Synthesis of N -Cbz-Substituted β3-Amino Ketones Utilizing 4-Substituted 1,3-Oxazinan-6-ones

Article abstract of DOI:10.1055/s-0032-1318345

Stereoselective synthesis of N-Cbz-substituted β-amino ketones exploiting the versatile 1,3-oxazin-6-one scaffold is reported. The 4-substituted 1,3-oxazinan-6-ones were enolized and acylated diastereoselectively by addition of various acyl halides. Acidic decarboxylation was then employed to smoothly transform the 5-acylated products to chiral β-amino ketones. This methodology further highlights the utility of the 1,3-oxazinan-6-one as a scaffold to access valuable synthons that are used in the peptidomimetic field. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318345

LETTER
▌823
lSetyternthesis of N-Cbz-Substituted β3-Amino Ketones Utilizing 4-Substituted 1,3-
Oxazinan-6-ones
N-Cbz-Substituted β3-Amino Ketones
Brad E. Sleebs,a,b Nghi H. Nguyen,c Andrew B. Hughes*c
a
The Walter and Eliza Hall Institute of Medical Research, Parkville 3010, Australia
b
Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
c
Department of Chemistry, La Trobe University, Victoria 3086, Australia
Fax +61(3)94791266; E-mail: tahughes@optusnet.com.au
Received: 07.02.2013; Accepted after revision: 12.02.2013
R1
N-methyl
Abstract: Stereoselective synthesis of N-Cbz-substituted β-amino
β3-amino
Cbz
OH
ketones exploiting the versatile 1,3-oxazin-6-one scaffold is report-
ed. The 4-substituted 1,3-oxazinan-6-ones were enolized and acyl-
ated diastereoselectively by addition of various acyl halides. Acidic
decarboxylation was then employed to smoothly transform the 5-
acylated products to chiral β-amino ketones. This methodology fur-
ther highlights the utility of the 1,3-oxazinan-6-one as a scaffold to
access valuable synthons that are used in the peptidomimetic field.
hydroxyl
2,3-amino
acids
N
acids
β
O
O
ref. 9
R1
R2
O
ref. 8
R1
Cbz
alkyl
2,3-amino
N
ref. 9
β
Cbz
O
acids
N
Key words: ketones, amino acids, acylation, ring opening, oxazi-
R1
R2
ref. 7
nanones
O
O
Cbz
dialkyl
N
2,2,3-amino
this
work
β
ref. 10
acids
O
O
β-Amino ketones are important synthetic precursors for
many syntheses1,2 and also have demonstrated biological
activity.3 There are numerous methods to gain access to β-
amino ketones, such as Michael addition of an amine sur-
rogate to an α,β-unsaturated ketone,4 via a Mannich reac-
tion,2,5 or by reduction of α,β-unsaturated ketones.6
However, many of these methods are limited in their use
and a large proportion do not produce chiral β-amino ke-
tones. To overcome the shortcomings of previous synthe-
ses, a stereoselective synthesis of β-amino ketones was
devised, starting from 1,3-oxazinan-6-ones.
R4
n
cyclic
Cbz
β3-amino
ketones
β
2,3-amino
acids
N
R3
O
O
Scheme 1 Transformations of the 1,3-oxazinan-6-one to produce
stereopure β-amino acid derivatives
The starting 1,3-oxazinan-6-ones 1–4 were easily pre-
pared in three steps from the parent N-protected α-amino
acids via the Arndt–Eistert homologation to produce the
corresponding β-amino acids. The β-amino acids were
then cyclized using a previously described method7–10 to
afford the N-protected 4-substituted 1,3-oxazinan-6-ones
1–4.
1,3-Oxazinan-6-ones have previously been utilized to
produce a variety of different β-amino acid derivatives.7–10
The versatility of the 1,3-oxazinan-6-one scaffold has
been shown to produce N-methyl β3-amino acids, 2-hy-
droxy,9 2-alkyl,9 and 2,2-dialkyl β3-amino acids,7 and re-
cently β2,3-cyclic amino acids10 (Scheme 1). Ring opening
of the 1,3-oxazinan-6-one has also been shown to produce
a variety of carboxylic acids, esters, and amides.7–10 Here-
in the versatility of the 1,3-oxazinan-6-one is further
exploited to produce chiral substituted β3-amino ketones.
It was proposed to produce the N-protected β3-amino ke-
tones in two steps from the 1,3-oxazinan-6-one. Firstly,
the 1,3-oxazinan-6-one would be enolized and then acyl-
ated by addition of an acyl halide. The 5-acylated oxazi-
nanone would then be subjected to an acid-mediated ring
opening followed by an in situ decarboxylation to produce
the N-protected β-amino ketone (Scheme 2).
The 5-position of the 1,3-oxazinan-6-one was then acylat-
ed using enolate chemistry.11 Enolization of the 1,3-oxa-
zinan-6-ones 1–4 was performed using LiHMDS as the
base at –78 °C. The acyl halide was then added at –78 °C.
The reaction was maintained at –78 °C for three hours be-
fore warming to –50 °C and quenching with an ammoni-
um chloride solution (Table 1).11 A combination of the 4-
substituted 1,3-oxazinan-6-ones 1–4 and various acyl ha-
lides were subjected to these conditions, and the results
are shown in Table 1. Moderate to good yields were ob-
tained across a range of different substrates, however, the
pivaloyl chloride used in entries 3, 6, and 9 consistently
gave the lowest yields (30%, 43%, and 28%, respective-
ly). Although the stereoselectivity of the 5-acylation reac-
tion is not of relevance, because the stereocenter is
removed in the next transformation to give the β-amino
ketone, in all cases the trans isomer was produced with
high diastereoselectivity (>95% dr, Table 1). The trans se-
SYNLETT 2013, 24, 0823–0826
Advanced online publication: 14.03.2013
DOI: 10.1055/s-0032-1318345; Art ID: ST-2012-B0561-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

824
B. E. Sleebs et al.
LETTER
ring
R1
O
O
O
R1
O
R1
O
opening and
decarboxylation
Cbz
Cbz
acylation
N
R2
Cbz
N
N
R2
H
O
Scheme 2 Proposed route to access β-amino ketones from 1,3-oxazinan-6-ones
lectivity was determined using coupling constants ob- the desired N-methyl β-amino ketone 25 was not obtained.
1
served in the H NMR spectra. The trans selectivity has The only product observed was the Cbz derivative of a
also been observed with both 5-alkylations and 5-hydrox- secondary amine 27. This was formed via an iminium spe-
ylations of numerous 4-substituted 1,3-oxazinan-6- cies 26 which is intercepted by a hydride anion from tri-
ones.7,9,10
ethylsilane. Possible uses of this unexpected reaction are
now being investigated.
The 5-acylated 1,3-oxazinan-6-ones 5–14 were then
transformed into the β-amino ketones under mild acidic To further elaborate the methodology demonstrated here
conditions (Table 1).12 The 5-acylated 1,3-oxazinan-6- to produce β-amino ketones, a 5-methylated 1,3-oxazi-
ones 5–14 were dissolved in a mixture of THF and 2 M nan-6-one 28 would be 5-acylated and then subsequently
HCl, and the mixture was heated at 50 °C for 4–6 h. Under subjected to acidic conditions to produce a disubstituted
the acidic conditions the 1,3-oxazinan-6-one ring opens to β2,3-amino ketone. The previously synthesized 5-methyl
produce the corresponding carboxylic acid. In situ decar- 1,3-oxazinan-6-one 28 was produced using enolate chem-
boxylation of the β-keto carboxylic acid and hydrolysis of
the iminium species then occurs to produce the β-amino
ketone (Scheme 3). The substituted β3-amino ketones 15–
24 were all prepared in high yields (Table 1).12,13
R1
R2
R1
R2
Cbz
Cbz
N
O
N
O
H
O
O
In an extension of this work, it was proposed that an N-
methyl β-amino ketone could also be produced using acid-
ic conditions. It has been established that reductive cleav-
age of the 1,3-oxazinan-6-one ring employing BF3·OEt2
or TFA and triethylsilane produces N-methyl β-amino ac-
ids.7–10 It was proposed to use the same acidic reductive
cleavage conditions to transform the 5-acylated 1,3-oxazi-
nan-6-one 5 into the N-methyl β-amino ketone 25
(Scheme 4). However, when this reaction was attempted
– HCOH
R2
H+
R1
O
R2
O
R1
R1
R2
H
N+
Cbz
Cbz
N+
O
H
Cbz
O
H
N
O
H
– CO2
O+
O
H
O
O
H
H
Scheme 3 Mechanism of the β-amino ketone formation
Table 1 Acylation of the 1,3-Oxazinan-6-ones 1–4 and β-Amino Ketone Formation 15–24
..
R1
R1
O
R1
O
Cbz
Cbz
b
a
Cbz
R2
N
N
R2
N
H
O
O
O
O
15–24
1–4
5–14
Entry
Oxazinanone
R1
R2
Product (yield, %)
Product (yield, %)
ee (%)
1
2
1
1
1
2
2
2
3
3
3
4
i-Pr
i-Pr
i-Pr
Et
5 (80)
6 (71)
15 (91)
16 (89)
17 (70)
18 (82)
19 (66)
20 (90)
21 (63)
22 (75)
23 (87)
24 (85)
97
100
99
Ph
3
t-Bu
Et
7 (30)
4
n-Bu
n-Bu
n-Bu
s-Bu
s-Bu
s-Bu
Bn
8 (79)
97
5
Ph
9 (65)
99
6
t-Bu
Et
10 (43)
11 (79)
12 (78)
13 (28)
14 (66)
100
98
7
8
Ph
100
98
9
t-Bu
Et
10
100
a Reaction conditions: (a) 1. LiHMDS, THF, –78 °C, 40 min; 2. R2COCl, –78 °C to –50 °C, 3 h; 3. NH4Cl; (b) 2 M HCl, THF, 50 °C, 4–6 h.
Synlett 2013, 24, 823–826 © Georg Thieme Verlag Stuttgart · New York

LETTER
N-Cbz-Substituted β3-Amino Ketones
825
i-Pr Et
BF3⋅OEt2
Et3SiH
i-Pr Et
Cbz
Cbz
N
O
N
O
O
O
25
5
H+
i-Pr Et
i-Pr Et
i-Pr Et
H+
Cbz
Cbz
N+
O
H
N
O
Cbz
N
O+
H
H
O
O+
O
O
Et3Si
i-Pr
H
i-Pr
Et
Et
+
Cbz
Cbz
N+
OH
N
O
26
27
Et3Si
H
Scheme 4 Attempted formation of the N-methyl β-amino ketone 25 and the mechanism of formation of the unexpected byproduct 27
istry and quenching with methyl triflate using established The methodology described again highlights the versatil-
conditions.7,9,10 The 5-methyl 1,3-oxazinan-6-one 28 was ity of the 1,3-oxazinan-6-one as a useful scaffold to access
then enolized and 5-acylated using benzoyl chloride to af- a diverse assortment of β-amino acids and β-amino ke-
ford 29 in moderate yield (40%). The 5,5-disubstituted tones for use in the peptidomimetic field.
1,3-oxazinan-6-one 29 was then subjected to acidic condi-
tions to produce the β-amino ketone as a mixture of dia-
stereoisomers 30 and 31 in a good yield (82%, Scheme 5).
Acknowledgment
We thank La Trobe University for the provision of a postgraduate
scholarship awarded to N.H.N. and the NHMRC (App. 1010326)
for funding B.E.S.
Although the stereochemistry was not the focus of this
transformation, because the stereocenter is epimerized un-
der the decarboxylation conditions, a sample of the trans
isomer was obtained during purification. This transforma-
tion further demonstrates the capacity of this methodolo-
Supporting Information for this article is available online at
gy to produce highly functionalized substituted β2,3-amino http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoprimntgirSatnoIuipfog
m
t
iornat
ketones.
In summary, the synthesis of chiral substituted β3-amino
ketones 15–24 has been described starting from 4-substi-
tuted 1,3-oxazinan-6-ones 1–4. The 1,3-oxazinan-6-ones
1–4 were acylated using enolate chemistry to afford the 5-
acylated 1,3-oxazinan-6-ones 5–14 in moderate to high
yields. The 5-acylated products 5–14 were then smoothly
transformed into the corresponding β-amino ketones 15–
24, under acidic conditions. This methodology was fur-
ther expanded to demonstrate that a disubstituted β2,3-ami-
no ketone (30 and 31) could also be produced starting
from the 5-methyl 4-substituted 1,3-oxazinan-6-one 28.
References and Notes
(1) (a) Barluenga, J.; Olano, B.; Fustero, S. J. Org. Chem. 1985,
50, 4052. (b) Bosch, J.; Rubiralta, M.; Domingo, A.; Sistaré,
J. J. Heterocycl. Chem. 1981, 18, 47. (c) Brough, P.; Pécaut,
J.; Rassat, A.; Rey, P. Chem. Eur. J. 2006, 12, 5134.
(d) Fisyuk, A. S.; Poendaev, N. V. Chem. Heterocycl.
Compd. 2003, 39, 895. (e) Fisyuk, A. S.; Ryzhova, E. A.;
Unkovskii, B. V. Chem. Heterocycl. Compd. 2001, 37, 597.
(f) Hansen, C. P.; Jensen, A. A.; Balle, T.; Bitsch-Jensen, K.;
Hassan, M. M.; Liljefors, T.; Fralund, B. Bioorg. Med.
Chem. Lett. 2009, 19, 87. (g) Holzgrabe, U. Arch. Pharm.
(Weinheim) 1988, 321, 767. (h) Keck, G. E.; Truong, A. P.
Org. Lett. 2002, 4, 3131. (i) King, F. D. Tetrahedron Lett.
1983, 24, 3281. (j) Lanter, J. C.; Chen, H.; Zhang, X.; Sui, Z.
Org. Lett. 2005, 7, 5905. (k) Richards, J. J.; Ballard, T. E.;
Huigens, R. W.; Melander, C. ChemBioChem 2008, 9, 1267.
(l) Son, P.-N.; Lai, J. T. J. Org. Chem. 1981, 46, 323.
(m) Winter, A.; Risch, N. Synthesis 2003, 2667. (n) Yagi, T.;
Aoyama, T.; Shioiri, T. Synlett 1997, 1063.
i-Pr
O
Cbz
b)
i-Pr
O
O
i-Pr
N
Ph
Ph
H
Cbz
Cbz
a)
N
Ph
N
30
O
O
O
i-Pr
O
28
29
(2) Webster, S. P.; Binnie, M.; McConnell, K. M. M.; Sooy, K.;
Ward, P.; Greaney, M. F.; Vinter, A.; Pallin, T. D.; Dyke, H.
J.; Gill, M. I. A.; Warner, I.; Seckl, J. R.; Walker, B. R.
Bioorg. Med. Chem. Lett. 2010, 20, 3265.
Cbz
N
H
31
(3) (a) Du, Y.; Li, Q.; Xiong, B.; Hui, X.; Wang, X.; Feng, Y.;
Meng, T.; Hu, D.; Zhang, D.; Wang, M.; Shen, J. Bioorg.
Med. Chem. 2010, 18, 4255. (b) Makarova, N.; Boreko, E.;
Moiseev, I.; Pavlova, N.; Zemtsova, M.; Nikolaeva, S.;
Vladyko, G. Pharm. Chem. J. 2001, 35, 480.
Scheme 5 Acylation of the 1,3-oxazinan-6-one 28 and β-amino ke-
tone (30 and 31) formation. Reagents and conditions: (a) 1. LiHMDS,
THF, –78 °C, 40 min; 2. PhCOCl, –78 °C to –50 °C, 3 h; 3. NH4Cl
(40%); (b) 2 M HCl, THF, 50 °C, 4–6 h (82%).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 823–826

826
B. E. Sleebs et al.
LETTER
(c) Schönenberger, H.; Bastug, T.; Bindl, L.; Adelheid, A.;
Adam, D.; Petter, A.; Zwez, W. Pharm. Acta Helv. 1969, 44,
691.
added dropwise and stirring was continued for 3 h at –78 °C.
The solution was then allowed to warm to –50 °C, and the
reaction was then quenched with sat. NH4Cl solution (5 mL).
The solution was diluted with EtOAc (20 mL) and washed
with H2O (20 mL). The organic layer was dried (MgSO4)
and concentrated in vacuo to give an oil. The oil was
subjected to flash column chromatography, eluting with 5–
30% EtOAc–hexane.
(4) (a) Davies, S. G.; McCarthy, T. D. Synlett 1995, 7, 700.
(b) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
(c) Gomtsyan, A. Org. Lett. 1999, 2, 11. (d) Wabnitz, T. C.;
Spencer, J. B. Tetrahedron Lett. 2002, 43, 3891.
(5) (a) Cardova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F. III. J. Am. Chem. Soc. 2002, 124, 1842.
(b) Das, B.; Reddy, K. R.; Ramu, R.; Thirupathi, P.;
Ravikanth, B. Synlett 2006, 1756. (c) Das, B.; Srilatha, M.;
Veeranjaneyulu, B.; Rama, Rao. B. Synthesis 2010, 803.
(d) Davis, F. A.; Yang, B.; Deng, J.; Zhang, J. ARKIVOC
2006, (viii), 120. (e) Eftekhari-Sis, B.; Abdollahifar, A.;
Hashemi, M. M.; Zirak, M. Eur. J. Org. Chem. 2006, 5152.
(f) Hartman, A. E.; Brophy, C. L.; Cupp, J. A.; Hodge, D. K.;
Peelen, T. J. J. Org. Chem. 2009, 74, 3952. (g) Jia, X.-D.;
Wang, X.-E.; Yang, C.-X.; Huo, C.-D.; Wang, W.-J.; Ren,
Y.; Wang, X.-C. Org. Lett. 2010, 12, 732. (h) Josephsohn, N.
S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004,
126, 3734. (i) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(j) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827. (k) Lou, S.; Dai, P.; Schaus, S.
E. J. Org. Chem. 2007, 72, 9998. (l) Lou, S.; Taoka, B. M.;
Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.
(m) Mei, H.; Xiong, Y.; Han, J.; Pan, Y. Org. Biomol.Chem.
2010, 9, 1402. (n) Notz, W.; Sakthivel, K.; Bui, T.; Zhong,
G.; Barbas, C. F. III. Tetrahedron Lett. 2001, 42, 199.
(o) Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292.
(p) Ranu, B. C.; Samanta, S.; Guchhait, S. K. Tetrahedron
2002, 58, 983. (q) Schunk, S.; Enders, D. Org. Lett. 2001, 3,
3177. (r) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2005,
128, 74. (s) Syu, S.-e.; Lee, Y.-T.; Jang, Y.-J.; Lin, W. J.
Org. Chem. 2011, 76, 2888. (t) Terada, M.; Machioka, K.;
Sorimachi, K. Angew. Chem. Int. Ed. 2006, 45, 2254.
(u) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List,
B. Nature (London) 2008, 452, 453. (v) Yang, J.-W.;
Stadler, M.; List, B. Angew. Chem. Int. Ed. 2007, 46, 609.
(6) Geng, H.; Huang, K.; Sun, T.; Li, W.; Zhang, X.; Zhou, L.;
Wu, W.; Zhang, X. J. Org. Chem. 2011, 76, 332.
Data for (4S,5R)-N-Benzyloxycarbonyl-4-isopropyl-5-
propionyl-1,3-oxazinan-6-one (5)
General Procedure 1 was followed for the acylation of
oxazinanone 1 (63 mg, 0.23 mmol) with propionyl chloride
(59.8 μL, 0.68 mmol), to afford the desired 5-substituted 1,3-
oxazinan-6-one 5 as a clear oil (crystallized on standing; 60
mg, 80% yield); mp 82–84 °C; Rf = 0.23 (20% EtOAc–
hexane); [α]D25 +116 (c 2.17, MeOH). 1H NMR (300 MHz,
CDCl3): δ = 7.33 (s, 5 H), 5.93 (d, 1 H, J = 9.9 Hz), 5.17 (s,
2 H), 4.93 (d, 1 H, J = 9.9 Hz), 4.59 (t, 1 H, J = 7.2 Hz), 3.73
(d, 1 H, J = 7.2 Hz), 2.84–2.73 (m, 1 H), 2.58–2.47 (m, 1 H),
1.88–1.77 (m, 1 H), 1.09 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H,
J = 7.2 Hz), 0.85 (d, 3 H, J = 7.2 Hz). 13C NMR (75 MHz,
CDCl3): δ = 202.7 167.3, 154.5, 134.9, 128.3, 128.1, 127.8,
72.9, 68.2, 55.9, 55.1, 36.5, 31.0, 18.3, 18.1, 7.2. IR (film):
νmax = 2967, 2940, 1748, 1717, 1458, 1412, 1258, 1123, 979
cm–1. HRMS (ESI–): m/z calcd for C18H23NO5 [M – H]–:
332.1503; found: 332.1496.
(12) General Procedure 2
Formation of the β3-Amino Ketones
The oxazinanone 15–24 was dissolved in a mixture of THF–
2 M HCl (1:1, 0.013 M solution), and the reaction mixture
was gently heated to 50 °C for 4–6 h. The THF was then
removed under reduced pressure. The aqueous solution was
taken up EtOAc and washed with H2O (3 × 10 mL) followed
by brine (1 × 10 mL). The organic layer was dried (MgSO4)
and evaporated in vacuo to give an oil. The oil was subjected
to flash column chromatography, eluting with 5–20%
EtOAc–hexane.
(13) Data for (5R)-(N-Benzyloxylcarbonyl-5-amino)-6-
methyl-heptan-2-one (15)
General Procedure 2 was followed for the hydrolysis of the
1,3-oxazinan-6-one 5 (31 mg, 0.09 mmol), and afforded the
β-amino ketone 15 as a white solid (24 mg, 92% yield); mp
75–77 °C; Rf = 0.50 (30% EtOAc–hexane); [α]D25 –3.6 (c
1.09, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.32–7.27
(m, 5 H), 5.14 (d, 1 H, J = 8.9 Hz), 5.06 (s, 2 H), 3.83–3.76
(m, 1 H), 2.61 (br d, 2 H, J = 5.7 Hz), 2.47–2.33 (m, 2 H),
1.89–1.80 (m, 1 H), 1.00 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H,
J = 4.2 Hz), 0.87 (d, 3 H, J = 4.5 Hz). 13C NMR (75 MHz,
CDCl3): δ = 210.0, 155.7, 136.3, 128.1, 127.6, 127.5, 66.2,
53.2, 43.9, 35.8, 31.2, 19.1, 18.2, 7.3. IR (film): νmax = 3325,
2940, 2878, 1709, 1682, 2539, 1454, 1416, 1308. HRMS
(ESI+): m/z calcd for C16H23NO3 [M + H]+: 278.1751; found:
278.1756. HPLC [Chiralpak AD-H, PE–2-PrOH (90:10),
25 °C, 254 nm]: tR (major) = 7.1 min; tR (minor) = 6.1 min,
97% ee.
(7) Nguyen, N. H.; Sleebs, B. E.; Hughes, A. B. Tetrahedron
2012, 68, 4745.
(8) (a) Sleebs, B. E.; Hughes, A. B. Helv. Chim. Acta 2006, 89,
2611. (b) Sleebs, B. E.; Hughes, A. B. Aust. J. Chem. 2006,
58, 778.
(9) Sleebs, B. E.; Hughes, A. B. J. Org. Chem. 2007, 72, 3340.
(10) Sleebs, B. E.; Nguyen, N. H.; Hughes, A. B. Tetrahedron
2013, 69, in press.
(11) General Procedure 1
5-Acylation of 1,3-Oxazinan-6-ones
A solution of the 1,3-oxazinan-6-one 1–4 (0.1 M in dry
freshly distilled THF) was cooled to –78 °C under an argon
atmosphere. Then LiHMDS (1.1 equiv of a 1.0 M solution in
THF) was added dropwise, and the solution was left to stir at
–78 °C for 40 min. The acylating agent (3.0 equiv) was then
Synlett 2013, 24, 823–826
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.