N-thioacyl 1,3-amino alcohols: Synthesis via ring-opening of oxiranes with thioamide dianions and applications as key intermediates leading to stereochemically defined 5,6-dihydro-4H-1,3-oxazines and 1,3-amino alcohols

Article abstract of DOI:10.1021/jo051378o

N-Thioacyl 1,3-amino alcohols were synthesized via the ring-opening of oxiranes with thioamide dianions generated from N-benzyl thioamides and BuLi in a highly regio- and stereoselective manner. The diastereomers of N-thioacyl 1,3-amino alcohols were read

Full text of DOI:10.1021/jo051378o

N-Thioacyl 1,3-Amino Alcohols: Synthesis via Ring-Opening of
Oxiranes with Thioamide Dianions and Applications as Key
Intermediates Leading to Stereochemically Defined
5,6-Dihydro-4H-1,3-oxazines and 1,3-Amino Alcohols
Toshiaki Murai,* Hiroaki Sano, Hiroyasu Kawai, Hideo Aso, and Fumitoshi Shibahara
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
mtoshi@cc.gifu-u.ac.jp
Received July 4, 2005
N-Thioacyl 1,3-amino alcohols were synthesized via the ring-opening of oxiranes with thioamide
dianions generated from N-benzyl thioamides and BuLi in a highly regio- and stereoselective
manner. The diastereomers of N-thioacyl 1,3-amino alcohols were readily separated by column
chromatography to give stereochemically defined N-thioacyl 1,3-amino alcohols. They underwent
intramolecular cyclization with Bu4NF and EtI to give 5,6-dihydro-4H-1,3-oxazines. The reaction
was specific with anti-N-thioacyl 1,3-amino alcohols, and cis-5,6-dihydro-4H-1,3-oxazines were
obtained with high efficiency, whereas the reaction of a syn-alcohol gave a thioimidate as a major
product. The reduction of N-thioacyl 1,3-amino alcohols with LiAlH4 gave N-alkyl 1,3-amino alcohols
in high yields. The use of optically active propylene oxide as a starting material gave the
corresponding oxazine and alcohols in optically pure forms.
SCHEME 1
Introduction
Although little information is available regarding
N-thioacyl 1,3-amino alcohols I, they are an interesting
class of compounds as key precursors leading to nitrogen
atom-containing heterocycles1 as well as skeletons in
biologically related molecules.2 Two representative pro-
cedures for their synthesis have been reported to date:
i.e., thioacylation of amines with dithioic acid esters or
dithioic acid salts (route A)1a,b,3 and thionation of N-acyl
1,3-amino alcohols (route B)1d,4 (Scheme 1).
In these reactions, the carbon skeletons of I were
preformed as in 1,3-amino alcohols II and N-acyl 1,3-
amino alcohols III, and the sulfur atom of I was intro-
duced to II and III in the final step to prepare I. Recently,
carbon-carbon bond-forming reactions using carbanions
(1) (a) Lawson, A.; Searle, C. E. J. Chem. Soc. 1957, 1556. (b)
Laduron, F.; Nyns, C.; Janousek, Z.; Viehe, H. G. J. Prakt. Chem. 1997,
339, 697. (c) Wipf, P.; Hayes, G. B. Tetrahedron 1998, 54, 6987. (d)
Leflemme, N.; Dallemagne, P.; Rault, S. Tetrahedron Lett. 2004, 45,
1503.
(2) (a) Brossmer, R.; Isecke, R.; Herrler, G. FEBS Lett. 1993, 323,
96. (b) Brossmer, R.; Gross, H. J. Methods Enzymol. 1994, 247, 153.
(c) Terada, T.; Kitajima, K.; Inoue, S.; Koppert, K.; Brossmer, R.; Inoue,
Y. Eur. J. Biochem. 1996, 236, 852. (d) Brossmer, R.; Klenk, H.-D.;
Herrler, G. Virology 1996, 218, 127. (e) Guzaev, A. P.; Manoharan, M.
J. Am. Chem. Soc. 2001, 123, 783. (f) Hwang, O.; Kim, G.; Jang, Y. J.;
Kim, S. W.; Choi, G.; Choi, H. J.; Jeon, S. Y.; Lee, D. G.; Lee, J. D.
Mol. Pharm. 2001, 59, 1249.
(3) (a) Sicher, J.; Pankova, M.; Jonas, J. Svoboda, M. Collect. Czech.
Chem. Commun. 1959, 24, 2727. (b) Drefahl, G.; Horhold, H. H. Chem.
Ber. 1961, 94, 1641. (c) Legrand, L.; Lozac’h, N. Phosphorus Sulfur
Relat. Elem. 1986, 26, 111. (c) Isecke, R.; Brossmer, R. Tetrahedron
1994, 50, 7445. (d) Katritzky, A. R.; Moutou, J.-L. Yang, Z. Synthesis
1995, 1497.
(4) Haske, B. J.; Matthews, M. E.; Conkling, J. A.; Perzanowski, H.
P. J. Org. Chem. 1967, 32, 1579.
10.1021/jo051378o CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/30/2005
8148
J. Org. Chem. 2005, 70, 8148-8153

N-Thioacyl 1,3-Amino Alcohols
TABLE 1. Ring-Opening of Oxiranes with Thioamide
Dianions 2 Derived from Thioamides 1 and BuLia
SCHEME 2. Ring-Opening of Propylene Oxide 3a
with a Thioamide Dianion 2a
derived from a wide range of thioamides have been
extensively studied.5 Among them, we noted that thio-
amide dianion 2a generated from thioamide 1a and BuLi
underwent ring-opening of propylene oxide (3a) to give
N-thioacyl 1-phenyl-1,3-amino alcohol 4aa6a during our
studies on the reactivity of reactive species derived from
thioamides6 (Scheme 2).
Characteristically, the carbanion adjacent to the ni-
trogen atom is selectively generated, and the oxirane is
electrophilically introduced to the carbon atom R to the
nitrogen atom. Since various types of oxiranes are readily
available,7 the protocol in Scheme 2 may provide a new
synthetic route to N-thioacyl 1,3-amino alcohols. We
report here details of the synthesis of N-thioacyl 1,3-
amino alcohols via the ring-opening of oxiranes with
thioamide dianions. Synthetic reactions with N-thioacyl
1,3-amino alcohols leading to 5,6-dihydro-4H-1,3-oxazines
and 1,3-amino alcohols are also reported.
Results and Discussion
Ring-Opening of Oxiranes with Thioamide Di-
anions. The wide applicability of the ring-opening of
oxiranes with thioamide dianions 2 is illustrated in Table
1. The thioamide dianions 2b and 2c were efficiently
generated from thioamides 1b and 1c with 2 equiv of
BuLi at 0 °C, and 3a was then added to the reaction
mixture at the same temperature. The ring-opening of
3a with 2b and 2c proceeded smoothly with high regio-
selectivity to give N-thioacyl 1,3-amino alcohol 4ab and
4ac in respective yields of 90 and 80% (entries 1 and 2).
The reaction of thioamide dianion 2a with monosubsti-
tuted oxirane 3b took place under reaction conditions
identical to those for 3a (entry 3), whereas the reaction
with oxiranes 3c and 3d was carried out below -45 °C
(entries 4 and 5). As a result, functional groups such as
methoxy and hydroxy groups and chlorine atom remained
intact and did not affect the regioselectivity, although the
stereoselectivity was slightly dependent on these sub-
stituents. The use of the oxirane bearing a tert-butyl
group 3e enhanced the stereoselectivity probably because
of the steric reason (entry 6). Notably, although products
4a-e were obtained as stereoisomeric mixtures, they
could be separated as single isomers by ordinary column
(5) For reviews, see: (a) Metzner, P. In Topics in Current Chemistry;
Page, P. C. B., Ed.; Springer-Verlag: Berlin, 1999; Vol. 204, p 127. (b)
Murai, T. In Topics in Current Chemistry; Kato, S., Ed.; Springer-
Verlag: Berlin, 2005; Vol. 251, p 247.
(6) (a) Murai, T.; Aso, H.; Tatematsu, Y.; Itoh, Y.; Niwa, H. J. Org.
Chem. 2003, 68, 8514. (b) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami,
M. J. Am. Chem. Soc. 2004, 126, 5968. (c) Murai, T.; Ohta, Y.; Mutoh,
Y. Tetrahedron Lett. 2005, 46, 3637.
(7) For recent reviews of the synthesis of oxiranes, see: (a) Lane,
B. S.; Burgess, K.; Chem. Rev. 2003, 103, 2457. (b) Shi, Y. Acc. Chem.
Res. 2004, 37, 488. (c) Yang, D. Acc. Chem. Res. 2004, 37, 497. (d)
Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611.
a The reaction was carried out as follows, unless otherwise
noted. Thioamide dianions 2 were treated with oxiranes 3 (1 equiv)
in THF at 0 °C for 1 h. b Isolated yield. c At -45 °C. d BuLi (3.5
equiv) and 3d (1.6 equiv) were used at -78 °C.
J. Org. Chem, Vol. 70, No. 20, 2005 8149

Murai et al.
chromatography on silica gel.8 In contrast to the reaction
with 3a-e, ring-opening of styrene oxide (3f) with
thioamide dianion 2a proceeded exclusively at the carbon
atom bearing a phenyl group to give 4f′ as a major
product (entry 7).9 In this reaction, the stereochemistry
of two successive carbon atoms was also controlled. The
trans-opening of oxiranes with thioamide dianions 2 was
proven by the reaction with cyclohexene oxide (3g) and
oxirane bearing an acetal group 3h to give two diaster-
eomers 4g, 4g′ and 4h, 4h′ out of four possible isomers
(entries 8 and 9). The high stereoselectivity of the ring-
opening of oxiranes was further illustrated by the reac-
tion with cis- (3i) and trans-2-butene oxide (3j) (entries
10 and 11). In the reaction with 3i, two diastereomers
4i and 4i′ were formed in a nearly equal ratio, whereas
the reaction with 3j gave the other two isomers 4j and
4j′.
TABLE 2. Intramolecular Cyclization of N-Thioacyl
1,3-Amino Alcohols 4 Leading to
5,6-Dihydro-4H-1,3-oxazines 5a
The ring-opening of 1,1,2-trisubstituted oxirane 3k
with 2a exhibited high regio- and stereoselectivity to give
N-thioacyl 1,3-amino alcohol 4k in good yield (entry 12).
The stereochemistry of syn-4d, 4f′, 4j′, and 4k was
unequivocally determined by X-ray molecular analyses.11
On the basis of the NMR spectra of these products, the
stereochemistry of other products 4 was determined.
Synthesis of 5,6-Dihydro-4H-1,3-oxazines via In-
tramolecular Cyclization of N-Thioacyl 1,3-Amino
Alcohols. Due to the broad utility of 5,6-dihydro-4H-1,3-
oxazines as key intermediates in organic syntheses,
several synthetic methods have been developed.12 In
particular, [1,4]-cycloaddition reactions of N-acyl imines
or iminiums with alkenes have been investigated to
achieve their stereoselective synthesis.13 Thus, the in-
tramolecular cyclization of N-thioacyl 1,3-amino alcohols
obtained was examined to obtain stereochemically de-
fined oxazines. The conversion of N-thioacyl 1,3-amino
alcohols to thiazines has been developed,1c,d,14 whereas
to the best of our knowledge their conversion to oxazines
has not been reported.
a The reaction was carried out as follows, unless otherwise
noted. N-Thioacyl 1,3-amino alcohols 4 were treated with Bu4NF
(2 equiv) and EtI (2 equiv) in THF at 0 °C for 1 h. b Isolated yield.
c Bu4NF (3 equiv) and EtI (4 equiv) were used.
After several disappointing results, we found that
treatment of anti-N-thioacyl 1,3-amino alcohols 4 with 2
equiv of Bu4NF, followed by the reaction with 2 equiv of
SCHEME 3
(8) The two diastereomers of N-thioacyl 1,3-amino alcohols 4 were
easily distinguished on the basis of their light yellow color during the
column purification.
(9) The ring-opening of styrene oxide (3f) with organolithium
reagents has often been carried out in the presence of Lewis acids to
obtain high regioselectivity and to avoid the rearrangement of 3f.10 In
contrast, regioselective ring-opening of 3f with thioamide dianion 2a
was achieved even in the absence of Lewis acids.
(10) (a) Imogai, H.; Larcheveque, M. Tetrahedron: Asymmetry 1997,
8, 965. (b) Botuha, C.; Haddad, M.; Larcheveque, M. Tetrahedron:
Asymmetry 1998, 9, 1929.
EtI, gave 4,6-cis-oxazines 5 in good yields (Table 2).
Functional groups such as methoxy group and fluorine
and chlorine atoms did not affect the reaction course, and
the corresponding products were obtained in yields of 54-
77% (entries 3-6). The intramolecular cyclization of
alcohols 4g-i proceeded with better efficiency than that
of other alcohols to give 4,5,6-trisubstituted oxazines
5g-i in higher yields (entries 7-9). Notably, the in-
tramolecular cyclization of alcohols 4 was specific with
anti-alcohols 4. The reaction of syn-4 did not give the
desired oxazines at all. For example, the reaction of syn-
4e with Bu4NF and EtI under conditions identical to
those in Table 2 gave the thioimidate 6e as a stereoiso-
meric mixture in 78% yield (Scheme 3). No ethylation
took place at the oxygen atom of 6e at this temperature.
(11) For details, see the Supporting Information.
(12) For recent examples, see: (a) Liu, S.; Mu¨ller, J. F. K.; Neu-
burger, M.; Schaffner, S.; Zehnder, M. Helv. Chim. Acta 2000, 83, 1256.
(b) Kuznetsov, V. V.; Brusilovskii, Y. E. Chem. Heterocycl. Commun.
2001, 37, 574. (c) Nakajima, N.; Saito, M.; Kudo, M.; Ubukata, M.
Tetrahedron 2002, 58, 3579. (d) Gaulon, C.; Gizecki, P.; Dhal, R.;
Dujardin, G. Synlett 2002, 952. (e) Nakajima, N.; Isobe, T.; Irisa, S.;
Ubukata, M. Heterocycles 2003, 59, 107. (f) Palko, M.; Hetenyi, A.;
Fueloep, F. J. Heterocycl. Chem. 2004, 41, 69. (g) Tse, M. K.; Doebler,
C.; Bhor, S.; Klawonn, M.; Maegerlein, H. H. Beller, M. Angew. Chem.,
Int. Ed. 2004, 43, 5255.
(13) (a) Gizecki, P.; Dhal, R.; Toupet, L.; Dujardin, G. Org. Lett. 2000,
2, 585. (b) Katritzky, A. R.; Ghiviriga, I.; Chen, K.; Tymoshenko, D.
O.; Abdel-Fattah, A. A. A. J. Chem. Soc., Perkin Trans. 2 2001, 530.
(c) Gizecki, P.; Dhal, R.; Poulard, C.; Gosselin, P.; Dujardin, G. J. Org.
Chem. 2003, 68, 4338.
(14) Nishio, T.; Konno, Y.; Ori, M.; Sakamoto, M. Eur. J. Org. Chem.
2001, 3553.
8150 J. Org. Chem., Vol. 70, No. 20, 2005

N-Thioacyl 1,3-Amino Alcohols
TABLE 3. Reduction of N-Thioacyl 1,3-Amino Alcohols
SCHEME 4
a
4 with LiAlH4
A plausible reaction pathway for the present reaction
is shown in Scheme 4.
The deprotonation from alcohols 4 with Bu4NF takes
place at both their nitrogen and oxygen atoms to form
dianions 7. Ethylation then proceeds selectively at the
sulfur atom to give thioimidates 8, probably because of
the greater nucleophilicity of thiolates compared to
alcoholates in 7. The thioimidates 8 undergo cyclization
through the attack of alcoholates to the carbon atom of
8 followed by the elimination of ethanethiolate, which
may be further trapped with excess EtI, to give oxazines
5 along with Et2S. For the reaction of anti-4, intra-
molecular cyclization may proceed via a six-membered
cyclic transition state, where two substituents (Ph and
R′) are oriented at the equatorial positions as in 4,6-cis-
8. On the other hand, the reaction of syn-4 may involve
unfavorable 4,6-trans-8 where 1,3-diaxial interaction may
be present. Consequently, no cyclization occurs with syn-
4.
Reduction of N-Thioacyl 1,3-Amino Alcohols. The
importance of stereochemically defined 1,3-amino alco-
hols has been well documented, and methods for their
synthesis have been extensively developed.15 For ex-
ample, construction of their stereocenters has involved
the reduction of 1,3-amino ketones,15g,i 1,3-imino
alcohols,15h,m and isoxazolines.15a,n The reduction of ste-
reochemically defined isoxazolidines15l,o also provides 1,3-
amino alcohols. Nevertheless, it is still not easy to obtain
stereochemically pure 1,3-amino alcohols with high ef-
ficiency. Therefore, the reduction of N-thioacyl 1,3-amino
alcohols 4 was tested since a variety of reducing agents
have been used for the reduction of thioamides. Among
a The reaction was carried out as follows, unless otherwise
noted. N-Thioacyl 1,3-amino alcohols 4 were treated with LiAlH4
(4 equiv) under reflux in THF for 15 min. b Isolated yield. c Under
reflux in Et2O for 2 h. d For 3 h.
these, LiAlH4 was used to efficiently reduce 4.16 The
results are shown in Table 3. In all cases, thiocarbonyl
groups in 4 were selectively converted to methylene
groups to give the corresponding 1,3-amino alcohols 9 in
high yields. While both Et2O and THF were effective as
solvents,17 the reaction in Et2O required a longer reaction
time.
(15) For recent examples of the stereoselective syntheses of 1-aryl-
1,3-amino alcohols, see: (a) Cicchi, S.; Bonanni, M.; Cardona, F.;
Revuelta, J.; Goti, A. Org. Lett. 2003, 5, 1773. (b) Davis, F. A.; Rao,
A.; Carroll, P. J. Org. Lett. 2003, 5, 3855. (c) Kuethe, J. T.; Comins, D.
L. Tetrahedron Lett. 2003, 44, 4179. (d) Rezaei, M.; Harris, T. M.; Rizzo,
C. J. Tetrahedron Lett. 2003, 44, 7513. (e) Josephsohn, N. S.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018. (f) Minter,
A.; Fuller, A. A.; Mapp, A. K. J. Am. Chem. Soc. 2003, 125, 6846. (g)
Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003,
125, 11208. (h) Kochi, T.; Tang, T. P. Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276. (i) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 16178. (j) Bernardi, L.; Bonini, B. F.; Comes-
Franchini, M.; Fochi, M.; Folegatti, M.; Grilli, S.; Mazzanti, A.; Ricci,
A. Tetrahedron: Asymmetry 2004, 15 245. (k) Rodriquez, A. C.; Ramos,
A. P.; Hawkes, G. E.; Berti, F.; Resmini, M. Tetrahedron: Asymmetry
2004, 15, 1847. (l) Revuelta, J.; Cicchi, S.; Brandi, A. Tetrahedron 2004,
45, 8375. (m) Matsubara, R.; Vital, P.; Nakamura, Y.; Kiyohara, H.;
Kobayashi, S. Tetrahedron 2004, 60, 9769. (n) Kennedy, A.; Nelson,
A.; Perry, A. Synlett, 2004, 967. (o) Chandrasekhar, S.; Babu, B. N.;
Ahmed, M.; Reddy, M. V.; Jagadeesh, S. B. Synlett 2004, 1303. (p)
Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. Synlett 2004, 1409.
(q) Cordova, A. Chem. Eur. J. 2004, 10, 1987.
Reaction with Enantiopure Propylene Oxide.
Finally, optically active propylene oxide was used as a
starting material in the present two-step synthesis of 5,6-
dihydro-4H-oxazines and 1,3-amino alcohols. The (S)-
propylene oxide was cleaved with thioamide dianion 2a
(16) (a) Seebach, D.; Lubosch, W.; Enders, D. Chem. Ber. 1976, 109,
1309. (b) Lubosch, W.; Seebach, D. Helv. Chim. Acta 1980, 63, 102. (c)
Goasdoue, C.; Gaudemar, M.; Mladenova, M. J. Organomet. Chem.
1981, 208, 279. (d) Goasdoue, C.; Goasdoue, N.; Gaudemar, M. J.
Organomet. Chem. 1984, 263, 273.
(17) In the reduction of 4c in THF, the chlorine atom was also
substituted with the hydrogen atom, but the reduction in Et2O gave
the desired product 9c.
J. Org. Chem, Vol. 70, No. 20, 2005 8151

Murai et al.
(15 mL) was added butyllithium (1.6 M solution in hexane,
6.50 mL, 10 mmol) at 0 °C under Ar atmosphere. The mixture
was stirred at that temperature for 0.5 h. After the addition
of propylene oxide (3a) (0.35 mL, 5.0 mmol), the mixture was
stirred at that temperature for 1 h. The reaction mixture was
poured onto water and extracted with Et2O (70 mL). The
organic layer was washed with water, dried over MgSO4,
filtered, and concentrated in vacuo. The resulting oil was
purified by column chromatography on silica gel (hexane/
AcOEt ) 1:1) to give anti-N-(3-hydroxy-1-phenylbutyl) 2,2-
dimethylpropanethioamide (0.541 g, 2.03 mmol, 41%, Rf )
0.25) and syn-N-(3-hydroxy-1-phenylbutyl) 2,2-dimethylpro-
panethioamide (0.645 g, 2.43 mmol, 49%, Rf ) 0.39) as a pale
yellow solid. Anti: mp 46-48 °C; IR (KBr) 3350, 3029, 2965,
SCHEME 5
SCHEME 6
SCHEME 7
1
2927, 1515, 1455, 1382, 1351, 1131, 757, 698 cm-1; H NMR-
(CDCl3) δ 1.22 (d, J ) 6.3 Hz, 3H), 1.34 (s, 9H), 1.93-1.96 (m,
1H), 1.97-1.98 (m, 1H), 2.60 (br, 1H), 3.87 (dqd, J ) 9.3, 6.3,
2.9 Hz, 1H), 5.62 (td, J ) 14.6, 6.3 Hz, 1H), 7.23-7.35 (m,
5H), 8.32 (br, 1H); 13C NMR(CDCl3) δ 24.6, 30.0, 44.5, 44.7,
58.5, 66.6, 126.5, 127.5, 128.8, 141.2, 212.3; MS (EI) m/z 265
(M+); HRMS calcd for C15H23NOS 265.1500, found 265.1476.
Syn: mp 65-67 °C; IR (KBr) 3237, 3027, 2969, 1524, 1386,
1359, 1120, 1070, 970, 758, 700 cm-1; 1H NMR(CDCl3) δ 1.21
(d, J ) 6.3 Hz, 3H), 1.38 (s, 9H), 1.92-2.01 (m, 2H), 2.50 (br,
1H), 3.87 (dqd, J ) 2.4, 3.4, 6.3 Hz, 1H), 5.97 (td, J ) 7.8, 2.4
Hz, 1H), 7.22-7.36 (m, 5H), 8.87 (br, 1H); 13C NMR(CDCl3) δ
23.9, 30.2, 43.2, 44.7, 57.1, 64.7, 126.3, 127.4, 128.8, 139.9,
212.3; MS (EI) m/z 265 (M+); HRMS calcd for C15H23NOS
265.1500, found 265.1509.
General Procedure for the Intramolecular Cyclization
of N-Thioacyl 1,3-Amino Alcohols. A Representative
Procedure for the Synthesis of (4R,6R)-5,6-Dihydro-2-(4-
fluorophenyl)-6-methyl-4-phenyl-(4H)-1,3-oxazine (5ac).
To a solution of N-(1R*,3R*)-3-hydroxy-1-phenylbutyl-4-fluo-
robenzenecarbothioamide (0.469 g, 1.55 mmol) in THF (16 mL)
was added tetrabuthylammonium fluoride (1.0 M solution in
THF, 3.30 mL, 3.30 mmol) at 0 °C under Ar atmosphere. The
mixture was stirred at that temperature for 0.5 h. After the
addition of ethyl iodide (0.27 mL, 3.4 mmol), the mixture was
stirred at that temperature for 0.5 h. The reaction mixture
was poured onto Et2O (40 mL), and the organic layer was
washed with 3 × 10 mL of water. The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The resulting
oil was purified by column chromatography on silica gel
(hexane/Et2O ) 1:1) to give (4R,6R)-5,6-dihydro-2-(4-fluoro-
phenyl)-6-methyl-4-phenyl-(4H)-1,3-oxazine (0.321 g, 1.19 mmol,
77%, Rf ) 0.71) as a white solid: mp 95-97 °C dec; IR (KBr)
derived from thioamide 1a and BuLi to form two dia-
stereomers 4l and 4l′ in a combined yield of 91% (Scheme
5).
The two diastereomers 4l and 4l′ were successfully
separated as a diastereomerically pure form. Compound
4l was subjected to intramolecular cyclization to form
enantiomerically pure oxazine 5l in good yield (Scheme
6).
Furthermore, the reduction of 4l and 4l′ with LiAlH4
produced 1,3-amino alcohols 9l and 9l′ as an enantio-
merically pure form (Scheme 7).
In summary, we have demonstrated the regio- and
stereoselective ring-opening of oxiranes with thioamide
dianions, followed by chromatographic separation, to give
stereochemically defined N-thioacyl 1,3-amino alcohols.
Intramolecular cyclization of N-thioacyl 1,3-amino alco-
hols with Bu4NF and EtI provided an efficient route to
stereochemically defined 5,6-dihydro-4H-1,3-oxazines with
high efficiency. This reaction was specific with anti-
alcohols. Highly efficient reduction of N-thioacyl 1,3-
amino alcohols was achieved with LiAlH4 to produce 1,3-
amino alcohols, where the relative stereochemistry of two
or three carbon centers is defined. The ready availability
of various types of optically active oxiranes has enhanced
the wide applicability of the present reaction, as exempli-
fied by the reaction of (S)-propylene oxide. Further
studies on the thioamide dianions and products obtained
here are in progress.
3027, 2975, 1652, 1603, 1507, 1283, 1152, 1138, 846, 700 cm-1
;
1H NMR (CDCl3) δ 1.42 (d, J ) 6.4 Hz, 3H), 2.29 (ddd, J )
13.7, 4.9, 2.4 Hz, 2H), 4.50 (dqd, J ) 11.7, 6.4, 2.4 Hz, 1H),
4.71 (dd, J ) 11.7, 4.9 Hz, 1H), 7.02-8.07 (m, 9H); 13C NMR
(CDCl3) δ 21.4, 38.7, 56.6, 71.7, 114.9 (d, JC-F ) 21.5 Hz),
126.4, 127.8, 128.6, 129.5 (d, JC-F ) 8.8 Hz), 130.2 (d, JC-F
)
2.4 Hz), 144.6, 155.1, 164.4 (d, JC-F ) 249.6 Hz); MS (EI) m/z
269 (M+). Anal. Calcd for C17H16FNO: C, 75.82; H, 5.99.
Found: C, 76.11; H, 6.04.
General Procedure for the Reduction of N-Thioacyl
1,3-Amino Alcohols. A Representative Procedure for the
Synthesis of syn-N-2,2-Dimethylpropyl 3-Hydroxy-1-phen-
ylbutylamine (9a). To a solution of lithium aluminum
hydride (0.0790 g, 2.08 mmol) in THF (2 mL) was added syn-
N- (3-hydroxy-1-phenylbutyl) 2,2-dimethylpropanethioamide
(0.1330 g, 0.501 mmol) at 0 °C, and the mixture was heated
at reflux for 15 min with stirring. Then, to the reaction mixture
were added water (0.079 mL), 15% NaOH aq (0.079 mL), and
water (0.237 mL) at 0 °C. The resulting oil was filtered and
concentrated in vacuo to give syn-N-2,2-dimethylpropyl 3-hy-
droxyphenylbutylamine (0.1097 g, 0.466 mmol, 93%) as a pale
yellow oil: IR (KBr) 3348, 2954, 2865, 1466, 1454, 1364, 1121,
909, 755, 733, 701 cm-1; 1H NMR (CDCl3) δ 0.91 (s, 9H, CH3),
1.18 (d, J ) 5.9 Hz, 3H, CH3), 1.75-1.86 (m, 2H, CH2), 2.26 (d,
J ) 11.2 Hz, 1H, CH2NH), 2.32 (d, J ) 11.2 Hz, 1H, CH2NH),
Experimental Section
General Procedures. All reactions were carried out under
an argon atmosphere.
General Procedure for the Synthesis of N-Thioacyl
1,3-Amino Alcohols. A Representative Procedure for the
Synthesis of N-3-Hydroxy-1-phenylbutyl 1,1-Dimethyl-
propanethioamide (4ab). To a solution of N-phenylmethyl
2,2-dimethylpropane thioamide (1b) (1.036 g, 5 mmol) in THF
8152 J. Org. Chem., Vol. 70, No. 20, 2005

N-Thioacyl 1,3-Amino Alcohols
3.90-3.99 (m, 2H, CHPh, CHOH), 7.24-7.37 (m, 5H, Ar); 13C
NMR (CDCl3) δ 23.0, 27.7 (CH3), 31.2 (C), 43.1, 60.0 (CH2),
65.3, 61.7 (CH), 126.5, 127.1, 128.5, 143.0 (Ar); MS (EI) m/z
235 (M+); HRMS calcd for C15H25NO 235.1936, found 235.1931.
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Spectroscopic data
for 4, 5, 6e, and 9 and tables of crystallographic data for syn-
4d, 4f′, 4j′, and 4k. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported in part
by a Grant-in-Aid for Scientific Research from the
JO051378O
J. Org. Chem, Vol. 70, No. 20, 2005 8153