Catalytic conjugate addition of heterocyclic compounds to α,β-unsaturated carbonyl compounds by hafnium salts and scandium salts

Article abstract of DOI:10.1016/j.tet.2007.02.091

The hafnium chloride (HfCl₄) and scandium chloride (ScCl₃) catalyzed conjugate additions of heterocyclic compounds, such as indoles, pyrrole, pyrazole, and imidazole, have been demonstrated. Hafnium chloride effectively catalyzed the

Full text of DOI:10.1016/j.tet.2007.02.091

Tetrahedron 63 (2007) 4172–4177
Catalytic conjugate addition of heterocyclic compounds
to a,b-unsaturated carbonyl compounds by hafnium
salts and scandium salts
b
b
Motoi Kawatsura,a, Sachiko Aburatani and Junichi Uenishi
*
aDepartment of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
bKyoto Pharmaceutical University, Misasagi, Kyoto 607-8412, Japan
Received 2 February 2007; revised 20 February 2007; accepted 21 February 2007
Available online 24 February 2007
Abstract—The hafnium chloride (HfCl4) and scandium chloride (ScCl3) catalyzed conjugate additions of heterocyclic compounds, such as
indoles, pyrrole, pyrazole, and imidazole, have been demonstrated. Hafnium chloride effectively catalyzed the conjugate addition of indoles to
a,b-unsaturated carbonyl compounds, and the addition product was obtained in high yield. The reaction of pyrrole was also catalyzed by
HfCl4 or ScCl3, and produced 2,6-dialkylated pyrroles up to 99% yields. Furthermore, the conjugate addition of the 1-position of the pyrazoles
and imidazole occurred, and produced several substituted heterocyclic compounds in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
enones, which can be catalyzed by other Lewis acids
(Scheme 1). As we have previously reported, the reaction of
indole (1a) to methyl vinyl ketone (5a) was effectively cat-
alyzed by Hf(OTf)4 and Sc(OTf)3 (Table 1, entries 1 and 3).
After our screening of several hafnium and scandium salts,
we found that hafnium chloride (HfCl4) and scandium chlo-
ride (ScCl3) are also effective catalysts for this reaction. The
reaction catalyzed by HfCl4 and ScCl3 proceeded smoothly
in an acetonitrile solvent at room temperature and gave the
addition product (6a) in a 93 and 92% isolated yields, re-
spectively (entries 2 and 4). The HfCl4 catalyzed addition re-
action of 1a to phenyl 1-propenyl ketone (5b) also occurred
in a quantitative yield even though it needed a longer reac-
tion time (entry 6). However, the reaction of 1a with a cyclic
enone (5c) gave 6c in low yield (entry 8). The addition
reaction of 1-methylindole (1b) to 5a catalyzed by Hf(OTf)4
and HfCl4 gave the product (6d) in a 50 and 99% yields,
respectively (entries 9 and 10). This result indicate that
HfCl4 is a superior catalyst compared to Hf(OTf)4 for this
reaction. The HfCl4 catalyzed reaction of 2-methylindole
Nitrogen-containing heterocycles are the key components
of some pharmacologically and biologically active com-
pounds,1 and the development of new and efficient transfor-
mations of heterocyclic compounds into several derivatives
has attracted much attention in organic synthesis. Recently,
several Lewis acids were found to catalyze the conjugate ad-
dition of heterocyclic compounds to electron deficient ole-
fins, and Bi,2 In,3 Yb,4 Sc,5 Al,6 Cu,7 Au,8 Zn,9 Sm,10 and
Ce11 salts were used for the addition of indole to a,b-enones.
We also reported that hafnium(IV) trifluoromethanesulfo-
nate {Hf(OTf)4} and scandium trifluoromethanesulfonate
{Sc(OTf)3} are effective Lewis acids for the conjugated ad-
dition of indoles to a,b-enones.12 On the other hand, there
are only a few reports about the Lewis acid catalyzed conju-
gated addition of pyrrole, pyrazole, and imidazole to a,b-un-
saturated carbonyl compounds.13 In this paper, we report the
hafnium(IV) chloride (HfCl4) and scandium(III) chloride
(ScCl3) catalyzed conjugated addition of heterocyclic com-
pounds to a,b-unsaturated carbonyl compounds.
2. Result and discussion
R2
N
R3
O
R2
2.1. Conjugate addition of indoles to a,b-enones
R1
1
R4
catalyst
Based on our previous research, we further examined the
conjugate addition of the 3-position of indoles to a,b-
CH3CN, r.t.
+
N
O
R1
R3
R4
Keywords: Conjugate addition; Heterocyclic compound; Hafnium chloride;
Scandium chloride; Lewis acid.
6
5
* Corresponding author. Tel./fax: +81 857 31 5179; e-mail: kawatsur@
chem.tottori-u.ac.jp
Scheme 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.091

M. Kawatsura et al. / Tetrahedron 63 (2007) 4172–4177
Table 1. Conjugate addition of indoles 1a–c to a,b-enones 5a–ca
4173
Entry
Indole (1)
Enone (5)
Catalyst
Time
Product 6
Yieldb (%)
O
1
2
3
4
Hf(OTf)4
HfCl4
Sc(OTf)3
ScCl3
10 min
15 min
2 h
85
93
90
92
O
N
H
N
H
6 h
5a
1a
6a
O
O
Ph
O
5
6
Hf(OTf)4
HfCl4
15 min
2 h
80
99
Ph
N
H
5b
6b
O
7
8
Hf(OTf)4
HfCl4
30 min
12 h
70
30
N
H
5c
6c
O
O
9
10
5a
Hf(OTf)4
HfCl4
15 min
20 min
50
99
N
Me
N
Me
1b
6d
Me
11
12
N
H
5a
Hf(OTf)4
HfCl4
10 min
4 h
80
99
Me
N
H
1c
6e
a
All reactions were carried out at rt: indoles (1.0 mmol), enones (1.5 mmol), catalyst (0.1 mmol), and CH3CN (5.0 mL).
Isolated yield by silica gel column chromatography.
b
(1c) also smoothly occurred even though it requires a
Hf(OTf)4 catalyzed conjugate addition reaction of 2 to meth-
yl vinyl ketone (5a) was very slow, but gave a mixture of 2,5-
dialkylated pyrrole 7a and 2-alkylated pyrrole 8a in 19 and
13% yields, respectively (Table 2, entry 1). Changing of the
solvent from CH3CN to CH2Cl2 effectively increased the
yield, but the ratio of 7a and 8a was almost the same (entry
longer reaction time than the reaction by Hf(OTf)4, but the
reaction still produced a 99% yield of product 6e (entries
11 and 12). In these reactions, we confirmed that Hf(OTf)4
forms a by-product from the dimerization and/or poly-
merization of indoles, but HfCl4 will not form such a by-
product under the catalytic conditions. This result explains
the reason why the reaction by HfCl4 is much slower, but
produced a higher yield compared to the reaction using
Hf(OTf)4.
Table 2. Reaction of pyrrole (2) to a,b-enones 5a–ca
Entry
Enone (5)
Catalyst
Solvent Time
(h)
Yieldb (%)
of 7 and 8
1
2
3
4
5
6
7
Hf(OTf)4 CH3CN 20
Hf(OTf)4 CH2Cl2 20
19 (7a) 13 (8a)
34 (7a) 27 (8a)
2.2. Reaction of pyrrole to a,b-enones
O
HfCl4
HfCl4
HfBr4
CH3CN
CH2Cl2
CH2Cl2
5
5
5
34 (7a)
63 (7a)
43 (7a)
10 (7a)
48 (7a)
7 (8a)
6 (8a)
0 (8a)
6 (8a)
7 (8a)
We extended this HfCl4 catalyst system to the reaction of
other heterocyclic compounds, and examined the conjugate
addition of pyrrole (2) to a,b-enones 5a–c (Scheme 2). The
5a
Sc(OTf)3 CH3CN 96
ScCl3
CH2Cl2
5
O
R2
R2
N
H
N
H
8
9
HfCl4
ScCl3
CH2Cl2
CH2Cl2
5
5
65 (7b)
99 (7b)
0 (8b)
0 (8b)
Ph
O
R1
R1
O
2
7
5b
catalyst
solvent, r.t.
+
and/or
O
O
10
11
HfCl4
ScCl3
CH2Cl2
CH2Cl2
5
5
0 (7c)
15 (7c)
0 (8c)
0 (8c)
R2
R1
R2
N
H
5c
R1
O
a
5
All reactions were carried out at rt: pyrrole (1.0 mmol), enones
(3.0 mmol), catalyst (0.1 mmol), and solvent (5.0 mL).
Isolated yield by silica gel column chromatography.
8
b
Scheme 2.

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M. Kawatsura et al. / Tetrahedron 63 (2007) 4172–4177
2). Again, we discovered that HfCl4 is a better catalyst for
the conjugate addition of 2 to 5a. The reaction, which was
catalyzed by HfCl4, in CH3CN decreased the formation of
2-alkylated pyrrole 8a, but the yield of the 2,5-dialkylated
pyrrole 7a did not change (entry 3). However, changing
the reaction solvent from CH3CN to CH2Cl2 increased the
yield of 7a to 63% (entry 4). The use of HfBr4 allowed the
selective formation of 7a, but the isolated yield was low (en-
try 5). Scandium chloride (ScCl3) in CH2Cl2 also effectively
catalyzed this reaction, but the yield was lower than the re-
sult from the HfCl4 catalyzed reaction (entry 7). On the other
hand, the addition reaction of pyrrole (2) to phenyl 1-propen-
yl ketone (5b) selectively formed the 2,5-dialkylated pyrrole
7b by using HfCl4 (entry 8). Interestingly, the reaction by
ScCl3 exhibited the selective formation of 7b in a 99% iso-
lated yield (entry 9). Unfortunately, the addition to a cyclic
enone (5c) did not occur by using HfCl4, and even the use
of ScCl3 resulted in a very low yield (entries 10 and 11).
R1
O
O
NH
N
3
N
N
R2
9
O
catalyst
+
or
or
R1
R2
2.3. Conjugate addition of pyrazole and imidazole
to a,b-unsaturated carbonyl compounds
solvent
r.t., 5 h
R1
NH
5
N
N
R2
4
N
We next demonstrated the reaction of pyrazole (3) and
imidazole (4) with a,b-unsaturated carbonyl compounds
(Scheme 3), and results are summarized in Table 3. Usually,
10
Scheme 3.
Table 3. HfCl4 or ScCl3 catalyzed conjugate addition of pyrazole (3) and imidazole (4) to a,b-unsaturated carbonyl compounds 5a–fa
Entry
3 or 4
Enone or enal (5)
Catalyst
Solvent
Product 9 or 10
Yieldb (%)
O
O
NH
N
1
2
HfCl4
ScCl3
CH2Cl2
CH2Cl2
72
51
N
N
3
5a
9a
O
O
3
4
HfCl4
ScCl3
CH2Cl2
CH2Cl2
94
21
N
N
Ph
Ph
5b
9b
O
5
6
HfCl4
ScCl3
CH2Cl2
CH2Cl2
90
99
N
N
O
O
5c
9c
N
N
O
7
ScCl3
CH2Cl2
99
5d
O
9d
O
O
8
9
10
11
Hf(OTf)4
HfCl4
Sc(OTf)3
ScCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
77
0
H
N
N
H
H
51
5e
9e
O
H
N
N
12
HfCl4
CH2Cl2
72
5f
9f
O
O
NH
13
14
HfCl4
ScCl3
CH2Cl2
CH2Cl2
0
0
N
N
N
5a
4
10a
O
N
O
15
16
17
HfCl4
HfCl4
ScCl3
CH2Cl2
CH3CN
CH2Cl2
50
79
6
N
5c
10b
a
All reactions were carried out at rt: pyrazole or imidazole (1.0 mmol), electron deficient olefins (2.4 mmol), catalyst (0.1 mmol), and solvent (5.0 mL).
Isolated yield by silica gel column chromatography.
b

M. Kawatsura et al. / Tetrahedron 63 (2007) 4172–4177
4175
the Michael addition of 3 at the 1-position to electron defi-
cient olefins requires a high temperature and/or base, but
we found that HfCl4 and ScCl3 effectively catalyzed the re-
action at room temperature. The reaction catalyzed by HfCl4
occurred with several a,b-enones and gave N-alkylated
products (9a–c) in good to excellent yields (Table 3, entries
1, 3, and 5). The catalyst activity of ScCl3 was lower than
that of HfCl4 for the reaction of pyrazole to 5a and b (entries
2 and 4). However, the coupling reaction of pyrazole with
cyclic enone such as 2-cyclohexen-1-one (5c) suggested
that ScCl3 was a slightly better catalyst than HfCl4, and
the reaction gave N-alkylation product 9c in a quantitative
isolated yield (entries 5 and 6). We also demonstrated the
addition of pyrazole to a,b-unsaturated aldehydes (5e and f),
and the reaction of 9d and f produced the corresponding
addition product in good yield as we expected (entries 9,
11, and 12). In this reaction, Hf(OTf)4 and Sc(OTf)3 didn’t
catalyze the reaction (entries 8 and 10). The addition reaction
at the 1-position of imidazole to a,b-enones was also demon-
strated. Unfortunately, the addition reaction of imidazole (4)
to methyl vinyl ketone (5a) didn’t occur (entries 13 and 14),
but HfCl4 effectively catalyzed the reaction of imidazole to
a cyclic enone 5c in CH3CN, and gave a 79% yield of product
10b (entry 16).
CHCl3. The combined organic layers were dried over
MgSO4 and evaporated. The residue was chromatographed
on silica gel (hexane/EtOAc¼4/1) to give 174 mg (93%)
of 4-(1H-indole-3-yl)butan-2-one (6a)3b. 1H NMR
(300 MHz, CDCl3), d: 7.94 (br s, 1H), 7.58 (d, J¼7.9 Hz,
1H), 7.34 (d, J¼7.9 Hz, 1H), 7.19 (td, J¼7.9, 1.3 Hz, 1H),
7.11 (td, J¼7.9, 1.3 Hz, 1H), 6.98 (d, J¼2.4 Hz, 1H), 3.05
(t, J¼7.4 Hz, 2H), 2.84 (t, J¼7.4 Hz, 2H), 2.13 (3H, s).
13C NMR (75 MHz, CDCl3), d: 208.8, 136.3, 127.1, 121.9,
121.4, 119.2, 118.6, 115.1, 111.1, 44.0, 30.0, 19.3. White
powder. Rf¼0.13 (20% EtOAc in hexane).
4.2.1. 3-(1H-Indole-3-yl)-1-phenylbutan-1-one (6b). 1H
NMR (300 MHz, CDCl3), d: 7.93–7.96 (m, 2H), 7.67 (dt,
J¼7.9, 0.7 Hz, 1H), 7.50–7.56 (m, 1H), 7.33–7.40 (m,
3H), 7.19 (ddd, J¼7.9, 7.0, 1.1 Hz, 1H), 7.11 (ddd, J¼7.9,
7.0, 1.1 Hz, 1H), 7.02 (d, J¼2.0 Hz, 1H), 3.77–3.88 (m,
1H), 3.47 (dd, J¼16.3, 4.9 Hz, 1H), 3.23 (dd, J¼16.3,
8.8 Hz, 1H), 1.45 (d, J¼7.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3), d: 199.8, 137.3, 136.6, 132.9, 128.5 (2C), 128.1
(2C), 126.3, 122.0, 121.5, 120.2, 119.2 (2C), 111.3, 46.5,
27.2, 21.0. IR (KBr) cmꢁ1: 3422 (N–H), 1680 (C]O).
EIMS m/z: 263 [M]+. EIHRMS m/z: 263.1314 (Calcd for
C18H17NO: 263.1310). Anal. Calcd for C18H17NO: C,
82.10; H, 6.51; N, 5.32. Found: C, 81.95; H, 6.41; N, 5.12.
White powder. Rf¼0.26 (20% EtOAc in hexane). Mp 88–
92 ꢀC.
3. Conclusion
In conclusion, we demonstrated that HfCl4 and ScCl3
catalyzed conjugate addition of indoles, pyrrole, pyrazole,
and imidazole to a,b-unsaturated carbonyl compounds. The
reactivity depends on the substrates and solvents, but HfCl4
exhibited excellent catalyst reactivity. Furthermore, we
confirmed that ScCl3 was also a good catalyst for some
combination of heterocyclic compounds to a,b-unsaturated
carbonyl compounds.
4.2.2. 3-(1H-Indole-3-yl)cyclohexanone (6c).11a 1H NMR
(300 MHz, CDCl3), d: 7.95 (br s, 1H), 7.54–7.57 (m, 1H),
7.29 (dt, J¼7.9, 1.1 Hz, 1H), 7.10 (ddd, J¼7.9, 7.0,
1.1 Hz, 1H), 7.05 (ddd, J¼7.9, 7.0, 1.1 Hz, 1H), 6.91 (dd,
J¼2.4, 0.7 Hz, 1H), 3.42–3.33 (m, 1H), 2.73 (ddt, J¼14.1,
4.8, 1.7 Hz, 1H), 2.56 (ddd, J¼14.1, 10.5, 1.1 Hz, 1H),
2.28–2.43 (m, 2H), 2.17–2.20 (m, 1H), 2.09–1.70 (m, 3H).
13C NMR (75 MHz, CDCl3), d: 211.8, 136.5, 126.1, 122.2,
120.3, 119.7, 119.3, 119.0, 111.3, 48.1, 41.5, 35.9, 31.7,
24.9.
4. Experimental section
4.1. General methods
4.2.3. 4-(1-Methylindole-3-yl)butan-2-one (6d).4b 1H
NMR (300 MHz, CDCl3), d: 7.56 (d, J¼8.0 Hz, 1H), 7.27
(d, J¼8.0 Hz, 1H), 7.20 (td, J¼8.0, 1.3 Hz, 1H), 7.09 (td,
J¼8.0, 1.3 Hz, 1H), 6.83 (s, 1H), 3.72 (s, 3H), 3.03 (t,
J¼7.4 Hz, 2H), 2.82 (t, J¼7.4 Hz, 2H), 2.13 (s, 3H). 13C
NMR (75 MHz, CDCl3), d: 208.7, 137.0, 127.5, 126.3,
121.5, 118.7 (2C), 113.6, 109.2, 44.3, 32.5, 30.0, 19.2.
Yellow oil. Rf¼0.27 (20% EtOAc in hexane).
All manipulations were carried out under a nitrogen atmo-
sphere. Nitrogen gas was dried by passage through P2O5.
NMR spectra were recorded on a JEOL JNM-AL300 spec-
trometer (300 MHz for 1H and 75 MHz for 13C). Chemical
shifts are reported in d ppm referenced to an internal SiMe4
standard for 1H NMR. Residual chloroform (d 77.0 for 13C)
was used as an internal reference for 13C NMR. 1H and 13
C
4.2.4. 4-(1H-2-Methylindole-3-yl)butan-2-one (6e).3b 1
H
NMR spectra were recorded in CDCl3 at 25 ꢀC. All reagents
and solvents were purchased from common commercial
sources and were used as received or purified by distillation
from appropriate drying agents.
NMR (300 MHz, CDCl3), d: 7.68 (br s, 1H), 7.39 (d,
J¼8.8 Hz, 1H), 7.19–7.15 (m, 1H), 7.05–6.95 (m, 2H),
2.89 (t, J¼7.7 Hz, 2H), 2.68 (t, J¼7.7 Hz, 2H), 2.29 (s,
3H), 2.02 (s, 3H). 13C NMR (75 MHz, CDCl3), d: 208.9,
135.3, 131.1, 128.3, 121.0, 119.1, 117.7, 110.2 (2C), 44.2,
30.2, 18.4, 11.5. Yellow oil. Rf¼0.25 (20% EtOAc in
hexane).
4.2. General procedure of conjugate addition of hetero-
cyclic compounds to a,b-enones: typical procedure
(entry 2 in Table 1)
4.2.5. 2,5-Bis(3-oxobutyl)pyrrole (7a).14 1H NMR
(300 MHz, CDCl3), d: 2.14 (s, 6H), 2.71–2.81 (m, 8H),
5.69 (d, J¼2.6 Hz, 2H), 8.43 (br s, 1H). 13C NMR
(75 MHz, CDCl3), d: 21.6 (2C), 30.0 (2C), 44.0 (2C),
104.8 (2C), 130.4 (2C), 209.1 (2C). Yellow oil. Rf ¼0.38
(50% EtOAc in hexane).
A mixture of indole 1 (117 mg, 1.0 mmol), methyl vinyl ke-
tone 2 (105 mg, 1.5 mmol), and HfCl4 (32 mg, 0.1 mmol) in
CH3CN (5 mL) was stirred at room temperature for 15 min.
After complete conversion, as indicated by TLC, the reac-
tion mixture was diluted with H2O and extracted with

4176
M. Kawatsura et al. / Tetrahedron 63 (2007) 4172–4177
4.2.6. 4-(1H-Pyrrol-2-yl)butan-2-one (8a). 1H NMR
(300 MHz, CDCl3), d: 2.14 (s, 3H), 2.77–2.83 (m, 4H),
5.86 (s, 1H), 6.06 (d, J¼2.6 Hz, 1H), 6.63 (d, J¼2.6 Hz,
1H), 8.46 (br s, 1H). 13C NMR (75 MHz, CDCl3), d: 21.3,
30.1, 44.2, 105.3, 107.8, 116.7, 136.6, 209.6. Yellow oil.
Rf¼0.15 (50% EtOAc in hexane). EIHRMS m/z: 137.0844
(Calcd for C24H24NO2: 137.0841).
4.2.13. 3-(1H-Pyrazol-1-yl)pentanal (9f). 1H NMR
(300 MHz, CDCl3), d: 0.71 (t, J¼7.7 Hz, 3H), 1.68–1.81
(m, 1H), 1.84–1.99 (m, 1H), 2.81 (ddd, J¼17.6, 4.8,
1.1 Hz, 1H), 3.16 (ddd, J¼17.6, 8.4, 1.1 Hz, 1H), 4.53
(septet, J¼4.8 Hz, 1H), 6.13 (t, J¼2.2 Hz, 1H), 7.36 (d,
J¼2.2 Hz, 1H), 7.45 (s, 1H), 9.61 (s, 1H). 13C NMR
(75 MHz, CDCl3), d: 10.4, 28.5, 48.6, 58.2, 104.8, 129.4,
139.6, 199.5. Yellow oil. Rf¼0.50 (50% EtOAc in hexane).
EIHRMS m/z: 152.0951 (Calcd for C8H12N2O: 152.0950).
4.2.7. 2,5-Bis(1-methyl-3-phenyl-3-oxopropyl)pyrrole
1
(7b). H NMR (300 MHz, CDCl3), d: 1.27 (d, J¼7.0 Hz,
3H), 1.28 (d, J¼7.0 Hz, 3H), 3.01–3.24 (m, 4H), 3.43 (quint,
J¼7.0 Hz, 2H), 5.74 (d, J¼2.6 Hz, 2H), 7.29–7.49 (m, 6H),
7.78–7.87 (m, 4H), 8.67 (br s, 1H). 13C NMR (75 MHz,
CDCl3), d: 19.9, 20.0, 27.8, 27.9, 47.1, 47.2, 102.6, 102.7,
128.1 (4C), 128.5 (2C), 128.6 (2C), 133.0, 133.1, 135.6
(2C), 137.1 (2C), 200.2 (2C). Yellow oil. Rf¼0.35 (20%
EtOAc in hexane). EIHRMS m/z: 358.1810 (Calcd for
C24H24NO2: 358.1807).
4.2.14. 3-(1H-Imidazol-1-yl)cyclohexanone (10b).2a 1H
NMR (300 MHz, CDCl3), d: 1.67–1.79 (m, 1H), 1.98–2.13
(m, 2H), 2.27–2.47 (m, 3H), 2.68 (dd, J¼13.9, 11.0 Hz,
1H), 2.80 (ddt, J¼13.9, 4.8, 1.5 Hz, 1H), 4.30–4.39 (m,
1H), 7.04 (s, 1H), 7.24 (s, 1H), 7.51 (s, 1H). 13C NMR
(75 MHz, CDCl3), d: 21.9, 32.4, 40.4, 48.7, 55.5, 116.7,
129.7, 135.2, 206.7. Yellow oil. Rf¼0.29 (EtOAc).
4.2.8. 1-Phenyl-3-(1H-pyrazol-1-yl)propan-1-one (9a).15
1H NMR (300 MHz, CDCl3), d: 2.14 (s, 3H), 3.05 (t,
J¼6.4 Hz, 2H), 4.39 (t, J¼6.4 Hz, 2H), 6.20 (t, J¼2.2 Hz,
1H), 7.42 (d, J¼2.2 Hz, 1H), 7.48 (d, J¼2.2 Hz, 1H). 13C
NMR (75 MHz, CDCl3), d: 19.0, 26.1, 32.2, 106.6,
126.5, 138.8, 207.9. Yellow oil. Rf¼0.27 (50% EtOAc in
hexane).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. M.K. acknowledges
the TORAYAward for Synthetic Organic Chemistry, Japan.
1
References and notes
4.2.9. 1-Phenyl-3-(1H-pyrazol-1-yl)butan-1-one (9b). H
NMR (300 MHz, CDCl3), d: 1.62 (d, J¼6.8 Hz, 3H), 3.32
(dd, J¼17.4, 6.8 Hz, 1H), 3.79 (dd, J¼17.4, 6.8 Hz, 1H),
5.06 (sextet, J¼6.8 Hz, 1H), 6.18 (t, J¼2.0 Hz, 1H), 7.40–
7.57 (m, 5H), 7.90–7.93 (m, 2H). 13C NMR (75 MHz,
CDCl3), d: 21.4, 45.3, 53.6, 104.8, 128.1 (2C), 128.6 (2C),
133.4 (2C), 136.7, 139.4, 197.4. Yellow oil. Rf¼0.30 (20%
EtOAc in hexane). EIHRMS m/z: 214.1108 (Calcd for
C13H14N2O: 214.1106).
1. Katrizky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic
Chemistry, 2nd ed.; Pergamon: Oxford, 2000.
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3704; (b) Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha,
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1
4.2.10. 3-(1H-Pyrazol-1-yl)cyclohexanone (9c). H NMR
(300 MHz, CDCl3), d: 1.66–1.81 (s, 1H), 2.01–2.12 (m,
1H), 2.22–2.29 (m, 2H), 2.41–2.46 (m, 2H), 2.82 (dd,
J¼14.5, 5.0 Hz, 1H), 2.99 (dd, J¼14.5, 10.0 Hz, 1H),
4.50–4.60 (m, 1H), 6.25 (t, J¼2.2 Hz, 1H), 7.41 (d,
J¼2.2 Hz, 1H), 7.54 (d, J¼2.2 Hz, 1H). 13C NMR
(75 MHz, CDCl3), d: 21.7, 31.8, 40.6, 47.7, 69.75, 105.3,
127.5, 139.4, 207.9. Yellow oil. Rf¼0.50 (50% EtOAc in
hexane). EIHRMS m/z: 164.0948 (Calcd for C9H12N2O:
164.0950).
4.2.11. 3-(1H-Pyrazol-1-yl)cyclopentanone (9d). 1H NMR
(300 MHz, CDCl3), d: 2.23–2.85 (m, 5H), 2.76 (dd, J¼9.5,
7.7 Hz, 1H), 4.94 (quint, J¼6.6 Hz, 1H), 6.24 (t,
J¼2.6 Hz, 1H), 7.41 (d, J¼2.6 Hz, 1H), 7.51 (d, J¼2.6 Hz,
1H). 13C NMR (75 MHz, CDCl3), d: 30.3, 36.8, 44.8, 58.6,
105.7, 127.9, 139.7, 215.0. Yellow oil. Rf¼0.40 (50% EtOAc
in hexane). EIHRMS m/z: 150.0795 (Calcd for C8H10N2O:
150.0793).
4.2.12. 3-(1H-Pyrazol-1-yl)propanal (9e).15 1H NMR
(300 MHz, CDCl3), d: 3.05 (t, J¼6.2 Hz, 2H), 4.43 (t,
J¼6.2 Hz, 2H), 6.19 (s, 1H), 7.41 (d, J¼2.2 Hz, 1H), 7.46
(s, 1H), 9.78 (s, 1H). 13C NMR (75 MHz, CDCl3), d: 43.8,
44.8, 105.5, 129.8, 139.7, 199.3. Yellow oil. Rf¼0.25 (50%
EtOAc in hexane).
8. (a) Arcadi, A.; Bianchi, G.; Chiarini, M.; Anniballe, G.;
Marinelli, F. Synlett 2004, 944–950; (b) Nair, V.; Vidya, N.;
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3859–3862; (c) Zou, X.; Wang, X.; Cheng, C.; Kong, L.;
Mao, H. Tetrahedron Lett. 2006, 47, 3767–3771.
11. (a) Bartoli, G.; Bartolacci, M.; Bosco, M.; Fogliam, G.;
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13. (a) Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G.
Tetrahedron Lett. 2001, 42, 8063–8065; (b) Evans, D. A.;
Fandrick, K. R. Org. Lett. 2006, 8, 2249–2252 and see also
Refs. 2a, 5e, 6a,d, 7b, and 11c.
14. Zhan, Z.-P.; Yu, J.-L.; Yang, W.-Z. Synth. Commun. 2006, 36,
1373–1382.
15. Stanovnik, B.; Svete, J. Sci. Synth. 2002, 12, 15–225.