Selective amination reactions of α-nitro aryl and heteroaryl enoates

Article abstract of DOI:10.1021/jo4012859

Highly functionalized tetrasubstituted alkenes were obtained by an unexpected amination reaction promoted by ethyl nosyloxycarbamate on various α-nitro aryl and heteroaryl enoates. A nitrene is likely the aminating species responsible for the observed insertion reaction leading to (E)-β-amino α-nitro enoates as the major products, regardless of the substrate configuration. The compounds, bearing two nitrogenous functional groups in different oxidation states, can be regarded as interesting synthons. In contrast, aziridination was observed for α-nitro alkyl enoates or β-nitro allylic alcohols.

Full text of DOI:10.1021/jo4012859

Note
pubs.acs.org/joc
Selective Amination Reactions of α‑Nitro Aryl and Heteroaryl Enoates
Stefania Fioravanti,* Lucio Pellacani, and Maria Cecilia Vergari
̀
Dipartimento di Chimica, Universita degli Studi di Roma “La Sapienza”, P.le A. Moro 5, I-00185 Roma, Italy
S
* Supporting Information
ABSTRACT: Highly functionalized tetrasubstituted alkenes
were obtained by an unexpected amination reaction promoted
by ethyl nosyloxycarbamate on various α-nitro aryl and
heteroaryl enoates. A nitrene is likely the aminating species
responsible for the observed insertion reaction leading to (E)-
β-amino α-nitro enoates as the major products, regardless of
the substrate configuration. The compounds, bearing two
nitrogenous functional groups in different oxidation states, can be regarded as interesting synthons. In contrast, aziridination was
observed for α-nitro alkyl enoates or β-nitro allylic alcohols.
he versatility of the nitro group, often called a “chemical
the domino synthetic procedure reported by us,15 some aryl
and heteroaryl α-nitro enoates were synthesized and then
tested in the amination reactions via carbamate to obtain
precursors of amino acids,16 bearing two nitrogenous functional
groups in different oxidation states in the same structure.
The amination with ethyl nosyloxycarbamate (NsONH-
CO2Et) was attempted on (E/Z)-1a; however, even when
some reaction conditions, such as temperatures (0 °C, rt, 40
°C), solvents (CH2Cl2 or THF), concentrations, molar ratios,
and/or inorganic bases (CaO or NaH), were changed, complex
crude mixtures were obtained in all cases. The 1H NMR
analysis always showed after ca. 1.5 h substrate signal
disappearance along with the appearance of two singlets
around 9.65 (major) and 9.87 ppm, as the only clear new
signals. The best reaction conditions were fixed by using a
molar ratio of 1a/CaO/NsONHCO2Et = 1:3:1.5 in CH2Cl2 at
room temperature with stirring for 1 h. After purification by
flash chromatography, the multifunctionalized isomers (2a)
were isolated, as the only amination products (Scheme 1).
1
Tchameleon”,
as a precursor of various functionalities
makes nitro alkenes attractive starting materials to obtain
variously functionalized nitro alkanes, compounds in which the
nitro group can be transformed into various useful functional
groups.2−6 Because of the significance of nitro alkenes in
organic synthesis, some methodologies have been developed
giving multifunctionalized structures by modifying both the
classical Henry addition/β-elimination procedure7 and using
the Morita−Baylis−Hillman condensation.8 Nitro alkenes are
among the most important Michael acceptors because of the
strong electron-withdrawing capacity of the nitro group.9,10
Efficient access to adjacent quaternary and tertiary stereo-
centers can be achieved through addition of substituted cyclic
or acyclic β-keto esters, α-cyano acetate, and dimethyl malonate
nucleophiles to nitro alkenes bearing aryl, heteroaryl, and alkyl
groups.11 Also, nitrogen nucleophiles, such as aza-anions
derived from alkyl nosyloxycarbamates (NsONHCO2R; Ns =
4-NO2C6H4SO2), gave, under heterogeneous conditions, aza-
Michael additions, followed by ring-closure reactions to
variously alkyl or aryl substituted nitro alkenes, leading to the
corresponding functionalized nitro aziridines.12,13 These latter
compounds are intriguing precursors of various aminated
compounds as well as of more complex heterocyclic
compounds.
Scheme 1. Amination Reaction of E/Z Mixture of Nitro
Enoates 1a
Recently, starting from conjugated dinitro dienes, a highly
stereoselective synthesis of ( )-bis(nitroaziridines) was re-
ported by us.14 The aziridination reactions led to the expected
compounds in very good yields, but, surprisingly, only starting
from alkyl substituted nitro alkenes. On the contrary, the
reactions were unsuccessful starting from dinitro dienes bearing
aryl groups.
Interested in these results and with the aim of obtaining
further data on the amination outcome of aryl nitro alkenes, we
decided to investigate the reactivity of various gem-disubstituted
aryl nitro alkenes, such as α-nitro cinnamates and hetero
analogues, which are versatile building blocks widely used in
organic synthesis as good Michael acceptors. Thus, following
Furthermore, the stereochemical reaction outcome appeared
quite intriguing. In fact, starting from a 40:60 E/Z mixture of
1a, the corresponding E/Z mixture of 2a was obtained with a
diastereomeric ratio of E/Z = 80:20, as determined from H
NMR spectra obtained from the crude mixture, suggesting that
the amination reaction takes place through an intermediate in
1
Received: June 14, 2013
Published: July 16, 2013
© 2013 American Chemical Society
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Note
which the configuration of the starting (E)-alkene was partially
lost.
mixtures clearly showed the same stereochemical results
starting both from various nitro alkenes and even from
mixtures of them. In fact, compounds 2 were always obtained
with an E/Z ratio = 80:20. Also, when the aminations were
performed starting from pure isomers (entries 9−12), the
reactions proceeded by a two-step process involving an
intermediate in which the free rotation around the single C−
C bond is permitted under thermodynamic control.
Interested in the obtained results, we decided to repeat the
amination reaction starting from pure α-nitro enoates (E)-1a
and (Z)-1a, with the hope of getting more insight on the
stereochemical outcome. Unexpectedly, the same diastereo-
meric ratio (80:20) of (E/Z)-2a was obtained, starting from
either pure (E)- or pure (Z)-alkene (Scheme 2).
On the basis of these data, the amination reaction was
attempted under heterogeneous conditions (NsONHCO2Et/
CaO/CH2Cl2) on the alkyl analogue (E/Z)-1i,15 in order to
study the influence of the β-substituent on the amination
reaction pathway.
Scheme 2. Amination Reactions of Pure (E)- and (Z)-Nitro
Enoates 1a
After only a few minutes, NMR analyses performed on the
crude mixture showed a completely different outcome for this
reaction, (E/Z)-1i being quantitatively converted into the
corresponding diastereomeric aziridines 3,3′ (95% yield) that
were formed as usual by a reaction via aza-anion12,13 in a
diastereomeric ratio (dr) very similar to that of the starting
alkenes (Scheme 3). The result could suggest that the observed
Next, we considered the amination reactions of the (E/Z)-α-
nitro enoates 1b−1h in order to study the reproducibility of the
observed amination pathway and stereochemical outcome and
so gain further data useful to explain the reaction of 1a. The
results are reported in Table 1.
Scheme 3. Aziridination of E/Z Mixture of Nitro Enoates 1i
with NsONHCO2Et
In all cases, the β-amino α-nitro enoates (E/Z)-2 were
obtained as the only amination products after flash chromatog-
raphy on silica gel, although in moderate yields, probably due to
loss during the purification process, and no starting material
was recovered. The most interesting data is the stereoselectivity
1
of the reactions. Surprisingly, H NMR analyses of the crude
Table 1. Amination Reactions of the (E/Z)-α-Nitro
Enoates
(E/Z)-2 may result from unstable and not isolable aryl
substituted aziridines by a successive rearrangement reaction.
To test this hypothesis, aziridines 3,3′ were stirred in the
presence of CaO, either at room temperature or at 40 °C, also
for long times, but in all cases, they were almost completely
recovered in the same diastereomeric ratio, thus indicating a
certain stability for these heterocyclic compounds.
ab c d
, , ,
If the hypothesis outlined above can be excluded,
tetrasubstituted alkenes 2 may be formed through an
unexpected regioselective attack of (ethoxycarbonyl)nitrene
(NCO2Et),17 formed in situ by an α-elimination reaction of the
corresponding aza-anion (NsON−CO2Et). To gain more
insight,18 tert-butyl nosyloxycarbamate (NsONHBoc) was
considered as a useful reagent because it is known19,20 to give
alkene aziridination reactions only through the aza-anion
pathway,21 the corresponding nitrene being not formed. The
aminations were separately attempted on nitro alkenes 1a and
1i carefully under the same reaction conditions and also while
changing some reaction parameters (molar ratios, reaction time,
concentration). Starting from 1i, N-Boc-protected aziridines
4,4′ were obtained in very high yields (95%) under the usual
conditions (Scheme 4), while all attempts to aminate 1a failed,
the unreacted substrate being always recovered.22
Scheme 4. Aziridination of E/Z Mixture of Nitro Enoates 1i
with NsONHBoc
a
Overall yields in the amination products after flash chromatography
on silica gel. For the yields of each isomer, see the Experimental
b
Section. Purified by flash chromatography on silica gel (eluent
c
hexane/ethyl acetate = 4:6). Purified by flash chromatography on
d
silica gel (eluent hexane/ethyl acetate = 8:2). Purified by flash
chromatography on silica gel (eluent hexane/ethyl acetate = 1:1).
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Scheme 5. Possible Pathway for the Synthesis of 2
The results seem to support the hypothesis that the synthesis
of (E/Z)-2 involves NCO2Et as an aminating agent, in contrast
to the possibility that these compounds can derive from an aza-
MIRC (Michael Initiated Ring Closure)12 reaction, followed by
the isomerization of highly unstable aziridine intermediates.
A possible reaction pathway involving a two-step reaction of
(ethoxycarbonyl)nitrene on aryl substituted 1 is proposed to
explain the stereochemical course of the amination reactions
(Scheme 5).
(E)-β-amino α-nitro enoates with good stereoselectivity,
regardless of the substrate configuration. It is well-known that
tetrasubstituted alkenes are very interesting compounds in
organic chemistry, often difficult to synthesize.27−32 Com-
pounds with structures similar to those reported here were
rarely present in the literature, as patents, and showed
insecticidal properties.33−35 In addition, obtained β-amino α-
nitro enoates can be regarded as interesting synthons.36
It is possible that the obtained tetrasubstituted alkenes 2
derive from the involvement of a triplet species (I). In the
intermediate II, the hydrogen abstraction reaction23 might be
much faster than the ring-closure reaction, leading to the vicinal
diradical species III, that mainly collapses after rotation around
the C−C single bond. In this way, major products were (E)-
vinyl carbamates, further stabilized by an intramolecular
hydrogen bond with the carbonyl group that, as is well-
known, forms hydrogen bonds stronger than a nitro group.24,25
Considering the possibility that the observed reaction
outcome may be due to the effect of the presence of two
geminal electron-withdrawing groups on the double bond, the
amination reactions with NsONHCO2Et were performed on
(E)-2-nitro allylic alcohols bearing various aryl or heteroaryl
substituents (Ph, p-NO2C6H4, p-OMe-C6H4, 2-furyl). No
amination reactions were observed even after long reaction
times (72 h) and independently from the nature of the
considered aryl residue. On the contrary, (E)-2-nitro allylic
alcohol 5 was quantitatively converted into the corresponding
aziridine 6, so showing the effectiveness of the aza-MIRC
reactions via carbamates even in the presence of a hydroxy
group (Scheme 6).
EXPERIMENTAL SECTION
■
IR spectra were recorded on an FT/IR spectrophotometer in CHCl3
as the solvent. 1H NMR and 13C NMR spectra were recorded by a 300
MHz NMR spectrometer. CDCl3 was used as the solvent and CHCl3
as the internal standard. HRMS analyses were performed using a
quadrupole time-of-flight (TOF) mass spectrometer equipped with an
ESI source and a syringe pump. The experiments were conducted in
the positive ion mode. NsONHCO2Et,37 NsONHBoc,20,38 and α-nitro
enoates 1a−1h15 were synthesized according to literature procedures.
Amination Reactions of Nitro Alkenes 1a−1g. General
Procedure. To a stirred CH2Cl2 (4 mL) solution of (E,Z)-1 (1
mmol) were added CaO (3 mmol) and NsONHBoc (1.5 mmol) at
room temperature. After the reactions were complete (TLC), hexane
was added, the crude mixtures were filtered, and the solvents were
removed in vacuo. The diastereomeric crude mixtures were purified by
flash chromatography on silica gel.
Synthesis of (Z)- and (E)-2a. Overall yield: 30%, from an (E/Z)-
alkene mixture, 29% from (Z)-alkene, 32% from (E)-alkene. Purified
by flash chromatography on silica gel (eluent: hexane/ethyl acetate =
7:3); νmax 3559, 3288, 1759, 1736, 1688, 1536 cm−1.
Ethyl (2Z)-3-[(Ethoxycarbonyl)amino]-3-(furan-2-yl)-2-nitro-
prop-2-enoate. (Orange oil, 18.6 mg from (E)-alkene): H NMR δ
1.20 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 4.20 (q, J = 7.1 Hz,
2H), 4.30 (q, J = 7.1 Hz, 2H), 6.54 (dd, J = 3.6 Hz, 1.7 Hz, 1H), 6.87
(dd, J = 3.5 Hz, 0.7 Hz, 1H), 7.63 (dd, J = 1.7 Hz, 0.7 Hz, 1H), 9.87
(br, 1H); 13C NMR δ 13.7, 14.0, 62.5, 62.7, 112.2 (2C), 117.3, 137.4,
142.2, 146.4, 151.0, 160.5; HRMS (ESI-QToF) m/z calcd for
C12H14N2NaO7 [M + Na]+ 321.0699, found 321.0691.
1
Scheme 6. Aziridination of 2-Nitro Allylic Alcohol (E)-5
Ethyl (2E)-3-[(Ethoxycarbonyl)amino]-3-(furan-2-yl)-2-nitro-
1
prop-2-enoate. (Orange oil, 74.0 mg from (E)-alkene): H NMR δ
1.26 (t, J = 7.1 Hz, 3H); 1.33 (t, J = 7.1 Hz, 3H); 4.16 (q, J = 7.1 Hz,
2H, CH2); 4.34 (q, J = 7.1 Hz, 2H); 6.51 (dd, J = 3.6 Hz, 1.8 Hz, 1H);
6.82 (dd, J = 3.6 Hz, 0.7 Hz, 1H) 7.59 (dd, J = 1.8 Hz, 0.7 Hz, 1H);
9.65 (br, 1H); 13C NMR δ 13.9; 14.1; 62.7; 62.8; 112.4 (2C); 116.6;
139.1; 141.4; 146.0; 151.7; 161.7; HRMS (ESI-QToF) m/z calcd for
C12H14N2NaO7 [M + Na]+ 321.0699, found 321.0703.
Synthesis of (Z)- and (E)-2b. Overall yield: 21% (62.6 mg).
Purified by flash chromatography on silica gel (eluent: hexane/ethyl
acetate = 8:2); νmax 3565, 3249, 1758, 1739, 1688, 1536 cm−1. Ethyl
(2Z)-3-[(ethoxycarbonyl)amino]-3-(furan-3-yl)-2-nitroprop-2-enoate
(brown oil, 12.5 mg): 1H NMR δ 1.15 (t, J = 7.1 Hz, 3H), 1.29 (t, J =
7.1 Hz, 3H), 4.19 (q, J = 7.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 6.51−
6.52 (m, 1H), 7.48−7.49 (m, 1H), 7.63−7.64 (m, 1H), 10.59 (br,
1H); 13C NMR δ 13.5, 14.1, 62.7, 63.2, 111.3, 124.2, 131.0, 143.4,
143.6, 143.8, 151.7, 162.1; HRMS (ESI-QToF) m/z calcd for
C12H14N2NaO7 [M + Na]+ 321.0699, found 321.0690. Ethyl (2E)-3-
[(ethoxycarbonyl)amino]-3-(furan-3-yl)-2-nitroprop-2-enoate (brown oil,
50.0 mg): 1H NMR δ 1.26 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H),
4.15 (q, J = 7.1 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 6.46−6.47 (m, 1H),
7.45−7.46 (m, 1H), 7.60−7.63 (m, 1H), 10.16 (br, 1H); 13C NMR δ
14.0 (2C), 62.6; 62.8; 110.8, 124.4, 129.1, 143.1, 143.3, 143.8, 151.5,
As expected,26 aziridine 6 was formed with total retention of
the alkene configuration, possibly due to the formation of the
intermediate complex IV in which the rotation around the C−
C single bond was inhibited.
These last results clearly show the influence of the ester
moiety on the amination of α-nitro enoates. The presence of
the ester group in the geminal position with respect to the nitro
group seems to modify the double bond polarization, thus
allowing formation of β-amino α-nitro enoates.
In conclusion, the synthesis of highly functionalized
tetrasubstituted alkenes characterized by the presence of two
nitrogenous functional groups in different oxidation states of α-
and β-positions was reported. The aminations most likely
involved a nitrene species that gave a formal regioselective
insertion reaction only on the benzyl C−H bonds, leading to
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162.0; HRMS (ESI-QToF) m/z calcd for C12H14N2NaO7 [M + Na]+
321.0699, found 321.0693.
Synthesis of (Z)- and (E)-2g. Overall yield: 23% from (Z)-alkene,
22% from (E)-alkene. Purified by flash chromatography on silica gel
(eluent: hexane/ethyl acetate = 8:2); νmax 3545, 3264, 1761, 1737,
1684, 1534 cm−1. Ethyl (2Z)-3-[(ethoxycarbonyl)amino]-2-nitro-3-(4-
methoxyphenyl)prop-2-enoate (pale yellow oil, 15.5 mg from (Z)-
alkene): 1H NMR δ 1.25 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H),
3.83 (s, 3H), 4.13 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 7.02−
7.08 (m, 2H), 7.31−7.36 (m, 2H), 10.60 (br, 1H); 13C NMR δ 13.5,
14.3, 55.3, 62.3, 63.0, 113.8, 121.9, 129.2 (2C), 129.8 (2C), 150.0,
151.1, 161.7, 163.0; HRMS (ESI-QToF) m/z calcd for C15H19N2O7
[M + H]+ 339.1192, found 339.1183. Ethyl (2E)-3-[(ethoxycarbonyl)-
amino]-2-nitro-3-(4-methoxyphenyl)prop-2-enoate (pale yellow oil, 62.2
mg from (Z)-alkene): 1H NMR δ 1.22 (t, J = 7.1 Hz, 4H), 1.31 (t, J =
7.1 Hz, 3H), 3.81 (s, 3H), 4.09 (q, J = 7.1 Hz, 2H), 4.36 (q, J = 7.1 Hz,
4H), 6.94−7.04 (m, 2H), 7.26−7.31 (m, 2H), 10.23 (br, 1H); 13C
NMR δ 14.0, 14.1, 55.2, 62.4, 62.6, 113.9, 121.6, 129.1 (2C), 129.6
(2C), 150.3, 151.8, 161.5, 162.2; HRMS (ESI-QToF) m/z calcd for
C15H19N2O7 [M + H]+ 339.1192, found 339.1201.
Synthesis of (Z)- and (E)-2h. Overall Yield: 27% (96.6 mg).
Purified by flash chromatography on silica gel (eluent: hexane/ethyl
acetate = 7:3); νmax 3559, 3244, 1755, 1738, 1689, 1551 cm−1. Ethyl
(2Z)-3-[(ethoxycarbonyl)amino]-2-nitro-3-(naphthalen-1-yl)prop-2-
enoate (brown oil, 19.3 mg): 1H NMR δ 1.02 (t, J = 7.1 Hz, 3H), 1.26
(t, J = 7.1 Hz, 3H), 4.10 (q, J = 7.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H),
7.41−7.53 (m, 2H), 7.61−7.69 (m, 2H), 7.86−7.96 (m, 2H), 8.11−
8.15 (m, 1H), 10.64 (br, 1H); 13C NMR δ 13.3, 14.1, 62.0, 63.1, 111.5,
124.7, 124.9, 126.3, 127.1, 128.5, 128.7, 131.3, 133.3, 135.9, 136.4,
147.9, 157.8, 161.6; HRMS (ESI-QToF) m/z calcd for C18H18N2NaO6
[M + Na]+ 381.1063, found 381.1071. Ethyl (2E)-3-[(ethoxycarbonyl)-
amino]-2-nitro-3-(naphthalen-1-yl)prop-2-enoate (brown oil, 77.3 mg):
1H NMR δ 1.05 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 4.10 (q, J
= 7.1 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 7.42−7.55 (m, 2H), 7.61−
7.70 (m, 2H), 7.84−7.95 (m, 2H), 8.19−8.23 (m, 1H); 10.37 (br,
1H); 13C NMR δ 13.4, 14.0, 62.6, 63.0, 111.7, 124.8, 125.0, 126.8,
127.1, 128.4, 128.6, 131.3, 133.1, 135.1, 136.2, 147.9, 157.7, 161.7;
HRMS (ESI-QToF) m/z calcd for C18H18N2NaO6 [M + Na]+
381.1063, found 381.1059.
Synthesis of (Z)- and (E)-2c. Overall yield: 24% (74.5 mg).
Purified by flash chromatography on silica gel (eluent: hexane/ethyl
acetate = 7:3); νmax 3566, 3268, 1754, 1733, 1684, 1535 cm−1. Ethyl
(2Z)-3-[(ethoxycarbonyl)amino]-2-nitro-3-(thiophen-2-yl)prop-2-enoate
(brown oil, 15.1 mg): 1H NMR δ 1.26 (t, J = 7.0 Hz, 3H), 1.33 (t, J =
7.0 Hz, 3H), 4.17 (q, J = 7.0 Hz, 2H), 4.34 (q, J = 7.0 Hz, 2H), 7.06−
7.09 (m, 1H), 7.28−7.30 (m, 1H), 7.62−7.64 (m, 1H), 10.26 (br,
1H); 13C NMR δ 13.9, 14.1, 62.2; 63.3, 115.1, 127.2, 130.6, 131.2,
131.4, 144.5, 151.9, 160.5; HRMS (ESI-QToF) m/z calcd for
C12H14N2NaO6S [M + Na]+ 337.0457, found 337.0463. Ethyl (2E)-
3-[(ethoxycarbonyl)amino]-2-nitro-3-(thiophen-2-yl)prop-2-enoate
(brown oil, 60.3 mg): 1H NMR δ 1.23 (t, J = 7.0 Hz, 3H), 1.35 (t, J =
7.0 Hz, 3H), 4.12 (q, J = 7.0 Hz, 2H), 4.31 (q, J = 7.0 Hz, 2H), 7.04−
7.07 (m, 1H), 7.24−7.26 (m, 1H), 7.59 (dd, J = 5.0 Hz, 1.1 Hz, 1H),
9.98 (br, 1H); 13C NMR δ 14.0, 14.1, 62.7, 62.8, 115.4, 127.4, 130.6,
131.1, 131.4, 144.5, 151.8, 161.7; HRMS (ESI-QToF) m/z calcd for
C12H14N2NaO6S [M + Na]+ 337.0457, found 337.0464.
Synthesis of (Z)- and (E)-2d. Overall yield: 27% (83.2 mg).
Purified by flash chromatography on silica gel (eluent: hexane/ethyl
acetate = 8:2); νmax 3566, 3268, 1754, 1733, 1684, 1535 cm−1. Ethyl
(2Z)-3-[(ethoxycarbonyl)amino]-2-nitro-3-phenylprop-2-enoate (yellow
1
oil, 16.6 mg): H NMR δ 1.10 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1
Hz, 3H), 4.12 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 7.26−7.65
(m, 5H), 10.66 (br, 1H); 13C NMR δ 14.2, 14.3, 62.8, 63.9, 112.0,
127.7, 128.2, 128.6 (2C), 129.5, 130.8, 148.8, 153.4, 162.5; HRMS
(ESI-QToF) m/z calcd for C14H16N2NaO6 [M + Na]+ 331.0906,
found 331.0897. Ethyl (2E)-3-[(ethoxycarbonyl)amino]-2-nitro-3-
1
phenylprop-2-enoate (yellow oil, 66.5 mg): H NMR δ 1.20 (t, J =
7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 4.07 (q, J = 7.1 Hz, 2H), 4.35 (q,
J = 7.1 Hz, 2H), 7.27−7.72 (m, 5H), 10.30 (br, 1H); 13C NMR δ 14.3
(2C), 62.6, 63.4, 111.8, 127.6, 128.0, 128.4 (2C), 129.2, 130.9, 147.9,
152.0, 160.6; HRMS (ESI-QToF) m/z calcd for C14H16N2NaO6 [M +
Na]+ 331.0906, found 331.0911.
Synthesis of (Z)- and (E)-2e. Overall yield: 24% (78.2 mg).
Purified by flash chromatography on silica gel (eluent: hexane/ethyl
acetate = 8:2); νmax 3565, 3262, 1761, 1734, 1686, 1542 cm−1. Ethyl
(2Z)-3-[(ethoxycarbonyl)amino]-2-nitro-3-(4-fluorophenyl)prop-2-enoate
(dark yellow oil, 15.6 mg): 1H NMR δ 1.11 (t, J = 7.1 Hz, 3H), 1.25 (t,
J = 7.1 Hz, 3H), 4.13 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H),
7.07−7.13 (m, 2H), 7.32−7.36 (m, 2H), 10.63 (br, 1H); 13C NMR δ
13.5, 13.9, 62.5, 63.0, 113.5, 115.7, 124.4 (2C), 130.3, 130.4, 131.0,
151.6, 162.3, 165.6; HRMS (ESI-QToF) m/z calcd for C14H15FN2-
NaO6 [M + Na]+ 349.0812, found 349.0820. Ethyl (2E)-3-[(ethoxy-
carbonyl)amino]-2-nitro-3-(4-fluorophenyl)prop-2-enoate (dark yellow
Synthesis of Aziridines 3,3′. To a stirred CH2Cl2 (4 mL)
solution of (E,Z)-1i (1 mmol) were added CaO (3 mmol) and
NsONHCO2Et (1.5 mmol) at room temperature. When the reaction
was complete (15 min), hexane was added and the crude mixture was
filtered and, after evaporation of solvents in vacuo, purified by flash
chromatography on silica gel to give pure 3 and 3′. Overall yield: 276.5
mg, 96%. Diethyl (2R*,3R*)-3-(2-methylpropyl)-2-nitroaziridine-1,2-
dicarboxylate (3) (pale yellow oil, 179.7 mg, 65%) νmax 1757, 1567,
1
1538 cm−1; H NMR δ 1.02 (d, J = 6.7 Hz, 6H), 1.28 (t, J = 7.1 Hz,
1
3H), 1.33 (t, J = 7.2 Hz, 3H), 1.52−1.61 (m, 1H), 1.84−1.97 (m, 2H),
3.42 (dd, J = 3.9 Hz, 8.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.41 (q, J =
7.2 Hz, 2H); 13C NMRδ 13.8, 14.1, 22.0, 22.1, 26.5, 36.9, 48.5, 63.8,
64.4, 89.7, 156.6, 161.1; HRMS (ESI-QToF) m/z calcd for
C12H20N2NaO6 [M + Na]+, 311.1219 found 311.1234. Diethyl
(2R*,3S*)-3-(2-methylpropyl)-2-nitroaziridine-1,2-dicarboxylate (3′)
(pale yellow oil, 96,8 mg, 35%) νmax 1757; 1567; 1538 cm−1; 1H
NMR δ 1.01 (d, J = 6.7 Hz, 6H), 1.27 (t, J = 7.1 Hz, 3H), 1.37 (t, J =
7.1 Hz, 3H), 1.62−1.71 (m, 1H), 1.84−1.99 (m, 2H), 3.49 (dd, J = 4.7
Hz, 8.2 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H);
13C NMR δ 13.8, 14.0, 22.0, 22.2, 26.6, 36.8, 49.0, 63.5, 63.8, 93.9,
155.9, 159.6; HRMS (ESI-QToF) m/z calcd for C12H20N2NaO6 [M +
Na]+ 311.1219, found 311.1227.
Synthesis of Aziridines 4,4′. To a stirred CH2Cl2 (4 mL)
solution of (E,Z)-1i (1 mmol) were added CaO (3 mmol) and
NsONHBoc (1.5 mmol) at room temperature. When the reaction was
complete (1.5 h), hexane was added and the crude mixture was filtered
and, after evaporation of solvents in vacuo, purified by flash
chromatography on silica gel to give pure 4 and 4′. Overall yield:
300.2 mg, 95%. 1-tert-Butyl 2-ethyl (2R*,3R*)-3-(2-methylpropyl)-2-
nitroaziridine-1,2-dicarboxylate (4) (pale yellow oil, 201.0 mg, 67%)
νmax 1756, 1557, 1538 cm−1; 1H NMR δ 1.02 (d, J = 6.7 Hz, 6H), 1.37
(t, J = 7.1 Hz, 3H), 1.46 (s, 9H), 1.61−1.70 (m, 1H), 1.83−1.97 (m,
2H), 3.49 (dd, J = 4.4 Hz, 8.5 Hz, 1H), 4.33−4.49 (m, 2H); 13C NMR
oil, 62.6 mg): H NMR δ 1.22 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1
Hz, 3H), 4.09 (q, J = 7.1 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 7.05−7.11
(m, 2H), 7.32−7.37 (m, 2H), 10.29 (br, 1H); 13C NMR δ 13.8, 14.0,
62.6, 62.7, 113.6, 115.9, 124.2, 125.4, 129.6, 129.8, 131.1, 150.7, 162.1,
165.5; HRMS (ESI-QToF) m/z calcd for C14H15FN2NaO6 [M + Na]+
349.0812, found 349.0796.
Synthesis of (Z)- and (E)-2f. Overall yield: 32%, from an (E/Z)-
alkene mixture, 27% from (Z)-alkene, 25% from (E)-alkene. Purified
by flash chromatography on silica gel (eluent: hexane/ethyl acetate =
8:2); νmax 3566, 3265, 1754, 1737, 1689, 1534 cm−1. Ethyl (2Z)-3-
[(ethoxycarbonyl)amino]-2-nitro-3-(4-nitrophenyl)prop-2-enoate (orange
1
oil, 22.6 mg from an (E/Z)-alkene mixture): H NMR δ 1.26 (t, J =
7.1 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 4.13 (q, J = 7.1 Hz, 2H), 4.38 (q,
J = 7.1 Hz, 2H), 7.56−7.62 (m, 2H), 8.24−8.31 (m, 2H), 1.60 (br,
1H); 13C NMR δ 13.5, 14.0, 62.8, 63.6, 112.3, 123.3, 124.3, 129.4
(2C), 135.8, 148.9, 149.1, 151.6, 162.4; HRMS (ESI-QToF) m/z calcd
for C14H15N3NaO8 [M + Na]+ 376.0757, found 376.0745. Ethyl (2E)-
3-[(ethoxycarbonyl)amino]-2-nitro-3-(4-nitrophenyl)prop-2-enoate (or-
1
ange oil, 90.4 mg from an (E/Z)-alkene mixture): H NMR δ 1.23
(t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 4.09 (q, J = 7.1 Hz, 2H),
4.38 (q, J = 7.1 Hz, 2H), 7.51−7.56 (m, 2H), 8.23−8.30 (m, 2H),
10.36 (br, 1H); 13C NMR δ 13.9, 14.1, 63.0, 63.1, 111.9, 123.6, 124.0,
128.8 (2C), 136.0, 148.7, 149.1, 151.5, 161.9; HRMS (ESI-QToF) m/
z calcd for C14H15N3NaO8 [M + Na]+ 376.0757, found 376.0763.
8206
dx.doi.org/10.1021/jo4012859 | J. Org. Chem. 2013, 78, 8203−8207

The Journal of Organic Chemistry
Note
δ 13.8, 21.8, 22.1, 26.5, 27.6, 37.0, 48.8, 63.3, 81.2, 89.5, 154.3, 159.8;
HRMS (ESI-QToF) m/z calcd for C14H24N2NaO6 [M + Na]+
339.1532, found 339.1545. 1-tert-Butyl 2-ethyl (2R*,3S*)-3-(2-methyl-
propyl)-2-nitroaziridine-1,2-dicarboxylate (4′) (pale yellow oil, 99.0 mg,
(13) Fioravanti, S.; Pellacani, L.; Stabile, S.; Tardella, P. A.; Ballini, R.
Tetrahedron 1998, 54, 6169−6176.
(14) Ciogli, A.; Fioravanti, S.; Gasparrini, F.; Pellacani, L.; Rizzato, E.;
Spinelli, D.; Tardella, P. A. J. Org. Chem. 2009, 74, 9314−9318.
(15) Fioravanti, S.; Pellacani, L.; Vergari, M. C. Org. Biomol. Chem.
2012, 10, 524−528.
1
33%) νmax 1756, 1557, 1538 cm−1; H NMR δ 1.01 (d, J = 6.7 Hz,
6H), 1.34 (t, J = 7.1 Hz, 3H), 1.46 (s, 9H), 1.50−1.59 (m, 1H), 1.85−
1.96 (m, 2H), 3.40 (dd, J = 3.7 Hz, 9.1 Hz, 1H), 4.36 (q, J = 7.1 Hz,
2H); 13C NMR δ; 13.8, 21.9, 22.1, 26.5, 27.7, 36.8, 48.4, 64.2, 80.9,
103.5, 155.0, 161.2; HRMS (ESI-QToF) m/z calcd for C14H24N2NaO6
[M + Na]+ 339.1532, found 339.1539.
(16) Armstrong, A.; Ferguson, A. Beilstein J. Org. Chem. 2012, 8,
1747−1752.
(17) For recent reviews on nitrene chemistry, see: (a) Pellissier, H.
Tetrahedron 2010, 66, 1509−1555. (b) Wentrup, C. Acc. Chem. Res.
2011, 44, 393−404. (c) Dequirez, G.; Pons, V.; Dauban, P. Angew.
Chem., Int. Ed. 2012, 51, 7384−7395. (d) Roizen, J. L.; Harvey, M. E.;
Synthesis of Ethyl 2-(Hydroxymethyl)(2R*,3R*)-3-(2-methyl-
propyl)-2-nitroaziridine-1-carboxylate (6). To a stirred CH2Cl2
(3 mL) solution of (E)-5 (1 mmol) were added CaO (3 mmol) and
NsONHCO2Et (1.5 mmol) at room temperature. When the reaction
was complete (1 h), hexane was added and the crude mixture was
filtered and, after evaporation of solvents in vacuo, purified by flash
chromatography on silica gel to give pure 6 as a pale yellow oil (236.2
mg, 96%). νmax 3432, 1732, 1559, 1537 cm−1; 1H NMR δ 1.00 (d, J =
1.3 Hz, 3H), 1.04 (d, J = 1.3 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.39−
1.69 (m, 2H), 1.80−2.00 (m, 1H), 2.50 (br, 1H), 3.34 (dd, J = 7.7 Hz,
5.1 Hz, 1H), 4.10 (d, J = 13.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.40
(d, J = 13.8 Hz, 1H); 13C NMR δ 14.2, 22.1, 22.3, 26.8, 36.9, 48.7,
59.8, 63.6, 78.7, 157.0; HRMS (ESI-QToF) m/z calcd for C10H18-
N2NaO5 [M + Na]+ 269.1113, found 269.1120.
Du Bois, J. Acc. Chem. Res. 2012, 45, 911−922.
For (ethoxy-
carbonyl)nitrene, see: (e) Lwowski, W. In Nitrenes; Lwowski, W., Ed.;
Interscience: New York, 1970; Chapter 6. (f) Lwowski, W. In Azides
and Nitrenes Reactivity and Utility; Scriven, E. F. V., Ed.; Academic
Press, Inc: Orlando, FL, 1984, pp 205−246.
(18) We attempted a photolysis reaction using ethyl azidoformate
(N3CO2Et) as a source of nitrene in CH2Cl2, but a very fast
polymerization reaction of the starting alkene 1a was observed:
Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron:
Asymmetry 1990, 1, 931−936.
(19) Hanessian, S.; Johnstone, S. J. Org. Chem. 1999, 64, 5896−5903.
(20) Fioravanti, S.; Marchetti, F.; Morreale, A.; Pellacani, L.; Tardella,
P. A. Org. Lett. 2003, 5, 1019−1021.
(21) Fioravanti, S.; Massari, D.; Morreale, A.; Pellacani, L.; Tardella,
P. A. Tetrahedron 2008, 64, 3204−3211.
ASSOCIATED CONTENT
■
S
* Supporting Information
(22) Various attempts to obtain amination products were made by
increasing the molar ratios between the substrates and the reagents,
changing the inorganic base (NaH), and/or lengthening the reaction
times (72 h), but no significant result was obtained.
(23) One of us reported the probable triplet (ethoxycarbonyl)nitrene
insertion into benzylic C−H bonds: Casagrande, P.; Pellacani, L.;
Tardella, P. A. J. Org. Chem. 1978, 43, 2725−2726.
1H and 13C NMR spectra of compounds (Z)-2a−2h and (E)-
2a−2h, 3, 3′, 4, 4′, and 6 are reported. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
(24) West-Nielsen, M.; Dominiak, P. M.; Wozniak, K.; Hansen, P. E.
J. Mol. Struct. 2006, 789, 81−91.
*E-mail: stefania.fioravanti@uniroma1.it. Fax: +39 06 490631.
Phone: +39 06 49913098.
(25) Gagnon, E.; Kenneth, T. M.; Malyz, E.; Wuest, J. D. Tetrahedron
2007, 63, 6603−6613.
Notes
(26) Fioravanti, S.; Marchetti, F.; Pellacani, L.; Ranieri, L.; Tardella,
P. A. Tetrahedron: Asymmetry 2008, 19, 231−236.
The authors declare no competing financial interest.
(27) Paek, S. M. Molecules 2012, 17, 3348−3358.
ACKNOWLEDGMENTS
■
(28) Shindo, M.; Matsumoto, K. Top. Curr. Chem. 2012, 327, 1−32.
(29) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Angew. Chem., Int. Ed. 2011,
50, 1692−1695.
We are grateful for financial support from the Universita
Studi di Roma “La Sapienza”.
̀
degli
(30) Negishi, E.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori,
H. Acc. Chem. Res. 2008, 41, 1474−1485.
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