A highly α-regioselective In(OTf)3-catalyzed N-nucleophilic substitution of cyclic Baylis-Hillman adducts with aromatic amines

Article abstract of DOI:10.1016/j.tet.2009.02.048

The highly α-regioselective N-nucleophilic substitution of B-H adducts bearing five (1a-f) or six-membered ring (5a-e) moieties with aromatic amines (2a-e) was developed under the catalysis of In(OTf)₃ (10 mol%). During the reaction the allylic

Full text of DOI:10.1016/j.tet.2009.02.048

Tetrahedron 65 (2009) 3473–3479
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A highly
a-regioselective In(OTf)3-catalyzed N-nucleophilic substitution
of cyclic Baylis–Hillman adducts with aromatic amines
*
Yu-Liang Liu, Li Liu , Dong Wang, Yong-Jun Chen
Beijing National Laboratory (BNLMS), Laboratory for Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly
membered ring (5a–e) moieties with aromatic amines (2a–e) was developed under the catalysis of
In(OTf)3 (10 mol%). During the reaction the allylic rearrangement from -product to -product occurred,
resulting in thermodynamically stable -product predominately.
Ó 2009 Elsevier Ltd. All rights reserved.
a-regioselective N-nucleophilic substitution of B–H adducts bearing five (1a–f) or six-
Received 20 November 2008
Received in revised form 12 February 2009
Accepted 13 February 2009
Available online 26 February 2009
g
a
a
Keywords:
Catalytic allylic amination
Cyclic B–H adduct
Aromatic amine
Allylic rearrangement
a
-Regioselectivity
1. Introduction
regioselective allylic substitution of cyclic B–H adducts with N-nu-
cleophiles is still a challenging problem.
Baylis–Hillman (B–H) adducts, which possess allylic hydroxyl
and Michael acceptor units, have been illustrated as valuable syn-
thons and starting materials for the synthesis of various biologically
active molecules.1 Recently B–H adduct as an electrophilic sub-
strate has achieved fruitful results in the allylic substitution re-
actions with various nucleophiles, including C-nucleophiles such as
arenes, hetero-arenes,2 and carbonion,3 as well as hetero-nucleo-
philes such as the compounds bearing –OH,4 –SH,5 and –NH6
groups. Among them, the carbon–nitrogen bond formation by N-
nucleophilic substitution plays an important role for the diversity of
synthetic compounds with biological activities.1,6,11a
Meanwhile, the B–H acetate was employed in the nucleophilic
substitutions better than the B–H adduct bearing allylic alcohol unit,
because hydroxyl group was usually considered as an inefficient
leaving group. However, the advantages of directly using allyl alco-
hol as an allylic reagent were noteworthy: no further functionali-
zation was required for the activation of hydroxyl group and water
was the sole by-product after the reaction. Although many methods
could be used toproceed the allylic amination of B–H acetates, the N-
nucleophilic substitution of B–H alcohols was seldom reported. In-
stead of allylic amination, the reaction of most B–H alcohols with
amines afforded related Michael addition products.12
Regioselective introductions of nucleophiles at either the
a- or
g-
Recently, we reported a highly a-regioselective Lewis acid
position of the B–H adduct have become powerful tools in synthetic
(AgOTf)-catalyzed allylation of cyclic B–H acetates with indoles as
C-nucleophiles.13 As a continuation of our research in the allyla-
tions with cyclic B–H adducts as the allylic reagents, herein, we
organic chemistry.7 Allylic substitution of most acyclic B–H adducts
could achieve regiocontrol either at
g-position by Lewis acid catalysis
and inorganic base promotion,8 or at
a-position mainly by organic
want to report highly a-regioselective N-nucleophilic substitution
base catalysts.9 On the other hand, condensation of polycyclic ring
system is the effort for the synthesis of heterocyclic compounds and
natural products. Cyclic B–H adducts derived from cyclic enones10
could acquire great success in generating fused cyclic framework.11
However, the allylicalkylationofcyclicB–Hadductscouldbedifferent
frommostacyclicB–Hadductsduetoits unsymmetricallysubstituted
allyl structure. The development of an efficient catalyst for the highly
of cyclic B–H adducts bearing allylic alcohol unit with aromatic
amines catalyzed by In(OTf)3.
2. Results and discussion
2.1. Catalytic allylic substitution of cyclic B–H adduct
1a with aniline 2a
Initially, the reaction of cyclic B–H adduct 1a and a simple aro-
matic amine, aniline 2a was carried out under various conditions
* Corresponding author. Tel.: þ86 10 62554614; fax: þ86 10 62554449.
E-mail address: lliu@iccas.ac.cn (L. Liu).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.048

3474
Y.-L. Liu et al. / Tetrahedron 65 (2009) 3473–3479
Table 1
O
Catalytic reactions of 1a with 2aa
O
NH2
OH
O
NH
R1
+
In(OTf)3 (10 mol%)
THF/4ÅMS, reflux
R2
+
O
R1
n
NH2
O
OH
R1
HN
n
R2
O
NH
Ph
+
n
+
Ph
R2
Ph
HN
n=1, 1a-f
n=2, 5a-e
2a-e
n=1, α-3a-l
n=2, α-6a-h
n=1, γ -4
γ-4a
1a
2a
α-3a
Scheme 1.
Entry
Catalyst
Solvent
Time (h)
Yieldb
a
/
gc
of a-3a (%)
proceeded smoothly to give the allylation products, a mixture of
3a and -4a, with the high -regioselectivity ( -/
-product¼12:1)
in 63% isolated yield of -3a in THF (entry 8).
Although DABCO and palladium catalyst exhibited good cata-
lytic ability for the reaction of acyclic B–H adducts with N-nu-
cleophiles,6 DABCO lost its catalytic ability in the reaction of cyclic
B–H adduct 1a (entry 10). Pd-catalyzed reaction of 1a with 2a
a-
1
2
3
4
5
6
7
8
AgOTf
InBr3
Zn(OTf)2
Sc(OTf)3
I2
In(OTf)3
In(OTf)3
In(OTf)3
DABCO
Pd(PPh)4
d
DCM
DCM
DCM
DCM
THF
DCM
THF
THF/4 Å MS
THF
12
12
10
10
12
12
12
12
32
24
24
dd
3
10
18
de
de
de
g
a
a g
a
dd
28
37
63
dd
62
dd
16:1
15:1
12:1
9
provided poor regioselectivity (
a
-/
g
-product¼1.9:1, entry 11). In
10f
11f
THF
THF/4 Å MS
1.9:1
the absence of catalyst, the reaction did not occur at all even
though 4 Å MS was added, and the starting materials were re-
covered (entry 11).
a
Reaction in refluxing solvent; catalyst loading: 10 mol %.
Yield of isolated product.
b
c
d
e
f
Determined by 1H NMR of crude reaction mixture.
No product determined.
2.2. The In(OTf)3-catalyzed allylic substitution of cyclic B–H
adducts with aromatic amines
No
g-product detected.
Reaction temperature: room temperature.
Subsequently, the reactions of various cyclic B–H adducts
bearing five (1a–f) or six-membered ring (5a–e) units and aromatic
amines (2a–e) were carried out in the presence of In(OTf)3
(10 mol %) in refluxing THF with 4 Å MS to give allylic substitution
(Table 1). Unfortunately, AgOTf did not exhibit any catalytic activity
(entry 1). Similarly, in the cases of InBr3, Zn(OTf)2, Sc(OTf)3, and
molecule I2 the reaction did not take place or proceeded sluggishly
(entries 2–5). The results indicated that the aromatic amines were
less reactive N-nucleophiles for the substitution reaction with
cyclic B–H adduct. Interestingly, In(OTf)3 was found to be more
effective as a catalyst (10 mol %) (entries 6 and 7).
To our delight, when molecular sieve (4 Å MS) was added as an
additive into the reaction mixture, which may played a role for
absorbing the water produced during the reaction, the reaction
products in good isolated yields with high
(Scheme 1, Table 2). For B–H adducts with five-membered ring, in
some cases a few -products could be isolated, while for B–H ad-
ducts with six-membered ring, the reaction became slow, but no
a-regioselectivities
g
g
-
products were observed in the product mixture. It was found that
when R1 was cyclohexyl group (1f), the reaction with aniline 2a
catalyzed by In(OTf)3 could also give the good yield (Table 2,
entry 9).
Table 2
In(OTf)3-catalyzed allylation reactions of B–H adducts with aromatic amines
Entry
B–H adduct
Amine
Time (h)
12
a
-Product
Yielda (%)
a/
gb
Me
O
OH
O
NH
1
1a
1a
1a
2b
2c
2d
a
a
a
-3b
-3c
-3d
65
10:1
11:1
13:1
Me
NH2
F
O
NH
2
3
12
12
64
67
F
NH2
NH2
MeO
Br
O
NH
MeO
O
NH
4
1a
2e
24
a
-3e
62
8:1
Br
NH2

Y.-L. Liu et al. / Tetrahedron 65 (2009) 3473–3479
3475
Table 2 (continued)
Entry
B–H adduct
Amine
Time (h)
a
-Product
Yielda (%)
a/
gb
O
OH
OH
OH
OH
O
NH
NH
NH
NH
5
6
7
1b
1c
1d
2a
2a
2a
12
a
a
a
-3f
67
9:1
15:1
15:1
NH2
F
F
O
O
12
12
-3g
-3h
66
63
Cl
Br
Cl
Br
O
O
O
O
8
9
1e
1f
2a
2a
12
12
a
a
-3i
-3j
62
75
10:1
Me
Me
O
OH
O
NH
c
Me
O
O
NH
NH
10
1b
2b
12
a
-3k
70
13:1
F
F
11
12
1c
5a
2c
2a
12
22
a
-3l
65
75
14:1
Cl
O
OH
O
NH
c
a
-6a
Me
O
NH
NH
c
13
14
5a
5a
2b
2c
20
20
a
a
-6b
-6c
68
71
F
O
c
(continued on next page)

3476
Y.-L. Liu et al. / Tetrahedron 65 (2009) 3473–3479
Table 2 (continued)
Entry
B–H adduct
Amine
Time (h)
a
-Product
Yielda (%)
a
/
gb
O
OH
OH
O
NH
NH
c
15
16
17
18
5b
5c
5d
5b
2a
2a
2a
2c
22
a
a
a
a
-6d
-6e
-6f
65
Me
Me
O
O
c
c
c
45
22
22
67
65
80
MeO
MeO
O
OH
O
NH
F
F
F
O
NH
-6g
Me
O
OH
O
NH
c
19
5e
2a
72
a
-6h
79
a
Isolated yield.
b
c
Determined by 1H NMR of crude reaction mixture.
No g-product detected in the product mixture.
2.3. Allylic rearrangement from
g
- to
a
-product
through chelated coordination mode A, instead of mono-co-
ordination mode B, which may result in Michael addition, the hy-
droxyl group would be activated and the nucleophiles could attack
In order to explicate the origin of the high
relationship between the conversion in the reaction of 1a with 2a
catalyzed by In(OTf)3/4 Å MS refluxed in THF and the ratio of -3a/
-4a in the product mixture was examined based on 1H NMR data
a-regioselectivity, the
at both a- and g-position. However, with the reaction proceeding,
a
the allylic rearrangement from
g
-product to
a
-product occurred. It
g
with reaction time. As shown in Table 3, initially the ratios of a- and
O
O
g-product were moderate (4.3:1–6.5:1). With increasing time, the
conversion reached 100%, while the ratio of
higher up to 12:1.
a
- to
g
-product became
Ph
O
Ph
+
NH
In(OTf)3, 10 mol%
THF, reflux, 4ÅMS
HN
Ph
HN
Moreover, under the reaction conditions, the pure
treated in the presence of the catalyst In(OTf)3 (10 mol %) for 12 h,
the product mixture was found to compose of -3a and -4a with
the ratio as high as 12:1 (Scheme 2). However, under the same
conditions, the treatment of pure -3a could not observe the
isomerization of -3a to -4a. It was suggested that there should be
an allylic rearrangement reaction14 from
-product to -product
g-4a was
γ-4a
(α/γ = 12:1)
γ-4a
α-3a
a
g
Scheme 2.
a
a
g
In
O
H
O
Ar
g
a
O
O
NH
occurred in the course of the reaction of cyclic B–H adduct with
+
aromatic N-nucleophiles, eventually reaching at thermodynamical
HN
equilibrium between
high as 12:1.
a- and g-product with a-regioselectivity as
ArNH2
Ar
α-product
γ-product
A
In summary of the experimental results, a plausible mechanism
could be proposed in Scheme 3. In In(OTf)3-catalyzed reaction,
In
H
H
O
O
O
O
Table 3
Relationship between conversion and ratio of a-3a to g
-4a with reaction timea
HN
Time
10 min
30 min
1 h
2 h
12 h
20 h
ArNH2
Ar
Conver. (%)
73
75
86
87
100
100
B
a
-3a/g-4a
4.3:1
6.5:1
9.0:1
9.2:1
11:1
12:1
a
Determined by 1H NMR.
Scheme 3.

Y.-L. Liu et al. / Tetrahedron 65 (2009) 3473–3479
3477
can be found that
compound, resulting in
a
-product is more thermodynamically stable
4.2.3. 2-[(p-Toluidino)(phenyl)methyl]cyclopent-2-enone (
Yellow solid, mp: 141–142 ꢀC. FTIR (KBr):
3421, 2986, 1745, 1563,
1490, 1372, 1308, 1098, 743 cmꢁ1. 1H NMR (300 MHz, CDCl3):
2.19 (s,
3H), 2.41 (m, 2H), 2.55 (m, 2H), 4.39 (br, 1H), 5.27 (br, 1H), 6.47 (d,
J¼8.3 Hz, 2H), 6.92 (d, J¼8.3 Hz, 2H), 7.20–7.46 (m, 6H). The value
was determined by the 1H NMR absorptions of the product mixture at
5.27 and 4.91 ppm. 13C NMR (75 MHz, CDCl3):
20.3, 26.6, 35.4, 55.2,
a-3b)
a-selection predominately.
n
d
3. Conclusion
a/g
Highly
a-regioselective In(OTf)3-catalyzed N-nucleophilic
d
substitution of cyclic B–H adducts with aromatic amines was de-
veloped. Duringthecourseof thereaction, allylic rearrangement from
113.9, 127.1, 127.1, 127.5, 128.7, 128.6, 141.2, 144.7, 146.9, 159.6, 208.2.
HRMS (EI): m/z calcd for C19H19NO (Mþ): 277.1467, found: 277.1465.
g-product to
a-product occurred, utilizing this rearrangement re-
action, -regiocontrol to the N-nucleophilic substitution of cyclic B–H
adducts could be realized. The synthetic method provided an efficient
route toaromaticallylicaminebearingcyclicunsaturated ketoneunit.
a
4.2.4. 2-[(4-Fluorophenylamino)(phenyl)methyl]cyclopent-2-
enone (
White solid, mp: 125–127 ꢀC. FTIR (KBr):
1621, 1511, 1217, 823, 780, 705, 516 cmꢁ1. 1H NMR (300 MHz, CDCl3):
a-3c)
n
3376, 3058, 2922,1695,
4. Experimental
4.1. General
d
8.09 (br s, 1H), 7.56 (d, J¼7.7 Hz, 1H), 7.38 (d, J¼8.9 Hz,1H), 7.19–7.14
(m, 2H), 7.08–7.03 (m, 1H), 6.88–6.83 (m, 1H), 6.77 (d, J¼1.6 Hz, 1H),
6.70 (d, J¼8.0 Hz, 1H), 5.89, 5.86 (dd, J¼1.0, 9.3 Hz, 2H), 5.81 (d,
J¼11.3 Hz, 1H), 5.29 (d, J¼11.3 Hz, 1H), 4.13–4.03 (m, 2H), 1.02 (t,
J¼7.1 Hz, 3H). The
a/g
value was determined by the 1H NMR absorp-
IR spectra were recorded with a Perkin–Elmer 782 IR spec-
trometer. 1H NMR and 13C NMR spectra were obtained in CDCl3 at
room temperature with a Bruker DMX-300 (300 MHz) spectro-
meter. Chemical shifts are given in parts per million relative to
tetramethylsilane (TMS). Mass spectra were recorded with a Bruker
APEX-2 spectrometer. Elemental analyses were performed with
a Carlo Erba 1102 Element Analysis instrument. Melting points
were measured with a Beijing-Taike X-4 apparatus and are un-
corrected. Unless otherwise noted, all reagents were obtained from
commercial suppliers and were used without further purification.
According to reference’s method,10 the cyclic B–H adducts (1a–f
and 5a–e) were synthesized.
tions of the product mixture at 5.28 and 4.87 ppm. 13C NMR (75 MHz,
CDCl3):
d
26.6, 35.3, 55.6, 114.7 (J¼7.35 Hz), 115.6 (J¼22.2 Hz), 127.0,
127.6, 128.8, 140.9, 143.3, 146.6, 156.1 (J¼ꢁ234.2 Hz), 159.9, 208.2.
HRMS (EI): m/z calcd for C18H16NOF (Mþ): 281.1216, found: 281.1214.
4.2.5. 2-[(3-Methoxyphenylamino)(phenyl)methyl]cyclopent-2-
enone (
Yellow solid, mp: 123–125 ꢀC. FTIR (film):
1562, 1459, 1303, 1183, 1016, 740 cmꢁ1. 1H NMR (300 MHz, CDCl3):
2.40–2.43 (m, 2H), 2.54–2.57 (m, 2H), 3.68 (s, 3H), 4.56 (br, 1H),
a-3d)
n
3409, 2923, 1747,
d
5.30 (s, 1H), 6.10 (s, 1H), 6.17 (dd, J¼8.0, 1.0 Hz, 1H), 6.25 (dd, J¼6.8,
1.3 Hz, 1H), 7.01 (t, J¼8.1 Hz, 1H), 7.21–7.39 (m, 5H), 7.46 (s, 1H); 13C
4.2. Typical procedure for allylation substitution reactions of
cyclic B–H adducts with aromatic amines
NMR (75 MHz, CDCl3): d 26.6, 35.4, 55.0, 55.0, 99.8, 103.2, 106.7,
127.0, 127.6, 128.8, 129.9, 141.0, 146.6, 148.4, 159.8, 160.7, 208.2.
HRMS (EI): m/z calcd for C19H19NO2 (Mþ): 293.1416, found: 293.1414.
To a suspension of 2-[hydroxy(phenyl)methyl]cyclopent-2-enone
1a (56.4 mg, 0.3 mmol), In(OTf)3 (16.9 mg, 0.03 mmol), and 4 Å MS
4.2.6. 2-[(4-Bromophenylamino)(phenyl)methyl]cyclopent-2-
(200 mg) in THF (2 mL), aniline 2a (41
m
L, 0.45 mmol) was added,
enone (
Yellow solid, mp: 152–153 ꢀC. FTIR (KBr):
2853.2, 1690, 1592, 1495, 1290, 1242, 814, 700, 501 cmꢁ1. 1H NMR
(300 MHz, CDCl3): 2.43 (m, 2H), 2.57 (m, 2H), 4.65 (br s, 1H), 5.26
(s, 1H), 6.42 (d, J¼7.8 Hz, 2H), 7.16–7.37 (m, 7H), 7.44 (s, 1H). The
value was determined by the 1H NMR absorptions of the product
mixture at 5.30 and 4.91 ppm. 13C NMR (75 MHz, CDCl3):
26.6,
35.3, 55.0, 109.6, 115.3, 127.0, 127.7, 128.8, 131.8, 140.5, 145.9, 146.3,
160.0, 208.2. HRMS (FAB): m/z calcd for C18H16NOBr (Mþ): 341.0415
and 343.0395, found: 341.0418 and 343.0398.
a-3e)
followed by stirring in refluxing THF under a nitrogen atmosphere for
12 h. After the reaction finished, the reaction mixture was cooled
downand filtered through a pad of diatomite. The filtratewas washed
with saturated NaHCO3 and extracted with CHCl3. The combined or-
ganic phase was dried over Na2SO4 and evaporated under vacuum to
give crude product, which was purified by flash chromatography on
silica gel (eluent: petroleum ether/ethyl acetate¼4:1) to give yellow
n 3377, 3054, 2918,
d
a/g
d
powder
yield). The
the product mixture at 5.31 and 4.92 ppm.
a
-3a (51.4 mg, 65% yield) and yellow foam
a/g
g-4a (6.5 mg, 8%
value was determined by the 1H NMR absorptions of
4.2.7. 2-[(Phenylamino)(4-fluorophenyl)methyl]cyclopent-2-
4.2.1. 2-[(Phenylamino)(phenyl)methyl]cyclopent-2-enone (
Yellow solid, mp: 142–143 ꢀC. FTIR (KBr):
3395, 3052, 2919,
1692, 1599, 1501, 749, 694 cmꢁ1. 1H NMR (300 MHz, CDCl3)
2.44
a
-3a)
enone (
Yellow solid, mp: 104–105 ꢀC. FTIR (KBr):
1695, 1601, 1504, 1434, 1225, 1004, 839, 748, 695, 518 cmꢁ1. 1H NMR
(300 MHz, CDCl3): 2.42 (m, 2H), 2.56 (m, 2H), 4.50 (br s, 1H), 5.28
(s,1H), 6.53 (d, J¼8.2 Hz, 2H), 6.69 (t, J¼7.3 Hz,1H), 6.98 (t, J¼8.6 Hz,
2H), 7.10 (m, 2H), 7.33–7.37 (m, 2H), 7.45 (s, 1H). The value was
determined by the 1H NMR absorptions of the product mixture at
5.28 and 4.87 ppm. 13C NMR (75 MHz, CDCl3):
26.6, 35.4, 54.3,
a-3f)
n
n 3380, 3053, 2922,
d
(m, 2H), 2.58 (m, 2H), 4.51 (br, 1H), 5.31 (s, 1H), 6.55 (d, J¼8.6 Hz,
d
2H), 6.69 (t, 1H, J¼7.3 Hz), 7.12 (dd, J¼8.5, 7.4 Hz, 2H), 7.24–7.48 (m,
6H); 13C NMR (75 MHz, CDCl3):
d
26.5, 35.3, 55.0, 113.7, 118.0, 127.0,
a/g
127.6, 128.7, 129.1, 141.0, 146.8, 147.0, 159.5, 208.0. HRMS (EI): m/z
calcd for C18H17NO (Mþ): 263.1310, found: 263.1308.
d
113.8, 115.6 (J¼21.3 Hz), 118.1, 128.7 (J¼8.0 Hz), 129.2, 136.8, 146.6,
146.8, 159.8, 162.2 (J¼ꢁ244 Hz). HRMS (EI): m/z calcd for
C18H16NOF (Mþ): 281.1216, found: 281.1214.
4.2.2. (E)-2-Benzylidene-3-(phenylamino)cyclopentanone (
A yellow foam. FTIR (KBr): 3368, 3053, 2923, 1709, 1609, 1501,
1444, 1310, 1183, 1079, 751, 695, 514 cmꢁ1 1H NMR (300 MHz,
CDCl3): 1.98–2.09 (m, 1H), 2.34–2.46 (m, 2H), 2.52–2.62 (m, 1H),
g-4a)
n
.
d
4.2.8. 2-[(Phenylamino)(4-chlorophenyl)methyl]cyclopent-2-
3.97 (br, 1H), 4.92 (br, 1H), 6.68 (d, J¼8.3 Hz, 2H), 6.81 (t, J¼7.3 Hz,
enone (
Yellow powder, mp: 138–140 ꢀC. FTIR (KBr):
1695, 1600, 1498, 1316, 1258, 1092, 1007, 747, 696, 512 cmꢁ1
NMR (300 MHz, CDCl3): 2.41–2.44 (m, 2H), 2.57–2.59 (m, 2H),
4.52 (br s, 1H), 5.28 (s, 1H), 6.52–6.54 (m, 2H), 6.70 (t, J¼7.3 Hz, 1H),
a-3g)
1H), 7.24–7.37 (m, 5H), 7.57–7.61 (m, 3H); 13C NMR (75 MHz,
n
3381, 3053, 2921,
1H
CDCl3):
d
25.5, 34.1, 52.1, 112.5, 117.1, 128.1, 128.5, 129.4, 130.4, 132.9,
.
135.8, 136.2, 145.1, 205.7. HRMS (EI): m/z calcd for C18H17NO (Mþ):
d
263.1310, found: 263.1308.

3478
Y.-L. Liu et al. / Tetrahedron 65 (2009) 3473–3479
7.08–7.14 (m, 2H), 7.23–7.28 (m, 4H), 7.45 (m, 1H); 13C NMR
(75 MHz, CDCl3): 26.6, 35.3, 54.4, 113.8, 118.2, 128.4, 128.9, 129.2,
4.2.14. 2-[(Phenylamino)(phenyl)methyl]cyclohex-2-enone (
Yellow powder, mp: 124–125 ꢀC. FTIR (KBr):
3392, 3052, 3031,
2928, 2875, 1667, 1600, 1500, 1426, 1376, 1315, 1251, 1172, 748, 697,
512 cmꢁ1. 1H NMR (300 MHz, CDCl3):
1.95 (m, 2H), 2.39 (m, 4H),
a-6a)
d
n
133.3, 139.6, 146.4, 146.7, 159.9, 208.0. HRMS (EI): m/z calcd for
C18H16NOCl (Mþ): 297.0920, found: 297.0918.
d
4.21 (br s, 1H), 5.42 (s, 1H), 6.50–5.53 (m, 2H), 6.67 (t, J¼7.3 Hz, 1H),
4.2.9. 2-[(Phenylamino)(4-bromophenyl)methyl]cyclopent-2-
7.02 (t, J¼4.1 Hz, 1H), 7.08–7.04 (m, 2H), 7.19–7.36 (m, 5H); 13C NMR
enone (
Yellow solid, mp: 151–152 ꢀC. FTIR (KBr):
2853,1693,1599,1495,1433,1258,1003, 826, 747, 695, 512 cmꢁ1. 1H
NMR (300 MHz, CDCl3): 2.39–2.47 (m, 2H), 2.60 (m, 2H), 4.55 (br
s, 1H), 5.29 (s, 1H), 6.54 (s, 1H), 6.57 (s, 1H), 6.72 (t, J¼7.3 Hz, 1H),
7.11–7.16 (m, 2H), 7.28–7.31 (m, 2H), 7.44–7.48 (m, 3H). The
value was determined by the 1H NMR absorptions of the product
mixture at 5.29 and 4.89 ppm. 13C NMR (75 MHz, CDCl3):
26.6,
a-3h)
(75 MHz, CDCl3): d 22.8, 38.7, 56.7, 113.5, 117.7, 127.3, 127.4, 128.6,
n
3347, 3051.8, 2915,
129.2, 139.4, 141.8, 146.7, 147.1, 198.5. HRMS (EI): m/z calcd for
C19H19NO (Mþ): 277.1467, found: 277.1469.
d
4.2.15. 2-[(p-Toluidino)(phenyl)methyl]cyclohex-2-enone (
Yellow solid, mp: 139–141 ꢀC. FTIR (KBr):
3388, 3048, 3021,
2923, 2862, 1667, 1598, 1503, 1427, 1374, 1313, 1249, 1171, 810, 750,
693, 510 cmꢁ1 1H NMR (300 MHz, CDCl3):
1.91–2.04 (m, 2H),
a-6b)
a
/g
n
d
.
d
35.3, 54.4, 113.8, 118.2, 121.4, 128.8, 129.2, 131.9, 140.2, 146.3, 146.6,
156.0, 208.0. HRMS (EI): m/z calcd for C18H16NOBr (Mþ): 341.0415
and 343.0395, found: 341.0413 and 343.0392.
2.20 (s, 3H), 2.36–2.46 (m, 4H), 4.08 (br s, 1H), 5.39 (s, 1H), 6.44 (d,
J¼8.3 Hz, 2H), 6.93 (d, J¼8.3 Hz, 2H), 7.03 (t, J¼4.0 Hz, 1H), 7.21–
7.36 (m, 5H); 13C NMR (75 MHz, CDCl3):
d 20.4, 22.8, 26.0, 38.8,
47.2, 113.6, 126.9, 127.3, 128.6, 129.7, 139.6, 142.0, 144.8, 146.6,
198.6. HRMS (EI): m/z calcd for C20H21NO (Mþ): 291.1623, found:
291.1625.
4.2.10. 2-[(Phenylamino)(p-tolyl)methyl]cyclopent-2-enone (
Yellow solid, mp: 128–129 ꢀC. FTIR (KBr):
3382, 3049, 3021,
2921, 2858, 1695, 1600, 1505, 1434, 1315, 1259, 1185, 746, 694,
516 cmꢁ1. 1H NMR (300 MHz, CDCl3):
2.35 (s, 3H), 2.44–2.48 (m,
a-3i)
n
d
4.2.16. 2-[(4-Fluorophenylamino)(phenyl)methyl]cyclohex-2-
2H), 260 (m, 2H), 4.54 (br s, 1H), 5.32 (s, 1H), 6.57 (s, 1H), 6.60 (s,
enone(
A yellow liquid. FTIR (KBr):
1511, 1377, 1217, 821, 703, 515 cmꢁ1
1.90–2.03 (m, 2H), 2.37–2.49 (m, 4H), 4.16 (br s, 1H), 5.35 (s, 1H),
a-6c)
1H), 6.72 (t, J¼7.3 Hz, 1H), 7.12–7.18 (m, 4H), 7.31 (s, 1H), 7.33 (s, 1H),
n
3383, 3057, 3034, 2938, 2880, 1667,
1H NMR (300 MHz, CDCl3):
7.51 (m, 1H). The
a
/g
value was determined by the 1H NMR ab-
.
sorptions of the product mixture at 5.32 and 4.91 ppm. 13C NMR
(75 MHz, CDCl3): 21.1, 26.6, 35.4, 54.7, 113.7, 117.9, 127.0, 129.2,
d
d
6.42–6.47 (m, 2H), 6.81 (d, J¼233.6 Hz) (t, J¼8.7 Hz, 2H), 6.99 (t,
129.5, 137.3, 138.0, 146.8, 147.0, 159.6, 208.3. HRMS (EI): m/z calcd
J¼4.1 Hz, 1H), 7.27–7.35 (m, 5H); 13C NMR (75 MHz, CDCl3):
d 22.7,
for C19H19NO (Mþ): 277.1467, found: 277.1469.
26.0, 38.7, 57.6, 114.4 (J¼7.3 Hz), 115.5 (J¼22.2 Hz), 127.2, 127.4,
128.6, 139.4, 141.6, 143.4, 146.9, 156.0 (J¼ꢁ233.6 Hz), 198.6. Anal.
Calcd for C19H18FNO: C, 77.27; H, 6.14; N, 4.74. Found: C, 77.32; H,
6.22; N, 4.92.
4.2.11. 2-[(Phenylamino)(cyclohexyl)methyl]cyclopent-2-
enone (
Yellow solid, mp: 78–79 ꢀC. FTIR (KBr):
2361,1690,1597,1502,1441,1251, 746, 686 cmꢁ1.1H NMR (300 MHz,
CDCl3):
a-3j)
n
3382, 3053, 2921, 2850,
4.2.17. 2-[(Phenylamino)(p-tolyl)methyl]cyclohex-2-enone (
Yellow solid, mp: 109–111 ꢀC. FTIR (KBr):
3388, 3026, 2923,
2862,1677, 1614, 1517, 1375, 1308,1248, 1173, 808, 702, 510 cmꢁ1. 1H
NMR (300 MHz, CDCl3): 1.92–2.04 (m, 2H), 2.31 (s, 3H), 2.37–2.49
a-6d)
d
0.90–1.28 (m, 5H), 1.57–1.80 (m, 5H), 1.92 (d, J¼12.8 Hz,
n
1H), 2.40–2.42 (m, 2H), 2.52–2.55 (m, 2H), 4.01 (d, J¼6.8 Hz, 1H),
4.22 (s,1H), 6.50 (d, J¼8.6 Hz, 2H), 6.63 (t, J¼7.3 Hz,1H), 7.10 (m, 2H),
d
7.33 (t, J¼2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
26.2, 26.4. 29.4,
(m, 4H), 4.17 (br s, 1H), 5.39 (s, 1H), 6.51 (d, J¼7.7 Hz, 2H), 6.68
30.3, 35.4, 41.3, 55.7, 113.2, 117.1, 129.2, 145.7, 147.6, 159.5, 209.3.
(t, J¼7.3 Hz, 1H), 7.04 (t, J¼4.0 Hz, 1H), 7.09–7.15 (m, 4H), 7.22–7.25
HRMS (EI): m/z calcd for C18H23NO (Mþ): 269.1780, found: 269.1783.
(m, 2H); 13C NMR (75 MHz, CDCl3):
d 21.1, 22.8, 25.9, 38.8, 56.7,
113.4, 117.6, 127.2, 129.1, 129.3, 137.0, 138.8, 139.4, 146.4, 147.1, 198.6.
4.2.12. 2-[(p-Toluidino)(4-fluorophenyl)methyl]cyclopent-2-
HRMS (EI): calcd for C20H21NO (Mþ): 291.1623, found: 291.1626.
enone (
Yellow solid, mp: 111–112 ꢀC. FTIR (KBr):
1668, 1511, 1377, 1312, 1217, 1165, 821, 774, 703, 515 cmꢁ1. 1H NMR
(300 MHz, CDCl3): 2.20 (s, 3H), 2.40–2.44 (m, 2H), 2.55–2.58 (m,
2H), 4.37 (br s, 1H), 5.26 (s, 1H), 6.45 (d, J¼8.4 Hz, 2H), 6.91–7.01 (m,
4H), 7.33–7.37 (m, 2H), 7.45 (t, J¼2.6 Hz, 1H). The value was
determined by the 1H NMR absorptions of the product mixture at
5.26 and 4.85 ppm. 13C NMR (75 MHz, CDCl3):
20.4, 26.6, 35.4,
a-3k)
n
3385, 3031, 2924,
4.2.18. 2-[(Phenylamino)(4-methoxyphenyl)methyl]cyclohex-2-
enone (
A yellow liquid. FTIR (KBr):
1505, 1374, 1247, 1173, 1032, 817, 749, 694 cmꢁ1. 1H NMR (300 MHz,
CDCl3): 1.92–2.04 (m, 2H), 2.35–2.44 (m, 4H), 3.76 (s, 3H), 4.16 (br
a-6e)
d
n 3389, 3043, 2922, 2862, 1666, 1602,
a
/g
d
s, 1H), 5.37 (s, 1H), 6.50 (d, J¼8.2 Hz, 2H), 6.67 (t, J¼7.3 Hz, 1H), 6.83
d
(d, J¼8.7 Hz, 2H), 7.03 (t, J¼4.1 Hz, 1H), 7.11 (t, J¼7.7 Hz, 2H), 7.26 (d,
54.6, 113.9, 115.5 (d, J¼21.4 Hz), 127.4, 128.7 (d, J¼8.0 Hz), 129.7,
137.0,144.5,146.8,159.7,162.2 (d, J¼244.2 Hz). HRMS (EI): m/z calcd
for C19H18NOF (Mþ): 295.1372, found: 295.1375.
J¼8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 22.8, 25.9, 38.8, 55.3,
56.4, 113.4, 114.0, 117.6, 128.4, 129.1, 133.9, 139.4. 146.3, 147.1, 158.9,
198.6. HRMS (EI): m/z calcd for C20H21NO2 (Mþ): 307.1572, found:
307.1574.
4.2.13. 2-[(4-Fluorophenylamino)(4-chlorophenyl)methyl]-
cyclopent-2-enone (
Yellow solid, mp: 107–111 ꢀC. FTIR (KBr):
2862, 1696, 1618, 1512, 1220, 1093, 1008, 818, 514 cmꢁ1
(300 MHz, CDCl3): 2.43 (m, 2H), 2.58 (m, 2H), 4.47 (br s, 1H), 5.21
(s, 1H), 6.44–6.49 (m, 2H), 6.81 (t, J¼8.7 Hz, 2H), 7.26–7.34 (m, 4H),
7.43 (t, J¼2.6 Hz, 1H). The
value was determined by the 1H NMR
absorptions of the product mixture at 5.21 and 4.82 ppm. 13C NMR
(75 MHz, CDCl3):
a
-3l)
4.2.19. 2-[(Phenylamino)(4-fluorophenyl)methyl]cyclopent-2-
n
3378, 3048, 2922,
1H NMR
enone (
White solid, mp: 104–106 ꢀC. FTIR (KBr):
1664, 1604, 1503, 1425, 1375, 1314, 1224, 1163, 822, 749,
694, 519 cmꢁ1 1H NMR (300 MHz, CDCl3):
1.68–2.04 (m, 2H),
a-6f)
.
n 3394, 3061, 2929,
d
.
d
a/g
2.36–2.44 (m, 2H), 4.18 (br s, 1H), 5.29 (s, 1H), 6.51 (d, J¼7.7 Hz, 2H),
6.69 (t, J¼7.3 Hz, 1H), 6.95–7.15 (m, 5H), 7.29–7.34 (m, 2H); 13C NMR
d
26.6, 35.2, 55.1, 114.8 (J¼7.4 Hz), 115.6
(75 MHz, CDCl3):
d
22.7, 25.9, 38.7, 56.5, 113.5, 115.4 (J¼ꢁ21.4 Hz),
(J¼ꢁ22.3 Hz), 128.3, 128.9, 133.4, 139.5, 143.0, 146.3, 156.2 (d,
J¼234.8 Hz), 159.9, 207.9. HRMS (EI): m/z calcd for C18H15NOFCl
(Mþ): 315.0826, found: 315.0829.
117.9, 128.8 (J¼8.0 Hz), 129.2, 137.5, 139.4, 146.9, 162.1 (J¼244.0 Hz),
198.5. HRMS (EI): m/z calcd for C19H18NOF (Mþ): 295.1372, found:
295.1375.

Y.-L. Liu et al. / Tetrahedron 65 (2009) 3473–3479
3479
3. For examples, see: (a) Bo¨rner, C.; Gimeno, J.; Gladiali, S.; Goldsmith, P. J.;
Ramazzotti, D.; Simon, W. Chem. Commun. 2000, 2433–2434; (b) Basavaiah, D.;
Satyanarayana, T. Org. Lett. 2001, 3, 3619–3622; (c) Zhang, Q.; Sun, S. G.; Hu, J.
L.; Liu, Q.; Tan, J. J. Org. Chem. 2007, 72, 139–143; (d) Zhong, W. H.; Zhao, Y. Z.;
Su, W. K. Tetrahedron 2008, 64, 5491–5496; (e) Mandal, S. K.; Paira, M.; Roy, S. C.
J. Org. Chem. 2008, 73, 3823–3827; (f) Kim, S. H.; Kim, K. H.; Kim, H. S.; Kim, J. N.
Tetrahedron Lett. 2008, 49, 1948–1951; (g) Singh, V.; Yadav, G. P.; Maulik, P. R.;
Batra, S. Tetrahedron 2008, 64, 2979–2991.
4.2.20. 2-[(4-Fluorophenylamino)(p-tolyl)methyl]cyclohex-2-
enone ( -6g)
White solid, mp: 104–106 ꢀC. FTIR (KBr):
1664, 1604, 1503, 1425, 1375, 1314, 1224, 1163, 822, 749, 694,
519 cmꢁ1. 1H NMR (300 MHz, CDCl3):
1.99–2.00 (m, 2H), 2.30 (s,
a
n
3394, 3061, 2929,
d
3H), 2.34–2.46 (m, 4H), 4.12 (br s, 1H, s), 5.32 (s, 1H), 6.41–6.46 (m,
2H), 6.80 (t, J¼8.7 Hz, 2H), 6.98 (t, J¼4.0 Hz, 1H), 7.10 (d, J¼7.9 Hz,
4. (a) Basavaiah, D.; Hyma, R. S.; Kumaragurubaran, N. Tetrahedron 2000, 56,
5905–5907; (b) Basavaiah, D.; Hyma, R. S.; Muthukumaran, K.; Kumaragur-
ubaran, N. Synthesis 2000, 217–219; (c) Reddy, C. R.; Kiranmai, N.; Babu, G. S. K.;
Sarma, G. D.; Jagadeesh, B.; Chandrasekhar, S. Tetrahedron Lett. 2007, 48, 215–
218; (d) Kim, H. S.; Gowrisankar, S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008,
49, 3858–3861; (e) Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008, 49,
1125–1128; (f) Ollevier, T.; Mwene-Mbeja, T. M. Tetrahedron 2008, 64,
5150–5155.
2H), 7.22 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 21.1, 22.7,
25.9, 38.7, 57.3, 114.3 (J¼7.3 Hz), 115.5 (J¼22.2 Hz), 127.1, 129.3,
137.0, 138.6, 139.5, 143.5, 146.7, 155.9 (J¼233.6 Hz), 198.6. HRMS
(EI): m/z calcd for C20H20NOF (Mþ): 309.1529, found: 309.1532.
5. Kamimura, A.; Morita, R.; Matsuura, K.; Omata, Y.; Shirai, M. Tetrahedron 2002,
43, 6189–6191.
4.2.21. 2-[(Phenylamino)(cyclohexyl)methyl]cyclohex-2-
enone (
A yellow liquid. FTIR (KBr):
1665, 1602, 1505, 1380, 1318, 1259, 117, 1091, 1026, 802, 751, 695,
494 cmꢁ1. 1H NMR (300 MHz, CDCl3):
0.87–1.13 (m, 2H), 1.16–1.31
a-6h)
6. For examples, see: (a) Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron 2005,
61, 1493–1499; (b) Lee, C. G.; Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Tetrahedron
Lett. 2004, 45, 7409–7413; (c) Pathak, R.; Madapa, S.; Batra, S. Tetrahedron 2007,
63, 451–460; (d) Rajesh, S.; Banerji, B.; Iqbal, J. J. Org. Chem. 2002, 67, 7852–
7857.
7. (a) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627–645; (b) Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1481–1490; (c) Shi,
Y. L.; Shi, M. Eur. J. Org. Chem. 2007, 2905–2916.
8. Selected examples: (a) Basavaiah, D.; Pandiaraju, S.; Padmaja, K. Synlett 1996,
393–395; (b) Im, Y. J.; Lee, H. R.; Kim, J. R. Tetrahedron Lett. 2003, 44, 2987–
2990; (c) Kabalka, G. W.; Venkataiah, B.; Dong, G. Org. Lett. 2003, 5, 3803–3805;
(d) Nag, S.; Pathak, R.; Kumar, M.; Shukla, P. K.; Batra, S. Bioorg. Med. Chem. Lett.
2006, 16, 3824–3828.
9. Selected examples: (a) Chung, Y. M.; Gong, J. H.; Kim, T. H.; Kim, J. N. Tetrahe-
dron Lett. 2001, 42, 9023–9026; (b) Cho, C.-W.; Krische, M. J. Angew. Chem., Int.
Ed. 2004, 43, 6689–6691; (c) Li, J.; Wang, X.; Zhang, Y. Tetrahedron Lett. 2005,
46, 5233–5237; (d) Jiang, Y. Q.; Shi, Y. L.; Shi, M. J. Am. Chem. Soc. 2008, 130,
7202–7203.
n
3400, 3053, 3021, 2959, 2924, 2870,
d
(m, 3H), 1.53–1.78 (m, 6H), 1.90–2.00 (m, 3H), 2.32–2.37 (m, 2H),
2.40–2.44 (m, 2H), 3.97 (d, J¼7.3 Hz, 1H), 4.18 (br s, 1H), 6.48
(d, J¼8.0 Hz, 2H), 6.63 (t, J¼7.3 Hz, 1H), 6.78 (t, J¼4.2 Hz, 1H), 7.11
(t, J¼7.6 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 21.8, 24.9, 25.2, 25.3,
25.5, 28.8, 29.8, 37.9, 41.0, 58.1, 112.2, 115.8, 128.1, 137.7, 145.4, 146.8,
198.6. HRMS (EI): m/z calcd for C19H25NO (Mþ): 283.1936, found:
283.1939.
Acknowledgements
We are grateful to thank National Natural Foundation of China
and Chinese Academy of Sciences for the financial support.
10. (a) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nakasawa, K. Tetrahedron Lett.
2004, 45, 5589–5592; (b) Luo, S.; Mi, X. L.; Xu, H.; Wang, P. G.; Cheng, J. P. J. Org.
Chem. 2004, 69, 8413–8422; (c) Matsui, K.; Takizawa, S.; Sasai, H. Tetrahedron
Lett. 2005, 46, 1943–1946; (d) Porzelle, A.; Williams, C. M.; Schwartz, B. D.;
Gentle, I. R. Synlett 2005, 2923–2926; (e) He, L.; Jian, T. Y.; Ye, S. J. Org. Chem.
2007, 72, 7466–7468.
References and notes
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