Catalytic hydrogenation of 5,6-dihydro-4H-1,2-oxazines bearing a functionalized methylene group at C-3

Article abstract of DOI:10.1002/ejoc.200800288

The catalytic hydrogenation of readily available methyl 2-(5,6-dihydro-4H-1,2-oxazin-3-yl)acetates 6 has been studied. Dihydrooxazines 6 without an alkoxy substituent at C-6 under mild hydrogenation conditions in methanol produce a dynamic mixture of enamines 7 and tetrahydro-2-furanamines 7′(α+β). These products can be transformed into 1,4-amino alcohols 8 under more robust hydrogenation conditions or into isomeric dihydrofurans 9 and 10 if the reduction is carried out in glacial acetic acid. Reduction of dihydrooxazines 6h,i, which possess an alkoxy substituent at C-6, under similar conditions affords pyrrolidine derivatives 12, 13 and 14. A general mechanistic scheme for the hydrogenation reaction that involves an initial N-O bond cleavage has been suggested. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800288

FULL PAPER
DOI: 10.1002/ejoc.200800288
Catalytic Hydrogenation of 5,6-Dihydro-4H-1,2-oxazines Bearing a
Functionalized Methylene Group at C-3
Alexey Yu. Sukhorukov,[a] Alexey V. Lesiv,[a] Oleg L. Eliseev,[a] Yulia A. Khomutova,[a]
Sema L. Ioffe,*[a] and Alexandra O. Borissova[b]
Keywords: Oxazines / Reduction / Furanamines / Imines / Amino acids
The catalytic hydrogenation of readily available methyl 2-
(5,6-dihydro-4H-1,2-oxazin-3-yl)acetates 6 has been studied.
Dihydrooxazines 6 without an alkoxy substituent at C-6 un-
der mild hydrogenation conditions in methanol produce a dy-
namic mixture of enamines 7 and tetrahydro-2-furanamines
7Ј(α+β). These products can be transformed into 1,4-amino
alcohols 8 under more robust hydrogenation conditions or
into isomeric dihydrofurans 9 and 10 if the reduction is car-
ried out in glacial acetic acid. Reduction of dihydrooxazines
6h,i, which possess an alkoxy substituent at C-6, under sim-
ilar conditions affords pyrrolidine derivatives 12, 13 and 14.
A general mechanistic scheme for the hydrogenation reac-
tion that involves an initial N–O bond cleavage has been sug-
gested.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
tions in the total synthesis of natural and biologically active
Six-membered cyclic oxime ethers, 5,6-dihydro-4H-1,2- nitrogen-containing compounds, for example, alkaloids,[1]
oxazines 1 or 1Ј (Scheme 1), have found numerous applica- unnatural amino acids[2] and amino sugars.[3]
Scheme 1. 5,6-Dihydro-4H-1,2-oxazines in organic synthesis.
In these syntheses, the reduction of the oximino fragment
is the key to the transformation of oxazines 1 and 1Ј into a
wide range of heterocyclic and acyclic products. Thus, de-
pending on the structures of oxazines 1 and 1Ј and the reac-
tion conditions, the reduction can lead to substituted[4a–4d]
and fused[5] pyrrolidines, pyrroles,[4e–4g] five-membered cy-
clic nitrones,[4b] δ-amino alcohols[2,6] and diketones[7]
[a] N. D. Zelinsky Institute of Organic Chemistry, Russian Acad-
emy of Sciences,
Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax: +7-495-1355328
E-mail: iof@ioc.ac.ru
[b] A. N. Nesmeyanov Institute of Organoelement Compounds,
Vavilov Str. 28, 119991 Moscow, Russian Federation
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 4025–4034
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4025

S. L. Ioffe et al.
FULL PAPER
Scheme 2. Synthesis and hydrogenation of 5,6-dihydro-4H-1,2-oxazines with a functionalized methylene group at C-3.
(Scheme 1). The major disadvantage of this strategy is the ically pure form by column chromatography on silica gel.
limited accessibility of oxazines 1 and 1Ј. Until recently, the The flexible equilibrium between compounds 7 and 7Ј was
only route to their synthesis was the [4+2] cycloaddition of confirmed by the solvent dependence of the ratio 7/7Ј (see
highly unstable α-nitroso olefins to electron-rich alkenes[8] below).[12]
(Scheme 1). In particular, this strategy seems ineffective for
the preparation of oxazines bearing functionalized alkyl
substituents at the C-3 atom. However, just recently, a quite
original approach to the synthesis of oxazines 1 from avail-
able nitroethane was suggested[9] (Scheme 2).
This approach seems to be the most attractive for the
preparation of dihydrooxazines 1ЈЈ bearing a CH2FG (FG
= functional group) substituent at the C-3 carbon atom.
Oxazines 1ЈЈ with FG = CO2Me and CH(CO2Me)2 are cur-
rently of particular interest because the functional group
can be involved in the reduction process, giving new types
of polyfunctionalized products. Accordingly we recently re-
ported[10] the synthesis of substituted oxaazaspironon-
anones 5 by the catalytic hydrogenation of dihydrooxazines
4 with FG = CH(CO2Me)2 (Scheme 2).
Scheme 3. Hydrogenation of dihydrooxazines 6 to enamines 7.
In this work we have studied the catalytic hydrogenation
of 2-(5,6-dihydro-4H-1,2-oxazin-3-yl)acetates
6 (FG =
CO2Me).[11]
Table 1. Preparation of enamines 7 from dihydrooxazines 6a–g.
Entry
6
R1
R2
R3
R4
Yield of 7+7Ј [%]
i
ii
Results and Discussion
1
2
3
4
5
6
7
a
b
c
d
e
f
Me
Ph
H
H
H
H
H
Me
Me
Me
Me
H
Me
Me
Me
Me
nPr
H
62
75
70
81
70[a]
59
Catalytic Hydrogenation of Dihydrooxazines 6
4-MeO-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-MeO-C6H4
Ph
It was discovered (Scheme 3, Table 1) that mild catalytic
hydrogenation of dihydrooxazines 6a–g, which do not con-
tain an alkoxy substituent at C-6, in the presence of Raney
nickel (20 bar H2, MeOH, room temp., 5 h) or Pd-C (20 bar
[b]
84
77
85
84
–
94
54
86
–(CH2)4–
–(CH2)3–
g
H
H2, MeOH, 60–70 °C, 2 h) furnishes a dynamic mixture of [a] In the hydrogenation at 40 bar H2, the total yield of 8b = 25%
(8ba/8bb = 1.1:1.0). [b] For more details, see Scheme 5.
enamines 7 and tetrahydro-2-aminofurans 7Ј(α+β) (herein-
after these mixtures are referred as enamines 7 for brevity).
It is evident that these products arise from the selective hy-
The conditions for the transformation 6Ǟ7, optimized
drogenolysis of the N–O bond in oxazines 6 and a subse- for model oxazine 6b, are presented in Scheme 3 (pro-
quent 1,3-proton shift of the activated proton from the cedures i and ii). The hydrogenation of 6b in the presence
CH2CO2Me fragment (the mechanism of the catalytic hy- of Raney nickel at a lower hydrogen pressure (e.g. 10 bar)
drogenation will be discussed below, see Scheme 8). En- resulted in incomplete conversion of the starting material.
amines 7 were isolated from the reaction mixtures in analyt- An increase of the hydrogen pressure up to 40 bar resulted
4026
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4025–4034

Catalytic Hydrogenation of 5,6-Dihydro-4H-1,2-oxazines
Scheme 4. Comparison of the catalytic hydrogenation of oxazines 6b and 6f with the hydrogenation of enamine 7b.
in a lowering of the yield of the mixture 7bp7Јb to 65% MeOH, 5 h), no conversion of 6b was observed, although
owing to the formation of products from exhaustive hydro- if the reduction of derivatives 6 was performed at 60–70 °C
genation, i.e. diastereomeric amino alcohols 8ba and 8bb (procedure ii in Table 1) the yields of the respective mixtures
(see entry 2 in Table 1 and Scheme 4).
7p7Ј were in most cases similar to those obtained by pro-
When the temperature used during hydrogenation was in- cedure i. However, hydrogenolysis of dihydrooxazine 6d in
creased (20 bar H2, 70–80 °C, 2 h) only amino alcohols 8b the presence of Pd-C proceeds in a more complicated man-
were obtained (yield 89%). The catalytic hydrogenation of ner (Scheme 5). The resulting reaction mixture is strongly
the corresponding enamine 7b under identical reaction con- acidic. After aqueous work-up and column chromatog-
ditions afforded amino alcohol 8b in a similar isomeric ra- raphy on silica gel, five products were identified: 6b (31%),
tio.
diastereomers 11ba and 11bb (yield: 20%, 11ba/11bb
=
At the same time, hydrogenations of 6b carried out in 1.0:1.5) and amino alcohols 8ba and 8bb (yield 14%, 8ba/
glacial acetic acid furnished only a mixture of isomeric fu- 8bb = 1.0:1.3). None of these products possess a chlorine
rans 9b and 10b (E/Z = 1:2, see also ref.[11]). Moreover, atom on the aromatic ring. Tetrahydrooxazine 11ba itself
heating enamine 7b in AcOH (70–80 °C, 1 h) led to a sim- can be hydrogenated to give diastereomerically pure amino
ilar result (see Scheme 4).
alcohol 8ba (20 bar H2, MeOH, 70 °C, 2 h, conversion of
The reduction of bicyclic oxazine 6f under similar condi- 11ba 43%, yield of 8ba 40%).[13] We believe that in the hy-
tions afforded only one regioisomer, tetrahydrofuran 10f drogenolysis of 6d under these conditions the reductive de-
(yield: 82%), as a mixture of three isomers (E-10fa/Z-10f/ halogenation takes place with the initial formation of dihy-
E-10fb = 8:5:1). Isomers E-10fa and Z-10f have a different drooxazine 6b and hydrogen chloride (Scheme 5). Subse-
configuration of the C=C double bond, whereas the minor quent protonation of the nitrogen atom in 6b by HCl fur-
isomer E-10fb differs from E-10fa in the relative configura- nishes cation A.[14] Hydrogenation of intermediate A leads
tion of the stereocentre at C-3. Dihydrofuran 9f (similar to to the products depicted in Scheme 5.
9b) was not generated in the hydrogenation of dihydrooxaz-
The presence or absence of the alkoxy group at C-6 can
ine 6f. However, the production of furan E-10fb with an be considered as the major factor that determines the type
inverse configuration of the stereocentre at C-3 indicates the of product in the hydrogenation of 5,6-dihydro-4H-1,2-ox-
intermediacy of 9f in the hydrogenation of dihydrooxazine azines (for example, see ref.[10]). Dihydrooxazines that do
6f.
not contain an alkoxy group at C-6 tend to form furan de-
In the hydrogenation of dihydrooxazine 6b, Pd-C proved rivatives or δ-amino alcohols, whereas dihydrooxazines with
to be less active than Raney nickel. When the hydrogenation an alkoxy substituent at C-6 produce pyrrolidine and pyr-
with Pd-C was carried out at room temp. (20 bar H2, role derivatives. In this context, it seems reasonable to dis-
Eur. J. Org. Chem. 2008, 4025–4034
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4027

S. L. Ioffe et al.
FULL PAPER
Scheme 5. Hydrogenation of dihydrooxazine 6d in the presence of Pd-C.
Scheme 6. Catalytic hydrogenation of dihydrooxazines 6h,i.
cuss the catalytic hydrogenation of oxazines 6h,i that bear
As one can see, apart from the usual hydrogenation prod-
a CH2CO2Me substituent at C-3 and an alkoxy group at C- ucts, pyrrolidines of type 13, enamines 12h and 14i were
6 (see Scheme 6 and Table 2).
also obtained. Their formation will be discussed in the next
section. Here it is worth mentioning that the employment
of the less active Pd-C catalytic system instead of Raney
nickel increases the yield of enamine 12h or 14i. Because
the free pyrrolidines 13h,i are labile and cannot be isolated
in an analytically pure form, they were transformed into
stable N-Boc derivatives 13Јh,i, which were then charac-
terized. Also, product 13Јi can be obtained directly from 6i
by hydrogenation in the presence of Boc2O (see Exp. Sect.).
It is evident that enamines 12h and 14i have a different
relationship with the corresponding pyrrolidines 13h,i. In-
deed, the hydrogenation of enamine 12h under similar con-
ditions to those used for the hydrogenation of dihydrooxaz-
Table 2. Hydrogenation of oxazines 6h,i.
Entry
6
Yields of pyrrolidines [%]
12h
14i
13
iii
iii
iv
iii
iv
iv
1
2
h
i
11[a] 53[b]
–
28
–
31
13h
13i
87[c]
–
–
–
52[d]
51[e]
[a] Mixture of 3,5-trans (12ha) and 3,5-cis (12hb) isomers in a 4.0:1.0
ratio. [b] 12ha/12hb = 3.0:1.0. [c] 13ha/13hb = 2.5:1.0. [d] 13ia/13ib/
13ic = 8.5:3.3:1.0. [e] 13ia/13ib = 1.0:3.7.
4028
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4025–4034

Catalytic Hydrogenation of 5,6-Dihydro-4H-1,2-oxazines
ine 6h (20 bar H2, Raney nickel, MeOH, 70–80 °C, 2 h)
According to this scheme the hydrogenation of 4 and 6
leads to a complex mixture of unidentified products. Pyr- starts with the initial cleavage of the endocyclic N–O bond
rolidine 13h was not identified in this mixture. However, the [step (1)] and the formation of imine B. A similar view con-
hydrogenation of pyrrolidine 14i (single stereoisomer) yields cerning the hydrogenation of six-membered cyclic oxime
a mixture of pyrrolidines 13ia and 13ib (Scheme 7). Remark- ethers has been suggested previously.[15] However, in a re-
ably, the ratio of 13ia/13ib is similar to that observed in the cent report,[5] the reduction of the oximino group in 5,6-
hydrogenation reaction of the corresponding dihydrooxaz- dihydro-4H-1,2-oxazines under catalytic hydrogenation
ine 6i under the same conditions with H2/Raney nickel and conditions was postulated to occur in the reverse order (i.e.,
H2/Pd-C (cf. footnotes to Table 2 and Scheme 7).
with initial reduction of the C=N double bond).
Note that intermediates B have never previously been
isolated or fixed. In this study the tautomers of B (as mix-
tures 7+7Ј) were obtained. These compounds are probably
thermodynamically more stable than imines B. The forma-
tion of 7+7Ј is preferable owing to the activation of CH2
protons with an adjacent electron-withdrawing CO2Me
group.[16] However, it cannot be ruled out that the enamines
7 are generated by catalytic hydrogenation of tautomers 15
(Scheme 9). The latter results from 1,3-C,N migration of a
flexible proton from the CH2CO2Me group.
It is evident that other isolated products from the hydro-
genation of oxazines 4 and 6 (5, 8, 9, 10) arise from the
imines B or their tautomers 7 and 7Ј (Scheme 8, route 1).
This conclusion is confirmed by the identical transforma-
tions of dihydrooxazine 6b and intermediate 7b upon treat-
ment with some reagents (see Scheme 4).
Scheme 7. Catalytic hydrogenation of enamine 14i.
Mechanistic Consideration of the Hydrogenation of
Oxazines 6
Scheme 8 depicts a general mechanism for the catalytic
hydrogenation of 5,6-dihydro-4H-1,2-oxazines that explains
If the oxazines 4 and 6 possess an alkoxy group at C-6
completely the data obtained in this study, as well as the (R3 = OAlk), the initially formed imines B can be trans-
results presented in previous reports on the hydrogenation formed consequently into intermediates C and D [route 2,
of dihydrooxazines 4 and 6.[10,11]
steps (2) and (3), Scheme 8]. Hydrogenolysis of pyrrolines
Scheme 8. General mechanistic scheme for the catalytic hydrogenation of 5,6-dihydro-4H-1,2-oxazines bearing a functionalized methylene
group at C-3.
Eur. J. Org. Chem. 2008, 4025–4034
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4029

S. L. Ioffe et al.
FULL PAPER
The different results of the hydrogenation of the oximino
ether 6h and enamine 12h on the one hand, and the similar-
ity of results of the hydrogenation of 6i and 14i (cf.
Scheme 7 and Table 2) on the other, support this interpret-
ation. The only difference was the absence of isomer 13ic
among the products of the hydrogenation of 14i in the pres-
ence of the Raney nickel catalyst. It is evident that this iso-
mer cannot arise from the diastereomerically pure 3,5-cis
isomer of enamine 14i. Perhaps step (5) of the catalytic hy-
drogenation of 6i with H2/Raney nickel (Scheme 8) is not
completely stereoselective. Therefore, besides 3,5-cis-14i, a
small amount of the corresponding 3,5-trans-isomer 14i is
generated. Yet this substance was never isolated or observed
in the reaction mixtures. The rate of transformation 3,5-
trans-14iǞ13ic is probably greater than the rate of hydro-
genation of the corresponding 3,5-cis isomer 14i.
Scheme 10 demonstrates that the catalytic hydrogenation
of dihydrooxazine 6i starts with the selective reduction of
the weak N–O bond. Indeed, specially obtained tetra-
hydrooxazine 11i yields only pyrrolidine 13i (as a mixture
of two isomers), whereas dihydrooxazine 6i affords two
types of pyrrolidines (13i and 14i) under the same condi-
tions. Therefore, products similar to 11i cannot be consid-
ered as intermediates in the hydrogenation of the cyclic
ethers of oximes. In other words, the hydrogenation of de-
rivatives 6 does not start with the reduction of the C=N
double bond. Furthermore, participation of the intermedi-
ate GЈ in the sequence leading from 6i to pyrrolidine 13i
seems unlikely because otherwise the ratios of isomers 13ib
and 13ic in both reactions (the hydrogenation reactions of
6i and 11i) would have been equal.
Scheme 9. Possible route to enamines 7 from dihydrooxazines 6.
D may lead to the final pyrrolidines 13, yet this does not
provide an explanation of how enamines 12 and 14 are
formed. At the same time, the presence of the CH2CO2Me
fragment at C-3 results in activation of the CH2 protons.
Therefore isomerization of the imines (Bp7) becomes pos-
sible. Subsequent elimination of R3H [step (2Ј)], cyclization
[step (3Ј)] and elimination of H2O [step (4Ј)] furnish inter-
mediates E. Hydrogenolysis of pyrrolines E [step (5)] yields
pyrrolines F (compare with product 14i). Finally, hydrogen-
ation of the C=C double bond in F [step (6)] affords pyrroli-
dines 13 as the final product of this multistep process. Note
that the key intermediates in the process, pyrrolines DЈ, can
be generated through alternative mechanistic pathways in-
volving the reversible isomerization of intermediates C
(CpCЈ) or D (DpDЈ).
As is illustrated in Scheme 8, of the isolated pyrrolidines
12h and 14i, only the latter is involved in the pathway that
leads to the target pyrrolidines 13. Pyrroline 12h is not a
part of this sequence and presumably arises from the inter-
molecular trapping of the intermediate E with methanol
(R4 = H, generated from oxazine 6h). It is assumed that
intermediate E (R4 = Me), which arises from the hydro-
genolysis of oxazine 6i, is not trapped with methanol be-
cause of the lower electrophilicity of the carbon atom in the
In this manner, according to Scheme 8, the key processes
of the catalytic hydrogenation of 6 are the cyclization and
isomerization of intermediate imines B. Previously, how-
ever, the hydrogenation of the C=N double bond in imines
B was considered as the only transformation leading to the
final pyrrolidines.[15]
Thus, the general sequence for the reduction of the oxim-
imine fragment and the steric hindrance of the methyl ino fragment in the cyclic ethers of oximes includes the ini-
group at C-5. tial hydrogenolysis of the N–O bond. It is evident that the
Scheme 10. Comparison of the hydrogenation reactions of oxazine 6i and tetrahydrooxazine 11i.
4030
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4025–4034

Catalytic Hydrogenation of 5,6-Dihydro-4H-1,2-oxazines
initial protonation of the nitrogen atom with acids can dras-
tically change the sequence of bond reduction (cf.
Scheme 5).
Support for the Structures of the Target Products
The structures and configurations of the stereocentres in
products 7a–g, 8b, 9b, 10b, 10f, 11b, 11i, 12h, 13Јh–i and
14i were established by elemental analysis, NMR (1H, 13C,
DEPT, COSY, HSQC, NOESY) and IR spectroscopy, as
well as by the chemical transformations illustrated in
Schemes 4, 5, 7 and 10.
Figure 1. Characteristic 2D NOESY correlations in 7 and 7Ј.
The flexible equilibrium 7p7Ј was established from the
solvent dependence of the ratio of 7/7Ј (see Table 3). In
CDCl3 solutions, cyclic form 7Ј is dominant for substrates
7a–d containing a tertiary alcohol moiety. In contrast, in
CD3CN, the predominant tautomeric form is the open-
chain enamine 7 (in CD3OD compound 7b exists solely as
an acyclic enamine).
by the “architecture” of the initial diastereomerically pure
oxazines 6. This was confirmed by the results of 2D
NOESY experiments for a mixture of 7g+7Јg(α+β) in
CDCl3.
Additional information on the structure of 7 was ob-
tained from the IR spectra recorded in CH3CN. Note that
these spectroscopic data are in close agreement with the
previously reported spectroscopic studies of 3-aminocro-
tonic esters.[17] First, the IR data support the existence of
the main functional groups in the structure of 7 (C=O ≈
1670 cm–1, C=CNH2 ≈ 1620 and ≈ 1560 cm–1, OMe ≈
1170 cm–1, C=C–H ≈ 795 cm–1; see ref.[17]). Secondly, all the
compounds studied (7a–g) presented four (or sometimes
three) bands in the ν(N–H) region (ca. 3630, ca. 3520, ca.
3450 and ca. 3330 cm–1). Unlike the first three ones, the
fourth band was almost insensitive to changes in concentra-
tion (studied for compound 7b) and therefore was attrib-
uted to the N–H bond intramolecularly bonded to the car-
boxylic group (literature values for such bonding in methyl
3-aminocrotonates are 3310–3340 cm–1 [17]). Also, the large
displacement of the ν(C=O) band to lower frequencies in 7
must be due to chelation.[18] This intramolecular hydrogen
bond can only exist in the Z isomers of enamines 7 (see
Table 3. Ratio of tautomers 7 and 7Ј in CDCl3 and CD3CN.
Products
CDCl3
CD3CN
7+7Ј
Ratio
Ratio
Ratio
Ratio
7/7Ј
α/β (for 7Ј)
7/7Ј
α/β (for 7Ј)
a
b
c
d
e
f
1.0:2.7
1.0:2.5
1.0:4.4
1.0:3.7
3.8:1.0
5.7:1.0
1.0:12.1
1.0:1.0
1.2:1.0
1.8:1.0
4.2:1.0
4.2:1.0
3.5:1.0
5.2:1.0
7 only
7 only
1.2:1.0
1.5:1.0
1.2:1.0
1.2:1.0
1.3:1.0
–
1.5:1.0
1.4:1.0 or 1.0:1.4[a]
1.3:1.0 or 1.0:1.3[a]
1.0:1.0
–
g
1.0:1.0
[a] The isomers were not assigned unambiguously due to their low
concentration and the overlapping of characteristic signals in the
1H NMR spectra with signals from the dominant acyclic tauto-
meric form.
1
Figure 1). In addition, the H NMR spectra of enamines 7
Compounds 7e,f, which contain a secondary alcohol in CD3CN show two signals arising from the NH2 group
moiety (R4 = H), in CD3CN and CDCl3 exist mainly in the (ca. 5.5 and ca. 7.8 ppm), which can be assigned to the che-
acyclic tautomeric form 7. In contrast, for compound 7g, lated and free NH protons.
which bears a fused cyclopentane ring, the cyclic form
The configuration of the C=C double bond in the pyr-
7Јg(α+β) was found to be predominant in CDCl3 (Table 3). rolidine 14i was similarly revealed. Among the characteris-
The acyclic tautomeric form 7 was detected as a single tic parameters the low-frequency shift of ν(C=O) band
geometrical isomer with a Z configuration of the double should be noted.
bond that is stabilized by an intramolecular hydrogen bond
The structure and the configuration of the double bond
[this configuration was originally established from the char- in furan E-10fa were unambiguously determined by single-
acteristic correlations between the protons at C-3 and C-9 crystal X-ray diffraction analysis (Figure 2).[19] The geomet-
in the 2D NOESY spectra (Figure 1)].
rical parameters of E-10fa fall in the range common for this
The relative configuration of the stereocentre at C-2 in type of compounds. In this molecule two cyclic fragments
the mixtures of tautomers 7Јα and 7Јβ was determined on are annelated through C-4 and C-5 atoms. The “tetra-
the basis of 2D NOESY experiments (characteristic NOE hydrofuran” fragment is characterized by the envelope con-
correlations are depicted in Figure 1). The configurations formation with a deviation of C-4 from the plane formed
of the stereocentres at C-3, C-4 and C-5 in the furan unit by other atoms of the ring of 0.67 Å [torsion angle C(5)
are identical for both isomers 7Јα and 7Јβ as it is governed O(1)C(2)C(3) is 1°].
Eur. J. Org. Chem. 2008, 4025–4034
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4031

S. L. Ioffe et al.
FULL PAPER
Peaks are reported in cm–1 with the following relative intensities: s
(strong), m (medium), w (weak), br (broad), sh (shoulder). Elemen-
tal analyses were performed by the Analytical Laboratory of the
Institute of Organic Chemistry and Analytical Laboratory of the
Institute of Organoelement Compounds. Melting points (uncor-
rected) were determined with a Kofler apparatus. Analytical thin-
layer chromatography was performed with Merck silica gel plates
with QF-254. Visualization was accomplished with UV light or
with a solution of ninhydrin in ethanol. Column chromatography
was performed using Merck Kieselgel 60, 230–400-mesh silica gel.
MeOH, hexane and AcOEt were distilled without drying agents.
Glacial acetic acid was recrystallized twice. The following chemicals
were purchased from Acros: Raney-Ni (50% slurry in water), 5%
palladium on charcoal, NaBH3CN, (tBuOCO)2O. Starting oxaz-
ines 6b–d,f,g were prepared from nitroethane according to the lit-
erature procedure.[9a,9c] Previously unknown oxazines 6a,e were
prepared by a procedure described in ref.[9c] from nitroethane, acet-
aldehyde, isobutylene or nitroethane, anisaldehyde and n-pentene
(15 and 14% yields, respectively). High-pressure hydrogenation was
carried out in a steel autoclave with the external heating and stir-
ring.
Figure 2. X-ray crystal structure of compound E-10fa recorded at
293(2) K.
Conclusions
Preparation of Raney Nickel: A 50% slurry of Raney-Ni in water
(5 mL) was washed with methanol (5ϫ10 mL). The catalyst was
used immediately after preparation.
The products of the reduction of oxazines 6, i.e. en-
amines 7, amines 8 and pyrrolidines 13, can be considered
as the esters of previously unknown β-amino acids (β-
amino acids are widely applied in modern bioorganic chem-
istry, e.g., in the synthesis of β-peptides[20]). The incorpora-
tion of fused furanosyl β-amino acids, related to the cyclic
tautomers 7Ј, into the structure of small peptides has been
reported recently.[12,21]
General Procedures for the Preparation of Dynamic Mixtures of En-
amines 7 and Tetrahydrofurans 7Ј
Procedure i: Raney-Ni (ca. 0.1 g in methanol) was added to a solu-
tion of oxazine 6 (1.0 mmol) in methanol (8.0 mL) was added. The
suspension was hydrogenated with vigorous stirring for 5 h at room
temp. (20 bar H2), filtered and concentrated in vacuo. The residue
In conclusion, a convenient method for the preparation was purified by column chromatography on silica gel (eluent: Ac-
OEt/hexane, 1:5Ǟ1:3Ǟ1:1). The yields of the target products 7
are presented in Table 1.
of substituted 5,6-dihydro-4H-1,2-oxazines 6 bearing a
CH2CO2Me group at C-3[9c] as well as effective procedures
for their reduction that have been developed here can be
assumed to be the basis of a novel strategy for the synthesis
of unnatural β-amino acids from nitroethane and other sim-
ple precursors.
Procedure ii: Pd-C (0.084 g) was added to a solution of oxazine 6
(1.0 mmol) in methanol (8.0 mL) . The suspension was hydroge-
nated with vigorous stirring for 2 h at 60–70 °C (20 bar H2), filtered
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel
(eluent: AcOEt/hexane,
1:5Ǟ1:3Ǟ1:1). The yields of the target products 7 are presented
in Table 1.
Experimental Section
Methyl
3-Amino-6-hydroxy-6-methyl-4-phenylheptanoate
(8b):
General Remarks: 1D and 2D NMR spectra were recorded at room
temperature with Bruker DRX-500 [1H (500.13 MHz), 1H–1H
COSY, HSQC (J = 145 Hz), NOESY (mixing time 900 ms)], AM-
300 (13C (75.13 MHz), INEPT, JMOD, 1H–1H COSY, HSQC,
NOESY) NMR spectrometers for 0.1–0.2  solutions in CDCl3 or
CD3CN. The chemical shifts (1H and 13C) are given in ppm relative
to the solvent signal.[22] All 1D and 2D NMR experiments were
performed using standard methods and Bruker NMR software.
Ratios of tautomers 7/7Ј(α+β) and stereoisomers 7Ј(α)/7Ј(β) were
determined from the relative integral intensity of characteristic sig-
nals in the 1H NMR spectra for samples obtained after column
chromatography. Acyclic tautomers 7 were characterized by NMR
in CD3CN, whereas cyclic tautomers 7Ј(α+β) were characterized
by NMR in CDCl3 as mixtures with acyclic tautomers. The ratios
of the stereoisomers of 9, 10, 11, 12 and 13 (prepared by catalytic
hydrogenation) were determined from the relative integral intensity
of characteristic signals in the 1H NMR spectra for samples ob-
tained after column chromatography or after filtration of the corre-
sponding reaction mixtures through a short pad of silica gel to
remove traces of catalyst. FTIR spectra were recorded with the
Bruker VECTOR-22 instrument for 0.1  solutions in CH3CN.
Raney-Ni (ca. 0.1 g in methanol) was added to a solution of dihy-
drooxazine 6b (0.131 g, 0.5 mmol) in methanol (4.0 mL). The sus-
pension was hydrogenated with vigorous stirring for 2 h at 70–
80 °C (20 bar H2), filtered and concentrated in vacuo. The residue
was purified by filtration through a short pad of silica gel (eluent:
AcOEt/hexane, 1:5Ǟ1:3Ǟ1:1ǞMeOH). Evaporation of the
methanol fraction gave a mixture of amino alcohols 8ba and 8bb as
a colourless oil (0.118 g, 89%, 8ba/8bb = 1.1:1.0).
Hydrogenation of Oxazine 6d over Pd-C: Hydrogenation of oxazine
6d was realized by procedure ii (per 0.5 mmol). The resulting reac-
tion mixture was filtered to remove the catalyst and concentrated
in vacuo. The residue was dissolved in CHCl3 (50 mL) and washed
with a saturated solution of K2CO3 (2ϫ30 mL). The aqueous
phase was back-extracted with CHCl3 (30 mL) and the combined
organic layers were washed with brine (30 mL) and dried (Na2SO4).
The solvent was evaporated in vacuo and the residue was subjected
to column chromatography on silica gel (eluent: AcOEt/hexane,
1:5Ǟ1:3Ǟ1:1ǞAcOEt/MeOH, 3:1). Three fractions were col-
lected after chromatographic separation. The first one contained a
mixture of dihydrooxazine 6b and tetrahydrooxazines 11ba and
4032
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4025–4034

Catalytic Hydrogenation of 5,6-Dihydro-4H-1,2-oxazines
11bb [Rf = 0.63 (AcOEt/hexane, 1:1)]. The second contained pure
oxazine 11ba [Rf = 0.61 (AcOEt/hexane, 1:1)]. The methanol/Ac-
OEt fraction contained a mixture of amino alcohols 8ba and 8bb.
Total yields: 6b (31%), 11ba (8%), 11bb (12%), 8b (14%, 8ba/8bb =
1.0:1.5).
Hydrogenation of 6-Alkoxy-Substituted Oxazines 6h,i
Procedure iii: Raney-Ni (ca. 0.1 g in methanol) was added to a solu-
tion of oxazine 6h or 6i (0.154 g, 0.5 mmol) in methanol (4.0 mL).
The suspension was hydrogenated with vigorous stirring for 2 h at
70–80 °C (20 bar H2), filtered and concentrated in vacuo. The resi-
due was subjected to column chromatography on silica gel (eluent:
AcOEt/hexane, 1:5Ǟ1:3Ǟ1:1ǞMeOH). The products were iso-
lated as indicated below.
Hydrogenation of Tetrahydrooxazine 11ba to Amino Alcohol 8ba: Pd-
C (0.008 g) was added to a solution of tetrahydrooxazine 11ba
(0.036 g, 0.1 mmol) in methanol (1.0 mL). The suspension was hy-
drogenated with vigorous stirring for 2 h at 70 °C (20 bar H2). The
resulting mixture was filtered and the solvents evaporated in vacuo.
The residue was subjected to flash chromatography on silica gel
(eluent: AcOEt/hexane, 1:1Ǟmethanol) to give two fractions. The
first fraction contained the initial tetrahydrooxazine 11ba (0.0205 g,
57%). The methanol fraction contained amino alcohol 8ba (0.014 g,
40%).
Procedure iv: Pd-C (0.04 g) was added to a solution of oxazine 6h
or 6i (0.154 g, 0.5 mmol) in methanol (4.0 mL). The suspension was
hydrogenated with vigorous stirring for 2 h at 70–80 °C (20 bar H2)
and then filtered and concentrated in vacuo. The residue was sub-
jected to column chromatography on silica gel (eluent: AcOEt/hex-
ane, 1:5Ǟ1:3Ǟ1:1ǞMeOH). The products were isolated and
characterized as indicated below.
Mixture of Pyrrolidines 12ha and 12hb: Pyrrolidine 12h was isolated
as the only product (yield: 53%, ratio 12ha/12hb = 3.0:1.0) from the
hydrogenation of 6h by procedure iv (eluent: for column
chromatography AcOEt/hexane, 1:5Ǟ1:3). However, pyrrolidine
12h was isolated as a minor product from the hydrogenation of 6h
by procedure iii (yield: 11%, 12ha/12hb = 4.0:1.0).
General Procedure for the Synthesis of Furan Derivatives 9 and 10
from Oxazines 6 (Procedure v): Raney-Ni (ca. 0.1 g in methanol)
was added to a solution of oxazine 6b or 6f (1.0 mmol) in acetic
acid (6.6 mL). The suspension was hydrogenated with vigorous stir-
ring for 1 h at 80 °C (20 bar H2). The resulting mixture was poured
into a mixture of EtOAc (100 mL) and a saturated solution of
Na2CO3 in water (100 mL). The aqueous phase was back-extracted
with EtOAc (50 mL) and the combined organic layers were washed
with brine (50 mL) and dried with Na2SO4. The solvent was evapo-
rated in vacuo and the residue was subjected to column chromatog-
raphy on silica gel (eluent: AcOEt/hexane, 1:10Ǟ1:5). Several frac-
tions were collected after chromatographic separation (for details
see below).
Pyrrolidines 13h and 13Јh: Unstable crude pyrrolidine 13h (oil,
structure supported by 1H and 13C NMR) was obtained as the
major product (yield: 87%, mixture of isomers, 13ha/13hb = 2.5:1.0)
from the hydrogenation of oxazine 6h by procedure iii (methanol
fraction).
Transformation of 13h to the Boc-Protected Pyrrolidine 13Јh: Pyr-
rolidine 13h was dissolved in CH2Cl2 (11 mL) and treated with
Boc2O (0.140 g, 0.65 mmol). The resulting mixture was kept for
48 h with occasional shaking, concentrated in vacuo and the resi-
due was subjected to column chromatography on silica gel (eluent:
AcOEt/hexane, 1:10Ǟ1:5) to give a mixture of pyrrolidines 13Јha
and 13Јhb (0.065 g, 37% from 6h, ratio 13Јha/13Јhb = 2.8:1.0).
Furan Derivatives 9b and 10b: Two fractions were collected after
chromatographic separation (procedure v). The first one [Rf = 0.78
(AcOEt/hexane, 1:1)] contained a mixture of 9b (total yield: 41%)
and E-10b (total yield: 12%), the second one [Rf = 0.61 (AcOEt/
hexane, 1:1)] contained only Z-10b (total yield: 25%).
Methyl
2-[rel-(Z)-(3S,5S)-5-Methyl-3-[4-(methoxy)phenyl]tetra-
For the characterization of the dihydrofurans 9b and Z-10b see
ref.[11]
hydro-2H-pyrrol-2-ylidene]acetate (14i): Pyrrolidine 14i was ob-
tained by procedure iii (yield: 28%) or iv (yield: 31%) from oxazine
6i (AcOEt/hexane fraction in the chromatographic separation).
Furan Derivatives 10f: Two fractions were collected after chromato-
graphic separation (procedure v). The first one [Rf = 0.69 (AcOEt/
hexane, 1:1)] contained isomer E-10fa (yield: 47%), the second [Rf
= 0.51 (AcOEt/hexane, 1:1)] contained a mixture of Z-10f (yield:
29%) and E-10fb (yield: 6%).
Pyrrolidines 13i and 13Јi: Crude unstable mixtures of pyrrolidines
13i were obtained as oils by hydrogenation of oxazine 6i over
Raney-Ni (procedure iii, methanol fraction, yield: 52%, ratio of
isomers 13ia/13ib/13ic = 8.5:3.3:1.0) or over Pd-C (procedure iv,
methanol fraction, yield: 51%, ratio of isomers 13ia/13ib = 1.0:3.7).
The two major isomers (13ia and 13ib) were characterized by NMR
analysis.
Crystals of E-10fa were obtained of sufficient quality for X-ray
crystallographic analysis. C18H22O4, M = 302.36, orthorhombic,
space group Pna21, a = 9.1511(18), b = 19.428(4), c = 9.0557(18) Å,
V = 1610.0(6) Å3, Z = 4, dcalcd. = 11.247 gcm–3, µ(Mo-Kα) =
0.087 cm–1, F(000) = 648. The intensities of 2136 reflections were
measured with a “CAD4 Enraf-Nonius” diffractometer (θ/2θ-scan,
graphite monochromator, 2θmax Յ 52°) and 1857 independent re-
flections [Rint = 0.0431] were used in further refinement. The refine-
ment converged to wR2 = 0.1042 and GOF = 1.000 for all indepen-
dent reflections [R1 = 0.0426 was calculated against F for 1491
observed reflections with IϾ2σ(I)].[19] All calculations were per-
formed by using SHELXTL PLUS 5.0.[23]
Transformation of 13i to the Boc-Protected Pyrrolidine 13Јi: Boc2O
(0.065 g, 0.3 mmol) was added to a solution of crude pyrrolidine
13i (0.053 g, 0.2 mmol, mixture of isomers 13ia/13ib = 1.0:3.7) in
CH2Cl2 (5 mL). The mixture was kept for 48 h with occasional
shaking. The solvent was evaporated in vacuo and the residue was
subjected to column chromatography on silica gel (eluent: AcOEt/
hexane, 1:10Ǟ1:5) to give pyrrolidine 13Јi as an oil (0.052 g, 71%,
ratio of isomers 13Јia/13Јib = 1.0:3.0).
Procedure for the Direct Hydrogenation 6iǞ13Јi: Boc2O (0.16 g,
0.73 mmol) and Raney-Ni (ca. 0.1 g in methanol) were added to a
solution of oxazine 6i (0.15 g, 0.49 mmol) in methanol (4.0 mL).
The suspension was hydrogenated with vigorous stirring for 2 h at
70–80 °C (20 bar H2), filtered, concentrated in vacuo and subjected
to column chromatography on silica gel (eluent: AcOEt/hexane,
1:10Ǟ1:5) to give pyrrolidine 13Јi as an oil (0.11 g, 62%, mixture
of isomers 13Јia/13Јib/13Јic = 8.1:2.5:1.0).
Synthesis of Furan Derivatives 9b and 10b from Enamine 7b (Pro-
cedure vi): A solution of enamine 7b (0.11 mmol) in acetic acid
(1.0 mL) was heated for 1 h at 70–80 °C with stirring and then
1
evaporated in vacuo. The H NMR spectrum of the residue (with
hexamethyldisiloxane as the internal standard) showed the presence
of dihydrofuran 9b (42%) and tetrahydrofurans Z-10b and E-10b
(total yield: 31%, ration 2.1:1.0) as the major products.
Eur. J. Org. Chem. 2008, 4025–4034
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4033

S. L. Ioffe et al.
FULL PAPER
g) S. Nakanishi, Y. Shirai, K. Takahashi, Y. Otsuji, Chem. Lett.
1981, 869–872.
[5] R. Zimmer, M. Collas, R. Czerwonka, U. Hain, H.-U. Reissig,
Synthesis 2008, 237–245.
[6] J. Angerman, R. Zimmer, M. Hoffman, H.-U. Reissig, Chem.
Ber. 1992, 125, 2243–2248.
[7] R. Zimmer, M. Collas, M. Roth, H.-U. Reissig, Liebigs Ann.
Chem. 1992, 709–714.
Methyl rel-[(3S,4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-
1,2-oxazinan-3-yl]acetate (11i): NaBH3CN was added to a stirred
solution of oxazine 6i (0.10 g, 0.33 mmol) in AcOH (1.5 mL) and
vigorously stirred for 2 h. Then the reaction mixture was diluted
with AcOEt (30 mL) and poured into a mixture of AcOEt (20 mL)
and a saturated solution of K2CO3 in water (50 mL). The aqueous
phase was back-extracted with EtOAc (2ϫ20 mL) and the com-
bined organic layers were washed with brine (50 mL) and dried
with Na2SO4. The solvent was evaporated in vacuo and the residue
was subjected to column chromatography on silica gel (eluent: Ac-
OEt/hexane, 1:10Ǟ1:5) to give tetrahydrooxazine 11i as a single
diastereomer (0.069 g, 67%).
[8] I. M. Lyapkalo, S. L. Ioffe, Russ. Chem. Rev. 1998, 67, 467–
484.
[9] a) A. Yu. Sukhorukov, M. S. Klenov, P. E. Ivashkin, A. V. Le-
siv, Yu. A. Khomutova, S. L. Ioffe, Synthesis 2007, 97–108; b)
M. S. Klenov, A. V. Lesiv, Yu. A. Khomutova, I. D. Nesterov,
S. L. Ioffe, Synthesis 2004, 1159–1170; c) O. L. Eliseev, P. E.
Ivashkin, A. G. Ostapenko, A. V. Lesiv, Yu. A. Khomutova,
S. L. Ioffe, A. L. Lapidus, Synlett 2006, 2239–2240.
[10] A. Yu. Sukhorukov, A. V. Lesiv, Yu. A. Khomutova, S. L.
Ioffe, Yu. V. Nelyubina, Synthesis 2008, 1205–1220.
[11] For a preliminary communication on the hydrogenation of di-
hydrooxazine 6b to furan derivatives 9b and 10b, see: A. Yu.
Sukhorukov, A. V. Lesiv, O. L. Eliseev, Yu. A. Khomutova,
T. N. Bondarenko, A. L. Lapidus, S. L. Ioffe, Mendeleev Com-
mun. 2007, 122–124.
Hydrogenation of Tetrahydrooxazine 11i to Pyrrolidine 13i: Raney-
Ni (ca. 30 mg) was added to a solution of tetrahydrooxazine 11i
(0.037 g, 0.12 mmol) in methanol (1.0 mL). The suspension was hy-
drogenated with vigorous stirring for 2 h at 70–80 °C (20 bar H2).
The resulting mixture was filtered and evaporated under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel (eluent: AcOEt/hexane, 1:5Ǟ1:1ǞMeOH). The meth-
anolic fraction contained 13i (0.027 g, 93%, 13ib/13ic = 1.4:1.0).
The crude 13i was transformed into derivative 13Јi by the procedure
described above (0.028 g, 64% from 11i, ratio 13iЈb/13Јic = 1.6:1.0).
[12] For ring–chain tautomerism in the related compounds, see: C.
Taillefumier, S. Thielges, Y. Chapleur, Tetrahedron 2004, 60,
2213–2224.
Supporting Information (see also the footnote on the first page of
[13] This result also allows one to assign unambiguously the signals
in the 1H and 13C NMR spectra of the mixture of dia-
stereomers 8ba and 8bb, obtained from dihydrooxazine 6b un-
der robust hydrogenation conditions (see Scheme 4).
[14] For the preparation of stable salts of 5,6-dihydro-4H-1,2-oxaz-
ines with strong acids, see: O. P. Shelyapin, I. V. Samartseva,
L. A. Pavlova, J. Org. Chem. USSR 1974, 10, 1524–1528.
[15] a) E. J. T. Chrystal, T. L. Gilchrist, W. Stretch, J. Chem. Res.
(S) 1987, 180–181; b) M. Buchholz, H.-U. Reissig, Eur. J. Org.
Chem. 2003, 3524–3533.
this article): Characterization data for all new compounds (m.p.,
1
Rf, H, 13C, INEPT, COSY, HSQC, NOESY NMR spectra, FTIR
and elemental analyses).
Acknowledgments
This study was supported by the Russian Foundation for Basic
Research (project no. 06-03-32607).
[16] However, stable tautomeric forms of imines, generated by the
hydrogenolysis of five-membered cyclic oxime ethers, have been
isolated: J. Zhang, D. P. Curran, J. Chem. Soc. Perkin Trans. 1
1991, 2627–2631, and references cited therein.
[17] A. Gomez Sanchez, A. M. Valle, J. Bellanato, J. Chem. Soc.
Perkin Trans. 2 1973, 15–20.
[18] M. Hesse, H. Meier, B. Zeeh, Spektroskopische Methoden in der
organischen Chemie, Thieme, Stuttgart, 1995, p. 49.
[19] CCDC-675782 (for E-10fa) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[1] a) J. Angermann, K. Homann, H.-U. Reissig, R. Zimmer, Syn-
lett 1995, 1014–1016; b) J. K. Gallos, V. C. Sarli, C. I. Stathakis,
T. V. Koftis, V. R. Nachmia, E. Coutouli-Argyropoulou, Tetra-
hedron 2002, 58, 9351–9357.
[2] a) J. K. Gallos, V. C. Sarli, A. C. Varvogli, C. Z. Papadoyanni,
S. D. Papaspyrou, N. G. Argyropoulos, Tetrahedron Lett. 2003,
44, 3905–3909; b) J. K. Gallos, V. C. Sarli, Z. S. Massen, A. C.
Varvogli, C. Z. Papadoyanni, S. D. Papaspyrou, N. G. Argyro-
poulos, Tetrahedron 2005, 61, 565–574.
[3] a) W. M. Best, J. M. MacDonald, B. W. Skelton, R. V. Stick,
M. G. Tilbrook, A. H. White, Can. J. Chem. 2002, 80, 857–866;
b) A. J. Humphrey, S. F. Parsons, M. E. B. Smith, N. J. Turner,
Tetrahedron Lett. 2000, 41, 4481–4485; c) M. Joubert, A. De-
foin, C. Tarnus, J. Streith, Synlett 2000, 1366–1368.
[4] a) R. Henning, U. Lerch, H. Urbah, Synthesis 1989, 265–268;
b) C. Hipelli, H.-U. Reissig, Liebigs Ann. Chem. 1990, 475–481;
c) K. Paulini, A. Gerold, H.-U. Reissig, Liebigs Ann. 1995,
667–671; d) A. A. Tishkov, H.-U. Reissig, S. L. Ioffe, Synlett
2002, 6, 863–866; e) C. Hippeli, R. Zimmer, H.-U. Reissig, Lie-
bigs Ann. Chem. 1990, 469–475; f) S. Nakanishi, Y. Otsuji, K.
Itoh, N. Hayashi, Bull. Chem. Soc. Jpn. 1990, 63, 3595–3600;
[20] E. Juaristi in Enantioselektive Synthesis β-Amino Acids, Wiley-
VCH, New York, 1996.
[21] C. Taillefumier, Y. Lakhrissi, M. Lakhrissi, Y. Chapleur, Tetra-
hedron: Asymmetry 2002, 13, 1707–1711.
[22] H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997,
62, 7512–7515.
[23] G. M. Sheldrick, SHELXTL, Structure Determination Software
Suite, v.5.10, Bruker AXS, Madison, Wisconsin, USA, 1998.
Received: March 18, 2008
Published Online: July 4, 2008
4034
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4025–4034