Oxidative C-H functionalization: A novel strategy for the acetoxylation/alkoxylation of arenes tethered to 3,4-dihydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2012.08.124

1-Aryl-3,4-dihydroisoquinolines undergo smooth acetoxylation/alkoxylation in the presence of 5 mol % Pd(OAc)₂ and a stoichiometric amount of PhI(OAc)₂ by means of C-H activation to produce the corresponding acetoxy- and alkoxy-1-aryl-3,4-dihydroisoquinoline derivatives respectively in good yields with high regioselectivity. It is a first example on oxidative functionalization of arenes tethered to dihydroisoquinoline moiety via the C-H activation.

Full text of DOI:10.1016/j.tetlet.2012.08.124

Tetrahedron Letters 53 (2012) 6091–6094
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative C–H functionalization: a novel strategy for the
acetoxylation/alkoxylation of arenes tethered to 3,4-dihydroisoquinolines
⇑
B. V. Subba Reddy , N. Umadevi, G. Narasimhulu, J. S. Yadav
Natural Product Chemistry, CSIR–Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Aryl-3,4-dihydroisoquinolines undergo smooth acetoxylation/alkoxylation in the presence of 5 mol %
Pd(OAc)2 and a stoichiometric amount of PhI(OAc)2 by means of C–H activation to produce the corre-
sponding acetoxy- and alkoxy-1-aryl-3,4-dihydroisoquinoline derivatives respectively in good yields
with high regioselectivity. It is a first example on oxidative functionalization of arenes tethered to dihy-
droisoquinoline moiety via the C–H activation.
Received 20 July 2012
Revised 28 August 2012
Accepted 29 August 2012
Available online 5 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1-Aryl-3,4-dihydroisoquinolines
Hypervalent iodine reagent
Acetoxylation
Alkoxylation
C–H activation
Tetrahydroisoquinoline derivatives (Fig. 1)1 are known to dis-
play a wide range of biological activities such as anticonvulsants
and neuroprotective agents for the treatment of neurodegenerative
diseases including ischemia, epilepsy, Alzheimer’s, and Parkinson’s
disease.2 They also exhibit antibacterial3 and anti-HIV activities.4
Furthermore, 1-aryl tetrahydroisoquinoline derivatives are the
antagonists of AMPA, NMDA, and dopamine D1 receptors which
facilitate the glutamate and dopamine neurotransmission in the
central nervous system.5 Furthermore, solifenacin is a currently
used drug for the treatment of overactive bladder.6 In particular,
1-aryl-3,4-dihydroisoquinolines are the known inhibitors of c-Jun
N-terminal kinases (JNK3) which are responsible for several dis-
eases such as neurodegeneration, rheumatoid arthritis, inflamma-
tory disorders, cancer, and diabetes.7 In addition to this, 1-aryl-
3,4-dihydroisoquinolines are known to inhibit the cell prolifera-
tion.8 Consequently, there is a great demand for the generation
of novel 1-aryl-3,4-dihydroisoquinoline libraries for biological
evaluation.
OH
MeO
MeO
MeO
MeO
O
O
O
N
N
N
O
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
(+)-Cryptostyline II
(+)-Cryptostyline III
Azapodophyllotoxin
MeO
MeO
MeO
N
O
N
N
MeO
O
OR
N
Cl
Solifenacin
JNK3 inhibitor
Leukemia cell
proliferation inhibitors
Recently, palladium catalyzed C–H bond activation has emerged
as a powerful tool for the direct functionalization of unactivated C–
H bonds.9,10 However, the direct functionalization of substrates
with similar C–H bonds tends to require a directing group.11As a
result, the substrate directed C–H bond activation has received sig-
nificant attention. In particular, the oxidation of aromatic C–H
bonds is a challenging task in organic synthesis.12 However, there
have been no reports on the oxidative functionalization of 1-aryl-
Figure 1. Examples of biologically active isoquinoline derivatives.
N
5 mol% Pd(OAc)2
N
+
PhI(OAc)2
DCE, reflux,
Ac2O
OAc
1
2
3a
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
Scheme 1. Acetoxylation of 1-phenyl-3,4-dihydroisoquinoline.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.124

6092
B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 6091–6094
Table 1
Pd(OAc)2-catalyzed acetoxylation/alkoxylation of 3,4-dihydroisoquinolines
Entry
Dihydroisoquinoline (1)
Product (3)a
Time (h)
3.0
Yieldb (%)
N
N
3a
3b
a
82
OAc
OAc
N
N
b
3.2
3.4
76
74
Me
N
Me
N
3c
c
OAc
Me
Me
MeO
MeO
N
N
MeO
MeO
3d
d
e
4.5
3.0
76
76
OAc
N
N
N
N
3e
OMe
OMe
3f
f
3.8
4.0
78
75
Me
N
Me
N
3g
g
OMe
Me
Me
MeO
MeO
N
N
MeO
MeO
h
6.2
3.0
73
72
3h
OMe
N
N
N
3i
i
OEt
OEt
N
3j
j
2.7
75
Me
Me

B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 6091–6094
6093
Table 1 (continued)
Entry
Dihydroisoquinoline (1)
Product (3)a
Time (h)
6.2
Yieldb (%)
MeO
MeO
N
N
3k
MeO
MeO
k
73
OEt
a
All products were characterized by NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography.
b
N
N
5 mol% Pd(OAc)2
MeOH, reflux
+
PhI(OAc)2
OMe
N
OAc
Reductive
elimination
OAc
3e
1
2
OAc
N
PdIV
N
Scheme 2. Alkoxylation of 1-phenyl-3,4-dihydroisoquinoline.
Pd(II)
(Y)
N
3,4-dihydroisoquinolines by means of C–H activation involving
ortho-chelating imino group.
In continuation of our interest on oxidative functionalization of
arenes,13 we herein report a novel strategy for the acetoxylation/
alkoxylation of arenes by means of substrate-directed C–H activa-
tion. The starting materials, 1-aryl-3,4-dihydroisoquinolines were
prepared by a known procedure.14 Initially, we attempted the acet-
oxylation of 1-phenyl-3,4-dihydroisoquinoline using 5 mol % of
PhI(OAc)2 and 5 mol % Pd(OAc)2 in the presence of stoichiometric
amount of acetic anhydride at 80 °C. The desired acetoxy product
was obtained in low yield (ca. 20%). The yield was notably in-
creased from 20% to 82% by increasing the amount of PhI(OAc)2
from 5 mol % to stoichiometric amount. Under the above condi-
tions, the reaction proceeds smoothly in 1,2-dichloroethane at
80 °C and provides the 2-(3,4-dihydroisoquinolin-1-yl)phenyl ace-
tate 3a in 82% yield (Scheme 1).
PhI
AcOH
PhI(OAc)2
N
N
PdII
(X)
Scheme 3. A plausible reaction pathway.
In this C–H activation, Pd(OAc)2 activates the aromatic C–H
bond via dihydroisoquinoline directed oxidative insertion. Ac2O
acts as an acetoxylating agent. PhI(OAc)2 acts as the terminal oxi-
dant. The efficiency of other oxidants such as Fe3O4, Ag2O, CuO,
MnO2, and 1,4-benzoquinone was tested for this reaction. To our
surprise, the yields were far from satisfactory when the reactions
were carried out with the above oxidants. Oxone was also found
to be less effective for the acetoxylation of arenes. Thus PhI(OAc)2
was found to be superior in terms of conversion. Next, the acetoxy-
lation was carried out using various amounts of Pd(OAc)2. Under
optimized conditions, the acetoxylation typically requires acetic
anhydride, 5 mol % Pd(OAc)2, and a stoichiometric amount of
PhI(OAc)2 to achieve the products in good yields. Next we per-
formed the acetoxylation at various temperatures in various sol-
vents. The reaction proceeds well in 1,2-dichloroethane and
nitromethane under reflux conditions. But the reaction was found
to be sluggish in acetonitrile and tetrahydrofuran. As solvent, 1,2-
dichloroethane gave the best results at 80 °C.
Under optimized conditions, various 1-aryl-3,4-dihydroisoquin-
olines such as p-methyl-1-phenyl- and m-methyl-1-phenyl- deriv-
atives underwent smooth acetoxylation (Table 1, entries a–c). In
the case of m-methyl substitution on the aromatic ring, the
acetoxylation took place selectively at less sterically hindered
ortho-position (Table 1, entry c). Furthermore, 6,7-dimethoxy-
1-phenyl-3,4-dihydroisoquinoline also participated well in the
acetoxylation (Table 1, entry d). Thus the acetoxylation of 1-
aryl-3,4-dihydroisoquinolines was highly ortho-selective affording
the acetoxylated products in good yields.
Next, we extended this method for the alkoxylation of 1-aryl-
3,4-dihydroisoquinolines. Accordingly, the treatment of 1-phenyl-
3,4-dihydroisoquinoline (1) with
a stoichiometric amount of
PhI(OAc)2 and 5 mol % Pd(OAc)2 in refluxing methanol or ethanol
gave the corresponding alkoxy products (3e–k) in good yields.
Thus, alkoxylation of arenes was achieved by merely changing
the solvent from 1,2-dichloroethane to methanol or ethanol
(Scheme 2).
Interestingly, several 1-aryl-3,4-dihydroisoquinoline deriva-
tives participated well in this oxidative functionalization. No acet-
oxylation was observed in the absence of either Pd(OAc)2 or
PhI(OAc)2. The products were characterized by NMR, IR, and mass
spectroscopy. The scope and generality of this process is illustrated
with respect to various 1-aryl-3,4-dihydroisoquinoline derivatives
and the results are presented in Table 1.15
Mechanistically, C–H bond activation proceeds likely via the
formation of a highly reactive PdII intermediate (X) as shown in
Scheme 3. By the addition of PhI(OAc)2 to (Ph-isoquin)2PdII com-
plex (X) generates the PdIV intermediate (Y). Reductive elimination
via carboxylate dissociation from a 5-coordinate cationic PdIV
intermediate (Y) facilitates the C–O bond formation.11m In this ap-
proach, 3,4-dihydroisoquinoline activates the unactivated C–H
bond of aryl group through ortho-chelating imino group
(Scheme 3).
In summary, we have developed a novel strategy for the
acetoxylation/alkoxylation of 1-aryl-3,4-dihydroisoquinolines by
means of C–H activation. This method is useful for the direct

6094
B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 6091–6094
were dried over anhydrous Na2SO4, concentrated in vacuo and purified by
column chromatography on neutral alumina (ethyl acetate/hexane, 4:6) to
afford the pure acetoxy aryl-3,4-dihydroisoquinoline. The products thus
obtained were characterized by IR, NMR and mass spectroscopy.
acetoxylation and alkoxylation of arenes tethered to 3,4-dihydro-
isoquinoline via the substrate-directed oxidative functionalization.
3a. IR (neat): m ;
max 3063, 2928, 2849, 1767, 1609, 1367, 1193, 1015, 748 cmÀ1
Acknowledgements
1H NMR (300 MHz, CDCl3): d 1.73 (s, 3H), 2.80 (t, 2H, J = 6.8 Hz), 3.85 (t, 2H,
J = 6.8 Hz), 7.01 (d, 1H, J = 7.5 Hz), 7.12–7.23 (m, 3H), 7.26–7.55 (m, 4H); 13C
NMR (75 MHz, CDCl3): d 20.3, 25.8, 47.3, 118.1, 122.7, 125.9, 126.8, 127.1,
127.3, 128.5, 129.9, 130.4, 130.8, 137.4, 148.3, 165.1, 168.6; ESI-MS: m/z: 266
(M+H).
NU thanks the UGC, GNL thanks the CSIR, New Delhi for the
award of fellowships.
3b. IR (neat): mmax 2975, 2932, 1735, 1603, 1457, 1374, 1270, 1109, 986,
References and notes
753 cmÀ1 1H NMR (500 MHz, CDCl3): d 1.72 (s, 3H), 2.34 (s, 3H), 2.76–2.85 (m,
;
2H), 3.79–3.90 (m, 2H), 6.96 (s, 1H), 7.14–7.24 (m, 2H), 7.36–7.43 (m, 2H), 7.67
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(d, 2H, J = 7.6 Hz); ESI-MS: m/z: 280 (M+H).
3c. IR (neat): m ;
max 2926, 1763, 1605, 1489, 1193, 1029, 825, 772 cmÀ1 1H NMR
(400 MHz, CDCl3): d 1.66 (s, 3H), 2.37 (s, 3H), 2.70–2.85 (m, 2H), 3.74–3.92 (m,
2H), 6.95–7.08 (m, 2H), 7.12–7.38 (m, 5H); ESI-MS: m/z: 280 (M+H), 318
(M+K).
3d. IR (neat):
m
;
max 2929, 2850, 1762, 1603, 1510, 1357, 1277, 1206, 1125, 1029,
949, 761 cmÀ1
1H NMR (300 MHz, CDCl3): d 1.81 (s, 3H), 2.69–2.77 (m, 2H),
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3.68 (s, 3H), 3.77–3.88 (m, 5H), 6.54 (s, 1H), 6.75 (s, 1H), 7.06 (d, 1H, J = 8.3 Hz),
7.13–7.17 (m, 1H), 7.27–7.37 (m, 2H); 13C NMR (75 MHz, CDCl3): d 20.3, 22.8,
41.5, 55.7, 55.8, 113.1, 123.1, 125.7, 128.2, 130.1, 131.8, 133, 133.7, 146.3,
148.8, 151.6, 169, 170.4; ESI-MS: m/z: 326 (M+H).
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A mixture of 1-aryl-3,4-dihydroisoquinoline (1 mmol), iodobenzenediacetate
(1.1 mmol), and Pd(OAc)2 (5 mol %) in alcohol (4 mL) was stirred under reflux
for a specified time (Table 1). After complete conversion, as indicated by TLC,
the solvent was removed and the resulting residue was diluted with water
(10 mL) and extracted with dichloromethane (3 Â 10 mL). The combined
organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and
purified by column chromatography on neutral alumina (ethyl acetate/hexane,
4:6) to afford the pure alkoxy aryl-3,4-dihydroisoquinoline. The products thus
obtained were characterized by IR, NMR, and mass spectroscopy.
8. Bermejo, A.; Andreu, I.; Suvire, F.; Leonce, S.; Caignard, D. H.; Renard, P.; Pierre,
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3e. IR (KBr):
m
max 3016, 2925, 2851, 1741, 1608, 1573, 1458, 1430, 1238, 1022,
;
970, 750 cmÀ1
1H NMR (300 MHz, CDCl3): d 2.85 (t, 2H, J = 6.8 Hz), 3.67 (s, 3H),
3.72–4.10 (m, 2H), 6.95 (t, 2H, J = 7.5 Hz), 7.03 (t, 1H, J = 7.5 Hz), 7.10–7.24 (m,
2H), 7.27–7.43 (m, 3H); 13C NMR (75 MHz, CDCl3): d 25.9, 47.5, 55.4, 110.9,
120.7, 126.5, 127.1, 128.6, 129.6, 130, 130.2, 130.3, 136.9, 157.1, 166.3; ESI-
MS: m/z: 238 (M+H); HRMS calcd for C16H16ON: 238.1226, found: 238.1216.
3f. IR (KBr):
m
max 3008, 2946, 2892, 2841, 1607, 1566, 1458, 1404, 1278, 1170,
1032, 929, 814, 745 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 2.41 (s, 3H), 2.82 (t, 2H,
J = 6.8 Hz), 3.65 (s, 3H), 3.67–4.01 (m, 2H), 6.70 (s, 1H), 6.81 (d, 1H, J = 7.5 Hz),
6.94 (d, 1H, J = 7.5 Hz), 7.06–7.32 (m, 4H); 13C NMR (75 MHz, CDCl3): d 21.6,
25.9, 47.5, 55.3, 111.7, 121.3, 125.7, 126.4, 1265.9, 127.1, 129.7, 129.9, 130.1,
136.9, 140.1, 157, 166.1; ESI-MS: m/z: 252 (M+H); HRMS calcd for C17H18NO:
252.1382, found: 252.1381.
3g. IR (neat): mmax 2927, 1728, 1613, 1501, 1462, 1245, 1030, 745 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d 2.32 (s, 3H), 2.75–2.93 (m, 2H), 3.65 (s, 3H), 3.67–
4.02 (m, 2H), 6.79 (d, 1H, J = 9.0 Hz), 6.96 (d, 1H, J = 7.5 Hz), 7.06–7.21 (m, 4H),
7.30 (t, 1H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): d 25.8, 29.6, 47.4, 55.4, 110.9,
114.2, 120.7, 126.5, 127.1, 128.7, 129.6, 129.9, 130.1, 136.9, 144.1, 157.1,
166.2; ESI-MS: m/z: 252 (M+H).
3h. IR (neat):
m
max 2929, 2841, 1742, 1604, 1512, 1460, 1355, 1274, 1208, 1118,
1024, 945, 866, 756 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 2.66–2.88 (m, 2H),
3.54–4.03 (m, 11H), 6.51 (s, 1H), 6.73 (s, 1H), 6.95 (d, 1H, J = 8.3 Hz), 7.04 (t, 1H,
J = 7.5 Hz), 7.32–7.43 (m, 2H); 13C NMR (75 MHz, CDCl3): d 25.6, 47.5, 55.4,
55.8, 55.9, 109.9, 110.8, 120.7, 122.6, 128.6, 130, 130.2, 130.7, 147.1, 150.6,
157, 165.5; LC–MS: m/z: 298 (M+H); HRMS calcd for C18H20NO3: 298.1437,
found: 298.1425.
3i. IR (neat):
m
max 3064, 2927, 2852, 1714, 1607, 1573, 1449, 1238, 1121, 1044,
;
927, 749 cmÀ1
1H NMR (300 MHz, CDCl3): d 1.01 (t, 3H, J = 6.8 Hz), 2.70–2.95
(m, 2H), 3.54–4.25 (m, 4H), 6.91 (d, 1H, J = 8.3 Hz), 6.95–7.08 (m, 2H), 7.11–
7.24 (m, 2H), 7.27–7.45 (m, 3H); 13C NMR (75 MHz, CDCl3): d 14.8, 25.9, 47.4,
63.7, 112.1, 120.7, 126.3, 126.8, 127, 129.9, 130, 130.1, 136.8, 156.5, 166.5; ESI-
MS: m/z: 252 (M+H); HRMS calcd for C17H18NO: 250.1382, found: 252.1374.
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13. (a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391; (b) Reddy, B.
V. S.; Ramesh, K.; Yadav, J. S. Synlett 2011, 169; (c) Reddy, B. V. S.; Revathi, G.;
Reddy, A. S.; Yadav, J. S. Synlett 2011, 2374; (d) Reddy, B. V. S.; Revathi, G.;
Reddy, A. S.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 5926; (e) Reddy, B. V. S.;
Narasimhulu, G.; Umadevi, N.; Yadav, J. S. Synlett 2012, 1364.
3j. IR (KBr):
m
max 2926, 2846, 1706, 1604, 1511, 1384, 1250, 1165, 1113, 1028,
;
825, 751 cmÀ1
1H NMR (300 MHz, CDCl3): d 1.00 (t, 3H, J = 6.8 Hz), 2.39 (s, 3H),
2.71–2.89 (m, 2H), 3.60–4.12 (m, 4H), 6.67 (s, 1H), 6.81 (d, 1H, J = 7.5 Hz), 6.96
(d, 1H, J = 7.5 Hz), 7.04–7.19 (m, 2H), 7.21–7.29 (m, 2H); 13C NMR (75 MHz,
CDCl3): d 21.5, 55.4, 55.5, 58.6, 60.3, 111.5, 116.4, 117.4, 128.5, 129.5, 129.9,
132.5, 132.6, 137.6, 145.2, 152, 152.3, 168.5; ESI-MS: m/z: 266 (M+H).
3k. IR (KBr):
m
max 2925, 2853, 1742, 1604, 1512, 1453, 1355, 1273, 1210, 1118,
1038, 947, 756 cmÀ1
;
1H NMR (500 MHz, CDCl3): d 1.07 (t, 3H, J = 6.6 Hz), 2.60–
14. (a) Yang, C. H.; Tai, C. C.; Sun, I. W. J. Mater. Chem. 2004, 14, 947.
15. Representative procedure for the acetoxylation of arenes: A mixture of 1-aryl-3,4-
dihydro-isoquinoline (1 mmol), iodobenzenediacetate (1.1 mmol), acetic
anhydride (1.1 mmol) and Pd(OAc)2 (5 mol %) in dichloroethane (4 mL) was
stirred under reflux for a specified time (Table 1). After complete conversion, as
indicated by TLC, the reaction mixture was diluted with water (10 mL) and
extracted with dichloromethane (3 Â 10 mL). The combined organic layers
2.92 (m, 2H), 3.49–4.18 (m, 10H), 6.53 (s, 1H), 6.73 (s, 1H), 6.92 (d, 1H,
J = 8.8 Hz), 7.03 (t, 1H, J = 7.7 Hz), 7.33–7.45 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 25.7, 47.4, 55.9, 56, 63.7, 109.8, 110.9, 112.1, 120.8, 122.8, 128.1, 130.1, 130.2,
130.7, 147.1, 150.6, 156.4, 165.9; ESI-MS: m/z: 312 (M+H); HRMS calcd for
C
19H22O3N: 312.1594, found: 312.1579.