Tandem Deoxygenation/Halogenation of N-Oxides Under Acylation Conditions: Scope and In Situ IR Spectroscopic Study

Article abstract of DOI:10.1002/ejoc.201900131

Acylation of cyclic nitronates with acyl bromides produces 3-bromomethyl-substituted 5,6-dihydro-2H-1,2-oxazines via an unusual multi-stage process involving deoxygenation of N-oxide and the formation of Br₂. Low-temperature in situ ATR FT-IR monitoring and DFT calculations revealed α-halo-substituted N,N-bis(oxy)amines as key intermediates of the process. The developed method was successfully exploited in the stereoselective synthesis of pharmaceutically relevant molecules.

Full text of DOI:10.1002/ejoc.201900131

A Journal of
Accepted Article
Title: Tandem Deoxygenation/Halogenation of N-Oxides under
Acylation Conditions: Scope and In Situ IR Spectroscopic Study
Authors: Roman S. Malykhin, Ivan S. Golovanov, Sema L. Ioffe, and
Alexey Sukhorukov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900131
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10.1002/ejoc.201900131
European Journal of Organic Chemistry
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Tandem Deoxygenation/Halogenation of N-Oxides under
Acylation Conditions: Scope and In Situ IR Spectroscopic Study
Roman S. Malykhin,[a],[b] Ivan S. Golovanov,[a] Sema L. Ioffe,[a] Alexey Yu. Sukhorukov[a],[c],[d],
*
Abstract: Acylation of cyclic nitronates with acyl bromides produces
3-bromomethyl-substituted 5,6-dihydro-2H-1,2-oxazines via an
unusual multi-stage process involving deoxygenation of N-oxide and
the formation of Br2. Low-temperature in situ ATR FT-IR monitoring
Chemical modifications of N-oxides of type 1 are usually
performed via three major routes (Scheme 1): (a) TMSOTf-
mediated nucleophilic addition to C=N bond;[6] (b) [3+2]-dipolar
1d]
cycloaddition;[1a,
(c) transformation into N-siloxyenamines
and
DFT
calculations
revealed
α-halo-substituted
N,N-
followed by Lewis acid-mediated SN’-substitution of TMSO-
group.[7] Recently, we reported a novel functionalization of
bis(oxy)amines as key intermediates of the process. The developed
method was successfully exploited in the stereoselective synthesis
of pharmaceutically relevant molecules.
nitronates
1
exploiting tandem acylation/[3,3]-sigmatropic
rearrangement process upon the action of R1COCl with Et3N
(Scheme 2).[8] As a continuation of these studies, here we report
that acylation of nitronates 1 in the absence of a base follows a
completely different pathway leading to N-acylated bromides 2
via an unusual deoxygenation of the N-oxide moiety.
Introduction
Over the last two decades, cyclic nitronates 1 (1,2-oxazine-N-
oxides and isoxazoline-N-oxides, Scheme 1) have gathered
much attention from organic chemists community.[1] The
availability of these heterocyclic N-oxides together with their
versatile reactivity make them useful intermediates in the
synthesis of stereochemically complex molecules.[2] Numerous
total syntheses of natural alkaloids and pharmaceutically active
molecules exploiting cyclic nitronates 1 have been developed by
Denmark,[1d, 3] our group,[4] and other researchers.[5]
Scheme 2. Modifications of cyclic nitronates 1 via acylation
Results and Discussion
Optimization and substrate scope studies
During our studies on the acylation of model cyclic nitronate 1a
we unexpectedly discovered that its treatment with an excess of
AcBr without Et3N resulted in the formation of primary bromide
2a in 41 % yield (Scheme 3). The yield of 2a was increased up
to 90 %, when AcBr/Ac2O mixture was used as an acetylating
agent.[9] In this reaction, tertiary bromide 3a was detected as an
intermediate, which could be isolated and subjected to acylation
to give 2H-1,2-oxazine 2a (vide infra).
Scheme 1. Synthesis and chemistry of cyclic nitronates 1
[a]
Mr. R. S. Malykhin, Mr. I. S. Golovanov, Prof., Dr. S. L. Ioffe, Dr.,
habil. A. Yu. Sukhorukov, N. D. Zelinsky Institute of Organic
Chemistry, Leninsky prospect, 47, Moscow, Russia, 119991
sukhorukov@ioc.ac.ru, https://twitter.com/SukhorukovAlex
Mr. R. S. Malykhin, Department of Chemistry, M. V. Lomonosov
Moscow State University
Ph
Ph
Br
Ac
CH2Cl2
Br
Ph
N
Br
AcBr
[b]
[c]
[d]
NAc
N
O
O
O
O
Russian Federation, Moscow, Leninskie gory, 1, str. 3, 119991
Dr., habil. A. Yu. Sukhorukov, Higher Chemical College, D.
Mendeleev University of Chemical Technology of Russia
Miusskaya sq., 9, Moscow, Russia, 125047
2a
, 90 %
3a
1a
Br
3 equiv. Ac /Ac2O, CH2Cl2, rt
Dr., habil. A. Yu. Sukhorukov, Plekhanov Russian University
of Economics, Stremyanny per. 36, Moscow, Russia 117997
Scheme 3. Acylation/rearrangement of model nitronate 1a to bromide 2a
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10.1002/ejoc.201900131
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A series of six-membered cyclic nitronates 1 were converted into
bromides 2 in good to high yields upon the action of an excess
of acyl bromide/acyl anhydride system within 3-24 h (procedure i
in Scheme 4). Electron-rich aromatic groups were not well-
tolerated as can be seen from the example of synthesis of
product 2h. A complex mixture of indecipherable products was
obtained in this experiment.
Scheme 5. Acylation of isoxazoline-N-oxide 1i
Mechanism studies
The multi-stage mechanism involved in the acylation of
nitronates 1 was a subject of special studies. When model 1,2-
oxazine-N-oxide 1a was treated with 1 equivalent of AcBr,
several products were detected after 30 minutes, namely tertiary
and primary bromides 3a and 4a, 1,2-oxazine 6a, and acetate
7a (Scheme 6). Remarkably, product 6a results from
deoxygenation of initial nitronate 1a. Moreover, a temporary
appearance of brown color was observed upon mixing nitronate
1a with AcBr indicating the formation of molecular bromine. This
was unambiguously proved by the interception of Br2 with
cyclohexene to give trans-1,2-dibromocyclohexane. In the case
of isoxazoline-N-oxide 1i, the formation and consumption of
bromine (λmax 411 nm) along with the formation of
deoxygenation product 6i could be followed directly by UV-Vis
spectroscopy (see Supporting information). In the reaction of
nitronate 1a with benzoyl iodide, the formation of 1,2-oxazine 6a
(43 %) and molecular iodine occurred (λmax 504 nm, spectral
yield ca. 70%) along with a complex mixture of other products.
Ph
Br
1 equiv. Ac
CH2Cl2, rt
30 min
Ph
Br
Ph
N
Scheme 4. One-pot synthesis of 3-bromomethyl-substituted 5,6-dihydro-2H-
1,2-oxazines 2 from nitronates 1
N
N
O
O
O
O
1a
3a
, 37 %
6a
, 27 %
Br2
Different acyl bromides were involved in the reaction with
nitronate 1a to give corresponding products 2a-f. In case when
acid anhydride was not readily available, acylation was
conducted with acyl bromide only (procedure ii in Scheme 4).
Generally, the yields were lower with more bulky acyl bromides,
which are likely to be less reactive in the acylation/[1,3]-
rearrangement of bromide 3a. Reaction of 1a with pivaloyl
bromide produced only tertiary bromide 3a (64 %), which was
not further pivaloylated. Products 2a,c,f could be prepared by
treatment of 3a with corresponding acyl bromides and even
chlorides, yet the overall yields were lower compared to the one-
pot procedure.
In contrast to six-membered cyclic nitronates, five-membered
isoxazoline-N-oxide 1i did not produce corresponding N-
acylated 2,5-dihydroisoxazole under these conditions (Scheme
5). Instead, a mixture of primary bromide 4i and isoxazole 5i
(likely resulting from the elimination of HBr from the
corresponding 4-bromoisoxazoline) was obtained. Treatment of
isolated 5i with AcBr/Ac2O did not result in any N-acylation
product that can be explained by a lower nucleophilicity of the
nitrogen atom in isoxazolines as compared to 1,2-oxazines.
Ph
AcO
Ph
N
Br
N
O
Br
Br
O
4a
, 4 %
7a
, 7 %
Scheme 6. Deoxygenation of model nitronate 1a upon acylation with AcBr
More strikingly, reaction with acetyl chloride afforded a mixture
of tertiary chloride 8a, 1,2-oxazine 6a, the product of its N-
acylation 9a and acetate 7a (Scheme 7). As an indication of the
generation of molecular chlorine, isomeric dichlorocyclohexenes
were formed, when reaction was carried out in the presence of
1,3-cyclohexadiene.
The initial nitronate 1a does not oxidize halide anions as was
demonstrated by its reaction with Bu4NX. Therefore, it is likely,
that dihalogen is produced from some reactive species
generated upon acylation of nitronates 1.
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10.1002/ejoc.201900131
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methods. On the other hand, computations support path 2 with a
reasonable calculated activation barrier of +19.4 kcal/mol (see
Supporting information for the full energy profile).
Scheme 7. Acylation of model nitronate 1a with AcCl
In order to identify any intermediates, low temperature in situ
ATR FT-IR monitoring of the acylation of nitronate 1a reaction
was performed (Figure 1).[10] At -65 °C, the formation of an
intermediate (I-1) together with the consumption of both AcCl
and nitronate was observed (ca. half of starting materials
reacted before the equilibrium was established, Figure 1A). The
position of ν(C=O) band at 1787 cm-1 suggests that acetyl is
bounded to an electronwithdrawing group, that is consistent with
either N-oxy,N-acyloxyiminium salt A or the covalently bonded
(A)
nitrosoacetal
B
(Scheme 8).[11] No increase of electrical
conductivity was observed in the course of intermediate I-1
formation both in CH2Cl2 or CH2Cl2/CH3CN (4 : 1) medium
suggesting that I-1 most likely has the covalent structure B.
Warming up the reaction mixture resulted in a slow formation of
products 6a and 7a (noticeable at -40 °C) along with the
consumption of residual AcCl and nitronate 1a (Figure 1B). At
-15 °C, a fast decay of intermediate I-1 to the reduced product
6a and AcOH was observed.
(B)
Figure 1. Low-temperature ATR FT-IR monitoring of acylation of nitronate 1a.
Conditions: 1a (1 equiv.), AcCl (1 equiv.), 1,3-cyclohexadiene (1 equiv.),
CH2Cl2. (A) Monitoring of the reaction progress at -65 °C. (B) Evolution of
intermediate I-1 upon warming up the reaction mixture
Ionic and covalent intermediates A and B can co-exist in
solution, and both of them can, in principle, undergo reduction
with a halide anion (Scheme 8). Thus, a single electron transfer
from X- to the cation A would lead to radical C, which can suffer
the N−O bond cleavage to give oxime derivative 6 and the
acyloxy radical (path 1). However, the calculated activation
barrier for an outer-shell electron transfer from Br- to A is too
high (+41.1 kcal/mol) for this process to take place with a
reasonable rate (calculated at DFT-D3 m062x aug-cc-pVTZ,
SMD (CH2Cl2) level of theory). Also, no products arising from
fragmentation of acyloxy radicals were detected by GC-MS.
Intermediate B can transform into the reduced product 6 via two
plausible pathways (Scheme 8). First is the attack of X- on the
halogen atom in B resulting in elimination of dihalogen and the
acetate anion (path 2).[12] Another possible mechanism is a
retro-ene reaction leading to product 6 and acyl hypohalide (path
3). In the experiment with cyclohexene as an intercepting agent
(Scheme 6), trace amounts of 2-bromocyclohexyl acetate
(formal product of AcOBr addition to the C,C-double bond) were
detected by GC-MS. However, DFT calculations of the path 3
demonstrate that the elimination of acyl hypobromite is an
endothermic process (+5.6 kcal/mol). Also, we were unable to
locate the transition state for this pericyclic process using DFT
Scheme 8. Plausible mechanisms for deoxygenation of nitronates 1 upon
acylation with acyl halides
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10.1002/ejoc.201900131
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Scheme 9. Plausible mechanisms for the acylation of nitronate 1a to bromide 2a
The deoxygenated product 6a is then acylated with AcBr to 2H-
1,2-oxazine 9a, which reacts with Br2 to give transient enamide
E (Scheme 9, route 1). The latter suffers a 1,3-halogen migration
to afford final primary bromide 2a. This mechanism was
confirmed experimentally by the fast conversion of isolated
intermediates 6a and 9a into bromide 2a upon the action of Br2
in the presence of AcBr/Ac2O system (spectral yield of 2a: 70 %
and 90 % after 2 h, respectively).
However, the observed formation of non-acylated bromides 3a
and 4a as intermediates cannot be explained by this mechanism.
In the absence of AcBr, reaction of 1,2-oxazine 6a with Br2 to
give 3a and 4a was found to be slow (ca. 50 % conversion after
3 h, 3a/4a = 4 : 1). We, therefore, suggested an alternative
mechanism for the formation of bromide 3a, which involves
deprotonation of intermediate A to give unstable enamine D
followed by SN’ substitution of acetate for the bromide anion
(Scheme 9, route 2). The generation of D is confirmed by the
isolation of product 7a resulting from its [3,3]-sigmatropic
rearrangement.[8] Conversion of tertiary bromide 3a into final
product 2a most likely occurs through acylation to enamide E
and subsequent 1,3-halogen migration (Scheme 9, route 1).[13]
In the acylation of bromide 3a with acetyl chloride, only trace
amounts of primary chloride 10a were formed indicating that the
migration of bromine in E is an intramolecular process (Scheme
10).[14]
Thus, our studies revealed that acylation of nitronates 1 into
bromides
2 proceeds through a complicated multi-stage
mechanism, which involves several competitive pathways
leading to the final product.
Synthetic utility of 5,6-dihydro-2H-1,2-oxazines 2
Bromomethyl-substituted 5,6-dihydro-2H-1,2-oxazines 2 can be
utilized as useful precursors to various pharmaceutically relevant
molecules (Scheme 11). Thus, nucleophilic substitution of
bromine in 2a for phtalimide moiety provided a nuclear factor
kappa B (NF-κB) inhibitor API,[15] which exhibits high potency
against inflammatory bowel disease in vivo and against colon
cancer in vitro. This synthesis is more efficient and
straightforward (2 steps from 1a, 75 % yield) as compared to the
previous one (3 steps from 1a, 52 % yield[16]), and it allows the
preparation of API on multi-grams scale.
Bromides of type 2 were also exploited as precursors of
derivatives of non-natural amino acids as shown in Scheme 11.
Substitution of bromine in 2 for the malonate anion afforded
products 11 in excellent yields. Same reaction with bromide 2c
bearing a chloroacetyl group produced fused bicyclic derivative
12. Hydrogenation of 2H-1,2-oxazines 11h,l,m over Pd-C gave
saturated 1,2-oxazines 13 selectively as all-cis-isomers. N−O
bond in oxazines 13 was surprisingly resistant toward further
catalytic hydrogenation or action of strong reducing agents
(Zn/AcOH, Na/Hg, Mo(CO)6, TiCl3, TiCl3/NaBH4). However, the
open-chain γ-amino acid derivative 14a was prepared by an
inverted sequence of bonds reduction in 11a: firstly the cleavage
of N−O bond in 11a was accomplished with VCl3/Zn system
followed by stereoselective hydrogenation of the C=C bond in
the resulting enamine on the second stage. Thus, depending on
the reagents used, 2H-1,2-oxazines 11 can serve as precursors
to either open-chain or cyclic γ-amino acid derivatives[17] bearing
up to four contiguous stereocenters.
Scheme 10. Acylation of tertiary bromide 3a with AcCl
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10.1002/ejoc.201900131
European Journal of Organic Chemistry
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G30-150/50 probe with PIR 900/1000 fiber. Electrical conductivity was
measured on a conductometer with a platinum 2-plate conductivity probe
InLab720. Quantum-chemical calculations were performed with the
Gaussian 16 Rev A.03 program (for details see Supporting information).
Column chromatography was performed using Kieselgel 40-60 µm 60A.
Analytical thin-layer chromatography was performed on silica gel plates
with QF-254. Visualization was accomplished with UV light and or
solution of anisaldehyde/H2SO4 in ethanol. AcCl, AcBr, CH2Cl2 and THF
were distilled from CaH2; DMF was distilled from CaH2 under reduced
pressure. Hexane, pentane, diethyl ether, methyl tert-butyl ether,
methanol and ethyl acetate were distilled without drying agents. Ac2O,
EtCOBr, (EtCO)2O, HBr (48
%
in water), cyclohexene, 1,3-
t
cyclohexadiene, dimethyl malonate, potassium phtalimide, BuOK, NaH
(60 % in mineral oil), 5%-Pd/C, zinc dust, VCl3 were commercial grade
and were used as received. Acyl bromides,[18] benzoyl iodide,[19] were
prepared according to previously published protocols. Previously
described racemic nitronates 1 were prepared according to known
procedures (see Supporting information for details).
General procedure for the acylation of nitronates 1 to N-acylated
bromides 2 (procedures i and ii). To a stirred solution of nitronate (1
mmol) (with 3 mmol of carboxylic acid anhydride for procedure i) in
CH2Cl2 (4.5 mL) was added acyl bromide (3 mmol) at rt. In most cases,
an instantaneous appearance of dark red color of Br2 was observed. The
mixture was maintained at rt for time indicated in Scheme 4 and then
transferred into a mixture of ethyl acetate (25 mL) and saturated aqueous
solution of K2CO3 (25 mL). Aqueous phase was back-extracted 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.
Scheme 11. Synthetic utility of 5,6-dihydro-2H-1,2-oxazines 2 (a R = Me, R1
=
Ph, R2 = H, R3,R4 = Me; c R = CH2Cl, R1 = Ph, R2 = H, R3,R4 = Me; h R = Me,
R1 = 4-MeOC6H4-, R2 = H; R3,R4 = Me; l R = Me, R1 = Ph, R2-R3 = -(CH2)3-, R4
= H; m R = Me, R1 = Ph, R2-R3 = -(CH2)4-, R4 = H)
1-(3-(Bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-
oxazin-2-yl)ethan-1-one (2a). Prepared according to procedure i from
438 mg (2 mmol) of nitronate 1a, reaction time – 3 h. Yield: 581 mg
(90 %). Oil. NMR spectra are in accordance with literature data.[16]
1-(3-(Bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-
Conclusions
oxazin-2-yl)propan-1-one (2b). Prepared according to procedure i from
109 mg (0.5 mmol) of nitronate 1a, reaction time – 24 h. Yield: 103 mg
(61 %). Mp = 46 – 49 °С (hexane-Et2O). Rf = 0.41 (AcOEt/hexane = 1 : 3).
1H NMR (300 MHz, Chloroform-d) δ 7.50 – 7.23 (m, 5H), 4.68 (s, 2H),
2.67 (q, J = 7.5 Hz, 2H), 2.40 (s, 2H), 1.39 (s, 6H), 1.22 (t, J = 7.5 Hz,
3H). 13C NMR (75 MHz, JMOD, CDCl3) δ 173.7 (C), 138.5 (C), 132.1 (C),
128.8 (2 CH), 128.1 (2 CH), 127.9 (CH), 125.9 (C), 79.5 (C), 43.3 (CH2),
28.5 (CH2), 27.4 (CH2), 25.7 (2 CH3), 8.9 (CH3). ESI-HRMS m/z: [M+H]+
In conclusion, we have demonstrated that acylation of cyclic
nitronates with acyl bromides in the absence of a base produces
3-bromomethyl-substituted
5,6-dihydro-2H-1,2-oxazines.
Mechanism studies revealed that this transformation involves
deoxygenation of the N-oxide moiety with the formation of Br2,
followed by bromination and allylic rearrengement. The
developed method was successfully exploited to access halo-
substituted oxime and N-oxyenamide derivatives, which are
useful building blocks in the synthesis of pharmaceutically
relevant molecules.
+
Calcd for C16H21BrNO2 338.0750 and 340.0730; Found 338.0749 and
340.0728.
1-(3-(Bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-
oxazin-2-yl)-2-chloroethanone (2c). Prepared according to procedure ii
from 219 mg (1.0 mmol) of nitronate 1a, reaction time – 24 h. Yield: 184
mg (52 %). Mp = 106 – 109 °C. Rf = 0.33 (AcOEt/hexane = 1 : 3). 1H
NMR (300 MHz, Chloroform-d) δ 7.50 – 7.23 (m, 5H), 4.65 (s, 2H), 4.48
(s, 2H), 2.45 (s, 2H), 1.43 (s, 6H). 13C NMR (75 MHz, DEPT135, CDCl3)
δ 164.8 (C), 137.8 (C), 131.3 (C), 128.8 (2 CH), 128.2 (CH), 127.9 (2 CH),
126.9 (C), 80.2 (C), 43.0 (CH2), 42.3 (CH2), 27.5 (CH2), 25.6 (2 CH3).
Anal. Calcd for C15H17BrClNO2: C, 50.23; H, 4.78; N, 3.91. Found: C,
50.23; H, 4.55; N, 3.85.
Experimental section
All reactions were carried out in oven-dried (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
time-of-flight (TOF) detector. GC-MS was performed with the DB-1MS
column 122-0132. Low-temperature FT-IR monitoring was conducted on
an infrared spectrometer equipped with MCT detector and ATR-P-Ge-
2-Bromo-1-(3-(bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-
1,2-oxazin-2-yl)ethanone (2d). Prepared according to procedure ii from
219 mg (1.0 mmol) of nitronate 1a, reaction time – 24 h. Yield: 204 mg
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10.1002/ejoc.201900131
European Journal of Organic Chemistry
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(51 %). Mp = 98 – 101 °С (hexane-Et2O). Rf = 0.62 (AcOEt/hexane = 1 :
1). 1H NMR (300 MHz, Chloroform-d) δ 7.48 – 7.20 (m, 5H), 4.63 (s, 2H),
4.24 (s, 2H), 2.45 (s, 2H), 1.43 (s, 6H). 13C NMR (75 MHz, DEPT135,
CDCl3) δ 165.1 (C), 137.8 (C), 131.4 (C), 128.8 (2 CH), 128.2 (CH),
(0.64 mmol) of nitronate 1e, reaction time – 3 h. Yield: 127 mg (76 %).
Mp = 82 – 84 °С (hexane-Et2O). NMR spectra are in accordance with
literature data.[16]
127.9 (2 CH), 127.3 (С), 80.3 (С), 43.1 (CH2), 27.6 (CH2), 27.5 (СН2),
1-(3-(Bromomethyl)-4,6,6-trimethyl-5,6-dihydro-2H-1,2-oxazin-2-
yl)propan-1-one (2k). Prepared according to procedure i from 157 mg
(1.0 mmol) of nitronate 1e, reaction time – 24 h. Yield: 164 mg (60 %). Oil.
Rf = 0.39 (AcOEt/hexane = 1 : 3). 1H NMR (300 MHz, Chloroform-d) δ
4.73 (s, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.09 (s, 2H), 1.79 (s, 3H), 1.27 (s,
6H), 1.15 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, DEPT135, CDCl3) δ
173.5 (C), 130.3 (C), 122.3 (C), 79.4 (C), 42.7 (CH2), 27.0 (CH2), 26.4
(CH2), 25.7 (2 CH3), 17.5 (CH3), 8.9 (CH3). ESI-HRMS m/z: [M+H]+ Calcd
+
25.7 (2 CH3). ESI-HRMS m/z: [M+H]+ Calcd for C15H18NO2Br2
:
401.9706; Found 401.9699.
2-Bromo-1-(3-(bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-
1,2-oxazin-2-yl)butan-1-one (2e). Prepared according to procedure ii
from 55 mg (0.25 mmol) of nitronate 1a, reaction time – 24 h. After
column chromatography the product was crystallized from hexane-Et2O
mixture at -20 °C. Yield: 41 mg (38 %). Slightly pink crystals. Mp = 112 –
116 °С (hexane-Et2O) with decomposition. Rf = 0.7 (AcOEt/hexane = 1 :
1). 1H NMR (250 MHz, Chloroform-d) δ 7.46 – 7.17 (m, 5H), 4.99 (t, J =
7.2 Hz, 1H), 4.78 (d, J = 10.5 Hz, 1H), 4.53 (d, J = 10.5 Hz, 1H), 2.45 (s,
2H), 2.32 – 2.03 (m, 2H), 1.48 (s, 3H), 1.39 (s, 3H), 1.12 (t, J = 6.8 Hz,
3H). 13C NMR (63 MHz, DEPT135, CDCl3) δ 168.1 (C), 138.1 (C), 131.6
(C), 128.8 (2 CH), 128.1 (CH), 127.9 (2 CH), 127.7 (C), 80.4 (C), 46.0
(CH), 43.2 (CH2), 28.8 (CH2), 27.7 (CH2), 26.1 and 25.6 (2 CH3), 12.3
(CH3). ESI-HRMS m/z: [M+H]+ Calcd for C17H22Br2NO2+ 431.9992; Found
431.9983.
+
for C11H19BrNO2 276.0594 and 278.0574; Found 276.0592 and
278.0570.
Rel-1-((4aR*,7aR*)-3-(bromomethyl)-4-phenyl-5,6,7,7a-
tetrahydrocyclopenta[e][1,2]oxazin-2(4aH)-yl)ethanone (2l). Prepared
according to procedure i from 239 mg (1.0 mmol) of nitronate 1f, reaction
time – 24 h. Yield: 235 mg (70 %). Oil. NMR spectra are in accordance
with literature data.[16]
Rel-1-((4aR*,8aR*)-3-(bromomethyl)-4-phenyl-4a,5,6,7,8,8a-
hexahydro-2H-benzo[e][1,2]oxazin-2-yl)ethanone (2m). Prepared
according to procedure i from 245 mg (1.0 mmol) of nitronate 1g,
reaction time – 24 h. Yield: 252 mg (72 %). Oil. NMR spectra are in
accordance with literature data.[16]
1-(3-(Bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-
oxazin-2-yl)-2-phenylethan-1-one (2f). Prepared according to
procedure ii from 219 mg (1.0 mmol) of nitronate 1a, reaction time – 24 h.
After column chromatography the product was crystallized from hexane-
Et2O mixture at -20 °C. Yield: 149 mg (37 %). White solid. Mp = 89 – 94
°С (hexane-Et2O) with decomposition. Rf = 0.41 (AcOEt/hexane = 1 : 3).
1H NMR (300 MHz, Chloroform-d) δ 7.47 – 7.25 (m, 10H), 4.68 (s, 2H),
3.99 (s, 2H), 2.42 (s, 2H), 1.38 (s, 6H). 13C NMR (75 MHz, DEPT135,
CDCl3) δ 170.5 (C), 138.3 (C), 134.8 (C), 131.8 (C), 129.6 (2 CH), 128.7
(2 CH), 128.5 (2 CH), 128.0 (2 CH), 127.9 (CH), 126.9 (CH), 126.3 (C),
79.8 (C), 43.3 (CH2), 41.2 (CH2), 28.1 (CH2), 25.6 (CH3). ESI-HRMS m/z:
Rel-1-((4aR*,5R*,8S*,8aR*)-3-(bromomethyl)-4-phenyl-4a,5,6,7,8,8a-
hexahydro-2H-5,8-methanobenzo[e][1,2]oxazin-2-yl)ethan-1-one (2n).
Prepared according to procedure i from 257 mg (1.0 mmol) of nitronate
1h, reaction time – 24 h. Yield: 264 mg (73 %). Mp = 127 – 130 °С
(hexane-Et2O) with decomposition. NMR spectra are in accordance with
literature data.[16]
+
[M+H]+ Calcd for C21H23BrNO2 400.0907 and 402.0887; Found
4-Bromo-3,6,6-trimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazine
(3a).
400.0899 and 402.0881.
To a stirred solution of nitronate 1a (219 mg, 1.0 mmol) in CH2Cl2 (4.5
mL) was added pivaloyl bromide (500 mg, 3.0 mmol) at rt. An
instantaneous appearance of dark brown color of Br2 and warming-up of
the reaction mixture was observed. The mixture was maintained at rt for
24 h and then transferred into a mixture of ethyl acetate (50 mL) and
saturated aqueous solution of K2CO3 (50 mL). Aqueous phase was back-
extracted with ethyl acetate (50 mL). Combined organic layers were
washed with water (50 mL), brine (50 mL), dried (Na2SO4) and
evaporated. The residue was subjected to column chromatography on
silica gel to give 181 mg (64 %) of 3a, further elution provided also 56 mg
(28 %) of 6a. Oil. Rf = 0.56 (AcOEt/hexane = 1 : 3). 1H NMR (300 MHz,
Chloroform-d) δ 7.49 (d, J = 7.5 Hz, 2H), 7.41-7.25 (m, 3H), 2.82 (d, J =
15.8 Hz, 1H), 2.55 (d, J = 15.8 Hz, 1H), 2.11 (s, 3H), 1.51 and 1.23 (2 s,
3Н and 3Н). 13C NMR (75 MHz, CDCl3) δ 155.4 (C), 142.1 (C), 128.7 (2
CH), 128.1 (CH), 126.9 (2 CH), 74.2 (C), 58.9 (CH), 53.1 (CH2), 28.6
(CH3), 24.9 (CH3) and 19.6 (CH3). ESI-HRMS m/z: [M+H]+ Calcd for
C13H17NOBr+ 282.0494 and 284.0468; Found 282.0488 and 284.0478.
1-(3-(Bromomethyl)-4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
1,2-oxazin-2-yl)ethan-1-one (2g). Prepared according to procedure i
from 253 mg (1 mmol) of nitronate 1b, reaction time – 3 h. Yield: 300 mg
(84 %). Mp = 135 – 138 °С (hexane-Et2O). NMR spectra are in
accordance with literature data.[16]
1-(3-(Bromomethyl)-4-(4-methoxyphenyl)-6,6-dimethyl-5,6-dihydro-
2H-1,2-oxazin-2-yl)ethan-1-one (2h). Prepared according to procedure i
from 75 mg (0.3 mmol) of nitronate 1c, reaction time – 24 h. Yield: 20 mg
(19 %). Oil. NMR spectra are in accordance with literature data.[16]
2-Acetyl-3-(bromomethyl)-6,6-dimethyl-5,6-dihydro-2H-1,2-oxazin-4-
yl benzoate (2i). Prepared according to procedure i from 100 mg (0.38
mmol) of nitronate 1d with an exception that 6 equivalents of Ac2O and 6
equivalents of AcBr were used, reaction time – 24 h. Yield: 109 mg
(78 %). Oil. Rf = 0.26 (AcOEt/hexane = 1 : 3). 1H NMR (300 MHz,
Chloroform-d) δ 8.12 (d, J = 7.7 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.51
(dd, J = 7.7, 7.6 Hz, 2H), 4.71 (s, 2H), 2.54 (s, 2H), 2.28 (s, 3H), 1.42 (s,
6H). 13C NMR (75 MHz, DEPT135, CDCl3) δ 170.1 (C), 164.1 (C), 137.3
(C), 134.1 (CH), 130.2 (2 CH), 128.8 (2 CH), 128.5 (C), 127.9 (C), 79.8
(C), 38.7 (CH2), 25.5 (2 CH3), 23.1 (CH2), 22.2 (CH3). ESI-HRMS m/z:
3,6,6-Trimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazine (6a). To a stirred
solution of nitronate 1a (100 mg, 0.46 mmol) in CH2Cl2 (1 mL) was added
a solution of benzoyl iodide (215 mg, 0.93 mmol) in CH2Cl2 (1 mL) at rt.
An instantaneous appearance of dark brown color of I2 and warming-up
of the reaction mixture was observed. The mixture was maintained at rt
for 3 h and then transferred into a mixture of ethyl acetate (50 mL) and
aqueous solution of Na2S2O3 (50 mL). Aqueous phase was back-
extracted with ethyl acetate (25 mL). Combined organic layers were
washed with saturated aqueous solution of K2CO3 (50 mL), water (50
mL), brine (50 mL), dried (Na2SO4) and evaporated. The residue was
[M+H]+ Calcd for C16H19BrNO4 368.0492 and 370.0472; Found
+
368.0490 and 370.0479.
1-(3-(Bromomethyl)-4,6,6-trimethyl-5,6-dihydro-2H-1,2-oxazin-2-
yl)ethan-1-one (2j). Prepared according to procedure i from 100 mg
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900131
European Journal of Organic Chemistry
FULL PAPER
subjected to column chromatography on silica gel to give 40 mg (43 %)
of 6a as a yellowish oil. Rf = 0.28 (AcOEt/hexane = 1 : 3). 1H NMR (300
MHz, Chloroform-d) δ 7.37-7.23 (m, 3H), 7.17 (d, J = 7.5 Hz, 2H), 3.31
(dd, J = 11.8, 7.9 Hz, 1H), 2.04 (dd, J = 13.5, 7.9 Hz, 1H), 1.90 (dd, J =
13.5, 11.8 Hz, 1H), 1.70 (s, 3H), 1.33 (s, 3H), 1.28 (s, 3H). 13C NMR (75
MHz, DEPT135, CDCl3) δ 155.7 (C), 140.8 (C), 129.0 (2 CH), 128.2 (2
CH), 127.1 (CH), 73.6 (C), 41.2 (CH2), 40.8 (CH), 28.6 (CH3), 22.8 (CH3),
20.00 (CH3). FT-IR (KBr): 2975, 2926, 1663, 1493, 1454, 1370, 1271,
1145, 1127, 924, 857, 779, 758, 703, 619 cm-1. ESI-HRMS m/z: [M+H]+
Calcd for C13H18NO+ 204.1383; Found 204.1389.
Reaction of nitronate 1a with 1 equivalent of acetyl bromide. To a
stirred solution of nitronate 1a (109 mg, 0.5 mmol) in CH2Cl2 (2.3 mL)
was added acetyl bromide (0.037 mL, 0.5 mmol) at rt. An instantaneous
appearance of dark red color of Br2 was observed. The mixture was
maintained at rt for 20 minutes and then transferred into a mixture of
ethyl acetate (25 mL) and saturated aqueous solution of K2CO3 (25 mL).
Aqueous phase was back-extracted with ethyl acetate (25 mL).
Combined organic layers were washed with water (20 mL), brine (20 mL),
dried (Na2SO4) and evaporated. Analysis of the residue by 1H NMR with
internal standard revealed the presence of tertiary bromide 3a (37 %),
primary bromide 4a[20] (4 %), 1,2-oxazine 6a (27 %) and acetate 7a[8]
(7 %).
Acylation of nitronate 1i. To a stirred solution of nitronate 1i (249 mg,
1.0 mmol) in CH2Cl2 (4.6 mL) was added acetic anhydride (0.283 mL, 3.0
mmol) followed by acetyl bromide (0.222 mL, 3.0 mmol) at rt. An
instantaneous appearance of dark red color of Br2 was observed. The
mixture was maintained at rt for 48 h (color almost disappeared), and
then transferred into a mixture of ethyl acetate (100 mL) and saturated
aqueous solution of K2CO3 (100 mL). Aqueous phase was back-
extracted with ethyl acetate (50 mL). Combined organic layers were
washed with water (100 mL), brine (100 mL), dried (Na2SO4) and
evaporated. The residue was subjected to a column chromatography on
silica gel to give 280 mg of chromatographically inseparable mixture of
bromide 4i (58 %) and isoxazole 5i (40 %) as colorless oil. Isoxazole 5i
was separated from bromide 4i by crystallization from hexane-Et2O
mixture.
Interception of molecular bromine in the acylation of nitronate 1a.
To a stirred solution of nitronate 1a (219 mg, 1.0 mmol) and cyclohexene
(0.5 mL, 5.0 mmol) in CH2Cl2 (4.6 mL) was added acetyl bromide (0.148
mL, 2.0 mmol) at rt. The mixture was maintained at rt for 30 minutes and
then transferred into a mixture of ethyl acetate (50 mL) and saturated
aqueous solution of K2CO3 (50 mL). Aqueous phase was back-extracted
with ethyl acetate (50 mL). Combined organic layers were washed with
water (40 mL), brine (40 mL), dried (Na2SO4) and evaporated at 300 Torr.
The residue was subjected to a column chromatography on silica gel,
which provided 92 mg (38 % based on nitronate 1a) of trans-1,2-
dibromocyclohexane (colorless liquid, NMR and MS data are in
agreement with literature data.[21]). In other fractions, mixtures of
products 2a (7 %), 6a (32 %), 7a (19 %), 9a (13 %) and 3,6,6-trimethyl-4-
phenyl-6H-1,2-oxazine[8] (11 %) were isolated.
Ethyl rel-(4S*,5S*)-3-(bromomethyl)-4-phenyl-4,5-dihydroisoxazole-
5-carboxylate (4i). Oil. Rf = 0.43 (AcOEt/hexane = 1 : 3). 1H NMR (300
MHz, Chloroform-d) δ 7.47 – 7.33 (m, 3H), 7.24 (d, J = 8.2 Hz, 2H), 5.00
(d, J = 5.8 Hz, 1H), 4.86 (d, J = 5.8 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.24
(d, J = 11.1 Hz, 1H), 3.69 (d, J = 11.1 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, DEPT135, CDCl3) δ 169.0 (C), 157.2 (C), 136.1 (C),
129.6 (2 CH), 128.7 (CH), 127.6 (2 CH), 86.5 (CH), 62.2 (CH2), 57.6 (CH),
1-(3,6,6-Trimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-2-yl)ethan-1-
one (9a). Oil. Rf = 0.38 (AcOEt/hexane = 1 : 3). 1H NMR (300 MHz,
HSQC, HMBC, Chloroform-d) δ 7.35 (dd, J = 7.3, 7.1 Hz, 2H, m-C6H5),
7.28 (m, 1H, p-C6H5), 7.21 (d, J = 7.1 Hz, 2H, m-C6H5), 2.37 (s, 2H, CH2),
2.26 (s, 3H, CH3C=O), 2.15 (s, 3H, CH3C=C), 1.38 (s, 6H, 2 CH3). 13C
NMR (75 MHz, HSQC, HMBC, DEPT135, CDCl3) δ 170.0 (C=O), 140.2
(i-C6H5), 130.9 (C=C-N), 128.7 (o-C6H5), 128.3 (m-C6H5), 127.0 (p-C6H5),
120.0 (C=C-N), 79.0 (C-O), 42.3 (CH2), 25.6 (2 CH3), 22.5 (CH3C=O),
17.6 (CH3C=C). FT-IR (KBr): 2975, 2930, 2856, 1677, 1442, 1378, 1344,
1291, 1267, 1145, 868, 764, 701, 619 cm-1. ESI-HRMS m/z: [M+H]+
Calcd for C15H20NO2+ 246.1489; Found 246.1491.
+
21.3 (CH2), 14.1 (CH3). ESI-HRMS m/z: [M+H]+ Calcd for C13H15BrNO3
312.0230 and 314.0210; Found 312.0229 and 314.0210.
Ethyl 3-methyl-4-phenylisoxazole-5-carboxylate (5i). White crystals.
Mp = 68 – 71 °C (hexane-Et2O). Rf = 0.43 (AcOEt/hexane = 1 : 3). 1H
NMR (300 MHz, Chloroform-d) δ 7.48 – 7.33 (m, 5H, C6H5), 4.32 (q, J =
7.2 Hz, 2H, CH2O), 2.29 (s, 3H, CH3), 1.28 (t, J = 7.2 Hz, 3H, CH3CH2).
13C NMR (75 MHz, DEPT135, HMBC, CDCl3) δ 160.4 (C=N), 157.3
(C=O), 155.7 (C), 154.6 (C), 129.7, 128.7 and 128.3 (o,m,p-C6H5), 125.2
(i-C6H5), 61.9 (CH2), 13.9 (CH2CH3), 10.6 (CH3). ESI-HRMS m/z: [M+H]+
Calcd for C13H14NO3+ 232.0968; Found 232.0976.
Interception of molecular chlorine in the acylation of nitronate 1a.
To a stirred solution of nitronate 1a (249 mg, 1.14 mmol) and 1,3-
cyclohexadiene (0.54 mL, 5.7 mmol) in CH2Cl2 (5.2 mL) was added
acetyl chloride (0.16 mL, 2.28 mmol) at rt. The mixture was maintained at
rt for 30 minutes and then transferred into a mixture of methyl tert-butyl
ether (50 mL) and saturated aqueous solution of K2CO3 (50 mL).
Aqueous phase was back-extracted with methyl tert-butyl ether (50 mL).
Combined organic layers were washed with water (40 mL), brine (40 mL),
dried (Na2SO4) and evaporated at 300 Torr. The residue was subjected
to a column chromatography on silica gel. Elution with hexane provided
12 mg (7% based on 1a) of a mixture of cis/trans isomers of 3,6-
dichlorocyclohex-1-ene and 3,4-dichlorocyclohex-1-ene (liquid, NMR and
GC-MS data are in agreement with literature data.[22]). Further elution
with hexane/AcOEt mixtures (20 : 1 → 10 : 1 → 5 : 1) provided 80 mg
(30 %) of tertiary chloride 8a,[8] 42 mg (15 %) of N-acylated derivative 9a,
66 mg (22 %) of acetate 7a, and 35 mg (15%) of 1,2-oxazine 6a.
Ethyl
rel-(4S*,5S*)-3-methyl-4-phenyl-4,5-dihydroisoxazole-5-
carboxylate (6i). To a stirred solution of nitronate 1i (125 mg, 0.5 mmol)
in CH2Cl2 (2.3 mL) at -25 oC was added acetic anhydride (0.141 mL, 1.5
mmol) followed by acetyl bromide (0.111 mL, 1.5 mmol). After keeping
for 20 min at this temperature, the reaction mixture was transferred into a
mixture of ethyl acetate (25 mL) and saturated aqueous solution of
K2CO3 (25 mL). Aqueous phase was back-extracted 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 87 mg (75 %)
of isoxazoline 6i as white solid. Mp = 69 – 73 °С (MeOH). Rf = 0.31
(AcOEt/hexane = 1 : 3). 1H NMR (300 MHz, Chloroform-d) δ 7.46 – 7.30
(m, 3H), 7.23 (d, J = 7.8 Hz, 2H), 4.88 (d, J = 5.7 Hz, 1H), 4.50 (d, J = 5.7
Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.89 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).
13C NMR (75 MHz, DEPT135, CDCl3) δ 170.0 (C), 157.1 (C), 137.0 (C),
129.4 (2 CH), 128.3 (CH), 127.6 (2 CH), 85.2 (CH), 61.9 (CH2), 61.5 (CH),
Acylation of tertiary bromide 3a with AcCl and AcBr. To a stirred
solution of bromide 3a (0.14 g, 0.5 mmol) in CH2Cl2 (2.3 mL) was added
acetyl chloride (0.071 mL, 1.0 mmol) at rt. 1H NMR analysis after 1 h and
3 h revealed the absence of 10a (yield of bromide 2a: 20 % and 25 %,
respectively). The mixture was kept for 72 h, and then concentrated in
vacuum. The residue was subjected to a column chromatography on
silica gel to give 0.123 g of an inseparable mixture containing bromide 2a
+
14.1 (CH3), 11.3 (CH3). ESI-HRMS m/z: [M+H]+ Calcd for C13H16NO3
234.1120; Found 234.1125.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900131
European Journal of Organic Chemistry
FULL PAPER
(0.116 g, 72 %) and chloride 10a (0.007 g, 5 %). Acylation of tertiary
bromide 3a with a mixture of AcBr (1 equiv.) and Ac2O (1 equiv.) afforded
71 % of primary bromide 2a after 24 h.
(0.5 mmol, 0.177 g) according to the procedure used for the synthesis of
11a. Yield: 0.178 g (88 %). Mp 95 − 96 °C (Et2O-pentane) (Lit.[4c] 90 − 92
°C). NMR spectra are in accordance with published data.[4c]
Parallel synthesis of 1-(3-(chloromethyl)-6,6-dimethyl-4-phenyl-5,6-
Dimethyl
rel-2-(((4aR*,7aR*)-2-acetyl-4-phenyl-2,4a,5,6,7,7a-
(11l).
dihydro-2H-1,2-oxazin-2-yl)ethan-1-one (10a). To
a solution of 3-
hexahydrocyclopenta[e][1,2]oxazin-3-yl)methyl)malonate
(chloromethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazine[20] (25
mg, 0.105 mmol) in CH2Cl2 (0.5 mL) was added Ac2O (11 µL, 0.116
mmol) followed by AcCl (7.5 µL, 0.105 mmol). The mixture was kept for
72 h, and then volatiles were removed in vacuum. The residue was
subjected to a column chromatography on silica gel to give 18 mg (61 %)
of chloride 10a as colorless oil. Rf = 0.34 (AcOEt/hexane = 1 : 3). 1H
NMR (300 MHz, Chloroform-d) δ 7.55 – 7.12 (m, 5H), 4.73 (t, J = 1.0 Hz,
2H), 2.44 (s, 2H), 2.31 (s, 3H), 1.41 (s, 6H). 13C NMR (75 MHz, DEPT135,
CDCl3) δ 170.1 (C), 138.2 (C), 131.7 (C), 128.7 (2 CH), 128.3 (2 CH),
127.9 (CH), 126.1 (C), 79.6 (C), 43.0 (CH2), 40.3 (CH2), 25.6 (2 CH3),
Prepared from bromide 2l (1.41 g, 4.2 mmol) according to the procedure
used for the synthesis of 11a. Yield: 1.59 g (98 %). Oil. Rf = 0.47
(AcOEt/hexane = 1 : 1). 1H NMR (250 MHz, CDCl3) δ 7.42 – 7.12 (m, 5H),
4.45 (t, J = 5.1 Hz, 1H), 3.73 (s, 3H), 3.63 (s and m, 4H), 3.36 (ddd, J =
15.0, 5.1, 2.5 Hz, 1H), 2.91 (dd, J = 15.0, 10.1 Hz, 1H), 2.56 – 2.39 (m,
1H), 2.23 (s, 3H), 2.19 – 2.08 (m, 1H), 1.91 – 1.59 (m, 3H), 1.49 – 1.34
(m, 2H). 13C NMR (63 MHz, CDCl3) δ 170.7 (C), 169.3 (C), 169.2 (C),
138.7 (C), 131.2 (C), 129.2 (C), 128.8 (2 CH), 128.5 (2 CH), 127.3 (CH),
84.7 (CH), 52.5 and 52.4 (2 CH3), 49.6 (CH), 44.9 (CH), 31.3 (2 CH2),
29.0 (CH2), 23.2 (CH2), 22.1 (CH3). ESI-HRMS m/z: [M+H]+ Calcd for
C21H26NO6+ 388.1755; Found 388.1768.
+
22.3 (CH3). ESI-HRMS m/z: [M+H]+ Calcd for C15H19ClNO2 280.1099
and 282.1070; Found 280.1105 and 282.1071. Same reaction conducted
with AcBr instead of AcCl (reaction time – 24 h) gave a mixture of
chloride 10a (spectral yield: 67 %) and bromide 2a (spectral yield: 18 %).
Dimethyl
rel-2-(((4aR*,8aR*)-2-acetyl-4-phenyl-4a,5,6,7,8,8a-
(11m).
hexahydro-2H-benzo[e][1,2]oxazin-3-yl)methyl)malonate
Prepared from bromide 2m (1.51 g, 4.32 mmol) according to the
procedure used for the synthesis of 11a. Yield: 1.49 g (86 %). White
foam. Rf = 0.41 (AcOEt/hexane = 1 : 1). 1H NMR (300 MHz, Chloroform-
d) δ 7.38 – 7.22 (m, 3H), 7.14 (d, 2H, J = 6.6 Hz), 4.19 (m, 1H), 3.75 (s,
3H), 3.65 (dd, J = 9.7, 5.7 Hz, 1H), 3.61 (s, 3H), 3.34 (ddd, J = 15.0, 5.7,
2.1 Hz, 1H), 2.95 (dd, J = 15.0, 9.7 Hz, 1H), 2.26 (s, 3H), 2.22 – 2.07 (m,
Low-temperature monitoring of the interaction of nitronate 1a with
AcCl. A solution of AcCl and 1,3-cyclohexadiene in CH2Cl2 (7.25 mL)
was placed in a round-bottom 4-necked flack equipped with an ATR(Ge)
FT-IR probe, platinum electrode, argon inlet, rubber septum and
magnetic stirring bar. The mixture was cooled to -65 oC under argon
atmosphere, and FT-IR spectra and conductivity were measured. A
solution of nitronate 1a in CH2Cl2 (0.75 mL) was slowly added via a
syringe. Reaction progress was monitored by measuring FT-IR spectra
(5 minutes intervals) and conductivity (30 seconds intervals). After 75 min,
no significant changes in spectra were detected. The reaction mixture
was slowly warmed up to 0 oC and FT-IR spectra/conductivity were
measured with 5 oC intervals. Results are shown in Figure 1 and in the
Supporting information.
2H), 1.80 – 1.44 (m, 5H), 1.42 – 1.25 (m, 1H), 1.19 – 1.04 (m, 1H). 13
C
NMR (75 MHz, DEPT135, CDCl3) δ 171.5 (C), 169.4 (C), 169.2 (C),
138.4 (C), 130.6 (C), 129.1 (2 CH), 128.4 (C), 128.3 (2 CH), 127.1 (CH),
79.6 (CH), 52.4 and 52.3 (2 CH3), 49.8 (CH), 40.2 (CH), 29.5 (CH2), 29.5
(CH2), 27.3 (CH2), 24.5 (CH2), 22.6 (CH3), 20.8 (CH2). ESI-HRMS m/z:
[M+Na]+ Calcd for C22H27NO6Na+ 424.1731; Found 424.1737.
Dimethyl 2,2-dimethyl-8-oxo-4-phenyl-3,5,7,8-tetrahydropyrido[1,2-
b][1,2]oxazine-6,6(2H)-dicarboxylate (12). To
a stirred solution of
2-((2-Acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-
yl)methyl)isoindoline-1,3-dione (API). To a stirred solution of bromide
2a (0.32 g, 1.0 mmol) in DMF (2.3 mL) was added potassium phtalimide
(0.278 g, 1.5 mmol). The mixture was stirred at 30-40 °C for 2 h and then
transferred into a mixture of Et2O (50 mL) and water (50 mL). Aqueous
phase was back-extracted with Et2O (100 mL). Combined organic layers
were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and
evaporated. The residue was subjected to a column chromatography on
silica gel to give 0.32 g (83 %) of API as a white solid. Mp = 137 − 139 °C
(with decomposition). NMR spectra are in accordance with published
data.[16]
dimethyl malonate (11.5 µL, 0.1 mmol) in anhydrous THF (0.4 mL) was
added NaH (12 mg, 60 % in mineral oil, 0.3 mmol) at 0 °C under inert
atmosphere. After stirring for 5 minutes, a solution of dihalide 2c (30 mg,
0.08 mmol) in anhydrous THF (0.2 mL) was added. The mixture was
stirred at rt for 3 h and then transferred into a mixture of AcOEt (10 mL)
and water (10 mL). Aqueous phase was back-extracted 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 a column chromatography on silica gel to give 19 mg (64 %)
of bicyclic derivative 12 as yellowish oil. Rf = 0.23 (AcOEt/hexane = 1 : 1).
1H NMR (300 MHz, Chloroform-d) δ 7.45 – 7.30 (m, 3H), 7.17 (d, J = 6.6
Hz, 2H), 3.71 (s, 6H), 3.08 (s, 2H), 3.03 (s, 2H), 2.41 (s, 2H), 1.39 (s, 6H).
13C NMR (75 MHz, DEPT135, CDCl3) δ 169.5 (2 C), 160.6 (C), 138.8 (C),
128.6 (4 CH), 127.4 (CH), 125.9 (C), 116.7 (C), 78.0 (C), 53.2 (2 CH3),
52.1 (C), 41.9 (CH2), 37.9 (CH2), 31.5 (CH2), 25.1 (2 CH3). ESI-HRMS
m/z: [M+H]+ Calcd for C20H24NO6+ 374.1598; Found 374.1590.
Dimethyl
2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-
oxazin-3-yl)methyl)malonate (11a) (typical procedure for the
synthesis of malonates 11). To a stirred solution of dimethyl malonate
(0.63 mL, 5.48 mmol) in DMF (4.5 mL) was added potassium tert-
butoxide (0.614 g, 5.48 mmol) at 0 °C under inert atmosphere. After
stirring for 5 minutes, a solution of bromide 2a (1.48 g, 4.57 mmol) in
DMF (7.0 mL) was added. The mixture was stirred at 30-40 °C for 3 h
and then transferred into a mixture of AcOEt (100 mL) and water (100
mL). Aqueous phase was back-extracted with ethyl acetate (100 mL).
Combined organic layers were washed with water (100 mL), brine (100
mL), dried (Na2SO4) and evaporated. The residue was subjected to a
column chromatography on silica gel to give 1.34 g (78 %) of malonate
11a as colorless oil, which solidified upon standing. Mp 61 − 64 °C (Lit.[16]
64 − 69 °C). NMR spectra are in accordance with published data.[16]
General procedure for hydrogenation of 2H-1,2-oxazines 11 to
saturated 1,2-oxazines 13. To a solution of 2H-1,2-oxazine 11 (0.5
mmol) in methanol (5 mL) in a vial was added 5%-Pd/C (0.15 g). The vial
was placed to a steel autoclave which was flushed and filled with
hydrogen to a pressure of 40 bar. The autoclave was heated to 40-50 °C
and the mixture was stirred at this temperature for the indicated time
period. Then the autoclave was cooled to r.t., slowly depressurized and
the catalyst was removed by filtration. The filtrate was concentrated in
vacuum, and the residue was subjected to a column chromatography on
silica gel to give the corresponding saturated 1,2-oxazine 13.
Dimethyl 2-((2-acetyl-4-(4-methoxyphenyl)-6,6-dimethyl-5,6-dihydro-
2H-1,2-oxazin-3-yl)methyl)malonate (11h). Prepared from bromide 2h
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10.1002/ejoc.201900131
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Dimethyl
rel-2-(((3S*,4R*)-2-acetyl-4-(4-methoxyphenyl)-6,6-
mixture of AcOEt (100 mL) and water (100 mL). Aqueous phase was
back-extracted with ethyl acetate (2×50 mL). Combined organic layers
were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and
evaporated. The residue was subjected to a column chromatography on
silica gel to give 131 mg (77 %) of dimethyl (E)-2-(2-acetamido-5-
dimethyl-1,2-oxazinan-3-yl)methyl)malonate (13h). Prepared from 165
mg (0.41 mmol) of 2H-1,2-oxazine 11h according to the general
procedure, reaction time – 4 h. Yield: 165 mg (96 %). White crystals. Mp
= 77 – 80 °C. Rf = 0.14 (AcOEt/hexane = 1 : 1). 1H NMR (500 MHz,
COSY, HSQC, CDCl3): δ = 1.31 and 1.40 (2 s, 6 H, 2 CH3), 1.62 (m, 2 H,
CH2CH(CO2CH3)2 and HC-5), 2.05 (s, 3 H, CH3С(O)), 2.16 (m, 2 H,
hydroxy-5-methyl-3-phenylhex-2-en-1-yl)malonate as
a
yellowish oil,
0.09
which solidified upon standing [Mp 118 120 °C. Rf =
=
–
CH2CH(CO2CH3)2 and HC-5), 3.17 (dd,
J
=
9.4, 4.9 Hz,
1
H,
(AcOEt/hexane = 1 : 1). 1H NMR (300 MHz, Chloroform-d) δ 8.83 (s, 1H),
7.43 – 7.10 (m, 5H), 3.73 (s, 6H), 3.65 (t, J = 8.1 Hz, 1H), 3.16 (d, J = 8.0
Hz, 2H), 2.63 (s, 2H), 2.30 (br, 1H), 2.09 (s, 3H), 1.18 (s, 6H). 13C NMR
(75 MHz, JMOD, CDCl3) δ 169.6 and 169.3 (3 С), 142.2 (C), 132.9 and
129.7 (2 C), 128.9, 128.3 and 126.6 (5 CH), 74.5 (C), 52.4 and 50.0 (2
СН3 and CH), 47.5 (СH2), 30.3 (2 CH3), 28.8 (CH2), 23.8 (CH3). ESI-
HRMS m/z: [M+H]+ Calcd for C20H28NO6+ 378.1911; Found 378.1912]. A
portion of product (0.065 g, 0.17 mmol) was dissolved in methanol (2.5
ml); the solution was placed in a vial and 5%-Pd/C (0.065 g) was added.
The vial was placed to a steel autoclave which was flushed and filled with
hydrogen to a pressure of 80 bar. The autoclave was heated to 70-80 °C
and the mixture was stirred at this temperature for 4 h. Then the
autoclave was cooled to r.t., slowly depressurized and the catalyst was
removed by filtration. The filtrate was concentrated in vacuum, and the
residue was subjected to a column chromatography on silica gel to give
29 mg (45 %) of N-acylated amine 14a as a colorless oil. Rf = 0.14
(AcOEt). 1H NMR (500 MHz, 250 MHz, COSY, HSQC, Chloroform-d) δ
7.36 – 7.16 (m, 5H, C6H5), 5.46 (d, J = 9.6 Hz, 1H, NH), 4.49 (dddd, J =
11.1, 9.6, 4.1, 3.1 Hz, 1H, CH-N), 3.70 (s, 3H, OCH3), 3.67 (s, 3H, OCH3),
3.36 (t, J = 7.0 Hz, 1H, CH-CO2), 3.02 – 2.75 (br s, 1Н, OH), 3.07 (ddd, J
= 7.1, 5.5, 4.1 Hz, 1H, CH-Ph), 2.17 (ddd, J = 14.3, 7.0, 3.1 Hz, 1H,
CH2CH-N), 2.02 (dd, J = 14.8, 7.1 Hz, 1H, CH2CHPh), 1.94 (s, 3H,
CH3CO), 1.78 (dd, J = 14.8, 5.5 Hz, 1H, CH2CHPh), 1.64 (ddd, J = 14.3,
11.1, 7.0 Hz, 1H, CH2CH-N), 1.19 and 1.13 (2 s, 3H and 3H). 13C NMR
(125 MHz, 63 MHz, HSQC, CDCl3) δ 170.8, 170.2 and 169.4 (3 C=O),
141.6 (i-C6H5), 128.7 and 127.0 (o,m,p-C6H5), 70.7 (C-O), 52.8 and 52.7
(2 CH3O), 51.7 (CH-N), 49.2 (CH-CO2), 46.1 (CH-Ph), 44.5 (CH2CHPh),
32.7 (CH2CH-N), 31.9 and 28.2 (2 CH3), 23.3 (CH3CO). ESI-HRMS m/z:
[M+Na]+ Calcd for C20H29NO6Na+ 402.1887; Found 402.1885.
CH2CH(CO2CH3)2), 3.31 (ddd, J = 14.0, 4.2, 4.0 Hz, 1 H, HaxC-4), 3.62 (s,
6 H, 2 CO2CH3), 3.76 (s, 3 H, ОCH3), 4.92 (ddd, J = 11.9, 4.2, 4.0 Hz, 1
H, HeqC-3), 6.84 (d, J = 8.5 Hz, 2 H, o-C6H4OCH3), 7.11 (d, J = 8.5 Hz, 2
H, m-C6H4OCH3). 13C NMR (125 MHz, HSQC, CDCl3):
δ = 20.1
(CH3С(O)), 21.9 and 28.7 (2 CH3), 24.0 (CH2CH(CO2CH3)2), 35.1 (C-5),
37.2 (C-4), 48.4 (CH2CH(CO2CH3)2), 51.2 (C-3), 52.5 (2 CO2CH3), 55.2
(OCH3), 80.0 (C-6), 114.1 (o-C6H4OCH3), 128.3 (m-C6H4OCH3), 131.5 (p-
C6H4OCH3), 158.5 (=C-О), 168.9 and 169.7 (N-C=O and 2 CO2CH3).
Anal. Calcd for C21H29NO7: H, 7.17; C, 61.90; N, 3.44. Found: H, 7.36; C,
61.92; N, 3.52.
Dimethyl
rel-2-(((3S*,4R*,4aR*,7aR*)-2-acetyl-4-
phenyloctahydrocyclopenta[e][1,2]oxazin-3-yl)methyl)malonate (13l).
Prepared from 155 mg (0.4 mmol) 2H-1,2-oxazine 11l according to the
general procedure, reaction time – 2 h. Yield: 79 mg (51 %). White solid.
Mp = 117 – 120 °C. Rf = 0.19 (AcOEt/hexane = 1 : 1). 1H NMR (500 MHz,
COSY, HSQC, CDCl3): δ = 1.73, 1.88, 1.97 and 2.13 (4 m, 1 H, 3 H, 1 H
and 1 H, -CH2-CH2-CH2-), 2.18 (s, 3 H, CH3С(O)), 2.22 (ddd, J = 13.8,
8.7, 2.3 Hz, 1 H, CH2CH(CO2CH3)2), 2.35 (ddd, J = 13.8, 12.0, 4.8 Hz, 1
H, CH2CH(CO2CH3)2), 2.42 (m, 1 H, HeqС-5), 3.34 (dd, J = 8.7, 4.8 Hz, 1
H, CH2CH(CO2CH3)2), 3.54 (dd, J = 5.2, 5.1 Hz, 1 H, HaxC-4), 3.68 and
3.70 (2 c, 6 H, 2 CO2CH3), 4.31 (m, 1 H, HC-6), 5.03 (ddd, J = 12.0, 5.2,
2.3 Hz, 1 H, HeqC-3), 7.21-7.40 (m, 5 H, o,m,p-C6H5). 13C NMR (125 MHz,
HSQC, CDCl3): δ = 19.9 (CH3С(O)), 23.4, 26.9, 27.0 and 30.4 (-CH2-
CH2-CH2- and CH2CH(CO2CH3)2), 41.8 (C-5), 43.2 (C-4), 49.5
(CH2CH(CO2CH3)2), 51.0 (C-3), 52.6 (2 CO2CH3), 87.1 (C-6), 126.8,
128.1 and 128.5 (o,m,p-C6H5), 139.2 (i-C6H5), 169.1 and 169.7 (N-C=O
and 2 CO2CH3). Characteristic 2D NOESY correlations: HC-4/HC-6, HC-
3/HC-4, HC-4/HC-5, CH2CH(CO2CH3)2/o-C6H5. Anal. Calcd for
C21H27NO6: H, 6.99; C, 64.77; N, 3.60. Found: H, 7.23; C, 64.41; N, 3.61.
Acknowledgements
Dimethyl rel-2-(((3S*,4R*,4aR*,8aR*)-2-acetyl-4-phenyloctahydro-2H-
benzo[e][1,2]oxazin-3-yl)methyl)malonate (13m). Prepared from 155
mg (0.39 mmol) of 2H-1,2-oxazine 11m according to the general
procedure, reaction time – 2 h. Yield: 97 mg (62 %). White solid. Mp =
150 – 153 °C. Rf = 0.20 (AcOEt/hexane = 1 : 1). 1H NMR (300 MHz,
CDCl3): δ = 1.15-1.29 and 1.57-1.96 (4 m, 8 H, -CH2-CH2-CH2-CH2-),
2.18 (s and m, 4 H, CH3С(O) and HeqС-5), 2.42 (ddd, J = 14.0, 9.2, 2.6
Hz, 1 H, CH2CH(CO2CH3)2), 2.54 (ddd, J = 14.0, 11.2, 5.3 Hz, 1 H,
CH2CH(CO2CH3)2), 3.28 (dd, J = 4.6, 4.6 Hz, 1 H, HaxC-4), 3.49 (dd, J =
9.2, 5.3 Hz, 1 H, CH2CH(CO2CH3)2), 3.72 and 3.75 (2 s, 6 H, 2 CO2CH3),
3.97 (m, 1 H, HaxC-6), 5.17 (ddd, J = 11.2, 4.6, 2.6 Hz, 1 H, HeqC-3),
7.25-7.42 (m, 5 H, o,m,p-C6H5). 13C NMR (75 MHz, JMOD, CDCl3): δ =
20.0 (CH3C(O)), 21.1, 24.1, 25.8, 28.8 and 30.6 (-CH2-CH2-CH2-CH2-
and CH2CH(CO2CH3)2), 37.9 (C-5), 46.2 (C-4), 49.7 (CH2CH(CO2CH3)2),
50.3 (C-3), 52.7 (2 CO2CH3), 83.4 (C-6), 126.6, 128.0 and 128.5 (o,m,p-
C6H5), 137.8 (i-C6H5), 169.4, 169.7 and 169.9 (N-C=O and 2 CO2CH3).
Anal. Calcd for C22H29NO6: H, 7.25; C, 65.49; N, 3.47. Found: H, 7.53; C,
65.18; N, 3.60.
This work was supported by Russian Science Foundation (grant
17-13-01411). Authors thank Dr. Yulia Khoroshutina and Dr.
Andrey Tabolin for taking 2D NMR spectra.
Keywords: acylation• nitronates • halogenation • rearrangement
• deoxygenation
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Entry for the Table of Contents
FULL PAPER
Acylation of N-oxides
Roman S. Malykhin, Ivan S. Golovanov,
Sema L. Ioffe, Alexey Yu. Sukhorukov*
Page No. – Page No.
Tandem Deoxygenation/Halogenation
of N-Oxides under Acylation
Conditions: Scope and In Situ IR
Spectroscopic Study
Unusual acylation of 1,2-oxazine-N-oxides with acyl bromides produces 3-
bromomethyl-substituted 2H-1,2-oxazines via the formation of molecular bromine
as intermediate. The developed process was successfully exploited in the
stereoselective synthesis of pharmaceutically relevant molecules.
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