Reactions of silyl nitronates with dimethylformamide dimethyl acetal as a new general procedure for the synthesis of 2-nitroenamines

Article abstract of DOI:10.1016/j.tetlet.2014.09.071

Silyl nitronates obtained in situ from the corresponding aliphatic nitro compounds react with dimethylformamide dimethyl acetal giving 2-nitroenamines in moderate to good yields. The reaction pathway is discussed.

Full text of DOI:10.1016/j.tetlet.2014.09.071

Tetrahedron Letters 55 (2014) 6220–6223
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactions of silyl nitronates with dimethylformamide dimethyl
acetal as a new general procedure for the synthesis of
2-nitroenamines
b
b
Alexander S. Shved a,b, Andrey A. Tabolin b, , Yulia A. Khomutova , Sema L. Ioffe
⇑
a Higher Chemical College of the Russian Academy of Sciences, D. I. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russian Federation
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, Moscow 119991, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2014
Revised 29 August 2014
Accepted 11 September 2014
Available online 21 September 2014
Silyl nitronates obtained in situ from the corresponding aliphatic nitro compounds react with dimethyl-
formamide dimethyl acetal giving 2-nitroenamines in moderate to good yields. The reaction pathway is
discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aliphatic nitro compounds
Push–pull alkenes
Silyl nitronates
Nitroenamines
Amide acetals
2-Nitroenamines serve as versatile intermediates in organic
synthesis (Scheme 1).1–3 Some bioactive compounds including
the anti-ulcer drugs Nizatidine4 and Ranitidine,5 as well as an
insecticide family6 possess a nitroenamine motif. Nucleophilic sub-
stitution of dialkylamino groups with activated arenes or aromatic
heterocycles,7 enolates,8 amines,9 hydroxide10 and Grignard
reagents11 gives rise to various nitroalkene derivatives. As such,
nitroenamines have been used as convenient precursors for 1,2-
aminoalcohols, which have been employed in total syntheses of
several natural compounds, such as (ꢀ)-detoxinine,3a (+)-castano-
spermine3b and (ꢀ)-rosmarinecine.3c Recently, an asymmetric
synthesis of 1,2-diamines based on organocatalytic addition of
aldehydes to 2-nitroenamines was reported.2
This makes these procedures only applicable to the simplest and
commercially available ANCs (nitromethane,14 nitroethane15 and
so forth), or activated ANCs (a
-nitroketones16 or nitroacetic acid
esters13). Considering the aforementioned facts, an efficient proce-
dure employing functionalized and inactivated ANCs is needed.
Synthesis of nitroenamines 1
We assumed that higher nitroalkanes could be involved in
nitroenamine synthesis by employing silyl nitronates 3. The latter
have proved themselves as useful synthetic equivalents of ANCs 2,
which react with greater selectivity under milder conditions.20
Employment of a silyl group avoids the occurrence of mobile
protons, thus making the crucial C–C bond forming step 3 ? 4
irreversible (Table 1).21 The presented strategy for the synthesis
of nitroenamines 1 involves three steps. In the first step (i) ANC
2 is converted into silyl nitronate 3 via a literature procedure,22 fol-
lowed by treatment at ꢀ78 °C with dimethylformamide dimethyl
acetal (DMFDMA) to give intermediate hemiaminal 4 (step ii).
Upon warming, the latter undergoes elimination of methanol
leading to the target nitroenamine 1 (step iii).23
Several types of nitroenamines can be outlined depending on
their substitution pattern. b-Substituted species 1 can be readily
synthesized by amination of the corresponding
a-nitroketones
[Scheme 2, (1)].12 In contrast, the synthesis of b-unsubstituted
nitroenamines 1 (R2 = H) requires other paths, since 2-nitroaldehy-
des are unstable and cannot be isolated.9 General methods for the
synthesis of 2-nitroenamines 1 (R2 = H) employ primary aliphatic
nitro compounds 2 (ANC) as precursors [Scheme 2, (2)].13–19 How-
ever, for aliphatic substituents R1 (R1 = Me, Et, etc.) the yields
decrease dramatically and an excess of the ANC is necessary.13–15
The data presented in Table 1 reveal that high yields can be
achieved for a wide variety of nitroenamines 1. In most cases there
was no need to exceed a stoichiometric amount of reagents.
Separation of target 1 from the by-product salt [DBUH]+Clꢀ was
accomplished by ether extraction (Et2O or t-BuOMe). For large
⇑
Corresponding author. Tel.: +7 499 135 5329; fax: +7 499 135 5328.
E-mail address: tabolin87@mail.ru (A.A. Tabolin).
http://dx.doi.org/10.1016/j.tetlet.2014.09.071
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. S. Shved et al. / Tetrahedron Letters 55 (2014) 6220–6223
6221
Table 1
Synthesis of nitroenamines 1 via silylation of ANCs 2
NO2
N
OSiMe3
NO2
i
ii
N
1
O
R
R
NuH
- HN
2
3
in situ
OMe
H
iii
NH2
NO2
*
NO2
NO2
*
HO
Nu
Me2N
Me2N
N
H
R
R
aminoalcohols
pyrroles
4
1
Entry
ANC
R
Yield of 1a (%)
Conversion of 2b (%)
O
NH2
1
2a
2a
2b
2c
2d
2d
2e
2f
2g
2h
2i
2j
2k
2l
CH2CH2CO2Me
CH2CH2CO2Me
CH2CH2C(O)Me
CH2CH(Me)CO2Me
CH(Me)CH2CO2Me
CH(Me)CH2CO2Me
1-Cyclohexenyl
H
Me
92
80
85
85
68
100
100
100
90
100
40
NH2
*
*
2c
3
*
H2N
diamines
chiral GABA derivatives
4
5
6d
7
n/d
e
H
H
45
75
95
90
65
N
S
NO2
8
9
n/d
n/d
100
100
96
NHMe
NO2
N
X1
10
11
12
13
14
Et
Ph
X2
N
H
78
CH2Ph
CH(Ph)CH2CO2Et
CH2CH2Ph
80 (35f)
41
Me2N
n/d
100
X1 = O, X2 = CH : Ranitidine
insecticides
75
X1 = S, X2 = N : Nizatidine
i: DBU (1.05 equiv), TMSCl (1.1 equiv), ꢀ15 °C ? rt, 40 min.
ii: DMFDMA (1.1 equiv), ꢀ78 °C, 1 h (for 1k: 2.2 equiv).
Scheme 1. Nitroenamines as biologically active compounds and useful intermedi-
ates in organic syntheses.
iii: ꢀ78 °C ? rt, overnight [for 1d: DBU (1 equiv), TMSCl (1 equiv), then ꢀ78 °C ? rt,
overnight].
a
Isolated yield.
b
Determined by integration of the 1H NMR spectra.
c
TBSCl was used instead of TMSCl.
Without addition of DBU/TMSCl at step iii.
Not determined.
Yield after purification by column chromatography on alumina.
R2
NO2
R1
R2
NO2
R1
d
(1)
e
N
O
f
R2 = alkyl, aryl: available
R2 = H: unstable
1
OSi
N
OMe
DMFDMA
CH2Cl2, r.t.
R2 = H
H
NO2
(2)
O
Me2N
Et
Et
NO2
4h
N
X
+
3h (Si = SiMe3)
X = OR, SR
R1
dr = 1.6:1
3'h (Si = SiMe2t -Bu)
85%, 3 d (for 33h)
71%, 4 d (for 33'h)
Scheme 2. Existing approaches for the synthesis of b-nitroenamines. Reagents and
conditions: X = OR: (a) Me2NCH(OMe)2, Temp (°C) (Refs. 16,17); (b) amine, HC(OR)3,
p-TsOH, Temp (°C) (Refs. 14,15,18). X = SR: (c) [Me2NCHSMe]+Iꢀ, KF, TEBAC, CH2Cl2,
rt (Ref. 19).
Scheme 3. Reaction of isolated silyl nitronates 3 and DMFDMA.
the conversion was 40%.25 Fortunately, the addition of DBU
(10 mol %) to the reaction mixture increased the conversion of 2d
from 40% to 90%. An even better effect was achieved by the addi-
tion of 1 equiv of a mixture of DBU/TMSCl, capable of trapping
the methanol. Thus the conversion of ANC 2d was increased to
100% (Table 1, cf. entries 5 and 6). However, for ANC 2k, this pro-
cedure was not successful. For the transformation of 2k ? 1k the
use of a twofold excess of DMFDMA was the method of choice
(see Table 1, entry 13).
scale preparations (36ꢀ50 mmol of ANC 2), Soxhlet extraction was
used. It is worthy of note that purification of products 1 via aque-
ous extraction or column chromatography was not efficient and led
to substantial loss of the target enamines 1 (e.g., see Table 1, entry
12), due to their high polarity and hydrolytic lability.9 If the nitro-
enamine possesses a high melting point, the separation of 1 and 2
was easily performed by recrystallization. Otherwise, full conver-
sion of the initial ANC 2 was preferable.
The structures of the obtained enamines 1 were supported by
1H and 13C NMR data, as well as by elemental analysis or HRMS
data. All nitroenamines 1 in chloroform solutions were observed
as (E)-isomers (NOESY data). This is in accordance with known
rules for E/Z-isomerism in similar substances.9,24
For the synthesis of enamines 1 more stable TBS-nitronates can
also be used (Table 1; cf. entries 1 and 2). However, branching at
the b-position of the carbon skeleton in ANC 2 (substrates 2d,e,k)
significantly diminished the conversion of ANC 2 and consequently
the yield of products 1; for example, for ANC 2d (Table 1, entry 6)
Studies on the mechanism
It was interesting to elucidate in more detail the mechanism of
nitroenamine 1 formation. To the best of our knowledge, there is
only one known example of a similar process [coupling of silyl nitr-
onates with a hemiaminal (TMSOCH2NMe2)].26 It turned out that
coupling of DMFDMA with isolated silyl nitronates 3h or 30h [sim-
ulation of step (ii), see Table 1] did not lead to enamine 1h, while
hemiaminal 4h was observed as the major product (Scheme 3).

6222
A. S. Shved et al. / Tetrahedron Letters 55 (2014) 6220–6223
NMe2
MeO OMe
DBU +
MeOH
DBUH+
NMe2
SiAlk3
O
DBUH+
Me2N
DBUH+,
DBU
O
N
O
N
OMeO
N
OMeO
N
H
O
N
MeO
DBU
O
Me2N
O
O
Me2N
O
Et
3h or 3'h
Alk3Si-DBU+
Et
Et
Et H
Et
DBU
A
1h
4h
Alk3Si-DBU+ + MeOH
DBUH+ + MeOSiAlk3
Scheme 4. Proposed mechanism for the formation of 1 from silyl nitronates 3.
Moreover, while the synthesis of nitroenamine 1h by the standard
procedure was completed within 24 h (Table 1, entry 10), conver-
sion of pure silyl nitronate 3h via the reaction with DMFDMA over
24 h exposure was only 76%. Several days were needed to reach
quantitative conversion. The structure of hemiaminal 4h was con-
firmed from 1H, 13C, COSY and HSQC data. Unfortunately, we did
not obtain accurate elemental analysis or HRMS data due to the
hydrolytic lability of the hemiaminal.
observed (according to 1H NMR) (Scheme 5). Presumably, in this
case, the activation of DMFDMA is due to the Lewis acidity of LiCl.
In conclusion, a new and efficient procedure for the synthesis of
nitroenamines 1 from ANCs 2 through in situ formed silyl nitro-
nates 3 is described. The mechanism of the reaction is elucidated.
Detailed investigations revealed the roles and interactions of the
reagents, intermediates and by-products.
Due to the hydrolytic instability of TMS-nitronate 3h, further
investigations were performed on its TBS-analogue 30h. Several
substances, including DBU, its salt [DBUH]+Clꢀ and chlorosilanes
SiCl (Si = SiMe3, SiMe2t-Bu) were tested as catalysts for the reaction
of 30h with DMFDMA (see Supplementary data for details). Pre-
sumably, activation of both the reaction components was neces-
sary for the successful synthesis of 1 (Scheme 4). The function of
hydrogen bond donors ([DBUH]+Clꢀ, MeOH) consists of the activa-
tion of DMFDMA by removal of the MeO group.27,28 Lewis bases
(e.g. DBU) activate the silyl nitronate 3 by its equilibrium conver-
sion into nitronate anion A. As mentioned before, when silyl nitro-
nate 3h was prepared in situ, a high yield of 1h was observed (see
Table 1). But in order to reach a similar yield with the isolated nitr-
onate, simultaneous use of both DBU and its salt [DBUH]+Clꢀ was
required. Thus, in the presented one-pot procedure for the synthe-
sis of enamines 1 from ANC 2, the in situ generation of silyl nitro-
nates 3 is important, since the by-product ([DBUH]+Clꢀ) catalyses
step ii (Table 1), i.e., C–C bond formation (3 ? 4). Obviously, the
nitronate anion A can be generated by treating ANC 2 with DBU.
However, performing the reaction of 2a and DMFDMA mediated
by DBU (10 mol %) and [DBUH]+Clꢀ (1 equiv) without prior silyla-
tion did not give enamine 1a in a yield higher than 60%. Moreover,
in the latter case, the use of a catalytic amount of [DBUH]+Clꢀ led to
prolonged (2 or more days) reaction times.29
Acknowledgments
This work was supported by the Russian Foundation for Basic
Research (Grant 12-03-00278) and the Program of the Russian
Academy of Sciences Presidium (8P).
Supplementary data
Supplementary data (experimental details, compound charac-
terization) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.071.
References and notes
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3h was obtained in situ from ANC 2h by treatment with n-BuLi and
TMSCl.30 After addition of DMFDMA to the reaction mixture, rapid
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1) n-BuLi
DMFDMA,
r.t.
OSiMe3
OMe
NO2
2) Me3SiCl
H
N
NO2
O
Me2N
Et
2h
- 78 °C to r.t.
Et
3h
Et
4h
98% (1H NMR)
dr = 1.3:1
21. For details on the reversibility of Henry and related reactions, see: (a) Seebach,
D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 33, 1–18; (b) Colvin, E. W.;
Scheme 5. Synthesis of hemiaminal 4h from 2h.

A. S. Shved et al. / Tetrahedron Letters 55 (2014) 6220–6223
6223
Seebach, D. J. Chem. Soc., Chem. Commun. 1978, 689–691; (c) Tikhonova, N. A.;
Babievskii, K. K.; Belikov, V. V. Russ. Chem. Bull. 1967, 842–844 (Izv. Akad. Nauk
SSSR, Ser. Khim. 1967, 877–880).
(CH2-2), 21.7 (CH2-1). Anal. Calcd for C8H14N2O4: C, 47.52; H, 6.98; N, 13.85.
Found: C, 47.53; H, 7.17; N, 13.79.; (b) Performing steps (ii) and (iii)
simultaneously at rt resulted in a lower yield of 1a, since the significant
amount of methanol eliminated in step (iii) led to desilylation of nitronate 3 to
give ANC 2 before the latter could undergo step (ii) completely.
24. (a) Ostercamp, D. L.; Taylor, P. J. J. Chem. Soc., Perkin Trans. 2 1985, 1021–1028;
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25. Increasing the reaction time during any of the steps i–iii (Table 1) did not
increase the yield of 1d nor the conversion of 2d.
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2636). However, the authors of this work did not perform any mechanistic
investigations.
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was previously reported in (a) Miran, S. M.; Kinoshita, H.; Tomohiro, Y.; Susan,
Md. A. B. H.; Watanabe, M. Chem. Commun. 2011, 12676–12678; (b) Coady, D.
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28. DMF itself failed to react with silyl nitronates under the reported conditions.
29. We did not consider the use of catalytic amounts of DBU and TMSCl, since the
reaction of nitro compound 2 will result in the formation of a DBU/[DBUH]+Clꢀ
mixture, the action of which is discussed.
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23. (a) General procedure for the synthesis of nitroenamines 1: To a 1 M solution
of ANC 2 in CH2Cl2 at ꢀ15 °C, DBU (1.05 equiv) was added dropwise. The
mixture was stirred for 20 min and TMSCl (1.1 equiv) was added. After 10 min,
the cooling bath was removed, the mixture was stirred for 40 min, cooled to
ꢀ78 °C and DMFDMA (1.1 equiv) was added dropwise. The mixture was stirred
at the same temperature for 1 h, slowly warmed to room temperature and left
overnight. As a rule, the resulting solution attained a dark red color. The
solvent was removed in vacuo. Et2O (20 ml/1 mmol of 2) was added to the
residue and the mixture was vigorously stirred (as a rule, insoluble [DBUH]+Clꢀ
solidified). The ether layer was decanted, and extraction was repeated several
times. The combined ether extracts were filtered through cotton wool and
evaporated to give the target enamine 1. Representative example: Methyl (4E)-
5-(dimethylamino)-4-nitropent-4-enoate (1a). Obtained from 2a (1.47 g,
10 mmol). Yield: 1.85 g (92%), orange crystalline solid, mp 74–78 °C. When
the reaction was scaled to 36 mmol of 2a, Soxhlet extraction with Et2O was
used to separate 1a and [DBUH]+Clꢀ. Yield: 6.45 g (89%). 1H NMR (300 MHz,
CDCl3): d = 8.24 (s, 1H, @CH), 3.59 (s, 3H, CO2Me), 3.15 (s, 6H, NMe2), 2.96 (t,
J = 7.4 Hz, 2H, CH2-2), 2.54 (t, J = 7.4 Hz, 2H, CH2-1). 13C NMR (75 MHz, CDCl3):
d = 173.2 (CO2Me), 149.5 (@CH), 122.3 (CNO2), 51.5 (CO2Me), 43.9 (NMe2), 32.7
30. MacDonald, F. K.; Carneiro, K. M. M.; Pottie, I. R. Tetrahedron Lett. 2011, 52,
891–893.