Synthesis of fluorinated 2,3-dihydropyran-4-ones by cyclocondensation of 1,3-dicarbonyl dianions with aldehydes

Article abstract of DOI:10.1016/j.jfluchem.2010.05.013

The reaction of the dianion of 1,1,1-trifluoro-pentane-2,4-dione with aldehydes and subsequent addition of hydrochloric acid afforded 2,3-dihydro-6-trifluoromethyl-pyran-4-ones. The reaction of the dianion of acetylacetone with fluorinated benzaldehydes g

Full text of DOI:10.1016/j.jfluchem.2010.05.013

Journal of Fluorine Chemistry 131 (2010) 892–897
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of fluorinated 2,3-dihydropyran-4-ones by cyclocondensation of
1,3-dicarbonyl dianions with aldehydes
Rasheed Ahmad Khera a, Munawar Hussain a, Rasheed Ahmad a, Aamer Saeed c, Alexander Villinger a,
Christine Fischer b, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b
¨
Leibniz-Institut fu¨r Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
c Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
A R T I C L E I N F O
A B S T R A C T
Article history:
The reaction of the dianion of 1,1,1-trifluoro-pentane-2,4-dione with aldehydes and subsequent addition
of hydrochloric acid afforded 2,3-dihydro-6-trifluoromethyl-pyran-4-ones. The reaction of the dianion
of acetylacetone with fluorinated benzaldehydes gave the corresponding fluorinated 2-aryl-2,3-
dihydro-6-methyl-pyran-4-ones. All reactions proceeded in very good yield and with very good
regioselectivity.
Received 12 February 2010
Received in revised form 21 May 2010
Accepted 29 May 2010
Available online 8 June 2010
ß 2010 Elsevier B.V. All rights reserved.
Keywords:
O-Heterocycles
Pyranones
Cyclizations
Regioselectivity
Dianions
1. Introduction
bioavailability and metabolic stability [7]. 5-Fluorouracil (anti-
neoplastic activity) ciprofloxacin and flurithromycin (antimicrobi-
2,3-Dihydropyran-4-ones are of considerable pharmacological
relevance and occur in a variety of natural products [1]. They have
been prepared by hetero-Diels–Alder reaction of aldehydes with
Danishefsky’s diene or related dienes [2]. A catalytic approach to
enantiomerically pure 2,3-dihydropyran-4-ones, based on the
condensation of 1,3-bis(silyloxy)-1,3-butadienes with aldehydes
using Lewis base-activated Lewis acids and subsequent TFA-
catalyzed cyclization, has also been developed [3]. Other syntheses
al activity), fluoxetine (prozac, antidepressant activity), and
faslodex (antitumor activity), efavirenz (antiviral activity), repre-
sent prominent fluorinated heterocycles which are used in the
clinic [8]. Fluoroalkylated compounds are also used as ligands [9]
in catalytic reactions and as organocatalysts [10]. Fluorinated 2,3-
dihydropyran-4-ones have only scarcely been reported so far [11].
Herein, we report, based on our preliminary studies [5d], the
synthesis of various fluorinated 2,3-dihydropyran-4-ones by
reaction of the dianion of 1,1,1-trifluoro-pentane-2,4-dione with
various aldehydes [11a]. In addition, we report the reaction of the
dianion of acetylacetone with various fluorinated aromatic
aldehydes.
are based on the palladium(II)-catalyzed oxidative cyclization of
b-
hydroxyenones [4a], the reaction of -ethoxy- -unsaturated
b
a,b
lactones [4b], the condensation of enol ethers derived from 1,3-
dicarbonyl compounds with aldehydes [4c], and on the reaction of
epoxides with lithiated dithianes and subsequent elaboration [4d].
An important method for synthesis of 2,3-dihydropyran-4-ones,
which has been applied to the synthesis of the natural product
stegobinone, relies on the reaction of 1,3-dicarbonyl dianions with
aldehydes and subsequent acid-mediated cyclization [5,6]. We
have recently reported a convenient variant of this transformation
[5d]. Fluorinated heterocycles are of great importance in the field
of medicinal and agricultural chemistry, due to their solubility,
2. Results and discussion
The reaction of the dianion of commercially available 1,1,1-
trifluoro-pentane-2,4-dione (1), generated by means of 2 equiv. of
LDA, with aldehydes 2a–l and subsequent addition of hydrochloric
acid (stirring for 15 min, then aqueous work-up) afforded the
2,3-dihydro-6-trifluoromethyl-pyran-4-ones 3a–l (Scheme 1 and
Table 1). The formation of the products can be explained by attack
of the terminal carbon atom of the dianion to the aldehyde and
subsequent acid-mediated cyclization upon addition of hydro-
chloric acid. Both aromatic, heterocyclic and aliphatic aldehydes
* Corresponding author at: Institut fu¨r Chemie, Universita¨t Rostock, Albert-
Einstein-Str. 3a, 18059 Rostock, Germany. Fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.05.013

[
R.A. Khera et al. / Journal of Fluorine C
F
hemistry 131 (2010) 892–897
893
Scheme 1. Synthesis of 3a–l: (i) (1) LDA (2.5 equiv.), THF, 0 8C, 1 h; (2) ꢀ78 8C, 1, 1 h;
(3) 2a–l, ꢀ78 ! 20 8C, 12 h; (ii) (1) HCl (10%), 15 min, 20 8C; (2) extraction (EtOAc).
Table 1
Synthesis of 3a–l.
2,3
R
Yield (%)a
a
b
c
d
e
f
Ph
80
62
72
83
85
63
60
81
71
78
79
83
2-ClC6H4
4-ClC6H4
4-MeC6H4
4-EtC6H4
3-(NO2)C6H4
4-(NO2)C6H4
4-PhC6H4
2-Thienyl
n-Hept
Fig. 2. Ortep plot of 6c (50% probability level).
g
h
i
could be successfully employed. All products were isolated in good
yields. The yields of products derived from electron-poor aromatic
aldehydes are lower than the yields of products derived from
electron-rich aromatic aldehydes and from aliphatic aldehydes.
The reaction of the dianion of acetylacetone (4) with
the fluorinated benzaldehydes 5a–f gave the 2-aryl-2,3-dihy-
j
k
l
n-Oct
n-Non
a
Isolated yields.
[(Schme_2)TD$FIG]
dro-6-methyl-pyran-4-ones 6a–f (Scheme
2 and Table 2).
Fluorine atoms and trifluoromethyl groups at all positions of
the phenyl group are tolerated and the products are isolated in
good yields.
The structures of 6a and 6c were independently confirmed by
X-ray crystal structure analyses (Figs. 1 and 2) [12].
3. Conclusions
In conclusion, we have reported the synthesis of 2,3-dihydro-6-
trifluoromethyl-pyran-4-ones by reaction of the dianion of 1,1,1-
trifluoro-pentane-2,4-dione with aldehydes and subsequent addi-
tion of hydrochloric acid. The reaction of the dianion of
acetylacetone with fluorinated benzaldehydes gave the corre-
sponding fluorinated 2-aryl-2,3-dihydro-6-methyl-pyran-4-ones.
All reactions proceeded in very good yield and with very good
regioselectivity.
Scheme 2. Synthesis of 6a–f: (i) (1) LDA (2.5 equiv.), THF, 0 8C, 1 h; (2) ꢀ78 8C, 4, 1 h;
(3) 5a–f, ꢀ78 ! 20 8C, 12 h; (ii) (1) HCl (10%), 15 min, 20 8C, (2) extraction (EtOAc).
Table 2
Synthesis of 6a–f.
5,6
R1
R2
R3
Yield (%)a
a
b
c
d
e
f
CF3
Cl
Cl
F
H
H
73
71
75
67
72
78
CF3
H
H
CF3
H
4. Experimental
H
H
F
H
General comments. All solvents were dried by standard methods
and all reactions were carried out under an inert atmosphere. For
1H and 13C NMR spectra the deuterated solvents indicated and
Bruker AVANCE 300 III and Bruker AVANCE 250 II machines were
used. Mass spectrometric data (MS) were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, H2O) or electrospray
ionization (ESI). The measurements were carried out using a
Finnigan MAT 95-XP (Thermo Electron), GC 6890N/MSD 5973
(Agilent), and 6210 Time-of-Flight LC/MS (Agilent) machine. For
preparative scale chromatography, silica gel (60–200 mesh) was
used. Melting points are uncorrected.
H
H
F
a
Isolated yields.
[(ig._1)TD$FIG]
4.1. General procedure for the synthesis of 2,3-dihydro-4H-pyran-4-
ones 3a–l and 6a–f
A THF solution of LDA (12.5 mmol) was prepared by addition of
nBuLi (5 mL, 12.5 mmol, 2.5 M solution in hexanes) to a THF
solution (15 mL) of diisopropylamine (1.26 g, 12.5 mmol) at 0 8C.
After stirring for 1 h, the solution was cooled to ꢀ78 8C and 2,4-
pentanedione (0.50 g, 5.0 mmol) was added. After stirring for 1 h at
ꢀ78 8C, aldehydes (5.0 mmol) were added and the solution was
Fig. 1. Ortep plot of 6a (50% probability level).

894
R.A. Khera et al. / Journal of Fluorine Chemistry 131 (2010) 892–897
allowed to warm to 20 8C within 24 h. Hydrochloric acid (10%,
15 mL) was added and the mixture was allowed to stand for
15 min. Ethyl acetate (25 mL) was added. The organic and aqueous
layers were separated and the latter was extracted with ethyl
acetate (3ꢁ 50 mL). The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (silica gel, heptanes/ethyl
acetate = 2:1) to give the product.
4.1.4. 2-(p-Tolyl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one (3d)
Starting with a THF solution of LDA (12.5 mmol), 1a (0.77 g,
5.0 mmol) and 2d (0.60 g, 5.0 mmol) in THF (15 mL), 3d was
isolated as a white solid (1.06 g, 83%), mp 81–82 8C. 1H NMR
(300 MHz, CDCl3):
d = 2.31 (s, 3 H, CH3), 2.66–2.97 (m, 2 H, HA,B),
5.47 (dd, J = 3.5, 13.6 Hz, 1 H, CH), 5.87 (q, J = 1.0 Hz, 1 H, CHOlf),
7.16–7.25 (m, 4 H, CHAr). 19F NMR (282 MHz, CDCl3):
NMR (62.9 MHz, CDCl3):
d
= ꢀ73.3. 13
C
d
= 21.2 (CH3Ar), 42.5 (CH2), 82.6 (CH),
105.8 (q, JC,F = 3.0 Hz, CHOlf), 118.3 (q, JC,F = 275.0 Hz, CF3), 126.2,
129.6 (CHAr), 133.3, 139.5 (CAr), 159.5 (q, JC,F = 37.6 Hz, COlf), 191.4
4.1.1. 2-Phenyl-6-(trifluoromethyl)-2H-pyran-4(3H)-one (3a)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2a (0.53 g, 5.0 mmol) in THF (15 mL), 3a was
isolated as a slightly yellow oil (0.97 g, 80%). 1H NMR (300 MHz,
(CO). IR (KBr):
n = 3039 (w), 2923 (w), 1679 (s), 1633 (s), 1411 (s),
1324 (m), 1271 (s), 1177 (s), 1142 (s), 1069 (s), 990 (m), 959 (m),
937 (m), 810 (s), 719 (m), 709 (m), 602 (m) cmꢀ1. MS (EI, 70 eV): m/
z (%) = 256 (M+, 7), 187 (8), 159 (8), 118 (100), 117 (51), 91 (15), 69
(12). HRMS (EI): calcd. for C13H11O2 F3 [M]+: 256.07057; found:
256.071111.
CDCl3):
d = 2.81 (ddd, J = 1.1, 3.6, 17.1 Hz, 1 H, HA), 3.01 (dd,
J = 13.6, 17.1 Hz, 1 H, HB), 5.61 (dd, J = 3.6, 13.7 Hz, 1 H, CH), 5.98 (q,
J = 1.0 Hz, 1 H, CHOlf), 7.41–7.47 (m, 5 H, CHAr). 19F NMR
(282.4 MHz, CDCl3):
d
= ꢀ73.3. 13C NMR (75.5 MHz, CDCl3):
d
= 42.7 (CH2), 82.6 (CH), 105.2 (q, JC,F = 2.8 Hz, CHOlf), 118 (q,
4.1.5. 2-(4-Ethylphenyl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one
(3e)
JC,F = 274.8 Hz, CF3), 126.1, 129.0, 129.4 (CHAr), 136.3 (CAr), 159.4
(q, JC,F = 37.3 Hz, COlf), 191.2 (CO). IR (KBr): = 3368 (w), 3093 (w),
n
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2e (0.67 g, 5.0 mmol) in THF (15 mL), 3e was
isolated as a colourless crystalline solid (1.15 g, 85%), mp 93–94 8C.
3067, 2976 (w), 2901 (w), 2707 (w), 1687 (s), 1638 (s), 1585 (m),
1498 (w), 1455 (w), 1413 (m), 1367 (w), 1270 (s), 1243 (m), 1194
(s), 1142 (s), 1067 (s), 986 (m), 941 (m), 877 (m), 828 (m), 756 (m),
695 (s), 620 (m) 593 (m), 533 (m) cmꢀ1. MS (EI, 70 eV): m/z
(%) = 242 (M+, 5), 173 (7), 145 (9), 117 (9), 105 (12), 104 (100), 103
(20), 78 (15), 77 (11), 69 (12), 51 (8). HRMS (ESI-TOF): calcd. for
1H NMR (300 MHz, CDCl3):
d = 1.17 (t, J = 7.6 Hz, 3 H, CH2CH3),
2.56–2.99 (m, 4 H, CH2CH3, HA,B), 5.46 (dd, J = 3.2, 13.6 Hz, 1 H, CH),
5.87 (q, 1.0 Hz, 1 H, CHOlf), 7.17–7.27 (m, 4 H, 1 H, CHAr). 19F NMR
(282 MHz, CDCl3):
(CH3), 28.6, 42.6 (CH2), 82.7 (CH), 105.0 (q, JC,F = 3.0 Hz, CHOlf),
117.9 (q, JC,F = 275.4 Hz, CF3), 126.3, 128.4 (CHAr), 133.2, 139.3
d
= ꢀ73.3. 13C NMR (75.5 MHz, CDCl3):
d = 15.2
C
C
12H8O2F3 [MꢀH]+: 241.04819. Found: 241.04775. Anal. calcd.
12H9O2F3: C, 59.51; H, 3.75. Found: C, 59.75; H, 3.92.
(CAr), 159.3 (q, J = 37.1 Hz, COlf), 191.4 (CO). IR (KBr):
n = 3027 (m),
4.1.2. 2-(2-Chlorophenyl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one
(3b)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2b (0.70 g, 5.0 mmol) in THF (15 mL), 3b was
isolated as a colourless oil (0.86 g, 62%). 1H NMR (300 MHz, CDCl3):
2967 (m), 2875 (m), 1688 (m), 1636 (m), 1600 (m), 1516 (m), 1410
(m), 1269 (s), 1194 (s), 1145 (s), 1067 (s), 984 (m), 940 (m), 827
(m), 793 (m), 710 (m), 636 (m), 544 (m) cmꢀ1. MS (EI, 70 eV): m/z
(%) = 270 (8), 173 (10), 133 (13), 132 (100), 117 (95), 115 (18), 91
(14), 69 (17). HRMS: calcd. for C14H13O2F3 [M]+: 270.08622; found:
270.085433.
d
= 2.81 (dd, J = 13.9, 17.1 Hz, 1 H, HA), 2.95 (ddd, J = 1.2, 3.6,
17.1 Hz, 1 H, HB), 5.97 (dd, J = 3.7, 14.0 Hz, 1 H, CH), 6.02 (q,
J = 1.0 Hz, CHOlf), 7.37–7.47 (m, 3 H, CHAr), 7.61–7.64 (m, 1 H, CHAr).
4.1.6. 2-(3-Nitrophenyl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one
(3f)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2f (0.75 g, 5.0 mmol) in THF (15 mL), 3f was isolated
as a solid (0.90 g, 63%), mp 102–103 8C. 1H NMR (300 MHz, CDCl3):
19F NMR (282 MHz, CDCl3):
d
= ꢀ73.2. 13C NMR (75.5 MHz, CDCl3):
d
= 41.7 (CH2), 79.7 (CH), 105.4 (q, JC,F = 3.0 Hz, CHOlf), 115.1 (q,
JC,F = 275.2 Hz, CF3), 127.0, 127.6, 129.9, 130.3 (CHAr), 131.7,
134.5 (CAr), 159.3 (q, JC,F = 36.9 Hz, COlf), 190.7 (CO). IR (KBr):
n
= 3034 (w), 2922 (w), 1678 (s), 1631 (s), 1410 (s), 1344 (m),
d = 2.79 (ddd, J = 1.2, 3.9, 16.9 Hz, 1 H, HA), 2.92 (dd, J = 13.4,
1261 (s), 1167 (s), 1152 (s), 1069 (s), 994 (m), 960 (m), 938 (m),
811 (s), 720 (m), 710 (m), 605 (m) cmꢀ1. MS (EI, 70 eV): m/z
(%) = 276 (M+, 8), 241 (13), 118 (100), 117 (51), 91 (15), 69 (12).
HRMS (ESI-TOF): calcd. for C12H9O2ClF3 [M+H]+: 277.02377;
found: 277.02388.
16.8 Hz, 1 H, HB), 5.63 (dd, J = 4.4, 13.9 Hz, 1 H, CH), 5.95 (brs, 1 H,
CHOlf), 7.57–7.62 (m, 1 H, CHAr), 7.67–7.73 (m, 1 H, CHAr), 8.21–
8.26 (m, 2 H, CHAr). 19F NMR (282 MHz, CDCl3):
d
= ꢀ73.1. 13C NMR
(75.5 MHz, CDCl3):
d = 42.6 (CH2), 81.2, 105.7 (q, JC,F = 3.0 Hz, 1 H,
CHOlf), 115 (q, JC,F = 275.2 Hz, CF3), 121.2, 124.3, 130.3, 131.9
(CHAr), 138.4, 148.6 (CAr), 159.0 (q, JC,F = 37.7 Hz, COlf), 189.8 (CO).
4.1.3. 2-(4-Chlorophenyl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one
(3c)
IR (KBr): n = 3093 (w), 3067 (w), 2912 (w), 2878 (w), 1688 (s), 1640
(s), 1531 (s), 1417 (m), 1353 (m), 1271 (s), 1192 (s), 1143 (s), 1075
(s), 1005 (m), 943 (m), 912 (m), 868 (m), 808 (s), 736 (m), 683 (s),
626 (m), 538 (m) cmꢀ1. GC–MS (EI, 70 eV): m/z (%) = 287 (M+, 43),
286 (6), 270 (8), 219 (13), 218 (100), 200 (14), 190 (12), 176 (84),
173 (28), 172 (13), 171 (12), 165 (17), 144 (25), 143 (20), 131 (12),
130 (10), 129 (17), 118 (11), 116 (19), 115 (64), 103 (17), 102 (33),
89 (12), 77 (13), 76 (14), 75 (11), 69 (49), 63 (12), 51 (12). HRMS
(ESI-TOF): calcd. for C12H7F3NO4 [MꢀH]+: 286.03327. Found:
286.03353. Anal. calcd. C12H8F3NO4: C, 50.19; H, 2.81; N, 4.88.
Found: C, 50.18; H, 2.82; N, 4.87.
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2c (0.70 g, 5.0 mmol) in THF (15 mL), 3c was
isolated as a colourless crystalline solid (1.04 g, 72%), mp 76–
77 8C. 1H NMR (300 MHz, CDCl3):
d = 2.69 (ddd, J = 0.9, 3.8,
17.0 Hz, 1 H, HA), 2.87 (dd, J = 13.3, 17.0 Hz, 1 H, HB), 5.48 (dd,
J = 3.8, 13.6 Hz, 1 H, CH), 5.88 (brs, 1 H, CHOlf), 7.25–7.36 (m, 4 H,
CHAr). 19F NMR (282 MHz, CDCl3):
CDCl3):
d
= ꢀ73.3. 13C NMR (62.9 MHz,
d
= 42.6 (CH2), 81.8 (CH), 105.3 (q, JC,F = 3.1 Hz, CHOlf),
118.7 (q, JC,F = 275.0 Hz, CF3), 127.5, 129.2 (CHAr), 135.4, 134.8
(CAr), 158.9 (q, JC,F = 37.0 Hz, COlf), 190.6 (CO). IR (KBr): = 3104
n
(w), 2884 (w), 1680 (s), 1634 (s), 1494 (s), 1410 (m), 1324 (m),
1274 (s), 1175 (s), 1141 (s), 1068 (s), 993 (m), 959 (m), 939 (m),
877 (m), 835 (s), 719 (m), 638 (m), 548 (m) cmꢀ1. MS (EI, 70 eV):
m/z (%) = 276 (M+, 6), 140 (33), 139 (12), 138 (100), 103 (23), 69
(13). HRMS (EI): calcd. for C12H8O2 F3Cl [M]+: 276.01594; found:
276.015382.
4.1.7. 2-(4-Nitrophenyl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one
(3g)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2g (0.75 g, 5.0 mmol) in THF (15 mL), 3g was
isolated as a colourless crystalline solid (0.86 g, 60%), mp 112 8C. 1H
NMR (300 MHz, CDCl3): d = 2.79 (ddd, J = 0.8, 4.5, 17.0 Hz, 1 H, HA),

R.A. Khera et al. / Journal of Fluorine Chemistry 131 (2010) 892–897
895
2.88 (dd, J = 12.7, 17.1 Hz, 1 H, HB), 5.64 (dd, J = 4.6, 12.7 Hz, 1 H,
(23), 95 (10), 85 (12), 84 (22), 83 (18), 82 (12), 81 (14), 70 (22), 69
(86), 68 (13), 67 (16), 56 (30), 55 (41), 54 (15), 43 (30), 42 (13), 41
(48), 39 (17), 29 (17). HRMS: calcd. for C13H19O2F3 [M]+: 264.3371;
found: 264.33711.
CH), 5.95 (brs, 1 H, CHOlf), 7.54–7.57 (m, 2 H, CHAr), 8.24–8.26 (m, 2
H, CHAr). 19F NMR (282 MHz, CDCl3):
d
= ꢀ73.3. 13C NMR
(62.9 MHz, CDCl3):
d = 42.7 (CH2), 81.1 (CH), 105.7 (q, JC,F = 3.0 Hz,
1 H, CHOlf), 118.8 (q, JC,F = 274.4 Hz, CF3), 124.1, 126.8 (CHAr), 143.8,
148.3 (CAr), 158.4 (q, JC,F = 37.6 Hz, COlf), 189.8 (CO). IR (KBr):
4.1.11. 2-Octyl-6-(trifluoromethyl)-2H-pyran-4(3H)-one (3k)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2k (0.71 g, 5.0 mmol) in THF (15 mL), 3k was
isolated as a slight yellow oil (1.10 g, 79%). 1H NMR (300 MHz,
n
= 3094 (w), 3068 (w), 2912 (w), 2879 (w), 1689 (s), 1640 (s), 1530
(s), 1418 (m), 1354 (m), 1270 (s), 1193 (s), 1144 (s), 1075 (s), 1005
(m), 944 (m), 912 (m), 868 (m), 807 (s), 737 (m), 684 (s), 626 (m),
539 (m) cmꢀ1. GC–MS (EI, 70 eV): m/z (%) = 287 (M+, 4), 218 (9),
162 (11), 150 (10), 149 (100), 119 (31), 103 (31), 102 (11), 91 (24),
77 (38), 69 (19), 51 (10). HRMS (EI): calcd. for C12H8O2F3 [M]+:
287.04054; found: 287.040243.
CDCl3):
d = 0.81 (t, J = 7.0 Hz, 3 H, CH3(CH2)(CH2)6), 1.19–1.46 (m,
12 H, CH3(CH2)6(CH2)), 1.58–1.88 (m, 2 H), 2.47–2.51 (m, 2 H, CH2),
4.43–4.52 (m, 1 H, CH), 5.74 (s, 1 H, CHOlf). 19F NMR (282 MHz,
CDCl3):
d
= ꢀ73.6. 13C NMR (75.5 MHz, CDCl3):
d = 13.0 (CH3), 21.5,
23.6, 28.0, 28.1, 28.2, 30.7, 32.9, 40.2 (CH2), 80.6 (CH), 103.4 (q,
4.1.8. 2-(Biphenyl-4-yl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one
(3h)
J = 3 Hz, CHOlf), 121.9 (q, JC,F = 276.4 Hz, CF3), 158.2 (q,
JC,F = 36.7 Hz, C), 190.7 (CO). IR (KBr):
n = 2925 (m), 2855 (m),
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2h (0.91 g, 5.0 mmol) in THF (15 mL), 3h was
isolated as a colourless crystalline solid (1.29 g, 81%), mp 124 8C. 1H
1691 (s), 1466 (m), 1417 (m), 1339 (w), 1269 (s), 1194 (s), 1149 (s),
1073 (m), 909 (m), 819 (m), 720 (w) cmꢀ1. MS (EI, 70 eV): m/z
(%) = 278 (M+, 2), 209 (18), 167 (13), 165 (100), 139 (45), 97 (14), 83
(15), 82 (12), 81 (10), 70 (18), 69 (52), 67 (10), 57 (12), 56 (17), 55
(30), 54 (10), 43 (19), 41 (33), 39 (10), 29 (11). HRMS: calcd. for
NMR (300 MHz, CDCl3): d = 2.75 (ddd, J = 1.0, 3.6, 17.1 Hz, 1 H, HA),
2.96 (dd, J = 13.6, 17.1 Hz, 1 H, HB), 5.56 (dd, J = 3.5, 13.6 Hz, 1 H,
CH), 5.90 (q, J = 1.0 Hz, 1 H, CHOlf), 7.36-7.43 (m, 4 H, CHAr), 7.51–
C
14H21F3O2 [M]+: 278.14882; found: 278.149378.
7.61 (m, 5 H, CHAr). 19F NMR (282 MHz, CDCl3):
d
= ꢀ73.2. 13C NMR
(75.5 MHz, CDCl3):
d
= 42.6 (CH2), 82.4 (CH), 105.2 (q, JC,F = 3.0 Hz,
4.1.12. 2-Nonyl-6-(trifluoromethyl)-2H-pyran-4(3H)-one (3l)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2l (0.78 g, 5.0 mmol) in THF (15 mL), 3l was isolated
as a colourless crystalline solid (1.21 g, 83%). 1H NMR (300 MHz,
CHOlf), 118.5 (q, JC,F = 275.0 Hz, CF3), 126.6, 127.1, 127.71, 127.7,
128.8 (CHAr), 135.1, 140.1, 142.5 (CAr), 159.7 (q, JC,F = 37.2 Hz, COlf),
191.1 (CO). IR (KBr):
n = 3057 (m), 3028 (m), 2991 (m), 2837 (m),
1712 (w), 1660 (s), 1601 (s), 1485 (m), 1432 (m), 1394, 1332, 1235
(s), 1000 (s), 950 (m), 898 (m), 873 (m), 762 (s), 731 (s), 701 (s) 657
(m) cmꢀ1. MS (EI, 70 eV): m/z (%) = 318 (M+, 32), 181 (16), 180
(100), 179 (13), 178 (18), 165 (10), 69 (10). HRMS (ESI-TOF): calcd.
for C18H14O2F3 [M+H]+: 319.09404; found: 319.09435.
CDCl3): d = 0.80 (t, J = 7.0 Hz, 3 H, CH3(CH2)8), 1.17–1.26 (m, 12 H,
CH2(CH2)6(CH2)2), 1.35–1.43 (m, 2 H, CH3(CH2)6(CH2)(CH2)), 1.60–
1.87 (m, 2 H, CH2), 2.47–2.51 (m, 2 H, CH2), 4.46–4.52 (m, 1 H, CH),
5.75 (brs, 1 H, CHOlf). 19F NMR (282 MHz, CDCl3):
d
= ꢀ73.6. 13C
NMR (75.5 MHz, CDCl3):
d = 14.0 (CH3), 22.6, 24.5, 29.1, 29.3, 29.4,
31.8, 32.3, 33.8, 41.3 (CH2), 81.6 (CH), 106.6 (q, J = 3 Hz, CHOlf),
118.5 (q, JC,F = 277.9 Hz, CF3), 159.2 (q, JC,F = 36.5 Hz, COlf), 191.8
4.1.9. 2-(Thien-2-yl)-6-(trifluoromethyl)-2H-pyran-4(3H)-one (3i)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2i (0.56 g, 5.0 mmol) in THF (15 mL), 3i was isolated
as a slight yellow oil (0.88 g, 71%). 1H NMR (300 MHz, CDCl3):
(CO). IR (KBr):
n = 2924 (m), 2854 (m), 1691 (s), 1466 (m), 1418
(m), 1340 (w), 1269 (s), 1195 (s), 1150 (s), 1073 (m), 912 (m), 820
(m), 720 (w) cmꢀ1. MS (EI, 70 eV): m/z (%) = 292 (M+, 1), 223 (14),
165 (100), 139 (30), 97 (11), 83 (12), 70 (12), 69 (35), 56 (10), 55
(22), 43 (15), 41 (25), 29 (10). HRMS: calcd. for C15H23O2F3 [M]+:
319.09404; found: 319.09435.
d
= 2.88 (ddd, J = 0.9, 4.3, 17 Hz, 1 H, HA), 3.03 (dd, J = 13.5, 17.0 Hz,
1 H, HB), 5.46 (brs, 1 H, CHOlf), 5.77 (dd, J = 4.2, 11.4 Hz, 1 H, CH),
7.04 (d, J = 3.3 Hz, 1 H, CHthienyl), 7.12 (t, J = 3.5 Hz, 1 H, CHthienyl),
7.39 (d, J = 5.0 Hz, 1 H, CHthienyl). 19F NMR (282 MHz, CDCl3):
d
= ꢀ73.2. 13C NMR (75.5 MHz, CDCl3):
d
= 42.3 (CH2), 76.2 (CH),
4.1.13. 6-Methyl-2-(2-(trifluoromethyl)phenyl)-2H-pyran-4(3H)-
one (6a)
Starting with a THF solution of LDA (12.5 mmol), 4 (0.50 g,
5.0 mmol) and 5a (0.87 g, 5.0 mmol) in THF (15 mL), 6a was
isolated as a colourless crystalline solid (0.94 g, 73%), mp 127 8C. 1H
105.3 (q, JC,F = 3.0 Hz, CHOlf), 118.3 (q, JC,F = 273.0 Hz, CF3), 126.3,
126.6, 127.3 (CHthienyl), 140.8 (Cthienyl), 159.3 (q, JC,F = 37.2 Hz, COlf),
191.6 (CO). IR (KBr):
n = 3086 (m), 3070 (m), 1686 (s), 1637 (m),
1410 (m), 1358 (m), 1317 (m), 1262 (s), 1193 (s), 1145 (s), 1065
(m), 965 (m), 823 (m), 701 (s) 640 (m) cmꢀ1. MS (EI, 70 eV): m/z
(%) = 248 (M+, 19), 111 (10), 110 (100), 109 (10), 69 (15). HRMS
NMR (300 MHz, CDCl3):
d = 2.00 (s, 3 H, CH3), 2.2.49 (ddd, J = 0.7,
3.7, 16.8 Hz, 1 H, HA), 2.64 (dd, J = 14.1, 16.9 Hz, 1 H, HB), 5.38 (s, 1
H, CHOlf), 5.69 (dd, J = 3.7, 14.0 Hz, 1 H, CH), 7.38-7.43 (m, 1 H,
CHAr), 7.55–7.62 (m, 2 H, CHAr), 7.71–7.74 (m, 1 H, CHAr). 19F NMR
(ESI-TOF): calcd. for
248.010271.
C
10H7O2F3S [M]+: 248.01134; found:
(282 MHz, CDCl3):
d
= ꢀ58.4. 13C NMR (75.5 MHz, CDCl3):
d = 21.0
4.1.10. 2-Heptyl-6-(trifluoromethyl)-2H-pyran-4(3H)-one (3j)
Starting with a THF solution of LDA (12.5 mmol), 1 (0.77 g,
5.0 mmol) and 2j (0.64 g, 5.0 mmol) in THF (15 mL), 3j was isolated
as a slight yellow oil (1.02 g, 78%). 1H NMR (300 MHz, CDCl3):
(CH3), 43.1 (CH2), 77.1 (q, JC,F = 2.3 Hz, CH), 105.3 (CHOlf), 125.9 (q,
J = 5.6 Hz, CHAr), 128.0, 128.7, 132.5 (CHAr), 123.9 (q,
JC,F = 274.3 Hz, CF3), 127.0 (q, JC,F = 32.1 Hz, CAr), 137.2 (q,
JC,F = 1.0 Hz, CHAr), 174.2 (COlf), 191.3 (CO). IR (KBr):
n = 3078
d
= 0.81 (t, J = 7.0 Hz, 3 H, CH3(CH2)(CH2)5), 1.19–1.26 (m, 8 H,
(w), 3017 (w), 2970 (w), 1660 (s), 1613 (s), 1486 (m), 1396 (m),
1359 (m), 1310 (s), 1288 (m), 1240 (m), 1152 (s), 1100 (s), 1060
(m), 1035 (m), 1000 (m), 948 (m), 879 (m), 810 (m), 770 (s), 751
(m), 652 (m), 548 (m) cmꢀ1. MS (EI, 70 eV): m/z (%) = 256 (M+, 5),
213 (23), 173 (11), 172 (100), 171 (40), 151 (24). HRMS (ESI-TOF):
calcd. for C13H12O2F3 [M+H]+: 257.0784; found: 257.0787.
CH3(CH2)4(CH2)2), 1.34–1.42 (m, 2 H, CH3(CH2)4(CH2)(CH2)), 1.59–
1.84 (m, 2 H), 2.50 (t, J = 7.1 Hz, 2 H, CH3(CH2)4(CH2)(CH2)), 4.44–
4.51 (m, 1 H, CH), 5.75 (brs, 1 H, CHOlf). 19F NMR (282 MHz, CDCl3):
d
= ꢀ73.6. 13C NMR (75.5 MHz, CDCl3):
d = 13.0 (CH3), 21.5, 23.6,
28.0, 28.1, 30.7, 32.9, 40.3 (CH2), 80.7 (CH), 103.6 (q, J = 3 Hz, CHOlf),
121.5 (q, JC,F = 276.5 Hz, CF3), 158.3 (q, JC,F = 36.9 Hz, C), 190.8 (CO).
IR (KBr):
n
= 2921 (m), 2852 (m), 1688 (s), 1465 (m), 1417 (m),
4.1.14. 2-(2-Chloro-3-(trifluoromethyl)phenyl)-6-methyl-2H-pyran-
4(3H)-one (6b)
Starting with a THF solution of LDA (12.5 mmol), 4 (0.50 g,
5.0 mmol) and 5b (1.04 g, 5.0 mmol) in THF (15 mL), 6b was
1340 (w), 1270 (s), 1197 (s), 1156 (s), 1073 (m), 909 (m), 820 (m),
720 (w) cmꢀ1. MS (EI, 70 eV): m/z (%) = 264 (M+, 16), 195 (29), 193
(10), 167 (16), 165 (100), 139 (68), 110 (17), 109 (10), 98 (11), 97

896
R.A. Khera et al. / Journal of Fluorine Chemistry 131 (2010) 892–897
isolated as a colourless crystalline solid (1.03 g, 71%), mp 137 8C. 1H
NMR (300 MHz, CDCl3): = 2.00 (s, 3H, CH3), 2.45–2.64 (m, 2 H,
H, CHAr), 7.28–7.36 (m, 1 H, CHAr). 19F NMR (282 MHz, CDCl3):
d
d
= ꢀ115.4. 13C NMR (62.9 MHz, CDCl3):
d = 21.0 (CH3), 42.3 (CH2),
HA,B), 5.38 (s, 1 H, CHOlf), 5.63 (dd, J = 4.2, 13.6 Hz, 1 H, CH), 7.35–
7.39 (m, 1 H, CHAr), 7.54 (d, 1 H, J = 8.3 Hz, 1 H, CHAr), 7.71–7.73 (m,
79.9 (CH), 105.3 (CHOlf), 113.0 (d, JF,C = 23.0 Hz, CHAr), 115.6 (d,
JF,C = 21 Hz, CHAr), 121.6 (d, JF,C = 3.7 Hz, CHAr), 130.8 (d,
JF,C = 8.7 Hz, CHAr), 140.6 (d, JF,C = 7.5 Hz, CAr), 162.1 (d,
1 H, CHAr). 19F NMR (282 MHz, CDCl3):
d
= ꢀ58.4. 13C NMR
(75.5 MHz, CDCl3):
d
= 20.9 (CH3), 43.0 (CH2), 76.6 (q, JC,F = 5.7 Hz,
JF,C = 246.5, CAr), 174.1 (COlf), 191.8 (CO). IR (KBr): n = 3067 (w),
CH), 105.4 (CHOlf), 121.7 (q, JC,F = 273 Hz, CF3), 125.6 (q,
JC,F = 31.3 Hz, CHAr), 127.4 (q, JC,F = 5.7 Hz, CHAr), 128.6 (q,
JC,F = 42.0 Hz, CHAr), 139.1 (q, JC,F = 28.1 Hz, CAr), 173.8 (COlf),
2921 (w), 1722 (w), 1666 (m), 1607 (s), 1590 (s), 1488 (m), 1448
(m), 1392 (s), 1392 (s), 1359 (m), 1326 (s), 1237 (s), 1041 (m), 1003
(s), 890 (m), 785 (s), 691 (s), 627 (w), 592 (w) cmꢀ1. GC–MS (EI,
70 eV): m/z (%) = 206 (M+, 6), 188 (7), 173 (6), 163 (22), 122 (100),
121 (14), 96 (13). HRMS: calcd. for C12H11O2F [M+]: 206.07376;
found: 206.07469. Anal. calcd. C12H11O2F: C, 69.89; H, 5.38. Found:
C, 69.74; H, 5.66.
190.6 (CO). IR (KBr):
n = 3117 (w), 2976 (w), 2926 (w), 1660 (w),
1601 (s), 1575 (m), 1440 (m), 1392 (m), 1330 (m), 1234 (m), 1557
(s), 1126 (m), 1105 (s), 1042 (m), 1000 (m), 958 (m), 880 (m), 848
(m), 770 (m), 706 (m), 596 (m) cmꢀ1. MS (EI, 70 eV): m/z (%) = 290
(M+, 6), 255 (16), 247 (16), 208 (49), 207 (15), 206 (100), 171 (39),
151 (14), 43 (13). HRMS (ESI-TOF): calcd. for C13H11ClO2F3 [M+H]+:
291.09305; found: 291.093056.
4.1.18. 2-(4-Fluorophenyl)-6-methyl-2H-pyran-4(3H)-one (6f)
Starting with a THF solution of LDA (12.5 mmol), 4a (0.50 g,
5.0 mmol) and 5f (0.62 g, 5.0 mmol) in THF (15 mL), 6f was isolated
as a colourless crystalline solid (0.81 g, 78%), mp 61–62 8C. 1H NMR
4.1.15. 2-(2-Chloro-4-(trifluoromethyl)phenyl)-6-methyl-2H-pyran-
4(3H)-one (6c)
(300 MHz, CDCl3):
d = 1.99 (s, 3 H, CH3), 2.50 (dd, J = 3.4, 16.8 Hz 1
Starting with a THF solution of LDA (12.5 mmol), 4 (0.50 g,
5.0 mmol) and 5c (1.04 g, 5.0 mmol) in THF (15 mL), 6c was
isolated as a colourless crystalline solid (1.09 g, 75%), mp 143 8C. 1H
H, HA), 2.70 (dd, J = 14.0, 16.6 Hz, 1 H, HB), 5.29 (dd, J = 3.8, 13.9 Hz,
1 H, CH), 5.36 (s, 1 H, CHOlf), 6.95–7.06 (m, 2 H, CHAr), 7.28–7.34 (m,
2 H, CHAr). 19F NMR (282 MHz, CDCl3):
(75.5 MHz, CDCl3): d = 21.1 (CH3), 42.3 (CH2), 80.1 (CH), 105.3
d
= ꢀ112.7. 13C NMR
NMR (300 MHz, CDCl3):
d
= 2.03 (s, 3 H, CH3), 2.47 (dd, J = 14.1,
14.1 Hz, 1 H, HA), 2.68 (ddd, J = 1.1, 3.5, 14.1 Hz, 1 H, HB), 5.40 (s, 1
H, CHOlf), 5.71 (dd, J = 3.5, 14.1 Hz, CH), 7.54 (d, J = 8.1 Hz, 1 H,
CHAr), 7.58 (s, 1 H, CHAr), 7.69 (d, J = 8.3 Hz, 1 H, CHAr). 19F NMR
(CHOlf), 115.7 (d, JF,C = 21.8 Hz, CHAr), 128.1 (d, JF,C = 7.2 Hz, CHAr),
134.0 (d, JF,C = 3 Hz, CAr), 162.8 (d, JF,C = 247.0, CAr), 174.2 (COlf),
192.0 (CO). IR (KBr):
n = 3295 (w), 3119 (w), 2966 (w), 2849 (w),
(282 MHz, CDCl3):
d
= ꢀ62.9. 13C NMR (75.5 MHz, CDCl3):
d
= 20.5
1898 (w), 1651 (m), 1600 (s), 1511 (m), 1426 (m), 1396 (m), 1335
(m), 1248 (m), 1219 (s), 1159 (m), 1024 (m), 997 (m), 903 (m), 818
(s), 659 (m), 554 (m) cmꢀ1. GC–MS (EI, 70 eV): m/z (%) = 206 (M+,
4), 188 (10), 163 (17), 122 (100), 121 (15), 96 (10), HRMS: calcd. for
(CH3), 40.8 (CH2), 77.3 (CH), 105.6 (CHOlf), 127.1 (q, JC,F = 272 Hz,
CF3), 131.8 (q, JC,F = 33.8 Hz, CAr), 124.2 (q, JC,F = 3.8 Hz, CHAr), 126.7
(q, JC,F = 3.8 Hz, CHAr), 127.7 (q, JC,F = 3.8 Hz, CHAr), 131.8 (q,
JC,F = 33.8 Hz, CAr), 140.2 (CAr), 173.8 (COlf), 190.9 (CO). IR (KBr):
C
C
12H11O2F [M+]: 206.07376; found: 206.073710. Anal. calcd.
12H11O2F: C, 69.89; H, 5.38. Found: C, 69.88; H, 5.56.
n
= 3092 (w), 2966 (w), 2848 (w), 1666 (s), 1613 (s), 1388 (m), 1319
(s), 1240 (m), 1118 (s), 1064 (m), 1006 (m), 945 (m), 846 (m), 815
(m), 713 (m), 649 (m), 538 (m) cmꢀ1. MS (EI, 70 eV): m/z (%) = 290
(M+, 4), 255 (13), 247 (15), 208 (32), 207 (11), 206 (100), 171 (27),
151 (17), 43 (10). HRMS: calcd. for C13H10ClO2F3 [M]+: 319.09404;
found: 319.09435.
Acknowledgements
Financial support from the State of Pakistan (HEC scholarship
for M. H.), from the DAAD (scholarship for R. A. K.), from the State of
Mecklenburg-Vorpommern (scholarship for M. H.) and from
Naubahar Bottling Co. Pepsi Cola Gujranwala Pakistan (for R. A.
K.) is gratefully acknowledged.
4.1.16. 2-(2-Fluorophenyl)-6-methyl-2H-pyran-4(3H)-one (6d)
Starting with a THF solution of LDA (12.5 mmol), 4a (0.50 g,
5.0 mmol) and 5d (0.62 g, 5.0 mmol) in THF (15 mL), 6d was
isolated as a slight yellow oil (0.69 g, 67%). 1H NMR (250 MHz,
References
CDCl3): d = 1.98 (s, 3 H, CH3), 2.51 (dd, J = 3.2, 16.8 Hz, 1 H, HB), 2.69
(dd, J = 14.1, 16.8 Hz, 1 H, HB), 5.35 (s, 1 H, CHOlf), 5.58 (dd, J = 3.6,
14.1 Hz, 1 H, CH), 6.96-7.03 (m, 1 H, CHAr), 7.09–7.14 (m, 1 H, CHAr),
7.22–7.29 (m, 1 H, CHAr), 7.39–7.45 (m, 1 H, CHAr). 19F NMR
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41 (1993) 1640.
(282 MHz, CDCl3):
d
= ꢀ118.2. 13C NMR (75.5 MHz, CDCl3):
d = 21.0
(CH3), 41.3 (CH2), 75.1 (d, JF,C = 3.1 Hz, CH), 105.2 (CHOlf), 115.8 (d,
JF,C = 21.7 Hz, CHAr), 124.5 (d, JF,C = 3.6 Hz, CHAr), 125.5 (d,
JF,C = 12.7 Hz, CHAr), 127.5 (d, JF,C = 3.4 Hz, CHAr), 130.4 (d,
JF,C = 8.3 Hz, CAr), 159.7 (d, JF,C = 247.8 Hz, CAr), 174.2 (COlf), 191.8
(CO). IR (KBr):
n = 3067 (w), 296 (w), 1722 (w), 1660 (m), 1605 (s),
1491 (m), 1436 (m), 1360 (m), 1330 (m), 1230 (m), 1151 (m), 1065
(m), 1001 (m), 950 (m), 871 (m), 810 (m), 755 (s), 657 (m), 553
(m) cmꢀ1. GC–MS (EI, 70 eV): m/z (%) = 206 (M+, 2), 163 (20), 123
(10), 122 (100), 121 (14), 96 (11). HRMS: calcd. for C12H11O2F [M]+:
206.07376; found: 206.07373. Anal. calcd. C12H11O2F: C, 69.89; H,
5.38. Found: C, 69.86; H, 5.51.
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4.1.17. 2-(3-Fluorophenyl)-6-methyl-2H-pyran-4(3H)-one (6e)
Starting with a THF solution of LDA (12.5 mmol), 4a (0.50 g,
5.0 mmol) and 5e (0.62 g, 5.0 mmol) in THF (15 mL), 6e was
isolated as a slight yellow oil (0.75 g, 72%). 1H NMR (300 MHz,
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d = 2.02 (d, 3 H, CH3), 2.53 (ddd, J = 1.0, 3.8, 16.7 Hz, 1 H,
HA), 2.68 (dd, J = 13.8, 16.8 Hz, 1 H, HB), 5.31 (dd, J = 3.8, 13.8 Hz, 1
H, CH), 5.36 (s, 1 H, CHOlf), 6.96–7.03 (m, 1 H, CHAr), 7.05–7.11 (m, 2
(c) B. Gao, Z. Yua, Z. Fua, X. Fenga, Tetrahedron Lett. 47 (2006) 1537;
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R.A. Khera et al. / Journal of Fluorine Chemistry 131 (2010) 892–897
897
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retrieving.html or can be ordered from the following address: Cambridge Crys-
tallographic Data Centre, 12 Union Road, GB-Cambridge CB21EZ; Fax: (+44)1223-
336-033; or deposit@ccdc.cam.ac.uk.
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