Nucleophilic addition of ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate to imines: An effective entry to novel gem-difluorinated amino esters and their derivatives

Article abstract of DOI:10.1055/s-2006-926225

Zinc- or tetrakis(dimethylamino)ethylene (TDAE)-mediated nucleophilic addition of ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate to imines afforded gem-difluorovinyl substituted β-amino esters (α-addition product) and gem-difluorinated δ-amino esters (γ-

Full text of DOI:10.1055/s-2006-926225

296
LETTER
Nucleophilic Addition of Ethyl 3-Bromodifluoromethyl-3-benzyloxyacrylate
to Imines: An Effective Entry to Novel gem-Difluorinated Amino Esters and
their Derivatives
Nucleophilic
Addition
o
e
f
Ethyl 3-B
i
romodi
m
fluoromethyl-3-ben
i
zyloxy
n
acrylate to Imines Peng,1 Jingwei Zhao, Ping He, Shizheng Zhu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhusz@mail.sioc.ac.cn
Received 17 October 2005
moiety was a masked hydroxy or carbonyl group. The
Abstract: Zinc- or tetrakis(dimethylamino)ethylene (TDAE)-me-
mode of addition (a or g) could be completely controlled
diated nucleophilic addition of ethyl 3-bromodifluoromethyl-3-
by the choice of mediator, zinc or TDAE, which produced
a-difluorovinyl substituted b-hydroxy esters and gem-di-
benzyloxyacrylate to imines afforded gem-difluorovinyl substituted
b-amino esters (a-addition product) and gem-difluorinated d-amino
esters (g-addition product) or their cyclized derivatives, depending fluorinated d-hydroxy esters, respectively. To extend the
on the mediator and the nature of substituents on the imines.
application of this building-block, the reaction of 1 with a
wide variety of imines was investigated by us, it was
found that the product distribution was dependent not only
on the reaction mediators but also the substituent pattern
on the imines.
Key words: nucleophilic addition, amino esters, bromodifluoro-
methylated acrylate, imines, gem-difluorinated
The difluoromethylene moiety (CF2) is a key subunit in
many fluorinated compounds of biological and pharma-
ceutical significance.2 It has been recognized as an isopo-
lar-isosteric substitute for oxygen and has been used in the
modification of some biologically active compounds.3
Fluorinated amino acids and their derivatives are an im-
portant class of non-natural compounds and have received
increasing interest from the fields of medicinal, agricul-
tural, and material sciences.4 Thus, in connection with our
work on the synthesis and bioactivity of fluorine-contain-
ing compounds,5 we were interested in the synthesis of
gem-difluorinated amino acids as new potent bioactive
compounds.
Since it was believed that the low electrophilicity of the
imines prepared from aromatic aldehydes and aromatic
amines could detrimentally affect the reaction, our initial
attempts were carried out with a sulfonimine, which is a
stronger electrophile than normal imines due to the strong
electron-withdrawing sulfonyl group.11 Under classical
Reformatsky reaction conditions, ethyl 3-bromodifluo-
romethyl-3-benzyloxyacrylate (1) smoothly reacted with
sulfonimines 2a–c in THF at 60 °C in the presence of zinc
powder. After three hours, the a-addition products (Refor-
matsky reaction type product), a-difluorovinyl substituted
b-amino esters 3a–c, were isolated exclusively in good
yield with the syn-diastereomer as the major product
(Scheme 1, Table 1, entry 1–3);12 no g-addition product
could be detected in the reaction mixture. The difluorovi-
nyl unit of the resulting b-amino ester is the key structure
of some fluoro-olefin derived enzyme inhibitors.13
Halogenodifluormethylated compounds are widely em-
ployed as the starting point for the construction of some
novel gem-difluorinated molecules.6,7 However, up to
now the reaction of b-halogenodifluoromethyl substituted
acrylates have only been reported independently by Kita-
zume and Hu;8 two fluorinated acrylates reacted with al-
dehydes in the presence of zinc to give the a-difluorovinyl
substituted b-hydroxy ester and the gem-difluorinated d-
hydroxy esters. Although their reaction with imines af-
forded intriguing fluorinated amino esters, this was not
further investigated by them, though it could be attributed
to the reduced electrophilicity of the imine9 compared
with carbonyl compounds resulting in the acrylates failing
to react with the imines.
R
R
NH
O
NH
O
R
OBn
Zn/THF
60 °C
N
α
Ar
OEt
OBn
γ
+
Ar
Ar
OEt
Br
CO2Et
+
β
F
F
F
F
OBn
F
F
1
2
anti-3
syn-3
Scheme 1
The stereochemical assignment was based on single-crys-
tal X-ray diffraction analysis of the major product ob-
tained from the reaction of acrylate 1 with imine 2b.
Although the syn/anti stereoselectivity was moderate,
these two diastereomers could be readily separated by
flash column chromatography. The reaction of acrylate 1
with imine 2d [PhCH=NC6F4(4-Cl)] gave the same a-cou-
pling product albeit in lower yield (Table 1, entry 4).
Previously,10 we found that ethyl 3-bromodifluoromethyl-
3-benzyloxyacrylate (1) could serve as an excellent mul-
tifunctional building-block for the convenient synthesis of
some CF2-containing substrates; the benzyl vinyl ether
SYNLETT 2006, No. 2, pp 0296–0300
0
1.
0
2.
2
0
0
6
Advanced online publication: 24.01.2006
DOI: 10.1055/s-2006-926225; Art ID: W06405ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nucleophilic Addition of Ethyl 3-Bromodifluoromethyl-3-benzyloxyacrylate to Imines
297
Table 2 Reaction of Ethyl 3-bromodifluoromethyl-3-benzyloxy-
acrylate 1 with Sulfonimines 2 Mediated by TDAE
Table 1 Reformatsky Reaction of Ethyl 3-Bromodifluoromethyl-3-
benzyloxylacrylate 1 with Imines 2
Entry Sulfonimine (2)
Time at r.t. (h) Productsa (%)
Entry Imine (2)
Time Product syn/antib
(h)
(%)a
1
2
3
4
5
6
2a Ar = Ph
9
4a (51), 5a (42)
4b (49), 5b (36)
4b (26), 5b (24)
4c (51), 5c (20)
4e (57), 5e (30)
4f (54), 5f (29)
1
2
2a Ar = Ph, R = Ts
3
3a (84)
3b (76)
61:23
42:34
2b Ar = 4-ClC6H4-
2b Ar = 4-ClC6H4-
2c Ar = 4-MeOC6H4-
2e Ar = 4-MeC6H4-
2f Ar = Furyl
4
2b Ar = 4-ClC6H4-,
3.5
3.5b
5
R = Ts
3
4
2c Ar = 4-MeOC6H4-,
R = Ts
3.5
2
3c (78)
3d (30)
48:30
7:23
4
2d Ar = Ph, R = 4-ClC6F4-
4
a Isolated overall yield.
a Yield determined by 19F NMR spectroscopy.
b THF as solvent instead of DMF.
b Based on the isolated yield.
Therefore, the 4-chlorotetrafluorophenyl has the same
character as sulfonyl, whose strong electron-withdrawing
power causes the corresponding imine to readily undergo
nucleophilic attack.
(Scheme 2) in acrylate 5 was assigned as trans. The yield
was dramatically diminished when the same reaction was
performed in THF (Table 2, entry 3) due to the low solu-
bility of the sulfonimine in THF.
Tetrakis(dimethylamino)ethylene (TDAE) is an excellent
electron donor, and it has the same reductive ability as
zinc.14 It was successfully utilized as a mediator instead of
zinc to promote the reaction of arylate 1 with sulfonimine
2. With a reaction time of one hour at –10 °C or four to
eight hours at ambient temperature in DMF, the g-additon
product, gem-difluorinated d-amino ester 4, was favored
over the a-addition product to predominantly give gem-
difluorinated d-amino esters 4 (Scheme 2).15 Meanwhile,
in situ formed b-amino esters 3 (a-addition product) lost
one molecule of p-toluenesulfonamide to give the novel
a-difluorovinyl substituted acrylate 5 as the minor prod-
uct under basic reaction conditions. Traces of the stereo-
isomer of acrylate 5 were obtained in some cases (Table 2,
entry 3–6); the olefinic proton signal appeared at higher
field than that of 5 in the 1H NMR spectrum. According to
the literature,16 when the olefinic proton was cis to the
ethoxy carbonyl group in trisubstituted alkenes such as
acrylate 5, its chemical shift should appear at lower field
than the trans configured olefin, thus, the 2,3-double bond
Our earlier concern with respect to the low electrophilicity
of imines prepared from aromatic aldehydes and primary
amines was relieved by the observation that in the pres-
ence of zinc powder imines 6 reacted with acrylate 1 in
THF at 60 °C. After five to six hours, the reaction was
quenched by the addition of a saturated aqueous solution
of NH4Cl, routine work-up followed by flash column
chromatography, and then separation furnished three
addition-cyclization products (7, 8, and 9) whose ratio
was dependent on the substituent pattern on the imines
(Scheme 3, Table 3).17
The reaction of imines 6a–c prepared from aromatic alde-
hydes and aromatic amines (except para-methoxybenzal-
dehyde and para-methoxyaniline) underwent a-coupling
and cyclization to produce trans-3-difluorovinyl sub-
stituted b-lactams 7a–c exclusively in good yield
(Table 3, entry 1–3). The trans configuration of lactam 7
was first confirmed by the 2–3 Hz vicinal coupling
H
O
Ts
Ar
2
Ts
NH OBn OEt
OBn
3
Ar
OEt
OBn
TDAE/DMF
–10 °C to r.t.
N
+
γ
α
+
Br
CO2Et
F
O
β
Ar
F
F
4
F
F
F
1
2
5
Scheme 2
O
R2
N
R2
O
R2
R1
OBn
α
β
R2
N
Zn/THF
60 °C
N
N
γ
+
+
R1
Br
CO2Et
F
+
CO2Et
R1
OBn
R1
F
F
F
F
F
F
F
6
1
BnO
8
7
9
Scheme 3
Synlett 2006, No. 2, 296–300 © Thieme Stuttgart · New York

298
W. Peng et al.
LETTER
Table 3 Reaction of Ethyl 3-Bromodifluoromethyl-3-benzyloxyacrylate 1 with Imines 6 Mediated by Zinc
Entry
Imine (6)
Products (%)a
b-Lactam
Azetidine
Pyridinone
1
6a R1 = Ph, R2 = Ph
7a (61)
7b (50)
7c (77)
7d (33)
7e (30)
7f (8)
2
6b R1 = 4-ClC6H4-, R2 = Ph
6c R1 = Ph, R2 = 4-ClC6H4-
6d R1 = 4-MeOC6H4-, R2 = Ph
6e R1 = Ph, R2 = 4-MeOC6H4-
6f R1 = Ph, R2 = Bn
3
4
9d (22)b
9e (20)
9f (36)
9g (66)
9h (37)
9i (34)b
9j (34)
9k (34)b
5
6
8f (17)
8g (17)
8h (10)
8i (19)
8j (19)
7
6g R1 = Furyl, R2 = Bn
8
6h R1 = trans-PhCH=CH-, R2 = Ph
6i R1 = 4-MeOC6H4-, R2 = Bn
6j R1 = 4-ClC6H4-, R2 = Bn
6k R1 = Furyl, R2 = Ph
9
10
11
a Isolated yield.
b The non-cyclized g-product was also obtained.
constants between the C-3 and C-4 proton on the cyclic Under the same reaction conditions, the reactions of imi-
lactam, which is attributed to a dihedral angle of almost nes 6f–j substituted by a non-aromatic substituent almost
90° between C-3 and C-4. This was further confirmed by completely underwent g-coupling followed by cycliza-
the single crystal X-ray diffraction analysis of lactam 7b. tion. However, besides the gem-difluorinated pyridinone
compound 9, a novel gem-difluorinated azetidine com-
Previous studies revealed that the active zinc species from
pound 8 was also obtained. The presence of an olefinic
acrylate 1 in THF exists as the g-carbon metallated form.10
proton signal at about 5.0 ppm in the 1H NMR spectrum
For the following reaction the energy level of transition
obviously indicates that this does not result from the a-
state B is lower than transition state A due to the bulky ef-
coupling reaction of acrylate 1 with imine, but in fact is
fect of the imine substituents (Figure 1), the reaction fol-
lowed the reaction pathway through transition state B to
give the corresponding anti-a-difluorovinyl substituted b-
amino ester, stereospecifically, which then underwent lac-
formed from the g-coupling reaction. Compound 8 was
further characterized as an azetidine because the ethoxy
group proton signals were still visible while, the benzyl-
oxy group proton signals are missing. The apparent ion
peak and the scission pattern in the mass spectrum strong-
ly support this structure. Due to the less demanding ring-
strain in aza-four-membered rings, the amino group of the
intermediate d-amino esters could also undergo intramo-
lecular Michael addition to the a,b-double bond, and then
elimination of benzyl alcohol gave azetidine 8. Based on
the NOSEY spectra of azetidine 8f which clearly exhibit-
ed the characteristic cross-peaks between the olefinic pro-
ton and the N-benzylic protons, the geometry of the
exocyclic double bond was assigned to be trans.18 These
first reported novel fluorinated four-membered aza-
heterocycles might represent a new class of b-amino acid
derivatives.
tamization to afford trans-b-lactam 7.
R1
H
EtO2C
R1
H
OBn
EtO2C
H
OBn
R2
ZnBr
N
N
versus
ZnBr
R2
H
F
F
F
F
B (quasi-axial)
A (quasi-equatorial)
Figure 1
In addition to b-lactams 7d and 7e, the reactions of imines
6d and 6e with acrylate 1 also provided the gem-difluori-
nated 5,6-dihydropyridin-2-ones 9d and 9e in comparable
yield (Table 3, entries 4, 5). Possibly due to the electron- In conclusion, the zinc- or TDAE-mediated reactions of b-
donating methoxy group, these two reactions gave not bromodifluoromethyl substituted acrylate 1 with diverse-
only the b-amino esters but the d-amino esters (g-cou- ly substituted imines were investigated, and some novel
pling) as intermediate products which also underwent gem-difluorinated amino esters and their derivatives were
lactamization to afford the 5,6-dihydropyridin-2-one obtained. It was found that the products and the product
compounds 9.
distribution were governed by the mediator and the nature
Synlett 2006, No. 2, 296–300 © Thieme Stuttgart · New York

LETTER
Nucleophilic Addition of Ethyl 3-Bromodifluoromethyl-3-benzyloxyacrylate to Imines
299
J = 8.7, 6.3 Hz), 5.82 (1 H, d, J = 8.7 Hz), 6.96–7.46 (13 H,
m). 19F NMR (282 MHz, CDCl3): d = –96.5 (1 F, d, J = 68.3
Hz), –110.9 (1 F, d, J = 68.3 Hz). MS: m/z (%) = 367 (1), 366
(1), 296 (5), 294 (14), 255 (1), 230 (1), 174 (2), 155 (14), 140
(1), 92 (8), 91 (100), 65(8), 51 (1). Anal. calcd for
of the substituents on the imines. A further study to ex-
plain the effect of mediator and substituent on the imine is
in progress and will be reported in due course.
C27H26ClF2NO5S: C, 58.96; H, 4.76; N, 2.55. Found: C,
58.99; H, 4.88; N, 2.54.
(13) Bey, P.; McCarthy, J. R.; McDonald, I. A. Selective
Fluorination, ACS Symposium Series 456, Chap. 8; Welch,
J. T., Ed.; American Chemical Society: Washington DC,
1991, 105–133.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (NNSFC) (No. 20372077 and 20532040) and Innovation
Foundation of Chinese Academy of Sciences for financial support.
(14) Wiberg, V. N. Angew. Chem., Int. Ed. Engl. 1968, 7, 766;
Angew. Chem. 1968, 80, 809.
References and Notes
(15) TDAE-Mediated Reaction of Acrylate 1 with Imines 2;
General Procedure To a solution of acrylate 1 (335 mg 1
mmol) and sulfonimine 2 (1 mmol) in anhyd DMF (4 mL)
cooled in an ice-salt bath under argon was added TDAE (239
mg, 0.29 mL, 1.2 mmol) dropwise via syringe over 0.5 h. A
red color developed immediately with the formation of a fine
white precipitate. The mixture was stirred vigorously for 1 h
under cooling and then warmed to r.t. When the reaction was
complete the orange red turbid solution was filtered and
quenched by the addition of a sat. aq solution of NH4Cl (8
mL). The mixture was extracted with EtOAc (3 × 20 mL),
and the combined organic extracts were washed with brine
(30 mL), dried (Na2SO4), and concentrated in vacuo to give
a residue, which was purified by flash chromatography (n-
hexane–EtOAc, 20:1→3:1) to give the expected d-amino
ester 4 and the novel difluorovinyl substituted acrylate 5 as
the by product. 4a White solid; mp 138–139 °C. IR (film):
3406, 3257, 2986, 1720, 1662, 1600, 1498, 1458, 1447,
1409, 1369, 1334, 1320, 1246, 1203, 1161, 1115, 1095,
1064, 1028, 929, 852, 816, 751, 698, 564 cm–1. 1H NMR
(300 MHz, CDCl3): d = 1.24 (3 H, t, J = 7.3 Hz), 2.31 (3 H,
s), 4.13 (2 H, q, J = 7.3 Hz), 4.96 (1 H, ddd, J = 12.6, 12.6,
10.2 Hz), 5.21 (2 H, AB system, J = 11.7 Hz), 5.56 (1 H, s),
5.64 (1 H, d, J = 10.2 Hz), 7.03–7.48 (14 H, m). 19F NMR
(282 MHz, CDCl3): d = –110.2. MS: m/z (%) = 486 (1, M+
– Et), 470 (1), 424 (2), 380 (9), 350 (7), 314 (2), 261 (5), 260
(32), 181 (3), 155 (16), 140 (2), 92 (8), 91 (100), 65 (6).
Anal. calcd for C27H27F2NO5S: C, 62.90; H, 5.28; N, 2.72.
Found: C, 62.97; H, 5.32; N, 2.81.
(1) Current address: Department of Medicinal Chemistry and
The Center for Protein Structure and Function, The
University of Kansas, 1251 Wescoe Hall Drive, Malott Hall
4070, Lawrence, KS 66045-7562, USA.
(2) (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(b) Burkholder, C. R.; Dolbier, W. R. Jr.; Medebielle, M. J.
Fluorine Chem. 2001, 109, 39.
(3) (a) Blackburn, G. M.; Jakeman, D. L.; Ivory, A. J.;
Williamson, M. P. Bioorg. Med. Chem. Lett. 1994, 4, 2573.
(b) Burke, T. R. Jr.; Smyth, M. S.; Otaka, A.; Nomizu, M.;
Roller, P. P.; Wolf, G.; Case, R.; Shoelson, S. E.
Biochemistry 1994, 33, 6490.
(4) (a) Enantiocontrolled Synthesis of Fluoro-organic
Compounds: Stereochemical Challenges and Biomedical
Targets; Soloshonok, V. A., Ed.; Wiley: Chichester, 1999.
(b) Fluorine-Containing Amino Acids: Synthesis and
Properties; Kukhar, V. P.; Soloshonok, V. A., Eds.; Wiley:
Chichester, 1995.
(5) (a) Wang, Y. L.; Zhu, S. Z. Org. Lett. 2003, 5, 745.
(b) Peng, W. M.; Zhu, S. Z. Synlett 2003, 187.
(6) (a) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561.
(b) Wilkinson, J. A. Chem. Rev. 1992, 92, 505.
(7) (a) Braum, M.; Vonderhagen, A.; Waldmueller, D. Liebigs
Ann. Chem. 1995, 1447. (b) Itoh, T.; Ohara, H.; Emoto, S.
Tetrahedron Lett. 1995, 36, 3531. (c) Watanabe, S.; Fujita,
T.; Sakamoto, M.; Takeda, H.; Kitazume, T.; Yamazaki, Y.
J. Fluorine Chem. 1997, 82, 1.
(8) (a) Tsukamoto, T.; Kitazume, T. Synlett 1992, 977. (b) Hu,
Q. S.; Hu, C. M. J. Fluorine Chem. 1997, 83, 87.
(9) Volkmann, R. A. Comprehensive Organic Synthesis, Vol. 1;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
355.
(16) Kinstle, T. H.; Mandanas, B. Y. Chem. Commun. 1968,
1699.
(17) The general procedure for zinc powder mediated reactions
was applied to imine 6. 7f Yellowish oil; Rf 0.2–0.3 (n-
hexane–EtOAc, 10:1). IR (film): 3064, 3032, 2923, 1763,
1496, 1455, 1398, 1361, 1282, 1137, 1084, 743, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.75 (1 H, d, J = 15.3 Hz),
3.85–3.88 (1 H, m), 4.42 (1 H, d, J = 3.0 Hz), 4.84–4.94 (3
H, m), 7.02–7.43 (15 H, m). 19F NMR (282 MHz, CDCl3):
d = –95.7 (1 F, d, J = 65.7 Hz), –109.8 (1 F, d, J = 65.7 Hz).
MS: m/z (%) = 405 (1), 380 (1), 350 (1), 333 (1), 315 (9), 314
(12), 273 (1), 253 (1), 194 (1), 181 (2), 162 (3), 140 (1), 131
(11), 106 (5), 91 (100), 77 (3), 65 (8), 51 (1). HRMS: m/z
calcd for C25H21F2NO2 (M+), 405.15404; found, 405.15897.
8f Yellowish oil; Rf 0.3–0.4 (n-hexane–EtOAc, 5:1). IR
(film): 3032, 2981, 2904, 1695, 1666, 1496, 1456, 1370,
1350, 1280, 1194, 1150, 1109, 1060, 699 cm–1. 1H NMR
(300 MHz, CDCl3): d = 1.26 (3 H, t J = 7.1 Hz), 4.10 (1 H,
d, J = 15.0 Hz), 4.17 (2 H, q, J = 7.1 Hz), 4.42 (1 H, d, J =
15.0 Hz), 4.85 (1 H, s), 5.09 (1 H, dd, J = 9.6, 3.9 Hz), 7.13–
7.43 (10 H, m). 19F NMR (282 MHz, CDCl3): d = –103.8 (1
F, dd, J = 216.3, 9.6 Hz), –114.0 (1 F, dd, J = 216.3, 3.9 Hz).
MS: m/z (%) = 343 (3), 314 (3), 298 (13), 271 (4), 250(72),
224 (2), 172 (2), 156 (2), 147 (3), 129 (7), 105 (6), 91 (100),
77 (3), 65 (11), 51 (2). Anal. calcd for C20H19F2NO2: C,
(10) Peng, W. M.; He, P.; Zhu, S. Z.; Li, Z. T. Tetrahedron Lett.
2004, 45, 3677.
(11) Lu, W. S.; Chan, T. H. J. Org. Chem. 2000, 65, 8589.
(12) Zinc Powder Mediated Reaction of Acrylate 1 with
Imines 2; General Procedure To a suspension of activated
zinc powder (100 mg, 1.5 mmol) and sulfonimine 2 (1
mmol) in THF (4 mL) was added acrylate 1 (335 mg, 1
mmol) dropwise over 5 minutes at 60 °C. The mixture was
stirred continuously at 60 °C for the time specified in
Table 1. The reaction was quenched by the addition of a sat.
aq solution of NH4Cl (5 mL) and extracted with Et2O (3 × 10
mL). The combined organic extracts were washed with brine
(30 mL), dried (Na2SO4), and the solvent was removed.
The residue was purified by chromatography on silica gel
(n-hexane–EtOAc, 3:1 or 5:1) to give a-difluorovinyl
substituted b-amino esters 3 as two diasteromers. syn-3b
White solid; mp 80–82 °C. IR (film): 3232, 3033, 2988,
1739, 1597, 1493, 1445, 1368, 1323, 1284, 1256, 1237,
1174, 1155, 1091, 1066, 1012, 961, 900, 813, 738, 724, 697,
673, 569, 542 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.22 (3
H, t, J = 7.2 Hz), 2.33 (3 H, s), 3.53–3.56 (1 H, m), 4.07–4.12
(2 H, m), 4.96 (2 H, AB system, J = 10.2 Hz), 5.17 (1 H, dd,
Synlett 2006, No. 2, 296–300 © Thieme Stuttgart · New York

300
W. Peng et al.
LETTER
69.96; H, 5.58; N, 4.08. Found: C, 70.14; H, 5.75; N, 3.83.
9f Yellowish heavy oil; Rf 0.3–0.4 (n-hexane–EtOAc, 3:1).
IR (film): 3461, 3064, 3032, 2922, 1711, 1665, 1632, 1496,
1452, 1431, 1396, 1365, 1238, 1199, 1138, 1096, 1063,
1029, 962, 849, 745, 701 cm–1. 1H NMR (300 MHz, CDCl3):
d = 3.49 (1 H, d, J = 15.3 Hz), 4.67 (1 H, dd, J = 16.5, 2.1
Hz), 4.98 (2 H, AB system, J = 12.0 Hz), 5.54–5.60 (2 H, m),
7.17–7.40 (15 H, m). 19F NMR (282 MHz, CDCl3): d = –89.1
(1 F, dd, J = 270.4, 16.5 Hz), –120.0 (1 F, dd, J = 270.4, 2.1
Hz). MS: m/z (%) = 405 (4), 386 (1), 314 (56), 288 (1), 250
(1), 226 (1), 196 (2), 174 (11), 140 (2), 118 (1), 106 (31), 92
(8), 91 (100), 79 (3), 77 (3), 65 (11), 51 (2). Anal. calcd for
C25H21F2NO2: C, 74.06; H, 5.22; N, 3.45. Found: C, 73.84;
H, 5.63; N, 3.21. HRMS: m/z calcd for C25H21F2NO2 (M+):
405.15404; found: 405.15448
(18) Karpov, A. S.; Muller, T. J. J. Synthesis 2003, 2815.
Synlett 2006, No. 2, 296–300 © Thieme Stuttgart · New York