A general metal-assisted synthesis of α-halo oxime ethers from nitronates and nitro compounds

Article abstract of DOI:10.1002/ejoc.201403083

An approach to the synthesis of α-halo oxime ethers from readily accessible nitronates and nitro compounds via bis-(oxy)enamines is reported. A key step of the strategy involves the unprecedented reaction of bis(oxy)enamines with a metal (Co, Zn, Mg, Mn)

Full text of DOI:10.1002/ejoc.201403083

FULL PAPER
DOI: 10.1002/ejoc.201403083
A General Metal-Assisted Synthesis of α-Halo Oxime Ethers from Nitronates
and Nitro Compounds
Alexey Yu. Sukhorukov,*[a] Maria A. Kapatsyna,[b] Tammy Lim Ting Yi,[c]
Hyeong Ryool Park,[c] Yana A. Naumovich,[b] Petr A. Zhmurov,[a] Yulia A. Khomutova,[a]
Sema L. Ioffe,[a,d] and Vladimir A. Tartakovsky[a]
Keywords: Nitro compounds / Nitrogen heterocycles / Oximes / Nucleophilic substitution / Halides
An approach to the synthesis of α-halo oxime ethers from
readily accessible nitronates and nitro compounds via bis-
(oxy)enamines is reported. A key step of the strategy in-
volves the unprecedented reaction of bis(oxy)enamines with
a metal (Co, Zn, Mg, Mn) halide that acts as both a promoter
and halide (Br, I, Cl) source. A variety of cyclic and acyclic
ethers of α-halo oximes, including previously unavailable tri-
methylsilyl ethers of α-iodo oximes, have been synthesized
in good-to-high yields.
have proved to be useful intermediates in the stereoselective
synthesis of unnatural β- and γ-amino acids,[6a,6b] function-
alized pyrrolidines,[3f,6a] pyrroles,[3f] tetrahydrofurans,[6c] di-
hydrofurans,[6d] γ-lactams,[6e] and oxaazaspirononanones.[6f]
Owing to their high synthetic potential, α-halo oxime ethers
1 have found widespread applications in the target-oriented
synthesis of natural and bioactive molecules both in acade-
mia[1,7,8] and the pharmaceutical industry.[9]
Although synthetic approaches to α-halo oximes are well
developed,[1j,2] the synthesis of their O-ethers 1, especially
cyclic ones, still represents a nontrivial task that lacks a
general solution (e.g., see ref.[8a]). In this work, a general
approach to the synthesis of cyclic and acyclic ethers of α-
halo oximes 1 from nitronates or aliphatic nitro compounds
has been developed.
Introduction
α-Halo oximes and their ethers 1 (Figure 1) are widely
used as versatile intermediates in organic synthesis as a re-
sult of their unique reactivity.[1] Acyclic α-halo oximes[1]
and their silyl ethers[2] serve as the major precursors of con-
jugated nitrosoalkenes, which are an important class of het-
erodienes in Diels–Alder reactions.[1,2] Nucleophilic substi-
tution of the halogen in oxime ethers 1 provides an easy
route to various functionalized oxime derivatives.[3]
Furthermore, α-halo oxime ethers 1 are convenient sub-
strates for palladium-catalyzed C–C cross-coupling,[4a] cata-
lytic carbonylation,[4b] and aza-Reformatsky reactions,[4c,4d]
as well as for coupling with organic cuprates.[4e]
Results and Discussion
Recently we reported the synthesis of six-membered cy-
clic ethers of α-halo oximes 1 by the silylation of readily
accessible nitronates 2 employing an excess of halotri-
methylsilane in the presence of a base [Scheme 1, Equa-
tion (1)].[3f,3g] In this process nitronate 2 is transformed into
a cyclic bis(oxy)enamine (3) upon reaction of the first
equivalent of the (CH3)3SiHal/base mixture [step (1)].[3h,3g]
The reaction of bis(oxy)enamine 3 with a second equivalent
of halotrimethylsilane affords the corresponding 3-halo-
methyl-5,6-dihydro-4H-1,2-oxazines 1 as a result of a for-
mal SNЈ substitution of the silyloxy group [step (2)].[3g] Our
extensive studies over the last few years[3f,6] have revealed
several substantial drawbacks to this method: 1) The tar-
geted products are usually obtained in low-to-moderate
yields (typically 35–60%) and their synthesis is poorly scal-
able;[3f] 2) the protocol is applicable only to six-membered
Figure 1. α-Halo oximes and their ethers 1.
Subsequent reductive transformation of the oxime group
provides access to a variety of polyfunctionalized nitrogen-
containing products.[5] In this context, six-membered cyclic
ethers of α-halo oximes are of special interest because they
[a] N. D. Zelinsky Institute of Organic Chemistry,
Leninsky prospect 47, 119991 Moscow, Russia
E-mail: sukhorukov@ioc.ac.ru
http://www.ioc.ac.ru/
[b] D. Mendeleev University of Chemical Technology of Russia,
Miusskaya square 9, 125047 Moscow, Russia
[c] National Junior College,
Hillcrest Road 37, 288913 Singapore, Singapore
[d] Moscow Chemical Lyceum,
Tamozhenniy proezd 4, 111033 Moscow, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403083.
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α-Halo Oxime Ethers from Nitronates and Nitro Compounds
cyclic nitronates, with acyclic nitronates not affording the Table 1. Reaction of model enamine 3a with metal and non-metal
corresponding α-halo oxime ethers 1 upon silylation;[10]
bromides.
3) only 3-methyl-substituted cyclic nitronates can efficiently
undergo the process, in the case that R ϶ H [Scheme 1,
Equation (1)] the desired products are formed in less than
20% yield;[3g] 4) only cyclic ethers of α-chloro and α-bromo
oximes can be obtained, the synthesis of the corresponding
iodides not being possible because of the highly reactive
character of iodotrimethylsilane.[3g]
Entry MBrn (equiv.)
Conditions (additive, solvent,
temperature, time)
Yield of
1a [%]
1
2
3
4
5
6
7
8
Me3SiBr (1.5)
PBr3 (1.0)
CH3CN, –30 °C, 0.5 h[a]
CH2Cl2, 20 °C, 2 h
CH2Br2/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, H2O, 20 °C, 1.5 h
65[a]
30
AlBr3 (1.0)
HBr (2.0)
0[b]
33[c,d]
0[e]
Et3NH+Br– (2.0) THF/CH2Cl2, 20 °C, 2 h
LiBr (2.0)
THF/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
DMF/CH2Cl2, 20 °C, 2 h
CH3CN/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
traces[c,f]
CaBr2 (2.0)[g]
MgBr2 (2.0)
InBr3 (1.0)
BiBr3 (1.0)
NiBr2 (2.0)
ZnBr2 (2.0)
MnBr2 (2.0)
CuBr2 (2.0)
CoBr2 (2.0)
CoBr2 (0.5)
CoBr2 (2.0)
CoBr2 (2.0)
CoBr2 (2.0)
LiBr (2.0) +
CoBr2 (0.1)
0[e]
71
9
79[h]
32[c]
14[i]
10
11
12
13
14
15
16
17
18
19
20
74[j]
80[k]
12[l]
89[m]
77[n]
89[c]
88[c]
90[c]
26[o]
THF/CH2Cl2, 20 °C, 2 h
Scheme 1. Known and suggested approaches to the synthesis of α-
halo oxime ethers 1 from nitronates 2.
2 equiv. H2O, THF/CH2Cl2, 20 °C, 2 h
MS 4 Å, THF/CH2Cl2, 20 °C, 2 h
4 equiv. Et3N, THF/CH2Cl2, 20 °C, 2 h
THF/CH2Cl2, 20 °C, 2 h
A more detailed study of process 2Ǟ1 revealed that
limitations 1–3 are associated only with step (2) (Scheme 1).
Thus, regardless of the nature of the initial cyclic nitronate
2, bis(oxy)enamines 3 are produced in nearly quantitative
yields in step (1).[3g,3h] Furthermore, step (1) also proceeds
smoothly for five-membered and acyclic nitronates 2 lead-
ing to the corresponding cyclic and acyclic N,N-bis(oxy)en-
amines 3.[10,11] We speculated that the replacement of halo-
trimethylsilane by less reactive metal halides in step (2) may
allow the selectivity to be improved and the substrate scope
of the process 3Ǟ1 to be expanded [Scheme 1, Equa-
tion (2)].
To validate this hypothesis, the interaction of model cy-
clic N,N-bis(oxy)enamine 3a with a series of bromides of
main group and transition metals as well as some non-met-
als was investigated (Table 1).
As expected, highly reactive non-metal bromides (HBr,
PBr3, Me3SiBr) and AlBr3 (Table 1, entries 1–4) led to the
desired 3-bromomethyl-1,2-oxazine 1a in poor yields ac-
companied by many byproducts among which cyclic oxime
[a] See ref.[3g] [b] Complex mixture of products that contains 27%
of 4a and 13% of 5a. [c] Yields determined by 1H NMR spec-
troscopy by using an internal standard. [d] Yield of 4a: 23%. [e]
Conversion of 3a: 0%. [f] Conversion of 3a: 35%. [g] CaBr2·xH2O
(x Յ 1) was used. [h] Yield of 4a: 21%. [i] Conversion of 3a: 24%.
[j] Yield of 4a: 13%. [k] Yield of 4a: 15%. [l] 3-Bromomethyl-substi-
tuted nitronate 6a was isolated as the major product (27%). [m]
Average of three experiments (Ϯ6%). [n] Conversion of 3a: 95%.
[o] Conversion of 3a: 38%.
derivatives 4a and 5a were identified (for selective synthesis product after aqueous work-up. The reaction of bismuth
of these products from cyclic nitronates, see ref.[11a–11c]). On bromide with 3a produced a complex mixture of products
the other hand, triethylammonium bromide did not react that contained only about 30% of the desired bromide 1a
with bis(oxy)enamine 3a at all (Table 1, entry 5). Similarly, (Table 1, entry 10). Transition-metal bromides, which are
no conversion of the starting material was observed in the softer Lewis acids, furnished product 1a in high yields, with
reaction with calcium bromide, and only traces of product the exception of nickel(II) and copper(II) bromides. The
1a were detected in the reaction of 3a with LiBr (Table 1, low yield of 1a and conversion of enamine 3a in the reac-
entries 6 and 7). In contrast, magnesium and indium brom- tion with NiBr2 may be associated with its poor solubility
ides furnished 1a in relatively good yields (Table 1, entries 8 in organic solvents (Table 1, entry 11). In the case of CuBr2,
and 9). In the case of indium bromide, 3-hydroxy-substi- the major product was found to be 3-bromo-
tuted 1,2-oxazine 4a (21%) was found to be the major by- methyl-substituted cyclic nitronate 6a, probably arising
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from an electrophilic bromination of bis(oxy)enamine 3a of CoBr2 as catalyst and LiBr as the source of the bromide
(Table 1, entry 14).[11d] The best result was obtained with anion (Table 1, entry 20). It is likely that the cobalt trimeth-
anhydrous cobalt(II) bromide in THF (Table 1, entry 15).
ylsiloxide arising from the reaction is sufficiently inert and
Further studies revealed that 0.5 equiv. of CoBr2 is not transformed back into CoBr2 upon the action of LiBr
enough for the formation of bromide 1a in 77% yield, {for stable complexes of Co[OSi(CH3)3]2 with LiBr see
which indicates that both bromine atoms are transferred ref.[12b]}.
from the cobalt to the carbon atom (Table 1, entry 16; for
As can be seen from Scheme 2, the CoBr2 procedure
the structure of the CoBr2 species in THF solution, see (procedure i) can be applied to a broad range of bis(oxy)-
ref.[12a]). However, the use of an excess of CoBr2 slightly enamines 3a–i,n leading to the corresponding products 1a–
increased the yield of product 1a (cf. entries 15 and 16 in i,n in high yields. In addition to six-membered cyclic bis-
Table 1). The reaction of enamine 3a with CoBr2 was found (oxy)enamines 3a–i, the five-membered analogue 3n also
to be insensitive to water; the process gave almost the same successfully reacted with CoBr2 (product 1n in Scheme 2).
yield under absolute conditions as in the presence of Importantly, cobalt(II) chloride and iodide also reacted
2 equiv. of water (cf. entries 17 and 18 in Table 1). Further- with bis(oxy)enamines 3 to yield the respective cyclic ethers
more, the addition of a base (triethylamine) did not influ- of α-chloro and α-iodo oximes (products 1q–1t in
ence the yield of bromide 1a substantially (Table 1, en- Scheme 2). It is noteworthy that cyclic ethers of α-iodo ox-
try 19). These results indicate that product 1a is formed di- imes such as 1r and 1s cannot be obtained by silylation
rectly in the reaction of enamine 3a with CoBr2 and not of the cyclic nitronates 2[3g] discussed above [see Scheme 1,
with HBr, which may be generated upon the hydrolysis of Equation (1) and discussion]. In contrast to cobalt(II)
the latter. Unfortunately, we were not able to synthesize 1a chloride, bromide, and iodide, cobalt fluoride proved to be
in the catalytic variant of the reaction by using 10 mol-% unreactive, evidently because of its poor solubility. At the
Scheme 2. Synthesis of the cyclic α-halo oxime ethers 1a–t by procedures i and ii, yields of the isolated products are given.
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α-Halo Oxime Ethers from Nitronates and Nitro Compounds
same time, the reaction of enamine 3a with the more soluble also poorly available; the only route to their synthesis is
CoF2·2H2O resulted in an indecipherable mixture of prod- the radical bromination of trimethylsilyl ethers of oximes.[8]
ucts.[13]
However, this method has a limited substrate scope because
The cyclic ethers of α-bromo oximes 1a–p can be readily many α-bromo oxime silyl ethers are thermally unstable.[8]
synthesized by a one-pot protocol from the corresponding Furthermore, primary bromides (such as 1v and 1w) cannot
nitronates 2 without isolation of the intermediate bis(oxy)- be synthesized by this route. Therefore the suggested ap-
enamines 3 (procedure ii, Scheme 2). In this procedure the proach significantly expands the range of available α-halo
nitronate is silylated with bromotrimethylsilane (1.1 equiv.) oxime silyl ethers.
in the presence of triethylamine followed by the addition of
a solution of CoBr2 in THF. As can be seen from the data
given in Scheme 2, the yields of bromides 1 obtained by the
one-pot procedure ii in most cases are higher or comparable
to those obtained by procedure i. These results as well as
the lability of bis(oxy)enamines 3 make the application of
the one-pot procedure ii more preferable for the synthesis
of bromides 1 than the two-step procedure i. However, the
cyclic ethers of α-iodo oximes should be synthesized in two
steps, that is, by the silylation of nitronates 2 with the (CH3)3-
SiBr/Et3N mixture followed by aqueous work-up to sepa-
rate the forming bis(oxy)enamines 3 from triethylammo-
nium bromide in the first step, and the subsequent reaction
of 3 with cobalt(II) iodide according to procedure i in the
second step. Application of the one-pot procedure ii in this
case would lead to a mixture of α-halo oxime ethers (see
below).
The yields of the cyclic ethers of α-bromo and α-chloro
oximes 1 are on average about 30% higher than those re-
ported in the literature[3f,3g] obtained by silylation of
nitronates 2 with an excess of (CH3)3SiBr or (CH3)3SiCl (cf.
the yields given in Scheme 2). The method developed here
is scalable, as demonstrated by the synthesis of bromide 1a
from 20 mmol of nitronate 2a by the one-pot procedure ii
while maintaining its efficiency (83% yield). Notably, not
only primary, but also secondary halides 1 can be obtained
from nitronates 2 with R ϶ H by using procedure ii (e.g.,
see 1m in Scheme 2[14]).
Another significant advantage of the metal-mediated ap-
proach developed is its applicability to acyclic bis(oxy)en-
amines 3 (procedure i, Scheme 3). The reactions of en-
amines 3u,v,z,aa with cobalt(II) halides furnished the corre-
sponding silyl ethers of α-halo oximes 1u–1aa in good-to-
high yields. The major side-reaction observed in these ex-
Scheme 3. Synthesis of trimethylsilyl ethers of α-halo oximes 1u–
periments was the rearrangement of acyclic bis(oxy)en-
ab by procedures i and iii: 3u, 7u (R1 = Ph, R = H); 3v, 7v, 8v (R1
amines 3 to produce trimethylsilyl ethers of α-silyloxy ox-
imes 8 (see Scheme 3).[15] In particular, in the reaction of
bis(oxy)enamine 3v with CoBr2, about 20% of the re-
arrangement product 8v was formed; in the case of the in-
ternal enamine 3ab (generated in situ from nitro compound
7ab), the corresponding α-silyloxy oxime ether 8ab was the
major product (yield 38%), whereas only a negligible
= CH2CH2CO2CH3, R = H); 3z, 7z, 8z (R1 = CH2Ph, R = H);
3aa, 7aa, 8aa (R1 = H, R = H); 3ab, 7ab, 8ab (R1 = H, R = CH3).
The yields of isolated products 1u–aa were recalculated with respect
1
to the purity of compounds determined by H NMR spectroscopy
using an internal standard (see the Exp. Sect.). * Single isomer with
unknown configuration.
α-Bromo oxime silyl ethers could be prepared in one-pot
amount of the desired trimethylsilyl α-bromo oxime ether from the corresponding nitro compounds, as demonstrated
1
1ab was detected by H NMR spectroscopy. The reactions by the synthesis of the products 1v and 1w (procedure iii,
of terminal bis(oxy)enamines 3u,v,z,aa with CoI2 proceeded Scheme 3). In procedure iii, the corresponding bis(oxy)en-
more smoothly than those with CoBr2. The corresponding amines 3u and 3v were generated in situ by the double sil-
trimethylsilyl α-iodo oxime ethers 1x–1aa were obtained in ylation of nitro compounds 7u and 7v with (CH3)3SiBr/
yields of about 80% and contained almost no impurities Et3N. The subsequent addition of a solution of CoBr2 in
(Scheme 3). Note that silyl ethers of α-iodo oximes are vir- THF furnished the target α-bromo oxime silyl ethers 1w
tually unknown.[16] Trimethylsilyl α-bromo oxime ethers are and 1v, respectively. Thus, procedure iii enables a single-step
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C–H activation of the usually inert β-carbon atom of the
Thus, the treatment of the diastereomerically pure cyclic
aliphatic nitro compounds.
bis(oxy)enamine 3ac bearing an ethoxy group at C-6 with
The structures of the new cyclic α-halo oxime ethers 1 CoBr2 produced the desired bromide in only moderate yield
were determined by 1H and 13C NMR and IR spectroscopy, and as a mixture of the major 4,6-trans isomer (1ac) and
high-resolution mass spectrometry, and elemental analysis. minor 4,6-cis epimer (1acЈ) (Scheme 5). Interestingly, under
α-Iodo oxime ethers are not stable at ambient temperature the same reaction conditions, isomeric bis(oxy)enamine
and decomposed upon exposure to light to produce molec- 3acЈ possessing an ethoxy group cis to the aryl furnished
ular iodine (λmax = 537 nm in hexane). α-Halo oxime the corresponding bromide 1acЈ in good yield and almost
silyl ethers 1v–1aa are also quite labile compounds and without epimerization (the amount of epimer product 1ac
easily underwent hydrolysis and polymerization even in was less than 4%, Scheme 5). Similarly, in the synthesis of
CDCl3.[8a,8c] Attempts to isolate these products in an ana- product 1g containing a ketal carbon atom (C-6), no notice-
lytically pure state were not successful because they decom- able epimerization was observed (see Scheme 2).
posed upon vacuum distillation or column chromatog-
The degree of epimerization and the yield of product 1ac
raphy.[17] At the same time, the crude products 1v–1aa obtained from bis(oxy)enamine 3ac depend on the nature
(Scheme 4) demonstrated a high degree of purity (typically of the metal bromide employed (Table 2). Thus, screening
1
80–90%, according to H NMR spectroscopy using an in- of metal bromides in the reaction with 3ac (generated in
ternal standard). The structures of 1v–1aa were unambigu- situ from nitronate 2ac, see top part of Scheme 6) revealed
ously determined by 1H, 13C, and 29Si NMR, IR spec- that the smallest amount of epimer 1acЈ and the highest
troscopy, and EI mass spectrometry. Further confirmation yield of 1ac were obtained with MgBr2 in THF (Table 2,
of the identity and purity of the products 1v–1aa was their entry 4, procedure iv).
facile methanolysis with TBAF in methanol[8a] to give
Table 2. Screening of metal bromides in the reaction with bis(oxy)-
enamine 3ac (generated in situ from nitronate 2ac).
stable α-methoxy oximes 9 (Scheme 4). The assignment of
signals of acyclic oxime derivatives 1 and 9 to E/Z isomers
was guided by the known relationships between the chemi-
cal shifts of atoms attached to the oxime group and its con-
figuration.[10c]
Entry MBrn (2 equiv.), solvent Yield of 1ac + 1acЈ [%][a] Ratio of 1ac/1acЈ[b]
1
CoBr2, THF/CH2Cl2
(procedure ii)
51
2.9:1.0
2
3
4
ZnBr2, THF/CH2Cl2
MnBr2, DMF/CH2Cl2
MgBr2, THF/CH2Cl2
(procedure iv)
63
56
70
4.4:1.0
5.7:1.0
5.8:1.0
5
6
NiBr2, DMF/CH2Cl2
InBr3, THF/CH2Cl2
8
7
0.9:1.0
4.0:1.0
[a] Yields of products isolated by column chromatography. [b] De-
1
termined by H NMR analysis of the crude reaction mixtures.
Partial epimerization of the acetal C-6 in 3ac provides
insights into the mechanism of the reaction of bis(oxy)en-
amines 3 with metal halides (Scheme 6). In fact, neither ini-
tial nitronate 2ac nor the final bromide 1ac underwent epi-
merization upon reaction with CoBr2/Et3NH+Br–. The
starting material was quantitatively recovered in these ex-
periments. This suggests that the reaction of bis(oxy)en-
amines 3 with metal halides proceeds via the generation of
the nitrosonium cation of type A, which may undergo 1,2-
oxazine ring-opening and epimerization through a revers-
ible ring/chain process AhBhAЈ (Scheme 6). The absence
of epimerization in the case of isomeric 4,6-cis-bis(oxy)en-
amine 3acЈ (Scheme 5) may be due to a high thermo-
dynamic preference for cation AЈ over cation A (Scheme 6).
Therefore it is likely that the transformation 3Ǟ1 proceeds
by SN1Ј substitution of the trimethylsilyloxy group by the
halide anion assisted by the metal ion acting as a Lewis
acid.
Scheme 4. Methanolysis of trimethylsilyl ethers of α-halo oximes
1v–aa.
The reactions of metal bromides with 6-alkoxy-substi-
tuted six-membered cyclic bis(oxy)enamines 3 warrants spe-
cial discussion. A significant complication in the case of
these substrates is the epimerization and destruction of the
acetal center at C-6, which is sensitive to Lewis acids
(Scheme 5).
Further evidence for the SN1Ј mechanism comes from
competition reactions of bis(oxy)enamine 3a with a mixture
of three cobalt halides. Despite the significant difference in
the nucleophilicity of the halide anions, all three cyclic α-
halo oxime ethers were obtained in comparable amounts
(see Scheme 7).[18] The absence of selectivity in the reactions
Scheme 5. Reaction of bis(oxy)enamines 3ac and 3acЈ with CoBr2:
1ac, 3ac (R1 = 4-CH3O-C6H4, R2 = OEt, R3 = H); 1acЈ, 3acЈ (R1
= 4-CH3O-C6H4, R2 = H, R3 = OEt).
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α-Halo Oxime Ethers from Nitronates and Nitro Compounds
Experimental Section
All reactions were performed in oven-dried (150 °C) glassware. Col-
umn chromatography was performed by using Kieselgel 40–60 μm
60A. 1D and 2D NMR spectra were recorded at room temperature
in CDCl3 with a Bruker AM 300 spectrometer. The chemical shifts
(1H, 13C) are given in ppm (δ) relative to the solvent signal. Multi-
plicities are indicated by s (singlet), d (doublet), t (triplet), q (quar-
tet), m (multiplet), and br. (broad). FTIR spectra were recorded
with a Bruker Alpha-T spectrometer. Peaks in IR spectra data are
reported in cm–1 along with the following relative intensities: s
(strong), m (medium), w (weak), br (broad), sh (shoulder). UV/Vis
spectra were recorded with a Shimadzu UVmini-1240 spectrometer
(data are reported in nm). Elemental analysis (average of two com-
bustions) was performed at the Analytical Laboratory of the N. D.
Zelinsky Institute of Organic Chemistry. HRMS was performed
with an electrospray ionization (ESI) spectrometer equipped with
a time-of-flight (TOF) detector. EI mass spectra were recorded with
a Finnigan MAT Incos 50 spectrometer (70 eV). Optical rotation
angles were measured with a DIP-360 polarimeter. Concentrations
c are given in g/100 mL, [α]D values are given in units of
10–1 degcm2 g–1. Analytical TLC was performed on precoated silica
gel plates (QF-254). Visualization was accomplished with UV light
and a solution of anisaldehyde/H2SO4 in ethanol. Tetrahydrofuran
was distilled first from LiAlH4, stored under sodium benzophenone
ketyl, and distilled by using a vacuum trap-to-trap technique prior
to use. CH2Cl2, MeCN, Et3N, and (CH3)3SiBr were distilled from
CaH2. Hexane and EtOAc were distilled without drying agents.
Commercial-grade pentane was used as received.
Scheme 6. Reaction of bis(oxy)enamine 3ac with CoBr2.
with cobalt halides implies the participation of a highly re-
active cationic intermediate and a reaction of SN1Ј charac-
ter.
All inorganic reagents, nitroethane, and 1-nitropropane were com-
mercial-grade and used as received. The initial cyclic nitronates
2a,[3h] 2b,[3f] 2c,[3f] 2e,[3f] 2f,[3g] 2g,[3h] 2h,[3g] 2m,[11a] 2n,[19] 2o,[20]
2p,[20] 2ac,[3h] and 2acЈ,[3h] and bis(oxy)enamines 3a,[3h] 3b,[11c]
3c,[11a] 3d,[3h] 3e,[11b] 3f,[3g] 3g,[3h] 3h,[3g] 3n,[20] 3u,[10b] 3v,[10a] 3z,[10c]
3aa,[10a] 3ab,[10a] 3ac,[3h] and 3acЈ[3h] were synthesized according to
known methods. Nitronates 2d, and 2j–l were prepared following
the procedure used for the synthesis of 2d[3h] with small modifica-
tions: for compounds 2d, 2j, and 2l, the reaction mixtures were kept
at –30 °C for 20 h, for compound 2k, the reaction mixture was kept
at –30 °C for 30 min.
Scheme 7. Competition reactions of bis(oxy)enamine 3a with a
(1R,2S,4S,4ЈS)-3,3,3Ј-Trimethyl-4Ј-phenyl-4Ј,5Ј-dihydrospiro[bicy-
clo[2.2.1]heptane-2,6Ј-[1,2]oxazine] 2Ј-Oxide (Nitronate 2i): A solu-
tion of camphene (4.08 g, 30 mmol) in CH2Cl2 (10 mL) followed
by SnCl4 (2.34 mL, 20 mmol) were added to a stirred solution of
[(1E)-2-nitroprop-1-en-1-yl]benzene[21] (3.26 g, 20 mmol) in CH2Cl2
(35 mL) at –60 °C under argon. The resulting deep-red solution
was stirred at around –60 °C for 0.5 h and then maintained for 48 h
at –30 °C with occasional stirring. Then the reaction mixture was
poured into a mixture of EtOAc (200 mL) and a saturated solution
of K2CO3 (200 mL), and the aqueous layer was back-extracted with
EtOAc (100 mL). The combined organic layers were then washed
mixture of cobalt halides.
Conclusions
The reactions of bis(oxy)enamines with metal (e.g., Co,
Zn, Mg, Mn) halides results in a transfer of the halide
anion to the carbon atom through a novel metal-assisted
SN1Ј-type substitution process. The reaction is general and
proceeds efficiently for both cyclic and acyclic bis(oxy)en- with a saturated solution of K2CO3 (50 mL), water (50 mL), and
brine (50 mL), dried (Na2SO4), and the solvents evaporated in
vacuo. The resulting white solid was triturated with pentane and
dried until a constant weight, yield 4.84 g (81%). White solid, m.p.
143–145 °C (with dec.), recrystallized from hexane. [α]D = –38.0 (c
= 1.0, CHCl3, 27 °C). 1H NMR (CDCl3, 300.13 MHz, COSY,
HSQC, NOESY): δ = 0.90 and 1.14 (2 s, 3 H and 3 H, 2 CH3),
1.24 (d, J = 10.6 Hz, 1 H, 7-H), 1.29–1.44 and 1.55–1.67 (2 m, 2
H and 2 H, 5-H and 6-H), 1.84 (s, 3 H, 8-H), 1.80–1.89 (m, 2 H,
4-H and 5Ј-H), 2.30 (m, 2 H, 7-H and 5Ј-H), 2.47 (d, J = 4.2 Hz,
1 H, 1-H), 3.53 (dd, J = 7.4, 10.7 Hz, 1 H, 4Ј-Hax), 7.19 (d, J =
7.0 Hz, 2 H, o-C6H5), 7.33 (t, J = 7.0 Hz, 1 H, p-C6H5), 7.37 (t, J =
amines. Based on the selective reactions of bis(oxy)en-
amines with cobalt halides, new one- and two-step pro-
cedures for the synthesis of cyclic and acyclic α-halo oxime
ethers from available nitronates and aliphatic nitro com-
pounds have been developed. These methods involve the
formal C–H activation of the usually inert β-carbon atom
of nitro compounds. The approach described herein does
not suffer from the drawbacks of previous methods and sig-
nificantly expands the range of α-halo oxime ethers avail-
able.
Eur. J. Org. Chem. 2014, 8148–8159
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8153

A. Yu. Sukhorukov et al.
FULL PAPER
7.0 Hz, 2 H, m-C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT, General Procedure for the Synthesis of Cyclic α-Halo Oxime Ethers
HSQC): δ = 17.2 (C-8), 22.4 and 23.7 (C-5 and C-6), 22.5 and 23.7 1a–p from Cyclic Nitronates 2a–p,ac (Procedure ii): Bromotrimeth-
(2 CH3), 33.4 (C-5Ј), 34.8 (C-7), 42.5 (C-1), 44.1 (C-4Ј), 44.9 (C-3), ylsilane (0.145 mL, 1.1 mmol) was added to a stirred solution of
49.3 (C-4), 92.3 (C-6Ј), 122.1 (C-3Ј), 127.6, 127.8, and 129.1 (o-, cyclic nitronate 2 (1 mmol) in CH2Cl2 (2 mL) and triethylamine
m-, p-C6H5), 140.6 (i-C6H5) ppm. Characteristic 2D NOESY corre-
(0.160 mL, 1.15 mmol) at 0 °C under argon. The mixture was
lation: 4Ј-Hax/1-H. C19H25NO2 (299.41): calcd. C 76.22, H 8.42, N stirred at 0 °C for 5 h. Then a solution of cobalt bromide (0.438 g,
4.68; found C 75.92, H 8.27, N 4.60.
2 mmol) in THF (4 mL) was added. After an additional 24 h at
room temperature, the resulting blue solution was diluted with
EtOAc (10 mL) and poured into a mixture of EtOAc (100 mL) and
a saturated solution of K2CO3 (100 mL; a 0.25 m NaHSO4 solution
can be used instead of K2CO3 to simplify the work-up). The aque-
ous layer was back-extracted with EtOAc (50 mL). The combined
organic layers were washed with a saturated solution of K2CO3
(50 mL), water (50 mL), and brine (50 mL), dried (Na2SO4), and
the solvents evaporated in vacuo. The products 1a,b,d,e,g–p,ac were
isolated by flash chromatography on silica gel, and the products 1c
and 1f by crystallization. The yields of the products are given in
Scheme 2 and Table 2.
(1R,2S,4S,4ЈS)-3,3-Dimethyl-3Ј-methylene-4Ј-phenyl-2Ј-[(trimethyl-
silyl)oxy]spiro[bicyclo[2.2.1]heptane-2,6Ј-[1,2]oxazinane] [Bis-
(oxy)enamine 3i]: A solution of bromotrimethylsilane (1.00 mL,
7.58 mmol) in CH2Cl2 (2.3 mL) was added to a stirred solution
of nitronate 2i (1.485 g, 4.96 mmol) and triethylamine (1.08 mL,
7.76 mmol) in CH2Cl2 (11.3 mL) at –78 °C under argon. The mix-
ture was kept at –78 °C for 48 h with occasional shaking, then di-
luted with hexane, and transferred into a mixture of hexane
(50 mL) and 0.25 m NaHSO4 (50 mL). The aqueous layer was
back-extracted with hexane (30 mL). The combined organic layers
were washed with 0.25 m NaHSO4 (30 mL), water (30 mL), and
brine (30 mL), dried (Na2SO4), and the solvents evaporated in
vacuo to give 1.835 g (90%) of bis(oxy)enamine 3i. Owing to the
labile character of 3i it was stored as a 0.5 m solution in CH2Cl2 at
–30 °C. Colorless oil. [α]D = +52.8 (c = 1.0, CHCl3, 27 °C). 1H
NMR (CDCl3, 300.13 MHz, COSY, HSQC): δ = 0.27 [s, 9 H,
Si(CH3)3], 0.90 and 1.06 (2 s, 3 H and 3 H, 2 CH3), 1.20 (d, J =
9.8 Hz, 1 H, 7-H), 1.27–1.41 and 1.48–1.59 (2 m, 2 H and 2 H, 5-
H and 6-H), 1.78 (s, 1 H, 4-H), 1.97 (dd, J = 6.1, 13.1 Hz, 1 H, 5Ј-
HЈeq), 2.01 (dd, J = 11.5, 13.1 Hz, 1 H, 5Ј-HЈax), 2.26 (d, J = 9.8 Hz,
1 H, 7-H), 3.25 (d, J = 3.1 Hz, 1 H, 1-H), 3.61 (dd, J = 6.1, 11.5 Hz,
1 H, 4Ј-HЈax), 3.85 (d, J = 1.5 Hz, 1 H, 8-H), 4.98 (d, J = 1.4 Hz,
1 H, 8-H), 7.27–7.39 (m, 5 H, o-, m-, p-C6H5) ppm. 13C NMR
(CDCl3, 75.47 MHz, DEPT, HSQC): δ = –0.6 [Si(CH3)3], 22.9 and
24.0 (2 CH3), 23.3 and 24.1 (C-5 and C-6), 34.9 (C-7), 35.1 (C-5Ј),
42.7 (C-1), 43.5 (C-4Ј), 45.0 (C-3), 49.7 (C-4), 88.1 (C-2), 96.5 (C-
8), 127.0, 128.5, and 128.9 (o-, m-, p-C6H5), 141.2 (i-C6H5), 158.6
(C-3Ј) ppm. 29Si NMR (CDCl3, 59.63 MHz, DEPT): δ = 25.9 ppm.
HRMS: calcd. for [C22H34NO2Si]+ 372.2353; found 372.2346;
calcd. for [C22H33NO2SiNa]+ 394.2173; found 394.2163. Purity de-
termined by 1H NMR with internal standard (trichloroethylene):
ca. 90%.
General Procedure for the Synthesis of α-Halo Oxime Ethers 1v,w
from Nitro Compounds 7u,v (Procedure iii): Bromotrimethylsilane
(0.275 mL, 2.1 mmol) was added to a stirred solution of nitro com-
pound 7u or 7v (1 mmol) in CH2Cl2 (2 mL) and triethylamine
(0.305 mL, 2.2 mmol) at 0 °C under argon. The mixture was kept
at 0 °C with occasional stirring for 96 (7u) or 24 h (7v). Then a
solution of cobalt bromide (0.438 g, 2 mmol) in THF (4 mL) was
added. After an additional 24 h at room temperature the resulting
blue solution was diluted with EtOAc (10 mL) and poured into a
mixture of EtOAc (100 mL) and a 0.25 m NaHSO4 solution
(100 mL). The aqueous layer was back-extracted with EtOAc
(50 mL). The combined organic layers were washed with NaHSO4
solution (50 mL), water (50 mL), and brine (50 mL), dried
(Na2SO4), and the solvents evaporated in vacuo. The resulting
crude products were dissolved in pentane and filtered through a
short column filled with charcoal (0.5 cm) and Celite (0.5 cm) lay-
ers to remove polymer products and traces of inorganic salts. The
filtrates were evaporated to give unstable products 1w and 1v,
respectively. The yields are given in Scheme 3.
Procedure for the Synthesis of 3-Bromomethyl-1,2-oxazine 1ac from
Nitronate 2ac (Procedure iv): Bromotrimethylsilane (0.145 mL,
1.1 mmol) was added to a stirred solution of cyclic nitronate 2ac
(1 mmol) in CH2Cl2 (2 mL) and triethylamine (0.160 mL,
1.15 mmol) at 0 °C under argon. The mixture was kept at 0 °C with
occasional stirring for 5 h. Then a slurry of magnesium bromide
(0.368 g, 2 mmol) in THF (4 mL) was added and the mixture was
left to stand at room temperature overnight. Then the mixture was
diluted with EtOAc (10 mL) and poured into a mixture of EtOAc
(100 mL) and a saturated solution of K2CO3 (100 mL). The aque-
ous layer was back-extracted with EtOAc (50 mL). The combined
organic layers were washed with a saturated solution of K2CO3
(50 mL), water (50 mL), and brine (50 mL), dried (Na2SO4), and
the solvents evaporated in vacuo. The residue was subjected to col-
umn chromatography on silica gel (eluent EtOAc/hexane = 1:10)
to give 0.23 g (70%) of a mixture of 1ac and 1acЈ as a colorless oil
(ratio 1ac/1acЈ = 5.8:1).
General Procedure for the Synthesis of α-Halo Oxime Ethers 1a–
i,n,q-aa,ac,acЈ from Bis(oxy)enamines 3a–i,n,u,v,z,aa,ac,acЈ (Pro-
cedure i): A solution of bis(oxy)enamine 3 (1 mmol) in CH2Cl2
(2 mL) was added to a stirred solution of cobalt(II) bromide, chlor-
ide, or iodide (2 mmol) in THF (4 mL) at room temperature under
argon. After 2 h of stirring the resulting blue solution was diluted
with EtOAc (10 mL) and poured into a mixture of EtOAc (100 mL)
and a saturated solution of K2CO3 (100 mL; for cyclic oxime ethers
1a–i,n,q–t,ac,acЈ, 0.25 m NaHSO4 solution can be used instead of
K2CO3 to dissolve the inorganic precipitate formed upon aqueous
work-up). The aqueous layer was back-extracted with EtOAc
(50 mL). The combined organic layers were washed with a satu-
rated solution of K2CO3 (or 0.25 m NaHSO4; 50 mL), water
(50 mL), and brine (50 mL), dried (Na2SO4), and the solvents evap-
orated in vacuo. The products 1a,b,d,e,g–i,n,q–t,ac,acЈ were purified
by flash chromatography on silica gel, and the products 1c and 1f
by crystallization. The unstable products 1u–aa were dissolved in
pentane and filtered through a short column filled with charcoal
(0.5 cm) and Celite (0.5 cm) layers to remove polymer products and
traces of inorganic salts. The filtrates were evaporated to give prod-
ucts 1v–aa, which were used for analytical purposes. The yields are
given in Schemes 2, 3, and 5. The yields of products 1u–1aa were
recalculated with respect to the purity of the compounds deter-
1
The H NMR spectra and physical properties of the products 1a–
g,j–l,q,ac,acЈ,4a,5a,6a are in agreement with data reported pre-
viously (see the Supporting Information). The atom labelling of the
products 1i,l,s as well as 2i,3i is depicted in Scheme 2.
rel-(4S,6S)-3-(Bromomethyl)-4-(4-methoxyphenyl)-6-phenyl-5,6-di-
hydro-4H-1,2-oxazine (1h): Yield 88 % (procedure i), 74 % (pro-
cedure ii). Colorless oil that solidified upon standing at 0 °C, m.p.
100–101 °C. Rf = 0.7 (EtOAc/hexane = 1:1). 1H NMR (CDCl3,
1
mined by H NMR spectroscopy with an internal standard.
8154
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 8148–8159

α-Halo Oxime Ethers from Nitronates and Nitro Compounds
300.13 MHz, COSY, HMQC): δ = 2.28 (ddd, J = 13.0, 11.9,
and 11m[11a] (4%). After column chromatography a fraction con-
11.5 Hz, 1 H, 5-Hax), 2.52 (dd, J = 13.0, 8.2 Hz, 1 H, 5-Heq), 3.68 taining both isomers in a ratio of 6.0:1.0 was obtained, which was
(d, J = 9.9 Hz, 1 H, CHBr), 3.82 (s, 3 H, OCH3), 4.02 (d, J = used for analytical purposes. White solid, m.p. 73–81 °C. Rf = 0.7
9.9 Hz, 1 H, CHBr), 4.13 (dd, J = 8.2, 11.5 Hz, 1 H, 4-Hax), 4.97
(d, J = 11.9 Hz, 1 H, 6-Hax), 6.92 (d, J = 8.3 Hz, 2 H, o- 300.13 MHz, COSY, HMQC): δ = 1.27–1.49 (m, 4 H, 7-H, 8-H, 9-
C6H4OCH3), 7.22 (d, J = 8.3 Hz, 2 H, m-C6H4OCH3), 7.33–7.46 H, 10-H), 1.58–1.79 (m, 4 H, 5-H, 8-H, 9-H, 10-H), 1.93 (d, J =
(EtOAc/hexane = 1:1). Major isomer: 1H NMR (CDCl3,
(m, 5 H, o-, m-, p-C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz, 6.8 Hz, 3 H, CH3), 2.06–2.10 (m, 1 H, 7-H), 3.57 (s, 1 H, 4-Heq),
DEPT, HMQC): δ = 31.4 (CH2Br), 34.2 (C-5), 35.7 (C-4), 55.4 3.81 (s, 3 H, H3CO), 4.01 (m, 1 H, 6-H), 4.46 (q, J = 6.8 Hz, 1 H,
(OCH3), 73.9 (C-6), 114.7 (o-C6H4OCH3), 126.6, 128.4, and 128.6 11-H), 6.89 (d, J = 8.6 Hz, 2 H, o-C6H4OCH3), 7.03 (d, J = 8.6 Hz,
(o-, m-, p-C6H5), 129.4 (m-C6H4OCH3), 132.6 (p-C6H4OCH3), 2 H, m-C6H4OCH3) ppm. 13C NMR (CDCl3, 75.47 MHz, HMQC,
139.0 (i-C6H5), 154.2 (C-O), 159.1 (C=N) ppm. C18H18BrNO2
(360.25): calcd. C 60.01, H 5.04, N 3.89; found C 59.89, H 4.90, N
4.02.
DEPT): δ = 20.0, 24.8, and 27.2 (C-8, C-9, C-10), 21.6 (CH3), 29.2
(C-7), 38.5 (C-5), 43.6 (C-4), 47.3 (C-11), 55.3 (OCH3), 69.3 (C-6),
114.4 (o-C6H4OCH3), 129.2 (m-C6H4OCH3), 133.2 (p-C6H4OCH3),
155.1 (C-O), 158.9 (C-3) ppm. Minor isomer: 1H NMR (CDCl3,
300.13 MHz, COSY, HMQC): δ = 1.27–1.49 (m, 4 H, 7-H, 8-H, 9-
H, 10-H), 1.44 (d, J = 7.1 Hz, 3 H, CH3), 1.58–1.79 (m, 4 H, 5-H,
8-H, 9-H, 10-H), 2.06–2.10 (m, 1 H, 7-H), 3.63 (s, 1 H, 4-Heq), 3.81
(s, 3 H, H3CO), 4.12 (m, 1 H, 6-H), 4.46 (q, J = 7.1 Hz, 1 H, 11-
H), 6.89 (d, J = 8.6 Hz, 2 H, o-C6H4OCH3), 7.05 (d, J = 8.6 Hz, 2
H, m-C6H4OCH3) ppm. 13C NMR (CDCl3, 75.47 MHz, HMQC,
DEPT): δ = 19.3, 25.1, 29.4, and 29.7 (C-7, C-8, C-9, C-10), 21.6
(CH3), 38.1 (C-5), 41.3 (C-4), 51.1 (C-11), 55.3 (OCH3), 68.9 (C-6),
114.1 (o-C6H4OCH3), 129.2 (m-C6H4OCH3), 133.9 (p-C6H4OCH3),
155.1 (C-O), 158.9 (C-3) ppm. C17H22BrNO2: C, 57.96; H, 6.29; N,
3.98; found C, 58.35; H, 6.49; N, 3.93.
(1R,2S,4S,4ЈS)-3Ј-(Bromomethyl)-3,3-dimethyl-4Ј-phenyl-4Ј,5Ј-di-
hydrospiro[bicyclo[2.2.1]heptane-2,6Ј-[1,2]oxazine] (1i): Yield 76%
(procedure i), 90% (procedure ii). White solid, m.p. 117–121 °C
(with dec.), recrystallized from hexane. Rf = 0.8 (EtOAc/hexane
= 1:1). [α]D = –6.6 (c = 1.0, CHCl3, 27 °C). 1H NMR (CDCl3,
300.13 MHz, COSY, HMQC, NOESY): δ = 0.91 (s, 3 H, CH3),
1.16 (s, 3 H, CH3), 1.20 (d, J = 10.3 Hz, 1 H, 7-H), 1.28–1.43 (m,
2 H, 6-H), 1.53–1.64 (m, 2 H, 5-H), 1.84 (dd, J = 13.9, 12.6 Hz, 1
H, 5Ј-HЈax), 1.85 (s, 1 H, 4-H), 2.19 (d, J = 10.3 Hz, 1 H, 7-H),
2.33 (dd, J = 13.9, 7.2 Hz, 1 H, 5Ј-HЈЈeq), 2.46 (d, J = 3.8 Hz, 1 H,
1-H), 3.65 (d, J = 9.8 Hz, 1 H, 8-H), 3.73 (dd, J = 12.6, 7.2 Hz, 1
H, 4Ј-Hax), 3.98 (d, J = 9.8 Hz, 1 H, 8-H), 7.26 (d, J = 7.4 Hz, 2
H, o-C6H5), 7.34 (t, J = 6.7 Hz, 1 H, p-C6H5), 7.39 (dd, J = 7.4,
6.7 Hz, 2 H, m-C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz,
HMQC, DEPT): δ = 22.3 and 24.2 (2 CH3), 22.4 and 23.8 (C-5
and C-6), 31.3 (C-5Ј), 31.8 (C-8), 34.6 (C-7), 39.1 (C-4Ј), 43.2 (C-
1), 44.6 (C-3), 49.3 (C-4), 87.8 (C-2), 127.6, 128.2, and 129.2 (o-,
m-, p-C6H5), 139.3 (i-C6H5), 156.0 (C-3Ј) ppm. Characteristic 2D
NOESY correlations: o-C6H5/5Ј-HЈax, 5Ј-HЈЈeq/6-H, 4Ј-Hax/1-H, 5-
Methyl 3-(Bromomethyl)-5-methyl-4,5-dihydroisoxazole-5-carboxyl-
ate (1n): Yield 84% (procedure i), 68% (procedure ii). Colorless oil.
1
Rf = 0.7 (EtOAc/hexane = 1:1). H NMR (CDCl3, 300.13 MHz): δ
= 1.66 (s, 3 H, CH3), 3.03 (d, J = 17.3 Hz, 1 H, CH), 3.60 (d, J =
17.3 Hz, 1 H, CH), 3.81 (s, 3 H, OCH3), 4.11 (d, J = 11 Hz, 1 H,
CHBr), 4.18 (d, J = 11 Hz, 1 H, CHBr) ppm. 13C NMR (CDCl3,
75.47 MHz, DEPT): δ = 23.1 (CH2), 23.4 (CH3), 44.5 (CH2Br),
53.0 (OCH3), 87.0 (C-O), 155.0 (C=N), 171.9 (C=O) ppm. FTIR
H/CH . FTIR (KBr): ν = 2939 (s, sh), 2860 (s), 1593 (s), 1493 (s),
˜
3
(neat): ν = 3031 (w), 2986 (m), 2956 (m), 2847 (w), 1741 (s), 1615
˜
1455 (s), 1423 (s), 1388 (m), 1366 (m), 1207 (s), 1093 (m), 1023 (s),
973 (s), 952 (s), 931 (m), 907 (s), 777 (s), 757 (s), 704 (s), 655 (m),
603 (m), 526 (s) cm–1. HRMS: calcd. for [C19H25BrNO]+
362.1114 and 364.1094; found 362.1110 and 364.1095.
C19H24BrNO (362.31): calcd. C 62.99, H 6.68, N 3.87; found C
63.09, H 6.57, N 4.07.
(m), 1435 (s, sh), 1378 (m), 1350 (m), 1304 (s), 1206 (s), 1175 (s),
1135 (m), 1104 (m), 986 (m), 918 (s), 850 (m), 767 (m), 672 (m),
625 (m) cm–1. HRMS: calcd. for [C7H11BrNO3]+ 235.9917 and
237.9900; found 235.9920 and 237.9902. C7H10BrNO3 (236.06):
calcd. C 35.62, H 4.27, N 5.93; found C 35.81, H 4.24, N 6.00.
3-(Bromomethyl)-5-(4-bromophenyl)-4,5-dihydroisoxazole (1o):
rel-(4S,4aR,5R,8S,8aR)-3-(Bromomethyl)-4-phenyl-4a,5,6,7,8,8a-
hexahydro-4H-5,8-methano-1,2-benzoxazine (1l): Yield 84% (pro-
cedure ii), m.p. 114–117 °C (with dec.), recrystallized from hexane.
Rf = 0.8 (EtOAc/hexane = 1:1). 1H NMR (CDCl3, 300.13 MHz,
COSY, HSQC, NOESY): δ = 1.07–1.18 (m, 2 H, 6-Hendo and 7-
Hendo), 1.22 (d, J = 10.5 Hz, 1 H, 9-HЈ), 1.47 (m, 1 H, 6-Hexo), 1.62
(m, 1 H, 7-Hexo), 2.04 (d, J = 4.0 Hz, 1 H, 5-H), 2.12 (d, J =
10.5 Hz, 1 H, 9-HЈЈ), 2.20 (dd, J = 10.1, 6.8 Hz, 1 H, 4a-Hax), 2.57
(d, J = 4.9 Hz, 1 H, 8-H), 3.30 (d, J = 10.1 Hz, 1 H, 4-Hax), 3.80
(d, J = 6.8 Hz, 1 H, 8a-Heq), 3.87 (d, J = 10.2 Hz, 1 H, 10-H), 3.91
(d, J = 10.2 Hz, 1 H, 10-H), 7.28–7.43 (m, 5 H, o-, m-, p-
C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz, HSQC): δ = 24.6 (C-
7), 28.5 (C-10), 29.0 (C-6), 33.4 (C-9), 40.3 (C-5), 42.1 (C-4), 42.3
(C-8), 53.4 (C-4a), 83.1 (C-8a), 127.6, 128.7, and 129.7 (o-, m-, p-
C6H5), 137.2 (i-C6H5), 171.0 (C-3) ppm. Characteristic 2D NOESY
correlations: 4a-Hax/8a-Heq, 4-Hax/o-C6H5, 8a-Heq/8-H, 4-Hax/5-H,
Yield 69 % (procedure ii). White solid, m.p. 48–50 °C (pentane/
1
Et2O = 5:1). Rf = 0.65 (EtOAc/hexane = 1:1). H NMR (CDCl3,
300.13 MHz): δ = 3.10 (dd, J = 17.1, 8.2 Hz, 1 H, HC), 3.56 (dd,
J = 17.1, 11.1 Hz, 1 H, HC), 4.21 (s, 2 H, CH2Br), 5.63 (dd, J =
11.1, 8.2 Hz, 1 H, HC), 7.22 (d, J = 8.3 Hz, 2 H, C6H4Br), 7.52 (d,
J = 8.3 Hz, 2 H, C6H4Br) ppm. 13C NMR (CDCl3, 75.47 MHz,
DEPT): δ = 23.4 and 42.7 (CH2 and CH2Br), 82.6 (CH), 122.4 (p-
C6H4Br), 127.5 and 132.0 (o-C6H4Br and m-C6H4Br), 139.3 (C-
Br), 154.6 (C=N) ppm. C10H9Br2NO (319.00): calcd. C 37.65, H
2.84, N 4.39; found C 37.70, H 2.77, N 4.24.
3-(Bromomethyl)-4-phenyl-4,5-dihydroisoxazole (1p): Yield 53 %
(procedure ii). Colorless oil. Rf = 0.8 (EtOAc/hexane = 1:1). 1H
NMR (CDCl3, 300.13 MHz): δ = 3.68 (d, J = 10.9 Hz, 1 H, CHBr),
4.26 (d, J = 10.9 Hz, 1 H, CHBr), 4.43 (dd, J = 8.0, 7.1 Hz, 1 H,
CH-C6H5), 4.64 (d, J = 11.0, 7.1 Hz, 1 H, CHO), 4.78 (d, J = 11.0,
8.0 Hz, 1 H, CHO), 7.21–7.45 (m, 5 H, o-, m-, p-C6H5) ppm. 13C
NMR (CDCl3, 75.47 MHz, DEPT): δ = 22.3 (CH2Br), 53.6 (CH),
77.8 (CH2O), 127.6, 128.2, and 129.4 (o-, m-, p-C6H5), 137.5 (i-
C6H5), 157.6 (C=N) ppm. C10H10BrNO (240.10): calcd. C 50.02,
H 4.20, N 5.83; found C 49.96, H 4.24, N 5.94.
8a-Heq/7-Hendo
,
4a-Hax/6-Hendo
,
4-Hax/9-HЈЈ, 4a-Hax/o-C6H5.
C16H18BrNO (320.23): calcd. C 60.01, H 5.67, N 4.37; found C
60.21, H 5.73, N 4.38.
rel-(4S,4aR,8aR)-3-(1-Bromoethyl)-4-(4-methoxyphenyl)-
4a,5,6,7,8,8a-hexahydro-4H-1,2-benzoxazine (1m): Obtained by
procedure ii from nitronate 2m as a mixture of two isomers in a
ratio of 2.0:1.0 (yield 56%) accompanied by products 10m[11a] (5%)
3-(Iodomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazine
(1r): Yield 90% (procedure i). White solid, m.p. 100–103 °C (hex-
Eur. J. Org. Chem. 2014, 8148–8159
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8155

A. Yu. Sukhorukov et al.
FULL PAPER
1
ane/Et2O = 5:1). Rf = 0.8 (EtOAc/hexane = 1:1). 1H NMR (CDCl3, (CDCl3, 59.63 MHz, INEPT, Z isomer): δ = 26.3 ppm. H NMR
300.13 MHz): δ = 1.35 and 1.38 (2 s, 3 H and 3 H, 2 CH3), 2.00
(CDCl3, 300.13 MHz, E isomer): δ = 0.16 [s, 9 H, Si(CH3)3], 2.55
(dd, J = 13.6, 11.9 Hz, 1 H, 5-Hax), 2.12 (dd, J = 13.6, 8.0 Hz, 1 (t, J = 7.0 Hz, 2 H, CH2-CH2), 2.66 (t, J = 7.0 Hz, 2 H, CH2-
H, 5-Heq), 3.50 (d, J = 9.3 Hz, 1 H, 8-H), 3.98 (dd, J = 11.9, 8.0 Hz, CH2), 3.66 (s, 3 H, CO2CH3), 4.15 (s, 2 H, CH2Br) ppm. 13C NMR
1 H, 4-Hax), 4.06 (d, J = 9.3 Hz, 1 H, 8-H), 7.24–7.41 (m, 5 H, o-,
m-, p-C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT): δ = 3.9
(C-8), 24.0 and 28.4 (2 CH3), 37.7 (C-4), 40.6 (C-5), 75.6 (C-6),
127.7, 128.3, and 129.4 (o-, m-, p-C6H5), 139.4 (i-C6H5), 156.3 (C-
(CDCl3, 75.47 MHz, DEPT, E isomer): δ = –0.8 [Si(CH3)3], 22.7,
30.1, and 33.5 (CH2-CH2 and CH2Br), 51.7 (OCH3), 157.1 (C=N),
173.0 (C=O) ppm. 29Si NMR (CDCl3, 59.63 MHz, INEPT, E iso-
mer): δ = 24.7 ppm. FTIR (neat): ν = 3435 (br, m), 2956 (s), 2851
˜
3) ppm. FTIR (thin film): ν = 3027 (m), 2974 (s), 2922 (s), 1602
(w), 1741 (s), 1620 (w), 1553 (m), 1438 (s), 1363 (m), 1317 (m),
1253 (s), 1201 (s), 1172 (s), 1111 (m), 974 (w), 923 (w, sh), 878 (s),
847 (s), 754 (m), 695 (w), 628 (w) cm–1. MS (EI): m/z (%) = 297
˜
(s), 1578 (s, sh), 1493 (s), 1454 (s), 1415 (s), 1384 (s), 1370 (s), 1317
(m), 1272 (s, sh), 1259 (m), 1159 (s), 1123 (s, sh), 1075 (s), 1030
(m), 1015 (m), 965 (s), 933 (s), 885 (s), 866 (s), 821 (m), 783 (s), and 295 (5) [M]+·, 282 and 280 (5) [M – CH3]+·, 264 and 266 (2)
758 (s, sh), 745 (s), 703 (s), 651 (m), 581 (m), 545 (s, sh) cm–1. UV/
[M – OCH3]+·, 202 (10) [M – CH2Br]+·, 113 (25) [M – CH2Br –
Vis (CH2Cl2): λmax = 228, 285 nm. C13H16INO (329.18): calcd. C OSi(CH3)3]+·, 73 (100) [(CH3)3Si]+·. Purity determined by 1H NMR
47.43, H 4.90, N 4.26; found C 47.43, H 4.77, N 4.21.
spectroscopy with internal standard (trichloroethylene): ca. 75%
(contains ca. 20% of 8v,[15] E/Z = 6.0:1.0).
rel-(4S,4aR,8aR)-3-(Iodomethyl)-4-(4-methoxyphenyl)-
4a,5,6,7,8,8a-hexahydro-4H-1,2-benzoxazine (1s): Yield 71% (pro-
cedure i). White solid, m.p. 86–90 °C (pentane). Rf = 0.5 (EtOAc/
2-Bromo-1-phenylethanone O-(Trimethylsilyl)oxime (1w): Yield
82% (procedure i), 70% (procedure iii). Colorless oil. Single isomer
with unknown configuration. 1H NMR (CDCl3, 300.13 MHz): δ =
0.32 [s, 9 H, Si(CH3)3], 4.45 (s, 2 H, CH2), 7.40–7.44 and 7.74–
7.77 (2 m, 3 H and 2 H, o-, m-, p-C6H5) ppm. 13C NMR (CDCl3,
75.47 MHz, DEPT): δ = –0.6 [Si(CH3)3], 17.9 (CH2), 126.2, 128.6,
and 129.7 (o-, m-, p-C6H5), 133.8 (i-C6H5), 157.2 (C=N) ppm. 29Si
1
hexane = 1:3). H NMR (CDCl3, 300.13 MHz, COSY, HSQC): δ
= 1.27–1.49 (m, 4 H, 7-H, 8-H, 9-H, 10-H), 1.57–1.80 (m, 4 H, 5-
H, 8-H, 9-H, 10-H), 2.04–2.11 (m, 1 H, 7-H), 3.64 (d, J = 1.5 Hz,
1 H, 4-Heq), 3.70 (d, J = 9.6 Hz, 1 H, 11-H), 3.81 (s, 3 H, H3CO),
4.01 (m, 1 H, 6-H), 4.16 (d, J = 9.6 Hz, 1 H, 11-H), 6.89 (d, J =
8.7 Hz, 2 H, o-C6H4OCH3), 7.07 (d, J = 8.7 Hz, 2 H, m-
C6H4OCH3) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT): δ = 5.1
(C-11), 20.1 and 24.8 (C-9 and C-10), 27.1 (C-8), 29.0 (C-7), 38.3
(C-5), 42.8 (C-4), 55.3 (OCH3), 69.4 (C-6), 114.4 (o-C6H4OCH3),
129.1 (m-C6H4OCH3), 132.9 (p-C6H4OCH3), 153.4 (C-O), 158.9
(C-3) ppm. HRMS: calcd. for [C16H21INO2]+ 386.0611; found
386.0607; calcd. for [C16H20INO2Na]+ 408.0431; found 408.0424.
C16H20INO2 (385.24): calcd. C 49.88, H 5.23, N 3.64; found C
49.98, H 5.00, N 3.59.
NMR (CDCl , 59.63 MHz, INEPT): δ = 27.6 ppm. FTIR: ν =
˜
3
3390 (br, m), 3218 (m), 3066 (m, sh), 2946 (m), 1682 (s, sh), 1596
(m), 1567 (s), 1449 (s), 1393 (m), 1349 (s, sh), 1280 (s), 1195 (m),
1014 (w), 1001 (w), 991 (w), 711 (m), 688 (s), 623 (w), 610 (w) cm–1.
MS (EI): m/z (%) = 287 and 285 (18) [M]+·, 272 and 270 (22) [M –
CH3]+·, 207 and 205 (3) [M – Ph]+·, 192 (5) [M – CH2Br]+·, 103
(38) [M – CH2Br – OSi(CH3)3]+·, 77 (72) [Ph]+·, 73 (100) [(CH3)3-
Si]+·. Purity determined by 1H NMR spectroscopy with internal
standard (trichloroethylene): ca. 90%.
Methyl 3-(Iodomethyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate
2-Iodo-1-phenylethanone O-(Trimethylsilyl)oxime (1x): Yield 86%
(procedure i). Colorless oil. Single isomer with Z configuration. 1H
NMR (CDCl3, 300.13 MHz): δ = 0.34 [s, 9 H, Si(CH3)3], 4.31 (s, 2
H, CH2), 7.38–7.46 and 7.72–7.77 (2 m, 3 H and 2 H, o-, m-, p-
C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT): δ = –11.3
(CH2), –0.6 [Si(CH3)3], 126.2, 128.6, and 129.7 (o-, m-, p-C6H5),
133.8 (i-C6H5), 158.3 (C=N) ppm. 29Si NMR (CDCl3, 59.63 MHz,
(1t): Yield 68% (procedure i). Yellowish oil unstable at room temp.
1
Rf = 0.4 (EtOAc/hexane = 1:3). H NMR (CDCl3, 300.13 MHz): δ
= 1.65 (s, 3 H, CH3), 3.07 (d, J = 17.2 Hz, 1 H, CH), 3.62 (d, J =
17.2 Hz, 1 H, CH), 3.8 (s, 3 H, OCH3), 4.02 (d, J = 10.3 Hz, 1 H,
CHI), 4.10 (d, J = 10.3 Hz, 1 H, CHI) ppm. 13C NMR (CDCl3,
75.47 MHz, DEPT): δ = –6.6 (CH2I), 23.4 (CH3), 45.0 (CH2), 53.0
(OCH3), 87.0 (C-O), 156.1 (C=N), 171.8 (C=O) ppm. HRMS:
calcd. for [C7H11INO3]+ 283.9778; found 283.9784; calcd. for
[C7H10INO3Na]+ 305.9598; found 305.9603.
INEPT): δ = 27.3 ppm. FTIR (neat): ν = 3060 (w), 2960 (s), 2926
˜
(w), 2902 (w), 1495 (w), 1444 (m), 1418 (m), 1324 (m), 1251 (s),
1159 (m), 1049 (m), 1028 (w), 947 (s), 892 (s), 851 (s), 767 (m), 754
(sh), 692 (m), 632 (w), 586 (w), 510 (w) cm–1. MS (EI): m/z (%) =
333 (3) [M]+·, 318 (2) [M – CH3]+·, 206 (27) [M – I]+·, 127 (2) [I]+·,
103 (33) [M – CH2I – OSi(CH3)3]+·, 77 (64) [Ph]+·, 73 (100) [(CH3)3-
Si]+·. Purity determined by 1H NMR spectroscopy with internal
standard (trichloroethylene): ca. 80%.
2-Chloro-1-phenylethanone O-(Trimethylsilyl)oxime (1u):[22] Yield
80% (procedure i). Colorless oil. Single isomer with unknown con-
figuration. 1H NMR (CDCl3, 300.13 MHz): δ = 0.32 [s, 9 H,
Si(CH3)3], 4.64 (s, 2 H, CH2), 7.35–7.46 and 7.72–7.80 (2 m, 3 H
and 2 H, o-, m-, p-C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz,
DEPT): δ = –0.7 [Si(CH3)3], 32.3 (CH2), 126.3, 128.5, and 129.6
(o-, m-, p-C6H5), 133.7 (i-C6H5), 157.0 (C=N) ppm. 29Si NMR
(CDCl3, 59.63 MHz, INEPT): δ = 27.6 ppm. MS (EI): m/z (%) =
243 and 241 (8 and 24) [M]+·, 228 and 226 (12 and 34) [M – CH3]+·,
192 (13) [M – CH2Cl]+·, 103 (44) [M – CH2Cl – OSi(CH3)3]+·, 77
(66) [Ph]+·, 73 (100) [(CH3)3Si]+·. Purity determined by 1H NMR
spectroscopy with internal standard (trichloroethylene): ca. 95%.
Methyl 5-Iodo-4-{[(trimethylsilyl)oxy]imino}pentanoate (1y): Yield
80% (procedure i). Yellowish oil unstable at room temp. Mixture
of isomers (ratio Z/E = 5:1). 1H NMR (CDCl3, 300.13 MHz, Z
isomer): δ = 0.19 [s, 9 H, Si(CH3)3], 2.63 (t, J = 6.3 Hz, 2 H, CH2),
2.75 (t, J = 6.3 Hz, 2 H, CH2), 3.67 (s, 3 H, OCH3), 3.87 (s, 2 H,
CH2I) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT, Z isomer): δ =
–8.3 (CH2I), –0.8 [Si(CH3)3], 27.8 and 30.0 (2 CH2), 51.7 (OCH3),
158.3 (C=N), 173.1 (C=O) ppm. 29Si NMR (CDCl3, 59.63 MHz,
Methyl 5-Bromo-4-{[(trimethylsilyl)oxy]imino}pentanoate (1v):
1
Yield 72% (procedure i), 57% (procedure iii). Colorless oil. Mixture
INEPT, Z isomer): δ = 26.1 ppm. H NMR (CDCl3, 300.13 MHz,
1
of isomers (ratio Z/E = 2.3:1). H NMR (CDCl3, 300.13 MHz, Z
E isomer): δ = 0.18 [s, 9 H, Si(CH3)3], 2.60 (m, 2 H, CH2), 2.67 (m,
isomer): δ = 0.17 [s, 9 H, Si(CH3)3], 2.60 (t, J = 6.5 Hz, 2 H, CH2- 2 H, CH2), 3.68 (s, 3 H, OCH3), 4.00 (s, 2 H, CH2I) ppm. 13C
CH2), 2.72 (t, J = 6.5 Hz, 2 H, CH2-CH2), 3.65 (s, 3 H, CO2CH3),
NMR (CDCl3, 75.47 MHz, DEPT, E isomer): δ = –0.7 [Si(CH3)3],
4.01 (s, 2 H, CH2Br) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT, 4.9 (CH2I), 30.1 and 30.5 (2 CH2), 51.8 (OCH3), 160.3 (C=N),
Z isomer): δ = –1.0 [Si(CH3)3], 21.0, 27.7, and 29.9 (CH2-CH2 and
CH2Br), 51.5 (OCH3), 157.1 (C=N), 173.0 (C=O) ppm. 29Si NMR
173.1 (C=O) ppm. 29Si NMR (CDCl3, 59.63 MHz, INEPT, E iso-
mer): δ = 26.2 ppm. FTIR (neat): ν = 2957 (s), 2906 (m), 2850 (w),
˜
8156
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 8148–8159

α-Halo Oxime Ethers from Nitronates and Nitro Compounds
1741 (s, C=O), 1438 (s), 1420 (m), 1363 (m), 1320 (m), 1252 (s),
1223 (m), 1197 (m), 1170 (s), 1093 (m), 1028 (w), 987 (w), 987 (m),
960 (m), 924 (s), 848 (s, sh), 754 (m), 698 (w), 628 (w), 543 (w), 485
(w), 437 (w) cm–1. MS (EI): m/z (%) = 343 (1) [M]+·, 328 (1) [M –
CH3]+·, 312 (2) [M – OCH3]+·, 216 (11) [M – I]+·, 202 (2) [M –
CH2I]+·, 127 (5) [I]+·, 113 (10) [M – CH2I – OSi(CH3)3]+·, 73 (75)
Z isomer): δ = 0.22 [s, 9 H, Si(CH3)3], 1.76 (d, J = 6.8 Hz, 3 H,
CH3), 5.34 (m, 1 H, CHI), 7.05 (d, J = 7.8 Hz, 1 H, HC=N) ppm.
1
The H NMR spectra of the E/Z isomers are in accordance with
literature data.[8b]
Methanolysis of Silyl Ethers of α-Halo Oximes 1v–z: A solution of
tetrabutylammonium fluoride (0.13 g, 0.5 mmol) in methanol
(2.5 mL) was added to a stirred solution of the crude trimethylsilyl
ether of the α-halo oxime (0.5 mmol) in methanol (2.5 mL). The
mixture was kept at room temperature for 48 h, evaporated in
vacuo, and the residue was subjected to column chromatography
on silica gel (eluent EtOAc/hexane gradient).
1
[(CH3)3Si]+·. Purity determined by H NMR spectroscopy with in-
ternal standard (trichloroethylene): ca. 85% (contains ca. 10% of
8v,[15] E/Z = 4.0:1.0).
1-Iodo-3-phenylacetone O-(Trimethylsilyl)oxime (1z): Yield 82%
(procedure i). Colorless oil. Mixture of isomers (ratio Z/E = 2.8:1).
1H NMR (CDCl3, 300.13 MHz, Z isomer): δ = 0.27 [s, 9 H,
Si(CH3)3], 3.72 and 3.77 (2 s, 2 H and 2 H, 2 CH2), 7.20–7.35 (m,
5 H, o-, m-, p-C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT,
Z isomer): δ = –9.2 (CH2I), –0.7 [Si(CH3)3], 38.5 (CH2C6H5), 127.0,
128.7, and 129.0 (o-, m-, p-C6H5), 136.7 (i-C6H5), 159.7
(C=N) ppm. 29Si NMR (CDCl3, 59.63 MHz, INEPT, Z isomer): δ
= 25.9 ppm. 1H NMR (CDCl3, 300.13 MHz, E isomer): δ = 0.25
[s, 9 H, Si(CH3)3], 3.85 and 3.97 (2 s, 2 H and 2 H, 2 CH2), 7.20–
7.35 (m, 5 H, o-, m-, p-C6H5) ppm. 13C NMR (CDCl3, 75.47 MHz,
Methyl 4-(Hydroxyimino)-5-methoxypentanoate (9v): Yield 70%
(from 1v), 72% (from 1y). For analytical purposes 9v was purified
by vacuum bulb-to-bulb distillation (0.4 Torr). Colorless liquid.
Mixture of isomers (ratio E/Z = 1.8:1). Rf = 0.4 (EtOAc/hexane =
1
1:1). H NMR (CDCl3, 300.13 MHz, E isomer): δ = 2.52–2.73 (m,
4 H, CH2-CH2), 3.30 (s, 3 H, CH2OCH3), 3.67 (s, 3 H, COOCH3),
3.97 (s, 2 H, CH2OCH3), 9.01 (br., 1 H, OH) ppm. 13C NMR
(CDCl3, 75.47 MHz, DEPT, E isomer): δ = 21.5 and 29.6 (CH2-
CH2), 51.7 (CO2CH3), 58.2 (OCH3), 72.7 (CH2OCH3), 157.0
1
DEPT,
E isomer): δ = –0.7 [Si(CH3)3], 3.89 (CH2I), 32.0
(C=N), 173.2 (C=O) ppm. H NMR (CDCl3, 300.13 MHz, Z iso-
(CH2C6H5), 126.7, 128.7, and 129.1 (o-, m-, p-C6H5), 136.7 (i-
mer): δ = 2.52–2.73 (m, 4 H, CH2-CH2), 3.35 (s, 3 H, CH2OCH3),
3.66 (s, 3 H, COOCH3), 4.29 (s, 2 H, CH2OCH3), 9.01 (br., 1 H,
OH) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT, Z isomer): δ =
25.8 and 30.4 (CH2-CH2), 51.7 (CO2CH3), 59.1 (OCH3), 67.1
(CH2OCH3), 158.4 (C=N), 173.3 (C=O) ppm. C7H13NO4 (175.18):
C 47.99, H 7.48, N 8.00; found C 47.93, H 7.62, N 8.15.
C6H5), 162.0 (C=N) ppm. 29Si NMR (CDCl3, 59.63 MHz, INEPT,
E isomer): δ = 25.9 ppm. FTIR (neat): ν = 3063 (w), 3029 (w), 2959
˜
(m), 2926 (w, sh), 2857 (w), 1602 (w), 1553 (w), 1531 (w), 1495 (m),
1454 (m), 1418 (m), 1252 (s), 1152 (m, sh), 1089 (m, sh), 1030 (s),
965 (s), 925 (m), 885 (s), 848 (s), 740 (s, sh), 700 (s), 628 (w), 576
(w), 540 (w), 462 (w) cm–1. MS (EI): m/z (%) = 347 (3) [M]+·, 332
(5) [M – CH3]+·, 220 (70) [M – I]+·, 127 (3) [I]+·, 117 (20) [M –
CH2I – OSi(CH3)3]+·, 91 (100) [PhCH2]+·, 73 (70) [(CH3)3Si]+·. Pu-
2-Methoxy-1-phenylethanone Oxime (9w): Yield 71% (from 1w),
62% (from 1x). Crystallized from pentane as only the E isomer
(m.p. 51–55 °C), which slowly isomerizes in CDCl3 solution to give
a mixture of E/Z isomers, ratio 1.0:3.0. Rf = 0.5 (EtOAc/hexane =
1
rity determined by H NMR spectroscopy with internal standard
(trichloroethylene): ca. 85% [contains ca. 15% of (E)-8z[15]].
1
1:1). H NMR (CDCl3, 300.13 MHz, E isomer): δ = 3.39 (s, 3 H,
OCH3), 4.35 (s, 2 H, CH2), 7.34–7.51 and 7.62–7.78 (2 m, 3 H and
2 H, o-, m-, p-C6H5), 9.40 (br., 1 H, OH) ppm. 13C NMR (CDCl3,
75.47 MHz, DEPT, E isomer): δ = 58.1 (OCH3), 73.5 (CH2), 127.0,
128.3, and 129.4 (o-, m-, p-C6H5), 133.6 (i-C6H5), 154.3
Iodoacetaldehyde O-(Trimethylsilyl)oxime (1aa): Compound 1aa
was obtained by procedure i from 7aa with some modifications:
Diethyl ether was used for work-up, all evaporations were con-
ducted at 400 Torr, yield 47% (procedure i). Volatile colorless oil
unstable at room temp. and upon exposure to light. Mixture of
isomers (ratio Z/E = 1.5:1). 1H NMR (CDCl3, 300.13 MHz, Z iso-
mer): δ = 0.25 [s, 9 H, Si(CH3)3], 3.92 (d, J = 6.6 Hz, 2 H, CH2I),
7.17 (t, J = 6.6 Hz, 1 H, CH) ppm. 13C NMR (CDCl3, 75.47 MHz,
DEPT, Z isomer): δ = –10.9 (CH2I), –0.9 [Si(CH3)3], 150.4
(C=N) ppm. 29Si NMR (CDCl3, 59.63 MHz, INEPT, Z isomer): δ
= 27.1 ppm. 1H NMR (CDCl3, 300.13 MHz, E isomer): δ = 0.22
[s, 9 H, Si(CH3)3], 3.89 (d, J = 7.0 Hz, 2 H, CH2I), 7.61 (t, J =
6.6 Hz, 1 H, CH) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT, E
isomer): δ = –1.9 (CH2I), –0.9 [Si(CH3)3], 151.7 (C=N) ppm. 29Si
NMR (CDCl3, 59.63 MHz, INEPT, E isomer): δ = 26.9 ppm.
1
(C=N) ppm. H NMR (CDCl3, 300.13 MHz, Z isomer): δ = 3.38
(s, 3 H, OCH3), 4.72 (s, 2 H, CH2), 7.34–7.51 and 7.62–7.78 (2 m,
3 H and 2 H, o-, m-, p-C6H5), 9.40 (br., 1 H, OH) ppm. 13C NMR
(CDCl3, 75.47 MHz, DEPT, Z isomer): δ = 58.7 (OCH3), 64.0
(CH2), 127.0, 128.4, and 129.4 (o-, m-, p-C6H5), 134.1 (i-C6H5),
1
156.4 (C=N) ppm. H NMR spectra of the E/Z isomers are in ac-
cordance with literature data.[23]
1-Methoxy-3-phenylacetone Oxime (9z): Yield 74% (from 1z). Col-
orless oil. Mixture of isomers (ratio E/Z = 17:1). Rf = 0.3 (EtOAc/
hexane = 1:3). 1H NMR (CDCl3, 300.13 MHz, E isomer): δ = 3.30
(s, 3 H, OCH3), 3.81 and 3.92 (2 s, 2 H and 2 H, CH2Ph and
CH2OCH3), 7.19–7.36 (m, 5 H, o-, m-, p-C6H5), 9.63 (br., 1 H,
OH) ppm. 13C NMR (CDCl3, 75.47 MHz, DEPT, E isomer): δ =
31.3 (CH2Ph), 58.1 (OCH3), 72.6 (CH2OCH3), 126.6, 128.6, and
129.3 (o-, m-, p-C6H5), 136.1 (i-C6H5), 157.0 (C=N) ppm. 1H NMR
(CDCl3, 300.13 MHz, Z isomer): δ = 3.32 (s, 3 H, OCH3), 3.63 (s,
2 H, CH2Ph), 4.25 (s, 2 H, CH2OCH3), 7.19–7.36 (m, 5 H, o-, m-,
p-C6H5), 9.63 (br., 1 H, OH) ppm. 13C NMR (CDCl3, 75.47 MHz,
DEPT, characteristic signals of Z isomer): δ = 36.8 (CH2Ph), 58.1
(OCH3), 66.0 (CH2OCH3), 126.8, 128.6, and 129.1 (o-, m-, p-
C6H5) ppm. C10H13NO2 (179.22): calcd. C 67.02, H 7.31, N 7.82;
found C 66.81, H 7.34, N 7.89.
FTIR (neat): ν = 2961 (s), 2926 (m), 2856 (m), 1734 (w), 1611 (w),
˜
1416 (m), 1254 (s), 1151 (m), 1096 (s, sh), 1021 (s), 930 (s), 875 (s),
848 (s), 805 (s), 752 (s), 695 (w), 558 (w) cm–1. MS (EI): m/z (%) =
257 (8) [M]+·, 242 (37) [M – CH3]+·, 130 (46) [M – I]+·, 127 (7)
[I]+·, 73 (100) [(CH3)3Si]+·. Purity determined by 1H NMR spec-
troscopy with internal standard (trichloroethylene): ca. 75% [con-
tains ca. 10% of (E)-8aa[15]].
2-Bromopropanal O-(Trimethylsilyl)oxime (1ab): Compound 1ab
was obtained as a mixture with 8ab[15] [ratios 1ab/8ab = 1:2.9, (E)-
1ab/(Z)-1ab = 6.7:1, (E)-8ab/(Z)-1ab = 3.9:1] by procedure iii em-
ploying K2CO3 instead of NaHSO4 for the aqueous work-up, yield
13%. Characterized by 1H NMR spectroscopy as a mixture with
Methoxyacetaldehyde Oxime (9aa): A solution of tetrabutylammo-
8ab.[15] 1H NMR (CDCl3, 300.13 MHz, E isomer): δ = 0.22 [s, 9 H, nium fluoride (0.20 g, 0.75 mmol) in methanol (3.8 mL) was added
Si(CH3)3], 1.85 (d, J = 6.8 Hz, 3 H, CH3), 4.71 (m, 1 H, CHI), 7.61
to a stirred solution of crude iodoacetaldehyde O-(trimethylsilyl)-
(d, J = 7.6 Hz, 1 H, HC=N) ppm. 1H NMR (CDCl3, 300.13 MHz, oxime (1aa; 0.194 g, 0.75 mmol) in methanol (3.8 mL). The mixture
Eur. J. Org. Chem. 2014, 8148–8159
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A. Yu. Sukhorukov et al.
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was kept at room temperature for 48 h and then evaporated under
normal pressure. The residue was subjected to flash chromatog-
raphy on silica gel (eluent pentane/Et2O = 1:1). The resulting frac-
tion was evaporated under normal pressure to give 0.046 g (69%)
of 9aa as a colorless volatile liquid. For analytical purposes 9aa was
additionally purified by vacuum bulb-to-bulb distillation (15 Torr).
Colorless volatile liquid. Mixture of isomers (ratio E/Z = 1.4:1). Rf
= 0.4 (EtOAc/hexane = 1:1). 1H NMR (CDCl3, 300.13 MHz, E
isomer): δ = 3.38 (s, 3 H, OCH3), 4.04 (d, J = 5.6 Hz, 2 H, CH2),
7.49 (t, J = 5.6 Hz, 1 H, HC=N), 8.05 (br., 1 H, OH) ppm. 13C
NMR (CDCl3, 300.13 MHz, DEPT, E isomer): δ = 58.4 (OCH3),
69.0 (CH2OCH3), 148.2 (C=N) ppm. 1H NMR (CDCl3,
300.13 MHz, Z isomer): δ = 3.41 (s, 3 H, OCH3), 4.29 (d, J =
3.1 Hz, 2 H, CH2), 6.88 (t, J = 3.1 Hz, 1 H, HC=N), 8.05 (br., 1
H, OH) ppm. 13C NMR (CDCl3, 300.13 MHz, DEPT, Z isomer):
δ = 59.0 (OCH3), 66.4 (CH2OCH3), 151.0 (C=N) ppm. The 1H
NMR spectra of the E/Z isomers are in accordance with literature
data.[24]
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It is likely that due to a high affinity towards silicon, the fluor-
ide anion attacks the trimethylsilyl group but not the carbon
atom. This leads to the generation of highly reactive nitrosoalk-
enes, which easily undergo oligomerization reactions (for a de-
tailed discussion of such processes see ref.[11b]).
Supporting Information (see footnote on the first page of this arti-
cle): 1H, 13C, 29Si, 2D NMR, IR, and UV spectra for all com-
pounds.
Acknowledgments
This work was supported by the Russian Science Foundation (pro-
ject 14-23-00150).
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8158
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Eur. J. Org. Chem. 2014, 8148–8159

α-Halo Oxime Ethers from Nitronates and Nitro Compounds
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Received: August 15, 2014
Published Online: November 19, 2014
Eur. J. Org. Chem. 2014, 8148–8159
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8159