Lithium-Free Synthesis of Sodium 2,2,6,6-Tetramethylpiperidide and Its Synthetic Applications

Article abstract of DOI:10.1002/adsc.201900215

Lithium-free synthetic methods for sodium 2,2,6,6-tetramethylpiperide (NaTMP) have been developed using sodium dispersion as a sole sodium source. The prepared NaTMP was used as a Br?nsted base, that exhibited some differences in reactivities from LiTMP. (Figure presented.).

Full text of DOI:10.1002/adsc.201900215

Title: Lithium-Free Synthesis of Sodium 2,2,6,6-Tetramethylpiperidide
and Its Synthetic Applications
Authors: Sobi Asako, Masato Kodera, Hirotaka Nakajima, and
Kazuhiko Takai
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10.1002/adsc.201900215
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Lithium-Free Synthesis of Sodium 2,2,6,6-
Tetramethylpiperidide and Its Synthetic Applications
Sobi Asako,a* Masato Kodera,a Hirotaka Nakajima,a Kazuhiko Takaia*
a
Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1
Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
e-mail: asako@cc.okayama-u.ac.jp, ktakai@cc.okayama-u.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
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lithium-ion batteries. In continuation of our research
Abstract. Lithium-free synthetic methods for sodium
2,2,6,6-tetramethylpiperide (NaTMP) have been developed interest in sustainable organic synthesis with
organosodium compounds,[7] we report here novel
using sodium dispersion as a sole sodium source. The
prepared NaTMP was used as a Brønsted base, that
exhibited some differences in reactivities from LiTMP.
direct syntheses of NaTMP using sodium dispersion
(SD) without the need for lithium compounds.
Synthetic applications of the prepared NaTMP are
also described in this work.
Keywords: Sodium; 2,2,6,6-tetramethylpiperidine;
Brønsted base; deprotonation
Metal amides have been widely utilized as
stoichiometric or catalytic bases in organic
syntheses,[1]
among
which
metal
2,2,6,6-
tetramethylpiperidide (TMP) has been recognized as
one of the most powerful Brønsted bases for its high
basicity and low nucleophilicity, comparing
favorably with diisopropylamide (DA) and
1,1,1,3,3,3-hexamethyldisilazide
(HMDS)
counterparts. While LiTMP has long had a leading
role in this field, recent progress in mixed metal
amides such as TMPMgCl•LiCl,[2] and TMPZnR2M
(M = Li, Na, or K)[3] has enabled milder and higher
Scheme 1. Synthesis of NaTMP Using Li Compounds.
chemo-
and
regioselective
metalation
by
deprotonation.[4]
We started the study by applying the known
procedures for the lithium-free preparation of NaDA
to NaTMP. Wakefield et al. reported that NaDA
In contrast to these metal TMPs, NaTMP has
rarely been utilized in organic synthesis by itself,
probably because of the lack of simple and efficient
preparative methods and lower stability and solubility
compared with LiTMP. Although several synthetic
methods for the preparation of NaTMP have been
reported, such as the deprotonation of TMPH with
could
be
directly
prepared
by
reacting
diisopropylamine and sodium dispersion in the
presence of isoprene as an electron carrier (Scheme
2A),[8,9] while Levine and Raynolds reported the
preparation of NaDA by the deprotonation of
diisopropylamine with phenylsodium prepared from
bromobenzene and sodium dispersion (Scheme
2B).[10]
n
nBuNa prepared from BuLi and NaOtBu (Scheme
1A),[5] and the transmetallation between LiTMP and
NaOtBu (Scheme 1B),[5] the methods require lithium
compounds and hence additional purification steps to
obtain lithium-free NaTMP, which may exhibit
different reactivity from that of lithium-containing
NaTMP.[6] Furthermore, the use of the latter may be
hampered by recent concerns about the scarcity of
lithium as well as its rapidly increasing price because
of competing consumption for the production of
1
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10.1002/adsc.201900215
Advanced Synthesis & Catalysis
[a]
The reaction was performed on a 0.5 mmol scale in
[b]
hexane (0.2 mL).
Yields were estimated by the
deuterium content of the 9-position of fluorene upon the
deprotonation of fluorene with NaTMP in hexane at
ambient temperature for 30 min followed by the D2O
quench. [c] 1.4 equiv of TMPH was used.
We next examined the method of Levine and
Raynolds, which uses in situ prepared phenylsodium
for the synthesis of NaTMP. Table 2 shows the
optimization study with a focus on the effects of
halobenzene and the amount of sodium dispersion in
the first step. We found that chlorobenzene was a
better source of phenylsodium than bromobenzene
because the formation of biphenyl via reductive
homocoupling was suppressed with chlorobenzene
and that tert-amyl alcohol was not a necessary
additive. To keep the concentration of chlorobenzene
low to facilitate 2-electron reduction and suppress
side reactions, chlorobenzene was slowly added to a
suspension of sodium dispersion in hexane. The use
of 2.1 equiv of sodium dispersion was found to be
optimal, and the conditions in entry 5 are referred to
as method B.
Scheme 2. Li-Free Synthesis of NaDA.
Following these procedures, we tested if the same
methods could be applied to the synthesis of NaTMP.
Instead of isolating NaTMP as a solid, as was the
case in Scheme 1, we evaluated the reaction yields of
NaTMP synthesis by the deuterium content of
fluorene after the deprotonation of the 9-position of
fluorene followed by the D2O quench. Several
titration methods using reported indicators[11] gave
similar results but had difficulty determining the
endpoints due to the black coloration of the NaTMP
suspension.
Table 2. Synthesis of NaTMP by Method B[a]
Table 1 summarizes the results of direct synthesis
of NaTMP from TMPH using sodium dispersion and
isoprene as an electron carrier. While a slower
reaction rate of NaTMP compared with that of NaDA
was expected due to increased electron density and
steric hindrance of TMPH, the initial attempt
following the method of Wakefield et al. afforded
NaTMP in 82% yield after 5 h in hexane (2.5 M) at
30 °C (entry 1). The reactions with 1 equiv of
isoprene afforded NaTMP in 78% and 64% yields,
after 5 h and 1 h, respectively (entries 2 and 3). The
results also show that the addition of N,N,N',N'-
tetramethylethylenediamine (TMEDA) accelerated
the reaction and produced NaTMP in 99% yield after
15 min (entries 4–6); the conditions in entry 6 are
referred to as method A. Other related Lewis bases
such as N,N,N',N'',N''-pentamethyldiethylenetriamine
and 1,2-dimethoxyethane were less effective.
[a]
The reaction was performed on a 0.5 mmol scale in
[b]
hexane (0.5 mL).
Yields were estimated by the
deuterium content of the 9-position of fluorene upon the
deprotonation of fluorene with NaTMP in hexane at
ambient temperature for 30 min followed by the D2O
quench. [c] Determined by 1H NMR.
Table 1. Synthesis of NaTMP by Method A[a]
With the two presented methods for the lithium-
free synthesis of NaTMP, we first explored the utility
of the base in the stereoselective Wittig reaction
(Scheme 3). Lithium salts are known to affect the
stereochemistry of the Wittig reaction, affording the
alkene products with a higher ratio of E-product.[12]
When the phosphonium salt was deprotonated with
LiTMP in THF/hexane and subsequently reacted with
2-naphthaldehyde, the alkene product was obtained in
88% yield with an E/Z ratio of 57/43. The E/Z ratio
could be improved to 10/90 (method A) and 7/93
(method B) by using NaTMP for the ylide formation
2
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10.1002/adsc.201900215
Advanced Synthesis & Catalysis
Table 3. Metalation of heteroarenes with NaTMP[a]
instead of LiTMP, while an improved ratio (16:84)
was still observed when NaTMP prepared in situ
from LiTMP and NaOtBu was used.
Scheme 3. Salt Effects on the Stereoselectivity of the
Wittig Reaction. [a] Isolated yields. [b] Determined by GC.
We next examined the terminal-to-internal double
bond isomerization reactions of 1-dodecene using a
catalytic amount of metal TMPs (Scheme 4).[9c]
While LiTMP did not catalyze the isomerization
reaction in hexane at rt, NaTMP smoothly converted
1-dodecene to 2-dodecene as a mixture of E/Z
stereoisomers, reflecting its higher Brønsted basicity
over LiTMP. It should be noted that NaTMP prepared
from LiTMP/NaOtBu was much less efficient under
these conditions.
[a] The reaction was performed on a 0.4 mmol scale using NaTMP
[d]
prepared by method B. [b] Isolated yields. [c] MeI (3.2 equiv).
Reaction at 50 °C in the presence of CuI (5 mol%). [e] Reaction
[g]
with CO2 at rt. [f] Reaction with electrophiles at –78 °C to rt.
Deprotonation with NaTMP (1.1 equiv) at 0 °C. [h] TMEDA (1
equiv) was added for deprotonation.
In conclusion, we have developed simple and
facile methods for preparing lithium-free NaTMP,
which have escaped the attention of synthetic
chemists for a long time. We also demonstrated
several cases in which NaTMP acts as a stronger and
more selective Brønsted base for organic synthesis
than LiTMP. Besides the scientific interest, the much
higher natural abundance and availability of sodium
compared with lithium make lithium-free NaTMP
attractive due to the growing demand for sustainable
synthesis.[13] Furthermore, there is growing awareness
of the advantages of organosodium compounds or
sodium dispersion.[9,14] Currently, we are revisiting
the utility of sodium reagents from the perspective of
modern organic synthesis, and further applications of
these reagents will be reported in due course.
Scheme 4. Base-Catalyzed Isomerization of 1-Dodecene.
[a] 1H NMR yields. [b] Determined by GC.
We then explored the synthetic utility of the in situ
prepared NaTMP as
a
Brønsted base for
functionalization of a variety of heteroarenes (Table
3). Benzothiophene, benzofuran, and dibenzofuran
were deprotonated under mild conditions and trapped
with various electrophiles. Carbon functional groups
were introduced by reactions with electrophiles such
as MeI, allylBr, benzoyl chloride, and CO2, and
heteroatoms such as Br, Cl, Si, B, and P groups could Experimental Section
also be introduced. Typically, the deprotonation of
heteroarenes was completed within 30 min at ambient
temperature.
General Procedure for Synthesis of NaTMP with
Sodium Dispersion (Method A): Isoprene (50 μL, 0.50
mmol) was added dropwise to a stirred hexane solution
(0.2 mL) of 2,2,6,6-tetramethylpiperidine (85 μL, 0.50
mmol), N,N,N',N'-tetramethylenediamine (74 μL, 0.50
mmol), and sodium dispersion (0.50 mmol, 26 wt%) in an
oven-dried test tube under argon, and the resulting mixture
was stirred at 30 °C for 15 min. Fluorene (99.7 mg, 0.6
mmol) and hexane (0.5 mL) were added to the reaction
mixture and the resulting mixture was stirred for 30 min,
3
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10.1002/adsc.201900215
Advanced Synthesis & Catalysis
followed by the addition of D2O. The yield of NaTMP was
estimated by the deuterium content of the 9-position of
fluorene by 1H NMR analysis.
LiTMP and NaTMP in the metallation of anisole in
combination with an organometallic trapping agent: R.
McLellan, M. Uzelac, L. J. Bole, L. M. Gil-Negrete, D.
R. Armstrong, A. R. Kennedy, R. E. Mulvey, E. Hevia. .
Synthesis 2019, 51, 1207–1215.
General Procedure for Synthesis of NaTMP with
Sodium Dispersion (Method B): Sodium dispersion (1.05
mmol, 26 wt%) and hexane (0.5 mL) were placed in an
oven-dried test tube under argon. After preparation of
PhNa by dropwise addition of PhCl (56.3 mg, 0.50 mmol)
and stirring at 30 °C for 30 min, 2,2,6,6-
tetramethylpiperidine (85 μL, 0.50 mmol) was added, and
the reaction mixture was stirred at 30 °C for 30 min.
Fluorene (99.7 mg, 0.6 mmol) and hexane (0.5 mL) were
added to the reaction mixture and the resulting mixture was
stirred for 30 min, followed by the addition of D2O. The
yield of NaTMP was estimated by the deuterium content of
the 9-position of fluorene by 1H NMR analysis.
[7] S. Asako, H. Nakajima, K. Takai, Nat. Catal. (doi:
10.1038/s41929-019-0250-6).
[8] a) D. Barr, A. J. Dawson, B. J. Wakefield, J. Chem. Soc.
Chem. Commun. 1992, 587, 204; b) P. C. Andrews, N.
D.R. Barnett, R. E. Mulvey, W. Clegg, P. A. O’Neil, D.
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Organomet. Chem. 1996, 518, 85–95.
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Algera, D. B. Collum, J. Org. Chem. 2016, 81, 11312–
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Acknowledgements
We thank Okayama University and KOBELCO ECO-Solutions
CO., Ltd. for financial support.
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4
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10.1002/adsc.201900215
Advanced Synthesis & Catalysis
COMMUNICATION
Lithium-Free Synthesis of Sodium 2,2,6,6-
Tetramethylpiperidide and Its Synthetic
Applications
Adv. Synth. Catal. Year, Volume, Page – Page
Sobi Asako,* Masato Kodera, Hirotaka Nakajima,
Kazuhiko Takai*
5
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