5,6-Dihydro-4H-1,2-oxazines in organic synthesis: Catalytic hydrogenation of [(5,6-dihydro-4H-1,2-oxazin-3-yl)methyl]malonates to methyl 7-oxo-1-oxa-6-azaspiro [4.4] nonane-8-carboxylates

Article abstract of DOI:10.1055/s-2008-106003

[(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates undergo a cascade transformation into substituted methyl 7-oxo-1-oxa-6-azaspiro[4.4]nonane-8- carboxylates under catalytic hydrogenation conditions over Raney nickel. A mechanistic scheme involving initial N-O bond cleavage with the formation of imines as key intermediates is suggested. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-106003

PAPER
1205
5,6-Dihydro-4H-1,2-oxazines in Organic Synthesis: Catalytic Hydrogenation
of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates to Methyl 7-Oxo-1-
oxa-6-azaspiro[4.4]nonane-8-carboxylates
C
atalytic
Hydroge
l
nation
e
x
ydro-4
H
-1,2
e
-oxazin-3-y
y
l)methyl]malonate
Y
s
u. Sukhorukov,a Alexey V. Lesiv,*a Yulia A. Khomutova,a Sema L. Ioffe,*a Yulia V. Nelyubinab
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax +7(495)1355328; E-mail: iof@ioc.ac.ru
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 29, 119991 Moscow,
Russian Federation
b
Received 14 November 2007; revised 11 December 2007
Dedicated to Professor H. Mayr on the occasion of his 60th birthday
which is that there is a very limited scope for the substitu-
ents at C3 because the range of available, appropriate ni-
trosoalkenes A is very small.5
Abstract: [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
undergo a cascade transformation into substituted methyl 7-oxo-1-
oxa-6-azaspiro[4.4]nonane-8-carboxylates under catalytic hydroge-
nation conditions over Raney nickel. A mechanistic scheme involv-
ing initial N–O bond cleavage with the formation of imines as key
intermediates is suggested.
Recently6 we developed a novel strategy for the synthesis
of polysubstituted 5,6-dihydro-4H-1,2-oxazines 4 from
available and absolutely stable nitroethane (Scheme 2). In
contrast to previously reported methodology,1–4 the
unique feature of this approach is the diversity of substit-
uents that can be introduced at the C3 position of the ox-
azine ring after functionalization of the methyl group
originating from nitroethane.
Key words: 5,6-dihydro-4H-1,2-oxazines, reduction, oxaaza-
spirononanones, imines
Six-membered cyclic ethers of oximes, 5,6-dihydro-1,2-
dihydro-4H-oxazines 1 and 1¢, can be considered as con-
venient precursors of natural and biologically active com-
pounds (e.g., alkaloids,1 unnatural a-amino acids,2 and
aminocarbohydrates3). The main significance of the ox-
azine ring in these syntheses is the stereoselective design
of the carbon skeleton of the target molecule; subsequent
reduction allows the preparation of individual stereoiso-
mers of substituted pyrrolidines 2 or 1,4-amino alcohols 3
(Scheme 1).4
This may result in new types of products at the step of hy-
drogenolysis of the oxazines 4. In particular, intramolecu-
lar cyclizations of intermediates or products of catalytic
hydrogenation can also involve the group FG.
Recently7 we reported a novel result of the hydrogenation
of oxazines 4 in acetic acid. If the above-mentioned ox-
azines do not contain an alkoxy group at C6, the dihydro-
furan derivatives 5 or 5¢ can be obtained instead of the
expected amino alcohols 3 (cf., Schemes 1 and 2).
According to this strategy, dihydrooxazines 1 are generat-
Herein we demonstrate that changing the solvent from
acetic acid to methanol for the catalytic hydrogenation of
oxazines 4 with Raney nickel results in the formation of
other furan derivatives, oxaazaspirononanones 6I–IV, i.e.
the FG is involved in the cyclization (Scheme 3, Table 1).
ed via [4+2] cycloaddition of highly unstable nitrosoalk-
enes
A
to the corresponding alkenes. Further
functionalization gives diastereomerically pure dihy-
drooxazines 1¢ that can be reduced to give target products
2 or 3. Apart from the instability of intermediates A, this
approach possesses another significant disadvantage,
Scheme 1
SYNTHESIS 2008, No. 8, pp 1205–1220
x
x
.
x
x
.2
0
0
8
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-106003; Art ID: P13207SS
© Georg Thieme Verlag Stuttgart · New York

1206
A. Yu. Sukhorukov et al.
PAPER
R1
O
R1
R1
O
EtNO2
Br substitution or
CO, Pd0, MeOH
R2
R3
R2
R3
3
R2
R3
Me3SiBr, Et3N
R1CHO
Br
FG
N
N
R3
R2
N
O
R4
R4
R4
O
4
R4
R
1 = Alk, Ar, OBz;
FG = CO2Me, CH(CO2Me)2,
OR, CH(COMe)CO2Me
NH2, N3, CH(CO2Me)CN
azolyl
R2, R3 = H, Alk
R
4 = H, Alk, OAlk, Ar
R2
R1
R2
R4
R1
R1
R1
R2
R3
H2, 20 bar, Ra-Ni
AcOH, 70–80 °C
R2
R3
or
H2, 20 bar, Ra-Ni
AcOH, 70–80 °C
FG
FG
N
FG
R3
R3
NH2
O
O
R4
O
OH
3
R4
R4
FG
4
5
5'
R3 and R4 ≠ OAlk
FG = CO2Me or CH(CO2Me)2
Scheme 2
R1
CO2Me
O
CO2Me
O
CO2Me
O
CO2Me
R1
R1
R1
R1
CO2Me
R2
R3
R2
R2
R3
H2, 70 bar, Ra-Ni
MeOH, 80 °C
R2
R2
+
+
+
O
N
N
N
N
N
CO2Me
O
O
O
O
R3
R3
R4
O
H
H
R3
H
H
R4
R4
R4
R4
4
6I
6II
6III
6IV
Scheme 3
The optimal procedure for the transformation of 4 into 6 yields of target 6b and in lower conversion of the initial
is illustrated in Scheme 3 (the conditions of the process oxazine 4b.8
were optimized for model oxazine 4b). A decrease of the
The treatment of 4b with sodium borohydride/cobalt(II)
hydrogen pressure as well as performing the hydrogena-
chloride in methanol at ambient temperature allows the
tion in other solvents (THF, EtOAc) or with palladium-
use of atmospheric pressure of hydrogen, but in this case
on-carbon instead of Raney nickel resulted in reduced
a great excess of reagents [NaBH4 (10 equiv), CoCl2 (1.5
Table 1 Synthesis of Oxaazaspirononanones 6
Entry
4, 6
R1
R2
R3
R4
Yield of 6
(%)
Ratio of isomersa
6I/6II/6III/6IV
1
2
3
4
5
6
7
a
b
c
d
e
f
Me
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
77
66
86
80
76
61
94
5.4:1.1:4.1:1.0
1.3:1.0:2.2:2.2
1.0:1.0:2.3:2.1
1.4:1.0:1.8:1.8
1.6:1.0:1.4:1.2
1.7:1.0:1.2:1.1
1.8:1.3:1.2:1.0
Ph
4-MeOC6H4
4-ClC6H4
Ph
–(CH2)4–
–(CH2)4–
–(CH2)3–
4-MeOC6H4
Ph
H
g
H
8
h
Ph
H
86
3.4:1.2:1.6:1.0
9
i
4-MeOC6H4
4-MeOC6H4
H
H
OEt
H
41b
0c
2.9:1.9:2.5:1.0
–
10
j
OMe
Me
a From NMR data after elution of the crude product (EtOAc–hexane, 1:1) through a short pad of silica gel.
b H2 (45 bar), Raney Ni, MeOH, 80 °C, Boc2O, Et3N; the second product is pyrrolidine 7 (33%) (see Scheme 4).
c Only pyrrole 8 is obtained (78%) (see Scheme 4).
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
1207
equiv)] is required to reach full conversion of 4b (the yield We believe that the first stage of this multistep process in-
of spiranonanone 6b is 55% and it is lower than that by volves reductive cleavage of the N–O bond leading to the
standard catalytic hydrogenation, see Table 1, entry 2).
formation of imine B (this conclusion is in line with pub-
lished data on the hydrogenation of six-membered cyclic
ethers of oximes,4 as well as the oximes themselves10).
The high reactivity of imines B allows them to be trans-
formed into a diverse number of possible final products,
but also it makes predictions of the results of these trans-
formations problematic. In addition to C=N bond hydro-
genation, the imino fragment in intermediate B can either
act as an electrophile or act as a nucleophile depending on
its structure. In these reactions, the presence (or absence)
of an alkoxy group at C6 can be considered as the main
determining criterion. If the oxazine 4 bears an alkoxy
group at C6 (R4 = OAlk), the initial semiacetal B trans-
forms rapidly into the corresponding carbonyl-containing
imine C (Scheme 4, Path 1). The latter undergoes in-
tramolecular recyclization to achieve pyrroline D, which
gives, after hydrogenation of the C=N bond, the final pyr-
rolidine 7 (route 1), or after elimination of water, pyrrole
8 (route 2).
Traces of water in the reaction mixture decrease the yield
of the target spiranone 6b (up to 54%) owing to generation
of lactam 9 (for details see discussion of Scheme 11). If
hydrogenation of 4b is carried out with ten equivalents of
water using ‘nondried’ Raney nickel (for preparation see
procedure b in experimental part) quick conversion of 4b
can be achieved at a lower pressure of hydrogen (40 bar,
80 °C, 1 h); however, lactam 9 dominates under these con-
ditions (~50% yield). Therefore, the transformation of 4
into 6 should be realized only under anhydrous conditions
and in the presence of a specially dried catalyst (see exper-
imental part).9
The spiranones 6 can be prepared in good to excellent
yields only for oxazines 4a–h without an alkoxy group at
C6. However, the hydrogenation of oxazine 4i in the pres-
ence of di-tert-butyl dicarbonate provides the respective
spiranone 6i in 41% yield and the desired formation of 6i
is accompanied by the formation of pyrrolidine 7
(Scheme 4). The catalytic hydrogenation of another ox-
azine 6j containing an alkoxy group at C6 furnished only
the corresponding pyrrole derivative 8. Interestingly, our
attempts to change the course of the reduction by perform-
ing the reaction under milder, as well as more robust con-
ditions, or by using palladium-on-carbon instead of Raney
nickel were unsuccessful.
The character of the resulting product (7 or 8) depends on
the relative rates of different processes: cyclization of C to
D, the hydrogenations of C and D, and elimination of wa-
ter from D. Examples of the reduction of 5,6-dihydro-4H-
1,2-oxazines to pyrroles11a–c and the reduction of 5,6-di-
hydro-4H-1,2-oxazines to pyrrolidines and fused
pyrrolidines1a,b,12 are available in the literature. There is
clear evidence, that pyrroles arise from intermediates D,
such as in the well-known Paal–Knorr reaction.11d Also, it
was proposed1b,12a that the formation of pyrrolidines oc-
curs via initial hydrogenolysis of the C=N bond in imines
C. Thus pyrroles and pyrrolidines should have different
precursors (D and C, respectively). By contrast, we be-
lieve that the reduction of the C=N bond occurs only after
The mechanistic aspects of the formation of spiranones 6
should be discussed in the context of a general consider-
ation of heterogeneous catalytic hydrogenation of ox-
azines 4 bearing a functional substituent CH2FG at C3
(Scheme 4). The sequence demonstrated in Scheme 4 ex-
plains the known literature data and is in good agreement
with results previously obtained in our studies7 and in the
present investigation.
R1
R1
R1
R1
R2
path 1
R3 = OAlk
R2
R3
R2
R3
H2, Ra-Ni
MeOH
R2
R4
FG
FG
FG
FG
R4
6
HN
4OH
– HOAlk
N
HN
N
O
OH
O
R4
R
4
B
C
D
route 1
route 2
R1
– H2O
R3, R4 = H, Alk
R1
path 2
Boc2O
An
An
R2
CO2Me
CO2Me
CO2Me
R3
R4
CO2Me
Me
N
Boc
N
FG
NH2
O
H
E
7
8
route 4
route 3
1 = An, R2 = H, R4 = H
trans (7I)/cis (7II) = 5.7:1
R
1 = An, R2 = H, R4 = Me
– NH3
– MeOH
R
R2
O
R2
R1
R1
R3
R4
FG = CH(CO2Me)2
An = 4-MeOC6H4
CO2Me
FG
R3
R4
O
N
H
5
6
O
Scheme 4
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

1208
A. Yu. Sukhorukov et al.
PAPER
An
An
An
O
An
O
CO2Me
CO2Me
CO2Me
H2, Ra-Ni
H2, Ra-Ni
MeOH
CO2Me
CO2Me
HO
N
H
HO
N
CO2Me
CO2Me
NH
CO2Me
N
EtO
H
4i
C'
D'
An
An
CO2Me
CO2Me
H2, Ra-Ni
Boc2O
N
Boc
N
CO2Me
CO2Me
7
trans (7I)/cis (7II) = 5.7:1
An
An
An
An
CO2Me
CO2Me
CO2Me
CO2Me
H2, Ra-Ni
MeOH
Me
– H2O
N
HO
Me
CO2Me
N
H
NH
CO2Me
N
CO2Me
CO2Me
MeO
O
Me
O
8
Me
4j
C''
D''
An = 4-MeOC6H4
Scheme 5
the cyclization of C to D, e.g. in cyclic imine D intermediate E (Scheme 6). After this transformation the
(Scheme 4).
NH2 fragment becomes exocyclic. Under acidic catalysis
intermediates E are able to eliminate ammonia furnishing
the respective dihydrofurans 5 (Scheme 4, route 3). By
contrast, under neutral conditions derivatives E undergo
intramolecular cyclization with participation of one of
methoxycarbonyl groups to afford oxaazaspirononanones
6 (Scheme 4, route 4).
This suggestion is supported with data shown in
Scheme 5. Indeed, intermediates C¢ and C¢¢ lead to quite
different products, pyrrolidine 7 and pyrrole 8, respective-
ly. At the same time, the iminium fragments of these in-
termediates are practically identical and, hence, it is
difficult to conceive their different behavior during the
hydrogenolysis of the C=N bond. However, the electro-
philicity of carbonyl group in the above-mentioned inter-
mediates C¢ and C¢¢ is quite different and owing to a
combination of electronic and steric factors, the rate of cy-
clization of C¢ to D¢ could be significantly higher than the
rate of cyclization of C¢¢ to D¢¢.
R1
R1
R2
FG
R2
FG
R3
NH
OH
N
H
R3
R4
O
H
R4
B
By this consideration one could underline that the stereo-
chemical outcome of hydrogenation of 5,6-dihydro-4H-
1,2-oxazines should depend on the stereochemistry of the
reduction of cyclic intermediate D (Scheme 4). However,
earlier it was proposed that this outcome depends on the
stereochemistry of the hydrogenation of acyclic interme-
diates C.1b
R2
R1
R1
O–
R2
R3
+
FG
FG
R3
NH2
O
R4
NH2
R4
E
Scheme 6
Thus, the catalytic hydrogenation of dihydrooxazines 4
bearing an alkoxy group at C6 results in recyclization with
ring contraction after initial N–O bond cleavage. As a re-
sult of this process, the oxygen atom becomes exocyclic
and is later eliminated to give the final heterocycle.
Attempts to isolate a-aminofuran E¢ or to trap its precur-
sor imine B with an external nucleophile (H2O, MeOH,
NaOMe, NaCN) to give lactam 10 were unsuccessful
(Scheme 7).
The hydrogenation of dihydrooxazines 4 that do not con-
tain an alkoxy group at C6, also begins with initial N–O
bond cleavage. However, in this case another recycliza-
tion is observed and the imine fragment is involved in the
process as an electrophilic center to give intermediate E
(Scheme 4, Path 2); an alternative pathway for the forma-
tion of amino acetals E involves the initial nucleophilic at-
tack of imine group at the OH-proton in the imine
In the scheme of generation of spiranones 6 (Scheme 7)
the cyclization of B to E seems to be the most intriguing.
The participation of imine intermediate B in the catalytic
hydrogenation of oxazines 4 was indirectly confirmed by
the similarity of the results of hydrogenation of the dihy-
drooxazine 4b and specially obtained related oxime 11
(Scheme 8); it is well known that catalytic reduction of
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
1209
Ph
O
Ph
Ph
CO2Me
CO2Me
CO2Me
H2, Ra-Ni
MeOH
CO2Me
Me
Me
O
N
CO2Me
NH
CO2Me
B'
NH2
Me
Me
OH
Me
Me
4b
E'
Nu or NuH
Ph
Ph
Ph
Nu
Nu
CO2Me
Me
Me
CO2Me
O
CO2Me
O
NH2 CO2Me
N
H
N
H
OH
Me
Me
OH
Me
Me
O
10
6b
Nu = MeO–, CN–
NuH = H2O, MeOH
Scheme 7
Ph
O
CO2Me
N
CO2Me
CO2Me
O
Me
Ph
Ph
Me
CO2Me
CO2Me
4b
H2, 70 bar, Ra-Ni
MeOH, 80 °C
N
NH
O
OH
Me
Me
H
Me
Ph
Me
CO2Me
CO2Me
6b
B
NOH
OH
Me
Me
yield of 6b: 66%; ratio of isomers 6bI/6bII/6bIII/6bIV = 1.3:1.0:2.2:2.2 (from 4b)
yield of 6b: 77%; ratio of isomers 6bI/6bII/6bIII/6bIV = 1.0:1.0:1.3:1.5 (from 11)
11
Scheme 8
oximes proceeds through the formation of the respective yl derivatives F, which undergo successive intramolecular
imines.10
cyclization and elimination of water affording dihydro-
furans 5. Acid-mediated hydrolysis of imines, as well as
oximes and their six-membered cyclic ethers is a well-
known process.14 However, this pathway seems unlikely,
because upon hydrogenation of oxazine 4b in aqueous
acetic acid, neither the rate of reaction nor the yield of tar-
get dihydrofuran 5b were increased.7
Several examples of processes involving intramolecular
trapping of imines or iminium cations by hydroxy or relat-
ed groups are known13 (Scheme 9), although the mecha-
nistic schemes suggested for these reactions are
hypothetical.
For a comprehensive picture, the sequence leading to di-
hydrofurans 5, which is an alternative to the conversion of
B to E and then 5, should be discussed (Scheme 10, path-
way b). This pathway includes the hydrolysis of imines B
with traces of water into the respective g-hydroxycarbon-
Attempts to perform the hydrogenation of oxazine 4b with
an acid that is stronger than acetic acid (HCl in dioxane–
MeOH) resulted in the predominant formation of lactam 9
(55%), while the yield of oxaazaspirononanone 6b de-
creased to 17% (Scheme 11).
Ref. 13a
COMe
COMe
COMe
LA
LAO
O
N O
+ N
N
– LA
+
O
N
N
O
O
O
O
O
MeOC
O
O
LA
Ref. 13b
Ar
CO2R1
NH
CO2R1
[H]
O
LA
N
H
N
R1O2C
O
O
N
O
R2
OH
R2
O
R2
R
R
1 = Me, Et
2 = H, Me, OMe
Scheme 9
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

1210
A. Yu. Sukhorukov et al.
PAPER
R1
R1
R2
R4
R1
R2
R4
R1
R2
R3
R2
R3
H2, Ra-Ni
AcOH
FG
pathway a
AcOH
– NH3
FG
FG
HN
R3
FG
N
O
R3
O
O
R4
NH2
OH
R4
4
E
5
B
H2O (traces)
AcOH
pathway b
X
R1
– H2O
R2
R4
R1
R2
R3
FG
FG
R3
O
O
OH
OH
R4
F
Scheme 10
Since acid-induced catalytic hydrogenation of amido ace-
tals of type 6 is known,15 the assumption that lactam 9
could be generated from the corresponding
spirononanone 6b needs to be taken into consideration.
However, attempts to reduce the C–O bond in
spirononanone 6b under the conditions depicted in
Scheme 11 were unsuccessful. Therefore, we believe that
lactam 9 arises from oxazinium cation G after the hydro-
genation of the C=N bond, e.g. the protonation of oxazine
4b leads to initial reduction of the C=N bond in the oximi-
no fragment.
EtNO2
AnCHO
Me2C=CH2
An
O
CO2Me
O
1. Dowex 50WX2-100,
H2O–dioxane, reflux, 12 h
An
O
N
H
N
H
2. TsOH, toluene
reflux, 5 h
Me
O
12c
Me
Me
Me
6c
yield: 84% (from 6c)
An = 4-MeOC6H4
In conclusion of the discussion related to the mechanism
of the catalytic hydrogenation of oxazines 4, it should be
emphasized that Scheme 4 is only hypothetic and it un-
doubtedly requires further consideration.
Scheme 12
less efficient owing to a greater number of steps and lower
yields of the target compounds.
As shown for the example of the spirononanone 6c, spi-
ranes of type 12, possessing an unsubstituted pyrrolidone
ring, can easily be obtained from simple and available pre-
cursors, nitroethane and the corresponding alkenes and al-
dehydes (Scheme 12).
As evident from Table 1, the compounds 6 are generated
as mixtures of four diastereomers that differ in the config-
uration at C5 and C8 (Scheme 3, Table 1).
Confirmation of the structure of spiranones 6 and determi-
nation of the stereochemistry of individual isomers re-
quires special discussion. The structure of products 6 was
supported by elemental analysis and X-ray data, as well as
by chemical transformation – decarboxylation of 6c to
give 12c. The presence of major structural fragments of
Close analogues of 6 and 12 are known as intermediates
in the total syntheses of alkaloids ( )-isostemonamide16
and cephalotaxine.17 However, literature approaches16–18
towards the synthesis of spiranes of type 12 seem to be
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
H2, Ra-Ni
Ph
+NH
NH
CO2Me
CO2Me
Me
O
Me
O
Cl–
Me
Me
G
N
Me
O
Me
4b
H2, Ra-Ni
CO2Me
O
H
2 (50 bar), Ra-Ni
Ph
O
Ph
1 equiv HCl, MeOH, 1,4-dioxane
80 °C
CO2Me
N
HN
OH
Me
Me
H2, Ra-Ni
1 equiv HCl, MeOH
1,4-dioxane, 80 °C
H
O
Me
Me
6b
9
Yield of 9 55%
ratio of isomers 1.3:1.5:1.3:1.0
Scheme 11
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
1211
1
oxaazaspirononanones 6 was confirmed by H and 13C mers, though isomers 6bIII and 6fI can be isolated from the
NMR. X-ray crystal data of 6bIII are demonstrated in corresponding pairs by crystallization.20
Figure 1.19
The relative configuration of stereocenters in 6I–IV was de-
termined by various NMR techniques (1H, 13C, COSY,
HSQC, DEPT, NOESY), which allowed signals in 1H and
13C spectra to be unambiguously assigned. The stereo-
chemical disposition of protons and other substituents
were established mainly from the results of 2D-NMR
NOESY experiments. Figure 2 represents the main char-
acteristic NOESY correlations for each of four isomers
6I–IV
.
Figure 1 General view of the compound 6bIII according to X-ray
diffraction data, C17H21NO4, M = 303.35, triclinic, space group P1, at
100 K: a = 9.2027(18), b = 9.4230(19), c = 10.645(2) Å,
a = 111.65(3), b = 98.67(3), g = 103.91(3)°, V = 803.0(4) Å3, Z = 2
(Z¢ = 1), dcalc = 1.255 g·cm–3, m(MoKa) = 0.89 cm–1, F(000) = 324.
Intensities of 3718 reflections were measured with a Bruker SMART
APEX2 CCD diffractometer [l(MoKa) = 0.71072 Å, w-scans, 2q <
54°] and 3496 independent reflections [Rint = 0.0249] were used in
further refinement. The structure was solved by direct method and re-
fined by the full-matrix least-squares technique against F2 in the ani-
sotropic-isotropic approximation. The hydrogen atom of the NH
group was located from the Fourier synthesis of the electron density.
The positions of H(C) atoms were calculated. All hydrogen atoms
were refined in the isotropic approximation in the riding model. For
6bIII the refinement converged to wR2 = 0.1005 and GOF = 1.002 for
all independent reflections [R1 = 0.0475 was calculated against F for
2422 observed reflections with I > 2s(I)]. All calculations were per-
formed using SHELXTL PLUS 5.0.
R1
R1
H
H
H
H''
H
H''
H'
8
H'
8
R2
R2
3
4
3
4
H
H
2
9
2
9
CO2Me
CO2Me
R4
R4
5
5
O
O
R3
R3
7
7
N
N
H
H
O
O
6I (rel-4S,5S,8R)
6II (rel-4S,5S,8S)
R1
H
R1
H
H
H
H''
H''
H'
H'
8
R2
R2
3
4
3
4
H
H
8
9
9
CO2Me
CO2Me
R4
5
R4
2
5
R32
O
O
R3
7
7
N
N
H
H
O
O
6IV (rel-4S,5R,8R)
6III (rel-4S,5R,8S)
Figure 2 Characteristic NOE correlations in spirononanones 6a–i.
In these spectra correlations of protons attached to C9 and
C8, as well as the correlations (or their absence) between
H9 and H4 were found to be the most important for deter-
mination of configuration. X-ray diffraction analysis of
spirononanone 6bIII revealed the same configuration as
deduced for this stereoisomer by NMR spectroscopy. This
circumstance confirms the correctness of all NMR assign-
ments (see Figures 1– 3).
The geometrical parameters of 6bIII fall in the range com-
mon for this type of compounds. In the molecule, two het-
erocyclic fragments are bonded together through C5. The
‘tetrahydrofuran’ fragment is characterized by the enve-
lope conformation with the deviation of C4 by 0.62 Å
from the plane formed by other atoms of the ring. The
same trend is observed for the nitrogen-containing hetero-
cycle. In this case the C9 atom deviates by 0.47 Å. These
two planes are practically perpendicular to each other and
corresponding dihedral angle is equal to 93.8(2)°. The
analysis of the crystal packing of 6bIII revealed that the
molecules are assembled into centrosymmetric dimers by
N–H···O hydrogen bonds of intermediate strength (N···O
separation and NHO angle are 2.910(2) Å and 165.1(1)°,
respectively) through the formation of six-membered hy-
drogen-bonded rings. The above associates are held to-
gether by a number of weak C–H···O and C–H···p contacts
thus resulting in the 3D-framework.
Chemical shifts of protons related to ‘tetrahydrofuran’ cy-
cle of spiranes 6 do not depend on the configuration of ste-
reocenters. At the same time, chemical shifts of protons
H9 and, especially, H8 were very informative in the stere-
ochemical assignment of isomers in their mixtures. The
1
diagnostic H NMR spectroscopic data for 6a–i are col-
lected in Table 2.
These data clearly indicate that H8 of isomers 6I and 6III
have a chemical shift in the small range (d = 3.6 to 3.7),
whereas these signals of isomers 6II and 6IV are shifted to
lower field. This effect becomes especially significant
when R1 is an aryl substituent. In this case the diamagnetic
shift is nearly 1.5 ppm. We believe, that the diamagnetic
shift of the H9 signal, is substantially connected with
anisotropic effects of the aromatic ring. Analysis of atom-
ic models of spiranes 6 clearly shows that the distance
from H8 to the plane of aromatic ring in isomers 6I and 6III
is almost one and a half times greater than the same dis-
tance in isomers 6II and 6IV.
The configuration of the stereocenters in the tetrahydrofu-
ran unit is identical for all isomers 6I–IV since it is gov-
erned by the ‘architecture’ of the initial diastereomerically
pure oxazines 4a–i. In most cases, mixtures of 6I–IV can be
separated by column chromatography to give two frac-
tions, containing pairs of isomers, 6I and 6II, 6III and 6IV
respectively. These pairs differ in the configuration of the
stereocenter at C5, while the isomers constituting one pair
have different configuration at the C8 stereocenter. Iso-
mer pairs cannot be separated into individual stereoiso-
In conclusion, catalytic hydrogenation of 5,6-dihydro-4H-
1,2-oxazines 4 that have the CH2CH(CO2Me)2 fragment
at C3 and do not contain an alkoxy group at C6 with
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

1212
A. Yu. Sukhorukov et al.
PAPER
16
17
18
Cl
17
16
17 OMe
15
14
14
Me
16
H'
15
14
4
H'
15
14
H''
H''
9
H'
8
10
3
H'
4
12 13
H''
H''
5
9
H'
8
5
4
Me
10
3
H'
H''
9
H''
12 13
H'
CO2Me
3
4
Me
11 Me
10Me
11Me
5
12 13
H''
2
H''
5
9 H'
CO2Me
8
O
Me
7
10
3
2
N
H
12 13
2
CO2Me
11
8 CO2Me
Me
O
7
N
2
O
7
O
11
N
H
O
O
6cI
Me
7
H
N
O
H
6aI
6bI
6dI
O
20
17
18
19
20
19
18
OMe
18
19
16
17
16
18
17
16
13
15
4 H''
12
13
H
3 H
17
4
12
12
H
13
12
11
3 H
4
H''
9
5
H''
5
11
9
7
9
H'
3
13 14
H'
3
H' 14
4 H''
5
15
16
15
CO2Me
14
5
9
7
2
11
11
H'
14 15
CO2Me
CO2Me
10
8
8
8
10 H 2
2
CO2Me
10 H
7
O
O
O
H
2
N
N
H
8
10 H
N
H
O
7
H
N
O
O
O
H
O
6eI
6fI
6gI
6hI
18
17
16
17 OMe
16
15
16
OMe14
15
14
12
13
15
14
14
11
10
H''
H
4
13
7
4
H'
3
7
6
9
3
5
8
9
9
10 11
2
5
6
H'
8
8
3
H''
1
CO2Me
12 13
CO2Me
2
CO2Me
5
3
2
10
7
13
Me
1
CO2Me
HN
OH
11
4
9
5
Me
4
O
2
11
Me
NOH CO2Me
O
CO2Me
1
12Me
7
N
6
OH
N
O
8
10
8
9
H
H
12 Me
O
6iI
9I/9II
8
11
17
16
16
15
OMe
14
15
13
14
4
For the stereochemistry of other isomers 6, see Scheme 3 and Figure 2
H''
H
H'
7
H'
3
2
4
3
10
12
5
11
H''
8
9
CO2Me
11
5
6
1
13
Me
8
HN
OH
Me
9
2
10
O
7
Me
12Me
N
H
O
O
9III/9VI
12cI
Figure 3
for samples, obtained by filtration of the corresponding reaction
mixtures through a short pad of silica gel to remove the traces of the
catalyst.
Raney nickel in methanol is an efficient method for the
synthesis of previously unknown oxaazaspirononanones
6.
Elemental analyses were performed by Analytical Laboratory of In-
stitute of Organic Chemistry and the Analytical Center of the Mos-
cow Chemical Lyceum. For diastereomeric mixtures 6I–6IV
elemental analyses was performed for one of the middle fractions of
chromatographic separation (consisting of all four isomers) after
evaporation of the solvent and verification of the sample in vacuum.
Melting points were determined on a Koffler melting point appara-
tus (uncorrected). Analytical TLC was performed on Merck silica
gel plates with QF-254. Visualization was accomplished with UV
light or with soln of ninhydrin in EtOH.
NMR spectra were measured for pairs of isomers 6I, 6II and 6III, 6IV,
obtained after column chromatography of crude products 6 (for 6b
and 6f NMR spectra were also measured for individual isomers 6bIII
and 6fI; isomer pairs 6gIII and 6gIV, 6hIII and 6hIV, 6iI and 6iII, re-
spectively, could not be fully separated from the corresponding iso-
mer pairs and were characterized in mixtures). 1D and 2D NMR
spectra were recorded at r.t. on Bruker DRX-500 [1H (500.13 MHz),
1H-1H COSY, HSQC (J = 145 Hz), NOESY (mixing time 900 ms)],
Bruker AM-300 and WM-250 (13C 75.13 or 62.5 MHz, INEPT,
JMOD) NMR spectrometers in CDCl3 (0.2 M solns). The chemical
shifts (1H and 13C) are given relative to the solvent signal.21 All 1D
and 2D NMR experiments were performed using standard methods
and Bruker NMR technique software. Atom-numbering is shown in
High-pressure hydrogenation was carried out in a steel autoclave.
The following reaction solvents and reagents were distilled from the
indicated drying agents: toluene (CaH2), 1,4-dioxane (CaH2), THF
(LiAlH4), Et3N (CaH2). Anhyd MeOH (for Raney Ni preparation,
procedure a and hydrogenation of oxazines 4a–h) was prepared by
distillation under Mg.
1
Figure 3. Ratios of isomers 6I, 6II, 6III, 6IV were determined by H
NMR (from the relative integral intensity of characteristic signals)
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
1213
Table 2 Characteristic 1H NMR Chemical Shifts for 6 [d (500.13
MHz, CDCl3)]
Methyl 2,2,4-Trimethyl-7-oxo-1-oxa-6-azaspiro[4.4]nonane-8-
carboxylate (6a)
Anal. Calcd for C12H19NO4: H, 7.94; C, 59.73; N, 5.81. Found: H,
7.62; C, 59.62; N, 5.84.
Isomer
6
6I
6II
6III
6IV
Mixture of 6aI and 6aII
Oil; ratio 6aI/6aII 85:15; Rf = 0.13 (EtOAc–hexane, 1:1).
6a
H8: 3.64
H9¢: 2.28
H9¢¢: 2.57
H8: 3.34
H9¢: 2.60
H9¢¢: 2.33
H8: 3.66
H9¢: 2.59
H9¢¢: 2.11
H8: 3.33
H9¢: 2.33
H9¢¢: 2.47
(4R*,5S*,8R*)-Isomer 6aI
1H NMR (500.13 MHz, CDCl3): d = 0.98 (d, J = 6.2 Hz, 3 H, 14-
CH3), 1.15 (s, 3 H, 10-CH3), 1.24 (s, 3 H, 11-CH3), 1.56 (dd,
J = 12.7, 12.7 Hz, 1 H, H3¢¢), 1.96 (dd, J = 12.7, 7.0 Hz, 1 H, H3¢),
2.28 (dd, J = 13.6, 9.2 Hz, 1 H, H9¢), 2.32 (m, 1 H, H4), 2.57 (dd,
J = 13.6, 8.8 Hz, 1 H, H9¢¢), 3.64 (dd, J = 8.8, 9.2 Hz, 1 H, H8), 3.72
(s, 3 H, 13-CH3), 7.75 (br, 1 H, NH).
6b
6c
6d
6e
6f
H8: 3.62
H9¢: 2.40
H9¢¢: 2.71
H8: 2.74
H9¢: 2.74
H9¢¢: 2.51
H8: 3.62
H9¢: 2.14
H9¢¢: 2.07
H8: 2.36
H9¢: 2.21
H9¢¢: 2.28
H8: 3.64
H9¢: 2.37
H9¢¢: 2.69
H8: 2.77
H9¢: 2.76
H9¢¢: 2.49
H8: 3.68
H9¢: 2.22
H9¢¢: 2.15
H8: 2.41
H9¢: 2.22
H9¢¢: 2.31
13C NMR (CDCl3): d = 13.1 (C14), 28.9 (C10), 30.1 (C11), 36.1
(C9), 41.5 (C4), 45.5 (C3), 47.3 (C8), 52.5 (C13), 80.1 (C2), 97.8
(C5), 170.1 (C12), 172.7 (C7).
H8: 3.63
H9¢: 2.41
H9¢¢: 2.64
H8: 2.78
H9¢: 2.73
H9¢¢: 2.49
H8: 3.63
H9¢: 2.32
H9¢¢: 2.32
H8: 2.49
H9¢: 2.13
H9¢¢: 2.32
Characteristic 2D-NOESY correlations: NH/11-CH3, NH/14-CH3,
NH/H3¢¢, H4/H3¢, H8/H9¢, H4/H9¢¢.
H8: 3.65
H9¢: 2.49
H9¢¢: 2.80
H8: 2.90
H9¢: 2.80
H9¢¢: 2.56
H8: 3.60
H9¢: 2.07
H9¢¢: 2.07
H8: 2.36
H9¢: 2.18
H9¢¢: 2.31
(4R*,5S*,8S*)-Isomer 6aII
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 0.92 (d,
J = 7.0 Hz, 3 H, 14-CH3), 2.33 (m, 1 H, H9¢¢), 2.60 (dd, J = 12.4, 6.6
Hz, 1 H, H9¢), 3.37 (dd, J = 10.9, 6.6 Hz, 1 H, H8).
H8: 3.64
H9¢: 2.45
H9¢¢: 2.75
H8: 2.89
H9¢: 2.78
H9¢¢: 2.51
H8: 3.58
H9¢: 2.04
H9¢¢: 2.04
H8: 2.37
H9¢: 2.16
H9¢¢: 2.25
13C NMR (CDCl3): d (selected signals from HSQC) = 35.9 (C9),
42.0 (C4), 44.8 (C3), 47.4 (C8).
Characteristic 2D-NOESY correlations: H9¢/H9¢¢, H8/H9¢¢.
6g
6h
6i
H8: 3.63
H9¢: 2.41
H9¢¢: 2.55
H8: 2.84
H9¢: 2.69
H9¢¢: 2.41
H8: 3.63
H9¢: 2.14
H9¢¢: 2.14
H8: 2.58
H9¢: 2.21
H9¢¢: 2.35
Mixture of 6aIII and 6aIV
Oil; ratio 6aIII/6aIV 7.0:2.0; Rf = 0.09 (EtOAc–hexane, 1:1).
H8: 3.63
H9¢: 2.40
H9¢¢: 2.56
H8: 2.87
H9¢: 2.72
H9¢¢: 2.33
H8: 3.60
H9¢: 2.12
H9¢¢: 2.12
H8: 2.55
H9¢: 2.19
H9¢¢: 2.28
(4R*,5R*,8S*)-Isomer 6aIII
1H NMR (500.13 MHz, CDCl3): d = 1.08 (d, J = 7.2 Hz, 3 H, 14-
CH3), 1.22 and 1.25 (2 s, 6 H, 10-CH3, 11-CH3), 1.54 (dd, J = 12.4,
10.0 Hz, 1 H, H3¢¢), 2.03 (dd, J = 12.4, 7.3 Hz, 1 H, H3¢), 2.11 (dd,
J = 13.2, 8.7 Hz, 1 H, H9¢¢), 2.42 (ddq, J = 10.0, 7.3, 7.2 Hz, 1 H,
H4), 2.59 (dd, J = 13.2, 8.1 Hz, 1 H, H9¢), 3.66 (dd, J = 8.7, 8.1 Hz,
1 H, H8), 3.72 (s, 3 H, 13-CH3), 7.25 (br, 1 H, NH).
H8: 3.68
H9¢: 2.64
H9¢¢: 2.75
H8: 3.14
H9¢: 2.89
H9¢¢: 2.58
H8: 3.58
H9¢: 2.13
H9¢¢: 1.97
H8: 2.85
H9¢: 2.12
H9¢¢: 2.31
13C NMR (CDCl3): d = 14.9 (C14), 29.7 and 30.3 (C10, C11), 34.0
(C9), 40.5 (C4), 45.8 (C3), 47.0 (C8), 52.5 (C13), 79.2 (C2), 98.0
(C5), 170.1 (C12), 172.7 (C7).
MeOH, hexane, EtOAc, and DMF were technical grade and dis-
tilled without drying agents. Column chromatography was per-
formed using Merck Kieselgel 60 (230–400 mesh) silica gel.
The following chemicals were purchased from the indicated
sources: Raney Ni (50% slurry in H2O) (Acros), Dowex 50WX2-
100 (Sigma-Aldrich), TsOH·H2O (Fluka), dimethyl malonate
(Acros), t-BuOK (Fluka), Boc2O (Acros), 5% Pd-C (Acros).
Characteristic 2D-NOESY correlations: NH/H4, 14-CH3/H3¢¢, H3¢/
H3¢¢, H8/H9¢¢, 14-CH3/H9¢.
(4R*,5R*,8R*)-Isomer 6aIV
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 1.03 (d,
J = 7.0 Hz, 3 H, 14-CH3), 1.56 (dd, J = 13.0, 13.0 Hz, 1 H, H3), 2.25
(m, 1 H, H4), 2.33 (m, 1 H, H9¢), 2.47 (dd, J = 13.5, 8.9 Hz, 1 H,
H9¢¢), 3.33 (dd, J = 8.9, 8.1 Hz, 1 H, H8), 6.07 (br, 1 H, NH).
Initial malonates 4 were prepared according to literature procedure
in four steps from nitroethane.6a
Preparation of Raney Nickel; Procedure a
13C NMR (CDCl3): d (selected signals from HSQC) = 13.4 (C14),
33.8 (C9), 42.6 (C4), 45.6 (C3), 47.6 (C8).
A 50% slurry of Raney Ni in H2O (100 mL) was washed with anhyd
MeOH (5 × 50 mL), dried in vacuo (0.4 Torr) at 100 °C for 1 h and
at r.t. for 2 h. The catalyst was stored under anhyd MeOH.
Characteristic 2D-NOESY correlations: H9¢/H9¢¢, H9¢/14-CH3, H8/
H9¢.
Preparation of Raney Nickel; Procedure b
A 50% slurry of Raney Ni in H2O (5 mL) was washed with MeOH
(5 × 10 mL). The catalyst was used immediately after preparation.
Methyl 2,2-Dimethyl-4-phenyl-7-oxo-1-oxa-6-aza-
spiro[4.4]nonane-8-carboxylate (6b)
Mixture of 6bI and 6bII
Oxaazaspirononanones 6a–h; General Procedure
Oil; ratio 6bI/6bII 1.0:1.0; Rf = 0.24 (EtOAc–hexane, 1:1).
To a soln of oxazine 4 (1.0 mmol) or oxime 11 (1.0 mmol) in anhyd
MeOH (5.0 mL) was added Raney Ni (ca. 0.1 g in MeOH, prepared
using procedure a). The suspension was hydrogenated at 70 bar H2
and 80 °C with intensive stirring for 2 h and then filtered and con-
centrated in vacuum. The residue was purified by column chroma-
tography (silica gel). Yields are presented in Table 1.
(4S*,5S*,8R*)-Isomer 6bI
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 2.32 (m, 1 H,
H3¢¢), 2.40 (dd, J = 13.5, 9.0 Hz, 1 H, H9¢), 2.71 (dd, J = 13.5, 9.4
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

1214
A. Yu. Sukhorukov et al.
PAPER
Hz, 1 H, 1 H, H9¢¢), 3.44 (m, 1 H, H4), 3.62 (dd, J = 9.4, 9.0 Hz, 1
H, H8).
Methyl 4-(4-Methoxyphenyl)-2,2-dimethyl-7-oxo-1-oxa-6-aza-
spiro[4.4]nonane-8-carboxylate (6c)
Anal. Calcd for C18H23NO5: H, 6.95; C, 64.85; N, 4.20. Found: H,
7.08; C, 64.96; N, 4.18.
13C NMR (CDCl3): d (selected signals from HSQC) = 35.9 (C9),
47.1 (C8).
Mixture of 6cI and 6cII
Characteristic 2D-NOESY correlations: NH/11-CH3, NH/H3¢¢, H4/
H9¢¢, H9¢/H8, H4/10-CH3, H4/H3¢, H3¢¢/11-CH3.
Oil; ratio 6cI/6cII 1.5:1.0; Rf = 0.20 (EtOAc–hexane, 1:1).
(4S*,5S*,8S*)-Isomer 6bII
(4S*,5S*,8R*)-Isomer 6cI
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 2.32 (m, 1 H,
H3¢¢), 2.51 (dd, J = 12.2, 6.2 Hz, 1 H, H9¢¢), 2.74 (m, 2 H, H8, H9¢),
3.44 (m, 1 H, H4).
1H NMR (500.13 MHz, CDCl3): d = 1.27 (s, 3 H, 10-CH3), 1.35 (s,
3 H, 11-CH3), 2.05 (m, 1 H, H3¢), 2.30 (m, 1 H, H3¢¢), 2.37 (dd,
J = 13.6, 9.4 Hz, 1 H, H9¢), 2.69 (dd, J = 13.6, 9.8 Hz, 1 H, H9¢¢),
3.37 (dd, J = 13.7, 7.0 Hz, 1 H, H4), 3.60 (s, 3 H, 13-CH3), 3.64 (dd,
J = 9.8, 9.4 Hz, 1 H, H8), 3.74 (s, 3 H, 18-CH3), 6.76 (d, J = 7.9 Hz,
2 H, H16), 7.15 (d, J = 7.9 Hz, 2 H, H15), 8.52 (br, 1 H, NH).
13C NMR (CDCl3): d (selected signals from HSQC) = 35.9 (C9),
47.7 (C8).
Characteristic 2D-NOESY correlations: NH/11-CH3, NH/H3¢¢, H4/
H9¢¢, H9¢¢/H8, H4/10-CH3, H4/H3¢, H3¢¢/11-CH3.
13C NMR (CDCl3): d = 29.1, 30.0 (C10, C11), 35.6 (C9), 43.1 (C3),
47.3 (C8), 51.9 (C4), 52.5 (C13), 55.1 (C18), 79.7 (C2), 97.6 (C5),
113.9 (C16), 127.5 (C14), 129.9 (C15), 158.9 (C17), 169.7 (C12),
172.3 (C7).
Unassigned signals of both isomers:
1H NMR (500.13 MHz, CDCl3): d = 1.29 and 1.30 (2 s, 6 H, 10-
CH3), 1.34 and 1.37 (2 s, 6 H, 11-CH3), 2.06 and 2.11 (2 dd,
J = 12.8, 6.8 Hz, 2 H, H3¢), 3.56 and 3.70 (2 s, 6 H, 13-CH3), 7.10–
7.45 (m, 5 H, H15, H16, H17), 8.00 and 8.40 (2 br, 2 H, NH).
Characteristic 2D-NOESY correlations: NH/H15, NH/11-CH3,
NH/H3¢¢, H4/H9¢¢, H9¢/H8.
13C NMR (CDCl3): d = 29.0 and 29.1 (C10), 29.8 and 30.1 (C11),
42.5 and 42.9 (C3), 52.5, 52.6, and 54.3 (C4 and C13), 79.8 and 80.3
(C2), 97.3 and 97.4 (C5), 127.6 and 127.8 (C15), 128.5, 128.6,
128.7, and 128.8 (C16 and C17), 135.5 and 135.6 (C14), 169.4 and
169.5 (C12), 171.5 and 172.6 (C7).
(4S*,5S*,8S*)-Isomer 6cII
1H NMR (500.13 MHz, CDCl3): d = 1.29 (s, 3 H, 10-CH3), 1.31 (s,
3 H, 11-CH3), 2.05 (m, 1 H, H3¢), 2.30 (m, 1 H, H3¢¢), 2.49 (dd,
J = 13.5, 9.6 Hz, 1 H, H9¢¢), 2.76 (dd, J = 13.5, 9.8 Hz, 1 H, H9¢),
2.77 (dd, J = 9.8, 9.6 Hz, 1 H, H8), 3.37 (dd, J = 13.7, 7.0 Hz, 1 H,
H4), 3.69 (s, 3 H, 13-CH3), 3.78 (s, 3 H, 18-CH3), 6.82 (d, J = 8.1
Hz, 2 H, H16), 7.19 (d, J = 8.1 Hz, 2 H, H15), 8.78 (br, 1 H, NH).
Mixture of 6bIII and 6bIV
Oil; ratio 6bIII/6bIV 1.0:1.0; Rf = 0.20 (EtOAc–hexane, 1:1).
13C NMR (CDCl3): d = 29.7, 29.3 (C10, C11), 35.7 (C9), 42.6 (C3),
47.8 (C8), 52.5 (C13), 53.6 (C4), 55.1 (C18), 80.2 (C2), 97.5 (C5),
114.1 (C16), 127.6 (C14), 129.8 (C15), 159.1 (C17), 169.6 (C12),
171.8 (C7).
(4S*,5R*,8S*)-Isomer 6bIII
Crystallized from mixture with 6bIV; mp 152–155 °C.
1H NMR (500.13 MHz, CDCl3): d = 1.33 (s, 3 H, 10-CH3), 1.38 (s,
3 H, 11-CH3), 2.07 (dd, J = 9.2, 11.0 Hz, 1 H, H9¢¢), 2.14 (dd,
J = 9.2, 11.0 Hz, 1 H, H9¢), 2.18 (dd, J = 13.0, 6.9 Hz, 1 H, H3¢),
2.29 (dd, J = 13.3, 13.0 Hz, 1 H, H3¢¢), 3.53 (s, 3 H, 13-CH3), 3.62
(dd, J = 9.2, 9.2 Hz, 1 H, H8), 3.71 (dd, J = 13.3, 6.9 Hz, 1 H, H4),
7.10–7.45 (m, 5 H, H15, H16, H17), 7.70 (br, 1 H, NH).
Characteristic 2D-NOESY correlations: NH/H15, NH/11-CH3,
NH/H3¢¢, H4/H9¢¢.
Mixture of 6cIII and 6cIV
Oil; ratio 6cIII/6cIV 1.0:1.0; Rf = 0.16 (EtOAc–hexane, 1:1).
13C NMR (CDCl3): d = 29.2 (C10), 30.4 (C11), 35.3 (C9), 42.5
(C3), 47.1 (C8), 52.5 (C4), 52.6 (C13), 79.0 (C2), 97.8 (C5), 127.9
(C17), 128.3 and 128.9 (C15 and C16), 135.9 (C14), 169.6 (C12),
171.3 (C7).
(4S*,5R*,8S*)-Isomer 6cIII
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 2.15 (dd,
J = 13.5, 9.7 Hz, 1 H, H9¢¢), 2.22 (dd, J = 13.5, 10.9 Hz, 1 H, H9¢),
3.68 (dd, J = 11.0, 9.4 Hz, 1 H, H8), 3.78 (s, 3 H, 18-CH3), 7.14 (d,
J = 7.5 Hz, 2 H, H15).
Characteristic 2D-NOESY correlations: NH/H4, H8/H9¢¢, H15/H9¢,
H4/H3¢, H15/H3¢¢, H4/10-CH3.
13C NMR (CDCl3): d (selected signals from HSQC) = 35.1 (C9),
47.1 (C8), 55.2 (C18).
Anal. Calcd for C17H21NO4: H, 6.98; C, 67.31; N, 4.62. Found: H,
6.80; C, 67.41; N, 4.65.
Characteristic 2D-NOESY correlations: NH/H4.
(4S*,5R*,8R*)-Isomer 6bIV
(4S*,5R*,8R*)-Isomer 6cIV
Described in mixture with 6bIII.
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 2.22 (dd,
J = 13.4, 10.0 Hz, 1 H, H9¢), 2.31 (m, 1 H, H9¢¢), 2.41 (dd, J = 9.2,
9.2 Hz, 1 H, H8), 3.78 (s, 3 H, 18-CH3), 7.18 (d, J = 7.5 Hz, 2 H,
H15).
1H NMR (500.13 MHz, CDCl3): d = 1.34 (s, 3 H, 10-CH3), 1.40 (s,
3 H, 11-CH3), 2.09 (m, 1 H, H3), 2.21 (dd, J = 13.1, 9.3 Hz, 1 H,
H9¢), 2.28 (dd, J = 13.1, 7.5 Hz, 1 H, H9¢¢), 2.31 (m, 1 H, H3), 2.36
(dd, J = 9.3, 7.5 Hz, 1 H, H8), 3.61 (m, 1 H, H4), 3.63 (s, 3 H, 13-
CH3), 7.10–7.45 (m, 5 H, H15, H16 and H17), 7.35 (br, 1 H, NH).
13C NMR (CDCl3): d (selected signals from HSQC) = 35.1 (C9),
47.9 (C8), 55.2 (C18).
13C NMR (CDCl3): d = 28.8 (C10), 30.6 (C11), 35.3 (C9), 41.2
(C3), 47.9 (C8), 50.7 (C4), 52.1 (C13), 79.0 (C2), 98.2 (C5), 127.5
(C17), 128.5 and 128.7 (C15 and C16), 137.1 (C14), 169.5 (C12),
173.2 (C7).
Characteristic 2D-NOESY correlations: NH/H4, H9¢/H8, H9¢/H15.
Unassigned signals of both isomers:
1H NMR (500.13 MHz, CDCl3): d = 1.33 and 1.34 (2 s, 6 H, 10-
CH3), 1.37 and 1.40 (2 s, 6 H, 11-CH3), 2.08, 2.15, and 2.24 (m, 1
H, 1 H and 2 H, 2 H3), 3.60 and 3.63 (dd, J = 13.5, 6.8 Hz, and dd,
J = 9.4, 9.4 Hz, 2 H, H4), 3.55 and 3.64 (2 s, 6 H, 13-CH3), 6.85 and
6.86 (2 d, J = 7.5, 4 H, H16), 7.60 and 7.87 (br, 2 H, NH).
Characteristic 2D-NOESY correlations: NH/H4, H8/H9¢, H15/H9¢,
H4/10-CH3.
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
1215
13C NMR (CDCl3): d = 28.7 and 29.2 (C10), 30.2 and 30.5 (C11),
41.2 and 42.6 (C3), 49.8 and 51.3 (C4), 52.4 and 52.5 (C13), 78.8
and 78.9 (C2), 97.6 and 98.1 (C5), 114.0 and 114.2 (C16), 127.6 and
128.9 (C14), 128.7 and 129.2 (C15), 158.8 and 159.0 (C17), 169.4
and 169.5 (C12), 171.2 and 173.2 (C7).
Characteristic 2D-NOESY correlations: NH/10-CH3, NH/H4, H9¢/
H8, H4/10-CH3, H9¢/H15, H3¢/10-CH3.
Unassigned signals of both isomers:
1H NMR (500.13 MHz, CDCl3): d = 1.35 and 1.36 (2 s, 3 H, 10-
CH3), 1.39 and 1.41 (2 s, 3 H, 11-CH3).
13C NMR (CDCl3): d = 28.7 and 29.1 (C10), 30.4 and 30.2 (C11),
35.1 and 35.0 (C9), 47.8 and 47.0 (C8), 52.6 and 52.5 (C13), 97.9
and 97.5 (C5), 129.6, 129.1, 129.0, and 128.8 (C15, C16), 135.4,
134.4, 133.7, and 133.3 (C14, C17), 169.3 and 169.1 (C12), 171.7
and 173.6 (C7).
Methyl 4-(4-Chlorophenyl)-2,2-dimethyl-7-oxo-1-oxa-6-aza-
spiro[4.4]nonane-8-carboxylate (6d)
Anal. Calcd for C17H20NO4Cl: H, 5.97; C, 60.45; N, 4.15. Found: H,
6.55; C, 60.93; N, 3.99.
Mixture of 6dI and 6dII
Oil; ratio 6dI/6dII 1.0:1.0; Rf = 0.20 (EtOAc–hexane, 1:1).
Methyl 5¢-Oxo-3-phenyl-hexahydro-3H-spiro[1-benzofuran-
2,2¢-pyrrolidine]-4¢-carboxylate (6e)
Anal. Calcd for C19H23NO4: H, 7.04; C, 69.28; N, 4.25. Found: H,
7.31; C, 69.13; N, 3.98.
(4S*,5S*,8R*)-Isomer 6dI
1H NMR (500.13 MHz, CDCl3): d = 1.28 (s, 3 H, 10-CH3), 1.35 (s,
3 H, 11-CH3), 2.10 (m, 1 H, H3¢), 2.32 (m, 1 H, H3¢¢), 2.41 (dd,
J = 13.5, 9.6 Hz, 1 H, H9¢), 2.64 (dd, J = 13.5, 8.5 Hz, 1 H, H9¢¢),
3.40 (dd, J = 13.2, 7.4 Hz, 1 H, H4), 3.59 (s, 3 H, 15-CH3), 3.63 (dd,
J = 9.6, 8.5 Hz, 1 H, H8), 7.10–7.45 (m, 4 H, H15, H16), 8.81 (br,
1 H, NH).
Mixture of 6eI and 6eII
Oil; ratio 6eI/6eII 1.3:1.0; Rf = 0.16 (EtOAc–hexane, 1:1).
(2S*,3S*,3aR*,4¢R*,7aR*)-Isomer 6eI
1H NMR (500.13 MHz, CDCl3): d = 1.15–1.25 (m, 1 H, H11), 1.30–
1.45 (m, 2 H, H12), 1.48–1.53 (m, 2 H, H10, H13), 1.60–1.65 (m, 2
H, H11, H13), 1.85 (m, 1 H, H10), 2.49 (dd, J = 13.3, 8.7 Hz, 1 H,
H9¢), 2.70 (m, 1 H, H3), 2.80 (m, 1 H, H9¢¢), 3.31 (d, J = 11.9 Hz, 1
H, H4), 3.65 (dd, J = 8.7, 9.6 Hz, 1 H, H8), 3.68 (s, 3 H, 15-CH3),
4.23 (m, 1 H, H2), 7.10–7.30 (m, 6 H, H17, H18, H19, NH).
13C NMR (CDCl3): d = 29.0 and 29.7 (C10, C11), 35.6 (C9), 42.9
(C3), 47.3 (C8), 52.6 (C13), 52.3 (C4), 80.0 (C2), 97.5 (C5), 128.7
and 130.4 (C15, C16), 132.3 and 134.1 (C14, C17), 168.5 (C12),
173.2 (C7).
Characteristic 2D-NOESY correlations: NH/11-CH3, NH/H3¢¢,
H15/H3¢¢, H4/H9¢¢, H8/H9¢, H4/10-CH3, H3¢/10-CH3, H3¢¢/11-CH3.
13C NMR (CDCl3): d = 21.0 (C12), 22.2 (C11), 25.2 (C13), 28.2
(C10), 38.1 (C9), 41.3 (C3), 46.9 (C8), 52.5 (C15), 54.9 (C4), 76.3
(C2), 96.7 (C5), 127.7 (C19), 128.4 and 128.8 (C17, C18), 135.6
(C16), 169.5 (C14), 171.8 (C7).
(4S*,5S*,8S*)-Isomer 6dII
1H NMR (500.13 MHz, CDCl3): d = 1.25 (s, 3 H, 10-CH3), 1.31 (s,
3 H, 11-CH3), 2.10 (m, 1 H, H3¢), 2.32 (m, 1 H, H3¢¢), 2.49 (dd,
J = 13.4, 9.2 Hz, 1 H, H9¢¢), 2.73 (dd, J = 13.4, 9.5 Hz, 1 H, H9¢),
2.78 (dd, J = 9.5, 9.2 Hz, 1 H, H8), 3.40 (dd, J = 13.2, 7.4 Hz, 1 H,
H4), 3.71 (s, 3 H, 15-CH3), 7.10–7.45 (m, 4 H, H15, H16), 9.10 (br,
1 H, NH).
Characteristic 2D-NOESY correlations: H3/H2, H17/H2, H17/H3,
H4/H9¢¢, H8/H9¢.
(2S*,3S*,3aR*,4¢S*,7aR*)-Isomer 6eII
1H NMR (500.13 MHz, CDCl3): d = 1.15–1.25 (m, 1 H, H11), 1.30–
1.45 (m, 3 H, H10, H12), 1.48–1.53 (m, 1 H, H13), 1.61–1.65 (m, 2
H, H11, H13), 1.95 (m, 1 H, H10), 2.56 (dd, J = 13.7, 9.5 Hz, 1 H,
H9¢¢), 2.70 (m, 1 H, H3), 2.80 (m, 1 H, H9¢), 2.90 (dd, J = 9.5, 7.3
Hz, 1 H, H8), 3.31 (d, J = 11.9 Hz, 1 H, H4), 3.70 (s, 3 H, 15-CH3),
4.23 (m, 1 H, H2), 6.80 (br, 1 H, NH), 7.10–7.40 (m, 5 H, H17, H18,
H19).
13C NMR (CDCl3): d = 29.0 and 29.7 (C10, C11), 35.7 (C9), 42.7
(C3), 47.8 (C8), 52.6 (C13), 53.7 (C4), 80.5 (C2), 97.5 (C5), 128.9
and 130.2 (C15, C16), 132.4 and 134.3 (C14, C17), 168.5 (C12),
172.1 (C7).
Characteristic 2D-NOESY correlations: NH/11-CH3, NH/H3¢¢,
H15/H3¢¢, H4/H9¢¢, H8/H9¢¢, H4/10-CH3, H3¢/10-CH3, H3¢¢/11-
CH3.
13C NMR (CDCl3): d = 20.5 (C12), 22.6 (C11), 24.1 (C13), 30.3
(C10), 37.6 (C9), 40.4 (C3), 47.5 (C8), 53.2 (C15), 55.2 (C4), 76.3
(C2), 96.6 (C5), 127.8 (C19), 128.4 and 128.8 (C17, C18), 135.2
(C16), 169.5 (C14), 171.8 (C7).
Mixture of 6dIII and 6dIV
Oil; ratio 6dIII/6dIV 1.0:1.0; Rf = 0.13 (EtOAc–hexane, 1:1).
(4S*,5R*,8S*)-Isomer 6dIII
Characteristic 2D-NOESY correlations: H3/H2, H17/H2, H17/H3,
NH/H3, H4/H9¢¢, H8/H9¢¢.
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 2.23 (m, 2 H,
H3), 2.32 (m, 2 H, H9), 3.56 (s, 3 H, 13-CH3), 3.63 (m, 1 H, H8),
3.72 (dd, J = 12.4, 7.0 Hz, 1 H, H4), 7.18 (d, J = 7.9 Hz, 2 H, H15),
7.30–7.35 (m, 2 H, H16), 8.21 (br, 1 H, NH).
Mixture of 6eIII and 6eIV
Oil; ratio 6eIII/6eIV 1.0:1.0; Rf = 0.19 (EtOAc–hexane, 1:1).
13C NMR (CDCl3): d (selected signals from HSQC) = 42.3 (C3),
50.0 (C4), 79.1 (C2).
(2R*,3S*,3aR*,4¢S*,7aR*)-Isomer 6eIII
1H NMR (500.13 MHz, CDCl3): d = 1.10–1.60 (m, 7 H, H10, H11,
H12, H13), 1.81–1.98 (m, 1 H, H10), 2.07 (m, 2 H, H9), 2.73 (m, 1
H, H3), 3.48 (d, J = 11.9 Hz, 1 H, H4), 3.55 (s, 3 H, 15-CH3), 3.60
(dd, J = 8.9, 8.9 Hz, 1 H, H8), 4.17 (m, 1 H, H2), 7.10–7.30 (m, 5
H, H17, H18, H19), 7.79 (br, 1 H, NH).
Characteristic 2D-NOESY correlations: NH/10-CH3, NH/H4.
(4S*,5R*,8R*)-Isomer 6dIV
1H NMR (500.13 MHz, CDCl3): d (selected signals) = 2.06 (m, 1 H,
H3¢), 2.10 (m, 1 H, H3¢¢), 2.13 (m, 1 H, H9¢), 2.32 (dd, J = 13.9, 8.8
Hz, 1 H, H9¢¢), 2.49 (dd, J = 8.8, 8.8 Hz, 1 H, H8), 3.61 (m, 1 H,
H4), 3.66 (s, 3 H, 13-CH3), 7.21 (d, J = 8.5 Hz, 2 H, H15), 7.30–
7.35 (m, 2 H, H16), 7.95 (br, 1 H, NH).
13C NMR (CDCl3): d = 20.4 (C12), 22.7 (C11), 25.1 (C13), 30.3
(C10), 35.7 (C9), 40.7 (C3), 46.9 (C8), 52.8 and 52.9 (C4, C15),
76.5 (C2), 98.1 (C5), 127.5 (C19), 128.4 and 128.8 (C17, C18),
136.6 (C16), 169.4 (C14), 173.2 (C7).
13C NMR (CDCl3): d (selected signals from HSQC) = 41.1 (C3),
51.3 (C4), 79.1 (C2).
Characteristic 2D-NOESY correlations: NH/H4, 9-CH2/H17, 9-
CH2/H8, H2/H3.
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

1216
A. Yu. Sukhorukov et al.
PAPER
(2R*,3S*,3aR*,4¢R*,7aR*)-Isomer 6eIV
13C NMR (CDCl3): d (selected signals from HSQC) = 37.6 (C9),
1H NMR (500.13 MHz, CDCl3): d = 1.10–1.60 (m, 7 H, H10, H11,
H12, H13), 1.81–1.98 (m, 1 H, H10), 2.18 (dd, J = 13.0, 9.2 Hz, 1
H, H9¢), 2.31 (dd, J = 13.0, 8.3 Hz, 1 H, H9¢¢), 2.36 (dd, J = 8.3, 9.2
Hz, 1 H, H8), 2.73 (m, 1 H, H3), 3.48 (d, J = 13.2 Hz, 1 H, H4), 3.68
(s, 3 H, 15-CH3), 4.17 (m, 1 H, H2), 7.10–7.40 (m, 5 H, H17, H18,
H19), 7.72 (br, 1 H, NH).
40.7 (C3), 47.0 (C8).
Characteristic 2D-NOESY correlations: 9-CH2/H17, 9-CH2/H8,
H2/H3.
(2R*,3S*,3aR*,4¢R*,7aR*)-Isomer 6fIV
1H NMR (500.13 MHz, CDCl3): d = 1.10–1.70 (m, 8 H, H10, H11,
H12, H13), 2.16 (dd, J = 13.5, 9.0 Hz, 1 H, H9¢), 2.25 (dd, J = 13.5,
8.3 Hz, 1 H, H9¢¢), 2.37 (dd, J = 8.3, 9.0 Hz, 1 H, H8), 2.70 (m, 1 H,
H3), 3.41 (d, J = 12.0 Hz, 1 H, H4), 3.66 (s, 3 H, 15-CH3), 3.75 (s,
3 H, 20-CH3), 4.13 (m, 1 H, H2), 6.83 (d, J = 8.3 Hz, 2 H, H18),
7.10 (d, J = 8.3 Hz, 2 H, H17), 7.74 (br, 1 H, NH).
13C NMR (CDCl3): d = 20.9 (C12), 23.1 (C11), 24.1 (C13), 30.3
(C10), 37.6 (C9), 38.9 (C3), 47.6 (C8), 52.3 and 52.4 (C4, C15),
76.2 (C2), 97.7 (C5), 127.5 (C19), 128.4 and 128.8 (C17, C18),
135.4 (C16), 169.5 (C14), 173.2 (C7).
Characteristic 2D-NOESY correlations: H4/NH, H2/H3, H17/H9¢,
H8/H9¢.
13C NMR (CDCl3): d (selected signals from HSQC) = 37.6 (C9),
40.7 (C3), 47.7 (C8).
Methyl 3-(4-Methoxyphenyl)-5¢-oxo-hexahydro-3H-spiro[1-
benzofuran-2,2¢-pyrrolidine]-4¢-carboxylate (6f)
Mixture of 6fI and 6fII
Characteristic 2D-NOESY correlations: H4/NH, H2/H3, H17/H9¢,
H8/H9¢.
Oil; ratio 6fI/6fII 1.5:1.0; Rf = 0.12 (EtOAc–hexane, 1:1).
Unassigned signals of both isomers:
13C NMR (CDCl3): d = 20.4 and 20.8 (C12), 22.8 and 23.2 (C11),
24.1 and 24.9 (C13), 30.2 and 30.4 (C10), 47.0 (C8), 51.6 and 51.8
(C4), 52.4 and 52.5 (C15), 55.2 (C20), 76.3 and 76.5 (C2), 97.8 and
98.2 (C5), 114.2 and 114.4 (C18), 126.9 and 128.3 (C16), 129.4 and
129.7 (C17), 158.9 and 159.0 (C19), 169.5 and 169.6 (C14), 171.4
and 173.4 (C7).
(2S*,3S*,3aR*,4¢R*,7aR*)-Isomer 6fI
Crystallized from mixture with 6fII; mp 159–165 °C.
1H NMR (500.13 MHz, CDCl3): d = 1.10–1.70 (m, 7 H, H10, H11,
H12, H13), 1.87 (m, 1 H, H10), 2.45 (dd, J = 13.1, 8.5 Hz, 1 H,
H9¢), 2.63 (m, 1 H, H3), 2.75 (dd, J = 13.1, 9.6 Hz, 1 H, H9¢¢), 3.24
(d, J = 11.1 Hz, 1 H, H4), 3.64 (dd, J = 8.5, 9.6 Hz, 1 H, H8), 3.66
(s, 3 H, 15-CH3), 3.74 (s, 3 H, 20-CH3), 4.20 (ddd, J = 9.9, 7.2, 2.5
Hz, 1 H, H2), 6.79 (d, J = 8.4 Hz, 2 H, H18), 7.08 (d, J = 8.4 Hz, 2
H, H17), 7.35 (br, 1 H, NH).
13C NMR (CDCl3): d = 20.8 (C12), 22.4 (C11), 24.8 (C13), 29.8
(C10), 37.7 (C9), 41.2 (C3), 47.0 (C8), 51.8 (C15), 53.5 (C4), 55.2
(C20), 76.3 (C2), 96.7 (C5), 114.2 (C18), 127.2 (C16), 129.6
(C17), 158.9 (C19), 169.6 (C14), 172.2 (C7).
Methyl 5¢-Oxo-3-phenyl-hexahydrospiro[2H-cyclopenta[b]fu-
ran-2,2¢-pyrrolidine]-4¢-carboxylate (6g)
Anal. Calcd for C18H21NO4: H, 6.71; C, 68.55; N, 4.44. Found: H,
6.74; C, 68.29; N, 4.15.
Mixture of 6gI and 6gII
Oil; ratio 6gI/6gII 1.4:1.0; Rf = 0.16 (EtOAc–hexane, 1:1).
Characteristic 2D-NOESY correlations: H3/H2, H17/H3, H4/H9¢¢,
H8/H9¢.
(2S*,3S*,3aR*,4¢R*,6aR*)-Isomer 6gI
1H NMR (500.13 MHz, CDCl3): d = 1.48–1.53 (m, 3 H, H10, H12),
1.55–1.75 (m, 2 H, H11), 1.80–1.90 (m, 1 H, H10), 2.41 (dd,
J = 13.6, 8.8 Hz, 1 H, H9¢), 2.55 (dd, J = 13.6, 9.0 Hz, 1 H, H9¢¢),
2.74 (d, J = 9.6 Hz, 1 H, H4), 3.07 (m, 1 H, H3), 3.57 (s, 3 H, 14-
CH3), 3.63 (dd, J = 8.8, 9.0 Hz, 1 H, H8), 4.61 (dd, J = 8.6, 8.6 Hz,
1 H, H2), 7.10–7.40 (m, 5 H, H16, H17, H18), 8.84 (br, 1 H, NH).
Anal. Calcd for C20H25NO5: H, 7.01; C, 66.83; N, 3.90. Found: H,
6.91; C, 67.15; N, 3.81.
(2S*,3S*,3aR*,4¢S*,7aR*)-Isomer 6fII
Described in mixture with 6fI.
13C NMR (CDCl3): d = 23.2 (C11), 31.7 (C12), 33.6 and 33.9 (C9,
C10), 47.3 (C8), 48.1 (C3), 52.5 (C14), 59.3 (C4), 82.3 (C2), 98.5
(C5), 127.5 (C18), 128.5 and 129.2 (C16, C17), 136.2 (C15), 169.5
(C13), 173.7 (C7).
1H NMR (500.13 MHz, CDCl3): d = 1.10–1.70 (m, 7 H, H10, H11,
H12, H13), 1.97 (m, 1 H, H10), 2.51 (dd, J = 13.7, 9.3 Hz, 1 H,
H9¢¢), 2.63 (m, 1 H, H3), 2.78 (dd, J = 13.7, 7.5 Hz, 1 H, H9¢), 2.89
(dd, J = 9.3, 7.5 Hz, 1 H, H8), 3.24 (d, J = 11.1 Hz, 1 H, H4), 3.71
(s, 3 H, 15-CH3), 3.76 (s, 3 H, 20-CH3), 4.20 (ddd, J = 9.9, 7.2, 2.5
Hz, 1 H, H2), 6.83 (d, J = 8.5 Hz, 2 H, H18), 7.09 (d, J = 8.5 Hz, 2
H, H17), 7.42 (br, 1 H, NH).
13C NMR (CDCl3): d = 20.4 (C12), 22.7 (C11), 24.0 (C13), 30.5
(C10), 37.4 (C9), 40.3 (C3), 47.6 (C8), 52.6 (C15), 54.2 (C4), 55.2
(C20), 76.4 (C2), 96.7 (C5), 114.3 (C18), 126.8 (C16), 129.9 (C17),
158.9 (C19), 169.6 (C14), 170.9 (C7).
Characteristic 2D-NOESY correlations: H2/H3, NH/H16, NH/H2,
NH/H3, H16/H2, H16/H3, H4/H9¢¢, H8/H9¢.
(2S*,3S*,3aR*,4¢S*,6aR*)-Isomer 6gII
1H NMR (500.13 MHz, CDCl3): d = 1.48–1.53 (m, 3 H, H10, H12),
1.55–1.75 (m, 2 H, H11), 1.80–1.90 (m, 1 H, H10), 2.41 (dd,
J = 13.9, 9.6 Hz, 1 H, H9¢¢), 2.69 (dd, J = 13.9, 6.2 Hz, 1 H, H9¢),
2.76 (d, J = 9.6 Hz, 1 H, H4), 2.84 (dd, J = 9.6, 6.2 Hz, 1 H, H8),
3.07 (m, 1 H, H3), 3.70 (s, 3 H, 14-CH3), 4.63 (dd, J = 8.6, 8.6 Hz,
1 H, H2), 7.10–7.40 (m, 5 H, H16, H17, H18), 8.78 (br, 1 H, NH).
Characteristic 2D-NOESY correlations: H3/H2, H17/H2, H17/H3,
NH/H3, H4/H9¢¢, H8/H9¢¢.
13C NMR (CDCl3): d = 23.2 (C11), 31.4 (C12), 33.6 and 33.9 (C9,
C10), 47.6 (C8), 47.9 (C3), 52.6 (C14), 60.6 (C4), 83.1 (C2), 98.5
(C5), 127.6 (C18), 128.6 and 129.2 (C16, C17), 136.4 (C15), 169.5
(C13), 172.5 (C7).
Mixture of 6fIII and 6fIV
Oil; ratio 6fIII/6fIV 3.4:3.8; Rf = 0.16 (EtOAc–hexane, 1:1).
(2R*,3S*,3aR*,4¢S*,7aR*)-Isomer 6fIII
1H NMR (500.13 MHz, CDCl3): d = 1.10–1.70 (m, 8 H, H10, H11,
H12, H13), 2.04 (m, 2 H, H9), 2.70 (m, 1 H, H3), 3.41 (d, J = 12.0
Hz, 1 H, H4), 3.53 (s, 3 H, 15-CH3), 3.58 (dd, J = 8.9, 8.9 Hz, 1 H,
H8), 3.75 (s, 3 H, 20-CH3), 4.13 (m, 1 H, H2), 6.85 (d, J = 8.4 Hz,
2 H, H18), 7.05 (d, J = 8.4 Hz, 2 H, H17), 7.66 (br, 1 H, NH).
Characteristic 2D-NOESY correlations: H2/H3, NH/H16, NH/H2,
NH/H3, H16/H2, H16/H3, H4/H9¢¢, H8/H9¢¢.
Mixture of 6gI, 6gII, 6gIII, and 6gIV
Oil; ratio 6gI/6gII/6gIII/6gIV 1.0:1.7:0.8:0.6; Rf = 0.14 (EtOAc–hex-
ane, 1:1).
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
1217
(2R*,3S*,3aR*,4¢S*,6aR*)-Isomer 6gIII
Mixture of 6hI, 6hII, 6hIII, and 6hIV
1H NMR (500.13 MHz, CDCl3): d = 1.48–1.53 (m, 3 H, H10, H12),
1.55–1.75 (m, 2 H, H11), 1.80–1.90 (m, 1 H, H12), 2.14 (m, 2 H,
H9), 3.01 (d, J = 8.8 Hz, 1 H, H4), 3.07 (m, 1 H, H3), 3.57 (s, 3 H,
14-CH3), 3.63 (m, 1 H, H8), 4.54 (m, 1 H, H2), 7.10–7.40 (m, 5 H,
H16, H17, H18), 7.35 (br, 1 H, NH).
Oil; ratio 6hI/6hII/6hIII/6hIV 3.1:1.0:10.0:4.7; Rf = 0.19 (EtOAc–
hexane, 1:1).
(1R*,2R*,4R*,4¢S*,5S*,6R*,7R*)-Isomer 6hIII
1H NMR (500.13 MHz, CDCl3): d = 0.90–1.10 (m, 3 H, H11, H12,
H14anti), 1.45 (m, 1 H, H12), 1.64 (m, 1 H, H11), 1.72 (m, 1 H,
H14syn), 2.05 (m, 1 H, H13), 2.12 (d, J = 9.2 Hz, 2 H, H9), 2.35 (d,
J = 3.0 Hz, 1 H, H10), 2.45 (m, 1 H, H3), 2.93 (d, J = 8.8 Hz, 1 H,
H4), 3.57 (s, 3 H, 16-CH3), 3.60 (t, J = 9.2 Hz, 1 H, H8), 3.84 (d,
J = 6.8 Hz, 1 H, H2), 7.20–7.40 (m, 5 H, H18, H19, H20), 7.52 (br,
1 H, NH).
13C NMR (CDCl3): d = 23.5 (C11), 30.2 (C9), 31.5 (C12), 33.6
(C10), 46.5 (C3), 48.1 (C8), 52.6 (C14), 56.9 (C4), 81.2 (C2), 98.5
(C5), 127.6 (C18), 128.7 and 129.2 (C16, C17), 136.9 (C15), 169.5
(C13), 173.1 (C7).
Characteristic 2D-NOESY correlations: NH/H4, H2/H3.
13C NMR (CDCl3): d = 23.5 (C11), 27.7 (C12), 31.9 and 32.2 (C9,
C14), 39.4 and 40.1 (C10, C13), 46.9 (C8), 50.6 (C3), 52.6 (C16),
54.8 (C4), 81.8 (C2), 97.5 (C5), 127.5 (C20), 128.7 and 129.2 (C18,
C19), 136.7 (C17), 169.2 (C15), 173.4 (C7).
(2R*,3S*,3aR*,4¢R*,6aR*)-Isomer 6gIV
1H NMR (500.13 MHz, CDCl3): d = 1.48–1.53 (m, 3 H, H10, H12),
1.55–1.75 (m, 2 H, H11), 1.80–1.90 (m, 1 H, H12), 2.21 (dd,
J = 13.7, 9.6 Hz, 1 H, H9¢), 2.35 (dd, J = 13.7, 6.4 Hz, 1 H, H9¢¢),
2.58 (m, 1 H, H8), 2.90 (d, J = 9.0 Hz, 1 H, H4), 3.12 (m, 1 H, H3),
3.68 (s, 3 H, 14-CH3), 4.54 (m, 1 H, H2), 7.10–7.40 (m, 6 H, H16,
H17, H18, NH).
Characteristic 2D-NOESY correlations: NH/H4, H2/H3, H18/H3,
H13/H4, H4/H14syn, H2C(9)/H8.
(1R*,2R*,4R*,4¢R*,5S*,6R*,7R*)-Isomer 6hIV
13C NMR (CDCl3): d = 23.4 (C11), 31.6 (C12), 32.1 (C9), 33.6
(C10), 46.9 (C3, C8), 52.6 (C14), 57.9 (C4), 80.6 (C2), 98.5 (C5),
127.5 (C18), 128.3 and 129.2 (C16, C17), 136.9 (C15), 169.5
(C13), 173.1 (C7).
1H NMR (500.13 MHz, CDCl3): d = 0.90–1.10 (m, 3 H, H11, H12,
H14anti), 1.45 (m, 1 H, H12), 1.64 (m, 1 H, H11), 1.72 (m, 1 H,
H14syn), 2.05 (m, 1 H, H13), 2.19 (dd, J = 13.0, 9.8 Hz, 1 H, H9¢),
2.28 (m, 1 H, H9¢¢), 2.35 (d, J = 3.7 Hz, 1 H, H10), 2.45 (m, 1 H,
H3), 2.55 (dd, J = 9.8, 6.2 Hz, 1 H, H8), 2.84 (d, J = 9.2 Hz, 1 H,
H4), 3.68 (s, 3 H, 16-CH3), 3.90 (d, J = 6.8 Hz, 1 H, H2), 7.20–7.40
(m, 6 H, H18, H19, H20, NH).
Characteristic 2D-NOESY correlations: H2/H3, H16/H9¢, H8/H9¢.
Methyl 5¢-Oxo-5-phenylspiro[3-oxatricyclo[5.2.1.02,6]decane-
4,2¢-pyrrolidine]-4¢-carboxylate (6h)
Anal. Calcd for C20H23NO4: H, 6.79; C, 70.36; N, 4.10. Found: H,
6.97; C, 70.17; N, 4.10.
13C NMR (CDCl3): d = 23.5 (C11), 27.7 (C12), 31.9 and 32.2 (C9,
C14), 39.4 and 40.1 (C10, C13), 47.5 (C8), 49.5 (C3), 52.6 (C16),
56.1 (C4), 81.7 (C2), 97.1 (C5), 127.6 (C20), 128.7 and 129.2 (C18,
C19), 136.5 (C17), 169.2 (C15), 171.5 (C7).
Mixture of 6hI and 6hII
Oil; ratio 6hI/6hII 1.4:1.0; Rf = 0.22 (EtOAc–hexane, 1:1).
Characteristic 2D-NOESY correlations: NH/H4, H2/H3, H13/H4,
H4/H14syn, H18/H9¢, H8/H9¢.
(1R*,2R*,4S*,4¢R*,5S*,6R*,7R*)-Isomer 6hI
1H NMR (500.13 MHz, CDCl3): d = 1.02 (m, 2 H, H11, H12), 1.10
(m, 1 H, H14anti), 1.42 (m, 1 H, H12), 1.45 (m, 1 H, H11), 1.63 (m,
1 H, H14syn), 2.02 (d, J = 3.6 Hz, 1 H, H13), 2.27 (d, J = 4.7 Hz, 1
H, H10), 2.40 (m, 2 H, H3, H9¢), 2.56 (dd, J = 13.7, 9.7 Hz, 1 H,
H9¢¢), 2.71 (d, J = 8.5 Hz, 1 H, H4), 3.60 (s, 3 H, 16-CH3), 3.63 (dd,
J = 8.8, 9.7 Hz, 1 H, H8), 3.94 (d, J = 6.2 Hz, 1 H, H2), 7.20–7.40
(m, 5 H, H18, H19, H20), 8.39 (br, 1 H, NH).
Methyl 2-Ethoxy-4-(4-methoxyphenyl)-7-oxo-1-oxa-6-aza-
spiro[4.4]nonane-8-carboxylate (6i) and Dimethyl {[1-(tert-
Butoxycarbonyl)-3-(4-methoxyphenyl)pyrrolidin-2-yl]meth-
yl}malonate (7)
Oxaazaspirononane 6i can be obtained as byproduct (20%) using
the previously reported procedure for the hydrogenation of 4i.6a The
optimized procedure is given below.
13C NMR (CDCl3): d = 23.4 (C11), 27.7 (C12), 31.1 (C14), 33.8
(C9), 39.7 and 40.2 (C10, C13), 47.2 (C8), 52.4 and 52.5 (C3, C16),
57.5 (C4), 83.5 (C2), 97.6 (C5), 127.5 (C20), 128.5 and 129.2 (C18,
C19), 136.4 (C17), 169.4 (C15), 173.4 (C7).
To a soln of 4i (0.3 g, 0.79 mmol) in MeOH (5 mL) was added
Boc2O (0.28 g, 1.28 mmol), Et3N (0.11 mL, 0.79 mmol), and Raney
Ni (c.a. 0.1 g in MeOH, prepared using procedure b). The mixture
was hydrogenated at 45 bar H2 and 80 ° C for 2 h. The resulting soln
was filtered and evaporated under reduced pressure. The products
were separated by column chromatography (silica gel, EtOAc–hex-
ane, 1:5 to 1:3 to 1:1).
Characteristic 2D-NOESY correlations: NH/H2, NH/H3, NH/H18,
H2/H3, H18/H3, H2/H11, H4/H14syn, H4/H13, H2/H10, H4/H9¢¢,
H8/H9¢.
Dimethyl {[1-(tert-Butoxycarbonyl)-3-(4-methoxyphenyl)pyr-
rolidin-2-yl]methylmalonate (7)
(1R*,2R*,4S*,4¢S*,5S*,6R*,7R*)-Isomer 6hII
1H NMR (500.13 MHz, CDCl3): d = 1.02 (m, 2 H, H11, H12), 1.10
(m, 1 H, H14anti), 1.42 (m, 1 H, H12), 1.45 (m, 1 H, H11), 1.63 (m,
1 H, H14syn), 2.01 (d, J = 3.9 Hz, 1 H, H13), 2.32 (d, J = 4.3 Hz, 1
H, H10), 2.33 (m, 2 H, H3, H9¢¢), 2.71 (d, J = 8.5 Hz, 1 H, H4), 2.72
(dd, J = 13.0, 9.7 Hz, 1 H, H9¢), 2.87 (dd, J = 9.7, 6.2 Hz, 1 H, H8),
3.70 (s, 3 H, 16-CH3), 3.94 (d, J = 6.2 Hz, 1 H, H2), 7.20–7.40 (m,
5 H, H18, H19, H20), 8.56 (br, 1 H, NH).
Oil; mixture of trans- and cis-isomers (7I/7II 5.7:1); Rf = 0.75
(EtOAc–hexane, 1:1); yield: 0.11 g (33%).
The NMR spectroscopic data are in agreement with the published
data for 7.6a
Methyl 2-Ethoxy-4-(4-methoxyphenyl)-7-oxo-1-oxa-6-aza-
spiro[4.4]nonane-8-carboxylate (6i)
Anal. Calcd for C18H23NO6: H, 6.64; C, 61.88; N, 4.01. Found: H,
6.81; C, 61.76; N, 3.80.
Mixture of 6iI, 6iII, and 6iIII
13C NMR (CDCl3): d = 23.4 (C11), 27.7 (C12), 31.1 (C14), 33.8
(C9), 39.4 and 40.2 (C10, C13), 47.4 (C8), 52.4 and 52.5 (C3, C16),
59.1 (C4), 84.3 (C2), 97.6 (C5), 127.5 (C20), 128.6 and 129.0 (C18,
C19), 136.7 (C17), 169.4 (C15), 172.2 (C7).
Characteristic 2D-NOESY correlations: NH/H2, NH/H3, NH/H18,
Oil; ratio 6iI/6iII/6iIII 3.1:1.6:1.0; Rf = 0.29 (EtOAc–hexane, 1:1).
H4/H14syn, H18/H3, H2/H10, H4/H9¢¢, H8/H9¢¢.
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

1218
A. Yu. Sukhorukov et al.
PAPER
Dimethyl {[3-(4-Methoxyphenyl)-5-methyl-1H-pyrrol-2-
(2S*,4S*,5S*,8R*)-Isomer 6iI
1H NMR (500.13 MHz, CDCl3): d = 1.23 (t, J = 7.3 Hz, 3 H, 11-
CH3), 2.26–2.48 (m, 2 H, H3), 2.64 (dd, J = 8.5, 13.3 Hz, 1 H, H9¢),
2.75 (dd, J = 9.6, 13.3 Hz, 1 H, H9¢¢), 3.51 and 3.81 (2 m, 2 H, H10),
3.60 (m, 1 H, H4), 3.68 (dd, J = 8.5, 9.6 Hz, 1 H, H8), 3.74 (s, 3 H,
13-CH3), 3.77 (s, 3 H, 18-CH3), 5.27 (m, 1 H, H2), 6.03 (br, 1 H,
NH), 6.84 (d, J = 8.1 Hz, 2 H, H16), 7.08 (d, J = 8.5 Hz, 2 H, H15).
yl]methyl)malonate (8)
Product 8 can be obtained using the procedure for hydrogenation of
4a–h in 78% yield. Best result was obtained using the procedure
given below.
To a soln of 4j (0.3 g, 0.79 mmol) in MeOH (15 mL) was added Pd/
C (5% Pd, 0.05 g) and the mixture was hydrogenated at 110 bar H2
and 100 ° for 4 h and at 100 bar H2 and r.t. for 18 h. The resulting
soln was filtered and evaporated under reduced pressure. The crude
product was purified by column chromatography (silica gel) to give
an oil that was unstable (oxidized in air); yield: 0.26 g (99%);
Rf = 0.59 (EtOAc–hexane, 1:1).
1H NMR (300.13 MHz, CDCl3): d = 2.24 (s, 3 H, 5-CH3), 3.25 (d,
J = 6.6 Hz, 2 H, H6), 3.68 (t, J = 6.6 Hz, 1 H, H7), 3.74 (s, 6 H, 9-
CH3), 3.83 (s, 3 H, 14-CH3), 5.90 (d, J = 2.2 Hz, 1 H, H3), 6.92 (d,
J = 8.8 Hz, 2 H, H12), 7.26 (d, J = 8.8 Hz, 2 H, H11), 8.35 (br, 1 H,
NH).
13C NMR (CDCl3): d = 15.2 (C11), 38.3 (C9), 38.7 (C3), 47.1 (C8),
49.8 (C4), 52.7 (C13), 55.3 (C18), 63.5 (C10), 97.5 (C5), 101.8
(C2), 114.4 (C16), 129.0 (C15), 130.2 (C14), 159.1 (C17), 169.6
and 171.7 (C7, C12).
Characteristic 2D-NOESY correlations: NH/H15, H2/H15, H4/
H9¢¢, H9¢/H8.
(2S*,4S*,5S*,8S*)-Isomer 6iII
1H NMR (500.13 MHz, CDCl3): d = 1.24 (t, J = 7.3 Hz, 3 H, 11-
CH3), 2.26–2.48 (m, 2 H, H3), 2.58 (dd, J = 9.7, 13.8 Hz, 1 H, H9¢¢),
2.89 (dd, J = 5.8, 13.8 Hz, 1 H, H9¢), 3.14 (dd, J = 5.8, 9.7 Hz, 1 H,
H8), 3.51 and 3.81 (2 m, 2 H, H10), 3.60 (m, 1 H, H4), 3.76 and 3.77
(2 s, 6 H, 13-CH3, 18-CH3), 5.27 (m, 1 H, H2), 6.42 (br, 1 H, NH),
6.84 (d, J = 8.1 Hz, 2 H, H16), 7.08 (d, J = 8.5 Hz, 2 H, H15).
13C NMR (CDCl3): d = 12.9 (C5), 25.3 (C6), 36.8 (C7), 52.7 (C9),
55.3 (C14), 106.6 (C3), 113.9 (C12), 121.9, 122.6, and 126.8 (C1,
C2, C4), 128.9 (C11), 129.4 (C10), 157.7 (C13), 170.0 (C8).
13C NMR (CDCl3): d = 15.2 (C11), 38.0 (C9), 38.7 (C3), 47.5 (C8),
50.7 (C4), 52.7 (C13), 55.3 (C18), 63.4 (C10), 97.6 (C5), 101.6
(C2), 114.4 (C16), 129.2 (C15), 130.2 (C14), 159.1 (C17), 169.6
and 170.9 (C7, C12).
Dimethyl (5-Hydroxy-2-(hydroxyimino)-5-methyl-3-phenyl-
hexyl)malonate (11)
t-BuOK (0.13 g, 1.2 mmol) was added to a stirred soln of dimethyl
malonate (0.16 g, 1.2 mmol) in DMF (1 mL) at 0 °C. After 5 min, a
soln
of
1-bromo-5-hydroxy-5-methyl-3-phenylhexan-2-one
Characteristic 2D-NOESY correlations: NH/H15, H2/H15, H4/
H9¢¢, H9¢¢/H8.
oxime6b (0.30 g, 1.0 mmol) in DMF (1.5 mL) was carefully added.
The resulting mixture was stirred at 60 °C for 2 h and poured into a
mixture of EtOAc (100 mL) and H2O (100 mL). The aqueous phase
was back-extracted with EtOAc (2 × 50 mL) and the combined or-
ganic layers were washed with brine (50 mL) and dried (Na2SO4).
The solvent was evaporated in vacuo and the residue was subjected
to column chromatography (silica gel) to give the corresponding
oxime as one isomer; yield: 0.28 g (78%); mp 95–103 °C; Rf = 0.23
(EtOAc–hexane, 1:1).
Mixture of 6iIII and 6iIV
Ratio 6i III/6iIV 1.3:1.0; mp 135–141 °C; Rf = 0.33 (EtOAc–hexane,
1:1).
(2S*,4S*,5R*,8S*)-Isomer 6iIII
1H NMR (500.13 MHz, CDCl3): d = 1.20 (t, J = 7.3 Hz, 3 H, 11-
CH3), 1.97 (dd, J = 8.7, 13.8 Hz, 1 H, H9¢¢), 2.13 (dd, J = 8.8, 13.8
Hz, 1 H, H9¢), 2.40 (m, 2 H, H3), 3.49 and 3.80 (2 m, 2 H, H10),
3.58 (m, 2 H, H8, H4), 3.67 (s, 3 H, 13-CH3), 3.78 (s, 3 H, 18-CH3),
5.33 (dd, J = 2.3, 4.7 Hz, 1 H, H2), 6.61 (br, 1 H, NH), 6.85 (d,
J = 8.1 Hz, 2 H, H16), 7.05 (d, J = 8.5 Hz, 2 H, H15).
1H NMR (300.13 MHz, CDCl3): d = 1.23 (s, 6 H, 11-CH3, 12-CH3),
1.76 (dd, J = 3.5, 15.8 Hz, 1 H, H3), 2.20 (m, 1 H, H3), 2.39 (m, 3
H, H5, OH), 3.66 and 3.74 (2 s, 6 H, 9-CH3, 10-CH3), 3.87 (dd,
J = 3.5, 10.5 Hz, 1 H, H2), 4.06 (m, 1 H, H6), 7.20–7.35 (m, 5 H,
H14, H15, H16), 10.35 (br, 1 H, NOH).
13C NMR (CDCl3): d = 28.2 and 29.0 (C11, C12), 30.5 (C5), 45.0
(C2), 47.9 (C3), 48.7 (C6), 52.6 (C9, C10), 70.3 (C4), 127.1, 128.2,
and 128.9 (C14, C15, C16), 142.1 (C13), 159.5 (C1), 169.5 (C9,
C10).
13C NMR (CDCl3): d = 15.2 (C11), 34.7 (C9), 40.4 (C3), 47.1 and
50.8 (C4, C8), 52.7 (C13), 55.2 (C18), 63.6 (C10), 98.6 (C5), 103.3
(C2), 114.1 (C16), 129.1 (C15), 131.7 (C14), 158.9 (C17), 169.7
and 171.8 (C7, C12).
Characteristic 2D-NOESY correlations: NH/H4, H2/H15, H15/H9¢,
H9¢¢/H8.
Anal Calcd for C18H25NO6: H, 7.17; C, 61.52; N, 3.99. Found: H,
7.10; C, 61.36; N, 4.05.
(2S*,4S*,5R*,8R*)-Isomer 6iIV
1H NMR (500.13 MHz, CDCl3): d = 1.21 (t, J = 7.3 Hz, 3 H, 11-
CH3), 2.12 (dd, J = 9.4, 13.9 Hz, 1 H, H9¢), 2.31 (dd, J = 7.0, 13.9
Hz, 1 H, H9¢¢), 2.40 (m, 2 H, H3), 2.85 (dd, J = 7.0, 9.4 Hz, 1 H,
H8), 3.49 and 3.80 (2 m, 2 H, H10), 3.58 (m, 1 H, H4), 3.71 (s, 3 H,
13-CH3), 3.78 (s, 3 H, 18-CH3), 5.26 (d, J = 6.4 Hz, 1 H, H2), 6.61
(br, 1 H, NH), 6.85 (d, J = 8.1 Hz, 2 H, H16), 7.08 (d, J = 8.5 Hz, 2
H, H15).
13C NMR (CDCl3): d = 15.2 (C11), 34.2 (C9), 38.7 (C3), 47.0 (C4),
51.1 (C8), 52.7 (C13), 55.2 (C18), 63.5 (C10), 98.3 (C5), 102.4
(C2), 114.3 (C16), 128.8 (C15), 130.0 (C14), 159.1 (C17), 169.3
and 171.0 (C7, C12).
Methyl 5-[(1R/S)-3-Hydroxy-3-methyl-1-phenylbutyl]-2-oxo-
pyrrolidine-3-carboxylate (9)
To a soln of oxazine 4b (0.1 g, 0.3 mmol) in MeOH (2.0 mL) was
added 4 M HCl in 1,4-dioxane (0.076 mL, 0.3 mmol) and Raney Ni
(c.a. 0.05 g in MeOH, prepared using procedure b). The suspension
was hydrogenated at 50 bar H2 and 70–80 °C with intensive stirring
for 2 h and then filtered and concentrated in vacuo. The residue was
purified by flesh chromatography (silica gel, EtOAc then MeOH).
The EtOAc fraction contained 6b [yield: 0.015 g (17%)], the MeOH
fraction contained 9 [yield: 0.05 g (55%)]; oil; mixture of isomers,
ratio 9I/9II/9III/9IV 1.3:1.5:1.3:1.0. Isomers 9I/9II and 9III/9IV, re-
spectively, cannot be unambiguously assigned by NMR.
Characteristic 2D-NOESY correlations: NH/H4, H2/H15, H15/H9¢,
H9¢/H8.
Anal. Calcd for C17H23NO4: H, 7.59; C, 66.86; N, 4.59. Found: H,
7.68; C, 66.02; N, 4.83.
Isomer 9I (1¢R*,3R*,5S*) or (1¢S*,3R*,5S*)
1H NMR (300.13 MHz, CDCl3): d (selected signals) = 1.80 (m, 1 H,
H7¢), 1.89 (m, 1 H, H5), 1.92 (m, 1 H, H5), 2.08 (m, 1 H, H7¢¢), 2.80
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates
1219
(ddd, J = 9.2, 6.1, 5.0 Hz, 1 H, H4), 3.22 (dd, J = 9.5, 4.2 Hz, 1 H,
H8), 3.92 (ddd, J = 9.2, 7.0, 7.0 Hz, 1 H, H3), 5.05 (br, 1 H, 1-OH),
7.15–7.31 (m, 5 H, H15, H16, H17).
13C NMR (62.5 MHz, CDCl3): d (selected signals) = 30.6 (C7), 47.7
(C4), 48.4 (C8), 59.5 (C3), 70.6 (C8).
(4S*,5S*)-Isomer 12cI
1H NMR (500.13 MHz, CDCl3): d = 1.31 (s, 3 H, 10-CH3), 1.38 (s,
3 H, 11-CH3), 1.63 (ddd, J = 17.6, 9.8, 5.5 Hz, 1 H, H8), 1.80 (m, 2
H, H9), 2.09 (dd, J = 12.8, 7.1 Hz, 1 H, H3¢), 2.25 (m, 1 H, H3¢¢),
2.31 (m, 1 H, H8), 3.55 (dd, J = 13.4, 7.1 Hz, 1 H, H4), 3.77 (s, 3 H,
16-CH3), 6.84 (d, J = 8.4 Hz, 2 H, H14), 7.14 (d, J = 8.4 Hz, 2 H,
H13), 7.95 (br, 1 H, NH).
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢/H8.
13C NMR (CDCl3): d = 29.0 (C10), 29.8 (C8), 29.9 (C11), 31.0
(C9), 41.8 (C3), 50.8 (C4), 55.2 (C16), 78.3 (C2), 99.1 (C5), 114.0
(C14), 128.1 (C12), 128.2 (C13), 158.9 (C15), 177.5 (C7).
Isomer 9II (1¢R*,3R*,5S*) or (1¢S*,3R*,5S*)
1H NMR (300.13 MHz, CDCl3): d (selected signals) = 1.97 (m, 2 H,
H5), 2.05 (m, 1 H, H7¢), 2.59 (ddd, J = 5.9, 6.6, 13.2 Hz, 1 H, H7¢¢),
2.82 (m, 1 H, H8), 2.89 (m, 1 H, H4), 4.11 (m, 1 H, H3), 5.05 (br, 1
H, 1-OH), 7.15–7.31 (m, 5 H, H15, H16, H17).
Characteristic 2D-NOESY correlations: NH/H13, H4/10-CH3,
H13/H3¢¢, H4/H3¢.
13C NMR (62.5 MHz, CDCl3): d (selected signals) = 29.5 (C7), 47.2
(C4), 47.6 (C8), 57.5 (C3).
(4R*,5S*)-Isomer 12cII
1H NMR (500.13 MHz, CDCl3): d = 1.28 (s, 3 H, 10-CH3), 1.37 (s,
3 H, 11-CH3), 1.89 (ddd, J = 17.3, 9.8, 4.9 Hz, 1 H, H8), 2.06 (dd,
J = 12.4, 7.1 Hz, 1 H, H3¢), 2.21 (m, 2 H, H9), 2.31 (m, 1 H, H3¢¢),
2.39 (ddd, J = 17.3, 9.8, 7.5 Hz, 1 H, H8), 3.35 (dd, J = 13.7, 7.1 Hz,
1 H, H4), 3.76 (s, 3 H, 16-CH3), 6.81 (d, J = 8.5 Hz, 2 H, H14), 7.18
(d, J = 8.5 Hz, 2 H, H13), 8.00 (br, 1 H, NH).
13C NMR (CDCl3): d = 29.0 (C10), 29.8 (C8), 29.9 (C11), 31.8
(C9), 43.2 (C3), 52.6 (C4), 55.2 (C16), 79.4 (C2), 99.1 (C5), 114.0
(C14), 128.1 (C12), 129.8 (C13), 158.9 (C15), 177.7 (C7).
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢/H8.
Isomer 9IIII (1¢R*,3S*,5S*) or (1¢S*,3S*,5S*)
1H NMR (300.13 MHz, CDCl3): d (selected signals) = 1.80 (m, 1 H,
H7¢¢), 1.89 (m, 1 H, H5), 1.95 (m, 1 H, H7¢), 2.05 (m, 1 H, H5), 2.90
(ddd, J = 9.5, 5.9, 5.2 Hz, 1 H, H4), 3.35 (dd, J = 10.3, 9.1 Hz, 1 H,
H8), 3.70 (m, 1 H, H3), 5.05 (br, 1 H, 1-OH), 7.15–7.31 (m, 5 H,
H15, H16, H17).
13C NMR (62.5 MHz, CDCl3): d (selected signals) = 31.4 (C7), 47.8
(C4), 48.8 (C8), 59.0 (C3), 70.6 (C6), 126.9 (C17).
Characteristic 2D-NOESY correlations: H4/10-CH3, H13/H3¢¢, H4/
H3¢.
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢¢/H8.
Anal. Calcd for C16H21NO3: H, 7.69; C, 69.79; N, 5.09. Found: H,
7.73; C, 69.71; N, 4.98.
Isomer 9IV (1¢R*,3S*,5S*) or (1¢S*,3S*,5S*)
1H NMR (300.13 MHz, CDCl3): d (selected signals) = 1.93 (m, 2 H,
H5), 2.31 (ddd, J = 8.1, 9.5, 12.7 Hz, 1 H, H7¢), 2.44 (ddd, J = 7.3,
8.8, 12.7 Hz, 1 H, H7¢¢), 2.96 (ddd, J = 2.2, 8.1, 11.4 Hz, 1 H, H4),
3.44 (dd, J = 9.5, 8.8 Hz, 1 H, H8), 3.76 (m, 1 H, H3), 5.05 (br, 1 H,
1-OH), 7.15–7.31 (m, 5 H, H15, H16, H17).
Acknowledgment
This study was supported by the Russian Foundation for Basic Re-
search (project no. 06-03-32607).
13C NMR (62.5 MHz, CDCl3): d (selected signals) = 29.2 (C7), 47.2
(C4), 48.2 (C8), 58.0 (C3).
References
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢¢/H8.
(1) (a) Angermann, J.; Homann, K.; Reissig, H.-U.; Zimmer, R.
Synlett 1995, 1014. (b) Buchholz, M.; Reissig, H.-U. Eur. J.
Org. Chem. 2003, 3524. (c) Gallos, J. K.; Sarli, V. C.;
Stathakis, C. I.; Koftis, T. V.; Nachmia, V. R.; Coutouli-
Argyropoulou, E. Tetrahedron 2002, 58, 9351.
Unassigned signals of 4 isomers:
1H NMR (300.13 MHz, CDCl3): d = 1.04, 1.06, 1.08, 1.09, 1.12,
1.15, 1.19 (7 s, 12 H, 12-CH3, 13-CH3), 3.68, 3.72, and 3.76 (3 s, 3
H, 11-CH3), 6.10, 6.83, 8.41, and 8.61 (4 br, 1 H, 2-NH).
(2) (a) Gallos, J. K.; Sarli, V. C.; Varvogli, A. C.; Papadoyanni,
C. Z.; Papaspyrou, S. D.; Argyropoulos, N. G. Tetrahedron
Lett. 2003, 44, 3905. (b) Gallos, J. K.; Sarli, V. C.; Massen,
Z. S.; Varvogli, A. C.; Papadoyanni, C. Z.; Papaspyrou, S.
D.; Argyropoulos, N. G. Tetrahedron 2005, 61, 565.
(3) (a) Best, W. M.; MacDonald, J. M.; Skelton, B. W.; Stick, R.
V.; Tilbrook, M. G.; White, A. H. Can. J. Chem. 2002, 80,
857. (b) Humphrey, A. J.; Parsons, S. F.; Smith, M. E. B.;
Turner, N. J. Tetrahedron Lett. 2000, 41, 4481. (c) Joubert,
M.; Defoin, A.; Tarnus, C.; Streith, J. Synlett 2000, 1366.
(4) Tsoungas, P. G. Heterocycles 2002, 57, 915.
(5) (a) Lyapkalo, I. M.; Ioffe, S. L. Russ. Chem. Rev. 1998, 67,
467. (b) Francotte, E.; Merenyi, R.; Vandenbulcke-Coyette,
B.; Vieche, H.-G. Helv. Chim. Acta 1981, 64, 1208.
(6) (a) Sukhorukov, A. Yu.; Klenov, M. S.; Ivashkin, P. E.;
Lesiv, A. V.; Khomutova, Yu. A.; Ioffe, S. L. Synthesis
2007, 97. (b) Klenov, M. S.; Lesiv, A. V.; Khomutova, Yu.
A.; Nesterov, I. D.; Ioffe, S. L. Synthesis 2004, 1159.
(c) Eliseev, O. L.; Ivashkin, P. E.; Ostapenko, A. G.; Lesiv,
A. V.; Khomutova, Yu. A.; Ioffe, S. L.; Lapidus, A. L.
Synlett 2006, 2239.
13C NMR (62.5 MHz, CDCl3): d = 27.8, 27.9, 28.5, 29.6, 30.8, 31.5,
31.8, and 31.9 (C12, C13), 43.8, 44.5, 48.0, and 48.6 (C5), 52.5,
52.6, and 52.7 (C11), 70.6 and 70.8 (C6), 126.7, 127.2, 128.0,
128.2, 128.3, 128.7, 128.9, and 129.0 (C15, C16, C17), 141.3,
142.0, 142.7, and 143.0 (C14), 170.4, 170.5, 173.1, 173.3, and
173.4 (C9, C10).
4-(4-Methoxyphenyl)-2,2-dimethyl-1-oxa-6-aza-
spiro[4.4]nonan-7-one (12c)
To a stirred soln of 6c (mixture of isomers 6cI/6cII/6cIII/
6cIV 1.0:1.0:2.3:2.1, 0.29 g, 0.87 mmol) in 1,4-dioxane–H2O (1:1, 2
mL) was added Dowex 50WX2-100 (0.29 g), the mixture was re-
fluxed for 12 h and then the solvent was evaporated. The residue
was dissolved in toluene (5 mL) and TsOH·H2O (0.02 g, 0.1 mmol)
was added. The resulting mixture was refluxed for 5 h, then concen-
trated in vacuum and the residue was subjected to column chroma-
tography (silica gel, hexane–EtOAc, 5:1 to 1:1 to 0:1) to give 12c
0.19 g (79% from 6c) as a white solid.
Mixture of 12cI and 12cII
Ratio 12cI/12cII 1.0:2.5; mp 202–208 °C Rf = 0.11 (EtOAc–hexane,
(7) Sukhorukov, A. Yu.; Lesiv, A. V.; Eliseev, O. L.;
Khomutova, Yu. A.; Bondarenko, T. N.; Lapidus, A. L.;
Ioffe, S. L. Mendeleev Commun. 2007, 122.
1:1).
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York

1220
A. Yu. Sukhorukov et al.
PAPER
(8) Hydrogenolysis of oxazine 4b with Pd/C (70 bar H2, MeOH,
80 °C, 2 h) resulted in low conversion of starting material
(40%) and the formation of two major products:
(13) (a) Chlenov, I. E.; Salamonov, Yu. V.; Tartakovsky, V. A.
Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1976,
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(14) For hydrolysis of imines see: (a) Pickard, P. L.; Vaughan,
D. J. J. Am. Chem. Soc. 1950, 72, 5017. For hydrolysis of
oximes see: (b) Buhler, D. R.; Schroeter, L. C.; Wechter, W.
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oximes see: (c) Monti, D.; Gramatica, P.; Speranza, G.;
Tagliapietra, S.; Manitto, A. Synth. Commun. 1986, 16, 803.
(d) Timms, G. H.; Wildsmith, E. Tetrahedron Lett. 1971, 12,
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oxazines see: (e) Zimmer, R.; Collas, M.; Roth, M.; Reissig,
H.-U. Liebigs Ann. Chem. 1992, 709.
oxaazaspirononanone 6b (yield: 20%) and lactam 9
(Scheme 11, yield: 17%). When the reaction is performed
under more robust conditions [H2 (150 bar), MeOH, 100 °C,
6 h] in addition to products 6b and 9 the corresponding
dihydrofuran 5b was obtained in 11% yield [Scheme 2,
R1 = Ph, R2 = H, R3 = R4 = Me, FG = CH(CO2Me)2].
(9) When the hydrogenation is carried out in the presence of
undried Raney nickel the yields of target spirononanones
decrease by 10–25% for the whole series of oxazines 4a–h.
(10) (a) Curran, D. P.; Brill, J. F.; Rakiewicz, D. M. J. Org. Chem.
1984, 49, 1654. (b) Rylander, P. N. Catalytic
Hydrogenation in Organic Synthesis; Academic Press: New
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Synthesis; Wiley: New York, 2001, 290–291.
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Chem. 1990, 469. (b) Nakanishi, S.; Otsuji, Y.; Itoh, K.;
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(12) (a) Chrystal, E. J. T.; Gilchrist, T. L.; Stretch, W. J. Chem.
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H. Synthesis 1989, 265. (c) Hippeli, C.; Reissig, H.-U.
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(19) CCDC 642140 contains the supplementary crystallographic
data for 6bIII. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk, by e-mailing or faxing a request
to deposit@ccdc.cam.ac.uk or +44(1223)336033,
respectively, or by writing to the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK.
(20) Treatment of the mixture of oxaazaspirononanones 6cIII and
6cIV (1:1) with some bases (Et3N, t-BuOK in THF at r.t.)
does not influence the ratio of isomers.
(21) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem.
1997, 62, 7512.
Synthesis 2008, No. 8, 1205–1220 © Thieme Stuttgart · New York