Diastereoselective synthesis of nitroso acetals from (S,E)-?-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO4

Article abstract of DOI:10.3762/bjoc.9.96

Chiral nonracemic aminated nitroso acetals were synthesized via diastereoselective multicomponent [4 + 2]/[3 + 2] cycloadditions employing new (S,E)-γ-nitrogenated nitroalkenes 5a-c as heterodienes, ethyl vinyl ether (EVE) as a dienophile, and selected electron- deficient alkenes as 1,3-dipolarophiles. The employment of different organic solutions of LiClO ₄ or LiCl as promoter systems provided the respective nitroso acetals with yields from 34-72% and good levels of diastereoselectivity. In addition, the nitroso acetal 9c was transformed to the pyrrolizidin-3-one derivative 14c, proving the usefulness of the route in the synthesis of an interesting chiral compound. The elucidation of the stereostructures was based on 2D COSY, NOESY and HSQC NMR experiments as well as an X-ray diffraction experiment.

Full text of DOI:10.3762/bjoc.9.96

Diastereoselective synthesis of nitroso acetals from
(S,E)-γ-aminated nitroalkenes via multicomponent
[4 + 2]/[3 + 2] cycloadditions promoted by
LiCl or LiClO4
Leandro Lara de Carvalho1, Robert Alan Burrow2
and Vera Lúcia Patrocinio Pereira*1,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 838–845.
1Núcleo de Pesquisas de Produtos Naturais, Laboratório de Síntese
Estereosseletiva de Substâncias Bioativas, Universidade Federal do
Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil and 2Departamento
de Química, Laboratório de Materiais Inorgânicos, Universidade
Federal de Santa Maria, 97105-900, Santa Maria, Rio Grande do Sul,
RS, Brazil
doi:10.3762/bjoc.9.96
Received: 20 January 2013
Accepted: 08 April 2013
Published: 30 April 2013
Associate Editor: B. Stoltz
Email:
Vera Lúcia Patrocinio Pereira* - patrocinio@correio.nppn.ufrj.br
© 2013 de Carvalho et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Tel.: +55 21 2562 6792; Fax: +55 21 2562 6512
Keywords:
chiral heterodiene; hetero-Diels–Alder reaction; pyrrolizidin-3-one;
solvent effect; tandem reaction
Abstract
Chiral nonracemic aminated nitroso acetals were synthesized via diastereoselective multicomponent [4 + 2]/[3 + 2] cycloadditions
employing new (S,E)-γ-nitrogenated nitroalkenes 5a–c as heterodienes, ethyl vinyl ether (EVE) as a dienophile, and selected elec-
tron-deficient alkenes as 1,3-dipolarophiles. The employment of different organic solutions of LiClO4 or LiCl as promoter systems
provided the respective nitroso acetals with yields from 34–72% and good levels of diastereoselectivity. In addition, the nitroso
acetal 9c was transformed to the pyrrolizidin-3-one derivative 14c, proving the usefulness of the route in the synthesis of an
interesting chiral compound. The elucidation of the stereostructures was based on 2D COSY, NOESY and HSQC NMR experi-
ments as well as an X-ray diffraction experiment.
Introduction
Conjugated nitroalkenes play an important role in cycloaddi- pounds can act as dienophiles or 1,3-dipolarophiles to provide
tion reactions providing useful nitrogenated cycloadducts with nitrocycloadducts of type 1 or nitroheterocycles of type 2, res-
varied synthetic applications (Scheme 1) [1-3]. These com- pectively [4,5]. In addition, nitroalkenes can act as heterodienes
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Beilstein J. Org. Chem. 2013, 9, 838–845.
Scheme 1: Reactivity of nitroalkenes and/or their respective nitronates in cycloaddition reactions.
reacting with suitable dienophiles, often in the presence of a or LiCl solutions have not been used in tandem nitroalkene
Lewis acid, to furnish cyclic nitronate derivatives of type 3 cycloadditions, although they are widely employed as
[1,3].
promoters in Diels–Alder (DA) and HDA reactions [12-17].
In particular, the reactivity of nitroalkenes with unactivated Regarding enantioselective processes, the majority of them have
olefins has been extensively investigated by Denmark and been associated with the employment of a specific Lewis acid
co-workers in [4 + 2] hetero-Diels–Alder (HDA) cycloaddi- and a selected chiral inductor connected to the enol ether moiety
tions [1,3] and, in some instances, the resulting cyclic nitronates to furnish nonracemic nitroso acetals diastereoselectively [1-3].
such as 3 (R2 = alkyl) were employed in various synthetic trans- In contrast, the use of a chiral pool strategy, wherein the
formations [6,7] (Scheme 1). In addition, Denmark’s group and nitroalkene is the chiral source, is still scarce. To the best of our
others investigated the tandem [4 + 2]/[3 + 2] nitroalkene cyclo- knowledge, only Chattopadhyaya et al. [18] and Cintas et al. [9]
addition employing unactivated olefins or enol ethers as utilized chiral nitroalkenes, synthesized from a nucleoside and a
dienophiles and electron-deficient alkenes as 1,3-dipolarophiles carbohydrate, respectively, to obtain nitroso acetals diastereo-
to furnish nitroso acetals of type 4 in an inter- or intramolecular selectively.
fashion [1-3,8,9]. These nitroso acetals can be transformed into
functionalized pyrrolizidin-3-ones and in sequence into alka- In our continued studies on the reactivity of chiral nonracemic
loid nuclei [1,3,10,11].
nitro compounds [19-26], we recently synthesized the
γ-aminated nitroalkenes 5a–c from L-alanine, L-phenylalanine
The majority of the tandem nitroalkene cycloadditions require and L-leucine, respectively, in five steps and 68–88% overall
the addition of a Lewis acid as a promoter reaction; however, a yield (Scheme 2). These electron-deficient nitroalkenes have
limited number of these species have been employed in these exhibited excellent stereochemical stability and reactivity in
reactions, e.g., SnCl4 or Ti(O-iPr)2Cl2 [1-3]. However, LiClO4 conjugate additions with varied nucleophiles. The 1,3-
Scheme 2: Synthetic route toward the chiral (S,E)-γ-aminated nitroalkenes 5a–c and their 1,3-diamine derivatives.
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Beilstein J. Org. Chem. 2013, 9, 838–845.
nitroamines adducts obtained from these additions can be shown in Table 1, entries 1–3 led us to use more polar solvents.
readily transformed into potentially useful chiral 1,3-diamines
[19].
Thus, the use of ethanol resulted in a decrease in the reaction
time affording a diastereoisomeric mixture in improved yields
Herein, we report the reactivity and diastereoselectivity of 5a–c (Table 1, entry 4). Similarly, when 5b was reacted in the pres-
as heterodienes in a multicomponent [4 + 2]/[3 + 2] cycloaddi- ence of methanol (Table 1, entry 5), a higher yield of 7b,b’ was
tion with ethyl vinyl ether (EVE) and selected electron-defi- achieved compared with ethanol or 2-propanol (Table 1, entries
cient alkenes in the presence of LiCl or LiClO4 as promoters. A 6 and 7). Next, the use of a more polar medium, such as an
study on the solvent effect was also accomplished. Eleven novel alcohol/water mixture 3:1 (Table 1, entries 8 and 9), caused no
aminated nitroso acetal derivatives were synthesized diastereo- significant change in the yields in comparison to Table 1,
selectively, and one of these was transformed into the corres- entries 4–7; however, the reaction time decreased considerably.
ponding pyrrolizidin-3-one derivative to establish the utility of These results demonstrate that the new chiral γ-aminated
these cycloadducts.
nitroalkenes 5a,b were reactive in these cycloadditions, even in
the absence of a promoter, providing the respective
cycloadducts diastereoselectively. In all entries, only two dia-
Results and Discussion
In an exploratory study to screen the best solvent system, the re- stereoisomers were obtained among the sixteen possibilities.
activity of 5a,b with EVE and methyl acrylate (MA) as a dipo- Additionally, no change in the sense of stereo induction was
larophile was evaluated in the absence of a promoter. In all noted regarding the solvent system employed.
experiments conducted, the cycloadducts were obtained in
18–70% yield with total chemo- and regioselectivity including The increase in the reaction rate on employing more polar
good levels of diastereoselectivity (Table 1). The nitroso acetal solvents can be explained through a large stabilization of the
6a and another unidentified diastereoisomer were obtained in dipolar [4 + 2] transition state (TS) [9,27]. Theoretical investi-
low yields after long reaction times from 5a when toluene and gations indicate that the TS of the HDA nitroalkene cycloaddi-
dichloromethane were employed as the solvents (Table 1, tions presents considerable charge transference and a large
entries 1 and 2). Similar behavior was observed when THF was degree of asynchronicity, but remains a concerted process. In
used (Table 1, entry 3). The modest solvent performances other words, the TS presents a high zwitterionic and polar char-
Table 1: Nitroso acetal synthesis via multicomponent [4 + 2]/[3 + 2] cycloadditions of 5a,b with EVE and methyl acrylate in several solvents.
entry
nitro alkene
solvent
timea (days)
cycloadducts
yield (%)b
d.r.c
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5b
5b
5b
5b
5b
PhMe
CH2Cl2
50
24
50
20
21
25
30
8
6a/ndd
6a/ndd
6a/ndd
6a/ndd
7b/7b’
7b/7b’
7b/7b’
7b/7b’
7b/7b’
18 (31)e
38 (15)e
20 (28)e
67
1.9 : 1.0
1.8 : 1.0
1.9 : 1.0
1.2 : 1.0
2.2 : 1.0
2.1 : 1.0
2.5 : 1.0
2.0 : 1.0
2.4 : 1.0
THF
ethanol
MeOH
70
ethanol
59
2-propanol
MeOH:H2O (3:1)
EtOH:H2O (3:1)
57 (7)e
62
7
70
aMonitored by thin layer chromatography. bPurified overall yields of the diastereoisomers mixture. cDiastereoisomeric ratio determined by 1H NMR
and 13C NMR analysis of the crude reaction mixtures. dDiastereoisomer with stereochemistry not defined. ePercentage of nitroalkene not reacted and
recovered after purification.
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acter without a zwitterionic intermediate specifically. In the pound, and the chiral nitroalkenes 5a–c with EVE and MA,
second step, the TS involved in [3 + 2] nitronate cycloadditions acrylonitrile (AN) or methyl vinyl ketone (MVK) were carried
shows lower charge transference and degree of asynchronicity, out using lithium salt solutions (Table 2). Initially, the reactiv-
and therefore, it is expected that a lower stabilizing effect is ity of 5d in lithium perchlorate solution 4.7 M in THF/H2O
caused by polar solvents [9,30,31]. Furthermore, when a frac- (3:1) (henceforth LPTW), (Table 2, entry 1) was investigated. A
tion of water is present in the medium, the hydrophobic effect mixture of only three diastereoisomers was obtained in good
can lead the reaction partners to collapse to a TS that is less yield and useful reaction time. When lithium chloride solution
hydrophobic and less destabilized than the initial state, 4.7 M in EtOH/H2O (3:1) (henceforth LCEW) was employed
promoting an increase in the reaction rate [17,28,29].
(Table 2, entry 2), the outcome was similar to that in Table 2,
entry 1. Lithium chloride is not appreciably soluble in THF and
Aiming to improve the efficiency of the cycloaddition reactions, for this reason ethanol was used as the solvent. The confirma-
LiCl or LiClO4 solutions were used as a reaction promoter. tion of the stereostructures of (+/−)-8d,d’ was accomplished by
These salts were chosen in particular because of their present comparison with NMR spectroscopic data available in the
high recyclability, low cost, and great applicability as promoters literature [9]. Based on these successes, 5a was reacted with
in cycloaddition processes [12-17]. Thus, the reactions between EVE and methyl acrylate in LPTW or LCEW solutions
the very reactive beta-nitrostyrene 5d, used as a model com- (Table 2, entries 3 and 4), respectively. In these experiments, a
Table 2: Nitroso acetal synthesis via multicomponent [4 + 2]/[3 + 2] cycloadditions of 5a–d with EVE and electron-deficient alkenes in the presence of
lithium salt solutions.
entry
nitro alkenes
EWG
reaction conditionsa
timeb (days)
cycloadducts (%)c
d.r.d
1
2
5d
5d
5a
5a
5b
5b
5b
5c
5a
5b
5b
5c
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
LiClO4/THF/H2Oe
LiCl/EtOH/H2Oe
LiClO4/THF/H2O
LiCl/EtOH/H2O
LiClO4/THF/H2O
LiCl/EtOH/H2O
LiClO4/EtOH/H2O
LiClO4/THF/H2O
LiClO4/THF/H2O
LiClO4/THF/H2O
LiClO4/THF/H2O
LiClO4/THF/H2O
2.5
2.5
2
8d/8d’/ndf (85)g
8d/8d’/ndf (77)g
6a (21)/ndf (16)
6a (17)/ ndf (17)
7b (51)/7b’ (21)
7b (43)/ 7b’ (17)
7b (47)/ 7b’ (19)
9c (35)/ 9c’ (19)
10a’ (31)/ ndf (30)
11b (30)/ ndf (23)
12b’ (35)/ 12b (18)
13c’ (27)/ 13c (7)
4.0:1.4:1.0
3.3:1.3:1.0
2.3:1.0
1.7:1.0
2.0:1.0
1.4:1.0
1.7:1.0
1.6:1.0
1.0:1.0
1.7:1.0
1.8:1.0
1.5:1.0
3
4
2
5
3
6
3
7
3
8
3
9
1
10
11
12
CN
3
COMe
COMe
3
2
aLithium salt solutions 4.7 M in organic solvent/water (3:1). bMonitored by thin-layer chromatography. cPurified by silica-gel column chromatography.
dDetermined by 1H NMR and 13C NMR analysis of the crude reaction mixtures. eReaction carried out at 10 °C. fDiastereoisomer with stereochemistry
not defined. gOverall yield of the diastereoisomeric mixture.
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mixture of two diastereoisomers was observed in low yield The cycloadditions with 5a–c were performed in concentrated
from which only 6a could be successfully isolated and identi- lithium salt solutions following similar protocols described in
fied.
the literature in which lithium perchlorate 5.0 M in diethyl ether
(LPDE) was employed successful as a promoter in Diels–Alder
On the other hand, better yields were achieved employing 5b or reactions. This solution was found to be a good reaction
5c, EVE and MA to furnish 7b,b’ and 9c,c’, respectively, in the medium causing a large enhancement in the reaction rate. More-
presence of LPTW or LCEW or even in lithium perchlorate over, the role of the lithium salt solution in the cycloaddition
solution 4.7 M in EtOH/H2O (3:1) (Table 2, entries 5–8). In reactions is still controversial and has been the subject of
these last entries, good levels of diastereoselectivity were discussion. The increase of the solvent internal pressure, caused
achieved, and the mixture of two diastereoisomers was sep- by the presence of lithium salt, and the Lewis acid catalysis by
arated successfully. The reaction of 5a or 5b with EVE and AN cation–substrate interaction have been utilized to explain this
as a dipolarophile provided a mixture of two diastereoisomers enhancement of the reaction rate [12-14].
from which only the respective cycloadducts 10a’ and 11b
could be isolated (Table 2, entries 9 and 10). In addition, 11b In the case of nitroalkene cycloadditions, performed in the pres-
was obtained as suitable crystals for an X-ray diffraction experi- ence of a Lewis acid, it is well documented that the rate acceler-
ment, (Figure 1) (Supporting Information File 2). Finally, reac- ation effect caused by the Lewis acid in the [4 + 2] step is due
tion of 5b or 5c with EVE and MVK provided the respective to lowering of the LUMO energy of the nitroalkene [1,6,32,33].
cycloadducts 12b,b’ and 13c,c’ in low yields and with the same Follow this judgment, we propose that the lithium cation could
degree of diastereoselectivity (Table 2, entries 11 and 12). In bind to one of the oxygen atoms of the nitro group, acting as a
these last two cases, the major diastereoisomers presented the Lewis acid, to promote the rate acceleration of the cycloaddi-
(S)-configuration in the CH(2) stereogenic center resulting from tions. In the [3 + 2]-step the role of the Lewis acid is not well
the endo approach of the smaller dipolarophile MVK by the Re established; however, it is reasonable to imagine that lithium
face of the nitronate. It is worthwhile to mention that, can be transferred from the nitronate to the electron-with-
depending of the nitroso acetal structure, an opening of the six- drawing group (EWG) of the 1,3-dipolarophile causing a
membered ring is caused due to a greater sensitivity to the reac- decrease in the activation energy of this step, as similarly
tion medium, leading to generation of the respective carbony- proposed by Domingos and co-workers in a PM3 study on
lated isoxazolines and, therefore, causing a decrease in yield. domino reactions with nitroalkenes [34]. Additionally, it is
These last compounds could be identified through 1H and possible that the high internal pressure of the solvent acts syner-
13C NMR spectroscopy. The signals at 9.5 ppm, and 201 and gistically to promote the enhancement of the reaction rate of
159 ppm revealed the presence of an aldehyde function and a 5a–c and should not be neglected.
sp2 carbon bond of an isoxazoline ring (spectra not related).
In all cycloadditions, independent of the lithium salt/solvent
system employed, no change was observed in the sense of
diastereoselection. All stereostructures were elucidated from IR,
1H NMR, 13C NMR, 2D COSY, HSQC and 2D NOESY exper-
iments (Supporting Information File 1). The absolute configura-
tions were assigned from 2D NOESY experiments and could be
corroborated by X-ray analysis of 11b, since the diastereoselec-
tion of the [4 + 2]-step was the same for all cycloadditions
investigated (Figure 1 and Figure 2).
Figure 2: 1D NOESY correlation between H2, H3a, H4 and H6 for all
Figure 1: ORTEP for nitroso acetal 11b.
nitroso acetals.
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Beilstein J. Org. Chem. 2013, 9, 838–845.
The determination of the vicinal H,H constant coupling of the HC(4) substituent and the alkoxy group in an axial position to
protons located in the six-membered ring was not so simple due maximize the stabilization generated by the anomeric effect
to the tendency of these frameworks to assume the twist-boat [9,33,41,42]. Thus, the competitive endo/exo approach of the
conformation, as shown in X-ray analysis of 11b (Figure 1). 1,3-dipolarophile occurred by the Re face on the opposite side
According to 1H NMR analysis of all cycloadducts, the protons to the bulky lateral chain at HC(4).
(H6) showed the highest vicinal J-coupling in the range of 7.3
Hz to 8.0 Hz suggesting a pseudoequatorial arrangement [35]. In order to prove the applicability of the aminated nitroso
The tendency to the pseudoaxial orientation of the alkoxy group acetals, the N–O bonds contained in 9c were easily cleaved
in nitroso acetals is associated with a stabilization generated by under hydrogenolysis conditions to give the corresponding
an anomeric effect [1,36]. The protons (H6) and (H4) were both pyrrolizidin-3-one 14c in 50% yield (Scheme 4). Pyrrolizidin-3-
irradiated in 2D NOESY experiments and a cis relationship one frameworks are important precursors of pyrrolizidine
between them was achieved for all cycloadducts. When the nuclei, which are largely widespread in nature, mainly in the
stereogenic center at HC(2) presents (S)-configuration, as in form of pyrrolizidine alkaloids [43].
7b’, 9c’, 10a’, 12b’ and 13c’, the 2D NOESY experiments
showed a cis relationship between (H2) and (H3a). In addition,
the range of the vicinal H,H constant coupling of (H2) spans
from 8.3 Hz to 10 Hz for all cycloadducts, and these high values
suggest the orientation of EWG close to the equatorial position.
In the [4 + 2] cycloadditions, the total facial diastereoselection
exhibited by 5a–c could be rationalized by a modified
Felkin–Anh TS model [37-40] in which the largest N,N-diben-
Scheme 4: Hydrogenolysis of 9c to pyrrolizidin-3-one 14c.
zylamino group is orthogonal to the electron-deficient C=C
bond (Scheme 3). Thus, the approach of the enol ether to the
β-nitro carbon was preferred by the less hindered Si face on the Conclusion
opposite side to the largest group. Secondary orbital and In summary, the multicomponent [4 + 2]/[3 + 2] cycloadditions
Coulombic interactions have been proposed to explain the endo using a new class of chiral γ-aminated nitroalkenes 5a–c
approach of the enol ethers [9,33,41].
showed good reactivity, chemo-, regio- and facial diastereose-
lection. In the absence of lithium salt solutions, polar solvents
such as EtOH or MeOH and the binary solvent systems EtOH/
H2O or MeOH/H2O (3:1) were more effective in promoting the
reaction in 7–8 days with 60–70% yield. The employment of
lithium salt solutions as the reaction medium decreased signifi-
cantly the reaction time to 1–3 days with similar overall yields
(34–72%). In addition, the aminated nitroso acetal 9c was
smoothly hydrogenolyzed to the correspondent pyrrolizidin-3-
one 14c in 50% yield. The route led to the obtainment of a great
number of new chiral aminated nitroso acetals (7, 9–13) and the
feasible synthesis of the pyrrolizidin-3-one scaffold. The good
reactivity and diastereoselectivity of the new chiral-γ-aminated
nitroalkenes 5a–c in multicomponent [4 + 2]/[3 + 2] cycloaddi-
tion besides conjugate addition [19] make them useful chiral
building blocks for diastereoselective synthesis.
Experimental
General
Scheme 3: Transition-state models to stereoselective approaches in
the multicomponent cycloadditions of 5a–c.
EtOH, MeOH, 2-propanol, toluene, LiClO4, LiCl, methyl vinyl
ketone, ethyl vinyl ether, methyl acrylate and acrylonitrile were
purchased from Aldrich, Acros or Merck and were used as
In the [3 + 2] cycloadditions, we believe that in the TS the received. CH2Cl2 was dried from CaH2, and THF was dried
respective nitronates present a half-chair conformation with the according to a literature procedure [44]. Melting points are
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Beilstein J. Org. Chem. 2013, 9, 838–845.
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spectra of IR, 1H NMR, 13C NMR, 2D COSY, HSQC and
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Supporting Information File 2
Dataset of X-ray crystallography and extended ORTEP
drawing of 11b.
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Acknowledgements
doi:10.1590/S0103-50532006000700006
We acknowledge the CAPES, FAPERJ and the CNPq for finan-
cial support. We also thank professor N. P. Lopes and C. B.
Barreto, Jr. and the National Center of Nuclear Magnetic Reso-
nance (CNRMN) IBqM/UFRJ.
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