Vinylogous Aza-Michael Addition of Urea Derivatives with p-Quinone Methides Followed by Oxidative Dearomative Cyclization: Approach to Spiroimidazolidinone Derivatives

Article abstract of DOI:10.1002/adsc.202100077

Herein, we report an efficient protocol for the synthesis of spiro-imidazolidinone-cyclohexadienones from p-quinone methides (p-QMs) and dialkyloxy ureas under mild conditions. The strategy follows a two-step process involving an initial vinylogous conjugate addition of urea derivatives to p-QMs, followed by oxidative dearomative cyclization of open-chain product to the projected spiro-imidazolidinones. This protocol exhibits good functional group tolerance and provides a straightforward method to access spiro-imidazolidinone-cyclohexadienones. In follow-up chemistry, we have shown the debenzylation of spiroimidazolidinones to give N-hydroxycyclic ureas. (Figure presented.).

Full text of DOI:10.1002/adsc.202100077

FULL PAPER
DOI: 10.1002/adsc.202100077
Vinylogous Aza-Michael Addition of Urea Derivatives with p-
Quinone Methides Followed by Oxidative Dearomative
Cyclization: Approach to Spiroimidazolidinone Derivatives
Navpreet Kaur,a Priyanka Singh,a and Prabal Banerjeea,*
a
Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
E-mail: prabal@iitrpr.ac.in
Manuscript received: January 19, 2021; Revised manuscript received: March 16, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100077
Abstract: Herein, we report an efficient protocol for the synthesis of spiro-imidazolidinone-cyclohexadie-
nones from p-quinone methides (p-QMs) and dialkyloxy ureas under mild conditions. The strategy follows a
two-step process involving an initial vinylogous conjugate addition of urea derivatives to p-QMs, followed by
oxidative dearomative cyclization of open-chain product to the projected spiro-imidazolidinones. This protocol
exhibits good functional group tolerance and provides a straightforward method to access spiro-
imidazolidinone-cyclohexadienones. In follow-up chemistry, we have shown the debenzylation of spiroimida-
zolidinones to give N-hydroxycyclic ureas.
Keywords: p-quinone methides; dialkyloxy ureas; metal-free cyclization; spiroimidazolidinones
Introduction
cyclohexadienone moiety is the main driving force for
these types of conjugate addition reactions. However,
Imidazolidin-2-ones and its analogues are ubiquitous the spirocyclization reactions of p-QMs are compara-
structural motifs found in natural products, pharma- tively less explored due to the requirement of the
ceuticals, and other biologically active compounds.[1] dearomatization of the reaction intermediate. In the
They often possess a broad range of biological past few years, many significant annulations have been
activities such as antitumor, antibiotic, and anti- developed using p-QMs like base-catalyzed [2+1]
hypertonic.[2] These N-containing heterocycles show spiro-cyclization reactions of p-QMs with prefunction-
versatile utility as useful structural synthons in organic alized nucleophiles such as 2-bromo malonate, sulfo-
synthesis.[3] Amid the various spirocyclic scaffolds in nium salts, sulfur, and ammonium ylides.[10] In 2016,
drug discovery, spiroimidazolidinone is a promising the Lin and Yao group and the Zhao group separately
structural motif.[4] Consequently, continuous efforts demonstrated the palladium-catalyzed [3+2] cyclo-
have been made towards the synthesis of this type of addition reaction of p-QMs with vinyl epoxides/
spirocyclic molecules.[5] On the other hand, it is worth cyclopropanes.[11] Recently, Su and co-workers dis-
considering that the cyclohexadienones are also the closed a base-catalyzed [3+2] cycloaddition of p-QMs
prevalent core structure found in many bioactive with in situ generated nitrile imines from hydrazonyl
natural products and have gained considerable impor- chlorides towards the construction of spiro-pyrazoline-
tance due to their abundance in pharmaceuticals.[6,7] cyclohexadienones (Scheme 1a).[12] In addition, Das
Hence, incorporation of spiroimidazolidinone and and co-workers also reported a base-catalyzed 1,6-
cyclohexadienone in one frame can be proved benefi- conjugate addition mediated [2+1] annulation of p-
cial for medicinal chemists.
QMs and pyrazolones to form bis-spiro compounds
During the past few years, p-quinone methides (p- (Scheme 1b).[13]
QMs) have emerged as one of the most desirable
Urea and its derivatives are recognized as crucial
components to access spiro-cyclohexadienones. In functionalities in the medicinal chemistry discipline
literature, p-QMs have been mainly known for their and constitute a key structural component of many
role as vinylogous Michael acceptors in various 1,6- FDA approved drugs.[14] The N-alkyloxy ureas have
conjugate addition reactions.[8,9] Aromatization of the attracted researchers’ considerable attention due to
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Table 1. Optimization of reaction conditions for 1,6-conjugate
addition.[a]
Entry Base[b]
Loading Time (h) Solvent[c] Yield
(equiv.)
(%)[d]
1.
2.
3.
4.
5.
6.
7.
8.
DBU
DBU
DIPEA
Et3N
DABCO
DMAP
Piperidine 1.5
Pyridine
DBU
DBU
DBU
1
3
1
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CH3CN
THF
70
90
50
70
20
10
1.5
1.5
1.5
1.5
1.5
16
17
18
18
18
18
1
n.r.[e]
n.r.
85
1.5
1.5
1.5
1.5
9.
10.
11.
Scheme 1. Spirocyclization reactions involving p-QMs.
1
1
78
70
toluene
[a] Unless otherwise stated, reactions were carried out with
1 equiv. of 1a, 1 equiv. of 2a at rt.
their involvement in
a number of remarkable
transformations.[15] In 2019, our group has reported the
synthesis of tetrahydropyrimidinones via ring-opening/
cyclization of donor-acceptor cyclopropanes with (un)
symmetrical ureas.[16a] Also, recently, we have docu-
[b] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA=N,N-
diisopropylethylamine, Et3N=triethylamine, DABCO=1,4-
diazabicyclo[2. 2. 2]octane, DMAP = 4-dimeth-
ylaminopyridine.
mented the palladium catalyzed regio- and stereo- [c] DCM=dichloromethane, CH3CN=acetonitrile, THF=tetra-
hydrofuran.
selective access to allylic urea/carbamate derivatives
from readily available vinyl ethylene carbonates and
substituted urea derivatives.[16b]
[d] isolated yields.
[e] n.r.=no reaction.
Encouraged by these results and studies, we tried to
exploit the reactivities of p-QMs and urea derivatives
as building blocks towards the construction of spiroi- 8). Further, to improve the product yield, solvents like
midazolidinones (Scheme 1c). To the best of our CH3CN, THF, and toluene were also screened using
knowledge, there have been no previous reports so far DBU (1.5 equiv.) as base. In all the cases, conjugate
for the synthesis of spiro-imidizolidinone-cyclohexa- addition product was obtained with compromised yield
dienones using p-QMs and dialkyloxy/diaryloxy ureas. (70-85%) as compared to reaction in DCM (Table 1,
Herein, an efficient method for the cyclization of urea entries 2 and 9–11).
derivatives with p-QMs has been delineated to con-
struct functionalized spiroimidazolidinones.
With the optimized conditions in hand (Table 1,
entry 2), initially, substrate scope with reference to p-
QMs was investigated (Table 2). A series of p-QMs
bearing electron-rich and electron-deficient substitu-
ents at the aromatic ring (Ar) 1a-1j were examined,
Results and Discussion
We commenced the present investigation by employing affording the 1,6-conjugate addition products 3aa–3ja
2,6-di-tert-butyl p-QM 1a and dibenzyloxyurea 2a as in moderate to good yields. p-QMs bearing electron-
model substrates in the presence of different bases. rich groups such as methoxy 1b, methyl 1c, benzyloxy
Initially, DBU (1 equiv.) was used as a base in DCM 1d at the p- position of the aryl ring (Ar) offered
(solvent), and fortunately, desired 1,6-conjugate addi- conjugate addition products 3ba–3da in good yields.
tion product was obtained with 70% yield. A subse- Compound 3ea having 3, 4-dimethoxy group as
quent increase in the yield to 90% was also observed substituent was obtained from p-QM 1e with 78%
when loading of DBU was increased to 1.5 equivalents yield. Also, this transformation demonstrated consis-
(Table 1, entries 1 and 2). Other organic bases such as tency with p-QMs 1f-1h bearing halogen group at aryl
DIPEA, Et3N, DABCO, DMAP proved less efficient ring. Compounds 3fa–3ha were obtained in good to
for this transformation (Table 1, entries 3–6). In the moderate yields. Substrates enduring electron-with-
case of piperidine and pyridine, both the starting drawing group (À NO2, À CF3) 1i-1j at the p- position
materials remain unconsumed (Table 1, entries 7 and of the aryl ring offered the addition products 3ia and
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Table 2. Scope of investigation with regard to p-QMs.[a,b]
Table 3. Scope of investigation with regard to urea.[a,b]
[a] Unless otherwise specified, all the reactions were carried out
in DCM (1 mL) at rt with 1a (0.181 mmol), 2 (0.181 mmol)
and DBU (0.270 mmol).
[a] Unless otherwise specified, all the reactions were carried out
in DCM (1 mL) at rt with 1 (0.181 mmol), 2a (0.181 mmol)
and DBU (0.270 mmol).
[b] Isolated yields are reported.
[b] Isolated yields are reported.
regioisomers, 3ag and 3ag’ which were separated by
column chromatography. The structures of the two
3ja in 65–68% yield. Further, p-QM 1k bearing regioisomers were confirmed by the NOE experiments
naphthyl group delivered the addition product 3ka in (see Supporting Information, SI). The correlation of N-
78% yield. Besides this, unsymmetrical p-QM 1l also H and benzyloxy CH2 protons with tert-butyl group
afforded the conjugate addition product 3la in good confirmed the regiochemistry of the formed compound
yield.
3ag’. Afterward, we also analyzed N-benzyloxy N’-
Next, the generality and viability of the reaction aryl or N’-benzyl unsymmetrical ureas 2h–2i and
was tested for dialkoxy/aryloxy ureas 2a–2k by found that the reaction went smoothly, rendering
reacting them with p-QM 1a (Table 3). Fortunately, N- products 3ah and 3ai as single regioisomers in good
benzyloxy ureas 2b–2e with 4-Cl, 4-F, 4-Br, 4-Me yields. The regioselective attack of N-benzyloxy nitro-
substitution afforded the conjugate addition products gen of unsymmetrical urea at the double bond of p-
3ab–3ae in appreciable yields. No profound effect on QM was presumably due to the higher nucleophilicity
1
yield was observed when N,N’-dimethoxy urea 2f was of the N-atom.[15] The H-NMR spectrum validated the
used as a conjugating partner, and compound 3af was formation of 3ai. The participation of N-benzyloxy
obtained with 80% yield. To evaluate the feasibility of group in 3ai was confirmed by the 1H NMR where the
the protocol with unsymmetrical ureas, N-benzyloxy triplet forN-H proton of the N-benzyl group appears at
N’-methoxy urea 2g was used as reactive partner. As 6.1 ppm. In contrast, N,N’-dialkyl urea 2j and N,N’-
expected, NMR data unveiled the formation of two biaryl urea 2k proved incompatible for the conjugate
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addition, probably due to the poor nucleophilicity of compound when CH3CN was replaced with other
the N-atom.[15]
solvents like DCM, THF, toluene, and DCE (Table 4,
Having synthesized a range of conjugate addition entries 8–11). On the other hand, various fluorinated
products, compound 3aa was subjected to undergo solvents like HFIP, TFA, TFE were also proved fatal
intramolecular dearomative ring closure to get the for the reaction (Table 4, entries 12–15). Hence,
desired spirocyclic product. Different oxidizing agents CH3CN was adopted as the solvent of choice for the
were screened for the final cyclization step. Oxidizing final cyclization due to the better yield. Another
agents, such as DDQ, CAN were found incompetent to hypervalent iodine oxidant PIFA was also screened,
execute the cyclization (Table 4, entries 1–5). Whereas, but comparatively lower yield (40%) was obtained for
hypervalent iodine reagent (diacetoxyiodo)benzene the product 4aa (Table 4, entry 16). Therefore, on the
(PIDA) (1 equiv.) in CH3CN proved compatible for the basis of above optimization studies, 2 equiv. of PIDA
transformation and final spirocyclized product 4aa in CH3CN at room temperature was used as an optimal
was obtained in low yield (25%) (Table 4, entry 6). reaction condition for the final spirocyclization.
Further, on increasing the loading of PIDA to 2 equiv.
With the optimized conditions in hand (Table 4,
the yield of the final product was improved to 65% entry 7), further cyclization of the conjugate addition
(Table 4, entry 7). In continuation, screening of differ- products was performed (Table 5). It was found that
ent solvents using PIDA (2 equiv.) as oxidant was conjugate addition products possessing moderately
carried out to increase the product yield. There was a electron-releasing groups like p-methyl, p-methoxy, p-
significant decrease in the yield of the final cyclized benzyloxy on the phenyl ring furnished the final
cyclized product 4ba–4da in 48–65% yield. In
contrast, the conjugate addition product with 3,4-
dimethoxy group on the phenyl ring showed compro-
mised yield for the cyclized product 4ea. Substrates
with F and Cl at the p-position of the phenyl ring gave
the desired product 4fa, 4ga in 55% and 60% yields,
respectively. The substrate with Br at the o-position
offered the final cyclized product 4ha with 58% yield.
The structure of 4ha was also ascertained by single-
crystal X-ray analysis.[17] The substrate with other
electron-withdrawing groups on the phenyl ring such
as À NO2, À CF3 were also well tolerated with the
reaction conditions, affording 4ia, 4ja in moderate
yields. Naphthyl substituted conjugate addition product
also participated in the cyclization reaction and offered
4ka in 57% yield. The conjugate addition product of
unsymmetrical p-QM 3la gave the desired product 4la
in 30% yield. The low yield of product 4la may be due
to the formation of other unidentified side products in
the reaction. Conjugate addition products 3ab-3af
with a range of N,N’-dialkyloxy ureas afforded their
respective product 4ab–4af in satisfactory yields.
Spirocyclized product 4ag, 4ag’ from the regioisomers
3ag, 3ag’ were also obtained in 45–48% yield.
Further, conjugate addition products 3ah, 3ai were
also tested for spirocyclization, but the formation of
the desired cyclized product was not observed,
possibly due to the lower nucleophilicity of the N-atom
or lack of the alkyloxy group giving the nitrenium ion.
Based on literature reports[18] and our observations,
a plausible mechanism is disclosed for the proposed
gradual transformation. Initial nucleophilic attack of
urea 2a on p-QMs 1a under basic conditions resulted
in the formation of fully aromatized open-chain
product 3aa through vinylogous aza-Michael addition.
As per literature reports, it is well established that in
the presence of hypervalent iodine reagents, N-alkylox-
yamides generates nitrenium ion.[18] Hence, it was
Table 4. Optimization of reaction conditions.[a]
[d]
Catalyst[b] Loading
(equiv.)
Solvent[c,g] T( C) Yield
°
Entry
no.
1.
2.
3.
4.
5.
6.
7.
DDQ
DDQ
DDQ
CAN
CAN
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIFA
1
2
2
2
2
1
2
2
2
2
2
1
2
2
2
2
DCM
MeOH
CH3CN
CH3CN
DCM
CH3CN
CH3CN
DCM
THF
toluene
DCE
HFIP
HFIP
TFA
0-rt n.r.[e]
0-rt n.r.
0-rt n.r.
rt
rt
n.r.
n.r.
0-rt 25
rt
rt
rt
rt
rt
65
40
45
40
34
8.
9.
10.
11.
12.
13.
14.
15.
16.
0-rt c.m.[f]
rt
c.m.
0-rt c.m.
0-rt c.m.
TFE
CH3CN
rt
40
[a] Reactions were carried out with 1 equiv. of 3a.
[b] DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, CAN=
cerium ammonium nitrate, PIDA=diacetoxy iodobenzene,
PIFA=(bis(trifluoroacetoxy)iodo)benzene.
[c] DCM=dichloromethane, MeOH=methanol, CH3CN= acet-
onitrile, THF= tetrahydrofuran, DCE=dichloroethane,
HFIP =hexafluoroisopropanol, TFA= trifluoroaceticacid,
TFE=2,2,2-trifluoroethanol.
[d] isolated yield.
[e] n.r.=no reaction.
[f] c.m.=complex mixture.
[g] anhydrous solvents.
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afford 1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione 4aa
(Scheme 2).
Table 5. Scope investigation with regard to 1,6- conjugate
addition products.[a,b]
Having sufficient spirocycles in hand, the following
transformation was carried out in sequential one pot
fashion. The conjugate addition product 3aa was
in situ generated in the reaction mixture starting from
p-QM 1a and urea derivative 2a in the presence of
DBU at rt in anhydrous CH3CN. After the complete
consumption of both the starting materials in the
reaction mixture as observed from thin layer chroma-
tography, PIDA (2 equiv.) was then added, and the
reaction mixture was further stirred at rt for 8 h. The
desired cyclized product 4aa was obtained in 35%
overall yield (Scheme 3).
Further, to investigate the synthetic potential of the
synthesized spiroimidazolidinones, the debenzylation
of the compound 4aa was executed using H2/PdÀ C
conditions. Product 5aa having N-hydroxy urea ring
attached cyclohexadienone was obtained with 80%
yield (Scheme 4). These N-hydroxy cyclic ureas can
act as crucial structural elements in various metal-
loenzyme inhibitors.[19]
In order to check the applicability of the proposed
protocol, a gram-scale synthesis for the stepwise
spirocyclization of p-QMs and dialkyloxy urea was
Scheme 2. Plausible mechanism for the stepwise cyclization.
[a] Unless otherwise stated, all the reactions were carried out in
anhydrous CH3CN (1 mL) at rt with 3 (0.171 mmol) and
PIDA (0.352 mmol).
Scheme 3. One-pot sequential synthesis of 4.
[b] Isolated yields.
anticipated that oxidizing agent (PIDA) might have
generated the nitrenium ion intermediate B from
conjugate addition product 3aa. As nitrenium ions are
highly susceptible to nucleophilic attack due to their
electrophilic nature, intermediate B could have under-
gone an intramolecular dearomative cyclization to
Scheme 4. Debenzylation of 4.
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(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
phenyl)(4-methoxyphenyl)methyl)urea (3ba): Yield=75 mg
also carried out under the optimized reaction con-
ditions. The final spirocyclized product was obtained
in 48% overall yield (Scheme 5).
(85%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
Melting Point: 179–181 C; H NMR (400 MHz, CDCl3): δ 8.12
1
°
(s, 1H), 7.37-7.18 (m, 12H), 6.84 (d, J=8.2 Hz, 2H), 6.79 (d,
J=7.7 Hz, 2H), 6.43 (s, 1H), 5.19 (s, 1H), 4.82 (s, 2H), 4.16 (d,
J=9.4 Hz, 1H), 4.05 (d, J=9.3 Hz, 1H), 3.79 (s, 3H), 1.37 (s,
18H); 13C-NMR (100 MHz, CDCl3): δ 160.2, 158.8, 153.3,
135.8, 135.6, 131.2, 129.3, 129.1, 128.8, 128.6, 128.6, 128.6,
113.6, 78.7, 78.3, 65.9, 55.3, 34.3, 30.4; IR (neat): 2960, 1679,
1511, 1452, 1356, 1236, 1178, 1116, 971, 895, 827, 697,
607 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated for
C37H45N2O5 597.3328, found 597.3269.
Conclusion
In conclusion, an efficient method for the formation of
spiro-imidazolidinone-cyclohexadienones via vinylo-
gous aza-Michael addition of urea derivatives (dialky-
loxy/diaryloxy ureas) with p-QMs followed by cycliza-
tion under mild conditions has been demonstrated.
This protocol has a wide substrate scope in terms of
both of the reactants and also demonstrates a sequential
one-pot approach. These scaffolds may seek attention
in pharmaceutical industries and organic synthesis due
to the diverse activities of imidazolidinones and cyclo-
hexadienones. Also, debenzylation of spiroimidazolidi-
nones gave biologically important N-hydroxy cyclic
ureas.
(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
phenyl)(p–tolyl)methyl)urea (3ca): Yield=82 mg (88%); Rf =
0.60 (EtOAc: Hexanes=2.0:8.0); White solid; Melting Point:
185–187 C; H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.35
1
°
(s, 4H), 7.29-7.17 (m, 8H), 7.10 (d, J=7.8 Hz, 2H), 6.80 (d,
J=7.5 Hz, 2H), 6.44 (s, 1H), 5.19 (s, 1H), 4.82 (s, 2H), 4.16 (d,
J=9.6 Hz, 1H), 4.04 (d, J=9.5 Hz, 1H), 2.32 (s, 3H), 1.37 (s,
18H); 13C-NMR (100 MHz, CDCl3): δ 160.1, 153.3, 136.9,
136.1, 135.8, 135.6, 134.5, 129.3, 129.1, 128.9, 128.8, 128.6,
128.5, 126.6, 78.6, 78.3, 66.2, 34.4, 30.4, 21.2; IR (neat): 3634,
2954, 1689, 1435, 1365, 1235, 1120, 739, 698 cmÀ 1; HRMS
(ESI, Q-TOF) m/z: [M+Na]+ Calculated for C37H44N2O4Na
603.3186, found 603.3199.
Experimental Section
Representative Procedure for Conjugate Addition
Eeaction of p-Quinone Methide (1) and Urea
Derivative (2)
(+/À )
1,3-bis(benzyloxy)-1-((4-(Benzyloxy)phenyl)(3,5-di-
(3da): Yield=
A round-bottom flask equipped with a magnetic stir bar was
charged with p-quinone methide 1 (0.181 mmol, 1 equiv.), urea
derivative 2 (0.181 mmol, 1 equiv.) and DBU (0.272 mmol,
1.5 equiv.). DCM (1 mL) was added as a solvent, and the
reaction mixture was stirred at room temperature until
completion of the reaction (as monitored by TLC). The solvent
was evaporated on a rotary evaporator and further purified by
silica gel column chromatography taking ethyl acetate/hexanes
as eluent to afford 3.
tert-butyl-4-hydroxyphenyl)methyl)urea
65 mg (80%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White
solid; Melting Point: 145–147 C; H NMR (400 MHz, CDCl3):
1
°
δ 8.13 (s, 1H), 7.43-7.16 (m, 17H), 6.91 (d, J=8.4 Hz, 2H),
6.79 (d, J=7.6 Hz, 2H), 6.43 (s, 1H), 5.18 (s, 1H), 5.04 (s, 2H),
4.82 (s, 2H), 4.16 (d, J=9.9 Hz, 1H), 4.05 (d, J=9.8 Hz, 1H),
1.37 (s, 18H); 13C-NMR (100 MHz, CDCl3): δ 160.1, 158.1,
153.3, 137.0, 135.8, 135.6, 134.5, 131.6, 130.2, 129.3, 129.2,
128.8, 128.6, 128.6, 128.0, 127.6, 126.5, 114.6, 78.7, 78.3, 70.1,
66.0, 34.4, 30.4; IR (neat): 2951, 1696, 1610, 1581, 1510, 1436,
1363, 1300, 1111, 1025, 894, 696, 535 cmÀ 1; HRMS (ESI, Q-
TOF) m/z: [M+Na]+ Calculated for C43H48N2O5Na 695.3441,
found 695.3461.
Spectral Data
(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
phenyl)(phenyl)methyl)urea (3aa): Yield=92 mg (90%); Rf =
(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
0.60 (EtOAc: Hexanes=2.0:8.0); White solid; Melting Point:
1
phenyl)(3,4-dimethoxyphenyl)methyl)urea (3ea): Yield=
°
162–164 C; H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 740–
68 mg (78%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White
solid; Melting Point: 152–154 C; H NMR (400 MHz, CDCl3):
7.17 (m, 15H), 6.78 (d, J=7.6 Hz, 2H), 6.48 (s, 1H), 5.20 (s,
1H), 4.83 (d, J=2.7 Hz, 2H), 4.15 (d, J=9.5 Hz, 1H), 4.02 (d,
J=9.5 Hz, 1H), 1.37 (s, 18H); 13C-NMR (100 MHz, CDCl3): δ
160.1, 153.4, 139.3, 135.8, 135.6, 134.4, 129.3, 129.1, 128.8,
128.6, 128.6, 128.5, 128.2, 127.3, 126.7, 78.7, 78.3, 66.4, 55.3,
34.4, 30.3; IR (neat): 3380, 2949, 1697, 1446, 1362, 1232,
1106, 945, 743, 646, 478 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+
H]+ Calculated for C36H43N2O4 567.3223, found 567.3214.
1
°
δ 8.14 (s, 1H), 7.36-7.32 (m, 5H), 7.28-7.17 (m, 5H), 6.96 (d,
J=9.0 Hz, 2H), 6.80 (d, J=7.8 Hz, 3H), 6.42 (s, 1H), 5.21 (s,
1H), 4.83 (s, 2H), 4.19 (d, J=9.5 Hz, 1H), 4.09 (d, J=9.6 Hz,
1H), 3.85 (s, 3H), 3.75 (s, 3H), 1.35 (s, 18H); 13C-NMR
(100 MHz, CDCl3): δ 160.2, 153.3, 148.5, 148.3, 135.8, 135.6,
134.5, 131.5, 129.3, 129.0, 128.8, 128.6, 128.6, 126.5, 121.4,
112.4, 110.7, 78.6, 78.3, 66.2, 55.9, 55.8, 34.4, 30.4; IR (neat):
2960, 1691, 1509, 1451, 1266, 1232, 1108, 947, 890, 669,
542 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+Na]+ Calculated for
C38H46N2O6Na 649.3250, found 649.3254.
(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
phenyl)(4-fluorophenyl)methyl)urea (3fa): Yield=75 mg
(80%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 195–197 C; H NMR (400 MHz, CDCl3): δ 8.13
(s, 1H), 7.39- 7.32 (m, 7H), 7.28-7.16 (m, 5H), 6.99 (t, J=
Scheme 5. Stepwise spirocyclization in gram scale.
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8.8 Hz, 2H), 6.77 (d, J=7.2 Hz, 2H), 6.46 (s, 1H), 5.23 (s, 1H),
4.83 (d, J=5.4 Hz, 2H), 4.16 (d, J=9.6 Hz, 1H), 4.02 (d, J=
9.3 Hz, 1H), 1.37 (s, 18H); 13C-NMR (100 MHz, CDCl3): δ
162.1 (d, J=245.5 Hz), 160.0, 153.5, 135.7, 135.1, 134.3,
130.4, 129.2 (d, J=12.1 Hz), 128.9, 128.6, 128.3, 126.6, 115.1
(d, J=21.3 Hz), 78.8, 78.3, 65.8, 34.4, 30.3; 19F (376 MHz,
CDCl3): δ=-115.2 ppm IR (neat): 2958, 1688, 1508, 1452,
1369, 1212, 1120, 976, 849, 747, 605, 530 cmÀ 1; HRMS (ESI,
Q-TOF) m/z: [M+H]+ Calculated for C36H42N2O4F 607.2948,
found 607.292.
(100 MHz, CDCl3): δ 159.8, 153.7, 143.6, 135.9, 135.7, 134.1,
129.5 (J=32.5 Hz), 129.2, 129.1, 129.0, 128.7, 127.5, 126.9,
125.2 (q, J=3.8 Hz), 124.2 (J=272.5 Hz), 78.9, 78.4, 66.1,
34.4, 30.3; 19F (376 MHz, CDCl3): δ=-62.3 ppm; IR (neat):
2947, 2922, 2887, 2865, 1693, 1435, 1324, 1170, 1114, 1017,
895, 749 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated
for C37H42N2O4F3 635.3082, found 635.3097.
(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
phenyl)(naphthalen-1-yl)methyl)urea (3ka) : Yield=68 mg
(78%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
(+/À )
1,3-bis(benzyloxy)-1-((4-Chlorophenyl)(3,5-di-tert-
butyl-4-hydroxyphenyl)methyl)urea (3ga): Yield=68 mg
Melting Point: 209–211 C; H NMR (400 MHz, CDCl3): δ 8.15
(s, 1H), 7.88-7.77 (m, 2H), 7.54-7.31 (m, 8H), 7.27-7.15 (m,
7H), 6.73 (d, J=7.5 Hz, 2H), 5.16 (s, 1H), 4.84 (s, 2H), 3.77
(d, J=9.6 Hz, 2H), 1.35 (s, 18H); 13C-NMR (100 MHz,
CDCl3): δ 159.6, 153.2, 135.8, 135.7, 135.2, 134.4, 133.7,
131.8, 129.3, 129.0, 128.8, 128.7, 128.6, 128.5, 126.6, 125.8,
125.1, 124.1, 78.5, 78.4, 62.6, 34.4, 30.4; IR (neat): 3408, 2954,
1676, 1432, 1363, 1232, 1116, 909, 857, 792, 740, 609 cmÀ 1;
HRMS (ESI, Q-TOF) m/z: [M+Na]+ Calculated for
C40H44N2O4Na 639.3199, found 639.3189.
(75%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 190–192 C; H NMR (400 MHz, CDCl3): δ 8.10
(s, 1H), 7.38-7.31 (m, 5H), 7.30-7.12 (m, 9H), 6.75 (d, J=
7.5 Hz, 2H), 6.41(s, 1H), 5.21 (s, 1H), 4.83 (d, J=11.3 Hz,
1H), 4.78 (d, J=11.4 Hz, 1H), 4.14 (d, J=9.8 Hz, 1H), 3.90 (d,
J=9.6 Hz, 1H), 1.35 (s, 18H); 13C-NMR (100 MHz, CDCl3): δ
159.9, 153.6, 137.9, 135.8, 135.7, 134.2, 133.1, 130.0, 129.3,
129.1, 128.9, 128.6, 128.4, 127.9, 126.7, 78.8, 78.3, 65.8, 34.4,
30.3; IR (neat): 3396, 3024, 2958, 1689, 1451, 1361, 1258,
1014, 978, 800, 606, 519 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M
+H]+ Calculated for C36H42N2O4Cl 601.2833, found 601.2838.
(+/À )
1,3-bis(benzyloxy)-1-((3-(tert-butyl)-4-hydroxy-5-
methylphenyl)(phenyl)methyl)urea (3la): Yield=85 mg
(82%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
(+/À )
1,3-bis(benzyloxy)-1-((2-Bromophenyl)(3,5-di-tert-
butyl-4-hydroxyphenyl)methyl)urea (3ha): Yield=62 mg
Melting Point: 150–152 C; H NMR (400 MHz, CDCl3): δ 8.15
(s, 1H), 7.40-7.34 (m, 7H), 7.33-7.17 (m, 7H), 6.97 (s, 1H),
6.81 (d, J=7.7 Hz, 2H), 6.46 (s, 1H), 4.83 (d, J=2.3 Hz, 3H),
4.14 (d, J=9.6 Hz, 1H), 4.03 (d, J=9.4 Hz, 1H), 2.18 (s, 3H),
1.35 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 160.0, 152.3,
139.3, 135.8, 135.5, 134.4, 129.3, 129.2, 128.9, 128.6, 128.6,
128.3, 127.4, 126.8, 122.8, 78.8, 78.3, 66.0, 34.6, 29.8, 16.2; IR
(neat): 3369, 2952, 1684, 1452, 1170, 911, 747, 698 cmÀ 1;
HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated for C33H37N2O4
525.2759, found 525.2753.
(72%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 152–154 C; H NMR (400 MHz, CDCl3): δ 8.13
(s, 1H), 7.57-7.19 (m, 10H), 7.15-7.10 (m, 3H), 6.80-6.76 (m,
3H), 5.19 (s, 1H), 4.83 (d, J=4.0 Hz, 2H), 4.04 (d, J=9.2 Hz,
1H), 3.95 (d, J=9.1 Hz, 1H), 1.37 (s, 18H); 13C-NMR
(100 MHz, CDCl3): δ 159.5, 153.4, 139.3, 135.8, 135.7, 134.2,
133.1, 129.3, 129.3, 129.0, 128.9, 128.6, 127.3, 126.4, 124.5,
78.8, 78.3, 65.9, 34.4, 30.4; IR (neat): 2957, 2880, 1696, 1585,
1433, 1399, 1235, 1024, 893, 698, 616 cmÀ 1; HRMS (ESI, Q-
TOF) m/z: [M+H]+ Calculated for C36H42N2O4Br 645.2328,
found 645.2300.
(+/À ) 1,3-bis((4-chlorobenzyl)oxy)-1-((3,5-di-tert-butyl-4-hy-
droxyphenyl)(phenyl)methyl)urea
(3ab):
Yield=91 mg
(82%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
phenyl)(4-nitrophenyl)methyl)urea (3ia): Yield=59 mg
Melting Point: 90–92 C; H NMR (400 MHz, CDCl3): δ 7.98
(s, 1H), 7.31-7.18 (m, 9H), 7.15-7.08 (m, 4H), 6.64 (d, J=
8.1 Hz, 2H), 6.39 (s, 1H), 5.14 (s, 1H), 4.71 (s, 2H), 4.05 (d,
J=10.1 Hz, 1H), 3.94 (d, J=9.9 Hz, 1H), 1.29 (s, 18H); 13C-
NMR (100 MHz, CDCl3): δ 160.0, 153.4, 139.0, 135.7, 134.9,
134.5, 134.3, 132.8, 130.6, 130.4, 128.8, 128.8, 128.2, 77.8,
77.5, 66.6, 34.4, 30.3; IR (neat): 2955, 1676, 1434, 1364, 1235,
1088, 1015, 847, 808, 732, 614, 542 cmÀ 1; HRMS (ESI, Q-
TOF) m/z: [M+Na]+ Calculated for C36H40N2O4NaCl2
657.2255, found 657.2263.
(68%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 155–157 C; H NMR (400 MHz, CDCl3): δ 8.16
(d, J=8.6 Hz, 3H), 7.52 (d, J=8.5 Hz, 2H), 7.40-7.35 (m, 4H),
7.33-7.18 (m, 6H), 7.12 (s, 1H), 6.77 (d, J=7.5 Hz, 2H), 6.54
(s, 1H), 4.86 (d, J=11.5 Hz, 1H), 4.80 (d, J=11.3 Hz, 1H),
4.04 (d, J=9.2 Hz, 1H), 3.95 (d, J=9.1 Hz, 1H), 1.37 (s, 18H);
13C-NMR (100 MHz, CDCl3): δ 159.6, 154.0, 147.4, 147.1,
136.1, 135.6, 133.9, 129.2, 129.2, 129.1, 128.7, 128.7 127.0,
126.9, 123.5, 79.0, 78.4, 65.9, 34.4, 30.3; IR (neat): 3627, 2956,
1691, 1520, 1435, 1346, 1236, 1120, 744, 699 cmÀ 1; HRMS
(ESI, Q-TOF) m/z: [M+H]+ Calculated for C36H42N3O6
612.3074, found 612.3075.
(+/À ) 1-((3,5-di-tert-butyl-4-hydroxyphenyl)(phenyl) meth-
yl)-1,3-bis((4-fluorobenzyl)oxy)urea (3ac): Yield=88 mg
(85%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 126–128 C; H NMR (400 MHz, CDCl3): δ 8.16
(+/À )
1,3-bis(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy
(3ja):
(s, 1H), 7.47-7.32 (m, 9H), 7.11 (t, J=8.5 Hz, 2H), 6.99 (t, J=
8.1 Hz, 2H), 6.89-6.83 (m, 2H), 6.55 (s, 1H), 5.29 (s, 1H), 4.87
(s, 2H), 4.23 (d, J=10.1 Hz, 1H), 4.12 (d, J=9.9 Hz, 1H), 1.45
(s, 18H); 13C-NMR (100 MHz, CDCl3): δ 163.0 (d, J=
248.3 Hz), 162.9 (d, J=246.6 Hz), 160.2, 153.4, 139.1, 135.7,
131.2 (d, J=8.5 Hz), 131.0 (d, J=8.5 Hz), 130.3, 128.7, 128.4,
128.3, 127.5, 126.7, 115.6 (d, J=21.5 Hz), 115.5 (d, J=
21.3 Hz), 77.9, 77.5, 66.5, 34.4, 30.3; 19F (376 MHz, CDCl3):
δ=-112.1 ppm, À 113.0 ppm; IR (neat): 3380, 2949, 1703,
phenyl)(4-(trifluoromethyl)phenyl)methyl)urea
Yield=54 mg (65%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0);
1
°
White solid; Melting Point: 166–168 C; H NMR (400 MHz,
CDCl3): δ 8.25 (s, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.58 (d, J=
8.0 Hz, 2H), 7.50-7.44 (m, 6H), 7.40- 7.28 (m, 4H), 6.87 (d, J=
7.6 Hz, 2H), 6.62 (d, J=7.6 Hz, 2H), 5.36 (s, 1H), 4.96 (d, J=
11.4 Hz, 2H), 4.91 (d, J=11.3 Hz, 1H), 4.27 (d, J=9.5 Hz,
1H), 4.11 (d, J=9.2 Hz, 1H), 1.48 (s, 18H); 13C-NMR
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1602, 1510, 1448, 1365, 1226, 833, 698,614 cmÀ 1; HRMS (ESI,
Q-TOF) m/z: [M+H]+ Calculated for C36H41N2O4F2 603.3013,
found 603.3034.
18H); 13C-NMR (100 MHz, CDCl3): δ 160.5, 153.4, 139.3,
135.6, 134.7, 129.1, 128.9, 128.7, 128.5, 128.2, 127.4, 126.6,
78.6, 66.5, 64.5, 34.4, 30.3; IR (neat): 3635, 2954, 1675, 1434,
1235, 1120, 996, 736, 698, 616 cmÀ 1; HRMS (ESI, Q-TOF) m/
z: [M+Na]+ Calculated for C30H38N2O4Na 513.2717, found
513.2729.
(+/À ) 1-((3,5-di-tert-butyl-4-hydroxyphenyl)(phenyl) meth-
yl)-1,3-bis((4-bromobenzyl)oxy)urea (3ad): Yield=93 mg
(76%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 130–132 C; H NMR (400 MHz, CDCl3): δ 8.13
(+/À ) 1-(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy phe-
(s, 1H), 7.58 (d, J =8.3 Hz, 2H), 7.47-7.28 (m, 11H), 6.75 (d,
J=8.3 Hz, 2H), 6.55 (s, 1H), 5.30 (s, 1H), 4.86 (d, J=1.8 Hz,
2H), 4.20 (d, J=9.9 Hz, 1H), 4.09 (d, J=9.8 Hz, 1H), 1.46 (s,
18H); 13C-NMR (100 MHz, CDCl3): δ 160.0, 153.4, 139.0,
135.7, 134.8, 133.2, 131.8, 131.8, 130.9, 130.6, 128.7, 128.3,
127.5, 126.6, 123.1, 122.7, 77.9, 77.5, 66.6, 34.4, 30.3; IR
(neat): 3632, 2955, 1676, 1434, 1364, 1235, 1121, 1070, 846,
737, 701 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+Na]+ Calcu-
lated for C36H40N2O4NaBr2 745.1251, found 745.1253.
nyl)(phenyl)methyl)-3-phenylurea
(3ah):
Yield=70 mg
(76%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 134–136 C; H NMR (400 MHz, CDCl3): δ 7.71
(s, 1H), 7.44 (d, J=7.6 Hz, 2H), 7.35-7.20 (m, 12H), 7.15-7.11
(m, 2H), 7.03-6.98 (m, 1H), 6.63 (s, 1H), 5.20 (s, 1H), 4.30 (d,
J=10.3 Hz, 1H), 4.23 (d, J=10.4 Hz, 1H), 1.38 (s, 18H); 13C-
NMR (100 MHz, CDCl3): δ 157.0, 153.3, 139.7, 138.0, 135.7,
134.9, 129.2, 129.1, 128.9, 128.9, 128.3, 127.3, 126.7, 123.5,
119.1, 79.3, 66.2, 34.4, 30.3; IR (neat): 2963, 1670, 1595, 1520,
1441, 1220, 1119, 915, 695, 583 cmÀ 1; HRMS (ESI, Q-TOF) m/
z: [M+H]+ Calculated for C35H41N2O3 537.3102, found
537.311.
(+/À ) 1-((3,5-di-tert-butyl-4-hydroxyphenyl)(phenyl) meth-
yl)-1,3-bis((4-methylbenzyl)oxy)urea (3ae): Yield=76 mg
(75%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 162–164 C; H NMR (400 MHz, CDCl3): δ 8.04
(+/À ) 3-benzyl-1-(benzyloxy)-1-((3,5-di-tert-butyl-4-hydrox-
yphenyl)(phenyl)methyl)urea (3ai): Yield=75 mg (80%);
Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid; Melting
(s, 1H), 7.31-7.08 (m, 11H), 6.93 (d, J=7.8 Hz, 2H), 6.59 (d,
J=7.8 Hz, 2H), 6.40 (s, 1H), 5.12 (s, 1H), 4.71 (s, 2H), 4.03 (d,
J=9.3 Hz, 1H), 3.89 (d, J=9.2 Hz, 1H), 2.29 (s, 3H), 2.23 (s,
3H), 1.30 (s, 18H); 13C-NMR (100 MHz, CDCl3): δ 160.0,
153.3, 139.3, 138.8, 138.4, 135.5, 132.8, 131.4, 129.4, 129.3,
129.2, 128.6, 128.2, 127.3, 78.5, 78.1, 66.3, 34.4, 30.3, 21.3,
21.3; IR (neat): 3633, 2954, 1690, 1435, 1363, 1235, 1120, 804,
738, 616 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated
for C38H47N2O4 595.3536, found 595.3539.
1
°
Point: 136–138 C; H NMR (400 MHz, CDCl3): δ 7.47 (d, J=
7.5 Hz, 2H), 7.36-7.19 (m, 11H), 7.03 (d, J=7.2 Hz, 2H), 6.99
(d, J=7.1 Hz, 2H), 6.56 (s, 1H), 6.16 (t, J=6.0 Hz, 1H), 5.21
(s, 1H), 4.34 (brs, 2H), 4.28 (d, J=10.4 Hz, 1H), 4.19 (d, J=
10.1 Hz, 1H), 1.39 (s, 18H); 13C-NMR (100 MHz, CDCl3): δ
160.3, 153.2, 139.8, 138.8, 135.5, 135.1, 129.2, 129.0, 128.7,
128.6, 128.2, 127.2, 127.2, 126.7, 78.6, 67.0, 44.0, 34.4, 30.3;
IR (neat): 3635, 3363, 2958, 1655, 1520, 1433, 1263, 994, 739,
697, 600 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated
for C36H43N2O3 551.3260, found 551.3274.
(+/À ) 1-((3,5-di-tert-butyl-4-hydroxyphenyl)(phenyl) meth-
yl)-1,3-dimethoxyurea (3af): Yield=56 mg (80%); Rf =0.60
(EtOAc: Hexanes=2.0:8.0); White solid; Melting Point: 151–
1
°
153 C; H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.39-7.21
(m, 5H), 7.13 (s, 2H), 6.41 (s, 1H), 5.19 (s, 1H), 3.72 (s, 3H),
3.20 (s, 3H), 1.38 (s, 18H); 13C-NMR (100 MHz, CDCl3): δ
160.3, 153.2, 139.2, 135.6, 128.9, 128.7, 128.1, 127.3, 126.0,
66.0, 64.7, 64.1, 34.4, 30.4; IR (neat): 3626, 3236, 2952, 1663,
1478, 1232, 1141, 1111, 1003, 932, 769, 696 cmÀ 1; HRMS
(ESI, Q-TOF) m/z: [M+H]+ Calculated for C24H35N2O4
415.2597, found 415.2586.
Representative Procedure for Spirocyclization of
Conjugate Addition Product 3
A round-bottom flask equipped with a magnetic stir bar was
charged with 3 (0.171 mmol, 1 equiv.) and diacetoxy iodoben-
zene (0.352 mmol, 2 equiv.) under an inert atmosphere. Anhy-
drous acetonitrile (1 mL) was added as a solvent to the reaction
mixture and stirred at room temperature until completion of the
reaction (as monitored by TLC). The solvent was evaporated on
a rotary evaporator and further purified by silica gel column
chromatography taking ethyl acetate/hexanes as eluent to afford
4.
(+/À ) 1-(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy phe-
nyl)(phenyl)methyl)-3-methoxyurea (3ag): Yield=34 mg
(40%); Rf =0.50 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 108–110 C; H NMR (400 MHz, CDCl3): δ 8.22
(s, 1H), 7.36-7.23 (m, 10H), 7.13 (s, 2H), 6.42 (s, 1H), 5.18 (s,
1H), 4.88 (s, 2H), 3.12 (s, 3H), 1.38 (s, 18H); 13C-NMR
(100 MHz, CDCl3): δ 159.9, 153.2, 139.2, 135.6, 129.5, 128.9,
128.6, 128.6, 128.2, 127.3, 126.2, 78.5, 66.1, 64.0, 34.4, 30.4;
IR (neat): 3635, 2954, 1675, 1434, 1235, 1120, 996, 736, 698,
616 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+Na]+ Calculated for
C30H38N2O4Na 513.2717, found 513.2729.
Spectral Data
(+/À ) 1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-phenyl-1,3-dia-
zaspiro[4.5]deca-6,9-diene-2,8-dione (4aa): Yield=64 mg
(65%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5); Yellow solid;
Melting Point: 120–122 C; 1H NMR (400 MHz, CDCl3): δ
°
7.34-7.19 (m, 13H), 7.05 (d, J=7.5 Hz, 2H), 6.32 (d, J=
2.8 Hz, 1H), 6.28 (d, J=2.8 Hz, 1H), 5.31 (d, J=9.8 Hz, 1H),
5.08-4.95 (m, 3H), 4.36 (s, 1H), 1.13 (s, 9H), 0.92 (s, 9H); 13C-
NMR (100 MHz, CDCl3): δ 185.0, 162.0, 151.7, 151.0, 136.4,
135.3, 135.3, 135.2, 131.7, 129.5, 129.3, 129.0, 128.8, 128.7,
128.5, 128.4, 128.1, 127.8, 79.5, 79.0, 68.9, 64.6, 35.0, 29.2,
28.8; IR (neat): 2955, 17159, 1646, 1455, 1365, 1296, 1009,
(+/À ) 3-(benzyloxy)-1-((3,5-di-tert-butyl-4-hydroxy phe-
nyl)(phenyl)methyl)-1-methoxyurea (3ag’): Yield=42 mg
(50%); Rf =0.60 (EtOAc: Hexanes=2.0:8.0); White solid;
1
°
Melting Point: 98–100 C; H NMR (400 MHz, CDCl3): δ 8.29
(s, 1H), 7.46 (d, J=7.6 Hz, 2H), 7.39-7.28 (m, 6H), 7.25 (s,
2H), 7.13-7.08 (m, 2H), 6.54 (s, 1H), 5.25 (s, 1H), 4.31 (d, J
=9.9 Hz, 1H), 4.31 (d, J=9.8 Hz, 1H), 3.67 (s, 3H), 1.42 (s,
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883, 745, 698 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+
Calculated for C36H41N2O4 565.3054, found 564.3066.
1144, 1010, 883, 745, 589 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M
+H]+ Calculated for C38H45N2O6 625.3278, found 625.3281.
(+/À )
1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(4-methoxy
phenyl)-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione (4ba):
(+/À )
1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(4-fluoro
(4fa):
phenyl)-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
Yield=58 mg (58%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
Yield=55 mg (55%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
1
1
°
°
White solid; Melting Point: 115–117 C; H NMR (400 MHz,
White solid; Melting Point: 180–182 C; H NMR (400 MHz,
CDCl3): δ 7.27-7.17 (m, 10H), 6.89 (d, J=8.7 Hz, 2H), 6.68 (d,
J=8.8 Hz, 2H), 6.27 (d, J=2.9 Hz, 1H), 6.17 (d, J=2.6 Hz,
1H), 5.19 (d, J=10.0 Hz, 1H), 4.98 (d, J=10.6 Hz, 1H), 4.89
(dd, J=10.3, 3.5 Hz, 2H), 4.23 (s, 1H), 3.68 (s, 3H), 1.04 (s,
9H), 0.89 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 185.0, 162.0,
160.1, 151.6, 150.9, 136.6, 135.4, 135.4, 129.4, 129.3, 129.2,
128.7, 128.7, 128.5, 128.4, 113.5, 79.4, 78.9, 68.6, 64.9, 55.4,
35.1, 35.0, 29.2, 28.8; IR (neat): 2956, 1756, 1642, 1513, 1454,
1365, 1248, 1173, 1011, 885, 808, 697, 530 cmÀ 1; HRMS (ESI,
Q-TOF) m/z: [M+H]+ Calculated for C37H43N2O5 595.3172,
found 595.3167.
CDCl3): δ 7.35-7.23 (m, 10H), 7.01-6.89 (m, 4H), 6.30 (d, J=
2.7 Hz, 1H), 6.24 (d, J=2.6 Hz, 1H), 5.27 (d, J=10.1 Hz, 1H),
5.06 (d, J=10.7 Hz, 1H), 4.98 (dd, J=10.3, 4.8 Hz, 2H), 4.32
(s, 1H), 1.18 (s, 9H), 0.95 (s, 9H); 13C-NMR (100 MHz,
CDCl3): δ 184.9, 163.0 (d, J=248.0 Hz), 161.9, 151.9, 151.3,
134.9, 129.6 (d, J=8.2 Hz), 129.5 129.3, 128.8, 128.5, 115.2
(d, J=21.8 Hz), 79.5, 78.9, 68.3, 64.6, 35.1, 35.1, 29.2, 28.8;
19F (376 MHz, CDCl3): δ=-112.1 ppm; IR (neat): 2955, 1759,
1644, 1508, 1364, 1285, 1218, 1000, 843, 550 cmÀ 1; HRMS
(ESI, Q-TOF) m/z: [M+H]+ Calculated for C36H40N2O4F
583.2972, found 583.2950.
(+/À ) 1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(p–tolyl)-1,3-di-
azaspiro[4.5]deca-6,9-diene-2,8-dione (4ca): Yield=56 mg
(56%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5); Orange solid;
(+/À )
1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(4-chloro
phenyl)-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione (4ga):
Yield=60 mg (60%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
White solid; Melting Point: 159–161 C; H NMR (400 MHz,
1
Melting Point: 131–133 C; 1H NMR (400 MHz, CDCl3): δ
°
°
7.33-725 (m, 10H), 7.04 (d, J=8.1 Hz, 2H), 6.94 (d, J=
8.0 Hz, 2H), 6.32 (d, J=2.8 Hz, 1H), 6.26 (d, J=2.7 Hz, 1H),
5.29 (d, J=10.0 Hz, 1H), 5.05 (d, J=10.7 Hz, 1H), 4.97 (dd,
J=10.7, 4.9 Hz, 2H), 4.33 (s, 1H), 2.29 (s, 3H), 1.12 (s, 9H),
0.92 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 185.1, 162.0,
151.5, 150.8, 138.9, 136.6, 135.5, 135.4, 135.3, 129.4, 129.3,
128.8, 128.7, 128.7, 128.5, 128.4, 127.7, 79.5, 79.0, 68.7, 64.7,
35.0, 29.2, 28.8, 21.2; IR (neat): 2953, 1760, 1642, 1453, 1304,
1248, 1078, 882, 806, 696, 504 cmÀ 1; HRMS (ESI, Q-TOF) m/
z: [M+H]+ Calculated for C37H43N2O4 579.3231, found
579.3223.
CDCl3): δ 7.37-7.23 (m, 10H), 7.20 (d, J=8.3 Hz, 2H), 6.94 (d,
J=8.5 Hz, 2H), 6.27 (d, J=2.7 Hz, 1H), 6.25 (d, J=2.8 Hz,
1H), 5.27 (d, J=10.1 Hz, 1H), 5.08-4.95 (m, 3H), 4.31 (s, 1H),
1.12 (s, 9H), 0.94 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ
184.8, 161.8, 152.0, 151.4, 136.1, 135.2, 135.1, 134.9, 134.8,
130.4, 129.5, 129.3, 129.1, 128.8, 128.5, 128.3, 79.5, 78.9,
68.3, 64.4, 35.1, 35.1, 29.2, 28.8; IR (neat): 2955, 1762, 1668,
1647, 1491, 1364, 1298, 1087, 1011, 884, 740, 507 cmÀ 1;
HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated for
C36H40N2O4Cl 599.2671, found 599.2677.
(+/À )
1,3-bis(benzyloxy)-4-(2-Bromophenyl)-7,9-di-tert-
(4ha):
(+/À )
1,3-bis(benzyloxy)-4-(4-(Benzyloxy)phenyl)-7,9-di-
tert-butyl-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione (4da):
Yield=50 mg (48%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
butyl-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
Yield=58 mg (58%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
White solid; Melting Point: 178–180 C; H NMR (400 MHz,
1
°
White solid; Melting Point: 94–96 C; 1H NMR (400 MHz,
CDCl3): δ 7.46 (d, 1H), 7.32-7.21 (m, 12H), 7.17-7.12 (m, 1H),
6.52 (d, J=2.7 Hz 1H), 6.18 (d, J=2.6 Hz, 1H), 5.19 (d, J=
10.1 Hz, 1H), 5.04-4.90 (m, 4H), 1.15 (s, 9H), 0.97 (s, 9H); 13C-
NMR (100 MHz, CDCl3): δ 185.0, 161.3, 151.0, 150.3, 136.8,
133.4, 130.4, 129.4, 128.8, 128.5, 128.5, 128.5, 79.9, 78.7,
67.1, 64.3, 35.1, 35.1, 28.9, 28.9; IR (neat): 2957, 1758, 1644,
1454, 1366, 1298, 996, 881, 743, 697, 494 cmÀ 1; HRMS (ESI,
Q-TOF) m/z: [M+H]+ Calculated for C36H40N2O4Br 643.2171,
found 643.214.
°
CDCl3): δ 7.33-7.29 (m, 3H), 7.27-7.15 (m, 12H), 6.88 (d, J=
8.6 Hz, 2H) 6.75 (d, J=8.6 Hz, 2H), 6.25 (d, J=2.6 Hz, 1H),
6.17 (d, J=2.6 Hz, 1H), 5.19 (d, J=9.9 Hz, 1H), 5.01-4.93 (m,
3H), 4.90 (d, J=10.5 Hz, 2H), 4.22 (s, 1H), 1.04 (s, 9H), 0.88
(s, 9H); 13C-NMR (100 MHz, CDCl3): δ 185.0, 162.0, 159.2,
151.6, 151.0, 136.6, 136.6, 135.4, 135.3, 129.5, 129.3, 129.2,
128.8, 128.7, 128.6, 128.5, 128.4, 128.1, 127.4, 123.8, 114.5,
79.4, 78.9, 70.1, 68.6, 64.9, 35.1, 35.0, 29.2, 28.9; HRMS (ESI,
Q-TOF) m/z: [M+H]+ Calculated for C43H47N2O5 671.3485,
found 671.3472.
(+/À )
1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(4-nitro
(4ia):
phenyl)-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
(+/À ) 1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(3,4-di meth-
Yield=48 mg (48%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
1
°
oxyphenyl)-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-
dione
White solid; Melting Point: 152–154 C; H NMR (400 MHz,
(4ea): Yield=39 mg (40%); Rf =0.50 (EtOAc: Hexanes=
CDCl3): δ 8.04 (d, J=8.6 Hz, 2H), 7.37-7.22 (m, 10H), 7.10 (d,
J=8.6 Hz, 2H), 6.28 (d, J=2.7 Hz, 1H), 6.24 (d, J=2.7 Hz,
1H), 5.28 (d, J=10.3 Hz, 1H), 5.06 (dd, J=10.9, 5.6 Hz, 2H),
4.99 (d, J=10.7 Hz, 1H), 4.40 (s, 1H), 1.12 (s, 9H), 0.90 (s,
9H); 13C-NMR (100 MHz, CDCl3): δ 184.6, 161.7, 151.9,
148.0, 139.2, 135.1, 135.0, 134.2, 129.6, 129.3, 129.0 129.0,
128.7, 128.6, 128.6, 123.2, 79.6, 78.7, 68.2, 64.1, 35.2, 29.2,
28.8; IR (neat): 2958, 1689, 1648, 1522, 1346, 1203, 976, 881,
852, 699 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated
for C36H40N3O6 610.2917, found 610.2926.
1.5:8.5); Yellow solid; Melting Point: 125–127 C; 1H NMR
°
(400 MHz, CDCl3): δ 7.26-7.17 (m, 10H), 6.66 (d, J=7.9 Hz,
2H), 6.58-6.53 (m, 2H), 6.26 (d, J=2.8 Hz, 1H), 6.23 (d, J=
2.7 Hz, 1H), 5.24 (d, J=9.9 Hz, 1H), 4.99 (d, J=10.7 Hz, 1H),
4.90 (dd, J=10.5, 3.9 Hz, 2H), 4.24 (s, 1H), 3.77 (s, 3H), 3.72
(s, 3H), 1.07 (s, 9H), 0.88 (s, 9H); 13C-NMR (100 MHz,
CDCl3): δ 185.1, 161.7, 151.5, 150.8, 149.5, 148.7, 136.7,
135.4, 135.3, 135.2, 129.3, 129.2, 128.8, 128.5, 128.5, 124.3,
120.6, 110.7, 110.7, 79.5, 79.0, 68.7, 64.7, 56.0, 55.9 35.0, 29.3,
28.9; IR (neat): 2924, 1759, 1644, 1514, 1454, 1364, 1298,
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(+/À )
1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(4-(trifluoro
methyl)phenyl)-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
2.8 Hz, 1H), 6.28 (d, J=2.7 Hz, 1H), 5.26 (d, J=10.0 Hz, 1H),
5.04-4.86 (m, 3H), 4.39 (s, 1H), 1.14 (s, 9H), 0.92 (s, 9H); 13C-
NMR (100 MHz, CDCl3): δ 184.9, 163.0 (d, J=247.0 Hz),
162.9 (d, J=247.0 Hz), 162.0, 152.0, 151.1, 136.1, 135.0,
131.6, 131.3 (d, J=8.3 Hz), 131.2 (d, J=8.1 Hz), 129.1, 128.2,
127.8, 115.5 (d, J=21.3 Hz), 115.4 (d, J=22.0 Hz)„ 78.7, 78.2,
68.9, 64.6, 35.0, 29.2, 28.8; 19F (376 MHz, CDCl3): δ=-
112.7 ppm, À 112.8 ppm; IR (neat): 2955, 1761, 1643, 1510,
1364, 1299, 1224, 1157, 1015, 824, 747, 508 cmÀ 1; HRMS
(ESI, Q-TOF) m/z: [M+H]+ Calculated for C36H39N2O4F2
601.2868, found 601.2878.
(4ja): Yield=50 mg (50%); Rf =0.50 (EtOAc: Hexanes=
1.5:8.5); White solid; Melting Point: 161–163 C; 1H NMR
°
(400 MHz, CDCl3): δ 7.39 (d, J=8.1 Hz, 2H), 7.27-7.16 (m,
10H), 7.04 (d, J=8.0 Hz, 2H), 6.21 (d, J=2.7 Hz, 1H), 6.17 (d,
J=2.7 Hz 1H), 5.23 (d, J=10.1 Hz, 1H), 5.02-4.89 (m, 3H),
4.32 (s, 1H), 1.06 (s, 9H), 0.82 (s, 9H); 13C-NMR (100 MHz,
CDCl3): δ 184.7, 161.8, 152.1, 151.5, 136.1, 136.0, 135.1,
134.6, 131.2 (J=32.2 Hz), 129.5, 129.3, 128.9, 128.6, 128.5,
128.3, 128.0, 125.1 (q, J=3.8 Hz), 123.7 (J=270.3 Hz)„ 79.6,
78.8, 68.3, 64.2, 35.1, 35.1, 29.2, 28.7; 19F (376 MHz, CDCl3):
δ=-62.6 ppm; IR (neat): 2922, 1761, 1646, 1454, 1367, 1320,
1164, 1066, 859, 735, 594 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M
+H]+ Calculated for C37H40N2O4F3 633.2940, found 633.2943.
(+/À )
1,3-bis((4-bromobenzyl)oxy)-7,9-di-tert-butyl-4-
(4ad):
phenyl-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
Yield=58 mg (58%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
1
°
White solid; Melting Point: 188–190 C; H NMR (400 MHz,
(+/À ) 1,3-bis(benzyloxy)-7,9-di-tert-butyl-4-(naphthalen-1-
CDCl3): δ 7.46 (d, J =8.3 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H),
7.28-7.19 (m, 3H), 7.16 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.1 Hz,
2H), 7.01 (d, J=7.2 Hz, 2H), 6.28 (d, J=2.8 Hz, 1H), 6.22 (d,
J=2.8 Hz, 1H), 5.21 (d, J=10.3 Hz, 1H), 5.00 (m, 3H), 4.35
(s, 1H), 1.11 (s, 9H), 0.90 (s, 9H);13C-NMR (100 MHz, CDCl3):
δ 184.8, 162.0, 152.0, 151.2, 136.0, 134.8, 134.3, 134.2, 131.7,
131.6, 131.5, 130.9, 130.9, 129.2, 128.2, 127.8, 123.0, 122.9,
78.6, 78.2, 69.0, 64.7, 35.1, 29.2, 28.8; IR (neat): 2995, 2951,
2864, 1765, 1644, 1487, 1364, 1302, 1249, 1071, 1013, 884,
748, 503 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated
for C36H39N2O4Br2 721.1260, found 721.1277.
yl)-1,3-diazaspiro
[4.5]deca-6,9-diene-2,8-dione
(4ka):
Yield=57 mg (57%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
White solid; Melting Point: 158–160 C; H NMR (400 MHz,
1
°
CDCl3): δ 7.81 (t, J=8.2 Hz, 2H), 7.54 (t, J =8.2 Hz, 2H),
7.47-7.16 (m, 13H), 6.53 (d, J=2.4 Hz, 1H), 6.15 (d, J=
2.4 Hz, 1H), 5.33-5.27 (m, 2H), 5.05-4.95 (m, 3H), 1.02 (s,
9H), 0.76 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 184.7, 161.7,
150.6, 150.3, 136.8, 136.1, 135.4, 135.2, 133.8, 131.6, 129.5,
129.4, 129.3, 129.1, 128.7, 128.5, 127.8, 126.3, 126.2, 125.7,
124.6, 122.9, 79.8, 79.0, 64.3, 64.2 34.9, 34.9, 28.8, 28.7; IR
(neat): 2922, 1763, 1649, 1455, 1365, 1289, 1016, 882, 777,
494 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated for
C40H43N2O4 615.3223, found 615.3208.
(+/À )
7,9-di-tert-butyl-1,3-bis((4-methylbenzyl)oxy)-4-
(4ae):
phenyl-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
Yield=62 mg (62%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
1
°
(+/À )
1,3-bis(benzyloxy)-7-(tert-butyl)-9-methyl-4-phenyl
White solid; Melting Point: 200–202 C; H NMR (400 MHz,
À 1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione (4la): Yield=
CDCl3): δ 7.24-6.94 (m, 13H), 6.23 (d, J=2.7 Hz, 1H), 6.14 (d,
J=2.7 Hz, 1H), 5.20 (d, J=9.9 Hz, 1H), 4.93 (d, J=10.8 Hz,
1H), 4.87 (dd, J=10.6, 4.3 Hz, 2H), 4.26 (s, 1H), 2.25 (s, 3H),
2.24 (s, 3H), 1.04 (s, 9H), 0.84 (s, 9H); 13C-NMR (100 MHz,
CDCl3): δ 185.0, 162.1, 151.5, 150.8, 138.6, 136.6, 135.4,
132.4, 132.2, 131.8, 129.5, 129.5, 129.2, 129.1, 128.9, 128.1,
127.8, 79.2, 78.8, 68.9, 64.6, 35.0, 29.1, 28.8, 21.3; IR (neat):
2995, 2953, 2865, 1760, 1642, 1458, 1364, 1250, 1076, 884,
799, 622, 499 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+
Calculated for C38H45N2O4 593.3379, found 593.3381.
30 mg (30%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5); White
1
°
solid; Melting Point: 145–147 C; H NMR (400 MHz, CDCl3):
δ 7.35-7.31 (m, 5H), 7.29-7.20 (m, 8H), 7.06 (d, J=7.9 Hz,
2H), 6.28 (s, 2H), 5.26 (d, J=10.0 Hz, 1H), 5.06-4.93 (m, 3H),
4.32 (s, 1H), 1.56 (s, 3H), 1.11 (s, 9H); 13C-NMR (100 MHz,
CDCl3): δ 185.0, 162.0, 150.4, 140.6, 138.2, 137.0, 135.2,
131.6, 129.8, 129.4, 129.1, 128.9, 128.7, 128.5, 128.4, 128.1,
127.9, 79.4, 79.0, 69.1, 64.7, 34.9, 34.9, 16.1; HRMS (ESI, Q-
TOF) m/z: [M+H]+ Calculated for C33H35N2O4 523.2590,
found 523.2597.
(+/À )
7,9-di-tert-butyl-1,3-dimethoxy-4-phenyl-1,3-diaza
(4af): Yield=64 mg
(+/À )
7,9-di-tert-butyl-1,3-bis((4-chlorobenzyl)oxy)-4-
(4ab):
spiro[4.5]deca-6,9-diene-2,8-dione
phenyl-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
(64%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5); White solid;
Melting Point: 180–182 C; 1H NMR (400 MHz, CDCl3): δ
°
Yield=59 mg (60%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
White solid; Melting Point: 171–173 C; H NMR (400 MHz,
1
°
7.31-7.25 (m, 3H), 7.19-7.12 (m, 2H), 6.59 (d, J=2.8 Hz, 1H),
6.33 (d, J=2.8 Hz, 1H), 4.45 (s, 1H), 3.91 (s, 3H), 3.83 (s, 3H),
1.24 (s, 9H), 0.92 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ
184.9, 161.4, 152.2, 151.3, 136.0, 134.8, 131.8, 129.1, 128.2,
127.6, 124.3, 120.6, 68.6, 65.9, 64.6, 64.5, 35.2, 35.0, 29.4,
28.8; IR (neat): 2950, 2865, 2819, 1750, 1645, 1457, 1365,
1299, 1078, 883, 622 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+
H]+ Calculated for C24H33N2O4 413.2440, found 413.2463.
CDCl3): δ 7.26-7.10 (m, 11H), 6.97 (d, J=7.5 Hz, 2H), 6.24 (d,
J=2.8 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 5.18 (d, J=10.3 Hz,
1H), 4.96 (m, 3H), 4.31 (s, 1H), 1.06 (s, 9H), 0.85 (s, 9H); 13C-
NMR (100 MHz, CDCl3): δ 184.8, 162.0, 152.0, 151.2, 136.1,
134.8, 134.8, 134.6, 133.8, 133.7, 131.5, 130.7, 130.6, 129.2,
128.7, 128.6, 128.2, 127.8, 78.6, 78.2, 68.9, 64.7, 35.1, 29.2,
28.8; IR (neat): 2953, 1762, 1644, 1492, 1459, 1364, 1249,
1091, 952, 811, 701, 495 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+
H]+ Calculated for C36H39N2O4Cl2 633.2287, found 633.2278.
(+/À )
3-(benzyloxy)-7,9-di-tert-butyl-1-methoxy-4-phenyl
À 1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione (4ag): Yield=
(+/À )
7,9-di-tert-butyl-1,3-bis((4-fluorobenzyl)oxy)-4-
(4ac):
24 mg (48%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5); White
solid; Melting Point: 148–150 C; H NMR (400 MHz, CDCl3):
δ 7.30-7.20 (m, 8H), 7.09-7.05 (m, 2H), 6.54 (d, J=2.8 Hz,
1H), 6.28 (d, J=2.9 Hz, 1H), 5.29 (d, J=9.9 Hz, 1H), 4.99 (d,
J=9.9 Hz, 1H), 4.39 (s, 1H), 3.81 (s, 3H), 1.21 (s, 9H), 0.91 (s,
1
°
phenyl-1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione
Yield=62 mg (63%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5);
White solid; Melting Point: 120–122 C; H NMR (400 MHz,
CDCl3): δ 7.34-7.18 (m, 6H), 7.10-6.90 (m, 7H), 6.32 (d, J=
1
°
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9H); 13C-NMR (100 MHz, CDCl3): δ 185.0, 161.5, 152.1,
151.2, 136.2, 135.3, 135.0, 131.7, 129.4, 129.0, 128.7, 128.4,
128.2, 127.7, 78.9, 69.0, 65.9, 64.5, 35.1, 35.0, 29.4, 28.8; IR
(neat): 2958, 1759, 1646, 1456, 1364, 1265, 1031, 882, 735,
699 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated for
C30H37N2O4 489.2751, found 489.2753.
Lindel, J. Org. Chem. 2006, 71, 9431–9439; c) T.
Yoshimitsu, T. Ino, T. Tanaka, Org. Lett. 2008, 10, 5457–
5460; d) M. G. Calvo, R. D. Meurer, J. Lisnock, H. G.
Bull, D. R. McMasters, M. E. McCann, S. G. Mills, R. J.
DeVita, K. L. Howell, Bioorg. Med. Chem. Lett. 2010,
20, 6929–6932.
[5] a) T. A. Ramirez, Q. Wang, Y. Zhu, H. Zheng, X. Peng,
R. G. Cornwall, Y. Shi, Org. Lett. 2013, 15, 4210–4213;
b) J.-A. Xiao, C.-M. Wang, G.-U. Ou, X.-Y. Zhangf, H.
Yang, Tetrahedron 2015, 71, 805–812.
(+/À )
1-(benzyloxy)-7,9-di-tert-butyl-3-methoxy-4-phenyl
À 1,3-diazaspiro[4.5]deca-6,9-diene-2,8-dione (4ag’): Yield=
22 mg (45%); Rf =0.50 (EtOAc: Hexanes=1.5:8.5); White
solid; Melting Point: 162–164 C; H NMR (400 MHz, CDCl3):
1
°
[6] a) E. M. Antunes, B. R. Copp, T. Samaai, M. T. Davies-
Coleman, Nat. Prod. Rep. 2005, 22, 62–72; b) J.
Liimatainen, M. Karonen, K. Wiinamaki, P. Eklund, R.
Sjoholm, K. A. Pihlaja, J. Sinkkonen, Angew. Chem.
2007, 119, 4226–4228; Angew. Chem. Int. Ed. 2007, 46,
4148–4150; c) Y.-W. Chin, A. A. Salim, B.-N. Su, Q.
Mi, H.-B. Chai, S. Riswan, L. B. S. Kardono, A.
Ruskandi, N. R. Farnsworth, S. M. Swanson, A. D. King-
horn, J. Nat. Prod. 2008, 71, 390–395; d) K. S.
MacMillan, D. L. Boger, J. Med. Chem. 2009, 52, 5771–
5780; e) H. Fan, J. Xiong, S.-B. Wu, J.-F. Hu, Chem.
Rev. 2011, 111, 5465–5491; f) L. Kaysser, P. Bernhardt,
S.-J. Nam, S. Loesgen, J. G. Ruby, P. Skewes-Cox, P. R.
Jensen, W. Fenical, B. S. Moore, J. Am. Chem. Soc.
2012, 134, 11988–11991; g) S.-G. Ma, R.-M. Gao, Y.
-H Li, J.-D. Jiang, N.-B. Gong, L. Li, Y. Lü, W.-Z. Tang,
Y.-B. Liu, J. Qu, H.-N. Lu, Y. Li, S.-S. Yu, Org. Lett.
2013, 15, 4450–4453; h) Y. Lai, T. Liu, R. Sa, X. Wei, Y.
Xue, Z. Wu, Z. Luo, M. Xiang, Y. Zhang, G. Yao, J. Nat.
Prod. 2015, 78, 1740–1744.
δ 7.38-7.22 (m, 8H), 7.17-7.09 (m, 2H), 6.38 (d, J=2.8 Hz,
1H), 6.30 (d, J=2.9 Hz, 1H), 5.07 (d, J=11.0 Hz, 1H), 4.97 (d,
J=11.1 Hz, 1H), 4.42 (s, 1H), 3.92 (s, 3H), 1.14 (s, 9H), 0.92
(s, 9H); 13C-NMR (100 MHz, CDCl3): δ 185.0, 161.5, 152.1,
151.2, 136.2, 135.3, 135.0, 131.7, 129.4, 129.0, 128.7, 128.4,
128.2, 127.7, 78.9, 69.0, 65.9, 64.5, 35.1, 35.0, 29.4, 28.8; IR
(neat): 2955, 1759, 1645, 1455, 1364, 1295, 1030, 882, 847,
698 cmÀ 1; HRMS (ESI, Q-TOF) m/z: [M+H]+ Calculated for
C30H37N2O4 489.2751, found 489.2753.
Acknowledgements
We gratefully acknowledge the financial support from the
Department of Science & Technology, New Delhi, and the
Council of Scientific and Industrial Research (CSIR-India).
N.K. and P.S. thank IIT Ropar for providing infrastructure and
other facilities related to this work.
References
[7] a) C.-S. Lee, J. P. McGovren, M. A. Warpehoski, M. A.
Mitchell, R. C. Kelly, P. A. Aristoff, L. H. Hurley,
Biochemistry 1988, 27, 3886–3892; b) J. P. Parrish, D. B.
Kastrinsky, S. E. Wolkenberg, Y. Igarashi, D. L. Boger, J.
Am. Chem. Soc. 2003, 125, 10971–10976; c) S. Canesi,
D. Bouchu, M. A. Ciufolini, Angew. Chem. 2004, 116,
4436–4438; Angew. Chem. Int. Ed. 2004, 43, 4336–4338;
d) M. S. Burge, D. J. Wardrop, Chem. Commun. 2004,
1230–1231; e) Z. Jin, Nat. Prod. Rep. 2005, 22, 111–
126; f) M. Ciufolini, N. Braun, S. Canesi, M. Ousmer, J.
Chang, D. Chai, Synthesis 2007, 3759–3772; g) L.
Pouysegu, D. Deffieux, S. Quideau, Tetrahedron. 2010,
66, 2235–2261; h) R. A. Bauer, T. A. Wenderski, D. S.
Tan, Nat. Chem. Biol. 2013, 9, 21–29.
[8] For selected examples see: a) W.-D. Chu, L.-F. Zhang,
X. Bao, X.-H. Zhao, C. Zeng, J.-Y. Du, G.-B. Zhang, F.-
X. Wang, X.-Y. Ma, C.-A. Fan, Angew. Chem. Int. Ed.
2013, 52, 9229–9233; b) L. Caruana, F. Kniep, T. K.
Johansen, P. H. Poulsen, K. A. Jørgensen, J. Am. Chem.
Soc. 2014, 136, 15929–15932; c) Y. Lou, P. Cao, T. Jia,
Y. Zhang, M. Wang, J. Liao, Angew. Chem. 2015, 127,
12302–12306; Angew. Chem. Int. Ed. 2015, 54, 12302–
12306; d) Z. Wang, Y. F. Wong, J. Sun, Angew. Chem.
2015, 46, 13915–13918; Angew. Chem. Int. Ed. 2015, 54,
13711–13714; e) Y.-H. Deng, X.-Z. Zhang, K.-Y. Yu, X.
Yan, J.-Y. Du, H. Huang, C.-A. Fan, Chem. Commun.
2016, 52, 4183–4186; f) N. Dong, Z.-P. Zhang, X.-S.
Xue, X. Li, J.-P. Cheng, Angew. Chem. 2016, 128, 1482–
[1] a) G. R. Pettit, J. McNulty, D. L. Herald, D. L. Doubek,
J.-C. Chapuis, J. M. Schmidt, L. P. Tackett, M. R. Boyd,
J. Nat. Prod. 1997, 60, 180–183; b) C.-S. Chang, Y.-T.
Lin, S.-R. Shih, C.-C. Lee, Y.-C. Lee, C.-L. Tai, S.-N.
Tseng, J.-H. Chern, J. Med. Chem. 2005, 48, 3522–3535;
c) K.-C. Lee, E. Venkateswararao, V. K. Sharma, S.-H.
Jung, Eur. J. Med. Chem. 2014, 80, 439–446.
[2] a) J. Chern, C. Chang, C. Tai, Y. Lee, C. Lee, I. Kang, C.
Lee, S. Shih, Bioorg. Med. Chem. Lett. 2005, 15, 4206–
4211; b) B. E. Blass, A. Fensome, E. Trybulski, R.
Magolda, S. J. Gardell, K. Liu, M. Samuel, I. Feingold,
C. Huselton, C. M. Jackson, L. Djandjighian, D. Ho, J.
Hennan, J. M. Janusz, J. Med. Chem. 2009, 52, 6531–
6534; c) C. P. Leslie, M. S. Biagetti, S. Bison, M.
Bromidge, R. D. Fabio, D. Donati, A. Falchi, M. J.
Garnier, A. Jaxa-Chamiec, G. Manchee, G. Merlo, D. A.
Pizzi, L. P. Stasi, J. Tibasco, A. Vong, S. E. Ward, L.
Zonzini, J. Med. Chem. 2010, 53, 8228–8240; d) Z.
Moussa, M. A. M. Sh El-Sharief, A. M. Sh El-Sharief,
Eur. J. Med. Chem. 2011, 46, 2280–2289.
[3] a) L.-F. Xiao, L.-W. Xu, C.-G. Xia, Green Chem. 2007,
9, 369–372; b) S. Lakhdar, B. Maji, H. Mayr, Angew.
Chem. 2012, 124, 5837–5840; Angew. Chem. Int. Ed.
2012, 51, 5739–5742.
[4] a) S. Jung, H. Lee, J. Song, H. Kim, S. Han, C. Lee, M.
Lee, D. Choi, J. Lee, Y. Chung, S. Yoon, E. Moon, H.
Hwang, S. Seong, D. Lee, Bioorg. Med. Chem. Lett.
1998, 8, 1547–1550; b) M. Zollinger, P. Mayer, T.
Adv. Synth. Catal. 2021, 363, 1–13
11
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
1486; Angew. Chem. Int. Ed. 2016, 55, 1460–1464; g) F.-
S. He, J.-H. Jin, Z.-T. Yang, X. Yu, J. S. Fossey, W. .-P.
Deng, ACS Catal. 2016, 6, 652–656; h) X.-Z. Zhang, Y.-
H. Deng, X. Yan, K.-Y. Yu, F.-X. Wang, X.-Y. Ma, C.-A.
Fan, J. Org. Chem. 2016, 81, 5655–5662; i) X. Li, X.
Xu, W. Wei, A. Lin, H. Yao, Org. Lett. 2016, 18, 428–
431; j) C. Yang, S. Gao, H. Yao, A. Lin, J. Org. Chem.
Deng, K.-J. Gan, X. Yan, K.-Y. Yu, F.-X. Wang, C.-A.
Fan, Org. Lett. 2017, 19, 1752–1755; e) L. Roiser, M.
Waser, Org. Lett. 2017, 19, 2338–2341; f) Z. Yuan, K.
Gai, Y. Wu, J. Wu, A. Lin, H. Yao, Chem. Commun.
2017, 53, 3485–3488; g) R. Pan, L. Hu, C. Han, A. Lin,
H. Yao, Org. Lett. 2018, 20, 1974–1977; h) L. Roiser, K.
Zielke, M. Waser, Synthesis 2018, 50, 4047–4054.
2016, 81, 11956–11964; k) S. Gao, X.-Y. Xu, Z.-B. [11] a) Z. Yuan, W. Wei, A. Lin, H. Yao, Org. Lett. 2016, 18,
Yuan, H.-P. Zhou, H. Yao, A. Lin, Eur. J. Org. Chem.
2016, 3006–3012; l) B. Harish, M. Subbireddy, O.
3370–3373; b) C. Ma, Y. Huang, Y. Zhao, ACS Catal.
2016, 6, 6408–6412.
Obulesu, S. Suresh, Org. Lett. 2019, 21, 1823–1827; [12] Y. Zhao, B. Chang, X. Zhao, R. Zhang, X. Liu, D.
m) C. Curti, L. Battistini, A. Sartori, F. Zanardi, Chem.
Rev. 2020, 120, 2448–2612; n) D. Li, Y. Yang, M. Zhang,
Huang, K.-H. Wang, C. Huo, Y. Hu, Y. Su, J. Org.
Chem. 2019, 84, 6719–6728.
L. Wang, Y. Xu, D. Yang, R. Wang, Nat. Commun. 2020, [13] S. B. Kale, P. K. Jori, T. Thatikonda, R. G. Gonnade, U.
11, 2559. Das, Org. Lett. 2019, 21, 7736–7740.
[9] For selected examples, see: a) A. Parra, M. Tortosa, [14] a) I. Gallou, Org. Prep. Proced. Int. 2007, 39, 355–383;
ChemCatChem 2015, 1524–1526; b) B. Huang, Y.-Y.
Shen, Z.-J. Mao, Y. Liu, S.-L. Cui, Org. Lett. 2016, 18,
b) M. Brindisi, A. Ghosh, J. Med. Chem. 2020, 63,
2751–2788.
4888–4891; c) C. Jarava-Barrera, A. Parra, A. Lopez, F. [15] a) A. Acharya, D. Anumandla, C. S. Jeffrey, Org. Lett.
Cruz-Acosta, D. Collado-Sanz, D. J. Cardenas, M.
Tortosa, ACS Catal. 2016, 6, 442–446; d) Y. Shen, J. Qi,
Z. Mao, S. Cui, Org. Lett. 2016, 18, 2722–2725; e) K.
Zhao, Y. Zhi, A. Wang, D. Enders, ACS Catal. 2016, 6,
2014, 16, 5112–5115; b) D. Anumandla, R. Littlefield,
C. S. Jeffrey, J. Am. Chem. Soc. 2015, 137, 14858–
14860; c) A. A. Rosser, A. A. Taherpour, B. W. Greatrex,
S. A. Glover, Aust. J. Chem. 2014, 67, 507–520.
657–660; f) S. Li, Y. Liu, B. Huang, T. Zhou, H. Tao, Y. [16] a) I. M. Taily, D. Saha, P. Banerjee, Eur. J. Org. Chem.
Xiao, L. Liu, J. Zhang, ACS Catal. 2017, 7, 2805–2809;
g) R. Zhuge, L. Wu, M. Quan, N. Butt, G. Yang, W.
2019, 7804–7813; b) I. M. Taily, D. Saha, P. Banerjee,
Org. Biomol. Chem. 2020, 6564–6570.
Zhang, Adv. Synth. Catal. 2017, 359, 1028–1036; h) N. [17] CCDC 2038941 (4ha) contains the supplementary
Molleti, J.-Y. Kang, Org. Lett. 2017, 19, 958–961; i) Y.
Zhao, B. Chang, Q. Ling, Y. Feng, X. Zhao, D. Huang,
K.-H. Wang, C. Huo, Y. Hu, Y. Su, Org. Biomol. Chem.
2020, 18, 4257–4266; j) F. P. Pauli, D. C. S. Costa, A. S.
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
Souza, L. S. M. Forezi, V. F. Ferreira, C. G. S. Lima, [18] a) M. S. Burge, W. Zhang, J. A. Ortiz, D. J. Wardrop,
F. C. Silva, Eur. J. Org. Chem. 2020, 2020, 2650–2692.
[10] a) Z. Yuan, X. Fang, X. Li, J. Wu, H. Yao, A. Lin, J.
Org. Chem. 2015, 80, 11123–11130; b) K. Gai, X. Fang,
Tetrahedron Lett. 2003, 44, 2587–2591; For reviews, see:
b) S. Maiti, M. T. Alam, A. Bal, P. Mal, Adv. Synth.
Catal. 2019, 361, 4401–4425.
X. Li, J. Xu, X. Wu, A. Lin, H. Yao, Chem. Commun. [19] a) B. C. Follows, P. J. Hergenrother, C. L. Franklin, S. F.
2015, 51, 15831–15834; c) X.-Z. Zhang, J.-Y. Du, Y.-H.
Deng, W.-D. Chu, X. Yan, K.-Y. Yu, C.-A. Fan, J. Org.
Chem. 2016, 81, 2598–2606; d) X.-Z. Zhang, Y.-H.
Martin, J. Org. Chem. 2000, 65, 4509–4514; b) J. A.
Day, S. M. Cohen, J. Med. Chem. 2013, 56, 7997–8007.
Adv. Synth. Catal. 2021, 363, 1–13
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Vinylogous Aza-Michael Addition of Urea Derivatives with
p-Quinone Methides Followed by Oxidative Dearomative
Cyclization: Approach to Spiroimidazolidinone Derivatives
Adv. Synth. Catal. 2021, 363, 1–13
N. Kaur, Dr. P. Singh, Dr. P. Banerjee*