Lewis acid catalyzed benzylic C-H bond functionalization of azaarenes; Addition to imines and enones

Article abstract of DOI:10.1055/s-0031-1291041

Lewis acid catalyzed benzylic C-H bond functionalization of alkyl-substituted azaarenes is described. The addition to N-tosyl imines proceeded under solvent-free conditions using various Lewis acids. Cu(OTf) ₂ was the best Lewis acid, and 1,2-a

Full text of DOI:10.1055/s-0031-1291041

SPECIAL TOPIC
▌2185
special topic
Lewis Acid Catalyzed Benzylic C–H Bond Functionalization of Azaarenes;
Addition to Imines and Enones
Lewis Acid Catalyzed C–H Functionalization
Hirotomo Komai,a Tatsuhiko Yoshino,a Shigeki Matsunaga,*a,b Motomu Kanai*a,b
a
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)56845206; E-mail: smatsuna@mol.f.u-tokyo.ac.jp; E-mail: kanai@mol.f.u-tokyo.ac.jp
b
Kanai Life Science Catalysis Project, ERATO, Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received: 06.04.2012; Accepted: 10.04.2012
methyl-substituted azaarenes under proton transfer condi-
Abstract: Lewis acid catalyzed benzylic C–H bond functionaliza-
tions. Our working hypothesis is shown in Scheme 1. Ac-
tion of alkyl-substituted azaarenes is described. The addition to N-
tivation of azaarenes by the coordination to a strong Lewis
acid would increase the acidity of benzylic C–H bonds.
tosyl imines proceeded under solvent-free conditions using various
Lewis acids. Cu(OTf)2 was the best Lewis acid, and 1,2-addition
proceeded at 60–120 °C, giving products in 23–92% yield. On the Cleavage of the C–H bond by either an external base (i.e.,
other hand, strongly Lewis acidic rare-earth metal triflates,
Sc(OTf)3 and Y(OTf)3, were essential to promote the 1,4-addition
of alkyl-substituted azaarenes to enones, and products were ob-
amide to electrophiles, such as imines or enones, would
tained in 60–96% yield.
azaarene 1) or counterions of a Lewis acid would generate
a metal enamide species.15 The addition of the metal en-
generate a metal-amide or an enolate intermediate, which
would afford the product upon protonation. In addition to
the ortho-methyl group activation, we envisioned that the
Key words: nitrogen heterocycles, C–H bond functionalization,
enones, imines, Lewis acids
strategy might also be applicable to compounds with a
para-methyl group by using the azaarene as an external
Metal-catalyzed C(sp3)-H bond functionalizations are
base.
valuable methods in organic synthesis.1,2 Among them,
C(sp3)-H bond activation/C–C bond-forming reactions of
azaarenes, such as pyridines, pyrimidines, quinolines, and
N
isoquinolines, provide straightforward access to useful
building blocks for the design and synthesis of biological-
N
N
N
N
N
N
ly active compounds. To realize the C(sp3)-H bond func-
tionalization of alkyl-substituted azaarenes, transition-
metal-catalyzed chelation-assisted methods for C–C bond
formation have been investigated by many groups.3 Fur-
ther studies to expand the reaction scope for the synthesis
of diverse sets of functionalized azaarenes by enabling the
use of various coupling partners are desirable. To comple-
ment transition-metal-catalyzed processes, Lewis acid
catalyzed couplings of alkyl-substituted azaarenes have
recently been investigated by Huang et al., Rueping et al.,
and other groups.4,5 We also communicated our prelimi-
nary results on the utility of rare-earth metal triflate for the
addition of 2-methyl-azaarenes to enones.5 In this manu-
script, we report full details of our efforts on Lewis acid
catalyzed benzylic C(sp3)-H bond functionalization of
alkyl-substituted azaarenes 1 (Figure 1); Cu(OTf)2-cata-
lyzed addition to imines, and Sc(OTf)3 and Y(OTf)3 cata-
lyzed addition to enones will also be discussed.
1a
1b
1c
1d
1e
1f
MeO2C
N
O
N
N
N
N
1g
1j
1h
1i
Figure 1 Structures of alkyl-substituted azaarenes 1a–i and benzox-
azole 1j
Lewis acid
(LA)
Y
Y
Y
N
N
N
HX
1
H
LA
(or HX•1)
LA
X
imine 2
or
enone 4
On the basis of precedents in Lewis acid catalyzed intra-
molecular C(sp3)-H functionalization,6–12 Lewis acid as-
sisted C(sp2)-H functionalization of pyridines and/or
quinolines,13 as well as our ongoing projects on acid/base-
catalyzed proton transfer processes,14 we envisioned the
use of a Lewis acid for the functionalization of ortho-
PG
R1
LA
PG
R1
HN
N
Y
Y
N
N
HX
(or HX•1)
3
or
or
LA
R2
O
R2
O
Y
Y
N
R3
N
R3
5
SYNTHESIS 2012, 44, 2185–2194
Advanced online publication: 14.05.2012
DOI: 10.1055/s-0031-1291041; Art ID: SS-2012-C0335-ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Working hypothesis for Lewis acid catalyzed C–H func-
tionalization of methyl-substituted azaarenes with imines and enones
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2186
H. Komai et al.
SPECIAL TOPIC
To test the feasibility of our hypothesis, lutidine 1a and addition of 1a to various imines proceeded smoothly at
tosyl-imine 2a were selected as model substrates. In the 80 °C, except for the less reactive 4-methoxy-substituted
previous reports on Lewis acid catalyzed addition of luti- imine, to give products in 76–92% yield.
dine to imines,4 relatively high temperature (120 °C) was
often required to efficiently promote the reaction. Initial
Ts
HN
Cu(OTf)2
attempts to promote the reaction at lower temperature re-
vealed that solvent-free conditions with excess lutidine 1a
(10 equiv) was suitable. As shown in Table 1, various
Lewis acids promoted the model reaction in moderate to
good yield at 80 °C. Among the metals screened,
Mg(OTf)2, Zn(OTf)2, Bi(OTf)3, Sc(OTf)3, and Cu(OTf)2
gave product 3aa in more than 80% yield after 24 hours;
the best reactivity was observed with Cu(OTf)2 (90% iso-
lated yield; Table 1, entry 8). Other less Lewis acidic cop-
per sources resulted in poor reactivity (Table 1, entries 9
and 10); thus Cu(OTf)2 was selected as the best catalyst
for the addition of azaarenes 1 to imines 2.
Ts
H
(10 mol%)
N
ArN
1a–f,j
+
Ph
neat
Ph
temp, 24 h
R
2a
3
R = H or Me
Ts
Ts
HN
HN
N
Ph
N
Ph
3aa
80 °C, 90%
HN
3ea
Ts
120 °C, 87% (2:1 dr)
Ts
N
Ph
N
HN
3ba
120 °C, 63%
Table 1 Effect of Lewis Acid on the Addition of Lutidine 1a to
Imine 2a
N
Ph
Ts
3fa
120 °C, 47%
N
HN
Ts
Ts
Lewis acid
(10 mol%)
HN
Ph
N
3ca
+
120 °C, 68%
N
neat
80 °C, 24 h
N
Ph
Ts
H
2a
Ph
N
HN
Ts
1a
3aa
HN
O
Ph
Entry
Lewis acid
Yield (%)a
N
Ph
3ja
120 °C, trace
3da
60 °C, 83%
1
2
Mg(OTf)2
Al(OTf)3
84
56
75
68
86
84
87
90b
34
35
Scheme 2 Copper-catalyzed addition of azaarenes 1a–f and benzox-
azole 1j to imine 2a. Reagents and conditions: 1 (10 equiv), imine 2a
(0.25 mmol), Cu(OTf)3 (10 mol%), solvent-free conditions, 60, 80 or
120 °C. Isolated yield after purification by silica gel column chroma-
tography is shown for each run.
3
In(OTf)3
4
Fe(OTf)3
5
Zn(OTf)2
Bi(OTf)3
On the other hand, the reactivity of 4-picoline (1c) was
strongly dependent on the reactivity of the imine. Good
yield was obtained for aryl imines with an electron-with-
drawing substituent, but poor to moderate results were ob-
served for less reactive imines (Scheme 3). Although
there remains room for improvement in the reactivity with
4-picoline (1c), the results with 1c are still noteworthy be-
cause previously reported Lewis acid catalyzed condi-
tions were not applicable to this substrate.4a,b On the other
hand, attempts to use enolizable aliphatic imines failed,
possibly due to undesirable isomerization of imines to en-
amides.
6
7
Sc(OTf)3
8
Cu(OTf)2
Cu(OAc)2
CuOTf·0.5PhMe
9
10
a Determined by 1H NMR analysis.
b Isolated yield after purification by column chromatography.
The substrate scope and limitations of donors are summa-
rized in Scheme 2. Benzylic C(sp3)-H bond activation of
methyl-substituted pyridines, quinoline, and pyrimidine
proceeded smoothly. 2-Picoline (1b) was less reactive
than 1a, and higher reaction temperature (120 °C) was re-
quired to obtain 3ba in 63% yield. As expected, the pres-
ent method was applicable to 4-picoline (1c), and 3ca was
obtained in 68% yield. 2-Methylquinoline (1d) showed
good reactivity even at 60 °C, giving 3da in 83% yield af-
ter 24 hours. With 2-ethylpyridine (1e) and 4-methyl-
pyrimidine (1f), the reactions were run at 120 °C, and
products were obtained in 87 and 47% yield, respectively.
On the other hand, only trace amounts, if any, product 3ja
was obtained with benzoxazole. As shown in Scheme 3,
In previous reports, Lewis acid catalyzed 1,2-addition re-
actions to imines and activated carbonyl compounds have
been achieved.4 In contrast, the 1,4-addition to electron-
deficient alkenes under catalytic conditions has not been
investigated.16 Thus, we tried to expand the electrophile
scope to enones; to this end, lutidine 1a and enone 4a were
selected as model substrates.
To our surprise, the reactivity of enones toward azaarenes
was much lower than imines, and Cu(OTf)2, which was
the best catalyst for imines, did not afford the product
(Table 2, entry 1). Because solvent-free conditions with
excess lutidine (1a) were not suitable for the 1,4-addition
reaction, reoptimization of the reaction was performed in
Synthesis 2012, 44, 2185–2194
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Lewis Acid Catalyzed C–H Functionalization
2187
Table 2 Optimization Studies for the Addition to Chalcone
Cu(OTf)2
Ts
R
Ts
N
(10 mol%)
HN
Lewis acid
(x mol%)
1a or 1c
+
O
Ph
O
ArN
neat
H
R
temp, 24 h
+
Ph
Ph solvent
temp
2
3
N
1a
N
Ph
4a
5aa
Ts
Ts
(2.5 equiv)
HN
N
HN
Entry Lewis acid
(x mol%)
Solvent
Temp Time Yield
N
(°C)
(h)
(%)a
3cb
3ab
120 °C, 45%
1
2
Cu(OTf)2 (20)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
14
14
14
14
14
14
14
14
14
14
14
14
14
14
48
72
48
0
0
80 °C, 72%
Ts
Ts
N
HN
Br
HN
Br
Al(OTf)3 (20)
In(OTf)3 (20)
Fe(OTf)3 (20)
Mg(OTf)2 (20)
Zn(OTf)2 (20)
Bi(OTf)3 (20)
Sc(OTf)3 (20)
Y(OTf)3 (20)
Gd(OTf)3 (20)
Sm(OTf)3 (20)
La(OTf)3 (20)
ScBr3 (20)
N
3
0
4
0
3cc
120 °C, 76%
3ac
80 °C, 89%
5
0
Ts
Ts
HN
N
HN
6
0
N
7
0
CF3
CF3
3ad
80 °C, 92%
3cd
120 °C, 82%
8
71
71
33
0
Ts
HN
Ts
9
N
HN
N
10
11
12
13
14
15
16
17
OMe
3ae
120 °C, 76%
OMe
3ce
120 °C, 23%
trace
51
30
73b
90b
90b
Ts
HN
Ts
N
HN
O
N
O
ScCl3 (20)
3af
80 °C, 76%
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
3cf
120 °C, 46%
Scheme 3 Copper-catalyzed addition of lutidine (1a) and 4-picoline
(1c) to imines 2: Reagents and conditions: 1 (10 equiv), imine 2 (0.25
mmol), Cu(OTf)3 (10 mol%), solvent-free conditions, 80 or 120 °C.
Isolated yield after purification by silica gel column chromatography
is shown for each run.
1,2-Cl2-C6H4 160
a Determined by 1H NMR analysis.
b Isolated yield after purification by column chromatography.
hours using 10 mol% Sc(OTf)3 (90% isolated yield; Table
2, entry 17).
chlorobenzene. Rescreening of other Lewis acids revealed
that Al(OTf)3, In(OTf)3, Fe(OTf)3, Mg(OTf)2, Zn(OTf)2,
and Bi(OTf)3, which were also useful for the addition to
imines, did not promote the desired reaction at all (Table
2, entries 2–7). On the other hand, the results using rare-
earth metal triflates [RE(OTf)3] were promising (Table 2,
entries 8–12). The reactivity changed in correlation with
the Lewis acidity of rare earth metal triflates (Sc, Y > Gd
> Sm, La) reported by Imamoto and co-workers,17 and 20
mol% Sc(OTf)3 and Y(OTf)3 gave the best reactivity
(71% yield in both cases; Table 2, entries 8 and 9). The
differing ability of Lewis acids to effect 1,2-addition and
1,4-addition implied that the activation of electrophiles by
Lewis acid in the presence of stoichiometric amounts of
Lewis basic azaarenes 1 would be a key to efficient pro-
motion of the 1,4-addition reaction. ScBr3 and ScCl3 were
also examined, but the yield was not satisfactory (Table 2,
entries 13 and 14). The reaction proceeded in good yield
with 10 mol% Sc(OTf)3, although a longer reaction time
was required at 120 °C (72 h, 90% isolated yield; Table 2,
entry 16). At 160 °C, the reaction was complete after 48
The substrate scope and limitations of donors is summa-
rized in Scheme 4. Benzylic C(sp3)-H of alkyl-substituted
pyridines, quinoline, isoquinoline, pyrimidine, phenanth-
roline, and benzoxazole were investigated. 2-Picoline
(1b) was less reactive than 1a, and 20 mol% Sc(OTf)3 at
160 °C was required to obtain 5ba in 74% yield. In con-
trast to the 1,2-addition to imines (Scheme 2 and Scheme
3), use of 4-picoline (1c) resulted in poor yield even at
high temperature and using high catalyst loading. At-
tempts to improve the yield with 1c as the donor was not
successful in 1,4-addition. 2-Ethylpyridine (1e) reacted
smoothly and selectively at the benzylic position. The use
of 10 mol% Y(OTf)3 at 120 °C was optimal for 2-ethyl-
pyridine (1e), and the product 5ea was obtained in 79%
yield after 48 hours; the diastereoselectivity was, howev-
er, poor (5:4 dr). Other azaarenes, such as quinoline, py-
rimidine, isoquinoline, and phenanthroline showed good
reactivity with 10 mol% Sc(OTf)3 at 120 °C, giving prod-
ucts 5da, 5fa, 5ga, and 5ia in 65–96% yield. Methyl-sub-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2185–2194

2188
H. Komai et al.
SPECIAL TOPIC
stituted pyridine 1h, bearing an ester functional group, Because the N-acylpyrrole unit can be regarded as an ester
was compatible under the reaction conditions, and 5ha surrogate, its synthetic utility was examined in a number
was obtained in 60% yield. 2-Methylbenzoxazole (1j) was of transformations.
also applicable, giving product 5ja in 76% yield.
Table 3 Scandium-Catalyzed Addition of Azaarene 1d to Enonesa
Sc(OTf)3
O
Ph
O
Sc(OTf)3
or
Y(OTf)3
(10 mol%)
(10 mol%)
ArN
+
ArN
Ph
Ph
N
Ph
R
solvent (1.0 M)
temp
R1
O
1d
+
1a–j
(2.5 equiv)
4a
R
5
R2
O
PhCl, 120 °C
R = H or Me
N
5
R1
R2
Ph
O
N
Ph
O
4
N
Ph
N
Ph
Entry R1
R2
4
Cat. Time 5
Yield
(%)b
1,2-Cl2C6H4, 160 °C
48 h, 5aa, 90%
PhCl, 120 °C
72 h, 5fa, 65%
(h)
Ph
O
1
2
3
4
5
6
7
8c
Ph
Ph
4-FC6H4
4b
Y
Y
36 5db 91
48 5dc 79
Ph
O
N
Ph
4-MeOC6H4 4c
1,2-Cl2C6H4, 160 °C
72 h, 5ba, 74%a
N
Ph
O
PhCl, 120 °C
72 h, 5ga, 75%
4-ClC6H4
4-MeOC6H4
Ph
Ph
4d Sc 72 5dd 86
Ph
4e
4f
Y
48 5de 81
MeO2C
N
Ph
O
Ph
2-thienyl
3-thienyl
Ph
Sc 72 5df 72
Ph
N
Ph
Ph
1,2-Cl2C6H4, 160 °C
72 h, 5ca, <10%a
PhCl, 120 °C
48 h, 5ha, 60%
Ph
4g Sc 72 5dg 93
2-furyl
4h
4i
Y
Y
36 5dh 85
48 5di 78
Ph
O
Ph
O
(E)-PhCH=CH Ph
N
a Reaction conditions: 1d (2.5 equiv), enone 4 (0.25 mmol), Sc(OTf)3
or Y(OTf)3 (10 mol%), solvent (1.0 M), 120 °C unless otherwise
N
Ph
N
PhCl, 120 °C
48 h, 5da, 95%
PhCl, 120 °C
72 h, 5ia, 96%
noted.
b Isolated yield after purification by silica gel column chromatogra-
Ph
O
phy.
c 20 mol% of Sc(OTf)3 was used.
N
Ph
O
N
Ph
O
Ph
PhCl, 120 °Cb
48 h, 5ea, 79% (5:4 dr)
1,2-Cl2C6H4, 160 °C
48 h, 5ja, 76%
Sc(OTf)3
O
(10 mol%)
1d (2.5 equiv)
Ph
O
O
Ph
N
Scheme 4 Scandium-catalyzed addition of azaarenes 1 to chalcone
4a: Reagents and conditions: 1 (2.5 equiv), chalcone 4a (0.25 mmol),
Sc(OTf)3 (10 mol%), solvent (1.0 M), 120–160 °C unless otherwise
noted. Isolated yield after purification by silica gel column chroma-
tography is shown for each run. a 20 mol% of Sc(OTf)3 was used. b 10
mol% of Y(OTf)3 was used instead of Sc(OTf)3.
PhCl, 120 °C
72 h
N
N
N
4j
5dj: 81%
NaOEt
Ph
5dj
EtOH, r.t., 20 min
OEt
The substrate scope of acceptors is summarized in Table
3. The reactions of chalcone derivatives 4b–e with either
an electron-withdrawing group or an electron-donating
group proceeded in good yield (79–91%). Heteroaryl-
substituted enones 4f–h were also applicable, giving the
products in 72–93% yield. With dienone 4i, 1,4-addition
predominated over 1,6-addition, and the 1,4-adduct 5di
was obtained in 78% yield.
6dj: 92%
pyrolidine, DBU
THF, 60 °C, 12 h
Ph
O
5dj
5dj
N
N
7dj: 84%
1) DIBAL-H, CH2Cl2
–78 °C, 10 min
Ph
O
2) (EtO)2P(O)CH2CO2Et
LiCl, DBU, MeCN
r.t., 1 h
N
OEt
Although the 1,4-addition to chalcone derivatives pro-
ceeded smoothly, less reactive alkenes, such as alkyl sub-
stituted enones and α,β-unsaturated esters, did not afford
the desired products. To compensate the limited generali-
ty of electrophiles, we investigated the use of α,β-unsatu-
rated N-acylpyrrole 4j as an electrophile (Scheme 5). The
reactivity of 4j was similar to that of chalcone deriva-
tives,18,19 and the product 5dj was obtained in 81% yield.
8dj: 85%
Scheme 5 1,4-Addition of 1d to α,β-unsaturated N-acylpyrrole 4j
and transformation of the N-acylpyrrole unit of 5dj
The N-acylpyrrole unit was readily converted into an ethyl
ester unit by treatment with sodium ethoxide at room tem-
Synthesis 2012, 44, 2185–2194
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Lewis Acid Catalyzed C–H Functionalization
2189
4-Methyl-N-[1-phenyl-2-(pyridine-4-yl)ethyl]benzenesulfon-
amide (3ca)
perature for 20 minutes, giving 6dj in 92% yield. Substi-
tution with pyrrolidine also proceeded smoothly in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at
60 °C for 12 hours (7dj; 84% yield). In addition to substi-
tution reactions, the reduction of 5dj with diisobutylalu-
minum hydride (DIBAL-H) gave pyrrole carbinols as
diastereomeric mixtures. Under Masamune–Roush condi-
tions,20 α,β-unsaturated ethyl ester 8dj, which can be re-
garded as 1,6-addition adduct of 1d, was obtained in 85%
yield (two steps) via generation of the aldehyde in situ
from the crude pyrrole carbinols.
Prepared according to General Procedure A.
Yield: 59.9 mg (68%); colorless liquid.
IR (neat): 3275, 3030, 2859, 1602, 1456, 1326, 1157, 1092, 811,
701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.34 (s, 3 H), 2.98 (dd, J = 7.4,
13.8 Hz, 1 H), 3.06 (dd, J = 7.0, 13.8 Hz, 1 H), 4.52 (ddd, J = 7.0,
7.0, 7.4 Hz, 1 H), 6.78–6.88 (m, 2 H), 6.92–7.02 (m, 2 H), 7.06–
7.19 (m, 4 H), 7.42–7.51 (m, 2 H), 8.20–8.40 (br s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.4, 43.2, 58.6, 124.6, 126.5,
126.9, 127.9, 128.6, 129.4, 137.1, 139.5, 143.3, 145.7, 149.6.
In summary, we have succeeded in the Lewis acid cata-
lyzed functionalization of benzylic C(sp3)-H in alkyl-
substituted azaarenes under proton transfer conditions.
The addition to N-Ts imines proceeded under solvent-free
conditions using various Lewis acids. Cu(OTf)2 was the
best Lewis acid, and 1,2-addition of various azaarenes in-
cluding 4-picoline proceeded at 60–120 °C, giving the de-
sired products in 23–92% yield. On the other hand,
strongly Lewis acidic rare earth metal triflates, Sc(OTf)3
and Y(OTf)3, were essential to promote the 1,4-addition
of alkyl-substituted azaarenes to enones and an α,β-unsat-
urated N-acylpyrrole, and products were obtained in 60–
96% yield. Transformation of the product from α,β-unsat-
urated N-acylpyrrole was also demonstrated.
MS (ESI): m/z = 375 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H20N2NaO2S+: 375.1143;
found: 375.1139.
4-Methyl-N-[1-phenyl-2-(pyridine-2-yl)propyl]benzenesulfon-
amide (3ea)
Prepared according to General Procedure A.
Yield: 79.6 mg (87%); colorless solid; diastereomeric mixture (dr
2:1).
IR (KBr): 3276, 1560, 1436, 1326, 1160, 1093, 915, 813, 669 cm–1.
1H NMR (500 MHz, CDCl3): δ (major isomer) = 1.18 (d, J = 7.4 Hz,
3 H), 2.25 (s, 3 H), 3.13–3.24 (m, 1 H), 4.46–4.55 (m, 1 H), 6.76 (d,
J = 8.0 Hz, 1 H), 6.81–6.88 (m, 2 H), 6.96–7.08 (m, 5 H), 7.28 (d,
J = 7.9 Hz, 1 H), 7.37–7.45 (m, 3 H), 7.76–7.80 (m, 1 H), 8.45–8.50
(m, 1 H); δ (minor isomer) = 1.21 (d, J = 7.0 Hz, 3 H), 2.30 (s, 3 H),
3.04–3.14 (m, 1 H), 4.53–4.60 (m, 1 H), 6.72 (d, J = 7.7 Hz, 1 H),
7.05–7.12 (m, 5 H), 7.34 (d, J = 6.4 Hz, 1 H), 7.44–7.50 (m, 3 H),
7.79–7.82 (m, 1 H), 8.49–8.54 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 15.1, 21.3, 45.7, 62.1, 121.9,
122.4, 126.4, 126.8, 127.0, 127.6, 129.0, 136.6, 137.3.139.2, 142.5,
148.6, 161.7; δ (second isomer) = 19.1, 21.5, 46.8, 62.6, 121.9,
123.4, 126.4, 126.8, 127.4, 127.9, 129.0, 136.7, 138.9, 143.4, 148.7,
162.1.
Infrared (IR) spectra were recorded with a JASCO FT/IR 410 Fou-
rier transform infrared spectrophotometer. NMR spectra were re-
corded with JEOL JNM-LA500 and JNM-ECX500 spectrometers,
operating at 500 MHz for 1H NMR and 125.65 MHz for 13C NMR.
Chemical shifts in CDCl3 are reported relative to CHCl3 (δ = 7.26
ppm for 1H NMR) and CDCl3 (δ = 77.0 ppm for 13C NMR) as an in-
ternal reference, respectively. ESI mass spectra were measured with
a Waters ZQ4000 spectrometer (LRMS), and a JEOL JMS-T100LC
AccuTOF spectrometer (HRMS). Column chromatography was
performed with silica gel Merck 60 (230–400 mesh ASTM). Reac-
tions were carried out using flame-dried glassware in anhydrous
solvents under an argon atmosphere.
LRMS (ESI): m/z = 389 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H22N2NaO2S+: 389.1300;
found: 389.1304.
4-Methyl-N-[1-phenyl-2-(pyrimidin-4-yl)ethyl]benzenesulfon-
amide (3fa)
Prepared according to General Procedure A.
Copper-Catalyzed Addition of 1 to 2; General Procedure A
(Scheme 2 and Scheme 3)
To a flame-dried test tube was added Cu(OTf)2 (0.025 mmol, 10
mol%) in a glove box. To the test tube were further added imine 2
(0.25 mmol) and azaarene 1 (2.5 mmol) at r.t. The mixture was
stirred at 120, 80 or 60 °C for 24 h, and then diluted with EtOAc and
quenched by passing through a short pad of silica gel. After evapo-
ration of the solvent, the crude residue was purified by flash silica
gel column chromatography (hexane–EtOAc, 4:1→1:1) to give 3.
Compounds 3aa, 3ba, 3da, 3ab, 3ac, 3ad, 3ae, and 3af are
known.3i,4a,b
Yield: 41.5 mg (47%); colorless solid; mp 106–107 °C.
IR (KBr): 3855, 3189, 2926, 2381, 1586, 1314, 1062, 964, 810, 705,
660 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.28 (s, 3 H), 2.97–3.09 (m, 2 H),
4.67–4.78 (m, 1 H), 6.43 (d, J = 6.4 Hz, 1 H), 6.85 (d, J = 4.9 Hz,
1 H), 6.98–7.15 (m, 8 H), 7.42–7.52 (m, 2 H), 8.34–8.53 (m, 1 H),
8.98 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.4, 44.0, 57.0, 121.6, 126.4,
127.0, 127.6, 128.4, 129.3, 137.4, 140.0, 143.0, 157.1, 158.2, 165.9.
MS (ESI): m/z = 376 [M + Na]+.
Scandium-Catalyzed Addition of 1 to 4a; General Procedure B
(Scheme 4 and Table 3)
To a flame-dried test tube was added Sc(OTf)3 or Y(OTf)3 (0.025
mmol, 10 mol%) in a glove box. To the test tube were further added
enone 4 (0.25 mmol), chlorobenzene or 1,2-dichlorobenzene (0.25
mL), and azaarene 1 (0.625 mmol), at r.t. The resulting mixture was
stirred at 120 or 160 °C for the time indicated in Scheme 4 and
Table 3, and then diluted with EtOAc and quenched by passing
through a short pad of silica gel. After evaporation of the solvent,
the crude residue was purified by flash silica gel column chroma-
tography (hexane–EtOAc, 10:1→4:1) to give 5.
HRMS (ESI): m/z [M + Na]+ calcd for C19H19N3NaO2S+: 376.1096;
found: 376.1092.
4-Methyl-N-[1-(naphthalene-1-yl)-2-(pyridine-4-yl)]benzene-
sulfonamide (3cb)
Prepared according to General Procedure A.
Yield: 45.2 mg (45% ); colorless solid; mp 110–112 °C.
IR (KBr): 3855, 3271, 2923, 1604, 1422, 1327, 1158, 1079, 743,
669 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2185–2194

2190
H. Komai et al.
SPECIAL TOPIC
1H NMR (500 MHz, CD3CN): δ = 2.10 (s, 3 H), 2.93 (dd, J = 8.5,
13.9 Hz, 1 H), 2.99 (dd, J = 6.1, 13.9 Hz, 1 H), 5.22 (ddd, J = 6.1,
8.0, 8.5 Hz, 1 H), 6.26 (d, J = 8.0 Hz, 1 H), 6.72–6.83 (m, 2 H),
6.86–6.96 (m, 2 H), 7.11–7.24 (m, 2 H), 7.20 (dd, J = 8.3, 8.3 Hz,
1 H), 7.27–7.40 (m, 3 H), 7.57 (d, J = 8.3 Hz, 1 H), 7.68 (dd, J = 2.5,
5.8 Hz, 1 H), 7.84 (d, J = 7.0 Hz, 1 H), 8.05–8.20 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C21H22N2NaO2S+: 405.1249;
found: 405.1240.
N-[1-(Furan-2-yl)-2-(pyridin-4-yl)ethyl]-4-methylbenzenesul-
fonamide (3cf)
Prepared according to General Procedure A.
Yield: 39.3 mg (46%); colorless solid; mp 115–118 °C.
IR (KBr): 3243, 2855, 1604, 1337, 1160, 1094, 846, 740, 660 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.39 (s, 3 H), 3.10 (dd, J = 7.3,
13.3 Hz, 1 H), 3.16 (dd, J = 5.8, 13.3 Hz, 1 H), 4.67–4.77 (m, 1 H),
5.83 (br s, 1 H), 5.93 (d, J = 8.9 Hz, 1 H), 6.14 (d, J = 1.3 Hz, 1 H),
6.77–6.92 (m, 2 H), 7.11–7.26 (m, 3 H), 7.55–7.64 (m, 2 H), 8.25–
8.43 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.4, 43.1, 55.3, 123.4, 125.5,
125.7, 126.3, 126.7, 127.4, 127.5, 128.9, 130.0, 130.1, 131.2, 134.7,
137.8, 138.7, 144.0, 147.6, 150.5.
MS (ESI): m/z = 425 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C24H22N2NaO2S+: 425.1300;
found: 425.1301.
13C NMR (125 MHz, CDCl3): δ = 21.4, 40.5, 52.2, 107.8, 110.3,
124.7, 126.8, 129.4, 137.5, 142.0, 143.2, 145.5, 149.4, 151.5.
MS (ESI): m/z = 365 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18N2NaO3S+: 365.0936;
N-[1-(2-Bromophenyl)-2-(pyridine-4-yl)ethyl]-4-methylben-
zenesulfonamide (3cc)
Prepared according to General Procedure A.
Yield: 81.7 mg (76%); colorless solid; mp 106–108 °C.
IR (KBr): 3855, 3651, 2402, 1603, 1420, 1328, 1157, 1092, 951,
661 cm–1.
found: 365.0941.
1H NMR (500 MHz, CDCl3): δ = 2.34 (s, 3 H), 2.77 (dd, J = 9.5,
14.1 Hz, 1 H), 3.03 (dd, J = 5.2, 14.1 Hz, 1 H), 4.91–5.06 (m, 1 H),
5.85 (d, J = 7.3 Hz, 1 H), 6.86–7.10 (m, 5 H), 7.13 (dd, J = 7.4,
7.4 Hz, 1 H), 7.21 (d, J = 7.4 Hz, 1 H), 7.45–7.50 (m, 3 H), 8.16–
8.72 (br, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.4, 41.8, 57.5, 122.3, 126.9,
127.8, 128.3, 129.1, 129.4, 132.9, 136.3, 139.2, 143.4, 145.4, 149.6.
4-(6-Methylpyridin-2-yl)-1,3-diphenylbutan-1-one (5aa)
Prepared according to General Procedure B.
Yield: 70.9 mg (90%); colorless solid; mp 86–87 °C.
IR (KBr): 3061, 2944, 1677, 1595, 1499, 1222, 760, 699 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.48 (s, 3 H), 3.17 (d, J = 7.6 Hz,
2 H), 3.35 (dd, J = 5.8, 16.5 Hz, 1 H), 3.41 (dd, J = 7.5, 16.5 Hz,
1 H), 3.90–4.00 (m, 1 H), 6.87 (d, J = 7.7 Hz, 1 H), 6.94 (d, J =
7.7 Hz, 1 H), 7.13–7.20 (m, 1 H), 7.23–7.32 (m, 4 H), 7.38–7.46
(m, 3 H), 7.50–7.56 (m, 1 H), 7.84–7.90 (m, 2 H).
13C NMR (CDCl3, 125 MHz): δ = 24.4, 41.6, 44.3, 45.2, 120.5,
120.7, 126.4, 127.6, 128.1, 128.4, 128.4, 132.8, 136.4, 137.2, 144.3,
157.7, 159.2, 198.8.
MS (ESI): m/z 453 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H19N2NaO2SBr+:
453.0248; found: 453.0240.
4-Methyl-N-{2-(pyridine-4-yl)-1-[4-(trifluoromethyl)phe-
nyl]ethyl}benzenesulfonamide (3cd)
Prepared according to General Procedure A.
MS (ESI): m/z = 338 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H21NNaO+: 338.1521;
found: 338.1515.
Yield: 86.1 mg (82%); colorless solid; mp 109–110 °C.
IR (KBr): 3855, 3736, 3066, 2852, 1606, 1421, 1325, 1160, 1067,
813, 661 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.32 (s, 3 H), 2.94 (dd, J = 7.0,
14.1 Hz, 1 H), 3.02 (dd, J = 8.0, 14.1 Hz, 1 H), 4.62 (ddd, J = 7.0,
7.3, 8.0 Hz, 1 H), 5.79–5.96 (m, 1 H), 6.78–6.94 (m, 2 H), 6.97–
7.16 (m, 4 H), 7.30–7.44 (m, 4 H), 8.30–8.40 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.3, 42.8, 58.1, 124.6, 125.4 (q,
3JC–F = 3.9 Hz), 126.0 (q, 1JC–F = 272 Hz), 126.8, 127.0, 129.4, 129.9
(q, 2JC–F = 32.6 Hz), 136.8, 143.5, 143.6, 145.3, 149.6.
1,3-Diphenyl-4-(pyridin-2-yl)butan-1-one (5ba)
Prepared according to General Procedure B.
Yield: 55.7 mg (74%); colorless solid; mp 89–90 °C.
IR (KBr): 3028, 2926, 1677, 1472, 1449, 1260, 985, 749, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.08 (dd, J = 7.3, 13.2 Hz, 1 H),
3.15 (dd, J = 7.9, 13.2 Hz, 1 H), 3.25–3.36 (m, 2 H), 3.81–3.90 (m,
1 H), 6.95–7.02 (m, 2 H), 7.05–7.09 (m, 1 H), 7.13–7.20 (m, 4 H),
7.29–7.37 (m, 2 H), 7.40–7.48 (m, 2 H), 7.75–7.81 (m, 2 H), 8.38–
8.44 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 41.7, 44.4, 45.1, 121.2, 123.6,
126.4, 127.6, 128.0, 128.4, 128.4, 132.8, 136.1, 137.2, 144.0, 149.2,
159.9, 198.6.
MS (ESI): m/z = 443 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19N2NaO2SF3 :
+
443.1017; found: 443.1023.
N-[1-(4-Methoxyphenyl)-2-(pyridine-4-yl)ethyl]-4-methylben-
zenesulfonamide (3ce)
Prepared according to General Procedure A.
MS (ESI): m/z = 324 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19NNaO+: 324.1364;
Yield: 22.0 mg (23%); colorless solid; mp 138–140 °C.
found: 324.1372.
IR (KBr): 3854, 3736, 3049, 1597, 1314, 1065, 971, 765, 705, 660
cm–1.
1,3-Diphenyl-4-(quinolin-2-yl)butan-1-one (5da)
Prepared according to General Procedure B.
1H NMR (500 MHz, CDCl3): δ = 2.35 (s, 3 H), 2.95 (dd, J = 8.0,
13.5 Hz, 1 H), 3.06 (dd, J = 7.0, 13.5 Hz, 1 H), 3.71 (s, 3 H), 4.44
(ddd, J = 7.0, 7.1, 8.0 Hz, 1 H), 5.52 (d, J = 7.1 Hz, 1 H), 6.61–6.65
(m, 2 H), 6.78–6.92 (m, 4 H), 7.04–7.13 (m, 2 H), 7.42–7.51 (m,
2 H), 8.30–8.33 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.4, 43.2, 55.2, 58.2, 113.9,
124.7, 126.9, 127.8, 129.4, 131.5, 137.3, 143.2, 146.0, 149.5, 159.1.
Yield: 83.4 mg (95%); colorless solid; mp 94–95 °C.
IR (KBr): 3061, 2943, 1677, 1595, 1507, 1416, 1224, 1076, 748,
701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.32–3.51 (m, 4 H), 4.04–4.13 (m,
1 H), 7.14–7.20 (m, 1 H), 7.21–7.32 (m, 5 H), 7.34–7.41 (m, 2 H),
7.44–7.52 (m, 2 H), 7.62–7.69 (m, 1 H), 7.74 (d, J = 8.3 Hz, 1 H),
7.81–7.87 (m, 2 H), 7.95–8.02 (m, 2 H).
MS (ESI): m/z = 405 [M + Na]+.
Synthesis 2012, 44, 2185–2194
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Lewis Acid Catalyzed C–H Functionalization
2191
13C NMR (125 MHz, CDCl3): δ = 41.4, 44.4, 45.8, 121.9, 125.8,
126.5, 126.8, 127.5, 127.6, 128.1, 128.4, 128.5, 128.9, 129.3, 132.8,
136.1, 137.1, 144.1, 147.8, 160.4, 198.7.
MS (ESI): m/z = 374 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H21NNaO+: 374.1521;
HRMS (ESI): m/z [M + Na]+ calcd for C25H21NNaO+: 374.1521;
found: 374.1529.
Methyl 6-(4-oxo-2,4-diphenylbutyl)nicotinate (5ha)
Prepared according to General Procedure B.
Yield: 52.1 mg (60%); colorless solid; mp 89–90 °C.
found: 374.1527.
IR (KBr): 3026, 2926, 1720, 1677, 1594, 1449, 1380, 1354, 1260,
1076, 749, 700 cm–1.
1,3-Diphenyl-4-(pyridin-2-yl)pentan-1-one (5ea)
Prepared according to General Procedure B as a 5:4 diastereomeric
mixture. Attempts to isolate each diastereoisomer resulted in fail-
ure.
1H NMR (500 MHz, CDCl3): δ = 3.19 (dd, J = 7.9, 13.4 Hz, 1 H),
3.32 (dd, J = 7.3, 13.4 Hz, 1 H), 3.36–3.44 (m, 2 H), 3.91 (s, 3 H),
3.92–3.98 (m, 1 H), 7.04–7.09 (m, 1 H), 7.13–7.34 (m, 5 H), 7.37–
7.45 (m, 2 H), 7.50–7.56 (m, 1 H), 7.84–7.90 (m, 2 H), 8.08 (dd, J =
1.9, 8.0 Hz, 1 H), 9.07 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 41.4, 44.5, 45.0, 52.2, 123.3,
123.7, 126.6, 127.5, 128.0, 128.5, 128.5, 133.0, 137.1, 143.5, 150.4,
164.5, 165.9, 198.4.
Yield: 62.2 mg (79%); colorless oil.
IR (neat): 3039, 2962, 1677, 1593, 1449, 1260, 749, 699 cm–1.
1H NMR (500 MHz, CDCl3): δ (major isomer) = 1.40 (d, J = 7.0 Hz,
3 H), 3.29–3.36 (m, 1 H), 3.42 (dd, J = 9.0, 16.3 Hz, 1 H), 3.54 (dd,
J = 4.9, 16.3 Hz, 1 H), 3.81–3.87 (m, 1 H), 6.88 (d, J = 8.0 Hz, 1 H),
6.99–7.19 (m, 4 H), 7.27–7.47 (m, 5 H), 7.49–7.53 (m, 1 H), 7.83–
7.87 (m, 2 H), 8.47 (d, J = 4.3 Hz, 1 H); δ (minor isomer) = 1.08 (d,
J = 7.0 Hz, 3 H), 2.99 (dd, J = 3.7, 16.2 Hz, 1 H), 3.20–3.29 (m,
2 H), 3.68–3.75 (m, 1 H), 6.99–7.14 (m, 5 H), 7.27–7.47 (m, 5 H),
7.61–7.66 (m, 1 H), 7.67–7.71 (m, 2 H), 8.58 (d, J = 4.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 17.4, 41.3, 46.6, 47.6, 121.1,
122.7, 126.1, 127.9, 128.0, 128.3, 128.4, 132.7, 136.6, 137.3, 142.8,
148.8, 164.1, 199.1; δ (second isomer) = 19.8, 44.0, 47.1, 47.8,
121.6, 122.4, 126.5, 128.0, 128.3, 128.3, 128.4, 132.6, 135.8, 137.1,
143.1, 149.3, 165.0, 198.9.
MS (ESI): m/z = 382 [M + Na]+.
+
HRMS (ESI): m/z [M + Na]+ calcd for C23H21NNaO3 : 382.1419;
found: 382.1414.
4-(9-Methyl-1,10-phenanthrolin-2-yl)-1,3-diphenylbutan-1-one
(5ia)
Prepared according to General Procedure B.
Yield: 99.9 mg (96%); colorless solid; mp 151–152 °C.
IR (KBr): 3051, 1678, 1449, 1380, 1260, 1075, 749, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.93 (s, 3 H), 3.49 (dd, J = 8.6,
16.8 Hz, 1 H), 3.57 (dd, J = 6.4, 14.1 Hz, 1 H), 3.66–3.74 (m, 2 H),
4.12–4.22 (m, 1 H), 7.13–7.18 (m, 1 H) 7.23–7.31 (m, 4 H), 7.33–
7.40 (m, 3 H), 7.41–7.44 (m, 1 H), 7.45–7.50 (m, 1 H), 7.66 (d, J =
8.9 Hz, 1 H), 7.69 (d, J = 8.9 Hz, 1 H), 7.81–7.86 (m, 2 H), 8.05 (d,
J = 8.2 Hz, 1 H), 8.10 (d, J = 8.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 25.9, 41.2, 44.6, 45.7, 123.1,
123.4, 125.4, 125.6, 126.4, 126.8, 127.2, 127.8, 128.1, 128.2, 128.4,
132.5, 136.1, 136.2, 137.2, 144.5, 145.4, 145.5, 159.1, 160.5, 199.0.
MS (ESI): m/z = 316 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H22NO+: 316.1701; found:
316.1700.
1,3-Diphenyl-4-(pyrimidin-4-yl)butan-1-one (5fa)
Prepared according to General Procedure B.
Yield: 49.1 mg (65%); colorless solid; mp 92–93 °C.
IR (KBr): 3033, 2929, 1676, 1580, 1470, 1380, 1075, 740, 701
cm–1.
MS (ESI): m/z = 439 [M + Na]+.
1H NMR (500 MHz, CDCl3): δ = 3.10 (dd, J = 8.5, 13.6 Hz, 1 H),
3.25 (dd, J = 6.5, 13.6 Hz, 1 H), 3.41 (d, J = 6.7 Hz, 2 H), 3.92–3.99
(m, 1 H), 7.00 (d, J = 6.2 Hz, 1 H), 7.14–7.26 (m, 5 H), 7.41–7.45
(m, 2 H), 7.52–7.56 (m, 1 H), 7.83–7.89 (m, 2 H), 8.49 (d, J =
5.1 Hz, 1 H), 9.06 (s, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C29H24N2NaO+: 439.1786;
found: 439.1789.
4-(Benzo[d]oxazol-2-yl)-1,3-diphenylbutan-1-one (5ja)
Prepared according to General Procedure B.
13C NMR (125 MHz, CDCl3): δ = 40.7, 44.2, 44.6, 121.3, 126.8,
127.5, 128.0, 128.6, 128.6, 133.1, 137.0, 143.1, 156.5, 158.6, 168.4,
198.2.
MS (ESI): m/z = 325 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H18N2NaO+: 325.1317;
Yield: 64.8 mg (76%); yellow solid; mp 107–108 °C.
IR (KBr): 2926, 1678, 1594, 1541, 1437, 1260, 1075, 749, 700
cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.25 (dd, J = 7.0, 15.0 Hz, 1 H),
3.32 (dd, J = 7.9, 15.0 Hz, 1 H), 3.37–3.44 (m, 2 H), 4.01–4.09 (m,
1 H), 7.07–7.13 (m, 1 H), 7.15–7.27 (m, 6 H), 7.31–7.39 (m, 3 H),
7.42–7.48 (m, 1 H), 7.50–7.56 (m, 1 H), 7.76–7.83 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 35.4, 39.1, 44.3, 110.4, 119.7,
124.1, 124.6, 126.9, 127.3, 128.0, 128.5, 128.7, 133.1, 136.9, 141.2,
143.0, 150.8, 165.0, 197.9.
found: 325.1309.
4-(Isoquinolin-1-yl)-1,3-diphenylbutan-1-one (5ga)
Prepared according to General Procedure B.
Yield: 65.8 mg (75%); colorless solid; mp 84–85 °C.
MS (ESI): m/z = 364 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H19NNaO2 : 364.1313;
IR (KBr): 2942, 1678, 1597, 1501, 1379, 1259, 1178, 1032, 903,
821, 701 cm–1.
+
1H NMR (500 MHz, CDCl3): δ = 3.44 (dd, J = 7.3, 17.0 Hz, 1 H),
3.50 (dd, J = 6.1, 17.0 Hz, 1 H), 3.62–3.73 (m, 2 H), 4.06–4.15 (m,
1 H), 7.11–7.17 (m, 1 H), 7.19–7.32 (m, 4 H), 7.34–7.42 (m, 2 H),
7.44–7.50 (m, 2 H), 7.57–7.70 (m, 2 H), 7.77 (d, J = 7.9 Hz, 1 H),
7.82–7.88 (m, 2 H), 8.26 (d, J = 8.3 Hz, 1 H), 8.32 (d, J = 5.8 Hz,
1 H).
13C NMR (125 MHz, CDCl3): δ = 41.2, 42.4, 44.5, 119.6, 125.4,
126.5, 127.2, 127.4, 127.5, 128.0, 128.4, 128.5, 129.9, 132.8, 136.3,
137.1, 141.6, 144.5, 159.8, 198.8.
found: 364.1324.
1-(4-Fluorophenyl)-3-phenyl-4-(quinolin-2-yl)butan-1-one
(5db)
Prepared according to General Procedure B.
Yield: 84.1 mg (91%); colorless solid; mp 89–90 °C.
IR (KBr): 3028, 2926, 1678, 1594, 1449, 1355, 1260, 985, 749, 700
cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.29–3.44 (m, 3 H), 3.45 (dd, J =
MS (ESI): m/z = 374 [M + Na]+.
5.5, 11.0 Hz, 1 H), 4.04–4.13 (m, 1 H), 6.99–7.07 (m, 2 H), 7.13–
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+
7.35 (m, 6 H), 7.46–7.52 (m, 1 H), 7.63–7.69 (m, 1 H), 7.75 (d, J =
8.3 Hz, 1 H), 7.82–7.92 (m, 2 H), 7.96 (d, J = 8.6 Hz, 1 H), 8.00 (d,
J = 8.3 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C26H23NNaO2 : 404.1626;
found: 404.1630.
3-Phenyl-4-(quinolin-2-yl)-1-(thiophen-2-yl)butan-1-one (5df)
13C NMR (125 MHz, CDCl3): δ = 41.1, 44.2, 45.8, 115.4 (d, 2JC–F
=
Prepared according to General Procedure B.
21.7 Hz), 121.9, 125.9, 126.5, 126.7, 127.5, 127.6, 128.5, 128.8,
129.3, 130.7 (d, 3JC–F = 9.3 Hz), 133.5, 136.2, 144.0, 147.8, 160.3,
165.5 (d, 1JC–F = 254 Hz), 197.1.
Yield: 64.3 mg (72%); colorless solid; mp 99–100 °C.
IR (KBr): 3053, 2922, 1677, 1595, 1449, 1262, 985, 749, 700 cm–1.
MS (ESI): m/z = 392 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H20FNNaO+: 392.1427;
1H NMR (500 MHz, CDCl3): δ = 3.28–3.45 (m, 4 H), 4.03–4.12 (m,
1 H), 7.03–7.08 (m, 1 H), 7.12–7.18 (m, 1 H), 7.19–7.35 (m, 5 H),
7.46–7.52 (m, 1 H), 7.53 (d, J = 4.9 Hz, 1 H), 7.63–7.72 (m, 2 H),
7.74 (d, J = 8.0 Hz, 1 H), 7.96–8.05 (m, 2 H).
found: 392.1432.
13C NMR (125 MHz, CDCl3): δ = 41.7, 45.1, 45.6, 121.9, 125.9,
126.6, 126.8, 127.5, 127.6, 127.9, 128.5, 128.9, 129.3, 131.9, 133.4,
136.2, 143.8, 144.6, 160.3, 191.5.
1-(4-Methoxyphenyl)-3-phenyl-4-(quinolin-2-yl)butan-1-one
(5dc)
Prepared according to General Procedure B.
Yield: 75.3 mg (79%); colorless solid; mp 109–110 °C.
MS (ESI): m/z = 380 [M + Na]+.
IR (KBr): 3060, 2942, 1678, 1597, 1502, 1416, 1258, 1226, 821,
746, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.28–3.43 (m, 4 H), 3.83 (s, 3 H),
4.01–4.10 (m, 1 H), 6.77–6.81 (m, 2 H), 7.09–7.15 (m, 1 H), 7.17–
7.34 (m, 5 H), 7.42–7.50 (m, 1 H), 7.63–7.69 (m, 1 H), 7.74 (d, J =
8.2 Hz, 1 H), 7.78–7.85 (m, 2 H), 7.91–8.03 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C23H19NNaOS+: 380.1085;
found: 380.1096.
3-Phenyl-4-(quinolin-2-yl)-1-(thiophen-3-yl)butan-1-one (5dg)
Prepared according to General Procedure B.
Yield: 83.0 mg (93%); colorless solid; mp 92–93 °C.
13C NMR (125 MHz, CDCl3): δ = 41.6, 44.0, 45.8, 55.4, 113.5,
121.9, 125.8, 126.4, 126.8, 127.5, 127.6, 128.4, 128.9, 129.2, 130.2,
130.3, 136.1, 144.2, 147.8, 160.5, 163.3, 197.2.
IR (neat): 3060, 2927, 1676, 1595, 1504, 1415, 1225, 1076, 748,
700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.24 (dd, J = 8.1, 16.2 Hz, 1 H),
3.30–3.45 (m, 3 H), 4.00–4.07 (m, 1 H), 7.10–7.12 (m, 1 H), 7.15–
7.30 (m, 6 H), 7.38 (d, J = 5.2 Hz, 1 H), 7.41–7.47 (m, 1 H), 7.62
(dd, J = 8.3, 8.3 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.93–8.02 (m,
3 H).
MS (ESI): m/z = 404 [M + Na]+.
+
HRMS (ESI): m/z [M + Na]+ calcd for C26H23NNaO2 : 404.1626;
found: 404.1629.
3-(4-Chlorophenyl)-1-phenyl-4-(quinolin-2-yl)butan-1-one
(5dd)
13C NMR (125 MHz, CDCl3): δ = 41.4, 45.6, 45.7, 121.9, 125.8,
126.0, 126.5, 126.8, 126.9, 127.5, 127.6, 128.5, 128.9, 129.3, 131.9,
136.1, 142.4, 144.0, 147.8, 160.3, 193.0.
MS (ESI): m/z = 380 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H19NNaOS+: 380.1085;
Prepared according to General Procedure B.
Yield: 82.8 mg (86%); colorless solid; mp 118–119 °C.
IR (KBr): 3060, 2941, 1678, 1597, 1502, 1416, 1258, 1226, 1075,
821, 746, 701 cm–1.
found: 380.1092.
1H NMR (500 MHz, CDCl3): δ = 3.28–3.42 (m, 3 H), 3.47 (dd, J =
5.5, 16.8 Hz, 1 H), 4.04–4.12 (m, 1 H), 7.16–7.24 (m, 5 H), 7.35–
7.42 (m, 2 H), 7.45–7.53 (m, 2 H), 7.64–7.69 (m, 1 H), 7.75 (d, J =
8.3 Hz, 1 H), 7.82–7.88 (m, 2 H), 7.98 (d, J = 8.6 Hz, 1 H), 8.01 (d,
J = 8.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 40.8, 44.2, 45.6, 121.8, 126.0,
126.8, 127.5, 128.0, 128.5, 128.6, 128.9, 129.0, 129.4, 132.1, 133.0,
136.2, 137.0, 142.6, 147.8, 159.9, 198.4.
3-(Furan-2-yl)-1-phenyl-4-(quinolin-2-yl)butan-1-one (5dh)
Prepared according to General Procedure B.
Yield: 72.5 mg (85%); yellow solid; mp 95–96 °C.
IR (KBr): 3061, 2926, 1678, 1595, 1448, 1260, 1076, 759, 700
cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.25–3.44 (m, 4 H), 4.07–4.16 (m,
1 H), 5.89 (br s, 1 H), 6.11 (br s, 1 H), 7.10–7.15 (m, 1 H), 7.21
(br s, 1 H), 7.30–7.36 (m, 2 H), 7.37–7.47 (m, 2 H), 7.53–7.64 (m,
1 H), 7.69 (d, J = 7.7 Hz, 1 H), 7.77–7.85 (m, 2 H), 7.90 (d, J =
8.0 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H).
MS (ESI): m/z = 408 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H20ClNNaO+: 408.1126;
found: 408.1131.
13C NMR (125 MHz, CDCl3): δ = 35.0, 41.8, 43.1, 105.7, 110.1,
121.8, 125.9, 126.8, 127.5, 128.1, 128.5, 129.0, 129.3, 132.9, 136.1,
137.0, 141.1, 147.8, 156.7, 160.0, 198.4.
3-(4-Methoxyphenyl)-1-phenyl-4-(quinolin-2-yl)butan-1-one
(5de)
Prepared according to General Procedure B.
MS (ESI): m/z = 364 [M + Na]+.
Yield: 77.1 mg (81%); colorless solid; mp 110–111 °C.
+
HRMS (ESI): m/z [M + Na]+ calcd for C23H19NNaO2 : 364.1313;
IR (KBr): 3060, 2940, 1678, 1597, 1502, 1416, 1226, 1075, 821,
746, 701 cm–1.
found: 364.1324.
1H NMR (500 MHz, CDCl3): δ = 3.35–3.46 (m, 3 H), 3.48 (dd, J =
5.5, 11.0 Hz, 1 H), 3.79 (s, 3 H), 4.05–4.12 (m, 1 H), 6.81–6.85 (m,
2 H), 7.22–7.27 (m, 3 H), 7.38–7.46 (m, 2 H), 7.49–7.58 (m, 2 H),
7.67–7.76 (m, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.86–7.92 (m, 2 H),
8.02–8.07 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 40.7, 44.6, 46.0, 55.1, 113.8,
121.9, 125.8, 126.8, 127.5, 128.0, 128.4, 128.5, 128.9, 129.3, 132.8,
136.1, 137.1, 147.8, 158.1, 160.5, 198.9.
(E)-1,5-Diphenyl-3-(quinolin-2-ylmethyl)pent-4-en-1-one (5di)
Prepared according to General Procedure B.
Yield: 73.6 mg (78%); yellow solid; mp 106–107 °C.
IR (KBr): 3060, 2927, 1678, 1593, 1449, 1260, 1075, 749, 700
cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.15 (dd, J = 7.6, 16.2 Hz, 1 H),
3.20–3.31 (m, 3 H), 3.62–3.71 (m, 1 H), 6.27 (dd, J = 7.9, 15.9 Hz,
1 H), 6.39 (d, J = 15.9 Hz, 1 H), 7.17–7.20 (m, 1 H), 7.21–7.27 (m,
4 H), 7.36–7.45 (m, 3 H), 7.46–7.55 (m, 2 H), 7.63–7.72 (m, 1 H),
MS (ESI): m/z = 404 [M + Na]+.
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SPECIAL TOPIC
Lewis Acid Catalyzed C–H Functionalization
2193
7.77 (d, J = 8.3 Hz, 1 H), 7.88–7.94 (m, 2 H), 8.01 (d, J = 7.9 Hz,
1 H), 8.07 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 39.1, 43.3, 44.2, 122.1, 125.9,
126.2, 126.8, 127.1, 127.5, 128.1, 128.4, 128.5, 128.9, 129.3, 130.4,
132.5, 132.9, 136.2, 137.2, 137.3, 160.4, 160.4, 199.0.
MS (ESI): m/z = 400 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C27H23NNaO+: 400.1677;
4 H), 3.35 (dd, J = 7.3, 13.7 Hz, 1 H), 3.42 (dd, J = 8.2, 13.7 Hz,
1 H), 3.92–4.01 (m, 1 H), 7.13–7.19 (m, 1 H), 7.22–7.28 (m, 2 H),
7.28–7.33 (m, 3 H), 7.44–7.51 (m, 1 H), 7.63–7.67 (m, 1 H), 7.74
(d, J = 7.1 Hz, 1 H), 7.98–8.04 (m, 2 H).
13C NMR (125 MHz, C6D6): δ = 24.1, 25.9, 40.8, 42.0, 45.2, 45.4,
46.5, 121.9, 125.7, 126.4, 126.8, 127.5, 127.6, 128.3, 128.7, 129.2,
136.0, 144.2, 147.6, 160.6, 169.7.
MS (ESI): m/z = 345 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C23H25N2O+: 345.1967; found:
found: 400.1684.
3-Phenyl-1-(1H-pyrrol-1-yl)-4-(quinolin-2-yl)butan-1-one (5dj)
Prepared according to General Procedure B.
345.1969.
(E)-Ethyl 5-Phenyl-6-(quinolin-2-yl)hex-2-enoate (8dj)
Yield: 69.0 mg (81%); yellow solid; mp 84–85 °C.
To a solution of 5dj (31.7 mg, 93.1 μmol) in CH2Cl2 (1.0 mL) at
78 °C was added DIBAL-H (1.0 M in hexane, 0.28 mL, 280 μmol).
After stirring for 10 min at 78 °C, the reaction was quenched with
sat. aq NH4Cl (5 mL). The mixture was extracted with EtOAc
(3 × 10 mL), and the combined organic layers were dried over
Na2SO4. After filtration and evaporation, the crude pyrrole carbi-
nols (mixture of diastereomers) were used in the next step without
further purification. To a suspension of flame-dried LiCl (12.3 mg,
290 μmol) in MeCN (0.20 mL) in a test tube were added ethyl di-
ethylphosphonoacetate (56 μL, 280 μmol) and DBU (70 μL, 470
μmol) at r.t. The mixture was stirred at r.t. for 10 min to afford HWE
reagent solution. To a solution of the crude pyrrole carbinols in
MeCN (0.050 mL) was added HWE reagent solution in MeCN by
using a syringe, using additional MeCN (0.10 mL) for rinsing. After
stirring for 1 h at r.t., the reaction was quenched with sat. aq NH4Cl
(5 mL). The mixture was extracted with EtOAc (3 × 10 mL) and the
combined organic layers were dried over Na2SO4. After filtration
and evaporation, the residue was purified by flash silica gel column
chromatography (hexane–Et2O, 4:1→3:1) to give 8dj.
IR (KBr): 3050, 2925, 1715, 1596, 1470, 1355, 1267, 1075, 739,
697 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.20 (dd, J = 8.6, 16.2 Hz, 1 H),
3.33–3.46 (m, 3 H), 4.03–4.11 (m, 1 H), 6.19–6.25 (m, 2 H), 7.15–
7.24 (m, 2 H), 7.25–7.35 (m, 6 H), 7.45–7.53 (m, 1 H), 7.65–7.71
(m, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.98–8.04 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 40.3, 41.6, 45.4, 112.9, 119.0,
121.8, 126.0, 126.8, 127.5, 127.5, 128.6, 128.9, 129.4, 136.3, 143.3,
147.8, 159.9, 169.0.
MS (ESI): m/z = 363 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H20N2NaO+: 363.1473;
found: 363.1481.
Ethyl 3-Phenyl-4-(quinolin-2-yl)butanoate (6dj)
To a solution of 5dj (16.8 mg, 49.4 μmol) in EtOH (0.30 mL) was
added NaOEt (6.7 mg, 98 μmol) at 0 °C. After stirred for 20 min at
r.t., the reaction was quenched with sat. aq NH4Cl (5 mL) and ex-
tracted with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine (10 mL) and dried over Na2SO4. After filtration
and evaporation, the residue was purified by flash silica gel column
chromatography (hexane–Et2O, 3:1) to afford 6dj.
Yield: 27.3 mg (85%); yellow oil.
IR (neat): 3060, 2981, 2927, 1716, 1654, 1599, 1504, 1267, 1205,
1040, 826, 756, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz, 3 H), 2.59–2.70
(m, 2 H), 3.25 (dd, J = 8.0, 13.6 Hz, 1 H), 3.33 (dd, J = 7.1, 13.6 Hz,
1 H), 3.43–3.51 (m, 1 H), 4.09 (q, J = 7.0 Hz, 2 H), 5.73 (d, J =
15.6 Hz, 1 H), 6.81 (ddd, J = 7.3, 7.3, 15.6 Hz, 1 H), 7.00 (d, J =
8.3 Hz, 1 H), 7.13–7.19 (m, 3 H), 7.22–7.27 (m, 2 H), 7.45–7.51
(m, 1 H), 7.65–7.71 (m, 1 H), 7.73 (d, J = 7.9 Hz, 1 H), 7.93 (d, J =
8.6 Hz, 1 H), 8.04 (J = 8.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.1, 25.9, 40.8, 42.0, 45.2, 45.4,
46.5, 121.9, 125.7, 126.4, 126.8, 127.5, 127.6, 128.3, 129.2, 136.0,
144.2, 147.6, 160.6, 169.7.
Yield: 14.5 mg (92%); yellow oil.
IR (neat): 3064, 2981, 2929, 1731, 1599, 1503, 1262, 1179, 1031,
755, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.07 (t, J = 7.3 Hz, 3 H), 2.74 (dd,
J = 8.8, 15.3 Hz, 1 H), 2.80 (dd, J = 6.1, 15.3 Hz, 1 H), 3.28–3.38
(m, 2 H), 3.78–3.87 (m, 1 H), 3.94 (q, J = 7.3 Hz, 2 H), 7.14 (d, J =
8.6 Hz, 1 H), 7.16–7.22 (m, 1 H), 7.24–7.29 (m, 4 H), 7.48–7.53
(m, 1 H), 7.68–7.73 (m, 1 H), 7.76 (d, J = 8.3 Hz, 1 H), 8.00 (d, J =
8.6 Hz, 1 H), 8.06 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.3, 40.8, 42.6, 46.0, 60.4, 122.1,
126.1, 126.8, 127.0, 127.7, 127.8, 128.6, 129.2, 129.6, 136.3, 143.6,
148.2, 160.4, 172.3.
MS (ESI): m/z = 346 [M + H]+.
+
HRMS (ESI): m/z [M + H]+ calcd for C23H24NO2 : 346.1807; found:
346.1806.
MS (ESI): m/z = 320 [M + H]+.
+
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO2 : 320.1651; found:
320.1652.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas ‘Molecular Activation Directed toward
Straightforward Synthesis’ from MEXT, ERATO from JST, and the
Naito Foundation.
3-Phenyl-1-(pyrrolidin-1-yl)-4-(quinolin-2-yl)butan-1-one (7dj)
To a solution of 5dj (20.6 mg, 60.5 μmol) in THF (0.20 mL) were
added pyrrolidine (25 μL, 300 μmol) and DBU (45 μL, 300 μmol).
The reaction mixture was warmed to 60 °C and stirred for 12 h. Af-
ter cooling to r.t., the reaction was quenched with sat. aq NH4Cl (5
mL) and extracted with EtOAc (3 × 10 mL). The combined organic
layers were dried over Na2SO4. After filtration and evaporation, the
residue was purified by flash silica gel column chromatography
(hexane–EtOAc, 1:1; then EtOAc–MeOH, 20:1) to afford 7dj.
References
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Yield: 17.6 mg (84%); yellow oil.
(2) For selected general reviews on C–H bond functionalization,
see: (a) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003,
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756, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.57–1.81 (m, 4 H), 2.62 (dd, J =
7.3, 15.0 Hz, 1 H), 2.71 (dd, J = 6.4, 15.0 Hz, 1 H), 3.10–3.33 (m,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2185–2194

2194
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SPECIAL TOPIC
H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 5094. (d) Sun,
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