Rapid access to 10-(Cyclohexylimino)-7,9-diazaspiro[45]decane-6,8-dione derivatives for HIV-1 reverse transcriptase inhibition via ruthenium-catalyzed ring-closing metathesis

Article abstract of DOI:10.1055/s-0033-1339179

HIV-1 reverse transcriptase, a multifunctional enzyme critical in the viral replication process, is an important target for suppression of virus spread. To date, there has been considerable effort to develop drugs against this enzyme with high activity and specificity, notably TNK-651 and its derivatives. In order to further improve the efficacy and to explore the structure-activity relationship, we have introduced the diazaspiro[4.5]decane-6,8-dione scaffold, with both a pyrimidine and an alicyclic ring, and have synthesized several new compounds in this class. Appreciable overall yield was achieved with minimized purification of the intermediates. Several compounds were tested against HIV-1 reverse transcriptase in vitro using nevirapine as a reference. One compound showed potent inhibitory activity, with an IC₅₀ value (ca. 1.65 μM) comparable to that of nevirapine. Our synthetic method provides a rapid access to compounds in this class. Thus, many other similar compounds can be further studied in a timely and cost-effective manner. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339179

PAPER
▌2273
paper
Rapid Access to 10-(Cyclohexylimino)-7,9-diazaspiro[4.5]decane-6,8-dione
Derivatives for HIV-1 Reverse Transcriptase Inhibition via Ruthenium-
Catalyzed Ring-Closing Metathesis
10-(Cyclohexylimino)-7,9-diazaspiro[4.5]decane-6,8-diones
Tongbo Zhang,a Shaotong Wu,a Yuanyuan Cao,a Yuhong Fu,a Ying Guo,a Liang Zhang,a Li Li,a Han Zhou,a
Xiangyi Liu,a Chao Li,a Xiaowan Tang,a Zhili Zhang,a Chao Tian,a Xiaowei Wang,*a Junyi Liu*a,b
a
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. of China
E-mail: xiaoweiwang@bjmu.edu.cn
b
The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, P. R. of China
Fax +86(10)82805203; E-mail: jyliu@bjmu.edu.cn
Received: 31.03.2013; Accepted after revision: 07.05.2013
propyl group at the C-5 position, since it may possess the
Abstract: HIV-1 reverse transcriptase, a multifunctional enzyme
same perpendicular configuration in space.
critical in the viral replication process, is an important target for
suppression of virus spread. To date, there has been considerable ef-
O
O
fort to develop drugs against this enzyme with high activity and
specificity, notably TNK-651 and its derivatives. In order to further
improve the efficacy and to explore the structure–activity relation-
ship, we have introduced the diazaspiro[4.5]decane-6,8-dione scaf-
fold, with both a pyrimidine and an alicyclic ring, and have
synthesized several new compounds in this class. Appreciable over-
all yield was achieved with minimized purification of the interme-
diates. Several compounds were tested against HIV-1 reverse
transcriptase in vitro using nevirapine as a reference. One com-
pound showed potent inhibitory activity, with an IC50 value (ca.
1.65 μM) comparable to that of nevirapine. Our synthetic method
provides a rapid access to compounds in this class. Thus, many
other similar compounds can be further studied in a timely and cost-
effective manner.
HN3
O
HN3
O
5
5
1
N
1
N
6
O
S
6
O
Ph
Ph
TNK-651
TNK-6132
3
3
O
O
5
5
HN7
HN7
1
9
9
1
O
N
N
Key words: heterocycles, olefination, antiviral agents, HIV, ring
O
N
N
closure, NNRTIs
O
R
O
R
1
2
Reverse transcriptase (RT) of human immunodeficiency
virus type 1 (HIV-1) is a multifunctional enzyme that is
crucial for HIV replication. Since identified, this enzyme
has been one of the most attractive targets in anti-HIV-1
drug development. Nowadays, non-nucleoside RT inhibi-
tors (NNRTIs) with unique antiviral potency and low tox-
icity are widely used in the clinic and have proven
effective in stopping HIV-1 replication. However, pa-
tients treated with NNRTIs are often found to develop
drug resistance very rapidly. Therefore, new NNRTIs
with novel scaffolds need to be developed in order to com-
bat this severe drug resistance. Among more than 50 dif-
ferent series of NNRTIs that have been reported so far,
TNK-651 and its derivative TNK-61321 (Figure 1) have
attracted our attention because of their unique scaffold, in
particular the isopropyl group at the C-5 position. Previ-
ous work has indicated that a bulky hydrophobic group
like isopropyl is needed in this class of compounds for the
activity against RT. We wondered if an alicyclic structure
such as spirocyclopentyl could be used to replace the iso-
R = Me, Et, Bn
target compounds
Figure 1 Structures of the target compounds
Compounds based on an azaspiro scaffold, as an impor-
tant class of new structures, have shown inhibitory effects
on many important biological targets including glycogen
phosphorylase,2 the NK1 receptor,3 glycine transporter 1
(GlyT1),4 aldose reductase5 and neuronal nicotinic acetyl-
choline receptors.6 However, the synthesis of such sys-
tems is not an easy task due to the lack of effective and
general methods to set up the center quaternary carbon
(Figure 1). In order to synthesize the 10-(cyclohexylimi-
no)-7,9-diazaspiro[4.5]dec-2-ene-6,8-diones 1 and 10-
(cyclohexylimino)-7,9-diazaspiro[4.5]decane-6,8-diones
2, a conventional route is described (Scheme 1) with ru-
thenium-catalyzed ring-closing metathesis (RCM) as the
key synthetic step.
Based on the structure–activity relationship studies of
NNRTIs, the conformational flexibility of compounds is
an important parameter for potency toward viral mutant
strains. For example, replacement of the C-6 aromatic
moiety of TNK-651 by a cyclohexylthio group resulted in
SYNTHESIS 2013, 45, 2273–2279
Advanced online publication: 25.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339179; Art ID: SS-2013-H0256-OP
© Georg Thieme Verlag Stuttgart · New York

2274
T. Zhang et al.
PAPER
TNK-6132 (Figure 1), which has an improved activity according to a previous report.9 Compound 3 was refluxed
against drug-resistant HIV-1 mutants. The rationalization with 2 M aqueous sodium hydroxide (4 equiv) overnight
has been that the cyclohexyl moiety, which possesses to afford 5-allyl-6-chlorouracil (4) in good yield (80%).
more conformational flexibility than the aromatic ring, For the subsequent alkylation step, we first tried to use
could fit into the binding pocket of HIV-1 RT more tight- chloromethyl ethers to install the N-substitution at posi-
ly.1 In accordance with the literature, we thought that a tion 1. Compound 4 was stirred with alkyl chloromethyl
spiro five-membered ring as the 5-substituent in the uracil ethers in N,N-dimethylformamide at room temperature for
ring could influence the conformation of an adjacent cy- 12 hours, using K2CO3 (or Cs2CO3) as base; however, in-
clohexylimino group (Figure 1) and affect the binding af- stead of the expected products, the corresponding N1,N3-
finity with HIV-1 RT.7 In addition, the introduction of the dialkyl derivatives were obtained. In order to improve the
cyclohexyl group at the imine position, with a better con- selectivity of the N-1 position, uracil 4 was silylated using
formational flexibility than an aromatic ring, would result N,O-bis(trimethylsilyl)acetamide (BSA) in N,N-dimeth-
in an efficient binding to mutant RT to improve the activ- ylformamide at room temperature and subsequently alkyl-
ity against HIV mutant strains.1,8
ated with the corresponding alkyl chloromethyl ethers to
give the desired 1-alkylated 5-allyl-6-chlorouracils 5 in
41–85% yield.10 Cyclohexylamine was then used both as
nucleophile and base to substitute the chloro group, fur-
nishing the key intermediate 5-allyl-6-(cyclohexylami-
no)pyrimidine derivatives 6 in good yield (80–85%).
Accordingly, several compounds based on the azaspiro
scaffold with two basic structures, 1 and 2, were designed
(Figure 1), and a synthetic route planned in such a way
that rapid medicinal chemistry optimization can be easily
made after the initial lead identification (Scheme 1).
In a subsequent alkylation reaction, the 4-O-alkylated by-
product was obtained when N-3 was not protected. We
concluded that it was necessary to introduce a protecting
group at N-3 before substitution at the C-5 position of
compounds 6 to avoid isomerization of the pyrimidine
ring. Of all the protecting groups that we have tried, only
the benzoyl group provided a satisfactory deprotection
yield without affecting other functional groups in this ex-
perimental setting. Protection was accomplished by stir-
ring the intermediates 6 with benzoyl chloride (1.2 equiv)
and triethylamine (1.2 equiv) in anhydrous dichlorometh-
ane at room temperature overnight, which afforded com-
pounds 7 in 88–95% yield (Scheme 1).
The key precursor to compounds 1 are the 1-(alkoxymeth-
yl)-5-allyl-6-(cyclohexylamino)pyrimidine-2,4(1H,3H)-
diones 6 (Scheme 1), which were synthesized in three
steps starting from 5-allyl-2,4,6-trichloropyrimidine (3)
Cl
O
O
N
a
HN
HN
c
b
Cl
N
Cl
O
N
H
Cl
O
N
Cl
5a–c
3
4
O
R
O
O
O
Bz
Bz
N3
HN3
N3
5
5
5
To effectively transform compounds 7 into 8, we used a
base to remove the proton from the secondary amine
group at C-6, which resulted in a carbanion at the C-5 po-
sition. The proposed mechanism is outlined in Scheme
2.11,12 In particular, sodium hydride was used as the appro-
priate base for the reaction, in which hydrogen gas would
be produced and removed from the system. Thus, the
equilibrium is driven to form the carbanion at C-5, with si-
multaneous formation of the C=N double bond.
1
N
1
N
1
N
6
6
O
N
O
NH
O
NH
e
d
O
R
O
R
O
R
8a–c
7a–c
6a–c
3
O
3
O
N
O
Bz
2
5
5
2
HN
N
HN7
7
h
f
g
9
1
9
1
O
N
N
O
N
O
N
N
Br
O
R
O
R
O
R
O
N
O
N
Bz
O
Bz
O
9a–c
1a–c
2a–c
N
N
– H2
a: R = Me
b: R = Et
c: R = Bn
N
NH
H–
O
R
O
R
Scheme 1 Synthetic route to target compounds 1 and 2. Reagents
and conditions: (a) 2 M aq NaOH (4 equiv), reflux, 12 h, 80%; (b) (1)
BSA (2.5 equiv), DMF, r.t., 30 min; (2) ROCH2Cl (1.0 equiv), DMF,
r.t., 6–9 h, 41–85%; (c) CyNH2 (2.5 equiv), dioxane, reflux, 24 h, 80–
85%; (d) BzCl (1.2 equiv), Et3N (1.2 equiv), CH2Cl2, r.t., overnight,
88–95%; (e) allyl bromide (1.2 equiv), NaH (1.2 equiv), anhyd DMF,
r.t., 1 h, 71–74%; (f) 1st generation Grubbs’ catalyst (5 mol%),
CH2Cl2, r.t., overnight, 75–85%; (g) 9 M NH3 in MeOH (10 equiv),
CH2Cl2, r.t., 1 h, 73–78%; (h) H2, 10% Pd/C, EtOAc, r.t., 36 psi, 1 h,
73–80%.
8
7
R = Me, Et, Bn
Scheme 2 Proposed mechanism for the formation of 8
The reaction was performed by stirring compounds 7 with
allyl bromide (1.2 equiv) in anhydrous N,N-dimethyl-
formamide while sodium hydride (60% dispersion in min-
Synthesis 2013, 45, 2273–2279
© Georg Thieme Verlag Stuttgart · New York

PAPER
10-(Cyclohexylimino)-7,9-diazaspiro[4.5]decane-6,8-diones
2275
eral oil) was added in portions.12 A color change of the Alkenes 1 were subjected to hydrogenation (H2, Pd/C,
solution from red to pale yellow is a good indication of the EtOAc, r.t., 36 psi, 1 h) to yield the target saturated deriv-
completeness of the reaction. Compounds 8 were obtained atives 2 (73–80%),15 in which the reaction time must be
1
in 71–74% yield; the structures were confirmed by H controlled to avoid hydrogenation of the C=N double
NMR spectroscopy.
bond.
Ring-closing metathesis (RCM) is a very powerful syn- Compounds 1a–c and 2a–c were tested for their activity
thetic tool for carbon–carbon bond formation.13 A ruthe- against HIV-1 RT in an assay using a poly(rA)/oli-
nium catalyst, namely 1st generation Grubbs’ catalyst, go(dT)15 homopolymer template with the HIV-1 antigen
was used in the RCM reaction. Thus, in order to form the detection ELISA method16 and nevirapine as a reference
azaspiro ring system containing the quaternary carbon compound. The results indicated that compound 2c has
center, compounds 8 were treated with Grubbs’ catalyst (5 potent inhibitory activity against HIV-1 RT with an IC50
mol%) in dichloromethane at room temperature overnight value of 1.65 μM, comparable to that of nevirapine
to give azaspiro compounds 9 in 75–85% yield.13c,14 The (IC50 = 4.37 μM).
formation of the ring-closed compounds 9 was confirmed
Here, we have reported an efficient strategy for the syn-
thesis of the 10-(cyclohexylimino)-7,9-diazaspi-
by their 1H NMR spectra that exhibited, in each case, sig-
nals located at δ ~5.60–5.85 ppm (representing CH=CH),
ro[4.5]dec-2-ene-6,8-dione 1 and 10-(cyclohexylimino)-
and by their high-resolution mass spectra which showed
7,9-diazaspiro[4.5]decane-6,8-dione 2 heterocyclic scaf-
fold via ring-closing metathesis. The overall yield is ac-
ceptable and the purification of intermediates is trouble-
free. Our ongoing efforts will presumably show that this
that the molecular weight of compounds 9 is 28 less than
that of the corresponding compounds 8 (see experimental
section).
Deprotection of the benzoyl group of derivatives 9 pro- strategy is also suitable for other azaspiro heterocyclic
ceeded successfully with ammonia (9 M) dissolved in scaffolds.
methanol to give target compounds 1 in 73–78% yield
(Scheme 1).
The biological results showed that target compound 2c
has potent inhibitory activity against HIV-1 RT, with an
IC50 value of 1.65 μM, which could be explained by favor-
O
N
O
O
able formation of π–π interactions between the phenyl
moiety at the terminus of the N-9 side chain and some ar-
omatic amino acid residues. Moreover, the double bond at
C-2,C-3 of target compounds 1 would be unfavorable for
improving the inhibitory activity. In light of the biological
activity of azaspiro derivatives, the 10-(cyclohexylimi-
no)-7,9-diazaspiro[4.5]dec-2-ene-6,8-dione 1 and 10-(cy-
Bz
O
HN
N
HN
NH
O
+
O
N
NH
N
N
O
EtO
EtO
EtO
9b
1b
1b'
clohexylimino)-7,9-diazaspiro[4.5]decane-6,8-dione
derivatives are currently under further investigation and
the results will be reported in due course.
2
Scheme 3 Deprotection of 9b. Reagents and conditions: 9 M NH3 in
MeOH (10 equiv), CH2Cl2, r.t., 1 h.
To avoid formation of the ring-opened byproduct 1b′
(Scheme 3), the methanolic ammonia must be added drop-
wise over a prolonged period of time. Crude product was
carefully separated by silica gel column chromatography
All reagents were purchased from commercial suppliers and used
without further purification. All solvents were dried and redistilled
before use. Flash chromatography was carried out with silica gel
(400 mesh). Analytical TLC was performed with silica gel GF254
with ethyl acetate–petroleum ether (1:3 v/v) as eluent. The plates, and the products were visualized by UV detection. Melting
structure of compound 1b′ was characterized by 1H NMR,
points were determined on an X4-type melting-point apparatus and
are uncorrected. FTIR spectra were recorded in the solid state as
KBr dispersions using a Nicolet NEXUS 470 FTIR spectrometer.
13C NMR, HSQC, HMBC and HRMS analysis. The main
supporting evidence for the location of the cleavage site
was provided by the HMBC data in which the methylene
signal (δH 4.79–4.81, 2 H, d, OCH2N) correlated with the
carbonyl carbon (δC 153.4, C=O) and the methylene car-
bon (δC 63.7, OCH2CH3) (Figure 2).
1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on a
Bruker AV-400 spectrometer. Chemical shifts (δ) are reported in
ppm referenced to internal TMS. Coupling constants (J) are report-
ed in hertz (Hz). The signals are expressed as s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet) or br (broad). ESI-MS spectra
were obtained with a Linear Scientific LDI-1700 mass spectrome-
ter. HRMS data were measured using ESI on a Bruker Daltonics
APEX IV spectrometer. Elemental analysis was performed by the
State Key Laboratory of Natural and Biomimetic Drugs, Peking
University with a Vario EL III CHN Analyzer (Elementar Analy-
sensysteme GmbH, Germany). All values for C, H and N were
found to be within +0.3% of theoretical values. Purity of all tested
compounds was >97%, as estimated by HPLC analysis (the major
peak accounted for >97% of the combined total peak area, as mon-
itored by a UV detector at 240 nm).
O
HN
153.4
O
171.3
NH
N
O
H
O
(4.80, 70.6)
63.7
Figure 2 HMBC correlations of 1b′
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2273–2279

2276
T. Zhang et al.
PAPER
5-Allyl-6-chloropyrimidine-2,4(1H,3H)-dione (5-Allyl-6-chlo-
rouracil, 4)
13C NMR (100 MHz, CDCl3): δ = 30.6, 72.1, 74.8, 112.7, 116.6,
127.7, 128.0, 128.5, 132.8, 137.1, 144.1, 150.5, 161.5.
A mixture of 5-allyl-2,4,6-trichloropyrimidine (3; 45 g, 0.2 mol),
NaOH (32 g, 0.8 mol) and H2O (400 mL) was refluxed with stirring
for 10–12 h, until a clear solution was obtained. After cooling, the
solution was washed with Et2O (60 mL), and the water phase was
acidified with concd aq HCl to pH 3–4. The white crystals formed
after standing for 2 h at r.t. were collected by filtration and recrys-
tallized (EtOH) to give 4.9
ESI-HRMS: m/z [M + Na]+ calcd for C15H15ClN2O3Na: 329.0669;
found: 329.0656.
Compounds 6a–c; General Procedure
CyNH2 (2.48 g, 0.025 mol, 2.5 equiv) was added to compound 5a–c
(0.01 mol) in dioxane (30 mL), and the resulting mixture was re-
fluxed for 24 h. When the reaction was complete (TLC), the vola-
tiles were evaporated under reduced pressure. CH2Cl2 (100 mL) was
added to the residue, and the mixture was washed with 1 M aq HCl
(80 mL) and sat. aq NaHCO3 (100 mL) successively. The organic
layer was dried (Na2SO4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography
(EtOAc–petroleum ether, 1:1 v/v).
Yield: 30 g (80%); white crystals; mp 212–214 °C.
1H NMR (400 MHz, DMSO-d6): δ = 3.05–3.06 (d, J = 6.0 Hz, 2 H),
5.00–5.04 (m, J1 = 10.0 Hz, J2 = 17.2 Hz, 2 H), 5.73–5.80 (m, 1 H),
11.39 (s, 1 H), 11.95 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 29.3, 108.3, 116.0, 134.5,
142.3, 150.1, 163.1.
5-Allyl-6-(cyclohexylamino)-1-(methoxymethyl)pyrimidine-
2,4(1H,3H)-dione (6a)
Yield: 2.34 g (80%); white solid; mp 135–138 °C.
Compounds 5a–c; General Procedure
To a suspension of 4 (1.86 g, 0.01 mol) in DMF (30 mL) was added
N,O-bis(trimethylsilyl)acetamide (5.1 g, 0.025 mol, 2.5 equiv), and
the resulting mixture was stirred for 30 min at r.t. to obtain a clear
solution. Then, the chloromethyl ether (0.01 mol, 1 equiv) was add-
ed, and the mixture was stirred at r.t. for 6–9 h. When the reaction
was complete (TLC), the solvent was completely evaporated under
reduced pressure. EtOAc (100 mL) was added to the residue, and
the mixture was washed with brine (70 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was chromato-
graphed on silica gel (EtOAc–petroleum ether, 1:5 v/v) to afford the
pure N1-alkylated product and part of the starting material.
IR (KBr): 3325, 3024, 2930, 2855, 1704, 1646, 1624, 1603, 1451,
1350 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.15–1.35 (m, 5 H), 1.61–1.64 (m,
1 H), 1.72–1.76 (m, 2 H), 1.95–1.97 (m, 2 H), 3.17–3.18 (d, J = 5.6
Hz, 2 H), 3.46 (s, 3 H), 3.48–3.50 (m, 1 H), 4.75–4.77 (d, J = 5.6
Hz, 1 H), 5.02–5.04 (m, 1 H), 5.06–5.07 (m, 1 H), 5.35 (s, 2 H),
5.88–5.95 (m, 1 H), 10.00 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.8, 25.3, 28.8, 34.7, 54.6, 56.6,
75.6, 92.2, 114.7, 136.2, 151.7, 153.5, 164.2.
ESI-MS: m/z = 294.4 [M + H]+, 316.4 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C15H24N3O3: 294.1818; found:
5-Allyl-6-chloro-1-(methoxymethyl)pyrimidine-2,4(1H,3H)-di-
one (5a)
Yield: 1.96 g (85%); white solid; mp 105–107 °C.
294.1817.
IR (KBr): 3435, 3163, 3124, 3019, 2825, 1732, 1677, 1639, 1603
cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.23–3.25 (d, J = 6.0 Hz, 2 H),
3.43 (s, 3 H), 5.01–5.04 (d, J = 10.0 Hz, 1 H). 5.07–5.12 (d, J = 17.2
Hz, 1 H), 5.45 (s, 2 H), 5.72–5.82 (m, 1 H), 10.39 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 30.5, 57.4, 76.2, 112.7, 116.5,
132.7, 144.1, 150.6, 161.7.
5-Allyl-6-(cyclohexylamino)-1-(ethoxymethyl)pyrimidine-
2,4(1H,3H)-dione (6b)
Yield: 2.61 g (85%); white solid; mp 176–179 °C.
IR (KBr): 3313, 3181, 3044, 2974, 2928, 2854, 2819, 1709, 1656,
1453, 1326, 996, 940, 910 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.17–1.33 (m, 8 H), 1.63–1.66 (m,
1 H), 1.74–1.78 (m, 2 H), 1.97–1.99 (m, 2 H), 3.18–3.19 (d, J = 5.2
Hz, 2 H), 3.50–3.58 (m, 1 H), 3.68–3.73 (q, J = 7.2 Hz, 2 H), 4.90–
4.92 (d, J = 9.2 Hz, 1 H), 5.04–5.09 (m, 2 H), 5.38 (s, 2 H), 5.88–
5.97 (m, 1 H), 8.67 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 15.0, 24.8, 25.3, 28.8, 34.8, 54.5,
64.7, 74.2, 91.8, 114.8, 136.2, 151.3, 153.6, 163.5.
ESI-HRMS: m/z [M + Na]+ calcd for C9H11ClN2O3Na: 253.0356;
found: 253.0367.
5-Allyl-6-chloro-1-(ethoxymethyl)pyrimidine-2,4(1H,3H)-di-
one (5b)
Yield: 1.83 g (75%); white solid; mp 117–119 °C.
IR (KBr): 3434, 3154, 3119, 3013, 2981, 2923, 2868, 2819, 1725,
1671, 1640, 1456, 1425, 1343, 960, 923 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.21–1.25 (t, J = 6.8 Hz, 3 H),
3.27–3.29 (d, J = 6.0 Hz, 2 H), 3.65–3.70 (q, J = 7.2 Hz, 2 H), 5.05–
5.08 (d, J = 10.0 Hz, 1 H) , 5.11–5.16 (d, J = 17.2 Hz, 1 H), 5.51 (s,
2 H), 5.76–5.86 (m, 1 H), 9.75 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 15.0, 30.6, 65.5, 74.8, 112.6,
116.6, 132.7, 144.3, 150.3, 161.3.
ESI-HRMS: m/z [M + Na]+ calcd for C10H13ClN2O3Na: 267.0512;
found: 267.0510.
ESI-MS: m/z = 308.5 [M + H]+, 330.5 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C16H26N3O3: 308.1974; found:
308.1972.
5-Allyl-1-(benzyloxymethyl)-6-(cyclohexylamino)pyrimidine-
2,4(1H,3H)-dione (6c)
Yield: 3.10 g (84%); white solid; mp 157–160 °C.
IR (KBr): 3355, 3150, 3064, 2975, 2935, 2855, 2819, 1715, 1648,
1599, 1484, 1463, 987, 935, 907, 745 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.11–1.29 (m, 5 H), 1.60–1.74 (m,
3 H), 1.93–1.96 (m, 2 H), 3.18–3.19 (d, J = 5.6 Hz, 2 H), 3.51–3.54
(m, 1 H), 4.71 (s, 2 H), 4.77–4.80 (d, J = 9.6 Hz, 1 H), 5.03–5.08
(m, 2 H), 5.48 (s, 2 H), 5.87–5.95 (m, 1 H), 7.32–7.37 (m, 5 H),
9.52–9.56 (s, 1 H).
5-Allyl-1-(benzyloxymethyl)-6-chloropyrimidine-2,4(1H,3H)-
dione (5c)
Yield: 1.26 g (41%); white solid; mp 104–106 °C.
IR (KBr): 3474, 3168, 3040, 2930, 2876, 2831, 1699, 1683, 1607,
1494, 1447, 980, 926, 747 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.23–3.25 (d, J = 6.0 Hz, 2 H),
4.69 (s, 2 H), 5.05–5.08 (d, J = 10.0 Hz, 1 H), 5.10–5.14 (d, J = 17.2
Hz, 1 H), 5.58 (s, 2 H), 5.74–5.83 (m, 1 H), 7.27–7.33 (m, 5 H),
10.07 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.8, 30.3, 33.8, 39.8, 59.6, 76.3,
79.1, 97.3, 119.8, 133.1, 133.2, 133.5, 141.2, 141.8, 156.6, 158.5,
169.0.
ESI-MS: m/z = 370.5 [M + H]+, 392.4 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C21H28N3O3: 370.2131; found:
370.2135.
Synthesis 2013, 45, 2273–2279
© Georg Thieme Verlag Stuttgart · New York

PAPER
10-(Cyclohexylimino)-7,9-diazaspiro[4.5]decane-6,8-diones
2277
Compounds 7a–c; General Procedure
Compounds 8a–c; General Procedure
To a soln of compound 6a–c (0.01 mol) in anhyd CH2Cl2 (30 mL)
was added BzCl (1.69 g, 0.012 mol, 1.2 equiv) and anhyd Et3N
(1.21 g, 0.012 mol, 1.2 equiv). The mixture was stirred at r.t. over-
night. When the reaction was complete (TLC), the solution was
washed with 1 M aq HCl (20 mL) and sat. aq NaHCO3 (30 mL) suc-
cessively. The organic layer was dried (Na2SO4), filtered and con-
centrated under reduced pressure. The residue was purified by flash
chromatography (EtOAc–petroleum ether, 1:5 v/v).
To a soln of compound 7a–c (0.001 mol) and allyl bromide (0.15 g,
0.0012 mol, 1.2 equiv) in anhyd DMF (20 mL) was added 60% NaH
(0.048 g, 0.0012 mol, 1.2 equiv) in portions, and the mixture was
stirred at r.t. for 1 h. After completion of the reaction as indicated
by TLC, the solution was concentrated under reduced pressure. The
residue was dissolved in EtOAc (50 mL) and washed with brine
(2 × 50 mL). The organic layer was dried (Na2SO4), filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography (EtOAc–petroleum ether, 1:10 v/v).
5-Allyl-3-benzoyl-6-(cyclohexylamino)-1-(methoxymethyl)py-
rimidine-2,4(1H,3H)-dione (7a)
Yield: 3.49 g (88%); pale yellow oil.
5,5-Diallyl-3-benzoyl-6-(cyclohexylimino)-1-(methoxymeth-
yl)dihydropyrimidine-2,4(1H,3H)-dione (8a)
Yield: 0.31 g (71%); white solid; mp 106–108 °C.
IR (KBr): 3365, 3193, 3073, 2930, 2853, 1747, 1713, 1694, 1643,
1602, 1535, 1449, 1423, 1088, 912, 790, 714 cm–1.
IR (KBr): 3081, 2931, 2853, 1756, 1713, 1678, 1655, 1599, 1547,
1450, 1417, 1345, 972, 942, 922, 785 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.19–1.34 (m, 5 H), 1.61–1.65 (m,
1 H), 1.75–1.79 (m, 2 H), 1.99–2.02 (m, 2 H), 3.19–3.20 (d, J = 5.6
Hz, 2 H), 3.46 (s, 3 H), 3.54–3.58 (m, 1 H), 4.92–4.95 (d, J = 5.6
Hz, 1 H), 5.08–5.13 (t, J = 10.0 Hz, 2 H), 5.34 (s, 2 H), 5.87–5.96
(m, 1 H), 7.45–7.49 (t, J = 7.6 Hz, 2 H), 7.59–7.63 (t, J = 7.6 Hz, 1
H), 7.91–7.94 (d, J = 7.2 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 1.33–1.44 (m, 3 H), 1.51–1.59 (m,
2 H), 1.73–1.76 (m, 3 H), 1.84–1.87 (m, 2 H), 2.91 (br, 4 H), 3.45
(s, 3 H), 4.03–4.05 (br, 1 H), 5.21–5.52 (m, 6 H), 5.76–5.86 (m, 2
H), 7.46–7.50 (t, J = 7.6 Hz, 2 H), 7.63–7.67 (t, J = 7.6 Hz, 1 H),
7.91–7.93 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 24.8, 25.3, 28.9, 34.8, 54.7, 56.9,
76.2, 91.6, 115.1, 129.1, 130.3, 132.1, 134.7, 136.0, 150.4, 151.7,
153.2, 162.7, 169.3.
ESI-MS: m/z = 398.5 [M + H]+, 420.4 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C22H28N3O4: 398.2080; found:
ESI-MS: m/z = 438.7 [M + H]+, 460.7 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C25H32N3O4: 438.23873;
found: 438.23921.
5,5-Diallyl-3-benzoyl-6-(cyclohexylimino)-1-(ethoxymethyl)di-
hydropyrimidine-2,4(1H,3H)-dione (8b)
Yield: 0.33 g (73%); white solid; mp 102–104 °C.
398.2078.
IR (KBr): 3079, 2927, 2852, 1756, 1714, 1677, 1656, 1600, 1552,
1438, 1417, 1345, 1313, 1092, 971, 942, 785 cm–1.
5-Allyl-3-benzoyl-6-(cyclohexylamino)-1-(ethoxymethyl)py-
rimidine-2,4(1H,3H)-dione (7b)
Yield: 3.70 g (90%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.19–1.23 (t, J = 6.8 Hz, 3 H),
1.32–1.43 (m, 3 H), 1.50–1.58 (m, 2 H), 1.67–1.75 (m, 3 H), 1.84–
1.86 (m, 2 H), 2.78–2.91 (br, 4 H), 3.63–3.68 (q, J = 6.4 Hz, 2 H),
4.04 (br, 1 H), 5.20–5.24 (m, 5 H), 5.55 (m, 1 H), 5.76–5.86 (m, 2
H), 7.46–7.50 (t, J = 7.6 Hz, 2 H), 7.63–7.66 (t, J = 7.6 Hz, 1 H),
7.91–7.93 (d, J = 7.6 Hz, 2 H).
ESI-MS: m/z = 474.7 [M + Na]+.
ESI-HRMS: m/z [M + Na]+ calcd for C26H33N3O4Na: 474.23633;
IR (KBr): 3363, 3170, 3073, 2974, 2931, 2855, 1747, 1713, 1646,
1601, 1533, 1450, 1215, 1087, 911, 892, 712 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.20–1.37 (m, 8 H), 1.62–1.65 (m,
1 H), 1.75–1.78 (m, 2 H), 1.99–2.03 (m, 2 H), 3.19–3.20 (d, J = 5.6
Hz, 2 H), 3.56–3.63 (m, 1 H), 3.67–3.72 (q, J = 6.8 Hz, 2 H), 5.07–
5.12 (br, 3 H), 5.38 (s, 2 H), 5.87–5.96 (m, 1 H), 7.44–7.48 (t,
J = 7.6 Hz, 2 H), 7.59–7.62 (t, J = 7.6 Hz, 1 H), 7.91–7.93 (d,
J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.9, 24.8, 25.3, 28.9, 34.8, 54.6,
65.0, 74.6, 91.3, 115.0, 129.0, 130.3, 132.1, 134.7, 136.1, 150.4,
153.3, 162.7, 169.4.
found: 474.23627.
5,5-Diallyl-3-benzoyl-1-(benzyloxymethyl)-6-(cyclohexylimi-
no)dihydropyrimidine-2,4(1H,3H)-dione (8c)
Yield: 0.38 g (74%); white solid; mp 88–90 °C.
ESI-MS: m/z = 412.5 [M + H]+, 434.5 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C23H30N3O4: 412.2236; found:
IR (KBr): 3248, 3089, 3034, 2931, 2855, 1750, 1713, 1679, 1656,
1598, 1548, 1498, 1450, 1422, 1347, 926, 788, 743 cm–1.
412.2227.
1H NMR (400 MHz, CDCl3): δ = 1.28–1.38 (m, 3 H), 1.55–1.62 (m,
2 H), 1.71–1.86 (m, 5 H), 2.67–3.01 (m, 4 H), 3.99–4.13 (m, 1 H),
4.73 (s, 2 H), 5.19–5.22 (br, 5 H), 5.63–5.67 (m, 1 H), 5.75–5.79 (m,
2 H), 7.30–7.36 (m, 5 H), 7.46–7.50 (t, J = 7.6 Hz, 2 H), 7.64–7.68
(t, J = 7.6 Hz, 1 H), 7.90–7.93 (d, J = 7.6 Hz, 2 H).
5-Allyl-3-benzoyl-1-(benzyloxymethyl)-6-(cyclohexylamino)py-
rimidine-2,4(1H,3H)-dione (7c)
Yield: 4.50 g (95%); pale yellow oil.
IR (KBr): 3356, 3152, 3065, 2922, 2853, 2815, 1713, 1640, 1600,
1547, 1484, 1452, 1422, 1367, 1326, 1069, 908, 890, 707 cm–1.
ESI-MS: m/z = 536.7 [M + Na]+.
1H NMR (400 MHz, CDCl3): δ = 1.18–1.34 (m, 5 H), 1.63–1.75 (m,
1 H), 1.75–1.78 (m, 2 H), 2.00–2.02 (m, 2 H), 3.21–3.22 (d, J = 5.2
Hz, 2 H), 3.59–3.62 (m, 1 H), 4.74 (s, 2 H), 4.98–5.00 (d, J = 9.6
Hz, 1 H), 5.08–5.13 (dq, J = 13.2 Hz, J = 1.6 Hz, 2 H), 5.49 (s, 2 H),
5.87–5.97 (m, 1 H), 7.34–7.39 (m, 5 H), 7.48–7.51 (t, J = 7.6 Hz, 2
H), 7.62–7.66 (t, J = 7.6 Hz, 1 H), 7.93–7.96 (d, J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 24.8, 25.3, 28.8, 34.8, 54.7, 71.7,
74.7, 91.7, 115.1, 128.0, 128.2, 128.6, 129.0, 130.4, 132.1, 134.7,
136.0, 136.7, 150.4, 153.2, 162.7, 169.3.
ESI-HRMS: m/z [M + H]+ calcd for C31H36N3O4: 514.27003;
found: 514.27108.
Compounds 9a–c; General Procedure
A soln of 1st generation Grubbs’ catalyst (82 mg, 5 mol%) in anhyd
CH2Cl2 (20 mL) was added via cannula to a soln of compound 8a–c
(0.002 mol) in CH2Cl2 (0.02 M). The resulting dark brown solution
was stirred at r.t. until TLC indicated that the starting material was
no longer present. The volatiles were removed under reduced pres-
sure, and the residue was purified by flash chromatography
(EtOAc–petroleum ether, 1:10 v/v).
ESI-MS: m/z = 474.6 [M + H]+, 496.6 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C28H32N3O4: 474.2393; found:
474.2395.
7-Benzoyl-10-(cyclohexylimino)-9-(methoxymethyl)-7,9-diaza-
spiro[4.5]dec-2-ene-6,8-dione (9a)
Yield: 0.61 g (75%); white solid; mp 129–131 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2273–2279

2278
T. Zhang et al.
PAPER
IR (KBr): 3066, 2935, 2856, 1753, 1716, 1684, 1654, 1597, 1535,
1450, 1334, 1085, 969, 890, 757, 711 cm–1.
13C NMR (100 MHz, CDCl3): δ = 24.3, 25.8, 34.3, 47.9, 49.4, 55.6,
57.8, 73.0, 77.2, 128.8, 150.0, 150.4, 174.4.
1H NMR (400 MHz, CDCl3): δ = 1.30–1.31 (m, 3 H), 1.49–1.51 (m,
2 H), 1.65–1.67 (m, 3 H), 1.74–1.92 (m, 2 H), 2.93–3.14 (m, 2 H),
3.16–3.28 (br, 2 H), 3.48–3.72 (br, 4 H), 5.02–5.84 (m, 4 H), 7.49–
7.50 (t, J = 7.6 Hz, 2 H), 7.65–7.68 (t, J = 7.6 Hz, 1 H), 7.91–7.93
(br, 2 H).
ESI-HRMS: m/z [M + H]+ calcd for C16H24N3O3: 306.1807; found:
306.1818.
Anal. Calcd for C16H23N3O3: C, 62.93; H, 7.59; N, 13.76. Found: C,
62.78; H, 7.66; N, 13.62.
ESI-HRMS: m/z [M + H]+ calcd for C23H28N3O4: 410.20743;
found: 410.20610.
10-(Cyclohexylimino)-9-(ethoxymethyl)-7,9-diazaspi-
ro[4.5]dec-2-ene-6,8-dione (1b)
Yield: 25 mg (78%); white solid; HPLC purity >98%; mp 98–
101 °C.
Anal. Calcd for C23H27N3O4: C, 67.46; H, 6.65; N, 10.26. Found: C,
67.25; H, 6.78; N, 10.25.
IR (KBr): 3195, 3072, 2927, 2854, 1738, 1697, 1638, 1447, 1372
cm–1.
7-Benzoyl-10-(cyclohexylimino)-9-(ethoxymethyl)-7,9-diazaspi-
ro[4.5]dec-2-ene-6,8-dione (9b)
Yield: 0.68 g (80%); white solid; mp 117–119 °C.
1H NMR (400 MHz, CDCl3): δ = 1.20–1.30 (m, 6 H), 1.40–1.48 (m,
2 H), 1.59–1.62 (m, 3 H), 1.76–1.79 (m, 2 H), 2.82–2.86 (d, J = 16.8
Hz, 2 H), 3.12–3.16 (d, J = 15.6 Hz, 2 H), 3.48 (br, 1 H), 3.64–3.70
(q, J = 6.8 Hz, 2 H), 5.03–5.49 (m, 2 H), 5.60–5.85 (m, 2 H), 8.13
(s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 15.3, 24.3, 25.8, 34.2, 47.8, 55.6,
65.3, 71.4, 77.3, 127.2, 128.8, 150.0, 150.6, 174.6.
IR (KBr): 2930, 2855, 1751, 1715, 1683, 1654, 1597, 1449, 1366,
969, 797, 757, 715 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.21–1.31 (m, 6 H), 1.49–1.51 (m,
2 H), 1.65–1.67 (m, 3 H), 1.74–1.90 (m, 2 H), 2.94–3.10 (m, 2 H),
3.18–3.42 (m, 2 H), 3.52–3.71 (m, 3 H), 5.07–5.83 (m, 4 H), 7.49–
7.52 (t, J = 7.2 Hz, 2 H), 7.64–7.67 (t, J = 7.2 Hz, 1 H), 7.91 (br, 2
H).
ESI-HRMS: m/z [M + H]+ calcd for C24H30N3O4: 424.22308;
found: 424.22362.
ESI-HRMS: m/z [M + H]+ calcd for C17H26N3O3: 320.19687;
found: 320.19756.
Anal. Calcd for C17H25N3O3: C, 63.93; H, 7.89; N, 13.16. Found: C,
63.65; H, 7.88; N, 13.19.
Anal. Calcd for C24H29N3O4: C, 68.06; H, 6.90; N, 9.92. Found: C,
68.04; H, 6.92; N, 9.96.
N1-Cyclohexyl-N1-[(ethoxymethyl)aminocarbonyl]cyclopent-3-
ene-1,1-dicarboxamide (1b′)
Yield: 4 mg (12%); white solid; mp 175–178 °C.
7-Benzoyl-9-(benzyloxymethyl)-10-(cyclohexylimino)-7,9-di-
azaspiro[4.5]dec-2-ene-6,8-dione (9c)
Yield: 0.82 g (85%); white solid; mp 137–138 °C.
1H NMR (400 MHz, CDCl3): δ = 1.13–1.24 (m, 6 H), 1.34–1.43 (m,
2 H), 1.61–1.72 (m, 3 H), 1.88–1.91 (m, 2 H), 2.93–2.97 (d, J = 15.2
Hz, 2 H), 3.09–3.13 (d, J = 15.6 Hz, 2 H), 3.56–3.61 (q, J = 7.2 Hz,
2 H), 3.75–3.79 (m, 1 H), 4.79–4.81 (d, J = 6.8 Hz, 2 H), 5.74 (s, 2
H), 5.83–5.85 (d, J = 7.2 Hz, 1 H), 8.83–8.84 (t, J = 5.6 Hz, 1 H),
9.18 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 15.0, 24.6, 25.3, 32.6, 41.7, 48.8,
59.7, 63.6, 70.6, 128.6, 153.2, 171.3, 174.1.
ESI-HRMS: m/z [M + Na]+ calcd for C17H27N3O4Na: 360.1893;
found: 360.1899.
IR (KBr): 3066, 2935, 2856, 1754, 1715, 1682, 1652, 1598, 1497,
1450, 1428, 1367, 1334, 1074, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.27–1.32 (m, 3 H), 1.51–1.53 (m,
2 H), 1.58–1.73 (m, 3 H), 1.74–1.90 (m, 2 H), 2.78–3.35 (m, 4 H),
3.52–3.77 (m, 1 H), 4.76 (s, 2 H), 5.11–5.81 (m, 4 H), 7.31–7.37 (m,
5 H), 7.49–7.53 (t, J = 7.6 Hz, 2 H), 7.65–7.68 (t, J = 7.6 Hz, 1 H),
7.87–7.89 (d, J = 7.6 Hz, 2 H).
ESI-MS: m/z = 486.3 [M + H]+, 508.3 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C29H32N3O4: 486.23873;
found: 486.23966.
9-(Benzyloxymethyl)-10-(cyclohexylimino)-7,9-diazaspi-
ro[4.5]dec-2-ene-6,8-dione (1c)
Yield: 28 mg (73%); white solid; HPLC purity >98%; mp 114–
117 °C.
Anal. Calcd for C29H31N3O4: C, 71.73; H, 6.43; N, 8.65. Found: C,
71.74; H, 6.55; N, 8.58.
IR (KBr): 3223, 3127, 3064, 2927, 2853, 1718, 1654, 1494, 1449,
1340 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.27–1.28 (m, 3 H), 1.46–1.63 (m,
5 H), 1.79 (br, 2 H), 2.74–2.78 (m, 2 H), 3.03–3.07 (m, 2 H), 3.47
(m, 1 H), 4.74 (s, 2 H), 5.60 (s, 2 H), 5.81 (s, 2 H), 7.28–7.35 (m, 5
H), 8.55 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.4, 25.9, 29.7, 34.3, 47.9, 49.3,
55.6, 72.0, 77.4, 127.3, 127.5, 128.3, 128.8, 138.8, 149.9, 150.6,
174.4.
Compounds 1a–c; General Procedure
A 9 M soln of NH3 in MeOH (0.11 mL, 10 equiv) was added drop-
wise to a soln of compound 9a–c (0.1 mmol) in anhyd CH2Cl2 (5
mL) at r.t., and the resulting solution was stirred at r.t. until TLC in-
dicated that the starting material was no longer present. Silica gel
(0.5 g) was added to the solution, and the resulting suspension was
concentrated to dryness under reduced pressure. A white solid was
obtained from preloaded silica gel column chromatography
(EtOAc–petroleum ether, 1:3 v/v).
ESI-HRMS: m/z [M + H]+ calcd for C22H28N3O3: 382.21252;
found: 382.21298.
10-(Cyclohexylimino)-9-(methoxymethyl)-7,9-diazaspi-
ro[4.5]dec-2-ene-6,8-dione (1a)
Yield: 23 mg (75%); white solid; HPLC purity >98%; mp 118–
122 °C.
Anal. Calcd for C22H27N3O3: C, 69.27; H, 7.13; N, 11.02. Found: C,
69.09; H, 7.18; N, 10.83.
IR (KBr): 3201, 3124, 2931, 2852, 1712, 1652, 1447, 1344, 1085
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26–1.27 (m, 3 H), 1.41–1.48 (q,
J = 10.8 Hz, 2 H), 1.59–1.62 (d, J = 14.0 Hz, 3 H), 1.78 (br, 2 H),
2.82–2.86 (d, J = 16.6 Hz, 2 H), 3.09–3.16 (m, 2 H), 3.45 (s, 4 H),
4.97–5.46 (m, 2 H), 5.59–5.85 (m, 2 H), 8.23 (s, 1 H).
Compounds 2a–c; General Procedure
To a soln of compound 1a–c (0.2 mmol) in EtOAc (10 mL) was
added 10% Pd on activated carbon (5 mg), and the resulting suspen-
sion was stirred under H2 atmosphere (36 psi) at r.t. for 1 h. The cat-
alyst was removed by filtration through Celite®, and the filtrate was
concentrated under reduced pressure to give 2 in good yield.
Synthesis 2013, 45, 2273–2279
© Georg Thieme Verlag Stuttgart · New York

PAPER
10-(Cyclohexylimino)-7,9-diazaspiro[4.5]decane-6,8-diones
2279
10-(Cyclohexylimino)-9-(methoxymethyl)-7,9-diazaspi-
ro[4.5]decane-6,8-dione (2a)
Yield: 47 mg (76%); white solid; HPLC purity >98%; mp 103–
105 °C.
Acknowledgment
This study was supported by the National Science Foundation of
China (20972011, 21042009, 21172014) and grants from the Mini-
stry of Science and Technology of China (2009ZX09301-010) for
financial support.
IR (KBr): 3278, 3114, 2936, 2852, 1743, 1712, 1666, 1469, 1449,
1423, 1386, 963, 767 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.31–1.34 (m, 3 H), 1.45–1.47 (m,
2 H), 1.59–1.63 (m, 3 H), 1.68–1.91 (m, 6 H), 2.08 (br, 2 H), 2.30
(br, 2 H), 3.47 (s, 3 H), 3.64 (s, 1 H), 4.97 (s, 2 H), 8.15 (s, 1 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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13C NMR (100 MHz, CDCl3): δ = 24.0, 25.6, 25.7, 33.8, 34.1, 57.2,
57.6, 58.4, 77.2, 77.6, 145.2, 152.4, 173.9.
ESI-HRMS: m/z [M + H]+ calcd for C16H26N3O3: 308.1970; found:
References
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Czifrák, K.; Batta, G.; Docsa, T.; Gergely, P.; Somsák, L.;
Praly, J.-P. Bioorg. Med. Chem. 2009, 17, 5696.
(3) Kubota, H.; Okamoto, Y.; Fu, J. M.; Ikeda, K.; Takeuchi,
M.; Shibanuma, T.; Isomura, Y. Bioorg. Med. Chem. Lett.
1998, 8, 1541.
308.1974.
Anal. Calcd for C16H25N3O3: C, 62.52; H, 8.20; N, 13.67. Found: C,
62.29; H, 8.26; N, 13.65.
10-(Cyclohexylimino)-9-(ethoxymethyl)-7,9-diazaspi-
ro[4.5]decane-6,8-dione (2b)
Yield: 51 mg (80%); white solid; HPLC purity >97%; mp 111–
114 °C.
(4) Pinard, E.; Ceccarelli, S. M.; Stalder, H.; Alberati, D.
Bioorg. Med. Chem. Lett. 2006, 16, 349.
(5) Da Settimo, F.; Primofiore, G.; La Motta, C.; Salerno, S.;
Novellino, E.; Greco, G.; Lavecchia, A.; Laneri, S.; Boldrini,
E. Bioorg. Med. Chem. 2005, 13, 491.
(6) Gao, F. L.; Wang, X.; Zhang, H. M.; Cheng, T. M.; Li, R. T.
Bioorg. Med. Chem. Lett. 2003, 13, 1535.
(7) Nissley, D. V.; Boyer, P. L.; Garfinkel, D. J.; Hughes, S. H.;
Strathern, J. N. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
13905.
IR (KBr): 3203, 3087, 2930, 2856, 1739, 1700, 1656, 1537, 1450,
1425, 1089, 982 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.21–1.25 (t, J = 10.8 Hz, 3 H),
1.31–1.35 (m, 3 H), 1.45–1.47 (m, 2 H), 1.55–1.67 (br, 4 H), 1.69–
1.86 (m, 5 H), 2.07 (br, 2 H), 2.32 (br, 2 H), 3.65–3.70 (m, 3 H), 5.02
(s, 2 H), 7.86 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 15.1, 24.1, 25.5, 25.7, 33.8, 34.1,
38.6, 57.2, 65.4, 70.7, 76.1, 145.3, 152.2, 173.7.
ESI-MS: m/z = 322.3 [M + H]+, 344.2 [M + Na]+.
(8) He, Y. P.; Long, J.; Zhang, S. S.; Li, C.; Lai, C. C.; Zhang,
C. S.; Li, D. X.; Zhang, D. H.; Wang, H.; Cai, Q. Q.; Zheng,
Y. T. Bioorg. Med. Chem. Lett. 2011, 21, 694.
(9) Ishikawa, I.; Khachatrian, V. E.; Melik-Ohanjanian, R. G.;
Kawahara, N.; Mizuno, Y.; Ogura, H. Chem. Pharm. Bull.
1992, 40, 846.
(10) Wang, X. W.; Lou, Q. H.; Guo, Y.; Xu, Y.; Zhang, Z. L.;
Liu, J. Y. Org. Biomol. Chem. 2006, 4, 3252.
(11) Wen, R. Organic Reactions for Drug Synthesis; Chemical
Industry Press: Beijing, 2002, 459.
ESI-HRMS: m/z [M + H]+ calcd for C17H28N3O3: 322.21252;
found: 322.21280.
Anal. Calcd for C17H27N3O3: C, 63.53; H, 8.47; N, 13.07. Found: C,
63.33; H, 8.47; N, 13.06.
9-(Benzyloxymethyl)-10-(cyclohexylimino)-7,9-diazaspi-
ro[4.5]decane-6,8-dione (2c)
Yield: 56 mg (73%); white solid; HPLC purity >98%; mp 130–
133 °C.
IR (KBr): 3208, 3089, 3032, 2932, 2854, 1734, 1698, 1671, 1498,
1450, 1417, 1372, 743 cm–1.
(12) Maki, Y.; Hiramitsu, T.; Suzuki, M. Tetrahedron 1980, 36,
2097.
1H NMR (400 MHz, CDCl3): δ = 1.29–1.45 (m, 5 H), 1.53–1.62 (m,
3 H), 1.70–1.77 (m, 6 H), 2.08 (br, 2 H), 2.33 (br, 2 H), 3.68 (m, 1
H), 4.73 (s, 2 H), 5.08 (s, 2 H), 7.28–7.36 (m, 5 H), 8.15 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.0, 25.5, 25.7, 33.8, 34.1, 57.2,
58.5, 72.0, 75.9, 77.2, 127.6, 127.9, 128.4, 137.4, 145.2, 152.1,
173.6.
(13) (a) Takahashi, H.; Yoshida, K.; Yanagisawa, A. J. Org.
Chem. 2009, 74, 3632. (b) Kurteva, V. B.; Afonso, C. A.
Chem. Rev. 2009, 109, 6809. (c) Baird, L. J.; Timmer, M. S.;
Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem. 2009,
74, 2271.
(14) (a) Burke, S. D.; Muller, N.; Beaudry, C. M. Org. Lett. 1999,
1, 1827. (b) Fustero, S.; Sanchez-Rosello, M.; Jimenez, D.;
Sanz-Cervera, J. F.; Del Pozo, C.; Acena, J. L. J. Org. Chem.
2006, 71, 2706. (c) Dowling, M. S.; Vanderwal, C. D.
J. Org. Chem. 2010, 75, 6908.
(15) (a) Nikas, S. P.; Alapafuja, S. O.; Papanastasiou, I.; Paronis,
C. A.; Shukla, V. G.; Papahatjis, D. P.; Bowman, A. L.;
Halikhedkar, A.; Han, X.; Makriyannis, A. J. Med. Chem.
2010, 53, 6996. (b) Cheng, X.; Waters, S. P. Org. Lett. 2010,
12, 205.
ESI-HRMS: m/z [M + H]+ calcd for C22H30N3O3: 384.22817;
found: 384.22841.
Anal. Calcd for C22H29N3O3: C, 68.90; H, 7.62; N, 10.96. Found: C,
68.62; H, 7.65; N, 10.85.
(16) Danel, K.; Larsen, E.; Pedersen, E. B. Synthesis 1995, 934.
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Synthesis 2013, 45, 2273–2279