New methodology for the synthesis of α,α-difluoroketones

Article abstract of DOI:10.1080/00397910801997637

A new methodology is described for the synthesis of α,α- difluorinated ketones by the addition of organolithium reagents to α,α-difluoro-N-methoxy-N-methyl amides (Weinreb amides). Copyright Taylor & Francis Group, LLC.

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New Methodology for
the Synthesis of α,α-
difluoroketones
Purakkattle Biju a
a Schering-Plough Research Institute, Kenilworth,
New Jersey, USA
Version of record first published: 12 Jun 2008.
To cite this article: Purakkattle Biju (2008): New Methodology for the Synthesis of
α,α-difluoroketones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:12, 1940-1945
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Synthetic Communications1, 38: 1940–1945, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801997637
New Methodology for the Synthesis
of a,a-Difluoroketones
Purakkattle Biju
Schering-Plough Research Institute, Kenilworth, New Jersey, USA
Abstract: A new methodology is described for the synthesis of a,a-difluorinated
ketones by the addition of organolithium reagents to a,a-difluoro-N-methoxy-N-
methyl amides (Weinreb amides).
Keywords: a,a-Difluoroketones; a,a-Difluoro-N-methoxy-N-methyl amides;
Pyruvic acid
The growing importance of fluorinated compounds in pharmaceutical[1]
and agrochemical[2] industry emphasizes the need for the development
of new methodologies for the synthesis of fluorinated compounds. In
medicinal chemistry, fluorine is often introduced at metabolically labile
sites[1c] to improve the metabolic stability of the drug candidates. Fluorine
can also be used to improve the physicochemical properties of drug mole-
cules,[1e] such as lipophilicity or basicity. Increasingly, in medicinal chem-
istry, fluorine has been used to enhance the binding affinity[1c,f] of the drug
candidate to the target proteins. Our own involvement in the design and
synthesis of a very potent class of fluorine containing CXCR2-CXCR1
dual antagonists[3] for treating various inflammatory diseases required
the synthesis of various a,a-difluoroketones 1. The unsuccessful a-
fluorination (Figure 1) of the furylethylketone 3 using the standard
enolate fluorination[4] and attempts of various unsuccessful Friedel–Crafts
acylations[5] of substituted furans with a,a-difluoroacid chlorides led to the
exploration of an alternate route for the synthesis of a,a-difluoroketones.
Although other cumbersome methods are available for the a-
fluorination[6] of ketones, we were interested in developing a simple
Received in the USA January 17, 2008
Address correspondence to Purakkattle Biju, Schering-Plough Research Institute,
Kenilworth, New Jersey, 07033, USA. E-mail: purakkattle.biju@spcorp.com
1940

a,a-Difluoroketones
1941
Figure 1. Unsuccessful electrophilic fluorination.
and general synthesis of difluoroketones from the readily available b-keto
acids or from the commercially available a,a-difluoro-carboxylic acids.
Herein, we report a simple and general route for the synthesis of a,a-
difluoroketones 1 from the corresponding Weinreb amides 2 by the
addition of aryl and hetero aryllithium reagents.
The commercially available pyruvic acid 5 was converted to the cor-
responding acid chloride by treatment with oxalyl choride, and sub-
sequent treatment with N,O-dimethylhydroxylamine hydrochloride and
triethylamine afforded the Weinreb amide 6. The amide 6 was converted
to the corresponding difluoroamide 7 by treatment with diethylaminosul-
furtrifluoride[7] (DAST) in dichloromethane in good yield (Scheme 1). The
amides 8 and 9 were prepared from the corresponding a,a-difluoro and
a-fluoro phenyl acetic acids through their acid chlorides and further treat-
ment with N,O-dimethylhydroxylamine hydrochloride and triethylamine.
Having obtained the difluoroamide 7, the addition of in situ prepared
2-lithiofuran[8] afforded the desired ketone 10 in 82% yield. Similarly,
ketones 11–14 were obtained in very good yield by the addition of the
corresponding lithiofurans to difluoroamides 7 and 8. The lithiofurans
Scheme 1. Reagents and conditions: i) Oxalylchloride, CH2Cl2, rt, 3 h, 80%, ii)
CH3ONHCH3 ꢀ HCl, Et3N, CH2Cl2, 0 ꢁC–rt, 82%, iii) DAST, CH2Cl2, reflux,
24 h; 70%.

1942
P. Biju
Table 1. Addition of R1Li to the fluoro Weinreb amides
Entry R1Li
Amide Product (ketone) Yield (%) Purity (%)
82
85
55
97
91
88
1
7
7
10
11
2
3
(a)
(b)
7
12
7
8
13
14
32
89
90
91
4
5
8
15
90
97
6
7
8
8
9
9
16
17
18
86
85
82
96
98
96

a,a-Difluoroketones
1943
were prepared in situ from 2-methylfuran and 3-isopropylfuran[9] by
treatment with n-butyl lithium at ꢂ78 ꢁC. In the case of 3-isopropyl
furan, treatment of n-butyllithium generated a mixture of regioisomeric
lithiofurans, which in turn produced regioisomeric ketones 12 and 13
as the major and minor products respectively (Table 1). Phenyl lithium
and thienyl lithium addition to the amides 8 and 9 produced the corre-
sponding ketones (15–18) in excellent yields.
In conclusion, we have developed a new simple methodology for the
convenient synthesis of various a,a-difluoro-aryl and hetero-aryl ketones
from the readily available difluoro Weinreb amides. These ketones can be
further converted to the corresponding difluoroalcohols or amines. This
methodology is very simple and straightforward compared to the existing
enolate fluorination to make difluorinated compounds.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian Inova spectrometer
(500 MHz for 1H NMR; 125 MHz for 13C NMR, 470 MHz for 19F
1
NMR) using TMS as an internal standard for H NMR and 13C NMR
and FCCl3 for 19F NMR). Infrared spectra were obtained on an ATI
Mattson genesis series FTIR. LCMS was recorded on a PE SCIEX
API 150 EX single-stage quadrupole mass spectrometer. Thin-layer chro-
matography (TLC) analysis was performed on silica-gel plates (Analtech
silica-gel GF plates). All products were purified by flash-column chroma-
tography using Whatman purasil 60 A silica gel (230–400 mesh).
General Procedure for the Synthesis of Difluorinated Amide 7
DAST (7.36 g, 0.0456 mol) was added to a solution of the keto-amide
6 (3.0 g, 0.0228 mol) in CH2Cl2 at 0 ꢁC under an N2 atmosphere. The
reaction mixture was brought to room temperature during an hour
and heated at 50 ꢁC for 24 h. The reaction mixture was cooled to 0 ꢁC,
carefully treated with saturated NaHCO3 solution, and extracted with
CH2Cl2(100 mL). The combined organic layer was washed with water
and brine and dried over anhydrous Na2SO4. The solution was filtered
over anhydrous sodium sulfate, and removal of the solvent under reduced
pressure gave the crude product, which was purified by column chroma-
tography using dichloromethane and n-pentane (1:10) to afford the
difluoro-amide 7(2.6 g; 74%) as a colorless liquid.
1
Compound 7: H NMR (500 MHz, CDCl3): d 3.72 (3H, s), 3.24
(3H, s), 1.81 (3H, t, J ¼ 19 z); 13C NMR (125 MHz, CDCl3): 164.1,
117.0 ( t, JC-F ¼ 249 Hz), 61.8, 32.8, 21.55 (t, JC-F ¼ 25 Hz); 19F NMR

1944
P. Biju
(470 MHz, FCCl3 in CDCl3): ꢂ97.33 (s); LCMS (m=z): 154.0 (M þ H)þ,
134. purity ¼ 96%.
General Procedure for the Synthesis of Difluorinated Ketones (10–18)
n-BuLi in hexane (5.2 mL, 0.01339 mol) was added dropwise to a solution
of the 2-methyl furan (1 g, 0.0122 mol) in anhydrous ether (15 mL) at
ꢂ78 ꢁC. The reaction mixture was warmed to room temperature, than
heated at 40 ꢁC for 45 min. The reaction mixture was cooled to ꢂ78 ꢁC
and a solution of the difluorinated amide 7 (2.23 g, 0.0146 mol) in anhy-
drous ether was added. The reaction mixture was stirred at ꢂ78 ꢁC for
4 h, slowly warmed to room temperature, and stirred continuously for
2 h. The reaction mixture was then cooled to 0 ꢁC and carefully treated
with saturated aqueous NH4Cl solution. The reaction mixture was
extracted with ether (50 mL); the combined organic layer was washed
with water and brine and dried over anhydrous Na2SO4. The solution
was filtered, and the solvent was removed under reduced pressure to give
the crude product, which was purified by column chromatography using
ethyl acetate and hexane (1:10) to afford the difluoro-ketone 11 (1.7 g,
80%) as a colorless liquid.
Compound 11: IR nmax (film) cmꢂ1: 2950, 1765, 1512, 1462, 1286; 1H
NMR (500 MHz, CDCl3): d 7.4 (1H, m), 6.24 (1H, J ¼ 3.5 Hz, 0.8 Hz;d
of q), 2.41 (3H, s); 1.82 (3H, t, J ¼ 19 Hz); 13C NMR (125 MHz, CDCl3):
177.0 (t, JC-F ¼ 31.7 Hz), 160.7, 146.7, 125.1, 118.5 (t, JCF ¼ 249 Hz),
109.7, 20.8 (t, JCF ¼ 25.3 Hz), 14.1; 19F NMR (470 MHz, FCCl3, in
CDCl3): ꢂ95.97 (2F, q, J ¼ 19.2 Hz). Purity ¼ 91%.
ACKNOWLEDGMENTS
We thank Drs. Arthur Taveras, T. K. Sasikumar, Robert Aslanian, and
John Piwinski from Schering-Plough Research Institute (SPRI). We also
thank the NMR and mass spectral groups of SPRI for spectral data.
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