S. Tamura et al. / Tetrahedron Letters xxx (xxxx) xxx
3
of ca. 11.3 mM whereas freshly opened THF held 0.15 mM of 6.
Declaration of Competing Interest
Anyhow, old THF involving 6 demanded caution due to its explosi-
bility and reactivity to create the unexpected products.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
From the results of investigation for solvent effect shown in
Table S1, we found that acetonitrile, 1,4-dioxane, and THF lead
comparatively better conversion yield despite mixed products.
Considering the solubility of each reagent in addition to conversion
yield, next we examined the N-ethylation reaction to aliphatic ami-
nes by NaBH(OAc)3 in acetonitrile. As shown in Table 1, the pri-
mary, secondary, and tertiary alkyl amines were treated with
NaBH(OAc)3 at 60 °C to furnish the desired N,N-diethylamines with
good yields except triphenylmethylamine (16). Therefore, it was
validated that our methodology can be applied to not only aro-
matic but also aliphatic amines. In case of the primary and sec-
ondary alkyl amines [1-octadecylamine (7), 1-hexylamine (8), 2-
phenylethanamine (9), cyclohexylamine (10), 2-octylamine (11),
1-phenylethanamine (12), and benzhydrylamine (13)], the N,N-
diethyl products were mainly obtained with a little amount of
acetylamides, but mono-ethyl products were hardly detected. On
the other hand, N-ethylation procedure which was applied to the
tertiary alkyl amines [1-adamantylamine (14) and 2,4,4-tri-
methyl-2-pentylamine (15)] gave N,N-diethylamines as major
products along with a little amount of mono-ethyl products, but
acetylamides were scarcely found. Although the steric hindrance
of tertiary alkyl amines was supposed to interfere with the induc-
tion of second ethyl group to nitrogen atom to afford the small
amount of mono-ethyl amines, the reason why the acetylated
products weren’t found remained to be uncovered. Furthermore,
only one ethyl group, not two, could be introduced into triphenyl-
methylamine (16), thus it was presumed that the bulkiness of
triphenyl structure kept off the introduction of the second ethyl
group. Anyway, our methodology was disclosed to applicable to
aliphatic amines and to hold the potency to construct various N-
containing compounds by using corresponding carboxylic acid.
As an additional discovery noticed through these trials, ethy-
lamine, diethylamine or their ammonium salt were sometimes
found from the reaction mixture. They were assumed to be derived
from acetonitrile via reduction although NaBH(OAc)3 has never
reported to enable to convert cyano moiety (–CN) to aminomethy-
lene (–CH2NH2). Accidental contamination of water wasn’t sup-
posed the reason because the premeditated addition of water to
the reaction mixture didn’t give these ethylamine derivatives con-
stantly. Thus, the reason and mechanism of this result remain to be
dissolved.
Acknowledgments
We are grateful to our laboratory staff, Dr. Tsujihara and Dr. Ina-
gaki, for measurement of spectroscopic data. This research didn’t
receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
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J = 8.6 Hz), 3.70 (2H, t, J = 5.8 Hz), 3.13 (2H, t, J = 6.3 Hz), 1.69 (4H, m). 13C NMR
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128.9, 121.1, 113.5, 62.7, 52.8, 38.6, 30.2, 23.1. HR-MS (ESI) m/z [M+H]+:
214.0995 (Calcd for C11H1735ClNO: 214.0993). 4: colorless oil. 1H NMR
(CDCl3, 500 MHz) d: 7.14 (2H, d, J = 9.1 Hz), 6.59 (2H, d, J = 9.1 Hz), 3.68 (2H, t,
J = 6.3 Hz), 3.32 (2H, q, J = 7.4 Hz), 3.26 (2H, t, J = 6.9 Hz), 1.62 (4H, m), 1.13 (3H,
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J = 8.6 Hz), 6.68 (2H, d, J = 8.6 Hz), 3.58 (2H, brt, J = ca. 6 Hz), 3.53 (1H, brs), 3.38
(2H, q, J = 6.9 Hz), 3.32 (2H, t, J = 7.7 Hz), 1.66 (2H, quint-like, J = 7.7 Hz), 1.55
(2H, m), 1.12 (3H, t, J = 6.9 Hz). 13C NMR (acetone-d6, 125 MHz) d: 147.7, 129.6,
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228.1151 (Calcd for C12H1935ClNO: 228.1150).
Conclusion
In conclusion, the mild reductive N-alkylation procedure by
using NaBH(OAc)3 with carboxylic acid which we previously inves-
tigated for aromatic amines was proved to be also effective for ali-
phatic amines. Furthermore, it was shown that the polarity of
solvents for the reaction might be relative with the reactivity and
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x-hydroxybutyl unit to nitrogen atom. About our
this method, much more still remains to be clear, for example,
mechanism of the reaction, variation of carboxylic acid, internal
reaction on the compounds bearing both amino and carboxyl moi-
ety, and so on. In particular, the reaction using the reagents pre-
pared in situ from NaBH4 and the carboxylic acid are deriving the
interesting outcomes. These trials to verify the effectiveness of
our procedure are now ongoing.
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Please cite this article as: S. Tamura, A. Sugawara, E. Sato et al., New approach for induction of alkyl moiety to aliphatic amines by NaBH(OAc)3 with car-