Asymmetric Fluorination of Enolates with Nonracemic N-Fluoro-2,10-Camphorsultams

Article abstract of DOI:10.1021/jo972045x

The asymmetric "electrophilic" fluorination of tertiary enolates by nonracemic N-fluoro-2,10-camphorsultams 3 affords quaternary α-fluoro carbonyl compounds in modest yield and ee. The highest asymmetric induction was observed for the fluorination of the sodium enolate of 2-methyl-1-tetralone (8a) by (-)-N-fluoro-2,10-(3,3-dichlorocamphorsultam) (3b) to give (S)-(+)-2-fluoro-2-methyl-1-tetralone (9a) in 70percent ee. The absolute configuration was established by X-ray crystallography of the corresponding diastereomeric β-hydroxy sulfoximine prepared from (±)-9a and the Johnson reagent. The asymmetric induction exhibited by 3 is opposite to that of the closely related enolate hydroxylation reagents nonracemic (camphorylsulfonyl)oxaziridines 4. The N-fluoro sultams 3 were prepared by fluorination (10percent F₂/N₂) of the corresponding sultams 5.

Full text of DOI:10.1021/jo972045x

J . Org. Chem. 1998, 63, 2273-2280
2273
Asym m etr ic F lu or in a tion of En ola tes w ith Non r a cem ic
N-F lu or o-2,10-Ca m p h or su lta m s
,
†
‡
‡
†
Franklin A. Davis,* Ping Zhou, Christopher K. Murphy, Gajendran Sundarababu,
†
‡
‡
‡
§
Hongyan Qi, Wei Han, Robert M. Przeslawski, Bang-Chi Chen, and Patrick J . Carroll
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, Department of
Chemistry, Drexel University, Philadelphia, Pennsylvania 19104, and Department of Chemistry,
University of Pennsylvania, Pennsylvania 19104
Received November 6, 1997
The asymmetric “electrophilic” fluorination of tertiary enolates by nonracemic N-fluoro-2,10-
camphorsultams 3 affords quaternary R-fluoro carbonyl compounds in modest yield and ee. The
highest asymmetric induction was observed for the fluorination of the sodium enolate of 2-methyl-
1
-tetralone (8a ) by (-)-N-fluoro-2,10-(3,3-dichlorocamphorsultam) (3b) to give (S)-(+)-2-fluoro-2-
methyl-1-tetralone (9a ) in 70% ee. The absolute configuration was established by X-ray crystal-
lography of the corresponding diastereomeric â-hydroxy sulfoximine prepared from (()-9a and the
J ohnson reagent. The asymmetric induction exhibited by 3 is opposite to that of the closely related
enolate hydroxylation reagents nonracemic (camphorylsulfonyl)oxaziridines 4. The N-fluoro sultams
3
2 2
were prepared by fluorination (10% F /N ) of the corresponding sultams 5.
The stereoselective replacement of hydrogen and hy-
droxyl groups by fluorine in biologically active molecules
is a common strategy for enhancing biological activity and
studying enzyme mechanism. Fluorine uniquely influ-
ences the basicity, acidity, and nonbonding interactions
of neighboring groups because of its extreme electrone-
gativity.1 Replacement of hydrogen by fluorine is often
regarded as an isosteric substitution despite the fact that
the chiral centers bears a fluorine. Of particular interest
are nonracemic R-fluoro carbonyl compounds 1, which are
fluorine analogues of the R-hydroxy carbonyl moiety
found in many biologically active compounds.7 Not only
do R-fluoro carbonyl compounds exhibit biological activ-
,8
8
ity, but they have also found utility as enzyme inhibitors,
,2
and in the study of enzyme mechanisms.8 Furthermore,
nonracemic R-fluoro carbonyl compounds are important
building blocks for the asymmetric construction of bio-
3
,4
their van der Waals radii are different (1.20 vs 1.47 Å).
The similarity of typical C-F and C-O bond lengths
1.39 vs 1.43 Å) and the possibility that fluorine may
active materials8
,9b,10
and ferroelectric devices.
11
(
function as a weak hydrogen bond acceptor suggest that
replacement of hydroxyl by fluorine in bioactive com-
pounds would result in useful analogues.1 Furthermore
the high C-F bond strength often protects fluorine from
metabolic transformations. For these reasons, plus the
importance of chirality in pharmacologically and biologi-
cally active molecules, the synthesis of enantiomerically
pure fluoroorganic molecules is of significance.6
,5
Recent efforts have focused on the asymmetric syn-
thesis of fluoroorganic molecules where at least one of
Optically active R-fluoro acids 1 (Z ) OH) have been
prepared by enzyme-catalyzed kinetic resolution of R-flu-
oro esters12 and 2-fluoro-2-substituted malonic esters.
13
†
Temple University.
Drexel University.
University of Pennsylvania.
‡
§
(7) For a review on the synthesis of chiral fluoroorganic compounds
see: Bravo, P.; Resnati, G. Tetraledron: Asymmetry 1990, 1, 661.
(8) For a review on R-fluorocarbonyl compounds see: Rosen, S.;
Filler, R. Tetrahedron 1985, 41, 1112.
(1) For reviews on biologically active organofluorine compounds
see: (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; J ohn Wiley & Sons: New York, 1991. (b) Welch, J . T.
Tetrahedron 1987, 43, 3123. (c) Filler, R.; Kobayashi, Y., Eds. Biome-
dicinal Aspects of Fluorine Chemistry; Kodanasha Ltd., Elsevier
Biomedical Press: Tokyo, New York, 1982. (d) Carbon-Fluorine Com-
pounds: Chemistry, Biochemistry and Biological Activities; Ciba
Foundation Symposium, Associated Scientific Publishers: Amsterdam,
(9) (a) Gershon, H.; Schulman, S. G.; Spevack, A. D. J . Med Chem.
1967, 10, 536. (b) Garrett, G. S.; Emge, T. J .; Lee, S. C.; Fischer, E.
M.; Dyehouse, K.; McIver, J . M. J . Org. Chem. 1991, 56, 4823.
(10) (a) Hoshi, H.; Aburaki, S.; Iimura, S.; Kyamasaki, T.; Naito,
T.; Kawaguchi, H. J . Antibiot. 1990, 43, 858. (b) Shiozaki, M.;
Kobayashi, Y.; Arai, M. Tetrahedron Lett. 1991, 32, 7021. (c) Bols, M.;
Szarek, W. A. J . Chem. Soc., Chem. Commun. 1992, 445. (d) Welch, J .
T.; Eswarakrishnan, S. J . Chem. Soc., Chem. Commun. 1985, 186. (e)
Dauben, W. G.; Greenfield, L. J . J . Org. Chem. 1991, 56, 5991. (f)
Takeuchi, Y.; Kazuhiro, N.; Koizumi, T.; J . Org. Chem. 1989, 54, 5453.
(11) Walba, D. M.; Razavi, H. A.; Clark, N. A.; Parmar, D. S. J . Am.
Chem. Soc. 1988, 110, 8686. Kitazume, T.; Ohnogi, T.; Ito, K. J . Am.
Chem. Soc. 1990, 112, 6608.
1
972.
2) Welch, J . T., Ed. Selective Fluorination in Organic and Bioor-
(
ganic Chemistry, ACS Symp. Series Vol. 456, American Chemical
Society, Washington, DC, 1991.
(
3) Bondi, A. J . Phys. Chem. 1964, 68, 441.
(4) O’Hagan, D.; Rzepa, H. S. J . Chem. Soc., Chem. Commun. 1997,
6
45.
5) For opposing views on the ability of fluorine to function as a
(
hydrogen bond acceptor see: Howard, J . A. K.; Hoy, V. J .; O’Hagan,
D.; Smith, G. T. Tetrahedron 1996, 52, 12613 and Dunitz, J . D.; Taylor,
R. Chem. Eur. J . 1997, 3, 98.
(12) Kalaritis, P.; Regenye, R. W. Org. Synth. 1990, 69, 10. Kalaritis,
P.; Regenye, R. W.; Partridge, J . J .; Coffen, D. L. J . Org. Chem. 1990,
55, 812.
(13) Kitazume, T.; Sato, T.; Kobayashi, T.; Lin, J . T. J . Org. Chem.
1986, 51, 1003.
(6) For recent reviews on selective fluorination see: (a) Wilkinson,
J . A. Chem. Rev. 1992, 92, 505. (b) Mascaretti, O. A. Aldrichimica Acta
1
9
993, 26, 47. (c) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996,
6, 1737.
(14) Lowe, G.; Potter, B. V. L. J . Chem. Soc., Perkin Trans. 1 1980,
2029.
S0022-3263(97)02045-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/19/1998

2
274 J . Org. Chem., Vol. 63, No. 7, 1998
Davis et al.
Fluorodeamination of chiral R-amino acids with retention
Sch em e 1
1
4
of configuration using HF-pyridine/sodium nitrite has
also been described.15 Treatment of enantiomerically
1
6
enriched R-hydroxy acids with fluoroamines and di-
ethylaminosulfur trifluoride (DAST)1
0a,14,17
likewise gives
these compounds, but with varying degrees of success.
Ethyl (R)-fluorohexanoate was prepared in 91% ee by
conversion of corresponding R-hydroxy ester to the me-
sylate followed by nucleophilic displacement with fluoride
ion.1
7a
The diastereoselective fluorination of chiral enolates
with electrophilic fluorination reagents6 and the enan-
tioselective amide acetal Claisen rearrangement de-
scribed by Welch19 are other useful sources of R-fluoro
carbonyl compounds. In this regard we have shown that
the highly diastereoselective (85-99%) fluorination of
chiral imide enolates with N-fluoro-o-benzenedisulfon-
c,18
2
0
imide (NFOBS) and N-fluorobenzenesulfonimide (NF-
2
0
21
Si) is a particularly general route to these materials.
first “electrophilic” asymmetric fluorinating reagent was
-)-N-fluoro-2,10-camphorsultam (3a ) prepared by Dif-
However, a disadvantage of any chiral auxiliary based
asymmetric synthesis is the necessity of preparing and
eventually removing the auxiliary without epimerization.
Indeed some racemization occurred in the alkaline hy-
drolysis of 2, but removal of the auxiliary was ac-
complished without racemization by reduction to the
(
2
2
ferding and Lang in 1988. However, the ee’s and yields
for enolate fluorinations with this reagent were generally
poor (vide infra). Enantiopure N-fluoro-N-tosylamines
also give low to moderate ee’s (2-54%) for the fluorina-
tion of tertiary enolates.23 Another reagent, a nonracemic
aminofluorosulfurane, a nucleophilic source of fluorine,
also gave low ee’s (16%) in the kinetic resolution of
2
1
â-fluorohydrin.
2
-(trimethylsiloxy)propanoate.24 In connection with our
interest in the asymmetric synthesis of R-fluoro carbonyl
compounds 1 we describe details of a synthetic and
mechanistic study of the asymmetric fluorination of
2
5
enolates using nonracemic N-fluorocamphorsultams 3.
This work is related to our studies on the asymmetric
hydroxylation of prochiral enolates using the closely
related (camphorylsulfonyl)oxaziridine 426 because the
chiral recognition mechanisms are likely to be similar
and the precursors of 4 are the precursors of 3 (Scheme
1
).
Syn th esis a n d Str u ctu r e of N-F lu or o-2,10-ca m -
An enantioselective fluorinating reagent for the reagent-
controlled asymmetric fluorination of prochiral enolates
to R-fluoro carbonyl compounds in high ee’s and predict-
able stereochemistry would be of considerable value. The
p h or su lta m s. Preparation of the N-fluoro-2,10-cam-
phorsultams (+)-3 was accomplished by direct fluorina-
2
7
tion of the corresponding camphorsultams (+)-5a -c
using 10% F /N and are summarized in Table 1. Pow-
2
2
dered NaF was added to scavenger HF. In addition to
the N-fluoro sultam (+)-3 two side products were ob-
served, the (camphorylsulfonyl)imines 6 and in the case
of (-)-5b, the (N,N-difluoroamino)camphorsulfonyl fluo-
ride (-)-7. The optimum temperature for fluorination
was -40 °C since lowering the temperature to -78 °C
produced no reaction and higher temperatures resulted
in decomposition. Somewhat higher yields; e.g. 10% were
observed at lower molar concentrations of 5 (Table 1:
compare entries 2 and 3, and 10 and 11), but had little
effect on the formation of the side products. The imines
(
15) (a) Olah, G. A.; Welch, J . Synthesis 1974, 652. (b) Olah, G. A.;
Prakash, G. K. S.; Chao, Y. L. Helv. Chim. Acta 1981, 64, 2528. (c)
Faustini, F.; De Munari, S.; Panzeri, A.; Villa, V.; Gandolfi, C. A.
Tetrahedron Lett. 1981, 22, 4533. (d) Yamazaki, T.; Welch, J . T.;
Plummer, J . S.; Gimi, R. H. Tetrahedron Lett. 1991, 32, 4267.
(16) (a) Wantanabe, S.; Fujita, T.; Usui, Y.; Kitamzume, T. J .
Fluorine Chem. 1986, 31, 247. (b) Hamman, S.; Barrelle, M.; Tetaz,
F.; Buguin, C. G. J . Fluorine Chem. 1987, 32, 85.
(
1, 2165. (b) Shiozaki, M.; Kobayashi, Y.; Arai, M. Tetrahedron Lett.
991, 32, 7021.
(
Dyehouse, K.; McIver, J . M. J . Org. Chem. 1991, 56, 4823. (b) Ihara,
M.; Taniguchi, N.; Kai, T.; Satoh, K.; Fukumoto, K. J . Chem. Soc.,
Perkin Trans. 1 1992, 221. (c) Iwaoka, T.; Murohashik, T.; Sato, M.;
Kaneko, C. Tetrahedron: Asymmetry 1992, 3, 1025. (d) Sato, M.;
Kitazawa, N.; Kaneko, C. Heterocycles 1992, 33, 105. (e) Kabore, L.;
Chebli, S.; Faure, R.; Laurent, E. Marquet, B.; Tetrahedron Lett. 1990,
17) (a) Focella, A.; Bizzarro, F.; Exon, C. Synth. Commun. 1991,
2
1
18) (a) Garrett, G. S.; Emge, T. J .; Lee, S. C.; Fischer, E. M.;
6
result from dehydrofluorination of 3 as evidenced by
the fact that 15-20% of 6b was obtained on treatment
of 3b under the fluorination conditions. As the polarity
3
1, 3137. (f) Hudlicky, M.; Merola, J . S. Tetrahedron Lett. 1990, 31,
403.
(
7
(22) Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 6087.
(23) Takeuchi, Y. Sato. A.; Suzuki, T.; Kameda, A.; Dohrin, M.;
Satoh, T.; Koizumi, T.; Kirk, K. L. Chem. Pharm. Bull. 1997, 45, 1085.
(24) Hann, G. L.; Sampsonl, P. J . Chem. Soc., Chem. Commun. 1989,
1650.
(25) Davis, F. A.; Zhou, P.; Murphy, C. K. Tetrahedron Lett. 1993,
34, 3971.
(26) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
(27) Davis, F. A.; Zhou, P.; Chen, B.-C., Phosphorus, Sulfur Silicon
1996, 115, 85.
19) Yamazaki, T.; Welch, J . T.; Plummer, J . S.; Gimi, R. H.
Tetrahedron Lett. 1991, 32, 4267.
20) Davis F. A.; Han, W.; Murphy, C. K. J . Org. Chem. 1995, 60,
730.
21) (a) Davis, F. A.; Han, W. Tetrahedron Lett. 1992, 33, 1153. (b)
(
4
(
Davis, F. A.; Qi, H. Tetrahedron Lett. 1996, 37, 4345. (c) Siddiqui, M.
A.; Marquez, V. E.; Driscoll, J . S.; Barchi, J . J . J r. Tetrahedron Lett.
1
994, 35, 3263. (d) Davis, F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi,
H. J . Org. Chem. 1997, 62, 7546.

Asymmetric Fluorination of Enolates
J . Org. Chem., Vol. 63, No. 7, 1998 2275
Ta ble 1. F lu or in a tion of Ca m p h or su lta m s 5 to N-F lu or oca m p h or su lta m s 3 a t -40 °C for 1.5 h
entry
sultam
conditions concentration/solvent
products (% yield)
(+)-3a (67) [75%]
δ 19F ppm of 3 (J ) Hz)
1
2
3
4
5
6
7
8
9
(-)-5a (X ) H)
(-)-5b (X ) Cl)
(0.1 M)/1:1 CHCl3:CFCl3
(0.1 M)/1:1 CHCl3:CFCl3
(0.2 M)/1:1 CHCl3:CFCl3
(0.2 M)/1:1 CHCl3:CFCl3
(0.4 M)/1:1 CHCl3:CFCl3
(0.2 M)/CHCl3
(0.2 M)/4:5:1 CHCl3:CFCl3:EtOH
(0.2M)/1:1 CHCl3:CFCl3
(0.2M)/1:1 CHCl3:CFCl3
(0.2M) CHCl3
-65.5 (br,s)
-53.9 d (48.4)
(+)-3b (67), (+)-6b (13), (-)-7 (5)
(+)-3b (56), 6b (9), (-)-7 (11)
(-)-3b (56), 6b (12), (-)-7 (10)
(-)-3b (58), 6b (11), (-)-7 (12)
(-)-3b (67), 6b (7), (-)-7 (11)
(-)-3b (35), 6b (0), (-)-7 (0)
(-)-3c (25), 6b (35)
(+)-5b (X ) Cl)
(+)-5c (X ) OMe)
(-)-5c (X ) OMe)
(+)-5c (X ) OMe)
(+)-5c (X ) OMe)
-55.6 d (44.0)
(-)-3c (31), 6b (40)
1
1
0
1
(-)-3c (42), 6b (21)
(0.6M) CHCl3
(-)-3c (34), 6b (33)
3 3 3
of the solvent increased from CHCl :CFCl to CHCl the
yield of the N-fluoro sultam increased, possibly due to
the greater solubility of the starting material (Table 1:
entries 4 and 6). The formation of byproducts 6 and 7
may involve fluorine radicals. Earlier studies on the
2
fluorination of steroidal alkenes with F indicated that
the low yields observed in less polar solvents occurred
from the generation of fluorine radicals resulting in
undesirable reactions.28 Rosen has presented evidence
that addition of proton donors such as ethanol suppresses
2
9
fluorine radical formation enhancing polar reactions.
Indeed fluorination of 5b in the presence of ethanol
completely eliminated the formation of 6b and 7 (Table
1
, entry 7). Unfortunately the yield of 3b was only 35%.
Products were isolated by flash chromatography after
filtration and removal of the solvent. The N-fluoro-2,10-
camphorsultams 3a -c are stable white crystalline solids
storable at room temperature for more than a year
without noticeable deterioration and giving satisfactory
elemental analyses.
F igu r e 1. Computer-generated X-ray structure of (+)-3b.
nitrogen, which may be pyramidal or planar, and the
fluorine’s steric and electronic environment. Although
electronegative atoms containing lone pairs of electrons
(e.g. halogens) are known to increase the barrier to
pyramidal inversion at nitrogen, sulfonyl groups fre-
quently decrease it.32 The fluorine atom in the F NMR
spectra of (+)-N-fluoro-camphorsultam (3a ) at 22 °C
appears as a broad singlet at -65.5 ppm relative to the
19
3
standard (CFCl ) rather than the expected doublet due
to coupling with the adjacent proton. On cooling to 0 °C
a second broad hump appeared at -54.0 ppm, and at -60
°
C these peaks were resolved into two doublets at -66.4
(J ) 48.8 Hz) and at -54.0 (J ) 73.3 Hz) ppm. The
relative intensities were 97:3. We interpret this to mean
that (+)-3a , at ambient temperatures, exists as a rapidly
equilibrating mixture of the endo and exo forms, but at
The structure of the ring-opened product (N,N-difluo-
roamino)camphorsulfonyl fluoride (-)-7 was determined
on the basis of its spectral properties. In the 19F NMR
-60 °C a nonequilibrating 97:3 endo/exo mixture. On the
other hand the fluorine NMR spectra of the dichloro and
dimethoxy N-fluoro sultams (+)-3b and (+)-3c were
doublets at -53.9 (J ) 48.4 Hz) and -55.6 (J ) 44.0 Hz)
ppm, respectively. On heating to 75 °C these absorptions
remained doublets, indicating that these sultams exist
exclusively in the sterically more favorable endo form.
spectra of 7 the diastereotopic NF
2
fluorines appear at δ
-144.5 and -164.2 ppm as doublets of a doublet coupled
with the adjacent methine proton. Their chemical shifts
are in accord with those previously reported for other
amino difluorides.30 The sulfonyl fluoride fluorine ap-
pears as a triplet at δ -147.1 ppm as a result of coupling
with the nearby methylene group. Additional support
for the structure of 7 is the report of a very similar ring-
opened product obtained in the fluorination of 3,3-
dimethyl-2,3-dihydro-1,2-benzothiazole 1,1-dioxide.31
The degree of asymmetric induction exhibited by 3a -c
will be dependent in large part on the geometry at
The X-ray crystal structure of (+)-N-fluoro-2,10-(3,3-
dichlorocamphorsultam) (3b), shown in Figure 1, con-
(28) Mann, J . Chem. Soc. Rev, 1987, 16, 381. Barton, D. H. R.; Lister-
J ames, J .; Hesse, R. H.; Pechet, M. M.; Rozen, S. J . Chem. Soc., Perkin
Trans. 1 1982, 1105.
(32) For leading references and a discussion of the factors influenc-
ing pyramidal nitrogen inverstion see: Davis, F. A.; J enkins, R. H.,
J r. in Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: New
York, 1984; Vol. 4, pp 313-353.
(29) Rozen, S.; Brand, M. J . Org. Chem. 1986, 51, 5143.
(30) Grakauskas, V.; Baum, K. J . Org. Chem. 1970, 35, 1545.
(31) Differding, E.; Bersier, P. M. Tetrahedron 1992, 48, 1595.

2
276 J . Org. Chem., Vol. 63, No. 7, 1998
Davis et al.
Sch em e 2
firms that the fluorine atom occupies the endo position.
The nitrogen atom is sp hybridized and pyramidal as
indicated by the C-N, N-S, and N-F bond angles of
approximately 107° as well as the fact that it is out of
the S, C, F plane by 0.57 Å.
A side-product isolated in 3-11% in the fluorination
of the sodium enolate of 8a was 2-chloro-2-methyl-2-
tetralone (10) (Table 2: entries 4, 5, 10). As previously
reported, this product arises from chlorination of the
3
3
3
enolate by the dichlorocamphorsulfonimine 6b and can
be completely suppressed by fluorination at -78 °C.
Enolate induced H-F elimination of 3b is responsible for
the formation of 6b which also reduces product yields.
The reason the â-keto ester enolates of 8a -d gave higher
yields is probably related to their lower basicity resulting
in less elimination. In addition to HF elimination, which
destroys the enolate, it can also be quenched by the acidic
R-imino protons in the sulfonimine 6a . Indeed when the
Asym m etr ic F lu or in a tion s. In a typical experiment
0
.8-1.5 equiv of N-fluoro sultams 3a -c were added to
the preformed kinetic enolates of 8a -f at -78 °C (Scheme
). However, fluorination at this temperature was slow,
2
and warming to 0 °C was required for completion in many
cases. Products were identified by comparison with
1
9
authentic samples and by F NMR. The ee’s were
determined using the chiral shift reagent Eu(hfc)
results are summarized in Table 2.
3
. These
2
enolate of 8a was treated with 6a followed by a D O
quench no incorporation of deuterium into 8a was
observed.
In general the N-fluoro dichloro sultam 3b gave better
yields and ee’s than did 3a . This is most likely related
to the greater reactivity of 3b where fluorinations oc-
curred at -78 °C vs rt for 3a . The highest asymmetric
induction was observed for the fluorination of the sodium
enolate of 2-methyl-1-tetralone (8a ) with 3b affording the
Absolu te Con figu r a tion of 2-F lu or o-2-m eth yl-1-
tetr a lon e (9a ). To design more effective enantioselective
N-F fluorinating reagents an understanding of chiral
recognition mechanism is important. This requires that
the absolute configurations of the product R-fluoro car-
bonyl compounds be known. Because the active site
structures of N-fluoro sultam (+)-3 and oxaziridine (+)-4
are similar it is anticipated that they will afford the same
sense of asymmetric induction in the fluorination and
hydroxylation of enolates. Consequently the enolate of
2
-fluoro-2-methyl-1-tetralone (9a ) in 76% ee and 53%
yield (Table 2; entry 6). For fluorination of â-ketone ester
enolates 8b-c, the ee’s were more modest and in the
range of 34-46% ee. The enolate of propiophenone (8e),
the only secondary enolate studied, gave racemic 9e
(Table 2: entry 29). The fact that 9e was racemic is
2
-methyl-1-tetralone (8a) on fluorination by (+)-3b should
give (R)-9a . To confirm this assumption (R)-(+)-hydroxy-
-methyl-1-tetralone (11), prepared in >95% ee by hy-
undoubtedly related to the ease with which it under goes
base-catalyzed epimerization under the reaction condi-
tions as a consequence of the enhanced acidity of the
2
3
3
R-fluoro proton.2
1a,b,d
droxylation of the sodium enolate of 8a with (+)-4b, was
treated with DAST.34 This nucleophilic fluorinating
reagent generally reacts with R-hydroxy carbonyl com-
pounds with inversion of configuration,3 although a few
examples are known where the configuration was re-
tained.35 Thus treatment of (+)-11 with DAST gave (-)-
While fluorination yields were quite
good for the N-fluoro-2,10-(3,3-dimethoxycamphorsultam)
(3c) the asymmetric induction was dismal (<5%). As
4b,c
previoulsy observed for hydroxylations using the corre-
sponding (camphorylsulfonyl)oxaziridines 4 the ee’s of 9
were dependent upon the geometry of the enolate, the
9
a in 20% yield and 70% ee. The major product,
counterion, the structure of 3 as well as the reaction
conditions (Table 2).39
identified by comparison with an authentic material, was
2
3
-methyl-1-naphthol (12) isolated in 54% yield (Scheme
). Unexpectedly, the signs of rotation of 9a prepared
3
6
(
33) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Reddy, T. R.;
Chen, B.-C. J . Org. Chem. 1992, 57, 7274.
34) (a) Middleton, W. J . Org. Chem. 1975, 40, 574. (b) For a review
(
(37) J ohnson, C. R.; Zeller, J . R. Tetrahedron 1984, 40, 1225.
(38) The X-ray structure of 14 will be published elsewhere.
(39) For a reviews on hydroxylation of enolates by N-sulfonylox-
of DAST see: Hudlicky, M. Organic React. 1988, 35, 513. (c) Fritz-
Langhals, E.; Schutz, G. Tetrahedron Lett. 1993, 34, 293.
(
35) (a) Danelon, G. O.; Mascaretti, O. A. J . Fluorine Chemistry
992, 56, 109. (b) Walba, D. M.; Razavi, H. A.; Clark, N. A.; Parmar,
D. S. J . Am. Chem. Soc. 1988, 110, 8686.
36) Batt, D. G.; J ones, D. G.; La Greca, S. J . Org. Chem. 1991, 56,
704.
aziridines see: (a) Davis, F. A.; Chen, B.-C. In Stereoselective
Synthesis, Helmchen, G., Hoffman, R. W., Mulzer, J ., Schaumann, E.,
Eds., Houben-Weyl, 1995; E21e, 4497. (b) Davis, F. A.; Sheppard, A.
C. Tetrahedron, 1989, 45, 5703. Davis, F. A.; Thimma Reddy, R. Compr.
Heterocycl. Chem. II. 1996, 1A, 365.
1
(
6

Asymmetric Fluorination of Enolates
J . Org. Chem., Vol. 63, No. 7, 1998 2277
Ta ble 2. Asym m etr ic F lu or in a tion of En ola tes Usin g N-F lu or oca m p h or su lta m s 3
by fluorination of the enolate of 8a with (+)-3b and by
DAST treatment of (R)-11 were the same; e.g. negative.
This means that despite the apparent similarities in
active site structures, (+)-3 and (+)-4 give different
senses of asymmetric induction. This brings into ques-
tion whether DAST actually reacts with (R)-11 with
inversion of configuration, particularly in light of the low
yield and the fact that 11 is a tertiary hydroxyl group.
To unequivocally assign the structure of 9 it was
necessary to prepare a solid derivative and determine its
absolute configuration by X-ray analysis. Ideally suited
for this purpose is the J ohnson reagent, (R)-(-)-N,S-
dimethyl-S-phenylsulfoximine (13).37 This reagent has
been employed in the resolution of ketones which is based
on its reversible addition to chiral ketones. Thus treat-
ment of (R)-13 with 1.1 equiv of n-BuLi at -78 °C gave
the corresponding R-lithio derivative to which was added
1.0 equiv of racemic 9a (Scheme 4). After quenching with
aqueous NH Cl the â-hydroxy sulfoximine diastereoiso-
4
mers were separated into two fractions by flash chroma-
tography. The first fraction consisted of two diastereo-
isomers in a 1:5 ratio while the second fraction 14 was
diastereomerically pure by NMR. X-ray crystal analysis
of the latter fraction revealed that the fluorine stereo-
center has the (S)-configuration.38 (S)-(-)-2-Fluoro-2-
methyl-1-tetralone (9a ) was regenerated in 87% yield by

2
278 J . Org. Chem., Vol. 63, No. 7, 1998
Davis et al.
Sch em e 3
Sch em e 5
Sch em e 4
refluxing 14 in 2-butanol for 2 h. This result verifies that
DAST reacts with (R)-(+)-11 with inversion of configu-
ration and that (+)-3 and (+)-4 give the opposite stereo-
induction with enolates.
Molecular recognition for the asymmetric hydroxyla-
tion of acyclic and cyclic ketone enolates by (camphoryl-
sulfonyl)oxaziridine derivatives 4 has been interpreted
in terms of “open” or “nonchelated” transition states.2
Based on the structure-reactivity trends, it was argued
that the primary transition-state control element is steric
in origin, as observed for other enantioselective oxida-
tions by these reagents. It was further assumed that
regardless of the actual solution structure of the enolate
the enolate-oxygen metal aggregate was the sterically
6,39,40
N
attacks the F-N bond in an S 2 fashion as proposed for
enolate hydroxylations by oxaziridines (Scheme 5). In
4
3
support of the S 2 mechanism for “electrophilic” fluorina-
N
tion by N-F reagents is the fact that rearranged products
were not detected in the fluorination of citronellic ester
enolate as would be expected of an ET mechanism
44
involving radical species. Beak has also shown that the
most demanding group in the vicinity of the enolate C-C
aryl bromide-alkyllithium exchange reaction either pro-
ceeds through a trigonal bipyramid structure or an S 2
N
bond.3
3,39
While this model has proven to be a useful
predictor of enolate hydroxylation stereochemistry, a few
exceptions have been noted. These include the hydroxy-
lation of a â-ketoester enolate used in the synthesis of
transition state.45 In 3 fluorine is more exposed and in
a less sterically encumbered environment than is the
oxygen atom in 4 (Figure 1). For the N-fluoro sultam 3
this results in reduced asymmetric induction compared
to 4; e.g. 70 vs 95%, respectively. This means that the
steric factors which made TS-3 of lowest energy for
enolate hydroxylations is apparently of less importance
for enolate fluorinations. In this regard TS-1 and TS-2
are favored because (+)-3b give (S)-9a in 70-75% ee.
Furthermore, in TS-2 there is the possibility of a stabiliz-
4
1
the AB segment of daunomycin and an eight-membered
cyclic lactone enolate employed in the synthesis of (+)-
lauercin.42 However, these exceptions may not be due
to a flawed model, but rather to the difficulty in evaluat-
ing the relevant nonbonded interactions.
Applying the enolate-hydroxylation model to the asym-
metric fluorination of the 2-methyl-1-tetralone (8a ) eno-
late requires the reasonable assumption that the enolate
(
40) Davis, F. A.; Towson, J . C.; Weismiller, M. C.; Lal, S.; Carroll,
P. J . J . Am. Chem. Soc. 1988, 110, 8477.
41) Davis, F. A.; Clark, C.; Kumar, A.; Chen, B.-C. J . Org. Chem.
994, 59, 1184.
42) Burton, J . W.; Clar, J . S.; Derrer, S.; Stork, T. C.; Bendall, J .
G.; Holmes, A. B. J . Am. Chem. Soc. 1997, 119, 7483.
(43) Bach, R. D.; Andres, J . L.; Davis, F. A. J . Org. Chem. 1992, 57,
613.
(44) Differding, E.; Ruegg, G. M.; Lang, L. W. Tetrahedron Lett.
1991, 32, 1779.
(
1
(
(45) Beak, P.; Allen, D. J . J . Am. Chem. Soc. 1992, 114, 3420.

Asymmetric Fluorination of Enolates
J . Org. Chem., Vol. 63, No. 7, 1998 2279
ing metal enolate chelation with the sulfonyl oxygens.43,46
(1R-exo)-(-)-2-(N,N-diflu or oam in o)-7,7-dim eth ylbicyclo-
2.2.1]h ep ta n e-1-m eth a n esu lfon yl F lu or id e (7). This com-
pound was isolated as a byproduct of the fluorination of (+)-
[
However, enolate fluorinations in the presence of HMPA,
known to disrupt metal chelation,47 failed to diminish the
2
0
5
b (10%): mp 105-106 °C; [R]
D
) -20.2 (c ) 1.4, CHCl
3
);
) δ 1.12
s, 3 H), 1.40 (s, 3 H), 1.93-2.12 (m, 2 H), 2.32-2.40 (m, 1 H),
2.61-2.64 (m, 1 H), 3.33-3.42 (m, 1 H), 3.76-3.82 (m, 1 H),
ee of 9a (Table 2: entry 7).
-1
1
IR (KBr) cm 2992, 1492, 1407, 1210; H NMR (CDCl
3
In summary electrophilic asymmetric fluorination of
tertiary enolates by N-fluoro-2,10-camphorsultams 3
afforded quaternary R-fluoro carbonyl compounds in
modest yield and ee. The sense of asymmetric induction
exhibited by these reagents is opposite that for the closely
related (camphorylsulfonyl)oxaziridine 4 hydroxylating
reagents.
(
1
3
4.37 (m, 2 H); C NMR (CDCl
52.0, 52.3, 62.4, 90.4 (m); 19F NMR (CDCl
13.7 Hz, J
dd, J
3
) δ 22.6, 23.0, 24.7, 30.7, 51.9,
) δ -144.5 (dd, J
) 33 Hz, 1 F), -147.1 (t, J ) 8.8 Hz, 1 F), -164.2
) 613.7 Hz, J ) 24.2 Hz, 1 F). Anal. Calcd for C10
NO S: C, 35.31; H, 4.15. Found: C, 35.42; H, 4.04.
+)-N-F lu or o-2,10-(3,3-d im eth oxyca m p h or su lta m ) (3c).
3
1
)
6
2
(
1
2
14
H -
Cl
2
F
3
2
(
The typical procedure for the preparation of (+)-3b was
followed, eluant: Et O/n-pentane, 50:50; yield 34%; mp 154-
56 °C, [R]20
Exp er im en ta l Section
2
-1
1
D
3
+49.6 (c 1.0, CHCl ); IR (KBr) cm 3006.5,
1342.1, 1156.8, 106.4; H NMR (CDCl ) δ 0.87 (s, 3 H), 1.27
1
Gen er a l P r oced u r e. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Ana-
lytical and preparative thin-layer chromatography was per-
formed on precoated silica gel plates (250 and 1000 µm)
purchased from Analtech Inc. TLC plates were visualized with
UV, in an iodine chamber or with phosphomolybdic acid unless
noted otherwise. THF was freshly distilled under nitrogen
from a purple solution of sodium and benzophenone. Elemen-
tal analyses were performed in the Department of Chemistry,
University of Pennsylvania, Philadelphia, PA.
3
(s, 3 H), 1.55-1.91 (m, 5 H), 2.19 (d, J ) 4.2 Hz, 1 H), 3.06-
3.42 (m, 2 H), 3.18 (s, 3H), 3.29 (s, 3 H); 13C NMR (CDCl ) δ
3
108.3, 76.4, 76.3, 50.0, 48.3, 48.2, 48.0, 46.9, 46.8, 33.5, 21.0,
20.6; 19F NMR (CDCl ) δ -55.6 (d, J ) 44.0 Hz). Anal. Calcd
3
for C H FNO S: C, 49.13; H, 6.87. Found: C, 49.04; H, 7.25.
1
2
20
4
Deter m in a tion of En a n tiom er ic P u r ity. The enantio-
meric purity of the R-fluoro carbonyl compounds were deter-
mined by chiral shift reagent experiments using increasing
amounts of [(3-heptafluoropropyl)hydroxymethylene)-(+)-cam-
3
Substrates 8 were purchased from Aldrich Chemical Co. and
used without additional purification unless otherwise noted.
Sultams 5a -c were prepared by reduction of the corresponding
phorato]europium(III) [Eu(hfc) ].
Gen er a l P r oced u r e for Asym m etr ic F lu or in a tion of
Ca r bon yl En ola tes 8 Usin g N-F lu or o Ca m p h or su lta m s
(
4
camphorsulfonyl)imines 6 with NaBH as previously de-
(
3). In a 25-mL oven-dried two-necked round-bottomed flask
2
7,48
scribed.
fitted with an argon bubbler, a rubber septum, and a magnetic
stirring bar was placed 3 mL of freshly distilled THF contain-
ing 0.4 mmol of 3. The reaction flask was cooled to -78 °C
(dry ice-acetone bath), and 0.6 mL (0.6 mmol, 1.5 equiv based
on the carbonyl compound) of a 1.0 M solution of either LDA,
NaHMDS, or KHMDS in THF was added. The mixture was
then stirred for 5 min at -78 °C, warmed to 0 °C, stirred for
an additional 45 min, and cooled to -78 °C. A solution of the
N-fluorocamphorsultam 3 (1.1 mmol) in 3 mL of THF was
quickly added to the reaction mixture. After the reaction was
complete, as indicated by TLC, the reaction mixture was
Fluorinations was carried out in the apparatus recom-
mended by Matheson Gas Products for the handling of dilute
concentrations of F /N . For a related apparatus see ref 49.
2 2
Ca u tion : Flu or in e is a poison ou s, cor r osive ga s wh ich
is a power fu l oxid a n t.
(
+)-N-F lu or o-2,10-(3,3-d ich lor oca m p h or su lt a m ) (3b).
In a 50 mL two-necked round-bottomed flask fitted with a
Teflon septum, a Teflon adapter with a Teflon outlet tube
attached to a soda lime tower, and a Teflon O-ring to hold the
Teflon tube was placed a solution of 3.0 g (10.6 mmol) of (+)-
2
,10-(3,3-dichlorocamphorsultam) (5b) in dry chloroform (50
4
quenched by addition of aqueous NH Cl (3 mL), ether (10 mL)
mL). To this solution was added 2.1 g (50 mmol) of NaF, dried
overnight under high vacuum. The reaction flask was cooled
to -40 °C (dry ice-acetonitrile bath), and dry nitrogen gas
at -78 °C was added, and the solution was warmed to room
temperature. The aqueous layer was extracted with ether (2
× 5 mL), the combined organic phases were washed with water
was passed into the solution. After 10 min, the N
stopped and fluorine gas (10% in N ) was introduced into the
solution. The flow rate of F was maintained at 60 mL/min,
2
flow was
4
(10 mL), brine (10 mL) and dried (MgSO ), and concentrated
2
to give an oil that was purified by preparative TLC (8% EtOAc
in pentane). Products were identified by comparison with
authentic samples and/or literature values.
2
and the reaction was continued until complete as indicated
by TLC (1.0-1.5 h). The fluorine gas flow was stopped, and
(-)-2-F lu or o-2-m eth yl-1-tetr a lon e (9a ): (50%), oil, 76%
2
the reaction mixture was purged with N for 15 min. The
ee [R]20 ) -21.5 (c 1.6, CHCl ); CD spectrum: molecular
D
3
solution was filtered, and the filtrate was washed with 20 mL
of CHCl and concentrated to give an oil which was purified
by column chromatography (CH Cl /n-pentane eluant, 70:30)
to give 2.13 g (67%) of (+)-3b: mp 161-162 °C; [R]
ellipticity [Q] (c 3.21, C H OH), 21 °C; [Q] -2833°; 19F NMR
2
5
325
3
(CDCl ) δ -154.4 (m). Its spectral properties were in agree-
3
ment with literature values.50,51
2
2
2
0
D
) +16.4
); IR (KBr) cm 2990, 1407, 1279, 1197, 1065;
(
+)-2-Ca r bom eth oxy-2-flu or o-1-tetr a lon e (9b): (90%),
-
1
(
c ) 1.3, CHCl
3
20
oil; 41% ee, [R]
D
) +6.12 (c 2.0, CHCl
3
); IR (NaCl) 1765 and
) δ 2.51-2.85 (m, 2 H), 3.0-
.28 (m, 2 H), 3.85 (s, 3 H), 7.23-7.41 (m, 2 H), 7.50-7.60 (m,
1
H NMR(CDCl
H), 2.31-2.43 (m, 1 H), 2.61 (d, J ) 4.2, 1 H), 3.36 (qAB, J
4.1 Hz, J
) 25.7 Hz, 2 H), 4.01 (d, J ) 44.9 Hz, 1 H); 13
NMR (CDCl
3
) δ 1.07 (s, 3 H), 1.46 (s, 3 H), 1.70-2.13 (m, 3
-1 1
1
3
1
3
1
695 (CdO) cm ; H NMR (CDCl
3
1
)
1
2
C
13
H), 8.05-8.11 (m, 1 H); C NMR (CDCl ) δ 24.9, 31.6, and
3
3
9
) δ 22.3, 23.2, 25.5, 31.9, 47.9, 48.0, 50.0, 61.8,
2.0 (d, J ) 22.2), 53.0, 91.7, and 94.8 (d, J ) 194.3 Hz), 127.3,
1
8
3.7, 91.6; F NMR (CDCl
3
) δ -53.9 (d, J ) 48.4 Hz). Anal.
28.5, 128.8, 130.4, 134.6, 142.1, 167.6 and 168.0 (d, J ) 25.8
Calcd for C10
H, 4.65.
H
14Cl
2
FNO
2
S: C, 39.75; H, 4.67. Found: C, 39.63;
19
Hz), 188.3 and 188.6 (d, J ) 18.1 Hz); F NMR (CDCl
3
) δ -156
(
m). Anal. Calcd for C12
C, 64.41; H, 4.78.
(+)-2-Ca r b om et h oxy-5,8-d im et h oxy-2-flu or o-1-t et r a l-
3
H11FO : C, 64.86; H, 4.95. Found:
(46) For examples of metal chelation involving sulfonyl oxygens
2
0
see: Trost, B. M.; Schmuff, N. R. J . Am. Chem. Soc. 1985, 107, 396.
Hellwinkel, D.; Lenz, R.; Lammerzahl, F. Tetrahedron 1983, 39, 2073.
Giblin, G. M. P.; Simpkins, N. S. J . Chem. Soc., Chem. Commun. 1987,
on e (9c): (95%), oil; 46% ee [R]
+4.93 (c 1.4, CHCl
); IR
D
3
-1
1
(
2
3
NaCl) 1762 and 1686 (CdO) cm ; H NMR (CDCl ) δ 2.48-
3
.78 (m, 2 H), 3.00-3.09 (t, J ) 6.0 Hz, 2 H), 3.70 (s, 3 H),
.81 (s, 3 H), 3.87 (s, 3 H), 6.79-6.87 (d, J ) 9.06 Hz, 1 H);
2
07. Hollstein, W.; Harms, K.; Marsch, M.; Boche, G. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1287.
47) For recent studies on the influence of HMPA on anion aggrega-
1
3
(
7.01-7.09 (d, J ) 9.06 Hz, 1 H); C NMR (CDCl ) δ 18.9, 22.9
3
tion see: Collum, D. B. Acc. Chem. Res. 1992, 25, 448. J ackman, L.
M.; Chen, X. J . Am. Chem. Soc. 1992, 114, 403.
and 23.2 (d, J ) 18.3 Hz), 30.2 and 30.5 (d, J ) 19.0 Hz), 52.8,
(
48) Weismiller, M. C.; Towson, J . C.; Davis, F. A. Organic Syntheses;
Wiley: New York, 1993; Coll. Vol. VIII, p 110.
49) Purrington, S. T.; Woodard, D. J . J . Org. Chem. 1991, 56, 142.
(50) Differding, E.; Lang, R. W. Helv. Chim. Acta 1989, 72, 1248.
(51) Differding, E.; Ofner, H. Synlett 1991, 187.
(

2
280 J . Org. Chem., Vol. 63, No. 7, 1998
Davis et al.
5
5.9 and 56.2 (d, J ) 18.3 Hz), 92.3 and 95.4 (d, J ) 194.4
septum, an argon bubbler, and a magnetic stirring bar was
placed 0.170 g (1 mmol) of (R)-(-)-N,S-dimethyl-S-phenylsul-
foximine in THF (5 mL) at -78 °C. n-BuLi (2.5 M in hexane,
0.44 mL, 1.1 mmol) was added to the reaction mixture, it was
stirred at room temperature for 15 min, the yellow solution
was cooled to -78 °C, and 0.178 g (1 mmol) of (()-9 in THF (1
mL) was added. The mixture was stirred for 45 min at -78
Hz), 110.3, 116.7, 120.3, 133.5, 149.8, 155.0, 167.8 and 168.2
1
9
(
(
5
d, J ) 25.8 Hz), 187.5 and 187.8 (d, J ) 18.4 Hz); F NMR
CDCl ) δ -155 (m). Anal. Calcd for C14 : C, 59.57; H,
.32. Found: C, 59.28; H, 5.22.
-)-2-Car boeth oxy-2-flu or ocyclopen tan on e (9d): (62%),
3
H15FO
5
(
2
0
19
oil; 34% ee [R]
D
-9.5 (c 5.24, CHCl
3 3
); F NMR (CDCl ) δ
-
164. Its spectral properties were in agreement with litera-
°C, quenched with saturated NH
ether (10 mL). The organic phase was washed with saturated
NaHCO (10 mL) and brine (10 mL), dried (MgSO ), and
4
Cl (1 mL), and diluted with
5
2
ture values.
(
+)-2-F lu or op h en ylp r op a n on e (9e): (41%), oil; racemic;
3
4
1
9
F NMR (CDCl
3
) δ -172.4 (m). Its spectral properties were
concentrated. The crude mixture was purified by flash chro-
matography (ether/n-hexane, 1:4) to give 0.016 g (10%) of 9,
0.11 g of fraction I and 0.122 g of fraction II (65% I+II).
Fraction I proved to be a mixture of two diastereomers in a
ratio of 1:5 by 19F NMR (δ -146.6 major, δ -151.0 minor).
Fraction II, a single diastereoisomer, was crystallized from
5
2
in agreement with literature values.
(
+)-Eth yl 2-flu or o-2-p h en ylp r op ion a te (9f): (54%), oil;
20 19
3
3% ee [R]
D
3 3
+0.92 (c 1.1, CHCl ); F NMR (CDCl ) δ -152.
Its spectral properties were in agreement with literature
values.
5
3
2
0
CH
2
Cl
2
and ether; mp: 124-5 °C; [R]
D
12.5 (c 1.13 CHCl
3
3
);
For m ation of (S)-(-)-2-Meth yl-2-flu or o-1-tetr alon e (9a)
Usin g Dieth yla m in osu lfu r Tr iflu or id e (DAST). In a 25
mL oven-dried two-necked flask equipped with a rubber
septum, an argon bubbler, and a magnetic stirring bar was
placed 0.10 g (0.57 mmol) of (R)-(+)-2-hydroxy-2-methyl-1-
1
9
1
F NMR (CDCl
3
) δ -149.7; H NMR (CDCl ), δ 7.75-6.80 (m,
9
2
2
H), 3.53 (d, J ) 14.7 Hz, 1 H), 3.35 (d, J ) 15.0, Hz 1 H,),
.96 (m, 1 H), 2.73-2.66 (m, 4 H, includes 3 H at 2.70), 2.37-
.29 (m, 1 H), 2.21-2.10 (m, 1 H), 1.83 (d, J ) 23.1 Hz, 3 H);
1
3
3
3
C NMR (CDCl ) δ 142-127 97.9 (d, J ) 174 Hz), 62.4 (d, J
tetralone (11, 95% ee) in CH
2
Cl
2
(3 mL). The reaction
3
)
4.0 Hz), 45.6, 31.5 (d, J ) 22.4 Hz), 29.5, 25.7 (d, J ) 4.0
Hz), 22.7 (d, J ) 26.4 Hz). Anal. Calcd for C21 S: C,
6.68; H, 6.38; N, 4.03. Found: C, 65.44; H, 6.35; N; 3.86.
Th er m olysis of â-Hyd r oxysu lfoxim in e 14. In a single-
mixture was cooled to -78 °C, and 0.138 g (0.86 mmol) of
DAST was added dropwise via syringe. After the addition was
complete, the reaction mixture was warmed to room temper-
ature, and aqueous sat. NH Cl (1 mL) was added dropwise
4
after the reaction was complete (TLC). The solution was
H
30FNO
2
6
necked round-bottomed flask equipped with a magnetic stir
bar and reflux condenser was placed 0.088 g (0.25 mmol) of
diluted with diethyl ether (10 mL), extracted with water (2 ×
1
4 in 2-BuOH (10 mL). The solution was refluxed for 2 h at
1
0 mL) and brine (2 × 10 mL), dried (MgSO
4
), and concen-
which time the solvent was concentrated, and the residue was
trated. Purification by prep TLC (8% ethyl acetate in pentane
2
0
purified by flash chromatography to give 0.011 g (87%) of 9a :
eluant) gave 0.02 g (20%) of 9a , 70% ee, [R]
CHCl ).
-Meth yl-1-n a p h th ol (12). This compound was isolated
in 54% yield from the DAST reaction described in the preced-
D
-20.8 (c 1.8,
2
0
[R]
D
-31.9 (c 1.95, CHCl
3
).
3
2
Ack n ow led gm en t. The work was supported by
grants from the National Science Foundation and the
National Institutes of Health.
3
6
1
ing section: mp 63-65 °C [lit. 64-66 °C]; H NMR (CDCl
δ 2.43 (s, 3 H), 5.08 (br s, exchangeable with D O, 1 H), 7.22-
.71 (m, 5 H), 8.10-8.18 (m, 1 H).
P r ep a r a tion of â-Hyd r oxy Su lfoxim in e (14). In a 25
mL oven-dried two-necked flask equipped with a rubber
3
)
2
7
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal struc-
ture data for (+)-4b and 14 (22 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(
52) Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetra-
hedron Lett. 1986, 27, 2715. Cousseau, J .; Albert, P. J . Org. Chem.
989, 54, 5380.
53) Takeuchi, Y.; Ogura, H.; Ishii, Y.; Koizumi, T. Chem. Pharm.
Bull. 1990, 38, 2404.
1
(
J O972045X