Synthesis of α-Nitro Carbonyls via Nitrations in Flow

Article abstract of DOI:10.1021/acs.joc.6b01634

Reported is a safe, rapid method for the synthesis of α-nitro esters via the trapping of nitronium ions. The two-stage nitration and subsequent deacetylation of readily available 1,3-dicarbonyl compounds was achieved using a biphasic semicontinuous approach. α-Nitro esters and amides were obtained in good overall yields (53-84%). Some of the α-nitro-1,3-dicarbonyl intermediates exhibit enhanced reactivity and undergo an acid-catalyzed Nef-type reaction to α-oxo-carbonyls.

Full text of DOI:10.1021/acs.joc.6b01634

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Note
Synthesis of #-Nitro Carbonyls via Nitrations in Flow
Anna Chentsova, Dmitry B Ushakov, Peter H Seeberger, and Kerry Gilmore
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01634 • Publication Date (Web): 06 Sep 2016
Downloaded from http://pubs.acs.org on September 7, 2016
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Synthesis of α-Nitro Carbonyls via Nitrations in Flow
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†,§
†,‡
Anna Chentsova , Dmitry B. Ushakov †,§, Peter H. Seeberger , and Kerry Gilmore
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†.
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*
†
- -
hlenberg 1, 14476 Potsdam, Germany
‡
t Berlin, Institute of Chemistry and Biochemistry, Arnimallee 22, 14195 Berlin,
Germany
Corresponding Author
*E-mail: kerry.gilmore@mpikg.mpg.de
§
These authors contributed equally to this work
ABSTRACT
Reported is a safe, rapid method for the synthesis of α-nitro esters, via the trapping of nitronium ions.
The two-stage nitration and subsequent deacetylation of readily available 1,3-dicarbonyl compounds
was achieved using a biphasic semi-continuous approach. α-Nitro esters and amides were obtained in
good overall yields (53–84%). Some of the α-nitro-1,3-dicarbonyl intermediates exhibit enhanced
reactivity and undergo an acid-catalyzed Nef-type reaction to α-oxo-carbonyls.
α-Nitro esters are valuable synthons in organic synthesis,1 that can, due to their 1,3-dipole nature and
the high acidity of the α-proton (pKa ~ 5.8), be further transformed in a variety of ways.2 They serve as
carbon nucleophiles3 and dipoles for heterocycle synthesis;1a,4 they can form phenyliodonium or diazo
ylide derivatives,5 the latter of which can participate in NH insertion/Mannich-type reactions.6
Moreover, α-nitro esters are intermediates for the synthesis of α-keto esters,7 γ-oxo acids,3f as well α-
amino acids.5c,7-8
Retrosynthetically, the α-nitro ester moiety offers two main disconnections (Scheme 1). The
functionalization of a nitroalkane with a CO2 synthon,9 is less common. One means of producing the
unsubstituted α-nitro ester is the self-condensation of nitromethane under harsh basic conditions
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followed by an acid-catalyzed esterification.10 Further alkylations or arylations of this core are
possible.8c,11
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More commonly, C-N bond formation is the key reaction. The nitro group can be introduced in either a
nucleophilic or electrophilic manner. The most direct approach involves the treatment of α-haloesters
with a nitrite anion.12 However, the substrate scope of this route is limited12a,13 and scavengers are
required to avoid the formation of α-oximinoesters.12b,14 Side product formation can be avoided
through a two-step process, transforming α-haloesters via the corresponding α-azidoester (Scheme 1).
The desired nitro derivatives are then generated under strong oxidizing conditions (HOF·CH3CN),
rendering this approach less amenable to sensitive substrates such as olefins and amines.15
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Scheme 1. Synthetic approaches for the synthesis of α-nitro esters.
The umpolung approach, where an electrophilic nitronium ion is captured by an enolizable
nucleophile, expands the potential pool of starting materials to β-keto esters. Early work by Sifniades
provided a homogeneous path, generating the key electrophile intermediate using an acetic
anhydride/nitric acid mixture.16 However, this approach is very temperature sensitive, resulting in side
product formation and – disturbingly – the “ejection of the reaction mixture from the reaction vessel”.17
Biphasic systems where a mixture of sulfuric acid and nitric acid (or NH4NO3) was added to a
chloroform solution of an acetoester at reduced temperatures offered better control over the reaction
conditions.17-18 The transformation requires vigorous stirring and careful temperature control over the
one to three hours it takes to complete. The resulting α-nitroacetate ester derivative is efficiently
deacylated to give the nitro ester. While there are few published examples for this process,16-19
continuous flow nitration of aromatic substrates has allowed for the safer handling of the corrosive
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strong acids,20 improved temperature control inside the reactor,21 and for the prevention of over-
nitration.22 In addition, biphasic reactions are significantly accelerated in flow due to the increased
interfacial area between the phases. Precise control of the reaction conditions in meso-flow reactors
should be a good basis for a general, safe, and broadly applicable process to generate valuable α-
nitro esters.
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The first step of the nitration/deacylation process (Scheme 2) is electrophile generation. The controlled
formation of a nitronium ion occurred rapidly in a 30 µL PTFE (polytetrafluoroethylene) reactor at 10
°C upon mixing pre-cooled fuming nitric acid (90+%, 1.2 equiv., 0.013 mL min–1) and concentrated
sulfuric acid (96%, 6 equiv., 0.080 mL min–1). After a 19 s residence time, the stream of α-
acetylbutyrolactone (1) in CH2Cl2 (0.36 m, 0.663 mL min–1) was introduced via a T-mixer. The biphasic
solution then passed through a second PTFE reactor (0.35 mL, 10 °C, residence time 28 s). The
solution was quenched by addition of the exiting stream to a stirred suspension of MgSO4 in CH2Cl2 at
room temperature. After completion of the reaction, the quenching agent was filtered off and the
solvent removed under reduced pressure. Deacylation occurred by addition and subsequent
evaporation of methanol. 1H NMR analysis revealed the desired α-nitrolactone 3 in 63% yield with 92%
conversion (Table 1, entry 1).
Scheme 2. Semi-continuous setup for the nitration/deacylation of 1,3-dicarbonyl compounds.
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Table 1. Optimization of nitration/deacylation of α-acetylbutyrolactone (1).a
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Res.
HNO3 H2SO4
equiv. equiv.
T
(°C)
Conversion
(%)b
Entry
1
time,
(s)
Yield (%)b
63
1.2
6
28c
10
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1.2
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54e
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0
>95
>95
>95
>95
>95
76
>95
>95
>95
>95
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10
80 (78 %)f
Reaction conditions: α-acetylbutyrolactone (1) in CH2Cl2 (0.36 M, 0.66 mL min-1); reactor volume 0.6 mL, 96%
a
H2SO4 and 90+% fuming HNO3 were used unless indicated, equivalents with respect to α-acetylbutyrolactone (1);
b
quench: 5 g MgSO4 in 20 mL CH2Cl2, rt; deacylation via addition of 2 mL of methanol. Determined using
c
d
e
mesitylene as internal standard; yield over two steps. Reactor volume 0.35 mL. 65% Nitric acid. Reactor
volume 0.7 mL. f Isolated yield in parentheses.
Both an increase in the residence time using a larger second reactor (0.6 mL, entry 2) as well as the
equivalents of nitric acid (entry 3) resulted in higher yields with complete conversion. While decreasing
amounts of sulfuric acid did not improve the yield (70%, entry 4), an increase to 7.8 equivalents (entry
5) afforded the desired compound in 79%. Further changes were not advantageous (entry 6). Use of
more dilute nitric acid (65%) resulted in the drop in both conversion and yield (entry 7). After additional
temperature screenings (entries 8–10), 1.4 equiv. nitric acid and 7.8 equiv. sulfuric acid at 10 °C were
found to be optimal with an overall residence time of 54 seconds for the nitration (entry 11). The
reaction was efficiently quenched with 1 g MgSO4 per 1 mL acid solution.23 The productivity of this
process, following off-line deacylation, is 1.47 g/hour of the desired 3-nitrodihydrofuran-2(3H)-one (3).
The optimized reaction conditions were tested on a range of 1,3-dicarbonyl compounds (Table 2).
α-Substituted acetoacetates bearing an additional ester group gave the corresponding α-nitro esters in
good yields (entries 1–2). Alkyl substituted substrates gave moderate [entries 3 (59%), 4 (53%)] to
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good yields (entry 5, 82%), with the nBu chain requiring slightly higher amounts of acid to achieve full
conversion (entry 6, 72%). Electron-withdrawing groups hinder the reaction, with ethyl 2-chloro-3-
oxobutanoate (16) necessitating higher temperature (20 °C), a longer reaction time (107 s), and
approximately twice as much acid (substrate: 0.2 M, entry 7).24
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Table 2. Nitration/deacylation of 1,3-dicarbonyl compounds in a semi-continuous flow system.a
Isolated
Entry
1
Substrate
Product
yield
(%)
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75
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82
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72b
84(b,d,e)
61;
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aStandard nitration conditions: 0.36 M solution in CH2Cl2 (0.663 mL min-1); 10 °C; residence time 54 s; HNO3
(90+%, 0.016 mL min–1), H2SO4 (96%, 0.103 mL min–1); for quenching and deacylation procedure see
b
Experimental Section. Yield determined over two steps. Higher amounts of acids used for complete conversion,
see Experimental Section. c1 M solution in CH2Cl2 (0.4 mL min–1), ‒5 to ‒3 °C; residence time 200 s; HNO3 (65%,
0.031 mL min–1), H2SO4 (96%, 0.110 mL min–1). Determined by NMR using mesitylene as internal standard;
d
eResidence time 107 s, 20 °C. fResidence time 107 s.
Several substrates suffer from competing reactions. Ethyl 2-benzylacetoacetate (18, entry 8) can also
undergo electrophilic aromatic substitution, and the previously optimized conditions resulted in only
71% conversion with multiple substituted products. The reaction was pushed to completion by
increasing the equivalents of acid (substrate: 0.16 M). The double nitrated scaffolds 19 (61%) and 20
(16%) were identified as the main products. This represents a limitation of the method, as nitration is
believed to occur first at the aromatic ring due to the observation of the solely aryl-nitrated ethyl 2-(4-
nitrobenzyl)-3-oxobutanoate (7%).
In the case of α-unsubstituted ethyl acetoacetate 21, two competing pathways following nitration can
occur due to the additional acidic proton: dimerization, which affords a substituted furoxan,17 and
dinitration of the α-position. These pathways could be partly suppressed using a more dilute nitronium
ion solution (65% nitric acid) and a larger second reactor (1.8 mL), providing the desired ethyl 2-
nitroacetate 22 in 70% yield (entry 9).25
Under the reaction conditions, several α-nitro acyl compounds exhibit enhanced reactivity resulting in
the formation of different functional groups. Nitration of N,N-diethyl-3-oxobutanamide 23 gave a
moderate yield of the α-nitro amide (entry 10, 54%) after a longer reaction time (107 s) and a change
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in the equivalents of nitronium ion (substrate: 0.2 M). One explanation for the lower yield is the
formation, post-nitration, of two side products; one resulting from the in situ deacylation and
dehydration of the nitro group (see Experimental Section for details).
9
No α-nitro product was observed for the 1,3-diacyl analog methyl 4-acetyl-5-oxohexanoate (25, entry
11). 4-Methoxy-4-oxobutanoic acid 26 was isolated as major product (34%). The formation of the
carboxylic acid is not surprising as an in situ deacylation would result in the formation of a secondary
α-nitro ketone, which is known to undergo fragmentation under strong acidic conditions to give the
corresponding carboxylic acid.26 The α-nitro ketone intermediate can also undergo a Nef reaction, as
indicated by the isolation of small amounts both α-oxime- and α-oxo-ketone from the same reaction
mixture.27
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Unexpectedly, this acid-catalyzed Nef reaction – which generally requires a nitronate intermediate –
becomes the predominant pathway for ethyl 2-oxocyclopentanecarboxylate 27. Compared to lactone
1, where the α-nitro-γ-lactone is obtained in high yield, the cyclopentanone ester provides α-oxo-ester
28 in 61% yield (entry 12). This result can be explained assuming the formation of the protonated aci-
nitro species 30 under strong acidic conditions, followed by a Nef reaction to give α-oxo-product 28
and oxime 31 – the latter of which was isolated in 5% yield (Scheme 3) and whose formation is known
to be dependent on the pH of the reaction medium.28
a
Scheme 3. Proposed pathway for the formation of 6-ethoxy-5,6-dioxohexanoic acid (28) and oxime 31. NMR
yield using mesitylene as internal standard (47% isolated yield).
In conclusion, a rapid, facile, and safe procedure for the α-nitration of 1,3-dicarbonyls via a two-step
nitration and deacylation process is disclosed. The controlled nitration in a continuous flow reactor
occurs rapidly (54–200 s). Following the quenching of excess H2SO4/HNO3 using MgSO4, deacylation
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is achieved in methanol/ethanol in batch. A range of α-nitro esters/amides were produced with
moderate-to-good yields (53–84%). Some α-nitro-1,3-dicarbonyl intermediates exhibit enhanced
reactivity and under the reaction conditions yielding either Nef α-oxo products or carboxylic acids.
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1. Experimental Section
General Information. All commercially available compounds and solvents were used without
purification. Sulfuric acid (96%) and fuming nitric acid (90+%) were purchased from Roth
(ROTIPURAN®, 4623.4) and Acros (ACS reagent, A0332793) respectively. Acids and substrates were
delivered into the reactor with the help of individual syringe pumps. Both flow reactors were built using
polytetrafluoroethylene (PTFE) tubing (1.59 mm outer diameter, 0.76 mm inner diameter) and
connected by ethylene tetrafluoroethylene (ETFE) T-mixers. All tubing, connectors and adapters were
purchased from IDEX Health and Science. All tubing and mixers were immersed in a water bath,
cooled with the help of immersion cooler. Column chromatography was performed using Macherey-
Nagel silica gel 60 M (0.04-0.063 mm). Preparative HPLC was performed using a semi-preparative
YMC-Pack Diol-300-NP column (150 x 20 mm). The compounds were visualized by UV (254 nm) and
by staining with an aqueous solution of potassium permanganate (prepared from 1.5 g KMnO4 and 10
g K2CO3 in 1.25 mL 10% NaOH in 200 mL water). In describing 1H and 13C NMR spectra the following
abbreviations were used to define the multiplicities (s = singlet, d = doublet, dd = doublet of doublets,
ddd = doublet of doublet of doublets, t = triplet, dq = doublet of quartets, m = multiplet, br = broad),
with coupling constants (J) in Hertz (Hz) and integration. Chemical shifts are reported in parts per
million (ppm) relative to residual solvent peaks () and are calibrated to the residual proton and carbon
resonance of CDCl3 (1H: 7.24, 13C: 77.16), CD3OD (1H: 3.31, 13C: 49.00).29 High resolution mass
spectra were obtained using ESI-Q-TOFmicro mass spectrometer and ESI-TOF mass spectrometer.
General procedure for nitration and deacylation step. Fuming nitric acid (90+%, 16 µL
min–1, 0.343 mmol/min) was mixed with sulfuric acid (96%, 103 µL min–1, 1.85 mmol/min) at 10 °C
(cooling bath was used) using a T-mixer. The resulting flow stream was passed through a 0.03 mL
PTFE-tubing (0.76 mm inner diameter) and mixed with the solution of the α-acetyl compound (0.36 M
in CH2Cl2, 0.663 mL min–1, 0.239 mmol/min) using second T-mixer at the same temperature. The
biphasic mixture was then passed through a 0.7 mL PTFE-tubing and collected in an Erlenmeyer flask
containing a stirred suspension of MgSO4 (5-10 g) in CH2Cl2 (20 mL) at room temperature. MgSO4
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was filtered of and the reaction mixture was concentrated under reduced pressure. If deacylation does
not occur in situ, the following procedure was performed: the residue was dissolved in 30 mL of the
corresponding alcohol (EtOH/MeOH) and stirred from 2 h to overnight (temperature varies from room
temperature to reflux depending on the substrate). After completion of the reaction the solvent was
removed under reduced pressure and the residue was purified by column chromatography.
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3-Nitrodihydrofuran-2(3H)-one (3): General nitration procedure was used (0.6 mL (5.58 mmol) of α-
acetylbutyrolactone (1) in CH2Cl2 (15 mL)). Quenching and deacylation procedure: for 11 mL of the
collected solution 5 g of MgSO4 and 20 mL CH2Cl2 were used. The reaction mixture was filtered,
treated with MeOH (2 mL) and concentrated under reduced pressure (30 °C). The residue was purified
by column chromatography (n-hexane/ethyl acetate 25:1 → 9:1 v/v) to give compound 3 (405 mg,
1
78%) as a orange oil. Rf = 0.16 (n-hexane/ethyl acetate = 3:2 v/v); H NMR (400 MHz, CDCl3): 2.82
(dddd, J = 14.0, 9.0, 7.4, 4.8 Hz, 1H), 2.96 (dddd, J = 14.4, 8.5, 7.3, 7.3 Hz, 1H), 4.38 (ddd, J = 9.2,
7.3, 7.3 Hz, 1H), 4.56 (ddd, J = 8.8, 4.9, 4.9 Hz, 1H), 5.38 (dd, J = 9.0, 7.4 Hz, 1H); 13C NMR (100
MHz, CDCl3): 27.9, 66.9, 82.2, 167.2; HRMS (ESI): [M+Na]+ calcd for C4H5NO4Na: 154.0116, found
154.0106, [M+K]+ calcd for C4H5NO4K: 169.9856 found 169.9845.
Dimethyl 2-nitrosuccinate (5): General nitration procedure was used (0.82 mL (5.05 mmol) of dimethyl
2-acetylsuccinate (4) in CH2Cl2 (13.2 mL)). Quenching and deacylation procedure: for 11 mL of the
collected solution 5 g of MgSO4 and 20 mL CH2Cl2 were used, the reaction mixture was filtered and
concentrated under reduced pressure. The residue was dissolved in 30 mL MeOH and stirred
overnight at room temperature. The solvent was removed under reduced pressure and the residue
was purified by column chromatography (n-hexane → n-hexane/ethyl acetate, 100:0 → 9:1 v/v) to give
compound 5 (569 mg, 75%) as a yellow oil. Rf = 0.49 (n-hexane/ethyl acetate = 5:1 v/v); 1H spectrum
matches with the literature data.30 1H NMR (400 MHz, CDCl3): 3.16 (dd, J = 17.7, 4.9 Hz, 1H); 3.38
(dd, J = 17.7, 9.2 Hz, 1H), 3.75 (s, 3H), 3.87 (s, 3H), 5.57 (dd, J = 9.2, 4.9 Hz, 1H); 13C NMR (100
MHz, CDCl3): 34.4, 52.8, 54.1, 83.1, 164.2, 168.9. HRMS (ESI): [M+Na]+ calcd for C6H9NO6Na:
214.0328, found 214.0322.
Diethyl 2-nitropentanedioate (7): General nitration procedure was used (1.0 mL (4.65 mmol) of diethyl
2-acetylpentanedioate (6) in CH2Cl2 (11.9 mL)). Quenching and deacylation procedure: for 10 mL of
the collected solution 5 g of MgSO4 and 20 mL CH2Cl2 were used, the reaction mixture was filtered
and concentrated under reduced pressure. The residue was dissolved in 30 mL EtOH and stirred
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overnight at room temperature. The solvent was removed under reduced pressure and the residue
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was purified by column chromatography (n-hexane/ethyl acetate 9:1 → 2:1 v/v) to give compound 7
1
(630 mg, 75%) as a colorless oil. Rf = 0.49 (n-hexane/ethyl acetate = 3:1 v/v); H spectrum matches
with the literature data.31 1H NMR (400 MHz, CDCl3): 1.26 (dd, J = 7.1, 7.1 Hz, 3H), 1.30 (dd, J = 7.1,
7.1 Hz, 3H), 2.39–2.61 (m, 4H), 4.15 (ddd, J = 7.1, 7.1, 7.1 Hz, 2H), 4.29 (ddd, J = 7.1, 7.1, 7.1 Hz,
2H), 5.27–5.32 (m, 1H); 13C NMR (100 MHz, CDCl3): 14.0, 14.3, 25.4, 29.7, 61.1, 63.3, 86.8, 164.3,
171.6. HRMS (ESI): [M+Na]+ calcd for C9H15NO6Na: 256.0797, found 256.0809.
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Ethyl 2-nitropropionate (9): General nitration procedure was used (ethyl 2-methylacetoacetate (8)
purity 95%, 0.75 mL (5.30 mmol) of substrate 8 in CH2Cl2 (13.25 mL)). Quenching and deacylation
procedure: for 10 mL of the collected solution 10 g of MgSO4 and 20 mL CH2Cl2 were used, the
reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in
30 mL EtOH and stirred for 3 hours at 80 °C (temperature of the oil bath). The solvent was removed
under reduced pressure and the residue was purified by column chromatography (n-hexane/ethyl
acetate 15:1 → 10:1 v/v) to give compound 9 (443 mg, 59%) as a yellow oil. Rf = 0.43 (n-hexane/ethyl
acetate = 5:1 v/v). Obtained NMR matches with the literature data.32 1H NMR (400 MHz, CDCl3): 1.29
(t, J = 7.1 Hz, 3H), 1.77 (d, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 5.19 (q, J = 7.1 Hz, 1H). 13C NMR
(100 MHz, CDCl3): 14.0, 15.8, 63.1, 83.3, 165.2.
Methyl 2-nitrobutanoate (11): General nitration procedure was used (0.72 mL (5.04 mmol) of methyl 2-
ethylacetoacetate (10) in CH2Cl2 (13.28 mL)). Quenching and deacylation procedure: for 11 mL of the
collected solution 10 g of MgSO4 and 20 mL CH2Cl2 were used, the reaction mixture was filtered and
concentrated under reduced pressure. The residue was dissolved in 30 mL MeOH and stirred for 130
minutes at 65 °C (temperature of the oil bath). The solvent was removed under reduced pressure and
the residue was purified by column chromatography (n-hexane/ethyl acetate 10:1 → 7:1 v/v) to give
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compound 11 (310 mg, 53%) as a yellow oil. Rf = 0.45 (n-hexane/ethyl acetate = 5:1 v/v); H NMR
(400 MHz, CDCl3): 1.04 (dd, J= 7.4, 7.4 Hz, 3H), 2.14-2.36 (m, 2H), 3.83 (s, 3H), 5.05 (dd, J= 9.3, 5.5
Hz, 1H); 13C NMR (100 MHz, CDCl3): 10.3, 24.1, 53.6, 89.4, 165.1; HRMS (ESI): [M+Na]+ calcd for
C5H9NO4Na: 170.0429, found 170.0419, [M+K]+ calculated for C5H9NO4K: 186.0169, found 186.0159.
Compound 11 was previously synthesized.9b
7-Ethoxy-6-nitro-7-oxoheptanoic acid (13) and 7-ethoxy-6-(hydroxyimino)-7-oxoheptanoic acid (13a):
General nitration procedure was used (ethyl 2-oxocyclohexanecarboxylate (12) purity 95%, 0.85 mL
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(5.31 mmol) of substrate 12 in CH2Cl2 (13.15 mL)). Quenching and deacylation procedure: for 4 mL of
the collected solution 5 g of MgSO4 and 20 mL CH2Cl2 were used, the reaction mixture was filtered
and concentrated under reduced pressure. The residue was dissolved in 30 ml mixture of EtOH and
water (2:1, v/v) and stirred overnight at 45 °C (temperature of the oil bath). The solvent was removed
under reduced pressure and the residue was purified by column chromatography (DCM/MeOH 50:1 →
5:2 v/v) to give compound 13 (275 mg, 82%) as a yellow-green solid and compound 13a (33.4 mg,
11%) as a yellow solid. Analytical data for compound 13: Rf = 0.30 (DCM/MeOH = 30:1 v/v); mp 57–
59 °C; 1H NMR (400 MHz, CDCl3):1.29 (t, J = 7.1 Hz, 3H), 1.40-1.49 (m, 2H) 1.66-1.74 (m, 2H), 2.10-
2.19 (m, 1H), 2.24-2.32 (m, 1H) , 2.36-2.39 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 5.09 (dd, J = 9.3, 5.4 Hz,
1H), 9-12 (br signal COOH); 13C NMR (100 MHz, CDCl3) 13.9, 23.8, 25.0, 29.9, 33.5, 63.2, 87.9,
164.5, 179.5; HRMS (ESI): [M+Na]+ calcd for C9H15NO6Na 256.0797, found 256.0796. Analytical data
for compound 13a: Rf = 0.5 (DCM/MeOH = 15:1 v/v); mp 98–100 °C; 1H NMR (400 MHz, CDCl3):1.33
(t, J = 7.1 Hz, 3H), 1.62-1.71 (m, 4H) 2.40 (t, J = 7.1 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H), 4.28 (q, J = 7.1
Hz, 2H), COOH and N-OH protons are not observed; 13C NMR (100 MHz, CDCl3) 14.1, 24.5, 24.6,
25.3, , 33.7, 62.0, 152.0, 163.2, 179.1; HRMS (ESI): [M+Na]+ calcd for C9H15NO5Na: 240.0848, found
240.0859.
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Ethyl 2-nitrohexanoate (15): Nitric acid (90+%, 16 µL/min, 0.343 mmol/min) was mixed with sulfuric
acid (96%, 103 µL/min, 1.85 mmol/min) at 10 °C using a T-mixer. The resulting flow stream was
passed through a 0.03 mL PTFE-tubing and mixed with the ethyl 2-acetylhexanoate (14) solution
(1.0 mL (5.11 mmol) of substrate 14 in CH2Cl2 (15 mL), 0.663 mL/min, 0.212 mmol/min) using second
T-mixer at the same temperature. The biphasic mixture was passed through 0.7 mL PTFE-tubing and
collected in an Erlenmeyer flask containing stirred suspension of MgSO4 in CH2Cl2 (for 11 mL of the
collected solution 5 g of MgSO4 and 20 mL CH2Cl2 were used) at room temperature. The reaction
mixture was filtered and concentrated under reduced pressure. The residue was dissolved in 30 mL
EtOH and stirred overnight at room temperature. The solvent was removed under reduced pressure
and the residue was purified by column chromatography (n-hexane → n-hexane/ethyl acetate, 100:0
→ 9:1 v/v) to give compound 15 (480 mg, 72%) as a colorless oil. Rf = 0.49 (n-hexane/ethyl acetate =
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2:1 v/v); H NMR (400 MHz, CDCl3): 0.90 (dd, J = 6.9, 6.9 Hz, 3H); 1.27 (dd, J = 7.1, 7.1 Hz, 3H),
1.32–1.42 (m, 4H), 2.05–2.15 (m, 1H), 2.18–2.31 (m, 1H), 4.25 (ddd, J = 7.1, 7.1, 7.1 Hz, 2H), 5.07
(dd, J = 9.4, 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): 13.8, 14.0, 22.1, 27.8, 30.1, 63.1, 88.3, 164.8;
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HRMS (ESI): [M+Na]+ calcd for C8H15NO4Na: 212.0899, found 212.0887, [M+K]+ calculated for
C8H15NO4K: 228.0638, found 228.0630. Compound 15 was previously synthesized.15,33
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Ethyl 2-chloro-2-nitroacetate (17): Nitric acid (90+%, 8 µL/min, 0.171 mmol/min) was mixed with
sulfuric acid (96%, 52 µL/min, 0.923 mmol/min) at 20 °C using a T-mixer. The resulting acid mixture
was passed through a 0.03 mL PTFE-tubing and mixed with the ethyl 2-chloro-3-oxobutanoate (16)
solution (substrate 16 purity 95%, 0.23 mL (1.6 mmol) substrate 16 in CH2Cl2 (7.77 mL), 0.332
mL/min, 0.066 mmol/min) at the same temperature. The biphasic mixture was passed through 0.7 mL
PTFE-tubing and collected in an Erlenmeyer flask containing stirred suspension of MgSO4 in CH2Cl2
(for 4 mL of the collected solution 5 g of MgSO4 and 20 mL CH2Cl2 were used) at room temperature.
The reaction mixture was filtered and concentrated under reduced pressure. The residue was
dissolved in 10 ml EtOH and stirred overnight at room temperature. The solvent was gently removed
under reduced pressure (room temperature) to give volatile compound 17 as a yellow oil (84%,
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determined by H NMR using mesitylene as internal standard). An analytically pure sample was
obtained by column chromatography (n-hexane/ethyl acetate 20:1 → 10:1 v/v). Rf = 0.60 (n-
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hexane/ethyl acetate = 2:1 v/v); Obtained H NMR matches with the literature data.34 1H NMR (400
MHz, CDCl3): 1.36 (t, J = 7.2 Hz, 3H), 4.39 (q, J = 6.7 Hz, 2H), 6.23 (s, 1H); 13C NMR (100 MHz,
CDCl3) 13.9, 64.9, 85.6, 160.7.
Ethyl 2-nitro-3-(4-nitrophenyl)propanoate (19), ethyl 2-nitro-3-(2-nitrophenyl)propanoate (20), and ethyl
2-(4-nitrobenzyl)-3-oxobutanoate (20a): Nitric acid (90+%, 16 µL/min, 0.343 mmol/min) was mixed with
sulfuric acid (96%, 103 µL/min, 1.852 mmol/min) at 10 °C using a T-mixer. The resulting acid mixture
was passed through a 0.03 mL PTFE-tubing and mixed with the ethyl 2-benzylacetoacetate (18)
solution (0.48 mL (2.26 mmol) of substrate 18 in CH2Cl2 (13.5 mL), 0.663 mL/min, 0.106 mmol/min) at
the same temperature. The biphasic mixture was passed through 0.7 mL PTFE-tubing and collected in
an Erlenmeyer flask containing stirred suspension of MgSO4 in CH2Cl2 (for 11 mL of the collected
solution 5 g of MgSO4 and 20 mL CH2Cl2 were used) at room temperature. The reaction mixture was
filtered and concentrated under reduced pressure. The residue was dissolved in 30 mL EtOH and
stirred overnight at 45 °C. The solvent was removed under reduced pressure to give compound 19
(61%), compound 20 (16 %) and compound 20a (7%). (Due to the tedious purification procedure, the
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yields were determined by H NMR using mesitylene as an internal standard). Analytically pure
samples of compound 20 as a yellow oil were obtained using purification by column chromatography
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(n-hexane/DCM 2:1 → 1:5 v/v). Compound 20a was isolated as a yellow oil from the same column,
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however was unable to be separated from the impurities according to H NMR. An analytically pure
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sample of compound 19 was obtained by purification using HPLC Hex/iPrOH (99:1, v/v). Analytical
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data for compound 19: Rf = 0.33 (n-hexane/DCM 1:4 v/v); H NMR (400 MHz, CDCl3):1.30 (t, J = 7.1
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Hz, 3H), 3.59 (dd, J = 14.8, 5.3 Hz, 1H), 3.68 (dd, J = 14.8, 9.5 Hz, 1H), 4.31 (q, J = 6.3 Hz, 2H), 5.36
(dd, J = 9.4, 5.7 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 8.20 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): 14.0, 35.9, 63.8, 88.4, 124.4, 130.1, 141.6, 147.8 163.5; HRMS (ESI): [M+Na]+ calcd for
C11H12N2O6Na: 291.0593, found 291.0585. Analytical data for compound 20: Rf = 0.63 (n-hexane/DCM
1:4 v/v); 1H NMR (400 MHz, CDCl3): 1.29 (t, J = 6.9 Hz, 3H), 3.71 (dd, J = 14.3, 9.8 Hz, 1H), 3.90 (dd,
J = 14.4, 4.9 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 5.66 (dd, J = 9.7, 5.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H),
7.50 (dd, J = 7.8, 7.8 Hz, 1H), 7.59 (dd, J = 7.5, 7.5 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H); 13C NMR (100
MHz, CDCl3): 14.0, 34.4, 63.5, 88.1, 125.9, 129.6, 129.7, 133.5, 134.2, 148.9, 163.8; HRMS-ESI:
[M+Na]+ calcd for C11H12N2O6Na 291.0593 found 291.0591. Analytical data for compound 20a:
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Obtained NMR matches with the literature data.35 Rf = 0.20 (n-hexane/DCM 1:4 v/v); H NMR (400
MHz, CDCl3): 1.22 (t, J = 7.2 Hz, 3H), 2.24 (s, 3H), 3.25 (t, J = 7.6 Hz, 2H), 3.78 (t, J = 8.0, 1H), 4.12 –
4.21 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): 14.2,
29.7, 33.6, 60.8, 62.0, 123.9, 129.9, 146.2, 147.0, 168.6, 201.3.
Ethyl 2-nitroacetate (22): Nitric acid (65%, 31 µL/min, 0.657 mmol/min) was mixed with sulfuric acid
(96%, 110 µL/min, 1.972 mmol/min) at -5 °C →-3 °C using a T-mixer (EtOH/N2 bath was used, volume
of the loop before second T-mixer 0.5 mL). The resulting acid mixture was passed through a 0.03 mL
PTFE-tubing and mixed with the ethyl acetoacetate (21) solution (6.5 mL (49 mmol) of substrate 21 in
CH2Cl2 (42.5 mL), 0.4 mL/min, 0.4 mmol/min) at the same temperature. The biphasic mixture was
passed through 1.8 mL PTFE-tubing and collected in an Erlenmeyer flask containing stirred
suspension of MgSO4 in CH2Cl2 (40.5 mL of solution was collected, 21 g of MgSO4 was used: for 1 mL
of the pumped H2SO4 2 g of MgSO4 was used) at room temperature, the reaction mixture was filtered,
dried over Na2SO4, treated with EtOH (1:1 v/v) and concentrated under reduced pressure (30 °C). The
residue was purified using Kugelrohr distillation at 100 °C, 11 mbar to give compound 22 (3.8 g, 70%)
as a yellow oil. In addition, 22% (determined by NMR using mesitylene as an internal standard) of
3,4-bis(ethoxycarbonyl)-1,2,5-oxadiazole 2-oxide (22b)4c was observed. Analytical data for compound
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spectrum matches with the literature data.36 13C NMR (100 MHz, CDCl3): 13.9, 63.3, 76.4, 162.1;
HRMS (ESI): [M+Na]+ calcd for C4H7NO4Na: 156.0273, found 156.0252.
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N,N-Diethyl-2-nitroacetamide (24), N,N-diethyl-2-(hydroxyimino)-3-oxobutanamide (24a), 3,4-
bis(diethylcarbamoyl)-1,2,5-oxadiazole 2-oxide (24b): Nitric acid (90+%, 8 µL/min, 0.171 mmol/min)
was mixed with sulfuric acid (96%, 52 µL/min, 0.923 mmol/min) at 10 °C using a T-mixer. The resulting
acid mixture was passed through a 0.03 mL PTFE-tubing and mixed with N,N-diethyl-3-
oxobutanamide (23) solution (0.16 mL (1.01 mmol) of substrate 23 in CH2Cl2 (4.84 mL), 0.332 mL/min,
0.066 mmol/min) at the same temperature. The biphasic mixture was passed through 0.7 mL PTFE-
tubing and collected in an Erlenmeyer flask containing stirred suspension of MgSO4 in CH2Cl2 (for 4
mL of the collected solution 5 g of MgSO4 and 20 mL CH2Cl2 were used) at room temperature. The
reaction mixture was filtered and concentrated under reduced pressure. Crude reaction mixture was
purified by column chromatography (n-hexane/ethyl acetate 5:1 →1:1 v/v) to give compound 24 (68.7
mg, 54%) as a yellow oil, compound 24b (23.4 mg, 10%) as a yellow oil and compound 24a (16.7 mg,
11%) as a light peach clear solid. Analytical data for compound 24: Rf = 0.19 (n-hexane/ethyl acetate =
2:1 v/v); 1H NMR (400 MHz, CDCl3): 1.17 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 3.24 (q, J = 7.2
Hz, 2H), 3.44 (q, J = 7.1 Hz, 2H), 5.27 (s, 2H); 13C NMR (100 MHz, CD3OD): 12.9, 14.2, 42.0, 43.3,
78.3, 163.2; HRMS (ESI): [M+Na]+ calcd for C6H12N2O3Na: 183.0746, found 183.0740. Analytical data
for compound 24a: Rf = 0.07 (n-hexane/ethyl acetate = 2:1 v/v); Obtained NMR matches with literature
data.37 1H NMR (400 MHz, CDCl3): 1.12 (t, J = 7.0 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H), 2.39 (s, 3H), 3.12
(q, J = 6.7 Hz, 2H), 3.52 (q, J = 7.0 Hz, 2H), 11.64 (s, 1H); 13C NMR (100 MHz, CDCl3): 12.7, 14.0,
25.7, 39.3, 42.9, 152.4, 164.2, 195.2. Analytical data for compound 24b: Rf = 0.31 (n-hexane/ethyl
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acetate = 2:1 v/v); H NMR (400 MHz, CDCl3): 1.18 – 1.32 (m, 12H), 3.31 (q, J = 7.2 Hz, 2H), 3.48-
3.55 (m, 4H), 3.59 (q, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): 12.6, 12.7, 14.4, 14.7, 40.5, 41.1,
43.3., 43.8, 111.5, 152.3, 154.8, 156.8; HRMS (ESI): [M+Na]+ calcd for C12H20N4O4Na: 307.1382,
found 307.1372, [M+K]+ calcd for C12H20N4O4K: 323.1122, found 323.1111.
4-Methoxy-4-oxobutanoic acid (26), methyl 4,5-dioxohexanoate (26a), methyl 4-(hydroxyimino)-5-
oxohexanoate (26b): General nitration procedure was used (0.38 mL (2.16 mmol) of substrate 25 in
CH2Cl2 (5.62 mL)). Quenching and deacylation procedure: for 4 mL of the collected solution 5 g of
MgSO4 and 20 mL CH2Cl2 were used, the reaction mixture was filtered and concentrated under
reduced pressure. Crude was purified by column chromatography (n-hexane /ethyl acetate 5:1 →1:1
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and then DCM → DCM/MeOH 100:1 → 60:1 → 5:1 v/v) to give compound 26 (65.4 mg, 34%) as an
yellow oil together with compound 26a (5.6 mg, 3%) as a yellow oil, and compound 26b (22.0 mg, 9%)
as a white amorphous solid. Additionally unreacted starting material was identified by 1H NMR but was
not isolated due to tedious purification procedure. Analytical data for compound 26: Obtained NMR
matches with the literature data.38 1H NMR (400 MHz, CDCl3): 2.60-2.69 (m, 4H), 3.69 (s, 3H), 8.5-9.5
(br, COOH); 13C NMR (100 MHz, CDCl3): 28.8, 29.1, 52.1, 172.8, 178.4. Analytical data for compound
26a: Rf = 0.4 (n-hexane/ethyl acetate =4:1 v/v); 1H NMR (600 MHz, CDCl3): 2.36 (s, 3H), 2.66 (t, J = 6
Hz 2H), 3.03 (t, J = 6 Hz, 2H), 3.69 (s, 3H); 13C NMR (151 MHz, CDCl3): 23.8, 27.8, 30.9, 52.1, 172.9,
197.1, 197.6; HRMS (ESI): [M+Na]+ calcd for C7H10O4Na: 181.0477, found 181.0478. Compound 26a
was previously synthesized.39 Analytical data for compound 26b: Rf = 0.37 (DCM/MeOH = 30:1 v/v);;
1H NMR (400 MHz, CDCl3): 2.37 (s, 3H), 2.52 (t, J = 7.8 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 3.67 (s, 3H),
7.89 (s, 1H); 13C NMR (100 MHz, CDCl3): 18.2, 25.4, 30.2, 52.0, 158.8, 173.2, 196.7; HRMS (ESI):
[M+Na]+ calcd for C7H11NO4Na: 196.0586, found 196.0579, [M+K]+ calcd for C7H11NO4K 212.0325,
found 212.0322.
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6-Ethoxy-5,6-dioxohexanoic acid (28), 6-ethoxy-5-(hydroxyimino)-6-oxohexanoic acid (31), 6-ethoxy-5-
nitro-6-oxohexanoic acid (28b): General nitration procedure was used (0.75 mL (5.06 mmol) of ethyl
2-oxocyclopentanecarboxylate (27) in CH2Cl2 (13.25 mL)). Quenching and deacylation procedure: for
11 mL of the collected solution 10 g of MgSO4 and 20 mL CH2Cl2 were used, the reaction mixture was
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filtered and concentrated under reduced pressure. Analysis of crude H NMR revealed formation of 6-
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ethoxy-5,6-dioxohexanoic acid (28) with the 61% yield determined by H NMR using mesitylene as
internal standard. Presumably ethyl 1-nitro-2-oxocyclopentanecarboxylate (29) was formed, as
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suggested by the H NMR spectrum (1H NMR (400 MHz, CDCl3): 2.05-2.13 (m, 2H), 2.53-2.61 (m,
2H), 2.81 (dt, J = 14.5, 7.3 Hz, 1H), 2.96 (dt, J = 14.0, 6.8 Hz, 1H), peaks corresponding to EtO-group
are overlapping with EtO-group of another compound) which, upon standing, spontaneously
undergoes a ring-opening reaction with atmospheric water to give compound 28b. The residue was
purified by column chromatography (n-hexane/ethyl acetate 15:1 → 10:1 and then DCM/MeOH 60:1
→ 15:1 v/v) to give compound 28 (353 mg, 47%) as a yellow oil, oxime 31 (42.2 mg, 5%) as a white
solid and compound 28b (33 mg, 4%) as a white solid. Analytical data for compound 28: Rf = 0.45
(DCM/MeOH = 15:1 v/v/v); Analytical data for the compound 28 matches with the literature data.40 1
H
NMR (400 MHz, CDCl3): 1.37 (t, J = 7.1 Hz, 3H), 1.97 (quin, J = 7.2 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H),
2.95 (t, J = 7.1 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 9-11 (br signal COOH); 13C NMR (100 MHz, CDCl3):
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14.0, 17.9, 32.6, 38.2, 62.6, 160.8, 179.2, 193.7. Analytical data for compound 31: Rf = 0.31
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(DCM/MeOH = 15:1 v/v/v); mp 106–108 °C; H NMR: (400 MHz, CDCl3): 1.35 (t, J = 7.1 Hz, 3H), 1.96
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(p, J = 6.9 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.73 (t, J = 7.0 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 10-12 (br
signal COOH), signal for N-OH proton is not observed; 13C NMR (100 MHz, CDCl3) 14.1, 21.0, 24.3,
33.6, 62.1, 151.9, 163.2, 178.2; HRMS (ESI): [M+Na]+ calcd for C8H13NO5Na 226.0691, found
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226.0686. Analytical data for compound 28b: Rf = 0.48 (DCM/MeOH = 15:1 v/v/v); mp 47–49 °C; H
NMR (400 MHz, CDCl3): 1.31 (dd, J = 7.1, 7.1 Hz, 3H), 1.67-1.80 (m, 2H), 2.18-2.27 (m, 1H), 2.29-
2.39 (m, 1H), 2.46 (t, J = 7.1 Hz, 2H), 4.29 (ddd, J = 7.1, 7.1 , 7.1 Hz, 2H), 5.12 (dd, J = 9.3, 5.5 Hz,
1H), 10-12 (br signal COOH); 13C NMR (100 MHz, CDCl3) 14.0, 20.8, 29.5, 33.0, 63.3, 87.8, 164.4,
178.7; HRMS (ESI): [M-H]+ calcd for C8H12NO6: 218.0665, found 218.0686.
2. Supporting Information
1H and 13C NMR spectra for all new compounds, optimization experiments to determine minimum
amount of desiccant needed for the quenching procedure
3. Author information
Notes
The authors declare no competing financial interest.
4. Acknowledgments
We gratefully acknowledge the financial support of the Max Planck Society. We also thank Fabian
Klautzsch and Sebastian Schmid for recording high-resolution mass spectra.
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