2,5-Dimethylbufotenine and 2,5-dimethylbufotenidine: novel derivatives of natural tryptamines found in Bufo alvarius toads

The structures of the dimethylated versions of two natural products found in toad secretions, bufotenine and bufotenidine, are reported, as well as the hydrate of 2,5-dimethylbufotenidine.


Chemical context
Bufotenine, the N,N-dimethyl analogue of serotonin, and bufotenidine, the N,N,N-trimethyl analogue of serotonin, were both identified in toad secretions in 1934 (Wieland et al., 1934). These and other indoalkylamines found in the paratoid glands of Bufo alvarius toads can lead to psychotropic activity in humans and other animals. Bufotenine is believed to have psychedelic properties due to its activity as a serotonin 2A agonist (Egan et al., 2000). Bufotenidine (5-HTQ) is a siteselective serotonin 5-HT 3 binder (Glennon et al., 1991), and has demonstrated paralytic activity in rats (Bhattacharya & Sanyal, 1972). The best known psychedelic compound in these secretions is the O-methylated version of bufotenine ] (Spencer Jr et al., 1987). Known as the 'God Molecule', 5-MeO-DMT has been used by humans in religious ceremonies where it is traditionally administered by smoking, or vaporizing the secretions of Bufo alvarius toads. 5-MeO-DMT has also been administered intravenously, though it is inactive through oral consumption (Weil & Davis, 1994). 5-Methoxy-2,N,N-trimethyltryptamine (5-MeO-2-Me-DMT, 2,5-dimethylbufotenine) was first reported in 1955, and crystallized as its picrate salt in two different forms (Shaw, ISSN 2056-9890 1955. A detailed synthesis of the freebase of the compound was reported by Alexander Shulgin, who also described its clinical effects on humans, with psychotropic activity occurring within an hour of oral consumption accompanied by physical stimulation (Shulgin & Shulgin, 2016). By contrast, 5-MeO-DMT is not orally active, unless consumed in combination with a monoamine oxidase inhibitor (MAOI). The methylation of the 2-position provides oral activity in 5-MeO-2-Me-DMT, likely by limiting its decomposition by monoamineoxidases, and also appears to reduce activity at the 5-HT 2A receptor, making it significantly less active than inhaled 5-MeO-DMT. Bioassays of this compound have shown it to be an agonist for the serotonin 5-HT 6 receptor (K i = 89 nM) (Glennon, et al. 2000) and the serotonin 5-HT 7 receptor (K i = 1,120 nM) (Vermeulen, et al. 2003).
Herein we report the structure of 5-methoxy-2,N,N-trimethyltryptammonium fumarate. We also report the synthesis of 5-methoxy-2,N,N,N-tetramethyltryptammonium iodide (a bufotenidine analogue), along with its structure. Lastly, we report the structure of the first solvate of 5-methoxy-2,N,N,Ntetramethyltryptammonium iodide as its hydrate.

Structural commentary
The asymmetric unit of bis(5-methoxy-2,N,N-trimethyltryptammonium) fumarate contains one tryptammonium cation and one half of a fumarate dianion (Fig. 1, left). The cation possesses a near planar unit containing the indole, the methyl and the methoxy groups, with mean deviation from planarity of 0.047 Å . The ethylamino group is turned away from this plane, with a C2-C9-C10-C11 torsion angle of À95.4 (2) . The hydrogens of the 2-methyl group carbon (C1) exhibit a rotational disorder over two positions with 50% occupancy. Half of the fumarate is present in the asymmetric unit, with the other half generated by inversion. The dianion is slightly distorted from planarity with an r.m.s. deviation of 0.076 Å . The carboxylate unit is delocalized with C-O distances of 1.222 (3) and 1.225 (2) Å .
The asymmetric unit of 5-methoxy-2,N,N,N-tetramethyltryptammonium iodide contains one tryptammonium cation and one iodide anion (Fig. 1, center). The indole ring, methyl and methoxy groups of the cation are near planar, with a mean deviation from planarity of 0.050 Å . The ethylammonium arm is turned away from the plane with a C7-C8-C9-C10 torsion angle of 100.9 (4) . The asymmetric unit of its hydrate contains one tryptammonium cation, one iodide anion, and one water molecule (Fig. 1, right). The tryptammonium cation is very similar to the non-hydrate, with a mean deviation from planarity of 0.043 Å for the indole ring, methyl and methoxy groups of the cation, and a C1-C8-C9-C10 torsion angle of 98.0 (2) . The metrical parameters of the three structures are very similar, with the major difference observed being the elongated N-C(methyl) bonds in the quaternary salts.

Supramolecular features
In the structure of 5-MeO-2-Me-DMT fumarate, the ammonium nitrogen exhibits a bifurcated N-HÁ Á Á(O,O) hydrogen bond with the two oxygens of a carboxylate unit, and the indole nitrogen is involved in an N-HÁ Á ÁO hydrogen bond with one of the carboxylate oxygens (Table 1). This series of N-HÁ Á ÁO hydrogen bonds connects the ions together in an infinite two-dimensional network parallel to the (101) plane. The six-membered rings of inversion-related indoles stack with parallel slippedinteractions [intercentroid distance = 3.9105 (15) Å , interplanar distance = 3.7688 (19) Å , and slippage = 1.043 (3) Å ]. The packing of 5-MeO-2-Me-DMT fumarate is shown at the top of Fig. 2.
In the structure of 5-MeO-2-Me-TMT iodide, the tryptammonium cation and the iodide anion are held together in the asymmetric unit via N--HÁ Á ÁI hydrogen bonds, between the indole nitrogen and the iodide ( Table 2). The six-membered rings of inversion-related indoles stack with parallel slippedinteractions [intercentroid distance = 3.716 (3) Å , interplanar distance = 3.488 (4) Å , and slippage = 1.282 (7) Å ] that pair the tryptammonium cations together as dimers in the solid state. The packing of 5-MeO-2-Me-TMT iodide is shown in the center of Fig. 2.

Figure 2
The crystal packing of bis ( interaction is elongated as the O-HÁ Á ÁI interactions weaken the amine-halide interaction.

Database survey
The structure of bufotenine (BUFTEN: Falkenberg, 1972) and its borane adduct (OYOCIQ: Moreira et al., 2015) have been reported. The unit cell of 5-MeO-DMT (QQQAGY: Bergin et al., 1968) and the single crystal structure of its hydrochloride (MOTYPT: Falkenberg & Carlströ m, 1971) are the other two structures reported for naturally occurring tryptamines of toads. The other simple 5-methoxy tryptamine whose structure is reported is the synthetic compound, 5-methoxy-N,N-diallyltryptamine (

Synthesis and crystallization
Crystals of 5-MeO-2-Me-DMT fumarate suitable for diffraction studies were obtained from the evaporation of a methanol solution of a commercial sample (The Indole Shop). 5-MeO-2-Me-TMT iodide was synthesized when 128 mg of 5-MeO-2-Me-DMT fumarate was dissolved in 6 mL of methanol, and 6 mL of methyliodide was added. The mixture was refluxed under an atmosphere of nitrogen for 12 h. The solvent was removed in vacuo to yield a bright-yellow powder. The powder was washed with diethyl ether to yield 127 mg of a light-yellow powder. The product was recrystallized from methanol and water to yield two different crystalline forms.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. The hydrogen atoms on the indole nitrogen of each structure (H1) and H2 in the fumarate structure were found from a difference-Fourier map and were refined isotropically, using DFIX restraints with N-H distances of 0.87 (1) Å . Isotropic displacement parameters were set to 1.2U eq of the parent nitrogen atom. The hydrogen atoms on the water of the hydrate structure (H1WA, H1WB) were found from a difference-Fourier map and were refined isotropically, using a DFIX restraint with an O-H distance of 0.88 (1) Å . Isotropic displacement parameters were set to 1.5U eq of the parent oxygen atom. All other hydrogen atoms were placed in calculated positions (C-H = 0.93-0.97 Å ). Isotropic displacement parameters were set to 1.2U eq (C) or 1.5U eq (C-methyl). A certain number of reflections is missing from the data of all three structures. This is likely a beamstop related technical issue which could not be resolved as of yet. For all 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).
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )

[2-(5-Methoxy-2-methyl-1H-indol-3-yl)ethyl]trimethylazanium iodide (umd2018f_a)
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.46 e Å −3 Δρ min = −0.80 e Å −3 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 I1 0.43011 (

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.