Convenient syntheses of enantiopure 1,2-oxazin-4-yl nonaflates and phosphates and their palladium-catalyzed cross-couplings

Article abstract of DOI:10.1055/s-0033-1339509

Efficient methods to prepare enantiopure 1,2-oxazin-4-yl nonaflates and phosphates were elaborated. The corresponding 1,2-oxazin-4-ones were transformed into their enolates and then quenched with nonafluorobutanesulfonyl fluoride or diphenyl chlorophosphate to provide the title compounds. Alternatively, the corresponding α-bromo ketones were subjected to Perkow reactions efficiently leading to the respective enol phosphates. A variety of palladium-catalyzed cross-couplings such as Kumada-Corriu, Sonogashira, Heck reactions or borylation reactions were studied, which delivered the expected new 4-substituted 1,2-oxazine derivatives generally in satisfactory yields. A few typical subsequent transformations were studied including a copper-catalyzed [3+2] cycloaddition with a galactose-derived azide. They demonstrate the synthetic potential of the newly prepared enantiopure 4-substituted 1,2-oxazines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339509

2752▌
PAPER
paper
Convenient Syntheses of Enantiopure 1,2-Oxazin-4-yl Nonaflates and
Phosphates and Their Palladium-Catalyzed Cross-Couplings
1,2-Oxazin-4-yl Nonaflates and Phosphates
Nima Moinizadeh, Robby Klemme, Marcus Kansy, Reinhold Zimmer,* Hans-Ulrich Reissig*
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
Received: 14.06.2013; Accepted after revision: 12.07.2013
we explored the enormous synthetic potential of the re-
sulting 3,6-dihydro-2H-1,2-oxazines utilizing their differ-
ent functional groups. The N–O bond, the acetal moiety,
and the enol ether unit allowed us a rapid generation of
Abstract: Efficient methods to prepare enantiopure 1,2-oxazin-4-
yl nonaflates and phosphates were elaborated. The corresponding
1,2-oxazin-4-ones were transformed into their enolates and then
quenched with nonafluorobutanesulfonyl fluoride or diphenyl chlo-
rophosphate to provide the title compounds. Alternatively, the cor- molecular complexity, that is, the synthesis of functional-
ized heterocycles8 and a versatile access to carbohydrate
responding α-bromo ketones were subjected to Perkow reactions
efficiently leading to the respective enol phosphates. A variety of
palladium-catalyzed cross-couplings such as Kumada–Corriu,
mations of 1,2-oxazines of type E into 1,2-oxazin-4-yl
Sonogashira, Heck reactions or borylation reactions were studied,
which delivered the expected new 4-substituted 1,2-oxazine deriv-
atives generally in satisfactory yields. A few typical subsequent
transformations were studied including a copper-catalyzed [3+2]
cycloaddition with a galactose-derived azide. They demonstrate the
synthetic potential of the newly prepared enantiopure 4-substituted
1,2-oxazines.
and peptide mimetics.9,10 Herein, we report the transfor-
nonaflates and phosphates and their subsequent palladi-
um-catalyzed cross-coupling reactions. A few transfor-
mations of the resulting 4-substituted 1,2-oxazine
derivatives are also described demonstrating the synthetic
potential of these new compounds in organic synthesis.
Key words: 1,2-oxazines, nonaflates, enol phosphates, cross-cou-
R
R
pling reaction, amino alcohol, triazoles
R
R
R
R
R
R
R
refs 1,2
N
O
+
N
O
1,2-Oxazines are valuable synthetic intermediates for the
construction of a variety of functionalized nitrogen-con-
taining compounds. Therefore, considerable efforts have
been directed to their synthesis and to transformations of
this versatile class of heterocycles. A number of methods
has been developed and the most common strategies syn-
thesizing 1,2-oxazines involve hetero-Diels–Alder reac-
tions using suitably functionalized nitroso intermediates,
either nitroso compounds as dienophiles1,2 or in situ gen-
erated nitrosoalkenes as heterodiene components3,4
(Scheme 1). These straightforward hetero-Diels–Alder re-
actions leading to 1,2-oxazines of type A or B were re-
cently supplemented by three different [3+3] strategies
employing nitrones as CNO-providing unit. The Lewis
acid promoted cycloaddition of donor-acceptor cyclopro-
panes to nitrones, as developed by Kerr et al.,5 is a new
method that led stereoselectively to C and that was al-
ready used in natural product synthesis. Doyle and co-
workers recently developed a Rh-catalyzed vinylcarbene
addition to nitrones providing densely functionalized 1,2-
oxazine derivatives D whose subsequent chemistry has
not been studied in detail.6 In 1999 our group discovered
a highly flexible approach for the construction of enantio-
pure 3,6-dihydro-2H-1,2-oxazines of type E by a stereo-
divergent [3+3] cyclization of lithiated alkoxyallenes with
carbohydrate-derived and other nitrones.7 Subsequently,
R
R
A
R
R
O
R
R
R
R
refs 3,4
+
+
N
N
R
O
B
RO2C CO2R
R
RO2C CO2R
R
ref 5
N
N
O
R
R
O
R
R
C
CO2R
OTBS
R
R
R
R
TBSO
R
ref 6
R
CO2R
+
N
N
O
O
N2
D
RO
R
R
R
R
RO
refs 7,8
+
•
N
N
O
O
E
Scheme 1 [4+2] and [3+3] strategies for the synthesis of 1,2-oxazine
derivatives.
SYNTHESIS 2013, 45, 2752–2762
Advanced online publication: 06.08.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
We previously reported the preparation of syn- and anti-
configured 1,2-oxazin-4-ones 3 by a two-step procedure
DOI: 10.1055/s-0033-1339509; Art ID: SS-2013-T0413-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,2-Oxazin-4-yl Nonaflates and Phosphates
2753
(Scheme 2).11 First, the electrophilic bromination of 3,6-
dihydro-2H-1,2-oxazines 1 with N-bromosuccinimide
gave 5-bromo derivatives 2 or 4, which were then subject-
ed to a debromination reaction either using Raney-
nickel12 or tris(trimethylsilyl)silane under standard condi-
tions,13 to afford the desired ketones syn- or anti-3 in good
overall yields.
BnO
O
O
O
O
O
O
O
a (43%)
N
N
or b (59%)
Bn
Bn
syn-5
syn-3
Scheme 3 Hydrogenolysis of 4-benzyloxy-1,2-oxazine syn-5 lead-
ing to syn-3. Reagents and conditions: a) H2, Pd (5%)/Al2O3, MeOH,
r.t., 8 h; b) Pd-black, cyclohexene, MeOH, EtOAc, reflux, 2 h.
MeO
O
O
O
O
O
b
O
O
O
Br
a
quant
anti-3 the 1,2-oxazine anti-6 was obtained in moderate
yield.
N
N
N
or c
85%
(1:1)
O
Bn
O
Bn
O
Bn
76%
syn-1
2
syn-3
O
O
NfO
O
O
O
O
MeO
O
a
O
O
O
O
b
O
O
O
Br
a
74%
N
N
75%
O
Bn
Bn
or c
N
N
N
O
Bn
84%
(1:1)
O
Bn
O
Bn
92%
syn-3
syn-6
anti-1
4
anti-3
O
O
NfO
O
Scheme 2 Conversion of D-glyceraldehyde-derived 1,2-oxazines
syn-1 and anti-1 into 1,2-oxazin-4-ones syn-3 and anti-3. Reagents
and conditions: a) NBS, MeCN, H2O, –40 °C, 1 h, then –40 °C to
10 °C, 3 h; b) Raney-Ni, THF, r.t., 1.5 h; c) (TMS)3SiH, AIBN, tolu-
ene, 75 °C, 2 h. NBS = N-bromosuccinimide.
O
O
a
N
O
N
61%
Bn
O
Bn
anti-3
anti-6
Scheme 4 Nonaflation of 1,2-oxazin-4-ones syn- and anti-3 leading
to 4-nonafloxy-substituted 1,2-oxazines syn- and anti-6. Reagents
and conditions: a) i. LHMDS, THF, –40 °C, 3 h; ii. NfF, –78 °C to r.t.,
overnight. NfF: nonafluorobutanesulfonyl fluoride, LHMDS: lithium
hexamethyldisilazide.
The direct synthesis of ketones 3 by acid-promoted hydro-
lysis of the enol ether units is not possible since the ace-
tonide moieties are cleaved considerably faster.14 In order
to find alternative one-pot procedures leading to 3 we sub-
jected the 4-benzyloxy-substituted 1,2-oxazine syn-515 to
hydrogenolysis catalyzed by palladium on alumina in
methanol (Scheme 3). After chromatographic purification
the expected ketone syn-3 was isolated in 43% yield. In
addition, the conversion of syn-5 to syn-3 was carried out
by means of transfer hydrogenolysis conditions. Treat-
ment of syn-5 with palladium black in the presence of cy-
clohexene in a refluxing methanol–ethyl acetate mixture
furnished the desired product syn-3 in reasonable yield.
We conclude from the results presented in Schemes 2 and
3 that the one-pot protocols are generally less time-con-
suming and produce less waste, but at present large scale
preparations of 3 are more efficiently performed via the
two-step process due to the excellent yields in both single
steps. In addition, the methoxy-substituted 1,2-oxazines
are produced with higher cost-efficacy due to the easy ac-
cessibility of methoxyallene in large quantities.
A useful alternative to enol nonaflates could be the corre-
sponding enol phosphates allowing their use as compo-
nents in transition-metal-catalyzed cross-couplings.18 It is
known that enol phosphates often display greater stability
than the corresponding perfluoroalkylsulfonates, more-
over, they are generally prepared using lower cost re-
agents. Deprotonation of syn-3 with LDA followed by
treatment of the generated enolate with 1.1 equivalents of
diphenyl chlorophosphate at –78 °C19 furnished 1,2-oxa-
zin-4-yl phosphate syn-7a as a single product in moderate
yield (Scheme 5). An attempt to increase the yield of syn-
7a using 1.5 equivalents of HMPA as additive was not
successful.20 Strikingly two products are formed and iso-
lated under these conditions, with the expected enol phos-
phate syn-7a being the major component. The isolated by-
product is proposed to be the 3,4,5,6-tetrahydro-2H-1,2-
oxazine derivative 8.21
With 1,2-oxazin-4-ones 3 in hand, we first performed the
nonaflation of these carbonyl compounds.16 A brief sur-
vey of the nonaflation showed that the deprotonation of
syn-3 using LHMDS as base at –40 °C in THF followed
by an addition of 10 equivalents of nonafluorobutanesul-
fonyl fluoride (NfF)17 as nonaflating reagent at –78 °C
improved the yield of the desired product syn-6 to 75%
yield (Scheme 4). Applying these optimized conditions to
Alternatively, the synthesis of enol phosphates may also
be achieved through a Perkow reaction with α-bromo-sub-
stituted ketones as precursors.18a,22 We therefore exam-
ined 2 and 4 in this transformation (Scheme 6). A clean
reaction occurred upon treatment of 5-bromo-1,2-oxazine
2 with 1.1 equivalents of trimethyl phosphite at room tem-
perature for one day giving the desired syn-configured
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2752–2762

2754
N. Moinizadeh et al.
PAPER
O
of PdCl2(PPh3)2 in refluxing THF provided the 4-phenyl-
substituted 1,2-oxazine derivative syn-9 in only 30% yield
(Scheme 7). Under ligand-free PdCl2-catalyzed
conditions25 no better result was observed and the expect-
ed product syn-9 was obtained in 25% yield.
O
O
(PhO)2PO
O
O
O
O
(PhO)2P OH
O
O
a or b
+
N
N
O
N
O
O
Bn
Bn
Bn
syn-3
syn-7a
8
O
Ph
O
O
method A:
method B:
48%
37%
0%
14%
(PhO)2PO
O
O
O
a (30%)
b (25%)
Scheme 5 Conversion of 1,2-oxazin-4-one syn-3 into 1,2-oxazin-4-
yl phosphate syn-7a. Reagents and conditions: a) Method A: i. LDA,
THF, –78 °C, 1 h, ii. (PhO)2POCl (1.1 equiv), THF, –78 °C, 1.5 h; b)
Method B: i. LDA, THF, –78 °C, 1 h, ii. HMPA (1.5 equiv), iii.
(PhO)2POCl (1.5 equiv), THF, –78 °C, 2 h.
N
N
Bn
O
Bn
syn-7a
syn-9
Scheme 7 Kumada–Corriu coupling of 1,2-oxazin-4-yl phosphate
syn-7a leading to 4-phenyl-1,2-oxazine derivative syn-9. Reagents
and conditions: a) PhMgCl, PdCl2(PPh3)2, THF, reflux, 2 d; b) PhMgBr,
PdCl2, THF, 50 °C, overnight.
enol phosphate 7b in 85% yield after purification by chro-
matography. In addition 15% of starting material 2 was
isolated as a single diastereomer, which could be identi-
fied as enantiopure (5R)-223 indicating that the two C-5
epimers of 2 show fairly different reaction rates in the
Perkow reaction. When this reaction was performed with
an increased amount of phosphite (2.2–2.5 equiv) and pro-
longed reaction times (3–4 d), complete conversion was
observed and the expected products were formed almost
quantitatively (96% syn-7b; 90% syn-7c). The reaction of
anti-configured 5-bromo-1,2-oxazine derivative 4 with
triethyl phosphite provided the expected enol phosphate
anti-7c in significantly lower yield (49%).
To our delight, the Kumada–Corriu coupling could be ef-
ficiently improved under microwave conditions.26 As
shown in Scheme 8, 1,2-oxazine syn-7c and PhMgCl or
4-MeOC6H4MgBr reacted cleanly in the presence of
Pd(PPh3)4 under microwave irradiation affording syn-9
and syn-10, respectively, in 46–57% yield. A control ex-
periment carried out with syn-7c and PhMgCl gave a sig-
nificantly lower yield (35%) of the expected compound
syn-9, indicating that conventional heating in THF under
reflux for one day is less efficient.27 Diastereomer anti-7c
was also exposed to the microwave-assisted coupling con-
ditions and it furnished the corresponding 4-aryl-substi-
tuted anti-9 and anti-10 in moderate yields (55–64%).
Attempts to carry out the Kumada–Corriu reaction with
nickel catalysts28 were disappointingly unsatisfactory;
they gave the expected 4-aryl-substituted 1,2-oxazines in
less than 10% yield.27
O
(RO)2PO
O
O
O
O
O
a
Br
N
b: R = Me 85% (96%)
c: R = Et 72% (90%)
N
O
Bn
O
Bn
2
syn-7b,c
R
O
O
a
(EtO)2PO
O
O
O
O
(EtO)2PO
O
O
O
O
O
Br
9: R = H
10: R = OMe 46%
57%
a
N
N
N
N
49%
O
Bn
O
Bn
O
Bn
O
Bn
syn-7c
syn-9,10
4
anti-7c
Scheme 6 Preparation of 1,2-oxazin-4-yl phosphates syn- and anti-
7. Reagents and conditions: a) P(OMe)3 or P(OEt)3, CH2Cl2, r.t., 1 d
(the yields given in brackets refer to the longer reaction times of 3–4
d).
R
O
a
(EtO)2PO
O
O
O
O
With the aim of preparing a series of 4-substituted 3,6-di-
hydro-2H-1,2-oxazines, we next focused our attention on
the functionalization of nonaflates 6 and enol phosphates
7 using palladium-catalyzed cross-coupling reactions. Ini-
tially, we adopted two reported protocols of Begtrup24 and
Skrydstrup25 describing the use of enol phosphates in pal-
ladium-catalyzed Kumada–Corriu couplings. Treatment
of syn-7a with phenylmagnesium chloride in the presence
9: R = H
10: R = OMe 55%
64%
N
N
O
Bn
O
Bn
anti-7c
anti-9,10
Scheme 8 Kumada–Corriu couplings of 1,2-oxazin-4-yl phosphates
7c leading to 4-aryl-substituted 1,2-oxazine derivatives 9 and 10. Re-
agents and conditions: a) PhMgCl or 4-MeOC6H4MgBr, Pd(PPh3)4,
THF, microwave irradiation, 50 °C, 30 min.
Synthesis 2013, 45, 2752–2762
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,2-Oxazin-4-yl Nonaflates and Phosphates
2755
Alkenyl and (hetero)aryl nonaflates are well established with trimethylsilylacetylene (11) under standard Sono-
components in a variety of palladium-catalyzed transfor- gashira conditions29,30 afforded the 4-(trimethylsilyl)ethy-
mations.16 Therefore, we tested one of the 1,2-oxazin-4-yl nyl-1,2-oxazine derivative syn-12 in good yield (Scheme
nonaflates as substrate in the Kumada–Corriu coupling 10). Under these conditions the coupling of anti-6 with
(Scheme 9). Gratifyingly, nonaflate syn-6 and 4- TIPS-acetylene (13) cleanly provided 1,2-oxazine anti-14
MeOC6H4MgBr in the presence of PdCl2(PPh3)2 reacted in similarly good yield (79%). The densely functionalized
even at room temperature smoothly affording the cross- imidazolyl-substituted alkyne 1531 gave the expected anti-
coupling product syn-10 in 61% yield. Surprisingly, the 16 in lower yield (49%).
Suzuki coupling of syn-6 with phenylboronic acid under
standard conditions provided syn-9 in only 46% yield.
nished the expected product syn-17 in 75% yield and a
The Heck-coupling of syn-6 with tert-butyl acrylate fur-
second compound in 6% yield (Scheme 11). The isolated
OMe
by-product was identified as the pyrrole derivative 18; its
formation can be explained in analogy to Kerr et al.5d
through a base-induced ring-opening of syn-17 followed
NfO
O
O
O
by a ring contraction and dehydration of a dihydropyrrole
intermediate.32 Alkenyl boronate reagents as required for
Suzuki–Miyaura reactions can be prepared by Pd-cata-
lyzed cross-couplings of alkenyl halides or perfluoroal-
kylsulfonates with suitable boron reagents, for example,
bis(pinacolato)diboron [B2(pin)2].33 The borylation of
syn-6 with B2(pin)2 under typical reaction conditions34 led
to the formation of 1,2-oxazin-4-yl boronic ester syn-19 in
good yield (Scheme 11). The installed new functional
groups of syn-17 or syn-19 should make these products to
very useful substrates for diversity oriented synthesis of
N,O-heterocycles. Possible subsequent reactions are
[4+2] cycloadditions, Michael additions, or Suzuki–
Miyaura cross-couplings leading to a variety of new 1,2-
oxazine derivatives.
O
O
a
N
N
61%
Bn
O
Bn
syn-6
syn-10
Scheme 9 Kumada–Corriu coupling of 1,2-oxazin-4-yl nonaflate
syn-6 leading to syn-10. Reagents and conditions: a) 4-
MeOC6H4MgBr, PdCl2(PPh3)2, THF, r.t., overnight.
We also employed the 1,2-oxazin-4-yl nonaflates as pre-
cursors for other palladium-catalyzed reactions and were
pleased to observe that the coupling of nonaflate syn-6
SiMe3
SiMe3
NfO
O
O
O
11
CO2t-Bu
CO2t-Bu
O
O
a
O
NfO
O
O
N
N
O
O
80%
Bn
O
Bn
a
O
+
N
syn-6
syn-12
N
N
O
O
Bn
Bn
Bn
Si(i-Pr)3
syn-17 (75%)
syn-6
18 (6%)
Si(i-Pr)3
NfO
O
O
O
13
O
O
a
N
N
O
O
79%
Bn
O
Bn
NfO
O
B
O
O
O
O
b
anti-6
anti-14
N
N
70%
Bn
O
Bn
Ph
N
Ph
syn-6
syn-19
Ph
N
Ph
N
Scheme 11 Heck-reaction and borylation of 1,2-oxazin-4-yl nona-
flate syn-6. Reagents and conditions: a) tert-butyl acrylate (1.5
equiv), Pd(OAc)2, LiCl, Et3N, DMF, 70 °C, overnight; b) B2(pin)2
(2.4 equiv), PdCl2(PPh3)2, KOPh, Ph3P, toluene, 60 °C, 2 h.
N
NfO
O
O
15
O
O
a
N
N
49%
O
Bn
O
Bn
The prepared new 4-aryl- and 4-alkynyl-substituted 1,2-
oxazine derivatives are versatile building blocks which
should be transformable into a variety of nitrogen-con-
taining compounds. Schemes 12 and 14 illustrate typical
examples. Among the established reactions of 1,2-oxa-
zines, hydrogenolysis is an often used option to generate
anti-6
anti-16
Scheme 10 Sonogashira couplings of 1,2-oxazin-4-yl nonaflates 6
leading to 4-alkynyl-substituted 1,2-oxazine derivatives syn-12, anti-
14, and anti-16. Reagents and conditions: a) alkyne 11, 13, or 15 (1.1–
1.5 equiv), PdCl2(PPh3)2, CuI, Et3N, toluene, r.t., overnight.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2752–2762

2756
N. Moinizadeh et al.
PAPER
new compound classes, for example, 1,4-amino alcohols
or pyrrolidine derivatives.3,4b,7–9 We therefore briefly ex-
amined the reductions of 4-phenyl-substituted 1,2-oxa-
zine syn-9 under earlier established conditions. Using
palladium on charcoal as catalyst 3-phenyl-1,4-amino al-
cohol derivative 20 was isolated in 59% yield as 85:15-
mixture of two diastereomers 20a,b. On the other hand,
the hydrogenolysis of syn-10 with the less reactive Raney-
nickel as catalyst furnished a mixture of allyl alcohol 21
as major product in 35% yield and the 1,4-amino alcohol
derivative 22 as second component in 17% yield. Accord-
ing to our previously published results35 for hydrogenoly-
ses of 4-methoxy-substituted 2H-1,2-oxazines like syn-1
with both catalyst systems, we assume that the major dia-
stereomers of 20a and 22 have the configurations at C-2
as depicted in Scheme 12.
Ar
O
O
O
N
Bn
A
Palladium on
charcoal
Raney-Nickel
H2
H2
Ar
Ar
O
H
O
O
O
N
HN
O
HO
Bn
B
21
H2
H2
Ph
O
Ph
Ph
O
O
O
O
O
a
Ar
Ar
O
O
+
O
O
N
NH2
NH2
59%
O
Bn
HO
HO
N
NHBn
22
(Ar = 4-MeOC6H4)
syn-9
20a
(85:15)
20b
O
H
HO
D
Ar
Ar
Ar
O
O
O
O
O
+
O
b
H2
(Ar = Ph)
N
NHBn
NHBn
O
Bn
HO
HO
Ph
O
syn-10
21 (35%)
22 (17%)
O
Scheme 12 Reductive ring openings of 4-aryl-1,2-oxazines syn-9
and syn-10: Reagents and conditions: a) H2, Pd(10%)/C, MeOH, r.t.,
overnight; b) H2, Raney-Ni, MeOH, r.t., overnight. Ar = 4-MeOC6H4.
NH2
HO
20
Scheme 13 Proposed mechanisms for the reductive ring openings of
4-aryl-1,2-oxazines depending on the catalyst used.
The dependence of product distribution on the catalyst
used revealed that different reaction mechanisms are op-
erating for the hydrogenolysis processes. As shown in
Scheme 13, the hydrogenolysis of syn-configured 1,2-ox-
azine A with palladium on charcoal very likely starts
with a fast debenzylation, followed by the reduction of the
C-4/C-5 double bond in B. The hydrogen attacks mainly
from the less hindered site (trans to the fairly bulky 3-di-
oxolanyl moiety) and generates intermediate D, which af-
ter cleavage of the N–O bond leads to the amino alcohol
20.36,37 In contrast, the hydrogenolysis of compounds A
with Raney-nickel first opens the N–O bond leading to 21.
A subsequent C=C-bond reduction of this intermediate
generates amino alcohol 22.
(Scheme 14). To our surprise, the subsequent reduction of
the triazole-linked carbohydrate–1,2-oxazine conjugate
23 in isopropanol under hydrogen atmosphere primarily
led to product 25 in moderate yield together with 20% of
reisolated starting material 23. No final N–O bond cleav-
age occurred to form the corresponding amino alcohol,
which apparently requires harsher conditions. The config-
uration at C-4 of the 1,2-oxazine ring of 25 was assigned
in analogy to earlier examples.
We could demonstrate in this report that enantiopure 1,2-
oxazin-4-yl nonaflates and phosphates are easily available
by straightforward methods. Their palladium-catalyzed
couplings allow the syntheses of a great variety of differ-
ently 4-substituted 1,2-oxazine derivatives, which are not
available by alternative methods and hence expand the
scope of heterocycles of this type for subsequent transfor-
mations. In three exemplary reactions (reductions and
click reaction) we demonstrated the potential of the new
4-substituted 1,2-oxazine derivatives for the synthesis of
complex enantiopure products.
Heterocycles such as anti-14 bearing an alkynyl substitu-
ent at C-4 position are versatile candidates for addition re-
actions and further synthetic transformations. For
example, deprotection with tetra-n-butylammonium fluo-
ride (TBAF) of anti-14 gave the corresponding 4-ethynyl-
substituted intermediate, which on reaction with the ga-
lactose-derived azide 2438 under typical conditions for
copper-catalyzed [3+2] cycloadditions39 furnished the 4-
(triazol-4-yl)-substituted compound 23 in 72% yield
Synthesis 2013, 45, 2752–2762
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,2-Oxazin-4-yl Nonaflates and Phosphates
2757
IR (neat): 3110–2850 (=C–H, C–H), 1685 (C=C), 1240, 1225, 1200
cm–1 (C–F).
TIPS
Bn
N
O
Ph
1H NMR (CDCl3, 500 MHz): δ = 1.35, 1.37 (2 s, 3 H each, CH3),
3.64 (br d, J ≈ 5.5 Hz, 1 H, 3-H), 3.84 (dd, J = 7.3, 9.1 Hz, 1 H, 5′-
H), 4.01–4.09 (m, 2 H, CH2Ph, 5′-H), 4.15 (d, J = 13.7 Hz, 1 H,
CH2Ph), 4.25 (dd, J = 3.7, 17.3 Hz, 1 H, 6-H), 4.45–4.57 (m, 2 H,
4′-H, 6-H), 6.08–6.10 (m, 1 H, 5-H), 7.28–7.45 (m, 5 H, C6H5).
O
O
O
O
O
O
a, b
O
N
N
N
AcO
72% (2 steps)
N
O
Bn
OAc
13C NMR (CDCl3, 125.8 MHz): δ = 25.6, 26.0 (2 q, CH3), 57.9 (t,
CH2Ph), 62.0 (d, C-3), 63.2 (t, C-6), 66.0 (t, C-5′), 75.1 (d, C-4′),
109.0 (s, CMe2), 117.8 (d, C-5), 127.6, 128.4, 128.8, 136.1 (3 d, s,
C6H5), 143.8 (s, C-4).
anti-14
23
c
35% (dr = 88:12)
19F NMR (CDCl3, 470 MHz): δ = –80.6 (CF3), –109.4, –120.7,
–125.8 (3 CF2).
Ph
H
N
O
O
MS (EI, 80 eV, 30–50 °C): m/z (%) = 573 (M+, 20), 472 (M –
O
Ph
O
O
+
+
C5H9O2 , 48), 290 (19), 210 (28), 101 (C5H9O2 , 23), 91 (Bn+, 100).
O
O
O
N3
AcO
HRMS (80 eV): m/z calcd for C20H20F9NO6S: 573.0868; found:
573.0848.
O
OAc
N
N
N
AcO
OAc
24
(3R,4′S)-2-Benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-4-
(nonafluorobutane-1-sulfonyloxy)-3,6-dihydro-2H-1,2-oxazine
(anti-6)
25
A soln of 1,2-oxazin-4-one anti-3 (0.200 g, 0.686 mmol) in THF (2
mL) was added to an LHMDS soln (1 M in THF, 1.03 mL, 1.03
mmol) at –40 °C under an argon atmosphere. After 3 h, the mixture
was cooled to –78 °C and NfF (0.61 mL, 3.43 mmol) was added.
The mixture was allowed to warm to r.t. overnight. It was then
quenched with sat. aq NH4Cl soln (10 mL) and the aqueous phase
was extracted with EtOAc (3 × 5 mL). The combined organic phas-
es were dried (Na2SO4), filtered, and the solvent was removed under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, hexanes–EtOAc, 6:1) to yield nonaflate anti-6
Scheme 14 Synthesis of galactose-conjugates 23 and 25. Reagents
and conditions: a) TBAF (1.05 equiv), THF, 1.5 h, r.t.; b) azide 24,
CuI, Et3N, TBTA, MeCN, r.t., overnight; c) H2, Pd (10%)/C, i-PrOH,
r.t., overnight. TBTA = tris[(1-benzyl)methyl]amine.
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 and Macherey & Nagel). Unless otherwise stated, yields re-
fer to analytically pure samples. 1H NMR [CHCl3 (δ = 7.26), TMS
(δ = 0.00) as internal standard] and 13C NMR spectra [CDCl3
(δ = 77.0) as internal standard] were recorded with Bruker AC 250,
DRX 500, or AV 700 or Jeol Eclipse 500 instruments in CDCl3 so-
lutions. Integrals are in accordance with assignments; coupling con-
stants are given in Hz. Missing signals of minor diastereomers are
overlapped by those of major diastereomers, or they could not be
unambiguously identified due to low intensity. IR spectra were re-
corded on a Nicolet 5 SXC FTIR spectrophotometer. MS and
HRMS analyses were 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 elemental analyses were recorded with ‘Elemen-
tal-Analyzers’ (Perkin-Elmer or Carlo Erba). Melting points were
measured with a Reichert apparatus or according to Boëtius with a
Rapido apparatus and are uncorrected. Optical rotations ([α]D) were
determined with Perkin-Elmer 141 or Perkin-Elmer 241 polarimeters
at the temperatures given. All other chemicals are commercially
available and were used without further purification.
21
(0.243 g, 61%) as a colorless viscous oil; [α]D –64.6 (c 0.55,
CHCl3).
IR (ATR): 3035–2850 (=C–H, C–H), 1690 (C=C), 1240, 1230,
1200 cm–1 (C–F).
1H NMR (CDCl3, 400 MHz): δ = 1.32, 1.35 (2 s, 3 H each, CH3),
3.17 (dd, J = 2.0, 8.4 Hz, 1 H, 3-H), 3.74 (dd, J = 5.4, 8.8 Hz, 1 H,
5′-H), 3.99, 4.13 (2 d, J = 13.0 Hz, 1 H each, CH2Ph), 3.74 (dd,
J = 6.4, 8.8 Hz, 1 H, 5′-H), 4.34 (dd, J = 3.4, 17.2 Hz, 1 H, 6-H),
4.45 (ddd, J = 5.4, 6.4, 8.4 Hz, 1 H, 4′-H), 4.60 (td, J = 2.1, 17.2 Hz,
1 H, 6-H), 6.07 (dd, J = 2.1, 3.4 Hz, 1 H, 5-H), 7.28–7.40 (m, 5 H,
C6H5).
13C NMR (CDCl3, 125.8 MHz): δ = 25.1, 26.3 (2 q, CH3), 57.0 (t,
CH2Ph), 61.1 (t, C-6), 62.4 (d, C-3), 68.3 (t, C-5′), 76.9 (d, C-4′),
110.3 (s, CMe2), 115.8 (d, C-5), 128.1, 128.7, 129.1, 135.9 (3 d, s,
C6H5), 145.3 (s, C-4).
19F NMR (CDCl3, 470 MHz): δ = –80.5 (CF3), –109.5, –120.8,
–125.7 (3 CF2).
HRMS (ESI-TOF): m/z calcd for C20H20F9NO6S + Na [M + Na]+:
596.0760; found: 596.0788.
(3S,4′S)-2-Benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-4-
(nonafluorobutane-1-sulfonyloxy)-3,6-dihydro-2H-1,2-oxazine
(syn-6)
(3S,4′S)-Dimethyl [2-Benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-
4′-yl)-3,6-dihydro-2H-1,2-oxazin-4-yl]phosphate (syn-7b)
5-Bromo-1,2-oxazine 2 (3.33 g, 9.00 mmol) and P(OMe)3 (1.2 mL,
9.99 mmol) were dissolved in CH2Cl2 (80 mL) under an argon at-
mosphere and the mixture was stirred at r.t. for 1 d. The solvent and
all volatile components were removed under reduced pressure and
the residue was purified by column chromatography (silica gel, hex-
anes–EtOAc, 3:1 to 1:2) to give enol phosphate syn-7b (3.08 g,
85%) and the diastereomerically pure (5R,3S,4′S)-2 (0.460 g, 15%).
A soln of 1,2-oxazin-4-one syn-3 (0.200 g, 0.686 mmol) in THF (2
mL) was added to an LHMDS soln (1 M in THF, 1.03 mL, 1.03
mmol) at –40 °C under an argon atmosphere. After 3 h, the mixture
was cooled to –78 °C and NfF (0.61 mL, 3.43 mmol) was added.
The mixture was allowed to warm to r.t. overnight. It was then
quenched with sat. aq NH4Cl soln (10 mL) and the aqueous phase
was extracted with EtOAc (3 × 5 mL). The combined organic phas-
es were dried (Na2SO4), filtered, and the solvent was removed under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, hexanes–EtOAc, 6:1) to yield nonaflate syn-6
5-Bromo-1,2-oxazine 2 (1.62 g, 4.36 mmol) and P(OMe)3 (1.4 mL,
11.7 mmol) in CH2Cl2 (45 mL) was stirred at r.t. under an argon at-
mosphere for 3 d. Workup and purification as described above gave
enol phosphate syn-7b (1.68 g, 96%).
22
(0.292 g, 75%) as a colorless viscous oil; [α]D +57.3 (c 0.72,
CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2752–2762

2758
N. Moinizadeh et al.
PAPER
Enol Phosphate syn-7b
C-5), 127.1, 128.1, 128.7, 137.3 (3 d, s, C6H5), 142.8 (d, JCP = 9 Hz,
C-4).
Colorless oil; [α]D22 +51.3 (c 0.9, CHCl3).
+
MS (EI, 80 eV, 100 °C): m/z (%) = 427 (M+, 2), 412 (M – CH3 , 1),
IR (KBr): 3085–2855 (=C–H, C–H), 1685 (C=C), 1290 (P=O),
1060 cm–1 (P–O).
+
326 (M – C5H9O2 , 84), 91 (Bn+, 100).
1H NMR (CDCl3, 500 MHz): δ = 1.35, 1.39 (2 s, 3 H each, CH3),
3.37 (br d, J = 7 Hz, 1 H, 3-H), 3.77, 3.81 (2 d, JHP = 8 Hz, 3 H each,
CH3O), 3.86 (dd, J = 7.6, 8.6 Hz, 1 H, 5′-H), 4.01 (dd, J = 5.6, 8.6
Hz, 1 H, 5′-H), 4.05–4.14 (m, 3 H, CH2Ph, 6-H), 4.39–4.41 (m, 1 H,
6-H), 4.45–4.52 (m, 1 H, 4′-H), 5.78 (mc, 1 H, 5-H), 7.21–7.42 (m,
5 H, C6H5).
13C NMR (CDCl3, 125.8 MHz): δ = 25.9, 26.4 (2 q, CH3), 54.8 (qd,
JCP = 6.5 Hz, CH3O), 57.9 (t, CH2Ph), 62.6 (dd, JCP = 5.5 Hz, C-3),
63.4 (t, C-6), 66.4 (t, C-5′), 74.9 (d, C-4′), 108.7 (s, CMe2), 109.3
(dd, JCP = 5 Hz, C-5), 127.2, 128.2, 128.7, 137.1 (3 d, s, C6H5),
142.7 (d, JCP = 9.5 Hz, C-4).
HRMS (80 eV): m/z calcd for C20H30NO7P: 427.1760; found:
427.1738.
Anal. Calcd for C20H30NO7P (427.4): C, 56.20; H, 7.07; N, 3.28.
Found: C, 55.98; H, 7.10; N, 3.17.
(3R,4′S)-Diethyl [2-Benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-
yl)-3,6-dihydro-2H-1,2-oxazin-4-yl]phosphate (anti-7c)
5-Bromo-1,2-oxazine 4 (1.18 g, 3.18 mmol) and P(OEt)3 (0.54 mL,
3.40 mmol) were dissolved in CH2Cl2 (45 mL) under an argon at-
mosphere and the mixture was stirred at r.t. for 1 d. The solvent and
all volatile components were removed under reduced pressure and
the residue was purified by column chromatography (silica gel, hex-
anes–EtOAc, 3:1 to 1:2) to give enol phosphate anti-7c (0.664 g,
49%) and starting material 4 (0.344 g, 28%, 5R/5S = 60:40); color-
less oil; [α]D22 –48.7 (c 0.74, CHCl3).
+
MS (EI, 80 eV, 100 °C): m/z (%) = 399 (M+, 6) 298 (M – C5H9O2 ,
86), 127 (12), 91 (Bn+, 100), 43 (13).
Anal. Calcd for C18H26NO7P (399.4): C, 54.13; H, 6.56; N, 3.51.
Found: C, 53.94; H, 6.48; N, 3.35.
IR (neat): 3080–2865 (=C–H, C–H), 1690 (C=C), 1290 (P=O),
1060 cm–1 (P–O).
5-Bromo-1,2-oxazine (5R,3S,4′S)-2
Pale yellow oil; [α]D22 –88.2 (c 0.5, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 1.25–1.34 (m, 12 H, CH3,
CH3CH2O), 3.19 (br d, J = 7.3 Hz, 1 H, 3-H), 3.89 (dd, J = 6.4, 8.2
Hz, 1 H, 5′-H), 4.08–4.22 (m, 8 H, 6-H, 5′-H, CH3CH2O, CH2Ph),
4.35–4.42 (m, 1 H, 6-H), 4.45 (dt, J = 6.4, 6.6 Hz, 1 H, 4′-H), 5.80
(mc, 1 H, 5-H), 7.23–7.41 (m, 5 H, C6H5).
13C NMR (CDCl3, 125.8 MHz): δ = 16.0 (qd, JCP = 6.5 Hz,
CH3CH2O), 25.2, 26.4 (2 q, CH3), 57.6 (t, CH2Ph), 61.2 (t, C-6),
62.0 (dd, JCP = 5 Hz, C-3), 64.4, 64.5 (2 dt, JCP = 6 and 5 Hz,
CH3CH2O), 67.4 (t, C-5′), 76.8 (d, C-4′), 107.7 (dd, JCP = 4.5 Hz, C-
5), 109.4 (s, CMe2), 127.4, 128.3, 128.8, 136.6 (3 d, s, C6H5), 143.4
(d, JCP = 9 Hz, C-4).
IR (neat): 3110–2880 (=C–H, C–H), 1730 cm–1 (C=O).
1H NMR (CDCl3, 500 MHz): δ = 1.38, 1.43 (2 s, 3 H each, CH3),
3.74 (dd, J = 7.2, 8.6 Hz, 1 H, 5′-H), 3.95, 4.48 (2 d, J = 14.5 Hz, 1
H each, CH2Ph), 3.99 (d, J = 7.8 Hz, 1 H, 3-H), 4.04–4.16 (m, 2 H,
5′-H, 6-H), 4.35–4.47 (m, 2 H, 5-H, 6-H), 4.56 (dt, J = 6.5, 7.8 Hz,
1 H, 4′-H), 7.22–7.40 (m, 5 H, C6H5).
13C NMR (CDCl3, 125.8 MHz): δ = 25.8, 26.6 (2 q, CH3), 49.2 (d,
C-5), 60.4 (t, CH2Ph), 67.1 (t, C-5′), 71.8 (d, C-4′), 74.9 (t, C-6),
77.1 (d, C-3), 110.1 (s, CMe2), 127.5, 128.5, 128.8, 137.5 (3 d, s,
C6H5), 195.5 (s, C-4).
+
MS (EI, 80 eV, 80 °C): m/z (%) = 427 (M+, 2), 412 (M – CH3 , 1),
MS (EI, 80 eV, 120 °C): m/z (%) = 371, 369 (M+, <1, <1), 357, 355
+
+
326 (M – C5H9O2 , 53), 101 (C5H9O2 , 8), 100 (11), 92 (OPOEt+,
+
+
(M – CH3 , 2, 2), 271, 269 (13, 12), 190 (88), 101 (C5H9O2 , 29), 91
100), 44 (27).
(Bn+, 100), 43 (CH3CO+, 17).
HRMS (80 eV): m/z calcd for C20H30NO7P: 427.1760; found:
427.1762.
Anal. Calcd for C16H20BrNO4 (370.2): C, 51.91; H, 5.44; N, 3.78.
Found: C, 52.01; H, 5.26; N, 3.81.
Kumada–Corriu Coupling Using Microwave Conditions; Gen-
eral Procedure
(3S,4′S)-Diethyl [2-Benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-
yl)-3,6-dihydro-2H-1,2-oxazin-4-yl]phosphate (syn-7c)
Under an argon atmosphere, the corresponding 1,2-oxazine (1
equiv) was placed in a microwave tube and dissolved in THF (10
mL). Then, the aryl Grignard reagent (4–4.5 equiv) and Pd(PPh3)4
(0.05 equiv) were added. The reaction mixture was irradiated in the
microwave oven for 30 min at 800 W and 50 °C. After cooling to
r.t., the mixture was quenched with H2O (1 mL), the phases were
separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were dried (Na2SO4), filtered,
and concentrated. The crude product was purified by column chro-
matography.
5-Bromo-1,2-oxazine 2 (0.810 g, 2.19 mmol) and P(OEt)3 (0.40
mL, 2.50 mmol) were dissolved in CH2Cl2 (20 mL) under an argon
atmosphere and the mixture was stirred at r.t. for 1 d. The solvent
and all volatile components were removed under reduced pressure
and the residue was purified by column chromatography (silica gel,
hexanes–EtOAc, 3:1 to 1:2) to give enol phosphate syn-7c (0.670 g,
72%) and starting material 2 (0.138 g, 17%, 5R/5S = 60:40).
5-Bromo-1,2-oxazine 2 (2.81 g, 7.60 mmol) and P(OEt)3 (2.6 mL,
16.7 mmol) in CH2Cl2 (60 mL) was stirred at r.t. under an argon at-
mosphere for 4 d. Workup and purification as described above gave
enol phosphate syn-7c (3.01 g, 90%); colorless oil; [α]D22 +40.7 (c
0.9, CHCl3).
(3S,4′S)-2-Benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-4-phe-
nyl-3,6-dihydro-2H-1,2-oxazine (syn-9)
According to the general procedure, 1,2-oxazine syn-7c (0.200 g,
0.468 mmol), PhMgCl (2 M in THF; 1.1 mL, 2.20 mmol), and
Pd(PPh3)4 (0.030 g, 0.026 mmol) in THF (10 mL) were used. The
crude product was purified by column chromatography (silica gel,
hexanes–EtOAc, 7:1 to 1:1) to give syn-9 (0.097 g, 57%) as a col-
orless solid; mp 98–101 °C; [α]D22 +127.3 (c 0.15, CHCl3), and bi-
phenyl (0.060 g, 27%).
IR (KBr): 3065–2840 (C–H, =C–H), 1680 (C=C), 1275 (P=O),
1030 cm–1 (P–O).
1H NMR (CDCl3, 500 MHz): δ = 1.20–1.40 (m, 12 H, CH3,
CH3CH2O), 3.38 (br d, J = 7.3 Hz, 1 H, 3-H), 3.88 (t, J = 8.2 Hz, 1
H, 5′-H), 4.04 (dd, J = 5.5, 8.2 Hz, 1 H, 5′-H), 4.10–4.23 (m, 7 H,
CH2Ph, CH3CH2O, 6-H), 4.37–4.55 (m, 2 H, 6-H, 4′-H), 5.77 (mc,
1 H, 5-H), 7.20–7.44 (m, 5 H, C6H5).
IR (KBr): 3105–2830 (=C–H, C–H), 1600 cm–1 (C=C).
13C NMR (CDCl3, 125.8 MHz): δ = 16.0 (dq, JCP = 6 Hz,
OCH2CH3), 26.0, 26.5 (2 q, 2 CH3), 57.9 (t, CH2Ph), 62.8 (dd,
1H NMR (CDCl3, 500 MHz): δ = 0.97, 1.26 (2 s, 3 H each, CH3),
3.41 (dd, J = 8.3, 8.5 Hz, 1 H, 5′-H), 3.72 (dd, J = 6.1, 8.5 Hz, 1 H,
5′-H), 4.02 (dd, J ≈ 2.1, 5.5 Hz, 1 H, 3-H), 4.12, 4.24 (2 d, J = 13.3
Hz, 1 H each, CH2Ph), 4.22 (dd, J = 3.3, 17.2 Hz, 1 H, 6-H), 4.53–
J
CP = 5 Hz, C-3), 63.6 (t, C-6), 64.5 (dt, JCP = 6 Hz, OCH2CH3),
66.5 (t, C-5′), 74.9 (d, C-4′), 108.7 (s, CMe2), 109.0 (dd, JCP = 4 Hz,
Synthesis 2013, 45, 2752–2762
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,2-Oxazin-4-yl Nonaflates and Phosphates
2759
4.59 (m, 2 H, 4′-H, 6-H), 6.12 (dd, J = 2.1, 3.3 Hz, 1 H, 5-H), 7.24–
7.48 (m, 10 H, C6H5).
forded the 4-alkynyl-substituted 1,2-oxazine syn-12 (58 mg, 80%)
as a pale yellow oil; [α]D22 +74.5 (c 0.5, CHCl3).
13C NMR (CDCl3, 125.8 MHz): δ = 25.6, 25.8 (2 q, CH3), 57.7 (t,
CH2Ph), 61.1 (d, C-3), 64.2 (t, C-6), 66.4 (t, C-5′), 76.6 (d, C-4′),
108.1 (s, CMe2), 124.4 (d, C-5), 126.1, 127.4, 127.6, 128.4, 128.8,
129.5, 134.3, 137.3, 140.0 (6 d, 3 s, C6H5, C-4).
IR (neat): 3180–2900 (=C–H, C–H), 2200 (C≡C), 1600 cm–1 (C=C).
1H NMR (CDCl3, 500 MHz): δ = 0.19 [s, 9 H, Si(CH3)3], 1.40,
1.405 (2 s, 3 H each, CH3), 3.40 (dd, J = 1.9, 6.9 Hz, 1 H, 3-H),
4.02–4.18 (m, 5 H, 6-H, CH2Ph, 5′-H), 4.35 (td, J = 2.7, 15.7 Hz, 1
H, 6-H), 4.67 (td, J = 6.9, 7.2 Hz, 1 H, 4′-H), 6.35 (d, J = 2.7 Hz, 1
H, 5-H), 7.21–7.33, 7.38–7.43 (2 m, 3 H, 2 H, C6H5).
+
MS (EI, 80 eV, 90 °C): m/z (%) = 351 (M+, 3), 250 (M – C5H9O2 ,
+
42), 91 (C7H7 , 100), 77 (12), 43 (44).
HRMS (80 eV): m/z calcd for C22H25NO3: 351.1834; found:
351.1826.
13C NMR (CDCl3, 125.8 MHz): δ = –0.25 [q, Si(CH3)3], 26.1, 26.6
(2 q, CH3), 58.1 (t, CH2Ph), 63.5 (d, C-3), 64.9 (t, C-6), 66.8 (t, C-
5′), 75.5 (d, C-4′), 95.8, 103.6 (2 s, C≡C), 108.7 (s, CMe2), 118.0 (s,
C-4), 127.1, 128.2, 128.6, 137.6 (3 d, s, C6H5), 135.0 (d, C-5).
Anal. Calcd for C22H25NO3 (351.5): C, 75.19; H, 7.17; N, 3.99.
Found: C, 75.09; H, 7.09; N, 3.96.
HRMS (80 eV): m/z calcd for C21H29NO3Si: 371.1917; found:
371.1927.
(3S,4′S)-2-Benzyl-4-(4-methoxyphenyl)-3-(2′,2′-dimethyl-1′,3′-
dioxolan-4′-yl)-3,6-dihydro-2H-1,2-oxazine (syn-10)
Kumada–Corriu Coupling Using Enol Phosphate: According to the
general procedure, 1,2-oxazine syn-7c (0.300 g, 0.702 mmol), 4-
MeOC6H4MgBr (0.5 M in THF; 5.6 mL, 2.80 mmol), and Pd(PPh3)4
(0.036 g, 0.032 mmol) in THF (10 mL) were used. The crude prod-
uct was purified by column chromatography (silica gel, hexanes–
EtOAc, 7:1 to 1:1) to give syn-10 (0.123 g, 46%) as a colorless wax
and 4,4′-dimethoxybiphenyl (0.066 g, 20%).
(3R,4′S)-2-Benzyl-4-[2-methyl-1,5-diphenyl-1H-imidazol-4-yl]-
3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-3,6-dihydro-2H-1,2-oxa-
zine (anti-16)
4-Nonafloxy-1,2-oxazine anti-6 (0.130 g, 0.226 mmol), alkyne 15
(0.065 g, 0.250 mmol), PdCl2(PPh3)2 (9 mg, 0.013 mmol), CuI (2
mg, 0.009 mmol), and Et3N (69 mg, 0.680 mmol) were dissolved in
toluene (5 mL) in a heat-gun-dried and argon-flushed flask and the
reaction mixture was stirred at r.t. overnight. Then, the mixture was
diluted with EtOAc and H2O (10 mL each), and the separated aque-
ous phase was extracted with EtOAc (2 × 10 mL). The combined
organic layers were washed with brine (10 mL), dried (Na2SO4),
and concentrated to dryness. Purification of the crude product by
column chromatography (silica gel, hexanes–EtOAc, 4:1 to 1:1) af-
forded the 4-alkynyl-substituted 1,2-oxazine anti-16 (59 mg, 49%)
as a pale yellow resin and the starting material anti-6 (28 mg, 22%);
[α]D23 –34.1 (c 0.53, CHCl3).
Kumada–Corriu Coupling Using Nonaflate: Nonaflate syn-6 (0.189
g, 0.33 mmol), 4-MeOC6H4MgBr (0.5 M in THF; 3.0 mL, 1.50
mmol), and PdCl2(PPh3)2 (0.012 g, 0.017 mmol) were dissolved in
THF (10 mL) under an argon atmosphere and the mixture was
stirred overnight at r.t. Then, the mixture was quenched with H2O
(1 mL), the phases were separated, and the aqueous layer was ex-
tracted with Et2O (3 × 10 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated. The crude product was
purified by column chromatography (silica gel, hexanes–EtOAc,
7:1 to 1:1) to yield syn-10 (0.076 g, 61%) as colorless crystals; mp
116–118 °C; [α]D22 +214.0 (c 0.52, CHCl3), and 4,4′-dimethoxybi-
phenyl (0.089 g, 56%).
IR (ATR): 3200–2850 (=C–H, C–H), 2195 (C≡C), 1600 cm–1
(C=C).
1H NMR (CDCl3, 250 MHz): δ = 1.25, 1.27 (2 s, 3 H each, CH3),
2.30 (s, 3 H, CH3), 3.53 (mc, 1 H, 3-H), 3.93–4.16, 4.23 (m, mc, 3 H,
2 H, 6-H, CH2Ph, 5′-H), 4.36 (d, J = 14.0 Hz, 1 H, CH2Ph), 4.67 (dt,
J = 5.2, 6.4 Hz, 1 H, 4′-H), 6.38 (mc, 1 H, 5-H), 7.11–7.55 (m, 15 H,
C6H5).
13C NMR (CDCl3, 100.6 MHz): δ = 13.9, 25.2, 26.3 (3 q, CH3), 58.7
(t, CH2Ph), 62.3 (d, C-3), 63.6, 65.8 (2 t, C-6, C-5′), 77.5 (d, C-4′),
85.5, 87.6 (2 s, C≡C), 109.3 (s, CMe2), 118.4, 120.8, 136.4, 136.6,
137.7, 145.7 (6 s, C-4, C6H5, imidazole), 127.2, 127.75, 127.81,
128.2, 128.4, 128.6, 128.87, 128.92, 129.7 (9 d, C6H5), 133.1 (d, C-
5).
IR (KBr): 3125–2830 (=C–H, C–H), 1610 cm–1 (C=C).
1H NMR (CDCl3, 500 MHz): δ = 1.01, 1.28 (2 s, 3 H each, CH3),
3.40 (dd, J = 8.2, 9.1 Hz, 1 H, 5′-H), 3.67–3.74 (m, 1 H, 5′-H), 3.79
(s, 3 H, OCH3), 3.96 (dd, J = 1.8, 5.5 Hz, 1 H, 3-H), 4.11 (d, J = 13.7
Hz, 1 H, CH2Ph), 4.20 (dd, J = 3.7, 16.4 Hz, 1 H, 6-H), 4.24 (d,
J = 13.7 Hz, 1 H, CH2Ph), 4.52–4.60 (m, 2 H, 4′-H, 6-H), 6.03 (mc,
1 H, 5-H), 6.74–6.99, 7.09–7.56 (2 m, 2 H, 7 H, C6H5, Ar).
13C NMR (CDCl3, 125.8 MHz): δ = 25.7, 26.0 (2 q, CH3), 55.2 (q,
OCH3), 57.7 (t, CH2Ph), 61.1 (d, C-3), 64.4 (t, C-6), 66.5 (t, C-5′),
76.6 (d, C-4′), 108.0 (s, CMe2), 113.8 (d, Ar), 123.0 (d, C-5), 127.2,
127.4, 128.5, 129.0, 129.6, 132.7, 139.1, 159.1 (d, s, 3 d, 3 s, C6H5,
Ar, C-4).
HRMS (ESI-TOF): m/z calcd for C34H34N3O3 [M + H]+: 532.2595;
found: 532.2577.
+
MS (EI, 80 eV, 120 °C): m/z (%) = 381 (M+, 10), 366 (M – CH3 ,
tert-Butyl (E)-3-[(3S,4′S)-2-Benzyl-3-(2′,2′-dimethyl-1′,3′-diox-
olan-4′-yl)-3,6-dihydro-2H-1,2-oxazin-4-yl]acrylate (syn-17)
and tert-Butyl (E)-3-[(4′S)-1-Benzyl-2-(2′,2′-dimethyl-1′,3′-di-
oxolan-4′-yl)-1H-pyrrol-3-yl]acrylate (18)
+
+
1), 280 (M – C5H9O2 , 100), 101 (C5H9O2 , 4), 91 (Bn+, 72), 43 (19).
HRMS (80 eV): m/z calcd for C23H27NO4: 381.1940; found:
381.1952.
A reaction flask containing syn-6 (0.272 g, 0.474 mmol) in DMF
(3.5 mL) was degassed and filled with argon. LiCl (32 mg, 0.760
mmol) and Et3N (0.144 g, 1.43 mmol) were added followed by tert-
butyl acrylate (92 mg, 0.712 mmol) and Pd(OAc)2 (6.4 mg, 0.029
mmol). After stirring at 70 °C overnight, the mixture was taken up
in EtOAc and H2O (10 mL each). The aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), and concentrated to
dryness. Purification of the crude product by column chromatogra-
phy (silica gel, hexanes–EtOAc, 4:1 to 1:1) afforded the 1,2-oxa-
zine syn-17 (144 mg, 75%) as a pale yellow solid and pyrrole 18 (10
mg, 6%) as a yellow oil.
Anal. Calcd for C23H27NO4 (381.5): C, 72.42; H, 7.13; N, 3.67.
Found: C, 72.71; H, 7.28; N, 3.56.
(3S,4′S)-2-Benzyl-4-[trimethylsilyl(ethynyl)]-3-(2′,2′-dimethyl-
1′,3′-dioxolan-4′-yl)-3,6-dihydro-2H-1,2-oxazine (syn-12)
4-Nonafloxy-1,2-oxazine syn-6 (118 mg, 0.200 mmol), trimethyl-
silylacetylene (11; 40 mg, 0.300 mmol), PdCl2(PPh3)2 (7.2 mg,
0.010 mmol), CuI (1.2 mg, 0.006 mmol), and Et3N (84 μL, 0.600
mmol) were dissolved in toluene (5 mL) in a heat-gun-dried and ar-
gon-flushed flask and the reaction mixture was stirred at r.t. over-
night. Then, the solvent was removed under reduced pressure and
the residue was dissolved in EtOAc (5 mL), washed with H2O (5
mL), and dried (Na2SO4). Purification of the crude product by col-
umn chromatography (silica gel, hexanes–EtOAc, 6:1 to 3:1) af-
1,2-Oxazine syn-17
[α]D21 +132.0 (c 0.15, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2752–2762

2760
N. Moinizadeh et al.
PAPER
IR (ATR): 3065–2870 (=C–H, C–H), 1710 (C=O), 1635 cm–1
(C=C).
HRMS (ESI-TOF): m/z calcd for C22H32BNO5 [M + H]+: 402.2451;
found: 402.2453.
1H NMR (CDCl3, 400 MHz): δ = 1.30, 1.35 (2 s, 3 H each, CH3),
1.48 (s, 9 H, t-C4H9), 3.70 (dd, J = 8.1, 8.4 Hz, 1 H, 5′-H), 3.78 (mc,
1 H, 3-H), 3.96 (dd, J = 6.3, 8.4 Hz, 1 H, 5′-H), 3.98, 4.07 (2 d,
J = 13.2 Hz, 1 H each, CH2Ph), 4.18 (dd, J = 3.2, 18.6 Hz, 1 H, 6-
H), 4.50 (d, J = 18.6 Hz, 1 H, 6-H), 4.58–4.61 (m, 1 H, 4′-H), 5.94
(d, J = 16.0 Hz, 1 H, =CH), 6.29 (mc, 1 H, 5-H), 7.19 (d, J = 16.0
Hz, 1 H, =CH), 7.25–7.38 (m, 5 H, C6H5).
13C NMR (CDCl3, 100.6 MHz): δ = 25.6, 26.3 (2 q, CH3), 28.1, 80.4
(q, s, t-C4H9), 57.9 (t, CH2Ph), 59.6 (d, C-3), 64.8 (t, C-6), 66.4 (t,
C-5′), 75.9 (d, C-4′), 108.3 (s, CMe2), 120.6 (d, =CH), 131.8 (s, C-
4), 127.5, 128.4, 128.6, 136.9 (3 d, s, C6H5), 132.5 (d, C-5), 142.9
(d, =CH), 166.4 (s, C=O).
Acknowledgment
Generous support of this work by the Deutsche Forschungsgemein-
schaft and Bayer HealthCare is most gratefully acknowledged. We
also thank Luise Schefzig, Xuan Pham, and Mehmet Zaralioglu
(Freie Universität Berlin) for their experimental assistance. The au-
thors thank one of the reviewers for valuable hints leading to a cor-
rection of the structure of compound 18.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are the remaining experimental details and copies of selected spec-
HRMS (ESI-TOF): m/z calcd for C23H31NO5 + Na [M + Na]+:
424.2094; found: 424.2096.
tra.SnugIiofop
r
imaotrtnSupgIpi
n
fotrai
o
n
t
Anal. Calcd for C23H31NO5 (401.5): C, 68.80; H, 7.78; N, 3.49.
Found: C, 68.94; H, 7.89; N, 3.49.
References
Pyrrole 18
[α]D21 +114.2 (c 0.3, CHCl3).
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16612.
IR (ATR): 3060–2890 (=C–H, C–H), 1710 (C=O), 1625 cm–1
(C=C).
1H NMR (CDCl3, 400 MHz): δ = 1.37 (s, 3 H, CH3), 1.50 (s, 12 H,
t-C4H9, CH3), 3.74 (t, J = 8.1 Hz, 1 H, 5′-H), 3.94 (dd, J = 7.6, 8.1
Hz, 1 H, 5′-H), 5.14 (d, J = 16.0 Hz, 1 H, CH2Ph), 5.26 (d, J = 16.0
Hz, 1 H, CH2Ph), 5.36 (mc, 1 H, 4′-H), 6.05 (d, J = 15.6 Hz, 1
H, =CH), 6.41 (d, J = 3.1 Hz, 1 H, 4-H), 6.59 (d, J = 3.1 Hz, 1 H, 5-
H), 7.00–7.05, 7.33–7.17 (2 m, 2 H, 3 H, C6H5), 7.79 (d, J = 15.6
Hz, 1 H, =CH).
13C NMR (CDCl3, 100.6 MHz): δ = 24.4, 26.3 (2 q, CH3), 28.4, 79.9
(q, s, t-C4H9), 51.1 (t, CH2Ph), 69.0 (t, C-5′), 69.8 (d, C-4′), 106.4
(d, C-4), 109.7 (s, CMe2), 116.2 (d, =CH), 120.5, 124.9, 126.5,
127.8, 128.9, 128.92, 137.8 (s, 4 d, 2 s, C6H5, C-5, C-2, C-3), 136.0
(d, =CH), 167.1 (s, C=O).
HRMS (ESI-TOF): m/z calcd for C23H29NO4 + Na [M + Na]+:
406.1989; found: 406.2042.
(3S,4′S)-2-Benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-4-
[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3,6-dihydro-2H-
1,2-oxazine (syn-19)
In a heat-gun-dried and argon-flushed flask, nonaflate syn-6 (0.215
g, 0.375 mmol), bis(pinacolato)diboron (0.105 g, 0.900 mmol),
KOPh (75 mg, 0.561 mmol), Ph3P (6 mg, 0.022 mmol), and
PdCl2(PPh3)2 (8 mg, 0.011 mmol) in anhyd toluene (3 mL) were
stirred at 60 °C for 2 h. After cooling to r.t., the mixture was diluted
with EtOAc (5 mL), washed with H2O and brine (1 × 3 mL each),
dried (Na2SO4), and the solvent was removed under reduced pres-
sure. The crude mixture was purified by column chromatography
(silica gel, hexanes–EtOAc, 6:1) to yield syn-19 (0.101 g, 70%) as
a pale yellow oil; [α]D22 +65.6 (c 0.31, CHCl3).
IR (ATR): 3065–2985, 2935–2850 (=CH, C–H), 1730 cm–1 (C=C).
1H NMR (CDCl3, 400 MHz): δ = 1.27 (s, 12 H, CH3), 1.38, 1.39 (2
s, 3 H each, CH3), 3.75 (dd, J = 1.7, 6.0 Hz, 1 H, 3-H), 3.80 (dd,
J = 8.2, 9.3 Hz, 1 H, 5′-H), 3.92 (dd, J = 5.7, 8.2 Hz, 1 H, 5′-H),
4.03, 4.05 (AB system, JAB = 14.3 Hz, 1 H each, CH2Ph), 4.12 (dd,
J = 3.0, 17.6 Hz, 1 H, 6-H), 4.41 (br td, J ≈ 2.0, 17.6 Hz, 1 H, 6-H),
4.54 (td, J = 5.9, 9.3 Hz, 1 H, 4′-H), 6.70 (mc, 1 H, 5-H), 7.19–7.43
(m, 5 H, C6H5).
13C NMR (CDCl3, 100.6 MHz): δ = 24.5, 25.0, 26.3, 26.7 (4 q,
CH3), 58.3 (t, CH2Ph), 61.1 (d, C-3), 66.5, 66.6 (2 t, C-5′, C-6), 75.4
(d, C-4′), 83.7 (s, C–O), 108.4 (s, CMe2), 127.0, 128.2, 128.5, 138.1
(3 d, s, C6H5), 141.7 (d, C-5). The signal for C-4 could not be de-
tected.
Synthesis 2013, 45, 2752–2762
© Georg Thieme Verlag Stuttgart · New York

PAPER
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