‘Foxtrot’ fumarate: a water-soluble salt of N,N-diallyl-5-methoxytryptamine (5-MeO-DALT)

The synthesis and solid-state structure of the fumarate salt of the synthetic psychedelic 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) is reported.


Chemical context
Psychotropic compounds have gained a lot of attention in recent years for their potential as therapeutics to treat depression, anxiety, post-traumatic stress disorder, and addiction, among other disorders (Nichols & Hendricks, 2020). 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine found in the parotid gland of some toads, and this compound has been explored for its clinical effects in treating mood disorders (Davis et al., 2018). 5-MeO-DMT is highly active at the serotonin (5-hydroxytryptamine, 5-HT) 2A receptor, which is the origin of its psychotropic activity. It can be administered via inhalation or injection, but does not function as a psychedelic when consumed orally (Weil & Davis, 1994). A recent report described the synthesis of a water-soluble succinate salt of 5-MeO-DMT (Sherwood et al., 2020). 5-Methoxy-N,N-diallyltryptamine (5-MeO-DALT) is a synthetic analogue of 5-MeO-DMT, which was synthesized in 2004 by Alexander Shulgin (Shulgin & Shulgin, 2016). The compound has potential as a therapeutic because it has a quick onset and rapid drop-off relative to other psychotropic tryptamines (Corkery et al., 2012). Unlike 5-MeO-DMT, 5-MeO-DALT demonstrates activity when consumed orally, further improving its potential as a drug candidate. 5-MeO-DALT ISSN 2056-9890 shows activity at a number of serotonin receptors, including 5-HT 1A , 5-HT 1D , 5-HT 2A , 5-HT 2B , 5-HT 6 and 5-HT 7 (Cozzi & Daley, 2016). As this class of molecules become more significant in the treatment of mood disorders, it is important to have analytically pure, well-characterized, crystalline material to study the unique impact of individual compounds from the diverse range of compounds. It is also important to explore the effects of analytically pure combinations of these compounds to explore potential entourage effects. To best administer these compounds orally active, water-soluble crystalline materials are ideal. To that end, we set out to synthesize a water-soluble salt of 5-MeO-DALT, and report the synthesis and structure of bis(5-methoxy-N,N-diallyltryptammonium) fumarate herein.

Structural commentary
The asymmetric unit of bis(5-methoxy-N,N-diallyltryptammonium) fumarate contains one tryptammonium cation and one half of a fumarate dianion (Fig. 1). The cation possesses a near planar indole ring, with a mean deviation from planarity of 0.011 Å . The methoxy group is turned slightly away from this plane, with a C2-C3-O1-C17 torsion angle of À13.9 (2) . The ethylamino group is turned away from this plane, with a C7-C8-C9-C10 torsion angle of À103.9 (2) . The second half of the fumarate dianion is generated by inversion, and the dianion is near planar, with a mean deviation from planarity of 0.057 Å . The carboxylate unit is delocalized, with C-O distances of 1.271 (2) and 1.240 (2) Å . The nature of this salt allows for it to have high solubility in water, while the freebase does not.

Supramolecular features
The tryptammonium cation and the fumarate dianion are linked together in the asymmetric unit through an N-HÁ Á ÁO hydrogen bond between the ammonium nitrogen and a carboxylate oxygen ( Symmetry code: (i) Àx þ 1; Ày þ 2; Àz þ 1.

Figure 2
The crystal packing of bis(5-methoxy-N,N-diallyltryptammonium) fumarate, viewed along the b axis. The N-HÁ Á ÁO hydrogen bonds (Table 1) are shown as dashed lines. Hydrogen atoms not involved in hydrogen bonding are omitted for clarity.

Database survey
The structure of the freebase of 5-MeO-DALT has previously been reported (CCDC 1995802;Chadeayne et al., 2020d). The other tryptamine fumarate salts reported are those of 4-hydroxy-N-methyl-N-isopropyltryptamine

Synthesis and crystallization
110 mg of 5-MeO-DALT freebase were dissolved in 10 mL of methanol and 47 mg of fumaric acid was added and refluxed overnight. 129 mg (82% yield) of white powder was obtained upon removal of solvent in vacuo. Single crystals suitable for X-ray diffraction were obtained by slow evaporation of an aqueous solution. The product was analysed by 1 H NMR and 13 C NMR

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydrogen atoms on the indole nitrogen (H1), and the amine (H2), were found in 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. 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 (CH,CH 2 ) or 1.5U eq (CH 3 ).  The hydrogen-bonding network along [111], which consists of R 4 4 (22) rings that are joined together by two parallel C 2 2 (14) and C 4 4 (28) chains. The three components described in graph-set notation and the combined chain are shown. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms not involved in hydrogen bonding are omitted for clarity. Hydrogen bonds are shown as dashed lines.

Acknowledgements
tions, formulations, novel crystalline forms, and methods of making and using the same.

Computing details
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.