Transition-Metal-Free Arylation of N -Alkyl-tetrahydroisoquinolines under Oxidative Conditions: A Convenient Synthesis of C1-Arylated Tetrahydro-isoquinoline Alkaloids

Article abstract of DOI:10.1055/s-0034-1378337

A simple protocol for the C1 arylation of tetrahydroisoquinolines with aryl Grignard reagents via diethyl azodicarboxylate (DEAD) mediated oxidative C-H activation under metal-free conditions has been developed. The target compounds, including some natura

Full text of DOI:10.1055/s-0034-1378337

2644▌
PAPER
paper
Transition-Metal-Free Arylation of N-Alkyl-tetrahydroisoquinolines under
Oxidative Conditions: A Convenient Synthesis of C1-Arylated Tetrahydro-
isoquinoline Alkaloids
C1-Arylated Tetrahydroisoquinolines
Kamal Nain Singh,*a Satinder V. Kessar,a Paramjit Singh,a Pushpinder Singh,b Manjot Kaur,a Aanchal Batraa
a
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India
Fax +91(172)2545074; E-mail: kns@pu.ac.in
b
Department of Chemistry, DAV University, Jalandhar 144025, India
Received: 06.05.2014; Accepted after revision: 27.05.2014
clization,7 and a modified Pummerer reaction.8 Apart
Abstract: A simple protocol for the C1 arylation of tetrahydroiso-
from these common procedures, a number of other meth-
quinolines with aryl Grignard reagents via diethyl azodicarboxylate
ods have also been developed.9
(DEAD) mediated oxidative C–H activation under metal-free con-
ditions has been developed. The target compounds, including some
naturally occurring alkaloids, were obtained in moderate to good
yields.
In the recent past, direct C–H bond activation under oxi-
dative conditions has attracted much attention as it pro-
vides efficient routes for the synthesis of biologically
active natural products.10 Enormous efforts have been
Key words: arylation, tetrahydroisoquinoline, C–H activation, al-
kaloids, metal-free
made for the modification of known methods and to de-
velop new procedures for the synthesis of C–H arylated
heterocyclic compounds.11 Metal-catalyzed arylation of
The tetrahydroisoquinoline motif forms the basic frame-
work of many naturally occurring alkaloids of pharma-
ceutical importance.1 In particular, 1-aryl-1,2,3,4-
tetrahydroisoquinolines are of wide biological signifi-
cance as they exhibit anti-HIV,2a,b antitumor,2c,d and anti-
bacterial activity.2e Various analogues of C1-arylated
tetrahydroisoquinolines (Figure 1) act as dopamine D1
like receptor antagonists3a,b and they are neuroprotective
agents for the treatment of Alzheimer’s and Parkinson’s
type diseases.3c,d Solifenacin (Figure 1) has been investi-
gated as a bladder-selective muscarinic M3 receptor an-
tagonist.4 Other naturally occurring alkaloids such as
cryptostylines I, II, and III (Figure 1) belong to this family
and show interesting pharmacological properties.5 The
synthesis of 1-aryl-tetrahydroisoquinolines is an attractive
area of research due to their applicability in the areas of
pharmaceutics and medicine. Earlier reported methods for
the synthesis of 1-aryl-tetrahydroisoquinolines include
Pictet–Spengler condensation,6 Bischler–Napieralski cy-
(un)protected tetrahydroisoquinolines at C1 has been
demonstrated by Schnürch and co-workers using tert-bu-
tyl hydroperoxide (TBHP) as an oxidant.11d Li and co-
workers have used copper salts as catalysts to couple 2-
phenyl-1,2,3,4-tetrahydroisoquinolines and other N-pro-
tected tetrahydroisoquinolines with indole,12a–d 2-naph-
thol,12e and arylboronic acids.12f One drawback here is that
removal of the phenyl group from the nitrogen is difficult
and further functionalization cannot be pursued.13 Klus-
smann and Schweitzer-Chaput described a two-step tert-
butyl hydroperoxide mediated C1 arylation of N-Cbz-, N-
Boc-, and N-benzyl-protected tetrahydroisoquinolines
catalyzed by a Brønsted acid.14 A one-step C1 arylation of
N-Cbz-protected tetrahydroisoquinolines using triphenyl-
carbenium perchlorate has been achieved by Xie et al.15 It
was also noted that such arylation reactions did not suc-
ceed with N-methyl-tetrahydroisoquinoline and only
overoxidation products were detected.14 Recently Li and
co-workers reported α-sp3 C–H arylation reactions of N-
R1
R2
MeO
MeO
MeO
MeO
MeO
N
N
NH
N
O
MeO
Me
R3
O
O
N
R1
R1 = R2 = H
1 = Cl, R2 = OH
solifenacin
Cl
R2
R
R1 = H, R2–R3 = -OCH2O-: cryptostyline I
1 = H, R2 = R3 = OMe: cryptostyline II
1 = R2 = R3 = OMe: cryptostyline III
R
R
Figure 1 C1-Arylated tetrahydroisoquinolines
SYNTHESIS 2014, 46, 2644–2650
Advanced online publication: 08.07.2014
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DOI: 10.1055/s-0034-1378337; Art ID: ss-2014-t0282-op
© Georg Thieme Verlag Stuttgart · New York

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C1-Arylated Tetrahydroisoquinolines
2645
Table 1 Optimization of Reaction Conditionsa
(4-methoxyphenyl) (N-PMP) and benzyl-protected tetra-
hydroisoquinolines using aryl Grignard reagents in the
presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) or hypervalent iodine(III) as oxidants under metal-
free conditions.16a,b The latest report describes the aryla-
tion of N-carbamoyl-protected tetrahydroisoquinolines
using sodium persulfate.16c In all these reports, N-aryl-tet-
rahydroisoquinolines or N-protected tetrahydroisoquino-
lines were used as substrates and, therefore, these
procedures could not be used for the one-step synthesis of
α-arylated N-methyl-tetrahydroisoquinolines. Some other
related coupling reactions of tertiary amines with different
nucleophiles have also been reported.17
MgBr
[O]
+
N
N
transition-metal-free
Me
Me
1a
2a
3a
Entry
Grignard (equiv) Oxidant
Solvent
Yieldb (%)
1
2
2
4
6
8
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DDQ
THF
THF
THF
THF
DMF
toluene
CHCl3
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
20
42
65
64
48
56
60
62
22
trace
trace
28
We recently reported our findings on the direct arylation
of a C–H bond in N-methyl-tetrahydroisoquinolines in-
volving the reactions of amino carbanions18 with in situ
generated benzyne intermediates.19 In continuation of our
interest in exploring new oxidative coupling reactions, in-
volving dithiolanes with ketones and indoles,20a forma-
mides with diphenyl diselenides,20b and our earlier finding
on the use of readily available diethyl azodicarboxylate as
a suitable oxidant in the regioselective alkynylation of N-
methyl-tetrahydroisoquinolines20c or unactivated aliphatic
tertiary amines,21 the direct coupling of the α-position in
N-alkyl tetrahydroisoquinolines with aryl Grignard re-
agents in the presence of diethyl azodicarboxylate seemed
a viable option. This article describes the outcome of these
investigations, which also resulted in a convenient and di-
rect route for the synthesis of 2-alkyl-1-aryl-1,2,3,4-tetra-
3
4
5c
6c
7c
8
9
10
11
12
13d
14e
15f
16g
17h
18i
19j
CAN
MCPBA
TBHP/I2
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
64
60
66
65
35
66
40
hydroisoquinolines
conditions.
under
transition-metal-free
Initially, we reacted 2-methyl-1,2,3,4-tetrahydroisoquino-
line (1a) with phenylmagnesium bromide (2 equiv) using
diethyl azodicarboxylate (1.1 equiv) in tetrahydrofuran at
room temperature for two hours under a nitrogen atmo-
sphere. The desired product 2-methyl-1-phenyl-1,2,3,4-
tetrahydroisoquinoline (3a) was obtained in 20% yield
(Table 1, entry 1). Use of four and six equivalents of
Grignard reagent increased the yield of 3a to 42% and
65%, respectively (entries 2 and 3). A further increase in
the amount of the Grignard reagent to eight equivalents
did not improve the yield (entry 4). Solvents like N,N-di-
methylformamide and toluene gave inferior results (en-
tries 5 and 6) while in case of chloroform and diethyl ether
3a was obtained in 60–62% yield (entries 7 and 8).
a Reaction conditions: 1a (1 equiv), oxidant (1.1 equiv), solvent (2
mL), r.t., 2 h.
b Isolated yield.
c The Grignard reagent was prepared in THF and the iminium cation
was generated in DMF, toluene or CHCl3.
d 3 h.
e 1 h.
Among the other oxidants which were investigated, 2,3- f Refluxing THF.
g CuI (5 mol%) was used as a catalyst.
dichloro-5,6-dicyano-1,4-benzoquinone22 afforded the
product in 22% yield (entry 9) while cerium ammonium
nitrate (CAN) and 3-chloroperoxybenzoic acid, were inef-
fective (entries 10 and 11). With the tert-butyl hydroper-
oxide/iodine23 system, the arylation reaction occurred to a
lesser extent (entry 12). Increasing the reaction time did
not improve the yield of 3a (entry 13), but decreasing the
reaction time somewhat lowered the yield (entry 14). No
improvement in the yield of 3a was observed with the use
of copper(I) iodide as a catalyst (entry 16). Using a higher
reaction temperature did not affect the reaction (entry 15).
The use of 0.5 equivalents of diethyl azodicarboxylate de-
h DEAD (0.5 equiv).
i DEAD (2.2 equiv).
j DEAD (3.3 equiv).
creased the product yield as expected, (entry 17). Increas-
ing the amount of oxidant to 2.2 equivalents only
marginally changed the yield of 3a (entry 18). Surprising-
ly, further increase in the amount of the oxidant to 3.3
equivalents depressed the yield (entry 19). Thus, the opti-
mized conditions for the coupling of 1a used 6 equivalents
of Grignard’s reagent in tetrahydrofuran using diethyl
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2644–2650

2646
K. N. Singh et al.
PAPER
azodicarboxylate as the oxidant and without the use of a well to afford 3j in 57% yield. 1-Naphthylmagnesium
metal salt (entry 3).
bromide (2e) and 2-methoxy-1-naphthylmagnesium bro-
mide (2f) also coupled effectively to give the correspond-
ing products 3e,f,k in 58–67% yields. 2-Ethyl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline (1d) was also
evaluated and the C1-arylated products 3n,o were ob-
tained in good yields. However, 2-benzyl-1,2,3,4-tetrahy-
droisoquinoline (1e) coupled to a lesser extent with 2a and
2b to furnish the products 3p and 3q in 51% and 40%
yields, respectively.
To investigate the scope and generality of the reaction,
various arylmagnesium bromides were reacted with dif-
ferently substituted N-methyl-tetrahydroisoquinolines un-
der the optimized conditions. Tetrahydroisoquinolines
1a–c coupled well with Grignard reagents 2a–f to give the
desired products 3a–m in moderate to good yields (55–
67%) (Scheme 1). The reaction tolerated methoxy/methyl
substituents on the phenyl rings of the coupling partners.
Even meta-substituted aryl Grignard reagent 2d worked
MgBr
R1
R1
R2
DEAD, THF, r.t.
+
N
transition-metal-free
R2
R3
R5
N
R3
R5
R4
1
2
1a: R1 = R2 = H, R3 = Me
2a: R4 = H, R5 = H
1b: R1 = R2 = OMe, R3 = Me
2b: R4 = OMe, R5 = H
R4
1c: R1 = OMe, R2 = OEt, R3 = Me 2c: R4 = Me, R5 = H
3
1d: R1 = R2 = OMe, R3 = Et
1e: R1 = R2 = H, R3 = Bn
2d: R4 = H, R5 = OMe
2e: R4 = naphthyl
2f: R4 = 2-methoxynaphthyl
N
N
N
Me
Me
Me
N
N
Me
Me
OMe
OMe
OMe
3a, 65%
3b, 60%
3c, 62%
3d, 55%
3e, 64%
MeO
MeO
MeO
MeO
N
N
MeO
Me
Me
MeO
Me
N
N
Me
MeO
OMe
3g, 60%
3f, 67%
3h, 58%
3l, 64%
3p, 51%
3i, 67%
MeO
EtO
MeO
MeO
MeO
MeO
N
Me
N
N
N
MeO
Me
Me
EtO
Me
OMe
OMe
3j, 57%
3k, 58%
3m, 65%
MeO
MeO
MeO
N
N
MeO
Et
Bn
N
N
Et
Bn
OMe
OMe
3q, 40%
3n, 68%
3o, 65%
Scheme 1 Substrate scope in oxidative C1 arylation of tetrahydroisoquinoline with Grignard reagents. Reagents and conditions: 1a (1 equiv),
DEAD (1.1 equiv), aryl Grignard reagent (6 equiv), THF (2 mL), r.t., 2 h; isolated yield based on 1.
Synthesis 2014, 46, 2644–2650
© Georg Thieme Verlag Stuttgart · New York

PAPER
C1-Arylated Tetrahydroisoquinolines
2647
MgBr
MeO
MeO
MeO
DEAD, THF, r.t.
+
Me
N
N
transition-metal-free
R3
R1
MeO
Me
R1
1b
R2
2g: R1 = OMe, R2 = OMe, R3 = H
2h: R1 = OMe, R2 = OMe, R3 = OMe
R3
R2
3r: R1 = OMe, R2 = OMe, R3 = H
cryptostyline II (58%)
3s: R1 = OMe, R2 = OMe, R3 = OMe
cryptostyline III (54%)
Scheme 2 Synthesis of cryptostyline alkaloids
With the aim of demonstrating the utility of this procedure very careful handling. Furthermore, the yields of the prod-
for the synthesis of naturally occurring alkaloids, we ap- ucts are significantly lower in many cases using this re-
plied these metal-free conditions to the synthesis of cryp- agent.9b
tostyline II (3r) and cryptostyline III (3s). The coupling of
1b with 2g and 2h afforded the products 3r and 3s in 58%
and 54% yield, respectively (Scheme 2).
A plausible mechanism for the coupling of 1a and 2a is
depicted in Scheme 3. As already established,14,20c,21,25 im-
inium ion A is formed during oxidation of tetrahydroiso-
This arylation procedure may be compared with that de- quinoline with diethyl azodicarboxylate. Subsequent
scribed by Costa and Radesca in which they used triphe- attack of the nucleophile 2a on iminium ion A furnishes
nylcarbenium tetrafluoroborate to generate iminium the arylated product 3a.
cation for further reaction with Grignard reagent.9b,24 It
In summary, a direct and convenient procedure for the
may be pointed out that triphenylcarbenium tetrafluoro-
synthesis of 1-aryl-2-methyl-tetrahydroisoquinoline via
borate is a corrosive and air-sensitive reagent that requires
oxidative coupling of N-alkyltetrahydroisoquinolines and
Grignard reagents using diethyl azodicarboxylate under
metal-free conditions has been developed. Moreover, the
synthesis of naturally occurring alkaloids cryptostyline II
COOEt
N
Me
N
and III has also been achieved.
+
N
N
COOEt
+
HN
Me
–N
1a
COOEt
Melting points were taken in open capillaries and are uncorrected.
1H NMR spectra were recorded on Bruker 400 MHz spectrometer
in CDCl3 solution relative to internal standard TMS. 13C NMR spec-
tra were obtained at 100 MHz and referenced to the internal solvent
signals (δ = 77.00). MS and HRMS data were obtained on Q-Tof
MicroTM Mass Spectrometer. Differently substituted starting
amines were prepared according to literature procedure.26 Products
were isolated and purified by column chromatography (silica gel,
hexane–EtOAc).
COOEt
Me
N
N
COOEt
+
–
H
HN
COOEt
2-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3a);7e,27
Typical Procedure
COOEt
COOEt
– N
HN
To a flame-dried two-necked round-bottom flask, charged with 1-
methyl-1,2,3,4-tetrahydroisoquinoline (1a, 0.2 mL, 1.36 mmol) in
THF (2 mL) was added DEAD (0.267 mL, 1.49 mmol) dropwise at
5–10 °C and the mixture was stirred for 15 min under N2. To this
was added phenylmagnesium bromide (2a, 8.16 mmol) in THF
slowly and the mixture was stirred at r.t. for 2 h. The reaction was
quenched with 10% HCl (20–25 mL), basified with Na2CO3, and
extracted with EtOAc (2 × 25 mL). The solvent was evaporated and
the residue was purified by column chromatography (silica gel,
230–400 mesh, EtOAc–hexane) to afford 3a (197 mg, 65%) as a
yellow oil.
MgBr
2a
N+
N
Me
Me
A
1H NMR (400 MHz, CDCl3–CCl4): δ = 7.23–7.16 (m, 5 H), 7.01–
6.85 (m, 3 H), 6.53 (d, J = 7.8 Hz, 1 H), 4.13 (s, 1 H), 3.19–3.01 (m,
2 H), 2.76–2.52 (m, 2 H), 2.14 (s, 3 H).
3a
13C NMR (100 MHz, CDCl3–CCl4): δ = 144.0, 138.5, 134.1, 129.7,
128.6, 128.3, 127.3, 125.9, 125.7, 71.6, 52.4, 44.4, 29.6.
Scheme 3 Plausible mechanism
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2644–2650

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K. N. Singh et al.
PAPER
1-(4-Methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline
1H NMR (400 MHz, CDCl3–CCl4): δ = 7.23–7.16 (m, 5 H), 6.48 (s,
1 H), 5.97 (s, 1 H), 4.07 (s, 1 H), 3.76 (s, 3 H), 3.47 (s, 3 H), 3.13–
2.98 (m, 2 H), 2.66–2.49 (m, 2 H), 2.14 (s, 3 H).
13C NMR (100 MHz, CDCl3–CCl4): δ = 147.5, 147.2, 144.0, 130.5,
129.6, 128.3, 127.4, 126.4, 111.6, 110.9, 71.2, 55.8, 55.7, 52.4,
44.4, 29.1.
(3b)
Yellow solid; yield: 206 mg (60%); mp 76–78 °C (Lit.19b 78–
80 °C).
1H NMR (400 MHz, CDCl3–CCl4): δ = 7.09–7.05 (m, 2 H), 7.00–
6.95 (m, 2 H), 6.89–6.85 (m, 1 H), 6.75–6.71 (m, 2 H), 6.54 (d, J =
7.8 Hz, 1 H), 4.08 (s, 1 H), 3.71 (s, 3 H), 3.21–3.12 (m, 1 H), 3.04–
2.99 (m, 1 H), 2.74–2.69 (m, 1 H), 2.56–2.50 (m, 1 H), 2.13 (s, 3 H).
13C NMR (100 MHz, CDCl3–CCl4): δ = 158.8, 138.8, 135.9, 134.1,
130.5, 128.5, 128.2, 125.8, 125.6, 113.5, 70.9, 55.0, 52.4, 44.3,
29.5.
6,7-Dimethoxy-1-(4-methoxyphenyl)-N-methyl-1,2,3,4-tetrahy-
droisoquinoline (3h)
Yellow solid; yield: 174 mg (58%); mp 93–95 °C (Lit.30 96–97 °C).
1H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 8.6 Hz, 2 H), 6.85 (d,
J = 8.6 Hz, 2 H), 6.59 (s, 1 H), 6.11 (s, 1 H), 4.20 (s, 1 H), 3.84 (s,
3 H), 3.80 (s, 3 H), 3.58 (s, 3 H), 3.20–3.08 (m, 2 H), 2.78–2.60 (m,
2 H), 2.25 (s, 3 H).
2-Methyl-1-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (3c)
Yellow oil; yield: 200 mg (62%).
1H NMR (400 MHz, CDCl3–CCl4): δ = 7.13–7.02 (m, 6 H), 6.95–
6.91 (m, 1 H), 6.60 (d, J = 7.8 Hz, 1 H), 4.17 (s, 1 H), 3.29–3.21 (m,
1 H), 3.12–3.08 (m, 1 H), 2.82–2.77 (m, 1 H), 2.64–2.58 (m, 1 H),
2.33 (s, 3 H), 2.21 (s, 3 H).
13C NMR (100 MHz, CDCl3–CCl4): δ = 140.8, 138.6, 136.6, 134.0,
129.9, 129.5, 128.9, 128.5, 128.2, 125.8, 125.6, 71.2, 52.3, 44.3,
29.5, 21.2.
13C NMR (100 MHz, CDCl3): δ = 158.8, 147.3, 146.9, 135.1, 131.4,
130.5, 130.1, 126.2, 114.5, 113.5, 111.3, 110.5, 70.0, 55.7, 55.1,
51.8, 43.9, 28.6.
6,7-Dimethoxy-2-methyl-1-(p-tolyl)-1,2,3,4-tetrahydroisoquin-
oline (3i)
Yellow oil; yield: 191 mg (67%).
1H NMR (400 MHz, CDCl3): δ = 7.15–7.12 (m, 4 H), 6.60 (s, 1 H),
6.12 (s, 1 H), 4.20 (s, 1 H), 3.84 (s, 3 H), 3.57 (s, 3 H), 3.17–3.07
(m, 2 H), 2.77–2.60 (m, 2 H), 2.33 (s, 3 H), 2.24 (s, 3 H).
HRMS (ES+): m/z [M + H]+ calcd for C17H20N: 237.1517; found:
238.1564.
13C NMR (100 MHz, CDCl3): δ = 147.2, 146.8, 140.0, 136.8, 130.0,
129.7, 129.3, 128.8, 128.6, 126.2, 111.3, 110.5, 70.3, 55.6, 51.7,
43.9, 28.6, 21.0.
HRMS (ES+): m/z [M + H]+ calcd for C19H24NO2: 297.1729; found:
298.1798.
1-(3,4-Dimethoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquino-
line (3d)19b
Yellow solid; yield: 211 mg (55%); mp 76–78 °C.
1H NMR (400 MHz, CDCl3): δ = 7.05–7.01 (m, 2 H), 6.94–6.89 (m,
1 H), 6.79–6.70 (m, 3 H), 6.60 (d, J = 7.8 Hz, 1 H), 4.11 (s, 1 H),
3.81 (s, 3 H), 3.74 (s, 3 H), 3.24–3.17 (m, 1 H), 3.11–3.06 (m, 1 H),
2.77–2.53 (m, 2 H), 2.18 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.0, 148.2, 134.0, 131.4, 128.3,
128.2, 125.9, 125.6, 122.1, 111.8, 110.2, 71.4, 55.8, 55.7, 52.5,
44.3, 29.3.
6,7-Dimethoxy-1-(3-methoxyphenyl)-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (3j)19b
Yellow oil; yield: 170 mg (57%).
1H NMR (400 MHz, CDCl3): δ = 7.16–7.14 (m, 1 H), 6.80–6.73 (m,
3 H), 6.53 (s, 1 H), 6.07 (s, 1 H), 4.16 (br s, 1 H), 3.78 (s, 3 H), 3.71
(s, 3 H), 3.51 (s, 3 H), 3.09–3.05 (m, 2 H), 2.71–2.58 (m, 2 H), 2.21
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.7, 147.6, 147.1, 129.2, 126.2,
122.2, 115.0, 113.0, 111.3, 110.7, 100.0, 55.9, 55.8, 55.3, 52.0,
44.1, 28.6.
2-Methyl-1-(naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline
(3e)
Yellow solid; yield: 237 mg (64%); mp 111–112 °C.
1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.5 Hz, 1 H), 7.72 (t,
J = 8.7 Hz, 2 H), 7.39–7.21 (m, 4 H), 7.09 (t, J = 8.8 Hz, 1 H), 6.98
(t, J = 7.4 Hz, 1 H), 6.77 (t, J = 7.5 Hz, 1 H), 6.47 (d, J = 7.8 Hz, 1
H), 4.70 (s, 1 H), 3.37–3.28 (m, 1 H), 3.17–3.12 (m, 1 H), 2.83–2.79
(m, 1 H), 2.64–2.57 (m, 1 H), 2.09 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.0, 138.6, 134.3, 133.8, 131.6,
128.9, 128.4, 128.3, 128.2, 127.4, 125.9, 125.8, 125.5, 125.3, 125.0,
53.3, 44.5, 29.3.
6,7-Dimethoxy-2-methyl-1-(naphthalen-1-yl)-1,2,3,4-tetrahy-
droisoquinoline (3k)
Yellow solid; yield: 185 mg (58%); mp 139–140 °C (Lit.31 140–142
°C).
1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.4 Hz, 1 H), 7.74–
7.69 (m, 2 H), 7.35–7.25 (m, 4 H), 6.57 (s, 1 H), 5.97 (s, 1 H), 4.70
(br s, 1 H), 3.76 (s, 3 H), 3.30 (s, 3 H), 3.27–3.11 (m, 2 H), 2.78–
2.73 (m, 1 H), 2.64–2.58 (m, 1 H), 2.14 (s, 3 H).
HRMS (ES+): m/z [M + H]+ calcd for C20H20N: 273.1517; found:
274.1534.
13C NMR (100 MHz, CDCl3): δ = 147.4, 147.1, 134.3, 130.3, 128.4,
128.2, 126.1, 125.5, 125.3, 110.8, 110.6, 55.6, 52.7, 44.3, 28.4.
1-(2-Methoxynaphthalen-1-yl)-2-methyl-1,2,3,4-tetrahydroiso-
quinoline (3f)28
Yellow solid; yield: 138 mg (67%); mp 107–108 °C.
7-Ethoxy-6-methoxy-2-methyl-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline (3l)19b
Yellow oil; yield: 170 mg (64%).
1H NMR (400 MHz, CDCl3): δ = 7.25–7.16 (m, 5 H), 6.53 (s, 1 H),
6.02 (s, 1 H), 4.10 (s, 1 H), 3.76–3.62 (m, 5 H), 3.05–3.01 (m, 2 H),
2.68–2.54 (m, 2 H), 2.16 (s, 3 H), 1.19 (t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.7, 145.1, 142.8, 129.2, 128.5,
127.2, 126.2, 125.5, 112.1, 109.8, 70.0, 63.1, 54.8, 51.2, 43.2, 27.9,
13.5.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 7.3 Hz, 1 H), 7.72–
7.60 (m, 2 H), 7.24 (d, J = 9.1 Hz, 1 H), 7.13–7.05 (m, 3 H), 6.96 (t,
J = 7.3 Hz, 1 H), 6.76 (t, J = 7.5 Hz, 1 H), 6.42 (d, J = 7.8 Hz, 1 H),
5.37 (s, 1 H), 3.89 (s, 3 H), 3.45–3.37 (m, 1 H), 3.19–3.16 (m, 1 H),
2.83 (d, J = 16 Hz, 1 H), 2.67–2.60 (m, 1 H), 2.07 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.4, 139.2, 134.0, 129.6, 128.1,
127.9, 126.7, 126.5, 125.8, 125.4, 123.3, 113.1, 62.2, 57.0, 54.4,
44.1, 29.9.
6,7-Dimethoxy-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquino-
line (3g)29
Yellow oil; yield: 162 mg (60%).
7-Ethoxy-6-methoxy-1-(4-methoxyphenyl)-2-methyl-1,2,3,4-
tetrahydroisoquinoline (3m)
Creamy solid; yield: 190 mg (65%); mp 85–87 °C (Lit.19b 87–89
°C).
Synthesis 2014, 46, 2644–2650
© Georg Thieme Verlag Stuttgart · New York

PAPER
C1-Arylated Tetrahydroisoquinolines
2649
1H NMR (400 MHz, CDCl3): δ = 7.10–7.07 (m, 2 H), 6.79–6.75 (m,
2 H), 6.52 (s, 1 H), 6.04 (s, 1 H), 4.08 (s, 1 H), 3.79–3.64 (m, 8 H),
3.09–2.99 (m, 2 H), 2.69–2.51 (m, 2 H), 2.16 (s, 3 H), 1.21 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 6.53–6.45 (m, 3 H), 6.09 (s, 1 H),
4.11 (br s, 1 H), 3.78 (s, 6 H), 3.74 (s, 6 H), 3.54 (s, 3 H), 3.11 (br s,
2 H), 2.69–2.58 (m, 2 H), 2.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.8, 147.7, 146.2, 130.5, 130.4,
126.4, 113.5, 113.1, 110.8, 70.2, 64.2, 55.8, 55.2, 52.1, 44.1, 28.8,
14.6.
13C NMR (100 MHz, CDCl3): δ = 153.0, 147.4, 146.9, 139.3, 137.1,
129.9, 126.3, 111.2, 110.6, 106.3, 71.6, 60.8, 56.1, 55.9, 55.7, 52.5,
44.4, 28.7.
2-Ethyl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquino-
line (3n)
Yellow solid; yield: 201 mg (68%); mp 73–74 °C.
Acknowledgement
We acknowledge financial support through scheme no
02(0131)/13/EMR-II sponsored by CSIR, New Delhi. A. Batra
thanks UGC for a research fellowship. NMR and Mass facilities
from SAIF, Panjab University are gratefully acknowledged.
1H NMR (400 MHz, CDCl3): δ = 7.23–7.13 (m, 5 H), 6.52 (s, 1 H),
6.09 (s, 1 H), 4.46 (s, 1 H), 3.77 (s, 3 H), 3.51 (s, 3 H), 3.09–3.04
(m, 1 H), 2.96–2.89 (m, 1 H), 2.74–2.68 (m, 1 H), 2.58–2.49 (m, 2
H), 2.35–2.26 (m, 1 H), 0.99–0.96 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 147.3, 146.9, 144.0, 130.1, 129.4,
128.0, 127.0, 126.8, 111.6, 110.7, 67.2, 55.7, 48.0, 46.3, 28.1, 11.6.
HRMS (ES+): m/z [M + H]+ calcd for C19H24NO2: 297.1729; found:
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
298.1802.
2-Ethyl-6,7-dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-tetrahy-
droisoquinoline (3o)
References
Yellow solid; yield: 182 mg (65%); mp 66–68 °C (Lit.32 64–66 °C).
(1) (a) Wang, S.; Onaran, M. B.; Seto, C. T. Org. Lett. 2010, 12,
2690. (b) Bentley, K. W. Nat. Prod. Rep. 2005, 22, 249.
(c) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669. (d) Ozturk, T. The Alkaloids; Vol. 53; Cordell, G. A.,
Ed.; Academic Press: New York, 2000, 120. (e) Charifson,
P. S. Drugs Future 1989, 14, 1179. (f) Menarchery, M. D.;
Lavanier, G. L.; Wetherly, M. L.; Guinaudeau, H.; Shamma,
M. J. Nat. Prod. 1986, 49, 745. (g) Wu, W.; Beal, J. L.;
Fairchild, E. H.; Doskotch, R. W. J. Org. Chem. 1978, 43,
580.
(2) (a) Chen, K.-X.; Xie, H.-Y.; Li, Z.-G. Bioorg. Med. Chem.
Lett. 2008, 18, 5381. (b) Cheng, P.; Huang, N.; Zhang, Q.;
Zheng, Y.-T. Bioorg. Med. Chem. Lett. 2008, 18, 2475.
(c) Kuo, C.-Y.; Wu, M. J.; Kuo, Y.-H. Eur. J. Med. Chem.
2006, 41, 940. (d) Kim, S. A.; Kwon, Y.; Kim, J. H.; Muller,
M. T.; Chung, I. K. Biochemistry 1998, 37, 16316.
(e) Tiwari, R. K.; Singh, D.; Singh, J.; Chhiller, A. K. Eur.
J. Med. Chem. 2006, 41, 40.
(3) (a) Minor, D. L.; Wyrick, S. D.; Charifson, P. S.; Watts, V.
J.; Nichols, D. E.; Mailman, R. B. J. Med. Chem. 1994, 37,
4317. (b) Charifson, P. S.; Wyrick, S. D.; Ademe Simmons,
R. M.; McDougald, D. L.; Mailman, R. B.; Hoffman, A. J.;
Bowen, J. P. J. Med. Chem. 1988, 31, 1941. (c) Gao, M.;
Kong, D.; Clearfield, A.; Zheng, Q.-H. Bioorg. Med. Chem.
Lett. 2006, 16, 2229. (d) Ludwig, M.; Hoesl, C. E.; HÖfner,
G.; Wanner, K. T. Eur. J. Med. Chem. 2006, 41, 1003.
(4) (a) Naito, R.; Yonetoku, Y.; Okamoto, Y.; Toyoshima, A.;
Ikeda, K.; Takeuchi, M. J. Med. Chem. 2005, 48, 6597.
(b) Ohtake, A.; Ukai, M.; Hatanaka, T.; Kobayashi, S.;
Ikeda, K.; Sato, S.; Miyata, K.; Sasamata, M. Eur. J.
Pharmacol. 2004, 492, 243.
1H NMR (400 MHz, CDCl3): δ = 7.10–7.06 (m, 2 H), 6.77–6.74 (m,
2 H), 6.52 (s, 1 H), 6.10 (s, 1 H), 4.43 (s, 1 H), 3.77 (s, 3 H), 3.72 (s,
3 H), 3.53 (s, 3 H), 3.09–3.03 (m, 1 H), 2.92–2.88 (m, 1 H), 2.74–
2.69 (m, 1 H), 2.57–2.51 (m, 2 H), 2.33–2.28 (m, 1 H), 1.00–0.97 (t,
J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.6, 147.4, 147.0, 130.5, 126.8,
113.4, 111.7, 110.8, 99.9, 66.6, 55.8, 55.2, 47.9, 46.2, 28.1, 11.6.
2-Benzyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3p)33
White solid; yield: 136 mg (51%); mp 118–120 °C.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.28 (m, 2 H), 7.24–7.10 (m,
8 H), 7.03–7.00 (m, 2 H), 6.92 (t, J = 7.8 Hz, 1 H), 6.65 (d, J = 7.5
Hz, 1 H), 4.52 (s, 1 H), 3.74 (d, J = 13.5 Hz, 1 H), 3.18 (d, J = 13.5
Hz, 1 H), 3.04–2.94 (m, 2 H), 2.71–2.65 (m, 1 H), 2.43–2.39 (m, 1
H).
13C NMR (100 MHz, CDCl3): δ = 144.4, 139.6, 138.5, 134.8, 129.7,
128.9, 128.8, 128.5, 128.3, 128.2, 127.3, 126.8, 125.9, 125.7, 68.9,
58.8, 47.3, 29.2.
2-Benzyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(3q)33
White solid; yield: 117 mg (40%); mp 148–150 °C.
1H NMR (400 MHz, CDCl3): δ = 7.22–7.13 (m, 7 H), 7.04–6.99 (m,
2 H), 6.95–6.87 (m, 1 H), 6.80–6.76 (m, 2 H), 6.66 (d, J = 7.8 Hz, 1
H), 4.50 (s, 1 H), 3.76 (s, 1 H), 3.71 (s, 3 H), 3.18–3.15 (m, 1 H),
3.00 (br s, 2 H), 2.71–2.67 (m, 1 H), 2.44 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.9, 130.8, 128.9, 128.5, 128.2,
126.9, 125.7, 113.7, 67.9, 59.5, 55.2, 47.2, 29.7.
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tet-
rahydroisoquinoline (3r)34
Yellow oil; yield: 181 mg (58%).
(5) Kurihara, K.; Yamamoto, Y.; Miyaura, N. Adv. Synth. Catal.
2009, 351, 260.
1H NMR (400 MHz, CDCl3): δ = 6.78–6.69 (m, 3 H), 6.53 (s, 1 H),
6.06 (s, 1 H), 4.07 (br s, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 3.75 (s, 3
H), 3.51 (s, 3 H), 3.12–3.06 (m, 2 H), 2.69–2.55 (m, 2 H), 2.18 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 149.1, 148.5, 147.1, 126.1, 122.3,
111.9, 111.3, 110.6, 110.3, 70.9, 56.2, 56.0, 55.8, 52.3, 44.1, 28.7.
(6) (a) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc.
2006, 128, 1086. (b) Taylor, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 10558. (c) Gitto, R.; Barreca, M. L.;
Luca, L. D.; Sarro, G. D.; Ferrerri, G. J. Med. Chem. 2003,
46, 197. (d) Ruchirawat, S.; Bhavakul, V.; Chaisupakitsin,
M. Synth. Commun. 2003, 33, 621. (e) Yamada, H.; Kawate,
T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa,
M. J. Org. Chem. 1998, 63, 6348. (f) Cox, E. D.; Cook, J. M.
Chem. Rev. 1995, 95, 1797.
6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (3s)
White solid; yield: 193 mg (54%); mp 139–141 °C (Lit.35 140–
141 °C).
(7) (a) Berenguer, I.; Aouad, N. E.; Andujar, S.; Romero, V.;
Suvire, F.; Freret, T. Bioorg. Med. Chem. 2009, 17, 4968.
(b) Doi, S.; Shirai, N.; Sato, Y. J. Chem. Soc., Perkin Trans.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2644–2650

2650
K. N. Singh et al.
PAPER
1 1997, 2217. (c) Suzuki, H.; Aoyagi, S.; Kibayashi, C.
Tetrahedron Lett. 1995, 36, 6709. (d) Landais, Y.; Robin, J.-
P. Tetrahedron 1992, 48, 7185. (e) Gray, N. M.; Cheng, B.
K.; Mick, S. J.; Lair, C. M.; Contreras, P. C. J. Med. Chem.
1989, 32, 1242. (f) Leander, K.; Luning, B. Tetrahedron
Lett. 1968, 9, 1393. (g) Ishiwata, S.; Itakura, K. Chem.
Pharm. Bull. 1968, 16, 778. (h) Reeve, W.; Eareckson, W.
M. J. Am. Chem. Soc. 1950, 72, 5195.
Macheroux, P.; Kroutil, W. Angew. Chem. Int. Ed. 2011, 50,
1068. (d) Allen, J. M.; Lambert, T. H. J. Am. Chem. Soc.
2011, 133, 1260. (e) Deb, M. L.; Dey, S. S.; Bento, I.;
Barros, M. T.; Maycock, C. D. Angew. Chem. Int. Ed. 2013,
52, 9791.
(18) (a) Kessar, S. V.; Singh, P.; Vohra, R.; Kaur, N. P.; Singh,
K. N. J. Chem. Soc., Chem. Commun. 1991, 568. (b) Kessar,
S. V.; Singh, P. Chem. Rev. 1997, 97, 721.
(8) Abe, K.; Saitoh, T.; Horiguchi, Y.; Utsunomiya, I.; Taguchi,
K. Biol. Pharm. Bull. 2005, 28, 1355.
(9) (a) Bender, C.; Liebscher, J. ARKIVOC 2009, (vi), 111.
(b) Costa, B. R.; Radesca, L. Synthesis 1992, 887.
(c) Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K.
Chem. Lett. 1990, 315.
(19) (a) Singh, K. N.; Singh, P.; Singh, P.; Deol, Y. S. Org. Lett.
2012, 14, 2202. (b) Singh, K. N.; Singh, P.; Sharma, E.;
Deol, Y. S. Synthesis 2014, 46, 1739.
(20) (a) Singh, K. N.; Singh, P.; Singh, P.; Maheshwary, Y.;
Kessar, S. V.; Batra, A. Synlett 2013, 24, 1963. (b) Singh, P.;
Batra, A.; Singh, P.; Kaur, A.; Singh, K. N. Eur. J. Org.
Chem. 2013, 7688. (c) Singh, K. N.; Singh, P.; Kaur, A.;
Singh, P. Synlett 2012, 23, 760.
(21) Xu, X.; Li, X. Org. Lett. 2009, 11, 1027.
(22) (a) Su, W.; Yu, J.; Li, Z.; Jiang, Z. J. Org. Chem. 2011, 76,
9144. (b) Cosner, C. C.; Cabrera, P. J.; Byrd, K. M.;
Thomas, A. M. A.; Helquist, P. Org. Lett. 2011, 13, 2071.
(c) Damu, G. L. V.; Selvam, J. P.; Rao, C. V.;
Venkateswarlu, Y. Tetrahedron Lett. 2009, 50, 6154.
(d) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242.
(e) Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
(f) Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317.
(23) Zhang, J.; Zhu, D.; Yu, C.; Wan, C.; Wang, Z. Org. Lett.
2010, 12, 2841.
(24) We are grateful to the reviewers for bringing to our notice in
reference 9b the references numbered 15, 17 and 24 which
are related to our work.
(25) Xu, X.; Li, X.; Ma, L.; Ye, N. J. Am. Chem. Soc. 2008, 130,
14048.
(26) (a) Wilson, M. W.; Govindachari, T. R. Org. React. 1951, 6,
74. (b) Marsden, R.; MacLean, D. B. Can. J. Chem. 1984,
62, 1392. (c) Miller, R. B.; Tsang, T. Tetrahedron Lett.
1988, 29, 6715.
(27) Kajita, M.; Niwa, T.; Fujisaki, M.; Ueki, M.; Niimura, K.
J. Chromatogr. B 1995, 669, 345.
(10) (a) Nobuta, T.; Fujiya, A.; Yamaguchi, T.; Tada, N.; Miura,
T.; Itoh, A. RSC Adv. 2013, 3, 10189. (b) Hari, D. P.; Konig,
B. Org. Lett. 2011, 13, 3852; and references therein.
(c) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am.
Chem. Soc. 2008, 130, 11005. (d) Li, Z.; Yu, R.; Li, H.
Angew. Chem. Int. Ed. 2008, 47, 7497. (e) Li, Z.; MacLeod,
P. D.; Li, C.-J. Tetrahedron: Asymmetry 2006, 17, 590.
(f) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672.
(g) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (h) Li, Z.;
Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(11) (a) Park, S. J.; Price, J. R.; Todd, M. H. J. Org. Chem. 2012,
77, 949. (b) Dhineshkumar, J.; Lamani, M.; Alagiri, K.;
Prabhu, K. R. Org. Lett. 2013, 15, 1092. (c) Alagiri, K.;
Devadig, P.; Prabhu, K. R. Chem. Eur. J. 2012, 18, 5160.
(d) Ghobrial, M.; Schnürch, M.; Mihovilovic, M. D. J. Org.
Chem. 2011, 76, 8781. (e) Tsang, A. S.-K.; Todd, M. H.
Tetrahedron Lett. 2009, 50, 1199.
(12) (a) Zhong, J.-J.; Meng, Q.-Y.; Wang, G.-X.; Chen, B.; Feng,
K.; Tung, C.-H.; Wu, L.-Z. Chem. Eur. J. 2013, 19, 6443.
(b) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem.
Soc. 2012, 134, 5317. (c) Ghobrial, M.; Harhammer, K.;
Mihovilovic, M. D.; Schnürch, M. Chem. Commun. 2010,
46, 8836. (d) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127,
6968. (e) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci.
U.S.A. 2006, 103, 8928. (f) Baslé, O.; Li, C.-J. Org. Lett.
2008, 10, 3661.
(28) Li, C.-J.; Mcleod, P.; Li, Z. P.; Feng, J. WO 2007,098,608,
2007.
(13) Tsang, A. S.-K.; Ingram, K.; Keiser, J.; Hibbert, D. B.; Todd,
M. H. Org. Biomol. Chem. 2013, 11, 4921.
(14) Schweitzer-Chaput, B.; Klussmann, M. Eur. J. Org. Chem.
2013, 666.
(15) Xie, Z.; Liu, L.; Chen, W.; Zheng, H.; Hu, Q.; Yuan, H.;
Lou, H. Angew. Chem. Int. Ed. 2014, 53, 3904.
(16) (a) Muramatsu, W.; Nakano, K.; Li, C.-J. Org. Lett. 2013,
15, 3650. (b) Muramatsu, W.; Nakano, K.; Li, C.-J. Org.
Biomol. Chem. 2014, 12, 2189. (c) Chen, W.; Zheng, H.;
Pan, X.; Xie, Z.; Zan, X.; Sun, B.; Liu, L.; Lou, H.
Tetrahedron Lett. 2014, 55, 2879.
(17) (a) Chu, L.; Zhang, X.; Qing, F.-L. Org. Lett. 2009, 11,
2197. (b) Son, Y. W.; Kwan, T. H.; Lee, J. K.; Pae, A. N.;
Lee, J. Y.; Cho, Y. S.; Min, S.-J. Org. Lett. 2011, 13, 6500.
(c) Schrittwieser, J. H.; Resch, V.; Sattler, J. H.; Lienhart,
W.-D.; Durchschein, K.; Winkler, A.; Gruber, K.;
(29) (a) Valpuesta, M.; Ariza, M.; Diaz, A.; Suau, R. Eur. J. Org.
Chem. 2010, 4393. (b) Jiashou, W.; Jian, L.; Jin, Z.; Jingen,
D. Synlett 2006, 2059.
(30) Ahluwalia, G. S.; Narang, K. S.; Rây, J. N. J. Chem. Soc.
1931, 2057.
(31) Ariza, M.; Diaz, A.; Suau, R.; Valpuesta, M. Eur. J. Org.
Chem. 2011, 6507.
(32) Voskressensky, L. G.; Listratova, A. V.; Borisova, T. N.;
Alexandrov, G. G.; Varlamov, A. V. Eur. J. Org. Chem.
2007, 6106.
(33) Ye, Z.-S.; Guo, R.-N.; Cai, X.-F.; Chen, M.-W.; Shi, L.;
Zhou, Y.-G. Angew. Chem. Int. Ed. 2013, 52, 3685.
(34) Umetsu, K.; Asao, N. Tetrahedron Lett. 2008, 49, 2722.
(35) Samano, V.; Ray, J. A.; Thompson, J. B.; Mook, R. A.; Jung,
D. K.; Koble, C. S.; Martin, M. T.; Bigham, E. C.; Regitz, C.
S.; Feldman, P. L. Org. Lett. 1999, 1, 1993.
Synthesis 2014, 46, 2644–2650
© Georg Thieme Verlag Stuttgart · New York