N-alkylation using sodium triacetoxyborohydride with carboxylic acids as alkyl sources

Article abstract of DOI:10.1248/cpb.c17-00716

A versatile N-alkylation was performed using sodium triacetoxyborohydride and carboxylic acid as an alkyl source. The combination of these reagents furnished products different from those given previously by a similar reaction. Moreover, the mild conditions of our method allowed some functional groups to remain through the reaction, whereas they would react and be converted into other moieties in the similar reductive N-alkylation reported previously. Herein, we provide a new procedure for the preparation of various compounds containing nitrogen atoms.

Full text of DOI:10.1248/cpb.c17-00716

Vol. 66, No. 1
Chem. Pharm. Bull. 66, 101–103 (2018)
101
Note
N-Alkylation Using Sodium Triacetoxyborohydride with Carboxylic
Acids as Alkyl Sources
Satoru Tamura,* Keigo Sato, and Tomikazu Kawano*
Department of Medicinal and Organic Chemistry, School of Pharmacy, Iwate Medical University; Yahaba, Iwate
028–3694, Japan.
Received September 4, 2017; accepted October 5, 2017
A versatile N-alkylation was performed using sodium triacetoxyborohydride and carboxylic acid as an
alkyl source. The combination of these reagents furnished products different from those given previously by
a similar reaction. Moreover, the mild conditions of our method allowed some functional groups to remain
through the reaction, whereas they would react and be converted into other moieties in the similar reductive
N-alkylation reported previously. Herein, we provide a new procedure for the preparation of various com-
pounds containing nitrogen atoms.
Key words sodium triacetoxyborohydride; N-alkylation; carboxylic acid
Many nitrogen-containing compounds have been discovered was presumed to be employed as an ethyl moiety. Moreover,
and are currently being used in medicinal, agricultural and during the screening to investigate the reactivity, NaBH(OAc)3
industrial chemistry. Accordingly, it is important to develop was revealed to display a different reactivity from the recently
N-alkylation methods specific to the N-containing compound reported reagents for N-alkylation using carboxylic acids,8,10)
being targeted, and thus there is a demand for novel proce- as shown in Tables 1 and 2. The introduction of a methyl
dures to prepare alkylated amines. One of best known of group to the nitrogen in indole (3) by NaBH(OAc)3 with for-
the traditional N-alkylation methods is reductive amination mic acid hardly proceeded, resulting in full recovery of 3,
using carbonyl compounds with reductive reagents. Thus, whereas the reported reagents gave N-methylindoline (4)10)
we attempted to induce methyl groups to p-chloroaniline (Table 1, entry 1). Moreover, pyrrole (5) could not be readily
(1) by sodium triacetoxyborohydride (NaBH(OAc)3) with alkylated by NaBH(OAc)3 but indoline (6) could be (entries 2,
1,3,5-trioxane as a methyl source under an acidic condition 3). Hence, it was suggested that the amines to be alkylated by
with acetic acid,1) but N,N-diethyl-p-chloroaniline (2) was ob- NaBH(OAc)3 with carboxylic acid should have some basicity.
tained as a major product (Fig. 1). Acetyl or acetoxyl groups Next, we found that the acetyl group on the aromatic ring in
were assumed to be consumed for the N-ethylation. Previous the substrate remained after N-alkylation by NaBH(OAc)3, but
reviews2,3) of reductive amination methods using carbonyl was reductively removed by the previously reported reagents8)
compounds have briefly mentioned such phenomena as side (entries 4, 5). This selectivity that N-alkylation was faster
reactions, and similar reactions using carboxylic acids with than reductive elimination of carbonyl moiety was confirmed
amines in the presence of sodium borohydride have already by the reactions of 4-aminobenzophenone (13) and p-ami-
been reported.4–7) In addition, other recent studies achieved nopropiophenone (15) (entries 6, 7). Thus, a carbonyl group
an improvement of N-alkylation using carboxylic acids as the next to aromatic ring was strongly suggested to endure in our
alkyl source by a single step reaction under a reductive condi- N-alkylation procedure. Additionally, as depicted in Table 2,
tion.8–10) Considering the various disadvantages of the tradi- levulinic acid (17) and p-chloroaniline (1) were treated with
tional reductive amination by carbonyl derivatives—such as NaBH(OAc)3 to give a γ-lactam (18) as a major product, while
the instability of aldehydes, low reactivity of ketone carbonyl a cyclic amine (19) was mainly obtained through reductive
and necessity of a stepwise protocol—carboxylic acids should removal of the carbonyl moiety under a previously reported
be a useful material, because they are normally more stable in condition10) (Table 2, entry 1). Neither conversion from acet-
air than aldehydes, and because various carboxylic acids are anilide nor that from p-chloroacetanilide into the correspond-
readily available. Thus, we further investigated N-alkylation ing ethylphenylamines proceeded by NaBH(OAc)3. Thus, the
by NaBH(OAc)3 with carboxylic acids as the alkyl source and mild reductive activity of NaBH(OAc)3 was suggested to allow
herein report the features of this reaction, which were differ- the carbonyl moiety in the amide group to survive under the
ent from those of the recently presented reactions.8,10)
N-alkylation reaction condition. When unsaturated carboxylic
acids, i.e., acrylic acid (20) or propiolic acid (23), were used
Results and Discussion
Carboxylic acids (R-COOH) were readily reacted with ani-
lines in the presence of NaBH(OAc)3 to furnish correspond-
ing N-CH2R derivatives. In the case of formic acid, N-formyl
(N-CHO) products were also given as well as N-methyl ones.
Treatment of anilines with only NaBH(OAc)3 without any
carboxylic acids also gave N-ethylanilines, but the reaction
was very slow. In this case, the acetyl group in the reagent
Fig. 1. N-Ethylation by NaBH(OAc)3 with Acetic Acid
*To whom correspondence should be addressed. e-mail: satamura@iwate-med.ac.jp; tkawano@iwate-med.ac.jp
© 2018 The Pharmaceutical Society of Japan

102
Chem. Pharm. Bull.
Vol. 66, No. 1 (2018)
Table 1. Comparison of Reactivity for Various N-Containing Compounds
NR: no reaction. —: no data. *Reaction condition: at 40°C for 5h in (CH2Cl)2.
Table 2. Comparison of Products by Using Various Carboxylic Acids as Alkyl Sources
—: no data. *p-Chloroaniline was used as a starting substrate. **Aniline was used as a starting substrate.

Vol. 66, No. 1 (2018)
Chem. Pharm. Bull.
103
1
for the N-alkylation by NaBH(OAc)3, Michael addition by low oil, H-NMR (500MHz, CDCl3) δ: 1.32 (3H, t, J=7.4Hz),
the amine proceeded prior to reductive amination to afford 2.50 (3H, s), 3.27 (1H, dq, J=5.7, 7.4Hz), 4.37 (1H, brs), 6.64
carboxylic acids, although the reported condition resulted in (1H, dd, J=8.1, 8.6Hz), 7.59 (1H, dd, J=2.3, 12.6Hz), 7.67
N-alkylation and hydrogenation to furnish a product in which (1H, dd, J=2.3, 8.6Hz). 13C-NMR (125MHz, CDCl3) δ: 14.5,
nitrogen was substituted with a saturated alkyl group (entries 26.0, 37.6, 109.7 (d), 114.0 (d), 126.8, 141.2 (d), 149.4, 151.3,
2, 3).10) This result allowed us to presume that N-alkylation by 195.7. IR (KBr) cm−1: 3438, 1666, 1611, 1537. Electrospray
NaBH(OAc)3 and carboxylic acid was a slower reaction than ionization-time-of-flight (ESI-TOF)-MS m/z: 182.0977 (Calcd
nucleophilic attack by the amines.
The mechanism of action was discussed in an article that
for C10H13FNO: 182.0976). MS m/z: 182 ([M+H]+).
1-(4-Ethylaminophenyl)propan-1-one (16) Colorless
1
reported a similar reductive N-alkylation; the authors sug- amorphous powder, H-NMR (500MHz, CDCl3) δ: 1.20 (3H, t,
gested that the mechanism was formation of an amide link- J=7.4Hz), 1.28 (3H, t, J=6.9Hz), 2.89 (2H, q, J=7.4Hz) 3.22
age, followed by reductive removal of the carbonyl moiety by (2H, dq, J=2.9, 6.9Hz), 4.14 (1H, brs), 6.55 (2H, d, J=8.8Hz),
hydride reagents.8) However, our approach was not expected 7.84 (1H, d, J=8.8Hz). 13C-NMR (125MHz, CDCl3) δ: 8.8,
to proceed in this manner, because the NaBH(OAc)3 used in 14.6, 30.9, 37.8, 111.2, 126.1, 130.4, 152.0, 199.1. IR (KBr)
our reaction produced the lactam product and could not reduce cm−1: 3351, 1653, 1592, 1565. ESI-TOF-MS m/z: 178.1234
the acetanilides to ethylphenylamines. The elucidation of the (Calcd for C11H16NO: 178.1226). MS m/z: 178 ([M+H]+).
detailed mode of action is ongoing.
N-(4-Chorophenyl)-N-ethyl-β-alanine
(21) Colorless
1
In conclusion, our N-alkylation by NaBH(OAc)3 and car- amorphous powder, H-NMR (500MHz, CDCl3) δ: 1.13 (3H,
boxylic acid showed milder reactivity than a similar reaction t, J=6.9Hz), 2.61 (2H, t, J=6.9Hz), 3.35 (2H, q, J=6.9Hz),
condition reported previously. So, our condition and the previ- 3.58 (2H, t, J=6.9Hz), 6.67 (2H, d, J=8.6Hz), 7.18 (2H, d,
ous condition sometimes furnished different products. There- J=8.6Hz). 13C-NMR (125MHz, CDCl3) δ: 12.1, 32.0, 45.9,
fore, a much wider range of compounds can be applied to 46.4, 114.7, 122.4, 129.2, 145.6, 177.2. IR (KBr) cm−1: 2971,
N-alkylation by NaBH(OAc)3. For example, a carbonyl group 1714, 1593, 1501. ESI-TOF-MS m/z: 226.0639 (Calcd for
next to aromatic ring, an amide carbonyl and a non-basic C11H1335ClNO2: 226.0640). MS m/z: 226 ([M−H]−).
nitrogens such as pyrrole could exist in the substrates and re-
main throughout the N-alkylation under our condition. In this
Acknowledgments We are thankful to Mr. S. Inagaki
way, our approach could be very useful for the preparation of (Iwate Medical University) for measurement of MS spectra
various compounds containing nitrogen, although further opti- and Dr. T. Tsujihara (Iwate Medical University) for measure-
mization of the reaction condition is necessary.
ment of IR spectra.
Conflict of Interest The authors declare no conflict of
Experimental
Materials and Instruments All reagents and solvents interest.
were used as received from commercial suppliers without any
further purification. All reactions were carried out under an
argon atmosphere using magnetic stirring. Reactions were
analyzed by TLC with detection under UV light (λ=254nm)
and/or by staining with phosphomolybdic acid in ethanol.
Column chromatography was performed on silica gel 60N
(spherical neutral, particle size 100–210µm) for purification of
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