Tandem double acylation/[3,3]-rearrangement of aliphatic nitro compounds: A route to α-oxygenated oxime derivatives

Article abstract of DOI:10.1039/c9ob01005j

A new tandem double acylation/rearrangement reaction of nitro compounds is described. It has a broad substrate scope allowing the mild and efficient synthesis of α-acyloxy oxime esters in high yields and regioselectivity. According to the obtained data, the mechanism for transformation was proposed. The utility of the obtained α-hydroxy oxime esters was demonstrated.

Full text of DOI:10.1039/c9ob01005j

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Nelyubina, A. Y. Sukhorukov, S. Ioffe and A. Tabolin, Org. Biomol. Chem., 2019, DOI:
10.1039/C9OB01005J.
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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C9OB01005J
ARTICLE
Tandem double acylation/[3,3]-rearrangement of aliphatic nitro
compounds: route to α-oxygenated oxime derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
c
a
a
Yulia A. Antonova, a,b Yulia V. Nelyubina, Alexey Yu. Sukhorukov, Sema L. Ioffe and Andrey A.
Tabolin *a
DOI: 10.1039/x0xx00000x
A new tandem double acylation/rearrangement reaction of nitro compounds is described. It has broad substrate scope
allowing the mild and efficient synthesis of α-acyloxy oxime esters in high yields and regioselectivity. According to the
obtained data, the mechanism for the transformation was proposed. Utility of the obtained α-hydroxy oxime esters was
demonstrated.
C=C–N–O-group with N–O-cleavage assisted rearrangement
looks very promising. This would allow the functionalization of
a carbon backbone of the parent nitro compound and the
synthesis of polyfunctional products.12 Herein we report
tandem double acylation/rearrangement of nitro compounds
leading to acylated α-hydroxyoxime derivatives (Scheme 1,
eq. 6).
Introduction
Rearrangement reactions constitute an important class of
organic transformations,1 being particularly attractive the
cases assisted by the cleavage of weak N–O bond.2 Its average
bond energy of 240 kJ/mol compared to the energies of other
common C–X bonds (290-380 kJ/mol for X=C,N,O) allows the
formation of carbon-carbon or carbon-heteroatom bond in a
thermodynamically predictable fashion. Representative
examples include Beckmann3 and Neber4 rearrangements as
well as multiple variants of hetero-Claisen rearrangements.5 In
a tandem process, rearrangement reactions are considered as
invaluable tools for the quick modification of organic
molecules. Some noticeable cases that involve the N–O bond
cleavage are Trofimov pyrrole synthesis (tandem oxime
vinylation, [3,3]-rearrangement, ring closure) (Scheme 1, eq.
1),6 exhaustive acylation of oximes (eq. 2),7 Bartoli indole
synthesis (tandem vinylation, [3,3]-rearrangement, ring
closure)8 (eq. 3), Fischer-like benzofuran synthesis (tandem
oxime formation, [3,3]-rearrangement, ring closure)9 (eq. 4)
and α-oxygenation of ketone (tandem enamine formation,
[3,3]-rearrangement) developed by Tomkinson et al. (eq. 5).10
The majority of the mentioned reactions rely on such starting
materials as hydroxylamines or oximes, i.e. compounds that
already possess single N–O bond. However, nitro compounds
could be useful precursors for the synthesis of compounds
possessing N–O-bond, including those with a reactive C=C–N–
O-moiety.11 Thus, the possibility to combine the generation of
Previous works
OH
O
O
O
O
HN
O
[3,3]
N
N
HN
HN
(1)
(2)
KOH
O
O
O
OH
O
O
N
[3,3]
N
Cl
N
N
N
O
O
O
O
O
R
R
R
R
R
NO2
H
NO
N
N
O
MgBr
MgBr
[3,3]
N
O
O
(3)
(4)
O
ONH2
O
O
O
N
N
NH [3,3]
NH
O
N
O
O
N
O
H
O
O
O
H2O
[3,3]
O
(5)
O
O
O
Presented work
O
O
O
O
O
O
O
NO2
(6)
Cl
Cl
[3,3]
N
N
N
O
O
O
O
O
Scheme 1 Use of N–O cleavage-assisted rearrangements in tandem reactions.
Results and discussion
a. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Leninsky prospect 47, 119991, Moscow, Russian Federation. E-mail:
tabolin87@mail.ru
For the optimization studies, nitro compound 1a and pivaloyl
chloride were used (Table 1). Among the used solvents (Entries
1-4) the highest yield and regioselectivity was achieved in
MeCN. Pyridine and DIPEA resulted in strong deceleration of
reaction (Entries 6-9). With NEt3 reaction was complete in 2
days, while use of DMAP as an additive allowed to shorten the
b. Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie
gory 1, 119991, Moscow, Russian Federation.
c. A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of
Sciences, Vavilov str. 28, 119991, Moscow, Russian Federation.
Electronic Supplementary Information (ESI) available: [Experimental data, remarks
on configuration determination, full optimization table, copies of NMR spectra and
HPLC data]. See DOI: 10.1039/x0xx00000x
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reaction time to 1 day (cf. Entries 4 and 10). Decreasing the
reaction temperature somewhat increased the regioselectivity,
while significantly decreased the reaction rate (Entries 5, 11).
Overall an optimal combination of yield/reaction
rate/selectivity was achieved using NEt3 as a base with
catalytic amounts of DMAP in MeCN at 0°C (Entry 10).
View Article Online
DOI: 10.1039
R(O)CO
R1
OC(O)R
N
/C9OB01005J
N
NO2
RC(O)Cl, NEt3,
R3
DMAP
R3
R3
R1
R2
R1
'
+
CH3CN,
0-25°C, 1-2d

R2
R2
OC(O)R
OC(O)R
1
2
2'
NOPiv
NOPiv
NOPiv
NOBz
Table 1 Optimization of the reaction conditions (See ESI for full details).
OPiv
An
OPiv
OBz
+
O
An
OPiv
NO2
NOPiv
NOPiv
2'a, 7%
2a, 75%
NOC(O)Ad
OC(O)Ad
Cl
2bb, 69%
2ba, 90%
NOBz NOPiv
OPiv
PivO
NOPiv
NOPiv
(2.2 equiv.)
+
An
1a
An
An
An
conditions
+
2a
2'a
OPiv
OBz
OPiv
2d, 51%
PivO
An
An = 4-MeOC6H4-
2bc, 88%
2ca, 79%
2cb, 59%
2'd, 17%
NOPiv
NOPiv
NOPiv
MeO2C
+
NOPiv
№
Base
(equiv.)
Solv.
T,
°C
time,
h
Recovery
Total yield
2а+2'a, %,
(ratio 2а:2'a) a
46 (4:1)
0
27 (4:1)
91 (15:1)
57 (only 2a)
2
MeO2C
1a, %a
Ph
An
+
An
OPiv
OPiv Ph
OPiv
2'f, 5%
OPiv
1
2
3
4
5
6
7
8
NEt3 (2.5)
NEt3 (2.5)
NEt3 (2.5)
NEt3 (2.5)
NEt3 (2.5)
DIPEA (2.5)
DIPEA (2.5)
NEt3 (1) +
DIPEA (1.5)
Py (2.5)
CH2Cl2
THF
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
0
0
0
0
-20
0
24
24
48
48
72
48
96
24
38
87
29
0
25
87
73
40
2f, 59%
NOPiv
2e, 38%
2'e, 38%
MeO2C
NOPiv
NOPiv
Ph
Ph
OPiv
OPiv
2h, 61%
OPiv
2i, 66%
25
0
23 (1:2)
50 (10:1)
2g, 69%
NOPiv
MeO2C
NOPiv
NOPiv
O
9
10
MeCN
MeCN
0
0
24
24
100
0
0
NEt3 (2.5) +
DMAP (0.1)
NEt3 (2.5) +
DMAP (0.1)
93 (10:1)
OPiv
OPiv
OTBS OPiv
2j, 63%
2k, 83%
2l, 66%
11
MeCN
-20
96
20
65 (20:1)
NOPiv
NOPiv
NOPiv
MeO
MeO
a Determined by 1H NMR with an internal standard (1,4-dinitrobenzene).
OTBS OPiv Ph
2m, 63%
OTBS OPiv
Ph
OPiv
2o, 63%a
With the optimized conditions in hand, we proceeded to apply
them on differently substituted nitro compounds 1 to test the
substrate scope (Scheme 2). As can be seen a rather high
variety of α-acyloxyoxime derivatives 2 was obtained in high
yields. Among tested acyl chlorides pivaloyl chloride, benzoyl
chloride and 1-adamantanecarbonyl chloride gave target
products 2b,c smoothly. Acyl chlorides possessing α-protons
(acetyl chloride, isobutyryl chloride) failed to give target
products presumably to the ease of ketene formation. Use of
more electrophilic reagent, e.g. p-nitrobenzoyl chloride, gave
intractable product mixtures. This can be attributed to the
2n, 75%
NOPiv
NOPiv
NOPiv
O
O
O
O
Ph
OPiv
Ph
2p, 87%a
OPiv
OPiv Ph
OPiv
2q, 80%a
2r, 79%a,b
Scheme 2 Synthesis of oxime esters 2 via tandem double acylation-rearrangement of
nitro compounds 1. Reagent ratio: RC(O)Cl (2.2 equiv.), NEt3 (2.5 equiv.), DMAP (0.1
equiv.). MeCN: 0.5 mL / 1 mmol of 1. Scale: 0.4-5 mmol of starting nitro compound 1.
An = 4-methoxyphenyl; Ad = 1-adamantyl. a Average yield for two diastereomers of
starting compound 1 (see Experimental/ESI). b Starting compound 1r with unprotected
OH-group, 3.4 equiv. of PivCl, 3.8 equiv. of NEt3 were used.
instability of intermediate acyl nitronates
3 and their
rearrangement into nitroso compounds (see proposed
mechanism, Scheme 3), that is in accordance with previous
results on the acylation of silyl nitronates.5a
Reactivity of nitro compounds 1 showed strong dependence
on their substitution pattern. Moderately sterically
encumbered nitro compounds 1 possessing CH3 and CH2-
groups at the β-position usually showed a full conversion of
starting materials after 1 day at 0 °C. Bulkier substrates, e.g.
those possessing a tertiary β-carbon, reacted slower thus
requiring higher temperatures (25 °C) and prolonged reaction
times (2 d). The regiochemistry of the process for non-
symmetric nitro compounds depended on the relative
bulkiness of β- and β’-positions of the substrate 1. Thus,
products 2a and 2f were obtained with moderate
2 | J. Name., 2012, 00, 1-3
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regiochemistry in favor of CH3-functionalization (2a,f) vs. including silyl ones (2l,m,n). The free hydroxyVliewgrAortuicple Ownlianes
CH2-functionalization (2'a,2’f), while oxime 2g was obtained as converted into pivalate ester (2r) but didDnOoIt: 1i0n.t1e03rf9e/Cre9OwBi0th10t0h5eJ
a sole product. Expectedly, low regioselectivity was observed desired tandem process. The carbonyl moiety was tolerated
for secondary β- and β’-carbons (2d:2’d = 3:1, 2e:2’e = 1:1). for cyclic product 2k, while for open-chain cases (2o,p,q) the
The competition between primary and tertiary β-positions protection was needed.13
resulted in the complete selectivity toward CH3-group The structures of obtained products were supported by 1H and
(products
2j-2r).
The
described
tandem 13C NMR spectra (including 2D) as well as by HRMS data. For
acylation/rearrangement process tolerated functional groups the oxime ester 2q single crystal X-ray analysis was also
such as ester (products 2f,g,j), acetal (2o,p), and ether performed (Figure 1).14
O
R
N
O
R
N
O
R
N
(1)
(2)
(3)
(4)
O
O
R
NO2
RC(O)Cl
[3,3]
NEt3
RC(O)Cl,
N
O
O
R
O
O
R
O
O
R
NEt3
O
O
O
O
O
1
3
A
4
(E)-2
for 2g
[2,3]
for 1o
for 1f
O
N
Ph
PivO
NOPiv
(
)
N
Me
N(OPiv)2
O
R
MeO2C
MeO
O
MeO2C
Me
OPiv
(E)-2g
CDCl3,
50 °C, 6 h
N(OPiv)2
OMe
N(OPiv)2
OMe
NOPiv
OPiv
MeO
MeO
Me
N
MeO2C
Ph
Ph
(E)-2g
+
MeO2C
6, 13%
5, 12%
OPiv
(Z)-2g
(Z)-2g : (E)-2g = 1:1
Scheme 3 The proposed mechanism and side-products of the reaction. Substituents R1-R3 at major reaction pathway are omitted for clarity.
DMAP is a known Lewis base additive for the acylation
reactions via N-acyl iminium cations. Secondly, it may
accelerate the deprotonation of nitro compound 1 as a less
sterically hindered base compared to NEt3. Next the
stability/reactivity of intermediate acyl nitronates 3 should be
mentioned. Occasional literature examples describe such
compounds as rather unstable even at low temperatures.16
Thus, they might have been expected to suffer some side
reactions like [2,3]-rearrangement or Nef reaction.17
Nevertheless the high yields of the target oximes 2 suggested
the fast step 2, i.e. the nitronate 3 is acylated at a much faster
rate than other side-processes.18 The intermediacy of cation A
is supported by the isolation of nitroso acetal 5 alongside the
product 2o. The formation of 5 should be explained by the
electrophilic ring closure and methoxy-group transfer.19 Side-
process associated with the reactivity of enamines 4 results in
the formation of enoxime 6. Here proposed reaction pathway
involves the heterolysis of N–O bond and proton abstraction
(Scheme 3). Yet rather synchronous nature of the
[3,3]-rearrangement is corroborated by the configuration of
the formed oxime C=N double bond. The predominant
migration of the acyloxy-group syn- to the double C=C bond in
enamine 4 should be expected. Indeed, usually oximes 2 were
isolated as E-isomers.20,21 As exemplified by the product 2g,
the E,Z-isomerization occurred at elevated temperatures
(Scheme 3).
Figure 1 General view of the compound 2q in representation of atoms via thermal
ellipsoids at 50% probability level.14
The proposed mechanism for the process is shown in the
Scheme 3. At the first step the nitro compound 1 is acylated to
give acyl nitronate 3, thus consuming one equivalent of acyl
chloride. At the second step intermediate 3 attacks second
equivalent of acyl chloride forming iminium cation A (step 2),
that is further β-deprotonated15 by a base giving rise to
enamine 4 (step 3). The [3,3]-rearrangement of 4 ultimately
gives target oxime ether 2 (step 4). The effect of catalytic
amounts of DMAP may be explained by two reasons. Firstly,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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As can be seen from Scheme
2
the tandem
View Article Online
DOI: 10.1039/C9OB01005J
NOH
NH2
acylation/rearrangement smoothly proceeded with secondary
nitro compounds 1. Use of primary nitro compound 1s did not
give any acyloxy-oxime derivatives, that can be ascribed to the
decomposition of intermediate nitronate 3s into nitrile
oxide B.22 Performing the reaction in the presence of styrene
allowed the isolation of the corresponding [3+2]-cycloaddition
product - isoxazoline 7 (Scheme 4).
An
An
An
i
iii
OPiv
OPiv
9, 46%
NOPiv
11, 87%
An
iv
NHPiv
O
i,
OPiv
An
2a
then ii
OH
10, 44%
OPiv
O
12, 47%
PivCl, NEt3,
DMAP, styrene
NO2
N
Ph
N
NOPiv
MeO2C
MeO2C
MeCN, 0°C, 1d
v
1s
7, 45%
Ph
An
Ph
OPiv
13, 47%
OPiv
[3+2]
2h
O
OPiv
i: NaBH4, NiCl26H2O, EtOH, r.t.,1h ; ii: DMAP (10 mol%), toluene, 100°C,
8 h iii: 7M NH3 in MeOH, r.t., 45 min; iv: Fe, TMSCl, AcOH, THF, r.t.,
30 min; then H2O, 15 min; v: AnCH=CHCHO, I2, NEt3, toluene; 120 °C, 10 h
An = 4-methoxyphenyl
O
:Base
N
N
MeO2C
MeO2C
H
3s
B
Scheme 6 Synthetic transformations of obtained oxime esters 2.
Scheme 4 Attempted acylation of primary nitro compound 1s.
Presented tandem reaction nicely complements asymmetric
organocatalysis. The addition of nitroethane to
Experimental
Determination of configuration of obtained compounds
cinnamaldehyde is known to give corresponding
γ-nitroaldehydes with high asymmetric induction at CH*–Ph,
albeit completely non-diastereoselective.23 Thus preparation
of nitro compound 1p gave the mixture of syn- and anti-
isomers in nearly equimolar ratio. The tandem
acylation/rearrangement sequence removed CH*–NO2
stereocenter giving rise to one enantiomer of oxime (S)-2p in
perfect yields (Scheme 5).
Determination of syn- or anti- relative configuration in nitro
compounds 1o-r was made using coupling constants between
CH–Ph and CH–NO2 protons: J (anti-isomer) > J (syn-isomer)
(see ESI for more details). Absolute configuration of CH*–Ph
stereocenter in anti-1p, syn-1p and 2p was assigned on the
basis of the literature data.23
General procedure for the synthesis of oxime esters 2 (GP).
The solution of nitro compound 1 in MeCN (2 mL/1 mmol of
nitro compound 1) was cooled to 0 °C in argon atmosphere.
NEt3 (2.5 equiv), DMAP (0.1 equiv), and, after additional 10
min, acyl chloride (2.2 equiv) were consequently added with
stirring. The reaction mixture was either left at the same
temperature (for 1a-c,f-i) or warmed to r.t. (for 1d,e,j-r) and
then maintained for 1 d (for 1a-c,f-h,j) or 2 d (for 1d,e,i,k-r).
After that it was transferred into EtOAc (25 mL)/ H2O(20 mL).
The organic layer was washed with NaHSO4 (0.5 M in H2O, 20
mL), brine (20 mL), dried (Na2SO4) and evaporated. The residue
was preadsorbed on Celite and subjected to column
chromatography on silica (eluent: PE/EtOAc) to give target
oxime esters 2. E,Z-configuration of oxime group was
determined based on 13C NMR (anti-arrangement towards
oxime OR-group results in higher chemical shift of α-carbon as
compared with syn-arrangement).21 Note: prolonged exposure
of oximes 2 at r.t. and higher temperatures (e.g, during
evaporation on a rotary evaporator) may result in partial E,Z-
isomerization).
NO2
O
NOPiv
ii
O
Ph
O
syn-1p, 41%
ee = 96%
O
ii
i
O
OPiv
Ph
+
NO2
(S)-2p,
O
from syn-1p:
89%, ee = 96%
from anti-1p:
90%, ee = 95%
Ph
O
Ph
Ph
Ph
OTMS
anti-1p, 39%
ee = 95%
N
H
8
i: 1. CH3CH2NO2, 8 (2 mol%), NEt3 (10 mol%), AcOH (10 mol%),
CH2Cl2/MeOH (9/1), r.t., 1d;
2. HOCH2CH2OH, TsOH (10 mol%), toluene, 80 °C, 1h;
ii: PivCl, NEt3, DMAP (10 mol%), MeCN, r.t., 2 d
Scheme 5 Asymmetric synthesis and acylation of nitro compounds 1p.
Acylated oximes are useful intermediates for organic
synthesis.24 Thus, to demonstrate the synthetic utility of
obtained products some further transformations were
performed (Scheme 6). Hydrogenation was accomplished to
give either O-protected (9) or N-protected (10) amino alcohol
derivatives.25 Oxime ester was selectively cleaved by the action
of methanolic ammonia (product 11), while the deoximation26
gave ketone 12. Finally, tri-substituted pyridine was prepared
starting from the oxime ester 2h.27
Characterization data for selected products 2 is presented
below. For other products 2 see ESI.
3-(4-Methoxyphenyl)-2-(pivaloyloxyimino)propyl pivalate 2a and
1-(4-Methoxyphenyl)-2-(pivaloyloxyimino)propyl pivalate 2’a
Oxime esters 2a and 2’a were obtained from nitro compound
1a (121 mg, 0.62 mmol) and pivaloyl chloride (0.17 mL, 0.17 g,
1.36 mmol) according to GP (0 °C,
1
d).
Column
4 | J. Name., 2012, 00, 1-3
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chromatography (eluent: PE/EtOAc, 10:1) afforded 191 mg (82 7.06 (d, J = 8.5 Hz, 2H, CHAr). 13C NMR (75 MHz, VDieEwPATrt,iclHe OSQnliCne,
%, 2а:2’а = 10:1 (1H NMR)) of target oxime esters as colorless HMBC, CDCl3): 2d: δ 10.9 (CH2Me), 20.6 (CH2Me), 27.16
DOI: 10.1039/C9OB01005J
oil, that solidifies in a fridge. Rf = 0.38 (PE/EtOAc, 5:1, (Me3C), 27.20 (Me3C), 38.7 (Me3C), 38.9 (Me3C), 55.2 (OMe),
anisaldehyde). Pure 2a was obtained by crystallization from 75.0 (CH–O), 114.4 (CHAr), 127.7 (CAr), 127.9 (CHAr), 159.8 (CAr–
PE/EtOAc, 20:1. mp = 33-35 °C (PE/EtOAc, 20:1). (E)-2a:(Z)-2a = OMe), 167.7 (C=N), 174.6 (C=O), 176.6 (C=O). 2’d: δ 18.0
1
10:1. H NMR (300 MHz, CDCl3): (E)-2a: δ 1.19 (s, 9H, t-Bu), (CHMe), 27.0 (Me3C), 27.1 (Me3C), 32.0 (CH2Ar), 38.6 (Me3C),
1.28 (s, 9H, t-Bu), 3.78 (s, 2H, CH2Ar), 3.79 (s, 3H, OMe), 4.72 38.7 (Me3C), 55.2 (OMe), 70.2 (CH–O), 114.4 (CHAr), 126.5
(s, 2H, CH2–O), 6.85 (d, J = 8.6 Hz, 2H, CHAr), 7.09 (d, J = 8.5 Hz, (CAr), 129.3 (CHAr), 158.5 (CAr–OMe), 165.9 (C=N), 174.6 (C=O),
2H, CHAr). (Z)-2a (characteristic signals): δ 3.75 (s, 2H, CH2Ar), 177.1 (C=O). HRMS (ESI): m/z calcd. for [C21H31NO5+Na+]:
4.85 (s, 2 H, CH2–O), 7.20 (d, J = 8.6 Hz, 2H, CHAr). 13C NMR (75 400.2094, found: 400.2096.
Methyl 2-methyl-5-(pivaloyloxy)-4-(pivaloyloxyimino)pentanoate
2g
MHz, DEPT, HSQC, HMBC, CDCl3): (E)-2a: δ 27.1 (Me3C), 27.2
(Me3C), 32.6 (CH2Ar), 38.7 (Me3C), 38.8 (Me3C), 55.3 (OMe),
63.1 (CH2–O), 114.4 (CHAr), 125.9 (CAr), 129.7 (CHAr), 158.8 (CAr–
OMe), 163.0 (C=N), 174.7 (C=O), 177.6 (C=O). (Z)-2a
(characteristic signals): δ 36.6 (CH2Ar), 58.2 (CH2–O), 129.9
Oxime ester 2g was obtained from nitro compound 1g (302
mg, 1.7 mmol) and pivaloyl chloride (0.47 mL, 0.46 g, 3.8
mmol) according to GP (0 °C, 1 d). Column chromatography
(eluent: PE/EtOAc, 7:1) afforded 409 mg (69 %) of target oxime
1
(CHAr), 164.0 (C=N). 2’a (characteristic signals): H NMR (300
MHz, CDCl3): δ 1.91 (s, 3H, CH3), 6.41 (s, 1H, CH–O), 7.36 (d, J =
8.6, 2H, CHAr). 13C NMR (75 MHz, DEPT, HSQC, HMBC, CDCl3): δ
11.7 (C(=N)–Me), 75.2 (CH–O), 127.7 (CHAr). HRMS (ESI): m/z
calcd. for [C20H29NO5+Na+]: 386.1938, found: 386.1927.
2-(Pivaloyloxyimino)cyclopentyl pivalate 2ba
ester 2g as colorless oil. Rf
= 0.36 (PE/EtOAc, 5:1,
anisaldehyde). Maintaining NMR sample of pure (E)-2g in
CDCl3 at 50 °C (oil bath) for 7 h resulted in ratio (E)-2g:(Z)-2g =
1:1. 1H NMR (300 MHz, CDCl3): (E)-2g: δ 1.24 (s, 9H, t-Bu), 1.25
(d, overlapped, 3H, CH–Me), 1.30 (s, 9H, t-Bu), 2.60 (dd, J =
13.3, 7.9 Hz, 1H, CH2a), 2.76 (dd, J = 13.3, 7.3 Hz, 1H, CH2b),
2.89 (app sex, J = 7.1 Hz, 1H, CH), 3.69 (s, 3H, CO2Me), 4.74-
4.84 (m, 2H, CH2–O). (Z)-2g (characteristic signals): δ 1.25 (s,
9H, t-Bu), 1.27 (s, 9H, t-Bu), 2.46 (dd, J = 15.4, 6.6 Hz, 1H, CH2a),
2.80-2.98 (m, 2H, CH and CH2b), 3.70 (s, 3H, CO2Me), 4.88-5.04
(m, 2H, CH2–O). 13C NMR (75 MHz, DEPT, CDCl3):(E)-2g: δ 17.2
(CH3), 27.1 (Me3C), 27.2 (Me3C), 30.8 (CH2), 36.4 (CH), 38.6
(Me3C), 38.8 (Me3C), 52.0 (CO2Me), 63.5 (CH2–O), 162.6 (C=N),
174.4 (C=O), 174.9 (C=O), 177.5 (C=O). (Z)-2g (characteristic
signals): δ 17.0 (CH3), 27.1 (Me3C), 27.2 (Me3C), 34.4 (CH2),
36.2 (CH), 38.7 (Me3C), 38.8 (Me3C), 51.9 (CO2Me), 59.4 (CH2–
O), 163.6 (C=N), 174.1 (C=O), 175.6 (C=O), 177.6 (C=O). HRMS
(ESI): m/z calcd. for [C17H29NO6+Na+]: 366.1887, found:
366.1883.
Oxime ester 2ba was obtained from nitro compound 1b (188
mg, 1.63 mmol) and pivaloyl chloride (0.45 mL, 0.43 g, 3.6
mmol) according to GP (0 °C, 1 d). Column chromatography
(eluent: PE/EtOAc, 10:1) afforded 414 mg (90 %) of target
oxime ester 2ba as white solid. Rf = 0.38 (PE/EtOAc, 5:1,
anisaldehyde). mp = 56-58 °C (PE). 1H NMR (300 MHz, CDCl3): δ
1.21 (s, 9H, t-Bu), 1.28 (s, 9H, t-Bu), 1.77-2.01 (m, 3H) and
2.03-2.13 (m, 1H) (2 × CH2), 2.52-2.77 (m, 2H, CH2), 5.59 (t, J =
5.4 Hz, 1H, CH–O). 13C NMR (75 MHz, DEPT, HSQC, CDCl3): δ
20.6 (CH2), 27.1 (Me3C), 27.3 (Me3C), 27.5 (CH2), 32.0 (CH2),
38.7 (Me3C), 38.8 (Me3C), 73.5 (CH–O), 171.1 (C=N), 174.8
(C=O), 177.3 (C=O). HRMS (ESI): m/z calcd. for
[C15H25NO4+Na+]: 306.1671, found: 306.1676.
2-(Pivaloyloxyimino)propyl pivalate 2ca
2-Phenyl-2-(pivaloyloxyimino)ethyl pivalate 2h
Oxime ester 2ca was obtained from nitro compound 1c (0.45
mL, 0.45 g, 5 mmol) and pivaloyl chloride (1.37 mL, 1.33 g, 11
mmol) according to GP (0 °C, 1 d). Column chromatography
(eluent: PE/EtOAc, 7:1) afforded 1.02 g (79 %) of target oxime
ester 2ca as slightly yellow oil. Rf = 0.33 (PE/EtOAc, 5:1,
anisaldehyde). NMR matches previously reported data.5a
1-(4-Methoxyphenyl)-2-(pivaloyloxyimino)butyl pivalate 2d and
Oxime ester 2h was obtained from nitro compound 1h
(150 mg, 1.0 mmol) and pivaloyl chloride (0.27 mL, 0.27 g, 2.2
mmol) according to GP (0 °C, 1 d). Column chromatography
(eluent: PE/EtOAc, 15:1) afforded 196 mg (61 %) of target
oxime ester 2h as colorless oil, that solidifies in a fridge. Rf =
0.49 (PE/EtOAc, 5:1, anisaldehyde). mp = 85-87 °C (PE).
1
4-(4-Methoxyphenyl)-3-(pivaloyloxyimino)butan-2-yl pivalate 2’d
(E)-2h:(Z)-2h = 1.7:1. H NMR (300 MHz, CDCl3): (E)-2h: δ 1.01
(s, 9H, t-Bu), 1.09 (s, 9H, t-Bu), 5.11 (s, 2H, CH2–O), 7.35-7.44
(m, 5H, CHPh). (Z)-2h: δ 1.01 (s, 9H, t-Bu), 1.33 (s, 9H, t-Bu),
5.29 (m, 2 H, CH2–O), 7.35-7.44 (m, 3H, CHPh), 7.61 (d, J = 7.8
Hz, 2H, CHPh). 13C NMR (75 MHz, DEPT, CDCl3): (E)-2h: δ 26.8
(Me3C), 26.9 (Me3C), 38.4 (Me3C), 38.7 (Me3C), 63.5 (CH2–O),
127.7 (CHPh), 128.2 (CHPh), 130.0 (CHPh), 130.3 (CPh), 162.5
(C=N), 174.8 (C=O), 177.4 (C=O). (Z)-2h (characteristic signals):
δ 26.8 (Me3C), 27.2 (Me3C), 38.6 (Me3C), 38.8 (Me3C), 57.3
(CH2–O), 128.1 (CHPh), 128.3 (CHPh), 130.5 (CHPh), 131.7 (CPh),
162.8 (C=N), 174.4 (C=O), 177.5 (C=O). HRMS (ESI): m/z calcd.
for [C18H25NO4+Na+]: 342.1676, found: 342.1674.
Oxime esters 2d and 2’d were obtained from nitro compound
1d (139 mg, 0.67 mmol) and pivaloyl chloride (0.19 mL, 0.18 g,
1.5 mmol) according to GP (r.t., 2 d). Column chromatography
(eluent: PE/EtOAc, 15:1, then 10:1) afforded 172 mg (68 %,
2d:2’d = 3:1 (1H NMR)) of target oxime esters as colorless oil,
that solidifies upon storage. Rf = 0.19 (PE/EtOAc, 9:1, UV,
1
anisaldehyde). mp (2d+2’d) = 120-122 °C (PE/EtOAc, 10:1). H
NMR (300 MHz, COSY, CDCl3): 2d: δ 0.98 (t, J = 7.6 Hz, 3H,
CH2Me), 1.27 (s, 18H, 2 × t-Bu), 2.22-2.38 (m, 2H, CH2Me), 3.78
(s, 3H, OMe), 6.39 (s, 1H, CH–O), 6.89 (d, J = 8.7 Hz, 2H, CHAr),
7.34 (d, J = 8.7 Hz, 2H, CHAr). 2’d: δ 1.12 (s, 9H, t-Bu), 1.18 (s,
9H, t-Bu), 1.38 (d, J = 6.6 Hz, CHMe), 3.69 (d, J = 14.5 Hz, 1H,
1-Phenyl-1-(pivaloyloxyimino)propan-2-yl pivalate 2i
CH2aAr), 3.76 (s, 2H, CH2Ar), 3.83 (d, J = 14.5 Hz, 1H, CH2bAr), Oxime ester 2i was obtained from nitro compound 1i (77 mg,
5.58 (q, J = 6.6 Hz, 1 H, CH–O), 6.82 (d, J = 8.5 Hz, 2H, CHAr), 0.47 mmol) and pivaloyl chloride (0.13 mL, 0.13 g, 1.03 mmol)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 10
ARTICLE
Journal Name
according to GP (0 °C, 2 d). Column chromatography (eluent: 177.5 (C=O). HRMS (ESI): m/z calcd. for [C23H35NO6+Na+]:
View Article Online
DOI: 10.1039/C9OB01005J
PE/EtOAc, 30:1, then 15:1) afforded 103 mg (66 %) of target 444.2357, found: 444.2353.
4-(1,3-Dioxolan-2-yl)-3-phenyl-2-(pivaloyloxyimino)butyl pivalate
oxime ester 2i as colorless oil, that solidifies in a fridge. Rf =
2p
0.56 (PE/EtOAc, 9:1, anisaldehyde). mp
= 115-118 °C
1
(PE/EtOAc, 10:1). (E)-2i:(Z)-2i = 1:1. H NMR (300 MHz, COSY,
for (E,Z)-mixture, CDCl3): δ 0.93 (s, 9H, t-Bu), 1.05 (s, 9H, t-Bu),
1.08 (s, 9H, t-Bu), 1.35 (s, 9H, t-Bu), 1.55 (d, J = 6.6 Hz, 3H, (E)-
isomer, Me), 1.73 (d, J = 7.0 Hz, 3H, (Z)-isomer, Me), 5.83 (q, J
= 6.6 Hz, 3H, (E)-isomer, CH–O), 6.13 (q, J = 7.0 Hz, 3H, (Z)-
isomer, CH–O), 7.28-7.43 (m, 5H ((E)-isomer) + 3H ((Z)-isomer),
CHPh), 7.59 (d, J = 7.9 Hz, 2H, (Z)-isomer, CHPh). 13C NMR (75
MHz, DEPT, HSQC, for (E,Z)-mixture, CDCl3): δ 17.8 (Me, (E)-
isomer), 18.2 (Me, (Z)-isomer), 26.7 (Me3C), 26.9 (2 × Me3C),
27.3 (Me3C), 38.4 (2 × Me3C), 38.6 (Me3C), 38.8 (Me3C), 66.3
(CH–O, (Z)-isomer), 70.3 (CH–O, (E)-isomer), 127.4 (CHPh),
128.0 (CHPh),128.1 (CHPh), 128.6 (CHPh), 129.4 (CHPh), 130.1
(CHPh), 131.1 (CPh), 131.2 (CPh), 166.4 (C=N), 167.4 (C=N), 174.3
(C=O), 174.7 (C=O), 177.3 (2 × C=O). HRMS (ESI): m/z calcd. for
[C19H27NO4+Na+]: 356.1832, found: 356.1838.
Oxime ester 2p was obtained from nitro compound anti-1p
(86 mg, 0.35 mmol) and pivaloyl chloride (0.10 mL, 0.10 g,
0.84 mmol) according to GP (r.t., 2 d). Column chromatography
(eluent: PE/EtOAc, 6:1) afforded 131 mg (89 %) of target oxime
ester 2p as colorless oil. Rf
= 0.28 (PE/EtOAc, 5:1,
anisaldehyde). Similar procedure for syn-1p (98 mg, 0.39
mmol) gave 140 mg (86%) of target oxime ester 2p. Similar
procedure for (+)-anti-1p (97 mg, 0.39 mmol) gave 145 mg
(90%, ee = 95%) of target oxime ester (–)-2p. Similar procedure
for (+)-syn-1p (90 mg, 0.36 mmol) gave 133 mg (89%, ee =
96%) of target oxime ester (–)-2p. (–)-(S)-2p: [a]24D = -93.5 (c =
1.0, MeOH, 96% ee, E-isomer). 1H NMR (300 MHz, COSY,
CDCl3): (E)-2p: δ 1.11 (s, 9H, t-Bu), 1.26 (s, 9H, t-Bu), 2.26-2.48
(m, 2H, CH2), 3.77-3.84 and 3.88-3.97 (m, 4H, OCH2CH2O), 4.66
(d, J = 13.1 Hz, 1H, CH2a–OPiv), 4.73 (d, J = 13.1 Hz, 1H, CH2b–
OPiv), 4.76 (t, J = 7.7 Hz, 1H, CHPh), 4.87 (t, J = 4.6 Hz, 1H,
CH(OCH2)2), 7.18-7.35 (m, 5H, Ph). (Z)-2p: δ 1.13 (s, 9H, t-Bu),
3-(tert-Butyldimethylsilyloxy)-2-(pivaloyloxyimino)butyl pivalate
2l
Oxime ester 2l was obtained from nitro compound 1l (111 mg, 1.28 (s, 9H, t-Bu), 2.17 (ddd, J = 13.9, 7.6, 4.3 Hz, 1H, CH2a),
0.48 mmol) and pivaloyl chloride (0.13 mL, 0.13 g, 1.06 mmol) 2.51 (ddd, J = 13.9, 7.6, 5.8 Hz, 1H, CH2a), 3.75-3.85 and 3.87-
according to GP (r.t., 2 d). Column chromatography (eluent: 3.96 (m, 4H, OCH2CH2O), 4.13 (t, J = 7.6 Hz, 1H, CHPh), 4.52 (d,
PE/EtOAc, 20:1) afforded 127 mg (66 %) of target oxime ester J = 14.7 Hz, 1H, CH2a–OPiv), 4.84 (dd, J = 5.8, 4.3 Hz, 1H,
2l as colorless oil. Rf = 0.67 (PE/EtOAc, 5:1, anisaldehyde). CH(OCH2)2), 4.94 (d, J = 14.7 Hz, 1H, CH2b–OPiv), 7.22-7.34 (m,
1
(E)-2l:(Z)-2l = 1:4. H NMR (300 MHz, COSY, CDCl3): (Z)-2l: δ 5H, Ph). 13C NMR (75 MHz, DEPT, HSQC, CDCl3): (E)-2p: δ 27.0
0.07 (s, 3 H, MeSi), 0.09 (s, 3 H, MeSi), 0.90 (s, 9H, t-BuSi), 1.25 (Me3C), 27.1 (Me3C), 34.9 (CH2), 38.6 (Me3C), 38.7 (Me3C), 39.5
(s, 9H, t-Bu-C), 1.29 (s, 9H, t-Bu-C), 1.43 (d, J = 6.5 Hz, 3H, СН3), (CHPh), 62.8 (CH2–OPiv), 64.9 and 65.0 (OCH2CH2O), 102.2
4.67 (d, J = 13.7 Hz, 1H, CH2a–OPiv), 5.12 (d, J = 13.7 Hz, 1Н, (CH(OCH2)2), 127.4 (CHPh), 127.7 (CHPh), 128.8 (CHPh), 137.8
CH2b–OPiv), 5.12 (q, J = 6.5 Hz, 1Н, СН–OTBS). (E)-2l (CPh), 164.2 (C=N), 174.6 (C=O), 177.5 (C=O). (Z)-2p: δ 27.0
(characteristic signals): δ 4.74 (q, J = 6.6 Hz, 1Н, СН–OTBS), (Me3C), 27.2 (Me3C), 37.0 (CH2), 38.7 (Me3C), 38.8 (Me3C), 43.6
4.82-4.92 (m, 2H, CH2–OPiv). 13C NMR (75 MHz, DEPT, HSQC, (CHPh), 58.2 (CH2–OPiv), 64.8 (OCH2CH2O), 102.4 (CH(OCH2)2),
CDCl3): (Z)-2l: δ -5.3 (MeSi), -4.9 (MeSi), 18.0 (C-Si), 21.6 (CH3), 127.4 (CHPh), 128.3 (CHPh), 128.8 (CHPh), 138.7 (CPh), 165.4
25.6 (t-BuSi), 27.2 (2 × Me3C–C), 38.7 (Me3C), 38.8 (Me3C), 60.9 (C=N), 174.5 (C=O), 177.5 (C=O). HRMS (ESI): m/z calcd. for
(CH2–O), 64.8 (CH–O), 167.4 (C=N), 174.0 (C=O), 177.6 (C=O). [C23H33NO6+H+]: 420.2381, found: 420.2374. HPLC separation
(E)-2l (characteristic signals): δ 22.0 (CH3), 54.8 (CH2–O), 68.8 conditions: column: Chiralpak AD-3, 250 x 4.6 mm, temp.
(CH–O). HRMS (ESI): m/z calcd. for [C20H39NO5Si+Na+]: 25 °C, eluent: Hexane-i-PrOH, 90:10, 1 mL/min, detection at
424.2490, found: 424.2485.
5,5-Dimethoxy-3-phenyl-2-(pivaloyloxyimino)pentyl pivalate 2o
207 nm. tR = 4.9 min (Z-isomer, minor), 5.2 min (Z-isomer,
major), 6.3 min (E-isomer, major), 7.1 (E-isomer, minor).
3-Phenyl-2-(pivaloyloxyimino)pentane-1,5-diyl bis(2,2-
Oxime ester 2o was obtained from nitro compound syn-1o
(125 mg, 0.49 mmol) and pivaloyl chloride (0.13 mL, 0.13 g, 1.1
mmol) according to GP (r.t., 2 d). Column chromatography
(eluent: PE/EtOAc, 15:1, then 9:1) afforded 15 mg of nitroso
acetal 5, 71 mg of mixture 2o+5 (2o:5 = 6:1 (1H NMR)) and 71
mg of oxime ester 2o as colorless oils. Total yields: 2o: 64 %, 5:
12 %. Similar procedure for anti-1o (177 mg, 0.7 mmol) gave
182 mg (62%) of target oxime ester 2o. Oxime ester 2o: Rf =
dimethylpropanoate) 2r
Oxime ester 2r was obtained from nitro compound syn-1r (86
mg, 0.42 mmol) according to GP (r.t., 2 d) with the change:
increasing amounts of pivaloyl chloride (3.4 equiv., 0.18 mL,
0.17 g, 1.4 mmol) and NEt3 (3.8 equiv., 0.22 mL, 0.16 g, 1.6
mmol) were taken. Column chromatography (eluent:
PE/EtOAc, 10:1) afforded 156 mg (82 %) of target oxime ester
2r as colorless oil, that solidifies in a fridge. Rf = 0.44
(PE/EtOAc, 5:1, anisaldehyde). mp = 73-75 °C (PE/EtOAc, 10:1).
Similar procedure for anti-1r (94 mg, 0.45 mmol) gave 160 mg
(77 %) of target oxime ester 2r. Only (E)-2r. 1H NMR (300 MHz,
CDCl3): δ 1.16 (s, 18H, 2 × t-Bu), 1.27 (s, 9H, t-Bu), 2.37 (app q, J
= 7.0 Hz, CH2(4)), 4.00-4.18 (m, 2H, CH2(5)–OPiv), 4.55 (app t,
J= 7.8 Hz, CHPh), 4.62-4.72 (m, 2H, CH2(1)–OPiv), 7.23-7.33 (m,
5H, Ph). 13C NMR (75 MHz, DEPT, HSQC, CDCl3): δ 27.07
(Me3C), 27.12 (Me3C), 27.18 (Me3C), 29.8 (CH2(4)), 38.63
1
0.36 (PE/EtOAc, 5:1, anisaldehyde). Only (E)-2o. H NMR (300
MHz, COSY, CDCl3): δ 1.15 (s, 9H, t-Bu), 1.28 (s, 9H, t-Bu), 2.32
(dd, J = 7.9, 5.7 Hz, 1H, CH2), 3.30 (s, 3H, OMe), 3.31 (s, 3H,
OMe), 4.34 (t, J = 5.7 Hz, 1H, CH(OMe)2), 4.62 (t, J = 7.9 Hz, 1H,
CHPh), 4.68 (s, 2 H, CH2–O), 7.24-7.35 (m, 5H, Ph). 13C NMR (75
MHz, DEPT, HSQC, CDCl3): δ 27.0 (Me3C), 27.1 (Me3C), 33.9
(CH2), 38.6 (Me3C), 38.7 (Me3C), 40.3 (CHPh), 52.4 (OMe), 53.7
(OMe), 62.8 (CH2–O), 102.3 (CH(OMe)2), 127.5 (CHPh), 127.7
(CHPh), 128.9 (CHPh), 137.7 (CPh), 164.1 (C=N), 174.6 (C=O),
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
(Me3C), 38.68 (Me3C), 38.74 (Me3C), 41.4 (CHPh), 62.2 (CH2(5)– (C=O). HRMS (ESI): m/z calcd. for [C15H23NO3+HV+]ie:w2A6rti6cl.e1O7n5lin1e,
DOI: 10.1039/C9OB01005J
OPiv), 62.7 (CH2(1)–OPiv), 127.7 (CHPh), 127.8 (CHPh), 129.0 found: 266.1743.
(CHPh), 137.2 (CPh), 163.4 (C=N), 174.3 (C=O), 177.4 (C=O), N-(1-Hydroxy-3-(4-methoxyphenyl)propan-2-yl)pivalamide 10
178.2 (C=O). HRMS (ESI): m/z calcd. for [C26H39NO6+Na+]:
484.2670, found: 484.2659.
O-Pivaloyl-N-(pivaloyloxy)-N-((3E)-1,4-dimethoxy-1-methylbut-3-
en-1-yl)hydroxylamine 5
Oxime ester 2a (94 mg, 0.26 mmol) was subjected to
hydrogenation as described for the synthesis of amine 9. Then
the solution of crude amine 9 and DMAP (3.1 mg, 0.03 mmol)
in toluene (0.52 mL) was heated at 100 °C (oil bath) for 8 h.
Obtained as a side-product during acylation of syn-1o. Rf = 0.44 The reaction mixture was evaporated and preadsorbed on
(PE/EtOAc, 5:1, anisaldehyde). Relative configuration of Celite®. Column chromatography (eluent: PE/EtOAc, 1:1, then
1
stereocenters was not determined. H NMR (300 MHz, CDCl3): PE/EtOAc/MeOH, 1:1:0.1) afforded 30 mg (44 %) of target
δ 1.13 (s, 9H, t-Bu), 1.25 (s, 9H, t-Bu), 1.28 (s, 3H, Me), 3.51 (s, amide 10 as colorless oil. Rf = 0.13 (PE/EtOAc, 1:1, Hanessian
1
3H, N–C–OMe), 3.52 (s, 3H, =CHOMe), 3.84 (d, J = 9.2 Hz, 1H, stain). H NMR (300 MHz, COSY, CDCl3): δ 1.13(s, 9H, t-Bu),
CHPh), 5.36 (dd, J = 12.7, 9.2 Hz, =CH–CH), 6.21 (d, J = 12.7 Hz, 2.77 (dd, J = 13.9, 7.6 Hz, 1H, CH2a–Ar), 2.87 (dd, J = 13.9, 6.9
1H, =CH–O), 7.19-7.35 (m, 5H, Ph). 13C NMR (75 MHz, DEPT, Hz, 1H, CH2b–Ar), 3.44 (br s, 1H, OH), 3.60 (dd, J = 11.0, 5.3 Hz,
HSQC, HMBC, CDCl3): δ 17.9 (Me), 26.8 (Me3C), 27.0 (Me3C), 1H, CH2a–O), 3.68 (dd, J = 11.0, 3.6 Hz, 1H, CH2b–O), 3.79 (s, 3H,
38.4 (Me3C), 38.5 (Me3C), 50.6 (CHPh), 52.2 (N–C–OMe), 56.2 OMe), 4.03-4.15 (m, 1H, CH–N), 5.89 (br d, J = 6.6 Hz, 1H, NH),
(=CHOMe), 98.7 (C–N), 104.1 (=CH–CH), 126.4 (CHPh), 128.3 6.85 (d, J = 8.5 Hz, 2H, CHAr), 7.14 (d, J = 8.5 Hz, 2H, CHAr). 13C
(CHPh), 129.3 (CHPh), 142.7 (CPh), 148.1 (=CH–O), 174.2 (C=O), NMR (75 MHz, DEPT, HSQC, HMBC, CDCl3): δ 27.5 (Me3C), 36.0
174.5 (C=O). HRMS (ESI): m/z calcd. for [C23H35NO6+Na+]: (CH2–Ar), 38.7 (Me3C), 52.9 (CH–N), 55.3 (OMe), 64.6 (CH2–O),
444.2357, found: 444.2374.
Methyl 3-(5-phenyl-4,5-dihydroisoxazol-3-yl)propanoate 7
114.0 (CHAr), 129.6 (CAr), 130.2 (CHAr), 158.4 (CAr–OMe), 179.4
(C=O). HRMS (ESI): m/z calcd. for [C15H23NO3+H+]: 266.1751,
found: 266.1748.
2-(Hydroxyimino)-3-(4-methoxyphenyl)propyl pivalate 11 and 2-
(Hydroxyimino)-1-(4-methoxyphenyl)propyl pivalate 11’
The solution of nitro compound 1s (115 mg, 0.78 mmol) in
MeCN (1.55 mL) was cooled to 0 °C in argon atmosphere.
Styrene (0.27 mL, 0.24 g, 2.3 mmol), NEt3 (0.27 mL, 0.19 g, 2.0
mmol), DMAP (9.5 mg, 0.08 mmol), and, after additional 10 Mixture of oxime esters 2a+2’a (121 mg, 0.33 mmol) was
min, pivaloyl chloride (0.21 ml, 0.21 g, 1.7 mmol) were dissolved in the solution of NH3 in MeOH (7M, 1.43 mL).
consequently added with stirring. The reaction mixture was Reaction mixture was stirred for 45 min at r.t., transferred into
maintained at the same temperature for 1 d, transferred into EtOAc (50 mL) / H2O(40 mL). The organic layer was washed
EtOAc (50 mL)/ H2O(40 mL). The organic layer was washed with NaHSO4 (0.5 M in H2O, 30 mL), brine (40 mL), dried
with NaHSO4 (0.5 M in H2O, 40 mL), brine (40 mL), dried (Na2SO4) and evaporated. Column chromatography (eluent:
(Na2SO4) and evaporated. The residue was subjected to PE/EtOAc, 6:1) afforded 80 mg (87 %) of target oxime 11+11’
column chromatography (eluent: PE/EtOAc, 6:1, then 3:1) to (11:11’ = 12:1 (1H NMR)) as colorless oil, that solidifies in a
give 82 mg (45%) of isoxazoline 7 as colorless oil. Rf = 0.42 fridge. Rf = 0.33 (PE/EtOAc, 5:1, UV, anisaldehyde). mp = 58-
(PE/EtOAc, 1:1, anisaldehyde). NMR matches previously 60 °C (PE/EtOAc, 20:1). (E)-11:(Z)-11 = 10:1. 1H NMR (300 MHz,
reported data.28
2-Amino-3-(4-methoxyphenyl)propyl pivalate 9
CDCl3): (E)-11: δ 1.21 (s, 9H, t-Bu), 3.76 (s, 2H, CH2Ar), 3.80 (s,
3H, OMe), 4.59 (s, 2H, CH2–O), 6.85 (d, J = 8.6 Hz, 2H, CHAr),
7.19 (d, J = 8.6 Hz, 2H, CHAr), 9.22 (br s, 1H, NOH). (Z)-11
(characteristic signals): δ 3.59 (s, 2H, CH2Ar), 4.95 (s, 2 H, CH2–
O). 13C NMR (75 MHz, DEPT, HSQC, HMBC, CDCl3): (E)-11: δ
27.1 (Me3C), 30.8 (CH2Ar), 38.8 (Me3C), 55.3 (OMe), 63.6 (CH2–
O), 114.1 (CHAr), 127.5 (CAr), 130.1 (CHAr), 155.4 (C=N), 158.4
(CAr–OMe), 178.0 (C=O). (Z)-11 (characteristic signals): δ 36.3
(CH2Ar), 58.4 (CH2–O), 129.8 (CHAr). 11’ (characteristic signals):
1H NMR (300 MHz, CDCl3): δ 1.86 (s, 3H, CH3), 6.30 (s, 1H, CH–
O), 7.31 (d, J = 8.7, 2H, CHAr). 13C NMR (75 MHz, DEPT, HSQC,
HMBC, CDCl3, characteristic signals): δ 10.4 (C(=N)–Me), 75.6
(CH–O), 127.8 (CHAr). HRMS (ESI): m/z calcd. for
[C15H21NO4+Na+]: 302.1363, found: 302.1362.
To the solution of oxime ester 2a (98 mg, 0.27 mmol) and
NiCl2∙6H2O (130 mg, 0.55 mmol) in EtOH (2.8 mL) NaBH4 (102
mg, 2.7 mmol) was added portionwise during 30 min at 0 °C.
The reaction mixture was stirred at r.t. for 1 h and transferred
into EtOAc (100 mL)/ H2O(75 mL). The water layer was
extracted with EtOAc (3 × 20 mL). The combined organic layer
was washed with brine (150 mL), dried (Na2SO4) and
evaporated to give crude amine 9. Column chromatography
(eluent: PE/EtOAc, 1:1, then PE/EtOAc/MeOH, 1:1:0.2)
afforded 33 mg (46 %) of target amine 9 as colorless oil. Rf =
1
0.13 (EtOAc, ninhydrine). H NMR (300 MHz, CDCl3): δ 1.25 (s,
9H, t-Bu), 1.90 (br s, 2H, NH2), 2.57 (dd, J = 13.6, 8.0 Hz, 1H,
CH2a–Ar), 2.78 (dd, J = 13.6, 5.5 Hz, 1H, CH2b–Ar), 3.29 (app br
quint, J = 6.2 Hz, 1H, CH–N), 3.80 (s, 3H, OMe), 3.92 (dd, J =
10.9, 6.8 Hz, 1H, CH2a–O), 4.05 (dd, J = 10.9, 4.5 Hz, 1H, CH2b– Ketone 12 was obtained similar to the reported procedure.26
O), 6.86 (d, J = 8.5 Hz, 2H, CHAr), 7.13 (d, J = 8.5 Hz, 2H, CHAr). To the solution of oxime esters 2a+2’a (145 mg, 0.4 mmol) in
3-(4-Methoxyphenyl)-2-oxopropyl pivalate 12 and 3-(4-
methoxyphenyl)-2-oxopropyl pivalate 12’
13C NMR (75 MHz, DEPT, HMBC, CDCl3): δ 27.3 (Me3C), 38.9 THF (4 mL) Fe powder (223 mg, 4 mmol), AcOH (2 drops) and
(Me3C), 39.5 (CH2–Ar), 51.7 (CH–N), 55.3 (OMe), 68.4 (CH2–O), TMSCl (2 drops) were consequently added. The reaction
114.0 (CHAr), 130.0 (CAr), 130.2 (CHAr), 158.3 (CAr–OMe), 178.3 mixture was stirred at r.t. for 0.5 h. Water (4 mL) was added.
The mixture was stirred for additional 15 min, transferred into
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There are no conflicts to declare.
EtOAc (55 mL)/ H2O (15 mL). The organic layer was washed
with NaHCO3 (sat. aq., 50 mL), brine (50 mL), dried (Na2SO4)
and evaporated. The residue was preadsorbed on Celite® and
subjected to column chromatography (eluent: PE/EtOAc, 10:1)
to give 50 mg (47 %) of target ketones 12+12’ (12:12’=11:1) as
colorless oil, that solidifies in a fridge. Rf = 0.47 (PE/EtOAc, 5:1,
anisaldehyde). mp = 29-31 °C (PE). 12: 1H NMR (300 MHz,
CDCl3): δ 1.28 (s, 9H, t-Bu), 3.68 (s, 2H, CH2–Ar), 3.81 (s, 3H,
OMe), 4.69 (s, 2H, CH2–O), 6.89 (d, J = 8.5 Hz, 2H, CHAr), 7.15
(d, J = 8.8 Hz, 2H, CHAr). 13C NMR (75 MHz, DEPT, CDCl3): δ 27.2
(Me3C), 38.7 (Me3C), 45.4 (CH2–Ar), 55.3 (OMe), 67.4 (CH2–O),
114.3 (CHAr), 124.8 (CAr), 130.5 (CAr), 158.9 (CAr–OMe), 177.8
View Article Online
DOI: 10.1039/C9OB01005J
Acknowledgements
This work was supported by the Russian Science Foundation
(grant 17-13-01411). The authors thank Dr. N. G. Kolotyrkina
and Dr. A. O. Chizhov (N. D. Zelinsky Institute of Organic
Chemistry) for registration of HRMS. X-ray diffraction data
were collected with the financial support from Ministry of
Science and Higher Education of the Russian Federation using
the equipment of the Center for molecular composition
studies of INEOS RAS.
1
(COO), 201.7 (C=O). 12’: H NMR (300 MHz, CDCl3): δ 1.30 (s,
9H, t-Bu), 2.12 (s, 3H, Me), 3.83 (s, 3H, OMe), 5.89 (s, 1H, CH–
O), 6.94 (d, J = 8.7 Hz, 2H, CHAr), 7.35 (d, J = 8.7 Hz, 2H, CHAr).
HRMS (ESI): m/z calcd. for [C15H20O4+Na+]: 287.1254, found:
287.1255.
Notes and references
1
Molecular Rearrangements in Organic Synthesis, Ed. C.M.
Rojas; John Wiley and Sons, Inc, 2015.
4-(4-Methoxyphenyl)-2-phenylpyridin-3-yl pivalate 13
2
(a) A. A. Tabolin and S. L. Ioffe, Chem. Rev., 2014, 114, 5426;
(b) I. Nakamura and M. Terada, Tetrahedron Lett., 2019, 60,
689; (c) M. M. A. Pereira and P. P. Santos, Rearrangements of
hydroxylamines, oximes and hydroxamic acids in the book
The chemistry of hydroxylamines, oximes and hydroxamic
acids, Eds Z. Rappoport, J. F. Liebman, John Wiley and Sons:
Chichester, England, 2009; pp 343-498.
Substituted pyridine 13 was obtained similar to the reported
procedure.27 The solution of oxime ester 2h (82.3 mg, 0.26
mmol), p-methoxycinnamaldehyde (63 mg, 0.39 mmol), NEt3
(18 µL, 13 mg, 0.13 mmol) and I2 (33 mg, 0.13 mmol) in
toluene (1.3 mL) was heated at 120 °C (oil bath) for 9 h. The
reaction mixture was transferred into EtOAc (50 mL)/ H2O (20
mL). The organic layer was washed with brine (30 mL), dried
(Na2SO4) and evaporated. Column chromatography (eluent:
PE/EtOAc, 9:1, then 7:1) afforded 43.7 mg (47 %) of target
pyridine 13 as yellow oil. Rf = 0.18 (PE/EtOAc, 5:1, UV). 1H NMR
(300 MHz, COSY, CDCl3): δ 0.93 (s, 9H, t-Bu), 3.86 (s, 3H, OMe),
6.98 (d, J = 8.6 Hz, 2H, CHAr), 7.30 (d, J = 5.0 Hz, 1H, CH(5)),
7.29-7.47 (m, 5H, CHAr and CHPh), 7.67 (d, J = 8.0 Hz, 2H, CHPh),
8.60 (d, J = 5.0 Hz, 1H, CH(6)). 13C NMR (75 MHz, DEPT, HSQC,
HMBC, CDCl3): δ 26.8 (Me3C), 38.7 (Me3C), 55.4 (OMe), 113.8
(CHAr), 124.1 (CH(5)), 127.7 (CAr), 128.0, 128.5, 129.1 and 130.2
(3×CHPh and CHAr), 137.3 (CPh), 142.7 (C(3)), 144.0 (C(4)), 146.9
(CH(6)), 153.7 (C(2)), 159.9 (CAr–OMe), 175.6 (C=O). HRMS
(ESI): m/z calcd. for [C23H23O3+H+]: 362.1751, found: 362.1752.
3
S. Chandrasekhar, The Beckmann and Related Reactions, in
Comprehensive Organic Synthesis II (Second edition), Eds. P.
Knochel, G. A. Molander, Elsevier Ltd, 2014, Vol. 7, pp. 770-
800.
4
5
W. F. Berkowitz, Org. React., 2012, 78, 321.
Selected examples: (a) A. O. Kokuev, Yu. A. Antonova, V. S.
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(a) B. A. Trofimov, A. I. Mikhaleva, E. Yu. Schmidt and L. N.
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Conclusions
In summary, a new tandem double acylation/rearrangement of
nitro compounds was investigated. The overall process
represents the C-H functionalization of β-position of starting
nitro compound with the concomitant conversion of nitro to
oxime moiety. Considering ready availability of starting nitro
compounds by simple means (Henry, Michael reactions) this
allows a quick increase in molecular complexity in a few steps.
The reaction has rather broad substrate scope, proceeds with
high regioselectivity and can be used in asymmetric synthesis.
Based on the obtained data, the mechanism for the
transformation including possible side-reactions was
proposed. Synthetic utility of the obtained α-hydroxy oxime
esters was demonstrated.
8
9
10 (a) C. S. Beshara, A. Hall, R. L. Jenkins, K. L. Jones, T. C. Jones,
N. M. Killeen, P. H. Taylor, S. P. Thomas and N. C. O.
Tomkinson, Org. Lett., 2005, 7, 5729; (b) C. S. Beshara, A.
Hall, R. L. Jenkins, R. T. Parry, S. P. Thomas and N. C. O.
Tomkinson, Chem. Commun., 2005, 1478; (c) D. A. Smithen,
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A. Strelenko and V. A. Tartakovsky, Synthesis, 1998, 181.
12 Selected reviews on the chemistry of aliphatic nitro
compounds: (a) D. Seebach, E. W. Colwin, F. Lehr and T.
Weller, Chimia, 1979, 33, 1; (b) R. Ballini and A. Palmieri,
Adv. Synth. Catal., 2018, 360, 2240; (c) A. Yu. Sukhorukov, A.
Conflicts of interest
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ARTICLE
A. Sukhanova and S. G. Zlotin, Tetrahedorn, 2016, 72, 6191;
(d) S. Z. Zard, Helvetica Chim. Acta, 2012, 95, 1730.
13 About silylation of γ-nitro carbonyl compounds, see: (a) A. A.
Tishkov, A. V. Kozintsev, I. M. Lyapkalo, S.L. Ioffe, V. V.
Kachala, Yu. A. Strelenko and V. A. Tartakovsky, Tetrahedron
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14 The Crystallographic information for compound 2q was
deposited in the Cambridge Crystallographic Data Centre
(CCDC 1906181).
View Article Online
DOI: 10.1039/C9OB01005J
15 Here β-descriptor is used with respect to the position in
starting nitro compound 1. For nitronate 3 it could be
already considered as an α-position.
16 (a) S. L. Ioffe, in the book Nitrile oxides, nitrones, and
nitronates in organic synthesis, 2nd edition, Ed. H. Feuer,
John Wiley and Sons, Inc., Hoboken, New Jersey, 2008, pp.
489–491; (b) V. I. Erashko, S. A. Shevelev, A. A. Fainzil’berg,
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Catal., 2015, 357, 2371.
18 (a) Spectra of crude oximes 2 did not show noticeable
amounts of side products, although in some cases we did
observe green-blue coloration of the reaction mixtures -
evidence for the formation of nitroso compounds. (b) Use of
1 equiv. of PivCl resulted in 22 % yield of 2a and incomplete
conversion (37% recovery) of 1a.
19 About electrophilic activity of nitronates, see: A. A. Tabolin,
A. Yu. Sukhorukov and S. L. Ioffe, Chem. Rec., 2018, 18, 1489.
20 i. e., anti-arrangement within RC(O)O–N=C–CHOC(O)R
moiety.
21 About 13C NMR determination of E,Z-configuration of oxime
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1972, 94, 4897; (b) G. E. Hawkes, K. Herwig and J. D. Roberts,
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Kitamura and K. Narasaka, Chem. Rec., 2002, 2, 268.
25 Ya. A. Naumovich, I. S. Golovanov, A. Yu. Sukhorukov and S.
L. Ioffe, Eur. J. Org. Chem., 2017, 6209.
26 M. Majireck, J. A. Witek and S. M. Weinreb, Tetrahedron
Lett., 2010, 51, 3555.
27 H. Huang, J. Cai, L. Tang, Z. Wang, F. Li and G.-J. Deng, J. Org.
Chem., 2016, 81, 1499.
28 L. Cecchi, F. De Sarlo and F. Machetti, Chem. Eur. J., 2008, 14,
7903.
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R(O)CO
N
NO2
View Article Online
DOI: 10.1039/C9OB01005J
R1
RC(O)Cl
R3
R1
R3

NEt3,
DMAP (10 mol%)

R2
R2
OC(O)R
59-90%
• broad substrate scope
• high regioselectivity
• one-pot
• carbon chain activation
Novel efficient regioselective method for the carbon chain activation of aliphatic nitro
compounds is described using tandem double acylation/[3,3]-rearrangement sequence.