Stereoselective amine addition to six-membered cyclic nitronates promoted by silyl triflate

Article abstract of DOI:10.1002/ejoc.201300511

Six-membered cyclic nitronates couple with amines or their N-silyl derivatives in a diastereoselective fashion to give 3-amino-substituted nitroso acetals in 53-89 % yield through silyl triflate electrophilic catalysis. Stereodifferentiation of this process is determined by thermodynamic control, which is realized due to reversibility of amine addition and a decreased nitrogen inversion barrier in the resulting nitroso acetals. Selected chemical transformations of nitroso acetals were examined. N-Silylamines add to six-membered nitronates with high diastereoselectivity. The reaction follows an original mechanism in which thermodynamic control plays the key role. Copyright

Full text of DOI:10.1002/ejoc.201300511

FULL PAPER
DOI: 10.1002/ejoc.201300511
Stereoselective Amine Addition to Six-Membered Cyclic Nitronates Promoted
by Silyl Triflate
Andrey A. Mikhaylov,*[a] Alexander D. Dilman,[a] Yulia A. Khomutova,[a]
Dmitry E. Arkhipov,[b] Alexander A. Korlyukov,[b] and Sema L. Ioffe*[a]
Keywords: Nucleophilic addition / C–C coupling / Diastereoselectivity / Amines / Reaction mechanisms
Six-membered cyclic nitronates couple with amines or their
N-silyl derivatives in a diastereoselective fashion to give 3-
amino-substituted nitroso acetals in 53–89% yield through
silyl triflate electrophilic catalysis. Stereodifferentiation of
this process is determined by thermodynamic control, which
is realized due to reversibility of amine addition and a de-
creased nitrogen inversion barrier in the resulting nitroso
acetals. Selected chemical transformations of nitroso acetals
were examined.
Introduction
The chemistry of six-membered cyclic nitronates 1 is cur-
rently an object of systematic investigations.[1] Enhanced
interest in this class of organic derivatives has been pro-
voked not only by the diversity of their chemical transfor-
mations,[1] but also by their applications in the syntheses of
natural products and medical substances.[2,3]
Coupling of nitronates 1 with π-nucleophiles mediated by
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)
gives rise to nitroso acetals 2 [Scheme 1, Path (a)].[4] This
reaction is a powerful method of creating C–C bonds, as
well as an effective mode of standard reactivity inversion
of aliphatic nitro compounds.[4a,4d,5] In contrast, analogous
coupling of nitronates 1 with N-nucleophiles is limited to a
single example:[4a,6] nitronate 1a interacts with N-silylenam-
ine to form nitroso acetal 3α [Scheme 1, Path (b)] instead
of the expected C–C coupling product of type 2. Moreover,
besides exclusive C–N bond formation, the stereochemistry
of the nucleophilic addition at the newly formed carbon
stereocenter in compound 3α, was opposite to that in prod-
ucts 2.
Scheme 1. Electrophilic activity of nitronates 1.
unknown,[7] however they can potentially serve as interme-
diates in organic synthesis.
Results and Discussion
Nitronate 1a and N-TBS-pyrrolidine 4a were chosen as
model substrates with which to examine the N,C-coupling
(Scheme 2). The reaction proceeded smoothly with TBSOTf
(0.15–0.20 equiv.) as a mediator, which was necessary for
intermediate formation of cation 5a+. It was found that sil-
ylamine 4a adds to nitronate 1a within 24 hours at –30 °C,
giving rise to the target nitroso acetal 3a in 79% yield. The
only observed byproduct was enoxime 6a,[8] which was
formed in quantities up to 15%. Attempts to minimize the
yield of 6a by decreasing the reaction temperature were un-
successful.
The current investigation focuses on mechanistic analysis
of addition of amines and their N-silyl derivatives to six-
membered cyclic nitronates 1. The target nitroso acetals 3
possess a specific structure and can be considered as amin-
als at the C-3 atom. Compounds of such type are almost
Nitroso acetal 3a was isolated as the only diastereoiso-
mer. The NMR spectra show a close resemblance of adduct
3a to the previously obtained nitroso acetal 3α, the struc-
ture of which was unambiguously determined by X-ray
analysis (see Scheme 1). First, this similarity allowed the
[a] N.D.Zelinsky Institute of Organic Chemistry,
Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax: +7-499-1355328
E-mail: iof@ioc.ac.ru
Homepage: http://www.ioc.ac.ru/modules/common/
showfile.php?file=labs/lab_08/index
[b] A. N. Nesmeyanov Institute of Organoelement Compounds,
Vavilova str. 28, 119991 Moscow, Russian Federation
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300511.
3
associated JH,H coupling constants of the products to be
compared. Considering the slow nitrogen inversion in the
O–N–O fragment,[9] the configuration of the nitrogen
5670
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5670–5677

Amine Addition to Six-Membered Cyclic Nitronates
Scheme 2. The C,N-coupling of 1a and 4a, and the stereochemistry of 3a. Reaction conditions: 1a (1.0 mmol), 4a (1.1 mmol), 2,6-lutidine
(0.25 mmol), TBSOTf (0.15 equiv.), CH2Cl2 (5.0 mL), –30 °C, 24 h.
stereocenter was also assigned according to resemblance of Table 1. Addition of silylpyrrolidine 4a to nitronates 1a–i.[a]
1
the H NMR spectra of 3a to that of 3α.[4a] The arrange-
ment of the entering amino-fragment in 3a was thus as-
signed as trans to the TBSO-group.
The conditions found for coupling of 1a with N-
silylamine 4a were applied for the representative nitronate
series 1b–i, containing a range of ring substituents. In all
cases, the desired aminals 3 were obtained in moderate to
high yields (Table 1). When nitronate 1d (R1 = OBz) was
utilized, the addition rate was significantly decreased, and
only 25% conversion along with 19% yield of a mixture of
the corresponding nitroso acetals (3d + 3dЈ) was observed
within 24 h. The low conversion of 1d might be associated
with a stabilization of cationic intermediate 5d+ through an-
chimeric assistance of the BzO group. Hence, exposure of
the reaction mixture 1d and 4a for one week resulted in an
84% yield of desired product mixture (3d + 3dЈ). Aminal 3c
was found to be unstable, and its yield was determined by
1H NMR spectroscopic analysis with an internal standard.
Products 3 can exist in the form of rapidly intercon-
verting conformations of a six-membered heterocycle.[4a,4b]
At the same time, lone pair inversion of the nitroso acetal
nitrogen cannot be excluded (see below). These circum-
stances make determination of the configuration and the
observed conformations of aminals 3 a rather difficult task.
X-ray diffraction analysis was undertaken for all crystalline
products 3 (3e, 3fЈ and 3h). Configurations and predomi-
nant conformations for other derivatives of 3 were deter-
mined by 1H NMR spectroscopic analysis. Values of vicinal
coupling constants of protons at C-3, C-4 and C-5 atoms
[a] Reaction conditions: nitronate 1 (1.0 mmol), silylamine 4a
were the key for the stereochemical assignment, along with
NOE observations and chemical shifts values of the proton
at C-3 (see the Supporting Information for details).
Configurations and the observed conformations of the
aminals 3 can be divided into several types. For most (3a–
e, 3g, and 3h) the predominant conformation coincides with
(1.1 mmol), 2,6-lutidine (0.25 mmol), TBSOTf (0.15 mmol),
CH2Cl2 (5.0 mL), –78 °C, 15 min, then 24 h, –30 °C. [b] Yield de-
termined by NMR spectroscopic analysis with trichloroethylene as
internal standard. [c] iЈЈ corresponds to the C-6 epimerization prod-
uct, see the Supporting Information for details.
that obtained for the isolated nitroso acetal 3α, with all endocyclic nitrogen invertomers became the main products
equatorial positions of substituents at N-2, C-3 and C-4.[4a] of C,N-coupling for nitronates 1i and 1j, containing equato-
The C,N-coupling proceeds in a diastereoselective fashion rial alkoxy-groups at C-6 (1i: R4 = OEt, 1j: R4 = OBu).
for most nitronates 1 except for 1d (R1 = OBz) and homo- Partial epimerization of the acetal center at C-6 in nitronate
logues 1i (R4 = OEt) and 1j (R4 = OBu). However, the new 3i, possessing less bulky alkoxy-group, was observed, poss-
stereocenter at C-3 is formed even in the latter cases with ibly due to the presence of Lewis acidic TBSOTf.
near 100% selectivity. Aminal 3dЈ exists in equilibrium with
Free pyrrolidine 7a may be involved in the reaction in-
3d, which evidently operates through a nitrogen and ring stead of its silylated derivative 4a. In this case at least one
inversion sequence (IN + IR). The reaction of nitronate 1f, equivalent of TBSOTf was used and a longer reaction time
containing two equatorial phenyl groups (R1, R4 = Ph) un- was needed. However, the diastereoselectivity of formation
expectedly afforded product 3fЈ with inverted nitrogen (cis- of the target nitroso acetal 3a and its yield suffered no sig-
arrangement of TBSO and pyrrolidinyl groups). Similarly, nificant decrease (cf. Table 2, entries 1 and 2).
Eur. J. Org. Chem. 2013, 5670–5677
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5671

A. A. Mikhaylov, S. L. Ioffe et al.
FULL PAPER
Table 2. Coupling of nitronates 1a and 1g with silylamines 4 and
amines 7.
Scheme 3. Conformations of cation 5+ and possible approaches of
Nu.
Entry
1
1
R3
Amine
Method[a]
A
3
Yield [%]
(dr)[b]
The configuration of previously reported[4a,4b] nitroso
acetal products 2 was determined by the relative steric hin-
drance of two possible nucleophile approaches to both con-
formations of cation 5+ (Scheme 3, conformations 5a+ and
1a Me
N-TBS-pyrroli-
dine
pyrrolidine
morpholine
4a
3a
79
2
3
4
5
6
7
8
9
1a Me
1a Me
1g OMe morpholine
1a Me
1a Me
1g OMe PhN(Me)TBS
7a
7b
7b
7c
7d
4e
4f
B
B
B
B
B
A
A
B
3a
3k
3l
3m
3n
3o
75
76
69
77
53
74
5
b+). In this case, a trans-antiperiplanar arrangement of the
Et2NH
Bn2NH
appearing nitrogen lone pair and entering nucleophile is a
priori preferable because of a stabilizing n–σ* interaction.
It was stated that the observed conformations of the formed
nitroso acetals 2 result from fast ring inversion (IR) in these
products.
1a Me
1a Me
nBuNHTBS
nBuNH2
3p/3p* 89 (1.8:1)
3p/3p* 65 (1:3.4)
7f
[a] Method A: CH2Cl2 (5.0 mL), nitronate 1 (1.0 mmol), TBS-
amine (1.1 mmol), 2,6-lutidine (0.25 mmol), then TBSOTf
It should be underlined that the stereochemistry of for-
mation of aminals 3 (Table 1) cannot be explained on the
basis of such simple considerations. The differences in the
stereochemistry of nitroso acetals 2 and 3 seem so funda-
mental that another mechanism must be proposed for the
formation of the latter. We therefore first examined whether
preliminary generation of cation 5+ from nitronate 1 is nec-
essary for C,N-coupling (as shown in Scheme 2). For this
purpose, we attempted to carry out the coupling of 1b and
4a in CD2Cl2 in the absence of TBSOTf. Under these condi-
tions the reaction did not occur at –30 °C, nor even at room
temperature. On this basis, it is therefore quite plausible
that an initial cationic species is required to generate the
target aminals 3. However, it should be concluded that the
observed trans-orientation of the amine residue and R1-sub-
stituent does not depend on the dominant conformation
of the corresponding cationic intermediate 5+. Indeed, the
dominant conformation of the cationic precursors for amin-
als 3a–c and 3e–h was found to be 5a+, and, respectively,
conformation 5b+ for 3d, 3i, and 3j (see Scheme 3 and pre-
liminary publication[4b]).
4
(0.15 mmol), –78 °C, 15 min, then 24 h at –30 °C. Method B:
CH2Cl2 (5.0 mL), nitronate 1 (1.0 mmol), 2,6-lutidine (1.05 mmol),
TBSOTf (1.15 mmol), then amine 7 (1.05 mmol), –78 °C, 15 min,
then 48 h at –30 °C. [b] Determined by 1H NMR spectroscopic
analysis (for details, see the Supporting Information).
The nature of the amines involved in C,N-coupling with
nitronates 1a and 1g was varied over a rather wide range
(Table 2). Secondary amines smoothly reacted under the
optimized conditions, and primary butylamine 7f and its
trialkylsilyl derivative 4f could also be subjected to this re-
action (Table 2, entries 8 and 9); however, a crucial decrease
in the diastereoselectivity was observed in the latter cases.
With free n-butylamine 7f (Method B), isomer 2p* becomes
the main component of the reaction mixture; unexpectedly,
this product had a cis-orientation of amine fragment and
Ph-group at the C-4 center.
It was shown with the example of morpholine 7b that
Method B was also applicable for nitronates 1 containing
an alkoxy-group at the C-6 center (Table 2, entry 4). In this
case, C,N-coupling was not accompanied by oxazine ring-
opening transformations[10] and the expected product 3l
was obtained in 69% yield.
The stereochemical conformation of products 3 does not
correlate with previously obtained data on the C,C-cou-
pling of nitronates 1 with π-nucleophiles, for which distal
approach to the observed most stable conformation (5a+ or
In summary, the C,N-coupling of nitronates 1 with
silylamine 4a is a more complex process than previously
investigated C,C-coupling of 1 with π-nucleophiles, at least
in terms of observed configurations of the resulting prod-
ucts 3.[4a,4b] Therefore, the mechanistic aspects of this pro-
cess were considered in greater detail.
5
b+) occurred, leading to the corresponding cis-adducts 2
(see Schemes 1, 2, and 3).[4a,4b] Furthermore, as previously
mentioned, the cis-orientation of the endocyclic nitrogen
lone pair and the entering amino-fragment in products 3 is
usually observed (see Table 1). However, such a stereochem-
ical outcome is not as strict as that for nitroso acetals 2, for
which the nitrogen lone pair was always positioned trans-
to the entering π-nucleophile fragment.
The contradictions between the stereochemical outcomes
of reactions of N-nucleophiles and π-nucleophiles can be
Mechanistic Considerations
Previously described C,C-coupling of nitronates 1 with resolved by assuming the following postulates: (1) reaction
π-nucleophiles proceeds via two cationic intermediates 5a+ of 5+ + 4 or 5+ + 7 is reversible, and (2) the inversion barrier
and 5b+, existing in fast equilibrium (Scheme 3).
for the endocyclic nitrogen of aminals 3 in the presence of
5672
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5670–5677

Amine Addition to Six-Membered Cyclic Nitronates
silyl Lewis acids is significantly lower than that in nitroso
acetals 2.
The reversibility coupled with a decreased nitrogen inver-
sion barrier can result in the progressive accumulation of
thermodynamically preferred isomers in the reaction mix-
ture. The C,N-coupling of cyclic nitronates 1 with amines
or their silyl derivatives might be approximated by a scheme
involving five equilibria (Scheme 4). Formation of any of
four plausible nitroso acetal diastereomers (3, 3Ј, 3* and 3#,
as marked in Scheme 4) could not be excluded.
Figure 1. NMR monitoring of 1a/4a coupling in the presence of
TBSOTf (0.2 equiv.). Fragment of 1H NMR spectra (δ = 4.50–
6.75 ppm).
was again suppressed and after methanol quenching of
TBSOTf the inversion was completely stopped (see Fig-
ure 1, spectrum e).
To verify the reversibility of amine 4 addition, a further
experiment was carried out (Scheme 5). A mixture of 1a,
4a, and TBSOTf was kept for 3 h at –30 °C (at this point
Scheme 4. Proposed mechanism of C,N-coupling.
A nine-hour, low-temperature NMR monitoring experi- the composition by NMR spectroscopic analysis was deter-
ment observing the reaction of 1a and 4a (Figure 1) was mined to be ca. 50% 3a* and 15% 3aЈ along with ca. 20%
carried out to investigate the suggested hypothesis. Just one unreacted 1a) and treated with TBSO(MeO)C=CH2. After
hour after addition of TBSOTf (0.2 equiv.), the conversion an additional 15 h at –30 °C, ketene acetal adduct 2a was
of 1a already achieved ca. 75%. Diastereomeric nitroso isolated in 80% yield along with residual aminal 3a
acetals 3a* and 3aЈ were found to become the main prod- (ca. 10%).[11]
ucts in ca. 3:1 ratio. Furthermore, signals of enoxime 6a,
Thus, the reversibility of C,N-coupling of nitronates 1
cation 5a+, final product 3a, and the fourth isomer 3a# were with amines was confirmed by the reduction of the 3a*/3aЈ
detected in a total amount of less than 15% (see Figure 1, ratio (the 3a*+3a#/3aЈ+3a ratio precisely) from 3:1 to 2:1
spectrum a). Besides its resemblance to analogous products in the course of the NMR-monitoring experiment, as well
2 in its spectral characteristics, the structure of 3a* was un- as nitronate 1a or cation 5a+ trapping by silyl ketene acetal
1
1
ambiguously confirmed by H-1H and H-13C-correlation in the second experiment.
techniques.
In addition, evidence can be found in the literature[12] for
The structure of 3aЈ was deduced on the basis of spin- the reversibility of interaction between imminium cations
1
spin coupling constants and on the resemblance of its H that have structures closely resembling those of intermedi-
NMR spectrum to that of 3fЈ (see the Supporting Infor- ates 5+, and amines.[13] Indirect evidence for the reversibility
mation for details). After an additional 7 h (see Figure 1, of formation of nitroso acetals 3 was observed in high-reso-
spectrum b), conversion of nitronate 1a achieved 97%, and lution mass-spectra with mild electrospray ionization (ESI).
yields of 3*, 3Ј, 3#, and 3 were 53, 24, 5, and 7%, respec- The main peaks obtained by this method correspond to cat-
tively.
ions with mass [(M + H) – amine 7]+ (cf. with cations 5+),
When the temperature was increased to 10 °C, dynamic and their intensity can exceed the intensity of standard mo-
equilibriums 3* p 3# and 3Ј p 3, corresponding to O–N– lecular ion peaks [M + H]+ by several times (Figure 2).
O nitrogen inversion took place; this became evident from
The configuration of adduct 3a* corresponds to the less
the broadening of the corresponding signals and the de- hindered distal approach of silylamine 4a to the respective
crease in the chemical shift difference for the indicated pairs dominant cation 5aa+ (Scheme 3), which was realized earlier
(see Figure 1, spectrum c). After repeated cooling to –30 °C for C,C-coupling of the corresponding nitronate 1a with π-
(see Figure 1, spectrum d) the endocyclic nitrogen inversion nucleophiles.[4a] At the same time, the configuration of ad-
Eur. J. Org. Chem. 2013, 5670–5677
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5673

A. A. Mikhaylov, S. L. Ioffe et al.
FULL PAPER
Scheme 5. Trapping of cation 5a+ (5aa+ or 5ba+) from intermediate nitroso acetals 3a* and 3aЈ on silylketene acetal.
Figure 2. Fragment of high-resolution mass-spectra of nitroso acetal 3a (ESI).
duct 3aЈ corresponds to the most hindered proximal ap-
proach of 4a to the same conformation of 5aa+.
The decrease in the nitrogen inversion barrier (see postu-
late 2 above) in aminals 3 is especially intriguing. For stan-
dard nitroso acetals, this barrier can exceed 25 kcal/mol;[9]
however, in the performed NMR experiment (see Figure 1,
spectrum c) the characteristic inversion can be observed
Scheme 6. Decrease in the nitrogen inversion barrier for known
acyclic analogue 8 through amine quaternization. Energy is given
even at temperatures below 20 °C. It is known[7] that
“amine” nitrogen quaternization by transformation of neu- in kcal/mol.
tral acyclic aminomethyl nitroso acetal 8 into methylated
cation 8*Me+ significantly decreases the nitrogen inversion
barrier in ONO fragments (Scheme 6). It is therefore rier decrease [δΔG϶ = ΔG϶(8) – ΔG϶(8*Me+) = 6.0 kcal/
reasonable to suppose that, under C,N-coupling conditions, mol] is in good agreement with experimental data (5.7 kcal/
TBSOTf could reversibly silylate the exocyclic nitrogen mol). Therefore, we can use this method for qualitative
atom in aminals 3, which makes inversion of 3* and 3Ј analysis of free energy decrease values of nitrogen inversion
easier.
barriers of the endocyclic nitrogen atom in quaternized
DFT calculations [B3LYP/6-31+g(d)][14] of nitrogen in- aminals 3.
version in 8 and 8*Me+ in gaseous phase without consider-
The calculation was carried out for four possible con-
ing counterion and solvent (see Scheme 6) are applicable at formers of simplified ring-unsubstituted model nitroso
least for qualitative analysis of free energy values of this acetal 3z, which can undergo ring and endocyclic nitrogen
process. Indeed, the calculated value for the inversion bar- inversions (Figure 3). Because ring inversion in the corre-
5674
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5670–5677

Amine Addition to Six-Membered Cyclic Nitronates
sponding oxazinanes had a much lower barrier (10–14 kcal/ 4–8 hours under standard conditions turned out to be
mol)[15] than endocyclic nitrogen inversion, we focused only ineffective because it left significant amounts of nitronate
on calculating the barrier to nitrogen inversion. Calculated 1a in the mixture. However, pyrrolidine 7a itself can remove
nitrogen atom inversion barriers for 3z ranged from 18.7 to excess TBSOTf from the reaction mixture. Reaction of 1a
28.3 kcal/mol, depending on the starting conformation. The with 2.5 equivalents of pyrrolidine 7a, performed with the
same calculations of barriers were also made for the corre- minimum required amount of TBSOTf (1.02 equiv.) fol-
sponding protonated and silylated species 3z*H+ and lowed by neutral Al2O3 chromatography gave mixture of
3z*SiMe3+. In both cases, the activation energy decreased isomers 3*/3#/3Ј/3 in 1:3:0:1 ratio and 70% yield.
in the same way as 8*Me+ (δΔG϶ = 7.0–10.0 kcal/mol for
3z*H+ and δΔG϶ = 4.6–21.0 for 3z*SiMe3+).[16] Frequency
Attempted Intramolecular Coupling
analysis showed the vibrations corresponding to imaginary
frequencies interacted with the neighboring amino group,
which indicates a large contribution of n-σ* interactions.
Summarizing the results of the calculation, it can be con-
cluded that the presence of the leaving group at the C-3
atom in nitroso acetals 3 can lower the inversion barrier
without dissociation.
Intramolecular C,N-coupling between the nitronate
function and the amino group was also investigated. Ac-
complishing this strategy could lead to alkaloids of type 12,
which are known cholinesterase inhibitors[17] (Scheme 7).
Scheme 7. Attempted intramolecular C,N-coupling. Reagents and
conditions: (i) CH3NO2 (5.0 equiv.), NH4OAc (5.0 equiv.), iPrOH,
reflux, 3 h; (ii) [TiCl2(OiPr)2] (4.0 equiv.), ethyl vinyl ether
(2.5 equiv.), CH2Cl2, –94 °C, 1 h; (iii) TBSOTf (1.5 equiv.), 2,6-luti-
dine (1.6 equiv.), CH2Cl2, –30 °C, 24 h.
To the best of our knowledge, no known synthetic ap-
proaches to nitronates 1 are compatible with a free amino
group.[1,2a] Therefore we chose a strategy involving the syn-
thesis of nitronate 1o with an N-Boc-protected meth-
ylamino fragment (Scheme 7). It was supposed that depro-
tection of the amino group in nitronate 1o would occur in
situ under the action of TBSOTf. Nitronate 1o was ob-
tained with [TiCl2(OiPr)2] catalysis[2] from available alde-
hyde 9[18] via nitrostyrene 10 (Scheme 7). Unfortunately, de-
protection at the last stage failed. Attempted Boc-removal
by TBSOTf treatment of nitronate 1o led to almost quanti-
tative formation of eneoxime 6o instead of target nitroso
acetal 11. Under mild biphasic conditions [HCl(aq.)/CH2Cl2]
cleavage did not occur, and under homogeneous conditions
(CF3CO2H in THF) initial nitronate 1o was transformed
into a mixture of unidentified products. It is interesting that
nitroalkene 10 can be deprotected much easier; in the sec-
ond step of the synthesis (Scheme 7, conditions ii) all unre-
acted 10 underwent Boc cleavage.
Figure 3. DFT calculations of endocyclic nitrogen inversion of
nitroso acetal 3z, its protonated and silylated derivatives 3z*H+,
+
and 3z*SiMe3
.
The results of the calculation suggest that an efficient
way to fix intermediate isomers 3*, 3#, and 3Ј is by neutral-
izing TBSOTf, which accelerates the establishment of equi-
libriums 3* p 5 p 3Ј, 3Јp 3, and 3* p 3#. Quenching of
Selected Transformations of Nitroso Acetals 3
Whereas the chemistry of five-membered cyclic nitroso
the C,N-coupling reaction of 1a and 4a with MeOH after acetals – N-alkoxy- and N-silyloxyisoxazolidines – has been
Eur. J. Org. Chem. 2013, 5670–5677
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5675

A. A. Mikhaylov, S. L. Ioffe et al.
stirred solution of nitronate
FULL PAPER
quite well investigated,[1,9] their six-membered analogues 2
and 3 remain poorly studied. For several nitroso acetals 2,
only peracidic oxidation is known.[5] Under these condi-
tions,[5] aminal 3a was transformed into lactone 13 in al-
most quantitative yield (Scheme 8). Trialkylsilanol elimi-
nation under acidic conditions is one of the most explored
reactions of five-membered nitroso acetals. For aminal 3a,
an analogous possibility was shown (3aǞ14 under action
of AcOH; Scheme 8) but still needs optimization. Further-
General Procedure B: To
a
1
(1.00 mmol), 2,6-lutidine (122 μL, 112 mg, 1.05 mmol) in CH2Cl2
(5 mL) at –78 °C, was added TBSOTf (264 μL, 304 mg,
1.15 mmol). The mixture was stirred for 5 min and then amine 7
(1.05 mmol) was added rapidly at –78 °C. The reaction mixture was
warmed to –30 °C and kept for 48 h at this temperature (freezer).
The mixture was poured into a mixture of saturated aqueous
NaHCO3 (10 mL) and hexane (10 mL). The organic layer was sepa-
rated and the aqueous layer was back-extracted with hexane (2ϫ
5 mL). The combined organic layers were washed with brine
more, we were able to oxidize aminal 3h to give dicarbonyl (10 mL), dried with Na2SO4, and the solvents were evaporated in
vacuo. The residue was subjected to column chromatography (silica
gel; EtOAc/hexane, 1:20Ǟ1:10) to give target nitroso acetal 3.
compound 15 under neutral conditions with active MnO2.
Typical Spectroscopic Data for Products 3
rel-(2S,3S,4R,4aS,8aR)-2-(tert-Butyldimethylsilyloxy)-8a-methoxy-
4-phenyl-3-(pyrrolidin-1-yl)octahydro-2H-benzo[e][1,2]oxazine (3h):
Yield 326 mg (73%; method A); white flakes; m.p. 76–78 °C (pent-
ane); TLC: Rf = 0.72 (EtOAc/hexane, 1:1; unstable on SiO2). 1H
NMR (300.13 MHz, 303 K, CDCl3, COSY): δ = 0.22 and 0.30 [2ϫ
s, 6 H, Si(CH3)2], 0.96 [s, 9 H, C(CH3)3], 0.98–1.18 [m, 2 H, CH2Cy],
1.25–1.45 [m, 7 H, CH2Cy (3 H), CH2Pyr (4 H)], 1.51–1.62 [m, 2 H,
3
3
3
CH2Cy], 1.88 [ddd, J ≈ J = 11.7, J = 3.3 Hz, 1 H, CHCy], 2.00
[br. d, J ≈ 10.6 Hz, 1 H, CH2Cy], 2.69 and 2.99 [2ϫ m, 4 H, CH2N],
3
3
3.22 [dd, J ≈ J = 11.0 Hz, 1 H, CH(ax)Ph], 3.77 [s, 3 H, OCH3],
4.01 [d, 3J = 10.5 Hz, 1 H, NCH(ax)N], 7.14–7.30 [m, 5 H,
Ph] ppm. 13C NMR (75.47 MHz, 303 K, CDCl3, HSQC): δ = –4.8
and –3.4 [Si(CH3)2], 17.6 [C(CH3)3], 22.2, 25.4, 26.0 and 30.3
(CH2Cy), 24.6 (CH2Pyr), 26.1 [C(CH3)3], 45.8 (CHPh), 47.5 (CH2N),
48.0 (OCH3), 50.1 (CHCy), 87.8 (CHN), 101.1 (OCO), 126.0 and
127.9 (CHo-Ph, CHm-Ph and CHp-Ph), 141.0 (Ci-Ph) ppm. 29Si NMR
(59.63 MHz, 303 K, CDCl3): δ = 26.41 ppm. C25H42N2O3Si
(446.70): calcd. C 67.22, H 9.48, N 6.27, Si 6.29; found C 67.12, H
9.41, N 6.10, Si 6.06.
Scheme 8. Selected transformations of aminals 3.
Conclusions
rel-(2S,3S,4R)-2-(tert-Butyldimethylsilyloxy)-3-diethylamino-6,6-di-
methyl-4-phenyl-[1,2]oxazinane (3m): Yield 303 mg (77%;
method B); colorless oil; TLC: Rf = 0.80 (EtOAc/hexane, 1:1). H
The C,N-coupling of nitronates 1 with amines 7 and its
silyl derivatives 4 has been accomplished and leads to the
corresponding nitroso acetals 3. DFT calculations and
NMR spectroscopic monitoring of the C,N-coupling con-
firmed thermodynamic control of the reaction. Such con-
trol is achievable due to the reversibility of the addition and
the decreased endocyclic nitrogen inversion barrier under
the reaction conditions. Selected chemical transformations
of products 3 were demonstrated.
1
NMR (300.13 MHz, 300 K, CDCl3): δ = 0.22 and 0.26 [2ϫ s, 6 H,
Si(CH3)2], 0.73 [t, 3J = 7.3 Hz, 6 H, 2ϫ CH3Et], 0.96 [s, 9 H,
2
C(CH3)3], 1.26 and 1.48 [2ϫ s, 6 H, C(CH3)2], 1.75 [dd, J = 13.2,
3J = 5.1 Hz, 1 H, CH2(eq)], 1.88 [dd, 2J ≈ 3J = 13.2 Hz, 1 H,
3
3
CH2(ax)], 2.66–2.86 [m, 4 H, N(CH2)2], 3.20 [ddd, J ≈ J = 12.4,
3J = 5.1 Hz, 1 H, CH(ax)Ph], 3.77 [d, 3J = 10.3 Hz, 1 H, NCH(ax)-
N], 7.15–7.38 [m, 5 H, Ph] ppm. 13C NMR (75.47 MHz, 300 K,
CDCl3):
δ = –4.7 and –3.1 [Si(CH3)2], 15.4 (CH3Et), 17.8
[C(CH3)3], 23.6 and 29.1 [C(CH3)2], 26.2 [C(CH3)3], 43.4 (CHPh),
45.1 (CH2Et), 46.1 (CH2CH), 75.9 [C(CH3)2], 88.5 (CHN), 126.0
(CHp-Ph), 127.0, 128.2 (CHPh), 143.5 (Ci-Ph) ppm. 29Si NMR
(59.63 MHz, 300 K, CDCl3): δ = 27.22 ppm. HRMS (ESI): m/z
calcd. for C22H40N2O2Si + H+ 393.2932; found 393.2939. HRMS
(ESI): m/z calcd. for C18H30NO2Si+ [M + H+ – Et2NH] 320.2035;
found 320.2040.
Experimental Section
General Procedure A: To
a stirred solution of nitronate 1
(1.00 mmol), 2,6-lutidine (29 μL, 27 mg, 0.25 mmol), and silylated
amine 4 (1.10 mmol) in CH2Cl2 (5 mL) at –78 °C, was added
TBSOTf (34 μL, 40 mg, 0.15 mmol). The reaction mixture was
warmed to –30 °C in 30 min and kept for 24 h (unless otherwise
mentioned) at this temperature (freezer) and was quenched with
EtOH (15 μL, 12 mg, 0.25 mmol). The temperature was then al-
lowed to reach ambient and the mixture was poured into a mixture
of saturated aqueous NaHCO3 (10 mL) and hexane (10 mL). The
organic layer was separated and the aqueous layer was back-ex-
tracted with hexane (2ϫ 5 mL). The combined organic layers were
washed with brine (10 mL), dried with Na2SO4, and the solvents
were evaporated in vacuo. The residue was subjected to column
chromatography (silica gel; EtOAc/hexane, 1:20Ǟ1:10Ǟ1:5) to
give target nitroso acetal 3.
X-ray Data: CCDC-932696 (for 3e), -932518 (for 3fЈ), and -932517
(for 3h) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the synthesis of the initial com-
pounds, physical constants and spectroscopic data for prepared
1
compounds, the results of DFT calculations, and copies of H, 13
C
NMR spectra for all novel compounds.
5676
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5670–5677

Amine Addition to Six-Membered Cyclic Nitronates
b) A. A. Tishkov, A. V. Lesiv, Y. A. Khomutova, Y. A. Stre-
lenko, I. D. Nesterov, M. Y. Antipin, S. L. Ioffe, S. E. Den-
mark, J. Org. Chem. 2003, 68, 9477–9480.
Acknowledgments
This work was performed with the financial support of the Russian
Foundation for Basic Research (grant number 12-03-00278-a) and
the President of Russian Federation Program for support of young
scientists and leading scientific schools (grant number NSH-
412.2012.3). The authors are grateful to Dr. M. I. Struchkova for
recording several NMR spectra and to the Higher Chemical Col-
lege of Russian Academy of Sciences for enabling A. M. to perform
the Gaussian calculations.
[9] V. F. Rudchenko, Chem. Rev. 1993, 93, 725–739.
[10] For nitronates 1, in the presence of the silyl triflate excess, ring-
chain tautomerism as well as ring opening reactions are pos-
sible, see: a) V. O. Smirnov, Y. A. Khomutova, A. A. Tishkov,
S. L. Ioffe, Russ. Chem. Bull. 2006, 55, 2061–2070; Izv. Akad.
Nauk, Ser. Khim. 2006, 55, 1983–1992; b) V. O. Smirnov, A. A.
Tishkov, S. L. Ioffe, G. V. Zatonsky, Y. A. Strelenko, W. A.
Smit, Mendeleev Commun. 2002, 12, 117–118.
[11] Apparently, the stabilizing trans-antiperiplanar arrangement of
the nitrogen lone pair and leaving group is needed for C–N
cleavage in nitroso acetals 3* and 3Ј in solution, as was found
for the C–NO2 bond in bicyclic nitroso acetals; for details see
ref.[12a]
[12] a) I. E. Chlenov, Doctor of science Thesis, Moscow, 1980, p.
148; b) N. Gravitz, W. Jencks, J. Am. Chem. Soc. 1974, 96, 499–
506.
[13] It is rather probable that our failed attempts to expand C,N-
coupling with amines on nitronates of other types (five-mem-
bered cyclic, acyclic) are also connected with the reversibility
of this process.
[1] S. L. Ioffe, in: Nitrile Oxides, Nitrones and Nitronates, in: Or-
ganic Synthesis 2nd ed. (Ed.: H. Feuer), John Wiley & Sons,
Chichester, UK, 2008, p. 435–748.
[2] a) S. E. Denmark, A. Thorarensen, Chem. Rev. 1996, 96, 137–
165; b) S. E. Denmark, J. J. Cottel, in: Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and
Natural Products (Eds.: A. Padwa, W. H. Pearson), John
Wiley & Sons, Chichester, United Kingdom, 2002, vol. 59, p.
83–167.
[3] A. Yu. Sukhorukov, Y. D. Boyko, Y. V. Nelyubina, S. Gerard,
S. L. Ioffe, V. A. Tartakovsky, L. Malleret, A. Belaaouaj, J.
Org. Chem. 2012, 77, 5465–5469.
[14] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Jr, Montgomery, T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pom-
elli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P.
Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui,
A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu,
A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,
M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, rev. C.02,
Gaussian, Inc., Wallingford, CT, 2004.
[15] a) J. B. Lambert, Y. Takeuchi, Cyclic Organonitrogen Stereody-
namics, VCH Publishers, New York, 1992, chapters 7.1.1 and
7.2.1, and references cited therein; b) F. G. Riddel, E. S. Terner,
A. Boyd, Tetrahedron 1979, 35, 259–261; c) F. G. Riddel, M. H.
Berry, E. S. Turner, Tetrahedron 1978, 34, 1415–1423.
[16] The greater decrease of δΔG϶ in case of ee and ae conformers
of 3z*SiMe3+ could be explained by the rather high energies of
silylation of the corresponding conformers of 3z.
[4] a) V. O. Smirnov, S. L. Ioffe, A. A. Tishkov, Y. A. Khomutova,
I. D. Nesterov, M. Y. Antipin, W. A. Smit, V. A. Tartakovsky,
J. Org. Chem. 2004, 69, 8485–8488; b) Y. A. Khomutova, V. O.
Smirnov, H. Mayr, S. L. Ioffe, J. Org. Chem. 2007, 72, 9134–
9140. For other types of nitronates, see: c) V. O. Smirnov, A. S.
Sidorenkov, Y. A. Khomutova, S. L. Ioffe, V. A. Tartakovsky,
Eur. J. Org. Chem. 2009, 3066–3074; d) V. O. Smirnov, Y. A.
Khomutova, V. A. Tartakovsky, S. L. Ioffe, Eur. J. Org. Chem.
2012, 3377–3384.
[5] A. S. Naumova, A. A. Mikhaylov, Y. A. Khomutova, M. I.
Struchkova, S. L. Ioffe, V. A. Tartakovsky, Eur. J. Org. Chem.
2012, 2219–2224.
[6] It should be noted that the closely related process – addition of
heteroatom-centered n-nucleophiles to C=O and C=N bonds
mediated by silyl Lewis acid – is a well-known synthetic
method, see: a) H. Vorbrüggen, in: Silicon-Mediated Transfor-
mations of Functional Groups, Wiley-VCH, Weinheim, Ger-
many, 2004, p 364; b) H. Fujioka, K. Yahata, O. Kubo, Y.
Sawama, T. Hamada, T. Maegawa, Angew. Chem. 2011, 123,
12440; Angew. Chem. Int. Ed. 2011, 50, 12232–12235; c) C.
De Risi, A. Dondoni, D. Perrone, G. P. Pollini, Tetrahedron
Lett. 2001, 42, 3033–3036.
[7] V. F. Rudchenko, S. M. Ignatov, I. I. Chervin, V. S. Nosova,
R. G. Kostyanovsky, Bull. Acad. Sci. USSR, Div. Chem. Sci.
(Engl. Transl.) 1986, 5, 1045–1052; Izv. Akad. Nauk SSSR,
Ser. Khim. 1986, 5, 1153–1160.
[17] G. S. Eadie, J. Biol. Chem. 1942, 146, 85–93.
[18] A. R. Kunzer, M. D. Wendt, Tetrahedron Lett. 2011, 52, 1815–
1818.
[8] For the mechanism of ene-oxime 6a formation, see: a) A. A.
Tishkov, I. M. Lyapkalo, A. V. Kozincev, S. L. Ioffe, Y. A. Stre-
lenko, V. A. Tartakovsky, Eur. J. Org. Chem. 2000, 3229–3233;
Received: April 9, 2013
Published Online: July 16, 2013
Eur. J. Org. Chem. 2013, 5670–5677
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5677