Acylation of Nitronates: [3,3]-Sigmatropic Rearrangement of in Situ Generated N-Acyloxy, N-oxyenamines

Article abstract of DOI:10.1021/acs.joc.8b01652

Acylation of nitronates affords α-acyloxyoxime derivatives via an umpolung functionalization of the α-position. This transformation involves generation of hitherto unknown N-acyloxy,N-oxyenamines and their fast [3,3]-sigmatropic rearrangement driven by the cleavage of the weak N-O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates possessing nonsymmetrically substituted α-positions. Application to the formal total synthesis of clausenamide and cis-clausenamide is presented.

Full text of DOI:10.1021/acs.joc.8b01652

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Article
Acylation of Nitronates. [3,3]-Sigmatropic Rearrangement
of in situ Generated N-acyloxy,N-oxyenamines
Aleksandr O. Kokuev, Yulia A. Antonova, Valentin S. Dorokhov, Ivan S. Golovanov,
Yulia V. Nelyubina, Andrey A. Tabolin, Alexey Yu. Sukhorukov, and Sema L. Ioffe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01652 • Publication Date (Web): 01 Aug 2018
Downloaded from http://pubs.acs.org on August 1, 2018
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Acylation of Nitronates. [3,3]-Sigmatropic Rearrangement of in situ Generated N-
acyloxy,N-oxyenamines
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Aleksandr O. Kokuev,†,‡ Yulia A. Antonova,†, Valentin S. Dorokhov,†,‡ Ivan S. Golovanov,†
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Yulia V. Nelyubina,║ Andrey A. Tabolin,† Alexey Yu. Sukhorukov,†,* Sema L. Ioffe†
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† N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect
47, 119991, Moscow, Russian Federation. Fax: +7 499 1355328; Tel: +7 499 1355329
‡
Higher Chemical College, D. I. Mendeleev University of Chemical Technology of Russia,
Miusskaya sq. 9, 125047, Moscow, Russian Federation
§
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie gory, 1,
119991, Moscow, Russian Federation
║
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
Vavilov str. 28, 119991, Moscow, Russian Federation
* E-mail: sukhorukov@ioc.ac.ru
Abstract: Acylation of nitronates affords αꢀacyloxy oxime derivatives via an umpolung
functionalization of αꢀposition. This transformation involves generation of hitherto unknown Nꢀ
acyloxy,Nꢀoxyenamines and their fast [3,3]ꢀsigmatropic rearrangement driven by the cleavage of
weak N−O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates
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possessing nonꢀsymmetrically substituted αꢀpositions. Application to the formal total synthesis
of clausenamide and cisꢀclausenamide is presented.
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Introduction
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[3,3]ꢀSigmatropic rearrangements are among the most indispensable tools in organic synthesis,
which are widely used to create carbonꢀcarbon and carbonꢀheteroatom bonds in an atomꢀ
economical and stereoselective manner.1 Of particular importance are sigmatropic
rearrangements accompanied by a formal functionalization of sp2 and sp3 CꢀH bonds. Typically,
in such processes, reactive 1,5ꢀene systems possessing a weak 3,3’ꢀconnection (e.g. nitrogenꢀ
nitrogen or nitrogenꢀoxygen σꢀbond) are exploited, which are generated by
deprotonation/enolization of stable precursors. The cleavage of a weak NꢀN/NꢀO bond and
formation of strong CꢀN/CꢀO bond in result of a [3,3]ꢀrearrangement is a thermodynamic driving
force in these reactions. Wellꢀknown examples include [3,3]ꢀrearrangements of Nꢀaryl,N’ꢀvinyl
hydrazines (Fisher indole synthesis2 and related reactions), Nꢀaryl,Oꢀvinyl hydroxylamines3 (in
particular, involved in Bartoli indole synthesis4), anionic rearrangements of Nꢀvinyl,Oꢀvinyl
hydroxylamines (involved in Trofimov pyrrole synthesis5), N,N′ꢀdiacylhydrazines6 and Nꢀ
acyl,N’ꢀvinyl hydrazines,7 etc.8
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[3,3]ꢀSigmatropic rearrangements of Nꢀvinyl,Oꢀacyl hydroxylamines8 were efficiently exploited
in umpolung CꢀHꢀfunctionalizations of hydroxamic acids derivatives9 (Scheme 1, eq. (1)), Nꢀ
oxides of aromatic heterocycles8 (Boekelheide rearrangement,10 Scheme 1, eq. (2)), aldehydes11
and ketones12 (Scheme 1, eq. (3)), and nitrones13 (Scheme 1, eq. (4)). Acylation of nitrones
followed by a [3,3]ꢀrearrangement of the resulting intermediate A to αꢀacyloxyimines is a useful
strategy to access vicinal aminoalcohols from ketones.14 Remarkably, nitrones, which are
unsubstituted at αꢀcarbon atom, reacted much slower as compared to substituted ones. In some
cases, intermediate Nꢀacyloxyꢀenamines A were found to be exceptionally stable and their [3,3]ꢀ
rearrangement required high temperatures to proceed.13a We reasoned that the presence of an
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extra oxyꢀgroup at the nitrogen atom (Nꢀacyloxy,Nꢀoxyenamines B) would result in a decrease of
the rearrangement’s activation barrier due to a mesomeric stabilization of the polar transition
state. This hypothesis was supported by our quantumꢀchemical calculations (vide infra) as well
as by the fact that Nꢀacyloxyꢀenamines A bearing a highly electron donating group R2 (for
example, alkoxyꢀgroup) entered the [3,3]ꢀrearrangement already at ꢀ78 °C.9,15 Therefore, here we
report our studies on the generation of Nꢀacyloxy,Nꢀoxyenamines B by acylation of nitronates 1
and their subsequent [3,3]ꢀsigmatropic rearrangement to αꢀacyloxyoxime derivatives 2. It is
noteworthy, that acylation of nitronates 1 has not been reported so far.
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Scheme 1. Oxygenation of various organic compounds using [3,3]ꢀrearrangement
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Results and discussion
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To verify our hypothesis, we performed quantumꢀchemical calculations of thermochemistry and
transition states for a [3,3]ꢀrearrangement of Nꢀacyloxyenamines A and Nꢀacyloxy,Nꢀ
oxyenamines B at rm062x/augꢀccꢀpVTZ+d level of theory (SMD model, CH2Cl2). Both
reactions were predicted to be highly exothermic demonstrating that the cleavage of weak
nitrogenꢀoxygen connection is a driving force of these processes. More importantly, the second
reaction had much lower activation energy (17.8 for TS2 vs 31.7 kcal/mol for TS1, Scheme 2).
Both transition states have highly ionic character as can be judged from large positive CM5
charges16 on the carbon and nitrogen atoms. Therefore, the rearrangement can be considered
more likely as a heterolytic rather than a perycyсlic reaction. Evidently, the presence of a second
oxyꢀgroup at the nitrogen atom stabilizes the positively charged carbon atom in the transition
state TS2. These theoretical results suggest that Nꢀacyloxy,Nꢀoxyenamines B should undergo
[3,3]ꢀrearrangement already at low temperatures.
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Scheme 2. Quantumꢀchemical calculations for [3,3]ꢀrearrangements of Nꢀoxyenamines A and B
In our initial experimental studies we examined acylation of model nitronate 1a to generate the
corresponding Nꢀacyloxy,Nꢀoxyenamine B intermediate. Experiments with AcX/Et3N system
under a variety of conditions were unsuccessful (Table 1, entries 1ꢀ5). Low conversions of initial
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nitronate 1a and complex mixtures of products were observed, presumably, because of the fast
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generation of reactive ketene from the acetylating agent upon the action of base.
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Table 1. Acylation of nitronate 1a: an optimization study
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Yields of products, %a
Conversion,
Entry
base
solvent temperature
RCOX
%
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2’
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1
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AcCl
Et3N
CH3CN
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ꢀ20 °C
ꢀ20 °C
rt
AcCl EtNiPr2 CH3CN
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AcCl
AcBr
Et3N
Et3N
CH3CN
CH3CN
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ꢀ
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rtb
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Ac2O
PivCl
PivCl
Et3N
Et3N
Et3N
CH3CN
CH3CN
CH3CN
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rt
> 99
> 99
> 99
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23 15
12 10
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0 °C
8
PivCl
Et3N CH3CN
85
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-
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-20 → 0 °C
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PivCl
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ꢀ78 °C
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CH2Cl2
CH2Cl2
THF
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PivCl
PivCl
PivCl
Et3N
Et3N
Et3N
81
> 99
96
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12
10
19
7
24 14
58 20
50 19
40 22
24 37
ꢀ
ꢀ
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
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toluene
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PivCl EtNiPr2 CH3CN
93
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ꢀ
PivCl
PivCl
Py
CH3CN
CH3CN
> 99
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DBU
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Yields and conversions were determined by 1H NMR analysis with an internal standard (trichloroethylene).
a
b Reaction time ꢀ 24 h.
This problem was overcome by switching to pivaloyl chloride (PivCl) as an acylating agent.
Upon treatment of nitronate 1a with PivCl/Et3N system, high conversion was achieved (Table 1,
entry 6). Four products were identified in this experiment, namely two cyclic acyloxyoxime
ethers 2b, 2b’, 6Hꢀ1,2ꢀoxazine 3 and tertiary chloride 4. Evidently, exoꢀacylated product 2b
arises from the [3,3]ꢀrearrangement of Nꢀacyloxy,Nꢀoxyenamine D, whilst endoꢀproducts 2b’, 3
and 4 are formed from the isomeric intermediate D’ (Scheme 3). Interestingly, the intermediate
Nꢀacyloxy,Nꢀoxyenamines D and D’ were never observed, and the formation of rearranged
products 2b and 2b’ proceeded fast already at ꢀ78 °C (Table 1, entry 9). This is in agreement
with low calculated activation energies for [3,3]ꢀrearrangements of D and D’ (ꢀG≠ 10.3 kcal/mol
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for both transformations, see Supporting information for the full calculated energy profile).
Moreover, all four products were stable under reaction conditions (as demonstrated by reactions
of pure samples of 2b, 2b’, 3 and 4 with PivCl/Et3N in CH3CN at rt), suggesting that they are
formed independently under kinetic control.
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Scheme 3. Acylation of nitronates 1: plausible mechanism (substituents at Cꢀ4 and Cꢀ6 are
omitted for clarity).
The regioselectivity of acylation proved to be highly dependent on the temperature, solvent and
base (Table 1, entries 6ꢀ15). Thus, lowering the reaction temperature resulted in the increase of
the amount of exoꢀproduct 2b over endoꢀproducts 2b’ and 3 (Table 1, cf. entries 6ꢀ8). In the
experiments carried out in less polar solvents (CH2Cl2, THF, toluene), more endoꢀproduct 2a’
and 6Hꢀ1,2ꢀoxazine 3 were generated (Table 1, cf. entries 7 and 10ꢀ12). Furthermore, switching
from Et3N to Hünig’s base or pyridine (in CH3CN) also resulted in the formation of 2’ and 3 as
major products (Table 1, cf. entries 7 and 13, 14). With DBU as a base, very low conversion of
starting nitronate 1b was observed (Table 1, entry 15). These results clearly indicate that the
direction of deprotonation of the initially formed cation C is highly dependent on numerous
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factors, yet the elimination of endoꢀproton can be almost completely suppressed by conducting
acylation in CH3CN with Et3N as a base at temperatures below 0 °C (Table 1, entry 8).
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Another important observation in our experiments was the formation of tertiary chloride 4 as a
sideꢀproduct in some cases. This product may result from an interrupted heterolytic [3,3]ꢀ
rearrangement process through the SN’ substitution of the acyloxyꢀgroup in the intermediate D’
for the chloride anion (Scheme 4). Indeed, DFT calculations (performed on a simplified model
with R = H) suggest that this reaction is favorable and proceeds via a highly ionic transition state
with low activation energy (Scheme 4).
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Scheme 4. Interrupted [3,3]ꢀrearrangement of intermediate D’: plausible mechanism
(substituents at Cꢀ4 and Cꢀ6 are omitted for clarity, δ values correspond to CM5 charges).
Having optimized conditions in hand, substrate scope of the transformation of nitronates 1 into
cyclic acyloxyoxime ethers 2 was studied (Scheme 5). Not only pivaloyl, but also benzoyl and
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even isobutyryl chloride were successfully involved in the reaction with nitronate 1a (products
2c,d). The acylation procedure proved to be applicable to a broad scope of fiveꢀ and sixꢀ
membered cyclic nitronates 1 and afforded corresponding acyloxyꢀsubstituted isoxazolines and
1,2ꢀoxazines 2 in good to high yields. In all cases, exclusive formation of the exoꢀacyloxy
product was observed. Furthermore, moderate stereoselectivity was observed in the
rearrangement of Nꢀacyloxyenamine D with R1 = Me (d.r. 3.3 : 1 for product 2h). The relative
configuration of major isomer was relꢀ(1S,4’S,6’S) as determined by XꢀRay analysis.17,18
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Scheme 5. Acylation of cyclic nitronates 1: substrate scope study
Substrates bearing sensitive acetal centers (see products 2g and 2h) and electronꢀrich aromatic
ring (products 2g,h,j,k) were tolerated (Scheme 5). Interestingly, fiveꢀmembered cyclic
nitronates 1 proved to be less reactive as compared to sixꢀmembered ones that can be attributed
to a less nucleophilicity of their Nꢀoxide moiety.19
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We further explored acylation of Oꢀsilyl nitronates 5, which are easily accessible by the
silylation of nitroalkanes (Scheme 6). Unlike the case of cyclic Oꢀalkyl nitronates 1, Oꢀsilyl
nitronates 5 gave acylated oximes ethers 6 in moderate yields only. Importantly, the pivaloyloxyꢀ
group, not the siloxyꢀgroup migrated to the carbon atom, as was deduced from 2D HMBC
spectra (no isomeric derivatives 7 were detected). This indicates that [3,3]ꢀrearrangement is
faster than a [1,3]ꢀshift20 in Nꢀacyloxy,Nꢀoxyenamines E.
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Scheme 6. Acylation of silyl nitronates 5
Two types of sideꢀproducts were identified in these experiments, namely bisꢀacylated αꢀ
hydroxyꢀoximes 8 and nitrosoꢀderivatives 9 (Scheme 7), which were isolated and characterized
is some cases (see Scheme 6 for yields). Since products 6 do not produce bisꢀacylated derivatives
8 upon treatment with PivCl, the latter may arise from a exchange of TBS group for acyl in
cations F, which are formed by acylation of initial silyl nitronate 5 (Scheme 7).19b Nitrosoꢀ
derivatives 9 are formed in result of an unusual migration of acyloxyꢀgroup from nitrogen to
carbon atom in cation F followed by elimination of the TBS group from cation H. DFT
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calculations on a model system suggest that this migration proceeds through cyclic intermediate
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G (see Supporting information for details).
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Scheme 7. Formation of sideꢀproducts during acylation of silyl nitronates 5.
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Scheme 8.Acylation of silyl nitronate 5c
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Pivaloylation of TBSꢀnitronate 5c possessing two types of αꢀhydrogen atoms resulted in a
mixture of regiosomeric products 6e and 6e’ accompanied by bisꢀpivaloylated products 8e/8e’
and enꢀoxime ether 10 (Scheme 8). Although products 6e and 8e with primary pivaloyloxyꢀ
group were predominant, the regioselectivity was lower as compared to cyclic nitronates (cf.
Scheme 8 and Table 1, entry 8).
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Finally, we tested our methodology in the synthesis of natural products. Recently, Tanda and
Yamasaki,21 reported total synthesis of alkaloids clausenamide22 and cisꢀclausenamide23
employing acyloxyꢀsubstituted isoxazoline 11 (Scheme 9) as a key precursor. The assembly of
isoxazoline 11 was achieved through a classical nitrile oxide/alkene [3+2]ꢀcycloaddition
strategy. We reasoned that this intermediate could be prepared in a simpler way by the
acylation/[3,3]ꢀrearrangement of isoxazoline Nꢀoxide 12 (Scheme 9).
Scheme 9. Synthesis of functionalized isoxazoline 11
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To verify this idea, nitronate 12 was prepared in a straightforward manner by the [4+1]
cycloannulation24 of ylide 14 with nitroalkene 13, which was assembled by condensation of
benzaldehyde with (2ꢀnitroethyl)benzene. Exclusively 4,5ꢀtrans stereoisomer of nitronate 12 was
obtained by this route. However, acylation of 12 proved to be challenging. No conversion was
observed in reaction with 4ꢀnitrobenzoyl chloride/Et3N or PivCl/Et3N acylation systems, likely
because of the reduced nucleophilicity of sterically hindered Nꢀoxide in 12. Fortunately, the use
of more electrophilic nitrobenzoyl triflate (generated from 4ꢀnitrobenzoyl chloride and AgOTf in
situ) proved to be more advantageous and provided a mixture of diastereomeric isoxazolines 11
and 11’ in moderate yield together with some amount of unreacted nitronate 12 (26%). The
desired stereoisomer 11 was easily separated from mixture with 11’ by crystallization from
methanol. Although tandem acylation/[3,3]ꢀrearrangement process is not stereoselective in case
of nitronate 12, the second isomer 11’ can be considered as a precursor of epiꢀclausenamide,25
which cannot be accessed by the approach of Tanda and Yamasaki.21
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Conclusions
In conclusion, we have developed tandem acylation/[3,3]ꢀsigmatropic rearrangement of
nitronates as a novel route to αꢀacyloxyoxime derivatives. Unlike Nꢀacyloxyꢀenamines, the
o
rearrangement of transient Nꢀacyloxy,Nꢀoxyenamines proceeds fast already at ꢀ78 C due to a
mesomeric stabilization of transition state with an extra oxyꢀgroup at the nitrogen atom. The
suggested mild umpolung αꢀoxygenation protocol is applicable to a large variety of nitronates of
cyclic and acyclic structures. Moreover, the process is regioselective in the case of nitronates
possessing nonꢀsymmetrically substituted αꢀpositions. Acylation/[3,3]ꢀrearrangement of
nitronates was successfully applied to the synthesis of known precursor of alkaloids
clausenamide and cisꢀclausenamide.
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Experimental section
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All reactions were carried out in ovenꢀdried (150°C) glassware. NMR spectra were recorded at
room temperature with residual solvents peaks as an internal standard. Multiplicities are
indicated by s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br
(broad). HRMS were measured on electrospray ionization (ESI) instrument with a timeꢀofꢀflight
(TOF) detector. Concentrations c in optical rotation angles are given in g/100 mL. [α]D values
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are given in 10ꢀ1 deg cm2 gꢀ1. Column chromatography was performed using Kieselgel 40ꢀ60 ꢁm
60A. Analytical thinꢀlayer chromatography was performed on silica gel plates with QFꢀ254.
Visualization was accomplished with UV light and or solution of anisaldehyde/H2SO4 in ethanol.
CH3CN, CH2Cl2, Et3N, EtNiPr2 and pyridine were distilled from CaH2, DBU was distilled from
CaH2 under reduced pressure. THF was distilled from LiAlH4. Hexane, petroleum ether, toluene,
pentane, methyl tertꢀbutyl ether, and ethyl acetate were distilled without drying agents. All
n
acylating reagents, DMAP, benzaldehyde, BuNH2, and AgOTf were commercial grade and
were used as received. Previously described nitronates 1 and 5 were prepared in accordance with
literature procedures (see Figure S1 in Supporting information for structures of nitronates and
corresponding references).
Quantumꢀchemical calculations were performed with the Gaussian 16 Rev A.03 program. For
calculations of thermodynamics and activation energies DFT D3 rm062x/augꢀccꢀpVTZ+d level
of theory was used. The solvent effects have been taken into account in all calculations (SMD
model), the approach of Martin and coꢀworkers was followed.26 Cartesian coordinates are given
in angstroms, absolute energies for all substances are given in hartrees. Analysis of vibrational
frequencies was performed for all optimized structures. All compounds except transition state
structures were characterized by only real vibrational frequencies, transition structures had one
imaginary frequency. Wavefunction stability was also checked for all calculations.
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General procedure for acylation of nitronate 1a (optimization study). To a stirred solution of
nitronate 1a (55 mg, 0.25 mmol) and base (0.5 mmol) in solvent (0.5 mL) was added acylating
agent (0.375 mmol) at the temperature indicated in Table 1 under argon atmosphere. The
reaction mixture was maintained at the same temperature for specified time and then transferred
into a mixture of methyl tertꢀbutyl ether (10 mL) and 0.25 M aqueous solution of NaHSO4 (10
mL). Aqueous phase was backꢀextracted with methyl tertꢀbutyl ether (10 mL). Combined
organic layers were washed with water (10 mL), brine (20 mL), dried (Na2SO4) and evaporated.
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The residue was analyzed by H NMR with internal standard (trichloroethylene). Yields of
products are given in Table 1. Experiments 4, 8, 12 and 14 from Table 1 were repeated on 1
mmol of nitronate 1a to isolate and characterize sideꢀproducts 2b’, 3 and 4.
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl acetate (2a). Isolated by
column chromatography from experiment 4 in Table 1. Yield: 39 mg (15 %). NMR spectra are in
accordance with literature data.27
3,6,6-Trimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-4-yl acetate (2a’). To a stirred solution
of nitronate 1a (107 mg, 0.5 mmol) and Et3N (0.233 mL, 1.7 mmol) in toluene (1 mL) was added
acetyl chloride (0.182 mL, 2.5 mmol) at rt under argon atmosphere. The reaction mixture was
maintained at the same temperature for 24 h and then transferred into a mixture of ethyl acetate
(25 mL) and saturated aqueous solution of K2CO3 (25 mL). Aqueous phase was backꢀextracted
with ethyl acetate (25 mL). Combined organic layers were washed with water (20 mL), brine (20
mL), dried (Na2SO4) and evaporated. The residue was subjected to a column chromatography on
silica gel to give 58 mg (44 %) of crude product 2a’. Described in a mixture with 6Hꢀ1,2ꢀoxazine
3 (ca. 10 %). Oil. Rf = 0.44 (hexaneꢀAcOEt = 3 : 1). 1H NMR (300 MHz, HMBC, CDCl3) δ 7.42
– 7.25 (m, 5H, 5 CHPh), 3.09 (d, J = 15.2 Hz, 1H, CH2), 2.58 (d, J = 15.2 Hz, 1H, CH2), 2.23 (s,
3H, CH3ꢀCO), 1.82 (s, 3H, CH3ꢀCN), 1.37 and 1.33 (2 s, 3H and 3H, 2 CH3). 13C NMR (75
MHz, HMBC, DEPT135, CDCl3) δ 169.2 (C=O), 156.4 (C=N), 139.70 (CPh), 128.5 (2 CHPh),
127.9 (CHPh) and 125.6 (2 CHPh), 77.0 (CꢀPh), 73.7 (CꢀO), 43.9 (CH2), 28.7 and 24.80 (2 CH3),
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22.1 (CH3ꢀCO), 16.8 (CH3ꢀCN). ESIꢀHRMS m/z: [M+H]+ Calcd for C15H20NO3 262.1438;
+
3
4
Found 262.1441.
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7
3,6,6-Trimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-4-yl
pivalate
(2b’).
Column
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chromatography of crude product from experiment 12 (Table 1) provided a fraction of pure 2b’
and a fraction of mixture of 2b’ and 3. Overall yield of 2b’: 77 mg (48 %). Oil. Rf = 0.44
(hexaneꢀAcOEt = 5 : 1). 1H NMR (300 MHz, HMBC, CDCl3) δ 7.45 – 7.23 (m, 5H), 3.00 (d, J =
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15.2 Hz, 1H), 2.62 (d, J = 15.2 Hz, 1H), 1.85 (s, 3H), 1.37 (s, 3H), 1.34 (s, 12H, Bu and CH3).
13C NMR (75 MHz, HMBC, CDCl3) δ 176.2 (C=O), 157.7 (C=N), 140.1 (CPh), 128.5 (2 CHPh),
127.8 (CHPh), 125.3 (2 CHPh), 76.6 (CꢀO), 73.8 (CꢀO), 44.9 (CH2), 39.7 (C(CH3)3), 28.7
(C(CH3)3), 27.2 (CH3), 25.1 (CH3), 16.7 (CH3). ESIꢀHRMS m/z: [M+Na]+ Calcd for
C18H25NO3Na+ 326.1727; Found 326.1721.
3,6,6-Trimethyl-4-phenyl-6H-1,2-oxazine (3). Isolated by semiꢀpreparative TLC
chromatography of a mixture of 2b’ and 3 obtained from experiment 12 (Table 1). Yield: 30 mg
1
(15 %). Oil. Rf = 0.83 (hexaneꢀAcOEt = 1 : 1). H NMR (300 MHz, CDCl3) δ 7.41 – 7.34 (m,
3H), 7.24 – 7.17 (m, 2H), 5.90 (s, 1H), 1.98 (s, 3H), 1.43 (s, 6H). 13C NMR (75 MHz, DEPT135,
CDCl3) δ 154.5 (C), 136.8 (C), 135.3 (CH), 129.5 (C), 128.4 (2 CH), 128.3 (2 CH), 127.9 (CH),
73.3 (C), 25.5 (2 CH3), 18.3 (CH3). ESIꢀHRMS m/z: [M+H]+ Calcd for C13H16NO+ 202.1226;
Found 202.1227.
4-Chloro-3,6,6-trimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazine (4). Isolated by column
chromatography from experiment 14 in Table 1. Yield: 69 mg (29 %). Oil. Rf = 0.63 (hexaneꢀ
1
AcOEt = 3 : 1). H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 7.1 Hz, 2H), 7.44 – 7.32 (m, 3H),
13
2.63 (d, J = 15.6 Hz, 1H), 2.46 (d, J = 15.6 Hz, 1H), 1.97 (s, 3H), 1.49 (s, 3H), 1.33 (s, 3H). C
NMR (75 MHz, DEPT135, CDCl3) δ 155.3 (С), 141.83 (С), 128.8, 128.0 and 125.9 (5 CH), 73.7
(C), 64.0 (C), 52.2 (CH2), 28.9 (CH3), 23.7 (CH3), 17.9 (CH3). ESIꢀHRMS m/z: [M+H]+ Calcd
for C13H17ClNO+ 238.0993 and 240.0964; Found 238.0985 and 240.0956.
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General procedure for the synthesis of acyloxy derivatives 2 from cyclic nitronates 1. To a
stirring solution of nitronate 1 (1 mmol) and Et3N (0.28 mL, 2.0 mmol) in MeCN (2 mL) was
added acyl chloride (1.5 mmol) at ꢀ20 °C under argon atmosphere. The reaction mixture was
slowly warmed up to 0 °C, maintained at the same temperature for specified time and then
transferred into a mixture of methyl tertꢀbutyl ether (25 mL) and 0.25 M aqueous solution of
NaHSO4 (25 mL). Aqueous phase was backꢀextracted with methyl tertꢀbutyl ether (25 mL).
Combined organic layers were washed with water (25 mL), brine (25 mL), dried (Na2SO4) and
evaporated. The residue was subjected to column chromatography on silica to give target 1,2ꢀ
oxazine or isoxazoline derivatives 2.
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(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl pivalate (2b). Prepared from
nitronate 1a (219 mg, 1.0 mmol) according to the general procedure, reaction time – 1 h. Yield:
1
250 mg (83 %). Oil. Rf = 0.77 (hexaneꢀAcOEt = 3 : 1). H NMR (300 MHz, CDCl3) δ 7.39 –
7.24 (m, 3H), 7.19 (d, J = 6.9 Hz, 2H), 4.42 (s, 2H), 3.56 (dd, J = 12.0, 7.9 Hz, 1H), 2.11 (dd, J =
13.6, 7.9 Hz, 1H), 1.93 (dd, J = 13.6, 12.0 Hz, 1H), 1.39 (s, 3H), 1.32 (s, 3H), 1.18 (s, 9H). 13C
NMR (75 MHz, JMOD, CDCl3) δ 177.6 (C), 154.4 (C), 139.4 (C), 129.1 (2 CH), 128.2 (2 CH),
127.5 (CH), 74.9 (C), 64.2 (CH2), 40.4 (CH2), 38.7 (C), 38.0 (CH), 28.4 (CH3), 27.1 (3 CH3),
22.5 (CH3). ESIꢀHRMS m/z: [M+H]+ Calcd for C18H26NO3 304.1907; Found 304.1903.
+
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl benzoate (2c). Prepared from
nitronate 1a (219 mg, 1.0 mmol) according to the general procedure, reaction time – 1 h. Yield:
281 mg (87 %). White solid. Mp 67 – 68 °C (Et2O/pentane). NMR spectra are in accordance with
literature data.27
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl isobutyrate (2d). Prepared
from nitronate 1a (55 mg, 0.25 mmol) according to general procedure, reaction time – 1 h. Yield:
1
62 mg (86 %). Mp = 30 – 32 °C (hexane). Rf = 0.75 (hexaneꢀAcOEt = 3 : 1). H NMR (300
MHz, CDCl3) δ 7.39 – 7.24 (m, 3H), 7.19 (d, J = 6.8 Hz, 2H), 4.46 (d, J = 12.7 Hz, 1H), 4.41 (d,
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J = 12.7 Hz, 1H), 3.56 (dd, J = 11.8, 7.9 Hz, 1H), 2.59 – 2.42 (sept, J = 7.0 Hz, 1H), 2.10 (dd, J
= 13.6, 7.9 Hz, 1H), 1.93 (dd, J = 13.6, 11.8 Hz, 1H), 1.39 (s, 3H), 1.32 (s, 3H), 1.13 (d, J = 7.0
Hz, 6H). 13C NMR (75 MHz, JMOD, CDCl3) δ 176.2 (C), 154.2 (C), 139.4 (C), 129.1 (2 CH),
128.2 (2 CH), 127.50 (CH), 74.9 (C), 64.0 (CH2), 40.4 (CH2), 38.0 (CH), 33.8 (CH), 28.4 (CH3),
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22.6 (CH3), 18.9 and 18.8 (2 CH3). ESIꢀHRMS m/z: [M+H]+ Calcd for C17H24NO3 290.1751;
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Found 290.1758.
(4,6,6-Trimethyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl pivalate (2e). Prepared from
nitronate 1b (157 mg, 1.0 mmol) according to general procedure, reaction time – 1 h. Yield: 190
1
mg (79%). Oil. Rf = 0.55 (hexaneꢀAcOEt = 3 : 1). H NMR (300 MHz, CDCl3) δ 4.88 (d, J =
12.3 Hz, 1H), 4.54 (d, J = 12.3 Hz, 1H), 2.48 – 2.31 (m, 1H), 1.85 (dd, J = 13.4, 7.4 Hz, 1H),
1.48 (dd, J = 13.4, 11.7 Hz, 1H), 1.32 (s, 3H), 1.21 (s, 9H), 1.19 (s, 3H), 1.16 (d, J = 7.1 Hz, 3H).
13C NMR (75 MHz, JMOD, CDCl3) δ 177.7 (C), 155.8 (C), 74.6 (C), 64.1 (CH2), 38.8 (CH2 and
C), 28.2 (CH), 27.1 (3 CH3), 24.8 (CH3), 23.1 (CH3), 16.8 (CH3). ESIꢀHRMS m/z: [M+H]+
+
Calcd for C13H24NO3 242.1751; Found 242.1750.
6,6-Dimethyl-3-((pivaloyloxy)methyl)-5,6-dihydro-4H-1,2-oxazin-4-yl
benzoate
(2f).
Prepared from nitronate 1c (100 mg, 0.38 mmol) according to general procedure, reaction time –
1
1 h. Yield: 75 mg (57%). Oil. Rf = 0.65 (hexaneꢀAcOEt = 3 : 1). H NMR (300 MHz, CDCl3) δ
8.01 (d, J = 6.9 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.47 (dd, J = 6.9, 7.5 Hz, 2H), 5.62 (dd, J =
7.0, 5.8 Hz, 1H), 5.02 (d, J = 12.6 Hz, 1H), 4.66 (d, J = 12.6 Hz, 1H), 2.31 (dd, J = 14.2, 7.0 Hz,
1H), 2.01 (dd, J = 14.0, 5.8 Hz, 1H), 1.40 (s, 6H), 1.13 (s, 9H). 13C NMR (75 MHz, CDCl3) δ
177.6 (C), 165.3 (C), 150.9 (C), 133.6 (CH), 129.7 (2 CH), 129.2 (C), 128.6 (2 CH), 75.1 (C),
62.6 (CH2), 59.7 (CH), 38.9 (C), 36.3 (CH2), 27.0 (3 CH3), 25.8 (CH3), 25.3 (CH3). ESIꢀHRMS
m/z: [M+H]+ Calcd for C19H26NO5 348.1805; Found 348.1803.
+
Rel-((4S,6S)-6-ethoxy-4-(4-methoxyphenyl)-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl pivalate
(2g). Prepared from nitronate 1d (199 mg, 0.75 mmol) according to the general procedure,
reaction time – 1 h. Yield: 210 mg (80 %). Oil. Rf = 0.55 (hexaneꢀAcOEt = 3 : 1). 1H NMR (300
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MHz, CDCl3) δ 7.13 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.17 (t, J = 2.7 Hz, 1H), 4.41
(s, 2H), 3.97 – 3.83 (m, 1H), 3.80 (s, 3H), 3.65 (m, 2H), 2.26 (ddd, J = 13.6, 7.7, 2.7 Hz, 1H),
2.09 (ddd, J = 13.6, 11.7, 2.8 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.17 (s, 9H). 13C NMR (75 MHz,
DEPT135, CDCl3) δ 177.4 (C), 159.0 (C), 156.9 (C), 131.0 (C), 129.3 (2 CH), 114.5 (2 CH),
95.9 (CH), 64.0 (CH2), 63.6 (CH2), 55.2 (CH3), 37.0 (C), 34.1 (CH), 32.9 (CH2), 27.1 (3 CH3),
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15.0 (CH3). ESIꢀHRMS m/z: [M+H]+ Calcd for C19H28NO5 350.1962; Found 350.1966.
+
6-Methoxy-4-(4-methoxyphenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazin-3-yl)ethyl pivalates
(2h). Prepared from nitronate 1e (100 mg, 0.36 mmol) according to the general procedure,
reaction time – 1 h. Yield: 105 mg (75 %). Mixture of relꢀ(1S,4’S,6’S) and relꢀ(1R,4’S,6’S)
stereoisomers, d.r. 3.3 : 1 (HPLC, C18, CH3CN/H2O = 60 : 40, 1 mL/min, 40 °C, retention times:
major ꢀ 7.2 min, minor ꢀ 7.7 min). The major isomer with relꢀ(1S,4’S,6’S) configuration was
separated by crystallization from methanol. Mp = 69ꢀ74 °C (MeOH). Rf = 0.48 (hexaneꢀAcOEt =
1
3 : 1). H NMR (300 MHz, relꢀ(1S,4’S,6’S)ꢀ2h, CDCl3, COSY, HSQC, HMBC) δ 7.20 (d, J =
8.7 Hz, 2H, mꢀC6H4OCH3), 6.89 (d, J = 8.8 Hz, 2H, oꢀC6H4OCH3), 5.11 (q, J = 6.5 Hz, 1H, CHꢀ
O), 3.80 (s, 3H, C6H4OCH3), 3.58 (dd, J = 12.2, 7.7 Hz, 1H, CHꢀAr), 3.31 (s, 3H, OCH3), 2.23
(dd, J = 13.4, 7.7 Hz, 1H, CH2), 1.91 (dd, J = 13.4, 12.2 Hz, 1H, CH2), 1.44 (s, 3H, CH3), 1.25
(d, J = 6.5 Hz, 3H, CHCH3), 1.19 (s, 9H, C(CH3)3). 13C NMR (75 MHz, relꢀ(1S,4’S,6’S)ꢀ2h,
CDCl3, HSQC, HMBC) δ 177.4 (C=O), 159.0 (=CꢀO), 158.6 (C=N), 131.2 (pꢀC6H4OCH3),
129.9 (2 mꢀC6H4OCH3), 114.5 (2 oꢀC6H4OCH3), 97.6 (CꢀO), 69.2 (CHꢀO), 55.3 (C6H4OCH3),
49.5 (OCH3), 39.7 (CH2), 39.3 (C(CH3)3), 36.4 (CHꢀAr), 27.3 (C(CH3)3), 21.5 (CH3), 18.6
+
(CHCH3). ESIꢀHRMS m/z: [M+H]+ Calcd for C20H30NO5 364.2115; Found 364.2118. Crystals
for XꢀRay analysis (CCDC 1848248) were prepared by recrystallisation of relꢀ(1S,4’S,6’S)ꢀ2h
1
from methanol. Minor isomer: Oil. H NMR (300 MHz, relꢀ(1R,4’S,6’S)ꢀ2h, CDCl3, COSY,
HSQC, HMBC) δ 7.10 (d, J = 8.5 Hz, 2H, mꢀC6H4OCH3), 6.86 (d, J = 8.5 Hz, 2H, oꢀ
C6H4OCH3), 5.09 (q, J = 6.4 Hz, 1H, CHꢀO), 3.79 (s, 3H, C6H4OCH3), 3.78 (dd, J = 12.1, 8.0
Hz, 1H, CHꢀAr), 3.28 (s, 3H, OCH3), 2.27 (dd, J = 13.5, 8.0 Hz, 1H, CH2), 1.91 (dd, J = 13.5,
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12.1 Hz, 1H, CH2), 1.45 (s, 3H, CH3), 1.28 (d, J = 6.4 Hz, 3H, CHCH3), 1.17 (s, 9H, C(CH3)3).
13C NMR (75 MHz, relꢀ(1R,4’S,6’S)ꢀ2h, CDCl3, HSQC, HMBC) δ 13C NMR (75 MHz, CDCl3)
δ 177.5 (C=O), 160.5 (C=N), 159.0 (=CꢀO), 132.5 (pꢀC6H4OCH3), 129.7 (2 mꢀC6H4OCH3),
114.5 (2 oꢀC6H4OCH3), 97.8 (CꢀO), 69.0 (CHꢀO), 55.3 (C6H4OCH3), 49.5 (OCH3), 39.7 (CH2),
38.7 (C(CH3)3), 37.2 (CHꢀAr), 27.2 (C(CH3)3), 21.4 (CH3), 17.0 (CHCH3). ESIꢀHRMS m/z:
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[M+H]+ Calcd for C20H30NO5 364.2118; Found 364.2118.
+
Synthesis of pivalate rel-(1R,4’S,6’S)-2h by pivaloylation of corresponding alcohol. To a
stirring solution of relꢀ(R)ꢀ1ꢀ((4S,6S)ꢀ6ꢀmethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀmethylꢀ5,6ꢀdihydroꢀ
4Hꢀ1,2ꢀoxazinꢀ3ꢀyl)ethanꢀ1ꢀol28 (50 mg, 0.18 mmol), Et3N (0.05 mL, 0.36 mmol) and DMAP
(2.1 mg, 0.017 mmol) in CH2Cl2 (0.3 mL) was added pivaloyl chloride (0.032 mL, 0.26 mmol) at
rt under argon atmosphere. The reaction mixture was stirred for 2.5 h and then transferred into a
mixture of ethyl acetate (10 mL) and 0.25 M aqueous solution of NaHSO4 (10 mL). Aqueous
phase was backꢀextracted with ethyl acetate (10 mL). Combined organic layers were washed
with water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated. The residue was subjected to
column chromatography on silica to give 42 mg (65 %) of 1,2ꢀoxazine relꢀ(1R,4’S,6’S)ꢀ2h as
colorless oil. NMR spectra and HPLC are in agreement with spectra of minor isomer obtained by
pivaloylation of nitronate 1e (see above).
((1R,2S,4S,4'S)-3,3-dimethyl-4'-phenyl-4',5'-dihydrospiro[bicyclo[2.2.1]heptane-2,6'-
[1,2]oxazin]-3'-yl)methyl pivalate (2i). Prepared from nitronate 1f (299 mg, 1.0 mmol)
according to the general procedure, reaction time – 1 h. Yield: 357 mg (93 %). Mp = 76ꢀ80 °C
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(pentane). Rf = 0.83 (hexaneꢀAcOEt = 3 : 1). [α]D = ꢀ5.8 (с = 1, AcOEt, 26 °C). H NMR (300
MHz, CDCl3) δ 7.41 – 7.27 (m, 3H), 7.23 – 7.17 (d, J = 8.1 Hz, 2H), 4.43 (d, J = 12.1 Hz, 1H),
4.38 (d, J = 12.1 Hz, 1H), 3.44 (dd, J = 12.7, 7.2 Hz, 1H), 2.43 (br d, J = 5.0 Hz, 1H), 2.31 (dd, J
= 13.8, 7.2 Hz, 1H), 2.21 (br d, J = 9.9 Hz, 1H), 1.89 – 1.74 (m, 2H), 1.67 – 1.49 (m, 2H), 1.45 –
1.25 (m, 2H), 1.20 (m, 1H), 1.17 (s, 9H), 1.16 (s, 3H), 0.90 (s, 3H). 13C NMR (75 MHz,
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DEPT135, CDCl3) δ 177.6 (C), 155.1 (C), 139.6 (C), 129.1 (2 CH), 128.2 (2 CH), 127.5 (CH),
87.1 (C), 64.3 (CH2), 49.4 (CH), 44.5 (C), 42.6 (CH), 40.1 (CH), 38.7 (C), 34.6 (CH2), 31.5
(CH2), 27.2 (3 CH3), 24.2 (CH3), 23.9 (CH2), 22.3 (CH3), 22.3 (CH2). Anal. Calcd for
C24H33NO3: C, 75.16; H, 8.67; N, 3.65. Found: C, 75.15; H, 8.62; N, 3.61.
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Rel-((4S,4aR,8aR)-4-(4-methoxyphenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazin-3-
yl)methyl pivalate (2j). Prepared from nitronate 1g (275 mg, 1.0 mmol) according to general
procedure, reaction time – 1 h. Yield: 336 mg (94%). Mp 79ꢀ80 °C (MeOtBuꢀpentane). Rf = 0.86
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(hexane : AcOEt = 1 : 1). H NMR (300 MHz, CDCl3) δ 7.06 (d, J = 8.5 Hz, 2H), 6.87 (d, J =
8.5 Hz, 2H), 4.62 (d, J = 12.5 Hz, 1H), 4.56 (d, J = 12.5 Hz, 1H), 4.04 (br s, 1H), 3.79 (s, 3H),
3.16 (s, 1H), 2.13ꢀ2.03, 1.79ꢀ1.53 and 1.50ꢀ1.21 (3 m, 1H, 4H and 4H), 1.12 (s, 9H). 13C NMR
(75 MHz, JMOD, CDCl3) δ 177.6 (C), 158.8 (C), 151.4 (C), 132.9 (C), 129.2 (2 CH), 114.3 (2
CH), 68.9 (CH), 64.5 (CH2), 55.3 (CH3), 43.5 (CH), 38.8 (CH), 38.7 (C), 29.2 (CH2), 27.5
(CH2), 27.0 (3 CH3), 25.0 (CH2), 19.8 (CH2). Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13; N,
3.90. Found: C, 69.81; H, 8.22; N, 3.90.
(4-(4-Methoxyphenyl)-4,5-dihydroisoxazol-3-yl)methyl pivalate (2k). Prepared from nitronate
1h (207 mg, 1.0 mmol) according to general procedure, reaction time – 48 h. Yield: 255 mg
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(88%). Mp = 40ꢀ41 °C (MeOtBuꢀpentane). Rf = 0.49 (hexaneꢀAcOEt = 3 : 1). H NMR (300
MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 13.2 Hz, 1H), 4.70
(m, 1H), 4.61 (d, J = 13.2 Hz, 1H), 4.42 – 4.27 (m, 2H), 3.80 (s, 3H), 1.14 (s, 9H). 13C NMR (75
MHz, JMOD, CDCl3) δ 177.6 (C), 159.4 (C), 157.1 (C), 129.7 (C), 128.6 (2 CH), 114.6 (2 CH),
77.4 (CH2), 57.6 (CH2), 55.3 and 53.8 (CH and CH3), 38.7 (C), 27.0 (3 CH3). Anal. Calcd for
C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found C, 66.06; H, 7.28; N, 4.64. Crystals for XꢀRay
analysis (CCDC 1848249) were prepared by recrystallisation of 2k from MeOtBuꢀpentane
mixture.
Methyl 5-methyl-3-((pivaloyloxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (2l). Prepared
from nitronate 1i (78 mg, 0.45 mmol) according to general procedure, reaction time – 48 h.
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Yield: 103 mg (89%). Rf = 0.75 (hexaneꢀAcOEt = 1 : 1). H NMR (300 MHz, CDCl3) δ 4.81 (s,
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2H), 3.75 (s, 3H), 3.47 (d, J = 17.5 Hz, 1H), 2.82 (d, J = 17.5 Hz, 1H), 1.59 (s, 3H), 1.18 (s, 9H).
13C NMR (75 MHz, DEPT135, CDCl3) δ 177.6 (C), 172.0 (C), 154.6 (C), 86.0 (C), 58.3 (CH2),
52.9 (CH3), 44.8 (CH2), 38.7 (C), 27.0 (3 CH3), 23.3 (CH3). ESIꢀHRMS m/z: [M+Na]+ Calcd for
C12H19NO5Na+ 280.1155; Found 280.1161.
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Rel-ethyl
(4S,5S)-4-(2-chlorophenyl)-3-((pivaloyloxy)methyl)-4,5-dihydroisoxazole-5-
carboxylate (2m). Prepared from nitronate 1j (71 mg, 0.25 mmol) according to general
procedure, with an exception that 3 equivalents of pivaloyl chloride and 4 equivalents of Et3N
were used, reaction time – 72 h. Yield: 46 mg (50%). Also, 28 mg (39%) of initial nitronate 1j
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were isolated by column chromatography. Oil. Rf = 0.81 (hexaneꢀAcOEt = 1 : 1). H NMR (300
MHz, CDCl3) δ 7.45 (dd, J = 7.0, 2.4 Hz, 1H), 7.38 – 7.25 (m, 2H), 7.17 (dd, J = 6.4, 2.9 Hz,
1H), 5.28 (d, J = 5.1 Hz, 1H), 4.92 (d, J = 5.1 Hz, 1H), 4.84 (d, J = 13.6 Hz, 1H), 4.72 (d, J =
13.6 Hz, 1H), 4.31 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.10 (s, 9H). 13C NMR (75 MHz,
DEPT135, CDCl3) δ 177.4 (C), 168.9 (C), 155.9 (C), 134.0 (C), 133.4 (C), 130.2 (CH), 129.8
(CH), 129.0 (CH), 128.0 (CH), 85.5 (CH), 62.2 (CH2), 57.4 (CH2), 54.5 (CH), 38.7 (C), 26.9 (3
CH3), 14.1 (CH3). ESIꢀHRMS m/z: [M+H]+ Calcd for C18H23ClNO5 368.1259 and 370.1231;
+
Found 368.1259 and 370.1242.
Benzo[d]isoxazol-3-ylmethyl pivalate (2n). Prepared from nitronate 1k (75 mg, 0.5 mmol)
according to general procedure, with an exception that 3 equiv. of PivCl (0.184 mL, 1.5 mmol)
and 4 equiv. of Et3N (0.28 mL, 2 mmol) were used; reaction time – 96 h. Yield: 77 mg (66 %).
Also, 12 mg of unreacted nitronate 1k were isolated from column chromatography (RSM: 16%).
Rf = 0.78 (hexaneꢀAcOEt = 1 : 1). 1H NMR (300 MHz, CDCl3) δ 7.76 (dd, J = 8.0, 1.0 Hz, 1H),
7.65 – 7.55 (m, 2H), 7.40 – 7.32 (m, 1H), 5.52 (s, 2H), 1.26 (s, 9H). 13C NMR (75 MHz,
DEPT135, CDCl3) δ 177.9 (C), 163.5 (C), 154.5 (C), 130.2 (CH), 123.9 (CH), 121.6 (CH), 120.5
(C), 110.1 (CH), 57.1 (CH2), 39.0 (C), 27.1 (3 CH3). ESIꢀHRMS m/z: [M+H]+ Calcd for
+
C13H16NO3 234.1125; Found 234.1133.
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tert-Butyldimethylsilyl 1-phenylethylideneazinate (5b). To a stirred solution of 1ꢀphenylꢀ1ꢀ
nitroethane (128 mg, 0.85 mmol) and TBSCl (135 mg, 0.89 mmol) in CH2Cl2 (0.85 ml) was
added NEt3 (0.14 ml, 1.02 mmol) at r.t. The reaction mixture was maintained at room
temperature overnight, diluted with petroleum ether (10 mL), stirred and filtered through a pad
of Celite®. The filtrate was evaporated and dilution with additional amount of petroleum ether
followed by filtration through Celite® was repeated. Final evaporation afforded 223 mg (ca.
100%) of target silyl nitronate 5b as slightly yellow oil, which solidifies in a freezer at ca. ꢀ20
°C. 1H NMR (300 MHz, CDCl3): δ = 0.37 (s, 6H), 0.93 (s, 9H), 2.39 (s, 3H), 7.31ꢀ7.41 (m, 3H),
7.74 (d, J = 7.3 Hz, 2H). 13C NMR (75 MHz, HSQC, HMBC, CDCl3): δ = ꢀ3.9 (Me2Si), 17.9
((CH3)3C and CH3), 26.0 ((CH3)3C), 122.7 (C=N), 128.0 (2 CHPh), 128.2 (2 CHPh), 128.3 (CHPh),
133.5 (CPh). ESIꢀHRMS m/z: [M+H]+ Calcd. for C14H24NO2Si+: 266.1571; Found: 266.1581.
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General procedure for the acylation of TBS-nitronates 5.
Solution of nitronate 1 in MeCN (2 mL/1 mmol of nitronate 1) was cooled to 0 °C (argon
atmosphere). After that NEt3 (1.5 equiv.) and acyl chloride (1.1 equiv.) were consequently added
with stirring. The reaction mixture was maintained at the same temperature for specified time
and poured into EtOAc (25 mL)/H2O (20 mL). Organic layer was washed with NaHSO4 (0.5 M
aq., 20 mL), brine (20 mL), dried (Na2SO4) and evaporated. The residue was preadsorbed on
Celite® and subjected to column chromatography on silica (eluent: petroleum ether/EtOAc, 20:1)
to give target oxime ethers. Configuration of C=N bond was not specially determined. Major
isomer can be assumed to be (E)ꢀisomer due to bulkiness of OOCR and OTBS groups.
2-(Tert-butyldimethylsilyloxyimino)propyl pivalate (6a). Prepared from nitronate 5a (102 mg,
0.5 mmol) and pivaloyl chloride (68 ꢁL, 66 mg, 0.55 mmol) according to general procedure,
reaction time – 2 h. Column chromatography (eluent: petroleum ether/EtOAc, 20 : 1) afforded 76
mg (53 %) of target oxime ether 6a and 20 mg (16%) of oxime ester 8a as sideꢀproduct.
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Colorless oil. Rf = 0.60 (petroleum ether/EtOAc, 5:1, anisaldehyde). H NMR (300 MHz,
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HMBC, CDCl3): δ = 0.16 (s, 6H, Me2Si), 0.93 (s, 9H, BuSi), 1.22 (s, 9H, BuꢀC), 1.88 (s, 3H,
Me), 4.61 (s, 2H, CH2). 13C NMR (75 MHz, CDCl3, DEPT, HMBC): δ = ꢀ5.3 (Me2Si), 11.8
(CH3), 18.1 (CꢀSi), 26.0 ((CH3)3CꢀSi), 27.2 ((CH3)3CꢀC), 38.8 ((CH3)3CꢀC), 65.3 (CH2), 157.1
(C=N), 177.9 (C=O). ESIꢀHRMS m/z: [M+H]+ Calcd. for C14H30NO3Si+: 288.1989; Found:
288.1988.
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2-(Pivaloyloxyimino)propyl pivalate (8a). Colorless oil. Rf = 0.29 (petroleum ether/EtOAc,
5:1, anisaldehyde). 1H NMR (300 MHz, CDCl3): δ = 1.22 (s, 9H), 1.28 (s, 9H), 1.99 (s, 3H), 4.74
(s, 2H). 13C NMR (75 MHz, CDCl3): δ = 13.2 (CH3), 27.1 (3 CH3), 27.2 (3 CH3), 38.7 (C), 38.9
(C), 64.5 (CH2), 161.8 (C), 174.7 (C), 177.7 (C). ESIꢀHRMS m/z: [M+Na]+ Calcd. for
C13H23NO4Na+: 280.1519; Found: 280.1519.
2-(Tert-butyldimethylsilyloxyimino)-2-phenylethyl pivalate (6b). Prepared from nitronate 5b
(138 mg, 0.52 mmol) and pivaloyl chloride (71 ꢁL, 70 mg, 0.58 mmol) according to general
procedure, reaction time – 2 h. Yield: 70 mg (39 %). Colorless oil. Rf = 0.79 (petroleum
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ether/EtOAc, 5:1, UV, anisaldehyde). H NMR (300 MHz, CDCl3): δ = 0.20 (s, 6H), 0.91 (s,
9H), 1.09 (s, 9H), 5.01 (s, 2H), 7.33ꢀ7.42 (m, 3H), 7.50ꢀ7.60 (m, 2H). 13C NMR (75 MHz,
CDCl3, DEPT): δ = ꢀ5.3 (2 CH3), 18.0 (C), 26.0 (3 CH3), 27.0 (3 CH3), 38.7 (C), 64.6 (CH2),
127.8 (2 CH), 128.6 (2 CH), 129.1 (CH), 131.3 (C) 156.3 (C), 177.8 (C). ESIꢀHRMS m/z:
[M+H]+ Calcd. for C19H32NO3Si+: 350.2146; Found: 350.2141.
2-(Tert-butyldimethylsilyloxyimino)propyl benzoate (6c). Prepared from nitronate 5a (143
mg, 0.7 mmol) and benzoyl chloride (90 ꢁL, 108 mg, 0.77 mmol) according to general
procedure, reaction time – 24 h. Yield: 92 mg (43 %). Colorless oil. Rf = 0.60 (petroleum
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ether/EtOAc, 5:1, UV, anisaldehyde). E:Z = 17:1. H NMR (300 MHz, HMBC, CDCl3): Eꢀ
isomer: δ = 0.19 (s, 6H, Me2Si), 0.95 (s, 9H, tBuSi), 2.00 (s, 3H, Me), 4.89 (s, 2H, CH2), 7.46 (t,
J = 7.5 Hz, 2H, CHPh), 7.58 (t, J = 7.0 Hz, 1H, CHPh), 8.07 (d, J = 7.5 Hz, 2H, CHPh). Zꢀisomer
(characteristic sigmal): δ = 5.25 (s, 2H, CH2). 13C NMR (75 MHz, CDCl3, DEPT, HMBC): δ = ꢀ
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5.3 (Me2Si), 12.0 (CH3), 18.1 (CꢀSi), 26.0 ((CH3)3C), 66.1 (CH2), 128.4 (2 CHPh), 129.7 (2
CHPh), 129.9 (CPh), 133.1 (CHPh) 156.9 (C=N), 166.1 (C=O). ESIꢀHRMS m/z: [M+H]+ Calcd.
for C16H26NO3Si+: 308.1683; Found: 308.1676.
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2-(Tert-butyldimethylsilyloxyimino)propyl 4-nitrobenzoate (6d). Prepared from nitronate 5a
(193 mg, 0.95 mmol) and pꢀnitrobenzoyl chloride (194 mg, 1.05 mmol) according to general
procedure, reaction time – 1 h. Column chromatography (eluent: petroleum ether/EtOAc, 20:1)
afforded 108 mg of target oxime ether 6d and 56 mg of a mixture containing 6d and nitroso
compound 9d (ratio 6d/9d = 1 : 6). Total yield of 6d: 116 mg (35%). Colorless oil. Rf = 0.67
(petroleum ether/EtOAc, 5:1, UV, anisaldehyde). E:Z = 11:1.1H NMR (300 MHz, HMBC,
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CDCl3): Eꢀisomer: δ = 0.15 (s, 6H, Me2Si), 0.92 (s, 9H, BuSi), 1.99 (s, 3H, Me), 4.92 (s, 2H,
CH2), 8.13ꢀ8.34 (m, 4H, CHAr). Zꢀisomer (characteristic sigmal): δ = 5.26 (s, 2H, CH2). 13C
NMR (75 MHz, CDCl3, DEPT, HMBC): Eꢀisomer: δ = ꢀ5.3 (Me2Si), 12.1 (CH3), 18.1 (CꢀSi),
26.0 ((CH3)3C), 66.7 (CH2), 123.5 (2 CHAr), 130.8 (2 CHAr), 135.2 (CAr), 150.6 (CAr), 156.0
(C=N), 164.2 (C=O). Zꢀisomer (characteristic sigmals): δ = 16.6 (CH3), 61.7 (CH2). ESIꢀHRMS
m/z: [M+H]+ Calcd. for C16H25N2O5Si+: 353.1527; Found: 353.1524.
2-Nitrosopropan-2-yl 4-nitrobenzoate (9d). Isolated by additional column chromatography
(eluent: petroleum ether/EtOAc, 50 : 1) of the mixture of 6d and 9d (ratio 6d/9d = 1 : 6)
obtained as described above. Yield: 42 mg (19%). Blue crystals. Mp = 62ꢀ64 °C (lit.39 65 °C). Rf
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= 0.50 (petroleum ether/EtOAc, 5:1, anisaldehyde). H NMR (300 MHz, HMBC, CDCl3): δ =
1.61 (s, 6H, CH3), 8.27ꢀ8.40 (m, 4H, CHAr). 13C NMR (75 MHz, CDCl3, HMBC): δ = 20.7 (2
CH3), 122.2 (C–NO), 123.6 (2 CHAr), 131.1 (2 CHAr), 135.2 (CAr), 150.8 (CAr–NO2), 162.6
(C=O). NMR matched previously reported data.29
Acylation of nitronate 5c. Acylation of nitronate 5c (142 mg, 0.52 mmol) with pivaloyl chloride
(71 ꢁL, 69 mg, 0.57 mmol) was carried out according to general procedure, reaction time – 24 h.
Column chromatography (eluent: petroleum ether/EtOAc, 20:1 → 3:1) afforded 92 mg (43 %) of
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mixture of target oxime ethers 6e and 6e’ (6e/6e’ = 4:1 according to H NMR) and 26 mg of
mixture of oximes ethers 8e, 8e’ and 10 (8e/8e’/10 = 10 : 1 : 2, yields 12%, 1%, 2%,
respectively) as colorless oils.
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mixture with 6e’. Rf = 0.53 (petroleum ether/EtOAc, 5 : 1, anisaldehyde). H NMR (300 MHz,
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HMBC, CDCl3): δ = 0.16 (s, 6 H, Me2Si), 0.93 (s, 9 H, BuSi), 1.22 (s, 9 H, BuꢀC), 2.54ꢀ2.66
(m, 4H, CH2), 3.68 (s, 3H, CO2CH3), 4.66 (s, 2H, CH2). 13C NMR (75 MHz, CDCl3, DEPT,
HMBC): δ = ꢀ5.4 (Me2Si), 18.1 (CꢀSi), 22.0 (CH2), 26.0 ((CH3)3CꢀSi), 27.2 ((CH3)3CꢀC), 29.8
(CH2), 38.8 ((CH3)3CꢀC), 51.7 (CO2CH3), 64.6 (CH2O), 158.7 (C=N), 172.9 (C=O), 177.8
(C=O). HPLCꢀHRMS (ESI) m/z: [M+H]+ Calcd. for C17H34NO5Si+: 360.2201; Found: 360.2204.
Methyl 4-(tert-butyldimethylsilyloxyimino)-3-(pivaloyloxy)pentanoate (6e’). Characterized in
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mixture with 6e. Rf = 0.53 (petroleum ether/EtOAc, 5:1, anisaldehyde). H NMR (300 MHz,
HMBC, CDCl3): δ = 0.14 (s, 6 H, Me2Si), 0.92 (s, 9 H, tBuSi), 1.20 (s, 9 H, tBuꢀC), 1.85 (s, 3 H,
CH3), 2.72 (dd, J = 15.8, 7.7, 1 H, CH2a), 2.87 (dd, J = 15.8, 6.2, 1 H, CH2b), 3.66 (s, 3H,
CO2CH3), 5.75 (dd, J = 7.7, 6.2, 1 H, CHO). 13C NMR (75 MHz, CDCl3, DEPT, HMBC): δ = ꢀ
5.4 (Me2Si), 11.4 (CH3), 18.1 (CꢀSi), 26.0 ((CH3)3CꢀSi), 27.0 ((CH3)3CꢀC), 36.5 (CH2), 38.8
((CH3)3CꢀC), 51.7 (CO2CH3), 70.8 (CHO), 158.1 (C=N), 170.2 (C=O), 177.2 (C=O). HPLCꢀ
HRMS (ESI) m/z: [M+H]+ Calcd. for C17H34NO5Si+: 360.2201; Found: 360.2206.
Methyl 5-(pivaloyloxy)-4-(pivaloyloxyimino)pentanoate (8e). Characterized in mixture with
8e’ and 10. Rf = 0.22 (petroleum ether/EtOAc, 5:1, anisaldehyde). 1H NMR (300 MHz, CDCl3,
t
t
COSY, HMBC): δ = 1.24 (s, 9H, Bu), 1.30 (s, 9H, Bu), 2.58ꢀ2.65 (m, 2H, CH2), 2.71ꢀ2.77 (m,
2H, CH2), 3.71 (s, 3H, CO2CH3), 4.81 (s, 2H, CH2). 13C NMR (75 MHz, CDCl3, DEPT, HSQC):
δ = 23.0 (CH2), 27.1 ((CH3)3C), 27.2 ((CH3)3C), 29.9 (CH2), 38.7 ((CH3)3C), 38.9 ((CH3)3C),
52.0 (CO2CH3), 63.7 (CH2O), 163.3 (C=N), 172.0 (C=O), 174.5 (C=O), 177.6 (C=O). HPLCꢀ
HRMS (ESI) m/z: [M+H]+ Calcd. for C16H28NO6 : 330.1911; Found: 330.1911.
+
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Methyl 3-(pivaloyloxy)-4-(pivaloyloxyimino)pentanoate (8e’). Characterized in mixture with
3
4
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8e and 10. Rf = 0.22 (petroleum ether/EtOAc, 5:1, anisaldehyde). H NMR (300 MHz, CDCl3,
5
6
7
8
t
t
COSY, HMBC): δ = 1.22 (s, 9 H, Bu), 1.29 (s, 9 H, Bu), 1.98 (s, 3 H, CH3ꢀCN), 2.85 (dd, J =
15.9, 8.5 Hz, 1 H, CH2a), 2.96 (dd, J = 15.9, 5.1 Hz, 1 H, CH2b), 3.70 (s, 3H, CO2CH3), 5.84 (dd,
J = 8.5, 5.1 Hz, 1 H, CHO). 13C NMR (75 MHz, CDCl3, DEPT, HSQC, characteristic signals): δ
= 12.6 (CH3), 36.8 (CH2), 70.4 (CHO). HPLCꢀHRMS (ESI) m/z: [M+H]+ Calcd. for
9
10
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+
C16H28NO6 : 330.1911; Found: 330.1911.
(2E)-Methyl 4-(pivaloyloxyimino)pent-2-enoate (10). Characterized in mixture with 8e and
1
8e’. Rf = 0.22 (petroleum ether/EtOAc, 5:1, anisaldehyde). H NMR (300 MHz, CDCl3, COSY,
t
HMBC): δ = 1.32 (s, 9H, Bu), 2.16 (s, 3H, CH3ꢀCN), 3.81 (s, 3H, CO2CH3), 6.38 (d, J = 16.2,
1H, =CH), 7.51 (d, J = 16.2, 1H, =CH). 13C NMR (75 MHz, CDCl3, DEPT, HSQC,
characteristic signals): δ = 11.8 (CH3), 126.4 (=CH), 140.2 (=CH). HPLCꢀHRMS (ESI) m/z:
[M+H]+ Calcd. for C11H18NO4 : 228.1230, Found: 228.1232.
+
(2-Nitroprop-1-ene-1,3-diyl)dibenzene (13). A mixture of (2ꢀnitroethyl)benzene30 (0.569 g,
3.76 mmol), benzaldehyde (0.39 mL, 3.76 mmol) and nꢀbutylamine (0.019 mL, 0.190 mmol)
was dissolved in toluene (1.6 mL), and the solution was refluxed with Hickman distillation head
for 9.5 h. Then the solvent was evaporated under vacuum and the residue was subjected to a
column chromatography on silica gel (eluent: petroleum ether → petroleum ether/EtOAc = 10:1)
to yield 0.763 g (85%) of nitroalkene 13 as a yellow oil, which was crystallized from methanol at
ꢀ78 °C. Mp = 38 – 40 °C (MeOH). 1H NMR matched previously reported data.31
3-Benzyl-5-(methoxycarbonyl)-4-phenyl-4,5-dihydroisoxazole 2-oxide (12). A solution of
methyl 2ꢀ(dimethylꢀl4ꢀsulfaneylidene)acetate 1432 (1.6 mL, 1 M) was added to nitroalkene 13
(0.319 g, 1.33 mmol). The resulting mixture was stirred at r.t. for 20 min and then kept at 0 °C
for 64 h. The solvent was evaporated under vacuum and the residue was subjected to a column
chromatography on silica gel (eluent: petroleum ether/EtOAc = 10:1 → 5:1 → 3:1) to yield
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0.288 g (69%) of 12 as white crystals. For analytical purposes it was recrystallized from
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hexane/MeOtBu = 1:1 mixture. Mp = 85ꢀ89 °C. Rf = 0.76 (hexane/EtOAc = 1:1). H NMR (300
5
6
7
8
9
MHz, CDCl3, HSQC, NOESY) δ 7.39 – 7.33 (m, 3H, CHPh), 7.26 – 7.21 (m, 3H, CHPh), 7.19 –
7.13 (m, 2H, CHPh), 7.08 – 7.00 (m, 2H, CHPh), 4.85 (d, J = 4.0 Hz, 1H, CHꢀCOOCH3), 4.31 (d,
J = 4.0 Hz, 1H, CHꢀPh), 3.91 (d, J = 15.6 Hz, 1H, CH2), 3.78 (s, 3H, OCH3), 3.23 (d, J = 15.6
Hz, 1H, CH2). 13C NMR (75 MHz, HSQC, CDCl3) δ 169.2 (C=O), 137.0 (CPh), 134.5 (CPh),
129.6, 128.9, 128.9, 127.6 and 127.4 (10 CHPh), 115.8 (C=N), 78.5 (CHꢀCOOCH3), 54.7 (CHꢀ
Ph), 53.1 (CH3), 31.3 (CH2). Characteristic 2DꢀNOESY correlations: PhꢀCH/oꢀPh; H3CO2Cꢀ
10
11
12
13
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CH/oꢀPh. ESIꢀHRMS m/z: [M+H]+ Calcd. for C18H18NO4 312.1230; Found 312.1226.
+
Methyl
3-(((4-nitrobenzoyl)oxy)(phenyl)methyl)-4-phenyl-4,5-dihydroisoxazole-5-
carboxylates (11 and 11’). Nitronate 12 (0.080 g, 0.257 mmol) was dissolved in dry acetonitrile
(0.5 mL) in a Schlenk flask under argon atmosphere and the solution was cooled to ꢀ20°C.
Triethylamine (0.075 mL, 0.540 mmol), 4ꢀnitrobenzoyl chloride (0.095 g, 0.514 mmol) and
silver trifluoromethanesulfonate (0.068 g, 0.257 mmol) were added to the reaction mixture with
intensive stirring. The mixture was allowed to warm to 0 °C and stirred at this temperature for 8
h, then kept at 0°C with occasional stirring for 82 h (3 days). Then, MeOtBu (15 mL) was added
and the resulting solution was poured into 0.25 M aqueous solution of NaHSO4 (15 mL). The
water layer was extracted with MeOtBu (2 × 10 mL), and the combined organic solution was
washed with brine (10 mL), dried over Na2SO4 and evaporated under vacuum. The residue was
subjected to a column chromatography on silica gel (eluent: hexane/EtOAc = 1:0 → 10:1 → 8:1)
to yield 0.091 g of yellow oil (a mixture of diastereomers and starting nitronate, ratio 11 : 11’ :
12 = 1.2 : 1.1 : 1). Crystallization from methanol provided 25 mg (21%) of isoxazoline 11. White
solid. Mp = 139 – 144 °C (MeOH). Lit.21 131 – 133 °C. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J
= 8.9 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 7.43 – 7.12 (m, 10H), 6.95 (s, 1H), 4.94 (d, J = 4.6 Hz,
1
1H), 4.48 (d, J = 4.6 Hz, 1H), 3.74 (s, 3H). H NMR matched previously reported data.21
Isoxazoline 11’ (yield: 20%) was characterized in mixture with nitronate 12 (ratio 11’ : 12 = 2 :
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1), which was obtained by column chromatography of mother liquor from crystallization of 11.
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Oil. Rf = 0.27 (hexane/EtOAc = 3:1). H NMR (300 MHz, 11’, HSQC, HMBC, CDCl3) δ 8.24
5
6
7
8
9
(d, J = 9.0 Hz, 2H, C6H4NO2), 8.12 (d, J = 9.0 Hz, 2H, C6H4NO2), 7.43 – 7.12 (m, 10H, 2 Ph),
6.47 (s, 1H, PhꢀCHꢀO), 4.94 (d, J = 5.2 Hz, 1H, CHꢀCO2CH3), 4.33 (d, J = 5.2 Hz, 1H, CHꢀPh),
3.77 (s, 3H, OCH3). 13C NMR (75 MHz, 11’, HSQC, HMBC, CDCl3) δ 170.4 (COOCH3), 163.3
(ArꢀCOO), 158.2 (C=N), 150.7 (=CꢀNO2), 135.9 (CPh), 134.6 (=CꢀCOO), 134.2 (CPh), 131.1 (2
C6H4NO2), 129.5, 129.1, 128.7, 128.1 and 127.7 (10 CHPh), 123.5 (2 C6H4NO2), 86.4 (CHꢀ
CO2CH3), 72.3 (PhꢀCHꢀO), 58.8 (CHꢀPh), 52.6 (OCH3). ESIꢀHRMS m/z: [M+Na]+ Calcd. for
C25H20N2O7Na+ 483.1163; Found 483.1156.
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SUPPORTING INFORMATION
Copies of NMR, HPLC, Xꢀray data, Cartesian coordinates, absolute energies for all optimized
geometries. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgement
This work was supported by Russian Science Foundation (Grant 17ꢀ13ꢀ01411). The authors
thank Dr. N. G. Kolotyrkina, Dr. A. O. Chizhov (N. D. Zelinsky Institute of Organic Chemistry)
and Dr. P. N. Solyev (V. A. Engelhardt Institute of Molecular Biology) for registration of
HRMS. Also, the contribution of the Center for molecular composition studies of INEOS RAS is
gratefully acknowledged.
References and notes
(1)
a) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. [3,3]ꢀSigmatropic rearrangements:
2009, 38, 3133;
recent applications in the total synthesis of natural products. Chem. Soc. Rev
.
b) Nubbemeyer, U. Recent Advances in Asymmetric [3,3]ꢀSigmatropic Rearrangements.
Synthesis 2003, 961; c) Blechert, S. The HeteroꢀCope Rearrangement in Organic Synthesis.
Synthesis 1989, 71.
(2)
Robinson, B. The Fischer Indole Synthesis. Chem. Rev. 1963, 63, 373.
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