Multi-component anion relay cascade of 1-acetylcyclopropanecarboxamides, aldehydes and acrylonitrile: Access to biscyanoethylated furo[3,2-c]pyridinones

Article abstract of DOI:10.1039/c2ob25550b

A highly efficient multi-component anion relay cascade reaction based on 1-acetylcyclopropanecarboxamides, aldehydes and acrylonitrile has been developed, which provides strategically novel and atom-economic access to biologically important biscyanoethylated furo[3,2-c]pyridinones. In this one-pot transformation, up to five bonds (one C-N, one C-O and three C-C bonds) were constructed.

Full text of DOI:10.1039/c2ob25550b

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PAPER
Multi-component anion relay cascade of 1-acetylcyclopropanecarboxamides,
aldehydes and acrylonitrile: access to biscyanoethylated furo[3,2-c]-
pyridinones†
Shaoxia Lin,a Ying Wei,a Fushun Liang,*a Baozhong Zhao,a Yanling Liub and Pengjun Liu*b
Received 14th March 2012, Accepted 16th April 2012
DOI: 10.1039/c2ob25550b
A highly efficient multi-component anion relay cascade reaction based on 1-
acetylcyclopropanecarboxamides, aldehydes and acrylonitrile has been developed, which provides
strategically novel and atom-economic access to biologically important biscyanoethylated furo[3,2-c]-
pyridinones. In this one-pot transformation, up to five bonds (one C–N, one C–O and three C–C bonds)
were constructed.
from tedious steps, low yields and poor regioselectivity, the
development of new and efficient synthetic methods toward
Introduction
Furo[3,2-c]pyridinone alkaloids are widespread among the Ruta-
ceae family of plants1 and display important biological activities
such as antifungal,2 antibiotic2 and antipsychotic properties,3
HIV protease inhibitors4 and K-Receptor Agonists5 (Scheme 1).
Synthetic approaches for the construction of this kind of hetero-
cycle have been reported,6 including oxidative,6a or photo-
induced cycloaddition6b,c of 4-hydroxypyridin-2(1H)-ones with
olefins, condensation of pyridone with ethyl pyruvate and p-
chlorothiophenol, reduction, and cyclization,6d rhodium-
mediated dipolar cycloaddition,6e palladium(0)-catalyzed
Suzuki6f or Sonogashira6g coupling, and other methods such as
multi-component reactions.6h Since most methods may suffer
highly functionalized furo[3,2-c]pyridinones is still required.
Recently, Dong et al. reported an efficient route to 2,3-dihy-
drofuro[3,2-c]pyridin-4(5H)-ones via a Vilsmeier-type reaction
from 1-aminoalkenoyl-1-carbamoylcyclopropanes in the pres-
ence of Tf2O in DMF.7 In our research on the synthetic potential
of β-ketoamides bearing both electrophilic and nucleophilic
centers toward various carbo- and heterocycles,8 we developed
facile and straightforward protocols to construct furo[3,2-c]pyri-
dinones from 1-alkenoylcyclopropanecarboxamides via either an
aza-oxy-carbanion relay cascade8a or halonium-initiated electro-
philic cascades.8b Anion relay chemistry (ARC) has been
demonstrated as an effective tactic for diversity-oriented syn-
thesis of architecturally complex natural and unnatural products.9
In our continued work, we aimed to further exploit the prep-
aration of diversely functionalized furo[3,2-c]pyridinones
through
a multi-component anion relay cascade reaction
(Scheme 2). Multi-component reactions have been refined in
recent years as powerful and useful tools in synthetic chemistry
and have attracted increasing attention due to the advantages of
greater efficiency, atom economy, and structural diversity and
complexity.10 The development of multi-component reactions
based on appropriately substituted cyclopropanes has been
reported by us8e and several other research groups.11 In the
Scheme 1 Naturally occurring alkaloids containing furo[3,2-c]pyridi-
none Motif.
aDepartment of Chemistry, Northeast Normal University, Changchun
130024, China. E-mail: liangfs112@nenu.edu.cn; Fax: (+86) 431-
85099759
bCollege of Chemistry and Chemical Engineering, Hainan Normal
University, Haikou 571158, China. E-mail: liupj12@126.com
†Electronic supplementary information (ESI) available: Experimental
details and characterization for all new compounds and crystal structure
data (CIF file). CCDC reference numbers 796156 (3a). For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ob25550b
Scheme 2 Multi-component cascade reaction leading to highly substi-
tuted furo[3,2-c]pyridinones.
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present reaction, a mixture of 1-acetylcyclopropanecarboxa-
mides, aldehydes and acrylonitrile was subjected to the one-pot
reaction, in which acrylonitrile was selected as the external elec-
trophile (i.e., anion acceptor). Acrylonitrile, as a useful synthon,
has found wide application in organic synthesis.12 As a result of
the research, a multi-component anion relay cascade was estab-
lished and highly functionalized biscyanoethylated furo[3,2-c]-
pyridinones were efficiently synthesized.
Results and discussion
Fig. 1 ORTEP drawing of 3a.
Table 2 Synthesis of biscyanoethylated furo[3,2-c]pyridinonesa
Initially, the model reaction of 1-acetyl-N-phenylcyclopropane-
carboxamide 1a (1.0 mmol), 4-methylbenzaldehyde 2a
(1.1 mmol) and acrylonitrile (1.2 mmol) in DMSO (4.0 mL) was
examined under basic conditions (Table 1).13 To our surprise,
biscyanoethylated furo[3,2-c]pyridinone 3a (instead of the
monocyanoethylated counterpart), was obtained in 39% yield
(Table 1, entry 1). The structure of 3a was confirmed by the X-
ray single-crystal diffraction (Fig. 1).14 Encouraged by this pre-
liminary result, we increased the amount of acrylonitrile to 2.5
equiv under the same conditions. Gratifyingly, the yield of 3a
was significantly improved to 88% (Table 1, entry 2). A further
increase in the amount of acrylonitrile to 5.0 equiv was not
required (Table 1, entry 3). Either cutting down the amount of
NaH to 1.2 equiv (Table 1, entry 4)15 or lowering the tempera-
ture to 60 °C (Table 1, entry 5) led to decreased yield. Reactions
performed in THF or DMF gave complicated mixtures (Table 1,
entries 6 and 7). Except NaH, other bases like t-BuONa and
t-BuOK, were also tested, but resulted in low yields (Table 1,
entries 8 and 9).
Entry
Ar
R
3
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
4-ClC6H4
4-OMeC6H4
2-Cl-4-OMeC6H3
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
2-MeC6H4
3,4-O2CH2C6H3
4-ClC6H4
2-ClC6H4
2-NO2C6H4
2-Furyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
88
82
88
86
76
85
92
78
81
—
85
93
—
90
—
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
c
10
11
12
13
14
15
2-Thienyl
4-Py
PhCHvCH
t-Bu
c
Under the optimized conditions, a range of multi-component
reactions were carried out with various doubly-EWG activated
substrates 1 and aldehydes 2 (Table 2). The reactions proceeded
smoothly to afford the corresponding highly substituted furo[3,2-
c]pyridinones 3 in good to excellent yields. The aryl substituents
Ar on the N atom of substrates 1 may be either electron-rich or
c
a Reactions were carried out with 1 (1.0 mmol), 2 (1.1 equiv),
acrylonitrile (2.5 equiv) in the presence of NaH (2.5 equiv) in DMSO
(4.0 mL) at 80 °C for 5 h. b Isolated yield. c Complex mixture was
observed.
Table 1 Optimization of the reaction conditionsa
electron-deficient (Table 2, entries 1–4).16 The scope of alde-
hydes 2 was also broad, including benzaldehyde (Table 2, entry
5), electron-rich aryl aldehydes (Table 2, entries 6 and 7), elec-
tron-deficient aryl aldehydes (Table 2, entries 8 and 9), hetero-
aryl aldehydes (Table 2, entries 11 and 12), and an alkenyl
aldehyde (Table 2, entry 14). However, multi-component reac-
tions with (hetero)arylaldehydes like 2-nitrobenzaldehyde and
pyridine-4-carboxyaldehyde containing strong electron-with-
drawing groups did not give satisfactory results (Table 2, entries
10 and 13).17 The reaction with alkylaldehydes like pivalalde-
hyde also gave a complex mixture (Table 2, entry 15). All pro-
ducts were characterized on the basis of the spectral and
analytical data (see the ESI†).18
In an isolated experiment, the reaction of 1a (1.0 mmol), 2a
(1.1 equiv) and acrylonitrile (2.5 equiv) with NaH (2.5 equiv) as
the base in DMSO (4.0 mL) at 80 °C was quenched with water
after proceeding for 1 h. As a result, 3-(4,8-dioxo-5-phenyl-6-(p-
tolyl)-5-azaspiro[2.5]octan-7-yl)propanenitrile 4 was isolated in
67% yield, along with the formation of furo[3,2-c]pyridinone 3a
Acrylonitrile
(equiv)
Solvent
(mL)
Yieldb
T (°C) (%)
Entry Base (equiv)
1
2
3
4
5
6
7
8
9
NaH (2.5)
NaH (2.5)
NaH (2.5)
NaH (1.2)
NaH (2.5)
NaH (2.5)
NaH (2.5)
t-BuONa (2.2)
t-BuOK (2.2)
1.2
2.5
5.0
2.5
2.5
2.5
2.5
2.5
2.5
DMSO
DMSO
DMSO
DMSO
DMSO
THF
DMF
DMSO
DMSO
80
80
80
80
60
80
80
80
80
39
88
87
55
23
—
—
15
45
a Reactions were carried out on a 1.0 mmol scale in 4.0 mL of solvent
with 1a (1.0 equiv) and 2a (1.1 equiv). b Isolated yield.
4572 | Org. Biomol. Chem., 2012, 10, 4571–4576
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Experimental
General methods
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. 1H NMR
and 13C NMR spectra were recorded at 25 °C and TMS as
internal standard.
Typical experimental procedure for the synthesis of
furo[3,2-c]pyridine
General procedure for the preparation of 3 (3a as an example):
To the stirred mixture of 1a (203 mg, 1.0 mmol) in DMSO
(4 mL) was added 2a (0.12 mL, 1.1 mmol), acrylonitrile
(0.16 mL, 2.5 mmol), and NaH (70%) (86 mg, 2.5 mmol) in one
portion at 80 °C. The starting material 1a was consumed as indi-
cated by TLC after 5 h, the reaction mixture was cooled to room
temperature and poured into water and then extracted with
CH2Cl2 (3 × 10 mL). The combined organic phase was washed
with water (3 × 10 mL), dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (silica gel, petroleum ether:
diethyl ether = 2 : 1) to give 3a (362 mg, 88%).
Scheme 3 Possible mechanism for the multi-component anion relay
cascade reaction.
in 13% yield. (eqn (1)). The result helps one to answer the ques-
tion of the biscyanoethylation sequence involved in the reaction.
Characterization data for furo[3,2-c]pyridine
3,3′-(4-Oxo-5-phenyl-6-(p-tolyl)-2,3,4,5,6,7-hexahydrofuro-
[3,2-c]pyridine-7,7-diyl)dipropanenitrile (3a). White solid. m.p.
1
106–108 °C. H NMR (500 MHz, CDCl3): δ = 1.53–1.58 (m,
1H), 1.81–1.84 (m, 1H), 1.87–1.90 (m, 1H), 2.35 (s, 3H),
2.51–2.58 (m, 3H), 3.07–3.14 (m, 2H), 4.43 (s, 1H), 4.66 (m,
2H), 6.94–6.96 (d, J = 7.5 Hz, 2H), 7.08–7.10 (d, J = 7.5 Hz,
2H), 7.13–7.19 (m, 3H), 7.24–7.26 (m, 2H); 13C NMR (CDCl3,
125 MHz): δ = 12.0, 12.9, 21.0, 27.1, 27.2, 33.3, 43.0, 72.7,
73.3, 107.0, 118.8, 119.0, 126.8, 127.0, 127.9, 128.9, 129.9,
133.4, 139.1, 141.3, 163.2, 166.5; MS calcd m/z 411.2, found
412.2 [(M + 1)]+. Anal. calcd for C26H25N3O2: C, 75.89; H,
6.12; N, 10.21; Found: C, 76.04; H, 6.14; N, 10.28.
ð1Þ
Based on all the results described above and our previous
research,8a a possible mechanism for the formation of 3 is pro-
posed, as depicted in Scheme 3. The overall transformation may
involve the following steps: aldol addition/aza-Michael addition/
Michael addition/1,3-H shift19/ring opening of cyclopropane and
recyclization20/Michael addition. The anion relay process can be
briefly described as amide anion → carbanion → enolate anion
→ carbanion. Final electrophile trapping terminates the relay.
3,3′-(5-(4-Chlorophenyl)-4-oxo-6-(p-tolyl)-2,3,4,5,6,7-hexahy-
drofuro[3,2-c]pyridine-7,7-diyl)dipropanenitrile
(3b). White
solid. m.p. 188–190 °C. 1H NMR (500 MHz, CDCl3): δ =
1.55–1.59 (m, 1H), 1.81–1.84 (m, 1H), 1.88–1.93 (m, 1H),
2.06–2.15 (m, 2H), 2.35 (s, 3H), 2.48–2.58 (m, 3H), 3.07–3.13
(m, 2H), 4.41 (s, 1H), 4.67–4.74 (m, 2H), 6.88–6.90 (d, J = 9.0
Hz, 2H), 7.06–7.08 (d, J = 7.5 Hz, 2H), 7.14–7.15 (d, J = 7.0
Hz, 2H), 7.20–7.22 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3,
125 MHz): δ = 12.2, 13.1, 21.1, 27.3, 27.4, 33.5, 43.1, 73.0,
73.5, 107.2, 118.5, 118.8, 128.0, 128.4, 129.2, 130.1, 132.5,
133.1, 139.6, 139.8, 163.3, 166.8. MS calcd m/z 445.2, found
446.2 [(M + 1)]+. Anal. calcd for C26H24Cl N3O2: C, 70.03; H,
5.42; N, 9.42; Found: C, 70.21; H, 5.47; N, 9.51.
Conclusion
In conclusion, we have developed an efficient multi-component
anion relay cascade to construct biscyanoethylated furo[3,2-c]-
pyridinones. The one-pot process involves aldol condensation,
multiple Michael additions, 1,3-H shift, ring opening of cyclo-
propane and recyclization, in which up to five bonds (one C–N,
one C–O and three C–C bonds21,22) were constructed in an
atom-economic manner. Further research on multi-component
cascade reactions about doubly-EWG activated cyclopropanes is
currently under investigation in our laboratory.
3,3′-(5-(4-Methoxyphenyl)-4-oxo-6-(p-tolyl)-2,3,4,5,6,7-hexa-
hydrofuro[3,2-c]pyridine-7,7-diyl)dipropanenitrile (3c). White
solid. m.p. 185–187 °C. 1H NMR (500 MHz, CDCl3): δ =
1.56–1.63 (m, 1H), 1.79–1.83 (m, 1H), 1.86–1.89 (m, 1H),
2.05–2.13 (m, 2H), 2.35 (s, 3H), 3.06–3.13 (m, 2H), 3.74 (s,
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3H), 4.56 (s, 1H), 4.65–4.72 (m, 2H), 6.75–6.77 (m, 2H),
6.82–6.84 (m, 2H), 7.09 (s, 2H), 7.12–7.14 (d, J = 8.0 Hz, 2H);
13C NMR (CDCl3, 125 MHz): δ = 12.2, 13.1, 21.1, 27.3, 27.3,
33.6, 43.0, 55.3, 73.3, 73.4, 107.3, 114.3, 118.6, 118.9, 128.1,
128.4, 128.0, 133.5, 134.0, 139.3, 158.2, 163.5, 166.3. MS calcd
m/z 441.2, found 442.2 [(M + 1)]+. Anal. calcd for C27H27N3O3:
C, 73.45; H, 6.16; N, 9.52; Found: C, 73.61; H, 6.19; N, 9.65.
C26H23N3O4: C, 70.73; H,5.25; N, 9.52; Found: C, 70.56; H,
5.23; N, 9.45.
3,3′-(6-(4-Chlorophenyl)-4-oxo-5-phenyl-2,3,4,5,6,7-hexahy-
drofuro[3,2-c]pyridine-7,7-diyl)dipropanenitrile (3h). White
solid. m.p. 204–206 °C. 1H NMR (500 MHz, CDCl3): δ =
1.75–1.79 (m, 2H), 1.90–1.94 (t, J = 19.5 Hz, 1H), 2.13–2.19
(m, 2H), 2.50–2.59 (m, 3H), 3.06–3.13 (m, 2H), 4.49 (s, 1H),
4.67–4.74 (m, 2H), 6.91–6.93 (d, J = 8.0 Hz, 2H), 7.15–7.21
(m, 3H), 7.25–7.26 (d, J = 6.5 Hz, 2H), 7.28–7.33 (t, J = 25.5
Hz, 2H); 13C NMR (CDCl3, 125 MHz): δ = 12.6, 13.3, 27.4,
27.5, 33.3, 43.2, 72.6, 73.8, 107.5, 118.8, 118.9, 127.3, 127.4,
129.5, 129.8, 125.3, 125.6, 141.2, 163.3, 166.8. MS calcd m/z
431.1, found 432.1 [(M + 1)]+. Anal. calcd for C25H22ClN3O2:
C, 69.52; H, 5.13; N, 9.73; Found: C, 69.75; H, 5.18; N, 9.84.
3,3′-(5-(2-Chloro-4-methoxyphenyl)-4-oxo-6-(p-tolyl)-2,3,4,5,6,7-
hexahydrofuro[3,2-c]pyridine-7,7-diyl)dipropanenitrile
(3d).
1
White solid. m.p. 182–184 °C. H NMR (500 MHz, CDCl3): δ
= 1.72–1.77 (t, J = 24.5 Hz, 2H), 1.87 (s, 1H), 2.05 (s, 1H), 2.12
(s, 1H), 2.34 (s, 3H), 2.57–2.61 (t, J = 20.5 Hz, 3H), 3.07–3.10
(t, J = 16.0 Hz, 2H), 3.82–3.86 (d, J = 20.0 Hz, 3H), 4.38 (s,
1H), 4.67–4.71 (m, 2H), 6.63 (s, 1H), 6.82–6.84 (d, J = 6.5 Hz,
1H), 7.12–7.15 (t, J = 16.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz): δ = 12.2, 12.8, 27.2, 27.6, 32.8, 42.9, 55.8, 70.5,
73.3, 106.6, 112.6, 118.9, 119.0, 124.8, 128.5, 129.3, 129.8.
130.8, 132.8, 139.2, 153.6, 163.3, 167.1. MS calcd m/z 475.2,
found 476.2 [(M + 1)]+. Anal. calcd for C27H26ClN3O3: C,
68.13; H, 5.51; N, 8.83; Found: C, 68.01; H, 5.46; N, 8.94.
3,3′-(6-(2-Chlorophenyl)-4-oxo-5-phenyl-2,3,4,5,6,7-hexahy-
drofuro[3,2-c]pyridine-7,7-diyl)dipropanenitrile (3i). White
solid. m.p. 194–196 °C. 1H NMR (500 MHz, CDCl3): δ =
1.73–1.80 (m, 1H), 1.84–1.90 (m, 1H), 1.97–2.04 (m, 1H),
2.13–2.19 (m, 1H), 2.23–2.29 (m, 1H), 2.45–2.51 (m, 1H),
2.59–2.61 (m, 2H), 3.07–3.16 (m, 2H), 4.67–4.76 (m, 2H), 5.24
(s, 1H), 6.92–6.93 (d, J = 7.0 Hz, 2H), 7.18–7.21 (t, 1H),
7.25–7.28 (t, J = 15.0 Hz, 2H), 7.30–7.33 (m, 2H), 7.34–7.38
(m, 1H), 7.62–7.64 (t, J = 10.0 Hz, 1H); 13C NMR (CDCl3,
125 MHz): δ = 12.6, 12.9, 27.0, 27.2, 33.8, 43.2, 66.8, 73.5,
107.2, 118.5, 118.8, 126.6, 127.0, 128.0, 129.1, 129.1, 130.5,
130.5, 133.5, 134.8, 140.7, 163.1, 166.3. MS calcd m/z 431.1,
found 432.1 [(M + 1)]+. Anal. calcd for C25H22ClN3O2: C,
69.52; H, 5.13; N, 9.73; Found: C, 69.71; H, 5.15; N, 9.79.
3,3′-(4-Oxo-5,6-diphenyl-2,3,4,5,6,7-hexahydrofuro[3,2-c]pyri-
dine-7,7-diyl)dipropanenitrile (3e). White solid. m.p. 86–88 °C.
1H NMR (500 MHz, CDCl3): δ = 1.51–1.56 (m, 1H), 1.80–1.83
(m, 1H), 1.83–1.91 (m, 1H), 2.06–2.15 (m, 2H), 2.52–2.59 (m,
3H), 3.08–3.14 (m, 2H), 4.48 (s, 1H), 4.66–4.73 (m, 2H),
6.94–6.95 (d, J = 7.5 Hz, 2H), 7.16–7.22 (m, 1H), 7.23–7.27 (m,
2H), 7.33–7.38 (m, 3H); 13C NMR (CDCl3, 125 MHz): δ = 12.1,
13.0, 27.3, 33.5, 43.0, 73.1, 73.4, 107.2, 118.7, 118.8, 126.9,
127.0, 128.1, 129.0, 129.3, 136.6, 141.2, 163.2, 166.4. MS calcd
m/z 397.2, found 398.2 [(M + 1)]+. Anal. calcd for C25H23N3O2:
C, 75.54; H, 5.83; N, 10.57; Found: C, 75.36; H, 5.75; N, 10.65.
3,3′-(6-(Furan-2-yl)-4-oxo-5-phenyl-2,3,4,5,6,7-hexahydrofuro-
[3,2-c]pyridine-7,7-diyl)dipropanenitrile
(3k). White
solid.
1
m.p. 186–188 °C. H NMR (500 MHz, CDCl3): δ = 1.73–1.79
(m, 1H), 1.97–2.00 (m, 1H), 2.05–2.13 (m, 2H), 2.37–2.49 (m,
2H), 2.53–2.59 (m, 2H), 3.01–3.13 (m, 2H), 4.64 (s, 1H),
4.66–4.74 (m, 2H), 6.24–6.27 (t, J = 12.5 Hz, 1H), 6.36–6.36
(d, J = 1.5 Hz, 1H), 7.00–7.01 (d, J = 7.5 Hz, 2H), 7.20–7.26
(m, 1H), 7.29–7.32 (m, 2H), 7.40–7.40 (d, J = 1.0 Hz, 1H); 13C
NMR (CDCl3, 125 MHz): δ = 11.9, 13.1, 27.0, 27.3, 31.5, 43.4,
65.8, 73.6, 107.2, 110.6, 111.0, 118.6, 118.8, 126.6, 127.0,
129.1, 140.9, 142.9, 149.5, 163.6, 166.5. MS calcd m/z 387.1,
found 388.1 [(M + 1)]+. Anal. calcd for C22H21N3O3: C, 71.30;
H, 5.46; N, 10.85; Found: C, 71.43; H, 5.52; N, 10.73.
3,3′-(4-Oxo-5-phenyl-6-(o-tolyl)-2,3,4,5,6,7-hexahydrofuro[3,2-
c]pyridine-7,7-diyl)dipropanenitrile (3f). White solid. m.p.
1
206–208 °C. H NMR (500 MHz, CDCl3): δ = 1.53–1.59 (m,
1H), 1.80–1.85 (m, 2H), 1.98 (s, 3H), 2.00–2.05 (m, 1H),
2.18–2.22 (m, 1H), 2.56–2.62 (m, 3H), 3.09–3.16 (m, 2H),
4.70–4.85 (m, 2H), 4.85 (s, 1H), 6.89–6.90 (d, J = 7.5 Hz, 2H),
7.09–7.11 (t, J = 8.0 Hz, 1H), 7.19–7.20 (d, J = 7.5 Hz, 2H),
7.22–7.27 (m, 3H), 7.57–7.59 (t, J = 8.5 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): δ = 12.4, 13.1, 19.9, 27.3, 27.7, 34.9, 43.0,
67.6, 73.4, 107.3, 118.6, 118.9, 127.1, 127.2, 127.4, 129.1,
131.6, 135.4, 135.5, 141.0, 163.0, 166.2. MS calcd m/z 411.2,
found 412.2 [(M + 1)]+. Anal. calcd for C26H25N3O2: C, 75.89;
H, 6.12; N, 10.21; Found: C, 76.02; H, 6.14; N, 10.25.
3,3′-(4-Oxo-5-phenyl-6-(thiophen-2-yl)-2,3,4,5,6,7-hexahydro-
furo[3,2-c]pyridine-7,7-diyl)dipropanenitrile (3l). White solid.
1
m.p. 162–164 °C. H NMR (500 MHz, CDCl3): δ = 1.71–1.77
(m, 1H), 2.04–2.18 (m, 3H), 2.21–2.26 (m, 1H), 2.49–2.55 (m,
2H), 2.63–2.70 (m, 1H), 3.04–3.12 (m, 2H), 4.70–4.74 (d, J =
19.5 Hz, 2H), 4.72 (s, 1H), 6.75–6.76 (d, J = 7.0 Hz, 1H),
6.89–6.91 (m, 1H), 6.95–6.97 (t, J = 7.5 Hz, 2H), 7.23–7.32 (m,
4H); 13C NMR (CDCl3, 125 MHz): δ = 11.6, 13.1, 25.6, 27.1,
30.6, 43.3, 69.2, 73.8, 107.1, 118.6, 118.8, 126.3, 126.9, 127.1,
127.2, 128.7, 129.2, 138.5, 141.0, 162.8, 167.4. MS calcd m/z
403.1, found 404.1 [(M + 1)]+. Anal. calcd for C23H21N3O2S: C,
68.46; H,5.25; N, 10.41; Found: C, 68.54; H, 5.27; N, 10.49.
3,3′-(6-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-5-phenyl-2,3,4,5,6,7-
hexahydrofuro[3,2-c]pyridine-7,7-diyl)dipropanenitrile
(3g).
1
White solid. m.p. 120–122 °C. H NMR (500 MHz, CDCl3): δ
= 1.72–1.84 (m, 2H), 1.89–1.94 (m, 1H), 2.08–2.16 (m, 2H),
2.47–2.56 (m, 3H), 3.03–3.09 (m, 2H), 4.38 (s, 1H), 4.66–4.72
(m, 2H), 6.00–6.01 (d, J = 4.0 Hz, 2H), 6.56 (s, 1H), 6.71–6.72
(d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.95–6.97 (d, J = 7.5 Hz, 2H),
7.19–7.22 (t, J = 14.5 Hz, 1H), 7.26–7.29 (t, J = 15.0 Hz, 2H);
13C NMR (CDCl3, 100 MHz): δ = 12.2, 13.0, 27.1, 33.4, 43.0,
72.9, 73.4, 101.6, 107.0, 107.7, 108.6, 118.6, 118.9, 122.1,
127.0, 127.1, 129.0, 130.2, 141.2, 148.2, 148.4, 163.0, 166.6.
MS calcd m/z 441.2, found 442.2 [(M + 1)]+. Anal. calcd for
(E)-3,3′-(4-Oxo-5-phenyl-6-styryl-2,3,4,5,6,7-hexahydrofuro-
[3,2-c]pyridine-7,7-diyl)dipropanenitrile (3n). White solid.
1
m.p. 201–203 °C. H NMR (500 MHz, CDCl3): δ = 1.91–1.93
4574 | Org. Biomol. Chem., 2012, 10, 4571–4576
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(d, J = 9.0 Hz, 1H), 2.12–2.15 (t, J = 14.0 Hz, 1H), 2.23–2.25
(t, 1H), 2.41–2.47 (m, 3H), 2.51–2.55 (m, 2H), 3.00–3.06 (m,
2H), 4.11 (d, J = 6.0 Hz, 1H), 4.67–4.72 (m, 2H), 6.14–6.19 (m,
1H), 6.35–6.38 (d, J = 16.0 Hz, 1H), 7.16–7.18 (d, J = 7.5 Hz,
2H), 7.28–7.36 (m, 8H); 13C NMR (CDCl3, 125 MHz) δ = 11.8,
12.9, 26.1, 27.3, 29.7, 42.4, 70.6, 73.5, 106.7, 118.7, 122.2,
126.6, 127.1, 127.8, 128.7, 129.2, 135.1, 135.9, 140.8, 163.3,
167.7, 171.7. MS calcd m/z 423.2, found 424.2 [(M + 1)]+.
Anal. calcd for C27H25N3O2: C, 76.57; H, 5.95; N, 9.92; Found:
C, 76.69; H, 6.01; N, 9.99.
3-(4,8-Dioxo-5-phenyl-6-(p-tolyl)-5-azaspiro[2.5]octan-7-yl)-
propanenitrile (4). White solid. m.p. 202–204 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.65 (s, 1H), 1.92 (s, 1H), 2.03–2.09
(m, 2H), 2.17–2.25 (m, 2H), 2.36 (s, 3H), 2.39–2.42 (m, 2H),
2.75 (m, 1H), 4.46 (m, 1H), 6.88–6.90 (d, J = 86.0 Hz, 2H),
6.97–6.99 (d, J = 99.5 Hz, 2H), 7.16–7.18 (d, J = 98.0 Hz, 2H),
7.29–7.35 (m, 3H). 13C NMR (CDCl3, 100 MHz): δ = 11.5,
12.6, 21.1, 23.6, 25.3, 27.6, 29.6, 33.4, 53.6, 70.2, 117.9, 118.7,
127.0, 127.2, 128.0, 128.8, 129.6, 130.5, 133.4, 139.6, 141.5,
168.0, 205.2. MS calcd m/z 358.2, found 359.2 [(M + 1)]+.
Anal. calcd for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82; Found:
C, 76.89; H, 6.17; N, 7.75.
Acknowledgements
Financial support from the NSFC (Nos. 20972027 and
21172034), Program for New Century Excellent Talents in Uni-
versity (NCET-11-0611), the Department of Science and Tech-
nology of Jilin Province (201215002), the Fundamental
Research Funds for the Central Universities (11SSXT129) and
Open Project of State Key Laboratory of Supramolecular Struc-
ture and Materials (sklssm201225) is gratefully acknowledged.
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This journal is © The Royal Society of Chemistry 2012