Synthesis of different types of valerolactams starting from 2,5-dihydrooxazoles

Article abstract of DOI:10.1016/j.tet.2009.10.107

Tricyclic valerolactams characterized by a variable heteroatom in γ-position, for example, sulfur, oxygen or nitrogen, were synthesized starting from 2,5-dihydrooxazoles. The chosen synthetic procedures included the addition of thiosalicylic acid as well

Full text of DOI:10.1016/j.tet.2009.10.107

Tetrahedron 66 (2010) 242–250
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Synthesis of different types of valerolactams starting from 2,5-dihydrooxazoles
*
Katharina Johannes, Ju¨rgen Martens
Institute of Pure and Applied Chemistry, University of Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26129 Oldenburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Tricyclic valerolactams characterized by a variable heteroatom in g-position, for example, sulfur, oxygen
Received 16 September 2009
Received in revised form 22 October 2009
Accepted 29 October 2009
or nitrogen, were synthesized starting from 2,5-dihydrooxazoles. The chosen synthetic procedures in-
cluded the addition of thiosalicylic acid as well as the addition of salicyl chloride. The nitrogen containing
lactams were prepared in a cycloaddition and subsequent oxidation.
Available online 1 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Imines
Valerolactams
Addition reactions
Diastereoselectivity
1. Introduction
Valerolactam substructures containing variable heteroatoms in
-position are numerously represented in heterocyclic compounds.
S
O
O
O
O
N
N
N
N
N
g
Heteroatoms taken into consideration are sulfur and oxygen as well
as nitrogen leading to the substructures I–III shown in Figure 1. In
literature, different ways to synthesize compounds including the
pointed substructures were described.1
O
1
O
2
O
3
O
4
Figure 2. 2,5-Dihydrooxazole 1 and the target structures 2–4.
Besides, some valerolactams show interesting characteristics as
biological active substances. Thiavalerolactams were reported, for
example, as anti-inflammatory agents3 and sodium channel
blockers4 used for the treatment of neurodegenerative conditions.
Oxavalerolactams structurally comparable to the aspired lactams
3 were described as modulators of neurotransmitters in the human
brain5 being useful for the treatment of mental disorders and dis-
eases of the nervous system.6 The aspired azavalerolactams 4 show
structural similarity with alkaloids, which are known for their anti-
inflammatory, antimicrobial and antidepressant activities7 as well
as their cytotoxicity.8 Furthermore, the N-heterocyclus of 2,5-
dihydrooxazoles 1 represents an interesting synthetic fragment
because the oxazolidin substructure is, for example, found in the
O
S
O
O
O
N
N
N
N
III
I
II
Figure 1. Valerolactam substructures I–III.
We focused our attention to the synthesis of tricyclic valer-
olactams 2–4 characterized by the emphasized substructures I–III
(Fig. 1). For this purpose, rarely used heterocyclic imines, the 2,5-
dihydrooxazoles 1, were chosen as starting material (Fig. 2). Due to
their aldiminic C]N-double bond, these reactive species 1 were
suited for addition reactions.2 Thus, we concentrated on different
addition reactions as preferred synthetic procedures leading to the
aspired target structures 2–4 (Fig. 2).
strong b
-lactamase inhibitor clavulanic acid.9
In addition, the 2,5-dihydrooxazoles 1 as well as comparable
compounds proved themselves in the synthesis of different lactam
systems, which were in the focus of our group in the recent past
(Fig. 3). For example, five-membered b-oxabutyrolactams IV were
prepared by addition of acid chloride followed by oxidation in the
presence of pyridinium chloro chromate.10 Five- or six-membered
* Corresponding author. Tel.: þ49 441 7983837; fax: þ49 441 7983757.
E-mail address: juergen.martens@uni-oldenburg.de (J. Martens).
lactams V (n¼1, 2) containing a sulfur in
b-, respectively, g-position
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.107

K. Johannes, J. Martens / Tetrahedron 66 (2010) 242–250
243
were synthesized by addition of thiocarboxylic acids to 2,5-dihy-
drothiazoles.11 Furthermore,
-unsaturated valerolactams VI
The g-thiavalerolactams 2a–f were prepared from 2,5-dihy-
a
,b
drooxazoles 1a–f and thiosalicylic acid by heating the reaction
mixture for several hours in toluene using a Dean–Stark apparatus.
Removing the formed water, the reaction was accelerated by dis-
placing the equilibrium between the intermediate proposed by
Tierney18 and the desired products 2a–f. The lactams 2a–f were
obtained in yields up to 74% (Table 1).
were obtained in a three-step synthesis comprising acid chloride
addition, Hosomi–Sakurai reaction and a ring-closing metathesis.12
In a comparable synthetic procedure
a
,b
-unsaturated
d-oxacapro-
lactams VII were formed.13
O
O
n
O
O
O
S
R
Table 1
O
N
N
N
N
g-Thiavalerolactams 2a–f
Imine
Lactam
R1
R2
R3
Yield (%)
dra (trans:cis)
O
IV
S
V
X
VI
X
VII
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
CH3
CH3
C6H5
C6H5
CH3
CH3
CH3
–(CH2)5–
CH3
–(CH2)5–
CH(CH3)2
C(CH3)3
CH3
27
43
50
74
57
40
d
d
n = 1 , 2
X = O, S
CH3
71:29
74:26
79:21
72:28
Figure 3. Lactam systems IV–VII prepared from 2,5-dihydrooxazoles and thiazoles.
H
H
a
Diastereomeric ratio determined from 1H NMR spectra of the crude product.
2. Results and discussion
According to
a procedure established in our group, the
2,5-dihydrooxazoles 1a–f were synthesized in an one-pot reaction
Starting from C5-chiral 2,5-dihydrooxazoles 1c,d as well as
using an
a-halogen aldehyde, aqueous ammonia and a carbonyl
C2-chiral 2,5-dihydrooxazoles 1e,f, we received two diastereomers
of the reaction products 2c–f in a ratio about dr¼75:25 as de-
termined from 1H NMR spectra of the crude product. According to
ROE experiments, the major diastereomers of 2c–f showed trans-
configuration concerning the substituents of the lowest priority,
the proton at C4 and the methyl moiety at C5 in the case of the
lactams 2c,d, respectively, the proton at C4 and the proton at C2 in
the case of the products 2e,f. These results were based on strong
NOEs observed in the ROE experiments as illustrated in Figure 4 for
the lactams 2c and 2f. In contrast, the ROE experiments of the
minor diastereomers of 2c–f showed cis-configuration between the
concerned moieties.
compound (aldehyde or ketone) (Scheme 1).14
R3
N
O
CH2Cl2, 0 °C
R3
R2
NH3
O
R1 Cl H2O
R1
O
R2
1a-f
Scheme 1. Synthesis of 2,5-dihydrooxazoles 1a–f.
Due to the great number of useable
a-halogen aldehydes
and carbonyl compounds, a high diversity of precursors was
available without high effort. By this way, some examples of
chiral imines 1c–f were synthesized. Thus, the subsequent
reactions were investigated concerning the aspect of
diastereoselectivity.
S
S
H
O
O
First, we presented the synthesis of tricyclic
g-thiavaler-
N
N
H
olactams 2a–f starting from 2,5-dihydrooxazoles 1a–f via addition
of thiosalicylic acid (Scheme 2). This type of reaction went back to
investigations of Erlenmeyer and Oberlin, respectively, Surrey
who independently reported the addition of thioglycolic acid to
acyclic imines.15 Modifying the used thiocarboxylic acids as well
as imines caused a broad expansion of this type of reaction.16
However, only a few examples for addition of thiosalicylic acid are
known.17
H
O
O
trans-2c
trans-2f
Figure 4. Observed NOEs for the major diastereomers of the lactams 2c and 2f.
The achieved results concerning the diastereoselectivity were
attributed to the use of the bulky thiosalicylic acid, which attacked
the imines 1a–f preferentially from the less shielded side. Conse-
quently, the sterically demanding substituents took the biggest
distance possible, that is, trans-configuration.
O
O
OH
S
OH
N
NH
R3
SH
toluene,
reflux
R3
R2
5O2
1a-f
Subsequently, the synthesis of
considered by addition of salicylic acid in analogous way to the
preparation of -thiavalerolactams 2a–f. However, exploratory
g-oxavalerolactams 3a–f was
R1
R1
R2
O
g
- H2O
experiments were not successful. Thus, we chose a synthesis
according to investigations of Ziegler.19 Starting from heterocy-
clic imines 1a–f, salicyl chloride20 prepared from salicylic acid
and oxalyl chloride was added. Thus, an N-acyliminium ion
stabilized by resonance was generated.21 Without isolation, the
intermediate closed the ring under elimination of hydrogen
S
O
R3
R2
N
R1
O
2a-f
chloride and led to the desired
(Scheme 3).
g-oxavalerolactams 3a–f
Scheme 2. Addition of thiosalicylic acid to 2,5-dihydrooxazoles 1a–f.

244
K. Johannes, J. Martens / Tetrahedron 66 (2010) 242–250
the acyl moiety strove for the biggest distance possible. Thus, the
O
ring closure took place from the less hindered side resulting
predominantly in trans-configurated lactams 3c,d. In the N-acyli-
minium ions forming the lactams 3e,f (Scheme 3), the bulky sub-
stituents at the carbon C2 (R2¼CH(CH3)2, C(CH3)3) displaced the
acyl moiety the way, that the reactive centre at the carbon C4 was
blocked from one side. Consequently, the attack was observed from
the less hindered side and cis-configurated lactams 3e,f were
obtained.
Cl
Cl
HO
R1
O
N
N
R3
R2
OH
R3
R2
5O2
1a-f
O
R1
benzene,
reflux
- HCl
The achieved diastereoselectivities in the synthesis of
g-
thiavalerolactams 2a–f compared to the results of -oxavaler-
g
O
O
N
olactams 3a–f showed obvious differences induced by divergent
courses of the reactions. More precisely, the obtained diaster-
eoselectivities were influenced by the new bond formed in the
first step of the addition reaction. Whereas the reaction of C5-
chiral imines 1c,d led to trans-configurated products in the case
of sulfur as well as oxygen containing lactams 2c,d and 3c,d,
starting from C2-chiral imines 1e,f the formation of trans-con-
figurated lactams 2e,f, respectively, cis-configurated lactams 3e,f
was observed.
R3
R1
R2
O
3a-f
Scheme 3. Addition of salicyl chloride to 2,5-dihydrooxazoles 1a–f.
The treatment of salicyl chloride and 2,5-dihydrooxazoles 1a–f
in anhydrous benzene at reflux for several hours followed by
The diastereomers 2c–f, 3c–f show a stable configuration under
the chosen reaction conditions as known for other cyclic N-acyl
1,3-heterocycles.22
column chromatography afforded the
yields up to 60% (Table 2).
g-oxavalerolactams 3a–f in
Inspired by works of Kametani, we aimed to synthesize
azavalerolactams 4a–f starting from 2,5-dihydrooxazoles 1a–f.23 In
comparison to previously prepared lactams 2 and 3, the -azava-
g-
Table 2
g-Oxavalerolactams 3a–f
R1
R2
R3
Yield (%)
dra (trans:cis)
g
Imine
Lactam
lerolactams 4 were characterized by insertion of nitrogen as part of
a C]N-double bond.
On heating anthranilic acid in the presence of thionyl chloride
an unstable sulfinamide anhydride was formed and dissociated to
an iminoketene. In a cycloaddition, this reactive species and the
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
CH3
CH3
C6H5
C6H5
CH3
CH3
CH3
–(CH2)5–
CH3
–(CH2)5–
CH(CH3)2
C(CH3)3
CH3
60
42
44
48
29
25
d
d
CH3
83:17
85:15
33:67
39:61
H
H
heterocyclic imines 1a–f should generate the g-azavalerolactams
a
Diastereomeric ratio determined from 1H NMR spectra of the crude product.
4a–f under elimination of hydrogen according to the results of
Kametani.24 But instead we obtained the dihydroquinazoline 5
starting from 2,5-dihydrooxazole 1a in a first exploratory experi-
ment (Scheme 4). Subsequent oxidation with potassium perman-
Starting from C5-chiral 2,5-dihydrooxazoles 1c,d, two
diastereomers of the
g-oxavalerolactams 3c,d were received in
ganate led to the desired g-azavalerolactam 4a.
a diastereomeric ratio about 85:15 as determined from the 1H NMR
spectra of the crude products. According to ROE experiments, the
proton at C4 and the methyl moiety at C5 in the major
diastereomers of 3c,d showed trans-configuration based on the
observed NOEs described in Figure 5 for lactam 3c. The results were
confirmed by comparison to ROE experiments of the minor
diastereomers of 3c,d showing cis-configuration.
HN
•
HN
O
SOCl2
O
rt
N
N
O
H2N
benzene,
HO
O
1a
O
5
reflux
KMnO4,
acetone,
reflux
O
H
O
H
O
O
N
N
H
O
O
N
O
N
trans-3c
cis-3f
O
4a
Figure 5. Observed NOEs for the major diastereomers of the lactams 3c and 3f.
Scheme 4. Generation of the g-azavalerolactams 4a.
When C2-chiral imines 1e,f were used, two diastereomers of the
products 3e,f were received in a diastereomeric ratio about 65:35.
The ROE experiments of the major diastereomers of 3e,f indicated
cis-configuration between the proton at C4 and the proton at C2.
These results were founded on the observed NOEs shown in Fig-
ure 5 for lactam 3f.
In order to develop a general procedure for the synthesis of g-
azavalerolactams 4a–f, we optimized the known reaction sequence
by integration of an oxidation as final step. We passed on the pu-
rification of the dihydroquinazolines and joined the oxidation to
the lactams 4a–f directly. The desired products 4a–f were obtained
in satisfactory yields up to 50% (Table 3).
In the case of the N-acyliminium ions leading to the lactams 3c,d
(Scheme 3), the bulky substituent at the carbon C5 (R1¼C6H5) and

K. Johannes, J. Martens / Tetrahedron 66 (2010) 242–250
245
Table 3
-Azavalerolactams 4a–f
4.2.1. (RS)-1,1,3,3-Tetramethyl-3,3a-dihydrooxazolo[4,3-b][1,3]benzo-
thiazin-9-one 2a. Following GP 1, 2,5-dihydrooxazole 1a (0.64 g,
5.0 mmol) and thiosalicylic acid (3.85 g, 25.0 mmol) were used. The
product was purified by column chromatography on silica gel
(solvent: n-hexane/ethyl acetate, 1:1) and obtained as yellow oil
g
N
O
N
(0.35 g, 27%); Rf¼0.89 (n-hexane/ethyl acetate, 1:1); IR:
2934, 1647, 1590, 1443, 1391, 1370, 744 cmꢁ1 1H NMR (500 MHz,
CDCl3): 1.45 (s, 3H, CH3), 1.51 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.79 (s,
3H, CH3), 5.15 (s, 1H, SCH), 7.25–7.29 (m, 2H, ArH), 7.35–7.39 (m, 1H,
ArH), 8.09–8.11 (m, 1H, ArH); 13C NMR (125 MHz, CDCl3):
25.7
n 2981,
R3
R1
R2
;
O
4a-f
d
Imine
Lactam
R1
R2
R3
Yield (%)
d
(CH3), 27.3 (CH3), 27.8 (CH3), 28.0 (CH3), 68.2 (SCH), 81.0
(OC(CH3)2CH), 96.9 (OC(CH3)2N), 126.2 (ArCH), 127.5 (ArCH), 130.0
(ArCH), 130.3 (ArC), 132.0 (ArCH), 134.7 (ArC), 161.6 (CO); MS (CI,
isobutane): m/z (%)¼264.1 (100) [MH]þ; HRMS (CI, isobutane): m/z
calcd for [C14H18NO2S]þ: 264.1058; found: 264.1060.
1a
1b
1c
1d
1e
1f
4a
4b
4c
4d
4e
4f
CH3
CH3
C6H5
C6H5
CH3
CH3
–(CH2)5–
CH3
–(CH2)5–
CH(CH3)2
C(CH3)3
CH3
48
36
50
49
38
22
CH3
H
H
CH3
4.2.2. (RS)-Spiro[3,3-dimethyl-3,3a-dihydrooxazolo[4,3-b][1,3]benzo-
thiazin-9-one-1,10-cyclohexane] 2b. Following GP 1, 2,5-dihydroox-
azole 1b (0.84 g, 5.0 mmol) and thiosalicylic acid (3.85 g,
25.0 mmol) were used. The product was crystallized from petrol
ether (40/60) and obtained as yellow solid (0.65 g, 43%); mp 112–
The
g-azavalerolactams 4a–f were characterized by their
amidine substructure offering the possibility for further function-
alisations as well as for use as synthetic reagent.25
115 ꢂC; IR:
NMR (500 MHz, CDCl3):
n
2936, 2863, 1650, 1591, 1445, 1383, 1152, 745 cmꢁ1; 1H
1.44 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.51–
3. Conclusions
d
1.55 (m, 1H, –(CH2)5–), 1.59–1.75 (m, 7H, –(CH2)5–), 2.58–2.66
(m, 2H, –(CH2)5–), 5.12 (s, 1H, SCH), 7.24–7.28 (m, 2H, ArH), 7.34–
7.37 (m, 1H, ArH), 8.07–8.09 (m, 1H, ArH); 13C NMR (125 MHz,
In conclusion, we were able to prepare tricyclic valerolactams
2a–f, 3a–f and 4a–f containing variable heteroatoms in
tion. The 2,5-dihydrooxazoles 1a–f used as precursors in the
respective reactions showed their high reactivity. The -thiava-
lerolactams 2a–f were received by addition of thiosalicylic acid
whereas the -oxavalerolactams 3a–f were synthesized by adding
salicyl chloride. Both, the lactams 2a–f and 3a–f were prepared
focussing on the aspect of diastereoselectivity. The -azavaler-
g-posi-
CDCl3):
d 23.1 (–(CH2)5–), 23.3 (–(CH2)5–), 24.7 (–(CH2)5–), 25.9
g
(CH3), 28.4 (CH3), 35.2 (–(CH2)5–), 35.5 (–(CH2)5–), 68.5 (SCH), 80.7
(OC(CH3)2CH), 98.7 (OCN), 126.2 (ArCH), 127.4 (ArCH), 130.1 (ArCH),
130.7 (ArC), 131.9 (ArCH), 134.7 (ArC), 161.7 (CO); MS (CI, iso-
butane): m/z (%)¼304.2 (100) [MH]þ; HRMS (CI, isobutane): m/z
calcd for [C17H22NO2S]þ: 304.1371; found: 304.1372.
g
g
olactams 4a–f were generated in a synthetic procedure starting
from anthranilic acid and thionyl chloride, following cycloaddition
and final oxidation.
4.2.3. 1,1,3-Trimethyl-3-phenyl-3,3a-dihydrooxazolo[4,3-b][1,3]ben-
zothiazin-9-one (3R
*
,3aR
*
)-2c and (3R
*
,3aS )-2c. Following GP 1,
*
2,5-dihydrooxazole 1c (0.95 g, 5.0 mmol) and thiosalicylic acid
(3.85 g, 25.0 mmol) were used. After column chromatography on
silica gel (solvent: n-hexane/ethyl acetate, 4:1) two diastereomers
4. Experimental
4.1. General methods
were isolated (3R
*
,3aR
*
)-2c and (3R
*
,3aS )-2c, ratio of
*
diastereomers 71:29 (determined from 1H NMR spectra of crude
product); total yield: 0.83 g, 51%.
Synthetic procedures were performed on a vacuum line using
standard Schlenk techniques under argon. All reagents and solvents
were of commercial grade and purified prior to use when neces-
sary. Preparative column chromatography was carried out using
Grace SiO2 (0.040–0.063 mm, type KG 60). TLC was performed on
Merck SiO2 F254 plates on aluminium sheets. IR spectra were
recorded on a Bruker Tensor 27 spectrometer equipped with
a GoldenGate diamond-ATR unit. 1H and 13C NMR spectra were
recorded with Bruker AMX R 500 and AM 300 spectrometers. NMR
chemical shifts are reported in parts per million using TMS as
internal standard. Assignments of the signals in the 13C NMR
spectrum were supported by measurements applying COSY and
J modulated techniques. CI–MS and HRMS spectra were recorded
on a Finnigan MAT 212 spectrometer.
4.2.3.1. Major diastereomer (3R
*
,3aR )-2c. Yellow solid (0.69 g,
*
42%); Rf¼0.68 (n-hexane/ethyl acetate, 4:1); mp 101–103 ꢂC; IR:
n
2977, 2931, 2854, 1646, 1591, 1440, 1387, 1371, 769, 734, 698 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d 1.65 (s, 3H, OC(CH3)2N), 1.73 (s, 3H,
OC(CH3)CH), 1.87 (s, 3H, OC(CH3)2N), 5.35 (s, 1H, SCH), 7.17–7.32 (m,
6H, ArH), 7.45–7.47 (m, 2H, ArH), 8.02–8.04 (m, 1H, ArH); 13C NMR
(125 MHz, CDCl3):
d 26.7 (OC(CH3)2N), 27.4 (OC(CH3)CH), 28.0
(OC(CH3)2N), 68.9 (SCH), 84.2 (OC(CH3)CH), 97.4 (OC(CH3)2N), 124.3
(ArCH),126.3 (ArCH),127.5 (ArCH),127.7 (ArCH),128.5 (ArCH),130.0
(ArC),130.1 (ArCH),132.1 (ArCH),134.6 (ArC),144.7 (ArC),161.4 (CO);
MS (CI, isobutane): m/z (%)¼326.0 (100) [MH]þ; HRMS (CI, iso-
butane): m/z calcd for [C19H20NO2S]þ: 326.1209; found: 326.1208.
4.2. General procedure for synthesis of
(GP 1)
g
-thiavalerolactams 2
4.2.3.2. Minor diastereomer (3R
8%); Rf¼0.56 (n-hexane/ethyl acetate, 4:1); IR:
1652, 1589, 1443, 1371, 771, 745, 698 cmꢁ1
CDCl3): 1.89 (s, 3H, OC(CH3)CH), 1.92 (s, 3H, OC(CH3)2N), 1.95 (s,
*
,3aS
*
)-2c. Yellow oil (0.14 g,
2984, 2928, 2855,
1H NMR (500 MHz,
n
;
Under exclusion of moisture, 1 equiv of 2,5-dihydrooxazole and
5 equiv of thiosalicylic acid were refluxed in toluene (30 mL) for
48 h using a Dean–Stark apparatus. After cooling down to room
temperature, the organic phase was washed with saturated sodium
bicarbonate solution (3ꢀ20 mL) and water (3ꢀ20 mL) and dried
with magnesium sulfate. After filtration, the solvent was removed
under reduced pressure and the crude product was purified as
described below.
d
3H, OC(CH3)2N), 5.56 (s, 1H, SCH), 7.15–7.17 (m, 1H, ArH), 7.22–7.25
(m, 1H, ArH), 7.29–7.32 (m, 1H, ArH), 7.37–7.44 (m, 3H, ArH), 7.57–
7.59 (m, 2H, ArH), 8.04–8.06 (m, 1H, ArH); 13C NMR (125 MHz,
CDCl3):
d 27.8 (OC(CH3)CH), 28.2 (OC(CH3)2N), 29.9 (OC(CH3)2N),
72.3 (SCH), 84.6 (OC(CH3)CH), 98.2 (OC(CH3)2N), 122.0 (ArCH),
125.9 (ArCH), 126.1 (ArCH), 127.7 (ArCH), 128.0 (ArCH), 128.3 (ArC),
129.9 (ArCH), 131.9 (ArCH), 137.0 (ArC), 141.8 (ArC), 162.3 (CO); MS

246
K. Johannes, J. Martens / Tetrahedron 66 (2010) 242–250
(CI, isobutane): m/z (%)¼326.2 (100) [MH]þ; HRMS (CI, isobutane):
m/z calcd for [C19H20NO2S]þ: 326.1215; found: 326.1214.
HRMS (CI, isobutane): m/z calcd for [C15H20NO2S]þ: 278.1215;
found: 278.1214.
4.2.5.2. Minor diastereomer (1R
*
,3aR )-2e. Colourless solid
*
4.2.4. Spiro[3-methyl-3-phenyl-3,3a-dihydrooxazolo[4,3-b][1,3]benzo-
(0.15 g, 11%); Rf¼0.54 (n-hexane/ethyl acetate, 6:1); mp 63–65 ꢂC;
thiazin-9-one-1,10-cyclohexane] (3R
*
,3aR
*
)-2d and (3R
*
,3aS )-
*
IR:
n ;
2970, 2931, 2853, 1644, 1592, 1402, 1386, 1149, 744 cmꢁ1 1H
2d. Following GP 1, 2,5-dihydrooxazole 1d (1.15 g, 5.0 mmol) and
thiosalicylic acid (3.85 g, 25.0 mmol) were used. After column
chromatography on silica gel (solvent: n-hexane/ethyl acetate, 5:1)
NMR (500 MHz, CDCl3):
d
0.83 (d, 3J¼7.0 Hz, 3H, CH(CH3)2), 1.03 (d,
3J¼7.1 Hz, 3H, CH(CH3)2), 1.40 (s, 3H, OC(CH3)2CH), 1.49 (s, 3H,
OC(CH3)2CH), 2.87 (dsept, 3J¼2.3 Hz, 3J¼7.0 Hz, 1H, CH(CH3)2), 5.12
(s, 1H, SCH), 5.33 (d, 3J¼2.3 Hz, 1H, OCHN), 7.25–7.28 (m, 1H, ArH),
7.32–7.38 (m, 2H, ArH), 8.11–8.13 (m, 1H, ArH); 13C NMR (125 MHz,
two diastereomers were isolated (3R
*
,3aR
*
)-2d and (3R
*
,3aS )-2d,
*
ratio of diastereomers 74:26 (determined from 1H NMR spectra of
crude product); total yield: 1.35 g, 74%.
CDCl3):
d 14.1 (CH(CH3)2), 18.2 (CH(CH3)2), 23.8 (OC(CH3)2CH), 26.6
(OC(CH3)2CH), 27.2 (CH(CH3)2), 70.8 (SCH), 80.5 (OC(CH3)2CH), 93.3
(OCHN), 126.0 (ArCH), 128.0 (ArCH),129.6 (ArC),130.2 (ArCH),132.0
(ArCH), 137.0 (ArC), 162.1 (CO); MS (CI, isobutane): m/z (%): 278.2
(100) [MH]þ; HRMS (CI, isobutane): m/z calcd for [C15H20NO2S]þ:
278.1215; found: 278.1214.
4.2.4.1. Major diastereomer (3R
*
,3aR )-2d. Yellow solid (0.98 g,
*
54%); Rf¼0.88 (n-hexane/ethyl acetate, 5:1); mp 118–120 ꢂC; IR:
n
2931, 2858, 1653, 1590, 1441, 1381, 1362, 771, 735, 698 cmꢁ1 1H
;
NMR (500 MHz, CDCl3): d 1.24–1.34 (m,1H, –(CH2)5–),1.46–1.49 (m,
1H, –(CH2)5–), 1.64–1.84 (m, 6H, –(CH2)5–), 1.72 (s, 3H, CH3), 2.51–
2.57 (m, 1H, –(CH2)5–), 2.66–2.72 (m, 1H, –(CH2)5–), 5.31 (s, 1H,
SCH), 7.15–7.23 (m, 3H, ArH), 7.26–7.29 (m, 3H, ArH), 7.47–7.49 (m,
4.2.6. 1-tert-Butyl-3,3-dimethyl-3,3a-dihydrooxazolo[4,3-b][1,3]benzo-
thiazin-9-one (1R
*
,3aS
*
)-2f and (1R
*
,3aR )-2f. Following GP 1, 2,5-
*
2H, ArH), 7.99–8.00 (m, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 23.3
dihydrooxazole 1f (0.78 g, 5.0 mmol) and thiosalicylic acid (3.85 g,
25.0 mmol) were used. After column chromatography on silica gel
(solvent: n-hexane/ethyl acetate, 5:1) two diastereomers were
(–(CH2)5–), 23.4 (–(CH2)5–), 24.7 (–(CH2)5–), 27.5 (CH3), 34.4
(–(CH2)5–), 35.8 (–(CH2)5–), 69.0 (SCH), 84.0 (OC(CH3)CH), 99.0
(OCN), 124.2 (ArCH), 126.2 (ArCH), 127.4 (ArCH), 127.7 (ArCH), 128.4
(ArCH), 130.1 (ArCH), 130.5 (ArC), 132.0 (ArCH), 134.4 (ArC), 145.0
(ArC), 161.6 (CO); MS (CI, isobutane): m/z (%)¼365.9 (100) [M]þ;
HRMS (ESI): m/z calcd for [C22H22NO2S]þ: 364.1366;
found: 364.1375.
isolated (1R
*
,3aS
*
)-2f and (1R
*
,3aR )-2f, ratio of diastereomers
*
72:28 (determined from 1H NMR spectra of crude product); total
yield: 0.59 g, 40%.
4.2.6.1. Major diastereomer (1R
34%); Rf¼0.81 (n-hexane/ethyl acetate, 5:1); IR:
1590, 1443, 1394, 1156, 740 cmꢁ1; 1H NMR (500 MHz, CDCl3):
*
,3aS
*
)-2f. Yellow oil (0.50 g,
2974, 2905, 1651,
0.99
n
4.2.4.2. Minor diastereomer (3R
*
,3aS )-2d. Yellow solid (0.37 g,
*
d
20%); Rf¼0.76 (n-hexane/ethyl acetate, 5:1); mp 117–118 ꢂC; IR:
n
(s, 9H, C(CH3)3), 1.28 (s, 3H, OC(CH3)2CH), 1.38 (s, 3H, OC(CH3)2CH),
4.90 (s, 1H, SCH), 5.50 (s, 1H, OCHN), 7.19–7.23 (m, 2H, ArH), 7.33–
7.37 (m, 1H, ArH), 7.97–7.99 (m, 1H, ArH); 13C NMR (125 MHz,
2961, 2935, 2859, 1656, 1590, 1443, 1370, 1361, 750, 773, 696 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d 1.60–1.78 (m, 6H, –(CH2)5–),1.81 (s, 3H,
CH3), 1.83–1.91 (m, 2H, –(CH2)5–), 2.58–2.67 (m, 2H, –(CH2)5–), 5.46
(s,1H, SCH), 7.07–7.09 (m,1H, ArH), 7.15–7.18 (m,1H, ArH), 7.21–7.24
(m, 1H, ArH),7.30–7.37 (m, 3H, ArH), 7.51–7.53 (m, 2H, ArH), 7.96–
CDCl3):
d 22.1 (OC(CH3)2CH), 24.1 (OC(CH3)2CH), 25.9 (C(CH3)3),
38.2 (C(CH3)3), 64.5 (SCH), 82.4 (OC(CH3)2CH), 95.1 (OCHN), 126.1
(ArCH), 126.3 (ArCH), 129.7 (ArCH), 129.8 (ArC), 131.8 (ArC), 132.1
(ArCH), 162.5 (CO); MS (CI, isobutane): m/z (%)¼292.2 (100) [MH]þ;
HRMS (CI, isobutane): m/z calcd for [C16H22NO2S]þ: 292.1371;
found: 292.1370.
7.98 (m,1H, ArH); 13C NMR (125 MHz, CDCl3):
d 23.3 (–(CH2)5–), 23.6
(–(CH2)5–), 24.7 (–(CH2)5–), 30.1 (CH3), 36.0 (–(CH2)5–), 36.3
(–(CH2)5–), 72.6 (SCH), 84.4 (OC(CH3)CH), 99.8 (OCN), 126.0 (ArCH),
126.1 (ArCH),127.6 (ArCH),128.0 (ArCH),128.3 (ArCH),130.0 (ArCH),
130.3 (ArC),131.8 (ArCH),137.1 (ArC),142.1 (ArC),162.4 (CO); MS (CI,
isobutane): m/z (%)¼366.4 (100) [MH]þ; HRMS (ESI): m/z calcd for
[C22H22NO2S]þ: 364.1366; found: 364.1378.
4.2.6.2. Minor diastereomer (1R
6%); Rf¼0.71 (n-hexane/ethyl acetate, 5:1); IR:
1591, 1442, 1389, 1370, 742 cmꢁ1; 1H NMR (500 MHz, CDCl3):
*
,3aR
*
)-2f. Yellow oil (0.09 g,
2964, 2931, 1668,
1.07
n
d
(s, 9H, C(CH3)3), 1.40 (s, 3H, OC(CH3)2CH), 1.51 (s, 3H, OC(CH3)2CH),
5.09 (s, 1H, SCH), 5.37 (s, 1H, OCHN), 7.34–7.40 (m, 2H, ArH), 7.45–
7.48 (m, 1H, ArH), 8.15–8.17 (m, 1H, ArH); 13C NMR (125 MHz,
4.2.5. 1-Isopropyl-3,3-dimethyl-3,3a-dihydrooxazolo[4,3-b][1,3]benzo-
thiazin-9-one (1R
*
,3aS
*
)-2e and (1R
*
,3aR )-2e. Following GP 1, 2,
*
5-dihydrooxazole 1e (0.71 g, 5.0 mmol) and thiosalicylic acid
(3.85 g, 25.0 mmol) were used. After column chromatography on
silica gel (solvent: n-hexane/ethyl acetate, 6:1) two diastereomers
CDCl3):
d 24.3 (OC(CH3)2CH), 26.1 (OC(CH3)2CH), 26.7 (C(CH3)3),
36.7 (C(CH3)3), 72.9 (SCH), 88.7 (OC(CH3)2CH), 97.3 (OCHN), 127.9
(ArCH), 128.0 (ArCH), 129.7 (ArC), 130.7 (ArCH), 133.3 (ArC), 133.4
(ArCH), 163.6 (CO); MS (CI, isobutane): m/z (%)¼292.2 (100) [MH]þ;
HRMS (CI, isobutane): m/z calcd for [C16H22NO2S]þ: 292.1371;
found: 292.1370.
were isolated (1R
*
,3aS
*
)-2e and (1R
*
,3aR )-2e, ratio of di-
*
astereomers 79:21 (determined from 1H NMR spectra of crude
product); total yield: 0.79 g, 57%.
4.2.5.1. Major diastereomer (1R
*
,3aS
*
)-2e. Colourless solid
4.3. General procedure for synthesis of
(GP 2)
g-oxavalerolactams 3
(0.64 g, 46%); Rf¼0.71 (n-hexane/ethyl acetate, 6:1); mp 87–91 ꢂC;
IR:
n 2976, 2962, 2933, 2875, 1641, 1590, 1444, 1416, 1385, 1157,
741 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
0.76 (d, 3J¼7.0 Hz, 3H,
Under exclusion of moisture, 1 equiv of 2,5-dihydrooxazole and
1.2 equiv of salicyl chloride in benzene (20 mL) were refluxed for
several hours. After cooling down to room temperature, the reaction
mixture was washed with saturated sodium bicarbonate solution
(3ꢀ20 mL) and water (3ꢀ20 mL) and dried with magnesium sulfate.
After filtration, the solvent was removed under reduced pressure
and the crude product was purified as described below.
CH(CH3)2), 1.02 (d, 3J¼7.1 Hz, 3H, CH(CH3)2), 1.39 (s, 3H,
OC(CH3)2CH), 1.43 (s, 3H, OC(CH3)2CH), 2.91 (dsept, 3J¼2.1 Hz,
3J¼7.0 Hz, 1H, CH(CH3)2), 4.94 (s, 1H, SCH), 5.39 (d, 3J¼2.1 Hz, 1H,
OCHN), 7.24–7.27 (m, 2H, ArH), 7.35–7.38 (m, 1H, ArH), 8.01–8.03
(m, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 13.7 (CH(CH3)2), 17.8
(CH(CH3)2), 22.3 (OC(CH3)2CH), 25.0 (OC(CH3)2CH), 28.4
(CH(CH3)2), 66.1 (SCH), 81.5 (OC(CH3)2CH), 92.7 (OCHN), 126.4
(ArCH), 127.4 (ArCH), 129.6 (ArCH), 130.7 (ArC), 132.1 (ArCH), 133.3
(ArC), 161.1 (CO); MS (CI, isobutane): m/z (%)¼278.2 (100) [MH]þ;
4.3.1. (RS)-1,1,3,3-Tetramethyl-3,3a-dihydrooxazolo[4,3-b][1,3]ben-
zoxazin-9-one 3a. Following GP 2, 2,5-dihydrooxazole 1a (0.64 g,

K. Johannes, J. Martens / Tetrahedron 66 (2010) 242–250
247
5.0 mmol) and salicyl chloride (0.94 g, 6.0 mmol) were used. The
product was purified by column chromatography on silica gel (sol-
vent: n-hexane/ethyl acetate, 1:1) and obtained as yellow solid
(0.74 g, 60%); Rf¼0.91 (n-hexane/ethyl acetate,1:1); mp 51–54 ꢂC; IR:
OC(CH3)CH), 6.89 (d, 3J¼8.2 Hz, 1H, ArH), 7.07 (ddd, 3J¼6.9 Hz,
3J¼7.8 Hz, 4J¼0.9 Hz, 1H, ArH), 7.29–7.33 (m, 1H, ArH), 7.37–7.40
(m, 3H, ArH), 7.59–7.62 (m, 2H, ArH), 7.91 (dd, 3J¼7.8 Hz, 4J¼1.6 Hz,
1H, ArH); 13C NMR (125 MHz, CDCl3):
d 27.1 (OC(CH3)2N), 28.1
n
3067, 2985, 2937, 1672, 1610, 1464, 1420, 1374, 760 cmꢁ1; 1H NMR
(OC(CH3)2N), 29.8 (OC(CH3)CH), 83.8 (OC(CH3)CH), 93.0
(OC(CH3)CH), 95.1 (OC(CH3)2N), 116.9 (ArCH), 119.2 (ArC), 122.8
(ArCH),126.7 (ArCH),127.4 (ArCH), 127.6 (ArCH),127.7 (ArCH), 134.1
(ArCH), 141.1 (ArC), 156.8 (ArC), 159.8 (CO); MS (CI, isobutane): m/z
(%)¼310.4 (73) [MH]þ; HRMS (CI, isobutane): m/z calcd for
[C19H20NO3]þ: 310.1443; found: 310.1443.
(500 MHz, CDCl3):
d 1.44 (s, 3H, OC(CH3)2CH), 1.47 (s, 3H,
OC(CH3)2CH), 1.65 (s, 3H, OC(CH3)2N), 1.76 (s, 3H, OC(CH3)2N), 5.28
(s, 1H, OC(CH3)2CH), 6.98 (dd, 3J¼8.2 Hz, 4J¼0.9 Hz, 1H, ArH), 7.12
(ddd, 3J¼7.1 Hz, 3J¼7.8 Hz, 4J¼0.9 Hz, 1H, ArH), 7.45 (ddd, 3J¼7.1 Hz,
3J¼8.2 Hz, 4J¼1.6 Hz, 1H, ArH), 7.94 (dd, 3J¼7.8 Hz, 4J¼1.6 Hz, 1H,
ArH); 13C NMR (125 MHz, CDCl3):
d 23.2 (OC(CH3)2CH), 26.7
(OC(CH3)2CH), 27.3 (OC(CH3)2N), 27.9 (OC(CH3)2N), 80.1
(OC(CH3)2CH), 91.5 (OC(CH3)2CH), 93.4 (OC(CH3)2N), 116.6 (ArCH),
119.2 (ArC), 122.8 (ArCH), 127.8 (ArCH), 134.1 (ArCH), 156.9 (ArC),
159.4(CO);MS(CI, isobutane):m/z(%)¼248.2(100)[MH]þ;HRMS(CI,
isobutane): m/z calcd for [C14H18NO3]þ: 248.1287; found: 248.1286.
4.3.4. Spiro[3-methyl-3-phenyl-3,3a-dihydrooxazolo[4,3-b][1,3]ben-
zoxazin-9-one-1,10-cyclohexane] (3R
*
,3aR
*
)-3d and (3R
*
,3aS )-
*
3d. Following GP 2, 2,5-dihydrooxazole 1d (1.15 g, 5.0 mmol) and
salicyl chloride (0.94 g, 6.0 mmol) were used. After column chro-
matography on silica gel (solvent: n-hexane/ethyl acetate, 5:1) two
diastereomers were isolated (3R
*
,3aR
*
)-3d and (3R
*
,3aS )-3d, ratio
*
4.3.2. (RS)-Spiro[3,3-dimethyl-3,3a-dihydrooxazolo[4,3-b][1,3]ben-
zoxazin-9-one-1,10-cyclohexane] 3b. Following GP 2, 2,5-dihy-
drooxazole 1b (0.84 g, 5.0 mmol) and salicyl chloride (0.94 g,
6.0 mmol) were used. The product was purified by column chro-
matography on silica gel (solvent: n-hexane/ethyl acetate, 2:1) and
obtained as colourless solid (0.61 g, 42%); Rf¼0.89 (n-hexane/ethyl
of diastereomers 85:15 (determined from 1H NMR spectra of crude
product); total yield: 0.84 g, 48%.
4.3.4.1. Major diastereomer (3R
41%); Rf¼0.63 (n-hexane/ethyl acetate, 5:1); IR:
1611, 1465, 1413, 754, 699 cmꢁ1; 1H NMR (500 MHz, CDCl3):
*
,3aR
*
)-3d. Colourless oil (0.72 g,
2932, 2860, 1673,
1.33–
n
d
acetate, 2:1); mp 115–119 ꢂC; IR:
n
2983, 2929, 2861, 1663, 1610,
1.42 (m,1H, –(CH2)5–),1.59–1.63 (m,1H, –(CH2)5–),1.73 (s, 3H, CH3),
1.75–1.89 (m, 6H, –(CH2)5–), 2.44–2.51 (m, 1H, –(CH2)5–), 2.66–2.72
(m, 1H, –(CH2)5–), 5.52 (s, 1H, OC(CH3)CH), 7.07 (dd, 3J¼8.2 Hz,
4J¼0.8 Hz, 1H, ArH), 7.13 (ddd, 3J¼7.0 Hz, 3J¼7.8 Hz, 4J¼0.8 Hz, 1H,
ArH), 7.30–7.33 (m, 1H, ArH), 7.38–7.42 (m, 2H, ArH), 7.47 (ddd,
3J¼7.0 Hz, 3J¼8.2 Hz, 4J¼1.6 Hz, 1H, ArH), 7.58–7.60 (m, 2H, ArH),
7.96 (dd, 3J¼7.8 Hz, 4J¼1.6 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
1464,1421, 749 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
1.26–1.32 (m,1H,
–(CH2)5–), 1.41 (s, 3H, CH3), 1.46 (s, 3H, CH3), 1.53–1.73 (m, 7H,
–(CH2)5–), 2.43–2.56 (m, 2H, –(CH2)5–), 5.25 (s, 1H, OC(CH3)2CH),
6.96 (dd, 3J¼8.2 Hz, 4J¼0.9 Hz, 1H, ArH), 7.10 (ddd, 3J¼6.8 Hz,
3J¼7.8 Hz, 4J¼0.9 Hz, 1H, ArH), 7.42 (ddd, 3J¼6.8 Hz, 3J¼8.2 Hz,
4J¼1.6 Hz,1H, ArH), 7.93 (dd, 3J¼7.8 Hz, 4J¼1.6 Hz,1H, ArH); 13C NMR
(125 MHz, CDCl3):
d
22.6 (–(CH2)5–), 23.0 (–(CH2)5–), 23.4 (CH3),
d 22.8 (–(CH2)5–), 23.2 (–(CH2)5–), 24.7 (–(CH2)5–), 25.3 (CH3), 35.5
24.6 (–(CH2)5–), 27.0 (CH3), 35.0 (–(CH2)5–), 36.2 (–(CH2)5–), 79.7
(OC(CH3)2CH), 91.5 (OC(CH3)2CH), 94.8 (OCN), 116.5 (ArCH), 119.5
(ArC), 122.7 (ArCH), 127.8 (ArCH), 134.0 (ArCH), 156.7 (ArC), 159.4
(CO); MS (CI, isobutane): m/z (%)¼288.2 (100) [MH]þ; HRMS (CI,
isobutane): m/z calcd for [C17H22NO3]þ: 288.1600; found: 288.1601.
(–(CH2)5–), 35.7 (–(CH2)5–), 83.0 (OC(CH3)CH), 91.7 (OC(CH3)CH),
95.3 (OCN), 116.7 (ArCH), 119.4 (ArC), 122.9 (ArCH), 124.5 (ArCH),
127.6 (ArCH), 127.9 (ArCH), 128.4 (ArCH), 134.1 (ArCH), 144.5 (ArC),
156.7 (ArC), 159.5 (CO); MS (CI, isobutane): m/z (%)¼350.3 (100)
[MH]þ; HRMS (CI, isobutane): m/z calcd for [C22H24NO3]þ:
350.1756; found: 350.1756.
4.3.3. 1,1,3-Trimethyl-3-phenyl-3,3a-dihydrooxazolo[4,3-b][1,3]ben-
zoxazin-9-one (3R
*
,3aR
*
)-3c and (3R
*
,3aS
*
)-3c. Following GP 2, 2,5-
4.3.4.2. Minor diastereomer (3R
7%); Rf¼0.54 (n-hexane/ethyl acetate, 5:1); IR:
1611, 1466, 1414, 758, 700 cmꢁ1 1H NMR (500 MHz, CDCl3):
1.36–1.41 (m, 1H, –(CH2)5–), 1.73–1.95 (m, 7H, –(CH2)5–), 1.82
*
,3aS
*
)-3d. Yellow oil (0.12 g,
dihydrooxazole 1c (0.95 g, 5.0 mmol) and salicyl chloride (0.94 g,
6.0 mmol) were used. After column chromatography on silica gel
(solvent: n-hexane/ethyl acetate, 3:1) two diastereomers were
n
2933, 2861, 1672,
;
d
isolated (3R
*
,3aR
*
)-3c and (3R
*
,3aS
*
)-3c, ratio of diastereomers
(s, 3H, CH3), 2.45–2.51 (m, 1H, –(CH2)5–), 2.60–2.66 (m, 1H,
–(CH2)5–), 5.62 (s, 1H, OC(CH3)CH), 6.87 (dd, 3J¼8.2 Hz, 4J¼0.9 Hz,
1H, ArH), 7.08 (ddd, 3J¼7.7 Hz, 3J¼8.5 Hz, 4J¼0.9 Hz, 1H, ArH),
7.29–7.33 (m, 1H, ArH), 7.37–7.40 (m, 3H, ArH), 7.59–7.61 (m, 2H,
ArH), 7.91 (dd, 3J¼7.7 Hz, 4J¼1.6 Hz, 1H, ArH); 13C NMR (125 MHz,
83:17 (determined from 1H NMR spectra of crude product); total
yield: 0.69 g, 45%.
4.3.3.1. Major diastereomer (3R
39%); Rf¼0.74 (n-hexane/ethyl acetate, 3:1); IR:
1612, 1466, 1415, 755, 700 cmꢁ1; 1H NMR (500 MHz, CDCl3):
*
,3aR
*
)-3c. Yellow oil (0.61 g,
2990, 2936, 1675,
1.70
n
CDCl3): d 22.8 (–(CH2)5–), 23.2 (–(CH2)5–), 24.7 (–(CH2)5–), 30.1
d
(CH3), 34.8 (–(CH2)5–), 36.6 (–(CH2)5–), 83.8 (OC(CH3)CH), 93.1
(OC(CH3)CH), 96.6 (OCN), 116.9 (ArCH), 119.5 (ArC), 122.7 (ArCH),
126.6 (ArCH), 127.4 (ArCH), 127.7 (ArCH), 127.8 (ArCH), 134.1
(ArCH), 141.5 (ArC), 156.7 (ArC), 160.0 (CO); MS (CI, isobutane): m/z
(%)¼350.3 (100) [MH]þ; HRMS (CI, isobutane): m/z calcd for
[C22H24NO3]þ: 350.1756; found: 350.1755.
(s, 3H, OC(CH3)2N), 1.74 (s, 3H, OC(CH3)CH), 1.91 (s, 3H, OC(CH3)2N),
5.53 (s, 1H, OC(CH3)CH), 7.07 (d, 3J¼8.2 Hz, 1H, ArH), 7.13 (ddd,
3J¼6.9 Hz, 3J¼7.8 Hz, 4J¼0.8 Hz, 1H, ArH), 7.29–7.32 (m, 1H, ArH),
7.37–7.40 (m, 2H, ArH), 7.47 (ddd, 3J¼6.9 Hz, 3J¼8.2 Hz, 4J¼1.6 Hz,
1H, ArH), 7.54–7.56 (m, 2H, ArH), 7.96 (dd, 3J¼7.8 Hz, 4J¼1.6 Hz, 1H,
ArH); 13C NMR (125 MHz, CDCl3):
d 25.1 (OC(CH3)CH), 27.5
(OC(CH3)2N), 27.5 (OC(CH3)2N), 83.2 (OC(CH3)CH), 91.8
(OC(CH3)CH), 94.0 (OC(CH3)2N), 116.8 (ArCH), 119.2 (ArC), 122.9
(ArCH), 124.5 (ArCH), 127.6 (ArCH), 127.8 (ArCH), 128.4 (ArCH),
134.2 (ArCH), 144.1 (ArC), 156.8 (ArC), 159.4 (CO); MS (CI, iso-
butane): m/z (%)¼310.4 (100) [MH]þ; HRMS (CI, isobutane): m/z
calcd for [C19H20NO3]þ: 310.1443; found: 310.1443.
4.3.5. 1-Isopropyl-3,3-dimethyl-3,3a-dihydrooxazolo[4,3-b][1,3]ben-
*
zoxazin-9-one (1R ,3aR
*
)-3e and (1R
*
,3aS )-3e. Following GP 2,
*
2,5-dihydrooxazole 1e (0.71 g, 5.0 mmol) and salicyl chloride
(0.94 g, 6.0 mmol) were used. After column chromatography on
silica gel (solvent: n-hexane/ethyl acetate, 6:1) two diastereomers
were isolated (1R
*
,3aR
*
)-3e and (1R
*
,3aS )-3e, ratio of
*
diastereomers 67:33 (determined from 1H NMR spectra of crude
product); total yield: 0.40 g, 31%.
4.3.3.2. Minor diastereomer (3R
5%); Rf¼0.63 (n-hexane/ethyl acetate, 3:1); IR:
1611, 1467, 1415, 758, 700 cmꢁ1 1H NMR (500 MHz, CDCl3):
(s, 6H, OC(CH3)2N, OC(CH3)CH), 1.89 (s, 3H, OC(CH3)2N), 5.63 (s, 1H,
*
,3aS
*
)-3c. Yellow oil (0.08 g,
2985, 2934, 1674,
1.82
n
;
d
4.3.5.1. Major diastereomer (1R
*
,3aR )-3e. Colourless solid
*
(0.29 g, 22%); Rf¼0.33 (n-hexane/ethyl acetate, 6:1); mp 94–95 ꢂC;

248
K. Johannes, J. Martens / Tetrahedron 66 (2010) 242–250
IR:
n
2962, 2933, 2877, 1681, 1610, 1467, 1428, 764 cmꢁ1
;
1H NMR
118.2 (ArC), 122.6 (ArCH), 127.6 (ArCH), 133.9 (ArCH), 155.3 (ArC),
159.1 (CO); MS (CI, isobutane): m/z (%)¼276.3 (100) [MH]þ;
HRMS (CI, isobutane): m/z calcd for [C16H22NO3]þ: 276.1600;
found: 276.1599.
(500 MHz, CDCl3):
d
0.73 (d, 3J¼6.9 Hz, 3H, CH(CH3)2), 1.01
(d, 3J¼6.9 Hz, 3H, CH(CH3)2), 1.36 (s, 3H, OC(CH3)2CH), 1.47 (s, 3H,
OC(CH3)2CH), 2.86 (dsept, 3J¼1.8 Hz, 3J¼6.9 Hz, 1H, CH(CH3)2), 5.11
(s, 1H, OC(CH3)2CH), 5.16 (d, 3J¼1.8 Hz, 1H, OCHN), 6.99 (d,
3J¼8.2 Hz, 1H, ArH), 7.09 (dd, 3J¼7.4 Hz, 3J¼7.8 Hz, 1H, ArH), 7.43
(ddd, 3J¼7.4 Hz, 3J¼8.2 Hz, 4J¼1.2 Hz, 1H, ArH), 7.93 (dd, 3J¼7.8 Hz,
4.4. General procedure for synthesis of
(GP 3)
g-azavalerolactams 4
4J¼1.2 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 13.5 (CH(CH3)2),
18.2 (CH(CH3)2), 22.1 (OC(CH3)2CH), 25.0 (OC(CH3)2CH), 27.4
(CH(CH3)2), 80.3 (OC(CH3)2CH), 91.5 (OCHN), 92.8 (OC(CH3)2CH),
116.8 (ArCH), 119.4 (ArC), 122.5 (ArCH), 128.1 (ArCH), 134.2 (ArCH),
157.2 (ArC), 160.6 (CO); MS (CI, isobutane): m/z (%)¼262.4 (100)
[MH]þ; HRMS (CI, isobutane): m/z calcd for [C15H20NO3]þ:
262.1443; found: 262.1443.
Under argon atmosphere, 1 equiv of anthranilic acid and 5 equiv
of thionyl chloride were refluxed in anhydrous benzene (30 mL) for
2–3 h. After cooling the reaction mixture to room temperature, the
excess of thionyl chloride and the solvent were removed under
reduced pressure at room temperature. Under exclusion of mois-
ture, the remaining yellow oil was resolved in anhydrous benzene
(10 mL) before 1 equiv of 2,5-dihydrooxazole dissolved in anhy-
drous benzene (10 mL) was added. After stirring overnight at room
temperature, the solvent was removed under reduced pressure.
The obtained crude product dissolved in acetone (15 mL) and
2.5 equiv of potassium permanganate were refluxed for 2 h. After
cooling to room temperature, the solid was filtered off and the
solvent was removed under reduced pressure. The crude product
was purified as described below.
4.3.5.2. Minor diastereomer (1R
*
,3aS )-3e. Colourless solid
*
(0.11 g, 8%); Rf¼0.47 (n-hexane/ethyl acetate, 6:1); mp 79–81 ꢂC; IR:
n
2962, 2932, 2875, 1673, 1612, 1468, 1431, 755 cmꢁ1 1H NMR
;
(500 MHz, CDCl3):
d
0.83 (d, 3J¼6.8 Hz, 3H, CH(CH3)2), 1.02
(d, 3J¼6.8 Hz, 3H, CH(CH3)2), 1.32 (s, 3H, OC(CH3)2CH), 1.47 (s, 3H,
OC(CH3)2CH), 2.73 (dsept, 3J¼1.8 Hz, 3J¼6.8 Hz, 1H, CH(CH3)2), 5.16
(s, 1H, OC(CH3)2CH), 5.35 (d, 3J¼1.8 Hz, 1H, OCHN), 6.97
(d, 3J¼8.2 Hz, 1H, ArH), 7.11 (dd, 3J¼7.0 Hz, 3J¼7.8 Hz, 1H, ArH), 7.43
(ddd, 3J¼7.0 Hz, 3J¼8.2 Hz, 4J¼1.0 Hz, 1H, ArH), 7.90 (dd, 3J¼7.8 Hz,
4.4.1. 1,1,3,3-Tetramethyl-3H-oxazolo[4,3-b]chinazolin-9-one
4a. Following GP 3, anthranilic acid (0.34 g, 2.5 mmol), thionyl
chloride (0.9 mL, 12.5 mmol), 2,5-dihydrooxazole 1a (0.32 g,
2.5 mmol) and potassium permanganate (0.99 g, 6.25 mmol) were
used. The product was purified by column chromatography on silica
gel (solvent: n-hexane/ethyl acetate, 2:1) and obtained as colour-
less solid (0.29 g, 48%); Rf¼0.69 (n-hexane/ethyl acetate, 2:1); mp
4J¼1.0 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 13.9 (CH(CH3)2),
17.3 (CH(CH3)2), 19.7 (OC(CH3)2CH), 24.3 (OC(CH3)2CH), 29.8
(CH(CH3)2), 80.3 (OC(CH3)2CH), 90.5 (OC(CH3)2CH), 90.6 (OCHN),
116.5 (ArCH), 119.2 (ArC), 122.9 (ArCH), 127.6 (ArCH), 134.0 (ArCH),
156.3 (ArC), 158.5 (CO); MS (CI, isobutane): m/z (%)¼262.3 (100)
[MH]þ; HRMS (CI, isobutane): m/z calcd for [C15H20NO3]þ:
262.1443; found: 262.1444.
114–116 ꢂC; IR:
777 cmꢁ1 1H NMR (500 MHz, CDCl3):
n
3068, 2987, 2936, 1670, 1634, 1606, 1469, 1378,
1.65 (s, 6H, OC(CH3)2N),
;
d
4.3.6. 1-tert-Butyl-3,3-dimethyl-3,3a-dihydrooxazolo[4,3-b][1,3]ben-
zoxazin-9-one (1R
2,5-dihydrooxazole 1f (0.78 g, 5.0 mmol) and salicyl chloride
(0.94 g, 6.0 mmol) were used. After column chromatography on
silica gel (solvent: dichloromethane) two diastereomers were iso-
1.85 (s, 6H, OC(CH3)2C), 7.46 (ddd, 3J¼7.0 Hz, 3J¼8.1 Hz, 4J¼1.1 Hz,
1H, ArH), 7.69 (dd, 3J¼8.1 Hz, 4J¼1.1 Hz, 1H, ArH), 7.74 (ddd,
3J¼7.0 Hz, 3J¼8.1 Hz, 3J¼1.3 Hz, 1H, ArH), 8.29 (dd, 3J¼8.1 Hz,
*
,3aR
*
)-3f and (1R
*
,3aS )-3f. Following GP 2,
*
4J¼1.3 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 27.4 (OC(CH3)2C),
28.2 (OC(CH3)2N), 81.2 (OC(CH3)2C), 97.1 (OC(CH3)2N), 121.3 (ArC),
126.4 (ArCH), 126.5 (ArCH), 127.1 (ArCH), 134.3 (ArCH), 149.6 (ArC),
159.3 (CO), 159.5 (CN); MS (CI, isobutane): m/z (%)¼245.1 (100)
[MH]þ; HRMS (CI, isobutane): m/z calcd for [C14H17N2O2]þ:
245.1290; found: 245.1294.
lated (1R
*
,3aR
*
)-3f and (1R
*
,3aS )-3f, ratio of diastereomers 61:39
*
(determined from 1H NMR spectra of crude product); total yield:
0.34 g, 25%.
4.3.6.1. Major diastereomer (1R
*
,3aR )-3f. Colourless solid
*
(0.22 g, 16%); Rf¼0.69 (dichloromethane); mp 78–80 ꢂC; IR:
n
2987,
d 1.07
4.4.2. Spiro[3,3-dimethyl-3H-oxazolo[4,3-b]chinazolin-9-one-1,10-cy-
clohexane] 4b. Following GP 3, anthranilic acid (0.34 g, 2.5 mmol),
thionyl chloride (0.9 mL, 12.5 mmol), 2,5-dihydrooxazole 1b
(0.42 g, 2.5 mmol) and potassium permanganate (0.99 g,
6.25 mmol) were used. The product was purified by column chro-
matography on silica gel (solvent: n-hexane/ethyl acetate, 2:1) and
obtained as yellow solid (0.24 g, 36%); Rf¼0.79 (n-hexane/ethyl
2898, 1685, 1611, 1470, 760 cmꢁ1; 1H NMR (500 MHz, CDCl3):
(s, 9H, C(CH3)3), 1.37 (s, 3H, OC(CH3)2CH), 1.49 (s, 3H, OC(CH3)2CH),
5.08 (s, 1H, OCHN), 5.11 (s, 1H, OC(CH3)2CH), 7.02 (dd, 3J¼8.2 Hz,
4J¼0.8 Hz, 1H, ArH), 7.11 (ddd, 3J¼7.0 Hz, 3J¼7.8 Hz, 4J¼0.8 Hz, 1H,
ArH), 7.45 (ddd, 3J¼7.0 Hz, 3J¼8.2 Hz, 4J¼1.6 Hz, 1H, ArH), 7.98 (dd,
3J¼7.8 Hz, 4J¼1.6 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 22.6
(OC(CH3)2CH), 25.7 (OC(CH3)2CH), 26.3 (C(CH3)3), 36.1 (C(CH3)3),
78.9 (OC(CH3)2CH), 94.5 (OC(CH3)2CH), 95.6 (OCHN), 116.7 (ArCH),
119.8 (ArC), 122.4 (ArCH), 128.5 (ArCH), 134.3 (ArCH), 157.6 (ArC),
162.4 (CO); MS (CI, isobutane): m/z (%)¼276.3 (100) [MH]þ, 218.2
(20) [MꢁC4H9]þ; HRMS (CI, isobutane): m/z calcd for [C16H22NO3]þ:
276.1600; found: 276.1598.
acetate, 2:1); mp 161–163 ꢂC; IR:
1469, 1381, 775 cmꢁ1
n
2939, 2855, 1680, 1632, 1607,
;
1H NMR (500 MHz, CDCl3):
d
1.31–1.42 (m,
1H, –(CH2)5–), 1.65 (s, 6H, OC(CH3)2C), 1.66–1.79 (m, 7H, –(CH2)5–),
2.70–2.76 (m, 2H, –(CH2)5–), 7.45 (ddd, 3J¼6.8 Hz, 3J¼8.0 Hz,
4J¼1.1 Hz, 1H, ArH), 7.69 (dd, 3J¼8.3 Hz, 4J¼1.1 Hz, 1H, ArH), 7.73
(ddd, 3J¼6.8 Hz, 3J¼8.3 Hz, 4J¼1.4 Hz, 1H, ArH), 8.29 (dd, 3J¼8.0 Hz,
4J¼1.4 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 22.5 (–(CH2)5–),
4.3.6.2. Minor diastereomer (1R
9%); Rf¼0.60 (dichloromethane); IR:
1418, 755 cmꢁ1; 1H NMR (500 MHz, CDCl3):
*
,3aS
2976, 2874, 1675, 1613, 1468,
1.00 (s, 9H, C(CH3)3),
*
)-3f. Colourless oil (0.12 g,
24.3 (–(CH2)5–), 28.5 (OC(CH3)2C), 35.2 (–(CH2)5–), 80.9
(OC(CH3)2C), 98.7 (OCN), 121.4 (ArC), 126.3 (ArCH), 126.6 (ArCH),
127.0 (ArCH), 134.2 (ArCH), 149.3 (ArC), 159.4 (CO), 159.9 (CN); MS
(CI, isobutane): m/z (%)¼285.2 (100) [MH]þ; HRMS (CI, isobutane):
m/z calcd for [C17H21N2O2]þ: 285.1603; found: 285.1601.
n
d
1.20 (s, 3H, OC(CH3)2CH), 1.46 (s, 3H, OC(CH3)2CH), 5.28 (s, 1H,
OCHN), 5.34 (s, 1H, OC(CH3)2CH), 6.92 (dd, 3J¼8.2 Hz, 4J¼0.9 Hz, 1H,
ArH), 7.08 (ddd, 3J¼7.6 Hz, 3J¼7.7 Hz, 4J¼0.9 Hz, 1H, ArH), 7.41 (ddd,
3J¼7.6 Hz, 3J¼8.2 Hz, 4J¼1.7 Hz, 1H, ArH), 7.85 (dd, 3J¼7.7 Hz,
4.4.3. (RS)-1,1,3-Trimethyl-3-phenyl-3H-oxazolo[4,3-b]chinazolin-9-
one 4c. Following GP 3, anthranilic acid (0.34 g, 2.5 mmol), thionyl
chloride (0.9 mL, 12.5 mmol), 2,5-dihydrooxazole 1c (0.47 g,
2.5 mmol) and potassium permanganate (0.99 g, 6.25 mmol) were
4J¼1.7 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 20.1
(OC(CH3)2CH), 23.9 (OC(CH3)2CH), 25.5 (C(CH3)3), 37.8 (C(CH3)3),
80.7 (OC(CH3)2CH), 90.7 (OCHN), 93.4 (OC(CH3)2CH), 115.9 (ArCH),

K. Johannes, J. Martens / Tetrahedron 66 (2010) 242–250
249
used. The product was purified by column chromatography on silica
gel (solvent: n-hexane/ethyl acetate, 3:1) and obtained as colour-
less solid (0.37 g, 50%); Rf¼0.69 (n-hexane/ethyl acetate, 3:1); mp
2.5 mmol) and potassium permanganate (0.99 g, 6.25 mmol) were
used. The product was purified by column chromatography on silica
gel (solvent: n-hexane/ethyl acetate, 4:1) and obtained as yellow
solid (0.14 g, 22%); Rf¼0.52 (n-hexane/ethyl acetate, 4:1); mp 68–
85–87 ꢂC; IR:
696 cmꢁ1
n 3064, 2984, 2931, 1674, 1635, 1609, 1472, 1370, 767,
;
1H NMR (500 MHz, CDCl3):
d
1.73 (s, 3H, OC(CH3)2N),
73 ꢂC; IR:
n 2957, 2902, 2856, 1685, 1644, 1607, 1470, 1381,
1.95 (s, 3H, OC(CH3)CH), 1.99 (s, 3H, OC(CH3)2N), 7.27–7.30 (m, 1H,
ArH), 7.34–7.38 (m, 2H, ArH), 7.48 (ddd, 3J¼6.8 Hz, 3J¼7.9 Hz,
4J¼1.0 Hz, 1H, ArH), 7.77 (ddd, 3J¼6.8 Hz, 3J¼8.1 Hz, 4J¼1.2 Hz, 1H,
ArH), 7.80–7.82 (m, 3H, ArH), 8.30 (dd, 3J¼7.9 Hz, 4J¼1.2 Hz, 1H,
772 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d 1.08 (s, 9H, C(CH3)3), 1.49 (s,
3H, OC(CH3)2C), 1.74 (s, 3H, OC(CH3)2C), 5.84 (s, 1H, OCHN), 7.46
(ddd, 3J¼7.2 Hz, 3J¼8.0 Hz, 4J¼1.0 Hz, 1H, ArH), 7.69 (dd, 3J¼8.4 Hz,
4J¼1.0 Hz, 1H, ArH), 7.74 (ddd, 3J¼7.2 Hz, 3J¼8.4 Hz, 4J¼1.4 Hz, 1H,
ArH), 8.27 (dd, 3J¼8.0 Hz, 4J¼1.4 Hz, 1H, ArH); 13C NMR (125 MHz,
ArH); 13C NMR (125 MHz, CDCl3):
d 26.4 (OC(CH3)2N), 27.5
(OC(CH3)2N), 30.6 (OC(CH3)2C), 83.4 (OC(CH3)2C), 97.7 (OC(CH3)2N),
121.4 (ArC), 125.1 (ArCH), 126.4 (ArCH), 126.6 (ArCH), 127.6 (ArCH),
127.8 (ArCH), 128.2 (ArCH), 134.3 (ArCH), 143.0 (ArC), 149.4 (ArC),
157.6 (CO), 159.2 (CN); MS (CI, isobutane): m/z (%)¼307.1 (100)
[MH]þ; HRMS (CI, isobutane): m/z calcd for [C19H19N2O2]þ:
307.1447; found: 307.1448.
CDCl3): d 25.6 (OC(CH3)2C), 26.0 (C(CH3)3), 28.2 (OC(CH3)2C), 38.0
(C(CH3)3), 81.5 (OC(CH3)2C), 97.1 (OCHN), 121.3 (ArC), 126.4 (ArCH),
126.8 (2ꢀArCH), 134.4 (ArCH), 149.1 (ArC), 160.6 (CO), 160.8
(CN);MS (CI, isobutane): m/z (%)¼273.3 (100) [MH]þ; HRMS (CI,
isobutane):
m/z
calcd
for
[C16H21N2O2]þ:
273.1603;
found: 273.1606.
4.4.4. (RS)-Spiro[3-methyl-3-phenyl-3H-oxazolo[4,3-b]chinazolin-9-
one-1,10-cyclohexane] 4d. Following GP 3, anthranilic acid (0.34 g,
2.5 mmol), thionyl chloride (0.9 mL, 12.5 mmol), 2,5-dihydroox-
azole 1d (0.57 g, 2.5 mmol) and potassium permanganate (0.99 g,
6.25 mmol) were used. The product was purified by column chro-
matography on silica gel (solvent: n-hexane/ethyl acetate, 2:1) and
obtained as yellow solid (0.41 g, 49%); Rf¼0.82 (n-hexane/ethyl
4.5. Preparation of (RS)-1,1,3,3-tetramethyl-3a,4-dihydro-3H-
oxazolo[4,3-b]chinazolin-9-one 5
Under argon atmosphere, anthranilic acid (0.34 g, 2.5 mmol)
and thionyl chloride (0.9 mL, 12.5 mmol) were refluxed in anhy-
drous benzene (30 mL) for 2–3 h. After cooling the reaction mixture
to room temperature, the excess of thionyl chloride and solvent
were removed under reduced pressure at room temperature. Under
exclusion of moisture, the remaining yellow oil was resolved in
anhydrous benzene (10 mL) before 2,5-dihydrooxazole 1a (0.32 g,
2.5 mmol) dissolved in anhydrous benzene (10 mL) was added.
After stirring overnight at room temperature, the solvent was
removed under reduced pressure. The product was purified by
column chromatography on silica gel (solvent: n-hexane/ethyl
acetate, 2:1) and obtained as colourless solid (0.17 g, 28%); Rf¼0.43
acetate, 2:1); mp 151–152 ꢂC; IR:
n
3067, 2934, 2853, 1676, 1629,
1601, 1470, 1444, 1375, 778, 767, 696 cmꢁ1 1H NMR (500 MHz,
CDCl3): 1.36–1.45 (m, 1H, –(CH2)5–), 1.51–1.56 (m, 1H, –(CH2)5–),
;
d
1.72–1.93 (m, 6H, –(CH2)5–), 1.95 (s, 3H, CH3), 2.48–2.54 (m, 1H,
–(CH2)5–), 2.87–2.93 (m, 1H, –(CH2)5–), 7.26–7.30 (m, 1H, ArH),
7.34–7.37 (m, 2H, ArH), 7.47 (ddd, 3J¼6.9 Hz, 3J¼8.0 Hz, 4J¼1.1 Hz,
1H, ArH), 7.76 (ddd, 3J¼6.9 Hz, 3J¼8.3 Hz, 4J¼1.3 Hz, 1H, ArH), 7.80
(dd, 3J¼8.3 Hz, 4J¼1.1 Hz, 1H, ArH), 7.82–7.84 (m, 2H, ArH), 8.29 (dd,
3J¼8.0 Hz, 4J¼1.3 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 22.5
(n-hexane/ethyl acetate, 2:1); mp 202–205 ꢂC; IR:
2937, 1631, 1612, 1423, 1373, 752 cmꢁ1; 1H NMR (500 MHz, CDCl3):
1.39 (s, 3H, OC(CH3)2CH), 1.40 (s, 3H, OC(CH3)2CH), 1.64 (s, 3H,
n 3293, 2980,
(–(CH2)5–), 22.7 (–(CH2)5–), 24.4 (–(CH2)5–), 30.9 (CH3), 33.5
(–(CH2)5–), 35.4 (–(CH2)5–), 83.3 (OC(CH3)C), 99.2 (OCN), 121.5
(ArC), 124.9 (ArCH), 126.5 (2ꢀArCH), 127.5 (ArCH), 127.7 (ArCH),
128.2 (ArCH), 134.2 (ArCH), 143.5 (ArC), 149.1 (ArC), 157.7 (CO),
159.4 (CN); MS (CI, isobutane): m/z (%)¼347.0 (100) [MH]þ; HRMS
(CI, isobutane): m/z calcd for [C22H23N2O2]þ: 347.1760;
found: 347.1759.
d
OC(CH3)2N), 1.77 (s, 3H, OC(CH3)2N), 4.12 (br s, 1H, NH), 4.94 (d,
3J¼1.9 Hz,1H, OC(CH3)2CH), 6.70 (dd, 3J¼8.1 Hz, 4J¼0.9 Hz,1H, ArH),
6.89 (ddd, 3J¼7.0 Hz, 3J¼7.8 Hz, 4J¼0.9 Hz, 1H, ArH), 7.30 (ddd,
3J¼7.0 Hz, 3J¼8.1 Hz, 4J¼1.4 Hz, 1H, ArH), 7.91 (dd, 3J¼7.8 Hz,
4J¼1.4 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 23.4
(OC(CH3)2CH), 26.4 (OC(CH3)2CH), 26.9 (OC(CH3)2N), 27.4
(OC(CH3)2N), 75.4 (OC(CH3)2CH), 80.4 (OC(CH3)2CH), 93.7
(OC(CH3)2N), 115.0 (ArCH), 117.6 (ArC), 120.0 (ArCH), 128.2 (ArCH),
133.4 (ArCH), 146.7 (ArC), 160.7 (CO); MS (CI, isobutane): m/z
(%)¼247.1 (100) [MH]þ; HRMS (CI, isobutane): m/z calcd for
[C14H19N2O2]þ: 247.1447; found: 247.1442.
4.4.5. (RS)-1-Isopropyl-3,3-dimethyl-3H-oxazolo[4,3-b]chinazolin-9-
one 4e. Following GP 3, anthranilic acid (0.34 g, 2.5 mmol), thionyl
chloride (0.9 mL, 12.5 mmol), 2,5-dihydrooxazole 1e (0.35 g,
2.5 mmol) and potassium permanganate (0.99 g, 6.25 mmol) were
used. The product was purified by column chromatography on silica
gel (solvent: n-hexane/ethyl acetate, 2:1) and obtained as yellow
solid (0.23 g, 38%); Rf¼0.78 (n-hexane/ethyl acetate, 2:1); mp 114–
Acknowledgements
115 ꢂC; IR:
774 cmꢁ1
n 3065, 2972, 2935, 2879, 1675, 1640, 1610, 1475, 1398,
;
1H NMR (500 MHz, CDCl3):
d
0.74 (d, 3J¼6.9 Hz, 3H,
The silica gel was generously supplied by Grace GmbH & Co. KG.
K.J. gratefully acknowledges the Heinz Neumu¨ller-Stiftung for
a doctoral fellowship.
CH(CH3)2), 1.12 (d, 3J¼6.9 Hz, 3H, CH(CH3)2), 1.54 (s, 3H, OC(CH3)2C),
1.70 (s, 3H, OC(CH3)2C), 3.06 (dsept, 3J¼2.1 Hz, 3J¼6.9 Hz, 1H,
CH(CH3)2), 5.81 (d, 3J¼2.1 Hz, 1H, OCHN), 7.46 (ddd, 3J¼6.9 Hz,
3J¼7.9 Hz, 4J¼1.1 Hz, 1H, ArH), 7.70 (dd, 3J¼8.3 Hz, 4J¼1.1 Hz, 1H,
ArH), 7.75 (ddd, 3J¼6.9 Hz, 3J¼8.3 Hz, 4J¼1.3 Hz, 1H, ArH), 8.29 (dd,
References and notes
3J¼7.9 Hz, 4J¼1.3 Hz, 1H, ArH); 13C NMR (125 MHz, CDCl3):
d 13.3
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