N-Cyclohexyltryptamine: freebase, bromide and fumarate

The crystal structure of the freebase of the monoalkyl tryptamine N-cyclohexyltryptamine is presented, along with those of its bromide and fumarate salts.


Chemical context
Tryptamine, an indole with a 2-aminoethyl sidechain, is a metabolite of the essential amino acid tryptophan. Tryptamine and its derivatives are an important class of biologically active compounds that are found in almost all organisms on Earth. In humans these compounds play significant roles ranging from the function of the gastrointestinal tract to neurotransmission and control subjective phenomena like happiness. The most abundant of these compounds, occurring naturally in the body, are primary tryptamines like tryptamine itself and serotonin (5-hydroxytryptamine; 5-HT) (Palego et al., 2016).
There are many well-known tertiary (dialkyl) tryptamines, including the natural products N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 4-hydroxy-N,N-dimethyltryptamine (psilocin) which are known agonists of the serotonin 2A (5-HT 2A ) receptor and elicit a psychedelic response in humans. These and similar compounds have attracted a great deal of interest due to their potential for treating conditions including depression (Mertens et al., 2020), end-of-life distress (Ross et al., 2021), post-traumatic stress disorder (Varker et al., 2021), pain (Ramaekers et al., 2021), and eating disorders (Spriggs et al., 2021). There are also many synthetic tertiary tryptamines used as pharmaceuticals including the triptans, which have long been used for the treatment of migraine headaches by activating the serotonin 1D (5-HT 1D ) receptor (Goadsby & Holland, 2018). The biological impact of primary and tertiary tryptamines has been recognized for a long time and continues to be studied in great detail today.
Much less studied are the secondary tryptamines, i.e. the monoalkyltryptamines; many of these compounds have been observed as natural products in plants. One study suggests that monoalkyltryptamines are generally less toxic than their dialkyltryptamine counterparts (Brimblecombe et al., 1964). For example, the LD 50 values for N-methyltryptamine (NMT) and N,N-dimethyltryptamine (DMT) in mice were 78 and 43 mg kg À1 , respectively. Recent studies have suggested that the psychedelic effects of compounds may not be necessary for the expression of therapeutic effects (Olson, 2021). Monoalkyl tryptamines like norpsilocin (4-hydroxy-N-methyltryptamine) are agonists of 5-HT 2A but do not produce head-twitch response (HTR) in mice, which is characteristic of classic psychedelics such as psilocybin and LSD (Sherwood et al., 2020;Glatfelter et al., 2022a). Human studies have found that the compound 5-tert-butyl-N-methyltryptamine is a full agonist of 5-HT 1D with a higher binding affinity (K i = 0.45 nM) and selectivity five times more potent (EC 50 = 0.22 nM) than the migraine drug naratriptan (EC 50 = 1.6 nM) (Xu et al., 1999;Slassi et al., 2000). These and other data points suggest that monoalkyltryptamines possess characteristics that are conducive to the development of medicines.
Continuing our exploration of monoalkyltryptamines, we present here the first crystal structure of a mono-cycloalkyltryptamine, N-cyclohexyltryptamine. The compound was synthesized in 1971 via the condensation of tryptamine with cyclohexanone followed by reduction with Raney Nickel (Gerecs et al., 1971). Herein, we report three structures of Ncyclohexyltryptamine compounds, including freebase, bromide and fumarate salts, the later of which represents the first fumarate salt of a mono-cycloalkyltryptamine.

Structural commentary
The molecular structure of the freebase of N-cyclohexyltryptamine (I) is shown in Fig. 1 (top left), as well as that of its bromide salt [(II), top right], and its fumarate salt [(III), bottom]. The asymmetric unit of (I) contains one full tryptamine (C 16 H 22 N 2 ) molecule. The asymmetric unit of the bromide salt (II) contains one N-cyclohexyltryptammonium (C 16 H 23 N 2 + ) cation and one bromide anion held together with an N2-H2AÁ Á ÁBr1 hydrogen bond. The asymmetric unit of the fumarate salt (III) contains one full N-cyclohexyltryptammonium (C 16 H 23 N 2 + ) cation and one half of a fumarate (C 4 H 2 O 4 2-) dianion, with the second half generated by inversion. The two ions are connected in the asymmetric unit through a N2-H2Á Á ÁO2 hydrogen bond. The fumarate dianion is near planar, with an r.m.s. deviation from planarity of 0.011 Å . In all three structures, the cyclohexyl group is in a chair configuration. Table 1 lists selected parameters for the three structures.

Supramolecular features
In the freebase, the tryptamine molecules are held together in infinite chains along [010] by N1-H1Á Á ÁN2 hydrogen bonds (  bromide anions are held together in two-dimensional sheets along (001) through a series of N-HÁ Á ÁBr hydrogen bonds (Table 3). In the fumarate salt, the tryptammonium cations and fumarate dianions are held together in an infinite threedimensional framework through a series of N-HÁ Á ÁO hydrogen bonds. The indole N-H and both ammonium N-H bonds hydrogen bond to oxygen atoms of the fumarate dianions (Table 4). The packing of N-cyclohexyltryptamine is shown in Fig. 2 for the freebase (left), the bromide (center) and the fumarate (right).

Figure 2
The crystal packing of freebase N-cyclohexyltryptamine (left), its bromide salt (center), and its fumarate salt (

Synthesis and crystallization
Crystals of N-cyclohexyltryptammonium bromide (II) suitable for X-ray diffraction studies were grown by slow evaporation of an ethanol solution of a commercial sample (ChemBridge).
The bromide salt was converted to freebase N-cyclohexyltryptamine (I) by stirring it in a biphasic mixture of dichloroethane and aqueous sodium hydroxide. The organic layer was isolated, washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to yield the freebase as a white powder. Crystals suitable for X-ray diffraction were grown by the slow evaporation of an acetone solution.

N-[2-(1H-Indol-3-yl)ethyl]cyclohexanamine (I)
Crystal data Monoclinic, P2 1 a = 8.5446 (6)  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 )    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 Br1 0.81840 (4) 0.64728 (5)   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.