N-fluoro-3-cyclohexyl-3-methyl-2,3-dihydrobenzo[1,2-d]isothiazole 1,1- dioxide: An efficient agent for electrophilic asymmetric fluorination of enolates

Full text of DOI:10.1021/jo9904011

5708
J . Org. Chem. 1999, 64, 5708-5711
N-F lu or o-3-cycloh exyl-3-m eth yl-2,3-
d ih yd r oben zo[1,2-d ]isoth ia zole 1,1-Dioxid e:
An Efficien t Agen t for Electr op h ilic
Asym m etr ic F lu or in a tion of En ola tes
Yoshio Takeuchi,* Takanori Suzuki, Akira Satoh,
Tomoki Shiragami, and Norio Shibata
F igu r e 1.
Faculty of Pharmaceutical Sciences, Toyama Medical and
Pharmaceutical University, Sugitani 2630,
Toyama 930-0194, J apan
Sch em e 1a
Received March 4, 1999
Electrophilic fluorination of enolates with N-F-type
reagents is a versatile method to directly replace hydro-
gen with fluorine at a specific site.1-5 Examples of
diastereoselective fluorination of chiral substrates using
achiral N-F agents have led to substrate-controlled
syntheses of chiral fluorinated compounds.6 However,
there are few successful methods for agent-controlled
enantioselective fluorination of achiral ketones, a process
that would offer many advantages over existing methods
for the enantioselective preparation of chiral monofluoro
organic compounds.7 A pioneering study for the agent-
controlled asymmetric fluorination was demonstrated by
Lang in 1988.8 In the fluorination of â-ketoester enolates
with N-fluorocamphorsultam 1 (Figure 1), ee reached
70%. The enantioselectivity was improved up to 75% for
the fluorination of 2-methyl-1-tetralone by the use of
N-fluoro-3,3-dichlorocamphorsultam 2.9 The conveniently
accessible agent 310 we recently reported was neither
a
Key: (a) c-C6H11MgBr, THF (70%); (b) (-)-menthoxyacetyl
chloride, NaH, THF (73%); (c) separation; (d) 2 N LiOH, aqueous
THF (93-96%); (e) 15% F2/He, spray-dried KF, CHCl3/CFCl3 (51-
65%).
sufficiently reactive toward carbanions nor stable enough
under usual conditions to be generally useful. In this
paper, we describe a simple synthesis of enantiomeric
N-fluoro-3-cyclohexyl-3-methyl-2,3-dihydrobenzo[1,2-d]-
isothiazole 1,1-dioxide (CMIT-F, 4), an agent that effects
asymmetric fluorinations of ketone metal enolates to
furnish optically active R-fluoroketones 5 with enantio-
selectivity reaching 88% ee.
* To whom correspondence should be sent. Phone: (81) 764-34-2281.
Fax: (81)-764-34-5053. E-mail: takeuchi@ms.toyama-mpu.ac.jp
(1) (a) Furin, G. In New Fluorinating Agents in Organic Synthesis;
German, L., Zemskov, S., Eds.; Springer-Verlag: Berlin, 1989; pp 35-
68. (b) Furin, G. G. Sov. Sci. Rev. B. Chem. 1991, 16, 1-140. (c)
Purrington, S. T.; Kagen, B. S.; Patrick, T. B. Chem. Rev. 1986, 86,
997-1018. (d) Singh, S.; DesMarteau, D. D.; Zuberi, S. S.; Witz, M.;
Huang, H.-N. J . Am. Chem. Soc. 1987, 109, 7194-7196. (e) Differding,
E.; Lang, R. W. Helv. Chim. Acta 1989, 72, 1248-1252. (f) Differding,
E.; Ofner, H. Synlett. 1991, 187-189. (g) Davis, F. A.; Zhou, P.;
Murphy, C. K. Tetrahedron Lett. 1993, 34, 3971-3974. (h) Davis, F.
A.; Han, W.; Murphy, C. K. J . Org. Chem. 1995, 60, 4730-4737. (i)
Cabrera, I.; Appel, W. K. Tetrahedron 1995, 51, 10205-10208.
(2) (a) Barnette,W. E. J . Am. Chem. Soc. 1984, 106, 452-454. (b)
Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Toh, H. T. J . Chem.
Soc., Perkin Trans. 1 1974, 732-738.
(3) (a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.;
Syvret, R. G. J . Chem. Soc. Chem. Commun. 1992, 595-596. (b) Abdul-
Ghani, M.; Banks, R. E.; Besheesh, M. K.; Sharif, I.; Syvret, R. G. J .
Fluorine Chem. 1995, 73, 255-257. (c) Lal, G. S.; Pez, G. P.; Syvret,
R. G. Chem. Rev. 1996, 96, 1737-1755.
(4) (a) Umemoto, T. Rev. Heteroatom Chem. 1994, 10, 123-154. (b)
Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.;
Tomita, K. J . Am. Chem. Soc. 1990, 112, 8563-8575.
(5) (a) Biomedical Aspects of Fluorine Chemistry; Filler, R., Koba-
yashi, Y., Eds.; Elsevier Biomedical Press: New York, 1982. (b) Welch,
J . T. Tetrahedron 1987, 43, 3123-3197.
(6) (a) Welch, J . T.; Seper, K. W. J . Org. Chem. 1988, 53, 2991-
2999. (b) Ihara, M.; Kai, T.; Taniguchi, N.; Fukumoto, K. J . Chem.
Soc., Perkin Trans. 1 1990, 2357-2358. (c) Davis, F. A.; Han, W.
Tetrahedron Lett. 1992, 33, 1153-1156. (d) Davis, F. A.; Reddy, R. E.
Tetrahedron: Asymmetry 1994, 5, 955-960. (e) Genet, J .-P.; Durand,
J .-O.; Roland, S.; Savignac, M.; J ung, F. Tetrahedron Lett. 1997, 38,
69-72. (f) Enders, D.; Potthoff, M.; Raabe, G.; Runsink, J . Angew.
Chem., Int. Ed. Engl. 1997, 36, 2362-2364. (g) McAtee, J . J .; Schinazi,
R. F.; Liotta, D. C. J . Org. Chem. 1988, 53, 2161-2167. (h) Davis, F.
A.; Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135-6138.
(7) Bravo, P.; Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661-
692.
The structure of CMIT-F (4) was designed to produce
a stable but reactive N-F bond and also to include steric
factors that will favor asymmetric induction. In particu-
lar, the planarity present in the 2,3-dihydrobenzo[1,2-d]-
isothiazole system seemed likely to strongly effect ster-
eochemical orientation in an ordered transition state.
This is important since no stereochemical bias can be
expected in the transfer of the small fluorine atom. An
important additional consideration is the fact that struc-
tural variations in these stereocontrolling groups are easy
to introduce because of our synthetic design. The prepa-
ration of 4 was accomplished in good yield in five steps
using a modification of the procedure reported1e (Scheme
1). The imine 6, which was prepared from saccharin by
Oppolzer’s method,11 was subjected to alkylation with
cyclohexylmagnesium bromide to give 7 in 70% yield.
Optical resolution of 7 was carried out by derivatization
with (-)-menthoxyacetyl chloride followed by separation
of the diastereomers (3R)-8 and (3S)-8 using column
chromatography on silica gel.12 Removal of the chiral
auxiliary of (3R)-8 and (3S)-8 was achieved smoothly with
(9) (a) Davis, F. A.; Han, W. Tetrahedron Lett. 1991, 32, 1631-1634.
(b) Davis, F. A.; Zhou, P.; Murphy, C. K.; Sundarababu, G.; Qi, H.;
Han, W.; Przeslawski, R. M.; Chen, B.-C.; Carroll, P. J . J . Org. Chem.
1998, 63, 2273-2280.
(10) Takeuchi, Y.; Satoh, A.; Suzuki, T.; Kameda, A.; Dohrin, M.;
Satoh, T.; Koizumi, T.; Kirk, K. L. Chem. Pharm. Bull. 1997, 45, 1085-
1088.
(8) Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 6087-
6090.
(11) Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G.
Tetrahedron Lett. 1990, 31, 4117-4120.
10.1021/jo9904011 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/07/1999

Notes
J . Org. Chem., Vol. 64, No. 15, 1999 5709
Ta ble 1. En a n tioselective F lu or in a tion of Keton es 9 w ith 4a
LiOH in aqueous THF13 to furnish (R)-7 and (S)-7 in an
optically pure state, respectively. Finally, fluorination of
(R)-7 and (S)-7 in CHCl3/CFCl3 with 15% F2/He14 in the
presence of spray-dried KF15 as an HF scavenger afforded
(R)-4 and (S)-4 as a stable, colorless crystalline solid,
purified by silica gel column chromatography followed by
recrystallization.16 The absolute stereochemistry of (R)-4
was determined through X-ray crystallographic analysis
of the N-camphorsulfonyl derivative of (R)-7.17
F igu r e 2. Possible transition-state model for the fluorination
of the lithium enolate of 9a with (R)-4.
Results of the fluorination of enolates with chiral 4 are
summarized in Table 1. Fluorination of the lithium
enolate of 2-methyl-1-tetralone (9a ) with (R)-4 in THF
furnished (S)-2-fluoro-2-methyl-1-tetralone (5a ) in 67%
yield with 74% ee, after the usual workup (entry 1). The
absolute stereochemistry of 5a was determined by com-
parison of the specific rotation with that reported by
Davis for the same compound.9 Fluorination with 4 in
the presence of HMPA resulted in a lower ee (entry 2),
an observation that has mechanistic implications (see
below). Similar fluorinations of other ketones, including
1-tetralones, 1-indanones, and 1-benzosuberones, with 4
were examined, and the corresponding optically active
R-fluoroketones 5 were obtained (entries 3-10).
Sch em e 2
yield with 66% ee, according to the similar method for
preparation of (S)-5a (Scheme 2).9 The absolute stereo-
chemistry of the other products was tentatively assigned
using the CD octant rule.19
For the determination of absolute stereochemistry of
5d , an alternative preparation was attempted, by treat-
ment of (S)-2-hydroxy-2-methyl-1-indanone (10, 73% ee)18
with DAST in CH2Cl2 at -78 °C, to give (R)-5d in 72%
On the basis of the X-ray crystallographic structure of
4 reported in a previous communication,17 the working
model for the S selectivity in the fluorination of 9a with
(R)-4 is shown in Figure 2. The nitrogen atom of 4 is
found to be highly pyramidalized, and the fluorine is
almost antiperiplanar with the bulky cyclohexyl group.
The chelation structure of lithium enolate of 9a in THF
solution is strongly indicated by the fact that addition of
HMPA resulted in lowering the enantioselectivity (Table
1, entry 2).
(12) Reaction of (()-7 with (+)-camphorsulfonyl chloride [see, ref
17] was difficult to carry to completion when carried out on a large
scale. For large scale optical resolution, condensation of (()-7 with (-)-
menthoxyacetyl chloride as a chiral auxiliary was much more effective.
Each diastereomer obtained was separated easily by column chroma-
tography on silica gel and subsequent hydrolysis with LiOH furnished
(R)-7 and (S)-7 in good yield.
(13) Oppolzer, W.; Kingma, A. J .; Pillai, S. K. Tetrahedron Lett. 1991,
32, 4893-4896.
(14) (a) Barton, D. H. R.; Hesse, R. H.; Markwell, R. E.; Pechet, M.
M. J . Am. Chem. Soc. 1976, 98, 3034-3035. (b) Barton, D. H. R.; Hesse,
R. H.; Markwell, R. E.; Pechet, M. M.; Rozen, S. Ibid. 1976, 98, 3036-
3037.
Advances in techniques of asymmetric syntheses have
resulted in the development of methodologies that give
complete enantioselection (>99% ee),20 a standard of
selectivity that is consonant with the requirements of
modern synthetic chemistry. Nonetheless, since the
previous maximum ee for asymmetric fluorinations was
(15) Ishikawa, N.; Kitazume, T.; Yamazaki, T.; Mochida, Y.; Tatsuno,
T. Chem. Lett. 1981, 761-764.
(16) (R)-4: mp 126-127 °C (CH2Cl2/hexane); [R]26 +48.0° (c 0.95,
D
CHCl3). (S)-4: mp 124-127 °C (CH2Cl2/hexane); [R]29 -49.2° (c 1.05,
D
CHCl3).
(19) (a) Lowe, G.; Potter, B. V. L. J . Chem. Soc., Perkin Trans. 1
1980, 2029-2032. (b) Kirk, D. N. Tetrahedron 1986, 42, 777-818.
(20) Chiral Auxiliaries and Ligands in Asymmetric Synthesis;
Seyden-Penne, J ., Ed.; J ohn Wiley & Sons: 1995. Asymmetric Catalysis
in Organic Synthesis; Noyori, R., Ed.; J ohn Wiley & Sons: 1994.
(17) Kakuda, H.; Suzuki, T.; Takeuchi, Y.; Shiro, M. Chem. Commun.
1997, 85-86.
(18) Masui, M.; Ando, A.; Shioiri, T. Tetrahedron Lett. 1988, 29,
2835-2838.

5710 J . Org. Chem., Vol. 64, No. 15, 1999
Notes
isomer (3S)-8: [R]27 -23.5 ° (c ) 1.37, CHCl3); IR (neat) 2933,
75%, in a reaction that proceeded in low chemical yield,
CMIT-F (4), with ee as high as 88%, represents a signif-
icant advance in agent-controlled asymmetric fluorina-
tion. Further structural modifications of 4 are currently
under investigation with the goal of achieving the
synthesis of optically pure R-fluoroketones.
D
1718, 1320, 1216 cm-1; 1H NMR (300 MHz) δ 0.28 (qd, J ) 12.6,
3 Hz, 1H, CHHCH2), 0.82 (d, J ) 6.6 Hz, 3H, MeCH), 0.85-
1.43, 1.55-1.87, 1.94-2.19 (each m, total 17H, CHHCH2, >CH-,
CH2, c-Hex), 0.93 (d, J ) 7.1 Hz, 6H, Me2CH), 1.97 (s, 3H, MeC),
2.37 (heptet d, J ) 7.1, 3 Hz, 1H, CHMe2), 2.75 (m, 1H, >CH-),
3.25 (td, J ) 10, 4 Hz, 1H, >CHO), 4.77 (s, 2H, OCH2O), 7.47
(d, J ) 7.7 Hz, 1H, ArH), 7.60 (t, J ) 7.7 Hz, 1H, ArH), 7.71 (t,
J ) 7.7 Hz, 1H, ArH), 7.79 (d, J ) 7.7 Hz, 1H, ArH); HRMS
calcd for C26H39NO4S 461.2600, found 461.2596. Anal. Calcd for
Exp er im en ta l Section
C
26H39NO4S: C, 67.64; H, 8.51; N, 3.03. Found: C, 67.83; H,
Gen er a l In for m a tion . Melting points were determined on
8.62; N, 2.87.
a Yanagimoto micro-melting-point apparatus and uncollected.
(3R)-3-Cycloh exyl-3-m eth yl-2,3-dih ydr oben zo[1,2-d]isoth i-
a zole 1,1-Dioxid e [(R)-7]. A solution of (3R)-8 (1.56 g, 3.40
mmol) in THF (25 mL) was treated with 2 N LiOH (25 mL),
and the resulting mixture was stirred for 3 h. The mixture was
extracted with CH2Cl2 (500 mL). The organic layer was washed
with saturated NaHCO3 (100 mL) and brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified
by recrystallization (AcOEt/hexane) to give (R)-7 (832 mg, 93%)
as colorless crystals. The product exhibited the same spectro-
scopic properties (NMR, IR and MS) as racemic 7: [R]29D +29.47°
(c ) 0.97, CHCl3); mp 221 °C (AcOEt/hexane).
IR spectra (cm-1) were recorded on
a Perkin-Elmer 1600
spectrometer. 1H NMR spectra were measured as solutions in
CDCl3, and chemical shifts are expressed in ppm relative to
internal Me4Si (0.00 ppm) and were recorded on a J EOL GX-
270 (270 MHz) or a Varian Gemini 300 (300 MHz) spectrometer.
19F NMR spectra were measured with CFCl3 as an internal
standard and were taken with a J EOL GX-270 (254 MHz)
spectrometer. Upfield shifts are quoted as negative δ values. EI
mass spectra were taken with a J EOL J MS-D300 spectrometer.
Column chromatography and preparative TLC were performed
on BW-200 (Fuji Silysia) and Kieselgel 60 (Merck, art. 7748),
respectively. All reactions involving oxygen- or moisture-sensi-
tive compounds were carried out under a dry N2 atmosphere.
Unless otherwise noted, reagents were added by syringe. THF
was distilled from sodium/benzophenone immediately prior to
use.
(3S)-3-Cycloh exyl-3-m eth yl-2,3-dih ydr oben zo[1,2-d]isoth i-
a zole 1,1-Dioxid e [(S)-7]. A solution of (3S)-8 (1.52 g, 3.30
mmol) in THF (25 mL) was treated with 2 N LiOH (25 mL),
and the resulting mixture was stirred for 3 h. The mixture was
extracted with CH2Cl2 (500 mL). The organic layer was washed
with saturated NaHCO3 (100 mL) and brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified
by recrystallization (AcOEt/hexane) to give (S)-7 (841 mg, 96%)
as colorless crystals. The product exhibited the same spectro-
3-Cycloh exyl-3-m eth yl-2,3-d ih yd r oben zo[1,2-d ]isoth ia -
zole 1,1-Dioxid e (7). A mixture of 6 (1.00 g, 5.52 mmol) and a
1.0 M solution of cyclohexylmagnesium bromide in ether (10.0
mL, 10.0 mmol) in THF (100 mL) was stirred at -40 °C for 24
h. HCl (10%, 10 mL) was added, stirring was continued for 5
min, and the organic layer was washed with water (20 mL). The
organic layer was washed with 10% sodium thiosulfate and brine
and dried over MgSO4. The solvent was evaporated to give a
solid, which was purified by recrystallization with AcOEt to
furnish 7 obtained as a colorless crystals (1.02 g, 70%): mp 181-
scopic properties (NMR, IR, and MS) as racemic 7: [R]29
D
-22.58° (c ) 1.01, CHCl3); mp 216-219 °C (AcOEt/hexane).
(3R)-N-F lu or o-3-cycloh exyl-3-m eth yl-2,3-d ih yd r oben zo-
[1,2-d ]isoth ia zole 1,1-Dioxid e [(R)-4]. To a stirred solution
of (S)-7 (810 mg, 3.06 mmol) in CFCl3/CFCl3 (1:1, 20 mL) in the
presence of spray-dried KF (532 mg, 9.18 mmol) was introduced
15% F2 gas in helium at -40 °C for 2-3 h. Insoluble materials
were removed by filtration, and concentration of the filtrate gave
a solid, which was purified by recrystallization (CH2Cl2/hexane)
to give (R)-4 (445 mg, 51%) as colorless crystals: mp 77-79 °C;
183 °C (AcOEt/hexane); IR (KBr) 3242, 1276, 1155 cm-1 1H
;
NMR (270 MHz) δ 0.98-2.02 (m, 11H, c-Hex), 1.61 (s, 3H, Me),
4.34 (brs, 1H, NH), 7.33 (d, J ) 7.8 Hz, 1H, ArH), 7.51 (t, J )
7.4 Hz, 1H, ArH), 7.63 (t, J ) 7.4 Hz, 1H, ArH), 7.75 (d, J ) 7.8
[R]26D +48.0° (c ) 0.95, CHCl3); IR (KBr) 2935, 1359, 1184 cm-1
;
Hz, 1H, ArH); MS m/z 266 (M+ + 1). Anal. Calcd for C14H19
-
19F NMR δ -58.5 (s); 1H NMR (270 MHz) δ 1.11-2.05 (m, 11H,
c-Hex), 1.65 (d, J ) 5.9 Hz, 3H, Me), 7.27-7.82 (m, 4H, ArH);
MS m/z 283 (M+), 264 (M+ - F), 200 (M+ - c-Hex); HRMS calcd
for C14H18FNO2S 283.1041, found 283.1017. Anal. Calcd for
NO2S: C, 63.36; H, 7.22; N, 5.28. Found: C, 63.02; H, 7.19; N,
5.20.
N-Men th oxyacetyl-3-cycloh exyl-3-m eth yl-2,3-dih ydr oben -
zo[1,2-d ]isoth ia zole 1,1-Dioxid e (8). A solution of 7 (3.30 g,
12.5 mmol) in THF (200 mL) was treated with NaH (60% oil
dispersion, 697 mg, 17.4 mmol) at 0 °C, and the resulting
mixture was stirred at room temperature for 1.5 h. (-)-
Menthoxyacetyl chloride (3.19 g, 13.7 mmol) was then added at
0 °C. The reaction mixture was allowed to warm slowly, stirred
overnight at room temperature, and then poured onto 5% NaOH
solution (50 mL). The mixture was extracted with ether (4 ×
100 mL). The combined organic layers were washed with 5%
NaOH solution (50 mL), water (50 mL), and saturated NH4Cl
(50 mL), dried (MgSO4), and concentrated in vacuo. The residue
was chromatographed (CH2Cl2/acetone 1:1) to give 8a and 8b
(4.20 g, 73%) as a mixture of diastereomers. Each diastereoiso-
mer was isolated by flash chromatography as a colorless oil.
(3R)-N-Men th oxya cetyl-3-cycloh exyl-3-m eth yl-2,3-d ih y-
d r oben zo[1,2-d ]isoth ia zole 1,1-Dioxid e [(3R)-8]. Less polar
C
14H18FNO2S: C, 59.34; H, 6.40; N, 4.94. Found: C, 59.14; H,
6.64; N, 4.86.
(3S)-N-F lu or o-3-cycloh exyl-3-m eth yl-2,3-d ih yd r oben zo-
[1,2-d ]isoth ia zole 1,1-Dioxid e [(S)-4]. To a stirred solution
of (S)-7 (338 mg, 1.27 mmol) in CFCl3/CFCl3 (1:1, 10 mL) in the
presence of spray-dried KF (221 mg, 3.81 mmol) was introduced
15% F2 gas in helium at -40 °C for 2-3 h. Insoluble materials
were removed by filtration, and concentration of the filtrate gave
a solid, which was purified by recrystallization (CH2Cl2/hexane)
to give (S)-4 (234 mg, 65%) as colorless crystals. The product
exhibited the same spectroscopic properties (NMR, IR, and MS)
as (R)-4: mp 77-79 °C; [R]29 -49.2° (c ) 1.05, CHCl3).
D
Gen er a l P r oced u r e for F lu or in a tion of 9: (S)-2-F lu or o-
2-m eth yl-1-tetr a lon e (5a ). To a mechanically stirred solution
of diisopropylamine (0.042 mL, 0.30 mmol) in THF (1.0 mL) was
added under nitrogen at 0 °C a 1.54 M solution of n-BuLi in
hexane (0.19 mL, 0.30 mmol). After the mixture was stirred for
15 min at 0 °C and then chilled to -78 °C, a solution of the
2-methyl-1-tetralone (9a ) (40.0 mg, 0.25 mmol) in THF (1.0 mL)
was added. The reaction mixture was stirred for 1 h at 0 °C and
then chilled to -40 °C. A solution of (R)-4 (78.0 mg, 0.28 mmol)
in THF (1 mL) was slowly added. The reaction mixture was
stirred overnight at -40 °C and then poured onto saturated
aqueous NH4Cl (5 mL). The aqueous layer was extracted with
AcOEt (3 × 50 mL). The combined organic layers were washed
with water (10 mL) and brine (10 mL), dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed (10%
AcOEt in hexane) by preparative TLC to give (S)-5a (29.6 mg,
isomer (3R)-8: [R]28 -69.3° (c ) 0.49, CHCl3); IR (neat) 2930,
D
1718, 1321, 1233, 1124 cm-1; H NMR (300 MHz) δ 0.30 (qd, J
1
) 12.6, 3 Hz, 1H, CHHCH2), 0.82 (d, J ) 6.6 Hz, 3H, MeCH),
0.84-1.45, 1.51-1.86, 1.93-2.16 (each m, total 17H, CHHCH2,
>CH-, CH2, c-Hex), 0.92 (d, J ) 7.1 Hz, 6H, Me2CH), 1.97 (s,
3H, MeC), 2.37 (heptet d, J ) 7.1, 3 Hz, 1H, CHMe2), 2.76 (m,
1H, >CH-), 3.25 (td, J ) 10, 4 Hz, 1H, >CHO), 4.71, 4.81 (ABq,
J ) 16.5 Hz, 2H, OCH2O), 7.47 (d, J ) 7.7 Hz, 1H, ArH), 7.60
(t, J ) 7.7 Hz, 1H, ArH), 7.71 (t, J ) 7.7 Hz, 1H, ArH), 7.79 (d,
J ) 7.7 Hz, 1H, ArH); HRMS calcd for C26H39NO4S 461.2600,
found 461.2590. Anal. Calcd for C26H39NO4S: C, 67.64; H, 8.51;
N, 3.03. Found: C, 67.43; H, 8.49; N, 3.34.
(3S)-N-Men th oxya cetyl-3-cycloh exyl-3-m eth yl-2,3-d ih y-
d r oben zo[1,2-d ]isoth ia zole 1,1-Dioxid e [(3S)-8]. More polar
67%, 74% ee) as a colorless oil: IR (neat) 2938, 1701 cm-1
;
19F
NMR δ -155.1 (qdd, J ) 22, 16.6, 9.2 Hz); 1H NMR (270 MHz)

Notes
J . Org. Chem., Vol. 64, No. 15, 1999 5711
δ 1.60 (t, J ) 22 Hz, 3H, Me), 2.21-2.57 (m, 2H, CH2), 2.95-
3.23 (m, 2H, CH2Ar), 7.25-8.09 (m, 4H, ArH); MS m/z 178 (M+);
HRMS calcd for C11H11FO 178.0794, found 178.0801 (ref 9).
(S)-2-Eth yl-2-flu or o-1-tetr alon e (5b). Fluorination of 2-ethyl-
1-tetralone (9b) (100 mg, 0.58 mmol) with diisopropylamine
(0.083 mL, 0.63 mmol), a 1.54 M solution of n-BuLi in hexane
(0.42 mL, 0.63 mmol), and (R)-4 (81.2 mg, 0.29 mmol) gave after
chromatography (10% AcOEt in hexane) (S)-5b (31 mg, 70%
(0.180 mL, 0.270 mmol), and (R)-4 (70.0 mg, 0.250 mmol) gave
after chromatography (10% AcOEt in hexane) (S)-5f (34 mg, 63%,
54% ee) as a light yellow oil: IR (neat) 3019, 1727, 1215 cm-1
;
19F NMR δ -154.7 (dddd, J ) 30, 23, 14, 13 Hz); H NMR (270
MHz) δ 2.95 (dd, J ) 30, 14 Hz, 1H, CHHAr), 3.15 (dd, J ) 23,
18 Hz, 1H, CHHAr), 3.38 (dd, J ) 18, 13 Hz, 1H, CHHAr), 3.41
(t, J ) 14 Hz, 1H, CHHAr), 7.38 (q, J ) 7.6 Hz, 2H, ArH), 7.62
(t, J ) 7.6 Hz, 1H, ArH), 7.81 (d, J ) 7.6 Hz, 1H, ArH); HRMS
calcd for C16H13FO 240.0950, found 240.0953.
1
based on 4, 72% ee) as a light yellow oil: IR (neat) 3020, 1700,
1
1216 cm-1
;
19F NMR δ -163.3 (m); H NMR (270 MHz) δ 1.04
2-Eth yl-2-flu or o-1-ben zosu ber on e (5g). Fluorination of
2-ethyl-1-benzosuberone (9g) (50.0 mg, 0.270 mmol) with diiso-
propylamine (0.0500 mL, 0.320 mmol), a 1.54 M solution of
n-BuLi in hexane (0.210 mL, 0.320 mmol), and (R)-4 (83.0 mg,
0.290 mmol) gave after chromatography (15% hexane in CH2-
Cl2) 5g (26.0 mg, 48%, 43% ee, note: 5g was obtained as an
inseparable mixture of 5g and 9g (32 mg, 5g:9g ) 88:12) as a
(t, J ) 7.4 Hz, 3H, Me), 1.79 (m, 2H, CH2), 2.40 (m, 2H, CH2),
3.06 (m, 2H, CH2Ar), 7.25 (d, J ) 7.6 Hz, 1H, ArH), 7.35 (d, J )
7.6 Hz, 1H, ArH), 7.52 (d, J ) 7.6 Hz, 1H, ArH), 8.06 (d, J ) 7.6
Hz, 1H, ArH); HRMS calcd for
192.0967.
C12H13FO 192.0950, found
(S)-2-Ben zyl-2-flu or o-1-tetr alon e (5c). Fluorination of 2-ben-
zyl-1-tetralone (9c) (60.0 mg, 0.250 mmol) with diisopropylamine
(0.0430 mL, 0.310 mmol), a 1.54 M solution of n-BuLi in hexane
(0.200 mL, 0.310 mmol), and (R)-4 (79.0 mg, 0.280 mmol) gave
after chromatography (10% AcOEt in hexane) (S)-5c (50.7 mg,
light yellow oil): IR (neat) 3019, 1215 cm-1
;
19F NMR δ -158.1
1
(m); H NMR (270 MHz) δ 0.92 (t, J ) 7.6 Hz, 3H, Me), 1.75-
2.25 (m, 6H, Me × 3), 2.84-3.17 (m, 2H, CH2Ar), 7.18-7.48 (m,
4H, ArH); HRMS calcd for C13H15FO 206.1107, found 206.1112.
2-Ben zyl-2-flu or o-1-ben zosu ber on e (5h ). Fluorination of
2-benzyl-1-benzosuberone (9h ) (50.0 mg, 0.200 mmol) with
diisopropylamine (0.0300 mL, 0.240 mmol), a 1.54 M solution
of n-BuLi in hexane (0.160 mL, 0.240 mmol), and (R)-4 (62.0
mg, 0.220 mmol) gave after chromatography (15% hexane in
benzene) 5h (21 mg, 39%, 18% ee) as a light yellow oil: IR (neat)
79%, 88% ee) as a light yellow oil: IR (neat) 2927, 1698 cm-1
;
19F NMR δ -158.8 (dddd, J ) 31.3, 16.6, 16.5, 5.5 Hz); 1H NMR
(270 MHz) δ 2.04-2.35 (m, 2H, CH2), 2.96-3.14 (m, 3H, CH2-
Ph, CHHAr), 3.23 (dd, J ) 17.3, 14.9 Hz, 1H, CHHAr), 7.26-
7.57 (m, 8H, ArH), 8.10 (d, J ) 7.8 Hz, 1H, ArH); MS m/z 254
(M+), 235 (M+ - F), 163 (M+ - Bn); HRMS calcd for C17H15FO
254.1107, found 254.1106.
3019, 1690, 1216 cm-1 19F NMR δ -153.8 (pentet, J ) 25 Hz);
;
1H NMR (270 MHz) δ 1.70-2.15 (m, 4H, CH2CH2), 2.91, 3.13
(each m, total 3H, CHHAr, CH2Ph), 3.30 (dt, J ) 17, 15 Hz, 1H,
CHHAr), 7.16-7.40 (m, 9H, ArH); HRMS calcd for C18H17FO
268.1263, found 268.1282.
(S)-2-F lu or o-2-m eth yl-1-in d a n on e (5d ). Fluorination of
2-methyl-1-tetralone (9d ) (40.0 mg, 0.270 mmol) with diisopro-
pylamine (0.0430 mL, 0.330 mmol), a 1.54 M solution of n-BuLi
in hexane (0.21 mL, 0.330 mmol), and (R)-4 (85.0 mg, 0.300
mmol) gave after chromatography (15% hexane in CH2Cl2) (S)-
5d (24.3 mg, 54%, 54% ee) as a light yellow oil: IR (neat) 3023,
P r ep a r a tion of (R)-5d fr om (S)-10. To a stirred solution of
(S)-1018 (83 mg, 0.512 mmol, 73% ee) in dry CH2Cl2 (3 mL) was
added DAST (124 mg, 0.769 mmol) at -78 °C. The temperature
was allowed to warm to room temperature over 1 h. The reaction
mixture was poured into water and extracted with AcOEt. The
organic extract was washed with brine, dried, and concentrated
in vacuo. The residue was purified by preparative TLC eluting
with 30% AcOEt in hexane to give (R)-5d (60.4 mg, 72%, 66%
ee) as a colorless oil. The product has the same spectroscopic
data (NMR, IR and MS) as (S)-5d from fluorination of 9d with
1730, 1218 cm-1
;
19F NMR δ -152.8 (quintet d, J ) 22.5, 11
1
Hz); H NMR (270 MHz) δ 1.63 (d, J ) 22.5 Hz, 3H, Me), 3.30
(dd, J ) 17, 11 Hz, 1H, CHHAr), 3.47 (dd, J ) 22.5, 17 Hz, 1H,
CHHAr), 7.43 (t, J ) 7.6 Hz, 2H, ArH), 7.67 (t, J ) 7.6 Hz, 1H,
ArH), 7.82 (d, J ) 7.6 Hz, 1H, ArH); MS m/z 165 (M+ + 1), 164
(M+), 149 (M+ - Me); HRMS calcd for C10H9FO 164.0637, found
164.0626; C10H10FO 165.0715, found 165.0694.
(S)-2-Eth yl-2-flu or o-1-in dan on e (5e). Fluorination of 2-ethyl-
1-tetralone (9e) (40.0 mg, 0.250 mmol) with diisopropylamine
(0.0420 mL, 0.300 mmol), a 1.54 M solution of n-BuLi in hexane
(0.19 mL, 0.300 mmol), and (R)-4 (78.0 mg, 0.280 mmol) gave
after chromatography (15% hexane in CH2Cl2) (S)-5e (32.7 mg,
73%, 20% ee) as a light yellow oil: IR (neat) 3021, 1727, 1216
(R)-4: [R]27 +28.2° (c ) 2.50, CHCl3).
D
Ack n ow led gm en t. This work was supported by a
Grant-in Aid for Scientific Research from the Ministry
of Education, Science, Sports and Culture, J apan.
cm-1 19F NMR δ -160.0 (tdd, J ) 26, 19, 15 Hz); 1H NMR (270
;
MHz) δ 1.01 (t, J ) 7.4 Hz, 3H, Me), 1.75-2.13 (m, 2H, CH2),
2.35 (d, J ) 19 Hz, 1H, CHHAr), 3.36 (d, J ) 15 Hz, 1H, CHHAr),
7.43 (m, 2H, ArH), 7.66 (t, J ) 7.6 Hz, 1H, ArH); HRMS calcd
for C11H11FO 178.0794, found 178.0793.
(S)-2-Ben zyl-2-flu or o-1-in dan on e (5f). Fluorination of 2-ben-
zyl-1-tetralone (9f) (50.0 mg, 0.230 mmol) with diisopropylamine
(0.0350 mL, 0.270 mmol), a 1.54 M solution of n-BuLi in hexane
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the camphorsulfonylation of 7 and hydrolysis of
the camphorsulfonyl derivative of 7. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9904011