Diastereo- and enantioselective hydrogenation of a challenging enamide derived from 4-phenyl-2-tetralone: An appealing shortcut towards enantiopure cis-2-aminotetraline derivatives

Article abstract of DOI:10.1002/asia.200900441

A clean, efficient, and diasteroselective (dr >95%) catalytic hydrogenation of the enamide N-(4- phenyl-3, 4-dihydronaphthalen-2-yl) propionamide (2a) using palladium on carbon is performed. This procedure provides the melatonin receptor ligand (±)-cis-4-

Full text of DOI:10.1002/asia.200900441

FULL PAPERS
DOI: 10.1002/asia.200900441
Diastereo- and Enantioselective Hydrogenation of a Challenging Enamide
Derived from 4-Phenyl-2-tetralone: An Appealing Shortcut Towards
Enantiopure cis-2-Aminotetraline Derivatives
Simone Lucarini,* Matteo Alessi, Annalida Bedini, Giorgia Giorgini,
Giovanni Piersanti,* and Gilberto Spadoni[a]
Dedicated to the 150th anniversary of Japan–UK diplomatic relations
Abstract: A clean, efficient, and dia-
steroselective (dr >95%) catalytic hy-
drogenation of the enamide N-(4-
phenyl-3,4-dihydronaphthalen-2-yl)pro-
pionamide (2a) using palladium on
carbon is performed. This procedure
provides the melatonin receptor ligand
(Æ)-cis-4-phenyl-2-propionamidotetra-
lin (cis-4-P-PDOT, 1a) and its 8-me-
thoxy analog. Furthermore, Rh and Ru
catalyzed homogeneous asymmetric
hydrogenation of the challenging race-
mic endocyclic enamide 2a with sever-
al chiral phosphine ligands is studied.
The best results, in terms of enantiose-
lectivity, for both diastereomers are ob-
tained when chiral Rh-Josiphos is used
as the catalyst.
Keywords: asymmetric synthesis ·
diastereoselectivity
· enamides ·
hydrogenation · rhodium
Introduction
(cis-4-P-PDOT, cis-1a).[6] The synthesis involved the ionic
reduction of the cyclic enamide, (Æ)-N-(4-phenyl-3,4-dihy-
dronaphthalen-2-yl)propionamide (2a) with Et3SiH (TES)
in trifluoroacetic acid (TFA) as the key step. We now de-
scribe a more complete study of the diasteroselective reduc-
tion of enamide 2a using different reducing agents (hydrides
and hydrogen) (Scheme 1). Moreover, as cis- and trans-4-P-
PDOT display different MT2 binding affinities (pKi 10.80 vs.
8.45, respectively),[7] it would be particularly interesting to
synthesize both cis-enantiomers to find out the eutomer.
Among all of the possible approaches, asymmetric catalysis
is the method of choice for the synthesis of enantiopure
compounds. In particular, transition metal-catalyzed asym-
metric hydrogenation is now the most reliable and widely
used synthetic tool for rapid access to optically active mole-
cules.[8] Accordingly, asymmetric catalytic hydrogenation of
trisubstituted endocyclic enamide 2a has been envisioned
(Scheme 1).
The reduction of organic compounds is perhaps the most
common type of reaction used in organic synthesis.[1] Un-
questionably, hydrogen is the cleanest reducing agent and
hydrogenation is the most important heterogeneous and ho-
mogeneous catalytic method used in synthetic organic
chemistry both on a laboratory and an industrial scale.[2] Re-
cently, asymmetric hydrogenation of prochiral functionalized
olefins, ketones, and imines, has been shown to be one of
the most effective and powerful methods for the synthesis of
chiral compounds in numerous applications.[3] Among func-
tionalized olefins, enamides, which are stable enamine surro-
gates,[4] have gained particular attention as useful intermedi-
ates for the preparation of many biologically active amines
with high optical purity.[5] Recently, we have reported a con-
venient protocol for the gram-scale synthesis of one of the
most interesting melatonin MT2 selective ligand, (Æ)-cis-N-
(4-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)propionamide
Despite the fact that 4-substituted-2-aminotetraline deriv-
atives display several interesting medicinal properties,[9] a lit-
[a] Dr. S. Lucarini, M. Alessi, A. Bedini, G. Giorgini, Dr. G. Piersanti,
Prof. G. Spadoni
Institute of Medicinal Chemistry
University of Urbino “Carlo Bo”
Piazza Rinascimento 6, 61029 Urbino (PU) (Italy)
Fax : (+39)722-303313
E-mail: simone.lucarini@uniurb.it
giovanni.piersanti@uniurb.it
Scheme 1. Key step to the synthesis of MT2 selective ligand cis-4-P-
PDOT (1a).
550
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 550 – 554

erature search revealed a surprising lack of precedents on
the use of hydrogenation (asymmetric and symmetric) as a
synthetic approach to the target structures. It appears that
even the cyclic enamides and encarbamates derived from 4-
unsubstituted-2-tetralone are very challenging substrates
employed as standards for testing new asymmetric hydroge-
nation methods. There are only a few ruthenium-[10] and rho-
dium-based[11] catalysts known to reduce these molecules
with moderate to good enantioselectivities. Only one exam-
ple, reported by the Reek group, claimed a 94% ee for the
reduction of commercially available N-(3,4-dihydro-naph-
thalen-2-yl)acetamide by a rhodium-based supramolecular
catalyst. A combinatorial approach combined with high-
throughput screening technique was used in this study.[11e]
The trisubstituted endocyclic enamide 2a, which contains a
stereogenic carbon center, is an even more complicated sub-
strate and requires a catalytic system that can overcome the
intrinsic substrate bias. In other words, the optimal catalyst
would potentially yield 50% of both enantiopure cis- and
trans-4-P-PDOT.[12]
worked at À108C in TFA, to afford the desired cis-4-P-
PDOT in 91% yield and 4:1 diastereoselectivity (entry 2).[6]
However, the reaction needed a strong Bronsted acid as a
solvent and proceeded slowly in the presence of a co-solvent
and/or with a decrease in the temperature (entries 1 and 3).
This would preclude application to more sensitive substrates,
as well as an asymmetric approach. When we attempted to
replace the TFA with a catalytic amount of Lewis acid, such
as ScACHTNUTGRENNG(U OTf)3 (entry 4), BiCAHTUNGTREN(NUGN OTf)3, and InCl3, only trace
amounts of product were obtained. Using different silanes
(entries 5 and 6), the reaction worked smoothly to give the
corresponding product with results comparable to those ob-
tained on using only TFA as the solvent. Interestingly, steri-
cally hindered tris(trimethylsilyl)silane lowered the cis/trans
ratio (dr=63%). We also tried the reaction with other hy-
dride reducing agents. Sodium borohydride, sodium cyano-
borohydride (entry 7), and sodium triacetoxy borohydride
worked well in the presence of TFA with results similar to
using TES. Lithium borohydrides (superhydride and l-selec-
tride), lithium aluminum hydrides, alanes, and borane either
gave complicated reaction mixtures or did not work at all.
As expected, upon using stronger hydride donors, the amide
moiety interferes with the double bond reduction and so the
corresponding amine and tetralone 3a were the main prod-
ucts. Tetralone 3a was also obtained when zinc powder in
TFA was used as the reducing agent at 808C for 16 h
(entry 10). One possible explanation could be that the
amide moiety was first reduced to give the enamine inter-
mediate, which then hydrolyzed to the tetralone. Trace
amounts of 1a were also obtained while using Hantzsch
ester in TFA (entry 11), whereas using a thiourea derivative
as a substoichiometric Bronsted acid in chloroform did not
work at all (entry 12). On the contrary, a quantitative yield
of cis-4-P-PDOT with a 95% diastereomeric ratio was ob-
tained in only 5 min using hy-
With all of this in mind, herein we document the optimi-
zation of the diastereoselective reduction of the racemic en-
amide 2a and the first preliminary studies towards its enan-
tioselective hydrogenation using ruthenium- and rhodium-
based catalysts.
Results and Discussion
The most significant results obtained for the diastereoselec-
tive reduction of enamide 2a are reported in Table 1.
First, we tried to improve the diastereoselectivity and
identify more viable reaction conditions for the reduction of
enamide 2a. The reported ionic reduction using TES
drogen (4 atm) with a catalytic
amount of palladium on carbon
Table 1. Optimization of diastereoselective reduction of racemic 2a.
(10%) at room temperature
(entry 13). The Pd-catalyzed hy-
drogenation of enamide 2a im-
proved the total yield for the
Entry
Reductant
Conditions
Yield[a]
dr cis/trans[b]
three step synthesis of cis-4-P-
PDOT from 38% to 51% (see
Scheme 2). This synthetic ap-
proach was also applied to the
synthesis of a new melatonin
receptor tetralin ligand (1b)
that bears a methoxy substitu-
ent in a position topologically
equivalent to the 5-methoxy
group of melatonin, essential
for biological activity. In this
case, in order to obtain the tet-
ralone 3b, we needed to change
the order of addition of the re-
agents.[13] We speculated that 2-
methoxyphenylacetyl chloride
1
2
3
4
5
6
7
8
TES[c]
CH3COOH, RT,16 h
n.r.[d]
91
trace
trace
97
–
TES[c]
CF3COOH, À108C, 20 min
81:19
–
–
71:29
63:37
80:20
–
–
–
–
–
TES[c]
CF3COOH/MeOH, À788C, 5 h
TES[c]
ScN
Me2PhSiH
CF3COOH, RT, 20 min
CF3COOH, RT, 20 min
CF3COOH/MeOH, 08C, 16 h
THF, RT, 16 h
A
98
NaCNBH3
95
l-selectride[e]
n.r.[d]
[g]
9
Red-Al[f]
THF, RT, 16 h
–
–
[h]
10
11
12
13
Zinc powder
Hantzsch ester[i]
Hantzsch ester[i]
H2 (4 atm)
CF3COOH, 808C, 16 h
CF3COOH, RT, 16 h
trace
n.r.[d]
>99
Thiourea[j], CHCl3, RT, 16 h
10% Pd/C, MeOH, RT, 5 min
95:5
[a] Yield of isolated product. [b] Determined by HPLC and confirmed by 1H NMR. [c] Triethyl silane. [d] No
reaction. [e] Li(sec-Bu)3BH 1m solution in THF. [f] Na(MeOCH2CH2O)2AlH2 1m solution in THF. [g] Enam-
ine and amine derived from the reduction of 2a were also observed together with the starting material by
HPLC-MS analysis. [h] Tetralone 3a was the main product by HPLC-MS analysis. [i] Diethyl 1,4-dihydro-2,6-
ACHTUNGTRENNUNG
dimethyl-3,5-pyridinedicarboxylate. [j] 1,3-bisACTHNUTRGNE[UNG 3,5-bis(trifluoromethyl)-phenyl]thiourea, (30%).
Chem. Asian J. 2010, 5, 550 – 554
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
551

S. Lucarini, G. Piersanti et al.
FULL PAPERS
The solvent played a role in the reaction and dichlorome-
thane gave the highest yield and enantioselectivity values
for both cis and trans isomers. A decrease in the tempera-
ture caused the reaction to slow down and after 24 h at 08C,
only 10% conversion was obtained with similar selectivity
(entry 5). Hydrogenation with a preformed (S)-BINAP-
[16]
RuBr2 catalyst required a higher pressure of hydrogen to
give acceptable conversion (entry 6 vs. entry 7). In addition,
a strong 4-phenylsubstituent bias gave predominately the
cis-diastereomer.
Several rhodium–phosphine complexes have been devel-
oped as efficient catalysts for the asymmetric hydrogenation
of acyclic enamides but only limited success has been ach-
ieved for the hydrogenation of cyclic enamides. Therefore,
the asymmetric hydrogenation of the cyclic enamide 2a with
several rhodium-ligand complexes was explored. Rational
selection of the commercially available chiral phosphines
was done on the basis of different factors, such as monoden-
tate or bidentate, steric–electronic effects, bite angle and C1
or C2 symmetry for bidentate ligands, and chirality on the
backbone or on phosphorus atoms. The most interesting re-
sults are reported in Table 3. As expected, C3-Tunephos
gave results comparable to the BINAP-Rh-based hydroge-
nation, whereas the monodentate phosphine Ph-BINEPINE
gave low enantioselectivity values. On the contrary, the com-
mercially available monodentate phosphoramidate, MONO-
PHOS, was unreactive. Bisphosphine ligands seem to be es-
sential in order to achieve enantioselectivity. However, the
central chiral-based bisphosphines, TANGPHOS, Me-
DUPHOS, and Quinoxaline did not provide the correspond-
ing product with good enantioselectivity.
Scheme 2. Synthesis of (Æ)-cis-1a and 1b. Reagents and conditions:
a) styrene, AlCl3, CH2Cl2, 08C, 30–45 min; b) Propionamide, PTSA
(10%), toluene, reflux using Dean–Stark apparatus, 2–3 h; c) H2 (4 atm),
Pd/C (10%), MeOH, RT, 5–10 min.
in the presence of a Lewis acid may undergo a self Friedel–
Craft acylation or, more likely, the AlCl3 may coordinate to
the more basic methoxy group, and thus lower the yield of
the reaction.
Given the excellent results obtained for the heterogene-
ous catalytic hydrogenation experiments, we decided to try
asymmetric approaches. The homogeneous hydrogenation of
enamide 2a at 1 atm using RhACHTUNTRGNEUNG(COD)2BF4 (10%) and PPh3
(20%) (at room temperature for 14 h) gave the correspond-
ing product in quantitative yield with a diastereomeric ratio
of 72%.
As the homogeneous Rh-catalysis was less affected by the
intrinsic substrate bias and slower than the heterogeneous
Pd/C-catalysis, we explored other combinations of metals
and ligands. The first chiral ligand tested was the well-
known bisphosphine (R)-(+)-BINAP, and the results are re-
ported in Table 2.
We were delighted to find that the C1 symmetrical Josi-
phos (R,S)-PPF-PtBu2-Rh-based catalyst worked well and
gave amide 1a in excellent yield and agreeable ee values
(64% and 76% ee for the cis and trans isomers, respective-
ly).[14] Even though the procedure is still not optimal, these
results encourage further stud-
Different solvents, temperatures, reaction times and cata-
lyst loadings were evaluated using the Rh-based catalyst.
ies.
Table 2. (R)-BINAPRhBF4 and (S)-BINAPRuBr2 hydrogenation of racemic 2a.
Conclusions
We have reported an almost
complete diastereoselective hy-
drogenation of endocyclic en-
amides derived from 4-phenyl-
2-tetralone using heterogeneous
palladium catalyzed hydrogena-
tion to give the racemic melato-
nin ligand cis-4-P-PDOT in a
cleaner, easier, and scalable
way. We have also reported the
asymmetric hydrogenation stud-
ies of the trisubstituted endocy-
clic chiral enamide 2a to pro-
vide cis-4-P-PDOT and trans-4-
Entry
Catalyst
T [8C], t [h]
Solvent
Yield[a]
dr[b]
ee[b]
cis
trans
1
2
3
4
(R)-BINAPRhBF4
45, 48
40, 20
35, 22
35, 18
0, 24
MeOH
Toluene
THF
95
74
88
98
10
15
69
69
79
74
57
50
91
97
17
17
19
35
35
65
49
38
57
53
50
50
53
50
CH2Cl2
MeOH
5
6
(S)-BINAPRuBr2
35, 16
50, 16
7[c]
[a] Yield of isolated product. [b] cis/trans and ee ratio were determined by chiral HPLC. [c] The reaction was
performed with H2 at 6 atm.
P-PDOT with
64%
and
552
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 550 – 554

Enantiopure Aminotetraline Derivatives
Table 3. Rh-based enantioselective hydrogenation of racemic 2a.[a]
(H,H)=8.1 Hz, 1H, ArH), 7.08–7.35 ppm (m, 6H, ArH); 13C NMR
ACHTUNGTRENNUNG
(50 MHz, CDCl3, 258C, TMS): d=38.2, 45.4, 46.5, 55.4, 108.4, 120.6,
122.2, 126.9, 127.4, 127.8, 128.8, 139.9, 142.2, 156.8, 209.5 ppm; MS (ESI):
m/z (%): 253 (100) [M+1]; elemental analysis: calcd (%) for C17H16O2
(252.3): C 80.93, H 6.39; found: C 80.78, H 6.35.
Phosphine
Chirality Yield[b] dr[c]
ee[c]
cis/trans cis trans
(R)-C3-TUNEPHOS
(S)-Ph-BINEPINE[d]
(R)-MONOPHOS[d]
Axial
92
92
trace
89
71
60
82
–
57
74
62
32 53
7
–
24 41
6
1
10
–
(Æ)-N-(8-Methoxy-4-phenyl-3,4-dihydronaphthalen-2-yl)propionamide
(2b): A solution of tetralone 3b (1.72 g, 6.8 mmol), propionamide (1.2 g,
16.4 mmol), and p-toluene sulfonic acid (0.13 g, 0.7 mmol) in toluene
(30 mL) was refluxed for 4 h under nitrogen atmosphere in a 50 mL
round-bottom flask equipped with a Dean Stark apparatus. After cooling
to room temperature, the unreacted propionamide precipitated, was fil-
tered off, and washed with cold toluene (2ꢂ2 mL). The resulting organic
phase was washed with a saturated solution of NaHCO3 (3ꢂ50 mL) and
water (3ꢂ50 mL), dried over Na2SO4 and concentrated under reduced
pressure. The crude enamide 2b was purified by flash chromatography
(silica gel, cyclohexane/EtOAc=7:3) followed by crystallization to give a
white solid (52% yield). Rf =0.32 (cyclohexane/EtOAc=7:3); m.p.: 195–
68C (acetone/Et2O); UV/Vis (MeOH): lmax =262, 269 nm; IR (nujol): n˜ =
T
Central
N
64
22
E
85
G
Planar
+
95
98
91
79
59
52
49
64
20 19
64 76
26 24
13 29
Josiphos (R,S)-PPF-PtBu2
Josiphos (R,S)-cy2PF-PtBu2
Josiphos (R,S)-PPF-Pxyl2
Central
[a] Reaction conditions: [RhACHTNUTRGNEU(GN COD)2BF4]-chiral phosphine (1:1.1, 10%
cat. loading), H2 (1 atm), 358C, CH2Cl2, 16 h. [b] Yield of isolated prod-
uct. [c] Determined by chiral HPLC. [d] Rh/monodentate ligand=1:2.1
ratio was used.
À1
1
À
3344 (N H), 1662 cm (C=O); H NMR (200 MHz, CDCl3, 258C, TMS):
d=1.18 (t, 3J(H,H)=7.4 Hz, 3H, NHCOCH2CH3), 2.29 (q, 3J
(H,H)=
7.4 Hz, 2H, NHCOCH2CH3), 2.68–2.95 (m, 2H, C3H2), 3.85 (s, 3H,
OMe), 4.18 (dd, 3J(H,H)=7.3, 8.7 Hz, 1H, CHPh2), 6.44 (d, 3J
(H,H)=
7.6 Hz, 1H, ArH), 6.54 (brs, 1H, NH), 6.74 (d, 3J
(H,H)=8.2 Hz, 1H,
ArH), 7.00 (dd, 3J
(H,H)=7.6, 8.1 Hz, 1H, ArH), 7.20–7.35 ppm (m, 6H,
N
ACHTUNGTRENNUNG
76% ee, respectively, using the Rhodium-(R,S)-PPF-PtBu2
Josiphos catalytic system. This is the first example of enan-
tioselective hydrogenation of an enamide derived from 4-
substituted-2-tetralones, a scaffold widely employed in me-
dicinal chemistry. Biological studies on the enantio-enriched
cis- and trans-4-P-PDOT are now underway and the results
will be reported in the near future.
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ArH+C1H); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=9.5, 30.8, 35.3,
44.4, 55.5, 109.0, 120.0, 123.6, 126.4, 126.6, 128.3, 128.5, 130.0, 133.0,
136.5, 143.6, 154.7, 172.1 ppm; MS (ESI): m/z (%): 308 (100) [M+1]; ele-
mental analysis: calcd (%) for C20H21NO2 (307.4): C 78.15, H 6.89,
N 4.56; found: C 78.26, H 6.86, N 4.53.
General procedure for Pd/C catalytic hydrogenation of enamides 2a and
2b: A solution of enamide (0.5 mmol) in methanol (12 mL) was hydro-
genated over 10% Pd/C (14 mg) at 4 atm of H2 for 5–10 min at room
temperature. The catalyst was filtered off over a celite plug and washed
with methanol (3ꢂ5 mL). The filtrate was concentrated under reduced
pressure to afford the crude tetraline which was directly purified by crys-
tallization.
Experimental Section
General Methods
Melting points were determined on a Bꢁchi B-540 capillary melting point
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were re-
corded 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 (J values) are given in Hertz (Hz). ESI-MS spectra were re-
corded on a Waters Micromass ZQ instrument. Only molecular ions
(M+1) are given. High-performance liquid chromatography was carried
out on the following apparatus: Shimadzu LC-10AT (liquid chromato-
graph), Shimadzu SPD-10A (UV detector), and Shimadzu C-R6A Chro-
matopac. Infrared spectra were obtained on a Nicolet Avatar 360 FTIR
spectrometer, and the transmittance is reported in cmÀ1. Column chroma-
tography purifications were performed under “flash” conditions using
Merck 230–400 mesh silica gel. Analytical thin-layer chromatography
(TLC) was carried out on Merck silica gel 60 F254 plates and preparative
thin-layer chromatography was carried out using Merck silica gel 60 F254
0.5 mm PTLC plates (20ꢂ20 cm). All chemicals were purchased from
commercial suppliers and used directly without any further purification.
(Æ)-cis-N-(4-Phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)propionamide
(1a): The physical-chemical properties were identical with those previ-
ously reported.[7]
(Æ)-cis-N-(8-Methoxy-4-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)propio-
namide (1b): White solid (68% yield). m.p.: 220–28C (acetone/n-
hexane); Rf =0.35 (dichloromethane/acetone=95:5); IR (nujol): n˜ =3336
À1
1
À
(N H), 1646 cm (C=O); UV/Vis (MeOH): lmax =273, 281 nm; H NMR
(200 MHz, CDCl3, 258C, TMS): d=1.15 (t, 3J
(H,H)=7.6 Hz, 3H,
NHCOCH2CH3), 1.75 (apt q, J
(H,H)=11.9 Hz, 1H, C3Ha), 2.18 (q, 3J-
(H,H)=7.6 Hz, 2H, NHCOCH2CH3), 2.35–2.49 (m, 2H, C3Hb+C1Ha),
3.34 (dd, 2J(C1Hb,C1Ha)=16.0 Hz, 3J
(C1Hb,C2H)=5.4 Hz, 1H, C1Hb),
3.84 (s, 3H, OMe), 4.24 (dd, 3J
(H,H)=5.1, 11.2 Hz, 1H, C4H), 4.32–4.36
(m, 1H, C2H), 5.44 (brd, 3J(H,H)=7.8 Hz, 1H, NH), 6.40 (d, 3J
(H,H)=
7.8 Hz, 1H, ArH), 6.69 (d, 3J(H,H)=8.1 Hz, 1H, ArH), 7.03 (dd, 3J-
(H,H)=7.8, 8.1 Hz, 1H, ArH), 7.22–7.34 ppm (5H, m, ArH); 13C NMR
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(50 MHz, CDCl3, 258C, TMS): d=9.9, 29.9, 30.7, 39.9, 45.5, 46.2, 55.3,
107.2, 121.6, 124.1, 126.4, 128.4, 128.5, 128.6, 140.1, 146.0, 156.9,
173.1 ppm; MS (ESI): m/z (%): 310 (100) [M+1]; elemental analysis:
calcd (%) for C20H23NO2 (309.4): C 77.64, H 7.49, N 4.53; found: C 77.59,
H 7.47, N 4.51.
Syntheses
(Æ)-8-Methoxy-4-phenyl-3,4-dihydronaphthalen-2
ACHTUNGTREN(NUNG 1H)-one (3b): Anhy-
drous aluminium trichloride (1.6 g, 12 mmol) was added to a solution of
freshly distilled styrene (0.69 mL, 6 mmol) and 2-methoxyphenylacetyl
chloride[15] (1.1 g, 6 mmol) in dry CH2Cl2 (100 mL) under nitrogen at
08C. The resulting mixture was stirred at 08C for a further 15 mins and
then quenched by a saturated solution of Seignette salt (100 mL). The or-
ganic phase was washed with a saturated solution of NaHCO3 (3ꢂ
50 mL), dried over Na2SO4 and concentrated under reduced pressure to
afford the crude tetralone 3b, which was purified by flash chromatogra-
phy (silica gel, cyclohexane/EtOAc=9:1) to give an oil (35% yield). Rf =
0.3 (cyclohexane/EtOAc=9:1); UV/Vis (MeOH): lmax =271, 279 nm;
General procedure for the Rhodium-catalyzed asymmetric hydrogenation
of enamide 2a: A Schlenk tube placed in a glove box was charged with
the opportune chiral ligand (0.027 mmol, 0.11 eq), bis(cyclooctadiene)r-
hodium tetrafluoroborate [RhACHTNUTRGNE(NUG COD)2BF4] (9.7 mg, 0.024 mmol, 0.10 eq),
and the enamide 2a (67 mg, 0.242 mmol, 1 eq). The tube was then taken
out from the glove box and charged with the appropriate degassed sol-
vent (4 mL) under argon. The resulting mixture was stirred for 15 min at
358C and the solution color turned to yellow-brown. The argon atmos-
phere was replaced with hydrogen (1 atm) and the reaction was stirred at
a suitable temperature until completion. The reaction mixture was fil-
tered over a celite plug and the solvent was removed under reduced pres-
sure. Diastereomeric ratio and enantiomeric excess were determined by
1H NMR (200 MHz, CDCl3, 258C, TMS): d=2.94 (d, 3J
2H, CH2), 3.59 (m, 2H, CH2), 3.87 (s, 3H, OMe), 4.47 (t, 3J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
6.2 Hz, 1H, CHPh2), 6.66 (d, 3J
ACHTUNGTRENNUNG
Chem. Asian J. 2010, 5, 550 – 554
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
553

S. Lucarini, G. Piersanti et al.
FULL PAPERS
HPLC on a Chiralcel (Chiralpak) AD-H column, with hexane/iPrOH=
Synth. Catal. 2002, 344, 1003–1007; d) C. Nꢄjera, J. M. Sansano,
Chem. Rev. 2007, 107, 4584–4671. For a recent example, see: e) J.
Chen, W. Zhang, H. Jeng, W. Li, G. Hou, A. Lei, X. Zhang, Angew.
Chem. 2009, 121, 814–816; Angew. Chem. Int. Ed. 2009, 48, 800–
802.
19:1 as eluent, flux 1.0 mLminÀ1
, l=262 nm; trans-4-P-PDOT: tr1=
10.8 min, tr2=14.5 min; cis-4-P-PDOT: tr1=17.5 min, tr2=21.7 min. The
crude material was purified by flash chromatography (silica gel, cyclohex-
ane/EtOAc=7:3) to afford the cis- and trans-4-P-PDOT as a mixture
(yield of isolated product, see Tables 2 and 3). A little amount of pure
cis-4-P-PDOT and trans-4-P-PDOT were obtained by purification of the
diastereomeric mixture using preparative thin layer chromatography (di-
chloromethane/acetone=95:5).[7]
[6] S. Lucarini, A. Bedini, G. Spadoni, G. Piersanti, Org. Biomol. Chem.
2008, 6, 147–150.
[7] G. Gatti, G. Piersanti, G. Spadoni, Farmaco 2003, 58, 469–476.
[8] a) H.-J. Federsel, Nat. Rev. Drug Discovery 2005, 4, 685–697;
b) C. S. Shultz, S. W. Krska, Acc. Chem. Res. 2007, 40, 1320–1326;
N. B. Johnson, I. C. Lennon, P. H. Moran, J. A. Ramsden, Acc.
Chem. Res. 2007, 40, 1291–1299.
[16]
Procedure for the (S)-BINAPRuBr2 catalyzed asymmetric hydrogena-
tion of enamide 2a: A Schlenk tube placed in a glove box was charged
with (S)-BINAP (16 mg, 0.024 mmol, 0.10 eq) and (cyclooctadiene)-bis(2-
[9] a) V. Soskic, J. Joksimovic, Curr. Med. Chem. 1998, 5, 493–512;
b) G. Bertolini, V. Vecchietti, M. Mabilia, G. Norcini, A. Restelli, F.
Santangelo, A. M. Villa, C. Casagrande, Eur. J. Med. Chem. 1992,
27, 663–672; c) R. G. Booth, J. A. Gingrich, PCT Int. Appl. WO
2009061436, 2009; d) S. D. Wyrick, R. G. Booth, A. M. Myers, C. E.
Owens, E. C. Bucholtz, P. C. Hooper, N. S. Kula, R. J. Baldessarini,
R. B. Mailman, J. Med. Chem. 1995, 38, 3857–3864; e) M. L. Dubo-
covich, M. L. Masana, S. Iacob, D. M. Sauri, Naunyn-Schmiedeberg’s
Arch. Pharmacol. 1997, 355, 365–375; f) C. Capone, C. Fabrizi, P.
Piovesan, M. C. Principato, P. Marzorati, O. Ghirardi, L. Fumagalli,
P. Carminati, M. G. De Simoni, Neuropsychopharmacology 2007, 32,
1302–1311.
[10] For examples of Ru-catalyzed hydrogenations of enamides and ene-
carbamates derived from 2-tetralone, see: a) J. L. Renaud, P. Dupau,
A.-E. Hay, M. Guingouain, P. H. Dixneuf, C. Bruneau, Adv. Synth.
Catal. 2003, 345, 230–238; b) P. Dupau, P. Le Gendre, C. Bruneau,
P. H. Dixneuf, Synlett 1999, 1832–1834; c) P. Dupau, C. Bruneau,
P. H. Dixneuf, Adv. Synth. Catal. 2001, 343, 331–334; d) M. Devo-
celle, A. Mortreux, F. Agbossou, J.-R. Dormoy, Tetrahedron Lett.
1999, 40, 4551–4554; e) D. M. Tschaen, L. Abramson, D. Cai, R.
Desmond, U.-H. Dolling, L. Frey, S. Karady, Y.-J. Shi, T. R. Verho-
even, J. Org. Chem. 1995, 60, 4324–4330; f) X. Sala , I. Serrano, M.
Rodriguez, I. Romero, A. Llobet, P. W. N. M. van Leeuwen, Catal.
Commun. 2008, 9, 117–119; g) H. Takaya, T. Ohta, N. Sayo, H. Ku-
mobayashi, S. Akutagawa, S. Inoue, I. Kasahara, R. Noyori, J. Am.
Chem. Soc. 1987, 109, 1596–1597; h) P. Dupau, P. C. Bruneau, P. H.
Dixneuf, Tetrahedron: Asymmetry 1999, 10, 3467–3471.
methylallyl)ruthenium [RuACHTUNTGRENUNG(COD)(MA)2] (8.0 mg, 0.024 mmol, 0.10 eq).
The tube was then taken out from the glove box and charged with de-
gassed and anhydrous acetone (4 mL) under argon. To this suspension, a
solution of HBr (0.22 mL, 0.29m solution prepared by diluting 48% aq
HBr in MeOH) was added and the suspension was stirred at room tem-
perature for 30 min. A yellow solid precipitated. The mixture was evapo-
rated under vacuum and the resulting catalyst was immediately used. The
enamide 2a (67 mg, 0.24 mmol, 1 eq) in anhydrous and degassed MeOH
(4 mL) was successively added to the catalyst. The argon atmosphere was
replaced with hydrogen and the reaction was stirred at the suitable tem-
perature for 16 h. The reaction mixture was filtered over a celite plug
and the solvent was removed under reduced pressure. Diastereomeric
ratio, enantiomeric excess, and isolated yield were determined as report-
ed above.
Acknowledgements
This work was supported by the Italian M.I.U.R. (Ministero dell’Istru-
zione, dell’Universitꢃa e della Ricerca). We would like to thank Dr. Luca
Giorgi and Prof. Franco Cozzi for fruitful discussions. We are grateful to
Prof. Serafino Gladiali for kindly providing a sample of the (S)-Ph-BI-
NEPINE ligand.
[1] P. G. Andersson, I. J. Munslow, Modern Reduction Methods , Wiley-
VCH, Weinheim, 2008.
[11] For examples of Rh-catalyzed hydrogenations of enamides and ene-
carbamates derived from 2-tetralone, see: a) Z. Zhang, G. Zhu, Q.
Jiang, D. Xiao, X. Zhang, J. Org. Chem. 1999, 64, 1774–1775; b) H.
Bernsmann, M. van den Berg, R. Hoen, A. J. Minnaard, G. Mehler,
M. T. Reetz, J. G. de Vries, B. L. Feringa, J. Org. Chem. 2005, 70,
943–951; c) R. Hoen, M. van den Berg, H. Bernsmann, A. J. Min-
naard, J. G. de Vries, B. L. Feringa, Org. Lett. 2004, 6, 1433–1436;
d) F. Guillen, M. Rivard, M. Toffano, J. Y. Legros, J. C. Daran, J.-C.
Fiaud, Tetrahedron 2002, 58, 5895–5904; e) X.-B. Jiang, L. Lefort,
P. E. Goudriaan, A. H. M. de Vries, P. W. N. M. van Leeuwen, J. G.
de Vries, J. N. H. Reek, Angew. Chem. 2006, 118, 1245–1249;
Angew. Chem. Int. Ed. 2006, 45, 1223–1227; f) G. Argouarch, O.
Samuel, H. B. Kagan, Eur. J. Org. Chem. 2000, 2885–2891; g) A. J.
Sandee, A. M. van der Burg, J. N. H. Reek, Chem. Commun. 2007,
864–866.
[2] a) P. N. Rylander, Hydrogenation Methods, Academic Press, New
York, 1990 and preceding volumes; b) M. Freifelder, Practical Cata-
lytic Hydrogenation, Wiley, New York, 1971; c) S. Nishimura, Hand-
book of Heterogeneous Catalytic Hydrogenation for Organic Synthe-
sis, Wiley, New York, 2001; d) M. Yamashita, M. Kobayashi, M. Su-
giura, K. Tsunekawa, T. Oshikawa, S. Inokawa, H. Yamamoto, Bull.
Chem. Soc. Jpn. 1986, 59, 175–178; e) H. G. de Vries, C. J. Elsevier,
Handbook of Homogeneous Hydrogenation, Wiley-VCH, Wein-
heim, 2007.
[3] For some recent books and reviews, see: a) I. Ojima, Catalytic
Asymmetric Synthesis, Wiley-VCH, Weinheim, 2000; b) R. Noyori,
Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994;
c) E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Comprehensive Asym-
metric Catalysis, Vol. 1, Springer, Berlin, 1999; d) G.-Q. Lin, Y.-M.
Li, A. S. C. Chan, Principles and Applications of Asymmetric Synthe-
sis, Wiley, New York, 2001; e) W. Tang, X. Zhang, Chem. Rev. 2003,
103, 3029–3070; f) W. S. Knowles, Angew. Chem. 2002, 114, 2096–
2107; Angew. Chem. Int. Ed. 2002, 41, 1998–2007; g) R. Noyori,
Angew. Chem. 2002, 114, 2108–2123; Angew. Chem. Int. Ed. 2002,
41, 2008–2022.
[12] For an illuminating example of asymmetric hydrogenation of a more
viable racemic encarbamate, derived from 4-aryl-1-tetralone, see: W.
Tang, Y. Chi, X. Zhang, Org. Lett. 2002, 4, 1695–1698.
[13] See Experimental Section.
[14] For applications of Solvias Josiphos ligands in asymmetric hydroge-
nation, see: a) H.-U. Blaser, W. Brieden, B. Pugin, F. Spindler, M.
Studer, A. Togni, Top. Catal. 2002, 19, 3–16; b) H.-U. Blaser, B.
Pugin, F. Spindler, M. Thommen, Acc. Chem. Res. 2007, 40, 1240–
1250.
[15] S. E. Cantor, D. S. Tarbel, J. Am. Chem. Soc. 1964, 86, 2902–2909.
[16] J. P. Genet, V. Ratovelomanana-Vidal, M. C. Cano de Andrade, X.
Pfister, P. Guerreiro, J. Y. Lenoir, Tetrahedron Lett. 1995, 36, 4801–
4804.
[4] a) D. R. Carbery, Org. Biomol. Chem. 2008, 6, 3455–3460; b) R.
Matsubara, S. Kobayashi, Acc. Chem. Rev. 2008, 41, 292–301.
[5] For some recent books and reviews, see: a) T. C. Nugent in Process
Chemistry in the Pharmaceutical Industry, Vol. 2 (Eds.: K. Gadama-
setti, T. Braish), CRC, Boca Raton, FL, 2008, p. 137; b) H.-U.
Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer, Adv.
Synth. Catal. 2003, 345, 103–151; c) M. van den Berg, R. M. Haak,
A. J. Minnaard, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, Adv.
Received: September 10, 2009
Published online: January 27, 2010
554
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 550 – 554