DMT analogues: N-ethyl-N-propyltryptamine and N-allyl-N-methytryptamine as their hydrofumarate salts

The structures of the hydrofumarate salts of two N,N-dimethyltryptamine (DMT) derivatives, the synthetic psychedelics N-ethyl-N-propyltryptamine (EPT) and N-allyl-N-methyltryptamine (MALT), are reported.

À , are reported. Both compounds possess a protonated tryptammonium cation, and a hydrofumarate anion in the asymmetric unit. The ethyl group of the EPT cation is modeled as a two-component disorder with 50% occupancy for each component. In the extended structure, N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds generate infinite two-dimensional networks parallel to the (001) plane for both compounds.

Chemical context
Ayahuasca is the traditional spiritual medicine of the indigenous people of the Amazon basin, and has a history of use in religious ceremonies dating back to the 1400 0 s or earlier. It is an herbal tea that is made by boiling a mixture of leaves and bark. The leaves of the Psychotria viridis plant contain about 0.3% of N,N-dimethyltryptamine (DMT) by mass, which is the primary psychoactive in ayahuasca. The bark of the Banisteriopsis caapi vine contains many different -carbolines; these -carbolines function as monoamine oxidase (MAO) inhibitors, which prevent the degradation of DMT in the human gut. Without the inhibition of monoamine oxidase, DMT is not orally active (Cameron & Olson, 2018).
In a report earlier this year, -carboline MAO inhibitors were identified in species of 'magic mushrooms', where the primary psychedelic, psilocin, can be similarly degraded by MAO. This is the first instance of a synchronous biosynthesis of an active ingredient and the inhibitor of its degradation in a natural psychedelic species (Blei et al., 2020). Psilocin (4-hydroxy-N,N-dimethyltryptamine) is orally active in the absence of MAO inhibitors, indicating that the 4-hydroxy substitution makes the compound more resistant to deamination by MAO (Sherwood et al., 2020). The presence of -carbolines in 'magic mushrooms' and the varied activity of psilocin and DMT bring many questions forward on the nature of cooperative activity among chemicals in psychotropic natural products.
This class of traditional psychedelics, as well as synthetic variants, have started to gain a great deal of interest as antidepressants and anxiolytics (Johnson et al., 2019;Jimé nez-Garrido et al., 2020). Given the renewed interest in using psychedelic tryptamines as therapeutics, there is growing urgency to perform fundamental physical and biological characterization on these compounds for the benefit of downstream research. This is particularly true in the examination of structure-activity relationships between compounds and also the examination of their cooperative biological activity. A better understanding of these areas would facilitate the research and development of formulations tailored for specific ailments. Two synthetic analogues of DMT are Nethyl-N-propyltryptamine (EPT) and N-methyl-N-allyltryptamine (MALT), both of which have very limited reports in literature (Ascic et al., 2012;Brandt et al., 2005a,b). The preparation of pure crystalline forms of these compounds is essential to conducting meaningful biological studies and ultimately developing drug products. Herein, we report the first solid-state structural characterization of EPT and MALT as their hydrofumarate salts, (I) and (II), including the first reported salt of MALT.

Structural commentary
The asymmetric unit of N-ethyl-N-propyltryptammonium hydrofumarate, (I), contains one tryptammonium cation and one hydrofumarate anion (Fig. 1). The cation possesses a near planar indole, with a mean deviation from planarity of 0.008 Å . The ethylamino group is slightly turned away from this plane with a C1-C8-C9-C10 torsion angle of 33.9 (4) . The ethyl group on the N-ethyl-N-propylamine is disordered over two orientations, with a 0.50:0.50 ratio for C14, C15 and C14A, C15A. The hydrofumarate anion deviates slightly from planarity with an r.m.s. deviation of 0.135 Å , and a carboxylate to carboxylate plane twist angle of 16.63 (14) .
The asymmetric unit of N-methyl-N-allyltryptammonium hydrofumarate, (II), contains one tryptammonium cation and one hydrofumarate anion (Fig. 2). The tryptammonium has a near planar indole, with a mean deviation from planarity of 0.007 Å . The ethylamino group is turned away from the plane of the indole, with a C1-C8-C9-C10 torsion angle of À105.5 (5) . The hydrofumarate is also near planar, with an r.m.s. deviation of 0.055 Å . The carboxylate is partially delocalized, with C-O distances of 1.239 (5) Å and 1.259 (4) Å . The asymmetric unit of N-methyl-N-allyltryptammonium hydrofumarate showing the atom labeling. Displacement ellipsoids are drawn at the 50% probability level. The hydrogen bond is shown by a dashed line.

Figure 1
The asymmetric unit of N-ethyl-N-propyltryptammonium hydrofumarate showing the atom labeling. Displacement ellipsoids are drawn at the 50% probability level. Dashed bonds indicate the disordered component of the structure. The hydrogen bond is shown by a dashed line.

Supramolecular features
The two moieties of the EPT salt, the tryptammonium cation and the hydrofumarate anion, are held together in the asymmetric unit via N2-H2Á Á ÁO1 hydrogen bonds. The indole of another tryptammonium cation interacts with a carbonyl oxygen of the hydrofumarate molecule through an N1-H1Á Á ÁO4 hydrogen bond (symmetry operation: 2 À x, 1 2 + y, 1 À z). The hydroxy group of the hydrofumarate interacts with a carboxylate oxygen of another hydrofumarate anion through an O3-H3AÁ Á ÁO2 hydrogen bond (symmetry operation: 1 + x, y, z). The hydrofumarate anions are linked together in chains along [100], which are linked together by the tryptammonium cations along [010], joining the ions into infinite two-dimensional networks parallel to the (001) plane (Table 1, Fig. 3).
The two moieties of the MALT salt, the tryptammonium cation and the hydrofumarate anion, are held together in the asymmetric unit via N2-H2Á Á ÁO1 hydrogen bonds. The hydroxy group of the hydrofumarate hydrogen bonds to the carboxylate oxygen of another hydrofumarate anion through O3-H3AÁ Á ÁO2 hydrogen bonds (symmetry code: À1 + x, y, z). One carbonyl oxygen, O2, of the hydrofumarate, the indole nitrogen, N1, of another tryptammonium cation (symmetry code: 1 À x, 1 2 + y, 1 2 À z), and a carbonyl oxygen, O4, of a different hydrofumarate anion (symmetry code: 1 + x, y, z) combine to form a three-centred (

Figure 3
The hydrogen bonding of a hydrofumarate ion in the structure of N-ethyl-N-propyltryptammonium hydrofumarate, with hydrogen bonds shown as dashed lines. Only one component of the disorder is shown, and hydrogen atoms not involved in hydrogen bonding are omitted for clarity. Symmetry codes:

Figure 4
The hydrogen bonding of a hydrofumarate ion in the structure of Nmethyl-N-allyltryptammonium hydrofumarate, with hydrogen bonds shown as dashed lines. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms not involved in hydrogen bonding are omitted for clarity. Symmetry codes:
berg, 1972), the bromide salt of DMT (QQQHIM: Falkenberg, 1972), and the freebase of N-methyl-N-propyltryptamine (WOHYAW: Chadeayne, Golen & Manke, 2019b). The core structure of the tryptamines in these compounds are similar, but the packing is very different given the lack of a similar counter-ion. The reaction of fumaric acid with the freebase of N-methyl-N-allyltryptamine to generate the hydrofumarate salt is similar to the reactions observed with psilacetin (Nichols & Frescas, 1999)  The only other N-allyltryptamine whose structure has been reported is 5-methoxy-N,N-diallyltryptamine (Chadeayne, Pham et al., 2020c), which is reported as the freebase and has not been reported as a salt.

Synthesis and crystallization
Single crystals of N-ethyl-N-propyltryptammonium hydrofumarate suitable for X-ray analysis were obtained from the slow evaporation of an aqueous solution of a commercial sample of EPT fumarate (The Indole Shop).
To prepare N-methyl-N-allyltryptammonium hydrofumarate, 134 mg of a commercial sample of N-methyl-N-allyltryptamine (The Indole Shop), which is a waxy solid that does not crystallize well, were dissolved in 10 mL of methanol, and 68 mg of fumaric acid were added. The mixture was refluxed for 12 h and solvent was removed in vacuo to obtain a waxy, yellow product. The material was recrystallized from ethanol to yield colorless single crystals suitable for X-ray diffraction. The product was also characterized by nuclear magnetic resonance

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. N and O-bound H atoms were located in difference-Fourier maps and refined with distance restraints of N2-C14 = N2-C14A =1.50 AE (10) For both structures, data collection: APEX3 (Bruker, 2018); cell refinement: SAINT (Bruker, 2018); data reduction: SAINT (Bruker, 2018); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: publCIF (Westrip, 2010). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.  (5)