Novel synthesis of fused spiro piperidone-cyclopropanes from cyclopropyl amides and electron-deficient alkenes

Article abstract of DOI:10.1039/d1ob00214g

We report here that a series of bridgedO,O-ketal fused spiro piperidone-cyclopropane derivatives3can be constructed with excellent yields and good diastereoselectivity by the one-pot reaction of 1-acylcyclopropanecarboxamides1with electron-deficient alkene2a(EWG = CHO)viathe domino process involving [4 + 2] annulation/intermolecular electrophilic addition/intramolecular cyclization. Furthermore, reactions of1with2b/2c(EWG = CN, COOMe), leading to spiro piperidone-cyclopropane derivatives4or5by base catalyst selection, were also presented.

Full text of DOI:10.1039/d1ob00214g

Organic &
Biomolecular Chemistry
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Novel synthesis of fused spiro piperidone-
cyclopropanes from cyclopropyl amides and
electron-deficient alkenes†
Cite this: Org. Biomol. Chem., 2021,
19, 3191
Xiao-Dan Han, a Gao-Liang Peng,b Hui-Bin Wang,a Lei Wu,a Jian-ping Fu,a
Zhong-Sheng Tang,a Ju-Wu Hu *a and Wei Xiong*a
We report here that a series of bridged O,O-ketal fused spiro piperidone-cyclopropane derivatives 3 can
be constructed with excellent yields and good diastereoselectivity by the one-pot reaction of 1-acylcy-
clopropanecarboxamides 1 with electron-deficient alkene 2a (EWG = CHO) via the domino process invol-
ving [4 + 2] annulation/intermolecular electrophilic addition/intramolecular cyclization. Furthermore,
reactions of 1 with 2b/2c (EWG = CN, COOMe), leading to spiro piperidone-cyclopropane derivatives 4 or
5 by base catalyst selection, were also presented.
Received 3rd February 2021,
Accepted 3rd March 2021
DOI: 10.1039/d1ob00214g
rsc.li/obc
Spiro-piperidine frameworks are embedded in a large quantity bicyclopropylidene via the sequence of cycloaddition and
of natural products and bioactive molecules and have attracted thermal rearrangement processes.8 In 2006, Kerr and co-
increasing attention in recent years.1 Numerous methods have workers reported a novel approach to spiropiperidine-2,4-
been developed to fabricate spiro-piperidine bearing a five- or diones through monoammonolysis of the diester moiety/
six-membered ring in the spiro system.2 However, less reliable DIBAL reduction/Horner–Emmons olefination followed by a
approaches are available for combining the three-membered base-induced ring formation.7a Furthermore, Padmavathi et al.
carbocycle and spiro-piperidine motifs into one complex mole- constructed a core structure with tetra substituted 4-piperi-
cule until now. In fact, a survey of literature studies revealed done under ultrasound-assistance.9 Afterward, Liu’s group
that cyclopropane is a privileged structural unit and has devised an alternative more straightforward way for the gene-
become a “star” molecule in drug design and exhibits a broad ration of spiropiperidine-2,4-diones through remote electronic
spectrum of pharmacological and biological properties, such effects, in which an aromatic substrate on the N atom is gener-
as antitumor,3 anti-malarial,4 anti-tuberculosis5 and insectici- ally required.10 Nevertheless, the majority of the developed
dal activities.6 Consequently, the incorporation of cyclopro- methods may suffer from precursor availability, the limited
pane units into spiro-piperidine scaffolds may enhance the substrate scope, harsh reaction conditions and tedious steps.
pharmacodynamic potential as well as structural diversity. In this regard, the development of facile and efficient synthetic
Meanwhile, spiro piperidine-cyclopropane derivatives also methods toward highly functionalized spiro piperidine-cyclo-
prove to be useful synthetic intermediates for building mole- propane from readily available starting materials under mild
cular complexity owing to their strain energy and the tendency conditions is highly desirable.
to release this strain through a ring-opening process, such as
for the synthesis of 7-azaindolines and caprolactams.7
1-Acylcyclopropanecarboxamides 1 bearing both C-electrophilic
and N-nucleophilic centers showed fascinating reactivities in
To the best of our knowledge, limited reports were dis- various types of reactions, especially in the synthesis of pyridin-2
closed on the synthesis of spiro piperidine-cyclopropane (1H)-ones,11 isoquinolinedione,12 furo[3,2-c]pyridinones13 and fur-
derivatives. In 1996, Goti and Brandi obtained 3-spirocyclopro- oquinoline derivatives.14 Lately, we described the synthesis of poly-
pane-4-pyridones successfully derived from nitrile oxides and substituted pyrrolidones from 1-acylcyclopropanecarboxamides,
alkynyl and PTSA in two steps.15 In connection with these studies
and motivated by our continuing interest in constructing a spiro
aDepartment of Applied Chemistry, Jiang Xi Academic of Sciences, Nanchang,
330096, China. E-mail: hjw19771985@163.com, xiongwei19821985@sina.com
bJiangxi university of Applied Science, Nanchang, 330100, China
piperidine-cyclopropane scaffold from 1, we envisioned whether a
polarized olefin, offering a CvC bond, would undergo a [4 + 2]
cycloaddition with 1 at its potentially reactive sites under appropri-
ate conditions to achieve the rapid synthesis of our target pro-
ducts. With this idea in mind, the reactions of substrates 1 with
different polarized olefins 2 were investigated. As a result of the
†Electronic supplementary information (ESI) available: CIF data for 3a and 5d,
copies of 1H, 13CNMR spectra for compounds 3a–n, 4a–h, 5a–i and noesy spectra
of compound 4f. CCDC 1948958 and 1948938. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/d1ob00214g
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research, the one-pot cascade process that allows access to NaOH (Table 1, entries 6–9). Among the solvents tested,
complicated spiro piperidone-cyclopropane derivatives is pre- CH3CN seemed to be the best choice. For example, with DMF
sented, which displays some significant advantages over tra- as the solvent, the yield of 3a was fairly low (Table 1, entry 10).
ditional stepwise strategies by energy consumption, and No desired 3a could be detected when the reaction was carried
increasing atom economy. Herein, we wish to communicate out in EtOH or xylene (Table 1, entries 11 and 12).
the results.
With the optimized conditions in hand, the scope of the
In the initial experiment, we selected 1-acetyl-N-phenylcy- reaction was studied and the results are summarized in
clopropanecarboxamide 1a as one of the model compounds, Table 2. It can be seen that the cascade reaction showed broad
which was easily prepared following the procedure described tolerance for various R1, R2 and R groups of substrates 1.
previously.16 Our selection of acrolein 2a as the second sub- Substrates 1a–g containing phenyl (entry 1), electron-rich
strate was the introduction of a strong electron-withdrawing (entries 2–5) and electron-deficient aryl (entries 6–7) R2 groups
group into the alkene, in which one of the carbons in CvC is on the N atom reacted smoothly with 2a to give bridged O,O-
nucleophilic, and the other one electrophilic (cross polariz- ketal fused spiro piperidone-cyclopropane 3a–g in excellent
ation). To our surprise, a new bridged O,O-ketal fused spiro yields. Similarly, a substrate with a Ph group at R1 was also
piperidone-cyclopropane 3a with simultaneous formation of applicable, giving rise to the desired product 3h in a promising
three new rings was isolated in 69% yield on treatment of 1a 81% yield (entry 8). Disappointingly, the reaction of N-benzyl
with 2.0 equiv. 2a in DABCO(1.0 equiv.)/CH3CN at 60 °C for counterpart 1i with 2a failed to deliver the corresponding
10 h (Table 1, entry 1). Driven by the complexity of bridged product 3i (entry 9). In the same line, the substrate carrying a
O,O-ketals, coupled with their remarkable biological pro- methyl group on the cyclopropane ring furnished 3j in 89%
perties,17 the one-pot entry to 3a was then carefully explored.
yield (entry 10). Moreover, the reactions of substrates 1 bearing
As a result, it was found that when DABCO (1.5 equiv.) was a vinyl group at R1, such as styrene (1k and 1l), cinnamon
used as the catalyst, the reaction gave 3a in 93% yield at 60 °C ethylene (1m) and 2-vinyl-furan (1n), were also reacted well,
with a reaction time of only 8 h (Table 1, entry 2). A further affording the corresponding products 3k–n in good yields
increase of the amount of DABCO (2.0 equiv.) afforded product (entries 11–14). The structure of 3 was determined by means of
3a in slightly reduced yield (Table 1, entry 3). By lowering the 1H-, 13C-NMR, and mass spectral data, and further by the X-ray
temperature to RT, the product 3a was observed only in a trace crystallographic data of 3a (see Fig. 1). Also the structure of 3j
amount even after prolonged stirring of the reaction mixture was easily inferred from the compound 4f, in which the rela-
(Table 1, entry 4). Performing the reaction of 1a and 2a under tive configuration of spiro-piperidino-cyclopropane is not
otherwise identical conditions as in entry 2 but at 80 °C for
8 h led to 3a in 38% yield (Table 1, entry 5). Screening of bases
revealed that DABCO is superior to DBU, K2CO3, t-BuOK and
Table 2 One-pot cascade leading to bridged O,O-ketal fused spiro
piperidone-cyclopropane
3 from 1-acylcyclopropanecarboxamides 1
and acrolein 2aa
Table 1 Optimization of the reaction conditionsa
3b yield
t (h) (%)
Entry 11 R1
R2
R
1
2
1a Me
1b Me
C6H5
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
8
8
8
9
10
8
8
10
12
9
10
10
11
8
93(3a)
95(3b)
92(3c)
91(3d)
87(3e)
88(3f)
85(3g)
81(3h)
0(3i)
89(3j)
86(3k)
79(3l)
75(3m)
81(3n)
Entry Base (equiv.)
T (°C) Solv.
t (h) 3a yieldb (%)
4-MeC6H4
4-MeOC6H4
2-MeC6H4
2,4-Me2C6H3
4-ClC6H4
2-ClC6H4
C6H5
CH2C6H5
4-MeOC6H4
C6H5
3
1c
Me
1
2
DABCO (1.0 equiv.) 60 CH3CN 10
DABCO (1.5 equiv.) 60
69
93
90
4c
5d
6
1d Me
1e Me
CH3CN
CH3CN
CH3CN 15
8
8
3
4
5
DABCO (2.0 equiv.) 60
DABCO (1.5 equiv.) rt
DABCO (1.5 equiv.) 80
1f
Me
Trace
38
44
7e
8
1g Me
1h C6H5
CH3CN
CH3CN
CH3CN 10
CH3CN
CH3CN
DMF
8
8
6
7
8
9
DBU (1.5 equiv.)
K2CO3 (1.5 equiv.)
t-BuOK (1.5 equiv.)
NaOH (1.5 equiv.)
60
60
60
60
9
1i
1j
Me
Me
16
10
11
12f
13
14
c
4
4
—
1k PhCHvCH
1l PhCHvCH
1m PhCHvCHCHvCH C6H5
1n furanCHvCH C6H5
c
—
2-MeC6H4
10
11
12
DABCO (1.5 equiv.) 60
DABCO (1.5 equiv.) 60
DABCO (1.5 equiv.) 60
8
15
15
25
0
0
EtOH
Xylene
a All reactions were carried out in CH3CN (5 mL) with 1 (1.0 mmol), 2a
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), and solvent (2.0 mmol), and DABCO (1.5 mmol) at 60 °C for 8–12 h. b Isolated
(5 mL). b Isolated yield. c A complex mixture.
yield. c dr = 1.4 : 1. d dr = 1.5 : 1. e dr = 1.1 : 1. f dr = 1.5 : 1.
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tion is still a formidable challenge in organic synthesis,20 and
then the divergent method for the synthesis of 4 or 5 was
probed.
To test the generality of this [4 + 2] approach, the reactions
of 2b–c with selected 1a–c, 1h–j and 1o (R1 = Me, R2 = Ph, R =
Me) were examined under identical conditions to those
described in Table 3, entry 2. Fortunately, a new class of spiro
piperidone-cyclopropane derivatives 4a–h was prepared in
good to high yields (Scheme 1). All of the structural assign-
1
Fig. 1 ORTEP drawing of compound 3a.
ments were unequivocally made on the basis of their H and
13C NMR spectra. And the identity of the relative configuration
has been defined by NOESY analyses of 4f, in which OH gave
no correlation with proton (H①) adjacent to the CN group, but
the Me (R1) group has some correlation with proton (H①) and
strong NOE cross peaks could be observed between OH and
H②, thereby allowing to assign the methyl group (R1), proton
(H①), and methylene on the same face.
In the following work, under the optimized conditions
(Table 3, entry 1), a range of reactions of 1a–e, 1g–i and 1p (R1
= Me, R2 = Ph, R = Ph) with 2b were carried out at 60 °C in
5 mL EtOH. Gratifyingly, all of them participated in this reac-
tion successfully to generate the products 5a–i in 87–98%
yields. However, the reaction with 2c gave none of the expected
cyclization product 5j but with a complex reaction system. One
possible reason is that the strong base has an important effect
on the ester group, leading to the decomposition of 5j.
Taken together, the present results and related
research,7b,12,13,15 plausible mechanisms for the synthesis of 3,
4 and 5 from 1-acylcyclopropanecarboxamides 1 and electron-
deficient alkenes (2a–c) are proposed, as depicted in
Scheme 2. The formation of 4 and 5 can be briefly described
as an amide anion from substrate 1(A) → N-nucleophilic
addition → carbanion(B) → intramolecular C-nucleophilic
addition to give cyclic products 4, followed by dehydration to
give 5. It is worth noting that when acrolein 2a was subjected
to the above reaction sequences, compound 4 (R3 = CHO) is
formed and subsequent base-triggered dehydrogenation was
performed to give a tertiary carbanion intermediate C, which
found to be altered. All of the reactions proceeded in a highly
diastereoselective manner and only one diastereoisomer was
obtained in most cases although the products contained four
stereocenters at least. Notably, substrates 1 with a substituent
located at the ortho position of the phenyl ring (1d–e, 1g and
1l) gave the corresponding products 3d–e, 3g and 3l in 79–91%
yields with different dr values, which may be attributed to the
atropisomers caused by the steric hindrance and clearly
detected from NMR spectroscopy.18
On the basis of the above experimental results, we reasoned
that the spiro piperidone-cyclopropane could be prepared
from 1 and other electron-deficient alkenes (e.g. acrylonitrile
2b and methyl acrylate 2c) via a [4 + 2] annulation in a single
step under base conditions. Detailed examination of the reac-
tion conditions indicated that 5-aza-spiro[2.5]octan-7-en-4-one
5a could be obtained in 96% yield from 1a (1.0 mmol) and 2b
(1.5 mmol) in the presence of t-BuOK (1.5 equiv.) at 60 °C for
8 h in EtOH (Table 3, entry 1). Interestingly, when DBU was uti-
lized to replace t-BuOK with CH3CN as the solvent for the reac-
tion, 5-aza-spiro[2.5]octan-4-one 4a was exclusively afforded in
89% yield (Table 3, entry 2). In addition, mediated by DABCO
(1.5 equiv.), a ring-expanding product 6a was formed in 98%
yield after the reaction mixture was stirred in xylene for 10 h at
60 °C (entry 3), which is consistent with Liang’s report.19 From
a synthetic point of view, the highly selective synthesis derived
from the same starting materials by reaction condition selec-
Table 3 Selective synthesis of 4aa or 5aa or 6aa under basic conditions
Entry
BASE (equiv.)
T (°C)
Solv.
Time (h)
4ab yield (%)
5ab yield (%)
6ab yield (%)
1
2
3
t-BuOK (1.5 equiv.)
DBU (1.5 equiv.)
DABCO (1.5 equiv.)
60
60
60
EtOH
CH3CN
Xylene
8
10
10
0
89
0
96
0
0
0
0
98
a The reactions were carried out in solvent (5 mL) with 1a (1.0 mmol), 2a (1.5 mmol), and base (1.5 mmol) at 60 °C. b Isolated yield.
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Scheme 1 Reaction scope of the base-induced [4 + 2] cycloaddition of 1 with electron-deficient alkene 2b/2c.
Scheme 2 Proposed mechanistic pathway leading to the formation of complicated spiro piperidone-cyclopropanes 3, 4 and 5.
can be stabilized by the adjacent aldehyde group. Next, direct
nucleophilic addition with another 2a leads to the intermedi-
Experimental section
ate D. Eventually, the 6,6,6-bridged ring system 3 could be All reagents were commercial and were used without further
formed via two consecutive O-nucleophilic additions with an purification. All products were purified by column chromato-
aldehyde group (D → E → 3).20d,21 In the cascade reactions, graphy over silica gel (200–300 mesh). Reactions were moni-
tandem C–N, C–O, and C–C bonds were established in one-pot tored by TLC, which was performed on precoated aluminum
with excellent yields.
sheets of silica gel 60 (F254). Melting points were uncorrected.
1
In conclusion, we have developed a novel and efficient Unless noted, the H NMR spectra were recorded at 400 MHz
tactic for the atom economical synthesis of bridged O,O-ketal in CDCl3 and the 13C NMR spectra were recorded at 100 MHz
fused spiro pyridone-cyclopropane derivatives 3 and spiro in CDCl3 with TMS as the internal standard. All coupling con-
piperidone-cyclopropanes 4 or 5 in good to excellent yields stants (J values) were reported in hertz (Hz). High-resolution
under mild reaction conditions by judicious selection of cyclo- mass spectra (HRMS) were obtained using a Bruker microTOF
propanes and electron-deficient alkenes as precursors. The IIfocus spectrometer (ESI). The compound 3a with dimension
protocol also provides a complementary platform for the reac- 0.18 × 0.17 × 0.16 mm3 and 5d with dimension 0.15 × 0.12 ×
tions of activated cyclopropanes with alkenes and the exten- 0.10 mm3 were glued on a glass fiber. Data of 3a were collected
sion of the scope of the methodology is currently under inves- at 150 K using graphite-monochromated Cu Kα radiation (λ =
tigation in our laboratory.
1.54184 Å) and the IP technique in the range of 5.424 < θ <
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66.583. And data of 5d were collected at 296 K using graphite- 37.6, 51.9, 52.0, 72.6 (2C), 91.4 (3C), 91.5, 126.7, 127.1, 127.4,
monochromated Mo Kα radiation (λ = 0.71073 Å) and the IP 127.5, 127.8, 128.0, 130.9, 131.2, 135.4, 135.5, 141.2, 141.5,
technique in the range of 3.52° < θ < 25.01°. Empirical absorp- 170.8, 171.0. HRMS (ESI-TOF) calcd for C19H24NO4 ([M + H]+):
+
tion correction was applied. The structures were solved by 330.1700, found: 330.1710.
1
direct methods and refined by the full-matrix least-squares
3e: White solid; m.p. 151–152 °C; 87% yield (10 h); HNMR
method on F2 using the SHELXL-2014 crystallographic soft- (CDCl3, 400 MHz) δ: 0.80 (q, J = 4.0 Hz, 1H), 1.03 (q, J = 5.0 Hz,
ware package. Anisotropic thermal parameters were used to 1H), 1.48–1.67 (m, 6H), 1.89–2.15 (m, 6H), 2.29 (s, 3H),
refine all non-hydrogen atoms. Hydrogen atoms were located 3.29–3.63 (m, 2H), 4.98 (s, 1H), 5.90 (d, J = 8.0 Hz, 1H), 6.90 (d,
from difference Fourier maps.
J = 8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 2H); 13CNMR (CDCl3,
100 MHz) δ: 8.0, 8.6, 15.9, 16.0, 16.3, 16.5, 17.1, 17.6, 20.9,
21.0, 22.4, 22.6, 26.6, 29.3, 37.4, 37.6, 52.0, 52.1, 72.6, 72.6,
126.4, 127.2, 127.7, 128.1, 131.6, 131.9, 134.9, 135.0, 137.5,
General procedure for the synthesis of bridged O,O-ketal fused
spiro piperidone-cyclopropane derivatives 3 (3a as an example)
To a 25 mL vial charged with 1a (203 mg, 1.0 mmol), DABCO 137.7, 138.6, 138.9, 171.0. HRMS (ESI-TOF) calcd for
(168 mg, 1.5 mmol) and acrolein 2a (0.13 mL, 2.0 mmol) was C20H26NO4 ([M + H]+): 344.1856, found: 344.1862.
+
1
added CH3CN (5 mL). Then the reaction mixture was allowed
3f: White solid; m.p. 158–160 °C; 88% yield (8 h); HNMR
to stir at 60 °C for 8 h. After the substrate 1a was consumed as (CDCl3, 400 MHz) δ: 0.84 (q, J = 4.0 Hz, 1H), 1.02–1.07 (m, 1H),
indicated by TLC, the mixture was poured into water (20 mL), 1.45–1.68 (m, 6H), 1.90–2.17 (m, 3H), 3.44 (d, J = 12.0 Hz, 1H),
and then extracted with dichloromethane (3 × 15 mL), and the 3.68 (d, J = 12.0 Hz, 1H), 4.98 (s, 1H), 5.83 (s, 1H), 7.13 (d, J =
combined organic phase was washed with water (3 × 20 mL), 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H); 13CNMR (CDCl3,
dried over Na2SO4 and distilled under reduced pressure to give 100 MHz) δ: 8.7, 16.0, 17.1, 22.5, 26.6, 29.6, 37.5, 52.4, 72.4,
a crude product. The crude product was purified by column 91.2, 91.4, 127.8, 129.3, 132.6, 141.2, 171.7. HRMS (ESI-TOF)
chromatography over silica gel using petroleum ether–acetone calcd for C18H21ClNO4 ([M + H]+): 350.1154, found: 350.1151.
+
1
(4 : 1) as the eluent, affording 3a in 93% yield.
3g: White solid; m.p. 170–172 °C; 85% yield (8 h); HNMR
1
3a: White solid; m.p. 155–157 °C; 93% yield (8 h); HNMR (CDCl3, 400 MHz) δ: 0.81(m, 1H), 1.10 (m, 1H), 1.50–1.70 (m,
(CDCl3, 400 MHz) δ:0.81 (t, J = 4.0 Hz, 1H), 0.83 (t, J = 4.0 Hz, 6H), 1.90–2.18 (m, 3H), 3.34–3.62 (m, 2H), 4.99 (s, 1H),
1H), 1.04–1.08 (m, 5H), 1.46–2.14 (m, 4H), 2.8 (s, 1H), 5.87–6.01 (m, 1H), 7.15–7.19 (m, 1H), 7.23–7.32 (m, 2H),
2.44–3.48 (s, 1H), 3.70–3.3.74 (s, 1H), 4.98 (s, 1H), 5.84 (s, 1H), 7.43–7.47 (m, 1H); 13CNMR (CDCl3, 100 MHz) δ: 8.2, 8.6, 16.0,
7.20 (t, J = 4.0 Hz, 2H), 7.25–7.36 (m, 1H), 7.37–7.39 (t, J = 4.0 16.8, 22.5, 26.6, 29.3, 29.4, 37.5, 37.7, 51.4, 51.7, 72.5, 72.7,
Hz, 2H); 13CNMR (CDCl3, 100 MHz) δ: 8.6, 16.0, 16.9, 22.4, 76.7, 77.2, 77.3, 91.2, 91.3, 91.4, 91.5, 128.0, 128.3, 129.0,
26.6, 29.5, 37.5, 52.5, 72.5, 91.3, 91.4, 126.5, 127.0, 129.3, 129.1, 129.2, 129.8, 130.3, 130.5, 132.4, 132.5, 139.6, 139.9,
+
+
142.7, 171.6. HRMS (ESI-TOF) calcd for C18H22NO4 ([M + H]+): 171.3, 171.5. HRMS (ESI-TOF) calcd for C18H21ClNO4 ([M +
316.1543, found: 316.1556.
3b: White solid; m.p. 156–158 °C; 95% yield (8 h); HNMR
H]+): 350.1154, found: 350.1153.
3h: White solid; m.p. 160–162 °C; 81% yield (10 h); 1HNMR
1
(CDCl3, 400 MHz) δ: 1.02 (t, J = 4.0 Hz, 1H ), 1.06 (t, J = 4.0 Hz, (CDCl3, 400 MHz) δ: 0.44 (q, J = 4.0 Hz, 1H), 0.47–1.15(m, 1H),
1H), 1.49–1.66 (m, 6H), 1.89–2.17 (m, 3H), 2.33 (s, 3H), 3.41 (d, 1.26–1.33(m, 1H), 1.51–1.56 (m, 1H), 1.82–1.90 (m, 2H),
J = 16.0 Hz, 1H), 3.70 (d, J = 12.0 Hz, 1H), 4.98 (s, 1H), 5.85 (s, 2.11–2.15 (m, 2H), 2.72 (s, 1H), 3.40 (d, J = 12.0 Hz, 1H), 3.63
1H), 7.05 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H); 13CNMR (d, J = 12.0 Hz, 1H), 5.32 (s, 1H), 5.95 (s, 1H), 7.26–7.28 (m,
(CDCl3, 100 MHz) δ: 8.5, 16.0, 16.8, 21.0, 22.4, 26.6, 29.5, 37.5, 3H), 7.33–7.43 (m, 5H), 7.55–7.57 (m, 2H); 13CNMR (CDCl3,
52.7, 72.5, 91.3, 91.4, 126.3, 129.8, 136.8, 140.2, 171.6. HRMS 100 MHz) δ: 12.1, 15.6, 18.9, 26.7, 30.2, 38.2, 51.7, 78.4, 91.8,
(ESI-TOF) calcd for C19H24NO4 ([M + H]+): 330.1700, found: 91.9, 126.2, 126.9, 127.1, 127.8, 128.2, 129.2, 142.2, 142.8,
+
+
330.1709.
3c: White solid; m.p. 174–175 °C; 92% yield (8 h); HNMR 378.1700, found: 378.1712.
(CDCl3, 400 MHz) δ: 0.81 (q, J = 4.0 Hz, 1H), 1.04 (q, J = 4.0 Hz, 3j: White solid; m.p. 178–180 °C; 89% yield (9 h); HNMR
172.9. HRMS (ESI-TOF) calcd for C23H24NO4 ([M + H]+):
1
1
1H), 1.44–1.66 (m, 6 H), 1.88–2.17 (m, 3H), 3.43(d, J = 16.0 Hz, (CDCl3, 400 MHz) δ: 0.88 (q, J = 4.0 Hz, 1H), 1.17 (d, J = 8.0 Hz,
1H), 3.69 (d, J = 12.0 Hz, 1H), 3.84 (s, 3H), 4.97 (s, 1H), 5.83 (s, 3H), 1.31 (q, J = 4.0 Hz, 1H), 1.46 (s, 3H), 1.61–1.68 (m, 1H),
1H), 6.85 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H); 13CNMR 1.90–2.15 (m, 4H), 3.37 (d, J = 12.0 Hz, 1H), 3.67 (d, J = 16.0
(CDCl3, 100 MHz) δ: 8.6, 16.0, 16.8, 22.4, 26.7, 29.5, 37.5, 52.9, Hz, 1H), 3.79 (s, 3H), 4.99 (s, 1H), 5.65 (s, 1H), 6.89 (q, J = 4.0
55.5, 72.5, 91.3, 91.4, 114.5, 114.6, 127.7, 135.6, 158.3, 171.9. Hz, 2H), 7.06 (d, J = 4.0 Hz, 2H); 13CNMR (CDCl3, 100 MHz) δ:
HRMS (ESI-TOF) calcd for C19H24NO5 ([M + H]+): 346.1649, 11.4, 13.5, 16.1, 21.0, 22.0, 26.7, 34.5, 37.3, 53.1, 55.5, 73.4,
+
found: 346.1643.
91.4, 91.7, 114.6, 127.7, 135.9, 158.3, 169.6. HRMS (ESI-TOF)
1
+
3d: White solid; m.p. 146–147 °C; 91% yield (9 h); HNMR calcd for C20H26NO5 ([M + H]+): 360.1806, found: 360.1811.
1
(CDCl3, 400 MHz) δ: 0.81(t, J = 6.0 Hz, 1H), 1.05 (q, J = 5.5 Hz,
3k: White solid; m.p. 170–172 °C; 86% yield (10 h); HNMR
1H), 1.53–1.68 (m, 6H), 1.91–2.17 (m, 6H), 3.33–3.66 (m, 2H), (CDCl3, 400 MHz) δ: 0.70 (q, J = 4.0 Hz, 1H), 1.16–1.20 (m, 1H),
4.99 (s, 1H), 5.92 (d, J = 12.0 Hz, 1H), 7.02 (d, J = 4.0 Hz, 1H), 1.52–1.71 (m, 3H), 1.99–2.10 (m, 3H), 3.56 (d, J = 12.0 Hz, 1H),
7.22 (t, J = 4.0 Hz, 3H); 13CNMR (CDCl3, 100 MHz) δ: 8.03, 8.63, 3.76 (d, J = 12.0 Hz, 1H), 5.19 (s, 1H), 5.91 (s, 1H), 6.40 (d, J =
15.9, 16.0, 16.4, 16.6, 17.2, 17.7, 22.4, 22.6, 26.5, 29.3, 37.4, 16.0 Hz, 1H), 6.83 (d, J = 16.0 Hz, 1H), 7.23–7.29 (m, 3H),
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7.31–7.44 (m, 7H); 13CNMR (CDCl3, 100 MHz) δ: 10.3, 16.4, 30.7, 38.8, 48.2, 70.0, 117.2, 126.3, 127.5, 129.4, 142.1, 169.7.
17.4, 26.7, 27.9, 38.2, 52.4, 75.8, 91.4, 91.9, 126.5, 126.7, 127.1, HRMS (ESI-TOF) calcd for C15H17N2O2 ([M + H]+): 257.1285,
+
128.1, 128.5, 128.8, 129.3, 130.8, 136.4, 142.8, 171.6. HRMS found: 257.1283.
+
(ESI-TOF) calcd for C25H26NO4 ([M + H]+): 404.1856, found:
4b: White solid; m.p. 163–165 °C; 83% yield (10 h); 1HNMR
(CDCl3, 400 MHz) δ: 1.02–1.08 (m, 2H), 1.09–1.25 (m, 1H), 1.37
404.1861.
1
3l: White solid; m.p. 181–182 °C; 79% yield (10 h); HNMR (s, 3H), 1.42–1.48 (m, 1H), 2.50 (s, 3H), 2.56 (s, 1H), 3.20 (dd, J
(CDCl3, 400 MHz) δ: 0.70–0.73 (m, 1H), 1.12–1.18 (m, 1H), = 8.0 Hz, 4.0 Hz, 1H), 3.72 (dd, J = 12.0 Hz, 8.0 Hz, 1H), 4.14
1.52–1.69 (m, 3H), 1.97–2.09 (m, 3H), 2.17–2.29 (m, 3H), (dd, J = 12.0 Hz, 4.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.21 (d, J
3.41–3.70 (m, 2H), 5.18 (s,1H), 5.96–5.98 (m, 1H), 6.45 (d, J = = 8.0 Hz, 2H); 13CNMR (CDCl3, 100 MHz) δ: 11.5, 14.2, 21.1,
16.0 Hz, 1H), 6.85 (d, J = 16.0 Hz, 1H), 7.06–7.11 (m, 1H), 23.5, 30.6, 38.3, 48.5, 69.9, 117.9, 126.3, 130.0, 137.4, 139.6,
+
7.21–7.30 (m, 8H); 13CNMR (CDCl3, 100 MHz) δ: 9.63, 10.3, 170.3. HRMS (ESI-TOF) calcd for C16H19N2O2 ([M + H]+):
16.3, 16.4, 16.9, 17.0, 17.3, 18.0, 18.4, 26.7, 27.6, 27.7, 38.1, 271.1441, found: 271.1447.
1
38.3, 51.8, 51.9, 75.8, 75.9, 91.5, 91.6, 91.8, 91.9, 126.6, 126.7,
4c: White solid; m.p. 151–153 °C; 87% yield (10 h); HNMR
127.2, 127.5, 127.6, 127.9, 128.0, 128.1, 128.4, 128.7, 128.8, (CDCl3, 400 MHz) δ: 1.08 (t, J = 4.0 Hz, 2H), 124 (d, J = 4.0 Hz,
130.8, 130.9, 131.0, 131.3, 135.3, 135.5, 136.4, 141.2, 141.6, 1H), 1.43 (s, 3H), 1.45 (m, 1H), 3.28 (t, J = 6.0 Hz, 1H), 3.74 (q,
+
170.9, 171.0. HRMS (ESI-TOF) calcd for C26H28NO4 ([M + H]+): J = 6.5 Hz, 1H), 3.81 (s, 3H), 4.18 (q, J = 5.5 Hz, 1H), 6.92 (d, J =
418.2013, found: 418.1998.
8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H); 13CNMR (CDCl3,
3m: White solid; m.p. 164–166 °C; 75% yield (11 h); 100 MHz) δ: 12.1, 14.2, 23.6, 30.6, 38.8, 48.5, 55.5, 69.9, 114.6,
1HNMR (CDCl3, 400 MHz) δ: 0.69–0.70 (m, 1H), 1.14–1.19 (m, 114.7, 117.3, 127.5, 127.6, 135.0, 158.6, 170.0. HRMS (ESI-TOF)
1H), 1.51–1.67 (m, 3H), 1.96–2.09(m, 3H), 2.56 (s, 1H), 3.51 (d, calcd for C16H19N2O3 ([M + H]+): 287.1390, found: 287.1395.
+
J = 12.0 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 5.16 (s, 1H), 5.87 (s,
4d: White solid; m.p. 164–166 °C; 74% yield (12 h); 1HNMR
1H), 6.00 (d, J = 16.0 Hz, 1H), 6.63 (m, 2H), 6.89 (q, J = 9.0 Hz, (DMSO-d6, 400 MHz) δ: 0.70–0.75 (m, 1H), 0.85 (t, J = 4.0 Hz,
1H), 7.22–7.29 (m, 3H), 7.32–7.44(m, 7H); 13CNMR (CDCl3, 1H), 1.05–1.10 (m, 1H), 1.32–1.39 (m, 1H), 3.27–3.30 (m, 1H),
100 MHz) δ: 10.2, 16.4, 17.3, 26.7, 27.9, 38.0, 52.3, 75.6, 91.3, 3.78–3.91 (m, 1H), 3.99–4.16 (m, 1H), 6.39 (s, 1H), 7.11–7.16
91.8, 126.4, 126.5, 127.1, 127.8, 128.7, 129.3, 131.2, 132.4, (m, 2H), 7.20–7.29 (m, 1H), 7.38–7.41 (m, 3H), 7.41–7.47 (m,
133.7, 136.9, 142.7, 171.6. HRMS (ESI-TOF) calcd for 2H), 7.49–7.57 (m, 2H); 13CNMR (DMSO-d6, 100 MHz) δ: 11.7,
C27H28NO4 ([M + H]+): 430.2013, found: 430.1996.
13.6, 29.4, 38.2, 48.4, 72.5, 119.0, 126.3, 126.6, 126.8, 128.2,
+
1
3n: White solid; m.p. 155–158 °C; 81% yield (8 h); HNMR 128.3, 129.0, 142.0, 142.6, 170.1. HRMS (ESI-TOF) calcd for
+
(CDCl3, 400 MHz) δ: 0.65–0.70 (m, 1H), 1.15–1.17 (m, 1H), C20H19N2O2 ([M + H]+): 319.1441, found: 319.1447.
1.50–1.68 (m, 3H), 1.92–2.08 (m, 3H), 2.77 (s, 1H), 3.57 (d, J =
4e: White solid; m.p. 113–115 °C; 81% yield (12 h);
12 Hz, 1H), 3.73 (d, J = 12 Hz, 1H), 5.15 (s, 1H), 5.87 (s, 1H), 1HNMR (CDCl3, 400 MHz) δ: 1.02–1.09 (m, 1H), 1.10–1.19 (m,
6.29–6.42 (m, 3H), 6.61 (d, J = 12.0 Hz, 1H), 7.23–7.29 (m, 3H), 2H), 1.34 (d, J = 4.0 Hz, 3H), 1.52–1.56 (m, 1H), 1.57 (s, 1H),
7.37–7.41(m, 3H); 13CNMR (CDCl3, 100 MHz) δ: 10.3, 16.4, 3.12–3.32 (m, 1H), 3.32–3.67 (m, 1H), 3.68–3.71 (m, 1H), 4.52
17.5, 26.7, 26.9, 38.1, 52.3, 75.6, 91.3, 91.9, 109.1, 111.5, 119.0, (d, J = 16.0 Hz, 1H), 4.73 (d, J = 16.0 Hz, 1H), 7.22–7.36 (m,
126.6, 126.9, 127.1, 129.3, 142.3, 142.7, 152.1, 171.6. HRMS 5H); 13CNMR (CDCl3, 100 MHz) δ: 11.8, 12.8, 23.4, 30.5, 38.1,
+
(ESI-TOF) calcd for C23H24NO5 ([M + H]+): 394.1649, found: 44.6, 50.5, 69.6, 117.7, 127.8, 128.0, 128.9, 136.2, 169.9.
394.1652.
HRMS (ESI-TOF) calcd for C16H19N2O2+([M + H]+): 271.1441,
found: 271.1452.
4f: White solid; m.p. 148–150 °C; 76% yield (8.5 h);
1HNMR (CDCl3, 400 MHz) δ: 1.07 (q, J = 4.0 Hz, 1H), 1.14 (d, J
General procedure for the synthesis of 5-aza-spiro[2.5]octan-4-
ones 4 (4a as an example)
DBU (0.225 mL, 1.5 mmol) was added to a stirring solution of = 8.0 Hz, 3H), 1.37 (q, J = 4.0 Hz, 1H), 1.55 (s, 3H), 1.62–1.71
1-acetyl-1-carbamoyl cyclopropane 1a (203 mg, 1.0 mmol) and (m, 1H), 2.00 (s, 1H), 3.36 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 3.75
acrylonitrile 2b (0.1 mL, 1.5 mmol) in CH3CN (5 mL). The (d, J = 12.0 Hz, 1H), 3.80 (s, 3H), 3.92 (dd, J = 12.0 Hz, 8.0 Hz,
resulting mixture was heated at 60 °C with constant stirring for 1H), 6.92 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H); 13CNMR
10 h. When 1a disappeared as monitored by TLC, the reaction (CDCl3, 100 MHz) δ: 11.7, 14.8, 18.6, 23.0, 36.9, 39.2, 49.2,
mixture was poured into a saturated NaCl solution (30 mL), 55.5, 69.4, 114.8, 117.5, 127.7, 134.7, 158.8, 168.3. HRMS
extracted with chloroform (3 × 10 mL), dried over Na2SO4, and (ESI-TOF) calcd for C17H21N2O3+([M + H]+): 301.1547, found:
distilled under reduced pressure to give a crude product. The 301.1551.
1
crude product was purified by column chromatography over
4g: White solid; m.p. 142–144 °C; 79% yield (9 h); HNMR
(CDCl3, 400 MHz) δ: 1.10 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 1.16 (d,
silica gel using petroleum ether–acetone (3 : 1) as the eluent.
1
4a: White solid; m.p. 135–138 °C; 89% yield (10 h); HNMR J = 4.0 Hz, 3H), 1.41 (t, J = 6.0 Hz, 1H), 1.58 (s, 3H), 1.65–1.73
(CDCl3, 400 MHz) δ: 1.06–1.13 (m, 2H), 1.26–1.29 (m, 1H), 1.43 (m, 1H), 1.82 (s, 1H), 3.40 (dd, J = 12 Hz, 4.0 Hz, 1H), 3.83 (t, J
(s, 3H), 1.50–1.54 (m, 1H), 1.75–1.81 (s, 1H), 3.28 (dd, J = 8.0 = 12.0 Hz, 1H), 3.97 (dd, J = 12.0 Hz, 8.0 Hz, 1H), 7.18 (d, J =
Hz, 4.0 Hz, 1H), 3.77 (dd, J = 12.0 Hz, 8.0 Hz, 1H), 4.20–4.25 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.42 (t, J = 6.0 Hz, 2H);
(m, 1H), 7.24 (q, J = 8.0 Hz, 2H), 7.30 (q, J = 4.0 Hz, 1H), 7.42(q, 13CNMR (CDCl3, 100 MHz) δ: 11.7, 14.8, 18.7, 23.1, 36.9, 39.2,
J = 8.0 Hz, 2H); 13CNMR (CDCl3, 100 MHz) δ: 12.1, 14.5, 24.7, 48.9, 69.4, 117.4, 126.5, 127.6, 129.5, 141.9, 168.1. HRMS
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(ESI-TOF) calcd for C16H19N2O2+([M + H]+): 271.1441, found: 4.0 Hz, 1H), 4.41 (dd, J = 16.0 Hz, 4.0 Hz, 1H), 7.00–7.08 (m,
271.1447.
3H); 13CNMR (CDCl3, 100 MHz) δ: 16.8, 16.9, 17.1, 17.2, 21.0,
4h: White solid; m.p. 157–159 °C; 80% yield (12 h); 1HNMR 26.8, 50.7, 101.3, 116.2, 126.6, 128.1, 132.0, 134.9, 137.5, 138.3,
(CDCl3, 400 MHz) δ: 0.89–0.94 (m, 1H), 1.01–1.06 (m, 1H), 152.8, 167.1. HRMS (ESI-TOF) calcd for C17H19N2O+([M + H]+):
1.21–1.25 (m, 1H), 1.26–1.34 (m, 1H), 1.44 (s, 3H), 1.60 (s, 1H), 267.1492, found: 267.1489.
3.10 (t, J = 4.0 Hz, 1H), 3.79 (t, J = 4.0 Hz, 1H), 3.82 (s, 3H),
5f: White solid; m.p. 145–147 °C; 87% yield (7.5 h); 1HNMR
4.20 (dd, J = 12.0 Hz, 8.0 Hz, 1H), 7.24–7.29 (m, 3H), 7.40 (t, J = (CDCl3, 400 MHz) δ: 1.32 (m, 2H), 1.77 (m, 2H), 1.90 (t, J = 4.0
8.0 Hz, 2H); 13CNMR (CDCl3, 100 MHz) δ: 11.5, 12.6, 25.5, Hz, 3H), 4.30 (q, J = 16.0 Hz, 1H), 4.46 (q, J = 16.0 Hz, 1H),
30.2, 48.4, 49.3, 52.6, 69.6, 126.6, 127.1, 129.3, 143.0, 170.8, 7.27–7.35 (m, 3H), 7.48–7.51 (m, 1H); 13CNMR (CDCl3,
+
172.9. HRMS (ESI-TOF) calcd for C16H20NO4 ([M + H]+): 100 MHz) δ: 16.8, 17.2, 17.4, 26.8, 50.0, 101.2, 116.1, 128.3,
290.1387, found: 290.1391.
129.4, 129.7, 130.6, 132.4, 138.6, 152.6, 167.6. HRMS (ESI-TOF)
calcd for C15H14ClN2O+([M + H]+): 273.0789, found: 273.0800.
5g: White solid; m.p. 154–156 °C; 95% yield (8 h); HNMR
(CDCl3, 400 MHz) δ: 1.05 (d, J = 4.0 Hz, 2H), 1.76 (d, J = 4.0 Hz,
General procedure for the synthesis of 5-aza-spiro[2.5]octan-7-
en-4-ones 5 (5a as an example)
1
To a solution of 1-acetyl-1-carbamoyl cyclopropane 1a (203 mg, 2H), 4.64 (s, 2H), 7.19 (d, J = 4.0 Hz, 2H), 7.34 (t, J = 6.0 Hz,
1.0 mmol) and acrylonitrile 2b (0.1 mL, 1.5 mmol) in EtOH 3H), 7.46 (t, J = 8.0 Hz, 5H); 13CNMR (CDCl3, 100 MHz) δ: 17.4,
(5 mL) at 60 °C was added (CH3)3COK (168 mg, 1.5 mmol) in 27.1, 51.2, 103.7, 115.7, 126.1, 127.6, 128.2, 128.8, 129.3, 129.5,
one portion. The reaction mixture was stirred for 8 h. After 1a 134.0, 141.5, 156.9, 168.0. HRMS (ESI-TOF) calcd for
was consumed as indicated by TLC, the resulting mixture was C20H17N2O+([M + H]+): 301.1335, found: 301.1340.
1
poured into a saturated NaCl solution (30 mL) under stirring.
5h: White solid; m.p. 85–87 °C; 93% yield (10 h); HNMR
Then the mixture was extracted with chloroform (3 × 10 mL) (CDCl3, 400 MHz) δ: 1.24 (q, J = 4.0 Hz, 2H), 1.75 (q, J = 4.0 Hz,
and dried over Na2SO4. Finally, the crude product was purified 2H), 1.80 (s,3H), 4.01 (d, J = 4.0 Hz, 2H), 4.63 (s, 2H), 7.25–7.27
by flash chromatography (silica gel, petroleum ether–acetone (m, 2H), 7.30–7.37(m, 3H); 13CNMR (CDCl3, 100 MHz) δ: 16.9,
5 : 1) to give 5a in 96% yield.
17.0, 26.5, 47.2, 50.3, 100.9, 116.3, 127.9, 128.3, 128.8, 135.8,
1
5a: White solid; m.p. 113–115 °C; 96% yield (8 h); HNMR 152.3, 167.6. HRMS (ESI-TOF) calcd for C16H17N2O+([M + H]+):
(CDCl3, 400 MHz) δ: 1.31 (q, J = 4.0 Hz, 2H), 1.77 (q, J = 4.0 Hz, 253.1335, found: 253.1341.
1
2H), 1.89 (t, J = 4.0 Hz, 3H), 4.47 (d, J = 4.0 Hz, 2H), 7.24 (t, J =
5i: White solid; m.p. 188–190 °C; 88% yield (10 h); HNMR
8.0 Hz, 2H), 7.31 (d, J = 4.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H); (CDCl3, 400 MHz) δ: 1.42 (s, 3H), 1.92 (q, J = 4.0 Hz, 1H), 2.50
13CNMR (CDCl3, 100 MHz) δ: 17.2, 17.3, 27.2, 50.7, 101.4, (q, J = 4.0 Hz, 1H), 3.11 (t, J = 8.0 Hz, 1H), 4.32 (d, J = 16 Hz,
116.2, 126.1, 127.6, 129.5, 141.5, 152.7, 167.8. HRMS (ESI-TOF) 1H), 4.73 (dd, J = 16 Hz, 4.0 Hz, 1H), 7.23–7.36 (m, 8H), 7.44 (t,
calcd for C15H15N2O+([M + H]+): 239.1179, found: 239.1176.
J = 8.0 Hz, 2H); 13CNMR (CDCl3, 100 MHz) δ: 18.2, 20.5, 35.1,
1
5b: White solid; m.p. 117–120 °C; 94% yield (8 h); HNMR 37.2, 50.0, 104.2, 116.3, 125.4, 127.3, 127.8, 128.9, 129.4, 129.5,
(CDCl3, 400 MHz) δ: 1.30 (q, J = 4.0 Hz, 2H), 1.75 (q, J = 4.0 Hz, 135.3, 141.6, 153.5, 168.3. HRMS (ESI-TOF) calcd for
2H), 1.87 (d, J = 4.0 Hz, 3H), 2.35 (s, 3H), 4.45 (d, J = 4.0 Hz, C21H19N2O+([M + H]+): 315.1492, found: 315.1496.
2H), 7.12 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H); 13CNMR
(CDCl3, 100 MHz) δ: 17.2, 21.1, 27.1, 50.8, 101.4, 116.2, 125.8,
130.0, 137.4, 138.9, 152.7, 167.8. HRMS (ESI-TOF) calcd for Conflicts of interest
C16H17N2O+([M + H]+): 253.1335, found:253.1338.
1
There are no conflicts to declare.
5c: White solid; m.p. 102–105 °C; 98% yield (8 h); HNMR
(CDCl3, 400 MHz) δ: 1.30 (q, J = 4.0 Hz, 2H), 1.75 (q, J = 4.0 Hz,
2H), 1.87 (t, J = 4.0 Hz, 3H), 3.81 (s, 3H), 4.43 (s, 2H), 6.92 (q, J
= 4.0 Hz, 2H), 7.16 (q, J = 4.0 Hz, 2H); 13CNMR (CDCl3,
100 MHz) δ:17.2, 27.1, 51.1, 55.5, 101.4, 114.7, 116.2, 127.3,
134.3, 152.7, 158.7, 167.9. HRMS (ESI-TOF) calcd for
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Grants 21862007) and the Jiangxi Provincial Science &
Technology Department (20181BBG70041, 20181ACF60025,
20192BCB23027, 20192BBF60042 and 2020-YZD-1) for finan-
cial support.
+
C16H17N2O2 ([M + H]+): 269.1285, found: 269.1279.
5d: White solid; m.p. 124–126 °C; 93% yield (10 h); 1HNMR
(CDCl3, 400 MHz) δ: 1.30 (q, J = 4.0 Hz, 2H), 1.76 (m, 2H), 1.89
(s, 3H), 2.19 (s, 3H), 4.24 (dd, J = 16.0, 4.0 Hz, 1H), 4.44 (dd, J =
16.0 Hz, 4.0 Hz, 1H), 7.12–7.15 (m, 1H), 7.24–7.28 (m, 3H);
13CNMR (CDCl3, 100 MHz) δ: 16.9, 17.0, 17.2, 17.3, 26.8, 50.6,
101.3, 116.2, 126.9, 127.5, 128.4, 131.3, 135.4, 140.1, 152.8,
167.1. HRMS (ESI-TOF) calcd for C16H17N2O+([M + H]+):
253.1335, found: 253.1337.
References
1 (a) A. Mondon and H. Callsen, Tetrahedron Lett., 1975, 16,
699; (b) D. R. Armour, S. P. Watson, N. A. Pegg,
N. M. Heron, D. Middlemiss, C. Chan, T. J. Cholerton,
T. Hubbard, M. V. Vinader, H. G. Davies, J. D. Cocker,
D. E. Bays and P. Ward, Bioorg. Med. Chem. Lett., 1995,
1
5e: White solid; m.p. 121–123 °C; 89% yield (10 h); HNMR
(CDCl3, 400 MHz) δ: 1.28 (d, J = 4.0 Hz, 2H), 1.75 (q, J = 4.0 Hz,
2H), 1.88(s, 3H), 2.14 (s, 3H), 2.32 (s, 3H), 4.23 (dd, J = 16 Hz,
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Organic & Biomolecular Chemistry
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