Ethyl α-fluoro silyl enol ether: Stereoselective synthesis and its aldol reaction with aldehydes and ketones

Article abstract of DOI:10.1021/jo010820+

Ethyl α-fluoro silyl enol ether is stereoselectively synthesized in high yield from inexpensive chlorofluoroacetate and Mg (or Zn) in DMF (or HMPA). Lewis acid promoted aldol reaction of this enol ether with aldehydes and ketones gives α-fluoro-β-hydroxy

Full text of DOI:10.1021/jo010820+

J . Org. Chem. 2002, 67, 3231-3234
3231
Eth yl r-F lu or o Silyl En ol Eth er : Ster eoselective Syn th esis a n d Its
Ald ol Rea ction w ith Ald eh yd es a n d Keton es
Xiao-Ting Huang and Qing-Yun Chen*
Laboratory of Fluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, 200032, Shanghai, China
chenqy@pub.sioc.ac.cn
Received August 13, 2001
Ethyl R-fluoro silyl enol ether is stereoselectively synthesized in high yield from inexpensive
chlorofluoroacetate and Mg (or Zn) in DMF (or HMPA). Lewis acid promoted aldol reaction of this
enol ether with aldehydes and ketones gives R-fluoro-â-hydroxy esters in good to excellent yields.
Sch em e 1
In tr od u ction
The Mukaiyama aldol reaction is one of the most
important means for C-C bond formation. Silyl enol
ethers react with aldehydes in the presence of Lewis acids
to give â-hydroxy carboxylates. Recently, using chiral
catalysts, not only various enatioselective Mukaiyama1
and vinylogous Mukaiyama2 aldol reactions have been
developed but also asymmetric reactions of R,R-difluoro
silyl enol ethers (1) with carbonyl compounds have been
reported.3 The utilization of 1 was further demonstrated
in fluorinated sugars and amino acid syntheses.4 Com-
pared with difluoro derivatives (e.g., 1), surprisingly,
much less attention was paid on the synthesis and
stereochemistry of R-fluoro-substituted enolates or R-flu-
oro silyl enol ethers (2) and their uses. The only report
by Welch in 1984 was the stereoselective synthesis of
R-fluoro enolates, R-fluorosilyl enol, and their reactions
with aldehydes.5 However, the enolates were generated
from extremely poisonous ethyl fluoroacetates, and the
silyl enol ether formed from R-fluoroacetate was an E/ Z
mixture that was liable to decompose above 50 °C.
Therefore,it is very desirable to find a convenient,
economic method for stereoselective synthesis of silyl enol
ether. In this paper, we present the synthesis of E-
configured ethyl R-fluoro silyl enol ether from inexpensive
chlorofluoroacetate and its use in the direct aldol reac-
tion.
Resu lts a n d Discu ssion
1. Ster eoselective Syn th esis of Eth yl r-F lu or o
Silyl En ol Eth er . It is known that difluoro silyl enol
ethers (1) are readily prepared by successive treatment
of R-halo-R,R-difluoroacetates with activated zinc metal
and trialkylchlorosilane in THF and then applied to the
synthesis of some useful racemates including R,R-difluoro
â-hydroxy esters.3,6 However, when we treated ethyl
chlorofluoroacetate (3) under the similar conditions, no
expected product, ethyl R-fluoro silyl enol ether (5), was
obtained. But, interestingly, in DMF or HMPA, 5 was,
indeed, formed in high yield from 3 (Scheme 1). The
results are listed in Table 1.
It was noted from Table 1 that the solvent plays a very
important role in this reaction. Moreover, only E-config-
ured ethyl R-fluoro silyl enol ether 5 was obtained in high
yield with Zn/HMPA or Mg/DMF. The configuration of 5
was specified by 1H-NOESY. The alkenyl-H had an NOE
effect with the H of -SiMe3 but no NOE effect with the
H of -OCH2CH3.
TMS-OTf-P r om oted Aldol Reaction of Eth yl r-Flu -
or o Silyl En ol Eth er (5) w ith Ar om a tic Ald eh yd es
in CH2Cl2. R,R-Difluoro silyl enol ethers (1) show high
reactivity toward aldehydes. For example, 1 reacts with
benzaldehyde in the absence of Lewis acid in dichlo-
romethane at -78 °C to give aldol adducts in 20% yield,3b
while at 40 °C, in 82% yield. Unexpectedly, we found that
alkene 5 is very inert. From -78 °C to room temperature,
in CH2Cl2 or CH3CN, its aldol reaction with benzaldehyde
did not take place in the presence of nearly all kinds of
ordinary Lewis acids (such as SnCl4, TiCl4, AlCl3, BF3‚
OEt2, TMS-OTf, Cu(OTf)2, and ZnCl2, etc.). Fortunately,
when refluxed in CH2Cl2 and catalyzed by TMS-OTf, 5
(1) For general reviews, see: (a) Noyori, T. Asymmetric catalysis
via chiral complex: selected examples. Asymmetric Catalysis in
Organic Synthesis; J ohn Wiley: New York 1994; Chapter 4. (b)
Sawamura, M.; Ito, Y. Asymmetric aldol reactions. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York,
1993; Chapter 7.2.
(2) Bluet, G.; Campagne, J .-M. J . Org. Chem. 2001, 66, 4293.
(3) (a) Iseki, K.; Kuroki, Y.; Asada, D.; Kobayashi, Y. Tetrahedron
Lett. 1997, 38, 1447. (b) Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi,
M.; Kishimoto, S.; Kobayashi, Y. Tetrhedron 1997, 53, 10271.
(4) Kukhar, V. P., Soloshonok, V. A., Eds. Fluorine-containing Amino
Acids Synthesis and Properties; J ohn Wiley & Sons: New York, 1995.
(5) Welch, J . T.; Seper, K.; Eswarakrishman, S.; Samartino, J . J .
Org. Chem. 1984, 49, 4720.
(6) (a) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. Tetrahedron Lett.
1988, 29, 1803. (b) Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa, S.;
Hashimoto, A.; Iitaka, Y.; Kobayashi, Y. Tetrahedron Lett. 1988, 25,
5291. (c) Burton, D. J .; Easdon, J . C. J . Fluorine Chem. 1988, 38, 125.
(d) Kitagawa, O.; Hashimoto, A.; Kobayashi, Y.; Taguchi, T. Chem. Lett.
1990, 1307. (e) Britton; Thomas, C. US 5618951, 1997. (f) Uneyama,
K.; Mizutani, G.; Maeda, K., Kato, T. J . Org. Chem. 1999, 64, 6717.
10.1021/jo010820+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/18/2002

3232 J . Org. Chem., Vol. 67, No. 10, 2002
Huang and Chen
Ta ble 1. Ster eoselective Syn th esis of Eth yl r-F lu or o
Sch em e 3
Silyl En ol Eth er
time convnb yieldc
entry Ma solvent (v/v)
3/M/4 T (°C) (h)
(%)
(%)
1
2
3
4
5
Zn THF
Zn HMPA
Zn DMF
1:1.1:1.1
1:1.1:1.2
1:1.1:1.2
1:1.1:1.2
40
25
50
50
40
4
1.5
3
8
6
0
0
100 80
50
0
Zn CH3CN
0
Zn DMF/HMPA ) 1:1.1:1.2
50
3:1
6
7
Mg DMF
Mg DMF
1:8:16
1:1.1:1.3
25
25
3
5
100 82
100 trace
a
b
Zinc powder was activated; magnesium was untreated. The
conversion of 3. c Isolated yield of 5.
Ta ble 3. Cu Cl-Ca ta lyzed Ald ol Rea ction of Eth yl
r-F lu or o Silyl En ol Eth er a
Sch em e 2
7
time convnb
yieldsc
(%)
7d
entry R1R2CO
(h)
(%)
products
syn/anti
1
6m
6m
6n
6o
6p
6q
6r
10
10
8
7
8
100
100
100
100
100
100
100
7m
7m
7n
7o
7p
7q
7r
84
55
82
80
75
76
72
53:47
2e
3
62:38
48:52
56:44
/
4
5
6
7
7
8
44:56
a
5/CuCl ) 1:1.10. b The conversion was based on 5 by 19F NMR.
c Isolated yields 7 in addition to a trace of HCF2CO2Et. The ratio
d
was determined by 19F NMR. e The reaction was performed
without CuCl.
Ta ble 2. TMS-OTf-Ca ta lyzed Ald ol Rea ction of Eth yl
r-F lu or o Silyl En ol Eth er a
7
aldehydes [such as butanal (6n ), but-2-enal (6o)], and
even ketones [such as cyclohexanone (6q) and acetophen-
one (6r )].8
time convnb
yieldc
(%)
7
entry R1R2CO
(h)
(%)
products
syn/antid
1
2
3
4
5
6a
6b
6c
6d
6e
6f
4
4
4
4
4
4
5
5
4
5
5
4
5
5
100
100
100
100
100
100
100
100
100
100
100
100
70
7a
7b
7c
7d
7e
7f
7g
7h
7i
81
85
80
87
80
83
60
72
78
75
74
65
53:47
54:46
50:50
56:44
50:50
52:48
44:56
50:50
44:56
50:50
50:50
50:50
It is important to note that the solvent, HMPA, is
essential for this reaction, as its absence results in
failure. The addition of CuCl to the reaction mixture
improves the yields of the products. For example, in the
reaction of 6m with 5, the yield of 7m was 84% in the
presence of 110 mol % of CuCl, while only 55% in its
absence (Scheme 3). The results are listed in Table 3.
In conclusion, we present here a convenient method
for stereoselective synthesis of ethyl R-fluoro silyl enol
ether from unexpensive chlorofluoroacetate. The success-
ful Mukaiyama aldol reaction of ethyl R-fluoro silyl enol
ether gives R-fluoro â-hydroxy esters in good to excellent
yields. The study on the asymmetric aldol reaction of 5
with aldehydes or ketones is in progress.
6
7
8
9
6g
6h
6i
10
11
12
13
14
6j
6k
6l
6m
6n
7j
7k
7l
60
a
b
TMS-OTf was catalytic amount (2%). The conversion was
based on 5 by 19F NMR. c Isolated yields of 7 in addition to a trace
of HCF2CO2Et. The ratio was determined by 19F NMR.
d
did react with benzaldehydes to give the aldol adducts 7
in good yields (Scheme 2).7 The results are listed in Table
2.
The data in Table 2 show that 5 could react well with
electron-deficient aromatic aldehydes, but not so well
with electron-rich aromatic ones and not at all with
aliphatic aldehydes.
3. Cu Cl-P r om oted Ald ol Rea ction of Eth yl r-F lu -
or o Silyl En ol Eth er (5) w ith Electr on -Rich Ar o-
m a tic Ald eh yd es, Alip h a tic Ald eh yd es, a n d Keton es
in HMP A. After several attempts, it was found that with
HMPA as a solvent, CuCl can promote the aldol reaction
of 5 with electron-rich aromatic aldehydes [such as
4-MeOC6H4CHO (6m ), 4-Me2NC6H4CHO (6p )], aliphatic
Exp er im en ta l Section
1H NMR spectra were recorded with TMS as an internal
standard (positive for upfield). 19F NMR spectra were recorded
using CF3COOH as an external standard (positive for upfield).
The solvent for NMR measurement was CDCl3 or CD3COCD3.
Caution: HMPA is carcinogenic.
1. Ster eoselective Syn th esis of Eth yl r-F lu or o Silyl
En ol Eth er in HMP A. To a mixture of activated zinc dust
(14.3 g, 0.24 mol) and HMPA (80 mL), stirred at 25 °C, under
nitrogen, was added chlorotrimethylsilane (32 mL, 0.24 mol).
The mixture was stirred at 25 °C for 90 min and cooled to 5
°C. Ethyl chlorofluoroacetate (3) (28.0 g, 0.20 mol) was added
dropwise. The cooling bath was removed, and the reaction was
allowed to a temperature of 30-40 °C for 5 h and 50 °C for an
additional 1 h. 19F NMR showed the conversion of chlorofluo-
roacetate was 100%. After the mixture was cooled, the
precipitate was filtered off and the product was extracted with
ether. The combined ether layer was washed with water and
(7) Here we describe the products having the syn or anti configu-
ration according to ref 5; i.e., when two substituents, fluorine and
hydroxyl, are on the same side of the molecule plane in a zigzig main
chain, the molecule is denoted as having a syn relationship, whereas
on the opposite side of this plane it is denoted as possessing an anti
relationship.
(8) Ito, H.; Ishizuka, T.; Tateiwa, J .; Hosomi, A. Tetrahedron Lett.
1998, 39, 6295.

Ethyl R-Fluoro Silyl Enol Ether
J . Org. Chem., Vol. 67, No. 10, 2002 3233
1
dried over anhydrous Na2SO4. After the ether was removed,
the crude product was distilled under reduced pressure to give
5 as a colorless oil (28.4 g, yield 80%), bp 83-85 °C/37 mmHg.
Eth yl r-flu or o silyl en ol eth er (5) (E-con figu r a tion ):
colorless oil; IR (film) (cm-1) 2966, 1752, 1720, 1369, 1254,
1533, 1353, 1219, 1097, 724; H NMR δ 1.16 and 1.25 (t, J )
7.1 Hz, 3H), 2.90 (s, 1H), 4.19 (m, 2H), 5.19-5.61 (m, 2H),
7.66-8.35 (m, 4H); 19F NMR δ 117.7 (dd, J ) 50.1, 18.7 Hz,
0.5F), 123.6 (dd, J ) 47.8, 26.0 Hz, 0.5F); MS m/z (relative
intensity) 257 (M+, 0.09), 152 (58.09), 106 (100.00), 78 (76.41),
1
29 (8.61); HRMS calcd for
257.0735.
C11H12FNO5 257.0699, found
1203, 1051, 853; H NMR δ 0.18 (s, 9H), 1.28 (t, J ) 7.2 Hz,
3H), 4.23 (q, J ) 7.2 Hz, 2H), 4.95 (d, J ) 48 Hz, 1H); 19F
NMR δ 150.2 (d, J ) 48 Hz, 1F); MS m/z (relative intensity)
178 (M+, 5.73), 135 (17.96), 79 (26.43), 73 (100.00), 45 (16.43);
HRMS calcd for C7H15FO2Si 178.0825, found 178.0834.
2. Ster eoselective Syn th esis of Eth yl r-F lu or o Silyl
En ol Eth er in DMF . To a mixture of magnesium (3.9 g, 0.16
mol) and chlorotrimethylsilane (34.7 g, 0.32 mol) in distilled
DMF (200 mL), cooled to 0 °C, under nitrogen, was added 3
(2.8 g, 20 mmol) dropwise. Then the mixture was stirred for
an additional 6 h at 25 °C. After removal of the excessive
chlorotrifluorosilane in a vacuum and of the residue magne-
sium by decantation, the product was extracted with ether.
The combined ether layer was washed with ice-cold water and
then dried over Na2SO4. After the ether was removed, the
crude product was distilled under reduced pressure to give 5
as a colorless oil (2.9 g, 82%).
Eth yl 2-flu or o-3-h yd r oxy-3-(2-n itr op h en yl)p r op a n oa te
(7f): white solid; 83% yield; IR (KBr) (cm-1) 3466, 2999, 1743,
1
1525, 1378, 1345, 1217, 1060, 861, 794, 717; H NMR δ 1.17
and 1.28 (t, J ) 7.2 Hz, 3H), 2.11 and 3.28 (s, 1H), 4.14 and
4.26 (q, J ) 7.2 Hz, 2H), 5.25 (td, J ) 44.5, 3.0 Hz, 1H), 5.83
(m, 1H), 7.60-8.08 (m, 4H); 19F NMR δ 110.6 (dd, J ) 47.6,
16.0 Hz, 0.52F), 126.4 (dd, J ) 47.6, 25.8 Hz, 0.48F); MS m/z
(relative intensity) 239 (M+ - 18, 0.91), 152 (100.00), 134
(53.51), 104 (54.86), 78 (43.63), 29 (9.43); HRMS calcd for
C
11H10FNO4 239.0593, found 239.0590.
Eth yl 2-flu or o-3-h ydr oxy-3-(4-m eth ylph en yl)pr opan oate
(7g). colorless oil; 60% yield; IR (film) (cm-1) 3482, 2985, 1748,
1375, 1297, 1210, 1109, 1062, 820, 771; 1H NMR δ 1.18 (t, J )
7.1 Hz, 3H), 3.04 (s, 1H), 2.31 (s, 3H), 4.05 and 4.15 (q, J )
7.1 Hz, 2H), 5.05 (m, 2H), 7.13-7.35 (m, 4H); 19F NMR δ 117.6
(dd, J ) 50.0, 18.0 Hz, 0.44F), 122.5 (dd, J ) 47.5, 25.8 Hz,
0.56F); MS m/z (relative intensity) 226 (M+, 0.64), 209 (100.00),
165 (16.85), 121 (65.66), 105 (11.59), 93 (35.81); HRMS calcd
for C12H15FO3 226.1005, found 226.0962.
3. Gen er a l P r oced u r e for TMS-OTf-P r om oted Ald ol
Rea ction of Eth yl r-F lu or o Silyl En ol Eth er (5) w ith
Ald eh yd es in CH2Cl2. To a solution of 6a (212 mg, 2 mmol)
and TMS-OTf (8 µL) in dry CH2Cl2 (5 mL) at room temperature
was added 5 (356 mg, 2 mmol). The mixture was refluxed for
4 h. 19F NMR showed the conversion of 5 was 100%. The
product was extracted with ether and dried over Na2SO4. After
removal of the ether, the residue was subjected to column
chromatography, using petroleum ether and ethyl acetate (5:
1) as eluant, to give 7a as a colorless oil (339 mg, 81%).
Eth yl 2-flu or o-3-h yd r oxy-3-p h en ylp r op a n oa te (7a ):9
colorless oil; 81% yield; IR (film) (cm-1) 3474, 2986, 1747, 1376,
Eth yl 2-flu or o-3-h ydr oxy-3-(3-m eth ylph en yl)pr opan oate
(7h ): colorless oil; 72% yield; IR (film) (cm-1) 3483, 2985, 1749,
1376, 1301, 1217, 1110, 1062, 754, 715. 1H NMR δ 1.18 (t, J )
7.1 Hz, 3H), 1.96 and 3.06 (s, 1H), 2.32 (d, J ) 3.5 Hz, 3H),
4.05 and 4.16 (q, J ) 7.1 Hz, 2H), 5.09 (m, 2H), 7.10-7.28 (m,
4H); 19F NMR δ 117.2 (dd, J ) 50.2, 16.6 Hz, 0.5F), 122.5 (dd,
J ) 48.7, 15.9 Hz, 0.5F); MS m/z (relative intensity) 226 (M+,
1.24), 206 (7.07), 121 (100.00), 105 (12.50), 93 (79.44), 91
(48.66), 77 (27.11); HRMS calcd for C12H15FO3 226.1005, found
226.0976.
1
1301, 1214, 1106, 1028; H NMR δ 1.19 (t, J ) 7.1 Hz, 3H),
1.96 and 3.07 (s, 1H), 4.05 and 4.15 (q, J ) 7.0 Hz, 2H), 5.02-
5.18 (m, 2H), 7.29-7.48 (m, 5H); 19F NMR δ 117.4 (dd, J )
50.0, 19.5 Hz, 0.53F), 122.8 (dd, J ) 47.5, 24.8 Hz, 0.47F); MS
m/z (relative intensity) 213 (M+ + 1, 3.80), 212 (M+, 1.24), 195
(66.81), 151 (17.41), 123 (21.08), 107 (100.00), 91 (15.50), 79
(48.19).
Eth yl 2-flu or o-3-(4-flu or oph en yl)-3-h ydr oxypr opan oate
(7i):10 colorless oil; 78% yield; IR (film) (cm-1) 3473, 2987, 1747,
1
1607, 1513, 1376, 1306, 1224, 1099, 1062, 841, 782. H NMR
δ 1.21 (t, J ) 7.2 Hz, 3H), 2.86 (s, 1H), 4.18 (q, J ) 7.2 Hz,
2H), 5.00-5.18 (m, 2H), 7.12 (m, 2H), 7.50 (m, 2H); 19F NMR
δ 34.2 (m, 1F), 117.9 (dd, J ) 50.0, 18.5 Hz, 0.44F), 123.0 (dd,
J ) 47.9, 26.0 Hz, 0.56F); MS m/z (relative intensity) 230 (M+,
3.16), 210 (6.90), 125 (100.00), 109 (10.84), 97 (36.63).
Eth yl 3-(4-ch lor oph en yl)-2-flu or o-3-h ydr oxypr opan oate
(7j):11 colorless oil; 75% yield; IR (film) (cm-1) 3467, 2986, 1747,
1494, 1376, 1307, 1217, 1093, 833, 745; 1H NMR δ 1.22 (t, J )
7.1 Hz, 3H), 1.98 and 3.28 (s, 1H), 4.07 and 4.16 (t, J ) 7.1
Hz, 2H), 5.04-5.25 (m, 2H), 7.37-7.53 (m, 4H); 19F NMR δ
117.7 (dd, J ) 50.0, 19.0 Hz, 0.5F), 124.5 (dd, J ) 47.8, 26.0
Hz, 0.5F); MS m/z (relative intensity) 246 (M+, 3.59), 226 (6.55),
141 (100.00), 77 (32.84).
Eth yl 2-flu or o-3-h yd r oxy-3-(4-tr iflu or om eth ylp h en yl)-
p r op a n oa te (7b): white solid; 85% yield; IR (KBr) (cm-1
)
1
3461, 2990, 1751, 1338, 1131, 1116, 859. H NMR δ 1.16 and
1.22 (t, J ) 7.1 Hz, 3H), 2.84 (s, 1H), 4.18 (m, 2H), 5.12-5.41
(m, 2H), 7.69 (m, 4H); 19F NMR δ -19.3 (s, 3F), 117.2 (dd, J )
48.5, 19.0 Hz, 0.54F), 124.5 (dd, J ) 47.8, 26.1 Hz, 0.46F); MS
m/z (relative intensity) 281 (M+ + 1, 11.97), 263 (55.04), 219
(60.85), 191 (42.09), 175 (67.25), 127 (100.00), 106 (55.10), 78
(58.37); HRMS calcd for C12H10F4O2 262.0616, found 262.0600.
Eth yl 2-flu or o-3-h yd r oxy-3-(3-tr iflu or om eth ylp h en yl)-
p r op a n oa te (7c): colorless oil; 80% yield; IR (film) (cm-1
)
Eth yl 3-(4-br om oph en yl)-2-flu or o-3-h ydr oxypr opan oate
1
3480, 2989, 1749, 1331, 1168, 1127, 1075, 807, 703; H NMR
δ 1.15 and 1.20 (t, J ) 7.1 Hz, 3H), 1.96 and 3.04 (s, 1H), 4.04-
4.21 (m, 2H), 5.15-5.30 (m, 2H), 7.57-7.85 (m, 4H); 19F NMR
δ -19.2 (s, 3F), 117.3 (dd, J ) 46.8, 20.0 Hz, 0.5F), 124.5 (dd,
J ) 47.4, 26.0 Hz, 0.5F); MS m/z (relative intensity) 281 (M+
+ 1, 22.72), 263 (94.21), 219 (100.00), 191 (52.69), 171 (43.84),
127 (59.26); HRMS calcd for C12H12F4O3 280.0722, found
280.0683.
(7k ): colorless oil; 74% yield; IR (film) (cm-1) 3456, 2990, 1754,
1
1217, 1205, 1099, 1011, 735. H NMR δ 1.12 and 1.22 (t, J )
7.1 Hz, 3H), 3.27 (s, 1H), 4.17 (q, J ) 7.1 Hz, 2H), 5.04-5.24
(m, 2H), 7.37-7.57 (m, 4H); 19F NMR δ 117.6 (dd, J ) 48.9,
19.0 Hz, 0.5F), 123.7 (dd, J ) 47.0, 16.0 Hz, 0.5F); MS m/z
(relative intensity) 290 (M+, 4.58), 272 (5.60), 187 (91.57), 185
(100.00), 157 (15.59), 106 (17.37), 78 (38.16); HRMS calcd for
C
11H12BrFO3 289.9953, found 289.9969.
Eth yl 2-flu or o-3-h yd r oxy-3-(4-n itr op h en yl)p r op a n oa te
(7d ): colorless oil; 87% yield; IR (film) (cm-1) 3502, 2987, 1759,
1608, 1524, 1350, 1217, 1108, 1015, 857, 724; 1H NMR δ 1.16
and 1.24 (t, J ) 7.1 Hz, 3H), 2.05 and 3.10 (s, 1H), 4.16 (m,
2H), 5.17-5.36 (m, 2H), 7.72-8.26 (m, 4H); 19F NMR δ 116.7
(dd, J ) 47.9, 19.5 Hz, 0.56F), 124.9 (dd, J ) 47.7, 26.1 Hz,
0.44F); MS m/z (relative intensity) 258 (M+ + 1, 5.18), 240
(5.16), 152 (63.67), 106 (100.00), 78 (89.71), 43 (52.33); HRMS
calcd for C11H10FNO4 239.0593, found 239.0587.
Eth yl 2-flu or o-3-h yd r oxy-3-(3-h yd r oxyp h en yl)p r op a n -
oa te (7l): colorless oil; 65% yield; IR (film) (cm-1): 3402, 2987,
1741, 1594, 1459, 1377, 1226, 1110, 1058, 1021, 861, 769, 721,
698; 1H NMR δ 1.20 (t, J ) 7.1 Hz, 3H), 2.10 and 3.35 (s, 2H),
4.19 (q, J ) 7.1 Hz, 2H), 4.98-5.18 (m, 2H), 6.75-7.20 (m,
4H); 19F NMR δ 117.1 (dd, J ) 47.8, 21.5 Hz, 0.5F), 122.3 (dd,
J ) 48.0, 24.1 Hz, 0.5F); MS m/z (relative intensity) 228 (M+,
18.87), 123 (100.00), 95 (75.59), 77 (25.66), 43 (45.03); HRMS
calcd for C11H13FO4 228.0797, found 228.0806.
Eth yl 2-flu or o-3-h yd r oxy-3-(3-n itr op h en yl)p r op a n oa te
Cu Cl-P r om oted Ald ol Rea ction of Eth yl r-F lu or o Silyl
En ol Eth er in HMP A. To a flask, with CuCl (110 mg, 1.11
(7e): colorless oil; 80% yield; IR (film) (cm-1) 3485, 2987, 1748,
(9) Mcbee, E. T.; Pierce, O. R.; Christman, D. L. J . Am. Chem. Soc.
1955, 77, 1981.
(10) Shen, Y.-C.; Qi, M. J . Chem. Res. 1993, 223.
(11) Elkik, E.; Francesh, C. Bull. Soc. Chim. Fr. 1973, 1281.

3234 J . Org. Chem., Vol. 67, No. 10, 2002
Huang and Chen
mmol) dissolved in 1 mL of anhydrous HMPA, were added 5
(178 mg, 1 mmol) and 6m (136 mg, 1 mmol) under nitrogen
protection. Then the mixture was stirred at 50 °C for 10 h.
19F NMR showed the conversion of 5 was 100%. The product
was extracted with ether and dried over Na2SO4. After the
removal of the ether, the residue was subjected to column
chromatography, using petroleum ether and ethyl acetate (5:
1) as eluant, to give 7m as a colorless oil (205 mg, 84%).
Eth yl 2-flu or o-3-h yd r oxy-3-(4-m eth oxyp h en yl)p r op a n -
oa te (7m ): colorless oil; 84% yield; IR (film) (cm-1) 3477, 2985,
Eth yl 4-(4-d im eth yla m in op h en yl)-2-flu or o-3-h yd r oxy-
p r op a n oa te (7p ): colorless oil; 75% yield; IR (film) (cm-1
)
3480, 2984, 2896, 1749, 1616, 1526, 1351, 1220, 1060, 947, 821,
1
757; H NMR δ 1.20 (t, J ) 7.1 Hz, 3H), 2.91 (s, 6H), 3.25 (s,
1H), 4.13 (q, J ) 7.0 Hz, 2H), 4.87-5.13 (m, 2H), 6.71 (m, 2H),
7.24 (m, 2H); 19F NMR δ 117.7 (dd, J ) 48.8, 20.0 Hz, 0.56F),
120.2 (dd, J ) 49.1, 23.0 Hz, 0.44F); MS m/z (relative intensity)
255 (M+, 9.90), 237 (0.91), 150 (100.00), 148 (13.83), 122
(14.27), 107 (10.32); HRMS calcd for C13H16FNO2 237.1165,
found 237.1167.
1
Eth yl flu or o-1-(h yd r oxycycloh exyl)a ceta te (7q):9 color-
less oil; 76% yield; IR (film) (cm-1) 3521, 2939, 1745, 1450,
1375, 1304, 1211, 1095, 1033, 858; 1H NMR δ 1.26 (t, J ) 7.1
Hz, 3H), 1.48-1.73 (m, 10H), 3.23 (s, 1H), 4.22 (q, J ) 7.1 Hz,
2H), 4.70 (d, J ) 48.4 Hz, 1H); 19F NMR δ 117.6 (d, J ) 48.5
Hz, 1F); MS m/z (relative intensity) 204 (M+, 3.12), 185 (10.60),
171 (45.96), 143 (45.99), 91 (89.17), 57 (100.00), 55 (74.32), 43
(59.61), 41 (60.91). Anal. Calcd for C10H17FO3: C, 58.81; H,
8.39; F, 9.30. Found: C, 58.68; H, 8.38; F, 9.23.
1747, 1614, 1516, 1252, 1105, 1031, 836, 776. H NMR δ 1.21
(t, J ) 7.3 Hz, 3H), 3.26 (s, 1H), 3.77 (s, 3H), 4.14 (q, J ) 7.2
Hz, 2H), 4.92-5.16 (m, 2H), 6.89 (m, 2H), 7.35 (m, 2H); 19F
NMR δ 117.9 (dd, J ) 50.2, 18.5 Hz, 0.53F), 121.6 (dd, J )
46.7, 24.5 Hz, 0.47F); MS m/z (relative intensity) 242 (M+,
6.82), 225 (100.00), 197 (3.58), 137 (26.55), 109 (9.65); HRMS
calcd for C12H15FO4 242.0954, found 242.0947.
Eth yl 2-flu or o-3-h yd r oxyh exa n oa te (7n ): colorless oil;
82% yield; IR (film) (cm-1) 3455, 2964, 1745, 1376, 1299, 1214,
1073, 1029, 856; 1H NMR δ 0.91 (t, J ) 7.0 Hz, 3H), 1.26 (t, J
) 7.1 Hz, 3H), 1.37-1.58 (m, 4H), 2.89 (s, 1H), 3.98 (m, 1H),
4.20 (m, 2H), 4.81 and 4.98 (t and d, J ) 1.8 and 3.4 Hz, 1H);
19F NMR δ 118.7 (dd, J ) 49.5, 21.0 Hz, 0.62F), 127.0 (dd, J
) 48.0, 26.2 Hz, 0.38F); MS m/z (relative intensity) 179 (M+
+ 1, 2.42), 178 (M+, 0.02), 161 (3.14), 107 (24.99), 106 (60.43),
78 (100.00), 55 (51.85), 43 (38.19). Anal. Calcd for C8H15FO3:
C, 53.92; H, 8.48; F, 10.66. Found: C, 53.76; H, 8.70; F, 10.80.
Eth yl 2-flu or o-3-h yd r oxy-4(E)-h exen oa te (7o): colorless
oil; 80% yield; IR (film) (cm-1) 3481, 2985, 1756, 1376, 1297,
1212, 1081, 1028, 969; 1H NMR δ 1.26 (t, J ) 7.2 Hz, 3H),
1.66 (m, 3H), 3.21 (s, 1H), 4.19 (q, J ) 7.1 Hz, 2H), 4.40 (m,
1H), 4.87 (ddd, J ) 48.0, 20.8, 3.5 Hz, 1H), 5.58 (m, 1H), 5.72
(m, 1H); 19F NMR δ 120.1 (dd, J ) 50.0, 21.9 Hz, 0.48F), 123.6
(dd, J ) 48.0, 23.9 Hz, 0.52F); MS m/z (relative intensity) 159
(M+ - 17, 3.03), 78 (24.30), 71 (100.00), 69 (16.22), 53 (11.44),
43 (22.80), 41 (20.55); HRMS calcd for C8H11FO2 158.0743,
found 158.0755.
Eth yl 2-flu or o-3-h yd r oxy-3-p h en ylbu ta n oa te (7r ):5 col-
orless oil; 72% yield; IR (film) (cm-1) 3501, 2987, 1749, 1449,
1
1376, 1304, 1209, 1091, 1028, 764, 701; H NMR δ 0.99 and
1.08 (t, J ) 7.1 Hz, 3H), 3.27 (s, 1H), 3.99 and 4.07 (q, J ) 7.1
Hz, 2H), 5.08 (dd, J ) 47.9, 7.2 Hz, 1H), 7.24-7.57 (m, 5H);
19F NMR δ 110.6 (d, J ) 47.9 Hz, 0.44F), 113.2 (d, J ) 48.0
Hz, 0.56F); MS m/z (relative intensity) 209 (M+ - 17, 2.22),
121 (100.00), 105 (17.75), 77 (10.51), 43 (53.33).
Ack n ow led gm en t. We thank the Natural Science
Foundation of China for support of this work.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and 19F
NMR spectra of 5, 7a ,b,e,g,i,n ,q,r . This material is available
free of charge via the Internet at http://pubs.acs.org.
J O010820+