An improved synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT): A selective MT2 melatonin receptor antagonist

Article abstract of DOI:10.1039/b713904g

A novel, efficient and diastereoselective procedure was developed for the gram-scale synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT), a selective MT₂ melatonin receptor antagonist. The synthetic strategy involved the conversion of 4

Full text of DOI:10.1039/b713904g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An improved synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT): a
selective MT2 melatonin receptor antagonist
Simone Lucarini, Annalida Bedini, Gilberto Spadoni and Giovanni Piersanti*
Received 11th September 2007, Accepted 19th October 2007
First published as an Advance Article on the web 13th November 2007
DOI: 10.1039/b713904g
A novel, efficient and diastereoselective procedure was developed for the gram-scale synthesis of
cis-4-phenyl-2-propionamidotetralin (4-P-PDOT), a selective MT2 melatonin receptor antagonist. The
synthetic strategy involved the conversion of 4-phenyl-2-tetralone to enamide followed by
diastereoselective reduction affording cis-4-P-PDOT in good yield. The mechanism of the reduction
step was explored by employing deuterated reagents.
Introduction
Most compounds endowed with biological interest are molecules
with a high degree of conformational freedom, which produces
several conformational isomers. Increasing the rigidity of bioactive
molecules is a valuable tool for investigating the stereochemical
features of small-molecule binding sites. In the case of simple
Fig. 1
flexible substances, such as arylethylamines, a method commonly
used to reduce the flexibility has been the modification of the
ethylamine fragment into a bicyclic system. For instance, the
tetralin skeleton has been successfully used as a rigid template for
the synthesis of non-indolic melatonin-like agents,1 and several
other substances possessing important biological activities.2,3
Melatonin (N-acetyl-5-methoxytryptamine, MLT), a neurohor-
mone mainly secreted by the pineal gland during dark periods,
is an indole derivative with a flexible ethylamido chain attached
at the C3 position. In mammals, melatonin modulates a variety
of cellular, neuroendocrine and physiological processes through
activation of at least two high-affinity G-protein coupled receptors,
named MT1 and MT2.4
Converging evidence from pharmacophore analysis, 3D-QSAR
and GPCR comparative modelling in the field of melatonin
receptor ligands has allowed the definition of the structural
requirements for MT2 selective antagonism.5–7 In particular, we
evidenced that the presence of a bulky substituent in an area
corresponding to positions 1 and 2 of the indole nucleus of MLT,
and “out-of-plane” from the indole ring, confers selectivity for the
MT2 receptor and leads to a reduction of intrinsic activity.8 The
melatonin receptor ligand 4-phenyl-2-propionamidotetralin (4-P-
PDOT, Fig. 1) fulfilled this requirement9 and is one of the most
interesting melatonin MT2 selective antagonists.
the most used pharmacological tools to identify functional MT2
receptors.
Although this compound has been used in small amounts in
in vitro tests to provide some understanding of the roles of MT1
and MT2 melatonin receptors,11–13 more precise and specific in
vivo animal experiments, where large amounts of compound are
required, are necessary to clarify the physiological role of both
receptors.
The need for multi-gram amounts of this very expensive
substance14 for in vivo studies prompted us to design a more
efficient, diastereoselective route to the more active cis-4-P-PDOT.
The method used in the first patent route,15 involved a base-
catalyzed condensation between phenylacetone and benzaldehyde,
followed by ring closure via an intramolecular Friedel–Crafts
alkylation with AlCl3 in CS2 to give 4-phenyl-2-tetralone. The
4-phenyl-2-propionamidotetralin 1 was obtained by reductive
amination with benzylamine, deprotection and finally acylation
with propionic anhydride according to the Schotten–Baumann
procedure. The overall yield for 4-P-PDOT prepared according to
this synthetic route was very low (ca. 1%) and moreover there is
no mention of the stereochemistry of the product synthesized.
Our initial approach to the synthesis of the cis-diastereoisomer
of compound 1 (Scheme 1)10 was based on the protocol reported
by Wyrick et al.16 and involved the synthesis of 4-phenyl-2-
tetralone 4 by cyclization of trans-1,4-diphenyl-3-buten-2-one 3 in
polyphosphoric acid followed by reduction with NaBH4 to give
a 85 : 15 cis–trans mixture of tetralols 5. The predominantly
cis-tetralol was epimerized via the ester intermediate 6 to the
trans-alcohol 7. The latter was converted to the cis-primary
amine 9 by tosylation, followed by reaction with sodium azide
in aqueous DMF then catalytical (10% Pd/C) hydrogenation.
Finally, the primary amine was converted to ( )-cis-4-phenyl-2-
propionamidotetralin 1 by acylation with propionic anhydride.
Recently, we examined the influence of different stereo-
chemistries of 4-phenyl-2-propionamidotetralin on the binding
affinity and intrinsic activity at human MT1 and MT2 receptors.10
The ( )-cis diastereoisomer of compound1 (Fig. 1) has higher
MT2 binding affinity (pKi = 10.8), as compared to its corre-
sponding trans-isomer (pKi = 8.45) and good selectivity for the
MT2 receptor (MT2/MT1 = 225) rendering cis-4-P-PDOT one of
Institute of Medicinal Chemistry, University of Urbino “Carlo Bo”, Pi-
azza del Rinascimento 6, 61029 Urbino (PU), Italy. E-mail: giovanni.
piersanti@uniurb.it; Fax: +39 0722 303313; Tel: +39 0722 303323
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Scheme 1 Precedented synthetic approach. Reagents: (a) PhCHO, NaOH, water, 60 ◦C, 18 h; (b) PPA, xylene, reflux, 2 h; (c) NaBH4, MeOH, reflux,
16 h; (d) DEAD, (C6H5)3P, PhCOOH, THF, 55 ◦C, 4 h; (e) NaOH, MeOH, reflux, 2 h; (f) TsCl, Py, 5 ◦C, 5 days; (g) NaN3, DMF–H2O, 50 ◦C, 4 h;
(h) H2 (4 atm.) 10% Pd/C, 2-propanol, rt, 24 h; (i) (C2H5CO)2O, Et3N, toluene, rt, 24 h.
The described synthetic procedure (Scheme 1) involved overall
nine tedious steps, several flash chromatography purifications, the
use of some hazardous reagents and the overall transformations
are not very efficient.
Herein we describe a more efficient synthesis of ( )-cis-4-P-
PDOT in only three steps and high overall yield that is suitable for
multigram-scale preparations.
fact in designing our synthetic route. Stereoselective reduction of
the newly formed enamide 10 (Scheme 2) would complete the
synthesis of the target compound.
The easy and direct route to the key enamide 10 was achieved by
condensation of primary propylamide with the cyclic ketone 4 in
the presence of p-toluenesulfonic acid as catalyst and continuous
removal of water using Dean–Stark apparatus.
Given our project’s ongoing synthesis of novel analogs of 4-P-
PDOT we required a general reduction procedure for enamides
which would be tolerant to functional groups. In addition, we
required the regiospecific delivery of a hydride equivalent to the
vinyl group in anticipation of the preparation of several 3H-labeled
analogs.
With all this in mind we thought to use ionic reduction
conditions for a chemo-, regio- and stereoselective reduction of
the enamide. We were delighted to find that treatment of the
substrate 10 with Et3SiH (TES) in the presence of trifluoroacetic
acid (TFA) furnished the desired product in excellent yield and
good diastereoselectivity (91% yield; 81 : 19 cis–trans ratio).
No reduction took place when acetic acid was used instead of
TFA. Attempts to further improve the diastereoselectivity by
lowering the temperature to −78 ◦C resulted in unacceptable low
conversion rates.
Results and discussion
As presented, with the improved synthesis of cis-1 reported in
Schemes 2 and 3, we first sought a more direct single step
synthesis of the key tetralone 4 through addition of styrene to
phenylacetyl chloride in the presence of aluminium chloride as
a catalyst, by analogy to what has been reported previously.17
Then, we explored the reactivity of this cyclic ketone with
nitrogen nucleophiles. Attempts to convert 4-phenyl-2-tetralone
to 4-phenyl-2-aminotetraline by reductive amination procedures
gave low yields of product15 or even no product at all16 as the
tetralone dimerized immediately in the presence of weak bases
such as the amines employed.
It is noteworthy, that the present method offers a highly atom
economic process to 4-P-PDOT.
The pure cis-isomer can be easily isolated by crystallization
(acetone–n-hexane). The physical–chemical properties and NMR-
spectra of compound cis-1 synthesized by the novel procedure
(Scheme 3) were identical to those previously reported.11
The mechanism of the reduction was briefly explored by
carrying out the reaction in the presence of deuterated and non-
deuterated reagents. Reduction of 10 using Et3SiD in place of
Et3SiH, resulted in high conversion to deuterium labeled 4-P-
PDOT d1-cis-1a (Fig. 2) in about the same time (10 min). In
contrast, by using CF3COOD only 4-P-PDOT d1-cis-1b was
Scheme 2 Retrosynthetic analysis.
1
obtained. Comparison of the H NMR signals for the CH and
Scheme 3 Novel synthetic approach. Reagents: (a) AlCl3, CH2Cl2, 0 ◦
C
30 min; (b) propylamide, PTSA cat., toluene, reflux, 4 h; (c) TES, TFA,
−10 ◦C, 10 min.
We envisioned, then, propionamide, as a less basic and nu-
cleophilic enough alternative to the amine, to couple with the
tetralone 4. In fact it is well-known that enamides can be easily
prepared by the acid catalyzed condensation of primary amides
with carbonyl compounds18 and we took advantage of this trivial
Fig. 2
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-CH2 groups of cis-1a and cis-1b with those of 1 showed simplified
1H NMR multiplet patterns due to substitution by 2H. This
was confirmed by analysis of the MS spectrum which revealed
almost complete mono-deuteriation (d1 95 atom%) and 13C NMR
confirmed the location of the deuterium exclusively at the C2 (45.3)
and C1 (36.5) for cis-1a and cis-1b respectively.
Based on these results we hypothesized the mechanism shown
in Scheme 4. The diastereoselectivity outcome of the reduction
can be explained by both the Burgi–Dunitz trajectory for hydride
approach to carbonyls and the Cieplak19 mode for the nucleophilic
addition to a carbonyl group with non-chelating a-substituents.
It is known that the stereochemistry of nucleophilic addition to
cyclohexanones is determined by two factors: steric hindrance
which favours the equatorial approach (b, Scheme 4), and electron
donation from the cyclohexanone’s rC–C bonds into the r* which
favours the axial approach (a, Scheme 4) since the carbon–
hydrogen bonds are better electron donors. Given the predominant
cis product, we can confidently assume that the electronic factors
prevail over the steric hindrance on substrate 10 in our reaction
conditions.
(J values) are given in hertz (Hz). ESI-MS spectra were taken on
a Waters Micromass ZQ instrument. Only molecular ions (M + 1)
are given. Infrared spectra were obtained on a Nicolet Avatar 360
FTIR spectrometer, absorbances are reported in cm−1. Column
chromatography purifications were performed under “flash” con-
ditions using Merck 230–400 mesh silica gel. Analytical thin-layer
chromatography (TLC) was carried out on Merck silica gel 60 F254
plates. All chemicals were purchased from commercial suppliers
and used directly without any further purification, including
the deuterated reagents [triethyl(silane-d) and trifluoroacetic
acid-d].
( )-4-Phenyl-3,4-dihydronaphthalen-2-one (4)
Freshly distilled styrene (1 g, 9.7 mmol, 1 equiv.) in dry
dichloromethane (120 mL) was added dropwise under nitrogen at
0 ◦C during 15 min to a stirred suspension of anhydrous aluminium
trichloride (3.9 g, 29 mmol, 3 equiv.) in dry dichloromethane
(130 mL) containing phenylacetyl chloride (1.5 g, 9.7 mmol, 1
◦
equiv.) and the mixture was stirred at 0 C for a further 15 min.
The reaction was quenched by a saturated solution of Seignette
salt (100 mL) and the organic solution was washed by a saturated
solution of sodium hydrogen carbonate (3 × 50 mL), dried
over sodium sulfate and concentrated under reduced pressure.
The crude material was filtered through a silica gel plug (eluent
cyclohexane–ethyl acetate, 7 : 3) and the resulting yellow oil was
◦
purified by Kugelrohr distillation (bp ca. 130 C–0.1 Torr)17,22
obtaining a light yellow oil (1.2 g, 5.4 mmol, yield 56%).
NMR dH (200 MHz, CDCl3) 2.90–3.01 (2 H, m, CH2), 3.65
(2 H, AB, JAB = 20.0 Hz, CH2), 4.48 (1 H, t, J = 6.6 Hz, CH), 7.01
(1 H, d, J = 7.0 Hz, ArH), 7.12–7.36 (8 H, m, ArH); IR (nujol)
mmax/cm−1 1720 (CO); ESI-MS (m/z) 223 (M + 1).
Scheme 4 Proposed mechanism.
There are certain advantages to our synthetic approach
(Scheme 3) over the previous routes as presented and all of
them can be included within the concepts of “atom economy”20
and “step economy”.21 Indeed precise control over the individual
reactivity of functional groups (chemoselectivity) without the need
to use protecting groups or useless interconversions of functional
groups, has been achieved increasing the brevity and efficiency of
the synthesis (only three steps and a high overall yield of 38%).
( )-N-(4-Phenyl-3,4-dihydronaphthalen-2-yl) propionamide (10)
To a 50 mL round-bottom flask equipped with a Dean–Stark
apparatus were introduced the tetralone 4 (1.5 g, 6.8 mmol, 1
equiv.), the propionamide (1.2 g, 16.9 mmol, 2.5 equiv.) and p-
toluenesulfonic acid (0.13 g, 0.7 mmol, 0.1 equiv.) in 30 mL
of toluene. The mixture was refluxed for 4 h under a nitrogen
atmosphere. After cooling down to room temperature, the pro-
pionamide was precipitated and filtered off. The organic solution
was washed by a saturated solution of sodium hydrogen carbonate
(3 × 50 mL) and water (3 × 50 mL), dried over sodium sulfate and
concentrated under reduced pressure. The enamide 10 was purified
by chromatography on silica gel (eluent cyclohexane–ethyl acetate,
7 : 3) and re-crystallized (diethyl ether–petroleum ether) obtaining
a light yellow solid (1.78 g, 6.4 mmol, yield 95%).
Conclusion
In summary, we have developed a new, practical and convenient
protocol for the synthesis of the MT2 melatonin receptor antag-
onist cis-4-P-PDOT, improving yields and reducing the time and
cost of the procedure, making the compound more easily accessible
for further biological evaluations.
NMR dH (200 MHz, CDCl3) 1.18 (3 H, t, J = 7.6 Hz,
NHCOCH2CH3), 2.29 (2 H, q, J = 7.6 Hz, NHCOCH2CH3),
2.70 (1 H, dd, J1 = 16.0 Hz, J2 = 9.4 Hz, C3Ha), 2.77 (1 H, dd,
J1 = 16.0 Hz, J2 = 7.6 Hz, C3Hb), 4.21 (1 H, t, J = 8.2 Hz,
CHPh2), 6.42 (1 H, br s, NH), 6.79 (1 H, d, J = 7.6 Hz, C1H), 7.01
(1 H, td, J1 = 7.4 Hz, J2 = 1.6 Hz, ArH), 7.11–7.32 (8 H m, ArH);
dC (50 MHz, CDCl3) 9.5, 30.7, 36.0, 44.3, 111.2, 126.0, 126.4,
126.7, 127.1, 127.4, 128.3, 128.6, 133.4, 134.9, 135.2, 143.6, 172.4;
Experimental
General
Melting points were determined on a Bu¨chi B-540 capillary
melting point apparatus and are uncorrected. 1H NMR and
13C NMR spectra were recorded on a Bruker AVANCE 200
spectrometer, using CDCl3 as solvent unless otherwise noted.
Chemical shifts (d scale) are reported in parts per million (ppm)
relative to the central peak of the solvent. Coupling constants
IR (nujol) mmax/cm−1 3337 (NH), 1655 (C C); ESI-MS (m/z): 278
=
(M + 1); mp 123–124 ◦C.
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( )-cis-N-(4-Phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)
propionamide (1)
C1Ha/Da), 3.19–3.27 (0.5 H, m, C1Hb/Db), 4.24 (1 H, dd, J1 =
5.6 Hz, J2 = 11.6 Hz, C4H), 4.31–4.44 (1 H, m, C2H), 5.54 (1 H,
br d, J = 7.4 Hz, NH), 6.80 (1 H, d, J = 7.4 Hz, ArH), 7.01–
7.34 (8 H, m, ArH); dC (50 MHz, CDCl3) 9.9, 29.9, 36.5 (1 C, t,
J = 19.0 Hz), 40.4, 45.5, 46.1, 126.23, 126.27, 126.5, 128.6, 128.7,
129.1, 129.5, 134.9, 138.8, 146.0, 173.2; IR (nujol) mmax/cm−1 3291
(NH), 3023 (ArH), 1671 (CO); ESI-MS (m/z): 281 (M + 1); mp
171–173 ◦C.
A solution of enamide 10 (0.07 g, 0.25 mmol, 1 equiv.) in
CF3COOH (2 mL) was cooled down to −10 ◦C and triethylsilane
was added dropwise (0.4 mL, 2.5 mmol, 10 equiv.). After
10 minutes the reaction was completed and a saturated solution
of sodium hydrogen carbonate was carefully added until the
pH was neutral. The mixture was extracted by dichloromethane
(3 × 50 mL) and the organic solution was washed by brine
(3 × 50 mL). The resulting organic solution was dried over
sodium sulfate and concentrated under reduced pressure. The
crude material was purified by flash chromatography (silica gel,
eluent cyclohexane–ethyl acetate, 7 : 3) to yield a mixture of cis- and
trans-diastereoisomers (cis–trans ratio 81 : 19, 0.064 g, 0.23 mmol,
yield 91%). The pure cis-1 (0.05 g, 0.18 mmol, yield 71%) can be
obtained by a single re-crystallization (acetone–n-hexane).
Acknowledgements
This work was supported by the Italian M. I. U. R. (Ministero
dell’Istruzione, dell’Universita` e della Ricerca). We would like to
thank Prof. Giuseppe Diamantini for analytical support.
References
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NMR dH (200 MHz, CDCl3) 1.15 (3 H, t, J = 7.6 Hz,
NHCOCH2CH3), 1.79 (1 H, apt q, J = 11.6 Hz, C3Ha), 2.22
(2 H, q, J = 7.6 Hz, NHCOCH2CH3), 2.37–2.46 (1 H, m, C3Hb),
2.79 (1 H, dd, J1 = 11.0 Hz, J2 = 15.8 Hz, C1Ha), 3.23 (1 H, ddd,
J1 = 1.8 Hz, J2 = 5.3 Hz, J3 = 15.8 Hz, C1Hb), 4.25 (1 H, dd, J1 =
5.5 Hz, J2 = 11.5 Hz, C4H), 4.32–4.46 (1 H, m, C2H), 5.54 (1 H,
brs d, J = 7.1 Hz, NH), 6.80 (1 H, d, J = 7.4 Hz, ArH), 7.01–7.37
(8 H, m, ArH); dC (50 MHz, CDCl3) 9.8, 29.8, 36.8, 40.4, 45.6,
46.1, 126.21, 126.24, 126.4, 128.56, 128.64, 129.0, 129.5, 134.9,
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The compound cis-1a was synthesized by reduction of 10 by
triethyl(silane-d) (TESD) following the procedure described above.
The pure cis-1a (yield 70%) was obtained by re-crystallization
(acetone).
dH (200 MHz, CDCl3) 1.15 (3 H, t, J = 7.6 Hz, NHCOCH2CH3),
1.79 (1 H, apt t, J = 12.0 Hz, C3Ha), 2.22 (2 H, q, J = 7.6 Hz,
NHCOCH2CH3), 2.41 (1 H, ddd, J1 = 12.4 Hz, J2 = 5.8 Hz, J3 =
2.1 Hz, C3Hb), 2.80 (1 H, d, J = 15.6 Hz, C1Ha), 3.22 (1 H, d, J =
15.6 Hz, C1Hb), 4.24 (1 H, dd, J1 = 5.6 Hz, J2 = 11.2 Hz, C4H),
5.62 (1 H, br s, NH), 6.79 (1 H, d, J = 7.5 Hz, ArH), 7.00–7.36
(8 H, m, ArH); dC (50 MHz, CDCl3) 9.9, 29.8, 36.8, 40.3, 45.3
(1 C, t, J = 21.5 Hz), 46.1, 126.24, 126.26, 126.5, 128.6, 128.7,
129.1, 129.5, 135.0, 138.7, 146.0, 173.2; IR (nujol) mmax/cm−1 3291
(NH), 3026 (ArH), and 1670 (CO); ESI-MS (m/z): 281 (M + 1);
mp 172–174 ◦C.
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( )-cis-N-(1-Deutero-4-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)
propionamide (cis-1b)
The compound cis-1b was synthesized by reduction of 10 by
triethylsilane using trifluoroacetic acid-d as a solvent following
the procedure described above. The pure cis-1b (yield 67%) was
obtained by re-crystallization (acetone).
dH (200 MHz, CDCl3) 1.15 (3 H, t, J = 7.6 Hz, NHCOCH2CH3),
1.78 (1 H, apt q, J = 11.7 Hz, C3Ha), 2.21 (2 H, q, J = 7.6 Hz,
NHCOCH2CH3), 2.36–2.47 (1 H, m, C3Hb), 2.75–2.86 (0.5 H, m,
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150 | Org. Biomol. Chem., 2008, 6, 147–150
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