Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via intramolecular 1,3-dipolar cycloaddition

Article abstract of DOI:10.3762/bjoc.15.200

Sterically shielded nitroxides of the pyrrolidine series have shown the highest resistance to reduction. Here we report the synthesis of new pyrrolidine nitroxides from 5,5-dialkyl-1-pyrroline N-oxides via the introduction of a pent-4-enyl group to the nitrone carbon followed by an intramolecular 1,3-dipolar cycloaddition reaction and isoxazolidine ring opening. The kinetics of reduction of the new nitroxides with ascorbate were studied and compared to those of previously published (1S,2R,3′S,4′S,5′S,2″R)-dispiro[(2-hydroxymethyl)cyclopentan-1,2′-(3′,4′-di-tert-butoxy)pyrrolidine-5′,1″-(2″-hydroxymethyl)cyclopentane]-1′-oxyl (1).

Full text of DOI:10.3762/bjoc.15.200

Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via intramolecular
1,3-dipolar cycloaddition
Yulia V. Khoroshunova1,2, Denis A. Morozov*1,2, Andrey I. Taratayko1,2,
Polina D. Gladkikh1,2, Yuri I. Glazachev3 and Igor A. Kirilyuk1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2036–2042.
1N.N. Vorozhtsov Institute of Organic Chemistry SB RAS,
Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russian
Federation, 2Novosibirsk State University, Pirogova Str. 2,
Novosibirsk 630090, Russian Federation and 3Voevodsky Institute of
Chemical Kinetics and Combustion SB RAS, Institutskaya 3,
Novosibirsk 630090, Russian Federation
doi:10.3762/bjoc.15.200
Received: 03 June 2019
Accepted: 09 August 2019
Published: 27 August 2019
Associate Editor: I. Baxendale
Email:
Denis A. Morozov* - m_falcon@nioch.nsc.ru
© 2019 Khoroshunova et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aldonitrone; 1,3-dipolar cycloaddition; pyrrolidine nitroxides;
1-pyrroline-N-oxide; sterically shielded nitroxide
Abstract
Sterically shielded nitroxides of the pyrrolidine series have shown the highest resistance to reduction. Here we report the synthesis
of new pyrrolidine nitroxides from 5,5-dialkyl-1-pyrroline N-oxides via the introduction of a pent-4-enyl group to the nitrone car-
bon followed by an intramolecular 1,3-dipolar cycloaddition reaction and isoxazolidine ring opening. The kinetics of reduction of
the new nitroxides with ascorbate were studied and compared to those of previously published (1S,2R,3′S,4′S,5′S,2″R)-dispiro[(2-
hydroxymethyl)cyclopentan-1,2′-(3′,4′-di-tert-butoxy)pyrrolidine-5′,1″-(2″-hydroxymethyl)cyclopentane]-1′-oxyl (1).
Introduction
Sterically shielded nitroxides are currently attracting much We recently reported the synthesis of sterically shielded pyrrol-
attention due to their high resistance to bioreduction [1,2]. It has idine nitroxide 1 via a stereospecific consecutive assembly of
been demonstrated that 2,2,5,5-tetraethylpyrrolidine nitroxides two spiro-(2-hydroxymethyl)cyclopentane moieties. These pro-
have the highest stability, sometimes exceeding that of trityl cedures included the addition of pent-4-enylmagnesium bro-
radicals [1]. Introduction of spirocyclic moieties has a smaller mide to the corresponding nitrone, oxidation to alkenylnitrone,
effect on the reduction rates of nitroxides than the introduction intramolecular 1,3-dipolar cycloaddition, and isoxazolidine ring
of linear alkyl substituents does; however, spirocyclic nitrox- opening. Nitroxide 1 showed both an unexpectedly low reduc-
ides may have much longer spin relaxation times at 70–125 K tion rate [6] and long relaxation times t1 and tm at room temper-
[3] and even at room temperature [4]. The latter effect may be ature [4]. Unexpectedly high resistance of this nitroxide to
useful for structural studies by means of PELDOR or DQC [5]. chemical reduction results from the configuration of the
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Beilstein J. Org. Chem. 2019, 15, 2036–2042.
hydroxymethyl groups, which are directed towards the nitroxide Results and Discussion
group, thereby making it more hindered. It is known that induc- Aldonitrones 5b,c were prepared similarly to the well-known
tive effects of substituents can strongly affect the rate of synthesis of 5,5-dimethyl-1-pyrroline-1-oxide (DMPO, 5a)
nitroxide reduction [7,8]; therefore, one could expect that the [9,10] from nitrocyclohexane and 3-nitropentane (Scheme 1). In
removal of electron-withdrawing tert-butoxy groups at posi- brief, the reaction of nitrocyclohexane and acrolein in a
tions 3 and 4 of the pyrrolidine ring of 1 (Figure 1) should lead CH3ONa/CH3OH solution afforded the corresponding
to a further decrease in the reduction rate of the nitroxide.
nitroaldehyde 3b with a 70% yield. Of note, the Michael addi-
tion of 3-nitropentane to acrolein was accompanied by remark-
able tarring and gave a much lower yield of nitroaldehyde 3c
(25%). The reactive aldehyde groups were protected via 1,3-
dioxolane assembly, and the resulting compounds were treated
with Zn dust and NH4Cl in a water–THF solution to reduce
nitro groups. The resulting hydroxylamines were treated with
hydrochloric acid to hydrolyse dioxolane moieties, and careful
basification resulted in intramolecular cyclisation givnig 5b,c
with a yield of 51% and 42%, respectively.
Figure 1: Structure of nitroxide 1.
Nitrones 5a–c readily react with 4-pentenylmagnesium bro-
mide. Quenching of the reaction mixtures with water under
Here we describe the synthesis of C1-symmetric racemic 3,4- aerobic conditions leads to partial oxidation of resultant
unsubstituted pyrrolidine nitroxides with only one spiro(2- N-hydroxypyrrolidines 6a–c to corresponding nitrones 7a–c.
hydroxymethyl)cyclopentane moiety. The rates of reduction of Therefore, this conversion was finalised via bubbling of air into
the new nitroxides with ascorbate were measured.
the solution in the presence of Cu(NH3)42+ (Scheme 2).
Scheme 1: The synthesis of aldonitrones 5a–c.
Scheme 2: The principal synthetic scheme for nitroxides 12a–c.
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Beilstein J. Org. Chem. 2019, 15, 2036–2042.
Samples of resulting 2-(pent-4-enyl)nitrones 7a–c remarkably ported a similar reversibility of the intramolecular cyclization of
deteriorate during storage under aerobic conditions with sterically hindered pent-4-enylnitrone of the 2H-imidazole
dark tar formation. A possible pathway of decay may include series [15].
oxidation of the ene-hydroxylamine tautomeric form to
vinylnitroxide; similar compounds are prone to various Treatment with Zn in an AcOH/EtOH/EDTA/Na2 mixture was
dimerisation reactions (Scheme 3) [11]. It is worth noting that performed for reductive isoxazolidine ring opening [15,16] pro-
in the mass spectrum of 7c, the [M − 1]+ ion was observed ducing aminoalcohols 9a–c in 85–95% yields (Scheme 2).
instead of the molecular ion. The easy loss of a hydrogen atom
is consistent with the susceptibility of 7c to oxidative decay We have previously reported that oxidation of secondary
(Scheme 3).
amines with a spiro(2-hydroxymethyl)cyclopentane moiety at
the α-carbon with the H2O2/WO42− system is ineffective where-
Intramolecular cycloaddition of similar nitrones is known to as conversion of these amines to the corresponding nitroxides
lead to hexahydro-1H-cyclopenta[c]isoxazoles [6,12]. Indeed, can be easily performed using m-chloroperbenzoic acid
heating of 7а–с at 145 °C in toluene for 30–60 min in a micro- (m-CPBA) [6,15]. Treatment of 9a with m-CPBA in dry chloro-
wave oven produced 8a–c (racemic mixtures; Scheme 2). The form at −10 °C afforded a nitroxide, which was isolated as
structure assignment was performed on the basis of 1H and orange oil with a yield of 73% (Scheme 4). An infrared spec-
13C NMR spectra and 1H,1H and 13C,1H correlations (see Sup- trum of the isolated compound showed a strong absorption band
porting Information File 1); the spectral data are in agreement at 1725 cm−1 typical for carbonyl compounds and no absorp-
with the literature on similar systems [6].
tion in the region 3100–3500 cm−1, suggesting that the
hydroxymethyl group was affected in the reaction. The mass
To decrease the tarring, the reaction was carried out in the pres- spectrum featured the molecular ion [M+] = 196.1335 corre-
ence of 2,2,6,6-tetramethylpiperidine-1-oxyl. It should be noted sponding to the molecular formula C11H18NO2, which matches
that heating of alkenyl nitrones 7a and 7b gives the correspond- element analysis data. These results allowed us to assign the
ing cycloadducts with yields close to quantitative, whereas for structure 15 to this nitroxide. Indeed, oxidation of amines with
nitrone 7c, the complete conversion could not be achieved peracids is known to proceed via oxoammonium cation forma-
either at 145 °C or at a higher temperature. According to the tion [17,18], and the latter can oxidize alcohols to carbonyl
1Н NMR spectra, the 8c/7c ratio never exceeded 3:1. Heating of compounds [19]. The close proximity of the hydroxymethyl
a pure sample of 8c under similar conditions caused the emer- group to the oxoammonium one favours the reaction. Treat-
gence of signals at 5.70, 4.92, and 4.87 ppm in the 1H NMR ment of 15 with NaBH4 in EtOH caused quantitative reduction
spectra. These signals were attributed to the protons of the ter- of the aldehyde group to the hydroxymethyl one, thus yielding
minal vinyl group of 7c. 1,3-Dipolar cycloaddition of nitrones 12a identical to that prepared by the alternative method (see
to alkenes is known to be reversible [13,14]. We recently re- below).
Scheme 3: A possible pathway of ketonitrone 7c self-transformations.
Scheme 4: Oxidation of aminoalcohol 9a.
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Beilstein J. Org. Chem. 2019, 15, 2036–2042.
To prevent oxidative reactions in the side chain, the hydroxy- signal at 2.26 ppm in the 1H NMR spectrum to the methine
methyl group in 9a–c was protected via acylation. Heating of proton on the C(9) carbon atom (see Supporting Information
9a–c with an excess of acetic anhydride in chloroform quantita- File 1). This signal in the 1H,1H-COSY spectrum contains two
tively afforded the corresponding esters 10a–c. The products of cross-peaks with hydrogens of the O–C(10)H2 group and two
acylation of the sterically hindered amino group were not additional cross-peaks with signals at 2.11 and 2.36 ppm, which
detected in the reaction mixture.
were assigned to the C(8)H2 group. The chemical shifts and
character of the splitting for this group of signals correspond to
Oxidation of 10а–c with m-CPBA yielded the desired nitrox- structural fragment O–C(10)H2–C(9)H–C(8)H2. The signals of
ides 11a–c as orange oils. IR spectra of the new nitroxides the C(8)H2 group in the COSY spectrum contain only two addi-
contained no absorption bands in the region of 3000–3600 cm−1 tional cross-peaks with the olefin signals at 5.64 and 5.86 ppm.
and did not have an intense band at 1740 cm−1 characteristic for Analysis of the 1H,13C-HSQC spectrum revealed that the latter
the ester C=O group. To confirm the structure of the nitroxides, protons are bound to carbon atoms with chemical shifts 135.3
alkoxyamines 16a–c were prepared by Matyjaszhewski's and 131.1 ppm, respectively, and this finding enabled the as-
method (Scheme 5) [20].
signment of these signals to the 1,2-disubstituted alkene moiety.
Thus, the NMR data presented above indicate the presence of
an isolated spin system, O–CH2–CH–CH2–CH=CH. A similar
analysis of the remaining complex multiplets at 1.56, 1.77, and
1.93 ppm as well as their correlation with the signals of carbon
atoms in the 1H,13C-HSQC spectra allowed us to assign these
signals to an isolated CH2–CH2 system. All these findings un-
ambiguously support the assignment of structure 18 to the iso-
lated alkoxyamine and structure 17 to the corresponding
nitroxide.
Scheme 5: The synthesis of alkoxyamines 16a–c.
Oxidation of aminoacetate 10a along with the expected forma-
tion of nitroxyl radical 11a, gave another nitroxide, 17, in 22%
yield. The IR spectra of 11a and 17 are very similar, showing
the bands typical for ester group vibrations and no bands that
could be attributed to the vibrations of OH or NH groups.
Besides that in the spectrum of compound 17, there are absorp-
tion bands near 3054 and 1620 cm−1, which denote the pres-
ence of a double C=C bond. To elucidate the structure, nitroxyl
radical 17 was converted into alkoxyamine 18 (Scheme 6) using
Scheme 6: The alkoxyamine 18 synthesis.
the literature method by Schoening et al. [21], and 1H and Therefore, 17 is formed due to hydrogen abstraction in the
13C NMR spectra, as well as two-dimensional 1H,1H-COSY spirocyclopentane ring. To the best of our knowledge, similar
and 1H,13C-HSQC and HMBC spectra were recorded (see Sup- transformations have never been observed before. Presumably,
porting Information File 1). Signals at 4.14 and 4.45 ppm in the formation of 17 occurs due to the close proximity of the N+=O
1H NMR spectrum were assigned to the hydrogen atoms of the group (in the intermediate strained oxoammonium cation) to the
O–C(10)H2 group. Analysis of the 1H,1H-COSY and 1H,13C- hydrogen atom of an adjacent methylene group of the cyclopen-
HSQC NMR spectra allowed us to unambiguously assign a tane ring (Scheme 7).
Scheme 7: A possible mechanism of nitroxide 17 formation.
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Beilstein J. Org. Chem. 2019, 15, 2036–2042.
The ester groups in 11a–c were easily cleaved in an nitroxides 11a–c show 0.035–0.04 mT lower hfs constants on
aqueous–methanol solution of ammonia. Nitroxides 12a–c were nitrogen atom compared to nitroxides 12a–c, presumably due to
isolated as orange compounds moderately soluble in water. intramolecular hydrogen bond formation. The difference in aN
Overall yields of these radicals via the acylation–oxi- between 11a–c and 12a–c is almost one order of magnitude
dation–deprotection pathway were in the range of 54–75%. Of lower for EPR spectra in water (0.005–0.006 mT), obviously
note, the use of a similar three-step procedure for the synthesis because strong intermolecular hydrogen bonds are formed due
of 1 from 19 increased the yield of this nitroxide from 20% [6] to solvation.
to 60% (Scheme 8).
The initial rates of the EPR signal decay were used to obtain the
The EPR spectra of nitroxides 12a–c and 1 acquired in a deoxy- rate constants of the nitroxide reduction by ascorbic acid (see
genated buffer revealed a significant difference in line widths Figure 2 and Supporting Information File 1).
(see Table 1 and Supporting Information File 1, Figures
S7–S10), with the broadest lines expectedly being shown by The rate constants for all these nitroxides are remarkably higher
12b. Introduction of spirocyclohexane moieties to α-carbons of than this constant for nitroxide 1. Even nitroxide 12c, which is
pyrrolidine nitroxides was found to cause strong broadening of the most stable among the new pyrrolidine nitroxides has a ca.
lines in the EPR spectra, presumably owing to unresolved hfc 6-fold higher reduction rate than 1 does, and both are less resis-
on the hydrogens at positions 2 and 6 of the cyclohexane ring tant to reduction than 2,2,5,5-tetraethyl-substituted pyrrolidine
[22]. It has been reported that EPR spectra of pyrrolidine or nitroxides are (k = 2 × 10−3 to 3.3 × 10−4 ) [1,25]. The rate of
imidazolidine nitroxides with pair(s) of geminal ethyl groups at reduction of 12a is close to that of 3-carboxy-2,2,5,5-tetra-
α-carbon atoms may feature large doublet hyperfine splittings methylpyrrolidine-1-oxyl [24]. Obviously, a single spiro-(2-
[23-25]. For imidazolidine nitroxides, these splittings were un- hydroxymethyl)cyclopentane moiety cannot provide higher
ambiguously attributed to hfc on one of four methylene hydro- reduction resistance than geminal ethyl groups can. Thus, esti-
gens of each pair of ethyls [23]. The difference in apparent mation of the steric effect of neighbouring substituents cannot
hyperfine coupling constant aH on these hydrogens is due to a account for the high reduction resistance of 1. Presumably, the
substituent at position 3 or 4 of the ring. This substituent symmetric structure with bulky substituents at positions 3 and 4
hinders rotation and affects the population of conformations of is an important factor for nitroxide stability. Due to the steric
neighbouring geminal ethyl groups, thereby preventing aver- repulsion of trans-oriented tert-butoxy groups and spiro
aging. In agreement with this conclusion, there are no large cyclopentane moieties in the symmetric structure of 1, the
splittings in the EPR spectrum of 12c, and the line width is a bit (2-hydroxymethyl)cyclopentane groups tightly embrace the
greater than that in the spectra of similar nonspirocyclic 3,4-un- nitroxide group making it less accessible for reductants. It is
substituted 2,2-diethylpyrrolidine nitroxides [26], implying free also noteworthy that the symmetric repulsion from both sides of
rotation of ethyl groups. In the EPR spectra in toluene the the pyrrolidine ring favours a planar nitroxide group and desta-
Scheme 8: Optimisation of the synthesis of nitroxide 1.
Table 1: Parameters of the EPR spectra (hyperfine coupling constants, aN; peak-to-peak linewidths, ΔBp-p; and g-factors), second order rate con-
stants of reduction with ascorbate and partition coefficients octanol-water (Kp) for nitroxides 1 and 12a–c.
Nitroxide
aN, mT
ΔBp-p, mT
g-factor
k2, M−1s−1
Kp
1
1.481
1.595
1.586
1.570
0.29
0.21
0.34
0.24
2.00553( 2)
2.00549( 2)
2.00553( 2)
2.00552( 2)
(3.6 0.2) × 10−3
(7.3 0.2) × 10−2
(4.6 0.5) × 10−2
(2.2 0.4) × 10−2
600
12
130
80
12a
12b
12c
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Beilstein J. Org. Chem. 2019, 15, 2036–2042.
Figure 2: Kinetics of the reduction of nitroxides 1 and 12a–c (0.3 mM) with ascorbate (50 mM) in 50 mM phosphate-citrate-borate buffer in the pres-
ence of glutathione (2 mM), at pH 7.4 and, temperature 293 K. Second-order rate constants, k (M−1s−1), for the initial rates of reduction are presented.
bilises the corresponding hydroxylamine with the sp3- Acknowledgements
hybridised nitrogen. Recently, we observed a similar effect for This work was supported by the Russian Foundation for Basic
(3S(R),4S(R))-2,2,5,5-tetraethyl-3,4-bis(hydroxymethyl)pyrrol- Research (grants No. 17-03-01132 [to Yu.V.K. & A.I.T., pyrro-
idine-1-oxyl, which manifested the highest resistance to reduc- line-N-oxides and alkoxyamines] and 18-53-76003 within the
tion among known nitroxides [25]. In contrast, structures 12a–c framework of the ERA.Net RUS+ project ST2017-382:
are asymmetric, and corresponding hydroxylamines could be NanoHyperRadicals [to D.A.M. & I.A.K., nitroxides and
additionally stabilised by hydrogen bonding between the writing]), by the Russian Science Foundation (grant No.
nitrogen atom and the proton of the hydroxymethyl group. 19‐13‐00235 to Yu.I.G. kinetics studies, and by the Ministry of
Science and Education of the Russian Federation (grant No.
Conclusion
14.W03.31.0034 to P.D.G., EPR measurements). We thank the
In this study, we again demonstrated feasibility of the general Multi-Access Chemical Research Center SB RAS for spectral
synthetic approach to sterically hindered spirocyclic nitroxides and analytical services.
based on an intramolecular 1,3-dipolar cycloaddition reaction in
ORCID® iDs
alkenylnitrones followed by isoxazolidine ring opening. The re-
sulting asymmetric pyrrolidine nitroxides have unexpectedly
high rates of reduction with ascorbate. These results lead us to
the assumption that symmetric structures with bulky substitu-
ents at positions 3 and 4 should be favoured for achieving
higher resistance to reduction.
Yulia V. Khoroshunova - https://orcid.org/0000-0003-2923-4241
Denis A. Morozov - https://orcid.org/0000-0003-2403-2843
Andrey I. Taratayko - https://orcid.org/0000-0002-9497-3385
Polina D. Gladkikh - https://orcid.org/0000-0002-8690-5067
Yuri I. Glazachev - https://orcid.org/0000-0003-4135-4991
Igor A. Kirilyuk - https://orcid.org/0000-0001-6033-0368
Supporting Information
Preprint
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2019.37.v1
Supporting Information File 1
Full experimental details and analytical data (UV, IR,
1H NMR, 13C NMR, and EPR experiments, and
microanalysis).
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-200-S1.pdf]
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