Synthesis of enantioenriched azo compounds: Organocatalytic Michael addition of formaldehyde N-tert-butyl hydrazone to nitroalkenes

Article abstract of DOI:10.1039/c2ob26963e

The unprecedented diaza-ene reaction of formaldehyde N-tert-butyl hydrazone with nitroalkenes can be efficiently catalyzed by an axially chiral bis-thiourea to afford the corresponding diazenes in good to excellent yields (60-96%) and moderate enantiosele

Full text of DOI:10.1039/c2ob26963e

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Synthesis of enantioenriched azo compounds:
organocatalytic Michael addition of formaldehyde
Cite this: Org. Biomol. Chem., 2013, 11,
326
N-tert-butyl hydrazone to nitroalkenes†
David Monge,*a Silvia Daza,a Pablo Bernal,b Rosario Fernández*a and José
M. Lassaletta*b
The unprecedented diaza–ene reaction of formaldehyde N-tert-butyl hydrazone with nitroalkenes can be
efficiently catalyzed by an axially chiral bis-thiourea to afford the corresponding diazenes in good to
excellent yields (60–96%) and moderate enantioselectivities, up to 84 : 16 er; additional transformation
of diazenes into their tautomeric hydrazones proved to be operationally simple and high-yielding,
affording bifunctional compounds which represent useful intermediates for the synthesis of enantio-
enriched β-nitro-nitriles and derivatives thereof.
Received 9th October 2012,
Accepted 9th November 2012
DOI: 10.1039/c2ob26963e
www.rsc.org/obc
Introduction
Diazenes (azo compounds, R–NvN–R′) constitute an important
family of compounds with traditional uses in organic chemistry
(Fig. 1).1 For example, the application of azodicarboxylates
(RO2C–NvN–CO2R) in organic synthesis as nitrogen electro-
philes/dienophiles2 and the use of aromatic azo compounds
(Ar–NvN–Ar′) in the industrial field of dyes are well established.
Additionally, the importance of NvN bonds in biologically
active molecules and the need for the development of new
antibiotics have stimulated the synthesis of new azo prodrugs
of general structure Ar–NvN–R (R = aryl or alkyl) which
release therapeutically active amine drugs upon site-specific
reduction by bacterial extracellular azoreductase enzymes and
in the human colon.3
However, the synthesis of aliphatic azo compounds is less
developed and still challenging, presumably due to their
inherent instability.4 In fact, only a few examples on the
enantioselective synthesis of azo compounds bearing a chiral
alkyl chain (Ar–NvN-alkyl* or alkyl-NvN-alkyl*) are known.
These include a radical carboamination/biocatalytic resolution
procedure5 and a recent report on the use of aminocatalysis
for the enantioselective conjugate addition of glyoxylate
Fig. 1 Important azo compounds.
hydrazones6 (Scheme 1). On the other hand, we have recently
reported on the use of H-bonding organocatalysts for the
highly enantioselective addition of formaldehyde N-tert-butyl
hydrazone to aromatic α-keto esters (formally heterocarbonyl–
ene reactions) leading to functionalized diazenylmethyl carbi-
nols.7 Herein, we present a related organocatalytic conjugate
addition of formaldehyde N-tert-butyl hydrazone to readily
available nitroalkenes (formally diaza–ene reaction) leading to
enantioenriched diazenes containing the synthetically versatile
nitro group.8
aDepartamento de Química Orgánica, Universidad de Sevilla, C/Prof. García
González, 1, 41012 Sevilla, Spain. E-mail: dmonge@us.es, ffernan@us.es;
Fax: +34 954624960; Tel: +34 954551518
bInstituto de Investigaciones Químicas CSIC-US, Américo Vespucio 49, E-41092
Sevilla, Spain. E-mail: jmlassa@iiq.csic.es; Fax: +34 954460565;
Tel: +34 954489563
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, catalyst synthesis, characterization data, NMR spectra for new com-
pounds, and HPLC traces. See DOI: 10.1039/c2ob26963e
326 | Org. Biomol. Chem., 2013, 11, 326–335
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affording mainly pyrazoles by the different reaction pathways
depicted in Scheme 2.10 In these reactions, the regioselectivity
is assumed to be controlled by the first nucleophilic attack. In
general, the attack by the NH group on the electron-deficient
β-carbon of the nitroalkene resulted in the regioselective for-
mation of 1,3,5-trisubstituted pyrazoles under either neutral
(heating in MeOH or ethylene glycol) or acidic conditions (10
equiv. of TFA in CF3CH2OH), presumably through hydrazo-
nium–nitronate intermediates A. Interestingly, strong bases
such as t-BuOK promoted the obtention of regioisomeric 1,3,4-
trisubstituted pyrazoles, presumably via type B intermediates.
It was during early investigations in our group that we recog-
nized the particular behaviour of formaldehyde phenylhydra-
zone giving the regioisomeric 1,4-disubstituted pyrazoles
under neutral conditions. This result suggested that the initial
attack takes place at the azomethine C-atom, assuming a step-
wise reaction pathway which leads to the final product via
intermediate C.
To the best of our knowledge, the reaction of monosubsti-
tuted formaldehyde hydrazones with nitroalkenes giving
access to azo compounds has not been described to date.11 We
envisioned that the presence of a phenyl group or a bulky tert-
butyl group on the amino nitrogen would efficiently inhibit
the reactivity of the nitrogen center, while the low steric hin-
drance around the azomethine carbon in formaldehyde deriva-
tives should allow performing C-selective conjugate additions
under mild conditions, eventually enabling the isolation of the
desired azo compounds. Additionally, the presence of an NH
group offers opportunities to establish additional interactions
with bifunctional H-bonding organocatalysts for the develop-
ment of the enantioselective version of the reaction.
Scheme 1 Synthesis of enantioenriched azo compounds.
In their pioneering work on the use of N-monosubstituted
hydrazones as acyl anion equivalents, Baldwin et al. showed
that the reactivity and the C- versus N-selectivity are strongly
influenced by the substitution pattern at nitrogen and the azo-
methine carbon, the reaction conditions (basic or thermal)
and the electrophilic partners.9 Reactions of N-monosubsti-
tuted hydrazones with nitroalkenes were reported to proceed
Scheme 2 Different reaction pathways for the addition of monosubstituted hydrazones to nitroalkenes.
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Scheme 3 Non-catalyzed addition of 1a–c to 2a,b.
Results and discussion
Initially, we examined the non-catalyzed reaction using form-
aldehyde N-monosubstituted hydrazones 1a–c and (E)-3-methyl-
1-nitrobut-1-ene (2a) or β-nitrostyrene (2b) as model aliphatic
and aromatic substrates, respectively (Scheme 3).
The first control experiments employing N-aryl-substituted
hydrazones were disappointing as 1b afforded a complex
mixture containing nitropyrazolidines,‡ and hydrazone 1c
showed low solubility in most common solvents. However,
experiments conducted with formaldehyde N-tert-butyl hydra-
zone 1a as a model reactant in CH3CN [10 M] at room tempera-
ture showed full conversion of both nitroalkenes (aliphatic, 2a
and aromatic, 2b) into the desired azo compounds 3a,b.§
Therefore, performing the reaction on a 2 mmol scale provides
an easy access to rac-3a and rac-3b in 88 and 97% yields,
respectively. Reaction rates were studied for the addition of 1a
to 2a in different solvents (see ESI†). Interestingly, polar
aprotic solvents such as CH3CN showed a better efficiency
(99% GC-yield in 24 h) whereas slower reactions [<50% GC-
yield, 24 h] were observed in hydrocarbons (cyclohexane,
toluene or hexane).
Previous studies had shown that chiral thiourea-based cata-
lysts are effective promoters for conducting the activation of
nitroalkenes towards nucleophilic attack in a highly enantio-
selective manner.12 Moreover, several H-bonding and Brønsted
acid organocatalysts13 were found to be compatible with N,N-
dialkylhydrazones and such type of activation appears a priori
to be particularly appropriate for this reaction. Hence, we per-
formed an extensive screening using different chiral hydrogen-
bond donor catalysts (Fig. 2). We first examined the reaction
between N-tert-butyl hydrazone 1a and nitroalkene 2a, in
hexane [0.1 M] at room temperature as the model system and
the results are collected in Table 1. The Jacobsen-type thiourea
catalysts 4a–c provided azo compound 3a in moderate conver-
sions and enantiomeric ratios (entries 1–3). We were pleased
to find that (1S,2R)-1-aminoindan-2-ol-derived thiourea 4d
Fig. 2 H-bonding organocatalysts tested.
efficiently accelerated the reaction with respect to the non-cata-
lyzed background reaction (>95% conversion, 24 h), unfortu-
nately affording 3a in low enantioselectivity (59 : 41 er, entry 4).
The related squaramide 4e afforded lower conversion and no
stereoselection (entry 5). Interestingly, bis-thiourea 4f afforded
moderate enantioselectivity (64 : 36 er, entry 6) whereas novel
bis-thioureas 4g–i, readily available from 1,3-bis(isothiocyana-
tomethyl)benzene, promoted poor conversions to nearly
racemic 3a (entries 7–9); the poor reactivity in this case is
attributed to the reduced acidity associated with the aliphatic
groups attached to both N atoms.14 Axially chiral 1,1′-binaph-
tyl-derived 4j efficiently catalyzed the model reaction leading
to 3a in good conversion (90%) and moderate enantioselectiv-
ity (64 : 36 er, entry 10). Finally, axially chiral bis-arylthiourea-
based organocatalysts15 4k–p were tested (entries 11–16) and
the results revealed 4k as the best catalyst, providing 3a with
full conversion and a moderate yet promising 74 : 26 er (entry
11). Analogue bis-urea 4l afforded 3a, also with full conversion
and 74 : 26 er, albeit in a slower reaction (entry 12). Notably,
any attempts to optimize the structure of catalyst 4k (installa-
tion of bromo substituents at C-3/C-3′ in 4m, or octahydro-ana-
logues 4n–p) resulted in less selective activations (entries
13–16).
‡The formation of 1,4-disubstituted pyrazoles (as described in Ref. 10d) was
observed for a sugar-derived nitroalkene in boiling methanol.
§Unfortunately, other aldehyde t-butyl-hydrazones were unreactive, even under
forcing conditions.
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Table 1 Screening of catalysts for the enantioselective addition of 1a to 2aa
providing 3b in full conversion and 72 : 28 er in hexane at
room temperature (entry 10). Hydrocarbons proved to be con-
venient solvents (entries 1–6 for 2a and 10, 11 for 2b), cyclo-
hexane being slightly superior (3a, 76 : 24 er; 3b, 78 : 22 er). A
higher dilution proved to be inconsequential, while a higher
concentration and/or higher (20 mol%) catalyst loading had a
detrimental effect on enantioselectivity, suggesting that self-
aggregation of the catalysts takes place under these conditions.
We were pleased to observe that running reactions at 0 °C in
methylcyclohexane or a 9 : 1 cyclohexane–toluene mixture led
to the isolation of 3a,b in up to 82 : 18 and 84 : 16 er, respect-
ively. These are better solvents than linear hydrocarbons and
helped to keep homogeneous solutions (entries 7, 8, 12, and
13). Further cooling to −10 °C resulted in longer reaction
times, while no enantioselectivity improvement was observed.
Remarkably, reducing the catalyst loading from 15 mol% to
10 mol% also had a negative effect on enantioselectivity
(entries 9 and 14).
To explore the scope of this Michael reaction, a representa-
tive set of alkyl and aryl substituted nitroalkenes 2 was made
to react with N-tert-butyl hydrazone 1a under the optimal reac-
tion conditions (Scheme 4). For γ,γ-dialkyl substituted
nitroalkenes, the azo compounds 3a and 3c,d were obtained in
high to excellent yields (89–96%) and moderate enantio-
selectivities (78 : 22 to 81 : 19 er). Nitroalkenes 2e,f having
linear alkyl substituents also afforded the products 3e,f in
high yields (88–91%), albeit in lower enantioselectivities
(63 : 37–66 : 34 er). In the aromatic series, the reaction tolerates
a range of substitution patterns. Thus azo compounds 3b, 3g
and 3i,k were formed in good yields (84–96%) and enantio-
meric ratios up to 84 : 16 (3b and 3g). Only the p-methoxy-
phenyl-substituted nitroalkene gave the desired product 3h in
lower yield (60%), probably due to a combination of the poorer
electrophilicity of the substrate 2h and its low solubility in the
reaction medium.
Entry
Cat.
Conv.b [%]
erd
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
60
65c
70c
>95
60c
90
rac
68 : 32
67 : 33
59 : 41
rac
64 : 36
rac
rac
rac
64 : 36
74 : 26
74 : 26
rac
70c
60c
60c
90
9
10
11
12
13
14
15
16
>95
>95c
>95
>95
90
rac
rac
rac
>95c
a Unless otherwise stated, reactions were performed with 1a
(0.15 mmol), 2a (0.1 mmol) and 4 (15 mol%) in hexane (1 mL) at rt for
1
24 h. b Determined by H NMR. c After 48 h. d Determined by HPLC on
chiral stationary phases.
Table 2 Optimization for the enantioselective addition of 1a to 2a,b catalyzed
by 4ka
Entry
2
Solvent
T [°C] t [h] Conv.b [%] erc
1
2
3
4
5
6
7
8
2a Hexane
rt
rt
rt
rt
rt
24
24
24
24
24
24
48
48
48
16
16
48
48
48
>95
85
74 : 26
60 : 40
68 : 32
63 : 37
76 : 24
74 : 26
82 : 18
81 : 19
63 : 37
72 : 28
78 : 22
80 : 20
84 : 16
66 : 34
2a Toluene
2a Pentane
2a Heptane
2a Cyclohexane
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
2a Methylcyclohexane rt
To further explore the efficiency of the developed method-
ology, reactions were performed on a 1 mmol scale,¶ as exem-
plified by the synthesis of 3a (75%, 80 : 20 er), 3b (95%, 80 : 20
er), and 3c (95%, 80 : 20 er).
2a Methylcyclohexane
2a CyH–toluene (9 : 1)
2a CyH–toluene (9 : 1)
2b Hexane
0
0
0
rt
rt
0
0
0
9d
10
11
12
13
14d
2b Cyclohexane
Diazenes 3 can be transformed into N-tert-butyl hydrazones
2b Methylcyclohexane
2b CyH–toluene (9 : 1)
2b CyH–toluene (9 : 1)
516 by means of
a simple acid-catalyzed isomerization
(Scheme 5). Treating optically active azo compounds 3a–e with
TFA in CH2Cl2 at 0 °C afforded pure hydrazones 5a–e in excel-
lent yields (90–95%) without the need for chromatographic
purifications and, importantly, without significant racemiza-
tion. It should be mentioned that tert-butyl hydrazones 5 are
relatively unstable compounds. However, the corresponding
a Reactions were performed with 1a (0.15 mmol), 2a,b (0.1 mmol) and
4k (15 mol%) in
1
mL of solvent. b Determined by 1H NMR.
c Determined by HPLC on chiral stationary phases. d 10 mol% of 4k
was used.
Having confirmed 4k as the most promising catalyst, an 5-TFA salt could be stored for several months at 0 °C.
optimization of the reaction parameters was performed for
The synthetic utility of products 5 was demonstrated
nitroalkenes 2a,b, as outlined in Table 2. Generally, good con- through their transformation into β-nitronitriles 7 (Scheme 6),
versions were obtained in all tested solvents; however, the which represent useful intermediates for the synthesis of
enantiomeric ratio of 3a significantly dropped in toluene β-amino acids.17 The direct oxidative cleavage of the hydrazone
(60 : 40 er, entry 2), CH3CN, Et2O or CH2Cl2 (racemic mixture).
In these cases the reaction rates are similar for the non-cata-
lyzed background and the catalyzed reaction (see ESI†). Aro-
¶Reactions were performed with 1a (1.5 mmol), 2 (1 mmol) and 4k (15 mol%) in
matic derivative 2b proved to be also a suitable substrate, dry cyclohexane–toluene (9 : 1) (10 mL) under argon at 0 °C for 72 h.
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Scheme 6 Synthesis of β-nitronitriles 7.
(MMPP·6H2O)18 leads to decomposition under standard con-
ditions. Therefore, N-methylation was accomplished first to
afford N,N-dialkyl hydrazones 6,19 which were then used for
subsequent racemization-free oxidative cleavage of the hydra-
zone moiety to afford the desired β-nitronitriles 7 in good
overall yields (7a: 58%, 7b: 71%, 2 steps). The absolute con-
figurations of (S)-7a,b were assigned by comparison of their
HPLC retention times with those of ent-7a,b previously
described in our group.20
Mechanistic aspects
To gain some insight into the substrate(s)–catalyst interactions
that lead to the observed stereoselectivity, we studied the reac-
tion of N,N-dimethyl hydrazone 1d with 2a using catalyst 4k.k
In contrast to the results obtained using 1a, the reaction with
1d afforded a racemic product in a much slower reaction,
suggesting that interactions involving the NH functionality
might play an important role. On the basis of the obtained
results, catalyst 4k is believed to act in a bifunctional fashion,
as previously proposed in the literature.15c Accordingly, the
nitroalkene is presumably activated by double hydrogen
bonding to a thiourea unit,21 while the hydrazone is directed
for the nucleophilic attack on the Si-face of the CvC bond by
a weak NH–S hydrogen bond with the second thiourea moiety
(Fig. 3), in agreement with the observed absolute
configuration.22
Scheme 4 Synthesis of enantioenriched azo compounds 3.
1H DOSY NMR (diffusion ordered spectroscopy) experi-
ments were performed to explore the hydrazone (1a)–catalyst
(4k) interactions in solution.23 As shown in Fig. 4, the
diffusion coefficients of the bis-thiourea 4k and tert-butyl
hydrazone 1a significantly decreased (ΔD = 0.33 and 0.82 for
4k and 1a, respectively) in a 1 : 1 mixture at 0.03 M, indicating
the existence of a significative association.
Further evidence for the interaction of 4k and 1a was pro-
vided by 1H NMR titration studies, in which the addition of
substoichiometric amounts of 4k to 1a resulted in
a
k Reaction was performed with 1d (0.15 mmol), 2a (0.1 mmol) and 4k (15 mol
%) in hexane (1 mL) at room temperature for 72 h. b30% of conversion (deter-
mined by 1H-NMR) into rac-adduct. c20% of conversion in the non-catalyzed
reaction.
Scheme 5 Transformation of adducts 3 into tert-butyl hydrazones 5.
moiety of 5 by the established oxidation/aza-Cope elimination
using
magnesium
monoperoxyphthalate
hexahydrate
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disappearance of thiourea NH protons. In contrast with low- while the low steric hindrance at the azomethine carbon
field shifts of thiourea NH signals generally showing the allows C-selective conjugate addition of 1a to nitroalkenes. The
presence of well-defined H-bonding complexation,24 these obser- reaction takes place spontaneously, but can be also accelerated
vations might indicate the existence of chemical exchange by H-bonding organocatalysts. The interaction of the reagent’s
processes causing signal broadening. Moreover, aromatic CH NH group with axially chiral bis-thiourea 4k appears to be
signals (A and G) next to the thiourea moiety undergo down- essential for the obtention of azo compounds 3 in good to
field shifts, suggesting conformational changes in catalyst 4k excellent yields (60–90%) and moderate enantioselectivities,
to accommodate an interaction with hydrazone 1a (Fig. 5).
up to 84 : 16 er. The synthesis of β-nitro-nitriles 7, direct pre-
Interestingly, the azomethine protons shift progressively cursors of β-amino acids, can be accomplished using a two-
upfield when 1a and 4k are mixed (Δδ = 0.03–0.05, 1a : 4k 2 : 1, step alkylation/oxidative cleavage protocol from tautomeric
see ESI†). These shifts reflect an increasing local electronic hydrazones 6.
density, as expected for the proposed weak (1a) NH–S (4k)
hydrogen bond depicted in Fig. 3.
Experimental
General methods
1H NMR spectra were recorded at 300 MHz, 400 MHz or
Conclusions
500 MHz; 13C NMR spectra were recorded at 75 MHz, 100 MHz
In conclusion, formaldehyde tert-butyl hydrazone 1a appears
as a convenient reagent for the synthesis of diazenes. As
expected, the presence of a single bulky tert-butyl group on the
amino nitrogen inhibits the reactivity of the nitrogen center
Fig. 5 1H NMR (500 MHz, 0.03 M, CD2Cl2) spectra for 4k (up) and
1 : 1 mixture of 4k and 1a (down).
a
Fig. 3 Stereochemical model.
Fig. 4 1H DOSY NMR (500 MHz, 0.03 M, CD2Cl2) of A: 4k; B: 1a; C: 4k + 1a.
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or 125 MHz, with the solvent peak used as the internal stan- 41.7, 38.5, 30.1, 29.3, 26.6, 26.4, 26.4, 26.3; HRMS (CI): calcu-
dard. The following abbreviations are used to indicate the mul- lated for [C13H26N3O2]+ 256.2025; found: 256.2021. The enan-
1
tiplicity in H NMR spectra: s, singlet; d, doublet; t, triplet; q, tiomeric ratio was determined by HPLC using a Chiralpak
quartet; dd, double doublet; m, multiplet; bs, broad signal. AD-H column [hexane–i-PrOH (98 : 2)]; flow rate 0.5 mL min−1
Analytical thin layer chromatography (TLC) was performed on τminor = 15.5 min, τmajor = 9.7 min.
;
0.25 mm silica gel 60-F plates and visualized by ultraviolet
(R,E)-1-(TERT-BUTYL)-2-(2-CYCLOPROPYL-3-NITROPROPYL)DIAZENE (3D).
irradiation and KMnO4, anisaldehyde or phosphomolybdic Yellow oil (96% yield); [α]2D5 −16.0 (c 1.0, CHCl3). (81 : 19 er); 1H
acid stains. Optical rotations were measured on a Perkin-Elmer NMR (300 MHz, CDCl3) δ 4.63 (dd, J = 12.1, 6.8 Hz, 1H), 4.53
341 MC polarimeter. The enantiomeric ratios (er) of the pro- (dd, J = 12.1, 7.1 Hz, 1H), 3.89 (dd, J = 12.8, 5.2 Hz, 1H), 3.82
ducts were determined by chiral stationary-phase HPLC (dd, J = 12.8, 7.2 Hz, 1H), 2.13–1.95 (m, 1H), 1.18 (s, 9H),
(Daicel Chiralpak AD-H, OD columns).
0.82–0.67 (m, 1H), 0.62–0.49 (m, 2H), 0.32–0.18 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 78.6, 70.3, 67.8, 42.5, 26.7, 13.4, 4.1,
3.7; HRMS (CI): calculated for [C10H20N3O2]+ 214.1556; found:
Materials
Unless otherwise noted, analytical grade solvents and commer- 214.1548. The enantiomeric ratio was determined by HPLC
cially available reagents, or catalysts, were used without further using a Chiralpak OD column [hexane–i-PrOH (99.5 : 0.5)]; flow
purification. For flash chromatography (FC) silica gel rate 0.25 mL min−1; τminor = 29.1 min, τmajor = 31.0 min.
(0.040–0.063 mm) was used. Formaldehyde hydrazones 1,25
(R,E)-1-(TERT-BUTYL)-2-[2-(NITROMETHYL)-4-PHENYLBUTYL]DIAZENE (3E).
1
not commercially available nitroalkenes 2,26 and catalysts 4d–f, Yellow oil (91% yield); [α]D25 −1.1 (c 1.3, CHCl3). (63 : 37 er); H
k–p27 were synthesized according to the literature.
NMR (400 MHz, CDCl3) δ 7.68–6.73 (m, 5H), 4.60 (dd, J = 12.5,
6.6 Hz, 1H), 4.44 (dd, J = 12.5, 6.7 Hz, 1H), 3.83 (dd, J = 13.1,
5.1 Hz, 1H), 3.76 (dd, J = 13.1, 6.7 Hz, 1H), 2.87–2.78 (m, 1H),
2.77–2.59 (m, 2H), 1.82–1.67 (m, 2H), 1.17 (s, 9H); 13C NMR
General procedure for the enantioselective 1,4-addition of
formaldehyde N-tert-butyl hydrazone 1a to nitroalkenes 2
Hydrazone 1a (17.7 μL, 0.15 mmol) was added to a solution of (100 MHz, CDCl3) δ 140.8, 128.5, 128.2, 126.1, 77.9, 68.6, 36.3,
nitroalkene 2 (0.1 mmol) and catalyst 4k (0.015 mmol) in 9 : 1 32.4, 31.7, 26.7; HRMS (CI): calculated for [C15H24N3O2]+
cyclohexane–toluene (1 mL) at 0 °C. The mixture was stirred 278.1869; found: 278.1865. The enantiomeric ratio was deter-
for ∼48 h. The enantiomerically enriched products 3 were puri- mined by HPLC using a Chiralpak AD-H column [hexane–i-
fied by FC (pentane/CH2Cl2). Enantiomeric ratios were deter- PrOH (97 : 3)]; flow rate 1 mL min−1; τminor = 5.2 min, τmajor
=
mined by HPLC analysis.
4.6 min.
(R,E)-1-(TERT-BUTYL)-2-[3-METHYL-2-(NITROMETHYL)BUTYL]DIAZENE (3A).
(R,E)-1-(TERT-BUTYL)-2-[2-(NITROMETHYL)HEPTYL]DIAZENE (3F). Yellow
Yellow oil (92% yield); [α]2D5 +6.8 (c 1.2, CHCl3). (81 : 19 er); H oil (88% yield); [α]2D5 −4.4 (c 1.1, CHCl3). (66 : 34 er); H NMR
NMR (300 MHz, CDCl3) δ 4.49 (dd, J = 12.7, 7.1 Hz, 1H), 4.42 (300 MHz, CDCl3) δ 4.57 (dd, J = 12.5, 6.7 Hz, 1H), 4.41 (dd, J =
(dd, J = 12.7, 6.5 Hz, 1H), 3.75 (dd, J = 13.1, 4.9 Hz, 1H), 3.61 12.5, 6.8 Hz, 1H), 3.78 (dd, J = 13.0, 5.0 Hz, 1H), 3.68 (dd, J =
(dd, J = 13.1, 8.3 Hz, 1H), 2.75–2.62 (m, 1H), 1.90–1.70 (m, 1H), 13.0, 7.1 Hz, 1H), 2.84–2.72 (m, 1H), 1.57–1.19 (m, 8H), 1.17 (s,
1.11 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H); 9H), 0.92–0.79 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 78.2, 69.0,
13C NMR (125 MHz, CDCl3) δ 76.5, 67.8, 67.4, 42.3, 28.4, 26.7, 67.8, 36.8, 31.6, 30.0, 26.7, 25.8, 22.4, 13.9; HRMS (CI): calcu-
19.7, 18.8; HRMS (CI): calculated for [C10H22N3O2]+ 216.1712; lated for [C12H26N3O2]+ 244.2025; found: 244.2028. The enan-
found: 216.1705. The enantiomeric ratio was determined by tiomeric ratio was determined by HPLC using a Chiralpak OD
1
1
HPLC using
a
Chiralpak AD-H column [heptane–i-PrOH column [hexane–i-PrOH (99.5 : 0.5)]; flow rate 0.25 mL min−1
;
(99.5 : 0.5)]; flow rate 0.5 mL min−1; τminor = 9.9 min, τmajor
9.6 min.
=
τminor = 23.6 min, τmajor = 25.0 min.
(R,E)-1-(TERT-BUTYL)-2-[3-NITRO-2-(P-TOLYL)PROPYL]DIAZENE
(3G).
(R,E)-1-(TERT-BUTYL)-2-(3-NITRO-2-PHENYLPROPYL)DIAZENE
(3B). Yellow oil (95% yield); [α]2D5 −36.5 (c 2.0, CHCl3). (84 : 16 er); 1H
Yellow oil (90% yield); [α]2D5 −25.3 (c 1.1, CHCl3). (84 : 16 er); 1H NMR (400 MHz, CDCl3) δ 7.20–6.98 (m, 4H), 4.81 (dd, J = 12.7,
NMR (300 MHz, CDCl3) δ 7.47–7.04 (m, 5H), 4.78 (dd, J = 12.8, 6.4 Hz, 1H), 4.69 (dd, J = 12.7, 8.2 Hz, 1H), 4.16–4.02 (m, 1H),
6.6 Hz, 1H), 4.67 (dd, J = 12.8, 8.2 Hz, 1H), 4.17–4.01 (m, 1H), 3.99 (dd, J = 6.9, 1.7 Hz, 2H), 2.30 (s, 3H), 1.14 (s, 9H); 13C
3.97 (dd, J = 6.9, 3.5 Hz, 2H), 1.07 (s, 9H); 13C NMR (125 MHz, NMR (125 MHz, CDCl3) δ 137.5, 134.7, 129.6, 127.6, 78.5, 70.8,
CDCl3) δ 137.8, 128.9, 127.8, 127.7, 78.3, 70.7, 67.9, 42.8, 26.6; 67.9, 42.5, 26.6, 21.0; HRMS (CI) calculated for [C14H22N3O2]+
HRMS (CI) calculated for [C13H19N3O2]+ 249.1477; found: 264.1712; found: 264.1706. The enantiomeric ratio was deter-
249.1469. The enantiomeric ratio was determined by HPLC mined by HPLC using a Chiralpak OD column [hexane–i-PrOH
using a Chiralpak OD column [hexane–i-PrOH (95 : 5)]; flow (95 : 5)]; flow rate 1 mL min−1; τminor = 6.0 min, τmajor
=
rate 1 mL min−1; τminor = 7.3 min, τmajor = 9.1 min.
9.0 min.
(R,E)-1-(TERT-BUTYL)-2-(2-CYCLOHEXYL-3-NITROPROPYL)DIAZENE
(3C).
(R,E)-1-(TERT-BUTYL)-2-[2-(4-METHOXYPHENYL)-3-NITROPROPYL] DIAZENE
1
Yellow oil (89% yield); [α]2D5 +2.9 (c 1.1, CHCl3). (78 : 22 er); H (3H). Yellow oil (60% yield); [α]D25 −0.9 (c 0.8, CHCl3). (71 : 29
1
NMR (300 MHz, CDCl3) δ 4.55 (dd, J = 11.2, 5.4 Hz, 1H), 4.49 er); H NMR (300 MHz, CDCl3) δ 7.15 (d, J = 8.7 Hz, 2H), 6.85
(dd, J = 11.2, 4.9 Hz, 1H), 3.82 (dd, J = 13.0, 4.9 Hz, 1H), 3.68 (d, J = 8.7 Hz, 2H), 4.81 (dd, J = 12.7, 6.3 Hz, 1H), 4.68 (dd, J =
(dd, J = 13.0, 8.3 Hz, 1H), 2.81–2.66 (m, 1H), 1.87–1.21 (m, 12.7, 8.1 Hz, 1H), 4.17–4.05 (m, 1H), 4.05–3.95 (m, 2H), 3.78 (s,
11H), 1.17 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 76.4, 67.7, 67.6, 3H), 1.15 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 159.1, 129.7,
332 | Org. Biomol. Chem., 2013, 11, 326–335
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128.8, 114.3, 78.6, 70.8, 67.9, 55.2, 42.2, 26.6; HRMS (CI) calcu- HRMS: calculated for [C10H22N3O2]+ 216.1712; found:
lated for [C14H22N3O3]+ 280.1661; found: 280.1657. The enan- 216.1707. The enantiomeric excess was determined by HPLC
tiomeric ratio was determined by HPLC using a Chiralpak using a Chiralpak AD-H column [hexane–i-PrOH (98 : 2)]; flow
AD-H column [hexane–i-PrOH (98 : 2)]; flow rate 0.5 mL min−1
τminor = 19.4 min, τmajor = 20.6 min.
;
rate 1 mL min−1; τminor = 7.2 min, τmajor = 6.8 min.
(S,E)-1-(TERT-BUTYL)-2-[3-METHYL-2-(NITROMETHYL)BUTYLIDENE] HYDRA-
(R,E)-1-(TERT-BUTYL)-2-[2-(2,4-DICHLOROPHENYL)-3-NITROPROPYL] ZINE 2,2,2-TRIFLUOROACETATE (5A-TFA). Yellow solid (95%); MP:
DIAZENE (3I). Yellow oil (96% yield); [α]D25 −10.4 (c 1.5, CHCl3). 90–92 °C; [α]2D5 −3.5 (c 0.8, CHCl3). (80 : 20 er); 1H NMR
(72 : 28 er); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 2.1 Hz, (300 MHz, CDCl3) δ 9.95 (s, 1H), 8.24 (d, J = 3.9 Hz, 1H), 4.77
1H), 7.21–7.17 (m, 2H), 4.82 (dd, J = 7.2, 2.4 Hz, 2H), 4.71–4.61 (dd, J = 13.9, 9.2 Hz, 1H), 4.43 (dd, J = 13.9, 4.8 Hz, 1H),
(m, 1H), 4.05 (dd, J = 6.6, 2.4 Hz, 2H), 1.13 (s, 9H); 13C NMR 3.35–3.21 (m, 1H), 2.09–1.94 (m, 1H), 1.34 (s, 9H), 1.01 (d, J =
(100 MHz, CDCl3) δ 134.8, 134.1, 133.7, 130.0, 129.4, 127.3, 6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz,
77.1, 68.7, 68.1, 38.6, 26.5; HRMS (CI) calculated for CDCl3) δ 169.2, 162.6 (q, JC–F = 35.9 Hz), 116.2 (q, JC–F
=
[C13H17Cl2N3O2]+ 318.0412; found: 318.0401. The enantiomeric 291.7 Hz), 73.2, 59.3, 46.5, 28.8, 24.9, 19.7, 18.9; HRMS: calcu-
ratio was determined by HPLC using a Chiralpak AD-H lated for [C10H22N3O2]+ 216.1712; found: 216.1711. The enan-
column [hexane–i-PrOH (98 : 2)]; flow rate 1 mL min−1; τminor
7.1 min, τmajor = 6.4 min.
=
tiomeric excess was determined by HPLC in the corresponding
hydrazone 5a.
(R,E)-1-[2-(2-BROMOPHENYL)-3-NITROPROPYL]-2-(TERT-BUTYL) DIAZENE
(S,E)-1-(TERT-BUTYL)-2-(3-NITRO-2-PHENYLPROPYLIDENE)HYDRAZINE (5B).
(3J). Brown oil (90% yield); [α]2D5 −16.6 (c 1.5, CHCl3). (72 : 28 Orange oil (93%); [α]D25 −71.7 (c 0.6, CHCl3). (79 : 21 er); 1H
1
er); H NMR (300 MHz, CDCl3) δ 7.60 (dd, J = 8.0, 1.2 Hz, 1H), NMR (300 MHz, CDCl3) δ 7.55–7.04 (m, 5H), 6.96 (d, J = 3.2 Hz,
7.33–7.18 (m, 2H), 7.17–7.10 (m, 1H), 4.88–4.82 (m, 2H), 1H), 4.97 (dd, J = 13.3, 8.4 Hz, 1H), 4.43 (dd, J = 13.3, 6.7 Hz,
4.80–4.68 (m, 1H), 4.08 (d, J = 6.5 Hz, 2H), 1.13 (s, 9H); 13C 1H), 4.36–4.26 (m, 1H), 1.08 (s, 9H); 13C NMR (75 MHz, CDCl3)
NMR (75 MHz, CDCl3) δ 137.3, 134.2, 129.8, 129.0, 128.3, δ 137.2, 136.6, 129.1, 128.3, 128.1, 77.3, 53.7, 46.0, 28.3;
125.4, 77.5, 69.8, 68.6, 41.9, 27.2; HRMS (CI) calculated for HRMS: calculated for [C13H20N3O2]+ 250.1556; found:
[C13H19BrN3O2]+ 328.0661; found: 328.0665. The enantiomeric 250.1557. The enantiomeric excess was determined by HPLC
ratio was determined by HPLC using a Chiralpak OD column using a Chiralpak AD-H column [hexane–i-PrOH (98 : 2)]; flow
[hexane–i-PrOH (95 : 5)]; flow rate 1 mL min−1; τminor
6.8 min, τmajor = 9.1 min.
=
rate 1.0 mL min−1; τminor = 12.6 min, τmajor = 11.5 min.
(S,E)-1-(TERT-BUTYL)-2-(2-CYCLOHEXYL-3-NITROPROPYLIDENE)
HYDRA-
(R,E)-1-(TERT-BUTYL)-2-[2-(FURAN-2-YL)-3-NITROPROPYL]DIAZENE (3K). ZINE (5C). Yellow oil (95%); [α]D25 −1.8 (c 0.9, CHCl3). (80 : 20 er);
Yellow oil (84% yield); [α]2D5 −10.2 (c 0.5, CHCl3). (77 : 23 er); 1H 1H NMR (300 MHz, (C6D6)) δ 6.40 (d, J = 4.5 Hz, 1H), 4.38 (dd,
NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 6.29 (s, 1H), 6.14 (d, J = J = 13.0, 9.6 Hz, 1H), 3.83 (dd, J = 13.0, 5.0 Hz, 1H), 2.84–2.70
3.0 Hz, 1H), 4.80 (d, J = 7.1 Hz, 2H), 4.34–4.19 (m, 1H), 4.05 (d, (m, 1H), 1.64–1.23 (m, 6H), 1.07 (s, 9H), 1.03–0.56 (m, 5H); 13
C
J = 7.3 Hz, 2H), 1.16 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.9, NMR (75 MHz, C6D6) δ 137.56, 75.3, 53.4, 45.4, 39.3, 30.4, 29.8,
142.3, 110.3, 107.5, 76.2, 68.1, 68.0, 36.7, 26.6; HRMS (CI) cal- 28.4, 26.6, 26.4, 26.3; HRMS: calculated for [C13H26N3O2]+
culated for [C11H17N3O3]+ 239.1270; found: 239.1276. The 256.1548; found: 256.1552. The enantiomeric excess was deter-
enantiomeric ratio was determined by HPLC using a Chiralpak mined by HPLC using a Chiralpak AD-H column [hexane–i-
AD-H column [hexane–i-PrOH (98 : 2)]; flow rate 0.5 mL min−1
τminor = 13.9 min, τmajor = 19.5 min.
;
PrOH (98 : 2)]; flow rate 1 mL min−1; τminor = 10.9 min, τmajor
=
8.4 min.
(S,E)-1-(TERT-BUTYL)-2-(2-CYCLOPROPYL-3-NITROPROPYLIDENE)
HYDRA-
General procedure for the transformation of azo compounds 3
into hydrazones 5
ZINE (5D). Yellow oil (90%); [α]D25 −63.8 (c 0.9, CHCl3). (77 : 23
1
er); H NMR (300 MHz, CDCl3) δ 7.05 (d, J = 3.6 Hz, 1H), 4.80
TFA (2 mL, 0.1 M in CH2Cl2) was added to a solution of azo (dd, J = 12.9, 8.2 Hz, 1H), 4.47 (dd, J = 12.9, 6.2 Hz, 1H),
compound 3 (0.2 mmol) in CH2Cl2 (0.1 mL) at 0 °C. The 2.47–2.26 (m, 1H), 1.11 (s, 9H), 0.66 (m, 1H), 0.61–0.50 (m,
mixture was stirred for 12–15 h. Satd NaHCO3 was added, and 2H), 0.35–0.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 138.7,
the mixture was extracted with Et2O and concentrated to 77.0, 53.6, 44.9, 28.2, 11.9, 3.7, 3.0; HRMS: calculated for
dryness to yield the pure hydrazones 5. Alternatively, excess of [C10H20N3O2]+ 214.0965; found: 214.0970. The enantiomeric
TFA could be evaporated as an azeotrope with toluene (3 × excess was determined by HPLC using a Chiralpak AD-H
1 mL) to obtain 5-TFA salts in high purity. Enantiomeric ratios column [hexane–i-PrOH (98 : 2)]; flow rate 1 mL min−1; τminor
were determined by HPLC analysis of the corresponding hydra- 11.7 min, τmajor = 10.7 min.
=
zones 5.
(S,E)-1-(TERT-BUTYL)-2-[3-NITRO-2-(P-TOLYL)PROPYLIDENE]
HYDRAZINE
(S,E)-1-(TERT-BUTYL)-2-[3-METHYL-2-(NITROMETHYL)BUTYLIDENE] HYDRA- (5E). Orange oil (90%); [α]D25 −54.1 (c 0.8, CHCl3). (78 : 22 er);
ZINE (5A). Yellow oil (90%); [α]2D5 −13.3 (c 1.0, CHCl3). (80 : 20 1H NMR (500 MHz, (CD3)CO) δ 7.18 (s, 4H), 7.09 (d, J = 3.7 Hz,
1
er); H NMR (300 MHz, CDCl3) δ 7.00 (d, J = 4.1 Hz, 1H), 4.75 1H), 5.05 (dd, J = 13.4, 8.7 Hz, 1H), 4.68 (dd, J = 13.4, 6.7 Hz,
(dd, J = 13.1, 9.0 Hz, 1H), 4.37 (dd, J = 13.1, 5.4 Hz, 1H), 1H), 4.37–4.32 (m, 1H), 2.30 (s, 3H), 1.14 (s, 9H); 13C NMR
3.13–2.99 (m, 1H), 1.96–1.81 (m, 1H), 1.12 (s, 9H), 0.97 (d, J = (75 MHz, CDCl3) δ 137.9, 137.6, 133.5, 129.8, 128.2, 77.4, 53.7,
6.9 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, 45.7, 28.3, 21.0; HRMS: calculated for [C14H22N3O2]+ 264.1712;
(CD3)2CO) δ 138.9, 77.1, 54.5, 47.7, 30.2, 29.5, 21.2, 20.2; found: 264.1708. The enantiomeric excess was determined by
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HPLC using
a Chiralpak AD-H column [hexane–i-PrOH
Acknowledgements
(98 : 2)]; flow rate 1.0 mL min−1; τminor = 12.0 min, τmajor
=
10.4 min.
We thank the Spanish ‘Ministerio de Ciencia e Innovación’
(grants CTQ2010-15297 and CTQ2010-14974), the European
FEDER funds and the Junta de Andalucía (grants 2008/
FQM-3833 and 2009/FQM-4537) for financial support. D.M.
acknowledges a “Juan de la Cierva” contract.
General procedure for the transformation of hydrazones 5 into
dialkylhydrazones 6
NaHCO3 (solid, 0.5 mmol, 42 mg) and MeI (1.5 mmol, 93 μL)
were added to a solution of hydrazone 5 (0.5 mmol) in MeOH
(1 mL) at room temperature and the mixture was stirred over-
night. Satd NaHCO3 was added, and the mixture was extracted
with Et2O and concentrated to dryness. Dialkylhydrazones 6
were isolated by FC (cyclohexane/Et2O).
(S,E)-1-(TERT-BUTYL)-1-METHYL-2-[3-METHYL-2-(NITROMETHYL)BUTYLI-
DENE]HYDRAZINE (6A). Yellow oil (70%/10% recovered 5a); [α]2D5
−6.5 (c 1.3, CHCl3). (80 : 20 er); 1H NMR (300 MHz, CDCl3) δ
6.59–6.46 (m, 1H), 4.77 (dd, J = 12.9, 9.1 Hz, 1H), 4.38 (dd, J =
12.9, 5.5 Hz, 1H), 3.21–3.05 (m, 1H), 2.57 (s, 3H), 2.00–1.81 (m,
1H), 1.15 (s, 9H), 0.99 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 130.3, 75.6, 58.5, 46.2, 31.7,
29.4, 26.9, 19.9, 18.8; HRMS: calculated for [C11H23N3O2]+
229.1790; found: 229.1786.
Notes and references
1 The Chemistry of the Hydrazo, Azo and Azoxy Groups, ed.
S. Patai, JohnWiley and Sons, Chichester, 1st edn, 1997.
2 J. Kosmrlj, M. Kocevar and S. Polanc, Synlett, 2009, 2217;
D. L. Boger and S. N. Weinreb, Hetero Diels-Alder Method-
ology in Organic Synthesis, Academic Press, San Diego,
1987.
3 D. A. Kennedy, N. Vembu, F. R. Fronczek and M. Devocelle,
J. Org. Chem., 2011, 76, 9641, and references therein.
4 For studies on aliphatic azo compounds and their thermal
and photochemical decomposition into radicals, see:
(a) T. König, In Free Radicals, ed. J. K. Kochi, Wiley,
New York, 1973, vol. I, p. 113; (b) P. S. Engel, Chem. Rev.,
1980, 80, 99; (c) M. Schmittel and C. Rüchardt, J. Am.
Chem. Soc., 1987, 109, 2750; (d) P. S. Engel, L. Pan, Y. Ying
and L. B. Alemany, J. Am. Chem. Soc., 2001, 123, 3706;
(e) P. S. Engel, C. Wang, Y. Chen, C. Rüchardt and
H. Beckhaus, J. Am. Chem. Soc., 1993, 115, 65.
(S,E)-1-(TERT-BUTYL)-2-(2-CYCLOHEXYL-3-NITROPROPYLIDENE)-1-METHYL-
HYDRAZINE (6B). Yellow oil (75%/10% recovered 5c); [α]2D5 −5.6 (c
1
0.9, CHCl3). (80 : 20 er); H NMR (300 MHz, CDCl3) δ 6.53 (d,
J = 3.9 Hz, 1H), 4.77 (dd, J = 12.9, 9.2 Hz, 1H), 4.40 (dd, J =
12.9, 5.4 Hz, 1H), 3.19–3.02 (m, 1H), 2.57 (s, 3H), 1.87–1.46 (m,
6H), 1.44–1.16 (m, 5H), 1.14 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 130.9, 75.6, 58.5, 45.9, 39.7, 31.7, 30.4, 29.7, 26.9, 26.5, 26.3
(2C); HRMS: calculated for [C14H27N3O2]+ 269.2103; found:
269.2096.
5 (a) F. R. Dietz, A. Prechter, H. Gröger and M. R. Heinrich,
Tetrahedron Lett., 2011, 52, 655; (b) A. Prechter, H. Gröger
and M. R. Heinrich, Org. Biomol. Chem., 2012, 10, 3384 and
references therein.
6 M. Fernández, U. Uria, J. L. Vicario, E. Reyes and
L. Carrillo, J. Am. Chem. Soc., 2012, 134, 11872.
7 A. Crespo-Peña, D. Monge, E. Martín-Zamora, E. Álvarez,
R. Fernández and J. M. Lassaletta, J. Am. Chem. Soc., 2012,
134, 12912.
8 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
New York, 2001; A. G. M. Barrett, Chem. Soc. Rev., 1991, 20,
95 and reviews cited therein.
9 (a) R. M. Adlington, J. E. Baldwin, J. C. Bottaro and
M. W. D. Perry, J. Chem. Soc., Chem. Commun., 1983, 1040;
(b) J. E. Baldwin, R. M. Adlington, J. C. Bottaro, A. U. Jain,
J. N. Kolhe, M. W. D. Perry and I. M. Newington, J. Chem.
Soc., Chem. Commun., 1984, 1095; (c) J. E. Baldwin,
R. M. Adlington and I. M. Newington, J. Chem. Soc., Chem.
Commun., 1986, 176; (d) J. E. Baldwin, R. M. Adlington,
J. C. Bottaro, J. N. Kolhe, M. W. D. Perry and A. U. Jain, Tet-
rahedron, 1986, 42, 4223; (e) J. E. Baldwin, R. M. Adlington,
J. C. Bottaro, J. N. Kolhe, I. M. Newington and
M. W. D. Perry, Tetrahedron, 1986, 42, 4235;
(f) J. E. Baldwin, R. M. Adlington, A. U. Jain, J. N. Kolhe
and M. W. D. Perry, Tetrahedron, 1986, 42, 4247;
(g) B. B. Snider, R. S. E. Conn and S. Sealfon, J. Org. Chem.,
1979, 44, 218.
General procedure for the transformation of dialkylhydrazones
6 into β-nitronitriles 7
To a cooled (0 °C) suspension of MMPP (1.5 mmol) in MeOH
(1 mL) was added dropwise a solution of the dialkylhydrazone
6 (0.3 mmol) in MeOH (2 mL). The mixture was stirred over-
night at room temperature and then poured into a mixture of
CH2Cl2 and water. The organic layer was separated, washed
with brine and water, and dried (MgSO4). The solvent was
removed and the residue purified by FC (cyclohexane/Et2O) to
afford pure β-nitronitrile 7.
(S)-3-METHYL-2-(NITROMETHYL)BUTANENITRILE
(7A). Yellow
oil
(83%); [α]2D5 +2.0 (c 1.4, CHCl3). (78 : 22 er). The enantiomeric
excess was determined by HPLC using a Chiralpak AD-H
column [hexane–i-PrOH (98 : 2)]; flow rate 1.0 mL min−1; τminor
= 20.4 min, τmajor = 23.9 min. Spectroscopic and analytical
data as previously reported.20
(S)-2-CYCLOHEXYL-3-NITROPROPANENITRILE (7B). Yellow oil (94%);
[α]2D5 −5.6 (c 1.1, CHCl3). (80 : 20 er). The enantiomeric excess
was determined by HPLC using a Chiralpak AD-H column
[hexane–i-PrOH (98 : 2)]; flow rate 1.0 mL min−1; τminor
=
64.7 min, τmajor = 36.1 min. Spectroscopic and analytical data
as previously reported.20
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Paper
10 1,3,5-Trisubstituted pyrazoles: (a) X. Deng and N. S. Mani, 17 N. Sewald, Angew. Chem., Int. Ed., 2003, 42, 5794.
Org. Lett., 2006, 8, 3505; (b) X. Deng and N. S. Mani, J. Org. 18 R. Fernández, C. Gasch, J. M. Lassaletta, J. M. Llera and
Chem., 2008, 73, 2412; 1,3,4-trisubstituted pyrazoles:
J. Vázquez, Tetrahedron Lett., 1993, 34, 141.
(c) X. Deng and N. S. Mani, Org. Lett., 2008, 10, 1307; 19 For general reviews on reactivity of N,N-dialkylhydrazones,
(d) 1,4-Disubstituted pyrazoles: M. Gómez-Guillén and
J. M. Lassaletta, Carbohydr. Res., 1991, 210, 175.
11 Addition of formaldehyde N,N-dimethylhydrazone to
nitroalkenes: (a) J. M. Lassaletta and R. Fernández, Tetra-
hedron Lett., 1992, 33, 3691; (b) J. M. Lassaletta,
see: (a) D. Enders, L. Wortmann and R. Peters, Acc. Chem.
Res., 2000, 33, 157; (b) R. Brehme, D. Enders, R. Fernández
and J. M. Lassaletta, Eur. J. Org. Chem., 2007, 5629;
(c) R. Lazny and A. Nodzewska, Chem. Rev., 2010, 110,
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