Synthesis of spirobarbiturate-pyrrolidinones: Via a domino aza-Michael/SN2 cyclization of barbiturate-derived alkenes with N-alkoxy α-haloamides

Article abstract of DOI:10.1039/c9ob01992h

A highly efficient domino aza-MIRC (Michael Induced Ring Closure) reaction between barbiturate-derived alkenes and N-alkoxy α-haloamides has been achieved in moderate to excellent yields. This reaction proceeds smoothly under mild conditions via a domino aza-Michael addition/intramolecular S_N2 sequence, providing a practical tool in the synthesis of bioactive molecules spirobarbiturate-3-pyrrolidinones.

Full text of DOI:10.1039/c9ob01992h

Organic &
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Synthesis of spirobarbiturate-pyrrolidinones via a
domino aza-Michael/SN2 cyclization of barbiturate-
derived alkenes with N-alkoxy α-haloamides†
Cite this: Org. Biomol. Chem., 2019,
17, 9200
Chuan-Chuan Wang,
‡
a,b Jing Zhou,‡c Zhi-Wei Ma,a Xiao-Pei Chena and
c
Ya-Jing Chen
*
Received 11th September 2019,
Accepted 2nd October 2019
A highly efficient domino aza-MIRC (Michael Induced Ring Closure) reaction between barbiturate-derived
alkenes and N-alkoxy α-haloamides has been achieved in moderate to excellent yields. This reaction pro-
ceeds smoothly under mild conditions via a domino aza-Michael addition/intramolecular SN2 sequence,
providing a practical tool in the synthesis of bioactive molecules spirobarbiturate-3-pyrrolidinones.
DOI: 10.1039/c9ob01992h
rsc.li/obc
Due to the importance of spirobarbiturate compounds,
various synthetic routes to these spiroheterocycles have been
Introduction
Barbiturates, namely barbituratic acids derivatives, are remark- explored to achieve bioactive molecules with complex ring
able scaffolds since they are prevalent in pharmacologically frameworks.2,3 Among them, the [2 + m] cycloaddition reactions
active compounds. Moreover, spirobarbiturates have continued of barbiturate-derived alkenes were proven to be powerful strat-
to gain attention in recent years because of their various egies for the construction of spirobarbiturate compounds.2 In
pharmacological properties, such as urease inhibitor, HIV-1 the last decade, a lot of barbiturate-derived alkenes based cyclo-
inhibitor, anticonvulsant, TACE inhibitor, MMP-13 inhibitor, addition reactions have been developed to access various spiro-
and anticancer activities (Fig. 1).1
barbiturates scaffolds, such as spirobarbiturate-cyclopentenes,2a
spirobarbiturate-cyclohexenes,2b spirobarbiturate-cyclopentano-
nes,2c and spirobarbiturate-cyclopropanes.2d
On the other hand, pyrrolidinones are important structural
motifs in natural products and medicinally important com-
pounds.4 Spirobarbiturate-pyrrolidinones with the combi-
nation of barbiturates and pyrrolidinones moieties are very
appealing in the search for medicinally active compounds.5
To the best of our knowledge, the only reported method to
construct spirobarbiturate-pyrrolidinones is the synthesis of
spirobarbiturate-4-pyrrolidinones, relying on time-consuming
multistep synthesis in low yields, starting from α-bromo
diethyl malonate (Scheme 1, eqn (1)).5a However, the synthetic
method of spirobarbiturate-3-pyrrolidinones has not been
uncovered up to now.5b Hence, development of new protocols
to construct such scaffolds is highly desirable. As part of our
continuing efforts on cyclization reactions,6 herein, we con-
sidered the formal [3 + 2] cycloaddition of barbiturate-derived
alkenes with N-alkoxy α-haloamides might be an efficient
tool to synthesize spirobarbiturate-3-pyrrolidinones (Scheme 1,
eqn (2)).
Fig. 1 Biologically active compounds containing the spiro-barbiturates
scaffolds.
aFaculty of Science, Henan University of Animal Husbandry and Economy,
No. 2 Yingcai Street, Huiji District, Zhengzhou 450044, Henan, PR China
bCollege of Chemistry, Zhengzhou University, 100 Science Avenue,
Zhengzhou 450001, Henan, PR China
cSchool of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation
Technologies, Ministry of Education of China, Co-innovation Center of Henan
Province for New Drug R & D and Preclinical Safety, Zhengzhou University,
100 Science Avenue, Zhengzhou 450001, Henan, PR China. E-mail: chenyj@zzu.edu.cn
†Electronic supplementary information (ESI) available: Copies of the NMR spec-
tras for all new compounds. See DOI: 10.1039/c9ob01992h
[3 + 2] annulations are highly powerful synthetic strategies
for the construction of five-membered rings. Particularly, these
annulations have also successfully been applied in the syn-
thesis of pyrrolidinones.7 Comesse developed the aza-Michael/
intramolecular nucleophilic substitution of Michael acceptors
‡These authors have contributed equally.
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Table 1 Optimization of the reaction conditionsa
Entry
Base
Solvent
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
Cs2CO3
Na2CO3
KOH
CH3CN
DCM
THF
25
25
25
25
25
25
25
25
25
35
35
35
83
92
84
59
NR
78
90
51
84
Toluene
HFIP
DCM
DCM
DCM
DCM
DCM
DCM
DCM
9
Scheme 1 Synthetic approach to spirobarbiturate-pyrrolidinones.
10
11c,d
12c
K2CO3
K2CO3
K2CO3
>99
>99
96
with α-bromoacetamides to synthesize pyrrolidinones in
49–69% yields.7a The strong basic conditions, using NaH in
this system limited the application. Moreover, N-alkoxy
α-haloacetamides are commonly used 3-atom synthons due to
their easy availability and high reactivity.8 Recently, Huang
established the [3 + 2] cycloaddition of α-substituted N-alkoxy
α-haloacetamides with aromatic ethylenes to prepare pyrrolidi-
nones via azaoxyallyl cation intermediates in 15–71% yields,
performed in HFIP at 50 °C.7b It was supposed that substi-
tuents on the α-position of N-alkoxy α-haloacetamides are
necessary to stabilize the formed azaoxyallyl cation species
and reactions with α-unsubstituted N-alkoxy α-haloacetamides
were not reported in this work. We have previously
demonstrated the powerful synthetic utility of α-unsubstituted
N-alkoxy α-haloacetamides with sulfamate-derived cyclic
imines to provide 4-imidazolidinones in good to excellent
yields under mild conditions.6 Herein, we present a new
a Unless otherwise noted, all reactions were carried out with 1a
(0.2 mmol), 2a (0.24 mmol), base (0.24 mmol) and 4 Å MS (100 mg) in
2 mL of solvent under air atmosphere. b Isolated yields. c Without 4 Å
MS. d N2 atmosphere.
obtained when the reaction was carried out at 35 °C for 24 h
(entry 10). Controlled experiment conducted without 4 Å MS
under N2 atmosphere also could provide 3aa in >99% yield
(entry 11). However, a slightly decreased yield (96%) was
observed under air atmosphere without 4 Å MS. Considering
the convenience of operation, the optimized conditions are as
follows: 1a reacts with 2a in DCM at 35 °C using K2CO3 as the
base in the presence of 4 Å MS under air atmosphere.
With the optimized conditions in hand, we then explored
the scope and functional group tolerance of barbiturate-
derived alkenes 1. As shown in Table 2, a series of barbiturate-
derived alkenes 1 were allowed to react with N-OBn α-Br acet-
amide 2a under optimized conditions, providing the desired
products in good to excellent yields. The position of the substi-
tuents and the electronic effect seemed to have no remarkable
influence on the reaction. Notably, barbiturate-derived alkenes
1 substituted by –OMe (1b, 1j, 1n) or –NO2 (1i, 1m, 1r) groups
on different positions of phenyl ring all reacted efficiently with
N-OBn α-Br acetamide 2a, affording the corresponding spiro-
formal [3
+
2] cycloaddition of barbiturate-derived
alkenes with α-unsubstituted and α-substituted N-alkoxy
α-haloacetamides to construct spirobarbiturate-3-pyrrolidi-
nones via a domino aza-Michael/intramolecular nucleophilic
substitution sequence.
Results and discussion
We commenced our work by examining the reaction between cyclic products in excellent yields. Moreover, whether using
barbiturate-derived alkene 1a and N-OBn α-Br acetamide 2a electron-rich (1b–1c, 1j, 1n–1o) or electron-deficient (1d–1i,
(Table 1). Firstly, we conducted the reaction at 25 °C for 24 h 1k–1m, 1p–1r) aryl-substituted barbiturate-derived alkenes 1,
with the use of K2CO3 and 4 Å MS in CH3CN under air atmo- the spirobarbiturate-pyrrolidinone products were all obtained
sphere, providing the desired product in 83% yield (entry 1). in good to excellent yields (3ba–3ra). 2,4-Dimethoxyl substi-
Other solvents (DCM, THF, Toluene and HFIP) were screened tuted alkene 1s also led to the desired product 3sa in 91%
and DCM displayed the best result, giving 3aa in 92% yield yield. Substrates with a naphthyl (1t–1u), thienyl (1v) or benzo-
(entries 2–5). It’s worth noting that the reaction did not give dioxolyl (1w) were all applicable in this reaction, affording the
any product by using HFIP as the solvent (entry 5). desired products (3ta–3wa) in excellent yields. Barbiturate-
Replacement of K2CO3 with other bases (Et3N, Cs2CO3, Na2CO3 derived alkenes bearing an alkyl group (1x–1y) were also com-
or KOH), the cyclization products could be also successfully patible with the current system, affording the desired spirobar-
obtained, albeit in decreased yields (51–90%, entries 6–9). biturate-pyrrolidinone products 3xa and 3ya in 96% and >99%
Most gratifyingly, almost quantitative yield (>99%) was yield, respectively.
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Table 2 Substrate scope for alkenyl compounds 1a,b
Table 3 Substrate scope for α-haloamides 2a,b
a Unless otherwise noted, all reactions were carried out with
(0.2 mmol), 2a (0.24 mmol), K2CO3 (0.24 mmol) and 4 Å MS (100 mg)
in 2 mL of DCM at 35 °C for 24 h under air atmosphere. b Isolated
yields.
1
a Unless otherwise noted, all reactions were carried out with 1a
(0.2 mmol), 2 (0.24 mmol), K2CO3 (0.24 mmol) and 4 Å MS (100 mg) in
2 mL of DCM at 35 °C for 24 h under air atmosphere. b Isolated yields.
c The trans : cis value is determined by 1H NMR spectroscopy.
Encouraged by the feasibility of this domino sequence, we
next explored the scope of α-haloamides 2. As summarized in
Table 3, when N-OBn α-Cl acetamide 2b was applied to this
formal [3 + 2] cycloaddition procedure, the expected product
3aa also could be obtained in 71% yield. Unsubstituted
N-alkoxy α-Br acetamides 2c and 2d with different substituents
(methyl, 2-naphthylmethylene) on oxygen atom, both pro-
duced the desired products spirobarbiturate-pyrrolidinones
(3ac–3ad) in excellent yields. When N-Bn α-Br acetamide 2e
was used as the material, the reaction failed to give the corres-
Scheme 2 Putative aza-Michael addition/intramolecular SN2 reaction
pathway.
ponding product 3ae under standard conditions, perhaps in Scheme 2, under the promotion of base, the deprotonation
owing to the weaker acidity of 2e than 2a. When using N-OBn on the nitrogen atom of N-alkoxy α-haloamides 2 and the con-
α-Br amides 2f–2j with different substituents (Me, Et, n-Pr, comitant aza-Michael addition to imines 1 leading to inter-
n-Bu or Ph) on α-position, the spirobarbiturate-pyrrolidinones mediate A could occur. Next the following intramolecular SN2
were all readily obtained in excellent yields. The trans configur- substitution reaction will generate the desired spirobarbitu-
ation of the major isomer (3af) was confirmed by 1H-NMR rate-pyrrolidinones.
NOE analysis. As expected, the steric hindrance on α-position
To further illustrate the preparative utility of this [3 + 2]
of the α-substituted N-alkoxy α-bromo amides 2 plays a crucial cyclization, a 2 mmol scale reaction was carried out under the
role in the reaction and α,α-dimethyl substituted N-OBn α-Br standard conditions, giving the desired product 3aa in a com-
amide 2k did not work under standard conditions.
parable yield (Scheme 3, eqn (1)). Furthermore, deprotection
On the basis of previous report6 and the observed results, of the N-OBn of 3aa was also realized, generating N-OH com-
we speculate that the reaction might occur through a cascade pound 4 and N-H compound 5 in 99% yield and 58% yield
aza-Michael addition/intramolecular SN2 pathway. As depicted respectively (Scheme 3, eqn (2) and (3)).
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to an internal SiMe4 standard for 1H NMR, chloroform-d
(δ 77.16) for 13C NMR. Datas for 1H NMR are recorded as
follows: chemical shift (δ ppm), multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad),
coupling constant (Hz) and integration. Datas for 13C NMR
and 19F NMR are reported in terms of chemical shift (δ, ppm).
High-resolution mass spectra (HRMS) were recorded on a
Thermo Q-Exactive Spectrometer (ESI).
General procedures for [3 + 2] annulation reaction
In a 10 mL test tube was sequentially added barbiturate-
derived alkenes 1 (0.2 mmol, 1.0 equiv.), K2CO3 (0.24 mmol,
1.2 equiv.), N-Alkoxy α-haloamides 2 (0.24 mmol, 1.2 equiv.),
4 Å MS (100 mg) and DCM (2.0 mL) under air atmosphere.
Then the tube was sealed and stirred at 35 °C. Once the bar-
biturate-derived alkenes 1 was completed consumption (24 h),
the reaction mixture was concentrated under reduced pressure
and the resulting residue was purified by flash column chrom-
atography on silica gel to afford the pure products 3. (PE/EA =
3/2 for 3aa–3fa, 3ha, 3ja–3ka, 3na–3ra, 3ta–3wa, 3ab, 3ad;
PE/EA = 1/1 for 3ga, 3ia, 3ma, 3sa; PE/EA = 2/1 for 3la, 3xa, 3af;
PE/EA = 4/3 for 3ac; PE/EA = 3/1 for 3ag–3ai).
Scheme 3 2 mmol scale synthesis of 3aa and deprotections of 3aa.
Conclusions
In conclusion, barbiturate-derived alkenes and N-alkoxy
α-haloamides can undergo cascade aza-Michael/intra-
molecular nucleophilic substitution reaction to afford spiro-
barbiturate-pyrrolidinones in good to excellent yields. This
cascade [3 + 2] cyclization was successfully performed under
air atmosphere and mild conditions with excellent tolerance of
a wide range of functional groups. This system does not
require strong bases or fluorinated solvents for successful
cycloaddition, perhaps owing to the high acidity of N-alkoxy
α-haloamides. This method not only further expands the syn-
thetic utility of N-alkoxy α-haloamides, but also provides a
practical strategy for the synthesis of spirobarbiturate-pyrrol-
idinones. Futher synthetic application investigation of this
method is in progress.
2-(Benzyloxy)-7,9-dimethyl-1-phenyl-2,7,9-triazaspiro[4.5]
decane-3,6,8,10-tetraone (3aa). Purification by column
chromatography on silica gel afforded the title compound as
colorless oil. 81 mg, >99% yield. 1H NMR (400 MHz, CDCl3)
δ 7.42–7.27 (m, 6H), 7.22–7.20 (m, 2H), 6.99–6.98 (m, 2H), 5.14
(d, J = 10.8 Hz, 1H), 4.88 (d, J = 10.4 Hz, 1H), 4.39 (s, 1H), 3.29
(s, 3H), 3.23 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 16.8 Hz, 1H), 2.66
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 169.6, 168.5, 166.7,
150.2, 134.9, 132.3, 130.2, 129.8, 129.1, 129.0, 128.6, 127.3,
77.6, 71.1, 55.4, 32.7, 29.5, 28.7 ppm. HRMS (ESI) m/z Exact
mass calcd for C22H22N3O5 [M
408.1548.
+
H]+: 408.1554, found
2-(Benzyloxy)-1-(4-methoxyphenyl)-7,9-dimethyl-2,7,9-triazaspiro
[4.5]decane-3,6,8,10-tetraon (3ba). Purification by column
chromatography on silica gel afforded the title compound as
colorless oil. 85 mg, 98% yield. 1H NMR (400 MHz, CDCl3)
δ 7.33–7.27 (m, 3H), 7.22–7.20 (m, 2H), 6.91–6.84 (m, 4H), 5.10
(d, J = 10.8 Hz, 1H), 4.85 (d, J = 10.4 Hz, 1H), 4.33 (s, 1H), 3.80
Experimental
General information
All reactions were performed in oven-dried glassware with (s, 3H), 3.28 (s, 3H), 3.19 (d, J = 17.2 Hz, 1H), 3.11 (d, J =
magnetic stirring under air atmosphere. Unless otherwise 17.2 Hz, 1H), 2.72 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3)
stated, all reagents were purchased from commercial suppliers δ 169.4, 168.7, 166.8, 161.0, 150.4, 135.0, 129.9, 129.1, 128.7,
and used without further purification. All solvents were puri- 128.6, 123.9, 114.3, 77.6, 70.9, 55.5 (2C), 32.5, 29.5, 28.9 ppm.
fied and dried according to standard methods prior to use. HRMS (ESI) m/z Exact mass calcd for C23H24N3O6 [M + H]+:
Organic solutions were concentrated under reduced pressure 438.1660, found 438.1657.
on a rotary evaporator or an oil pump. Reactions were moni-
2-(Benzyloxy)-7,9-dimethyl-1-(p-tolyl)-2,7,9-triazaspiro[4.5]
tored through thin layer chromatography (TLC) on silica gel- decane-3,6,8,10-tetraone (3ca). Purification by column chrom-
precoated glass plates. Subsequent to elution, plates were visu- atography on silica gel afforded the title compound as color-
alized using UV radiation at 254 nm and by staining with less oil. 84 mg, >99% yield. 1H NMR (400 MHz, CDCl3)
aqueous potassium permanganate or ethanolic phosphomo- δ 7.33–7.27 (m, 3H), 7.23–7.20 (m, 2H), 7.16–7.14 (m, 2H),
lybdic acid solution. Flash column chromatography was per- 6.87–6.85 (m, 2H), 5.12 (d, J = 10.8 Hz, 1H), 4.87 (d, J =
formed using silica gel (300–400 mesh). Nuclear Magnetic 10.4 Hz, 1H), 4.33 (s, 1H), 3.28 (s, 3H), 3.20 (d, J = 16.8 Hz,
Resonance (NMR) spectras were acquired on a Varian Mercury 1H), 3.13 (d, J = 16.8 Hz, 1H), 2.69 (s, 3H), 2.35 (s, 3H) ppm.
400 operating at 400, 100 and 376 MHz for 1H, 13C and 19F, 13C NMR (100 MHz, CDCl3) δ 169.5, 168.6, 166.8, 150.3, 140.3,
respectively. Chemical shifts are reported in δ ppm referenced 134.9, 129.9, 129.6, 129.2, 129.1, 128.6, 127.2, 77.6, 71.0, 55.4,
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32.5, 29.5, 28.8, 21.4 ppm. HRMS (ESI) m/z Exact mass calcd 1H NMR (400 MHz, CDCl3) δ 7.60–7.58 (m, 2H), 7.36–7.29
for C23H24N3O5 [M + H]+: 422.1710, found 422.1702.
(m, 3H), 7.22–7.20 (m, 2H), 7.07–7.05 (m, 2H), 5.12 (d, J = 10.8
2-(Benzyloxy)-1-(4-fluorophenyl)-7,9-dimethyl-2,7,9-triazaspiro Hz, 1H), 4.90 (d, J = 10.8 Hz, 1H), 4.32 (s, 1H), 3.30 (s, 3H),
[4.5]decane-3,6,8,10-tetraone (3da). Purification by column 3.21 (d, J = 16.8 Hz, 1H), 3.14 (d, J = 16.8 Hz, 1H), 2.65 (s, 3H)
chromatography on silica gel afforded the title compound as ppm. 13C NMR (100 MHz, CDCl3) δ 169.1, 168.3, 166.4, 150.1,
white solid. mp 157–159 °C. 80 mg, 94% yield. 1H NMR 136.6, 134.8, 132.3 (q, J = 33.0 Hz, 1C), 129.9, 129.3, 128.8,
(400 MHz, CDCl3) δ 7.36–7.28 (m, 3H), 7.22–7.20 (m, 2H), 127.9, 125.8 (q, J = 3.3 Hz, 1C), 123.7 (q, J = 272.0 Hz, 1C), 77.6,
7.06–7.02 (m, 2H), 6.96–6.92 (m, 2H), 5.11 (d, J = 10.8 Hz, 1H), 70.3, 55.0, 32.8, 29.6, 28.7 ppm. 19F NMR (376 MHz, CDCl3)
4.87 (d, J = 10.8 Hz, 1H), 4.32 (s, 1H), 3.29 (s, 3H), 3.20 (d, J = δ −62.9 ppm. HRMS (ESI) m/z Exact mass calcd for C23H21F3N3O5
16.8 Hz, 1H), 3.12 (d, J = 16.8 Hz, 1H), 2.72 (s, 3H) ppm. [M + H]+: 476.1428, found 476.1417.
13C NMR (100 MHz, CDCl3) δ 169.2, 168.5, 166.6, 163.7 (d, J =
2-(Benzyloxy)-7,9-dimethyl-1-(4-nitrophenyl)-2,7,9-triazaspiro
249.0 Hz, 1C), 150.2, 134.9, 129.9, 129.3, 129.2 (d, J = 4.0 Hz, [4.5]decane-3,6,8,10-tetraone (3ia). Purification by column
1C), 128.7, 128.2 (d, J = 4.0 Hz, 1C), 116.1 (d, J = 22.0 Hz, 1C), chromatography on silica gel afforded the title compound as
77.6, 70.4, 55.2, 32.7, 29.5, 28.8 ppm. 19F NMR (376 MHz, white solid. mp 192–194 °C. 90 mg, >99% yield. 1H NMR
CDCl3) δ −110.0 ppm. HRMS (ESI) m/z Exact mass calcd for (400 MHz, CDCl3) δ 8.25–8.22 (m, 1H), 7.73–7.72 (m, 1H), 7.55
C22H21FN3O5 [M + H]+: 426.1460, found 426.1449.
(d, J = 8.0 Hz, 1H), 7.37–7.29 (m, 4H), 7.22–7.20 (m, 2H), 5.14
2-(Benzyloxy)-1-(4-chlorophenyl)-7,9-dimethyl-2,7,9-triazaspiro (d, J = 10.8 Hz, 1H), 4.92 (d, J = 11.2 Hz, 1H), 4.38 (s, 1H), 3.31
[4.5]decane-3,6,8,10-tetraone (3ea). Purification by column (s, 3H), 3.21 (d, J = 16.8 Hz, 1H), 3.14 (d, J = 17.2 Hz, 1H), 2.71
chromatography on silica gel afforded the title compound as (s, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) δ 168.5, 168.3,
white solid. mp 130–132 °C. 75 mg, 85% yield. 1H NMR 166.7, 150.5, 147.6, 136.0, 134.4, 133.8, 130.2, 129.2, 128.7,
(400 MHz, CDCl3) δ 7.37–7.28 (m, 5H), 7.22–7.20 (m, 2H), 128.3, 124.2, 122.0, 76.0, 65.7, 54.3, 32.5, 29.0, 28.1 ppm.
6.89–6.87 (m, 2H), 5.11 (d, J = 10.8 Hz, 1H), 4.87 (d, J = 10.8 HRMS (ESI) m/z Exact mass calcd for C22H21N4O7 [M + H]+:
Hz, 1H), 4.29 (s, 1H), 3.29 (s, 3H), 3.19 (d, J = 16.8 Hz, 1H), 453.1405, found 453.1365.
3.12 (d, J = 16.8 Hz, 1H), 2.72 (s, 3H) ppm. 13C NMR (100 MHz,
2-(Benzyloxy)-1-(3-methoxyphenyl)-7,9-dimethyl-2,7,9-tri-
CDCl3) δ 169.2, 168.4, 166.5, 150.2, 136.2, 134.8, 130.9, 129.9, azaspiro[4.5]decane-3,6,8,10-tetraone (3ja). Purification by
129.21, 129.19, 128.71, 128.69, 77.6, 70.3, 55.1, 32.6, 29.5, column chromatography on silica gel afforded the title com-
1
28.8 ppm. HRMS (ESI) m/z Exact mass calcd for C22H21ClN3O5 pound as colorless oil. 80 mg, 92% yield. H NMR (400 MHz,
[M + H]+: 442.1164, found 442.1157.
CDCl3) δ 7.35–7.23 (m, 6H), 7.95–6.92 (m, 1H), 6.57–6.55
2-(Benzyloxy)-1-(4-bromophenyl)-7,9-dimethyl-2,7,9-triazaspiro (m, 2H), 5.17 (d, J = 10.4 Hz, 1H), 4.91 (d, J = 10.8 Hz, 1H), 4.37
[4.5]decane-3,6,8,10-tetraone (3fa). Purification by column (s, 1H), 3.79 (s, 3H), 3.30 (s, 3H), 3.24 (d, J = 16.8 Hz, 1H), 3.13
chromatography on silica gel afforded the title compound as (d, J = 16.8 Hz, 1H), 2.73 (s, 3H) ppm. 13C NMR (100 MHz,
white solid. mp 138–140 °C. 97 mg, >99% yield. 1H NMR CDCl3) δ 169.7, 168.5, 166.7, 160.1, 150.3, 134.9, 133.9, 130.1,
(400 MHz, CDCl3) δ 7.48–7.46 (m, 2H), 7.35–7.28 (m, 3H), 129.8, 129.1, 128.7, 119.4, 115.9, 112.6, 77.6, 71.1, 55.5, 55.4,
7.23–7.20 (m, 2H), 6.83–6.81 (m, 2H), 5.11 (d, J = 10.8 Hz, 1H), 32.8, 29.5, 28.8 ppm. HRMS (ESI) m/z Exact mass calcd for
4.88 (d, J = 10.8 Hz, 1H), 4.26 (s, 1H), 3.29 (s, 3H), 3.19 (d, J = C23H24N3O6 [M + H]+: 438.1660, found 438.1654.
16.8 Hz, 1H), 3.12 (d, J = 16.8 Hz, 1H), 2.72 (s, 3H) ppm.
2-(Benzyloxy)-1-(3-fluorophenyl)-7,9-dimethyl-2,7,9-triazaspiro
13C NMR (100 MHz, CDCl3) δ 169.2, 168.4, 166.5, 150.2, 134.8, [4.5]decane-3,6,8,10-tetraone (3ka). Purification by column
132.2, 131.5, 129.9, 129.2, 129.0, 128.7, 124.4, 77.6, 70.4, 55.0, chromatography on silica gel afforded the title compound as
32.6, 29.6, 28.8 ppm. HRMS (ESI) m/z Exact mass calcd for white solid. mp 168–170 °C. 77 mg, 91% yield. 1H NMR
C22H21BrN3O5 [M + H]+: 486.0659, found 486.0655.
(400 MHz, CDCl3) δ 7.36–7.29 (m, 4H), 7.29–7.21 (m, 2H),
4-(2-(Benzyloxy)-7,9-dimethyl-3,6,8,10-tetraoxo-2,7,9-triazaspiro 7.11–7.07 (m, 1H), 6.74–6.70 (m, 2H), 5.14 (d, J = 10.4 Hz, 1H),
[4.5]decan-1-yl)benzonitrile (3ga). Purification by column 4.89 (d, J = 10.8 Hz, 1H), 4.33 (s, 1H), 3.29 (s, 3H), 3.20 (d, J =
chromatography on silica gel afforded the title compound as 16.8 Hz, 1H), 3.12 (d, J = 16.8 Hz, 1H), 2.74 (s, 3H) ppm.
white solid. mp 130–132 °C. 60 mg, 70% yield. 1H NMR 13C NMR (100 MHz, CDCl3) δ 169.5, 168.4, 166.5, 162.9 (d, J =
(400 MHz, CDCl3) δ 7.63–7.61 (m, 2H), 7.39–7.29 (m, 3H), 248.0 Hz, 1C), 150.2, 135.1 (d, J = 7.0 Hz, 1C), 134.8, 130.7 (d,
7.21–7.20 (m, 2H), 7.04–7.02 (m, 2H), 5.11 (d, J = 11.2 Hz, 1H), J = 9.0 Hz, 1C), 129.9, 129.2, 128.7, 123.0 (d, J = 3.0 Hz, 1C),
4.90 (d, J = 11.2 Hz, 1H), 4.28 (s, 1H), 3.30 (s, 3H), 3.19 (d, J = 117.3 (d, J = 21.0 Hz, 1C), 114.4 (d, J = 23.0 Hz, 1C), 77.7,
16.8 Hz, 1H), 3.13 (d, J = 16.8 Hz, 1H), 2.70 (s, 3H) ppm. 70.4, 55.1, 32.8, 29.5, 28.8 ppm. 19F NMR (376 MHz, CDCl3)
13C NMR (100 MHz, CDCl3) δ 169.0, 168.2, 166.2, 150.0, 137.8,
134.8, 132.5, 130.0, 129.4, 128.8, 128.2, 117.8, 114.1, 77.7, 70.1, C22H21FN3O5 [M + H]+: 426.1460, found 426.1450.
δ −110.8 ppm. HRMS (ESI) m/z Exact mass calcd for
54.8, 32.8, 29.6, 28.8 ppm. HRMS (ESI) m/z Exact mass calcd
2-(Benzyloxy)-1-(3-chlorophenyl)-7,9-dimethyl-2,7,9-triazaspiro
[4.5]decane-3,6,8,10-tetraone (3la). Purification by column
for C23H21N4O5 [M + H]+: 433.1506, found. 433.1498.
2-(Benzyloxy)-7,9-dimethyl-1-(4-(trifluoromethyl)phenyl)-2,7,9- chromatography on silica gel afforded the title compound as
triazaspiro[4.5]decane-3,6,8,10-tetraone (3ha). Purification by white solid. mp 162–164 °C. 77 mg, 88% yield. 1H NMR
column chromatography on silica gel afforded the title com- (400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 7.24–7.22 (m, 2H),
pound as white solid. mp 158–160 °C. 84 mg, 88% yield. 6.96–6.95 (m, 1H), 6.84–6.82 (m, 1H), 5.14 (d, J = 10.8 Hz, 1H),
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4.89 (d, J = 10.8 Hz, 1H), 4.28 (s, 1H), 3.29 (s, 3H), 3.19 (d, J = m/z Exact mass calcd for C22H21BrN3O5 [M + H]+: 486.0659,
16.8 Hz, 1H), 3.12 (d, J = 16.8 Hz, 1H), 2.75 (s, 3H) ppm. found 486.0652.
13C NMR (100 MHz, CDCl3) δ 169.4, 168.3, 166.4, 150.1, 135.2,
2-(Benzyloxy)-7,9-dimethyl-1-(2-(trifluoromethyl)phenyl)-
134.8, 134.6, 130.4, 130.2, 129.9, 129.2, 128.7, 127.4, 125.5, 2,7,9-triazaspiro[4.5]decane-3,6,8,10-tetraone (3qa). Purification
77.7, 70.4, 55.2, 32.7, 29.5, 28.8 ppm. HRMS (ESI) m/z Exact by column chromatography on silica gel afforded the title com-
mass calcd for C22H21ClN3O5 [M + H]+: 442.1164, found pound as white solid. mp 109–110 °C. 88 mg, 93% yield.
442.1154.
1H NMR (400 MHz, CDCl3) δ 7.66–7.58 (m, 2H), 7.51–7.44 (m,
2-(Benzyloxy)-7,9-dimethyl-1-(3-nitrophenyl)-2,7,9-triazaspiro 2H), 7.34–7.29 (m, 3H), 7.24–7.22 (m, 2H), 5.17 (s, 1H), 5.03 (d,
[4.5]decane-3,6,8,10-tetraone (3ma). Purification by column J = 10.8 Hz, 1H), 4.88 (d, J = 10.8 Hz, 1H), 3.32–3.28 (m, 4H),
chromatography on silica gel afforded the title compound as 3.10 (d, J = 16.8 Hz, 1H), 2.77 (s, 3H) ppm. 13C NMR (100 MHz,
colorless oil. 90 mg, >99% yield. 1H NMR (400 MHz, CDCl3) CDCl3) δ 168.9, 168.2, 166.7, 150.2, 134.2, 132.1, 131.0, 130.6,
δ 8.18–8.16 (m, 2H), 7.37–7.29 (m, 3H), 7.22–7.19 (m, 2H), 130.1, 129.8, 129.1, 128.7 (q, J = 30.3 Hz, 1C), 128.6, 126.5 (q,
7.13–7.11 (m, 2H), 5.09 (d, J = 11.2 Hz, 1H), 4.90 (d, J = 11.2 J = 5.7 Hz, 1C), 123.9 (q, J = 272.7 Hz, 1C), 77.3, 64.5, 54.0,
Hz, 1H), 4.38 (s, 1H), 3.31 (s, 3H), 3.19 (d, J = 17.2 Hz, 1H), 34.3, 29.4, 28.9 ppm. 19F NMR (376 MHz, CDCl3) δ −57.1 ppm.
3.14 (d, J = 16.8 Hz, 1H), 2.71 (s, 3H) ppm. 13C NMR (100 MHz, HRMS (ESI) m/z Exact mass calcd for C23H21F3N3O5 [M + H]+:
CDCl3) δ 168.9, 168.2, 166.1, 150.0, 148.9, 139.7, 134.8, 130.0, 476.1428, found 476.1422.
129.4, 128.8, 128.5 (2C), 124.0 (2C), 77.7, 69.8, 54.7, 32.9, 29.7,
28.9 ppm. HRMS (ESI) m/z Exact mass calcd for C22H21N4O7 [4.5]decane-3,6,8,10-tetraone (3ra). Purification by column
[M + H]+: 453.1405, found 453.1366.
chromatography on silica gel afforded the title compound as
2-(Benzyloxy)-7,9-dimethyl-1-(2-nitrophenyl)-2,7,9-triazaspiro
2-(Benzyloxy)-1-(2-methoxyphenyl)-7,9-dimethyl-2,7,9-triazaspiro white solid. mp 182–183 °C. 89 mg, 99% yield. 1H NMR
[4.5]decane-3,6,8,10-tetraone (3na). Purification by column (400 MHz, CDCl3) δ 7.90–7.87 (m, 1H), 7.64–7.60 (m, 1H),
chromatography on silica gel afforded the title compound as 7.47–7.43 (m, 1H), 7.39–7.37 (m, 1H), 7.27–7.17 (m, 3H),
colorless oil. 87 mg, >99% yield. 1H NMR (400 MHz, CDCl3) 7.13–7.11 (m, 2H), 4.99 (s, 1H), 4.931–4.930 (m, 2H), 3.28 (s,
δ 7.31–7.23 (m, 6H), 7.13–7.12 (m, 1H), 7.00–6.96 (m, 1H), 3H), 3.08 (d, J = 16.8 Hz, 1H), 2.87 (d, J = 16.8 Hz, 1H), 2.75 (s,
6.83–6.81 (m, 1H), 5.07 (d, J = 10.8 Hz, 1H), 5.02 (s, 1H), 4.94 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 169.7, 167.1, 167.0,
(d, J = 10.8 Hz, 1H), 3.66 (s, 3H), 3.28 (s, 3H), 3.19 (d, J = 16.8 150.4, 148.3, 134.7, 133.9, 131.3, 130.3, 129.51, 129.46, 129.3,
Hz, 1H), 3.11 (d, J = 16.8 Hz, 1H), 2.65 (s, 3H) ppm. 13C NMR 128.8, 125.2, 77.7, 64.5, 52.9, 36.0, 29.5, 28.9 ppm. HRMS (ESI)
(100 MHz, CDCl3) δ 169.2, 168.9, 167.0, 156.9, 150.8, 135.0, m/z Exact mass calcd for C22H21N4O7 [M + H]+: 453.1405,
130.8, 129.7, 128.90, 128.86, 128.6, 121.0, 120.6, 110.2, 77.3, found 453.1366.
63.5, 55.7, 54.2, 32.9, 29.4, 28.6 ppm. HRMS (ESI) m/z Exact
2-(Benzyloxy)-1-(2,4-dimethoxyphenyl)-7,9-dimethyl-2,7,9-
mass calcd for C23H24N3O6 [M
438.1654.
+
H]+: 438.1660, found triazaspiro[4.5]decane-3,6,8,10-tetraone (3sa). Purification
by column chromatography on silica gel afforded the title
2-(Benzyloxy)-7,9-dimethyl-1-(o-tolyl)-2,7,9-triazaspiro[4.5] compound as colorless oil. 79 mg, 85% yield. 1H NMR
decane-3,6,8,10-tetraone (3oa). Purification by column (400 MHz, CDCl3) δ 7.34–7.24 (m, 5H), 7.00 (d, J = 8.4 Hz,
chromatography on silica gel afforded the title compound as 1H), 6.48 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 6.36 (d, J = 2.0 Hz,
white solid. mp 162–163 °C. 84 mg, >99% yield. 1H NMR 1H), 5.03 (d, J = 10.8 Hz, 1H), 4.92 (d, J = 10.8 Hz, 1H), 4.89 (s,
(400 MHz, CDCl3) δ 7.34–7.28 (m, 3H), 7.25–7.20 (m, 4H), 1H), 3.80 (s, 3H), 3.63 (s, 3H), 3.27 (s, 3H), 3.18 (d, J =
7.18–7.15 (m, 1H), 7.12–7.10 (m, 1H), 5.16 (d, J = 10.8 Hz, 1H), 16.8 Hz, 1H), 3.07 (d, J = 16.8 Hz, 1H), 2.71 (s, 3H) ppm.
4.83 (d, J = 10.8 Hz, 1H), 4.79 (s, 1H), 3.25 (s, 3H), 3.23 (d, J = 13C NMR (100 MHz, CDCl3) δ 169.3, 168.7, 167.0, 161.8,
16.8 Hz, 1H), 3.16 (d, J = 16.8 Hz, 1H), 2.69 (s, 3H), 1.83 (s, 3H) 158.0, 150.9, 135.0, 129.76 (1C), 129.75 (2C), 128.8, 128.5,
ppm. 13C NMR (100 MHz, CDCl3) δ 169.4, 168.6, 166.9, 150.3, 112.7, 104.7, 98.2, 77.3, 63.4, 55.7, 55.6, 55.4, 32.5, 29.3,
136.0, 135.1, 131.2, 129.9, 129.8, 129.6, 129.1, 128.8, 127.8, 28.7 ppm. HRMS (ESI) m/z Exact mass calcd for C24H26N3O7
126.4, 77.6, 66.4, 55.0, 33.2, 29.5, 28.8, 18.2 ppm. HRMS (ESI) [M + H]+: 468.1765, found 468.1760.
m/z Exact mass calcd for C23H24N3O5 [M + H]+: 422.1710,
2-(Benzyloxy)-7,9-dimethyl-1-(naphthalen-1-yl)-2,7,9-triazaspiro
found 422.1701.
[4.5]decane-3,6,8,10-tetraone (3ta). Purification by column
2-(Benzyloxy)-1-(2-bromophenyl)-7,9-dimethyl-2,7,9-triazaspiro chromatography on silica gel afforded the title compound as
[4.5]decane-3,6,8,10-tetraone (3pa). Purification by column white solid. mp 183–185 °C. 91 mg, >99% yield. 1H NMR
chromatography on silica gel afforded the title compound as (400 MHz, CDCl3) δ 7.90–7.86 (m, 2H), 7.53–7.42 (m, 4H),
white solid. mp 169–171 °C. 97 mg, >99% yield. 1H NMR 7.34–7.31 (m, 1H), 7.24–7.20 (m, 4H), 7.10–7.08 (m, 1H), 5.37
(400 MHz, CDCl3) δ 7.51–7.49 (m, 1H), 7.37–7.32 (m, 4H), (s, 1H), 5.24 (d, J = 10.8 Hz, 1H), 4.95 (d, J = 10.8 Hz, 1H), 3.26
7.27–7.26 (m, 1H), 7.25–7.24 (m, 1H), 7.22–7.18 (m, 2H), 5.09 (d, J = 16.8 Hz, 1H), 3.14 (d, J = 16.8 Hz, 1H), 3.10 (s, 3H), 2.29
(d, J = 11.2 Hz, 1H), 5.05 (s, 1H), 4.90 (d, J = 11.2 Hz, 1H), 3.28 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 169.7, 168.7, 166.8,
(s, 3H), 3.20 (d, J = 16.4 Hz, 1H), 3.10 (d, J = 16.8 Hz, 1H), 2.75 149.7, 135.0, 133.8, 130.7, 130.2, 129.9, 129.6, 129.1, 128.8,
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 168.6, 168.4, 166.5, 127.1, 126.8, 126.2, 126.1, 125.3, 120.7, 77.4, 65.9, 55.4, 33.5,
150.4, 134.7, 133.3, 131.7, 131.3, 130.1, 129.8, 129.2, 128.9, 29.4, 28.3 ppm. HRMS (ESI) m/z Exact mass calcd for
127.9, 123.2, 77.5, 68.1, 54.1, 33.2, 29.6, 28.8 ppm. HRMS (ESI) C26H24N3O5 [M + H]+: 458.1710, found 458.1701.
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2-(Benzyloxy)-7,9-dimethyl-1-(naphthalen-2-yl)-2,7,9-triazaspiro solid. mp 167–170 °C. 75 mg, >99% yield. H NMR (400 MHz,
[4.5]decane-3,6,8,10-tetraone (3ua). Purification by column CDCl3) δ 7.40–7.34 (m, 5H), 4.99 (d, J = 11.2 Hz, 1H), 4.94 (d,
chromatography on silica gel afforded the title compound as J = 11.6 Hz, 1H), 3.28 (s, 3H), 3.25 (d, J = 2.4 Hz, 1H), 3.24 (s,
white solid. mp 112–114 °C. 91 mg, >99% yield. 1H NMR 3H), 3.18 (d, J = 16.8 Hz, 1H), 2.74 (d, J = 16.8 Hz, 1H),
(400 MHz, CDCl3) δ 7.85–7.78 (m, 3H), 7.56–7.51 (m, 2H), 1.66–1.59 (m, 1H), 0.98 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.8 Hz,
7.44–7.43 (m, 1H), 7.34–7.25 (m, 3H), 7.21–7.19 (m, 2H), 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 169.2, 167.8, 166.7,
7.05–7.03 (m, 1H), 5.15 (d, J = 10.8 Hz, 1H), 4.90 (d, J = 10.8 150.8, 135.1, 130.3, 129.1, 128.6, 77.5, 70.0, 53.2, 32.9, 31.8,
Hz, 1H), 4.52 (s, 1H), 3.31 (s, 3H), 3.25 (d, J = 16.8 Hz, 1H), 29.6, 29.5, 22.1, 16.9 ppm. HRMS (ESI) m/z Exact mass calcd
3.20 (d, J = 16.8 Hz, 1H), 2.51 (s, 3H) ppm. 13C NMR (100 MHz, for C19H24N3O5 [M + H]+: 374.1710, found 374.1699.
CDCl3) δ 169.5, 168.6, 166.7, 150.2, 134.9, 133.9, 133.0, 129.9,
2-Methoxy-7,9-dimethyl-1-phenyl-2,7,9-triazaspiro[4.5]decane-
129.7, 129.1, 128.9, 128.6, 128.1, 128.0, 127.4 (2C), 127.2, 3,6,8,10-tetraone (3ac). Purification by column chromatography
123.8, 77.7, 71.3, 55.4, 32.6, 29.5, 28.7 ppm. HRMS (ESI) m/z on silica gel afforded the title compound as colorless oil.
1
Exact mass calcd for C26H24N3O5 [M + H]+: 458.1710, found 66 mg, >99% yield. H NMR (400 MHz, CDCl3) δ 7.43–7.37 (m,
458.1701.
3H), 7.17–7.15 (m, 2H), 4.91 (s, 1H), 3.77 (s, 3H), 3.36 (s, 3H),
2-(Benzyloxy)-7,9-dimethyl-1-(thiophen-3-yl)-2,7,9-triazaspiro 3.28 (d, J = 17.2 Hz, 1H), 3.09 (d, J = 16.8 Hz, 1H), 2.69 (s, 3H)
[4.5]decane-3,6,8,10-tetraone (3va). Purification by column ppm. 13C NMR (100 MHz, CDCl3) δ 170.5, 168.5, 167.0, 150.2,
chromatography on silica gel afforded the title compound as 132.0, 130.2, 129.2, 127.0, 72.2, 55.6, 33.6, 29.6, 28.7 ppm.
white solid. mp 135–137 °C. 76 mg, 92% yield. 1H NMR HRMS (ESI) m/z Exact mass calcd for C16H18N3O5 [M + H]+:
(400 MHz, CDCl3) δ 7.36–7.27 (m, 4H), 7.22–7.19 (m, 2H), 332.1241, found 332.1269.
7.08–7.07 (m, 1H), 6.80–6.79 (m, 1H), 5.12 (d, J = 10.4 Hz, 1H),
7,9-Dimethyl-2-(naphthalen-2-ylmethoxy)-1-phenyl-2,7,9-tri-
4.85 (d, J = 10.4 Hz, 1H), 4.58 (s, 1H), 3.29 (s, 3H), 3.23 (d, J = azaspiro[4.5]decane-3,6,8,10-tetraone (3ad). Purification by
16.8 Hz, 1H), 3.10 (d, J = 16.8 Hz, 1H), 2.83 (s, 3H) ppm. column chromatography on silica gel afforded the title com-
13C NMR (100 MHz, CDCl3) δ 169.5, 168.5, 167.0, 150.3, 134.8, pound as white solid. mp 149–150 °C. 84 mg, 92% yield. 1H
133.8, 129.8, 129.1, 128.6, 127.4, 126.0, 125.4, 77.8, 66.9, 55.1, NMR (400 MHz, CDCl3) δ 7.85–7.71 (m, 4H), 7.54–7.49 (m, 2H),
33.0, 29.5, 29.0 ppm. HRMS (ESI) m/z Exact mass calcd for 7.43–7.31 (m, 4H), 7.00–6.97 (m, 2H), 5.32 (d, J = 10.8 Hz, 1H),
C20H20N3O5S [M + H]+: 414.1118, found 414.1110.
5.07 (d, J = 10.8 Hz, 1H), 4.35 (s, 1H), 3.24 (d, J = 17.2 Hz, 1H),
1-(Benzo[d][1,3]dioxol-5-yl)-2-(benzyloxy)-7,9-dimethyl-2,7,9- 3.19 (d, J = 16.8 Hz, 1H), 3.05 (s, 3H), 2.66 (s, 3H) ppm.
triazaspiro[4.5]decane-3,6,8,10-tetraone (3wa). Purification by 13C NMR (100 MHz, CDCl3) δ 169.6, 168.4, 166.5, 150.2, 133.5,
column chromatography on silica gel afforded the title com- 133.1, 132.3, 132.2, 130.2, 129.5, 128.9, 128.38, 128.35, 127.8,
pound as white solid. mp 166–168 °C. 84 mg, 93% yield. 127.3, 126.9, 126.8, 126.5, 77.9, 71.0, 55.2, 32.3, 29.2,
1H NMR (400 MHz, CDCl3) δ 7.36–7.28 (m, 3H), 7.25–7.23 (m, 28.7 ppm. HRMS (ESI) m/z Exact mass calcd for C26H24N3O5
2H), 6.74 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 1.6 Hz, 1H), 6.38 (dd, [M + H]+: 458.1710, found 458.1701.
J = 8.0 Hz, J = 1.6 Hz, 1H), 5.99 (s, 2H), 5.11 (d, J = 10.8 Hz,
2-(Benzyloxy)-4,7,9-trimethyl-1-phenyl-2,7,9-triazaspiro[4.5]
1H), 4.88 (d, J = 10.8 Hz, 1H), 4.26 (s, 1H), 3.27 (s, 3H), 3.17 decane-3,6,8,10-tetraone (trans-3af). Purification by column
(d, J = 16.8 Hz, 1H), 3.11 (d, J = 17.2 Hz, 1H), 2.81 (s, 3H) ppm. chromatography on silica gel afforded the title compound as
13C NMR (100 MHz, CDCl3) δ 169.5, 168.5, 166.7, 150.4, 149.2, white solid. 54 mg, 64% yield. mp 205–207 °C. 1H NMR
148.4, 134.9, 129.9, 129.1, 128.6, 125.8, 121.4, 108.5, 107.3, (400 MHz, CDCl3) δ 7.36–7.29 (m, 8H), 6.92–6.90 (m, 2H), 5.03
101.8, 77.6, 71.0, 55.4, 32.5, 29.5, 29.0 ppm. HRMS (ESI) m/z (d, J = 11.6 Hz, 1H), 4.98 (d, J = 11.6 Hz, 1H), 4.28 (s, 1H), 3.60
Exact mass calcd for C23H22N3O7 [M + H]+: 452.1452, found (q, J = 7.1 Hz, 1H), 3.29 (s, 3H), 2.89 (s, 3H), 1.25 (d, J = 7.2 Hz,
453.1444.
3H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.7, 167.0, 165.4,
2-(Benzyloxy)-1-cyclohexyl-7,9-dimethyl-2,7,9-triazaspiro[4.5] 150.6, 135.4, 132.5, 129.90, 129.88, 129.01, 128.97, 128.5,
decane-3,6,8,10-tetraone (3xa). Purification by column chrom- 127.1, 78.0, 69.0, 60.0, 36.4, 29.1, 9.7, 1.1 ppm. HRMS (ESI)
atography on silica gel afforded the title compound as white m/z Exact mass calcd for C23H24N3O5 [M + H]+: 422.1710,
1
solid. mp 168–170 °C. 80 mg, 96% yield. H NMR (400 MHz, found 422.1706.
CDCl3) δ 7.40–7.34 (m, 5H), 4.98 (d, J = 11.6 Hz, 1H), 4.93 (d,
2-(Benzyloxy)-4,7,9-trimethyl-1-phenyl-2,7,9-triazaspiro[4.5]
J = 11.6 Hz, 1H), 3.28 (s, 3H), 3.21 (s, 3H), 3.18 (d, J = 16.8 Hz, decane-3,6,8,10-tetraone (cis-3af). Purification by column
1H), 3.12 (d, J = 1.6 Hz, 1H), 2.73 (d, J = 16.8 Hz, 1H), 1.73–1.71 chromatography on silica gel afforded the title compound as
(m, 3H), 1.59–1.56 (m, 3H), 1.25–1.20 (m, 1H), 1.10–1.03 (m, white solid. 30 mg, 36% yield. mp 119–120 °C. 1H NMR
4H) ppm. 13C NMR (100 MHz, CDCl3) δ 169.1, 167.7, 166.7, (400 MHz, CDCl3) δ 7.40–7.25 (m, 6H), 7.20–7.18 (m, 2H),
150.8, 135.2, 130.3, 129.0, 128.5, 77.5, 69.7, 53.4, 42.3, 33.0, 7.06–7.04 (m, 2H), 5.23 (d, J = 10.0 Hz, 1H), 4.91 (d, J =
32.2, 29.53, 29.49, 27.6, 27.2, 26.1, 25.8 ppm. HRMS (ESI) m/z 10.0 Hz, 1H), 4.64 (s, 1H), 3.55 (q, J = 7.0 Hz, 1H), 3.28 (s, 3H),
Exact mass calcd for C22H28N3O5 [M + H]+: 414.2023, found 2.76 (s, 3H), 1.24 (d, J = 6.8 Hz, 3H) ppm. 13C NMR (100 MHz,
414.2018.
CDCl3) δ 172.7, 167.9, 164.8, 149.9, 134.9, 131.9, 130.1, 129.7,
2-(Benzyloxy)-1-isopropyl-7,9-dimethyl-2,7,9-triazaspiro[4.5] 129.1, 128.9, 128.6, 127.3, 70.9, 61.8, 41.2, 29.4, 28.3, 10.1,
decane-3,6,8,10-tetraone (3ya). Purification by column chrom- 1.2 ppm. HRMS (ESI) m/z Exact mass calcd for C23H24N3O5
atography on silica gel afforded the title compound as white [M + H]+: 422.1710, found 422.1701.
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2-(Benzyloxy)-4-ethyl-7,9-dimethyl-1-phenyl-2,7,9-triazaspiro was concentrated in vacuo to yield the pure product 4 as a pale
1
[4.5]decane-3,6,8,10-tetraone (trans-3ag). Purification by white powder (63 mg, 99% yield). H NMR (400 MHz, CDCl3)
column chromatography on silica gel afforded the title com- δ 9.36 (s, 1H), 7.42–7.40 (m, 3H), 7.17–7.15 (m, 2H), 5.05 (s,
pound as white solid. mp 155–157 °C. 86 mg, >99% yield. 1H), 3.44 (d, J = 16.8 Hz, 1H), 3.39 (s, 3H), 3.15 (d, J = 16.8 Hz,
1H NMR (400 MHz, CDCl3) δ 7.36–7.29 (m, 8H), 6.91–6.89 (m, 1H), 2.64 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.5,
2H), 5.02 (d, J = 11.2 Hz, 1H), 4.98 (d, J = 11.2 Hz, 1H), 4.23 (s, 168.5, 167.0, 150.2, 132.0, 130.2, 129.2, 127.0, 72.2, 55.6,
1H), 3.56–3.52 (m, 1H), 3.31 (s, 3H), 2.88 (s, 3H), 2.17–2.10 (m, 33.6, 29.6, 28.7 ppm. HRMS (ESI) m/z Exact mass calcd for
1H), 1.69–1.62 (m, 1H), 0.80 (t, J = 7.6 Hz, 3H) ppm. 13C NMR C15H14N3O5 [M − H]−: 316.0939, found 316.0915.
(100 MHz, CDCl3) δ 170.5, 167.1, 165.8, 150.7, 135.4, 132.7,
General procedures for the synthesis of 5
129.9 (3C), 128.99, 128.95, 128.5, 127.2, 78.0, 69.2, 58.3, 42.9,
29.1, 19.0, 12.5, 1.1 ppm. HRMS (ESI) m/z Exact mass calcd for Compound 3aa (0.2 mmol, 1.0 equiv.) was dissolved in THF
C24H26N3O5 [M + H]+: 436.1867, found 436.1842.
(2 mL) and then Ni (6 mg) was added. The reaction mixture
2-(Benzyloxy)-7,9-dimethyl-1-phenyl-4-propyl-2,7,9-triazaspiro was stirred under H2 atmosphere for 12 h at room tempera-
[4.5]decane-3,6,8,10-tetraone (trans-3ah). Purification by ture. After filtration through a Celite pad, the crude product
column chromatography on silica gel afforded the title com- was purified by flash chromatography to yield the pure
pound as white solid. mp 132–135 °C. 85 mg, 95% yield. 1H product 5 as a white powder (35 mg, 58% yield). 1H NMR
NMR (400 MHz, CDCl3) δ 7.36–7.29 (m, 8H), 6.91–6.89 (m, 2H), (400 MHz, CDCl3) δ 7.38–7.37 (m, 3H), 7.15–7.14 (m, 2H),
5.02 (d, J = 11.2 Hz, 1H), 4.98 (d, J = 11.2 Hz, 1H), 4.22 (s, 1H), 6.66 (s, 1H), 5.04 (s, 1H), 3.40 (d, J = 16.8 Hz, 1H), 3.36 (s,
3.61–3.58 (m, 1H), 3.30 (s, 3H), 2.87 (s, 3H), 2.09–2.00 (m, 1H), 3H), 2.95 (d, J = 16.8 Hz, 1H), 2.64 (s, 3H) ppm. 13C NMR
1.59–1.51 (m, 1H), 1.35–1.30 (m, 1H), 1.04–0.96 (m, 1H), 0.86 (100 MHz, CDCl3) δ 175.1, 168.8, 167.5, 150.3, 134.3, 130.3,
(t, J = 7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.6, 129.3, 126.1, 67.9, 60.2, 37.2, 29.4, 28.4 ppm. HRMS (ESI) m/z
167.1, 165.9, 150.7, 135.4, 132.7, 129.92, 129.89, 128.98, Exact mass calcd for C15H16N3O4 [M + H]+: 302.1135, found
128.94, 128.5, 127.2, 78.0, 69.2, 58.6, 41.3, 29.2, 29.1, 27.9, 302.1129.
21.3, 14.1 ppm. HRMS (ESI) m/z Exact mass calcd for
C25H28N3O5 [M + H]+: 450.2023, found 450.1999.
2-(Benzyloxy)-4-butyl-7,9-dimethyl-1-phenyl-2,7,9-triazaspiro Conflicts of interest
[4.5]decane-3,6,8,10-tetraone (trans-3ai). Purification by
column chromatography on silica gel afforded the title com-
There are no conflicts to declare.
pound as white solid. mp 197–198 °C. 72 mg, 78% yield.
1H NMR (400 MHz, CDCl3) δ 7.38–7.29 (m, 8H), 6.91–6.89 (m,
2H), 5.02 (d, J = 11.2 Hz, 1H), 4.98 (d, J = 11.6 Hz, 1H), 4.23 (s,
Acknowledgements
1H), 3.60–3.56 (m, 1H), 3.30 (s, 3H), 2.88 (s, 3H), 2.12–2.03 (m,
We are grateful for financial support from the doctoral
research startup fund of Henan University of Animal
Husbandry and Economy (No 24030093), the China
Postdoctoral Science Foundation (No 2016M592301) and the
Key Scientific Research Project of Colleges and Universities in
Henan Province (No 17A150021, 20B150007). We acknowledge
Prof. Chen-Guo Feng (SIOC) for his help in the preparation of
this manuscript.
1H), 1.62–1.53 (m, 1H), 1.31–1.23 (m, 3H), 0.95–0.90 (m, 1H),
0.82 (t, J = 3.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3)
δ 170.6, 167.1, 165.7, 150.7, 135.4, 132.7, 129.91, 129.88, 129.0,
128.9, 128.5, 127.2, 78.0, 69.1, 58.6, 41.4, 30.0, 29.2, 29.1,
25.4, 22.6, 13.8 ppm. HRMS (ESI) m/z Exact mass calcd for
C26H30N3O5 [M + H]+: 464.2180, found 464.2157.
2-(Benzyloxy)-7,9-dimethyl-1,4-diphenyl-2,7,9-triazaspiro[4.5]
decane-3,6,8,10-tetraone (trans-3aj). Purification by column
chromatography on silica gel afforded the title compound as
white solid. mp 207–209 °C. 74 mg, 77% yield. 1H NMR
Notes and references
(400 MHz, CDCl3) δ 7.38–7.27 (m, 11H), 7.25–7.24 (m, 2H),
7.16–7.14 (m, 2H), 5.35 (d, J = 10.0 Hz, 1H), 5.00 (d, J = 10.0 1 (a) D. B. Ramachary, Y. V. Reddy, A. Banerjee and
Hz, 1H), 4.93 (s, 1H), 4.88 (s, 1H), 3.31 (s, 3H), 3.56 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ 170.6, 168.2, 164.1, 149.6,
134.8, 132.2, 132.0, 130.0, 129.9, 129.7, 129.1, 128.9, 128.7,
128.4, 127.5, 77.5, 70.0, 63.5, 51.7, 29.5, 28.2 ppm. HRMS (ESI)
m/z Exact mass calcd for C28H26N3O5 [M + H]+: 484.1867,
found 484.1861.
S. Banerjee, Org. Biomol. Chem., 2011, 9, 7282;
(b) G. M. Ziarani, S. Asadi, S. Faramarzi and M. Amanlou,
Iran. J. Pharm. Res., 2015, 14, 1105; (c) S. Kesharwani,
N. K. Sahu and D. V. Kohli, Pharm. Chem. J., 2009, 43, 315;
(d) R. K. Bhaskarachar, V. G. Revanasiddappa, S. Hegde,
J. P. Balakrishna and S. Y. Reddy, Med. Chem. Res., 2015, 24,
3516; (e) J. J. W. Duan, L. Chen, Z. Lu, B. Jiang, N. Asakawa,
J. E. Sheppeck II, R.-Q. Liu, M. B. Covington, W. Pitts,
S.-H. Kim and C. P. Decicco, Bioorg. Med. Chem. Lett., 2007,
17, 266; (f) V. N. Ingle, P. K. Gaidhane, S. S. Dutta,
P. P. Naha and M. S. Sengupta, J. Carbohydr. Chem., 2006,
25, 661.
General procedures for the synthesis of 49
Compound 3aa (0.2 mmol, 1.0 equiv.) was dissolved in MeOH
(2 mL) and then 10% Pd/C (6 mg) was added. The reaction
mixture was stirred under H2 atmosphere for 4 h at room
temperature. After filtration through a Celite pad, the filtrate
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2 (a) Y. Liu, W. Yang, Y. Wu, B. Mao, X. Gao, H. Liu, Z. Sun, 5 (a) S.-H. Kim, A. T. Pudzianowski, K. J. Leavitt, J. Barbosa,
Y. Xiao and H. Guo, Adv. Synth. Catal., 2016, 358, 2867;
(b) H. Liu, Y. Liu, C. Yuang, G.-P. Wang, S.-F. Zhu, Y. Wu,
B. Wang, Z. Sun, Y. Xiao, Q.-L. Zhou and H. Guo, Org. Lett.,
2016, 18, 1302; (c) X. Gao, Z. Li, W. Yang, Y. Liu, W. Chen,
P. A. McDonnell, W. J. Metzler, B. M. Rankin, R. Liu,
W. Vaccaro and W. Pitts, Bioorg. Med. Chem. Lett., 2005, 15,
1101; (b) J. Duan, B. Jiang, L. Cheng, Z. Lu, J. Barbosa and
W. Pitts, US WO03053941A2, 2003.
C. Zhang, L. Zheng and H. Guo, Org. Biomol. Chem., 2017, 6 J. Zhou, H. Zhang, X.-L. Chen, Y.-L. Qu, Q. Zhu, C.-G. Feng
15, 5298; (d) Y. Zhu, S. Zhao, M. Zhang, X. Song and and Y.-J. Chen, J. Org. Chem., 2019, 84, 9179.
J. Chang, Synthesis, 2019, 51, 899; (e) A. S. Girgis, H. Farag, 7 (a) S. Comesse, M. Sanselme and A. Daïch, J. Org. Chem.,
N. S. M. Ismail and R. F. George, Eur. J. Med. Chem., 2011,
46, 4964; (f) H.-W. Zhao, T. Tian, B. Li, Z. Yang, H.-L. Pang,
X.-Q. Song and X.-Q. Chen, J. Org. Chem., 2015, 80, 10380;
(g) H.-W. Zhao, T. Tiang, H.-L. Pang, B. Li, X.-Q. Chen,
Z. Yang, W. Meng, X.-Q. Song, Y.-D. Zhao and Y.-Y. Liu, Adv.
Synth. Catal., 2016, 358, 2619; (h) E. Soleimani and
H. Yazdani, Tetrahedron Lett., 2015, 56, 1635; (i) S. Nagaraju,
K. Sathish, B. Paplal and D. Kashinath, Tetrahedron Lett.,
2017, 58, 2865; ( j) K. A. Krasnov, P. V. Dorovatovskii,
2008, 73, 5566; (b) Y. Zhang, H. Ma, X. Liu, X. Cui, S. Wang,
Z. Zhan, J. Pu and G. Huang, Org. Biomol. Chem., 2018, 16,
4439; (c) M. K. Ghorai and D. P. Tiwari, J. Org. Chem., 2010,
75, 6173; (d) S. Sternativo, B. Battistelli, L. Bagnoli, C. Santi,
L. Testaferri and F. Marini, Tetrahedron Lett., 2013, 54, 6755;
(e) N. M. Leonard and K. A. Woerpel, J. Org. Chem., 2009, 74,
6915; (f) I. Allous, S. Comesse, M. Sanselme and A. Daïch,
Eur. J. Org. Chem., 2011, 5303; (g) A. El Bouakher, A. Martel
and S. Comesse, Org. Biomol. Chem., 2019, 17, 8467.
Y. V. Zubavichus, T. V. Timofeeva and V. N. Khrustalev, 8 (a) D. Ji and J. Sun, Org. Lett., 2018, 20, 2745; (b) C. Li,
Tetrahedron, 2017, 73, 542; (k) Z. Huang, Q. Zhao, G. Chen,
H. Wang, W. Lin, L. Xu, H. Liu, J. Wang, D. Shi and Y. Wang,
Molecules, 2012, 17, 12704; (l) Y. Hu and D.-Q. Shi,
J. Heterocycl. Chem., 2013, 50, E121; (m) A. N. Vereshchagin,
M. N. Elinson, E. O. Dorofeeva, T. A. Zaimovskaya,
N. O. Stepanov, S. V. Gorbunov, P. A. Belyakov and
G. I. Nikishin, Tetrahedron, 2012, 68, 1198.
3 (a) S. Kotha and G. Sreevani, Synthesis, 2018, 50, 4883;
(b) S. Zhang, Z. Shi, W. Cao, T. Gao and H. Deng, J. Chem.
Res., 2009, 381; (c) P. Singh and K. Paul, J. Heterocycl. Chem.,
2006, 43, 607; (d) K. Mori, S. Sueoka and T. Akiyama, Chem.
Lett., 2011, 40, 1386; (e) L. L. Gozalishvili, T. V. Beryozkina,
I. V. Omelchenko, R. I. Zubatyuk, O. V. Shishkin and
N. N. Kolos, Tetrahedron, 2008, 64, 8759.
4 (a) M. W. Cappi, W.-P. Chen, R. W. Flood, Y.-W. Liao,
S. M. Roberts, J. Skidmore, J. A. Smith and
N. M. Williamson, Chem. Commun., 1998, 10, 1159;
(b) K. Takahashi, M. Midori, K. Kawano, J. Ishihara and
S. Hatakeyama, Angew. Chem., Int. Ed., 2008, 47, 6244;
(c) A. Enz, D. Feuerbach, M. U. Frederiksen, C. Gentsch,
K. Hurth, W. Müller, J. Nozulak and B. L. Roy, Bioorg. Med.
Chem. Lett., 2009, 19, 1287; (d) R. D. Long and K. D. Moeller,
J. Am. Chem. Soc., 1997, 119, 12394; (e) C. C. Musonda,
K. Jiang, Q. Ouyang, T.-Y. Liu and Y.-C. Chen, Org. Lett.,
2016, 18, 2738; (c) O. Eyicim, S. Issever, N. Ocal, S. Gronert
and I. Erden, Tetrahedron Lett., 2018, 59, 3674;
(d) C. S. Jeffrey, K. L. Barnes, J. A. Eickhoff and C. R. Carson,
J. Am. Chem. Soc., 2011, 133, 7688; (e) R. Singh, K. Nagesh,
D. Yugandhar and A. V. G. Prasanthi, Org. Lett., 2018, 20,
4848; (f) H.-W. Zhao, Y.-D. Zhao, Y.-Y. Liu, L.-J. Zhao,
X.-Q. Song, X.-Q. Chen, H.-L. Pang, J. Du and N.-N. Feng,
RSC Adv., 2017, 7, 55106; (g) J. Xuan, X. Cao and X. Cheng,
Chem. Commun., 2018, 54, 5154; (h) K. Zhang, X. Xu,
J. Zheng, H. Yao, Y. Huang and A. Lin, Org. Lett., 2017, 19,
2596; (i) Q. Jia, D. Li, M. Lang, K. Zhang and J. Wang, Adv.
Synth. Catal., 2017, 359, 3837; ( j) M. C. DiPoto and J. Wu,
Org. Lett., 2018, 20, 499; (k) H.-W. Zhao, Y.-D. Zhao, Y.-Y. Liu,
L.-J. Zhao, N.-N. Feng, H.-L. Pang, X.-Q. Chen, X.-Q. Song
and J. Du, RSC Adv., 2017, 7, 12916; (l) A. Acharya,
D. Anumandla and C. S. Jeffrey, J. Am. Chem. Soc., 2015, 137,
14858; (m) A. Acharya, J. A. Eickhoff, K. Chen, V. J. Catalano
and C. S. Jeffrey, Org. Chem. Front., 2016, 3, 330;
(n) A. Acharya, K. Montes and C. S. Jeffrey, Org. Lett., 2016,
18, 6082; (o) H.-W. Zhao, Y.-D. Zhao, Y.-Y. Liu, J. Du,
H.-L. Pang, X.-Q. Chen, X.-Q. Song and N.-N. Feng,
Eur. J. Org. Chem., 2017, 3466.
J. Gut, P. J. Rosenthal, V. Yardley, R. C. Carvalho de Souza 9 A. Tutov, O. Bakulina, D. Darin and M. Krasavin,
and K. Chibale, Bioorg. Med. Chem., 2006, 14, 5605. Tetrahedron Lett., 2018, 59, 1511.
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