Stereospecific Synthesis of Unprotected, α,β-Disubstituted Tryptamines and Phenethylamines From 1,2-Disubstituted Alkenes via a One-Pot Reaction Sequence

Abstract

Unprotected, α,β-disubstituted tryptamines and phenethylamines are obtained by a one-pot, metal-free sequence that proceeds by the in situ formation of aziridinium salts followed by Friedel-Crafts reaction with electron-rich (hetero)arenes. Both steps are facilitated by hexafluoroisopropanol as solvent. The one-pot sequence was effective for diversely substituted indoles and 1,3,5-trimethoxybenzene, for cyclic and acyclic alkenes, and proceeded in a stereospecific fashion for both (E)-and (Z)-1,2-disubstituted alkenes. Moreover, one-pot morpholine addition to an aziridinium salt provided a diamine.

Graphical Abstract

Aziridines are readily prepared from alkene feedstocks and have considerable potential as intermediates for the convergent synthesis of pharmaceutically relevant amine-containing compounds.¹ In particular, the Friedel-Crafts addition of electron-rich (hetero)arenes to protected aziridines is an efficient approach for the synthesis of biomedically relevant tryptamines and phenethylamines (Scheme 1a),^2,3 although additional steps are required for aziridine synthesis and protecting group removal. In a conceptually related work, we recently described a HFIP-mediated,⁴ metal-free three-component synthesis of alkyl trifluoromethyl sulfides (Y = SCF₃) that proceeded via in situ formation of a three-membered thiiranium salt, followed by Friedel-Crafts addition (Scheme 1b).⁵ We wondered whether HFIP might also facilitate the formation of analogous aziridinium salts (Y = NH₂) and whether they might also undergo Friedel-Crafts addition (Scheme 1b). Significantly, important advances have been made for the direct synthesis and elaboration of unprotected aziridines from alkenes,⁶ including a metal-free approach for the synthesis of aziridinium salts in HFIP.^6a Related to our goals, Moran, Leboeuf and coworkers recently reported an elegant approach for the Fe(II)-catalyzed synthesis of aziridinium salts from electron-deficient aryl and alkyl monosubstituted alkenes followed by Friedel-Crafts addition of electron-rich (hetero)arenes (Scheme 1c).⁷ Herein we report the HFIP-mediated metal-free synthesis of α,β-disubstituted tryptamines and phenethylamines in a one-pot stereospecific sequence for both (E)-and (Z)-1,2-disubstituted alkenes (Scheme 1d).

Scheme 1.

Friedel-Craft Reactions of Aziridines

We first explored formation of aziridinium salt 3a based upon conditions reported by Jat, Tiwari and coworkers for the synthesis of unprotected aziridines (Table 1).^6a Under the optimized conditions, reaction of cyclohexene (1a) and NsO-NHBoc (2a) as the limiting reagent in HFIP at 45 °C gave the aziridinium salt 3a in 73% yield (entry 1). TFE as solvent resulted in greatly reduced yield (entry 2) and DCE did not provide any of the aziridinium salt 3a (entry 3). HFIP has a pronounced effect due to its high ionizing and hydrogen-bond donating ability, which is helpful in stabilizing cationic species formed during the reaction sequence. At the same time, the low nucleophilicity of HFIP helps to suppress the ring-opening side reaction between the aziridinium salt and the reaction solvent thereby improving the efficiency of both the formation of the aziridinium salt and its Friedel-Crafts reaction (vide infra).^4a Formation of the 3a was sensitive to temperature, with 20 and 60 °C both resulting in a lower yield (entries 4 and 5). Increasing the alkene stoichiometry from 1.5 to 3 equivalents gave the same product yield (entry 6). Finally, the aminating reagent used by Jat, Tiwari and coworkers, TsO-NHBoc (2b) was evaluated but gave a lower yield of the aziridinium salt 3a (entry 7).

Table 1.

Optimization of Aziridination Step

Entry	Variation from standard conditions	%Yieldb
1	None	73%
2	In TFE	21%
3	In DCE	0%
4	Performed at 20 °Cc	25%
5	Performed at 60 °Cc	55%
6	3 equiv of 1a	74%
7	TsO-NHBoc (2b) reagent	50%

^aConditions: 0.3 mmol of 1a, 0.2 mmol of 2a.

^bYields determined by ¹H NMR relative to PhSiMe₃ as a standard.

^cReaction set up at 20 °C and then placed into a water bath (20 °C) or a pre-heated oil bath (60 °C) for the reaction time noted.

We next evaluated the one-pot reaction sequence with the aziridinium salt 3a prepared in situ under the optimized conditions (entry 1, Table 1) and with N-methylindole (4a) as the Friedel-Crafts reaction partner (see Table 2). Under the optimized conditions conducted at 90 °C and with a 16 hour reaction time, α,β-disubstituted tryptamine product 5a was obtained in 72% overall yield from the limiting reagent NsO-NHBoc (2a) (entry 1). When the Friedel-Crafts reaction was performed at 20 °C, product 5a was not formed (entry 2); however, at 60 °C, 90 °C, or 110 °C, approximately equivalent amounts of 5a were obtained (entries 1, 3 and 4). In addition, at 60 °C, complete conversion was achieved in two hours to give 5a in 70% overall yield (entry 5). However, we selected 90 °C and a 16 hour reaction time as the standard reaction conditions given that different (hetero)arenes could be expected to undergo the reaction at different rates. When the concentration of the Friedel-Crafts reaction was doubled to 0.2 M, only a slight reduction in yield of 5a was observed (entry 6). Finally, TsO-NHBoc (2b) was also evaluated as an aminating reagent to give the desired product 5a, though it was obtained in a lower 52% overall yield based upon the limiting reagent 2b.

Table 2.

Variation of Conditions for Friedel-Crafts Step

Entry	Variation from standard conditions	%Yieldb
1	None	72%
2	Performed at 20 °C	0%
3	Performed at 60 °C	70%
4	Performed at 110 °C	65%
5	2 h reaction time	70%
6	Performed at 0.2 M	65%
7	TsO-NHBoc reagent (2b)	52%

^aConditions: 1 mmol of 4aand 3aprepared in situ from 0.3 mmol of 1aand 0.2 mmol of 2aaccording to standard conditions of aziridination (see Table 1).

^bYields determined by ¹H NMR relative to PhSiMe₃ as a standard.

We next explored the scope of the (hetero)arene reactant for the one-pot reaction sequence (Scheme 2). N-Methylindole provided the constrained tryptamine 5a in 70% and 68% isolated overall yield and as a single stereoisomer when performed at reaction scales of 0.2 mmol and 1 mmol, respectively. The anti-relationship for the two substituents on the cyclohexyl ring of 5a was assigned by the >10 Hz coupling constant for the vicinal methine hydrogens, consistent with their diaxial orientation with a 180° dihedral angle. Mechanistically, the anti-relationship results from nucleophilic attack on the aziridinium ion with inversion of stereochemistry. We next evaluated the effect of substitution at different sites on the indole ring. Addition of a methyl group on the 2-position of N-methylindole provided 5b in a lower 51% yield. A bromine substituent was next evaluated because it provides a versatile handle for further synthetic elaboration and could be incorporated at the 4- (5c), 5- (5d), 6- (5e), and 7- (5f) positions with only a modest variation in the overall yield from 53 to 65%. 5-Methoxy-1-methyl-1H-indole, which has the oxygenation substitution pattern of the important tryptamine neurotransmitter serotonin, provided 5g in a reasonable 55% overall yield. Additionally, a more electron-deficient indole ring with a methyl ester substituent was an effective substrate, providing 5h in 45% yield. Significantly, N-benzyl indole provided 5i with a readily cleaved N-benzyl substituent in excellent overall yield. For all these 2-unsubstituted indoles, no 2-substituted Friedel-Crafts products were detected, showing good selectivity toward the 3-position of the indole ring.

Scheme 2.

Hetero(arene) Scope^a

^aConditions: 1 mmol of 4, and 3 prepared in situ from 0.3 mmol of 1 and 0.2 mmol of 2a. Isolated yields of pure product after chromatography. ^bReaction performed with 5 mmol of 4a, 1.5 mmol of 1a, and 1 mmol of 2a. ^cFriedel-Crafts reaction performed at 110 °C.

We next evaluated indoles without substitution on the indole nitrogen. The reaction sequence provided 5j in a modest overall yield when free indole was used as a reactant, with competitive dimerization of the indole determined to be a side reaction by LCMS analysis of the unpurified product. This result is consistent with literature on the polymerization of indole under acidic conditions.⁸ A methyl substituent at the 2- and 7-positions on the indole ring moderately improved the overall yield of 5k and 5l, respectively, and a phenyl substituent at the 2-position provided 5m in 70% overall yield. Finally, when the reaction was conducted with the electron-rich arene 1,3,5-trimethoxybenzene, the constrained phenethylamine 5n was obtained in good overall yield. Less electron-rich arenes such as benzene and anisole were also evaluated, however, they were not nucleophilic enough to undergo Friedel-Crafts addition under our optimized reaction conditions.

We also evaluated a variety of alkenes and first explored cyclic alkenes with different ring sizes (Scheme 3). While cyclopentene provided 5o in a comparable overall yield to cyclohexene, cycloheptene gave a significantly lower yield of the desired product 5p. Acyclic alkenes were also effective substrates. Notably, (Z)- and (E)-3-hexene gave the α,β-diethyl substituted tryptamine products, 5q and 5r, respectively, as single stereoisomers. The relative stereochemistry for addition products 5q and 5r were assigned by analogy to 5a where inversion of stereochemistry occurred upon nucleophilic attack on the aziridinium ion. A tryptamine product 5s with α,β-dimethyl substitution was also obtained upon utilizing (Z)-2-butene as the alkene reactant. Terminal monosubstituted alkenes were not effective substrates. Product 5t could not be obtained from styrene because decomposition of the aziridinium occurred during its formation. Moreover, while vinyl cyclohexene provided tryptamine products without any detectable cationic rearrangement, the two regioisomers, 5u and 5u’, were obtained with only modest regioselectivity. These results are consistent with the related studies of Moran, Leboeuf and coworkers who observed that effective reactions only occurred when electron deficient (hetero)aryl and alkyl monosubstituted alkenes were utilized.⁷

Scheme 3.

Alkene Scope^a

^aConditions: 1 mmol of 4, and 3 prepared in situ from 0.3 mmol of 1 and 0.2 mmol of 2a. Isolated yields of pure product after chromatography.

We also performed preliminary studies on a one-pot, metal-free sequence to prepare N-alkyl α,β-disubstituted tryptamines (eq 1). Specifically, the same reaction conditions were utilized for the one-pot sequence employing the N-methyl aminating reagent 6 to give N-methyl aziridinium salt 7, which was reacted in situ with N-methylindole to give the N-methyl tryptamine 8 as a single stereoisomer in 62% overall yield.

(1)

Additionally, we investigated the viability of amines as nucleophiles to access vicinal diamines with morpholine (9) as a representative amine input (eq 2). For this transformation, a reaction temperature of 45 °C along with 5 equivalents of 9 as the nucleophilic input were utilized in the second step and provided the vicinal diamine 10 as a single stereoisomer in 50% overall yield.

(2)

In summary, an efficient metal-free, one-pot sequence has been developed for the stereospecific preparation of α,β-disubstituted tryptamines and phenethylamines from readily available (Z)- and (E)-disubstituted alkenes and electron-rich (hetero)arene reactants. Vicinal diamines can also be accessed by employing amines in place of the electron-rich (hetero)arenes as nucleophiles for the aziridinium opening step. By utilizing HFIP as the solvent, this synthetic approach eliminates the need for metal catalysts in either step of the one-pot sequence and thus expedites the synthesis of free amines from commercially available alkenes. We anticipate that this chemistry will have utility in medicinal chemistry applications given the importance of tryptamines and phenethylamines as neurotransmitters, pharmaceutical agents, and clinical candidates.⁹

Data Availability Statement

The data underlying this study are available in the published article and its online supplementary material.