Synthesis of novel (phenylalkyl)amines for the investigation of structure-activity relationships: Part 3. 4-Ethynyl-2,5-dimethoxyphenethylamine (=4-ethynyl-2,5-dimethoxybenzeneethanamine; 2C-YN)

Article abstract of DOI:10.1002/hlca.200390224

An easy and efficient pathway for the preparation of 4-ethynyl-2,5-dimethoxyphenethylamine (=4-ethynyl-2,5-dimethoxybenzeneethanamine; 2C-YN; 1) was developed, an ethynyl analogue of the potent 5-HT_2A/C agonists, e.g., 4-iodo-2,5-dimethoxy-amphetamine (DOI; 2b). The ethynyl moiety was introduced by a Pd-catalyzed Sonogashira reaction of (trimethylsilyl)ethyne with N-(trifluoroacetyl)-protected 4-iodo-2,5-dimethoxyphenethylamine (7) in almost quantitative yield within only 1 h. Removal of the Me₃Si group was accomplished with Bu₄NF. Final N-deprotection by NaOH treatment afforded the novel phenethylamine 1 in an overall yield of 88percent.

Full text of DOI:10.1002/hlca.200390224

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Helvetica Chimica Acta Vol. 86 (2003)
Synthesis of Novel (Phenylalkyl)amines for the Investigation of
StructureÀActivity Relationships
Part 31)
4-Ethynyl-2,5-dimethoxyphenethylamine (ˆ4-Ethynyl-2,5-
dimethoxybenzeneethanamine; 2C-YN)
by Daniel Trachsel
R¸ttelistrasse 16, CH-4416 Bubendorf (e-mail: daniel_trachsel@gmx.ch)
An easy and efficient pathway for the preparation of 4-ethynyl-2,5-dimethoxyphenethylamine (ˆ4-
ethynyl-2,5-dimethoxybenzeneethanamine; 2C-YN; 1) was developed, an ethynyl analogue of the potent 5-
HT2A/C agonists, e.g., 4-iodo-2,5-dimethoxy-amphetamine (DOI; 2b). The ethynyl moiety was introduced by a
Pd-catalyzed Sonogashira reaction of (trimethylsilyl)ethyne with N-(trifluoroacetyl)-protected 4-iodo-2,5-
dimethoxyphenethylamine (7) in almost quantitative yield within only 1 h. Removal of the Me3Si group was
accomplished with Bu4NF. Final N-deprotection by NaOH treatment afforded the novel phenethylamine 1 in an
overall yield of 88%.
Introduction. In continuation of the foregoing research [1][2], the aim was to find
a convenient synthesis of 4-ethynyl-2,5-dimethoxyphenethylamine (ˆ4-ethynyl-2,5-
dimethoxybenzeneethanamine; 1; 2C-YN). A large number of phenylalkylamines of
the general structure 2 was prepared and investigated by numerous researchers [3a j]
including compounds with a wide variety of substituents at the 4-position (e.g., halo,
alkyl, alkylthio, alkoxy, nitro, CF3, and others). At first, these phenylalkylamines were
attractive due to the fact that they generally are potent hallucinogens (R ˆ H or Me).
Later, such compounds were found to be potent ligands for the serotonin 5-HT2A/C
receptors, displaying low nanomolar affinity [4a f], but none of them exhibited higher
selectivity for 5-HT2A vs. 5-HT2C receptors [4e][4f]. The induction of hallucinogenesis
seems to be principally mediated through the agonistic activation of the 5-HT2A
receptor [5].
1
)
Part 1, [1]; Part 2, [2].

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2755
Although numerous compounds of the general structure 2 have been described, an
ethynyl group has not yet been introduced at position 4. From the geometric point of
view, the ethynyl group can be considered isosteric with nitrile. They both are planar
and linear and, therefore, in plane with the aromaticsystem. The Table summarizes
some physicochemical data for the ethynyl group compared to other 4-substituents
resulting in some of the most-potent 4-substituted 2,5-dimethoxy-a-methylbenzenee-
thanamines 2a d investigated in in vitro and in vivo studies [3j][6] (compound 2d had
considerably lower affinity at 5-HT2A2) sites [4f][6] but is used for structural
comparison). The hydrophobicity of the para-substituents of 2a c is considerably
higher, but the ethynyl group has substantially higher hydrophobic character than the
CN group. The ability to attract or repulse electrons (Hammett constant s) of the
ethynyl group is comparable to that of the Br- and I-atom, and the high electro-
negativity is in the range of that of the CF3 group. The molar refraction is comparable
to that of Br.
Table 1. Some Physicochemical Data of 4-Substituents Used in 2,5-Dimethoxybenzenealkanamines 2
a
b
Substituent
Hydrophobicity px
)
Hammett constant sp
)
Electro negativityc)
Molar refractiond)
Br
I
CF3
CꢀN
CꢀCH
0.86
1.12
0.88
0.23
0.18
0.54
0.66
0.23
2.8
2.5
3.3 3.5
3.2 3.3
3.3
8.88
13.94
5.02
6.33
9.55
À 0.57
0.40
a) Relative partition coefficients of substituted benzenes is an octanol/H2O solvent system [7]. b) Taken from
[7] for para-substituted compounds. c) Values for Br and I are from the Pauling scale, for groups from [8].
Depending on its calculation method, several values are obtained. d) Approximate measure of stericbulk [7].
Although the corresponding a-methylphenethylamines
2
(ˆa-methyl-
benzeneethanamines ˆ amphetamines; R ˆ Me) are usually more potent and have
longer duration of action in vivo [3j], only the phenethylamine derivative was
prepared. Earlier in vitro studies showed that the presence of an a-methyl group has
little effect on 5-HT2A/C affinity [4e][9][10]. Thus, phenethylamines have about the
same affinity as their racemic a-methyl congeners (amphetamines) towards these
binding sites. The increased in vivo potency seems to be due to the increased metabolic
stability [4e][11]. In addition, the increased hydrophobicity [12] and the intrinsic
activity on the receptor [3j] seems to play an important role.
Results and Discussion. First attempts to introduce the ethynyl group with the aim
to synthesize 1 were made by the method of Buckle and Rockell [13]. Thus, 1,4-
dimethoxybenzene (3) was acetylated to give acetophenone 4 (Scheme 1). Compound
4 was chlorinated by treatment with PCl5. Subsequent dehydrodehalogenation under
basicocnditions yielded 2-ethynyl-1,4-dimethoxybenzene ( 5). Different conditions
were investigated to introduce the carboxaldehyde function by a Vilsmeier formylation.
Probably due to the high reactivity of the nucleophilic ethynyl group, there was always
immediate formation of a black tar, and the desired aldehyde 6 could not be isolated.
2
)
Note that the 5-HT2 receptor has been renamed to 5-HT2A.

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Helvetica Chimica Acta Vol. 86 (2003)
Initially, it was planned to convert aldehyde 6 to the corresponding nitrostyrene by
condensation with MeNO2. Subsequent reduction with a hydride reagent (e.g., alane
(AlH3)) should have afforded the desired phenethylamine 1.
Scheme 1
a) CH3COCl, AlCl3, CH2Cl2. b) 1. PCl5, benzene; 2. KOH, EtOH. c) N-Methylformanilide, POCl3.
To avoid the transformation of 5 into 6, a cross-coupling (Negishi) route was
chosen. Negishi and co-workers [14] developed a method for the direct introduction of
an ethynyl group into iodoarenes with ethynylmetals and [Pd(PPh3)4] as catalyst. The
reaction yields terminal alkynes and has the advantage that no protection-deprotection
of the yne moiety is needed. Accordingly, N-(trifluoroacetyl)-protected 2,5-dimethoxy-
4-iodophenethylamine 7 was treated with ethynylzincbromide (generated in situ from
ethynylmagnesium bromide and dry ZnBr2 in THF) as shown in Scheme 2. The reaction
was very slow, and only traces of the desired product 9 were formed. However, on
application of the less-direct method (Sonogashira coupling) with ethynyltrimethylsi-
lane as described by Thorand and Krause [15], the transformation was successfully
accomplished. Thereby, ethynyltrimethylsilane was allowed to react with 7 in the
presence of Et3N and catalytic amounts of CuI and [PdCl2(PPh3)2] in THF at room
temperature (Scheme 2). The reaction to compound 8 was complete within 1 h, and no
by-products were detected. As described in [15], it was not necessary to degas the
solvent. Compound 8 could be used for further transformation without purification.
The removal of the Me3Si and CF3CO protecting groups is well known and was
achieved according to standard procedures (Bu4NF and aq. NaOH solution, resp.).
Starting from 7, the overall yield for the preparation of 1 was 88%.
Compound 1 as well as 9 are important templates for the preparation of further
derivatives. The ethynyl group can easily be converted into various other functionalities
for structure-activity-relationship (SAR) studies, including to diyne or polyyne
derivatives (by Pd-catalyzed coupling), to conjugated alkene derivatives (via hydro-
boration), and by further functionalization to esters, ethers, thioethers, and halogen
compounds. Partial hydrogenation of 1 (which would afford the new compound 4-
ethenyl-2,5-dimethoxyphenethylamine; 2C-V) or of an alkylated alkyne derivative
(which would lead to (Z)- or (E)-alkene derivatives, depending on the hydrogenation
method) is also an option. This remains to be investigated in future work.
It is important to note that the halide atom attached to the arene moiety of 7 was I.
The Sonogashira coupling should as well be possible with the corresponding bromo
derivative (e.g., 4-bromo-2,5-dimethoxyphenethylamine; 2C-B, which is more easily
available than the iodo compound) since the compounds described in [15] were all
prepared from the corresponding bromoarenes. The a-methyl congener of 1, DOYN,

Helvetica Chimica Acta Vol. 86 (2003)
2757
Scheme 2
a) HCꢀCZnBr, [Pd(PPh3)4], THF. b) [PdCl2(PPh3)2 (2 mol-%), CuI (4 mol-%), Et3N, Me3SiCꢀCH, THF. c)
Bu4NF, THF. d) 5m aq. NaOH, MeOH.
should be available via the same syntheticpathway from the corresponding iodo- or
bromoarene derivative.
A Hansch analysis of a series of 4-substituted 2,5-dimethoxyamphetamines [6] gave
a significant correlation between 5-HT2A affinity and the hydrophobicity of the 4-
substituents. The measured 5-HT2A binding data for compound 2d bearing the 4-CN
substituent showed an affinity of approximately two orders of magnitude lower than
that of 2a,b [4f][6]. For the binding affinity at the 5-HT2A receptor, the comparison of
the physicochemical data for 4-substituents (Table) suggests that compound 1 should
have substantially higher affinity than 4-cyano-2,5-dimethoxyamphetamine (2d;
DOCN) or the a-demethyl congener thereof.
Due to the small size of the ethynyl group, 1 could have agonistic properties at the 5-
HT2A receptor, since the measurement of the functional activity of phenylalkylamines
of type 2 bearing a large lipophilic4-substituent ( e.g., hexyl, octyl, 3-phenylpropyl)
showed that these ligands typically lead to antagonistic or at least partially agonistic
effects, and phenylalkylamine analogs of 2 with a small lipophilicsubstituent at the 4-
position exhibit agonisticbehavior [6][10].
The ethynyl group is a substituent rarely seen attached to aromatic systems in
pharmaceuticals, probably due to the only recently developed methods for its
introduction, and the potential for metabolic instability due to its relatively acidic,
terminal H-atom. However, several compounds bearing an ethynyl group were
developed and investigated (e.g., 4-ethynylphenylalanine (10) as a potent tryptophan-
hydroxylase inhibitor [16][17], TarcevaTM (11) as a therapeuticantitumor agent [18],
and the potent H3-receptor antagonist 12 with high oral CNS activity [19]). Studies on
the in vitro mechanism of the oxidation of p-bonds of p-substituted ethynylbenzenes by
CYP450 [20] showed that the role of metabolite formation was strongly dependant on
the electronic properties of additional substituents. An additional NO2 group led to
slow metabolism. With an additional Me group, the metabolism was fast. This suggests
that 2C-YN (1) bearing two MeO groups and an alkyl side chain would be metabolized

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Helvetica Chimica Acta Vol. 86 (2003)
quite fast. This and the above suggestions regarding the binding properties at the 5-
HT2A receptor remain to be investigated.
Experimental Part
General. All compounds were commercially available and were used without further purification. Products
were dried at 50-608. TLC Monitoring: silica gel plates F254, standard UV lamps for detection. M.p.: B¸chi 535;
uncorrected. IR Spectra: Perkin-Elmer Spectrum-One FT-IR system; in cmÀ1 1H- and 13C-NMR Spectra:
.
Bruker AM-300 spectrometer; at 300 (1H) and 75 MHz (13C); d in ppm, J in Hz.
N-{2-{2,5-Dimethoxy-4-[2-(trimethylsilyl)ethynyl]phenyl}ethyl}-2,2,2-trifluoroacetamide (8). A flame-dried
apparatus was charged with 2,2,2-trifluoro-N-[2-(4-iodo-2,5-dimethoxyphenyl)ethyl]acetamide (7; 1.0 g,
2.48 mmol) [3j][9] (caution: 7 must not be contaminated by iodine monochloride from the previous reaction),
CuI (20 mg, 0.1 mmol), [PdCl2(PPh3)2] (35 mg, 0.05 mmol), and dry THF (5 ml) under Ar. Then Et3N (1.0 g,
9.9 mmol) was added in one portion. After stirring for 1 min, ethynyltrimethylsilane (0.51 g, 5.2 mmol) in THF
(1.0 ml) was added during 5 min (according to [15], slow addition prevents the formation of diynes). After
stirring for 1 h, the conversion was complete, and the solvent was evaporated. The residue was taken up in
AcOEt. Filtration through Celite and evaporation of the filtrate afforded a viscous oil which slowly crystallized:
1
0.90 g (97%) of 8. Beige solid. M.p. 104 1058. H-NMR (CDCl3): 6.94 (s, 1 arom. H); 6.88 (br. s, NH); 6.63
(s, 1 arom. H); 3.84 (s, MeO); 3.82 (s, MeO); 3.55 (q, CH2NH); 2.90 (t, ArCH2); 0.30 (s, Me3Si).
N-[2-(4-Ethynyl-2,5-dimethoxyphenyl)ethyl]-2,2,2-trifluoroacetamide (9). A soln. of 8 (0.87 g, 2.33 mmol)
in THF (25 ml) was treated with 1m Bu4NF in THF (11.0 ml) and stirred for 2 h. The mixture was quenched with
sat. aq. NH4Cl soln. (70 ml) and extracted with AcOEt (3 Â 40 ml), the combined extract washed with brine,
dried (Na2SO4), and evaporated, and the obtained viscous brownish oil further purified by flash chromatog-
1
raphy (silica gel (50 g) hexanes/AcOEt 2 :1 ! 1:1): 0.64 g (91%) of 9. Beige solid. M.p. 126 1278. H-NMR
(CDCl3): 6.99 (s, 1 arom. H); 6.90 (br. s, NH); 6.67 (s, 1 arom. H); 3.87 (s, MeO); 3.82 (s, MeO); 3.59
(q, CH2NH); 3.34 (s, HCꢀC); 2.93 (t, ArCH2).
4-Ethynyl-2,5-dimethoxybenzeneethanamine Hydrochloride (1 ¥ HCl; 2C-YN ¥ HCl). A soln. of 9 (0.63 g,
2.09 mmol) in MeOH (120 ml) was treated with aq. 5m NaOH (35 ml) and stirred for 4 h. The mixture was
diluted with Et2O (150 ml), the aq. phase further extracted with Et2O (3 Â 50 ml), and the combined org. phase
washed with H2O (2 Â 50 ml), dried (Na2SO4), and evaporated. The residual oil (reacts with CO2 very quickly;
should be stored under an inert gas if used as free base) was dissolved in anh. Et2O (10 ml) and the soln.
neutralized with anh. 1m HCl in Et2O. The crystals were filtered off, washed with Et2O, and dried: 0.44 g (88%)
of 1 ¥ HCl. Off-white crystals. M.p. 207 2088. IR (KBr): 3279, 2962, 2907, 2062, 1504, 1467, 1400, 1219, 1034, 859,
1
699. H-NMR (D2O): 6.97 (s, 1 arom. H); 6.80 (s, 1 arom. H); 3.71 (s, MeO); 3.66 (s, MeO); 3.61 (s, HCꢀC);
‡
3.10 (t, CH2NH3 ); 2.84 (t, ArCH2). 13C-NMR (D2O): 154.04; 151.00; 127.64; 116.02; 114.02; 109.36; 83.03;
80.08; 56.36; 56.12; 39.72; 28.61.
The author thanks Dr. Daniel Bur for the in silico modeling, visualizations, and helpful discussions, and Dr.
Christoph Boss and David Lehmann for their helpful comments and corrections.
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Received February 18, 2003