General methodology for the chemoselective N-alkylation of (2,2,6,6)-tetramethylpiperidin-4-ol: Contribution of microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2018.12.020

A convenient method to access a broad variety of N-alkyl-(2,2,6,6)-tetramethylpiperidin-4-ol compounds is reported. The thermal treatment of a mixture of (2,2,6,6)-tetramethylpiperidin-4-ol and allyl or benzyl bromide derivatives gave the corresponding N–alkylated compounds in good yields while leaving the hydroxyl functional group intact. Whereas 40 h were needed to reach complete conversion, microwave irradiation allowed the reaction time to be reduced (20 min) and improved the yields in most cases.

Full text of DOI:10.1016/j.tetlet.2018.12.020

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
General methodology for the chemoselective N-alkylation of (2,2,6,6)-
tetramethylpiperidin-4-ol: Contribution of microwave irradiation
Romain Membrat a, Alexandre Vasseur b, Laurent Giordano a, Alexandre Martinez a, Didier Nuel a
a Aix-Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
b Université de Lorraine, CNRS, L2CM, F-54000 Nancy, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method to access a broad variety of N-alkyl-(2,2,6,6)-tetramethylpiperidin-4-ol compounds
is reported. The thermal treatment of a mixture of (2,2,6,6)-tetramethylpiperidin-4-ol and allyl or benzyl
bromide derivatives gave the corresponding N–alkylated compounds in good yields while leaving the
hydroxyl functional group intact. Whereas 40 h were needed to reach complete conversion, microwave
irradiation allowed the reaction time to be reduced (20 min) and improved the yields in most cases.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 2 November 2018
Revised 30 November 2018
Accepted 10 December 2018
Available online xxxx
Keywords:
Chemoselective alkylation
Functional tolerance
Microwave assisted reactions
Sterically hindered amines
Introduction
photosensibilizing effects of 1 in polypropylene [10]. For at least
these two reasons, the N-alkylation reaction of 1 has been well
Sterically Hindered Amine (SHA) is a term coined by Sartori and
Savage in 1983 to define any primary or secondary amine deriva-
tives in which the amino group is bonded to a tertiary carbon atom
and a secondary or tertiary carbon atom, respectively [1]. They
have long been known for their performance in carbon dioxide
removal for gas steaming in industrial chemical processes [2–4].
(2,2,6,6)-Tetramethylpiperidin-4-ol derivatives 1 belong to this
compound class and have added an extra-dimension to applica-
tions over the last two decades. Indeed, 1 is a synthetic precursor
of TEMPOL [5] which is a well-known nitroxyl radical of major
interest in organic synthesis [6], as well as polymer chemistry
[7]. TEMPOL exhibits not only a higher oxidation potential than
its TEMPO analogue [8], but also represents a low cost alternative
[6]. In this context, Rychnovsky and co-workers showed that the
catalytic activity of TEMPOL could be three times higher than that
of TEMPO when grafted to a polymeric carrier via the OH moeity
[9]. Using N-allyl (2,2,6,6)-tetramethylpiperidin-4-ol as a precursor
of TEMPOL was essential to achieve the grafting procedure. In
another context, 1–derived N-alkylated compounds are also useful
for commercial polymeric material stabilization [10,11]. In partic-
ular, N-alkyl substitution enables significant modulation of the
studied, but the development of an efficient protocol remains
desirable as the literature precedent is scarce in this regard [12].
Whiten and co-workers carried out the synthesis of N-ethyl, N-
methyl and N-hydroxymethylanthra-none-(2,2,6,6)-tetramethyl-
piperidin-4-ol from 1 in moderated to good yields, using classical
SN2 reaction conditions (Scheme 1, a) [13].
Banert and co-workers thereafter capitalized on this contribu-
tion to reinvestigate the synthesis of triacetonamine derivatives,
without however studying neither the scope nor alternatives to
reduce the reaction time [14]. Alternatively, Novelli and co-work-
ers proposed a double Michael addition-based approach for the
synthesis of N-benzyl-(2,2,6,6)-tetramethylpiperidin-4-one from
phorone and benzylamine (Scheme 1, b) [15]. Although this
method provides the expected compound in a good yield, multiple
purification steps by column chromatography strongly limits its
attractiveness. Later, Rychnovsky’s group reported the synthesis
of three N-allyl-(2,2,6,6)-tetramethyl-piperidin-4-ol compounds
in good yields [9]. The reaction was conducted in a sealed tube
using two equivalents of (2,2,6,6)-tetramethylpiperidin-4-ol 1 with
regard to the electrophile (Scheme 1, c). Herein, we report that this
method is convenient for the preparation of N-benzyl and N-allyl-
(2,2,6,6)-tetramethylpiperidin-4-ol in good to high yields, includ-
ing on gram-scale when performed in an autoclave. The scope
was examined and the effect of microwave irradiation on the pro-
cess was also investigated to optimize its effectiveness.
E-mail address: didier.nuel@centrale-marseille.fr (L. Giordano)
https://doi.org/10.1016/j.tetlet.2018.12.020
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: R. Membrat, A. Vasseur, L. Giordano et al., General methodology for the chemoselective N-alkylation of (2,2,6,6)-tetram-
ethylpiperidin-4-ol: Contribution of microwave irradiation, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.020

2
R. Membrat et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Reported procedures for the N-alkylation of 1.
Results and discussion
During preliminary investigations, we observed that classical
Hoffmann alkylation conditions relying on the use of an inorganic
Brønsted base such as K2CO3 or CsCO3 in DMF were unsuccessful.
Specifically, the nucleophilicity gap between oxygen and nitrogen
is narrowed due to the high steric hindrance caused by the four
methyl groups positioned at the two carbons adjacent to the nitro-
gen atom. Accordingly, all our attempts led to an intractable mix-
ture of O- and N-alkylated products [14]. Moreover, acylation of the
hindered amine and subsequent reduction of the amide using a
hydride source (LiAlH4, PhSiH3, or BH3ÁTHF) only allowed recovery
of the starting material. Buchwald–Hartwig coupling reaction-
based strategies [16,17] also proved to be poorly chemoselective.
In addition, it is important to note that the alkylation of (2,2,6,6)-
tetramethylpiperidin-4-one was unviable because: (i) protons at
the a-position of the ketone are labile even under mildly basic con-
ditions, thus leading to enol formation and then to the correspond-
ing C-alkylated and aldol products [14]. (ii) no general
methodology is reported to chemically reduce the ketone without
alteration of the integrity of the C–N bond. These unsuccessful
attempts highlighted the difficulty in achieving the chemoselective
N-alkylation of 1. As the Rychnovsky’s approach [9] was promising
but unexplored, we first examined its scope using a slightly mod-
ified procedure.
Scheme 2. Scope of the process via thermal treatment. Reagents and conditions: 1
(12.7 mmol), 2 (6.35 mmol), toluene (20 mL), 130 °C, 40 h, autoclave; aIsolated
yield.
Alkylation in an autoclave
A wide variety of electrophiles were screened under Rych-
nowsky’s conditions (see Scheme 2) but using an autoclave instead
of a sealed tube in order to achieve better control of the experi-
ment as well as to support possible scaling up. The treatment of
1 with benzyl bromide (0.5 equiv.) as the electrophile at 130 °C
for 40 h gave the expected product 3a in 88% isolated yield after
simple filtration through a short pad of silica gel (Scheme 2). We
then explored the aromatic ring substitution effect. Using bro-
mobenzyl bromide as the electrophile gave the corresponding N-
alkylated product in similar yield whatever the position of the
halide atom on the aromatic ring (Scheme 2, see 3b–d). A large
number of 4-substituted benzyl bromides also reacted smoothly
under these conditions (Scheme 2, see 3e–i), indicating that the
reaction proceeds independently of the electron density localized
on the aromatic ring moiety. Electron withdrawing or donating
group-possessing electrophiles were efficiently reacted, including
Scheme 3. Model reaction for optimizing the microwave assisted alkylation.
when strong electron-withdrawing groups were involved
(Scheme 2, see 3e and 3h). Allylic bromide derivatives could also
be used as electrophiles (Scheme 2, see 3l–q). The important point
of this strategy lies in the absence of a Brønsted base in the reac-
tion mixture, thus enabling base sensitive substrates to be
accessed. Nitrile (Scheme 2, see 3j) as well as ester groups
(Scheme 2, see 3g, 3o–p) were also compatible with these condi-
Please cite this article as: R. Membrat, A. Vasseur, L. Giordano et al., General methodology for the chemoselective N-alkylation of (2,2,6,6)-tetram-
ethylpiperidin-4-ol: Contribution of microwave irradiation, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.020

R. Membrat et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1
Optimization of the process using microwave irradiation.a.
Entry
Solvent
T (°C)
Time (min.)
1 (%)b
N-Alkyl 1 (%)b
O-Alkyl 1 (%)b
1
2
3
4
5
6
7
8
9
10
Neat
Neat
Neat
Neat
Neat
Neat
DMF
Toluene
Toluene
Toluene
230
230
230
250
250
180
230
230
230
250
5
66
48
35
21
44
35
22
75
3
28
44
53
66
52
60
54
24
90
86
6
8
10
20
7
5
24
1
7
14
10
20
5
2
30
20
5
20
20
1
a
Reagents and conditions: 1 (0.127 mmol), 2a (0.0635 mmol), dry solvent (0.2 mL) or Neat in a G10 tube at 250 W.
b
Conversion measured by 1H NMR spectroscopy.
tions. Interestingly, the use of styrene oxide as the electrophile
allowed the synthesis of 3s possessing a benzyl alcohol in 52% iso-
lated yield and without any trace of elimination products. Starting
from allyl or benzyl dibromide resulted in the formation of 3t and
3u, respectively, in 69% yield. It is noteworthy that the method left
the second electrophilic moiety intact even in the presence of a
large excess of 1, therefore offering the opportunity to increase
the functional diversity of the structure. Finally, the reaction was
conducted on a large scale (8 g) for the synthesis of 3a and an iso-
lated yield similar to that previously discussed was obtained (81%).
It should be stressed that the excess of 1 could be recovered as the
ammonium salt from the aqueous layer and recycled after treat-
ment with base (93%). However, despite the good yields and
remarkable chemoselectivity, this strategy is limited by the reac-
tion duration.
Microwave assisted chemoselective N-alkylation of 1
Microwave irradiation represents a powerful tool to improve
the efficiency of organic reactions [18]. The basic principle of
microwave heating relies on the ability of polar compounds to
selectively absorb the radiation and to convert electromagnetic
energy into heat by dielectric losses [19]. This technology enables
significant improvements in reactivity, namely chemical rate accel-
eration, higher yields, or modifications in selectivity [20]. Since
microwave irradiation has been largely used for amine alkylation
[21–24], we decided to investigate the effect of this technology
on the reaction duration. In order to optimise the microwave
parameters, the model reaction presented in Scheme 3 was stud-
ied. Results of the optimization experiments are given in Table 1.
Using the same 1/2a ratio as in Scheme 2 under neat conditions
at 250 W and 230 °C gave 34% conversion after 5 min including 6%
of the undesired O-alkylated product (Table 1, entry 1). Changes to
the temperature and/or the reaction duration resulted in either
poor conversions or the loss of chemoselectivity (Table 1, entries
2–6). Use of the good irradiation absorbing solvent DMF led to sig-
nificant formation of the O–alkylated product (Table 1, entry 7).
Finally, the best reactivity/selectivity ratio was obtained when
the reaction was carried out in toluene at 230 °C for 20 min. Under
these conditions, a 97% conversion was attained with excellent
chemoselectivity towards the N-alkyl product (Table 1, entries 8–
10). These microwave based-conditions were then applied to a
selection of electrophiles in order to compare the results with
those obtained by the standard thermal treatment. For the major-
ity of compounds, microwave heating allowed the reaction time to
be reduced (20 min) and improved the yields (Scheme 4, see 3a–d,
3g, 3i, 3k, 2–15% increase in isolated yield). However, lower yields
were obtained for products 3e–f, 3h and 3r. Regarding compound
3v, the disappointing result could be explained by its sensitivity to
degradation as a result of CAN bond cleavage. For the other prod-
ucts we propose that energy absorption is partly enabled from the
polar moiety of the electrophiles which act as a molecular radiator
[25,26]. This assumption is supported by the reactivity observed
under neat conditions (Table 1, entries 2–7). Very polar sub-
stituents such as trifluoromethoxy, trifluoromethyl or nitro
(Scheme 4, see 3e–f, 3h) could promote very high energy transfer
Scheme 4. Scope of the microwave assisted transformation. Reagents and condi-
tions: 1 (12.7 mmol), 2 (6.35 mmol), dry toluene (20 mL) in a G30 tube, 250 W,
230 °C, 20 min; aIsolated yield; yields obtained via thermal treatment are in
parentheses.
Please cite this article as: R. Membrat, A. Vasseur, L. Giordano et al., General methodology for the chemoselective N-alkylation of (2,2,6,6)-tetram-
ethylpiperidin-4-ol: Contribution of microwave irradiation, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.020

4
R. Membrat et al. / Tetrahedron Letters xxx (xxxx) xxx
causing degradation while a less polar long carbon chain-possess-
ing compound such as geranyl (Scheme 3, 3r) is probably not
absorbent enough to inhibit the reactivity. Finally, these conditions
were tested on a large scale (5 g) for product 3a without alteration
of the yield (89%).
pounds) to this article can be found online at https://doi.org/10.
1016/j.tetlet.2018.12.020.
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Acknowledgments
This work was supported by Ministère de l’Enseigenement
supérieur et de la Recherche (R. Membrat PhD grant, French Min-
istry). We thank Dr. Valérie Monnier and Dr. Christophe Chendo
for HRMS analysis (Spectropole, Fédération des Sciences Chimiques
de Marseille). Special thanks to Arnaud Treuvey for his efficient
technical support.
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Appendix A. Supplementary data
Supplementary data (Experimental procedures for the transfor-
mations described in Schemes 3 and 4 are provided, along with 1H
NMR, 13C NMR, IR, and HRMS spectra and spectral data for all com-
Please cite this article as: R. Membrat, A. Vasseur, L. Giordano et al., General methodology for the chemoselective N-alkylation of (2,2,6,6)-tetram-
ethylpiperidin-4-ol: Contribution of microwave irradiation, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.020