. Infrared values (n) are quoted in reciprocal
centimeters (cm21), and NMR chemical shifts (d) are quoted in parts per
million (ppm).
Methyl 3,5-Di-tert-butylsalicylate (2)
In a four-necked flask provided with mechanical stirrer, dropping funnel, ther-
mometer, and condenser, 30 g (0.2 mol) of methyl salicylate, 37 g (0.5 mol) of
tert-butyl alcohol, and 20 mL of methyl alcohol were mixed. While vigorously
stirring and keeping the temperature of the reacting mixture between 0 and
58C, 70 mL of 97% sulfuric acid was slowly added dropwise. After
complete addition, stirring at room temperature continued for 5 h. The
mixture was then filtered and the solid washed with water to neutral pH.
The product was recrystallized from 150 mL of methanol. Yield: 94%, mp:
748C. Anal. elem. C16H24O3: calcd. C, 72.69; H, 9.15; found C, 72.65; H,
9.32.1H NMR: 11.36 (s, 1H, OH), 7.70, 7.52 (d, d, 2.55 Hz, 2H, arom.),
3.94 (s, 3H, OCH3), 1.43, 1.30 (s, s, 18H, CMe3). 13C NMR: 171.7 (1C,
C55O), 158.9, 140.4, 137.2, 130.4, 123.5, 111.3 (6C, arom.), 52.2 (1C,
OCH3), 35.1, 34.2 (2C, CMe3), 31.4, 29.4 (6C, CMe3). GC-MS: Mþ 264
(264.1). FT-IR: 3398 (OH), 3091, 2690 (CH), 1673 (C55O).
3,5-Di-tert-butylsalicylic Acid (3)
To a solution of 2 (5.8 g, 0.02 mol) in 150 mL of methanol, KOH (6.7 g,
0.11 mol) dissolved in 50 ml of water was added. The resulting mixture was
refluxed with stirring for 4 h, and then poured into 500 mL of an ice–10%
HCl mixture, stirred, and filtered. The white solid was recrystallized from
50 mL of methanol. Yield: 75%, mp: 161–1628C. Anal. elem. C15H22O3:
1
calcd. C, 71.97; H, 8.86; found C, 72.00; H, 8.73. H NMR: 12.10 (s, 1H,
COOH), 10.80 (s, 1H, OH), 7.80, 7.64 (d, d, 2.45 Hz, 2H, arom.), 1.30, 1.26
(s, s, 18H, CMe3). 13C NMR: 176.7 (1C, C55O), 160.4, 141.3, 138.4, 132.1,
125.2, 111.3 (6C, arom.), 35.6, 32.1 (2C, CMe3), 31.5, 29.8 (6C, CMe3).
FT-IR: 3400–2900 (OH), 2962 (CH), 1649 (C55O).
N,N-Di-methyl-3,5-di-tert-butylsalicylamide (4)
A solution of 3 (15.8 g, 0.06 mol) in 30 mL of thionyl chloride and a catalytic
amount of DMF were stirred for 12 h at room temperature. When the reaction
was finished, the excess of thionyl chloride was removed under reduced
pressure in a rotary evaporator, and the solid was treated with 20 mL of
CH2Cl2 and again evaporated. This treatment was repeated once. The
residue was then dissolved in 30 mL of pyridine and cooled to 08C, and a

Highly Hindered Ketones
2395
catalytic amount of dimethylaminopyridine (DAMP) was added. Then 27 mL
(10.8 g, 0.24 mol) of 40% aqueous NH(CH3)2 were dropped into the cooled
solution. The mixture was stirred until it reached room temperature. The
solution was finally poured into 500 ml of an ice–10% HCl mixture and
filtered. The solid was recrystallized in 75 mL of ethanol. Yield: 93%, mp:
122–1248C. Anal. elem. C17H27NO2: calcd. C, 73.65; H, 9.75; N, 5.05.
1
Found C, 74.15; H, 10.98; N, 5.17. H NMR: 10.04 (s, 1H, OH), 7.36, 7.12
(d, d, 2.45 Hz, 2H, arom.), 3.14 [s, 6H, N(CH3)2], 1.42, 1.29 (s, s, 18H,
CMe3). 13C NMR: 173.3 (1C, C55O), 155.6, 139.5, 137.4, 126.7, 123.0,
116.3 (6C, arom.), 38.4 [2C, N(CH3)2], 35.1, 34.2 (2C, CMe3), 31.4, 29.5
(6C, CMe3). GC-MS: Mþ 277 (277.2). FT-IR: 3123 (OH), 2957 (CH), 1610
(C55O).
2,4-Di-tert-butyl-6-acylphenols (5a–5c)
General Method
A commercial solution of the corresponding organolithium compound
(0.045 mol) was cooled to 08C, and N,N-di-methyl-3,5-di-tert-butylsalicyla-
mide (5 g, 0.018 mol), dissolved in 30 mL of the THF, was slowly added
dropwise. The solution was then stirred for 2 h at room temperature, and
100 mL of 10% HCl were added. The mixture was extracted with 50 mL of
ethyl acetate, and the aqueous layer was extracted again. The organic
extracts were combined, washed with 100 mL of brine, and dried over
Na2SO4, the solvent was rotovapped. The solid was recrystallized from
ethanol.
2,4-Di-tert-Butyl-6-ethanoylphenol (5a). Yield: 92%, mp: 47–498C. Anal.
elem. C16H24O2: calcd. C, 77.42; H, 9.67; found C, 77.84; H, 10.87. H
1
NMR: 13.02 (s, 1H, OH), 7.61, 7.60 (s, s, 2H, arom.), 2.69 (s, 3H, CH3),
1.47, 1.37 (s, s, 18H, CMe3). 13C NMR: 205.2 (1C, C55O), 160.1, 140.1,
138.1, 131.3, 124.4, 118.9 (6C, arom.), 35.2, 34.3 (2C, CMe3), 31.4, 29.4
(6C, CMe3), 26.9 (1C, CH3). GC-MS: Mþ 248 (248.2). FT-IR: 3120 (OH),
2960 (CH), 1638 (C55O).
2,4-Di-tert-butyl-6-pentanoylphenol (5b). Yield: 75%, mp: 61–638C. Anal.
elem. C19H30O2: calcd. C, 78.60; H, 10.44; found C, 79.01; H, 10.59. H
1
NMR: 13.12 (s, 1H, OH), 7.60, 7.64 (d, d, 2.42 Hz, 2H, arom.), 2.99
(t, 7.6 Hz, 2H, CH2-a), 1.74 (q, 7.6 Hz, 2H, CH2-b), 1.45 (sex, 7.7 Hz, 2H,
CH2-g), 1.42, 1.32 (s, s, 18H, CMe3), 0.97 (t, 7.3 Hz, 3H, CH3). 13C NMR:
207.7 (1C, C55O), 160.2, 141.1, 139.8, 131.1, 123.7, 119.1 (6C, arom.),
38.3 (1C, CH2-a), 35.1, 34.3 (2C, CMe3), 31.4, 29.4 (6C, CMe3), 27.1 (1C,
CH2-b), 22.5 (1C, CH2-g), 13.9 (1C, CH3). GC-MS: Mþ 290 (290.3).
FT-IR: 3409 (OH), 2959 (CH), 1648 (C55O).

´
C. A. Jimenez and J. B. Belmar
2396
2,4-Di-tert-butyl-6-(2,2-di-methyl)propanoylphenol (5c). Yield: 61%, mp:
56–578C. Anal. elem. C19H30O2: calcd. C, 78.60; H, 10.44. Found C,
1
78.45; H, 10.26. H NMR: 13.35 (s, 1H, OH), 7.90, 7.50 (d, d, 2.12 Hz, 2H,
arom.), 1.47 (s, 3H, COCH3), 1.43, 1.32 (s, s, 18H, CMe3). 13C NMR:
212.5 (1C, C55O), 161.1, 138.4, 130.1, 124.9, 116.5 (6C, arom.), 44.6 (1C,
COCCH3), 35.3, 34.3 (2C, CMe3), 31.4, 29.4 (6C, CMe3), 29.2 (3C,
COCMe3). MS: Mþ 290 (290.3). FT-IR: 3230 (OH), 2920 (CH), 1651 (C55O).
ACKNOWLEDGMENTS
´
This research was supported by the University of Concepcion through the
grant DIUC 205.023.041-1.0.
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