W. Alves de Barros, Marcelo Pereira Queiroz, L. da Silva Neto et al.
Tetrahedron Letters 66 (2021) 152804
Fig. 2. Significant correlations observed in the NOESY spectra of 3 and 4.
Fig. 1. Representative structure of NBOMes and NBOHs.
was also established based on the NOE correlations between the
aromatic hydrogens and the methoxy groups (Figs. 2 and S10).
Having amines 2, 3 and 4 in hand, our efforts were then directed
to the preparation of the corresponding Schiff bases followed by
reduction using NaBH4. The reactions were carried out in a single
pot under microwave irradiation (30 min, 70 °C; MWI) [32]. Salicy-
laldehyde and 2-methoxybenzaldehyde were used to obtain
NBOHs (25H-, 25I- and 25B-NBOH) and NBOMes (25H-, 25I- and
25B-NBOMe), respectively (Scheme 2).
Seeking to assess the robustness of the proposed route, 25H-
NBOH and 25H-NBOMe were synthesized on a 1.2 g scale. For all
synthesized NBOH compounds, we performed a single crystal X-
ray diffraction on their hydrochloride derivatives (Scheme 2).
be noted that these phenethylamines are very expensive (1.0 mg
costs up to 57.5 US dollars, Sigma-Aldrich, CAS Number: 56281-
37-9). In addition, the few procedures available starting from sim-
ple materials have multiple steps and low yields. Nichols and co-
workers reported the synthesis of 25I-NBOMe in 10 steps and
5.1% overall yield [17]. Karlsen and co-workers synthesized inter-
mediates 3 and 4 in 6 steps and 30% and 35% overall yield, respec-
tively [18]. Therefore, we proposed that NBOMes and NBOHs could
be synthesized from 2-(2,5-dimethoxyphenyl)ethan-1-amine 2
and its halogenated derivatives as intermediates (Scheme 1).
Amine 2 was easily obtained from 2,5-dimethoxybenzaldehyde
using the Henry reaction, followed by dehydration of the Henry
adduct, providing 1 in 79% yield [19]. The reduction of 1 with
LiAlH4 provided 2 in 74% yield (Scheme 1) [20]. In order to obtain
halogenated (X = I or Br) substituted phenethylamines, it was nec-
essary to introduce such halogens at position 4 of 2-(2,5-dimethox-
yphenyl)ethan-1-amine (2, Scheme 1). Due to the higher
prevalence of 25I-, 25B-NBOMe and 25I-, 25B-NBOH in Brazil
[21–24], this series of halogens was prepared. 2-(4-Iodo-2,5-
dimethoxyphenyl)ethan-1-amine (3) was synthesized using I2
under Ag2SO4 catalysis in ethanol. Amine 3 was obtained in 40%
yield after 48 h (Scheme 1) and the regioselectivity of the iodide
substitution was established based on the NOE correlations
between the aromatic hydrogens and the methoxy groups (Figs. 2
and S7) [18].
Conclusion
The synthesis of three NBOHs (25H-, 25I- and 25B-NBOH; 9–
38% overall yield) and three NBOMes (25H-, 25I- and 25B-NBOMe;
7–33% overall yield) from inexpensive and commercially available
aldehydes is reported. The X-ray structures of 25H-, 25I- and 25B-
NBOH.HCl are also reported. Furthermore, our approach should
provide a general entry for preparing such substances for pharma-
cological and forensic purposes.
Declaration of Competing Interest
Various bromination methodologies were evaluated for the syn-
thesis of 2-(4-bromo-2,5-dimethoxyphenyl)ethan-1-amine
4
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.
(Table 1). We attempted to use Br2 in AcOH [17], N-bromosuccin-
imide (NBS) in acetonitrile [25–28], and Br2 in THF under pyridine
catalysis (Entries 1–3, respectively; Table 1), however, a low con-
version of 2 to 4 (<10%) was observed. The purification of such ami-
nes was also challenging, since both compounds had similar
polarity and were consequently difficult to separate by column
chromatography. The 1,4-dioxane-Br complex is a mild brominat-
ing agent, which has been used for the bromination of activated
aromatic systems [29,30]. Gratifyingly, the use of Br2 in a mixture
of AcOH/1,4-dioxane (1:1) gave amine 4 in 53% yield after 72 h
(Entry 5; Table 1) [31]. In addition, the workup procedures used
in this reaction (see ESI) provided the pure desired amine 4 as a
crystalline material. The regioselectivity of bromine substitution
Acknowledgments
This study was funded by the Fundação de Amparo à Pesquisa
do Estado de Minas Gerais (FAPEMIG/Brazil; Grant #RED- 00042-
16), Conselho Nacional de Desenvolvimento Científico e Tec-
nológico (CNPq/Brazil; Grant #429121/2018-0) and Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil –
Finance Code 001 – Process #88881.516313/2020-01). ADF is
recipient of research fellowship from CNPq/Brazil.
Scheme 1. a) Preparation of amines 2 and 3. b) 50% probability ellipsoid plot for the non-hydrogen atoms of amine 2 as the acetate salt (hydrogen atoms are arbitrary radius
spheres, counterion not shown in the ellipsoid diagram).
2