Synthesis of the 3-(3,4,5-trimethoxyphenyl)-pyrrolidine: A new conformationally constrained mescaline analogue

Article abstract of DOI:10.1080/00397910701356504

The total synthesis of the 3-(3,4,5-trimethoxyphenyl)-pyrrolidine, a new and conformationally constrained mescaline analogue, was accomplished in a concise and efficient manner. The synthetic route encompassed only 4 steps from the starting N-Cbz-3-pyrrol

Full text of DOI:10.1080/00397910701356504

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Synthesis of the 3-(3,4,5-Trimethoxyphenyl)-
pyrrolidine: A New Conformationally
Constrained Mescaline Analogue
Ricardo de L. Barreto a , Laura B. L. R. Nascimbem a & Carlos Roque Duarte
Correia a
a Chemistry Institute, State University of Campinas (UNICAMP), Campinas,
São Paulo, Brazil
Published online: 22 Jun 2007.
To cite this article: Ricardo de L. Barreto , Laura B. L. R. Nascimbem & Carlos Roque Duarte Correia (2007)
Synthesis of the 3-(3,4,5-Trimethoxyphenyl)-pyrrolidine: A New Conformationally Constrained Mescaline
Analogue, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 37:12, 2011-2018
To link to this article: http://dx.doi.org/10.1080/00397910701356504
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Synthetic Communicationsw, 37: 2011–2018, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701356504
Synthesis of the 3-(3,4,5-Trimethoxyphenyl)-
pyrrolidine: A New Conformationally
Constrained Mescaline Analogue
Ricardo de L. Barreto, Laura B. L. R. Nascimbem, and
Carlos R. D. Correia
Chemistry Institute, State University of Campinas (UNICAMP),
Campinas, Sa˜o Paulo, Brazil
Abstract: The total synthesis of the 3-(3,4,5-trimethoxyphenyl)-pyrrolidine, a new and
conformationally constrained mescaline analogue, was accomplished in a concise and
efficient manner. The synthetic route encompassed only 4 steps from the starting N-
Cbz-3-pyrrolidine, in 46% overall yield. The route features a highly effective
Heck arylation of the non-activated olefin N-Cbz-3-pyrrolidine with the 3,4,5-
trimethoxybenzene diazonium tetrafluoroborate. The hemiaminal (lactamol) Heck
adduct was converted to the mescaline analogue in a sequence of reactions: (a) dehy-
dration of the intermediate hemiaminal 3 with trifluoroacetic acid anhydride, (b) hydro-
genation/hydrogenolysis of the endocyclic enecarbamate 6 with H2-Pd/C, and
(c) formation of the rather stable mescaline analogue in the form of a hydrochloride
salt. The target molecule constitutes a new mescaline analogue with potential
activity towards 5-HT2 dopamine receptors.
Keywords: arenediazonium tetrafluoroborates, 3-aryl pyrrolidines, heck arylation,
mescaline analogues
INTRODUCTION
Mescaline, an important hallucinogenic alkaloid, was discovered in 1896 by
Heffer.[1] Mescaline is found in the small cactus peyote Lophophora williamsii
(Cactaceae), and its structure corresponds to the rather simple alkaloid
Received in the USA November 7, 2006
Address correspondence to Carlos Roque Duarte Correia, Instituto de Quımica,
´
UNICAMP, P. O. Box 6154, Campinas, Sa˜o Paulo, 13084-971 Brazil. E-mail: roque@
iqm.unicamp.br
2011

2012
R. de L. Barreto, L. B. L. R. Nascimbem, and C. R. D. Correia
Figure 1. Mescaline and the target molecule 2.
Scheme 1. Retrosynthesis of the new mescaline analogue 2.
3,4,5-trimetoxyphenylethylamine shown in Fig. 1. Mescaline acts on the central
nervous system (CNS) because of its interaction with dopamine receptors,
especially with those of the 5HT2 type. These receptors mediate many
important physiological processes, such as vascular and nonvascular contrac-
tion of the smooth muscle, humor perception, anxiety, and feed behavior.[2]
Mescaline has been used as a hallucinogen in experimental psychiatry.
To evaluate the structure–activity relationship (SAR), many analogues of the
prototype mescaline have been investigated.[3–7] Hence, structural modifications
of its basic framework are of importance to optimize biological activity and
develop new drugs for treatment of CNS disorders, such as schizophrenia and
depression.[2,8,9] Herein we describe the total synthesis of a new analogue of
mescaline bearing a pyrrolidine ring as the conformational constraining element.
Our synthetic strategy was centered on a Heck arylation of the protected
3-pyrroline 5 with an electron-rich arenediazonium salt to furnish the
intermediate endocyclic enecarbamate 6. Catalytical hydrogenation of enecar-
bamate 6 followed by hydrogenolysis would then provide the target molecule
2 (Scheme 1).
RESULTS AND DISCUSSION
The synthetic route was initiated with the preparation of the trimethoxybenze-
nediazonium tetrafluoroborate 4 following the protocol of Schiemann.[10] It

3-(3,4,5-Trimethoxyphenyl)-pyrrolidine
2013
Scheme 2. Preparation of the arenediazonium tetrafluoroborate 4.
involved the diazotization reaction of 3,4,5-trimethoxyaniline in an acidic
medium with sodium tetrafluoroborate (Scheme 2). The average yield for
this reaction was 93%. Trimethoxybenzenediazonium tetrafluoroborate 4
was obtained as a stable, crystalline solid. Diazotation of 3,4,5-trimethoxyani-
line can also be carried out under neutral conditions following Milner’s
protocol, albeit in slightly lower yields.[11]
With the 3,4,5-trimethoxybenzenediazonium tetrafluoroborate in hand,
we then prepared the olefin N-Cbz-3-pyrroline by means of olefin metathesis
following Grubbs’s protocol.[12] As described in Scheme 3, diallylamine was
converted into the desired 3-pyrroline in 95% isolated yield after two steps
(N-protection and olefin metathesis).
The critical step in the overall route involved a Heck arylation of N-Cbz-3-
pyrroline 5 with arenediazonium salt 4 (Scheme 4). Heck arylation was accom-
plished by employing the conditions developed by Correia and coworkers,[13]
under base-free conditions and using palladium acetate as catalyst to provide
Scheme 3. Protection and metathesis of diallylamine.
Scheme 4. Heck arylation of N-Cbz-pyrroline and dehydration of lactamol.

2014
R. de L. Barreto, L. B. L. R. Nascimbem, and C. R. D. Correia
Scheme 5. Synthesis of the mescaline constrained analogue 2 in the hydrochloride
form.
lactamol 3 in 91% yield as a rather stable oil. Most probably, enecarbamate 6 is
the primary adduct of this Heck reaction. However, as observed previously, the
reaction medium turns acidic as arylation proceeds. Under acidic conditions, the
N-acyl enamine moiety undergoes hydration to form the lactamol 3. Formation
of the lactamol 3 during the Heck arylation is a critical event that prevents
further arylation of the electron-rich olefin present in enecarbamate 6.[13]
Also noteworthy is that these Heck arylations of N-pyrroline are amenable to
multigram-scale production.
Having the stable lactamol in hand, dehydration was cleanly and efficiently
carried out using trifluoroacetic anhydride and 2,6-lutidine in refluxing
toluene[14] to give the desired endocyclic enecarbamate 6 in good overall
yields (ꢀ72% yield over two steps).
The last steps in the synthetic route involved a simultaneous Cbz removal
and an enamine reduction. These transformations were carried out on a single
step employing H2/Pd-C; that is, hydrogenolysis followed by catalytic hydro-
genation provided the target 2-aryl-pyrrolidine 2 in 65% isolated yield in the
form of a stable hydrochloride after acidification of the medium with 6M HCl
(Scheme 5).
CONCLUSION
A new and conformationally constrained analogue of mescaline was syn-
thesized in a straightforward and concise manner. The key step was an
efficient Heck arylation of a N-protected 3-pyrroline using an electron-rich
arenediazonium tetrafluoroborate, which provided the key lactamol intermedi-
ate 3 in good yield. Lactamol 3 was cleanly converted into the unsaturated
mescaline analogue after dehydration to provide the endocyclic enecarbamate
4. A concomitant hydrogenolysis–catalytic hydrogenation of enecarbamate 4
provided the new mescaline analogue 2. The overall synthesis involved only
four steps from N-Cbz-3-pyrrolidine and was carried out in 46% overall yield.
Biological essays of this new potential 5-HT2 ligand are ongoing, and
results will be disclosed in due course.

3-(3,4,5-Trimethoxyphenyl)-pyrrolidine
EXPERIMENTAL
2015
General Procedures
Unless noted otherwise, reactions were carried out under an atmosphere of dry
nitrogen or argon, in oven-dried glassware. Methylene chloride, hexane, and tri-
ethylamine were distilled from CaH2 prior to use. Acetonitrile was used as ACS-
grade solvent without any further purification. All the reagents were purchased
from traditional commercial sources and were used without further purification.
Flash column chromatography was performed employing Merck silica gel 60
(230–400 mesh). Thin-layer chromatography (TLC) was performed on
Merck silica-gel 60/F-254 aluminum-backed plates and was visualized by
UV radiation and/or phosphomolybdic acid. Analytical high-performance
liquid chromatography (HPLC) was carried out on an HP 1100 series chromato-
graph equipped with a UV detector. Capillary GLC analyses were performed on
a Hewlett-Packard 6890 chromatograph equipped with fused-silica-gel
capillary column (30 m ꢀ 0.32 mm) wall coated with HP-5. Melting points
were measured on a Thomas Hoover capillary melting-point apparatus and
are uncorrected. Nuclear magnetic resonance spectra (1H and 13C NMR)
were recorded as solutions in the indicated solvents on Varian Gemini 300 or
Brucker AC-300P spectrometer. Chemical shifts are reported in parts per
million (d units) relative to tetramethylsilane as internal standard (1H NMR).
Infrared spectra were recorded on a Thermo Nicolet 200 spectrometer. Low-res-
olution mass spectra were obtained on a Shimadzu QP5000 spectrometer,
equipped with a HP-1 column (0.20 mm ꢀ 20 m) or on a ESI Applied Biosys-
tems MDS SCIEX, model Q Trap LC/MS/MS System, and high-resolution
mass spectra on a VG Autospec Instrument.
Preparation of the Arenediazonium Tetrafluoroborate 4
To a solution of 1 g of trimethoxyaniline (5.5 mmol) in 1.5 mL of water, 1.5 mL
of concentrated HCl were added. The mixture was stirred vigorously for
ꢀ20 min and then placed in a salted ice bath at 258C. To the cooled
solution, a freshly prepared aqueous solution of NaNO2 (0.49 g of NaNO2
dissolved in 1 mL of H2O) was slowly added. After 15 min, an aqueous
solution of NaBF4 (0.845 g of NaBF4 dissolved in 1.7 mL of H2O) was
added at once, causing the formation of a precipitate. The reaction mixture
was filtered, and the solid was washed with cold Et2O. The solid was
collected and dissolved in 16.5 mL of acetone, and the resulting solution was
filtered. To the filtrate, 11 mL of cold Et2O were added, causing the pre-
cipitation of the arenediazonium tetrafluoroborate. The mixture was filtered
and the solid dried in air to provide 1.43 g of the arenediazonium tetrafluorobo-
rate 4 (93% yield). MW (g/mol): 282.0; mp: 114–1168C; IR (lmax, film,
cm21): 3105, 2277, 1587, 1493, 1475, 1425, 1314, 1243, 1129, 1022, 980;

2016
R. de L. Barreto, L. B. L. R. Nascimbem, and C. R. D. Correia
1H NMR (300 MHz, CDCl3, d): 4.0 (6H, s); 4.2 (3H, s); 8.2 (2H, s). ESI-MS
(Mþ): 195.2.
Preparation of N-Cbz-3-pyrroline 5[12]
To a solution of diallylamine (1.55 g, 2 mL, 16 mmol) in 50 mL of dry
dichloromethane, 4.5 mL of triethylamine (32 mmol) were added. The
solution was cooled in an ice bath, and benzyl chloroformate was added
(2.73 g, 2.3 mL, 16 mmol). The ice bath was removed, and the reaction
mixture was stirred for 12 h. The reaction mixture was diluted with 20 mL
of CH2Cl2 and transferred to a separatory funnel. The organic layer was
separated and then washed successfully with water, saturated NaHCO3, and
brine. Next, the organic layer was dried with anhydrous sodium sulfate and
filtered, and the solvent was removed in vacuo. A colorless oil corresponding
to N-(Cbz)-diallylamine was obtained in quantitative yield.
The N-(Cbz)-diallylamine prepared previously (1.237 g, 5.35 mmol) was
dissolved in 10 mL of dry dichloromethane and transferred to a flask contain-
ing a solution of the Grubbs catalyst (91 mg, 0.11 mmol) in 40 mL of dry
dichloromethane. The reaction mixture was stirred under argon for 5 h at
room temperature, after which the rubber septum was removed, and the
reaction was left stirring for an addition hour to deactivate the catalyst. The
solvent was then evaporated in vacuo, and the product was purified by flash
chromatography (hexane/EtOAc ¼ 80:20), furnishing 1.031 g of the N-Cbz-
pyrroline 5 as homogeneous material by TLC in 95% yield. MW: 203.24
g/mol; IR (lmax, film, cm21): 3095, 3077, 3043, 2961, 2909, 2863, 1708,
1
1627, 1435, 1360, 1331, 1209, 1128, 977; H NMR (300 MHz, CDCl3, d):
4.2 (4H, brs); 5.2 (2H, s); 5.78 (2H, m); 7.3–7.4 (5H, m).
Preparation of Lactamol 3
To a solution of 540 mg of the N-Cbz-pyrroline 5 (2.7 mmol) in 13 mL of
CH3CN/H2O (1:1; v/v), 1.125 g of the arenediazonium salt 4 (4.0 mmol)
and 60 mg of Pd(OAc)2 (10 mol %) were added. The reaction mixture was
stirred for 3 h at room temperature, when total consumption of the pyrroline
was observed by TLC analysis. The reaction mixture was then diluted with
ethylacetate (ꢀ40 mL), transferred to a separatory funnel, and extracted with
saturated NaHCO3 and NaCl. The organic layer was collected, dried over
anhydrous Na2SO4, and filtered, and the solvent was evaporated in vacuo.
The product was purified by flash chromatography (hexane/EtOAc ¼ 1:1) to
provide 0.936 g (91% yield) of an oil (homogeneous by TLC), corresponding
to a mixture of diastereomeric lactamols 3 (cis and trans). MW: 387.43 g/mol;
Rf ¼ 0.32 (hexane/EtOAc ¼ 1:1), IR (lmax, film, cm21): 3440, 2937, 2838,
1
1698, 1589, 1509, 1450, 1419, 1357, 1328, 1238, 1184, 1124, 1008, 698. H

3-(3,4,5-Trimethoxyphenyl)-pyrrolidine
2017
NMR (300 MHz, CDCl3, d): 2.3 (2H, m); 3.3–3.5 (1H, m); 3.85 (9H, s, OMe);
4.0 (2H, m); 5.15 (2H, s); 5.65 (1H, dd, J ¼ 5.1, 11.3 Hz); 6.45 (2H, m, Ar); 7.4
(5H, m, Ar). 13C NMR (75 MHz, CDCl3, d): 155.3 (C), 153.4 (C), 136.0 (C),
128.2 (CH), 104.2 (CH), 82.0 (CH), 67.1 (CH2), 60.8 (CH3), 56.2 (OCH3),
52.4 (CH2), 42.9 (CH), 40.2 (CH2).
Preparation of the Enecarbamate 6
To a solution of 90 mg of the lactamol (0.23 mmol) in 2.3 mL of dry toluene,
115 mL (5.0 equiv) of 2,6-lutidine (1.0 mol) and 0.3 mL (0.7 mmol) of a 7M
solution of trifluoroacetic anhydride were added under argon in an ice bath at
08C. The reaction was allowed to reach rt. After 2 h at rt, the reaction mixture
was refluxed for 30 min, then cooled to room temperature, diluted with 20 mL
of EtOAc, transferred to a separatory funnel, and extracted with saturated
solutions of NaHCO3 and NaCl. The organic layer was separated, dried
over anhydrous Na2SO4, and filtered, and the solvent was evaporated in
vacuo. Flash chromatography (hexane/EtOAc ¼ 60:40) provided 67.3 mg
of enecarbamate 6 as homogeneous material by TLC, in 81% yield. MW:
369.41 g/mol; Rf ¼ 0.28 (hexane/EtOAc ¼ 8:2) phosphomolybdic acid; IR
(lmax, film, cm21): 2937, 2834, 2358, 1704, 1616, 1589, 1508, 1455, 1417,
1
1336, 1234, 1124, 1008, 759, 698. H NMR (300 MHz, CDCl3, d): 3.7 (1H,
m); 3.9 (9H, s, OMe); 4.1 (1H, m); 5.1 (1H, brs); 5.2 (2H, d, J ¼ 7.7 Hz);
6.4 (2H, s, Ar); 6.7–6.9 (1H, d, J ¼ 3.7 Hz); 7.4 (5H, m, Ar). 13C NMR (75
MHz, CDCl3, d): 153.5 (C), 152.0 (C), 140.0 (C), 128.5 (CH), 111.9 (CH),
104.1 (CH), 67.3 (CH2), 60.1 (CH3), 56.1 (CH3), 53.9 (CH2), 49.0 (CH),
45.7 (CH); MS: m/z (rel. intensity) 369 (82.5) [M]þ, 325 15, 234 (17.5),
205 (22.5), 91 100, 65 (14). HRMS m/z calcd. for C21H23NO5, 369.15762;
found 369.15758.
Preparation of 3-(3,4,5-Trimethoxyphenyl)-pyrrolidine 2
To a solution of 180 mg of the enecarbamate 6 (0.49 mmol) in 4 mL of EtOAc,
52 mg of Pd-C 10 mol % (0.5 mmol) were added. The resulting suspension
was purged with H2 for ꢀ10 min and then stirred under hydrogen (a filled
balloon) for 2 h. When TLC analysis indicated complete consumption of the
enecarbamate, the reaction mixture was filtered through a short pad of
Celite,w and the solvent was partially evaporated to a ꢀ5-mL volume. To
this concentrated EtOAc solution of the free amine, a drop (ꢀ0.2 mL) of a
6M HCl solution was added, and the mixture was cooled in ice to give
75 mg of a white precipitate after filtration, corresponding to the hydrochlo-
ride 2 (65% yield). MW: 273.60 g/mol; mp: .2208C (decomp.). Rf ¼ 0.12
(CHCl3/MeOH ¼ 9:1). IR: 2933, 2872, 2839, 1687, 1589, 1507, 1458,
1
1421, 1319, 1237, 1119, 1004, 824. H NMR (300 MHz, D2O, d): 2.0 (2H,

2018
R. de L. Barreto, L. B. L. R. Nascimbem, and C. R. D. Correia
m); 2.3 (1H, m); 3.1 (2H, t, J ¼ 11.0 Hz); 3.2–3.5 (2H, m); 3.6 (2H, s); 3.7
(6H, s); 6.6 (2H, s). 13C NMR (75 MHz, D2O, d): 152.3 (C), 135.5 (C),
104.4 (CH), 61.4 (C), 60.5 (CH3), 55.8 (CH3), 50.3 (CH2), 46.6 (CH2), 42.8
(CH), 31.1 (CH2). ESI-MS (Mþ): 238.3.
ACKNOWLEDGMENTS
We thank FAPESP (Research Supporting Agency of the State of Sa˜o Paulo)
and CNPq (Brazilian National Research Council) for financial support of
the project. RLB also thanks FAPESP for a doctoral fellowship.
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