Highly efficient Cu-catalyzed oxidative coupling of tertiary amines and?siloxyfurans

Article abstract of DOI:10.1016/j.tet.2008.10.078

A mild, selective, and efficient protocol for the synthesis of γ-aminoalkyl butenolides via the oxidative coupling between tertiary amines and siloxyfurans catalyzed by simple copper salts was developed. Compared with the reported method, our method emplo

Full text of DOI:10.1016/j.tet.2008.10.078

Tetrahedron 65 (2009) 158–163
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient Cu-catalyzed oxidative coupling of tertiary amines
and siloxyfurans
*
*
Youming Shen, Ze Tan , De Chen, Xunbo Feng, Mo Li, Can-Cheng Guo , Chengliang Zhu
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, selective, and efficient protocol for the synthesis of g-aminoalkyl butenolides via the oxidative
Received 23 September 2008
Accepted 24 October 2008
Available online 26 October 2008
coupling between tertiary amines and siloxyfurans catalyzed by simple copper salts was developed.
Compared with the reported method, our method employs copper catalyst instead of the expensive
rhodium catalyst. Besides TBHP, both O2 and H2O2 can also be utilized as oxidant to effect the coupling.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
reaction would be greatly enhanced since the price of copper is
significantly lower than rhodium, especially when the reaction is
One of the challenges synthetic organic chemists facing in the
21th century is the development of mild, selective, and efficient
C–C bond formation reactions via CH-activation mode.1–5 The
CH-activation of tertiary amines, an important class of organic
compounds, has attracted a lot of attentions lately6–9 because the
iminium ion generated in situ could participate in a plethora of
different transformations.10 Inspired by earlier seminar work by
run on large scale. Herein, we report that the oxidative coupling
between tertiary amines and siloxyfurans can be efficiently cataly
zed by simple copper salts using either TBHP or O2 as the oxidant.
cat. Rh, 60 °C
1.2 eq. TBHP, MeOH
O
N
ð1Þ
O
N
OTIPS
O
Murahashi on the Ru-catalyzed a-cyanation of tertiary amines via
CH-activation,8 Li et al. recently developed a series of elegant C–C
bond formation reactions (referred by Li as cross-dehydrogenative
couplings) between tertiary amines and a variety of nucleophiles
such as nitro alkanes,9e,i terminal alkynes,9a indoles,9d malonates,9c
malononitriles,9c 2-naphthol,9f and phenylboronic acids9j as well as
Morita–Baylis–Hillman (MBH) adducts9f employing copper salt as
catalyst and anhydrous TBHP as the oxidant. Even more impressive
is that they were able to develop an enantioselective coupling be-
tween terminal alkynes and the sp3 C–H bonds adjacent to nitrogen
in tetrahydroisoquinolines.9b This method could provide rapid ac-
cess to several biologically important chiral tetrahydroisoquinoline
alkanoids.
2. Results and discussion
We began our study by examining different copper salts as the
catalysts using N,N-dimethyl aniline (1) and siloxyfuran 2 as the
coupling partners and the results are shown in Table 1. We were
glad to discover that running the reaction in methanol in the
presence of 5% CuCl at 55 ꢀC for 3 h led to the formation of the
desired g-aminoalkyl butenolide in 69% yield (Table 1, entry 1). Out
of the various copper salts tried, CuBr was found to be the best,
affording the desired product in 78% yield while other copper salts
such as CuBr2, CuCl2, CuI, Cu(OAc)2, and CuO were less effective
(Table 1, entries 2–7). Replacing the solvent methanol with ethanol
resulted in a sizable decrease in terms of product yield (entry 8).
Though the use of 1.2 equiv of anhydrous TBHP proved to be suf-
ficient, it is discovered that 1 equiv excess of 1 is needed in order to
obtain high product yield. Control experiment also showed that no
desired butenolide was formed in the absence of copper catalyst
(entry 9). As a result, we decided to set running the reaction at
55 ꢀC in the presence of 5% CuBr as the standard reaction condition.
Under the standard condition, various amines were coupled
with different siloxylfurans and the results are listed in Table 2. In
all cases, the desired products were formed in moderate to
good yields. It should be noted that besides N,N-dimethyl anilines,
In 2006, Doyle reported an efficient oxidative Mannich reaction
between tertiary amines and siloxyfurans using TBHP as oxidant
catalyzed by Rh2(cap)4, allowing a fast and expedient route for the
synthesis of g-aminoalkyl butenolides (Eq. 1). Similar to the cross-
dehydrogenative coupling reactions, an iminium species was pro-
posed as the reaction intermediate and this raise the possibility that
the same transformation could be catalyzed bycopper salts as well. If
this assumption turns out to be true, the synthetic utility of this
* Corresponding authors. Tel.: þ86 0731 882 2400; fax: þ86 0731 8822484.
E-mail addresses: ztanze@gmail.com (Z. Tan), ccguo@hnu.cn (C.-C. Guo).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.078

Y. Shen et al. / Tetrahedron 65 (2009) 158–163
159
Table 1
N,N-methyl alkyl anilines could also participate in the reaction
satisfactorily, and the coupling only occurred at the methyl
substituent selectively (Table 2, entry 3). Cyclic amines such as
pyrrolidines and tetrahydroisoquinolines could also be effectively
coupled. Unlike other amines, it only requires 1 equiv of N-phenyl
tetrahydroisoquinoline for its efficient coupling with 2 to take
place, furnishing the desired butenolide in 73% yield. The coupling
reaction also took place when T-HYDRO (70% tBuOOH in H2O) was
used in place of anhydrous TBHP, though the yields are lower by
5–12%. Other siloxylfurans such as 5-methyl and 5-allyl substituted
siloxyfurans 3 and 4 could also couple with anilines and pyrrolidine
derivatives satisfactorily (Table 2, entries 6–10).
As satisfactory as the above procedure is, the desire to use
a cleaner oxidant prompted us to investigate the possibility of using
O2 as the oxidant. Since the side product derived from O2 is water, its
use would enhance the synthetic value of this transformation even
further. Much to our delight, we found N-phenyl tetrahydro
isoquinoline could couple efficiently with siloxyfuran 2 in the
presence of 5% CuBr under a balloon of O2 (1 atm) at 55 ꢀC and the
desired coupling product was isolated in 60% yield after 4 h. Further
Optimization of reaction conditions
5% Cu salt, 55 °C
1.2 eq. TBHP, MeOH, 3 h
O
N
O
N
OTIPS
O
1
2 eq.
1 eq.
2
Entry
Catalyst
Yielda (%)
1
2
3
4
5
6
7
8
9
CuCl
CuBr
69
78
75
70
52
67
6
CuBr2
CuCl2
CuCl2
Cu(OAc)2
CuO
CuBrb
None
55
None
a
All yields are isolated yields.
Ethanol was used instead of MeOH.
b
Table 2
The oxidative coupling of tertiary amines and siloxyfurans catalyzed by CuBr using TBHP as oxidant
Entry
Amine
2-Siloxyfuran
Product
Yielda,b (%)
R¼H
78
70 (64)
66
60
40
R¼Me
R¼Br
O
1
2
R
N
O
R
N
N
R¼Ph
R¼HCO
O
N
O
2
2
74
Me
Me
R¼H, R1¼Et
68
67
55
O
R
N
R1
3
4
2
2
R¼Me, R1¼Et
O
O
R
N
R¼Me, R1¼nBu
R1
Ar¼Ph
72 (60)
53
50
Ar¼p-MePh
Ar¼p-MeOPh
O
N
Ar
N
Ar
(dr = 1-1.7:1)
5
2
73 (68)c
O
O
(dr = 1:1)
N
Ph
N
Ph
R¼H
70
75
Me
OTIPS
O
6
7
R
N
O
O
R¼Me
R
N
Me
(3)
O
N
O
N
3
64
60
Me
Me
Me
O
8
9
3
O
N
Ph
N
Ph
(dr = 4:1)
O
Me
R¼H
68
70
Allyl
OTIPS
O
R
N
O
(4)
R¼Me
R
N
O
N
O
N
10
4
60
Me
All yields are isolated yields.
The yields in parenthesis are those obtained with T-HYDRO.
Only 1 equiv of N-phenyl tetrahydroisoquinoline is used.
Me
a
b
c

160
Y. Shen et al. / Tetrahedron 65 (2009) 158–163
Table 3
test revealed CuBr2 to be a superior catalyst, whereas other catalysts
are less efficient (Table 3). On the other hand, switching to the use of
air resulted in a much more sluggish and messier reaction.
Optimization of reaction conditions
5% Cu salt, 55 °C
O2 (1 atm), MeOH, 4 h
Using CuBr2 as the catalyst, various substituted anilines and
pyrrolidines could couple with siloxyfurans 2–4 and the results are
summarized in Table 4 (entries 1–6). Compared to the reaction
using TBHP as the oxidant, the yields are generally lower and, de-
spite its earlier success, N,N-dimethyl aniline was found to be un-
suitable for the reaction when O2 was used as the oxidant. We also
briefly examined the coupling reaction using another green oxidant
H2O2 (30% in water). The coupling also took place satisfactorily and
the yields are comparable to those obtained with O2 (Table 4, en-
tries 7–10). With H2O2, N,N-dimethyl aniline was found to be a vi-
able substrate (Table 4, entry 7). In order to probe the possible
reaction mechanism, N,N-dimethyl aniline was subjected to the
standard reaction condition using methanol as the solvent in the
absence of siloxyfuran 2. NMR analysis of the crude product in-
dicated the formation of compound 5 in about 50% yield. Switching
the solvent methanol to CH2Cl2 gave the compound 6 instead.
These results are consistent with the ones reported by Doyle when
O
OTIPS
O
1 eq.
N
Ph
N
Ph
O
(dr = 1:1)
1 eq.
2
Entry
Catalyst
Yielda (%)
1
2
3
4
5
6
7
CuBr
60
82
70
57
55b
45
20
CuBr2
CuCl2
CuCl
CuI
Cu(OAc)2
CuO
a
All yields are isolated yields.
Reaction run for 20 h.
b
Table 4
Cu-Catalyzed oxidative coupling of tertiary amines with siloxyfurans using O2 or H2O2 as oxidant
Entry
Amine
2-Siloxyfuran
Product
Yielda (%)
R¼H
<15
68
1b
2
O
O
R
N
O
O
R¼Me
R
R
N
R¼Me
R1¼Et
R¼Me
R1¼nBu
55
40
2b
2
2
R
N
N
R1
R1
O
Ar¼Ph
65
62
3b
O
N
Ar
N
Ar
Ar¼p-MeOPh
(dr = 1-1.5:1)
4b
2
3
82
60
O
O
N
Ph
N
Ph
(dr = 1:1)
O
N
O
5b
N
Me
Me
6b
7c
8c
4
2
2
58
50
65
O
Me
N
N
O
Me
N
O
N
O
N
O
Me
O
Me
N
O
9c
2
2
64
58
O
N
N
Ph
(dr = 1:1)
Ph
O
N
O
10c
N
Me
Me
a
All yields are isolated yields.
O2 was used as the oxidant.
H2O2 was used as the oxidant.
b
c

Y. Shen et al. / Tetrahedron 65 (2009) 158–163
161
rhodium was used as the catalyst. It also gave support to the notion
4.2. Representative experimental procedure
that an iminium ion intermediate was generated in situ. Pre-
liminary mechanistic study also indicated that all three reactions
proceeded smoothly in the presence of 2 equiv of BHT, a free radical
inhibitor. This result strongly suggests that reaction may not in-
volve a radical process. In accord with others,9 a tentative mecha-
nism is proposed in Scheme 1. It is thought that an iminium species
is first generated by copper catalysis and the copper-coordinated
To a mixture of 1 mmol of 2-triisopropylsiloxylfuran, 2 mmol of
N,N-dimethyl aniline, and 0.05 mmol of CuBr in 1 mL of CH3OH was
added 1.2 mmol of TBHP (5–6 M in decane) (or 1.2 mmol of T-HY-
DRO (70% tBuOOH in water) or 1 atm O2 or 1.2 mmol of H2O2 (30% in
water)). The mixture was heated to 55 ꢀC for 3 h before it was
cooled to room temperature. The mixture was diluted and extrac-
ted with ether. Solvent was evaporated and the residue was puri-
fied by column chromatography on silica gel to give the desired
product (4:1 hexanes/EtOAc).
iminium ion is then trapped by the siloxyfuran to form the
aminoalkyl butenolide.
g-
cat. Cu, 23 °C
4.2.1. Synthesis of 5-[(methylphenylamino)methyl]-2(5H)-furanone
OMe
1.2 eq. TBHP
1H NMR (400 MHz, CDCl3)
d
7.48 (d, J¼5.6 Hz, 1H), 7.26
ð2Þ
ð3Þ
N
N
MeOH
(t, J¼8.0 Hz, 2H), 6.79–6.72 (m, 3H), 6.13 (dd, J¼5.6, 1.6 Hz, 1H), 5.27
5
(dd, J¼5.6, 1.6 Hz, 1H), 3.69 (d, J¼5.6 Hz, 2H), 3.03 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 172.46, 154.43, 147.98, 129.04 (2C), 121.61,
116.88, 111.93 (2C), 81.85, 54.49, 39.12; IR (neat) 1757 cmꢁ1 (C]O);
MS (CI) m/z: 204 [Mþ1]þ; HRMS (EI) calcd for C12H13NO2 [M]þ
203.0946, found 203.0948.
cat. Cu, 23 °C
t
OOBu
TBHP
N
N
CH2Cl2
6
4.2.2. Synthesis of 5-{[methyl(4-methylphenyl)amino]methyl}-
2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.47 (dd, J¼5.6, 1.6 Hz, 1H), 7.07
(d, J¼8.0 Hz, 2H), 6.65 (d, J¼8.8 Hz, 2H), 6.13 (dd, J¼6.0, 2.0 Hz, 1H),
R2
[Cu]OR
R3
5.28–5.25 (m, 1H), 3.65 (d, J¼6.0 Hz, 2H), 3.00 (s, 3H), 2.26 (s, 3H);
N
13C NMR (100 MHz, CDCl3)
d 172.69, 154.55, 146.19, 129.92 (2C),
R1
R2
OTIPS
O
126.77, 122.09, 112.63 (2C), 81.97, 55.37, 39.66, 20.18; IR (neat)
1751 cmꢁ1 (C]O); MS (CI) m/z: 218 [Mþ1]þ; HRMS (EI) calcd for
C13H15NO2 [M]þ 217.1103, found 217.1109.
O
N
R1
CH2R3
R2
+ TBHP or O2
or H2O2
N
R1
O
[Cu]
4.2.3. Synthesis of 5-{[(4-bromophenyl)methylamino]methyl}-
2(5H)-furanone
R3
1H NMR (400 MHz, CDCl3)
d
7.39 (dd, J¼5.2, 1.2 Hz, 1H), 7.25 (d,
Scheme 1.
J¼8.8 Hz, 2H), 6.51 (d, J¼8.8 Hz, 2H), 6.08 (dd, J¼6.0, 2.0 Hz, 1H),
5.19–5.16 (m, 1H), 3.63 (dd, J¼15.2, 5.6 Hz, 1H), 3.56 (dd, J¼15.6,
6.0 Hz,1H), 2.92 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 171.43,152.96,
3. Conclusion
146.27, 131.05 (2C), 121.47, 112.89 (2C), 108.39, 80.83, 53.88, 38.66;
IR (neat) 1756 cmꢁ1 (C]O); MS (CI) m/z: 282 [Mþ1]þ; HRMS (EI)
calcd for C12H12BrNO2 [M]þ 281.0051, found 281.0047.
In summary, we have developed a mild, selective, and efficient
oxidative coupling protocol for the coupling of tertiary amines and
siloxyfurans to synthesize
g
-aminoalkyl butenolides using simple
4.2.4. Synthesis of 5-[(biphenyl-4-yl-methylamino)methyl]-2(5H)-
furanone
copper salts as catalyst. The reaction could be run using TBHP, O2, or
H2O2 as the oxidant though the best yields are achieved with an-
hydrous TBHP. Our results are comparable to those reported and
the use of a relatively cheap copper catalyst in place of expensive
rhodium catalyst could be beneficial for large scale preparations.
Further investigations are currently underway to develop new
transformations as well as to gain more insight into the reaction
mechanism.
1H NMR (400 MHz, CDCl3)
d
7.48–7.41 (m, 5H), 7.33 (t, J¼7.6 Hz,
2H), 7.22–7.17 (m, 1H), 6.70 (d, J¼8.8 Hz, 2H), 6.07 (dd, J¼5.6, 2.0 Hz,
1H), 5.23–5.20 (m, 1H), 3.70–3.59 (m, 2H), 2.98 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 171.60, 153.29, 146.55, 139.71, 129.09 (2C),
127.69 (2C), 126.97 (2C), 125.26 (2C), 121.29, 111.50 (2C), 80.95,
53.91, 38.62; IR (neat) 1753 cmꢁ1 (C]O); MS (CI) m/z: 280 [Mþ1]þ;
HRMS (EI) calcd for C18H17NO2 [M]þ 279.1259, found 279.1250.
4. Experimental
4.2.5. Synthesis of 4-{[(2,5-bihydro-5-oxo-2-furanyl)methyl]meth-
ylamino}benzaldehyde
4.1. General information
1HNMR(400 MHz, CDCl3)
d
9.77 (s,1H), 7.76 (d, J¼8.8 Hz,2H), 7.53
(dd, J¼5.6, 1.2 Hz, 1H), 6.76 (d, J¼8.8 Hz, 2H), 6.18 (dd, J¼5.6, 2.0 Hz,
All solvents and reagents were purchased from the suppliers
and used without further purification. Yields reported are for iso-
lated yields unless otherwise stated. 1H NMR (400 MHz) and 13C
NMR (100 MHz) spectra were recorded in CDCl3 at room temper-
ature on a Varian INOVA-400 spectrometer. The chemical-shift
scale is based on internal TMS. MS spectra were performed on an
Agilent 1100 series mass spectrometer. HRMS analyses were per-
formed on a Shimadzu QP-2000 mass spectrometer. IR spectra
were recorded by Thermo Electron Nicolet FTIR-6700 instrument.
TLC analyses were performed on silica gel plates and column
chromatography was conducted over silica gel (mesh 200–300).
1H), 5.33–5.30 (m,1H), 3.91 (dd, J¼15.6, 4.8 Hz,1H), 3.73 (dd, J¼15.2,
6.0 Hz, 1H), 3.14 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 190.27, 172.12,
153.38, 152.66, 132.02 (2C), 126.13, 122.80, 111.25 (2C), 81.72, 54.14,
39.86; IR (neat) 1755, 1595 cmꢁ1 (C]O); MS (CI) m/z: 232 [Mþ1]þ;
HRMS (EI) calcd for C13H13NO3 [M]þ 231.0895, found 231.0891.
4.2.6. Synthesis of 5-{[methyl(3-methylphenyl)amino]methyl}-
2(5H)-furanone
1H NMR (400 MHz, CDCl3)
(m,1H), 6.59 (d, J¼7.2 Hz,1H), 6.52 (d, J¼5.6 Hz, 2H), 6.12 (dd, J¼6.0,
2.0 Hz, 1H), 5.26–5.25 (m, 1H), 3.66 (d, J¼6.0 Hz, 2H), 3.00 (s, 3H),
d
7.48 (dd, J¼5.6, 1.2 Hz, 1H), 7.16–7.11

162
Y. Shen et al. / Tetrahedron 65 (2009) 158–163
2.32 (s, 3H); 13C NMR (100 MHz, CDCl3)
139.05, 129.14, 121.96, 118.20, 112.95, 109.41, 81.93, 54.90, 39.45,
21.82; IR (neat) 1754 cmꢁ1 (C]O); MS (CI) m/z: 218 [Mþ1]þ; HRMS
(EI) calcd for C13H15NO2 [M]þ 217.1103, found 217.1108.
d
172.62, 154.51, 148.22,
5.35–5.34 (m, 0.36H) [4.99–4.97 (m, 0.51H)], 4.30–4.27 (m, 0.42H)
[3.80–3.77 (m, 0.61H)], 3.76 (d, J¼3.6 Hz, 3H), 3.61–3.54 (m, 1H),
3.17–3.08 (m, 1H), 2.14–1.65 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
172.96 (2C), 156.13, 153.78, 151.75, 151.57, 141.72, 141.50, 122.71,
121.52, 115.06 (2C), 114.87 (2C), 113.60 (2C), 113.31 (2C), 84.38,
82.72, 61.08, 59.57, 55.77, 55.74, 50.13, 49.90, 28.10, 25.24, 24.27,
23.36; IR (neat) 1758 cmꢁ1 (C]O); MS (CI) m/z: 260 [Mþ1]þ; HRMS
(EI) calcd for C15H17NO3 [M]þ 259.1208, found 259.1212.
4.2.7. Synthesis of 5-[(ethylphenylamino)methyl]-2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.43 (dd, J¼5.6, 1.2 Hz, 1H), 7.19–7.15
(m, 2H), 6.68–6.62 (m, 3H), 6.07 (dd, J¼5.6, 2.0 Hz, 1H), 5.19–5.15
(m, 1H), 3.61 (dd, J¼15.2, 6.0 Hz, 1H), 3.50 (dd, J¼15.2, 6.0 Hz, 1H),
3.46–3.26 (m, 2H), 1.09 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.2.13. Synthesis of 5-(1,2,3,4-tetrahydro-2-phenyl-1-
isoquinolinyl)-2(5H)-furanone
d
171.69, 153.75, 145.95, 128.49 (2C), 121.08, 116.06, 111.43 (2C),
80.84, 51.88, 44.77, 10.85; IR (neat) 1752 cmꢁ1 (C]O); MS (CI) m/z:
218 [Mþ1]þ; HRMS (EI) calcd for C13H15NO2 [M]þ 217.1103, found
217.1104.
1H NMR (400 MHz, CDCl3)
d
7.41 (dd, J¼6.0, 1.6 Hz, 1H), 7.28 (dd,
J¼6.0, 2.0 Hz,1H), 7.23–7.05 (m,12H), 6.89 (d, J¼8.0 Hz, 2H), 6.79 (d,
J¼8.0 Hz, 2H), 6.75–6.70 (m, 2H), 6.00 (dd, J¼5.6, 2.0 Hz, 1H), 5.81
(dd, J¼5.6, 1.6 Hz, 1H), 5.34–5.32 (m, 1H), 5.24–5.22 (m, 1H), 5.07 (d,
J¼4.4 Hz, 1H), 4.81 (d, J¼6.0 Hz, 1H), 3.70–3.64 (m, 1H), 3.53–3.45
(m, 2H), 3.36–3.30 (m, 1H), 3.94–2.84 (m, 4H); 13C NMR (100 MHz,
4.2.8. Synthesis of 5-{[ethyl(4-methylphenyl)amino]methyl}-
2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.42 (d, J¼5.2 Hz, 1H), 6.99 (d,
CDCl3) d 171.60, 171.48, 153.74, 152.68, 147.93, 147.88, 134.71, 134.33,
J¼8.4 Hz, 2H), 6.56 (d, J¼8.4 Hz, 2H), 6.06 (dd, J¼5.6, 1.6 Hz, 1H),
5.17–5.14 (m, 1H), 3.60 (dd, J¼15.2, 6.0 Hz, 1H), 3.45 (dd, J¼15.2,
6.4 Hz,1H), 3.41–3.25 (m, 2H), 2.18 (s, 3H),1.07 (t, J¼6.8 Hz, 3H); 13C
131.41, 130.95, 128.46 (2C), 128.39 (2C), 127.62, 127.43, 127.12,
126.81, 126.75, 126.55, 125.37, 124.98, 121.48, 121.18, 117.82, 117.66,
113.51 (2C), 113.44 (2C), 84.89, 84.44, 60.66, 59.54, 42.96, 42.41,
27.24, 26.22; IR (neat) 1759 cmꢁ1 (C]O); MS (CI) m/z: 292 [Mþ1]þ;
HRMS (EI) calcd for C19H17NO2 [M]þ 291.1259, found 291.1253.
NMR (100 MHz, CDCl3) d 171.76, 153.93, 143.85, 128.99 (2C), 125.53,
120.96, 111.98 (2C), 80.90, 52.20, 45.01, 19.15, 10.92; IR (neat)
1755 cmꢁ1 (C]O); MS (CI) m/z: 232 [Mþ1]þ; HRMS (EI) calcd for
C14H17NO2 [M]þ 231.1259, found 231.1247.
4.2.14. Synthesis of 5-methyl-5-[(methylphenylamino)methyl]-
2(5H)-furanone
4.2.9. Synthesis of 5-{[n-butyl(4-methylphenyl)amino]methyl}-
2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.30 (d, J¼5.6 Hz, 1H), 7.19–7.13 (m,
2H), 6.66 (t, J¼7.2 Hz, 1H), 6.59 (d, J¼8.4 Hz, 2H), 5.87 (d, J¼5.6 Hz,
1H), 3.63 (d, J¼15.6 Hz, 1H), 3.57 (d, J¼16.0 Hz, 1H), 2.91 (s, 3H), 1.45
1H NMR (400 MHz, CDCl3)
d
7.41 (dd, J¼5.6, 0.8 Hz, 1H), 6.98 (d,
J¼8.8 Hz, 2H), 6.55 (d, J¼8.8 Hz, 2H), 6.05 (dd, J¼5.6, 1.6 Hz, 1H),
5.17–5.14 (m, 1H), 3.62 (dd, J¼15.2, 6.0 Hz, 1H), 3.46 (dd, J¼14.8,
6.4 Hz, 1H), 3.32–3.14 (m, 2H), 2.18 (s, 3H), 1.49–1.46 (m, 2H), 1.29–
1.23 (m, 2H), 0.86 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 171.08, 156.84, 147.77, 128.20
(2C), 120.35, 116.00, 110.96 (2C), 89.65, 57.80, 39.03, 20.88; IR (neat)
1753 cmꢁ1 (C]O); MS (CI) m/z: 218 [Mþ1]þ; HRMS (EI) calcd for
C13H15NO2 [M]þ 217.1103, found 217.1104.
d
171.76, 153.97, 143.97, 128.97 (2C), 125.41, 120.86, 111.95 (2C),
80.74, 52.69, 50.73, 27.92, 19.16 (2C), 12.94; IR (neat) 1754 cmꢁ1
(C]O); MS (CI) m/z: 260 [Mþ1]þ; HRMS (EI) calcd for C16H21NO2
[M]þ 259.1572, found 259.1545.
4.2.15. Synthesis of 5-methyl-5-{[methyl(4-methylphenyl)-
amino]methyl}-2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.36 (d, J¼6.0 Hz, 1H), 7.03
(d, J¼8.8 Hz, 2H), 6.58 (d, J¼8.8 Hz, 2H), 5.94 (d, J¼6.0 Hz,1H), 3.68–
4.2.10. Synthesis of 5-(1-phenyl-2-pyrrolidinyl)-2(5H)-furanone
3.59 (m, 2H), 2.96 (s, 3H), 2.24 (s, 3H), 1.51 (s, 3H); 13C NMR
1H NMR (400 MHz, CDCl3)
d
7.46–7.40 (m, 2H), 7.30–7.22 (m, 4H),
(100 MHz, CDCl3) d 172.13, 157.95, 146.76, 129.71 (2C), 126.22,
6.78–6.72 (m, 4H), 6.58 (d, J¼8.4 Hz, 2H), 6.18–6.16 (m, 2H), 5.40–
5.38 (m, 1H), 5.04–5.01 (m, 1H), 4.39–4.36 (m, 1H), 3.86 (t, J¼7.2 Hz,
1H), 3.63–3.55 (m, 2H), 3.23–3.16 (m, 2H), 2.15–1.68 (m, 8H); 13C
121.29, 112.15 (2C), 90.70, 59.16, 40.15, 21.89, 20.14; IR (neat)
1751 cmꢁ1 (C]O); MS (CI) m/z: 232 [Mþ1]þ; HRMS (EI) calcd for
C14H17NO2 [M]þ 231.1259, found 231.1257.
NMR (100 MHz, CDCl3) d 171.82 (2C), 154.97, 152.64, 146.02, 145.83,
128.49 (2C), 128.32 (2C), 121.79, 120.67, 116.26, 116.04, 111.67 (2C),
111.43 (2C), 83.07, 81.42, 59.54, 58.11, 48.41, 48.21, 26.90, 24.24,
23.12, 22.24; IR (neat) 1757 cmꢁ1 (C]O); MS (CI) m/z: 230 [Mþ1]þ;
HRMS (EI) calcd for C14H15NO2 [M]þ 229.1103, found 229.1109.
4.2.16. Synthesis of 5-methyl-5-{[methyl(3-methylphenyl)amino]-
methyl}-2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.37 (d, J¼5.6 Hz, 1H), 7.13–7.09 (m,
1H), 6.56 (d, J¼7.6 Hz, 1H), 6.47 (d, J¼6.0 Hz, 2H), 5.95 (d, J¼5.6 Hz,
1H), 3.72–3.61 (m, 2H), 2.98 (s, 3H), 2.31 (s, 3H), 1.52 (s, 3H); 13C
4.2.11. Synthesis of 5-[1-(4-methylphenyl)-2-pyrrolidinyl]-2(5H)-
furanone
NMR (100 MHz, CDCl3) d 171.10, 156.87, 147.85, 137.95, 128.00,
120.28, 116.94, 111.73, 108.21, 89.68, 57.80, 39.06, 20.93, 20.90; IR
(neat) 1753 cmꢁ1 (C]O); MS (CI) m/z: 232 [Mþ1]þ; HRMS (EI)
calcd for C14H17NO2 [M]þ 231.1259, found 231.1250.
1H NMR (400 MHz, CDCl3)
d 7.40–7.32 (m, 1H), 7.03–6.97 (m,
2H), 6.57 (d, J¼8.4 Hz, 1H), 6.41 (d, J¼8.4 Hz, 1H), 6.11–6.07 (m, 1H),
5.31–5.29 (m, 0.62H) [4.93–4.90 (m, 0.37H)], 4.27–4.24 (m, 0.63H)
[3.72 (t, J¼7.6 Hz, 0.38H)], 3.55–3.46 (m,1H), 3.12–3.03 (m,1H), 2.19
(d, J¼4.8 Hz, 3H), 2.05–1.62 (m, 4H); 13C NMR (100 MHz, CDCl3)
4.2.17. Synthesis of 5-methyl-5-(1-phenyl-2-pyrrolidinyl)-2(5H)-
furanone
d
171.90 (2C),155.20, 152.77,143.96,143.81, 128.99 (2C),128.81 (2C),
1H NMR (400 MHz, CDCl3)
d 7.38–7.26 (m, 1H), 7.18–7.12 (m, 2H),
125.45, 125.20, 121.75, 120.54, 111.71 (2C), 111.43 (2C), 83.28, 81.55,
59.80, 58.25, 48.66, 48.49, 27.07, 24.19, 23.20, 22.27, 19.21 (2C); IR
(neat) 1757 cmꢁ1 (C]O); MS (CI) m/z: 244 [Mþ1]þ; HRMS (EI) calcd
for C15H17NO2 [M]þ 243.1259, found 243.1250.
6.70–6.64 (m, 1H), 6.62–6.60 (m, 2H), 5.96 (d, J¼5.6 Hz, 0.87H) [5.74
(d, J¼5.6 Hz, 0.21H)], 4.03 (d, J¼8.4 Hz, 0.24H) [3.90 (d, J¼7.6 Hz,
0.98H)], 3.60–3.50 (m, 1H), 3.20–3.10 (m, 1H), 2.10–1.97 (m, 4H),
1.39 (s, 3H); 13C NMR (100 MHz, CDCl3)
d171.18 (2C), 159.31, 157.06,
147.11, 147.04, 128.04 (2C), 127.97 (2C), 119.34, 119.12, 116.28, 115.89,
112.65 (2C), 112.07 (2C), 83.18, 81.45, 62.53, 61.32, 49.90, 49.63,
26.66, 26.23, 23.16, 22.97, 21.02, 19.31; IR (neat) 1755 cmꢁ1 (C]O);
MS (CI) m/z: 244 [Mþ1]þ; HRMS (EI) calcd for C15H17NO2 [M]þ
243.1259, found 243.1266.
4.2.12. Synthesis of 5-[1-(4-methoxyphenyl)-2-pyrrolidinyl]-2(5H)-
furanone
1H NMR (400 MHz, CDCl3)
d
7.48–7.39 (m, 1H), 6.89–6.83 (m,
2H), 6.68 (d, J¼9.2 Hz, 1H), 6.53 (d, J¼9.2 Hz, 1H), 6.19–6.15 (m, 1H),

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4.2.18. Synthesis of 5-allyl-5-[(methylphenylamino)methyl]-2(5H)-
furanone
1H NMR (400 MHz, CDCl3)
d
7.33 (d, J¼6.0 Hz, 1H), 7.26–7.20 (m,
2H), 6.73 (t, J¼7.2 Hz, 1H), 6.65 (d, J¼8.8 Hz, 2H), 5.96 (d, J¼6.0 Hz,
1H), 5.74–5.63 (m, 1H), 5.21–5.16 (m, 2H), 3.79 (d, J¼15.6 Hz, 1H),
3.66 (d, J¼15.6 Hz, 1H), 2.97 (s, 3H), 2.66–2.54 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d 171.95, 156.32, 148.74, 130.12, 129.17 (2C),
122.37, 120.56, 116.99, 111.95 (2C), 92.24, 57.58, 40.08, 39.63; IR
(neat) 1755 cmꢁ1 (C]O); MS (CI) m/z: 244 [Mþ1]þ; HRMS (EI)
calcd for C15H17NO2 [M]þ 243.1259, found 243.1264.
4.2.19. Synthesis of 5-allyl-5-{[methyl(4-methylphenyl)amino]-
methyl}-2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.32 (d, J¼5.6 Hz, 1H), 7.02 (d,
J¼8.4 Hz, 2H), 6.56 (d, J¼8.4 Hz, 2H), 5.95 (d, J¼5.6 Hz, 1H), 5.70–
5.62 (m, 1H), 5.19–5.14 (m, 2H), 3.74 (d, J¼15.6 Hz, 1H), 3.62 (d,
J¼15.6 Hz,1H), 2.93 (s, 3H), 2.65–2.53 (m, 2H), 2.24 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 172.00, 156.47, 146.71, 130.16, 129.65 (2C),
126.13, 122.23, 120.42, 112.10 (2C), 92.26, 57.89, 40.15, 39.54, 20.09;
IR (neat) 1755 cmꢁ1 (C]O); MS (CI) m/z: 258 [Mþ1]þ; HRMS (EI)
calcd for C16H19NO2 [M]þ 257.1416, found 257.1402.
4.2.20. Synthesis of 5-allyl-5-{[methyl(3-methylphenyl)amino]-
methyl}-2(5H)-furanone
1H NMR (400 MHz, CDCl3)
d
7.32 (d, J¼6.0 Hz, 1H), 7.12–7.08 (m,
1H), 6.55 (d, J¼7.2 Hz, 1H), 6.46 (d, J¼6.0 Hz, 2H), 5.95 (d, J¼5.6 Hz,
1H), 5.73–5.62 (m, 1H), 5.20–5.15 (m, 2H), 3.77 (d, J¼16.0 Hz, 1H),
3.63 (d, J¼15.6 Hz, 1H), 2.95 (s, 3H), 2.66–2.54 (m, 2H), 2.30 (s, 3H);
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13C NMR (100 MHz, CDCl3)
d 171.98, 156.39, 148.79, 138.86, 130.11,
128.94, 122.24, 120.46, 117.88, 112.68, 109.16, 92.25, 57.54, 40.06,
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Acknowledgements
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Support of this work by the Hunan University 985 project and
a grant from the National Science Foundation of China (No.
20702012) are gratefully acknowledged.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.10.078.
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