Isoquinoline derivatives via stepwise regioselective sp2 and sp3 C-H bond functionalizations

Article abstract of DOI:10.1021/jo300237s

Efficient and practically attractive stepwise ruthenium- and palladium-catalyzed regioselective C-H bond functionalizations were achieved to produce 4-substituted tetrahydroisoquinoline derivatives featuring various heteroaromatic substructures in moderat

Full text of DOI:10.1021/jo300237s

Note
pubs.acs.org/joc
Isoquinoline Derivatives via Stepwise Regioselective sp2 and sp3 C−H
Bond Functionalizations
Tarek Boudiar,†,‡ Zeyneb Sahli,§ Basker Sundararaju,§ Mathieu Achard,§ Zahia Kabouche,‡
Henri Doucet,§ and Christian Bruneau*,§
†Centre de Recherche en Biotechnologies, BPE 73, Ali Mendjli, Nouvelle Ville, 25000 Constantine, Algeria
‡Laboratoire d’Obtention de Substances Ther
Constantine, Algeria
́
apeutiques (LOST), Dep
́
artement de chimie, Universite
́
Mentouri-Constantine, 25000
§UMR 6226 CNRS, Universite
Cedex, France
́
de Rennes 1, Sciences Chimiques-Catalyse et Organomet
́
alliques, Campus de Beaulieu-35042 Rennes
S
* Supporting Information
ABSTRACT: Efficient and practically attractive stepwise
ruthenium- and palladium-catalyzed regioselective C−H
bond functionalizations were achieved to produce 4-
substituted tetrahydroisoquinoline derivatives featuring various
heteroaromatic substructures in moderate to good yields. Both
ruthenium- and palladium-based catalytic processes generated
nontoxic and easily separable side products.
onsidering the importance of cyclic amines and alkaloids
C
in industry as dyes and as pharmaceutical and agro-
chemical drugs, straightforward and environmentally benign
approaches for the preparation of these compounds still
represents a challenging task for chemists.1,2 Among them,
tetrahydroisoquinoline (THIQ) derivatives constitute an
important class of compounds with numerous biological
properties such as anti-HIV,3 antitumor,4 and antipsychotic5
activities. They are actually produced by multistep methods,
and new direct synthetic routes to access THIQ derivatives are
highly desired and at the center of active research activities.
Main THIQ derivatives arise from the functionalization at
position 1 via cross dehydrogenative coupling (CDC)6−8 or at
position 3 with multistep syntheses.4b,9 In contrast, function-
alization at position 4 is scarce.10 In recent years, C−H bond
functionalization involving activation of inert C−H bonds to
allow direct C−C coupling has attracted considerable attention
since this type of reaction minimizes the reaction steps and
therefore the number of purification processes and the
production of wastes and fullfills the criteria of sustainability
and green chemistry. In our laboratory, we have recently
described, on one hand, the first ruthenium-catalyzed C(β)−H
functionalization of various cyclic amines and highlighted the
formation of reactive enamine intermediates via hydrogen
autotransfer processes11−13 (Figure 1) and, on the other hand,
the regioselective palladium-catalyzed C(5) functionalization of
five-membered heterocycles.14,15
Figure 1. C(β)−H alkylation of cyclic amines via multi-hydrogen
transfer processes.
to diverse C(4)-substituted products containing functionalized
heteroaromatic subunits via stepwise ruthenium and palladium
C−H bond functionalizations.
We started our study by examining the feasibility of the C(4)
alkylation of the tetrahydroisoquinoline 1a with various
heteroaromatic aldehydes 2. Selective alkylation was carried
out in toluene at 150 °C using 2.5 mol % of the ruthenium
catalyst I (Figure 1) and formic acid as the final hydrogen
donor to fully convert enamine and iminium intermediates
(Table 1). After optimizing the amount of camphorsulfonic
acid (CSA), it was found that the best reaction conditions were
obtained using 8 mol % of CSA leading to 69% isolated yield of
3a starting from 2-furaldehyde 2a (Table 1, entry 1). Similar
results were obtained with substituted furaldehyde 2g reaching
62% yield (entry 7). Interestingly, reaction of 3-furaldehyde 2f
stabilized with BHT afforded 4-substituted THIQ 3f in
excellent yield (entry 6). 1-Methyl-2-carboxaldehyde pyrrole
2b exhibited lower reactivity, affording the expected product 3b
in 30% yield along with noticeable amounts of byproducts
resulting from the partial hydrogenation and hydrolysis of the
pyrrole structure (entry 2). The influence of the position of the
In order to take advantage of these two catalytic trans-
formations, we evaluated the reactivity of the THIQ core
structure with unexplored formyl heterocycles. Herein, we
report on environmentally attractive and selective trans-
formations of the tetrahydroisoquinoline core providing access
Received: February 13, 2012
Published: March 15, 2012
© 2012 American Chemical Society
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Note
a
Table 1. Ruthenium-Catalyzed C(4) Alkylation of 1a
Scheme 1. Incompatible Substrates for C(4) Alkylation of 1a
and aryl bromides 4 (1 equiv) were reacted in the presence of
Pd(OAc)2 using dimethylacetamide as the solvent in the
presence of potassium acetate acting as base to assist the
deprotonation of the heteroaromatic substrates 3. Examination
of the Pd(OAc)2 loading showed that 0.5 mol % was the best
condition affording the expected arylated THIQ 5, whereas
higher catalyst loading inhibited the reaction.16 For the
substrate 3a featuring a furan heterocycle, reactions proceeded
smoothly, affording exclusively the C′(5)-arylated products 5a−
e in 64−95% isolated yields along with only trace amounts of
the undesired Ullmann-type aryl bromide homocoupling
byproducts (Table 2, entries 1−5). With para-substituted
electron-deficient aryl bromides, moderate yields were obtained
with 4a and 4b (Table 2, entries 1 and 2). The highly electron-
deficient 4-bromonitrobenzene 4e gave the best result, yielding
5e in 95% isolated yield (Table 2, entry 5). The meta-
substituted bromobenzonitrile 4c exhibited a reactivity similar
to that of 4b (Table 2, entry 3). In addition, to further explore
the scope of the arylation postfunctionalization, we selected the
substrate 3c containing a 2′-substituted thiophene structure to
test the arylation reaction. Good reactivities and high
regioselectivities with formation of the carbon−carbon bond
at C′(5) were obtained in all cases, and products 5f−i were
isolated in 54−73% yields (Table 2, entries 6−9). Again 4-
bromonitrobenzene 4e gave the best result, yielding 5j in 96%
yield (Table 2, entry 10). In contrast, reactions of 3′-substituted
thiophene 3d were more sluggish. The major formation of
homocoupling byproducts was observed, together with the
formation of two arylated compounds in almost equimolar ratio
resulting from the C′(2) and C′(5) functionalization of 3d in
low yields17 (not presented in Table 2). A crucial advantage of
the sequential procedure is illustrated by the formation of the
aldehydes 5a and 5f in good yields, whereas the direct
ruthenium-catalyzed reaction starting from a dialdehyde
substrate and 1a would have led to a mixture of products
resulting from the two different possible C−C bond
formations.
a
All reactions were carried out at 0.2 M concentration in toluene at
150 °C for 15 h under an inert atmosphere with 2/1a/[Ru]/CSA in
1/1/0.025/0.08 molar ratio. Isolated yield.
b
carboxaldehyde substituent on the starting thiophene ring was
next investigated. After purification, the 2-formylthiophenes 2c
and 2e afforded the expected C(4)-alkylated compounds 3c
and 3e in 71 and 95% yield, respectively (Table 1, entries 3 and
5). The same reactivity was observed with 3-thiophenecarbox-
aldehyde 2d, and 3d was isolated in 83% yield (Table 1, entry
4).
C(4) Alkylation of 1a with heterocycles 2h and 2i containing
electron-withdrawing groups such as cyano and nitro groups
led to the formation of the expected compounds in only little
amounts, and byproducts featuring amino groups resulting
from the reduction of these hydrogen acceptors under our
reaction conditions were detected (Scheme 1). In order to gain
access to highly functionalized C(4)-alkylated tetrahydroiso-
quinolines, we investigated a sequential selective sp2 C−H
functionalization of the heteroaromatic moieties with a range of
aryl bromides via palladium-catalyzed regioselective arylation
(Table 2). Thus, tetrahydroisoquinolines 3a and 3c (1.5 equiv)
In summary, a sequence involving two consecutive and
highly regioselective metal-catalyzed functionalizations of
THIQ and heteroaromatics is reported. The reactions occur
through sp3 C−H and sp2 C−H bond functionalization and
generate KBr, carbon dioxide, and water as the major side
products. The overall sequential procedure also represents a
double functionalization of aromatic heterocycles. It is
noteworthy that the two-step procedure makes possible the
preparation of products 5g and 5j, which was not possible from
the direct ruthenium-catalyzed reaction (3h and 3i in Scheme
1), pointing out the complementarity of the two catalytic
transformations. These achievements also demonstrate the
potential of C−H functionalization as a viable and eco-friendly
tool toward the access to various alkaloids.
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Note
purification. Proton magnetic resonance (1H NMR) spectra were
recorded on 400, 300, and 500 MHz spectrometers, and carbon
magnetic resonance (13C NMR) spectra were performed at 100 and 75
MHz. CDCl3 was the solvent used for the NMR analysis. Chemical
shifts were reported in parts per million downfield from internal
Me4Si. HRMS were recorded on a Q-TOF2 mass spectrometer with
an ESI source.
a
Table 2. Palladium-Catalyzed C′(5) Arylation of 3
General Procedure I for the C4 Alkylation of 1a: To a stirred
solution of tetrahydroisoquinoline 1a (0.840 mmol, 1 equiv) and
aldehyde 2 (1 mmol, 1.2 equiv) in 4 mL of toluene were added
sequentially catalyst I (2.5 mol %) and camphorsulfonic acid (8 mol
%). Then the reaction mixture was stirred at 150 °C for 15 h. After
cooling the reaction mixture, formic acid (1.5 equiv) was added and
the resulting mixture was stirred at 150 °C for an additional hour. After
concentration, the residue was directly purified by column
chromatography (Et2O/PE (petroleum ether)) to afford the C4-
alkylated amines 3.
4-(Furan-2-ylmethyl)-2-phenethyl-1,2,3,4-tetrahydroisoqui-
noline 3a: Prepared according to general procedure I after
purification through column chromatography (Et2O/PE 2:8) in 69%
yield (184 mg) as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.52
(d, J = 1.2 Hz, 1H), 7.42−7.30 (m, 5H), 7.30−7.23 (m, 3H), 7.20−
7.15 (m, 1H), 6.41 (dd, J = 1.8, 3.0 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H),
4.02 (d, J = 14.6 Hz, 1H), 3.62 (d, J = 14.6 Hz, 1H), 3.38−3.27 (m,
1H), 3.21−3.11 (m, 2H), 3.07−2.76 (m, 5H), 2.63 (dd, J = 3.2, 11.3
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 154.6, 140.9, 140.5, 137.8,
134.9, 128.7, 128.4, 128.2, 126.4, 126.1, 125.9, 125.8, 110.1, 106.5,
60.0, 56.6, 54.0, 38.2, 34.7, 33.7; HRMS calcd for C22H24NO [M +
H]+ 318.18579, found [M + H]+ 318.1859.
4-((1-Methyl-1H-pyrrol-2-yl)methyl)-2-phenethyl-1,2,3,4-tet-
rahydroisoquinoline 3b: Prepared according to general procedure I
after purification through column chromatography (Et2O/PE 2:8) in
1
30% yield (82 mg) as a colorless oil; H NMR (300 MHz, CDCl3) δ
7.35−7.23 (m, 5H), 7.23−7.17 (m, 2H), 7.16−7.10 (m, 2H), 6.58 (br
s, 1H), 6.14 (br s, 1H), 6.00 (br s, 1H), 4.01 (d, J = 15.0 Hz, 1H), 3.52
(d, J = 15.0 Hz, 1H), 3.48 (s, 3H), 3.10−3.02 (m, 1H), 3.00−2.86 (m,
3H), 2.83−2.75 (m, 2H), 2.57 (dd, J = 3.0, 11.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 140.5, 138.1, 134.9, 131.9, 128.7, 128.3, 128.2,
126.4, 126.1, 125.9, 125.8, 120.9, 106.9, 106.5, 60.2, 56.4, 54.2, 39.4,
33.6, 33.5, 32.9; HRMS calcd for C23H27N2 [M + H]+ 331.21742,
found [M + H]+ 331.2168.
2-Phenethyl-4-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroiso-
quinoline 3c: Prepared according to general procedure I after
purification through column chromatography (Et2O/PE 2:8) in 71%
1
yield (198 mg) as a colorless oil; H NMR (500 MHz, CDCl3) δ
7.31−7.15 (m, 9H), 7.08−7.06 (m, 1H), 6.93 (dd, J = 3.3, 5.2 Hz,
1H), 6.73 (d, J = 3.3 Hz, 1H), 3.90 (d, J = 14.8 Hz, 1H), 3.51 (d, J =
14.8 Hz, 1H), 3.29 (dd, J = 10.8, 14.3 Hz, 1H), 3.17−3.07 (m, 2H),
2.91−2.75 (m, 3H), 2.72−2.65 (m, 1H), 2.50 (dd, J = 3.6, 11.6 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 143.5, 140.5, 137.8, 134.8, 128.7,
128.4, 128.3, 126.7, 126.5, 126.3, 126.0, 125.9, 125.6, 123.5, 60.0, 56.5,
53.6, 41.4, 36.3, 33.7, HRMS calcd for C22H24NS [M + H]+
334.16295, found [M + H]+ 334.1631.
2-Phenethyl-4-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroiso-
quinoline 3d: Prepared according to general procedure I after
purification through column chromatography (Et2O/PE 2:8) in 83%
1
yield (232 mg) as a colorless oil; H NMR (300 MHz, CDCl3) δ
7.32−7.24 (m, 5H), 7.21−7.15 (m, 4H), 7.09−7.08 (m, 1H), 6.95 (d, J
= 4.7 Hz, 1H), 6.86 (s, 1H), 3.92 (d, J = 14.8 Hz, 1H), 3.53 (d, J =
14.8 Hz, 1H), 3.10−2.98 (m, 3H), 2.89−2.63 (m, 5H), 2.50 (dd, J =
3.1, 11.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 141.1, 140.5, 138.2,
134.8, 128.8, 128.5, 128.4, 128.3, 126.5, 126.2, 125.9, 125.8, 125.3,
121.5, 60.1, 56.5, 54.0, 40.1, 36.7, 33.7; HRMS calcd for C22H23NNaS
[M + Na]+ 356.14489, found [M + Na]+ 356.1451.
4-((3-Methylthiophen-2-yl)methyl)-2-phenethyl-1,2,3,4-tet-
rahydroisoquinoline 3e: Prepared according to general procedure I
after purification through column chromatography (Et2O/PE 2:8) in
95% yield (278 mg) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ
7.33−7.13 (m, 9H), 7.08−7.06 (m, 1H), 6.57 (dq, J = 2.9, 1.5 Hz,
1H), 6.52 (d, J = 3.1 Hz, 1H), 3.90 (d, J = 15.0 Hz, 1H), 3.51 (d, J =
a
All reactions were carried out at 0.04 M concentration in DMAc at
150 °C for 15 h under an inert atmosphere with 3/4/AcOK/
Pd(OAc)2 in 1.5/1/2/0.005 molar ratio. Isolated yield.
b
EXPERIMENTAL SECTION
■
General Information: All reactions were carried out under argon
atmosphere in dried glassware with magnetic stirring. Toluene was
distilled under conventional methods and stored under argon
atmosphere. Unless otherwise noted, all reagents and solvents were
purchased from commercial suppliers and used without further
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Note
15.0 Hz, 1H), 3.20 (dd, J = 10.9, 14.8 Hz, 1H), 3.10−3.02 (m, 2H),
2.93−2.64 (m, 5H), 2.51 (dd, J = 3.8, 11.7 Hz, 1H), 2.46 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 141.3, 140.6, 138.0, 137.8, 134.9, 128.7,
128.6, 128.5, 128.3, 126.5, 126.2, 125.9, 125.3, 124.7, 60.1, 56.6, 53.6,
41.3, 36.6, 33.8, 15.3; HRMS calcd for C23H26NS [M + H]+ 348.1786,
found [M + H]+ 348.1782.
141.0, 140.5, 137.6, 134.9, 134.1, 133.5, 132.8, 128.7, 128.5, 128.3,
126.5, 126.2, 126.0, 125.9, 125.5, 119.1, 111.4, 109.6, 106.3, 59.9, 56.5,
54.2, 38.3, 34.9, 33.7; HRMS calcd for C29H27N2O [M + H]+
419.21234, found [M + H]+ 419.2122.
4-((5-(Naphthalen-1-yl)furan-2-yl)methyl)-2-phenethyl-
1,2,3,4-tetrahydroisoquinoline 5d: Prepared according to general
procedure II after purification through column chromatography
(Et2O/PE 2:8) in 67% yield (18,7 mg); 1H NMR (300 MHz,
CDCl3) δ 8.47−8.43 (m, 1H), 7.91−7.73 (m, 3H), 7.54−7.46 (m,
3H), 7.33−7.06 (m, 9H), 6.65 (d, J = 3.2 Hz, 1H), 6.15 (d, J = 3.2 Hz,
1H), 3.95 (d, J = 15.0 Hz, 1H), 3.54 (d, J = 15.0 Hz, 1H), 3.38−3.27
(m, 1H), 3.20−3.05 (m, 2H), 2.99−2.69 (m, 5H), 2.61 (dd, J = 3.3,
11.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 154.8, 151.9, 140.4,
137.7, 134.9, 133.9, 130.1, 128.7, 128.4, 128.3, 128.1, 126.5, 126.4,
126.2, 125.9, 125.9, 125.8, 125.6, 125.5, 125.3, 125.3, 110.0, 108.6,
60.0, 56.6, 54.3, 38.4, 34.9, 33.7; HRMS calcd for C32H30NO [M +
H]+ 444.23274, found [M + H]+ 444.2329.
4-(Furan-3-ylmethyl)-2-phenethyl-1,2,3,4-tetrahydroisoqui-
noline 3f: Prepared according to general procedure I after purification
through column chromatography (Et2O/PE 2:8) in 90% yield (238
1
mg) as a colorless oil; H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H),
7.20−7.06 (m, 8H), 7.02 (s, 1H), 6.98−6.97 (m, 1H), 6.19 (s, 1H),
3.78 (d, J = 14.8 Hz, 1H), 3.44 (d, J = 14.8 Hz, 1H), 2.94−2.88 (m,
1H), 2.80−2.57 (m, 7H), 2.44 (dd, J = 11.6, 3.2 Hz, 1H ; 13C NMR
(75 MHz, CDCl3) δ 142.8, 140.5, 139.9, 138.3, 134.9, 128.7, 128.3,
128.2, 126.4, 126.1, 125.9, 125.8, 123.3, 111.1, 60.1, 56.6, 54.0, 39.4,
33.7, 31.1; HRMS calcd for C22H24NO [M + H]+ 318.18579, found
[M + H]+ 318.1856.
4-(Benzofuran-2-ylmethyl)-2-phenethyl-1,2,3,4-tetrahydroi-
soquinoline 3g: Prepared according to general procedure I after
purification through column chromatography (Et2O/PE 2:8) in 62%
yield (190 mg) as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.52
(t, J = 8.0 Hz, 2H), 7.37−7.20 (m, 10 H), 7.13−7.11 (m, 1H), 6.33 (s,
1H), 3.98 (d, J = 15.0 Hz, 1 h), 3.55 (d, J = 15.0 Hz, 1H), 3.44−3.36
(m, 1H), 3.27 (dd, J = 10.0, 14.0 Hz, 1H), 3.13 (dd, J = 3.8, 14.3 Hz,
1H), 2.96−2.81 (m, 4H), 2.77−2.68 (m, 1H), 2.57 (dd, J = 3.4, 11.7
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 157.7, 154.7, 140.5, 137.7,
134.9, 128.8, 128.7, 128.5, 128.3, 126.5, 126.2, 126.0, 125.9, 123.2,
122.4, 120.3, 110.7, 103.6, 59.9, 56.5, 54.0, 37.9, 35.3, 33.7; HRMS
calcd for C26H26NO [M + H]+ 368.20144, found [M + H]+ 368.2015.
General Procedure II for the C′5 Arylation of Amines 3: To a
stirred solution of amine 3 (30 mg, 1.5 equiv) and arylbromides 4 (1
equiv) in 2 mL of N,N-dimethylacetamide were added sequentially
potassium acetate (2 equiv) and PdOAc2 (0.5 mol %), and the
resulting mixture was stirred at 150 °C for 15 h. After evaporation of
the solvent, the crude mixture was suspended on silica and purified by
column chromatography to afford the C′5-arylated compounds 5.
4-(5-((2-Phenethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-
methyl)furan-2-yl)benzaldehyde 5a: Prepared according to
general procedure II after purification through column chromatog-
4-((5-(4-Nitrophenyl)furan-2-yl)methyl)-2-phenethyl-1,2,3,4-
tetrahydroisoquinoline 5e: Prepared according to general
procedure II after purification through column chromatography
1
(Et2O/PE 2:8) in 95% yield (26 mg); H NMR (300 MHz, CDCl3)
δ 8.24 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.35−7.18 (m,
9H), 7.12−7.10 (m, 1H), 6.82 (d, J = 3.0 Hz, 1H), 6.11 (d, J = 3.0 Hz,
1H), 3.95 (d, J = 15.0 Hz, 1H), 3.54 (d, J = 15.0 Hz, 1H), 3.33−3.26
(m, 1H), 3.24−3.17 (m, 1H), 3.06 (dd, J = 4.0, 14.0 Hz, 1H), 2.97−
2.68 (m, 5 H), 2.60 (dd, J = 3.3, 11.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 157.3, 150.3, 145.9, 140.5, 137.5, 136.6, 135.0, 128.7, 128.4,
128.3, 126.5, 126.2, 126.1, 126.0, 124.3, 123.3, 110.0, 109.8, 59.9, 56.4,
54.2, 38.4, 34.9, 33.7; HRMS calcd for C28H27N2O3 [M + H]+
439.20217, found [M + H]+ 439.2022.
4-(5-((2-Phenethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-
methyl)thiophen-2-yl)benzaldehyde 5f: Prepared according to
general procedure II after purification through column chromatog-
1
raphy (Et2O/PE 1:9) in 61% yield (16 mg); H NMR (300 MHz,
CDCl3) δ 10.01 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz,
1H), 7.30−7.17 (m, 10H), 7.10−7.07 (m, 1H), 6.71 (d, J = 3.3 Hz,
1H), 3.94 (d, J = 15.0 Hz, 1H), 3.51 (d, J = 15.0 Hz, 1H), 3.30 (dd, J =
11.6, 15.4 Hz, 1H), 3.17−3.09 (m, 2H), 2.92−2.65 (m, 5H), 2.54 (dd,
J = 3.7, 12.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 191.4, 145.9,
140.6, 140.5, 140.3, 137.6, 135.0, 134.7, 130.4, 128.8, 128.4, 128.3,
127.2, 126.6, 126.3, 126.1, 126.0, 125.5, 124.9, 60.1, 56.4, 53.7, 41.4,
36.8, 33.8; HRMS calcd for C29H28NOS [M + H]+ 438.18916, found
[M + H]+ 438.1893.
1
raphy (Et2O/PE 3:7) in 64% yield (17.1 mg); H NMR (300 MHz,
CDCl3) δ 9.97 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz,
2H), 7.33−7.05 (m, 9H), 6.77 (d, J = 3.1 Hz, 1H), 6.08 (d, J = 3.1 Hz,
̀
1H), 3.93 (d, J = 15.0 Hz, 1H), 3.52 (d, J = 15.a Hz, 1H), 3.31−3.22
(m, 1H), 3.15−2.98 (m, 2H), 2.94−2.68 (m, 5H), 2.58 (dd, J = 3.6,
11.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 191.5, 156.5, 142.3,
140.4, 138.9, 137.5, 136.3, 134.4, 130.3, 128.7, 128.4, 128.3, 126.5,
126.2, 126.0, 126.0, 123.4, 109.6, 109.2, 60.0, 56.5, 54.2, 38.4, 35.0,
33.7, HRMS calcd for C29H28NO2 [M + H]+ 422.21200, found [M +
H]+ 422.2117.
4-(5-((2-Phenethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-
methyl)furan-2-yl)benzonitrile 5b: Prepared according to general
procedure II after purification through column chromatography
(Et2O/PE 3:7) in 67% yield (17.9 mg); 1H NMR (300 MHz,
CDCl3) δ 7.70 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.33−7.09
(m, 9H), 6.72 (d, J = 3.3 Hz, 1H), 6.07 (d, J = 3.3 Hz, 1H), 3.92 (d, J
= 15.0 Hz, 1H), 3.51 (d, J = 15.0 Hz, 1H), 3.28−3.06 (m, 3H), 2.98−
2.64 (m, 5H), 2.56 (dd, J = 2.9, 13.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 157.0, 151.0, 140.8, 137.9, 135.4, 135.2, 132.9, 129.1, 128.8,
128.7, 126.9, 126.7, 126.5, 126.5, 123.8, 119.5, 110.0, 109.6, 60.4, 56.9,
54.6, 38.8, 35.4, 34.2; HRMS calcd for C29H27N2O [M + H]+
419.21234, found [M + H]+ 419.2124.
3-(5-((2-Phenethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-
methyl)furan-2-yl)benzonitrile 5c: Prepared according to general
procedure II after purification through column chromatography
(Et2O/PE 3:7) in 67% yield (17.8 mg); 1H NMR (300 MHz,
CDCl3) δ 7.86 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.60 (t, J
= 8.0 Hz, 1H), 7.42−7.16 (m, 10H), 7.14−7.06 (m, 1H), 6.11 (d, J =
3.0 Hz, 1H), 3.96 (d, J = 15.0 Hz, 1H), 3.54 (d, J = 15.0 Hz, 1H),
3.39−3.26 (m, 1H), 3.18−3.06 (m, 2H), 3.06−2.70 (m, 5H), 2.60 (dd,
J = 3.6, 11.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 156.2, 148.4,
4-(5-((2-Phenethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-
methyl)thiophen-2-yl)benzonitrile 5g: Prepared according to
general procedure II after purification through column chromatog-
1
raphy (Et2O/PE 1:9) in 54% yield (14.1 mg); H NMR (300 MHz,
CDCl3) δ 7.63 (m, 4H), 7.36−7.16 (m, 10H), 6.70 (d, J = 3.3 Hz,
1H), 3.92 (d, J = 15.0 Hz, 1H), 3.50 (d, J = 15.0 Hz, 1H), 3.30 (dd, J=
11.0, 14.6 Hz, 1H), 3.20−3.03 (m, 2H), 2.88−2.67 (m, 5H), 2.53 (dd,
J = 2.5, 10.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 146.1, 140.5,
139.9, 138.8, 137.5, 134.9, 132.6, 128.8, 128.4, 128.3, 127.2, 126.6,
126.2, 126.1, 126.0, 125.5, 124.9, 118.9, 110.0, 60.0, 56.4, 53.6, 41.4,
36.8, 33.7; HRMS calcd for C29H27N2S [M + H]+ 435.1895, found [M
+ H]+ 435.1891.
3-(5-((2-Phenethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-
methyl)thiophen-2-yl)benzonitrile 5h: Prepared according to
general procedure II after purification through column chromatog-
1
raphy (Et2O/PE 1:9) in 69% yield (18 mg); H NMR (300 MHz,
CDCl3) δ 7.82 (s, 1H), 7.76 (dt, J = 7.8, 1.5 Hz, 1H), 7.53−7.42 (m,
2H), 7.33−7.08 (m, 10H), 6.70 (d, J = 2.9 Hz, 1H), 3.95 (d, J = 14.8
Hz, 1H), 3.53 (d, J = 14.8 Hz, 1H), 3.30 (dd, J = 11.3, 15.4 Hz, 1H),
3.17−3.09 (m, 2H), 2.93−2.67 (m, 5H), 2.57 (dd, J = 2.6, 11.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 144.1, 139.4, 138.5, 136.5, 134.8,
133.9, 129.1, 128.6, 128.4, 127.8, 127.6, 127.4, 127.3, 126.0, 125.6,
125.3, 125.1, 125.0, 123.1, 112.0, 59.1, 55.3, 52.6, 40.3, 35.7, 32.7;
HRMS calcd for C29H27N2S [M + H]+ 435.1895, found [M + H]+
435.1893.
4-((5-(Naphthalen-1-yl)thiophen-2-yl)methyl)-2-phenethyl-
1,2,3,4-tetrahydroisoquinoline 5i: Prepared according to general
3677
dx.doi.org/10.1021/jo300237s | J. Org. Chem. 2012, 77, 3674−3678

The Journal of Organic Chemistry
Note
procedure II after purification through column chromatography
(Et2O/PE 3:7) in 73% yield (20.3 mg); 1H NMR (300 MHz,
CDCl3) δ 8.31−8.29 (m, 1H), 7.91−7.83 (m, 2H), 7.58−7.56 (m,
1H), 7.51−7.47 (m, 3H), 7.32−7.22 (m, 4H), 7.21−7.16 (m, 5H),
7.08 (s,1H), 6.80 (s, 1H), 3.93 (d, J = 14.8 Hz, 1H), 3.52 (d, J = 14.8
Hz, 1H), 3.35−3.30 (m, 1H), 3.23−3.17 (m, 2H), 2.96−2.73 (m, 5H),
2.61−2.53 (m,1H); 13C NMR (75 MHz, CDCl3) δ 144.1, 140.5,
139.8, 137.9, 135.0, 133.8, 132.7, 131.7, 128.8, 128.5, 128.3, 128.3,
128.1, 127.9, 127.0, 126.5, 126.3, 126.2, 126.0, 125.9, 125.9, 125.7,
125.2, 123.4, 59.2, 55.5, 52.7, 40.5, 35.7, 32.8; GC−MS m/z (%) 459
(M+, 3%), 398 (12%), 357 (21%), 333 (60%).
43, 581. (e) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(f) Jones, K. M.; Klussmann, M. Synlett 2012, 159.
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Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312. (b) Li, Z.; Li, C. J. Org.
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(8) Selected recent examples: (a) Ghobrial, M.; Schnurch, M.;
̈
Mihovilovic, M. D. J. Org. Chem. 2011, 76, 8781. (b) Jones, K. M.;
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4-((5-(4-Nitrophenyl)thiophen-2-yl)methyl)-2-phenethyl-
1,2,3,4-tetrahydroisoquinoline 5j: Prepared according to general
procedure II after purification through column chromatography
(Et2O/EP 1:9) in 96% yield (26.1 mg); 1H NMR (300 MHz,
CDCl3) δ 8.17 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.62−7.06
(m, 9H), 7.05−7.04 (m, 1H), 6.68 (d, J = 3.0 Hz, 1H), 3.91 (d, J =
15.0 Hz, 1H), 3.46 (d, J = 15.0 Hz, 1H), 3.25 (dd, J = 11.0, 14.0 Hz,
1H), 3.13−3.05 (m, 2H), 2.85−2.63 (m, 5H), 2.50 (dd, J = 3.0, 11.3
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 145.8, 145.2, 139.8, 139.5,
138.5, 136.5, 133.9, 127.7, 127.4, 127.3, 126.4, 125.6, 125.3, 125.2,
125.0, 124.6, 124.4, 123.3, 59.1, 55.4, 52.6, 40.4, 35.8, 32.7; HRMS
calcd for C28H27N2O2S [M + H]+ 455.17933, found [M + H]+
455.1795.
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Toupet, L.; Bruneau, C. Adv. Synth. Catal. 2010, 352, 3141.
(12) Sundararaju, B.; Achard, M.; Sharma, G. V. M; Bruneau, C. J.
Am. Chem. Soc. 2011, 133, 10340.
(13) Reviews: (a) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds 3 and
5. This material is available free of charge via the Internet at
http://pubs.acs.org.
́
R. H. Chem. Rev. 2010, 110, 681. (c) Guillena, G.; Ramon, D. J.; Yus,
AUTHOR INFORMATION
Corresponding Author
*E-mail: christian.bruneau@univ-rennes1.fr.
Notes
■
M. Chem. Rev. 2010, 110, 1611. (d) Yamaguchi, R.; Fujita, K.-I.; Zhu,
M. Heterocycles 2010, 81, 1093.
(14) (a) Pozgan, F.; Roger, J.; Doucet, H. ChemSusChem 2008, 1,
̌
404. (b) Dong, J. J.; Roy, D.; Roy, R. J.; Ionita, M.; Doucet, H.
Synthesis 2011, 3530.
The authors declare no competing financial interest.
(15) Reviews: (a) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
(b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
(c) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (d) Bellina, F.;
Rossi, R. Tetrahedron 2009, 65, 10269. (e) Roger, J.; Gottumukkala, A.
L.; Doucet, H. ChemCatChem 2010, 2, 20.
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Vries, J. G. Org. Lett. 2003, 5, 3285.
ACKNOWLEDGMENTS
■
The authors thank the ANDRS and DG-RSDT for the financial
support to T.B., and The Ministry of Higher Education and
Research of Algeria for a PNE fellowship to Z.S. Thanks are
also due to CEFIPRA/IFCPAR (IFC/A/3805-2/2008/1720)
for a grant to B.S.
(17) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko,
M. F. Org. Lett. 2003, 5, 301.
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