gem-Difluorosubstituted NH-azomethine ylides in the synthesis of 4-fluorooxazolines via the three-component reaction of imines, trifluoroacetophenones and CF2Br2

Article abstract of DOI:10.1016/j.tetlet.2007.12.037

A simple one-step synthesis of a new class of fluorinated heterocycles, 4-fluoro-3-oxazolines, from diarylmethanimines, trifluoroacetophenones and CF₂Br₂ is described. The reaction proceeds via the sequential formation of difluorocarbene and a gem-difluorosubstituted NH-azomethine ylide, followed by 1,3-dipolar cycloaddition with a ketone.

Full text of DOI:10.1016/j.tetlet.2007.12.037

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1237–1240
gem-Difluorosubstituted NH-azomethine ylides in the synthesis of
4-fluorooxazolines via the three-component reaction of imines,
trifluoroacetophenones and CF2Br2
a
a,
a
b
*
Kirill A. Khistiaev , Mikhail S. Novikov , Alexander F. Khlebnikov , Joerg Magull
a Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Petrodvorets, Russia
b Institute of Inorganic Chemistry of Georg-August University, Go¨ttingen, D-37077 Go¨ttingen, Tammannstrasse 4, Germany
Received 25 October 2007; revised 27 November 2007; accepted 6 December 2007
Available online 14 December 2007
Abstract
A simple one-step synthesis of a new class of fluorinated heterocycles, 4-fluoro-3-oxazolines, from diarylmethanimines, trifluoro-
acetophenones and CF2Br2 is described. The reaction proceeds via the sequential formation of difluorocarbene and a gem-difluorosub-
stituted NH-azomethine ylide, followed by 1,3-dipolar cycloaddition with a ketone.
Ó 2007 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition of azomethine ylides with
compounds containing carbon–carbon and carbon–oxygen
multiple bonds is an attractive synthetic approach to
pyrrole and oxazole derivatives. Such a strategy has the
advantage of synthetic efficiency and high regio- and stereo-
selectivity. Most syntheses have been realized using N-
substituted azomethine ylides, resulting in the formation
of N-aryl or N-alkyl heterocycles.1 For the synthesis of
N-unsubstituted azaheterocycles via 1,3-dipolar cycloaddi-
tion, NH-azomethine ylides2 or the so-called N-metallated
azomethine ylides1c,3 can be used. Furthermore, N-unsub-
stituted azomethine ylides with good leaving groups (CN,
OTMS, STMS, SCH3, SSnBu3, etc.) are nitrile ylide equiv-
alents4 and can be used for the preparation of pyrroline,5
oxazoline,6 and other heterocycles.7
acids,11 and condensation of aldehydes with N-unsubsti-
tuted a-amino acids,12 making it possible to introduce
CO2R, CN, NRR0, and @NR functional groups into the
target heterocycles. C-Halogen-substituted NH-azome-
thine ylides are unknown though the corresponding N-
substituted iminium ylides are widely used for the synthesis
of halogenated, and in particular, fluorinated heterocycles.13
In this work, we report the first example of the genera-
tion of gem-difluorosubstituted NH-azomethine ylides,
their trapping by 1,3-dipolar cycloaddition with trifluoro-
acetophones and their utilization for the synthesis of a
new class of fluorinated heterocycles-4-fluoro-3-oxazolines.
The only method for the generation of fluorinated azo-
methine ylides is the reaction of fluoro- and difluoro-
carbenes with compounds containing C@N bonds.13a
Difluorocarbene was generated in situ by the reduction
of dibromodifluoromethane with lead in the presence of
tetrabutylammonium bromide.13b To form gem-difluoro-
substituted NH-azomethine ylides, we used diphenyl-
methanimine 1a as the starting imine, and a,a,a-
trifluoroacetophenone 2a was used for trapping dipole
4a. Stirring a mixture of imine 1a, a,a,a-trifluoroacetophe-
none, CF2Br2, lead filings, and Bu4NBr in dichloromethane
in the ratio 1:1:1:1:1:120 for 42 h gave rise to fluoro-oxaz-
oline 3a in 15% yield after chromatographic purification
The known methods for the generation of NH-azo-
methine ylides involve desilylation of nitrogen-containing
silanes,2b ring opening of aziridines,8 prototropy of azo-
methines,2a,c,d 1,2- and 1,4-silatropy of a-silylimines
and a-silylamides, respectively,5a,9 1,4-stannotropy of N-
(stannylmethyl)thioamides,10 decarboxylation of a-amino
*
Corresponding author. Fax: +7 812 428 6939.
E-mail address: Mikhail.Novikov@pobox.spbu.ru (M. S. Novikov).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.037

1238
K. A. Khistiaev et al. / Tetrahedron Letters 49 (2008) 1237–1240
The structure of compound 3a was determined from IR,
CF2Br2
Pb, Bu4NBr
1H, 13C, and 19F NMR spectra, and confirmed by single
crystal X-ray data (Fig. 1).15
H
N
Ph
Ph
Ph
Ph
[:CF2]
Ph
Ph
The second product of the reaction was the unstable diflu-
oroimine 5a, formation of which was detected by chromato-
graphic and NMR methods. This compound easily
hydrolyses but it is possible to isolate it by flash chromato-
graphy on silica with 10% of benzophenone. The difluoro-
NH
N
CHF2
F
F
1a
5a
4a
Ph
1
O
methyl group of difluoroimine 5a was apparent in the H
F3C
F
NMR spectrum as a triplet at d 6.35 (1JHF 70.6 Hz). The trip-
let signal for the carbon of this fragment in the 13C NMR
spectrum was found at d 115.2 (1JHF 232 Hz). The triplet
at d 176.7 (1JHF 15.7 Hz) was attributed to the imine func-
tion. Difluoroimine 5a is the product of a formal 1,2-H-shift
in azomethine ylide 4a. To improve the yield of oxazoline 3a
and to diminish the formation of by-product 5a we per-
formed the reaction of imine 1a with difluorocarbene under
different conditions, varying the concentrations of reagents,
their ratio, and dispersiveness of lead (lead filings or active
pyrophoric lead). The optimization of conditions and the
results are summarized in Table 1. The best yield of oxazo-
line 3a was obtained with the molar ratio of reagents
Ph2C@NH:CF2Br2:Pb:Bu4NBr:PhCOCF3:CH2Cl2 equal
2
H
N
Ph
Ph
Ph
Ph
N
F
F
CF3
O
O
-HF
CF3
Ph
3a
Ph
Scheme 1. The reaction of diphenylmethanimine 1a with difluorocarbene.
(Scheme 1).14 This three-component reaction proceeds via
two reactive intermediates—difluorocarbene and the
gem-difluorosubstituted NH-ylide 4a. The NH-ylide then
participates in a 1,3-dipolar cycloaddition to give an inter-
mediate, which undergoes dehydrofluorination.
Fig. 1. X-ray structure of compound 3a.
Table 1
Optimization of the reaction conditions for the synthesis of oxazoline 3a from diphenylmethanimine 1a and trifluoroacetophenone 2a
Entry Imine
(mmol)
Pb
(mmol)
Bu4NBr
(mmol)
CF2Br2
(mmol)
PhC(O)CF3
(mmol)
CH2Cl2
(mL)
Generation of
CF2
Reaction time
(h)
Yield of 3a
(%)
1
2
3
4
5
6
2
4
1
1
6
6
12
3
6
6
12
3
6
6
12
3
6
6
10
3
25
10
20
3
A
A
B
A
C
42
6
18
168
120
15
66
38
50
37
3
3
3
6
3
Reaction conditions: A: (lead/ultrasound irradiation); B: (active lead/magnetic stirring without ultrasound irradiation); C: (lead/magnetic stirring without
ultrasound irradiation).

K. A. Khistiaev et al. / Tetrahedron Letters 49 (2008) 1237–1240
1239
facilitates isomerization of the ylides to the corresponding
difluoroimines 5.
R1
N
R1
R2
F
It was found that fluorooxazolines 3 were stable under
acidic conditions. For example, compound 3f did not
decompose in refluxing conc. hydrochloric acid over 8 h.
At the same time, the fluorine can be easily replaced via
reaction with nucleophilic reagents (Scheme 3). Treatment
of oxazoline 3a with potassium hydroxide in DMSO gave
rise to lactam 6 in 91% yield. Methoxy-derivative 7 was
obtained as a product of the reaction of oxazoline 3a with
sodium methoxide in methanol in 94% yield. N-Nucleo-
philes easily react with compound 3a at room temperature.
Treatment of oxazoline 3a with morpholine for 2 days gave
rise to compound 8 in 76% yield. Compound 9 was
obtained in 88% yield via reaction of oxazoline 3a with
methyl glycinate hydrochloride in a mixture of Et3N and
DMSO.
In summary, a simple one-step synthesis of a new class
of fluorinated heterocycles, 4-fluoro-3-oxazolines, from
diarylmethanimines, trifluoroacetophenones, and CF2Br2
is described. This three-component reaction proceeds via
two reactive intermediates—difluorocarbene and a gem-
difluorosubstituted NH-azomethine ylide. Besides the main
reaction—cycloaddition with the C=O bond—gem-di-
fluorosubstituted NH-ylides undergo a formal 1,2-H-shift
with the formation of N-(difluoromethyl)diarylmethani-
mines. This isomerization explains the decrease in yield of
oxazolidines from imines which contain strong electron-
withdrawing substituents on the phenyl rings.
R3
[:CF2]
NH
+
R2
O
O
CF3
F3C
2a-
e
R3
3a-
1a-
e
i
Scheme 2. The synthesis of fluorooxazolines 3a–i.
Table 2
Preparation of fluoro-oxazolines 3a–i
Imine
R1
R1
Ketone R3
Oxazoline Yield (%)
1a
1b
1c
1d
1e
1a
1a
1a
1a
a
H
H
4-Cl
2a
2a
H
H
H
H
H
3a
3b
3c
3d
3e
66
61
10a
12
38
63
54
76
74
4-Cl
4-Cl
4-CF3
3-CF3
H
4-CN 2a
4-CF3 2a
3-CF3 2a
H
H
H
H
2b
2c
2d
2e
4-CH3 3f
H
H
H
4-Cl
4-F
3g
3h
3-CF3 3i
Mixture of stereoisomers.
to 1:3:3:3:3:78 with ultrasonication of the reaction mixture
at 40 °C (entry 2). The use of active lead did not increase
the yield of the desired product in contrast to the results
obtained earlier for N-substituted imines.13b With optimized
conditions in hand, we synthesized oxazolines 3b–i starting
from substituted diarylmethanimines 1b–e and acetophe-
nones 2b–e (Scheme 2 and Table 2).14
Acknowledgment
The decrease in yield of oxazolidines having electron-
withdrawing substituents on the phenyl rings is probably
accounted for by the increase of the acidity of ylides 4
derived from imines 1c–e and this increase of acidity
We gratefully acknowledge the Russian Foundation for
Basic Research (Project No. 08-03-00112).
References and notes
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H
Ph
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CF3
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4484–4517.
MeONa
MeOH
KOH
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Ph
N
N
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Rep. Inst. Adv. Mater. Stud. 1988, 2, 149–177; (c) Kawashima, K.;
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Noguchi, M. Tetrahedron 2007, 63, 1630–1643; also see references
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Ph
Ph
HN
O
N
F
Ph
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Ph
8
CF3
O
Ph
3a
CF3
3. (a) Kanemasa, S. In Synthetic Applications of 1,3-Dipolar Cyclo-
addition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: New York,
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2002, 1371–1387; (d) Grigg, R.; Sridharan, V. In Advances in
Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich CT, 1993;
CO2Me
Ph
N
NH
HCl
H2N
CO2Me
Ph
O
Ar
CF3
Et3N, DMSO
9
Scheme 3. The reactions of fluoro-oxazoline 3a with O- and N-
nucleophiles.

1240
K. A. Khistiaev et al. / Tetrahedron Letters 49 (2008) 1237–1240
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14. A typical experimental procedure for the synthesis of fluoro-oxazo-
lines 3a–i is as follows. A flask containing freshly prepared lead filings
(0.64 g, 6 mmol) and dichloromethane (10 mL) was charged with
Bu4NBr (1.93 g, 6 mmol), diarylmethanimine (2 mmol), aryltrifluoro-
methyl ketone (6 mmol) and CF2Br2 (0.55 mL, 6 mmol). The flask
was tightly stoppered, immersed in an ultrasonic cleaner (160 W) and
irradiated with ultrasound at 40 °C until the lead was consumed
completely (6–20 h). The solvent was removed under reduced
pressure, and the residue was separated by column chromatography
on silica to afford oxazolines 3a–i. Crystalline products were
recrystallised from hexane or a mixture of hexane–Et2O.
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15. Data for selected compounds: 3a (colourless solid), mp 111–112 °C
(hexane–Et2O). IR (CHCl3): 1740 (C@N) cmꢀ1. 1H NMR (300 MHz,
CDCl3): 7.23–7.69 (m, 15H, HPh). 13C NMR (75 MHz, CDCl3): 84.9
2
3
(quintet, C5, JCF = 32.9 Hz), 107.5 (d, C2, JCF = 21.9 Hz), 122.1
(qd, CF3, 1JCF = 287.2 Hz, 3JCF = 4.9 Hz), 125.8, 128.2, 128.3, 128.6,
129.8, 130.9, 131.0, 141.8, 142.2 (CPh), 157.9 (d, C4, 1JCF = 298.7 Hz).
19F NMR (188 MHz, CDCl3, ext. standard C6F6): 80.0 (q, F–C4, JFF
3.2 Hz), 86.7 (d, CF3, JFF 3.2 Hz). Anal. Calcd for C22H15F4NO: C,
68.57; H, 3.92; N, 3.63. Found: C, 68.53; H, 4.07; N, 3.42. X-ray data
for compound 3a: C22H15F4NO, M = 385.36, monoclinic, space
10. Komatsu, M.; Kasano, Y.; Yonemori, J.-i.; Oderaotoshi, Y.; Mina-
kata, S. Chem. Commun. 2006, 526–528.
11. Grigg, R.; Gunaratne, H. Q. N. Chem. Commun. 1982, 384–386.
˚
group P21/c, a = 9.0134(10), b = 22.6457(19), c = 9.8100(10) A,
3
3
˚
`
12. (a) Coldham, I.; Crapnell, K. M.; Fernandez, J.-C.; Moseley, J. D.;
b = 117.129(8)°, V = 1782.07(30) A , Z = 4, d = 1.436 g/cm , MoKa
˚
Rabot, R. J. Org. Chem. 2002, 67, 6181–6187; (b) Grigg, R.;
Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 180–181;
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Soc., Chem. Commun. 1984, 182–183; (d) Grigg, R.; Sridharan, V.;
Surendrakumar, S. Tetrahedron 1988, 44, 4953–4966.
radiation, k = 0.71073 A, T = 133 K. Crystallographic data have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC-666525. Compound 7: (colourless solid), mp 129.5–130 °C
(methanol). 1H NMR (300 MHz, CDCl3): 4.16 (s, 3H, CH3), 7.19–
7.69 (m, 15H, HPh). 13C NMR (75 MHz, CDCl3): 57.9 (OCH3), 86.1
2
1
13. (a) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. Russ. Chem.
Rev. 2005, 74, 171–193; (b) Novikov, M. S.; Khlebnikov, A. F.;
Sidorina, E. S.; Kostikov, R. R. J. Chem. Soc., Perkin Trans. 1 2000,
231–237; (c) Novikov, M. S.; Khlebnikov, A. F.; Shevchenko, M. V.
J. Fluorine Chem. 2003, 123, 177–181; (d) Voznyi, I. V.; Novikov, M.
S.; Khlebnikov, A. F.; Kostikov, R. R. Russ. Chem. Bull. 2004, 53,
1087–1091; (e) Voznyi, I. V.; Novikov, M. S.; Khlebnikov, A. F.
Synlett 2005, 1006–1008; (f) Novikov, M. S.; Khlebnikov, A. F.;
Voznyi, I. V.; Besedina, O. V.; Kostikov, R. R. Russ. J. Org. Chem.
2005, 41, 361–369; (g) Khlebnikov, A. F.; Voznyi, I. V.; Novikov, M.
S.; Kostikov, R. R. Russ. J. Org. Chem. 2005, 41, 560–566; (h)
Novikov, M. S.; Khlebnikov, A. F.; Shevchenko, M. V.; Kostikov, R.
(q, C5, JCF = 31.3 Hz), 108.7 (C2), 122.7 (q, CF3, JCF = 287 Hz),
125.9, 126.0, 127.5, 127.6, 127.9, 128.0, 129.1, 132.7, 143.7, 144.1
(CPh), 162.9 (C4). Anal. Calcd for C23H18F3NO2: C, 69.52; H, 4.57;
N, 3.52. Found: C, 69.51; H, 4.63; N, 3.54. Compound 8: (colourless
solid), mp 142–143 °C (hexane–Et2O). IR (CHCl3): 1650 (C@N)
cmꢀ1 1H NMR (300 MHz, CDCl3): 7.19–7.6 (m, 15H, HPh), 3.29–
.
3.73 (m, 8H, CH2).13C NMR (75 MHz, CDCl3): 47.6 (CH2), 66.1
(CH2), 89.4 (q, C5, JCF = 29.3 Hz), 110.1 (C2), 123.59 (q, CF3, JCF
288 Hz), 126.1, 126.3, 127.4, 127.5, 127.6, 127.6, 128.2, 128.3, 129.3,
129.8, 135.1, 145.9, 146.3 (CPh), 157.24 (C4). Anal. Calcd for
C26H23F3N2O2: C, 69.02; H, 5.12; N, 6.19. Found: C, 69.14; H,
5.13; N, 6.29.
2
1