Ring enlargement of carbohydrate-derived 1,2-Oxazines to enantiopure 5-Bromo-1,2-oxazepines and subsequent palladium-catalyzed reactions

Article abstract of DOI:10.1055/s-0029-1217126

Dibromocarbene addition to d-glyceraldehyde-derived 1,2-oxazines syn-1 and anti-1 provided dibromocyclopropane intermediates syn-3 and anti-3, which smoothly reacted with methanol under ring enlargement to furnish 5-bromo-1,2-oxazepine derivatives syn-4 a

Full text of DOI:10.1055/s-0029-1217126

304
PAPER
Ring Enlargement of Carbohydrate-Derived 1,2-Oxazines to Enantiopure
5-Bromo-1,2-oxazepines and Subsequent Palladium-Catalyzed Reactions
C
arbohydrate-Deri
h
ved 3, 6-Dih
m
2
H
-1,2-oxazin
e
es d Al-Harrasi,a,b Sebastian Fischer,a Reinhold Zimmer,a Hans-Ulrich Reissig*a
a
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
b
Department of Chemistry, College of Science, Sultan Qaboos University, Alkhod 123, Sultanate of Oman
Received 14 August 2009
remarkable diversity (Scheme 1). The oxazepine moiety
has been found in many pharmaceutically important
compounds8 and 1,2-oxazepines9 in particular are versa-
tile compounds, from which many interesting product
Abstract: Dibromocarbene addition to D-glyceraldehyde-derived
1,2-oxazines syn-1 and anti-1 provided dibromocyclopropane inter-
mediates syn-3 and anti-3, which smoothly reacted with methanol
under ring enlargement to furnish 5-bromo-1,2-oxazepine deriva-
tives syn-4 and anti-4. Related 1,2-oxazines such as arabinose- classes, for example, amino substituted polyols (hep-
derived compounds furnished the 1,2-oxazepine derivatives syn-4e
and anti-4f with fair efficacy. The alkenyl bromide moiety of 1,2-
oxazepine derivatives syn-4 and anti-4 was then exploited for the
introduction of new substituents via palladium-catalyzed C–C bond
forming processes (Sonogashira, Suzuki, Stille, and Heck reac-
tions). These transformations led to a series of new highly substitut-
ed 1,2-oxazepine derivatives syn-5 or anti-5–11 being of
considerable interest for further synthetic elaborations.
tanose derivatives) or stereodefined piperidines, can be
prepared. Moreover, several 1,2-oxazepine derivatives
are known to be potential opioid analgesics.9b
Br
OR OR
n
Br
OR OR
n
OR
OR
N
R
N
R
Key words: 1,2-oxazines, carbene additions, cyclopropanes, ring
enlargement, 1,2-oxazepines, palladium catalysis, alkynes
O
R
O
R
A
B
n = 1, 3
Over the years, we have systematically explored the
chemistry of alkoxyallenes for the construction of nitro-
gen-containing heterocycles including pyrrolidine alka-
OR
N
OR
n
OR
N
RO
OR
RO
R
OR
Br
OR
loids,
substituted
imidazole
derivatives,
and
n
R
functionalized pyridines.1 The stereocontrolled [3+3] cy-
clization of lithiated alkoxyallenes and carbohydrate-
derived nitrones is a particularly interesting example dem-
onstrating the synthetic utility of these fascinating C3
building blocks.2 It furnishes novel enantiopure 3,6-dihy-
dro-2H-1,2-oxazines of type A, which are remarkably
versatile precursors for the synthesis of a multitude of
biologically active target compounds. Reductive, acid-
induced and Lewis acid promoted transformations lead to
aminopolyols, hydroxylated pyrrolidines and azetidine
derivatives,3 or carbohydrate4 and sugar amino acid mi-
metics.5
R
R
R
O
O
D
C
Scheme 1 Transformation of carbohydrate-derived 3,6-dihydro-
2H-1,2-oxazines A into 1,2-oxazepine derivatives C and D via dibro-
mocyclopropanes B.
We started this investigation with the cycloaddition of in
situ generated dichlorocarbene. Treatment of D-glyceral-
dehyde-derived 1,2-oxazine syn-1a dissolved in chloro-
form with 50% aqueous solution of sodium hydroxide in
the presence of a phase-transfer catalyst10 afforded the
corresponding dichlorocyclopropane derivative syn-2a in
56% yield (Scheme 2). Not unexpectedly, a diastereomer-
ic mixture was obtained (ratio 65:35), since the highly re-
The full extent of the synthetic utility of 3,6-dihydro-2H-
1,2-oxazines A has yet to be explored. Moreover, the elec-
tron-rich enol ether moiety of A was not fully exploited
for the introduction of additional substituents or function-
al groups. Herein, we present full details6 involving dibro-
mocarbene cycloadditions7 to this activated double bond
of A to furnish the ring-enlarged 5-bromo-1,2-oxazepine
derivatives of type C via the intermediate dibromocyclo-
propanes B. The palladium-catalyzed reactions of C pro-
vided new highly substituted 1,2-oxazepines D of
Cl
OR
O
Cl
OR
O
O
O
a
N
N
56%, dr = 65:35
O
Bn
O
Bn
syn-1a
syn-2a
R = CH2CH2SiMe3
SYNTHESIS 2010, No. 2, pp 0304–0314
Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217126; Art ID: T16109SS
x
x
.
x
x
.2
0
0
9
Scheme 2 Conversion of D-glyceraldehyde-derived 1,2-oxazine
syn-1a into dichlorocarbene adduct syn-2a. Reagents and conditions:
a) CHCl3, 50% aq NaOH, Et3BnNCl, r.t., 2 d.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantiopure 5-Bromo-1,2-oxazepines
305
active dichlorocarbene only moderately differentiates the
diastereotopic faces of the 1,2-oxazine ring.
Br
OMe
OMe
Br
OMe
MeO
Br
R
Br
R
R
MeOH
+
When the reaction was carried out under identical condi-
tions, but by replacing chloroform with bromoform, no
product was isolated. Instead, the starting material had un-
dergone fast decomposition. This problem could be avoid-
ed by employing a large excess of potassium fluoride as
an additive. Similar observations have been recorded in
literature for related reactions.10 Under these conditions,
the addition of dibromocarbene to the anti-configured 1,2-
oxazine derivatives anti-1a,b took place smoothly and
gem-dibromocyclopropane derivatives anti-3a,b were
isolated in 55% and 65% yield, respectively. Again the
diastereoselectivity was only moderate (Scheme 3). The
separation of the two diastereomers, though it is possible
in all cases, was not attempted except for characterization
purposes. Subsequent solvolysis of dibromocyclopropane
derivatives in refluxing methanol with potassium
carbonate10 furnished the ring-enlarged 5-bromo-1,2-ox-
azepine derivatives anti-4a/b in reasonable yields
(Scheme 3).
N
– Br–
N
O
N
O
Bn
Bn
Bn
O
B
C
E
Scheme 4 Mechanism of the ring opening of compounds 3 leading
to 5-bromo-1,2-oxazepines 4.
companied with significant decomposition products
which account for the moderate yields of the resulting 1,2-
oxazepines. However, no side products could be isolated.
Encouraged by these results and to further examine the
general applicability of this method, the ring enlargement
reactions of other 1,2-oxazine derivatives were carried
out. When the corresponding syn-1,2-oxazines syn-1a,b
were treated with bromoform and 50% aqueous sodium
hydroxide and potassium fluoride in the presence of a cat-
alytic amount of benzyltriethylammonium chloride for
two days, diastereomeric mixtures of the dibromo deriva-
tives syn-3a,b were isolated. No separation of the diaste-
reomers was attempted and the mixtures were then
refluxed in methanol in the presence of anhydrous potas-
sium carbonate for 20 hours. The expected 5-bromo-1,2-
oxazepine derivative syn-4a was isolated after column
chromatography in 41% yield over two steps, whilst syn-
4b was obtained in 49% (Scheme 5). Thus, 1,2-oxazines
syn-1 and anti-1, being available in a stereodivergent
manner from the D-glyceraldehyde derived nitrone,2a,c
could be converted into the two diastereomeric ring-en-
larged homologues syn- and anti-4 in a straightforward
fashion.
Br
OR
O
Br
OR
O
O
O
a
N
N
3a: 55%, dr = 65:35
3b: 65%, dr = 68:32
O
Bn
O
Bn
anti-3a,b
anti-1a,b
4a: 62%
4b: 53%
a: R = CH2CH2SiMe3
b: R = Me
b
O
OR
MeO
O
Br
Br
OR
O
Br
OR
O
O
O
a
N
Bn
O
N
N
3a: dr = 66:34
3b: 54%, dr = 70:30
O
Bn
O
Bn
anti-4a,b
syn-3a,b
syn-1a,b
Scheme 3 Synthesis of dibromocarbene adducts anti-3a,b and 5-
bromo-1,2-oxazepine derivatives anti-4a,b. Reagents and conditions:
a) CHBr3, 50% aq NaOH, KF, Et3BnNCl, r.t., 2 d; b) K2CO3, MeOH,
reflux, 20 h.
a: R = CH2CH2SiMe3
b: R = Me
b
There are many reports in literature dealing with the ring
opening of dihalocyclopropanes7 and it is well established
that a stereospecific opening of the cyclopropane ring is
concerted with the departure of the leaving group.7e The
mechanism for our examples is depicted in Scheme 4. The
cyclopropyl cation resulting from the loss of halogen from
B simultaneously rearranges in such a way, that the devel-
oping allyl cation E is immediately stabilized by the meth-
oxy group. Trapping by a nucleophilic solvent like
methanol will then provide the 7-membered heterocycle
C. The presence of an alkoxy group (methoxy or trimeth-
ylsilylethoxy) is essential in stabilizing the transition state
of this electrocyclic reaction.7g The ring enlargement of
our compounds 3 under these conditions is apparently ac-
O
OR
MeO
O
Br
N
Bn
O
4a: 41% over 2 steps
4b: 49%
syn-4a,b
Scheme
5
Synthesis of 5-bromo-1,2-oxazepines syn-4a,b.
Reagents and conditions: a) CHBr3, 50% aq NaOH, KF, Et3BnNCl,
r.t., 2 d; b) K2CO3, MeOH, reflux, 20 h.
To further screen the scope of this route to new enan-
tiopure and highly functionalized 1,2-oxazepine deriva-
tives we investigated the dibromocarbene additions to 1,2-
oxazines either bearing other alkoxy groups or different
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

306
A. Al-Harrasi et al.
PAPER
OR1
the simplicity and flexibility of the method certainly com-
pensates this limitation.
Br
MeO
OR1
Br
OR1
Br
R2
R2
Bn
R2
Bn
a
b
The prepared enantiopure 5-bromo-1,2-oxazepines syn-
and anti-4 should allow smooth access to many interesting
product classes, for example, amino substituted polyols
(heptanose derivatives) or stereodefined piperidines. The
presence of a bromoalkenyl moiety, however, makes
these intermediates also ideal precursors for palladium-
catalyzed coupling reactions. First, 1,2-oxazepine deriva-
tive syn-4b was selected to examine Sonogashira cross-
coupling reactions11 and subjected to the standard proto-
col with phenylacetylene using 5 mol% Pd(OAc)2, Ph3P,
CuI, and diisopropylamine as base (Table 1). This proce-
dure proved to be successful and hence phenylacetylene
was cross-coupled to bromo derivative syn-4b to afford
the disubstituted alkyne syn-5 in 95% yield.
N
O
N
N
Bn
O
O
1
3
4
Br
Br
OR
O
O
OR
MeO
O
O
Br
N
N
O
Bn
Bn
O
R = Me
syn-3c
syn-4c
51%
33%, dr = 60:40
Br
Br
OR
O
O
OR
MeO
O
O
Br
Table 1 summarizes additional transformations employ-
ing anti-4b as precursor, demonstrating that
Sonogashira11 or Suzuki reaction12 provide compounds
such as anti-5, anti-6, and anti-7, respectively, in excel-
lent yields. Gratifyingly, Stille13 and Heck couplings14 to
1,2-oxazepine anti-4b also took place smoothly furnish-
ing 1,3-dienes anti-8 and anti-9 with very good efficacy.
These compounds should be interesting partners for
Diels–Alder reactions, which may lead to novel enan-
tiopure skeletons incorporating a 1,2-oxazepine ring.
Thus, structurally highly diverse compounds should be
accessible by this route.
N
N
R = Bn
O
Bn
49%, dr = 55:45
Bn
O
syn-3d
54%, dr = 82:18
syn-4d
Br
O
O
OR
MeO
Br
OR
O
O
O
O
O
Br
O
N
N
O
R = TMSE
Bn
O
Bn
syn-4e
58%, dr = 60:40
syn-3e
35%, dr = 60:40
Arabinose-derived 5-bromo-1,2-oxazine anti-4f also un-
derwent smooth palladium-catalyzed transformations as
demonstrated by the synthesis of Suzuki-coupling product
anti-10 and the phenylalkynyl substituted compound anti-
11 obtained by Sonogashira reaction (Scheme 7). Without
any optimization the yields for these couplings were in the
range of 65%. All these examples demonstrate that the
scope of the chain-elongation of carbohydrate derivatives
Br
O
O
O
OR
MeO
Br
OR
O
O
O
Br
O
N
N
O
O
Bn
O
Bn
R = Me
anti-4f
74%
anti-3f
46%, dr = 70:30
Scheme 6 Synthesis of various 5-bromo-1,2-oxazepines anti- and
syn-4. Reagents and conditions: a) CHBr3, 50% aq NaOH, KF,
Et3BnNCl, r.t., 2 d; b) K2CO3, MeOH, reflux, 20 h.
O
O
O
OR
O
OR
MeO
MeO
Ph
O
O
Br
a
chiral side chains at C-3 (Scheme 6). Thus, the O-cyclo-
hexylidene derivative syn-4c was available as desired via
dibromocyclopropane syn-3c. The related benzyloxy sub-
stituted compound syn-3d smoothly underwent ring en-
largement to the expected 5-bromo-1,2-oxazepine
derivative syn-4d with one diastereomer clearly predomi-
nating in this case. Finally, two D-arabinose-derived 1,2-
oxazines were subjected to the two-step sequence. The
syn-configured precursor provided cyclopropane deriva-
tive syn-3e only in low yield, but the transformation to the
5-bromo-1,2-oxazepine syn-4e proceeded quite efficient-
ly (58%). The related anti-configured intermediate anti-3f
was obtained in 46% yield and converted into the ring-
enlarged heterocycle anti-4f in a remarkably good yield of
74%. These examples clearly demonstrate that the devel-
oped two-step method for the preparation of enantiopure
O
Bn
O
N
N
PhB(OH)2
O
O
Bn
anti-4f
anti-10
68%
R = Me
Ph
O
O
O
OR
O
OR
MeO
MeO
O
O
Br
b
O
Bn
O
N
O
N
Ph
O
Bn
anti-4f
anti-11
63%
R = Me
Scheme 7 Cross-coupling reactions of D-arabinose-derived 5-bro-
mo-1,2-oxazepine anti-4f leading to substituted 1,2-oxazepines anti-
10,11. Reagents and conditions: a) Pd(OAc)2 (5 mol%), Ph3P (0.2
5-bromo-1,2-oxazepine derivatives apparently has a fairly equiv), K2CO3 (1.5 equiv), DMF, 70 °C, 12 h; b) Pd(OAc)2 (5 mol%),
Ph3P (0.2 equiv), CuI (5 mol%), i-Pr2NH, DMF, r.t., 10 h.
broad scope. Although the yield are often only moderate
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

PAPER
Enantiopure 5-Bromo-1,2-oxazepines
307
Table 1 Cross-Coupling Reactions of syn-4b and anti-4b Leading to Substituted 1,2-Oxazepines 5–9a
RO
O
O
RO
RO
RO
O
O
Br
R
N
N
Bn
Bn
R = Me
O
O
4b
5–9
1,2-Oxazepine Reagent
Conditions
a
Product
Yield
95%
Ph
O
O
RO
RO
RO
O
O
syn-4b
syn-5
Ph
N
Bn
O
Ph
RO
anti-4b
anti-4b
a
a
anti-5
anti-6
95%
72%
Ph
N
Bn
O
O
MeO
RO
RO
O
OMe
N
Bn
O
O
RO
RO
O
anti-4b
anti-4b
anti-4b
b
c
d
anti-7
anti-8
anti-9
80%
94%
82%
Ph
PhB(OH)2
N
Bn
O
O
RO
RO
O
SnBu3
N
Bn
O
O
RO
RO
O
CO2Me
MeO2C
N
Bn
O
a Reaction conditions: a) Pd(OAc)2 (5 mol%), Ph3P (0.2 equiv), CuI (5 mol%), i-Pr2NH, DMF, r.t., 10 h; b) Pd(OAc)2 (5 mol%), Ph3P (0.2
equiv), K2CO3 (1.5 equiv), DMF, 70 °C, 10 h; c) Pd(OAc)2 (10 mol%), Ph3P (0.2 equiv), DMF, 65 °C, 3 h; d) Pd(OAc)2 (5 mol%), LiCl (3
equiv), Et3N (1 equiv), DMF, 70 °C, 10 h.
Reactions were generally performed under argon in flame-dried
flasks, and the components were added by syringe. Products were
purified by flash chromatography on silica gel (230–400 mesh,
Merck). Unless otherwise stated, yields refer to analytically pure
samples. 1H NMR [CHCl3 (d = 7.26 ppm), TMS (d = 0.00 ppm) as
internal standard] and 13C NMR spectra [CDCl3 (d = 77.0 ppm) as
internal standard] were recorded on Bruker AC 250, DRX 500, or
AV 700 or Joel Eclipse 500 instruments in CDCl3 solutions. Inte-
grals are in accordance with assignments; coupling constants are
given in Hz. Missing signals of minor diastereomers are overlapped
by those of major diastereomers, or they could not be unambiguous-
ly identified due to low intensity. IR spectra were recorded on Nico-
let 5 SXC FTIR spectrometer. MS and HRMS analyses were
following the sequence nitrone, 1,2-oxazine derivative, 5-
bromo-1,2-oxazepine, and coupling product is obviously
very broad and it will hence allow the modification of car-
bohydrates into libraries of interesting compounds in a
most flexible fashion.
In summary, starting from easily available 3,6-dihydro-
2H-1,2-oxazines 1 we have developed a convenient route
to enantiopure 1,2-oxazepine derivatives. First experi-
ments show that palladium-catalyzed couplings smoothly
occur leading to building blocks, which should be highly
suitable for diversity orientated synthesis.15
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

308
A. Al-Harrasi et al.
PAPER
performed with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT 95 (EI,
70 eV), and MAT CH7A (EI, 80 eV, 3 kV) instruments. The ele-
mental analyses were determined using ‘Elemental-Analyzers’
(Perkin-Elmer or Carlo Erba). Melting points were measured with a
Reichert apparatus and are uncorrected. Optical rotations ([a]D)
were determined with a Perkin-Elmer 141 or Perkin-Elmer 241 po-
larimeter at the temperatures given. All other chemicals are com-
mercially available and were used without further purification.
oxazine derivative anti-3b (232 mg, 64%, dr = 68:32). The diaste-
reomers could be separated by HPLC (hexane–EtOAc, 8:1).
anti-3b (Major Diastereomer)
Colorless crystals; [a]D22 +22.0 (c 1.0, CHCl3).
IR (KBr): 3090–3050 (=C–H), 2990–2940 (C–H), 1060 cm–1 (C–
O–C).
1H NMR (500 MHz, CDCl3): d = 1.36, 1.43 (2 s, 3 H each, CH3),
2.03 (d, J = 5.0 Hz, 1 H, 1-H), 3.72 (s, 3 H, OCH3), 3.50 (d, J = 14.8
Hz, 1 H, NCH2Ph), 3.72 (d, J = 11.7 Hz, 1 H, 2-H), 3.83 (d, J = 2.2
Hz, 1 H, 5-H), 4.08 (dd, J = 5.0, 11.7 Hz, 1 H, 2-H), 4.14 (t, J = 7.6
Hz, 1 H, 5¢-H), 4.18 (t, J = 7.6 Hz, 1 H, 5¢-H), 4.35 (d, J = 14.8 Hz,
1 H, NCH2Ph), 4.87 (dt, J = 2.2, 7.6 Hz, 1 H, 4¢-H), 7.13–7.29 (m,
5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = 23.5, 26.0 (2 q, CH3), 30.7 (d,
C-1), 40.1 (s, C-7), 57.0 (q, OCH3), 59.1 (t, NCH2Ph), 63.9 (s, C-5¢),
64.1 (t, C-2), 65.0 (t, C-5), 66.6 (s, C-6), 74.3 (d, C-4¢), 108.0 (s, C-
2¢), 126.8, 128.1, 128.2, 139.4 (3 d, s, C6H5).
(5S,4¢S)-4-Benzyl-7,7-dichloro-5-(2¢,2¢-dimethyl-1¢,3¢-dioxolan-
4¢-yl)-6-[2-(trimethylsilyl)ethoxy]-3-oxa-4-azabicyclo[4.1.0]-
heptane (syn-2a)
Aqueous solution of NaOH (50%, 3 mL) was added to a vigorously
stirred solution of 1,2-oxazine syn-1a (300 mg, 0.780 mmol) in
CHCl3 (3 mL) containing BnEt3NCl (4.0 mg). The reaction mixture
was stirred at r.t. overnight, then diluted with H2O (5 mL), and ex-
tracted with CH2Cl2 (3 × 5 mL) to give 273 mg of the crude product.
This was purified by column chromatography (silica gel, hexane–
EtOAc, 16:1) to yield colorless crystals of syn-2a 140 mg (56%) as
a mixture of diastereomers (65:35); mp 59–61 °C.
MS (EI, 80 eV, 80 °C): m/z (%) = 477 (M+ <1), 462 (M+ – Me, 3),
,
IR (KBr): 3085–3030 (=CH), 2895–2870 (C–H), 1060 cm–1 (C–O).
+
476 (M+ – C5H9O2, 9), 101 (C5H9O2 , 63), 91 (CH2Ph+, 100).
Anal. Calcd for C18H23Br2NO4 (477.2): C, 45.31; H, 4.86; N, 2.94.
Found: C, 45.77; H, 5.04; N, 2.91.
Major Diastereomer
1H NMR (500 MHz, CDCl3): d = 0.05 [s, 9 H, Si(CH3)3], 0.90–1.20
(m, 2 H, CH2Si), 1.36, 1.44 (2 s, 3 H each, CH3), 2.08 (dd, J = 3.3,
9.0 Hz, 1 H, 1-H), 3.42–3.98 (m, 1 H, 5-H), 3.47 (dt, J = 7.2, 9.2 Hz,
1 H, OCH2), 3.60 (d, J = 15.1 Hz, 1 H, CH2Ph), 3.76 (dt, J = 6.2,
9.2 Hz, 1 H, OCH2), 3.87 (dd, J = 3.3, 12.2 Hz, 1 H, 2-H), 4.17 (dd,
J = 9.0, 12.2 Hz, 1 H, 2-H), 4.24 (dd, J = 6.0, 8.7 Hz, 1 H, 5¢-H),
4.33 (dd, J = 7.0, 8.7 Hz, 1 H, 5¢-H), 4.45–4.48 (m, 1 H, 4¢-H), 4.55
(d, J = 15.1 Hz, 1 H, CH2Ph), 7.29–7.35 (m, 5 H, C6H5).
anti-3b (Minor Diastereomer)
Colorless oil.
IR (film): 3090–3050 (=C–H), 2990–2940 (C–H), 1060 cm–1 (C–
O–C).
1H NMR (500 MHz, CDCl3): d = 1.35, 1.45 (2 s, 3 H each, CH3),
2.14 (dd, J = 3.1, 8.8 Hz, 1 H, 1-H), 3.47 (s, 3 H, OCH3), 3.49 (d,
J = 3.1 Hz, 1 H, 5-H), 3.60 (d, J = 14.5 Hz, 1 H, NCH2Ph), 3.75 (dd,
J = 3.1, 12.2 Hz, 1 H, 2-H), 3.94 (t, J = 8.0 Hz, 1 H, 5¢-H), 4.15 (d,
J = 14.5 Hz, 1 H, NCH2Ph), 4.18 (t, J = 8.0 Hz, 1 H, 5¢-H), 4.25 (dd,
J = 8.8, 12.2 Hz, 1 H, 2-H), 4.77 (dt, J = 3.1, 8.0 Hz, 1 H, 4¢-H),
7.23–7.34 (m, 5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = –1.3 [q, Si(CH3)3], 18.3 (t,
CH2Si), 26.2, 26.7 (2 q, CH3), 33.1 (d, C-1), 38.3 (s, C-7), 59.9 (t,
CH2Ph), 63.4 (d, C-4¢), 64.4 (t, C-2), 64.9 (t, OCH2), 65.0 (d, C-5),
66.2 (t, C-5¢), 68.8 (s, C-6), 74.2 (d, C-4¢), 109.1 (s, C-2¢), 126.7,
128.0, 128.1, 138.7 (3 d, s, C6H5).
13C NMR (125.8 MHz, CDCl3): d = 23.5, 26.0 (2 q, CH3), 30.7 (d,
C-1), 40.1 (s, C-7), 57.0 (q, OCH3), 59.1 (t, NCH2Ph), 62.8 (t, C-5),
64.1 (t, C-2), 64.5 (s, C-6), 66.4 (s, C-5¢), 73.6 (d, C-4¢), 108.0 (s, C-
2¢), 126.8, 127.9, 128.1, 137.5 (3 d, s, C6H5).
Minor Diastereomer (Additional Signals)
1H NMR (500 MHz, CDCl3): d = 0.06 [s, 9 H, Si(CH3)3], 1.39, 1.46
(2 s, 3 H each, CH3), 1.83 (br d, J = 5.2 Hz, 1 H, 1-H), 3.53 (d,
J = 8.8 Hz, 1 H), 3.61–3.67, 3.81–3.86 (2 m, 1 H, 3 H), 4.08 (dd,
J = 5.4, 6.6 Hz, 1 H, 5¢-H), 3.90 (d, J = 13.9 Hz, 1 H, CH2Ph), 4.35,
4.49–4.54 (mc, m, 1 H, 2 H).
MS (EI, 80 eV, 80 °C): m/z (%) = 477 (M+, <1), 462 (M+ – Me, 3),
+
476 (M+ – C5H9O2, 9), 101 (C5H9O2 , 63), 91 (CH2Ph+, 100).
13C NMR (125.8 MHz, CDCl3): d = –1.4 [q, Si(CH3)3], 18.2 (t,
CH2Si), 25.6, 26.4 (2 q, CH3), 29.4 (d, C-1), 67.0 (d, C-5), 69.3 (s,
C-6), 109.2 (s, C-2¢), 126.6, 128.03, 128.13, 139.1 (3 d, s, C6H5).
Dibromocarbene Addition to 1,2-Oxazines 1, Followed by Sol-
volysis; General Procedure 1 (GP1)
A solution of NaOH (9 equiv) and KF (2.5 g/mmol) in H2O (2.5 mL/
mmol) was added to a vigorously stirred solution of 1,2-oxazine 1
(1 equiv) in CHBr3 (1.6 mL/ mmol) containing BnEt3NCl (3.5 mg/
mmol). The biphasic mixture was stirred for 2 d at r.t., then diluted
with H2O (5 mL/mmol) and extracted with Et2O (3 × 5 mL/mmol).
The combined Et2O extracts were washed with brine (5 mL/mmol),
dried (Na2SO4), and concentrated. The excess of CHBr3 was re-
moved under high vacuum. The residue was purified by column
chromatography. The resulting diastereomeric mixture of dibro-
mocyclopropanes was refluxed with anhyd K2CO3 (3.8 equiv) in
MeOH (4 mL/mmol) for 20 h under argon. The reaction mixture
was cooled to r.t., diluted with H2O (5 mL/mmol), and extracted
with CH2Cl2 (3 × 5 mL/mmol). The combined organic extracts were
dried (Na2SO4) and concentrated. The product was purified by col-
umn chromatography.
MS (EI, 80 eV, 100 °C): m/z (%) = 474 (M+, <1), 457 (M+ – Me,
+
<1), 400 (M+ – Me3Si, <1), 372 (M+ – C5H9O2, 12), 101 (C5H9O2 ,
+
24), 91 (C7H7 , 100), 73 (C3H9Si+, 75).
Anal. Calcd for C22H33Cl2NO4Si (474.5): C, 55.69; H, 7.01; N, 2.95.
Found: C, 55.18; H, 6.81; N, 2.76.
(1S,5R,6R,4¢S)- and (1R,5R,6S,4¢S)-4-Benzyl-7,7-dibromo-5-
(2¢,2¢-dimethyl-1¢,3¢-dioxolan-4¢-yl)-6-methoxy-3-oxa-4-azabi-
cyclo[4.1.0]heptane (anti-3b)
A solution of NaOH (270 mg) and KF (1.90 g) in H2O (2 mL) was
added to a vigorously stirred solution of 1,2-oxazine anti-1b (230
mg, 0.751 mmol) in CHBr3 (1.2 mL) containing BnEt3NCl (2.5
mg). The biphasic mixture was stirred for 2 d at r.t., then diluted
with H2O (2 mL), and extracted with Et2O (3 × 5 mL). The com-
bined Et2O extracts were washed with brine (5 mL), dried (Na2SO4),
and concentrated. The excess of CHBr3 was removed under high
vacuum. The residue was purified by column chromatography (sil-
ica gel, hexane–EtOAc, 4:1) to give the dibromo-substituted 1,2-
(3R,4¢S)-2-Benzyl-5-bromo-3-(2¢,2¢-dimethyl-1¢,3¢-dioxolan-4¢-
yl)-4-methoxy-4-[2-(trimethylsilyl)ethoxy]-2,3,4,7-tetrahydro-
[1,2]oxazepine (anti-4a)
A solution of NaOH (500 mg) and KF (3.10 g) in H2O (3 mL) was
added to a vigorously stirred solution of anti-1a (490 mg, 1.25
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

PAPER
Enantiopure 5-Bromo-1,2-oxazepines
309
mmol) in CHBr3 (2.1 mL) containing BnEt3NCl (4.2 mg) as de-
scribed in GP1. The resulting residue was purified by column chro-
matography (hexane–EtOAc, 8:1) to give 386 mg (55%,
dr = 65:35) of anti-3a. The diastereomeric mixture of dibromocy-
clopropane derivative anti-3a was refluxed with anhyd K2CO3 (541
mg, 3.92 mmol) in MeOH (7 mL) for 20 h under argon. The product
was purified by column chromatography (silica gel, hexane–
EtOAc, 9:1) to give pure anti-4a in 220 mg (62%) as a colorless oil;
[a]D22 –76.5 (c 0.32, CHCl3).
(3S,4¢S)-2-Benzyl-5-bromo-3-(2¢,2¢dimethyl-1¢,3¢-dioxolan-4¢-
yl)-4-methoxy-4-[2-(trimethylsilyl)ethoxy]-2,3,4,7-tetrahydro-
[1,2]oxazepine (syn-4a)
1,2-Oxazine syn-1a (200 mg, 0.510 mmol) and t-BuOK (170 mg,
1.53 mmol) were suspended in anhyd Et2O (2 mL) at –40 °C fol-
lowed by the dropwise addition of CHBr3 (0.30 mL, 3.38 mmol).
The reaction mixture was warmed slowly to r.t. and stirred over-
night. The residue was purified by column chromatography (hex-
ane–EtOAc, 8:1). The resulting diastereomeric mixture (64:36) of
dibromocyclopropane syn-3a was refluxed with anhyd K2CO3 (880
mg, 0.640 mmol) in MeOH (1 mL) for 12 h under argon as de-
scribed in GP1. The product was purified by column chromatogra-
phy (silica gel, hexane–EtOAc, 9:1) to yield 107 mg (41% from
IR (film): 3090–3030 (=C–H), 2985–2845 (C–H), 1670 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 0.03 [s, 9 H, Si(CH3)3], 0.85–0.98
(m, 2 H, CH2Si), 1.33, 1.34 (2 s, 3 H each, CH3), 3.18 (s, 3 H,
OCH3), 3.34 (d, J = 5.2 Hz, 1 H, 3-H), 3.47 (ddd, J = 6.2, 9.1, 10.7
Hz, 1 H, CH2O), 3.68 (ddd, J = 5.9, 9.1, 10.7 Hz, 1 H, CH2O), 4.06
(dd, J = 6.4, 8.7 Hz, 1 H, 5¢-H), 4.09 (dd, J = 8.1, 8.7 Hz, 1 H, 5¢-H),
4.24–4.28 (m, 2 H, 4¢-H, NCH2Ph), 4.30 (d, J = 11.3 Hz, 1 H,
NCH2Ph), 4.36 (dd, J = 1.3, 13.5 Hz, 1 H, 7-H), 4.44 (d, J = 13.5
Hz, 1 H, 7-H), 6.69 (br s, 1 H, 6-H), 7.20–7.37 (m, 5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = –1.4 [q, Si(CH3)3], 17.8 (t,
CH2Si), 25.8, 26.5 (2 q, CH3), 49.3 (q, OCH3), 58.2 (t, NCH2Ph),
58.4 (t, OCH2), 63.6 (t, C-7), 67.3 (d, C-3), 67.5 (t, C-5¢), 75.0 (d,
C-4¢), 99.2 (s, C-4), 108.3 (s, C-2¢), 108.8 (d, C-6), 127.1, 128.1,
128.2, 138.3 (3 d, s, C6H5), 135.6 (s, C-5).
22
syn-1a) of pure syn-4a as a colorless oil; [a]D +13.0 (c 0.49,
CHCl3).
IR (film): 3090–3030 (=C–H), 2985–2845 (C–H), 1670 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 0.03 [s, 9 H, Si(CH3)3], 0.75–0.98
(m, 2 H, CH2Si), 1.39, 1.40 (2 s, 3 H each, CH3), 3.12 (s, 3 H,
OCH3), 3.37 (d, J = 6.7 Hz, 1 H, 3-H), 3.51–3.57 (m, 2 H, CH2O),
3.75–3.79 (m, 1 H, 5¢-H), 4.01 (d, J = 14.6 Hz, 1 H, CH2Ph), 4.02
(dd, J = 5.4, 8.5 Hz, 1 H, 5¢-H), 4.22 (dd, J = 1.2, 12.8 Hz, 1 H, 7-
H), 4.33 (d, J = 14.6 Hz, 1 H, CH2Ph), 4.50 (ddd, J = 5.1, 5.4, 6.7
Hz, 1 H, 4¢-H), 4.62 (d, J = 12.8 Hz, 1 H, 7-H), 6.58 (br s, 1 H, 6-
H), 7.25–7.40 (m, 5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = –1.4 [q, Si(CH3)3], 17.8 (t,
CH2Si), 26.3, 26.8 (2 q, CH3), 49.3 (q, OCH3), 58.6 (t, OCH2), 59.7
(t, NCH2Ph), 67.2 (t, C-5¢), 67.8 (d, C-3), 68.3 (t, C-7), 73.4 (d, C-
4¢), 99.7 (s, C-2¢), 108.0 (d, C-6), 109.0 (s, C-4), 126.9, 128.1,
128.3, 138.6 (3 d, s, C6H5), 136.9 (s, C-5).
MS (EI, 80 eV, 110 °C): m/z (%) = 515 (M+, <1), 513 (M+, <1), 500
(M+ – Me, 1), 498 (M+ – Me, 1), 442 (M+ – SiMe3, 1), 440 (M+ –
+
SiMe3, 1), 101 (C5H9O2+ 18), 91 (CH2Ph+, 100), 73 (SiMe3 , 74).
HRMS: m/z [M+ – Me] calcd for C22H3079BrNO5Si: 498.1311;
found: 498.1332.
MS (EI, 80 eV, 110 °C): m/z (%) = 513 (M+ <1), 514 (M+ + H, 1),
,
(3R,4¢S)-2-Benzyl-5-bromo-3-(2¢,2¢-dimethyl-1¢,3¢-dioxolan-4¢-
yl)-4,4-dimethoxy-2,3,4,7-tetrahydro[1,2]oxazepine (anti-4b)
A solution of NaOH (600 mg) and KF (4.10 g) in H2O (4 mL) was
added to a vigorously stirred solution of anti-1b (500 mg, 1.64
mmol) in CHBr3 (2.7 mL) containing BnEt3NCl (5.5 mg) as de-
scribed in GP1. The resulting residue was purified by column chro-
matography (hexane–EtOAc, 4:1) to give 511 mg (65%,
dr = 68:32) of anti-3b. The diastereomeric mixture of dibromocy-
clopropane derivative anti-3b was refluxed with anhyd K2CO3 (872
mg, 6.27 mmol) in MeOH (7 mL) for 20 h under argon. The product
was purified by column chromatography (silica gel, hexane–
EtOAc, 9:1) to afford 241 mg (53%) of pure anti-4b as a colorless
oil; [a]D22 –84.2 (c 0.45, CHCl3).
412 (M+ – TMSE, 1), 101 (TMSE+, 17), 91 (CH2Ph+, 53), 73
(Me3Si+, 100).
Anal. Calcd for C23H33BrNO5Si (514.5): C, 53.69; H, 7.05; N, 2.72.
Found: C, 53.11; H, 6.82; N, 2.66.
(3S,4¢S)-2-Benzyl-5-bromo-3-(2,2-dimethyl-1,3-dioxolan-4¢-yl)-
4,4-dimethoxy-2,3,4,7-tetrahydro[1,2]oxazepine (syn-4b)
A solution of NaOH (600 mg) and KF (4.10 g) in H2O (4 mL) was
added to a vigorously stirred solution of syn-1b (500 mg, 1.64
mmol) in CHBr3 (2.7 mL) containing BnEt3NCl (5.5 mg) as de-
scribed in GP1. The resulting residue was purified by column chro-
matography (hexane–EtOAc, 4:1) to give 420 mg (54%,
dr = 70:30) of syn-3b. The diastereomeric mixture of dibromocy-
clopropane syn-3b was refluxed with anhyd K2CO3 (590 mg, 4.28
mmol) in MeOH (7 mL) for 20 h and under argon. The product was
purified by column chromatography (silica gel, hexane–
EtOAc, 9:1) to give pure syn-4b in 185 mg (49%) as a colorless oil;
[a]D22 +21.5 (c 1.3, CHCl3).
IR (film): 3090–3030 (=C–H), 2985–2845 (C–H), 1635 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 1.33, 1.36 (2 s, 3 H each, CH3),
3.19, 3.29 (2 s, 3 H each, OCH3), 3.28 (d, J = 5.6 Hz, 1 H, 3-H), 4.07
(dd, J = 6.4, 8.7 Hz, 1 H, 5¢-H), 4.11 (dd, J = 7.9, 8.7 Hz, 1 H, 5¢-H),
4.29 (mc, 1 H, 4¢-H), 4.30, 4.34 (2 d, J = 14.0 Hz, 1 H each,
NCH2Ph), 4.37 (dd, J = 1.1, 13.5 Hz, 1 H, 7-H), 4.47 (d, J = 13.5
Hz, 1 H, 7-H), 6.70 (br s, 1 H, 6-H), 7.24–7.40 (m, 5 H, C6H5).
IR (film): 3090–3030 (=C–H), 2985–2845 (C–H), 1635 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 1.40, 1.405 (2 s, 3 H each, CH3),
3.12, 3.24 (2 s, 3 H each, OCH3), 3.34 (d, J = 6.4 Hz, 1 H, 3-H), 3.76
(dd, J = 8.2, 9.1 Hz, 1 H, 5¢-H), 4.00 (dd, J = 5.5, 8.2 Hz, 1 H, 5¢-H),
4.03 (d, J = 14.9 Hz, 1 H, NCH2Ph), 4.21 (dd, J = 1.5, 12.8 Hz, 1 H,
7-H), 4.35 (d, J = 14.9 Hz, 1 H, NCH2Ph), 4.43–4.53 (m, 1 H, 4¢-H),
4.62 (d, J = 12.8 Hz, 1 H, 7-H), 6.59 (br s, 1 H, 6-H), 7.20–7.43 (m,
5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = 26.3, 26.5 (2 q, CH3), 49.2, 49.4
(2 q, OCH3), 59.5 (t, NCH2Ph), 66.7 (d, C-3), 67.0 (t, C-5¢), 68.8 (t,
C-7), 72.9 (d, C-4¢), 99.5 (s, C-4), 107.4 (d, C-6), 108.3 (s, C-2¢),
126.8, 128.1, 128.3, 138.6 (3 d, s, C6H5), 136.3 (s, C-5).
13C NMR (125.8 MHz, CDCl3): d = 25.7, 26.3 (2 q, CH3), 49.0, 49.1
(2 q, OCH3), 58.1 (t, NCH2Ph), 63.6 (t, C-7), 66.7 (d, C-3), 67.2 (t,
C-5¢), 74.9 (d, C-4¢), 99.2 (s, C-4), 108.5 (d, C-6), 108.9 (s, C-2¢),
127.1, 128.2, 128.6, 138.0 (3 d, s, C6H5), 135.3 (s, C-5).
MS (EI, 80 eV, 100 °C): m/z (%) = 429 (M+, 1), 427 (M+, 1), 414
(M+ – Me, 1), 412 (M+ – Me, 1), 398 (M+ – OMe, <1), 396 (M+ –
OMe, <1), 329 (M+ – C5H9O2, 6), 327 (M+ – C5H9O2, 6), 91
(CH2Ph+, 100).
HRMS: m/z [M+] calcd for C19H2679BrNO5: 427.0994; found:
427.0995.
MS (EI, 80 eV, 130 °C): m/z (%) = 429 (M+, <1), 427 (M+, <1), 414
Anal. Calcd for C19H26BrNO5 (428.3): C, 53.28; H, 6.12; N, 3.27.
Found: C, 53.10; H, 5.91; N, 2.68.
(M+ – Me, 2), 412 (M+ – Me, 2), 329 (M+ – C5H9O2, 18), 327 (M+ –
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

310
A. Al-Harrasi et al.
PAPER
C5H9O2, 18), 194 (C6H9O281Br+, 61), 192 (C6H9O279Br+, 62), 91
(CH2Ph+, 100).
HRMS: m/z [M+] calcd for C19H2679BrNO5: 427.0994; found:
syn-3d
1H NMR (400 MHz, CDCl3): d = 1.32, 1.35, 1.38, 1.44 (4 s, 1.65 H,
1.65 H, 1.35 H, 1.35 H, CH3), 2.05 (d, J = 5.2 Hz, 0.55 H, 1-H), 2.25
(dd, J = 4, 8.5 Hz, 0.45 H, 1-H), 3.54–3.69, 3.77–3.90, 4.11–4.39,
4.55–4.79 (4 m, 2 H, 2 H, 4 H, 3 H), 7.22–7.41 (m, 10 H, C6H5).
427.0957.
Anal. Calcd for C19H26BrNO5 (428.3): C, 53.28; H, 6.12; N, 3.27.
Found: C, 53.22; H, 6.12; N, 3.20.
syn-4d (Major Isomer)
IR (film): 3090–3030 (=C–H), 2985–2895 (C–H), 1635 cm–1
(C=C).
(3S,4¢S)-2-Benzyl-5-bromo-3-(1¢,4¢-dioxaspiro[4.5]dec-2¢-yl)-
4,4-dimethoxy-2,3,4,7-tetrahydro[1,2]oxazepine (syn-4c)
According to GP1, syn-1c (0.371 g, 1.07 mmol) and BnEt3NCl (7
mg) in CHBr3 (2.7 mL) was treated with NaOH (380 mg) and KF
(2.71 g) in H2O (4 mL). The resulting residue was purified by col-
umn chromatography (hexane–EtOAc, 4:1) to give 182 mg (33%,
dr = 60:40) of syn-3c. Then syn-3c (95 mg, 0.183 mmol) was re-
fluxed with anhyd K2CO3 (152 mg, 1.10 mmol) in MeOH (3 mL)
for 20 h under argon. Purification by column chromatography (sili-
ca gel, hexane–EtOAc, 4:1) gave 43 mg (51%) of syn-4c as a pale
yellow oil; [a]D22 –14.0 (c 0.15, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.35, 1.39 (2 s, 3 H each, CH3),
3.15 (s, 3 H, OCH3), 3.47 (d, J = 6.5 Hz, 1 H, 3-H), 3.87 (dd, J = 8.4,
8.8 Hz, 1 H, 5¢-H), 3.99 (dd, J = 5.6, 8.4 Hz, 1 H, 5¢-H), 4.07 (d,
J = 14.8 Hz, 1 H, NCH2Ph), 4.29 (dd, J = 1.4, 12.9 Hz, 1 H, 7-H),
4.37 (d, J = 14.8 Hz, 1 H, NCH2Ph), 4.52–4.69 (m, 4 H, 4¢-H, 7-H,
OCH2Ph), 6.67 (br s, 1 H, 6-H), 7.23–7.47 (m, 10 H, C6H5).
1H NMR (400 MHz, CDCl3): d (additional data for the minor isomer
of syn-4d) = 1.40, 1.43 (2 s, 3 H each, CH3), 3.30 (s, 3 H, OCH3),
3.43 (d, J = 6.8 Hz, 1 H, 3-H), 3.80 (dd, J = 8.5, 8.8 Hz, 1 H, 5¢-H),
4.15 (dd, J = 1.5, 12.8 Hz, 1 H, 7-H), 6.71 (br s, 1 H, 6-H).
syn-3c
13C NMR (125.8 MHz, CDCl3): d = 26.2, 26.3*, 26.6*, 26.7 (4 q,
CH3), 49.5, 49.8* (2 q, OCH3), 59.5 (t, NCH2Ph), 63.2, 63.7* (2 d,
C-3), 66.7*, 67.0*, 67.2, 67.4 (4 t, C-5¢, OCH2Ph), 68.9 (t, C-7),
73.02, 73.08* (2 d, C-4¢), 100.1 (s, C-4), 107.46, 107.48* (2 s, C-
2¢), 108.3, 108.8* (2 d, C-6), 126.9*, 127.0, 127.5*, 127.8, 128.0,
128.1*, 128.2, 128.3, 128.4, 128.5, 128.55*, 137.4, 137.7*, 138.5,
138.7* (11 d, 4 s, C6H5), 136.5, 136.7* (2 s, C-5). Signals of the
minor diastereomer are marked with *.
1H NMR (400 MHz, CDCl3): d = 1.33–1.75 (m, 10 H, CH2), 1.94 (d,
J = 5.2 Hz, 0.6 H, 1-H), 2.13 (dd, J = 3.5, 8.5 Hz, 0.4 H, 1-H), 3.39
(s, 1.2 H, OCH3), 3.42–3.46 (m, 1 H, 5-H), 3.52 (s, 1.8 H, OCH3),
3.56, 3.64 (2 d, J = 15.0 Hz, 1 H each, NCH2Ph), 3.74 (dd, J = 3.6,
12.4 Hz, 0.4 H, 2-H), 3.79 (br d, J = 11.9 Hz, 0.6 H, 2-H), 3.83–
3.92, 4.05–4.15, 4.19–4.29, 4.36–4.47, 4.58–4.66 (5 m, 1 H, 1H, 2
H, 1 H, 1 H), 7.20–7.40 (m, 5 H, C6H5).
13C NMR (100.6 MHz, CDCl3): d = 25.2, 25.3*, 35.3, 35.8*, 36.1,
36.4* (6 t, CH2), 31.2, 33.4* (2 d, C-1), 38.7*, 40.7 (2 s, C-7), 57.0
(q, OCH3), 60.0, 60.2* (2 t, NCH2Ph), 63.8*, 64.1 (2 s, C-6), 65.0*,
65.7, 66.6*, 68.4 (4 t, C-5, C-2), 65.7*, 67.0 (2 s, C-5¢), 73.9, 74.3*
(2 d, C-4¢), 109.9*, 110.0 (2 s, C-2¢), 126.8, 128.2, 128.3, 138.8*,
139.0 (3 d, 2 s, C6H5). Signals of the minor diastereomer are marked
with *.
HRMS: m/z [M + Na+] calcd for C25H3081BrNO5 + Na: 528.1185;
found: 528.1194.
(3S,4¢S,5¢R,4¢¢R)-2-Benzyl-5-bromo-3-(2¢,2¢,2¢¢,2¢¢-tetramethyl-
[4¢,4¢¢]bi[1¢,3¢-dioxolanyl]-5¢-yl)-4-methoxy-4-[2-(trimethyl-
silyl)ethoxy]-2,3,4,7-tetrahydro[1,2]oxazepine (syn-4e)
According to GP1, syn-1e (0.344 g, 0.727 mmol) and BnEt3NCl (6
mg) in CHBr3 (2.3 mL) was treated with NaOH (260 mg) and KF
(1.83 g) in H2O (2 mL). The resulting residue was purified by col-
umn chromatography (hexane–EtOAc, 8:1) to give 163 mg (35%,
dr = 60:40) of syn-3e. Then syn-3e (91 mg, 0.137 mmol) was re-
fluxed with anhyd K2CO3 (114 mg, 0.831 mmol) in MeOH (2.5 mL)
for 20 h under argon. Purification by column chromatography (sili-
ca gel, hexane–EtOAc, 4:1) gave 49 mg (58%, dr = 60:40) of syn-
4e as a colorless resin.
syn-4c
IR (film): 3090–3030 (=C–H), 2935–2860 (C–H), 1635 cm–1
(C=C).
1H NMR (400 MHz, CDCl3): d = 1.23–1.75 (m, 10 H, CH2), 3.13,
3.24 (2 s, 3 H each, OCH3), 3.34 (br d, J = 6.9 Hz, 1 H, 3-H), 3.74
(dd, J = 8.4, 9.3 Hz, 1 H, 3¢-H), 4.02 (dd, J = 5.4, 8.4 Hz, 1 H, 3¢-H),
4.05 (d, J = 15.1 Hz, 1 H, NCH2Ph), 4.22 (dd, J = 1.3, 12.8 Hz, 1 H,
7-H), 4.39 (d, J = 15.1 Hz, 1 H, NCH2Ph), 4.48 (ddd, J = 5.4, 6.9,
9.3 Hz, 1 H, 2¢-H), 4.64 (d, J = 12.8 Hz, 1 H, 7-H), 6.58 (br s, 1 H,
6-H), 7.22–7.46 (m, 5 H, C6H5).
13C NMR (100.6 MHz, CDCl3): d = 24.1, 24.2, 25.2, 35.7, 36.3 (5 t,
CH2), 49.3, 49.4 (2 q, OCH3), 59.8 (t, NCH2Ph), 66.8 (t, C-3¢), 67.2
(d, C-3), 68.9 (t, C-7), 72.4 (d, C-2¢), 99.6 (s, C-4), 108.1 (s, C-5¢),
108.2 (d, C-6), 126.8, 128.1, 128.2, 138.8 (3 d, s, C6H5), 136.3 (s,
C-5).
syn-3e
1H NMR (400 MHz, CDCl3): d = 0.04, 0.05 [2 s, 9 H, Si(CH3)3],
0.96–1.10 (m, 2 H, SiCH2), 1.34, 1.37*, 1.39, 1.41*, 1.44*, 1.48*,
1.55 (7 s, 12 H, CH3), 2.06 (d, J = 5.0 Hz, 0.6 H, 1-H), 2.13 (dd,
J = 1.5, 7.2 Hz, 0.4 H, 1-H), 3.58–3.75, 3.91–4.34 (2 m, 3 H, 8.4 H),
4.39 (d, J = 13.5 Hz, 0.6 H, NCH2Ph), 7.21–7.38 (m, 5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = –1.4*, –1.37 [2 q, Si(CH3)3],
18.4 (t, CH2Si), 25.3, 25.6*, 26.3*, 26.8, 26.85*, 26.9, 27.4, 27.6*
(8 q, CH3), 31.5 (d, C-1), 42.3 (s, C-7), 58.34, 58.41* (2 t, NCH2Ph),
63.6 (d, C-5), 64.2 (t, C-2), 65.5 (s, C-6), 66.8 (t, C-5¢¢), 67.6 (t,
OCH2), 77.1, 77.8 (2 d, C-4¢¢, C-5¢), 79.9 (d, C-4¢), 109.6, 109.9 (2
s, C-2¢, C-2¢¢), 126.8, 128.1, 128.2, 128.6*, 138.6 (4 d, s, C6H5). Sig-
nals of the minor diastereomer are marked with *.
HRMS: m/z [M + Na+] calcd for C22H3081BrNO5 + Na: 492.1185;
found: 492.1192.
(3S,4¢S)-2-Benzyl-4-benzyloxy-5-bromo-3-(2,2-dimethyl-1,3-di-
oxolan-4¢-yl)-4-methoxy-2,3,4,7-tetrahydro[1,2]oxazepine (syn-
4d)
According to GP1, syn-1d (0.626 g, 1.64 mmol) and BnEt3NCl (10
mg) in CHBr3 (5.2 mL) was treated with NaOH (589 mg) and KF
(4.16 g) in H2O (5 mL). The resulting residue was purified by col-
umn chromatography (hexane–EtOAc, 4:1) to give 442 mg (49%,
dr = 55:45) of syn-3d as a pale yellow oil. Then syn-3d (100 mg,
0.180 mmol) was refluxed with anhyd K2CO3 (150 mg, 1.09 mmol)
in MeOH (3 mL) for 20 h under argon. Purification by column chro-
matography (silica gel, hexane–EtOAc = 4:1) gave 49 mg (54%,
dr = 82:18) of syn-4d as a colorless oil.
syn-4e
IR (film): 3090–3040 (=C–H), 2990–2895 (C–H), 1630 cm–1
(C=C).
1H NMR (250 MHz, CDCl3): d = 0.03*, 0.05 [2 s, 9 H, Si(CH3)3],
0.83–1.05 (m, 2 H, SiCH2), 1.20*, 1.255, 1.26, 1.29*, 1.33*, 1.36,
1.40, 1.45* (8 s, 12 H, CH3), 3.16, 3.17* (2 s, 3 H, OCH3), 3.19*,
3.36 (2 mc, 1 H, 3-H), 3.38–3.79, 3.85–4.25, 4.30–4.65 (3 m, 3 H, 5
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

PAPER
Enantiopure 5-Bromo-1,2-oxazepines
311
H, 3 H, 7-H), 6.60, 6.77* (2 br s, 0.6 H, 0.4 H, 6-H), 7.21–7.48 (m,
5 H, C6H5).
Sonogashira Cross-Coupling Reactions of 1,2-Oxazepines 4;
General Procedure 2 (GP2)
A reaction flask containing 1,2-oxazepine derivative 4 (1 equiv),
Ph3P (0.2 equiv), Pd(OAc)2 (5 mol%), and CuI (5 mol%) was de-
gassed and filled with argon. DMF (5 mL/mmol) and i-Pr2NH (2.5
mL/mmol) were added followed by an alkyne (1.2–1.7 equiv). After
stirring at r.t. for 10 h, the mixture was diluted with H2O (8 mL/
mmol) and extracted with Et2O (3 × 5 mL/mmol). The combined or-
ganic extracts were washed with H2O (5 mL/mmol) and brine (5
mL/mmol), dried (Na2SO4), and concentrated to dryness.
13C NMR (100.6 MHz, CDCl3): d = –1.38, –1.34* [2 q, Si(CH3)3],
17.6*, 17.9 (2 t, CH2Si), 25.3, 25.7*, 26.3*, 26.4*, 26.5, 27.0, 27.1*,
27.5 (8 q, CH3), 48.84*, 48.87 (2 q, OCH3), 57.1*, 57.9, 58.5*, 59.7
(4 t, NCH2Ph, OCH2), 63.6, 63.8* (2 t, C-7), 65.4, 67.5* (2 d, C-3),
67.9 (t, C-5¢¢), 75.5*, 76.6, 77.5, 77.7, 77.8*, 79.1* (6 d, C-4¢, C-4¢¢,
C-5¢), 98.9, 99.2* (2 s, C-4), 107.1, 109.7* (2 d, C-6), 108.8*, 109.1,
109.3*, 110.1 (4 s, C-2¢, C-2¢¢), 127.0, 127.4, 128.26, 128.33, 128.6,
129.1, 137.6*, 138.7 (6 d, 2 s, C6H5), 135.3*, 136.0 (2 s, C-5). Sig-
nals of the minor diastereomer are marked with *.
(3S,4¢S)-2-Benzyl-4,4-dimethoxy-3-(2¢,2¢-dimethyl-1¢,3¢-diox-
olan-4¢-yl)-5-phenylethynyl-2,3,4,7-tetrahydro[1,2]oxazepine
(syn-5)
HRMS: m/z [M + Na+] calcd for C28H4479BrNO7 + Na: 636.1968;
found: 636.1947.
A reaction flask containing syn-4b (50 mg, 0.117 mmol), Ph3P (6.2
mg, 0.024 mmol), Pd(OAc)2 (1.3 mg, 0.006 mmol), and CuI (1.1
mg, 0.006 mmol) was degassed and filled with argon. DMF (0.54
mL) and i-Pr2NH (0.27 mL) were added followed by phenylacety-
lene (14 mg, 0.140 mmol) as described in GP2. The residue was pu-
rified by column chromatography (silica gel, hexane–EtOAc, 9:1)
to afford pure syn-5 (50 mg, 95%) as a colorless oil; [a]D22 +192.4
(c 0.53, CHCl3).
(3R,4¢S,5¢R,4¢¢R)-2-Benzyl-5-bromo-3-(2¢,2¢,2¢¢,2¢¢-tetramethyl-
[4¢,4¢¢]bi[1¢,3¢-dioxolanyl]-5¢-yl)-4,4-dimethoxy-2,3,4,7-tetra-
hydro[1,2]oxazepine (anti-4f)
According to GP1, anti-1f (1.05 g, 2.58 mmol) and BnEt3NCl (9
mg) in CHBr3 (4.7 mL) was treated with NaOH (940 mg) and KF
(6.50 g) in H2O (7 mL). The resulting residue was purified by col-
umn chromatography (hexane–EtOAc, 4:1) to give 692 mg (46%,
dr = 70:30) of anti-3f as colorless crystals; mp 136–139 °C. Then,
anti-3f (682 mg, 1.18 mmol) was refluxed with anhyd K2CO3 (622
mg, 4.44 mmol) in MeOH (8 mL) for 22 h under argon. Purification
by column chromatography (silica gel, hexane–EtOAc, 4:1) gave
465 mg (74%) of anti-4f as a colorless resin; [a]D22 +130.5 (c 0.3,
CHCl3).
IR (film): 3080–3030 (=C–H), 2985–2850 (C–H), 1685, 1600 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 1.40, 1.41 (2 s, 3 H each, CH3),
3.15, 3.28 (2 s, 3 H each, OCH3), 3.43 (d, J = 6.9 Hz, 1 H, 3-H), 3.80
(dd, J = 8.5, 9.1 Hz, 1 H, 5¢-H), 4.06 (d, J = 13.8 Hz, 1 H, NCH2Ph),
4.07 (mc, 1 H, 5¢-H), 4.38 (d, J = 13.8 Hz, 1 H, NCH2Ph), 4.40 (mc,
1 H, 7-H), 4.54 (ddd, J = 5.5, 6.9, 9.1 Hz, 1 H, 4¢-H), 4.82 (d,
J = 12.8 Hz, 1 H, 7-H), 6.15 (s, 1 H, 6-H), 7.24–7.47 (m, 10 H,
C6H5).
13C NMR (125.8 MHz, CDCl3): d = 26.4, 26.6 (2 q, CH3), 49.2, 49.4
(2 q, OCH3), 59.6 (t, NCH2Ph), 67.4 (t, C-5¢), 67.5 (d, C-3), 68.4 (t,
C-7), 73.1 (d, C-4¢), 84.4 (s, C≡C), 96.6 (s, C-4), 98.3 (s, C≡C),
107.4 (s, C-2¢), 109.1 (d, C-6), 122.8 (s, C-5), 126.8, 128.1, 128.2,
128.3, 128.5, 131.4, 138.8, 143.5 (6 d, 2 s, C6H5).
anti-3f
1H NMR (250 MHz, CDCl3): d = 1.34, 1.35, 1.40, 1.43, 1.52, 1.54
(6 s, 12 H, CH3), 2.08–2.10 (m, 1 H, 1-H), 3.56 (s, 3 H, OCH3),
3.59–3.76 (m, 1 H), 3.78 (d, J = 14.0 Hz, 1 H, NCH2Ph), 3.87–4.19
(m, 5 H), 4.27 (d, J = 14.0 Hz, 1 H, NCH2Ph), 4.37 (dd, J = 3.9, 7.1
Hz, 0.3 H, 4¢-H), 4.45–4.53 (m, 0.7 H, 4¢-H), 7.19–7.39 (m, 5 H,
C6H5).
13C NMR (100.6 MHz, CDCl3): d = 25.5*, 25.6, 26.5, 26.76*, 26.8,
27.1*, 27.2, 27.3* (8 q, CH3), 31.6, 31.8* (2 d, C-1), 41.55*, 41.6
(2 s, C-7), 57.2 (q, OCH3), 57.2 (t, NCH2Ph), 62.1*, 62.2 (2 d, C-5),
65.3 (s, C-6), 65.6, 66.1* (2 t, C-2), 67.3*, 67.6 (2 t, C-5¢¢), 76.9,
77.3* (2 d, C-4¢¢), 78.2, 78.6 (2 d, C-4¢, C-5¢), 109.1, 109.9 (2 s, C-
2¢, C-2¢¢), 127.0, 127.05*, 128.0*, 128.1, 128.4, 137.5, 137.55* (5
d, 2 s, C6H5). Signals of the minor diastereomer are marked with *.
MS (EI, 80 eV, 90 °C): m/z (%) = 449 (M+, 3), 434 (M+ – Me, 2),
348 (M+ – C5H9O2, 5), 214 (100), 91 (CH2Ph+, 30).
HRMS: m/z [M+] calcd for C27H31NO5: 449.2202; found: 449.2219.
Anal. Calcd for C27H31NO5 (449.6): C, 72.14; H, 6.95; N, 3.12.
Found: C, 71.44; H, 6.67; N, 2.93.
Anal. Calcd for C23H31Br2NO6 (577.3): C, 47.85; H, 5.41; N, 2.43.
Found: C, 47.66; H, 5.44; N, 2.49.
(3R,4¢S)-2-Benzyl-4,4-dimethoxy-3-(2¢,2¢-dimethyl-1¢,3¢-diox-
olan-4¢-yl)-5-phenylethynyl-2,3,4,7-tetrahydro[1,2]oxazepine
(anti-5)
anti-4f
IR (film): 3090–3035 (=C–H), 2985–2890 (C–H), 1630 cm–1
(C=C).
A reaction flask containing anti-4b (50 mg, 0.117 mmol), Ph3P (6.2
mg, 0.024 mmol), Pd(OAc)2 (1.3 mg, 0.006 mmol), and CuI (1.1
mg, 0.006 mmol) was degassed and filled with argon. DMF (0.54
mL) and i-Pr2NH (0.27 mL) were added followed by phenylacety-
lene (14 mg, 0.140 mmol) as described in GP2. The residue was pu-
rified by column chromatography (silica gel, hexane–EtOAc, 9:1)
to afford pure anti-5 (50 mg, 95%) as a colorless oil; [a]D22 –241.9
(c 0.85, CHCl3).
1H NMR (700 MHz, CDCl3): d = 1.15, 1.36, 1.38, 1.45 (4 s, 3 H
each, CH3), 3.11 (d, J = 7.3 Hz, 1 H, 3-H), 3.18, 3.26 (2 s, 3 H each,
OCH3), 3.74 (dd, J = 7.3, 7.5 Hz, 1 H, 5¢-H), 3.92 (d, J = 7.3 Hz, 2
H, 5¢¢-H), 4.35 (d, J = 13.1 Hz, 1 H, NCH2Ph), 4.40, 4.41 (AB sys-
tem, JAB = 13.0 Hz, 1 H each, 7-H), 4.47 (dt, J = 2.6, 7.3 Hz, 1 H,
4¢-H), 4.49 (d, J = 13.1 Hz, 1 H, NCH2Ph), 4.61 (dd, J = 2.6, 7.5 Hz,
1 H, 4¢¢-H), 6.78 (s, 1 H, 6-H), 7.24–7.26, 7.30–7.33, 7.39–7.42 (3
m, 1 H, 2 H, 2 H, C6H5).
IR (film): 3080–3030 (=C–H), 2985–2835 (C–H), 1685 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 1.35, 1.38 (2 s, 3 H each, CH3),
3.21, 3.31 (2 s, 3 H each, OCH3), 3.33 (d, J = 6.0 Hz, 1 H, 3-H), 4.12
(dd, J = 6.6, 8.8 Hz, 1 H, 5¢-H), 4.15 (dd, J = 7.8, 8.8 Hz, 1 H, 5¢-H),
4.31–4.36 (m, 2 H, NCH2Ph, 4¢-H), 4.39 (d, J = 13.9 Hz, 1 H,
NCH2Ph), 4.57 (dd, J = 1.0, 13.4 Hz, 1 H, 7-H), 4.63 (d, J = 13.4
Hz, 1 H, 7-H), 6.26 (s, 1 H, 6-H), 7.25–7.45 (m, 10 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = 25.7, 26.3 (2 q, CH3), 48.9, 49.1
(2 q, OCH3), 57.8 (t, NCH2Ph), 62.9 (t, C-7), 67.3 (d, C-3), 67.4 (t,
C-5¢), 74.9 (d, C-4¢), 84.4 (s, C≡C), 96.5 (s, C-4), 98.0 (s, C≡C),
13C NMR (176.1 MHz, CDCl3): d = 25.6, 26.15, 26.17, 27.1 (4 q,
CH3), 48.6, 49.1 (2 q, OCH3), 56.9 (t, NCH2Ph), 61.5 (t, C-7), 63.8
(t, C-5¢¢), 66.3 (d, C-3), 75.6 (d, C-4¢¢), 76.6 (d, C-5¢), 77.8 (d, C-4¢),
99.5 (s, C-4), 108.8, 109.2 (2 s, C-2¢, C-2¢¢), 109.7 (d, C-6), 127.3,
128.3, 129.3, 137.2 (3 d, s, C6H5), 134.9 (s, C-5).
HRMS: m/z [M + Na+] calcd for C24H3479BrNO7 + Na: 552.1392;
found: 552.1421.
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

312
A. Al-Harrasi et al.
PAPER
108.5 (s, C-2¢), 109.8 (d, C-6), 122.9 (s, C-5), 127.1, 128.2, 128.3,
128.5, 128.7, 131.4, 138.2, 142.3 (6 d, 2 s, C6H5).
MS (EI, 80 eV, 90 °C): m/z (%) = 425 (M+, 1), 410 (M+ – Me, 2),
190 (100), 91 (CH2Ph+, 56).
MS (EI, 80 eV, 140 °C): m/z (%) = 449 (M+, 3), 434 (M+ – Me, 3),
HRMS: m/z [M+] calcd for C25H31NO5: 425.2202; found: 425.2198.
348 (M+ – C5H9O2, 2), 214 (100), 91 (CH2Ph+, 35).
(3R,4¢S)-2-Benzyl-4,4-dimethoxy-3-(2¢,2¢-dimethyl-1¢,3¢-diox-
olan-4¢-yl)-5-vinyl-2,3,4,7-tetrahydro[1,2]oxazepine (anti-8)
A reaction flask containing anti-4b (40 mg, 0.094 mmol) in DMF
(0.5 mL) was degassed and filled with argon. Ph3P (4.9 mg, 0.019
mmol) and Pd(OAc)2 (2.1 mg, 0.009 mmol) were added followed
by addition of vinyltributyltin (32.8 mg, 0.103 mmol). After stirring
at 65 °C for 3 h, the mixture was taken up in EtOAc (1.5 mL),
washed with H2O (2 × 2 mL) and brine (2 mL). The organic layer
was dried (Na2SO4) and concentrated to dryness. The residue was
purified by column chromatography (silica gel, hexane–
EtOAc, 6:1) to afford pure anti-8 (33 mg, 94%) as a colorless oil;
[a]D22 –99.9 (c 1.36, CHCl3).
HRMS: m/z [M+] calcd for C27H31NO5: 449.2202; found: 449.2197.
(3R,4¢S)-2-Benzyl-4,4-dimethoxy-3-(2¢,2¢-dimethyl-1¢,3¢-diox-
olan-4¢-yl)-5-(3-methoxyprop-1-yn-1-yl)-2,3,4,7-tetrahydro-
[1,2]oxazepine (anti-6)
A reaction flask containing anti-4b (50 mg, 0.117 mmol), Ph3P (6.2
mg, 0.024 mmol), Pd(OAc)2 (1.3 mg, 0.006 mmol), and CuI (1.1
mg, 0.006 mmol) was degassed and filled with argon. DMF (0.54
mL) and i-Pr2NH (0.27 mL) were added followed by methyl prop-
argyl ether (14 mg, 0.200 mmol) as described in GP2. The residue
was purified by column chromatography (silica gel, hexane–
EtOAc, 9:1) to afford pure anti-6 (35 mg, 72%) as a colorless oil;
[a]D22 –148.2 (c 0.66, CHCl3).
IR (film): 3085–3030 (=C–H), 2985–2835 (C–H), 1650, 1605 cm–1
(C=C).
IR (film): 3080–3030 (=C–H), 2985–2835 (C–H), 1685 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 1.32, 1.35 (2 s, 3 H each, CH3),
3.15, 3.29 (2 s, 3 H each, OCH3), 3.30 (s, 1 H, 3-H), 4.04 (dd,
J = 6.4, 8.7 Hz, 1 H, 5¢-H), 4.12 (dd, J = 8.2, 8.7 Hz, 1 H, 5¢-H),
4.29–4.34 (m, 3 H, NCH2Ph, 4¢-H), 4.36 (d, J = 13.2 Hz, 1 H, 7-H),
4.44 (d, J = 13.2 Hz, 1 H, 7-H), 5.28 (d, J = 9.5 Hz, 1 H, 2¢¢-H), 5.42
(d, J = 15.9 Hz, 1 H, 2¢¢-H), 6.52 (dd, J = 9.5, 15.9 Hz, 1 H, 1¢¢-H),
6.53 (s, 1 H, 6-H), 7.21–7.39 (m, 5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = 25.8, 26.3 (2 q, CH3), 48.8, 48.9
(2 q, OCH3), 57.9 (t, NCH2Ph), 60.8 (t, C-7), 67.2 (d, C-3), 67.3 (t,
C-5¢), 75.6 (d, C-4¢), 98.0 (s, C-4), 108.4 (s, C-2¢), 121.0 (t, C-2¢¢),
129.1 (d, C-6), 127.1, 128.2, 128.7, 130.8 (3 d, s, C6H5), 130.3 (d,
C-1¢¢), 138.4 (s, C-5).
1H NMR (500 MHz, CDCl3): d = 1.31, 1.35 (2 s, 3 H each, CH3),
3.15, 3.28, 3.37 (3 s, 3 H each, OCH3), 3.27 (d, J = 6.3 Hz, 1 H, 3-
H), 4.07 (dd, J = 6.7, 8.9 Hz, 1 H, 5¢-H), 4.10 (dd, J = 8.0, 8.9 Hz, 1
H, 5¢-H), 4.21 (mc, 2 H, OCH2), 4.28 (ddd, J = 6.3, 6.7, 8.0 Hz, 1 H,
4¢-H), 4.31, 4.32 (AB system, JAB = 14.0 Hz, 1 H each, NCH2Ph),
4.47, 4.49 (AB system, JAB = 13.5 Hz, 1 H each, 7-H), 6.07 (br s, 1
H, 6-H), 7.24–7.38 (m, 5 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = 25.8, 26.3 (2 q, CH3), 48.9,
49.0, 57.7 (3 q, OCH3), 57.7 (t, NCH2Ph), 60.3 (t, OCH2), 62.8 (t,
C-7), 67.2 (d, C-3), 67.4 (t, C-5¢), 75.0 (d, C-4¢), 81.3, 92.3 (2 s,
C≡C), 97.8 (s, C-4), 108.5 (s, C-2¢), 109.8 (d, C-6), 127.1, 128.2,
128.7, 138.2, 143.0 (3 d, 2 s, C6H5, C-5).
MS (EI, 80 eV, 40 °C): m/z (%) = 375 (M+, 19), 360 (M+ – Me,
100), 344 (M+ – OMe, 42).
MS (EI, 80 eV, 80 °C): m/z (%) = 417 (M+, <1), 402 (M+ – Me, 2),
316 (M+ – C5H9O2, 2), 182 (100), 91 (CH2Ph+, 26).
HRMS: m/z [M+] calcd for C21H29NO5: 375.2046; found: 375.2044.
HRMS: m/z [M+] calcd for C23H31NO6: 417.2152; found: 417.2136.
Anal. Calcd for C21H29NO5 (375.5): C, 67.18; H, 7.79; N, 3.73.
Found: C, 67.61; H, 7.15; N, 3.15.
(3R,4¢S)-2-Benzyl-4,4-dimethoxy-3-(2¢,2¢-dimethyl-1¢,3¢-diox-
olan-4¢-yl)-5-phenyl-2,3,4,7-tetrahydro[1,2]oxazepine (anti-7)
A reaction flask containing anti-4b (50 mg, 0.117 mmol), Ph3P (6.2
mg, 0.024 mmol), and Pd(OAc)2 (1.3 mg, 0.006 mmol), was de-
gassed and filled with argon. DMF (0.54 mL) and K2CO3 (24 mg,
0.176 mmol) were added, followed by phenylboronic acid (16 mg,
0.129 mmol). After stirring at 70 °C for 10 h, the mixture was dilut-
ed with H2O (1.5 mL) and extracted with Et2O (3 × 5 mL). The
combined organic extracts were washed with H2O (5 mL) and brine
(5 mL), dried (Na2SO4), and concentrated to dryness. The residue
was purified by column chromatography (silica gel, hexane–
EtOAc, 9:1) to afford pure anti-7 (40 mg, 80%) as a colorless oil;
[a]D22 –109.0 (c 0.65, CHCl3).
(3R,4¢S)-3-{2-Benzyl-4,4-dimethoxy-3-(2¢,2¢-dimethyl-1¢,3¢-di-
oxolan-4¢-yl)-2,3,4,7-tetrahydro[1,2]oxazepin-5-yl}acrylic Acid
Methyl Ester (anti-9)
A reaction flask containing anti-4b (80 mg, 0.187 mmol) in DMF
(0.9 mL) was degassed and filled with argon. LiCl (24 mg, 0.561
mmol) and Et3N (0.03 mL, 0.187 mmol) were added followed by
methyl acrylate (0.013 mL, 0.187 mmol) and Pd(OAc)2 (2.1 mg,
0.009 mmol). After stirring at 70 °C for 10 h, the mixture was taken
up in EtOAc (1.5 mL), washed with H2O (2 × 2 mL) and brine (2
mL). The organic layer was dried (Na2SO4) and concentrated to dry-
ness to give 85 mg of the crude product. This was purified by col-
umn chromatography (silica gel, hexane–EtOAc, 4:1) to afford pure
22
anti-9 (66 mg, 82%) as colorless crystals; mp 102–104 °C; [a]D
–134.4 (c 1.2, CHCl3).
IR (film): 3085–3030 (=C–H), 2985–2840 (C–H), 1600 cm–1
(C=C).
IR (KBr): 3085–3030 (=C–H), 2985–2840 (C–H), 1700 (C=O),
1650, 1615 cm–1 (C=C).
1H NMR (500 MHz, CDCl3): d = 1.35, 1.38 (2 s, 3 H each, CH3),
3.27, 3.36 (2 s, 3 H each, OCH3), 3.41 (d, J = 5.1 Hz, 1 H, 3-H), 4.08
(dd, J = 6.5, 8.5 Hz, 1 H, 5¢-H), 4.19 (dd, J = 8.1, 8.5 Hz, 1 H, 5¢-H),
4.33 (d, J = 14.4 Hz, 1 H, NCH2Ph), 4.38 (d, J = 14.4 Hz, 1 H,
NCH2Ph), 4.43 (ddd, J = 5.1, 6.4, 8.6 Hz, 1 H, 4¢-H), 4.48 (d,
J = 13.3 Hz, 1 H, 7-H), 4.57 (dd, J = 1.0, 13.3 Hz, 1 H, 7-H), 7.07
(br s, 1 H, 6-H), 7.15–7.40 (m, 10 H, C6H5).
13C NMR (125.8 MHz, CDCl3): d = 25.7, 26.3 (2 q, CH3), 48.9, 49.0
(2 q, OCH3), 58.3 (t, NCH2Ph), 62.3 (t, C-7), 67.2 (t, C-5¢), 67.4 (d,
C-3), 75.2 (d, C-4¢), 98.2 (s, C-4), 108.3 (s, C-2¢), 129.8 (d, C-6),
126.9, 127.4, 128.3, 128.5, 128.7, 131.4, 131.8, 135.8, 136.6 (6 d, 3
s, C6H5, C-5).
1H NMR (500 MHz, CDCl3): d = 1.29, 1.33 (2 s, 3 H each, CH3),
3.14, 3.30 (2 s, 3 H each, OCH3), 3.28 (d, J = 6.4 Hz, 1 H, 3-H), 3.74
(s, 3 H, CO2CH3), 4.03 (dd, J = 6.4, 8.7 Hz, 1 H, 5¢¢-H), 4.07 (dd,
J = 7.7, 8.7 Hz, 1 H, 5¢¢-H), 4.25 (td, J = 6.4, 7.7 Hz, 1 H, 4¢¢-H),
4.34, 4.36 (AB system, JAB = 14.0 Hz, 1 H each, NCH2Ph), 4.47,
4.51 (AB system, JAB = 13.5 Hz, 1 H each, 7-H), 6.06 (d, J = 15.1
Hz, 1 H, 6-H), 6.69 (d, J = 12.1 Hz, 1 H, 2¢¢-H), 7.22–7.38 (m, 5 H,
C6H5), 7.46 (dd, J = 12.1, 15.1 Hz, 1 H, 1¢¢-H).
13C NMR (125.8 MHz, CDCl3): d = 25.7, 26.2 (2 q, CH3), 48.9, 51.7
(2 q, COCH3), 57.8 (t, NCH2Ph), 60.6 (t, C-7), 67.2 (d, C-3), 67.4
(t, C-5¢), 74.6 (d, C-4¢), 97.9 (s, C-4), 108.6 (s, C-2¢), 109.8 (d, C-6),
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

PAPER
Enantiopure 5-Bromo-1,2-oxazepines
313
126.0 (d, C-2¢¢), 127.1, 128.2, 128.7, 136.2 (3 d, s, C6H5), 137.9 (d,
C-1¢¢), 139.4 (s, C-5).
Acknowledgment
Generous support of this work by the Deutsche Forschungsgemein-
schaft, the Deutsche Akademische Austauschdienst (fellowship to
A. A.-H.), the Fonds der Chemischen Industrie, and the Bayer Sche-
ring Pharma AG is most gratefully acknowledged. We also thank
Dr. Wolfgang Schade (Technische Universität Dresden) for preli-
minary studies on the dihalocarbene cycloadditions and Valentin
Kunz for his experimental assistance.
MS (EI, 80 eV, 100 °C): m/z (%) = 433 (M+,<1), 418 (M+ – Me, 1),
332 (M+ – C5H9O2, 2), 139 (100), 91 (CH2Ph+, 47).
HRMS: m/z [M+] calcd for C23H31NO7: 433.2101; found: 433.2105.
(3R,4¢S,5¢R,4¢¢R)-2-Benzyl-3-(2¢,2¢,2¢¢,2¢¢-tetramethyl[4¢,4¢¢]-
bi[1¢,3¢-dioxolanyl]-5¢-yl)-4,4-dimethoxy-5-phenyl-2,3,4,7-tet-
rahydro[1,2]oxazepine (anti-10)
According to the preparation of anti-7, anti-4f (166 mg, 0.313
mmol), Ph3P (17 mg, 0.065 mmol), Pd(OAc)2 (3.5 mg, 0.016
mmol), K2CO3 (64 mg, 0.471 mmol), and phenylboronic acid (43
mg, 0.345 mmol) in DMF (1.5 mL) was stirred at 70 °C for 12 h.
After workup, the resulting residue was purified by column chroma-
tography (silica gel, hexane–EtOAc, 4:1) to afford pure anti-10
(112 mg, 68%) as a colorless resin; [a]D22 +85.1 (c 0.21, CHCl3).
References
(1) For a recent review, see: Brasholz, M.; Reissig, H.-U.;
Zimmer, R. Acc. Chem. Res. 2009, 42, 45.
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Reissig, H.-U. Eur. J. Org. Chem. 2005, 1003. For
alternative approaches to synthetically very versatile 1,2-
oxazines, see: (d) Zimmer, R.; Reissig, H.-U. Angew.
Chem., Int. Ed. Engl. 1988, 27, 1518; Angew. Chem. 1988,
100, 1576. (e) Hippeli, C.; Zimmer, R.; Reissig, H.-U.
Liebigs Ann. Chem. 1990, 469. (f) Hippeli, C.; Reissig,
H.-U. Liebigs Ann. Chem. 1990, 475. (g) Reissig, H.-U.;
Hippeli, C.; Arnold, T. Chem. Ber. 1990, 123, 2403.
(h) Reissig, H.-U.; Homann, K.; Hiller, F.; Zimmer, R.
Synthesis 2007, 2681. (i) Zimmer, R.; Collas, M.;
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Linder, I.; Reissig, H.-U. Beilstein J. Org. Chem. 2009, 5,
No. 44.
IR (film): 3100–3030 (=C–H), 2990–2840 (C–H), 1600 cm–1
(C=C).
1H NMR (250 MHz, CDCl3): d = 1.17, 1.31, 1.41, 1.42 (4 s, 3 H
each, CH3), 3.21 (d, J = 7.4 Hz, 1 H, 3-H), 3.23, 3.33 (2 s, 3 H each,
OCH3), 3.84–3.97, 4.39–4.53 (2 m, 3 H, 4 H), 4.58 (d, J = 12.7 Hz,
1 H, 7-H), 4.67–4.71 (m, 1 H), 7.15–7.45 (m, 11 H, 6-H, C6H5).
13C NMR (100.6 MHz, CDCl3): d = 25.6, 26.14, 26.19, 27.2 (4 q,
CH3), 48.4, 49.0 (2 q, OCH3), 57.0 (t, NCH2Ph), 59.8 (t, C-7), 63.8
(t, C-5¢¢), 66.7 (d, C-3), 75.6 (d, C-4¢), 77.1, 77.6 (2 d, C-4¢¢, C-5¢),
98.0 (s, C-4), 108.9, 109.3 (2 s, C-2¢, C-2¢¢), 115.3 (d, C-6), 127.3,
127.5, 128.3, 128.4, 128.8, 129.4, 131.4, 135.6, 137.6 (6 d, 3 s,
C6H5, C-5).
HRMS: m/z [M + Na+] calcd for C30H39NO7 + Na: 548.2624; found:
548.2710.
(3) (a) Pulz, R.; Watanabe, T.; Schade, W.; Reissig, H.-U.
Synlett 2000, 983. (b) Pulz, R.; Al-Harrasi, A.; Reissig,
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Al-Harrasi, A.; Pulz, R.; Reissig, H.-U.; Brüdgam, I. Eur. J.
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(3R,4¢S,5¢R,4¢¢R)-2-Benzyl-3-(2¢,2¢,2¢¢,2¢¢-tetramethyl[4¢,4¢¢]-
bi[1¢,3¢-dioxolanyl]-5¢-yl)-4,4-dimethoxy-5-(phenylethynyl)-
2,3,4,7-tetrahydro[1,2]oxazepine (anti-11)
According to GP2, anti-4f (120 mg, 0.227 mmol), Ph3P (16 mg,
0.065 mmol), Pd(OAc)2 (2.4 mg, 0.011 mmol), and CuI (1.8 mg,
0.011 mmol) was degassed and filled with argon. Then, DMF (0.7
mL) and i-Pr2NH (0.4 mL) were added followed by phenylacety-
lene (39 mg, 0.385 mmol). The resulting residue was purified by
column chromatography (silica gel, hexane–EtOAc, 4:1) to afford
23
pure anti-11 (79 mg, 63%) as a colorless resin; [a]D +233.9 (c
0.23, CHCl3).
IR (film): 3090–3030 (=C–H), 2980–2830 (C–H), 1620 cm–1
(C=C).
1H NMR (400 MHz, CDCl3): d = 1.20, 1.35, 1.37, 1.44 (4 s, 3 H
each, CH3), 3.19, 3.29 (2 s, 3 H each, OCH3), 3.20 (d, J = 7.6 Hz, 1
H, 3-H), 3.77 (t, J = 7.4 Hz, 1 H, 4¢-H), 3.91–3.98 (m, 2 H, 5¢-H),
4.35 (d, J = 13.2 Hz, 1 H, NCH2Ph), 4.50 (d, J = 13.2 Hz, 1 H,
NCH2Ph), 4.53 (mc, 1 H, 4¢-H), 4.55 (d, J = 12.8 Hz, 1 H, 7-H),
4.62–4.66 (m, 2 H, 7-H, 4¢¢-H), 6.32 (s, 1 H, 6-H), 7.24–7.35, 7.39–
7.45 (2 m, 6 H, 4 H, C6H5).
13C NMR (100.6 MHz, CDCl3): d = 25.6, 26.21, 26.25, 27.1 (4 q,
CH3), 48.6, 49.1 (2 q, OCH3), 56.9 (t, NCH2Ph), 61.2 (t, C-7), 63.8
(t, C-5¢¢), 67.3 (d, C-3), 75.7 (d, C-4¢¢), 76.7 (d, C-5¢), 77.9 (d, C-4¢),
84.4, 97.9 (2 s, C≡C), 96.5 (s, C-4), 108.8, 109.3 (2 s, C-2¢, C-2¢),
110.6 (d, C-6), 122.8, 127.3, 128.3, 128.5, 129.3, 131.4, 137.5,
141.8 (s, 5 d, 2 s, C6H5, C-5).
HRMS: m/z [M + Na+] calcd for C32H39NO7 + Na: 572.2624; found:
572.2628.
Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York

314
A. Al-Harrasi et al.
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Synthesis 2010, No. 2, 304–314 © Thieme Stuttgart · New York