Terminal oxazolinyloxiranes: synthesis, reaction with amines and regioselective β-lithiation

Article abstract of DOI:10.1016/j.tet.2009.08.040

The synthesis of terminal oxazolinyloxiranes, even in enantioenriched form, has been performed by Darzens-type reaction of lithiated chloroalkyloxazolines with benzotriazolylmethanol (BtCH₂OH) or by chloromethylation of 2-acyl-2-oxazolines. The

Full text of DOI:10.1016/j.tet.2009.08.040

Tetrahedron 65 (2009) 8745–8755
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Terminal oxazolinyloxiranes: synthesis, reaction with amines
and regioselective b-lithiation
,
Leonardo Degennaro a, Vito Capriati a, Claudia Carlucci a, Saverio Florio a
*
,
Renzo Luisi a, Irene Nuzzo a, Corrado Cuocci b
a
`
Dipartimento Farmaco-Chimico, Universita degli Studi di Bari and Consorzio Interuniversitario Nazionale CINMPIS, Via E. Orabona 4, I-70125 Bari, Italy
b Istituto di Cristallografia (IC-CNR), Via Amendola 122/o, I-70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2009
Received in revised form 23 July 2009
Accepted 7 August 2009
Available online 20 August 2009
The synthesis of terminal oxazolinyloxiranes, even in enantioenriched form, has been performed by
Darzens-type reaction of lithiated chloroalkyloxazolines with benzotriazolylmethanol (BtCH2OH) or by
chloromethylation of 2-acyl-2-oxazolines. The synthetic utility of such oxiranes based on their ability to
act either as electrophiles, undergoing ring-opening reactions with nucleophiles, or as nucleophiles in
form of the oxiranyl anions, generated by stereoselective
b
-deprotonation, has been investigated.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Scheme 1) or via the Darzens-like reaction of lithiated haloalkylox-
azolines with formaldehyde or a synthetic equivalent (path b,
Scheme 1).
Di-, tri- and tetrasubstituted oxazolinyloxiranes, promptly avail-
able by the Darzens reaction of 2-haloalkyloxazolines and carbonyl
compounds,1 have become very useful building blocks in synthetic
Herein, we wish to report the synthesis of 2-acyl-2-oxazolines,
their conversion into the corresponding
oxiranes and reactions of the latter with nucleophiles. The b
a
-substituted oxazolinyl-
-lith-
organic chemistry. As
a- or
b
-lithiated derivatives, which could be
seen as masked epoxyenolates and homoenolates, oxazolinyloxir-
anes2 have been successfully employed for the stereoselective syn-
thesis of a variety of substances such as optically active cyclopropane
iation-trapping sequence (LTS) of the above epoxides has been
investigated as well.
carboxylates,3 spirocyclic compounds,4 oxazolinyl allylic alcohols,5
iminooxetanes,6
a
-epoxy-
b
-aminoacids and
a,b-epoxy-g-amino
7
2. Results and discussion
acids.8 Terminal oxazolinyloxiranes, which seem to be even more
interesting from the synthetic point of view, are very rare. To the best
of our knowledge, there is just one patent on the synthesis of such
compounds, which relies on the Corey reaction of 2-benzoyloxazo-
lines.9 We envisaged two main strategies for the preparation of
terminal oxazolinyloxiranes, based either on the reaction of 2-acyl-
2-oxazolines with halogenated methylene nucleophiles (path a,
2.1. Synthesis of 2-acyl-2-oxazolines
Our work began with the preparation of 2-acyl-2-oxazolines 2.
The existing methods for the synthesis of this type of ketones, in-
cluding lithiation/electrophile trapping with oxygen10 and the
SeO2-oxidation of 2-alkyloxazoline, suffer from low yields.11 The
adaptation of the methodology reported for the synthesis of 2-acyl-
2-oxazoles,12 based on the copper-mediated acylation of 2-oxazo-
lylzinc, to 4,4-dimethyl-2-oxazoline 1 proved to be successful also
for the synthesis of 2-acyl-2-oxazolines 2. When 4,4-dimethyl-2-
oxazoline 1 was reacted with n-BuLi at ꢀ78 ꢁC and then trans-
metallated with ZnCl2/CuI, the putative bimetallic intermediate 3
could be trapped with acylchlorides giving 2-acyl-2-oxazolines 2a–
g in moderate to good yields (Table 1, entries 1–7).
X
O
N
O
O
R
O
R
O
CH =O
+
CH2X
R
+
2
N
path b
N
path a
R2
R2
R2
R1
R1
R1
X = Leaving Group
2-Acyl-2-oxazolines 2 proved to be very sensitive to acidic
conditions (even to the residual HCl of the CDCl3 solution) un-
dergoing the known rearrangement to the dihydrooxazinones 4
almost quantitatively (Scheme 2).10,13 Nevertheless, the rear-
rangement could be avoided working under inert conditions and in
the absence of Lewis acids and proton sources.
Scheme 1.
* Corresponding author.
E-mail address: florio@farmchim.uniba.it (S. Florio).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.040

8746
L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
Four optically active terminal oxazolinyloxiranes (2S,40R)-,
Table 1
Preparation of 2-acyl-2-oxazolines 2
(2R,40R)-, (2R,40S)- and (2S,40S)-10 were prepared starting from
2-benzoyloxazoline (S)-816 or from an equimolar mixture of di-
astereomeric oxazolines (1R,40R)/(1S,40R)-9 (Scheme 4). In both
cases (ClCH2Li-mediated epoxidation or Darzens reaction), a mix-
ture of two diastereomeric oxiranes was obtained (dr¼1:1), which
could be easily separated by preparative HPLC. It is worth noting
that the Darzens methodology gave better overall yields.
1) nBuLi, THF,
-78 °C, 20 min
2) ZnCl2, 0 °C,
R
N
R
O
CuI(ZnCl)
N
N
N
Lewis Acid
or H+
RCOCl
O
45 min
O
O
O
O
1
3) CuI, 10 min
2a-g
4a-g
3
Entry RCOCl
2-Acyl-2-oxazoline 2 (yield %)a Oxazinone 4 (yield %)
The absolute configuration of the optically pure stereoisomer
1
4-Cl–C6H4COCl 2a (45) 4a (>98)
(2R,40S)-10 was determined by an X-ray analysis (Fig. 1).17
2
PhCOCl
Me3CCOCl
2-FurylCOCl
2b (70)
2c (60)
2d (45)
4b (>98)
4cb (0)
4d (>98)
4e (>98)
4f (>98)
4g (>98)
3b
4
5
6
7
2-Br–C6H4COCl 2e (60)
PhCH]CHCOCl 2f (35)
3-F–C6H4COCl 2g (75)
a
Isolated yield.
b
A complex mixture of products was observed in the crude.
OLA
OLA
O
N
O
R
R
O
N
O
O
LA
O
N
N
R
R
2
4
LA = Lewis Acid
Scheme 2.
Figure 1. ORTEP diagram of compound (2R,40S)-10.
2.2. Synthesis of terminal oxazolinyloxiranes
2.3. Oxazolinyloxirane-ring-opening reaction with secondary
amines
With 2-acyl-2-oxazolines in hand, the preparation of terminal
a,a-disubstituted oxazolinyloxiranes was pursued. Treatment of
Next, the reactivity of oxazolinyloxiranes was investigated with
reference to their capability to behave as electrophiles and nucleo-
philes in the form of oxiranyl anions. Oxazolinyloxiranes 6b, (2S,40S)-
and (2R,40S)-10 were used as model compounds. Treatment of 6b
with secondary amines such as Et2NH, pyrrolidine, piperidine and
morpholine at 60 ꢁC in ethanol, gave aminoalcohols 11a–c,e,
respectively, in very good yield (Table 2, entries 1–3, 5). Likely for
steric reasons, no reaction was observed with N-benzyl-tert-
butylamine and a lower yield of the expected aminoalcohol 11d
was obtained in the case of N-allylcyclohexylamine (Table 2, entry 4).
2-acyl-2-oxazolines 2b,c with ClCH2Li, generated from ClCH2I
and n-BuLi in THF at ꢀ78 ꢁC, gave chlorohydrins 5a,b (not iso-
lated), which were straightforwardly converted into epoxides
6a,b (50–60% yield) upon treatment with NaOH (Scheme 3).
Alternatively, terminal oxazolinyloxiranes 6b,c could be prepared
in good yield (70–90%) by lithiation of 2-chloroalkyl-2-oxazolines
7a,b followed by hydroxymethylation with benzotriazolyl-
methanol (BtCH2OH), a synthetic equivalent of formaldehyde
(Scheme 3).14,15
1) LDA, THF, 78 °C
2) BtCH2OH
NaOH
R OH
N
O
R
Cl
R
3) NaOH, iPrOH
O
iPrOH
ClCH2I, nBuLi
THF, 78 °C
Cl
N
N
2b,c
O
O
5a,b
6b: R = Ph, 70%
6c: R = CH3, 90%
7a: R = CH3
7b: R = Ph
6a: R = tBu, 60%
6b: R = Ph, 50%
6a-c
Scheme 3.
The reaction of optically active oxazolinyloxiranes (2R,40S)- and
(2S,40S)-10 with pyrrolidine, diethylamine and triazole afforded
highly enantioenriched aminoalcohols 11f–h and 11i–k, re-
spectively, in excellent yields (Table 2, entries 6–11). The triazole
derivatives 11h and 11k are particularly appealing considering that
some oxazolinyl triazolylmethylcarbinols have been reported to act
as efficient antifungal agents.18 Aminoalcohols 11 were found to be
particularly prone to undergo smooth hydrolysis of the oxazolinyl
ring, under acidic conditions or in the presence of silica gel, to give
1) nBuLi/ClCH2I
THF, 78 °C
2) NaOH/iPrOH
Ph
Ph
Ph
O
O
N (S)
N
(S)
(R)
O
(2R,4'S)-10
(S)
O
(2S,4'S)-10
N (S)
+
+
O
O
(S)-8
35% overall
1) LDA, THF, 78 °C
2) BtCH2OH
3) NaOH, iPrOH
(R)
(R)
O
Ph
O
(R)
(S)
N
N (R)
N
Cl
O
O
interesting
related to unnatural
definition).19 As reported in Table 2,
a
-hydroxy-
b
b
-aminoalkanamides 12, which are strictly
2,2-amino acids (according to Seebach’s
-hydroxy- -amino-
Ph
O
70% overall
Ph
(2R,4'R)-10
(2S,4'R)-10
(1R,4'R)/(1S,4'R)-9
a
b
dr =1:1
alkanamides 12a–i could be easily obtained in racemic or enan-
Scheme 4.
tioenriched form.

L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
8747
Table 2
Table 3
Ring-opening reaction of oxazolinyloxirane
Stereoselective lithiation and nucleophilic reactivity of terminal oxazolinyloxir-
anyllithium 6b–Li
Ph
O
N
CH3
CH3
Ph
Ha
Ha
Hb
Ph
O
Ha
Ph
1) E+
2) H+
3H
N
O
O
2 R
2 R3
O
OH
R1
iPrLi/TMEDA
R
O
O
R
O
( )-6b
SiO2
Amine
EtOH
60 °C
THF, time
N
Li
N
E
O
N
R
N
N
or
N
-110 °C
O
R1
R
12a-i
(2S,4'S)-10
or
13a-k
6b-Li
11a-k
6b
(2R,4'S)-10
Ph
OH
N
N
O
N
O
Entry Oxazoline Amine
R
R1 R2 R3 Aminoalcohol Amide
11 (yield %) 12 (yield %)
12a (>98)a
O
iPr
+
Ph OH
Ph OH
1
2
3
4
(ꢂ)-6b
Diethylamine CH3 CH3 Ph OH 11a (>98)a
Pyrrolidine
Piperidine
N-Allylcyclo-
hexylamine
Morpholine
15
(E)-14
5-19%
a
11b (>98)a
11c (>98)a
11d (46)b
12b (>98)
12c (>98)a
12d (46)b
(<10%)
other products
Electrophile (Eþ)
Time
Oxazolinyloxirane 13
Yield %a
5
6
7
8
11e (90)b
12e (90)b
(2R,40S)-10 Pyrrolidine
Diethylamine
i-Pr H
OH Ph 11f (>98)a,c 12f (>98)a
11g (>98)a,c 12g (>98)a
D2O
Me3SiCl
20 min
13a
13b
13c
13d
13e
13f
13g
13h
13i
50 (85% D)
0b
90
77
74
68
68
50
25c
35
25c
24
Triazolee
11h (90)b,c
d
(i-Pr)3SiCl
AllylMe2SiCl
PhMe2SiCl
Ph2MeSiCl
Bu3SnCl
9
(2S,40S)-10 Pyrrolidine
Diethylamine
Ph OH 11i (>98)a,d 12h (>98)a
10
11
11j (>98)a,d 12i (>98)a
Triazolee
11k (84)b,d
d
20 min
5 min
a
Based on the crude reaction mixture; no further purification was needed.
Isolated yield.
In this case, enantioenriched oxazolinyloxirane (2R,40S)-10 (er >98:2) was
MeI
b
c
AllylBr
PhCHOd
13j
13k
Cyclopentanoned
employed.
d
Enantioenriched oxazolinyloxirane (2S,40S)-10 (er >98:2) was employed.
Reaction run in DMF at 50 ꢁC.
a
e
Isolated yield.
In situ quenching conditions.
b
c
In this case, two diastereomers formed, dr¼78:22, calculated by 1H NMR on the
2.4. Epoxide functionalization by stereospecific b-lithiation
crude reaction mixture.
d
The reaction was performed in Et2O as the solvent, recovering about 50% of the
starting oxirane.
The possibility that the above oxazolinyloxiranes, once lithiated,
could be employed for the epoxide functionalization, as in the case
of other oxazolinyloxiranyllithiums,20 was evaluated. Lithiation of
6b under optimized experimental conditions (i-PrLi, 3 equiv, ꢀ98/
ꢀ110 ꢁC, 20 min) produced lithiated species 6b–Li which, upon
treatment with D2O, furnished deuterated oxirane 13a in 50% yield
and 85% D (Table 3). The formation of 13a was accompanied by
variable amount of enediol (E)-14 (5–19%),21 which likely results
from an ‘eliminative dimerization’ of 6b–Li (the typical carbene-
like reactivity often associated to a
-lithiated ethers),22 and alcohol
Figure 2. Panels (a) and (b) represent 1D-NOESY spectra of 6b obtained after applying a selective pre-irradiation of protons Ha and Hb, respectively. Panel (c) represents 1H NMR
spectrum of 6b.

8748
L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
15 (<10%) most probably as the result of nucleophilic attack of
i-PrLi at the oxirane ring. Enediol (E)-14 was obtained with high
stereoselectivity (75%, E/Z >98:2) by carrying out the deprotona-
tion reaction in Et2O at ꢀ98 ꢁC with LDA and TMEDA.23 The capture
Petroleum ether refers to the 40–60 ꢁC boiling fraction. For the 1H
and 13C NMR spectra (1H NMR 400, 500 MHz; 13C NMR 100,
125 MHz), CDCl3, DMSO-d6 and CD3OD were used as the solvent.
MS-ESI analyses were performed on LC/MSD trap system VL.
Melting points were uncorrected. Analytical thin layer chroma-
tography (TLC) was carried out on precoated 0.25 mm thick plates
of Kieselgel 60 F254; visualization was accomplished by UV light
(254 nm) or by spraying a solution of 5% (w/v) ammonium mo-
lybdate and 0.2% (w/v) cerium(III) sulfate in 100 mL 17.6% (w/v) aq
sulfuric acid and heating to 200 ꢁC for some time until blue spots
appear. All reactions involving air-sensitive reagents were per-
formed under nitrogen in oven-dried glassware using syringe-
septum cap technique.
of b-lithiated oxazolinyloxirane 6b–Li with other electrophiles was
investigated. At ꢀ110 ꢁC, in situ trapping of 6b–Li with various
alkyl(aryl)silylchlorides furnished
b-silylated oxazolinyloxiranes
13b–f in very good yield (68–90%) (Table 3),24 whereas external
trapping with Bu3SnCl, MeI, allylbromide, PhCHO and cyclo-
pentanone took place with a lower yield (24–50%), furnishing
oxiranes 13g–k, due to the previously described side reactions.
In all cases, the reaction proceeded in a stereoselective way,
always involving a retentive substitution cis to the oxazoline ring as
ascertained by 1D-NOESY experiments (see Supplementary data),
thus proving that the lithiated intermediate 6b–Li is configura-
tionally stable. The only diastereotopic proton removed was Hb cis
to the oxazolinyl ring likely due to the coordinating and stabilizing
effect of the oxazolinyl group on the lithiated intermediate.25 By
using as a model compound oxazolinyloxirane 6b, the assignment
of the two diastereotopic protons Ha and Hb was accomplished by
detecting positive NOE effects, after applying selective 1H pre-ir-
radiations within a double pulsed field gradient spin-echo NOE
(DPFGSE-NOE) sequence (Fig. 2).26
4.2. General procedure for the preparation of 2-acyl-2-
oxazolines (2a–g)
To a solution of 4,4-dimethyl-2-oxazoline (198 mg, 2 mmol) in
THF (15 mL) at ꢀ78 ꢁC, under a nitrogen atmosphere, n-BuLi
(1.1 equiv, 0.9 mL hexanes solution, 2.5 M) was added. The resulting
yellow solution was stirred for 20 min and ZnCl2 (4 mmol, 4 mL of
a 1 M solution in ether) was then added. The mixture was warmed
to 0 ꢁC, stirred for 45 min and anhydrous CuI (380 mg, 2 mmol) was
added. After 10 min, acylchloride (2 mmol) was also added. The
reaction was over within 1 h. The organic solution was diluted with
AcOEt and washed sequentially with 1:1 NH4OH/water, water and
brine. Flash chromatography (silica gel, petroleum ether/AcOEt 7:3)
afforded 2-acyl-2-oxazoline (2a–g).
Pre-irradiation of Ha enhanced ortho-aromatic proton Hc
(Fig. 2a), whereas pre-irradiation of Hb slightly enhanced reso-
nances of both the oxazoline geminal methyl groups and the oxa-
zoline methylenic protons (He and Hd, Fig. 2a and Supplementary
data). The diastereomeric hydroxyalkylated oxiranes derived from
benzaldehyde,13j-major and 13j-minor (dr¼78:22), once separated
by chromatography, were found to equilibrate in solution to the
corresponding spirocyclic compounds, which could be hydrolyzed
4.2.1. 4-Chlorophenyl(4,4-dimethyl-2-oxazolin-2-yl)ketone (2a).9 White
solid, mp 95.7ꢀ97.7 ꢁC, yield 45%. 1H NMR (500 MHz, CDCl3):
to the
a
,b
-epoxy-
g
-butyrolactones3,7 (R
*
,S
*
,R
*
)-16 and (R
*
,R
*
,R
*
)-16,
d
¼8.25 (d, 3JH,H¼8.7 Hz, 2H), 7.44 (d, 3JH,H¼8.7 Hz, 2H), 4.13 (s, 2H),
respectively (Scheme 5).27
1.42 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3):
d
¼182.5, 157.4, 140.8,
133.1, 132.1, 128.8, 78.8, 69.3, 28.1 ppm. GC–MS (70 eV) m/z 237
[M]þ (9), 209 (11), 194 (9), 141 (28), 99 (24), 69 (18), 57 (83), 56
H
O
Ph
H
(100), 55 (16), 41 (41). FT-IR (KBr):
n
¼3082, 2970, 1675, 1632, 1150,
O
O
O
N
OH
N
992 cmꢀ1
.
Ph
H
TFA
61%
H
O
O
H
Ph
Ph
Ph
Ph
H
H
O
4.2.2. (4,4-Dimethyl-2-oxazolin-2-yl)phenylketone (2b).10 Yellow oil,
O
(R*,S*,R*)-16
13j-major
yield 70%. 1H NMR (500 MHz, CDCl3):
d
¼8.27 (d, 3JH,H¼7.0 Hz, 2H),
7.62 (t, 3JH,H¼7.0 Hz, 1H), 7.48 (t, 3JH,H¼8.0 Hz, 2H), 4.15 (s, 2H), 1.45
H
O
H
O
O
(s, 6H) ppm. GC–MS (70 eV) m/z 203 [M]þ (6), 175 (9), 119 (13), 105
(100), 91 (13), 77 (38), 51 (11). FTIR (film):
N
O
OH
H
N
TFA
59%
Ph
Ph
n
¼1670, 1630 cmꢀ1
.
Ph
O
O
H
H
Ph
Ph
H
Ph
H
O
O
(R*,R*,R*)-16
4.2.3. 1-(4,4-Dimethyl-2-oxazolin-2-yl)-2,2-dimethylpropan-1-one
(2c). Yellow oil, yield 60%. 1H NMR (500 MHz, CDCl3):
¼4.01 (s,
2H), 1.35 (s, 6H), 1.31 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3):
¼199.2, 156.5, 78.3, 68.5, 44.1, 27.9, 26.2 ppm. GC–MS (70 eV) m/z
13j-minor
d
Scheme 5.
d
3. Conclusions
183 [M]þ (7), 140 (28), 99 (24), 70 (18), 57 (83), 56 (100), 55 (16), 41
(41). FT-IR (KBr):
n
¼2970, 1704, 1463, 1366, 1042, 1000 cmꢀ1. HRMS
In conclusion, in this paper terminal oxazolinyloxiranes were
synthesized by two routes and their reactivity was investigated.
New and interesting aminoalcohols 11 and 12 could be obtained by
an oxazolinyloxirane-ring-opening reaction with secondary
amines, whereas more functionalized oxazolinyloxiranes and
epoxylactones were formed upon a preliminary stereospecific
(ESI), calcd for C10H18NO2, [MþH]þ: 184.1338. Found: 184.1336.
4.2.4. (4,4-Dimethyl-2-oxazolin-2-yl)furan-2-yl-ketone (2d). White
solid, mp 86.5ꢀ88 ꢁC, yield 45%. 1H NMR (500 MHz, CDCl3):
¼7.89
d
(dd, JH,H¼3.6, 0.8 Hz, 1H), 7.72 (dd, JH,H¼1.6, 0.8 Hz, 1H), 6.56 (dd,
3JH,H¼3.6, 1.6 Hz, 1H), 4.11 (s, 2H), 1.38 (s, 6H) ppm. 13C NMR
b-lithiation. Work is in progress to further expand the synthetic
(125 MHz CDCl3):
d
¼170.0, 157.1, 150.4, 149.0, 124.9, 112.7, 79.0,
utility of terminal oxazolinyloxiranes and their derivatives.
68.9, 28.0 ppm. GC–MS (70 eV) m/z 193 [M]þ (8), 165 (7), 109 (12),
95 (100), 70 (8). FT-IR (KBr):
n
¼3145, 2975, 1675, 1629, 1467, 1031,
4. Experimental
4.1. General
993, 780 cmꢀ1. HRMS (ESI), calcd for C10H12NO3, [MþH]þ: 194.0817.
Found: 194.0810.
4.2.5. 2-Bromophenyl-(4,4-dimethyl-2-oxazolin-2-yl)ketone(2e). White
Tetrahydrofuran (THF) was freshly distilled under a nitrogen
atmosphere over sodium/benzophenone ketyl. Compounds 7a,b1
and (S)-816 were prepared according to the reported procedures.
solid, mp 58.2–59.2 ꢁC, yield 60%. 1H NMR (500 MHz, CDCl3):
d
7.60
3
(dd, JH,H¼7.6, 1.2 Hz, 1H), 7.57 (dd, JH,H¼7.5, 1.8 Hz, 1H), 7.40 (dt,
JH,H¼7.5, 1.2 Hz, 1H), 7.36 (dt, JH,H¼7.6, 1.8 Hz, 1H), 4.17 (s, 2H), 1.38

L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
8749
(s, 6H) ppm. 13C NMR (125 MHz, CDCl3):
d
¼186.3, 157.9, 137.9, 133.5,
CDCl3):
d
¼7.59–7.54 (m, 1H), 7.43–7.37 (m, 2H), 7.33–7.26 (m, 1H),
132.9, 130.6, 127.3, 120.6, 79.8, 69.0, 27.7 ppm. GC–MS (70 eV) m/z
4.38 (s, 2H), 1.41 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3):
d¼158.7,
283 [M]þ (13), 202 (100), 185 (96), 182 (99), 174 (20), 157 (27), 155
154.3,136.2,132.2,131.0,129.8,127.5,121.4, 74.3, 55.6, 24.1 ppm. GC–
(28), 148 (23), 76 (20), 75(18). FT-IR (KBr):
n
¼3059, 2973, 1693,
MS (70 eV) m/z 283 [M]þ (6), 225 (33), 183 (98), 181 (100), 102 (41),
1638, 1187, 983, 756 cmꢀ1. El. An. C12H12BrNO2: calcd C, 51.09; H,
4.29; N, 4.96; found C, 50.91; H, 4.32; N, 4.84.
56 (71). FT-IR (KBr):
El. An. C12H12BrNO2: calcd C, 51.09; H, 4.29; N, 4.96; found C, 50.91;
H, 4.42; N, 4.64.
n
¼3059, 2973, 1733, 1638, 1187, 983, 756 cmꢀ1
.
4.2.6. (2E)-1-(4,4-Dimethyl-2-oxazolin-2-yl)-3-phenylprop-2-en-1-
one (2f). White solid, mp 93ꢀ95 ꢁC, yield 35%. 1H NMR (500 MHz,
4.3.5. 5,5-Dimethyl-3-styryl-5,6-dihydro[1,4]oxazin-2-one (4f). Waxy
CDCl3):
d
¼7.88 (d, J¼15.9 Hz, 1H), 7.67ꢀ7.63 (m, 2H), 7.59 (d,
yellow solid, yield >98%. 1H NMR (300 MHz, CDCl3):
d
¼7.67 (d,
J¼15.9 Hz, 1H), 7.44ꢀ7.36 (m, 3H), 4.13 (s, 2H), 1.40 (s, 6H) ppm. 13C
3JH,H¼16.5 Hz, 1H), 7.55–7.50 (m, 2H), 7.36–7.26 (m, 3H), 7.10 (d,
NMR (125 MHz, CDCl3):
d
¼181.0, 159.3, 146.2, 134.2, 131.2, 129.0,
3JH,H¼16.5 Hz,1H), 4.18 (s, 2H),1.33 (s, 6H) ppm. 13C NMR (125 MHz,
128.9, 121.5, 79.5, 68.7, 28.1 ppm. GC–MS (70 eV) m/z 229 [M]þ
CDCl3):
d
¼155.7, 153.9, 138.8, 135.6, 129.4, 128.7, 127.7, 121.9, 74.2,
(79), 200 (25), 186 (46), 145 (90), 131 (100), 103 (92), 102 (28), 77
54.7, 24.8 ppm. GC–MS (70 eV) m/z 229 [M]þ (63), 170 (40), 129
(62). FT-IR (KBr):
C14H15NO2: calcd C, 73.34; H, 6.59; N, 6.11; found C, 73.52; H, 6.72;
N, 5.88.
n
¼1684, 1633, 1605, 1339, 1059 cmꢀ1. El. An.
(100), 115 (35), 56 (23). FT-IR (KBr):
n
¼2974, 2933, 1735, 1629, 1581,
1102, 745, 690 cmꢀ1. El. An. C14H15NO2: calcd C, 73.34; H, 6.59; N,
6.11; found C, 73.61; H, 6.72; N, 5.81.
4.2.7. 3-Fluorophenyl-(4,4-dimethyl-2-oxazolin-2-yl)ketone (2g). White
4.3.6. 3-(3-Fluorophenyl)-5,5-dimethyl-5,6-dihydro[1,4]oxazin-2-
solid, mp 56.2–57 ꢁC, yield 75%. 1H NMR (500 MHz, CDCl3):
d
¼8.09–
8.06 (m, 1H), 8.00–7.97 (m, 1H), 7.46–7.41 (m, 1H), 7.30–7.26 (m, 1H),
4.12 (s, 2H), 1.41 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3):
one (4g). White solid, mp 62–63 ꢁC, yield >98%. 1H NMR (500 MHz,
CDCl3):
7.16–7.10 (m, 1H), 4.26 (s, 2H), 1.37 (s, 6H) ppm. 13C NMR (125 MHz,
CDCl3):
d¼7.75–7.71 (m, 1H), 7.70–7.65 (m, 1H), 7.38–7.32 (m, 1H),
d¼182.3,
162.3 (d, JF,C¼247.0 Hz), 157.2, 136.5 (d, JF,C¼7.7 Hz), 130.1 (d,
JF,C¼7.6 Hz), 126.4 (d, JF,C¼2.9 Hz), 121.1 (d, JF,C¼21.0 Hz), 117.3 (d,
JF,C¼25.7 Hz), 78.8, 69.2, 28.0 ppm. GC–MS (70 eV) m/z 221 [M]þ (11),
d
¼162.4 (d, JF,C¼245.7 Hz),154.7,154.5 (d, JF,C¼2.8 Hz),136.1
(d, JF,C¼7.6 Hz), 129.7 (d, JF,C¼8.0 Hz), 124.5 (d, JF,C¼2.8 Hz), 117.7 (d,
JF,C¼21.3 Hz), 115.5 (d, JF,C¼23.7 Hz), 74.2, 55.2, 24.5 ppm. GC–MS
(70 eV) m/z 221 [M]þ (13),163 (50), 122 (100), 95 (16), 56 (75). FT-IR
124 (8), 123 (100), 95 (30), 75 (9). FT-IR (KBr):
n
¼3084, 2968, 2928,
1682, 1628, 1585, 1240, 1126, 998 cmꢀ1. El. An. C12H12FNO2: calcd C,
65.15; H, 5.47; N, 6.33; found C, 64.98; H, 5.47; N, 6.13.
(KBr):
n
¼2972, 1725, 1649, 1580, 1445, 1276, 1180, 948, 678 cmꢀ1. El.
An. C12H12FNO2: calcd C, 65.15; H, 5.47; N, 6.33; found C, 64.91; H,
5.67; N, 6.03.
4.3. Preparation of 5,5-dimethyl-5,6-dihydro[1,4]-
oxazin-2-ones (4a–g)
4.4. Chlorination of the (4S)-2-benzyl-4-isopropyl-2-
oxazoline was carried out as reported in Ref. 1a to give an
inseparable mixture 1:1 of diastereomers of 2-(1-chloro-1-
phenylmethyl)-(4S)-isopropyl-2-oxazoline (9)
By leaving the 2-acyloxazoline in CDCl3 solution for few days it
was possible to observe, by 1H NMR, the spontaneous conversion of
2-acyloxazoline into the corresponding oxazinone. Alternatively,
a solution of 2-acyloxazoline in AcOEt (15 mg/mL) added of silica
gel (30–100 mg) was kept under magnetic stirring at rt until con-
version was complete (TLC or GC monitoring). The solution was
filtered on a Celite pad, washed with CH2Cl2 (10–30 mL) and the
solution was concentrated under reduced pressure to leave the
resulting oxazinone.
Colourless oil, 75%. 1H NMR (CDCl3, 500 MHz, selected data):
d
¼7.57–7.52 (m, 2H), 7.41–7.33 (m, 6H), 5.62 (s, 2H), 4.35 and 4.34
(2ꢃd, AB system, JH,H¼8.0 Hz, 1H), 4.32 and 4.30 (2ꢃdd, AB system,
JH,H¼8.0,1.4 Hz,1H), 4.09 (dd, like t, JH,H¼8.2 Hz,1H), 4.06 (dd, like t,
3
JH,H¼8.2 Hz, 1H), 1.88–1.80 (m, 1H), 1.77 (sextet, JH,H¼6.5 Hz, 1H),
3
3
0.98 (d, JH,H¼6.5 Hz, 3H), 0.92 (d, JH,H¼6.5 Hz, 3H), 0.91 (d,
3JH,H¼6.6 Hz, 3H), 0.82 (d, JH,H¼6.6 Hz, 3H) ppm. 13C NMR (CDCl3,
3
4.3.1. 3-(4-Chlorophenyl)-5,5-dimethyl-5,6-dihydro[1,4]oxazin-2-
125 MHz):
d
¼163.9 and 164.0, 136.3 and 136.4, 128.9 and 129.0,
one (4a). Waxy solid, yield >98%. 1H NMR (300 MHz, CDCl3):
128.6, 127.7 and 127.8, 71.9 and 72.0, 71.0 and 71.1, 55.1, 32.3 and
d
¼7.86 (d, 3JH,H¼8.7 Hz, 2H), 7.33 (d, 3JH,H¼8.7 Hz, 2H), 4.24 (s, 2H),
32.4, 18.5 and 18.6, 17.8 and 17.9 ppm. GC–MS (70 eV) m/z (rel int.)
1.34 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3):
d
¼154.8, 154.6, 137.1,
237 [M]þ (3), 202 (100), 125 (72). FT-IR (film):
n
¼2960, 1664, 1185,
132.5, 130.0, 128.3, 74.3, 55.1, 24.5 ppm. GC–MS (70 eV) m/z 237
1024, 968, 758, 697 cmꢀ1
.
[M]þ (15),181 (15),179 (47),140 (33),138 (100), 56 (72). FT-IR (KBr):
n
¼3078, 2970, 1728, 1632, 1150, 992 cmꢀ1. El. An. C12H12ClNO2:
4.5. General procedures for the preparation of terminal
calcd C, 60.64; H, 5.09; N, 5.89; found C, 60.71; H, 5.09; N, 5.65.
a
-substituted oxazolinyloxiranes 6a–c, (2S,40S)-, (2R,40S)-,
(2S,40R)- and (2R,40R)-10
4.3.2. 3-Phenyl-5,5-dimethyl-5,6-dihydro[1,4]oxazin-2-one (4b). In
agreement with literature (see Refs. 10 and 13).
4.5.1. Method A, using 2-acyloxazolines. Preparation of 6b is repre-
sentative. Toa stirred and pre-cooled (ꢀ78 ꢁC) THF solution(5 mL) of
benzoyloxazoline 2b (204 mg, 1.0 mmol) and chloroiodomethane
(211 mg, 1.2 mmol) a solution of n-BuLi (1.3 mmol, 2.5 M in hexane)
was added dropwise. The resulting orange mixture was stirred for
1 h at this temperature, quenched with saturated aq NH4Cl, extrac-
ted with AcOEt (3ꢃ10 mL) and concentrated in vacuo to give the
crude chlorohydrin, which was converted into the epoxide 6b upon
treatment with NaOH 10% w/w in i-PrOH (3 mL) and purified by
column chromatography (silica gel, petroleum ether/AcOEt 7:3).
4.3.3. 3-(2-Furyl)-5,5-dimethyl-5,6-dihydro[1,4]oxazin-2-one (4d). Waxy
solid, yield >98%. 1H NMR (300 MHz, CDCl3):
d
¼7.52 (dd, JH,H¼3.6,
0.8 Hz, 1H), 7.38 (dd, JH,H¼1.6, 0.8 Hz, 1H), 6.46 (dd, JH,H¼3.6, 1.6 Hz,
1H), 4.21 (s, 2H), 1.35 (s, 6H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼153.8, 149.4, 147.8, 145.7, 118.5, 112.1, 74.3, 54.4, 24.7 ppm. GC–
MS (70 eV) m/z 193 [M]þ (67), 135 (99), 94 (100), 95 (100), 56 (87).
FT-IR (KBr):
n
¼3372, 3141, 2973, 2605, 1738, 1652, 1465, 1053,
768 cmꢀ1. HRMS (ESI), calcd for C10H12NO3, [MþH]þ: 194.0817.
Found: 194.0810.
4.5.2. Method B, using the Darzens-type reaction. Preparation of 6b
is representative. To a stirred and pre-cooled (ꢀ78 ꢁC) THF solution
(10 mL) of LDA (5.58 mmol), chlorobenzyloxazoline 7b (415 mg,
4.3.4. 3-(2-Bromophenyl)-5,5-dimethyl-5,6-dihydro[1,4]oxazin-2-
one (4e). White solid, mp 61ꢀ63 ꢁC, yield >98%. 1H NMR (300 MHz,

8750
L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
1.86 mmol) and, after 2 h, benzotriazolylmethanol (3.72 mmol,
5 mL in THF) were added dropwise. The resulting orange mixture
was stirred for 3 h at this temperature, quenched with saturated aq
NH4Cl, extracted with Et2O (3ꢃ20 mL) and the solvent evaporated
in vacuo to give the crude chlorohydrin, which was converted into
the epoxide 6b, upon treatment with NaOH 2% w/w in i-PrOH
(5 mL), and purified by flash chromatography (silica gel, petroleum
ether/AcOEt 9:1).
(CDCl3, 125 MHz):
d
¼163.9, 135.3, 128.4, 128.3, 126.5, 72.3, 70.5,
55.6, 55.0, 32.2, 18.7, 17.8 ppm. GC–MS (70 eV) m/z (rel int.) 231
[M]þ (13), 215 (16),172 (67),144 (19),105 (100), 77 (22). FT-IR (KBr):
n
¼2960, 1668, 1452, 1256, 1133, 969, 767, 702 cmꢀ1. El. An.
C14H17NO2: calcd C, 72.70; H, 7.41; N, 6.06; found C, 72.64; H, 7.30;
N, 6.12. er: >99:1 [tR¼31.1 min] by HPLC employing a Daicel Chir-
acel OD-H column (250ꢃ4.6 mm), n-hexane/i-PrOH 99:1, flow
20
0.5 mL/min, 230 nm, [
a
]
ꢀ87.1 (c 1, CHCl3).
D
20
4.5.2.1. 3-(4,4-Dimethyl-2-oxazolin-2-yl)-2,2-dimethyl-1,2-epoxy-
4.5.2.7. Compound (þ)-(2S,40R)-10. [
a]
þ87.8 (c 1, CHCl3).
D
butane (6a). Colourless oil, yield 60% (Method A). 1H NMR (CDCl3,
2
400 MHz):
d
¼3.91 and 3.87 (2ꢃd, AB system, JH,H¼8.15 Hz, 2H),
4.6. General procedure for the preparation of amino-
alcohols 11a–g and 11i–j
2.87 and 2.82 (dd, AB system, 2JH,H¼5.1 Hz, 1H), 1.21 (s, 6H), 0.98 (s,
9H) ppm. 13C NMR (CDCl3, 150 MHz):
d
¼162.9, 78.8, 66.8, 60.4, 49.6,
32.4, 28.0, 27.8, 25.7 ppm. GC–MS (70 eV) m/z 197 (1) [M]þ 154 (70),
140 (40), 113 (87), 98 (100), 57 (92), 56 (44). FT-IR (film):
¼2971,
HRMS (ESI), calcd for C11H19NaNO2,
Preparation of 11b is representative. To a solution of oxazoli-
nyloxirane 6b (50 mg, 0.23 mmol) in dry EtOH (3 mL), pyrrolidine
(24 mg, 0.34 mmol) was added and the mixture was stirred for 24 h
at 60 ꢁC. Then, the solvent and the excess of amine were removed in
vacuo to give the aminoalcohol 11b. The products 11d,e,h,k were
purified by flash chromatography (silica gel, petroleum ether/ethyl
acetate 1:1).
n
1659, 1367, 1124 cmꢀ1
.
[MþNa]þ: 220.1313. Found: 220.1316.
4.5.2.2. 2-(4,4-Dimethyl-2-oxazolin-2-yl)-2-phenyloxirane (6b). Col-
ourless oil, yield 50% (Method A), yield 70% (Method B). 1H NMR
(CDCl3, 500 MHz):
d
¼7.50–7.45 (m, 2H), 7.38–7.33 (m, 3H), 4.01 (s,
2H), 3.52 (d, 2JH,H¼6.1 Hz,1H), 2.96 (d, 2JH,H¼6.1 Hz,1H),1.32 (s, 3H),
4.6.1. N,N-Diethyl-1-(4,4-dimethyl-2-oxazolin-2-yl)-1-phenylethanol-
1.31 (s, 3H) ppm. 13C NMR (CDCl3, 100 MHz):
d¼162.3, 135.2, 128.3,
amine (11a). Pale yellow oil, yield >98%. 1H NMR (CDCl3,
128.1, 126.3, 79.4, 67.6, 55.3, 55.0, 28.0, 27.9 ppm. GC–MS (70 eV) m/z
600 MHz):
d
¼7.63–7.59 (m, 2H), 7.34–7.27 (m, 3H), 3.94 and 3.89
217 [M]þ (6), 216 (17), 200 (7), 186 (4), 129 (5), 105 (100), 91 (13), 77
(2ꢃd, AB system, 2JH,H¼8.2 Hz, 2H), 3.52 (d, 2JH,H¼13.2 Hz, 1H), 2.78
2
(17), 56 (6), 41 (5). FT-IR (film):
n
¼3383, 2973, 1667, 1449,
(d, JH,H¼13.2 Hz, 1H), 2.51–2.64 (m, 4H), 1.27 (s, 3H), 1.25 (s, 3H),
1275 cmꢀ1
.
HRMS (ESI), calcd for C13H15NaNO2, [MþNa]þ:
0.97 (t, 3JH,H¼7.1 Hz, 6H) ppm. 13C NMR (CDCl3, 150 MHz):
¼167.6,
d
240.1000. Found: 240.1009.
144.7, 128.1, 127.3, 124.8, 79.4, 71.2, 67.8, 62.0, 47.5, 28.0, 11.7 ppm.
GC–MS (70 eV) m/z (rel int.) 290 [M]þ (<1%), 105 (12), 86 (100), 77
4.5.2.3. 2-(4,4-Dimethyl-2-oxazolin-2-yl)-1,2-epoxypropane (6c). Col-
(7), 58 (6). FT-IR (film):
n
¼3383, 2970, 1660, 1448, 1066 cmꢀ1
.
ourless oil, yield 90% (Method B). 1H NMR (CDCl3, 400 MHz):
HRMS (ESI), calcd for C17H26N2NaO2, [MþNa]þ: 313.1892. Found:
d
¼3.92 (s, 2H), 3.14 (d, 2JH,H¼5.9 Hz, 1H), 2.76 (d, 2JH,H¼5.9 Hz, 1H),
313.1884.
1.58 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H) ppm. 13C NMR (CDCl3,
100 MHz):
d
¼163.9, 79.5, 69.5, 66.8, 53.0, 28.2, 28.1, 18.7 ppm. GC–
4.6.2. 1-(4,4-Dimethyl-2-oxazolin-2-yl)-1-phenyl-2-(pyrrolidin-1-yl)-
MS (70 eV) m/z 155 (6) [M]þ 140 (17), 95 (7), 70 (4), 43 (5). FT-IR
ethanol (11b). Pale yellow oil, yield >98%. 1H NMR (CDCl3,
3
3
(film):
n
¼2971, 1659, 1367, 1124 cmꢀ1. HRMS (ESI), calcd for
600 MHz):
d
¼7.60 (d, JH,H¼7.6 Hz, 2H), 7.32 (t, JH,H¼7.6 Hz, 2H),
C8H13NaNO2, [MþNa]þ: 178.0844. Found: 178.0839.
7.25 (t, JH,H¼7.3 Hz, 1H), 4.86–4.23 (br s, 1H), 3.91 and 3.89 (2ꢃd,
3
2
2
AB system, JH,H¼8.2 Hz, 2H), 3.49 (d, JH,H¼12.7 Hz, 1H), 2.92 (d,
2JH,H¼12.7 Hz, 1H), 2.61–2.48 (m, 4H), 1.69–1.67 (m, 4H), 1.24 (s,
4.5.2.4. (ꢀ)-(2S,40S)-2-(4-Isopropyl-2-oxazolin-2-yl)-2-phenyl-
oxirane [(2S,40S)-10]. Colourless oil, yield 25% (Method A), yield 35%
(Method B). Separation by preparative HPLC employing a Porasil
column (300ꢃ19 mm), n-hexane/EtOAc 9:1, flow 15 mL/min. 1H
3H), 1.22 (s, 3H) ppm. 13C NMR (CDCl3, 150 MHz):
d¼167.6, 142.6,
128.1, 127.4, 125.0, 79.5, 72.2, 67.1, 64.1, 54.9, 28.0, 23.9 ppm. GC–
MS (70 eV) m/z (rel int.) 288 [M]þ (<1%), 105 (12), 84 (100), 85 (6),
NMR (CDCl3, 500 MHz):
d
¼7.52–7.43 (m, 2H), 7.38–7.33 (m, 3H),
77 (7), 55 (5). FT-IR (film):
n
¼3383, 2988, 1660, 1447, 1069 cmꢀ1
.
2
3
2
4.30 (dt, JH,H¼7.6 Hz, JH,H¼1.5 Hz, 1H), 3.52 (d, JH,H¼6.1 Hz, 1H),
HRMS (ESI), calcd for C17H24N2NaO2, [MþNa]þ: 311.1735. Found:
4.06–3.99 (m, 2H), 2.92 (d, 2JH,H¼6.1 Hz, 1H), 1.90–1.70 (m, 1H), 0.94
311.1737.
3
3
(d, JH,H¼6.5 Hz, 3H), 0.87 (d, JH,H¼6.5 Hz, 3H) ppm. 13C NMR
(CDCl3, 125 MHz):
d
¼163.9, 135.3, 128.3, 128.1, 126.4, 72.3, 70.5,
4.6.3. 1-(4,4-Dimethyl-2-oxazolin-2-yl)-1-phenyl-2-(piperidin-1-yl)-
55.4, 54.9, 32.3, 18.5, 17.8 ppm. GC–MS (70 eV) m/z (rel int.) 231
ethanol (11c). White solid, mp 91–94 ꢁC, yield >98%. 1H NMR
[M]þ (13), 215 (12), 172 (45), 144 (14), 105 (100), 77 (23). FT-IR
(CDCl3, 500 MHz):
d
¼7.60 (d, 3JH,H¼7.6 Hz, 2H), 7.33 (t, 3JH,H¼7.6 Hz,
(film):
n
¼2960, 1664, 1185, 1024, 968, 758, 697 cmꢀ1. er >99:1
2H), 7.28–7.25 (m, 1H), 5.88–4.88 (br s, 1H), 3.94 and 3.91 (2ꢃd, AB
2
2
[tR¼25.4 min] by HPLC employing a Daicel Chiracel OD-H column
system, JH,H¼8.1 Hz, 1H), 3.40 (d, JH,H¼13.2 Hz, 1H), 2.72 (d,
2JH,H¼13.2 Hz, 1H), 2.55 (br s, 2H), 2.43–2.40 (m, 2H), 1.54–1.50 (m,
4H), 1.40–1.38 (m, 2H), 1.28 (s, 3H), 1.26 (s, 3H) ppm. 13C NMR
(250ꢃ4.6 mm), n-hexane/i-PrOH 99:1, flow 0.5 mL/min, 230 nm,
20
[
a]
ꢀ45.6 (c 1, CHCl3). HRMS (ESI), calcd for C14H17NaNO2,
D
[MþNa]þ: 254.1157. Found: 254.1152.
(CDCl3, 150 MHz):
d
¼167.7, 142.9, 128.2, 127.4, 124.9, 79.6, 71.7, 67.1,
66.5, 55.6, 28.02, 28.01, 26.2, 23.8 ppm. GC–MS (70 eV) m/z (rel int.)
20
4.5.2.5. Compound (þ)-(2R,40R)-10. [
a]
þ44.8 (c 1, CHCl3).
302 [M]þ (<1%), 105 (15), 98 (100), 77 (8). FT-IR (KBr):
n¼3332,
D
2933, 1642, 1530, 1069 cmꢀ1. HRMS (ESI), calcd for C18H26N2NaO2,
4.5.2.6. (ꢀ)-(2R,40S)-2-(4-Isopropyl-2-oxazolin-2-yl)-2-phenyl-
oxirane [(1R,40S)-10]. White solid, mp 65–67 ꢁC (hexane), yield 25%
(Method A), yield 35% (Method B). Separation by preparative HPLC
employing a Porasil column (300ꢃ19 mm), n-hexane/EtOAc 9:1,
[MþNa]þ: 325.1892. Found: 325.1897.
4.6.4. N-Allyl-N-cyclohexyl-1-(4,4-dimethyl-2-oxazolin-2-yl)-1-phenyl-
ethanolamine (11d). Pale yellow oil, yield 46%. 1H NMR (CDCl3,
flow 15 mL/min. 1H NMR (CDCl3, 500 MHz):
d
¼7.51–7.47 (m, 2H),
500 MHz):
d
¼7.60–7.57 (m, 2H), 7.33–7.26 (m, 3H), 5.78–5.68 (m,
7.36–7.31 (m, 3H), 4.29 (t, 3JH,H¼7.9 Hz, 1H), 4.05–3.99 (m, 2H), 3.51
1H), 5.62–5.12 (br s, 1H), 5.07–5.03 (m, 2H), 3.94 and 3.88 (2ꢃd,
2JH,H¼7.9 Hz, 2H), 3.52 (d, 2JH,H¼13.4 Hz, 1H), 3.23 and 3.04 (2ꢃdd,
AB system, 2JH,H¼14.6, 3JH,H¼6.7 Hz, 2H), 2.79 (d, 2JH,H¼13.4 Hz,1H),
2
2
(d, JH,H¼6.1 Hz, 1H), 2.98 (d, JH,H¼6.1 Hz, 1H), 1.82–1.75 (m, 1H),
0.95 (d, 3JH,H¼6.5 Hz, 3H), 0.88 (d, 3JH,H¼6.5 Hz, 3H) ppm. 13C NMR

L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
8751
2.48–2.38 (m,1H),1.69–1.58 (m, 5H),1.55 (m,1H),1.27 (s, 3H),1.25 (s,
3H), 1.20–0.97 (m, 4H) ppm. 13C NMR (CDCl3, 150 MHz):
23.8, 18.9, 17.9, 11.7 ppm. ESI-MS [MþH]þ 305. FT-IR (film):
n
¼2964,
d¼167.8,
1663, 1385, 1067, 699 cmꢀ1. El. An. C18H28N2O2: calcd C, 71.02; H,
9.27; N, 9.20; found C, 71.23; H, 9.32; N, 9.07.
143.4,136.8,128.2,127.3,124.8,116.8, 79.5, 71.2, 67.1, 59.9, 58.6, 53.9,
30.0, 28.6, 28.1, 28.0, 26.1, 26.0 ppm. ESI-MS m/z: 379 [MþNa]þ. FT-IR
(film):
n
¼2928, 2854, 1660, 1449, 1070 cmꢀ1. HRMS (ESI), calcd for
4.7. General procedure for the preparation of amino-
alcohols 11h and 11k
C22H32N2NaO2, [MþNa]þ: 379.2361. Found: 379.2365.
4.6.5. 1-(4,4-Dimethyl-2-oxazolin-2-yl)-2-morpholin-4-yl-1-phenyl-
To a pre-cooled (0 ꢁC) solution of triazole (16 mg, 0.23 mmol) in
3 mL of dry DMF, NaH (0.46 mmol) and, after 15 min, the oxirane
(2R,40S)-10 were added. The mixture was stirred for 2 h at 50 ꢁC.
Then, the reaction mixture was quenched with saturated aq NH4Cl,
extracted with AcOEt (3ꢃ5 mL), and the solvent evaporated in
vacuo to give the crude aminoalcohol 11h, which was purified by
column chromatography on silica gel (EtOAc/methanol 95:5).
ethanol (11e). Pale yellow oil, yield 90%. 1H NMR (CDCl3, 600 MHz):
d
¼7.57 (d, 2JH,H¼8.2 Hz, 2H), 7.33–7.26 (m, 3H), 3.95 and 3.93 (2ꢃd,
2
AB system, JH,H¼8.2 Hz, 2H), 3.66–3.60 (m, 4H), 3.34 (d,
2JH,H¼13.2 Hz, 1H), 2.77 (d, JH,H¼13.2 Hz, 1H), 2.60–2.54 (m, 2H),
2
2.52–2.48 (m, 2H), 1.26 (s, 6H) ppm. 13C NMR (CDCl3, 150 MHz):
d
¼167.6, 142.1, 128.3, 127.6, 124.9, 79.8, 72.8, 67.1, 66.2, 58.2, 54.7,
28.1, 27.9 ppm. GC–MS (70 eV) m/z (rel int.) 304 [M]þ (<1%), 204
(4), 105 (15), 100 (100), 77 (6), 56 (6). FT-IR (film):
n
¼3383, 2965,
4.7.1. (ꢀ)-(1R,40S)-1-(4-Isopropyl-2-oxazolin-2-yl)-1-phenyl-2-(1H-
20
1668, 1446, 1069 cmꢀ1. HRMS (ESI), calcd for C17H24N2NaO3,
1,2,4-triazol-1-yl)ethanol (11h). Colourless oil, yield 90%, [a]
D
[MþNa]þ: 327.1684. Found: 327.1688.
ꢀ39.1 (c 1, CHCl3). 1H NMR (CDCl3, 500 MHz):
¼8.20 (s, 1H), 7.85
d
(d, 3JH,H¼1.6 Hz, 1H), 7.72–7.61 (m, 2H), 7.44–7.30 (m, 3H), 4.96 (dd,
3
4.6.6. (þ)-(1R,40S)-1-(4-Isopropyl-2-oxazolin-2-yl)-1-phenyl-2-pyr-
2JH,H¼14.2, JH,H 1.1 Hz, 1H), 4.72–4.60 (br s, 1H), 4.45 (d,
rolidin-1-yl-ethanol (11f). Colourless oil, yield >98%, [
a
]
þ8.2 (c 1,
2JH,H¼14.1 Hz, 1H), 4.39 (td, JH,H¼8.8, JH,H¼1.1 Hz, 1H), 4.09 (td,
20
2
3
D
CHCl3).1H NMR (CDCl3, 300 MHz):
d
¼7.67–7.60 (m, 2H), 7.38–7.23 (m,
2JH,H¼8.8, JH,H¼1.1 Hz, 1H), 3.77–3.68 (m, 1H), 1.61–1.49 (m, 1H),
3
3
3
3
3H), 4.27 (dd, like t, JH,H¼7.7 Hz, 1H), 3.99–3.85 (m, 2H), 3.52 (d,
0.81 (t, JH,H¼6.7 Hz, 3H), 0.75 (d, JH,H¼6.7 Hz, 3H) ppm. 13C NMR
2JH,H¼12.6 Hz, 1H), 2.95 (d, JH,H¼12.6 Hz, 1H), 2.57–2.47 (m, 4H),
(CDCl3, 125 MHz):
d
¼167.0, 151.4, 144.9, 138.8, 128.6, 125.5, 74.2,
2
1.82–1.69(m,1H),1.69–1.62(m, 4H), 0.94(d,3JH,H¼6.6 Hz,3H),0.82(d,
73.0, 71.5, 57.0, 32.4, 19.0, 18.0 ppm. ESI-MS m/z: 301 [MþH]þ. FT-IR
3JH,H¼6.6 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz):
d
¼169.0, 151.4,
(film):
n
¼3144, 2960, 1664, 1508, 1277, 1136, 1028, 948, 706 cmꢀ1
.
142.6, 128.0, 127.3, 125.1, 72.7, 71.8, 70.6, 64.2, 55.0, 32.3, 23.8, 18.9,
El. An. C16H20N4O2: calcd C, 63.98; H, 6.71; N, 18.65; found C, 64.08;
H, 6.51; N, 18.68.
17.9 ppm. FT-IR (film):
n
¼2960, 1661, 1448, 1385, 1228, 1049,
700 cmꢀ1. HRMS (ESI), calcd for C18H27N2O2, [MþH]þ: 303.2073.
Found: 303.2074.
4.7.2. (ꢀ)-(1S,40S)-1-(4-Isopropyl-2-oxazolin-2-yl)-1-phenyl-2-(1H-
20
1,2,4-triazol-1-yl)ethanol (11k). Colourless oil, yield 84%,
[a]
D
4.6.7. (þ)-(1R,40S)-N,N-Diethyl-1-(4-isopropyl-2-oxazolin-2-yl)-1-
ꢀ33.1 (c 1, CHCl3). 1H NMR (CDCl3, 500 MHz):
¼8.15 (s, 1H), 7.85 (s,
d
20
phenylethanolamine (11g). Colourless oil, yield >98%, [
a
]
þ14.4 (c
1H), 7.61 (m, 2H), 7.39–7.26 (m, 3H), 4.91 (d, 2JH,H¼14.2 Hz,1H), 4.77
(br s, 1H), 4.42 (d, 2JH,H¼14.2 Hz, 1H), 4.35 (t, 3JH,H¼8.8 Hz, 1H), 4.04
D
1, CHCl3). 1H NMR (CDCl3, 400 MHz):
d
¼7.60–7.56 (m, 2H), 7.33–
3
7.26 (m, 2H), 7.24–7.18 (m, 1H), 5.6–5.02 (br s, exchanges with D2O,
(t, JH,H¼8.8 Hz, 1H), 3.82–3.75 (m, 1H), 1.55 (m, 1H), 0.81 (t,
2
3
1H), 4.29–4.17 (m, 1H), 3.92–3.82 (m, 2H), 3.46 (d, JH,H¼13.5 Hz,
3JH,H¼6.7 Hz, 3H), 0.75 (d, JH,H¼6.7 Hz, 3H) ppm. 13C NMR (CDCl3,
2
1H), 2.81 (d, JH,H¼13.5 Hz, 1H), 2.56–2.40 (m, 4H), 1.78–1.65 (m,
125 MHz):
d
¼167.0, 151.4, 144.8, 138.8, 128.6, 125.4, 74.3, 73.1, 71.6,
3
3
1H), 0.93 (t, JH,H¼6.6 Hz, 6H), 0.91 (d, JH,H¼6.9 Hz, 3H), 0.79 (d,
57.1, 32.4, 18.7, 18.4 ppm. ESI-MS m/z: 301 [MþH]þ. FT-IR (film):
3JH,H¼6.6 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz):
d
¼169.0, 143.2,
n
¼3132, 2962, 1667, 1505, 1274, 1137, 755 cmꢀ1. El. An. C16H20N4O2:
128.0, 127.2, 124.9, 71.9, 71.5, 70.5, 62.1, 47.5, 32.5, 19.1, 18.0,
calcd C, 63.98; H, 6.71; N, 18.65; found C, 63.78; H, 6.59; N, 18.60.
11.7 ppm. ESI-MS m/z 305 [MþH]þ. FT-IR (film):
¼2966, 1661,
n
1449, 1386, 1067, 700 cmꢀ1. HRMS (ESI), calcd for C18H29N2O2,
4.8. General procedure for the preparation of amides 12a–i
[MþH]þ: 305.2230. Found: 305.2236.
Aminoalcohols 11 were spontaneously transformed into the
corresponding hydroxyamides 12 simply by leaving them in
a CDCl3 solution and monitoring by 1H NMR the course of the re-
action. Usually, it could take from 1 to 4 weeks. Alternatively,
a solution of 11 in CHCl3 (5 mL/mmol) added of silica gel (50 mg/
mmol) was stirred at rt until conversion was complete (TLC or GC
monitoring). The solution was filtered on a Celite pad, washed with
CH2Cl2 (10–30 mL) and the solution concentrated under reduced
pressure to leave the hydroxyamide 12.
4.6.8. (ꢀ)-(1S,40S)-1-(4-Isopropyl-2-oxazolin-2-yl)-1-phenyl-2-pyr-
20
rolidin-1-yl-ethanol (11i). Colourless oil, yield >98%, [
a
]
ꢀ73.1 (c
D
3
1, CHCl3). 1H NMR (CDCl3, 500 MHz):
d
¼0.80 (d, JH,H¼6.6 Hz, 3H),
0.92 (d, 3JH,H¼6.6 Hz, 3H),1.82–1.65 (m, 5H), 2.58–2.51 (m, 4H), 2.92
2
2
(d, JH,H¼12.6 Hz, 1H), 3.49 (d, JH,H¼12.6 Hz, 1H), 3.94–3.88 (m,
1H), 3.97 (dd, like t, 3JH,H¼7.7 Hz, 1H), 4.20 (dd, like t, 3JH,H¼8.2 Hz,
1H), 7.35–7.23 (m, 3H), 7.59–7.64 (m, 2H). 13C NMR (CDCl3,
75 MHz):
d
¼18.0, 19.0, 23.9, 32.6, 55.0, 64.1, 70.7, 72.0, 72.4, 125.1,
127.4, 128.1, 142.7, 169.0. ESI-MS m/z: 303 [MþH]þ. FT-IR (film):
n
¼3413, 2960, 1661, 1448, 1385, 1228, 1049, 700 cmꢀ1. HRMS (ESI),
4.8.1. 2-Hydroxy-N-(1-hydroxymethyl-1-methylethyl)-2-phenyl-3-
(N,N-diethylamino)propanamide (12a). Colourless oil, yield >98%.
calcd for C18H27N2O2, [MþH]þ: 303.2073. Found: 303.2078.
1H NMR (CDCl3, 300 MHz):
d
¼7.62–7.57 (m, 2H), 7.36–7.28 (br s,
2
4.6.9. (ꢀ)-(1S,40S)-N,N-Diethyl-1-(4-isopropyl-2-oxazolin-2-yl)-1-
1H), 7.30–7.18 (m, 3H), 6.04–4.47 (br s, 1H), 3.59 (d, JH,H¼13.2 Hz,
20
2
phenylethanolamine (11j). Colourless oil, yield >98%, [
a
]
ꢀ86.3 (c
1H), 3.48 and 3.47 (2ꢃd, AB system, JH,H¼11.7 Hz, 2H), 2.60–2.46
D
1, CHCl3). 1H NMR (CDCl3, 300 MHz):
d
¼7.58–7.53 (m, 2H), 7.32–
(m, 5H), 1.23 (s, 3H), 1.16 (s, 3H), 0.96 (t, 3JH,H¼7.0 Hz, 3H) ppm. 13
C
7.27 (m, 2H), 7.25–7.19 (m, 1H), 6.0–5.06 (br s, exchanges with D2O,
NMR (CDCl3, 75 MHz):
d
¼175.8, 142.3, 128.2, 127.3, 124.7, 74.0, 70.6,
1H), 4.17 and 4.14 (2ꢃd, AB system, 2JH,H¼8.0 Hz, 1H), 3.96 (dd, like
60.6, 55.6, 47.0, 24.5, 24.4, 11.8 ppm. FT-IR (film):
n
¼3400, 2966,
3
2
t, JH,H¼8.0 Hz, 1H), 3.92–3.84 (m, 1H), 3.55 (d, JH,H¼13.5 Hz, 1H),
2831, 1651, 1519, 1448, 1069 cmꢀ1
. HRMS (ESI), calcd for
2
2.71 (d, JH,H¼13.5 Hz, 1H), 2.63–2.44 (m, 4H), 1.73 (sextet,
C17H29N2O3, [MþH]þ: 309.2178. Found: 309.2177.
3JH,H¼6.6 Hz, 1H), 0.93 (t, JH,H¼7.3 Hz, 6H), 0.91 (d, JH,H¼6.9 Hz,
3
3
3H), 0.80 (d, JH,H¼6.6 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz):
4.8.2. 2-Hydroxy-N-(1-hydroxymethyl-1-methylethyl)-2-phenyl-3-
3
d
¼169.1, 143.4, 128.1, 127.2, 124.8, 71.9, 71.4, 70.5, 61.8, 47.5, 32.6,
(pyrrolinin-1-yl)propanamide (12b). Colourless oil, yield >98%. 1H

8752
L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
NMR (CDCl3, 300 MHz):
d
¼7.62–7.54 (m, 2H), 7.35–7.18 (m, 4H),
FT-IR (film):
n
¼3400, 2966, 2831,1651,1519,1448,1069 cmꢀ1. HRMS
5.80–4.77 (br s, 1H), 3.51 (d, 2JH,H¼12.4 Hz, 1H), 3.49 (s, 2H), 2.82 (d,
2JH,H¼12.4 Hz, 2H), 2.70–2.52 (m, 4H),1.80–1.70 (m, 4H),1.24 (s, 3H),
(ESI), calcd for C18H31N2O3, [MþH]þ: 323.2335. Found: 323.2336.
1.17 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz):
d¼175.4, 142.0, 128.4,
4.8.8. (ꢀ)-(2S,10S)-2-Hydroxy-N-(1-hydroxymethyl-2-methyl-
127.8, 125.0, 75.6, 70.7, 63.0, 55.9, 54.5, 24.9, 24.6, 24.1 ppm. FT-IR
propyl)-2-phenyl-3-pyrrolidin-1-yl-propanamide (12h). White solid,
20
(film):
n
¼3400, 2966, 2831,1651,1519,1448,1069 cmꢀ1. HRMS (ESI),
mp 97–99 ꢁC, yield >98%, [
a
]
ꢀ65.1 (c 1, CHCl3). 1H NMR (CDCl3,
D
calcd for C17H27N2O3, [MþH]þ: 307.2022. Found: 307.2027.
300 MHz):
d
¼7.67–7.57 (m, 2H), 7.42–7.33 (br s, 1H), 7.33–7.23 (m,
2
3H), 4.1–2.12 (br s, 2H), 3.62–3.46 (m, 4H), 2.90 (d, JH,H¼12.4 Hz,
4.8.3. 2-Hydroxy-N-(1-hydroxymethyl-1-methylethyl)-2-phenyl-3-
1H), 2.72–2.54 (m, 4H),1.85–2.02 (m,1H),1.82–1.76 (m, 4H), 0.93 (d,
3
(piperidin-1-yl)propanamide (12c). White solid, mp 100–102 ꢁC,
3JH,H¼6.6 Hz, 3H), 0.87 (d, JH,H¼6.6 Hz, 3H) ppm. 13C NMR (CDCl3,
yield >98%. 1H NMR (CDCl3, 300 MHz):
d¼7.60–7.54 (m, 2H), 7.35–
75 MHz):
d
¼175.4, 141.9, 128.2, 127.6, 124.8, 75.6, 64.1, 62.7, 58.0,
7.18 (m, 4H), 6.04–4.66 (br s,1H), 3.48 (s, 2H), 3.47 (d, 2JH,H¼13.2 Hz,
54.4, 28.7, 23.7, 19.6, 18.7 ppm. FT-IR (film):
n¼3400, 2934, 2831,
2
1H), 2.59–2.40 (m, 2H), 2.48 (d, JH,H¼13.2 Hz, 1H), 2.44–2.35 (m,
1655, 1521, 1450, 1032 cmꢀ1. HRMS (ESI), calcd for C18H29N2O3,
[MþH]þ: 321.2172. Found: 321.2178. El. An. C18H28N2O3: calcd C,
71.49; H, 8.67; N, 9.26; found C, 71.63; H, 8.92; N, 8.97.
2H), 1.62–1.46 (m, 4H), 1.45–1.35 (m, 2H), 1.24 (s, 3H), 1.16 (s,
3H) ppm. 13C NMR (CDCl3, 75 MHz):
d
¼175.8, 142.4, 128.4, 127.7,
125.0, 74.6, 70.8, 65.6, 56.0, 55.1, 26.3, 24.9, 24.8, 23.9 ppm. ESI-MS
m/z: 343 [MþNa]þ. FT-IR (film):
n
¼3400, 2966, 2831, 1651, 1519,
4.8.9. (þ)-(2S,10S)-2-Hydroxy-N-(1-hydroxymethyl-2-methyl-
1448, 1069 cmꢀ1. El. An. C18H28N2O3: calcd C, 67.47; H, 8.81; N, 8.74;
found C, 67.23; H, 8.42; N, 8.77.
propyl)-2-phenyl-3-(N,N-diethylamino)propanamide (12i). White
20
solid, mp 81–83 ꢁC, yield >98%, [
a
]
D
þ15.2 (c 1, CHCl3). 1H NMR
(CDCl3, 300 MHz):
d
¼7.67–7.57 (m, 2H), 7.40–7.33 (br s, 1H), 7.33–
4.8.4. 2-Hydroxy-N-(1-hydroxymethyl-1-methylethyl)-2-phenyl-3-
7.18 (m, 3H), 3.61 (d, 2JH,H¼13.5 Hz, 1H), 3.57–3.44 (m, 3H), 2.57 (d,
2JH,H¼13.5 Hz, 1H), 2.63–2.46 (m, 4H), 1.95–1.86 (m, 1H), 0.96 (t,
(N-allyl-N-cyclohexylamino)propanamide (12d). Pale yellow solid,
mp 82–84 ꢁC, yield >98%. 1H NMR (CDCl3, 300 MHz):
d
¼7.62–7.56
3JH,H¼7.0 Hz, 3H), 0.93 (d, JH,H¼6.6 Hz, 3H), 0.87 (d, JH,H¼6.6 Hz,
3
3
(m, 2H), 7.34–7.21 (m, 4H), 5.78–5.65 (m, 1H), 5.14–5.05 (m, 1H),
3H) ppm. 13C NMR (CDCl3, 75 MHz):
d¼176.2, 142.8, 128.1, 127.3,
5.07–5.03 (m, 2H), 5.46–4.56 (br s, 1H), 3.57 (d, 2JH,H¼13.5 Hz, 1H),
124.7, 74.2, 64.1, 60.8, 57.6, 47.0, 28.6, 19.6, 18.5, 11.8 ppm. ESI-MS
2
3.48 and 3.47 (2ꢃd, AB system, JH,H¼11.7 Hz, 2H), 3.19–3.02 (m,
[MþH]þ 323. FT-IR (film):
n
¼3430, 2966, 1648, 1519, 1448,
2
2H), 2.58 (d, JH,H¼13.5 Hz, 1H), 2.49–2.39 (m, 1H), 1.85–1.51 (m,
1069 cmꢀ1. El. An. C18H30N2O3: calcd C, 67.05; H, 9.38; N, 8.69;
found C, 67.18; H, 9.39; N, 8.60.
6H), 1.23 (s, 3H), 1.16 (s, 3H), 1.20–0.97 (m, 4H) ppm. 13C NMR
(CDCl3, 150 MHz):
d
¼175.9, 142.4, 135.9, 128.1, 127.4, 124.8, 117.4,
73.9, 70.7, 59.4, 57.1, 55.8, 53.2, 31.1, 27.1, 26.0, 25.9, 25.7, 24.7,
4.9. General procedure for the preparation of
-oxazolinyloxiranes 13b–f
b-silylated-
24.6 ppm. ESI-MS m/z: 397 [MþNa]þ. FT-IR (film):
n
¼2928, 2854,
a
1660, 1449, 1070 cmꢀ1. El. An. C22H34N2O3: calcd C, 70.55; H, 9.15;
N, 7.48; found C, 70.75; H, 9.10; N, 7.27.
To a stirred and pre-cooled (ꢀ110 ꢁC) THF solution (10 mL) of
oxazolinyloxirane 6b (100 mg, 0.46 mmol), TMEDA (0.2 mL,
1.38 mmol) and silylchloride (1.38 mmol), a solution of i-PrLi
(1.38 mmol, 1.9 mL, 0.7 M in pentane) was added dropwise. The
resulting orange mixture was stirred for 1 h at this temperature and
then allowed to warm to rt, quenched with saturated aq NH4Cl,
extracted with Et2O (3ꢃ5 mL), and the combined organic phases
were dried with Na2SO4. Removal of the solvent in vacuo gave
a yellow oil, which was purified by column chromatography (1:9 to
2:4 EtOAc/petroleum ether) to give silyloxiranes 13b–f.
4.8.5. 2-Hydroxy-N-(1-hydroxymethyl-1-methylethyl)-2-phenyl-3-
(piperidin-1-yl)propanamide (12e). White solid, mp 69–72 ꢁC, yield
>98%.1H NMR (CDCl3, 300 MHz):
d
¼7.60–7.54 (m, 2H), 7.35–7.18 (m,
4H), 5.44–4.66 (br s, 2H), 3.67–3.54 (m, 4H), 3.48 (d, 2JH,H¼13.2 Hz,
1H), 3.45 (s, 2H), 2.53 (d, 2JH,H¼13.2 Hz, 1H), 2.54–2.38 (m, 2H), 1.20
(s, 3H), 1.14 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz):
d
¼175.0, 141.5,
128.2, 127.6, 124.6, 74.7, 70.3, 66.8, 65.2, 55.6, 53.9, 24.5, 24.4 ppm.
ESI-MS m/z: 345 [MþNa]þ. FT-IR (film):
¼3400, 2966, 2831, 1651,
n
1519, 1448, 1069 cmꢀ1. El. An. C17H26N2O4: calcd C, 63.37; H, 8.13; N,
8.69; found C, 63.23; H, 8.22; N, 8.77.
4.9.1. (1R
*
,2S
*
)-2-Trimethylsilyl-1-(4,4-dimethyl-2-oxazolin-2-yl)-1-
phenylepoxyethane (13b). Colourless oil, yield 90%. 1H NMR (CDCl3,
4.8.6. (ꢀ)-(2R,10S)-2-Hydroxy-N-(1-hydroxymethyl-2-methyl-
400 MHz):
d
¼7.53–7.49 (m, 2H), 7.35–7.31 (m, 3H), 3.97 and 3.96
propyl)-2-phenyl-3-pyrrolidin-1-yl-propanamide (12f). Colourless
(2ꢃd, AB system, 2JH,H¼8.2 Hz, 2H), 2.42 (s, 1H), 1.30 (s, 3H), 1.28 (s,
20
oil, yield >98%, [
a
]
ꢀ33.8 (c 0.5, CHCl3). 1H NMR (CDCl3,
3H), 0.16 (s, 9H) ppm. 13C NMR (CDCl3, 100 MHz):
d
¼161.9, 138.5,
D
300 MHz):
d
¼7.67–7.57 (m, 2H), 7.42–7.33 (br s, 1H), 7.33–7.23 (m,
128.3, 128.1, 125.7, 79.1, 67.8, 62.5, 59.7, 28.2, 28.1, ꢀ2.47 ppm. GC–
3H), 4.30–3.12 (br s, 2H), 3.73–3.45 (m, 1H), 3.63–3.55 (m, 2H), 3.55
MS (70 eV) m/z (rel int.) 289 (14) [M]þ, 275 (23), 274 (100), 246 (12),
2
2
(d, JH,H¼12.4 Hz, 1H), 2.85 (d, JH,H¼12.4 Hz, 1H), 2.70–2.50 (m,
202 (20), 105 (97), 73 (86). FT-IR (film):
n
¼2967, 2929, 1670, 1450,
4H), 1.85–1.75 (m, 1H), 1.79–1.68 (m, 4H), 0.81 (d, 3JH,H¼6.6 Hz, 3H),
1248 cmꢀ1
.
HRMS (ESI), calcd for C18H23NNaO2Si, [MþNa]þ:
0.75 (d, 3JH,H¼6.6 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz):
d¼175.7,
312.1396. Found: 312.1392.
142.1, 128.1, 127.4, 124.7, 75.4, 64.5, 62.9, 57.4, 54.4, 29.2, 23.9, 19.3,
18.4 ppm. FT-IR (film):
n
¼3350, 2943, 2831, 1655, 1523, 1449,
4.9.2. (1R
1-phenylepoxyethane (13c). Colourless oil, yield 77%. 1H NMR
(CDCl3, 400 MHz):
¼7.52–7.57 (m, 2H), 7.34–7.26 (m, 3H), 3.92 (br
s, 2H), 2.50 (s, 1H), 1.27 (s, 3H), 1.25 (s, 3H), 1.20–1.10 (m, 18H), 1.03
(s, 6H) ppm. 13C NMR (CDCl3, 100 MHz):
*
,2S
*
)-2-Triisopropylsilyl-1-(4,4-dimethyl-2-oxazolin-2-yl)-
1028 cmꢀ1. HRMS (ESI), calcd for C18H29N2O3, [MþH]þ: 321.2172.
Found: 321.2177.
d
4.8.7. (ꢀ)-(2R,10S)-2-Hydroxy-N-(1-hydroxymethyl-2-methylpropyl)-
d¼161.9, 139.1, 128.3, 128.0,
2-phenyl-3-(N,N-diethylamino)propanamide (12g). Colourless oil,
125.9, 79.0, 67.7, 60.3, 59.4, 28.1, 27.8,18.9, 11.4 ppm. GC–MS (70 eV)
20
yield >98%, [
d
a]
ꢀ55.6 (c 1, CHCl3). 1H NMR (CDCl3, 300 MHz):
m/z (rel int.) 373 (10) [M]þ, 331 (27), 330 (100), 276 (10), 258 (20),
D
¼7.67–7.57 (m, 2H), 7.42–7.33 (br s, 1H), 7.33–7.18 (m, 3H), 4.25–
59 (10). FT-IR (film):
n
¼2943, 2866, 1669, 1463, 1095 cmꢀ1. HRMS
3.12 (br s, 2H), 3.70–3.48 (m, 4H), 2.66–2.46 (m, 5H), 1.85–1.72 (m,
(ESI), calcd for C22H36NO2Si, [MþH]þ: 374.2515. Found: 374.2511.
3
3
1H), 0.97 (t, JH,H¼7.0 Hz, 3H), 0.81 (d, JH,H¼6.6 Hz, 3H), 0.75 (d,
3JH,H¼6.6 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz):
d
¼176.2, 142.7,
4.9.3. (1R
*
,2S
*
)-2-Allyldimethylsilyl-1-(4,4-dimethyl-2-oxazolin-2-
128.1,127.3,124.7, 74.2, 64.4, 60.6, 57.3, 47.0, 29.1,19.3,18.3,11.7 ppm.
yl)-1-phenylepoxyethane (13d). Colourless oil, yield 74%. 1H NMR

L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
8753
(CDCl3, 500 MHz):
d
¼7.54–7.49 (m, 2H), 7.40–7.24 (m, 3H), 5.88–
100 MHz):
d
¼163.5, 138.6, 128.2, 127.8, 126.0, 124.8, 79.4, 67.8, 65.1,
¼2957,
HRMS (ESI), calcd for
5.78 (m, 1H), 4.93 (dq, JH,H¼16.9, 1.5 Hz,1H), 4.96–4.86 (m, 1H), 3.99
and 3.98 (2ꢃd, AB system, 2JH,H¼8.2 Hz, 2H), 2.48 (s, 1H), 1.76–1.74
(m, 2H), 1.33 (s, 3H), 1.31 (s, 3H), 0.18 (s, 3H), 0.17 (s, 3H) ppm. 13C
58.2, 29.0, 28.4, 28.2, 27.4, 13.7, 10.8 ppm. FT-IR (film):
n
2924, 2854, 1661, 1463, 1377 cmꢀ1
.
C25H41NNaO2Sn, [MþNa]þ: 530.2057. Found: 530.2059.
NMR (CDCl3, 125 MHz):
d¼161.9, 138.3, 133.7, 128.3, 128.1, 125.7,
114.0, 79.1, 67.8, 61.2, 59.6, 28.2, 28.1, 22.2, ꢀ4.6, ꢀ4.7 ppm. GC–MS
(70 eV) m/z (rel int.) 315 (7) [M]þ, 274 (100), 220 (29), 203 (23), 202
(95), 139 (27), 105 (29). HRMS (ESI), calcd for C18H26NO2Si, [MþH]þ:
316.1733. Found: 316.1732.
4.10.3. (1R
*
,2R )-1-(4,4-Dimethyl-2-oxazolin-2-yl)-1-phenyl-1,2-ep-
*
oxypropane (13h). Colourless oil, yield 40%, inseparable mixture of
13h and 6b. 1H NMR (CDCl3, 400 MHz, selected data for 13h):
d
¼7.49–7.47 (m, 2H), 7.34–7.28 (m, 3H), 3.98 (s, 2H), 3.19 (q,
3JH,H¼5.5 Hz, 1H), 1.45 (d, JH,H¼5.5 Hz, 3H), 1.32 (s, 3H), 1.30 (s,
3
4.9.4. (1R
*
,2S
*
)-2-Dimethylphenylsilyl-1-(4,4-dimethyl-2-oxazolin-
3H) ppm. 13C NMR (CDCl3, 100 MHz, selected data):
d
¼160.8, 136.2,
2-yl)-1-phenylepoxyethane (13e). Colourless oil, yield 68%. 1H NMR
128.4, 128.2, 125.9, 94.4, 79.2, 62.3, 59.9, 28.4, 28.1, 15.0 ppm. GC–
(CDCl3, 400 MHz):
d
¼7.62–7.57 (m, 3H), 7.48–7.53 (m, 2H), 7.37–
MS (70 eV) m/z (rel int) 231 (1) [M]þ, 142 (5), 115 (7), 106 (9), 105
7.25 (m, 5H), 3.80 and 3.78 (2ꢃd, AB system, 2JH,H¼8.1 Hz, 2H), 2.61
(100), 89 (6), 77 (16), 56 (6). FT-IR (film):
n
¼2973, 1739, 1667, 1449,
(s, 1H), 0.43 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H), 0.47 (s, 3H) ppm. 13C
1275 cmꢀ1. HRMS (ESI), calcd for C14H17NNaO2, [MþH]þ: 254.1157.
NMR (CDCl3, 100 MHz):
d¼161.9, 138.3, 136.5, 133.0, 132.9, 129.6,
Found: 254.1153.
129.5, 129.2, 128.2, 127.9, 127.7, 78.9, 67.7, 61.8, 59.9, 28.1, 28.0, ꢀ3.7,
ꢀ3.9 ppm. GC–MS (70 eV) m/z (rel int.) 351 (11) [M]þ, 336 (72), 274
(48), 207 (87), 135 (100), 105 (80), 77 (22), 44 (23). FT-IR (film):
4.10.4. (1R
epoxyethane (13i). Colourless oil, yield 35%. 1H NMR (CDCl3,
400 MHz):
*
,2R
*
)-2-Allyl-1-(4,4-dimethyl-2-oxazolin-2-yl)-1-phenyl-
n
¼2964, 2928, 1661, 1428, 1118 cmꢀ1
.
HRMS (ESI), calcd for
d
¼7.52–7.47 (m, 2H), 7.40–7.34 (m, 3H), 5.98–5.81 (m,
C21H26NO2Si, [MþH]þ: 352.1733. Found: 352.1742.
1H), 5.23 (dq, JH,H¼17.1, 1.6 Hz, 1H), 5.16 (dq, J¼10.4, 1.1 Hz, 1H), 4.01
(s, 2H), 3.18 (t, 3JH,H¼5.8 Hz, 1H), 2.54–2.37 (m, 2H), 1.36 (s, 3H), 1.34
4.9.5. (1R
*
,2S
*
)-2-Diphenylmethylsilyl-1-(4,4-dimethyl-2-oxazolin-
(s, 3H) ppm. 13C NMR (CDCl3,125 MHz):
d
¼160.9,136.1, 132.6, 128.4,
2-yl)-1-phenylepoxyethane (13f). Colourless oil, yield 68%. 1H NMR
126.1, 118.0, 79.4, 67.8, 65.1, 59.9, 33.9, 28.4, 28.1 ppm. GC–MS
(CDCl3, 400 MHz):
d
¼7.70–7.20 (m, 15H), 3.48 and 3.39 (2ꢃAB
(70 eV) m/z (rel int.) 256 (1) [Mꢀ1]þ, 216 (23), 152 (12), 105 (100),
system, 2JH,H¼8.0 Hz, 2H), 2.89 (s, 1H), 1.01 (s, 3H), 0.95 (s, 3H), 0.74
77 (21). FT-IR (film):
n
¼2967, 1668, 1520, 1450, 1190, 759, 698 cmꢀ1
.
(s, 3H) ppm. 13C NMR (CDCl3, 100 MHz):
d
¼161.9, 137.0, 135.0, 134.7,
HRMS (ESI), calcd for C16H20NO2, [MþH]þ: 258.1494. Found:
129.7, 129.6, 128.3, 128.2, 128.0, 127.9, 125.9, 78.5, 67.5, 61.0, 60.0,
258.1490.
27.7, 27.6, ꢀ5.1 ppm. GC–MS (70 eV) m/z (rel int.) 413 [M]þ (<1%),
214 (18), 200 (18), 199 (100), 137 (10), 77 (6). FT-IR (film):
n
¼3069,
4.10.5. (1R
*
,2R
*
,3R )-1,3-Diphenyl-3-(4,4-dimethyl-2-oxazolin-2-yl)-
*
2962, 1666, 1428, 1119, 792 cmꢀ1
.
HRMS (ESI), calcd for
2,3-epoxypropan-1-ol and 3,3-dimethyl-7,9-diphenyl-8,9-epoxy-1,6-
dioxa-4-azaspiro[4.4]nonane (13j-major). Colourless oil, yield 19%,
1:1 unseparable mixture. 1H NMR (CDCl3, 500 MHz, selected data):
C26H28NO2Si, [MþH]þ: 414.1889. Found: 414.1884.
4.10. General procedure for the preparation
of oxazolinyloxiranes 13a,g–k
d
¼7.71–7.25 (m, 20H, spirocyclic and hydroxyalkylated forms),
5.06 (s, 1H, spirocyclic form), 4.86 (d, J¼7.0 Hz, 1H, spirocyclic
2
form), 4.05 and 4.04 (2ꢃd, AB system, JH,H¼9.1 Hz, 2H, hydroxy-
To a stirred and pre-cooled (ꢀ110 ꢁC) THF solution (10 mL) of
oxazolinyloxirane 3b (100 mg, 0.46 mmol) and TMEDA (0.2 mL,
1.38 mmol), a solution of i-PrLi (1.38 mmol, 1.9 mL, 0.7 M in pen-
tane) was added dropwise and, after 20 min, the suitable electro-
phile was added neat or in (0.5 M) THF solution if solid (1.38 mmol).
The resulting mixture was stirred for 1 h at this temperature and
then allowed to warm to rt, quenched with saturated aq NH4Cl,
extracted with Et2O (3ꢃ5 mL), and the combined organic phases
were dried with Na2SO4. Removal of the solvent in vacuo gave
a yellow oil, which was purified by column chromatography (1:4 to
1:9 EtOAc/petroleum ether) to give the desired oxirane 13. In the
case of oxiranes 13j,k, Et2O was used as the solvent at ꢀ98 ꢁC, and
the carbonyl compound was added after 5 min.
alkylated form), 3.86 (s, 1H, spirocyclic form), 3.71 and 3.50 (2ꢃd,
2
AB system, JH,H¼7.7 Hz, 2H, spirocyclic form), 3.34 (d, J¼6.9 Hz,
1H, hydroxyalkylated form), 1.34 and 1.32 (2ꢃs, 6H, hydroxyalky-
lated form), 1.26 and 0.75 (2ꢃs, 6H, spirocyclic form) ppm. 13C
NMR (CDCl3, 100 MHz, selected data):
d
¼161.3 (C]N, hydrox-
yalkylated form), 139.7, 136.5, 135.4, 131.7, 128.7, ꢀ126.1 (Ar C–H),
119.1 (spiro C), 79.7, 76.7, 76.2, 70.8, 69.2, 67.7, 66.2, 63.8, 60.8, 55.1,
28.3, 28.2, 28.1, 28.0 ppm. FT-IR (film):
n
¼3178, 2925, 1673, 1452,
1364, 1164, 1048, 757, 698 cmꢀ1. ESI-MS m/z: 324 [MþH]þ. El. An.
C20H21NO3: calcd C, 74.28; H, 6.55; N, 4.33; found C, 74.18; H, 6.39;
N, 4.60.
4.10.6. (1R
*
,2S
*
,3S )-1,3-Diphenyl-3-(4,4-dimethyl-2-oxazolin-2-yl)-
*
2,3-epoxypropan-1-ol and 3,3-dimethyl-7,9-diphenyl-8,9-epoxy-1,6-di-
4.10.1. (1R
*
,2R
*
)-2-Deuterio-1-(4,4-dimethyl-2-oxazolin-2-yl)-1-
oxa-4-azaspiro[4.4]nonane (13j-minor). Colourless oil, 1:1 unseparable
phenylepoxyethane (13a). Colourless oil, yield 50% (85% D). 1H NMR
(CDCl3, 500 MHz, selected data):
mixture, yield 6%. 1H NMR (CDCl3, 500 MHz, selected data):
d¼7.82–
d
¼7.48 (d, 3JH,H¼7.9 Hz, 2H), 7.38–
7.74 (m, 2H, spirocyclic form), 7.53–7.46 (m, 2H, hydroxyalkylated
form), 7.41–7.24 (m, 8H, hydroxyalkylated form), 7.46–7.26 (m, 4H,
spirocyclic form), 7.25–7.06 (m, 4H, spirocyclic form), 5.49 (d, J¼2.6 Hz,
1H, hydroxyalkylated form), 4.66 (s, 1H, spirocyclic form), 4.52
(dd, J¼8.4, 2.6 Hz, 1H, hydroxyalkylated form), 4.13 and 4.09 (2ꢃd, AB
7.33 (m, 3H), 4.01 (s, 2H), 2.96 (s, 1H), 1.32 (s, 3H), 1.31 (s, 3H) ppm.
13C NMR (CDCl3, 125 MHz, selected data):
d¼162.5, 135.3, 128.4,
128.3, 126.4, 79.6, 67.7, 55.5, 54.8 (t, JC,D¼27.4 Hz), 28.0, 27.9 ppm.
GC–MS (70 eV) m/z 218 (6) [M]þ, 217 (17), 201 (7), 187 (4), 130 (5),
2
106 (100), 92 (13), 78 (17), 57 (6), 42 (5). FT-IR (film):
n¼3383, 2973,
system, JH,H¼8.4 Hz, 2H, hydroxyalkylated form), 4.06 and 4.01
1739, 1667, 1449, 1275 cmꢀ1. HRMS (ESI), calcd for C13H14DNNaO2,
(2ꢃd, AB system, JH,H¼8.0 Hz, 2H, spirocyclic form), 3.76 (s, 1H,
2
[MþNa]þ: 241.1062. Found: 241.1069.
spirocyclic form), 3.14 (d, J¼8.4 Hz, 1H, hydroxyalkylated form),
2.37 (br s, 1H, spirocyclic form), 1.41 and 1.37 (2ꢃs, 6H, hydrox-
yalkylated form), 1.26 and 1.13 (2ꢃs, 6H, spirocyclic form) ppm. 13C
4.10.2. (1R
*
,2S
*
)-2-Tributyltin-1-(4,4-dimethyl-2-oxazolin-2-yl)-1-
phenylepoxyethane (13g). Colourless oil, yield 50%. 1H NMR (CDCl3,
NMR (CDCl3, 100 MHz, selected data):
d
¼161.3 (C]N, hydroxyalky-
400 MHz):
d
¼7.49–7.45 (m, 2H), 7.36–7.29 (m, 3H), 3.97 and 3.96
lated form), 139.6, 136.5, 135.4, 131.6, 128.7ꢀ126.1 (Ar C–H), 119.2
(2ꢃd, AB system, 2JH,H¼8.2 Hz, 2H), 2.82 (s, 1H), 1.64–1.54 (m, 12H),
(spiro C), 79.8, 77.5, 76.2, 70.8, 69.2, 67.7, 66.2, 63.9, 60.9, 57.0, 28.3,
1.38–1.25 (m, 12H), 1.02–0.97 (m, 9H) ppm. 13C NMR (CDCl3,
28.1, 27.8, 26.5 ppm. FT-IR (film):
n
¼3178, 2925, 1673, 1452 cmꢀ1
.

8754
L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
HRMS (ESI), calcd for C16H22NO3, [MþH]þ: 324.1600. Found:
pressure. Column chromatography (AcOEt/petroleum ether, 1:9)
furnished epoxylactones 16.
324.1606.
4.10.7. Unseparable mixture 1:3 of 1-[3-(4,4-dimethyl-2-oxazolin-2-
yl)-3-phenyloxiranyl]cyclopentanol and 3,3-dimethyl-13-phenyl-
4.12.1. (1R
one 16. Waxy solid, yield 59%. 1H NMR (CDCl3, 500 MHz):
7.49 (m, 2H), 7.46–7.37 (m, 6H), 7.34–7.27 (m, 2H), 5.57 (s, 1H), 4.19
(s, 1H) ppm. 13C NMR (CDCl3, 125 MHz):
170.3, 134.6, 129.7, 129.5,
*
,4R
*
,5R
*
)-1,4-Diphenyl-3,6-dioxabicyclo[3.1.0]hexan-2-
d
¼7.56–
12,13-epoxy-1,6-dioxa-4-azadispiro[4.1.4.2]tridecane
13k. White
solid, mp¼81–83 ꢁC, yield 24%. 1H NMR (CDCl3, 500 MHz, selected
d
data):
d
¼7.64–7.53 (m, 2H, spirocyclic form), 7.48–7.41 (m, 2H,
129.3, 128.7, 126.9, 126.0, 124.8, 79.1, 67.6, 59.2 ppm. GC–MS (70 eV)
hydroxyalkylated form), 7.38–7.25 (m, 3H, hydroxyalkylated form
and 3H spirocyclic form), 4.2 and 3.99 (2ꢃd, AB system,
2JH,H¼8.0 Hz, 2H, hydroxyalkylated form), 3.61 and 3.35 (2ꢃd, AB
m/z 252 (<1) [M]þ, 207 (20), 105 (100), 77 (26), 44 (25). FT-IR (KBr):
n
¼3065, 2919, 2850, 1779, 1451, 1311, 1139, 1042, 942, 754,
696 cmꢀ1. HRMS (ESI), calcd for C16H12NaO3, [MþNa]þ: 275.0684.
2
system, JH,H¼7.3 Hz, 2H, spirocyclic form), 3.53 (s, 1H, spirocyclic
Found: 275.0678.
form), 3.09 (s, 1H, hydroxyalkylated form), 2.15–1.48 (m, 16H, spi-
rocyclic and hydroxyalkylated forms), 1.31 (s, 6H, hydroxyalkylated
form), 1.23 and 0.67 (2ꢃs, 6H, spirocyclic form) ppm. 13C NMR
4.12.2. (1R
*
,4S
*
,5R )-1,4-Diphenyl-3,6-dioxabicyclo[3.1.0]hexan-2-
*
one 16. White solid, mp 126–128 ꢁC, yield 61%. 1H NMR (CDCl3,
(CDCl3, 100 MHz, selected data):
d¼162.0 (C]N, hydroxyalkylated
500 MHz):
d
¼7.64–7.40 (m, 10H), 5.55 (d, 3JH,H¼1.6 Hz, 1H), 4.35 (d,
form),136.3,132.1, 128.7,128.4,128.1,127.6,125.4, 118.9 (spiro C), 87.3,
3JH,H¼1.6 Hz, 1H) ppm. 13C NMR (CDCl3, 125 MHz):
¼170.1, 133.2,
d
79.7, 79.6, 71.5, 67.1, 66.2, 56.6, 38.6, 38.2, 35.3, 33.8, 28.1, 27.6, 26.4,
129.4, 129.3, 128.7, 128.6, 128.1, 126.9, 77.9, 66.2, 60.4 ppm. GC–MS
24.4, 23.9, 23.8 ppm. FT-IR (film):
n
¼3361, 2965, 1665, 1448, 1254,
(70 eV) m/z 252 (1) [M]þ, 207 (8), 105 (100), 90 (13), 77 (25). FT-IR
1054, 698 cmꢀ1. El. An. C18H23NO3: calcd C, 71.73; H, 7.69; N, 4.65,
4.11; found C, 71.63; H, 7.65; N, 4.61.
(KBr):
n
¼3064,1774, 1317, 1244,1152, 1062, 963, 762, 745, 697 cmꢀ1
.
El. An. C16H12O3: calcd C, 76.17; H, 4.79; found C, 75.83; H, 4.87.
4.11. General procedures and spectral data for (E)-enediol (14)
Acknowledgements
To a stirred and pre-cooled (ꢀ98 ꢁC) Et2O solution (7 mL) of
oxazolinyloxirane 6b (74 mg, 0.34 mmol) and TMEDA (1.38 mmol),
a Et2O solution of LDA (1.38 mmol, 0.3 M) was added dropwise. The
resulting orange mixture was stirred for 3 h at this temperature,
quenched with saturated aq NH4Cl, extracted with EtOAc (3ꢃ5 mL)
and the combined organic phases were dried with Na2SO4. Removal
of the solvent in vacuo gave a yellow oil that was purified by column
chromatography (3:2 EtOAc/petroleum ether) to give (E)-14 (75%).
This work was carried out under the framework of the National
Project ‘Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni’ by the University of Bari. We are grateful to Prof. Lucio
Pellacani of the Department of Chemistry of the University of Rome
‘La Sapienza’ for performing HRMS analyses.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.08.040.
4.11.1. (1R
yl)-1,4-diphenyl-but-2-ene-1,4-diol (14). White solid, yield 85%, mp
152–153 ꢁC. 1H NMR (CDCl3, 500 MHz):
¼7.53–7.47 (m, 4H), 7.36–
*
,2E,4R
*
)-1,4-Bis-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-
d
References and notes
7.24 (m, 6H), 6.60 (s, 2H), 4.21 (br s, exchanges with D2O, 2H), 4.08
and 4.03 (2ꢃd, AB system, 2JH,H¼8.0 Hz, 4H), 1.29 (s, 12H) ppm. 13
C
1. (a) Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R.; Tralli, C.; Troisi, L. Synthesis
2001, 15, 2299–2306; (b) Florio, S.; Capriati, V.; Luisi, R. Tetrahedron Lett. 2000,
41, 5295–5298; (c) Abbotto, A.; Capriati, V.; Florio, S.; Luisi, R.; Pippel, D. J.
Tetrahedron 2001, 57, 6775–6786.
NMR (CDCl3, 125 MHz):
d¼168.3, 141.7, 131.6, 128.5, 128.3, 128.0,
126.1, 81.2, 74.5, 66.7, 28.1, 28.0 ppm. ESI-MS m/z: 435 (11) [MþH]þ,
457 (100) [MþNa]þ. FT-IR (KBr):
¼3326, 2975, 1632, 1450, 1151,
n
2. The configurational stability of a-lithiated oxazolinyloxiranes has been recently
1031, 697 cmꢀ1. El. An. C26H30N2O4: calcd C, 71.87; H, 6.95; N, 6.44;
found C, 71.97; H, 6.65; N, 6.48.
investigated by means of a multinuclear magnetic resonance study, supported
by an in situ IR spectroscopy: Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.; Spina,
A. J. Org. Chem. 2008, 73, 9552–9564.
´
3. Florio, S.; Perna, F. M.; Luisi, R.; Barluenga, J.; Fan˜anas, F. J.; Rodriguez, F. J. Org.
Chem. 2004, 69, 9204–9207.
4.11.2. 1-(4,4-Dimethyl-2-oxazolin-2-yl)-3-methyl-1-phenylbutan-1-
ol (15). Colourless oil, <10%. 1H NMR (CDCl3, 500 MHz):
d¼7.64–
4. Luisi, R.; Capriati, V.; Degennaro, L.; Florio, S. Tetrahedron 2003, 59, 9713–9718.
5. Perna, F. M.; Capriati, V.; Florio, S.; Luisi, R. J. Org. Chem. 2002, 67, 8351–8359.
6. Perna, F. M.; Capriati, V.; Florio, S.; Luisi, R. Tetrahedron Lett. 2003, 44, 3477–
3481.
7. Luisi, R.; Capriati, V.; Degennaro, L.; Florio, S. Org. Lett. 2003, 5, 2723–2726.
8. Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R.; Punzi, P. Org. Lett. 2006, 8, 4803–
4806.
7.60 (m, 2H), 7.38–7.30 (m, 3H), 4.09 and 4.03 (2ꢃd, AB system,
3JH,H¼8.2 Hz, 2H), 3.80 (br s, exchanges with D2O, 1H), 2.06 (dd,
JH,H¼14.2, 6.6 Hz, 1H), 1.96 (dd, JH,H¼14.2, 5.5 Hz, 1H), 1.84 (heptet,
3JH,H¼6.5 Hz, 1H), 1.32 (s, 3H), 0.9 (d, 3JH,H¼6.5 Hz, 3H), 1.21 (s, 3H),
3
0.97 (d, JH,H¼6.5 Hz, 3H) ppm. 13H NMR (CDCl3, 500 MHz):
9. Patent, Jpn. Kokai Tokyo Koho, JP 83-47333, 1983.
d
¼169.4, 143.8, 128.0, 127.2, 125.3, 80.9, 74.7, 66.7, 48.0, 28.1, 28.0,
10. Hansen, J. F.; Wang, S. J. Org. Chem. 1976, 41, 3635–3637.
24.5, 23.6, 22.8 ppm. GC–MS (70 eV) m/z 261 (1) [M]þ, 204 (100),
11. Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1996, 61, 2044–2060.
12. Harn, N. K.; Gramer, C. J.; Anderson, B. A. Tetrahedron Lett. 1995, 36, 9453–9456.
13. Koch, T. H.; Olesen, J. A.; De Niro, J. J. Org. Chem. 1975, 40, 14–19.
14. Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165–1167; For
a leading review on the use of BtCH2OH, see: Katritzky, A. R.; Manju, K.; Singh, S.
K.; Meher, N. K. Tetrahedron 2005, 61, 2555–2581 and references therein.
15. It is worth noting that terminal oxazolinyloxirane 6c could not be obtained
from the corresponding 2-acyl-2-oxazoline because of its instability; indeed, it
undergoes a fast rearrangement to the corresponding oxazinone.
16. Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122, 6321–6322.
17. CCDC 720194 contains the supplementary crystallographic data for compound
(2R,40S)-10. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk. The absolute configura-
tion to the remaining stereoisomers was assigned comparing their optical ro-
tation values and taking into account that of oxazolinyloxirane (2R,40S)-10.
18. (a) Ogata, M.; Matsumoto, H.; Takahashi, K.; Shimizu, S.; Kida, S.; Murabayashi,
A.; Shiro, M.; Tawara, K. J. Med. Chem. 1987, 30, 1054–1068; (b) Ichikawa, T.;
Yamada, M.; Yamaguchi, M.; Kitazaki, T.; Matsushita, Y.; Higashikawa, K.; Itoh,
105 (68). FT-IR (film):
n
¼3391, 2954, 1658, 1463, 1366, 1278, 1139,
1070, 698 cmꢀ1
.
HRMS (ESI), calcd for C16H24NO2, [MþH]þ:
262.1807. Found: 262.1809.
4.12. General procedure and spectral data for the preparation
of epoxylactones (1R
*
,4R
*
,5R
*
)-16 and (1R
*
,4S
*
,5R )-16
*
To the equilibrating mixture of the spirocyclic compound and
hydroxyalkyl derivative 13j (100 mg, 0.3 mmol) in dioxane/H2O
(4:1, 5 mL) CF3COOH (0.26 mmol, 20 mL) was added and the
resulting mixture stirred for 24 h at rt. Then, the reaction mixture
was poured into water, extracted with AcOEt (3ꢃ10 mL), dried on
Na2SO4, filtered and the volatiles were removed under reduced

L. Degennaro et al. / Tetrahedron 65 (2009) 8745–8755
8755
K. Chem. Pharm. Bull. 2001, 49, 1110–1119; (c) Monfort, N.; Archelas, A.; Furstoss,
R. Tetrahedron: Asymmetry 2002, 13, 2399–2401.
19. Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R. Tetrahedron Lett. 2007, 48, 8651–
be isolated and fully characterized. The E configuration was established by
considering the doublet of doublets arising from 13C satellites for the peaks at
6.77 and 6.44 ppm in its 1H NMR spectrum. The larger splitting due to 1J13C–H is
3
8654; For a leading review on
b- and
g
-amino acids, see: Seebach, D.; Beck, A.
162.9 Hz, while the smaller one due to a JH–H splitting is 15.3 Hz. The mag-
K.; Bierbaum, D. Chem. Biodivers. 2004, 1, 1111–1239.
20. (a) Capriati, V.; Florio, S.; Luisi, R. Synlett 2005, 1359–1369; (b) Capriati, V.;
Florio, S.; Luisi, R. Chem. Rev. 2008, 108, 1918–1942.
21. Hodgson, D. M.; Bray, D. C.; Kindon, N. D. Org. Lett. 2005, 7, 2305–2308.
22. For leading references on Li/OR carbenoids, see: (a) Boche, G.; Bosold, F.;
Lohrenz, J. C. W.; Opel, A.; Zulauf, P. Chem. Ber. 1993, 126, 1873–1885; (b) Boche,
G.; Lohrenz, J. C. W. Chem. Rev. 2001, 101, 697–756.
nitude of the latter gives evidence for a trans arrangement of the vinylic hy-
drogens (see Supplementary data).
24. For a related work on the in situ silylation of highly reactive terminal oxir-
anyllithiums, see: Hodgson, D. M.; Norsikian, S. L. M. Org. Lett. 2001, 3, 461–463.
25. For another example of oxazolinyl-promoted-b-lithiation, see: Luisi, R.; Cap-
riati, V.; Di Cunto, P.; Florio, S.; Mansueto, R. Org. Lett. 2007, 9, 3295–3298.
26. Neuhaus, D.; Williamson, M. The Nuclear Overhauser Effect in Structural and
Conformational Analysis; VCH: New York, NY, 1989; p 264.
23. Running the reaction in toluene at ꢀ78 ꢁC with i-PrLi and TMEDA, a mixture of
E and Z enediols 14 formed almost exclusively (85%, E/Z¼75:25). 1H NMR
analysis of the crude revealed the presence of two sets of vinylic protons likely
to be ascribed to two differently configured enediols. In particular, the Z isomer
is present as a mixture of at least three different conformers slowly equili-
27. The relative configuration of the two epoxylactones 16 was ascertained from
the coupling constant values of the two vicinal protons according to their di-
3
hedral angle (3JH–Hz0 Hz for (R
*
,R
*
,R
*
)-16; JH-H¼1.6 Hz for (R
,S ,R )-16) as
* * *
already reported for similar compounds, see: (a) Jakubowski, A. A.; Guziec, F. S.;
Sugiura, M.; Tam Chan, C.; Tishler, M. J. Org. Chem. 1982, 47, 1221–1228; (b)
Boeckman, R. K.; Thomas, E. W. J. Am. Chem. Soc. 1979, 101, 987–994.
brating on the NMR time scale probably because of
a locked geometry
(3JH–H¼10.2 Hz). However, by flash-chromatography, only enediol (E)-14 could