Enantioselective synthesis of unsymmetrical diaryl-substituted spirocyclohexanonepyrazolones through a cascade [4+2] double Michael addition

Article abstract of DOI:10.1002/adsc.201200925

The spirocyclic pyrazolones are an important class of molecular structures with significant biological and pharmaceutical activities. Herein, we demonstrate that the combination of a Cinchona-based chiral primary amine and an ortho-fluorobenzoic acid is an efficient catalyst system for the double Michael addition of arylidenepyrazolones with α,β-unsaturated ketones, providing chiral unsymmetrical 6,10-diaryl-substituted spiro[cyclohexanone- pyrazolone] derivatives in high yields (up to 98%) with good diastereoselectivities and excellent enantioselectivities (up to 88:12 dr, 99% ee). Copyright

Full text of DOI:10.1002/adsc.201200925

UPDATES
DOI: 10.1002/adsc.201200925
Enantioselective Synthesis of Unsymmetrical Diaryl-Substituted
Spirocyclohexanonepyrazolones through a Cascade [4+2]Double
Michael Addition
Jin-Xin Zhang,a Nai-Kai Li,a Zhao-Min Liu,a Xiao-Fei Huang,a Zhi-Cong Geng,a
and Xing-Wang Wanga,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
Fax : (+86)-512-6588-0378; e-mail: wangxw@suda.edu.cn
Received: October 17, 2012; Revised: December 12, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200925.
Abstract: The spirocyclic pyrazolones are an impor-
tant class of molecular structures with significant
biological and pharmaceutical activities. Herein, we
demonstrate that the combination of a Cinchona-
based chiral primary amine and an ortho-fluoroben-
zoic acid is an efficient catalyst system for the
double Michael addition of arylidenepyrazolones
with a,b-unsaturated ketones, providing chiral un-
symmetrical 6,10-diaryl-substituted spiro[cyclohex-
synthesis of the optically active pyrazolone deriva-
tives,[7] so far only few asymmetric cascade methodol-
ogies[8] have been developed for the construction of
enantioenriched spirocyclic[9] pyrazolones. In 2011,
Rios and co-workers have reported a cascade Mi-
chael/Michael/intramolecular aldol reaction sequence,
affording the multistereogenic chiral spiro[pyrazo-
lone-cyclohexenecarbaldehyde] compounds in moder-
ate to good yields with excellent enantioselectivi-
ties.[10] Very recently, our group has demonstrated that
optically active spiro[pyrazolone-cyclohexones] could
be efficiently synthesized through a cascade [5+
ACHTUNGTRENNUNGanone-pyrazolone] derivatives in high yields (up to
98%) with good diastereoselectivities and excellent
enantioselectivities (up to 88:12 dr, 99% ee).
Keywords: arylidenepyrazolones; enantioselectivity;
Michael addition; organic catalysis
Pyrazolone skeletons are a valuable class of molecular
motifs occurring in many natural products and syn-
thetic compounds of pharmaceutical interest.[1] Some
examples are shown in Scheme 1, whereby P38 is
a very effective inhibitor for the treatment of inflam-
mation,[2] while the HIV-1 integrase inhibitor[2,3] and
hydantoin have specific activities against bacteria.[4]
In particular, chiral spirocyclic pyrazolones with a qua-
ternary stereogenic center are promising subsets of
the spirocyclic family with potential biological and
pharmaceutical activities. Thus, the development of
catalytic enantioselective synthetic protocols for the
efficient preparation of this type of compounds has
been of considerable interest for organic chem-
ACHTUNGTRENNUNG
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Jin-Xin Zhang et al.
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1]double Michael reaction between divinyl ketones metrical spiro[cyclohexanone-pyrazolone] derivatives,
and pyrazolones.[11] In that work we have found that via a cascade [4+2]double Michael addition between
in the presence of 20 mol% of quinine-derived pri- arylmethylene pyrazolones and a,b-unsaturated ke-
mary amine and 40 mol% of Boc-d-Phg-OH, the re- tones. Under the optimized conditions, a variety of
actions of symmetrical 1,5-diaryl divinyl ketones with chiral spiro[cyclohexanone-pyrazolones] bearing un-
various substituents on phenyl groups, irrespective of symmetrical diaryl substituents on the cyclohexanone
their electron-donating or electron-withdrawing backbone were obtained in high yields with good dia-
nature, proceeded smoothly under the optimized con- stereoselectivities and excellent enantioselectivities
ditions, to give the corresponding spirocyclohexano- [Scheme 2, Eq. (iii).]
nepyrazolones in reasonable yields with moderate to
We proposed our synthetic approach through a cas-
good diastereomeric ratios (dr) and good to excellent cade double Michael reaction between arylidenepyra-
enantioselectivities [Scheme 2, Eq. (i)]. However, the zolones and a,b-unsaturated ketones[12] involving en-
amine and/or iminium ion intermediates. It is note-
worthy that the combination of a Cinchona alkaloid-
derived primary amine with an organic protonic
acid[13] has often been used as a powerful catalyst in
many enantioselective enamine and iminium ion-
mediated transformations.[14] With this in mind, we
started to examine the model reaction between ben-
zylidenepyrazolone 1a and benzylideneacetone 2a,
using 20 mol% quinidine-derived primary amine[15]
I
or its pseudoenantiomer II as catalysts and 40 mol%
benzoic acid A1 as an additive. Initially, several com-
monly used solvents were screened for the reaction at
room temperature. As shown in Table 1, the reaction
proceeded smoothly in THF to provide the double
Michael adducts in 55% overall yield with three pairs
of diastereomers, albeit with over 90% ee for two
major diastereomers (entry 1). CH2Cl2, n-hexane, tol-
uene, and PhCl, were further examined as the reac-
tion media, and toluene was found to be optimal, af-
fording the desired product 3a in 92% yield, 84:16 dr,
and 99% ee for both major and minor diasteroisomers
(entry 5 vs. entries 2–4). Subsequently, some homo-
logues of toluene were investigated under the cataly-
sis of the amine catalyst I and benzoic acid A1, but
none of them has shown better catalytic results in
terms of both reactivity and diastereoselectivity
(Table 1, entries 6–9). Finally, quinine-derived primary
amine catalyst II, a pseudo-enantiomer of I has also
been also examined in the reaction under otherwise
identical conditions. Although the enantioselectivities
remain excellent for both diastereomers, some decline
in yield and diastereoselectivity of 3a was observed
for this case (entry 10).
Scheme 2. The construction of multistereogenic symmetrical
or non-symmetrical diaryl-substituted spiro[cyclohexanone-
pyrazolones] through a cascade [5+1] or [4+2]double Mi-
chael addition.
diastereoselectivity declines significantly for the un-
In order to explore the influence of the organic
symmetrical 1,5-diaryl-substituted divinyl ketones as protonic acid on reactivity and diastereoselectivity of
the Michael acceptors, presumably as a result of the this transformation, a variety of achiral and/or chiral
difficulty of the catalyst in differentiating the two Brønsted acids was examined in combination with
enantiofaces of the substrate attacked by the nucleo- amine catalyst I, and the results are shown in Table 2.
phile during the first Michael addition step. In this It was found that for the benzoic acid derivatives
case, the corresponding [5+1]double Michael reac- (Figure 1) screened in the reaction, A2 and A3 bear-
tion gave an almost equal amount of diastereomers in ing an electron-withdrawing group (NO2 or CF3) on
low yield, albeit with excellent enantioselectivity for the phenyl ring led to the product 3a with higher dia-
two major diastereomers [Scheme 2, Eq. (ii)]. In the stereo- and enantioselectivities, albeit in lower yields
present work, we report an alternative organocata- (entries 2 and 3 vs. 1). In contrast, the use of aromatic
lyzed protocol for the asymmetric synthesis of unsym- acids A5 or A6 bearing an electron-donating group
2
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Enantioselective Synthesis of Unsymmetrical Diaryl-Substituted Spirocyclohexanonepyrazolones
Table 1. Examination of catalysts and solvents.[a]
Entry
Catalyst/Additive
Solvent
Yield [%][b]
dr [%][c]
ee [%][c]
1
2
3
4
5
6
7
8
9
I/A1
I/A1
I/A1
I/A1
I/A1
I/A1
I/A1
I/A1
I/A1
II/A1
THF
55
81
58
86
92
93
65
93
95
84
12:35:53
50:50
47:53
64:36
84:16
75:25
89:11
72:28
75:25
69:31
11/98/93
98/91
96/96
99/99
99/99
99/99
99/96
99/98
99/99
CH2Cl2
n-hexane
PhCl
toluene
o-xylene
m-xylene
p-xylene
mesitylene
toluene
10
À98/À99
[a]
Reactions were performed with 1 (0.2 mmol), 2 (0.4 mmol) and catalyst loading I or II (20 mol%)/A1 (40 mol%), in sol-
vents (2.0 mL) at room temperature.
Yield of isolated product.
Determined by chiral HPLC.
[b]
[c]
Table 2. Screening of achiral and chiral Brønsted acids.[a]
Entry
Catalyst/Additive
Yield [%][b]
dr [%][c]
ee [%][c]
1
2
3
4
5
6
7
8
I/A1
I/A2
I/A3
I/A4
I/A5
I/A6
I/A7
I/A8
92
60
62
96
94
89
63
76
85
trace
54
trace
trace
78
84:16
91:9
92:8
85:15
77:23
71:29
6:83:11
87:13
86:14
nd
13:73:14
nd
nd
82:18
75:25
86:14
99/99
98/99
99/99
99/99
99/98
99/99
88/98/99
99/99
98/99
nd
99/98/99
nd
nd
97/99
À96/À96
99/99
9
I/A9
10
11
12
13
14
15
16[d]
I/A10
I/A11
I/A12
I/A13
I/A14
II/A14
I/A4
60
60
[a]
Unless noted otherwise, reactions were performed with 1 (0.2 mmol), 2 (0.4 mmol) and catalyst loading I or II
(20 mol%)/A1–A14 (40 mol%), in toluene (2.0 mL) at room temperature.
[b]
[c]
[d]
Yield of isolated product.
Determined by chiral HPLC.
At 08C.
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lectivities (entries 5 and 6 vs. 1). When ortho-fluoro-
benzoic acid A4 was used as the additive, the combi-
nation of amine catalyst I/A4 turned out to be opti-
mal in terms of both reactivity and stereoselectivity
for this transformation, affording the corresponding
product 3a in 96% yield with good diastereo- and ex-
cellent enantioselectivities (entry 4). The stronger
acid TFA seemed to have a detrimental effect on
both the reactivity and diastereoselectivity, although
high enantioselectivities were retained for the three
diastereomers (entry 7). Some chiral Brønsted acids
A8–A14 were also tested for this reaction. Intriguing-
ly, the combinations of (R)-BINOL-derived chiral
phosphoric acid A10, camphorsulfonic acid A12 and
A13 with I, respectively, were found to be inactive for
the catalysis of this transformation, only giving the
target product 3a in trace amounts under otherwise
identical conditions (entries 10, 12 and 13). The use of
the other amine catalyst/chiral acid additive pairs af-
forded the desired products in excellent enantioselec-
tivities, but with reduced yields and/or diastereoselec-
tivities (entries 8, 9, 11 and 14). Overall, the combina-
tion I/A4 turned out to be the optimal catalytic
system with respect to the double Michael addition of
benzylidenepyrazolone 1a with benzylideneacetone 2a
in toluene at room temperature.
Figure 1. The catalysts screened in this study.
(Me, OMe) afforded product 3a in high yields and ex-
With the optimized reaction conditions in hand, we
cellent enantioselectivities but with lower diastereose- further examined the scope and limitations of the
Table 3. Substrate scope of I/A4-catalyzed double Michael addition of benzylidenepyrazolone 1a with a,b-unsaturated ke-
tones 2a–l.[a]
Entry
Ar
Yield [%][b]
dr [%][c]
ee [%][c]
1
2
3
4
5
6
7
8
4-Br-C6H4 (2a)
4-Cl-C6H4 (2b)
3-Cl-C6H4 (2c)
4-F-C6H4 (2d)
3a/96
3b/95
3c/98
3d/95
3e/90
3f/93
3g/77
3h/79
3i/84
3j/86
3k/88
3l/82
85:15
84:16
88:12
83:17
84:16
82:18
58:37:5
82:18
85:15
88:12
51:49
73:27
99/99
97/–
99/99
99/99
99/99
99/95
99/96/94
99/99
99/83
99/99
99/99
99/99
2-F-C6H4 (2e)
4-CF3-C6H4 (2f)
2,4-(MeO)2C6H3 (2g)
2-MeO-C6H4 (2h)
4-i-Pr-C6H4 (2i)
4-Me-C6H4 (2j)
1-naphthyl (2k)
2-thienyl (2l)
9
10
11
12
[a]
Reactions were performed with 1a (0.2 mmol), 2a–l (0.4 mmol) and catalyst loading I (20 mol%)/A4 (40 mol%), in tolu-
ene (2.0 mL) at room temperature.
Yield of isolated product.
Determined by chiral HPLC.
[b]
[c]
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Enantioselective Synthesis of Unsymmetrical Diaryl-Substituted Spirocyclohexanonepyrazolones
Table 4. Substrate scope of I/A4-catalyzed double Michael addition of a,b-unsaturated pyrazolone derivatives 1b–l with a,b-
unsaturated ketones.[a]
Entry
1 (Ar, R1, R2)
R3
Product/Yield [%][b]
dr [%][c]
ee [%][c]
1
2
3
4
5
6
7
8
1b (C6H5, CH3, 4-F-C6H4)
1c (C6H5, CH3, 3,5-(MeO)2C6H3)
1d (C6H5, CH3, 4-ClC6H4)
1e (C6H5, CH3, 3-Me-C6H4)
1b (C6H5, CH3, 4-F-C6H4)
1c (C6H5, CH3, 3,5-(MeO)2C6H3)
1d (C6H5, CH3, 4-Cl-C6H4)
1e (C6H5, CH3, 3-Me-C6H4)
1f (C6H5, C6H5, C6H5)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
4-Me-C6H4 (2j)
4-Me-C6H4 (2j)
4-Me-C6H4 (2j)
4-Me-C6H4 (2j)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
3-Cl-C6H4 (2c)
Me (2m)
3m/93
3n/96
3o/95
3p/89
3q/83
3r/78
3s/88
3t/84
3u/60
<10
3v/90
3w/90
3x/88
3y/93
<10
82:18
88:12
83:17
86:14
72:28
80:20
68:32
78:22
11:43:46
–
74:26
70:30
84:16
88:12
–
99/95
99/99
97/95
94/99
92/99
98/96
94/94
98/–
9
–/99/99
–
10[d]
11
12
13
14
15[d]
16[d]
1g (C6H5, CF3, C6H5)
1h (4-Br-C6H4, CH3, C6H5)
1i (3-Cl-C6H4, CH3, C6H5)
1j (4-Me-C6H4, CH3, C6H5)
1k (4-MeO-C6H4, CH3, C6H5)
1l (C6H5, CH3, Cy)
99/99
98/99
99/99
91/99
–
1a (C6H5, CH3, C6H5)
<10
–
–
[a]
Unless noted otherwise, reactions were performed with 1 (0.2 mmol), 2 (0.4 mmol) and catalyst loading I (20 mol%)/A4
(40 mol%), in toluene (2.0 mL) at room temperature for 10 h.
Yield of isolated product.
Determined by chiral HPLC.
Reactions were performed for 24 h.
[b]
[c]
[d]
double Michael addition between benzylidenepyrazo- ed ketones 2k and 2l containing fused aromatic or
lone 1a with a,b-unsaturated ketones 2a–l under the heteroaromatic rings were also suitable substrates for
catalyst loading of 20 mol% quinidine-derived pri- this reaction, to provide the desired products 3k and
mary amine I and 40 mol% ortho-fluorobenzoic acid 3l in good yields (88% and 82%) with excellent enan-
A4 in toluene at room temperature, and the results tioselectivities (99% ees for both diastereomers), re-
are summarized in Table 3. The reactions proceeded spectively, albeit with less satisfactory diastereoselec-
smoothly to give the corresponding adducts in good tivities (51:49 and 73:27 drs) (Table 3, entries 11 and
to excellent yields with moderate to good diastereose- 12).
lectivities and excellent enantioselectivities. While ex-
As demonstrated in Table 4, the combination of I/
cellent enantioselectivities were retained for all de- A4 was also applied in the double Michael addition
sired products 3a–l, the steric hindrance and electron- of a,b-unsaturated ketones 2c and 2j with benzylid-
ic properties of the substituents on the phenyl ring of
benzylideneacetone derivatives 2a–l seem to have above optimized reaction conditions. The benzylid-
some influence on the reactivity and diastereoselectiv- enepyrazolone derivatives 1b–e bearing electron-do-
ACHTUNGTRENeNGNU nepyrazolone derivatives 1b–e in toluene under the
AHCTUNGTRENNUNG
ity of the reactions. Generally, electron-withdrawing nating or electron-withdrawing substituents on the
substituents on the phenyl ring of benzylideneacetone phenyl rings were amenable to the procedure, and all
derivatives 2a–f showed high reactivity and selectivity the reactions proceeded smoothly to give the desired
to give expected products in 90–98% yields and 82:18 products in good yields (78–96%), moderate to good
to 88:12 drs (Table 3, entries 1–6), whereas electron- diastereoselective ratios (68:32 to 88:12 dr) and excel-
donating substituents on the phenyl ring of benzylid- lent enantioselectivities (92–99% ee) (entries 1–8).
ACHTUNGTRENNUNGeneacetone derivatives 2g–j provided the correspond- However, when 1 f was used, changing the methyl
ing products in lower yields (77–86%) with varying group to phenyl group in comparision with 1a, inferi-
levels of diastereoselectivities (from 58:37:5 to 88:12 or diastereoselectivity (11:43:46 dr) and yield (60%)
drs) (Table 3, entries 7-10). Apparently, a,b-unsaturat- were obtained, probably due to the effect of the steric
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Jin-Xin Zhang et al.
UPDATES
ther improvement on diastereoselectivity and expan-
sion of the substrate scope of this catalytic system, as
well as biological evaluations of the resulting spiro-
compounds will be undertaken in the future.
Experimental Section
General Information
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification.
All reactions were carried out in air and using undistilled
solvents, without any precautions to exclude moisture unless
otherwise mentioned. Organic solutions were concentrated
under reduced pressure on a rotary evaporator. Reactions
were monitored by thin-layer chromatography (TLC) on
silica gel precoated glass plates (0.2Æ0.03 mm thickness,
GF-254, particle size 0.01–0.04 mm). Chromatograms were
visualized by fluorescence quenching with UV light at
254 nm. Flash column chromatography was performed using
Figure 2. The X-ray crystal structure of 3a.
1
silica gel (particle size 0.04–0.05 mm). H (400 MHz) and 13C
hindrance for the first Michael addition (Table 4,
entry 9). Trifluoromethyl-substituted benzylidenepyra-
zolone 1g was proved to be an ineffective substrate
for this transformation (Table 4, entry 10). Subse-
quently, benzylidenepyrazolones 1h–k bearing differ-
ent aryl groups on the nitrogen have also been inves-
tigated for the double Michael addition, all the reac-
tions proceeded smoothly to give expected adducts in
excellent yields (88–93%) with good diastereoselectiv-
ities (70:30 to 88:12 drs) and excellent enantioselec-
tivities (91–99% ees) (Table 4, entries 11–14). In addi-
tion, both aliphatic substituted a,b-unsaturated ke-
tones and alkylidenepyrazolones were respectively
tested in this reaction, such as 1l and pent-3-en-2-one
2m. Unfortunately, under our optimized conditions,
catalyst I/A4 was found to be ineffective for the trans-
formation involving these compounds (Table 4, en-
tries 15 and 16). To our delight, the single crystal of
(100 MHz) NMR spectra were recorded in CDCl3 using
TMS as the internal reference. Chemical shifts (d ppm) are
relative to the resonance of the deuterated solvent as the in-
ternal standard (CDCl3, d=7.26 ppm for proton NMR, d=
1
77.00 ppm for carbon NMR). H NMR data are reported as
follows: chemical shift (d, ppm), multiplicity (s=singlet, d=
doublet, q=quartet, sep=septet, m=multiplet), coupling
constants (J) and assignment. Data for 13C NMR are report-
ed in terms of chemical shift (d, ppm). High-resolution mass
spectra (HR-MS) for all the compounds were determined
on Micromass GCT-TOF mass spertrometer with EI or ESI
sources. The enantiomeric excess (ee) of the products was
determined by HPLC using a Chiralcel OD-H column
(0.46 cmꢂ25 cm), Chiralpak AD-H (0.46 cmꢂ25 cm), Chir-
alpak I A (0.46 cmꢂ25 cm) with 2-propanol/hexane as the
eluent. Optical rotation data were examined in CHCl3 solu-
tion at 258C and [a]D25 values are reported in 10À1 dgcm2 gÀ1
concentration (c) is reported in g/100 mL.
;
compound 3a was obtained by recrystallization from General Experimental Procedures for the
hexane/acetone, which allowed us to make an unam- Asymmetric Double Michael Addition Reaction
biguous assignment of the trans configuration of C-
Pyrazolones derivatives 1 (0.2 mmol), a,b-unsaturated ke-
tones 2 (0.4 mmol), catalyst I (20 mol%), o-F-PhCOOH
(40 mol%) were stirred in toluene (2.0 mL) at room temper-
ature for 10 h in air. Then the reaction mixture was directly
subjected to flash column chromatography on silica gel (pe-
1 and C-5 stereocenters by X-ray crystallographic
analysis, and the newly formed three carbon centers
were all designated to be of the R configuration.
(Figure 2).[16]
In summary, we have developed an efficient proto- troleum ether/ethyl acetate=5:1) to afford the correspond-
ing products 3.
col for the construction of enantiomerically enriched
unsymmetrical diaryl-substituted spirocyclo[hexa-
none-pyrazolones] via a cascade [4+2]double Mi-
chael addition reaction between arylideneacetones
with arylidenepyrazolones, which is catalyzed by
a combination of a Cinchona-based chiral primary
amine and ortho-fluorobenzoic acid. All explored cas-
cade double reactions could provide the spirocyclo-
Characterization Data of Michael Addition Products
3
6-(4-Bromophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro-
AHCTUNGTREG[NNUN 4.5]dec-3-ene-1,8-dione (3a): white solid; yield: 93.5 mg
(96%), 85:15 dr, 99% eemajor, 99% eeminor. The dr and ee
values were determined by HPLC [Daicel Chiralpak AD-H
with hexane/i-PrOH (80:20) as the eluent, flow:
ACHTUNGTRENNUNG
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
=
=
6
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Enantioselective Synthesis of Unsymmetrical Diaryl-Substituted Spirocyclohexanonepyrazolones
23.545 min; [a]D25: +42.9 (c 0.42 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.50–7.49 (m, 2H), 7.42–7.40 (m,
1H), 7.35–7.28 (m, 5H), 7.20–7.10 (m, 4H), 7.03–6.99 (m,
2H), 3.91–3.79 (m, 2H), 3.64 (dd, J=14.2, 3.0 Hz, 1H), 3.36
(dd, J=16.4, 5.2 Hz, 1H), 2.96 (dd, J=16.4, 9.2 Hz, 1H),
2.61 (dd, J=16.0, 3.2 Hz, 1H), 1.64 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=209.0, 174.6, 160.6, 138.3, 136.9,
135.7, 131.8, 129.5, 129.0, 128.9 128.2, 127.7, 125.8, 122.1,
119.9, 61.6, 44.2, 41.8, 41.1, 40.5, 15.7; IR (KBr): nmax =1707,
1600, 1494, 1401, 758, 693 cmÀ1; ESI-MS (%): m/z=487.1
[M+H]+; HR-MS (ESI): m/z=487.1023 [M+H]+, calcd. for
C27H24BrN2O2: 487.1021.
127.8, 126.0, 119.9, 115.9, 115.6, 62.2, 44.2, 41.8, 41.5, 40.7,
15.9; IR (KBr): nmax =1709, 1598, 1503, 1401, 1227, 838, 760,
694 cmÀ1
;
ESI-MS (%): m/z=427.2 [M+H]+; HR-MS
(ESI): m/z=427.1823 [M+H]+, calcd. for C27H24FN2O2:
427.1822.
6-(2-Fluorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro-
AHCTUNGTREG[NNUN 4.5]dec-3-ene-1,8-dione (3e): white solid; yield: 76.9 mg
(90%), 84:16 dr, 99% eemajor, 99% eeminor. The dr and ee
values were determined by HPLC [Daicel Chiralpak OD-H
with hexane/i-PrOH (80:20) as the eluent; flow:
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
=
16.664 min; minor diastereoisomer tmajor =26.041 min; [a]2D5:
1
6-(4-Chlorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro-
+59.0 (c 0.41 in CHCl3); H NMR (400 MHz, CDCl3): d=
A
7.50–7.48 (m, 2H), 7.41–7.37 (m, 1H), 7.32–7.25 (m, 5H),
7.16–7.11 (m, 4H), 7.01 (t, J=7.2 Hz, 1H), 6.94–6.89 (m,
1H), 4.19 (dd, J=14.2, 3.0 Hz, 1H), 3.97 (dd, J=10.4,
4.8 Hz, 1H), 3.87–3.79 (m, 1H), 3.29 (dd, J=16.4, 4.4 Hz,
1H), 3.07 (dd, J=16.6, 10.6 Hz, 1H), 2.56 (dd, J=16.6,
3.0 Hz, 1H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
208.8, 174.9, 161.3, 138.1, 137.2, 129.6, 129.6, 129.2, 129.0,
128.8, 128.1, 127.6, 125.7, 124.6, 123.9, 123.8, 119.8, 115.5,
115.3, 61.6, 43.8, 40.9, 40.5, 33.6, 15.3; IR (KBr): nmax =1709,
1596, 1496, 1400, 758, 699 cmÀ1; ESI-MS (%): m/z=427.2
[M+H]+; HR-MS (ESI): m/z=427.1803 [M+H]+, calcd. for
C27H24FN2O2: 427.1822.
(95%), 84:16 dr, 97% eemajor. The dr and ee values were de-
termined by HPLC [Daicel Chiralpak OD-H with hexane/i-
PrOH (80:20) as the eluent, flow: 1.0 mLminÀ1, l=254 nm]:
major diastereoisomer tmajor =19.132 min, tminor =22.827 min;
minor diastereoisomer t=30.645 min; [a]2D5: +45.8 (c 0.45 in
CHCl3); H NMR (400 MHz, CDCl3): d=7.51–7.41 (m, 2H),
7.35–7.29 (m, 4H), 7.18–7.16 (m, 4H), 7.12–7.01 (m, 4H),
3.92–3.72 (m, 2H), 3.65 (dd, J=14.4, 2.4 Hz, 1H), 3.37 (dd,
J=16.4, 5.2 Hz, 1H), 2.97 (dd, J=16.4, 9.2 Hz, 1H), 2.61
(dd, J=16.0, 2.8 Hz, 1H), 1.65 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=209.0, 174.6, 160.5, 138.3, 137.0, 135.2, 134.0,
132.7, 129.1, 129.0, 128.8, 128.2, 127.7, 125.8, 119.7, 61.7,
44.2, 41.8, 41.2, 40.5, 15.7; IR (KBr): nmax =1708, 1597, 1495,
1402, 834, 758, 692 cmÀ1; ESI-MS (%): m/z=443.2 [M+
H]+; HR-MS (ESI): m/z=443.1530 [M+H]+, calcd. for
C27H24ClN2O2: 443.1526.
4-Methyl-2,6-diphenyl-10-[4-(trifluoromethyl)phenyl]-2,3-
diazaspiroACTHNUTRGNEUG[N 4.5]dec-3-ene-1,8-dione (3f): white solid; yield:
88.7 mg (93%), 82:18 dr, 99% eemajor, 95% eeminor. The dr and
ee values were determined by HPLC [Daicel Chiralpak AD-
H
with hexane/i-PrOH (80:20) as the eluent, flow:
1.0 mLminÀ1, l=210 nm]: major diastereoisomer tmajor
12.777 min, tminor =9.827 min; minor diastereoisomer tmajor
=
ACHTUNGTRENNUNG[4.5]dec-3-ene-1,8-dione (3c): white solid; yield: 86.8 mg
=
(98%), 88:12 dr, 99% eemajor, 99% eeminor. The dr and ee
values were determined by HPLC [Daicel Chiralpak OD-H
with hexane/i-PrOH (80:20) as the eluent, flow:
27.728 min,
t
minor =17.306 min; [a]2D5: +51.8 (c 0.39 in
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.57–7.39 (m, 4H),
7.33–7.25 (m, 6H), 7.20–7.11 (m, 4H), 3.95–3.83 (m, 2H),
3.72 (dd, J=14.2, 2.6 Hz, 1H), 3.37 (dd, J=16.4, 5.2 Hz,
1H), 2.99 (dd, J=16.6, 9.4 Hz, 1H), 2.63 (dd, J=16.0,
2.4 Hz, 1H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
208.5, 174.6, 160.3, 159.8, 140.7, 138.2, 137.0, 130.6, 130.3,
129.1, 128.9, 128.7, 128.3, 128.0, 127.8, 127.7, 126.0, 125.7,
119.8, 61.7, 44.2, 42.2, 41.0, 40.6, 15.8; IR (KBr): nmax =1710,
1602, 1498, 1326, 1123, 844, 761, 696 cmÀ1; ESI-MS (%): m/
z=477.2 [M+H]+; HR-MS (ESI): m/z=477.1765 [M+H]+,
calcd. for C28H24F3N2O2: 477.1784.
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
25.862 min; minor diastereoisomer tmajor =29.257 min; [a]2D5:
+46.9 (c 0.41 in CHCl3); H NMR (400 MHz, CDCl3): d=
7.53–7.50 (m, 2H), 7.40–7.25 (m, 5H), 7.21–7.04 (m, 7H),
3.93–3.78 (m, 2H), 3.64 (d, J=16.8 Hz, 1H), 3.38 (dd, J=
21.8, 6.2 Hz, 1H), 3.00–2.96 (m, 1H), 2.63 (d, J=20 Hz,
1H), 1.65 (s, 3H); 13C NMR (100 MHz, CDCl3): d=208.8,
174.6, 160.4, 138.6, 138.3, 137.0, 134.4, 132.7, 129.9, 129.0,
128.8, 128.4, 128.2, 128.0, 127.6, 125.8, 119.8, 61.6, 44.1, 42.1,
41.0, 40.5, 15.7; IR (KBr): nmax =1709, 1591, 1494, 1402, 758,
6-(2,4-Dimethoxyphenyl)-4-methyl-2,10-diphenyl-2,3-
diazaspiroACTHNGUETRNNU[G 4.5]dec-3-ene-1,8-dione (3g): white solid; yield:
694 cmÀ1
(ESI): m/z=443.1527 [M+H]+, calcd. for C27H24ClN2O2:
443.1526.
72.2 mg (77%), 58:37:5 dr, 99% ee on the 58% disteroisom-
er, 96% ee on the 37% disteroisomer, 94% ee on the 5%
disteroisomer. The dr and ee values were determined by
HPLC [Daicel Chiralpak AD-H with hexane/i-PrOH
(80:20) as the eluent, flow: 1.0 mLminÀ1; l=254 nm]: 58%
diastereoisomer tmajor =22.460 min, tminor =21.256 min; 37%
diastereoisomer tmajor =39.709 min, tminor =11.938 min; 5%
ACHTUNGTRENNUNG[4.5]dec-3-ene-1,8-dione (3d): white solid; yield: 81.1 mg
(95%), 83:17 dr, 99% eemajor, 99% eeminor. The dr and ee
values were determined by HPLC [Daicel Chiralpak OD-H
with hexane/i-PrOH (80:20) as the eluent, flow:
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
diastereoisomer tmajor =6.682 min, t
minor =7.354 min; [a]2D5:
1
15.365 min; minor diastereoisomer tmajor =23.249 min; [a]2D5:
+21.9 (c 0.47 in CHCl3); H NMR (400 MHz, CDCl3): d=
7.48 (d, J=7.6 Hz, 2H), 7.34–7.28 (m, 3H), 7.12–7.08 (m,
6H), 6.38–6.34 (m, 1H), 6.28 (d, J=2.0 Hz, 1H), 4.27 (d, J=
14.0 Hz, 1H), 3.97–3.94 (m, 1H), 3.86–3.81 (m, 1H), 3.66 (s,
3H), 3.65 (s, 3H), 3.21 (dd, J=16.6, 4.2 Hz, 1H), 3.06 (dd,
J=16.6, 11 Hz, 1H), 2.48 (d, J=16.4 Hz, 1H), 1.71 (s, 3H);
13C NMR (100 MHz, CDCl3): d=210.1, 175.4, 162.0, 160.1,
157.2, 138.3, 137.3, 129.4, 128.7, 128.7, 127.5, 125.4, 119.9,
+54.5 (c 0.40 in CHCl3); H NMR (400 MHz, CDCl3): d=
7.50–7.42 (m, 2H), 7.34–7.28 (m, 4H), 7.17–7.10 (m, 4H),
6.90–6.86 (m, 2H), 3.94–3.80 (m, 2H), 3.66 (dd, J=14.2,
2.6 Hz, 1H), 3.33 (dd, J=16.4, 4.8 Hz, 1H), 2.99 (dd, J=
16.4, 10.0 Hz, 1H), 2.62 (dd, J=16.0, 2.8 Hz, 1H), 1.69 (s,
3H).;13C NMR (100 MHz, CDCl3): d=209.3, 174.9, 163.7,
160.7, 138.5, 137.2, 132.6, 129.7, 129.6, 129.2, 129.0, 128.3,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
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Jin-Xin Zhang et al.
UPDATES
119.1, 117.5, 104.6, 98.0, 62.0, 55.3, 55.0, 43.5, 41.6, 40.4, 33.2,
4-Methyl-6-(naphthalen-1-yl)-2,10-diphenyl-2,3-diazaspiro-
15.5; IR (KBr): nmax =1710, 1600, 1500, 1032, 832, 757,
ACHTUNGTRENNUNG
696 cmÀ1
;
ESI-MS (%): m/z=469.2 [M+H]+; HR-MS
(ESI): m/z=469.2129 [M + H]+, calcd. for C29H29N2O4:
469.2127.
6-(2-Methoxyphenyl)-4-methyl-2,10-diphenyl-2,3-diaza-
spiroACHTUNGTRENNUNG[4.5]dec-3-ene-1,8-dione (3h): white solid; yield:
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
8.131 min, tminor =12.222 min; minor diastereoisomer tmajor
=
=
69.4 mg (79%), 82:18 dr, 99% eemajor, 99% eeminor. The dr and
ee values were determined by HPLC [Daicel Chiralpak AD-
9.309 min, tminor =11.142 min; [a]2D5: À96.8 (c 0.41 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.92–7.79 (m, 8H), 7.69–
7.65 (m, 3H), 7.56–7.37 (m, 14H), 7.25–7.21 (m, 4H), 7.15
(s, 5H), 4.83–4.73 (m, 2H), 3.99–3.81 (m, 6H), 2.93–2.71 (m,
4H), 1.01 (s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=210.0, 209.6, 175.6, 175.1, 161.3, 161.2, 139.8,
137.7, 137.5, 135.9, 134.4, 134.1, 133.8, 131.9, 130.7, 129.7,
129.5, 129.3, 129.0, 129.0, 128.9, 128.9, 128.8, 128.6, 128.5,
128.2, 127.7, 127.1, 126.8, 126.3, 126.1, 125.9, 125.7, 125.7,
125.3, 124.4, 122.5, 121.5, 119.9, 119.6, 60.4, 60.3, 47.2, 43.5,
H
with hexane/i-PrOH (80:20) as the eluent, flow:
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
15.772 min; minor diastereoisomer tmajor =11.591 min, tminor
=
=
10.905 min; [a]D25: À9.2 (c 0.5 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.64–7.42 (m, 2H), 7.27–7.26 (m,
3H), 7.11–7.12 (m, 6H), 6.84–6.71 (m, 3H), 4.37 (d, J=
13.6 Hz, 1H), 3.97 (m, 1H), 3.84–3.76 (m, 1H), 3.69 (s, 3H),
3.25–3.21 (m, 1H), 3.11–3.05 (m, 1H), 2.51 (d, J=16.0 Hz,
1H), 1.72 (s, 3H); 13C NMR (100 MHz, CDCl3): d=210.0,
175.3, 161.9, 156.3, 138.3, 137.2, 128.9, 128.8, 128.7, 128.0,
127.6, 125.6, 125.1, 120.9, 120.0, 119.1, 110.3, 61.9, 55.1, 43.7,
41.4, 40.5, 33.6, 15.6; IR (KBr): nmax =1704, 1593, 1493, 1370,
1237, 1023, 759, 695 cmÀ1; ESI-MS (%): m/z=439.2 [M+
H]+; HR-MS (ESI): m/z=439.2006 [M+H]+, calcd. for
C28H27N2O3: 439.2022.
43.2, 42.4, 42.1, 41.3, 39.2, 35.4, 16.0, 15.5; IR (KBr): nmax
=
1703, 1595, 1497, 1377, 1011, 771, 696 cmÀ1; ESI-MS (%): m/
z=459.2 [M+H]+; HR-MS (ESI): m/z=459.2059 [M+H]+,
calcd. for C31H27N2O2, 459.2067.
4-Methyl-2,6-diphenyl-10-(thiophen-2-yl)-2,3-diazaspiro-
AHCTUNGTREG[NNUN 4.5]dec-3-ene-1,8-dione (3l): white solid; yield: 68.1 mg
(82%), 73:27 dr, 99% eemajor, 99% eeminor. The dr and ee
values were determined by HPLC [Daicel Chiralpak OD-H
with hexane/i-PrOH (80:20) as the eluent, flow:
6-(4-Isopropylphenyl)-4-methyl-2,10-diphenyl-2,3-diaza-
spiroACHTUNGTRENNUNG[4.5]dec-3-ene-1,8-dione (3i): white solid; yield: 75.8 mg
(84%), 85:15 dr, 99% eemajor, 83% eeminor: The dr and ee
values were determined by HPLC on Daicel Chiralpak AD-
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
17.745 min, tminor =40.106 min; minor diastereoisomer tmajor
=
=
H
with hexane/i-PrOH (80:20) as the eluent; flow:
27.187 min; [a]D25: +23.6 (c 0.36 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.64–7.62 (d, J=8.0 Hz, 2H), 7.35–
7.31 (m, 4H), 7.20–7.10 (m, 5H), 6.85–6.82 (m, 2H), 4.01
(dd, J=13.8, 3 Hz, 1H), 3.85–3.77 (m, 2H), 3.47 (dd, J=
16.0, 5.6 Hz, 1H), 2.86 (dd, J=16.0, 7.6 Hz, 1H), 2.78 (dd,
J=16.0, 2.8 Hz, 1H), 1.57 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=208.5, 174.6, 160.9, 139.7, 138.8, 129.2, 128.9,
128.3, 128.0, 127.8, 127.0, 125.7, 125.6, 124.9, 119.7, 61.7,
45.1, 43.1, 40.8, 37.8, 15.7; IR (KBr): nmax =1708, 1595, 1496,
1398, 756, 690 cmÀ1; ESI-MS (%): m/z=415.2 [M+H]+;
HR-MS (ESI): m/z=415.1464 [M+H]+, calcd. for
C25H23N2O2S: 415.1480.
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
8.126 min, tminor =9.291 min; minor diastereoisomer tmajor
=
=
30.943 min,
t
minor =16.820 min; [a]2D5: +54.7 (c 0.59 in
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.39–7.37 (m, 2H),
7.31–7.25 (m, 4H), 7.18–7.12 (m, 4H), 7.05 (m, 4H), 3.95
(dd, J=10.2, 4.8 Hz, 1H), 3.89–3.82 (m, 1H), 3.63 (dd, J=
14.2, 3 Hz, 1H), 3.29 (dd, J=16.6, 4.6 Hz, 1H), 3.02 (dd, J=
16.8, 10.4 Hz, 1H), 2.76 (sep, J=6.8 Hz, 1H9; 2.65 (dd, J=
16.4, 2.8 Hz, 1H), 1.74 (s, 3H), 1.10 (d, J=6.8 Hz, 6H);
13C NMR (100 MHz, CDCl3): d=209.7, 175.1, 160.8, 148.9,
138.7, 137.3, 133.8, 129.1, 128.9, 128.2, 127.9, 127.7, 126.7,
125.9, 120.3, 62.4, 43.7, 42.3, 41.3, 40.7, 33.9, 24.0, 15.9; IR
(KBr): nmax =1708, 1599, 1500, 1401, 836, 759, 695 cmÀ1; ESI-
MS (%): m/z=451.2 [M+H]+; HR-MS (ESI): m/z=
451.2379 [M+H]+, calcd. for C30H31N2O2: 451.2386.
6-(3-Chlorophenyl)-10-(4-fluorophenyl)-4-methyl-2-
phenyl-2,3-diazaspiroACHTUNTGRNEUNG[4.5]dec-3-ene-1,8-dione (3m): white
solid; yield: 85.7 mg (93%), 82:18 dr, 99% eemajor, 95%
eeminor. The dr and ee values were determined by HPLC
[Daicel Chiralpak AD-H with hexane/i-PrOH (80:20) as the
eluent, flow: 1.0 mLminÀ1, l=254 nm]: major diastereoiso-
mer tmajor =10.143 min, tminor =13.381 min; minor diastereo-
isomer tmajor =14.660 min, tminor =11.941 min; [a]2D5: +49.0 (c
4-Methyl-2,6-diphenyl-10-p-tolyl-2,3-diazaspiroACTHNUTRGNEUG[N 4.5]dec-3-
ene-1,8-dione (3j): white solid; yield: 72.8 mg (86%), 88:12
dr, 99% eemajor, 99% eeminor. The dr and ee values were deter-
mined by HPLC [Daicel Chiralpak AD-H with hexane/i-
PrOH (80:20) as the eluent; flow: 1.0 mLminÀ1, l=254 nm]:
major diastereoisomer tmajor =10.948 min; minor diastereo-
isomer tmajor =17.781 min; [a]2D5: +41.7 (c 0.41 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.52 (d, J=8 Hz, 2H),
7.34–7.29 (m, 4H), 7.17–7.11 (m, 4H), 7.01 (dd, J=18.2,
8.0 Hz, 4H), 3.90–3.83 (m, 2H), 3.65 (dd, J=14, 2.8 Hz,
1H), 3.39 (dd, J=16.0, 5.2 Hz, 1H), 2.95 (dd, J=16.4,
9.2 Hz, 1H), 2.63 (dd, J=16.2, 3 Hz, 1H), 2.19 (s, 3H), 1.63
(s, 3H); 13C NMR (100 MHz, CDCl3) d 209.6, 175.0, 160.9,
138.7, 137.8, 137.3, 133.7, 129.3, 129.0, 128.8, 128.1, 127.8,
127.6, 125.6, 119.9, 61.8, 44.4, 42.1, 41.6, 40.7, 21.0, 15.7; IR
(KBr): nmax =1708, 1598, 1499, 1399, 758, 695 cmÀ1; ESI-MS
(%): m/z=423.2 [M+H]+; HR-MS (ESI): m/z=423.2053
[M+H]+, calcd. for C28H27N2O2: 423.2073.
1
0.35 in CHCl3); H NMR (400 MHz, CDCl3): d=7.50–7.48
(m, 2H), 7.34–7.32 (m, 2H), 7.20–7.10 (m, 6H), 7.03–6.99
(m, 3H), 3.95–3.79 (m, 2H), 3.63–3.59 (m, 1H), 3.33–3.29
(m, 1H), 2.98 (dd, J=15.8, 10.6 Hz, 1H), 2.64 (d, J=
16.0 Hz, 1H), 1.75 (s, 3H); 13C NMR (100 MHz, CDCl3):
d=208.7, 174.6, 160.3, 138.5, 137.0, 134.6, 134.2, 132.9, 130.2,
129.4, 129.32, 129.0, 128.6, 128.2, 126.1, 120.0, 116.3, 116.1,
61.9, 43.4, 42.2, 41.0, 40.7, 15.9; IR (KBr): nmax =1709, 1597,
1503, 1405, 1226, 838, 760, 692 cmÀ1; ESI-MS (%): m/z=
461.1 [M+H]+; HR-MS (ESI): m/z=461.1411 [M+H]+,
calcd. for C27H23ClFN2O2: 461.1432.
6-(3-Chlorophenyl)-10-(3,5-dimethoxyphenyl)-4-methyl-2-
phenyl-2,3-diazaspiro
ACHTUNGTRENN[UNG 4.5]dec-3-ene-1,8-dione (3n): white
solid; yield: 96.6 mg (96%), 88:12 dr, 99% eemajor, 99%
8
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Synthesis of Unsymmetrical Diaryl-Substituted Spirocyclohexanonepyrazolones
eeminor. The dr and ee values were determined by HPLC
[Daicel Chiralpak AD-H with hexane/i-PrOH (90:10) as the
eluent, flow: 0.6 mLminÀ1, l=254 nm]: major diastereoiso-
mer tmajor =25.662 min, tminor =36.593 min.; minor diastereo-
isomer tmajor =37.498 min, tminor =59.511 min; [a]2D5: +65.3 (c
13.992 min; [a]D25: +48.0 (c 0.45 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.50–7.48 (m, 2H), 7.36–7.32 (m,
2H), 7.18–7.10 (m, 4H), 7.05–6.99 (m, 5H), 3.94–3.83 (m,
2H), 3.62 (dd, J=14.2, 2.6 Hz, 1H), 3.34 (dd, J=16.4,
5.2 Hz, 1H), 2.97 (dd, J=16.2, 9.8 Hz, 1H), 2.64 (dd, J=
16.4, 3.2 Hz, 1H), 2.21 (s, 3H), 1.73 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=209.4, 174.9, 160.6, 138.0, 137.1,
135.3, 133.4, 129.7, 129.4, 128.8, 127.6, 125.8, 119.9, 116.1,
1
0.50 in CHCl3); H NMR (400 MHz, CDCl3): d=7.52 (d, J=
8.0 Hz, 2H), 7.35–7.31 (m, 2H), 7.18–7.14 (m, 4H), 7.05–
7.04 (m, 1H), 6.36 (s, 1H), 6.23 (s, 2H), 3.89–3.77 (m, 2H),
3.64 (s, 6H), 3.61–3.57 (m, 1H), 3.26 (dd, J=16.8, 4.4 Hz,
1H), 2.97 (dd, J=16.4, 10.4 Hz, 1H), 2.61 (d, J=15.2 Hz,
1H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3): d=208.8,
174.9, 161.2, 160.6, 140.5, 138.6, 137.2, 136.0, 134.5, 130.1,
129.0, 128.6, 128.3, 126.1, 125.9, 119.8, 105.8, 99.8, 62.0, 55.5,
44.0, 42.4, 41.0, 40.5, 15.9; IR (KBr): nmax =1712, 1598, 1485,
1154, 1061, 842, 738, 697 cmÀ1; ESI-MS (%): m/z=503.2
[M+H]+; HR-MS (ESI): m/z=503.1716 [M+H]+, calcd. for
C29H28ClN2O4: 503.1738.
115.9, 62.0, 43.5, 42.1, 41.4, 40.7, 21.0, 15.8; IR (KBr): nmax
=
1709, 1600, 1506, 1402, 1228, 833, 757, 690 cmÀ1; ESI-MS
(%): m/z=441.2 [M+H]+; HR-MS (ESI): m/z=441.1969
[M+H]+, calcd. for C28H26FN2O2: 441.1978.
6-(3,5-Dimethoxyphenyl)-4-methyl-2-phenyl-10-p-tolyl-
2,3-diazaspiroACHTUNTRGNEUNG[4.5]dec-3-ene-1,8-dione (3r): white solid;
yield: 75.3 mg (78%), 80:20 dr, 98% eemajor, 96% eeminor. The
dr and ee values were determined by HPLC [Daicel Chiral-
pak AD-H with hexane/i-PrOH (80:20) as the eluent, flow:
6-(3-Chlorophenyl)-10-(4-chlorophenyl)-4-methyl-2-
phenyl-2,3-diazaspiroACHTUNTGRNEUNG[4.5]dec-3-ene-1,8-dione (3o): white
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
8.982 min, tminor =10.782 min; minor diastereoisomer tmajor
=
=
solid; yield: 90.6 mg (95%), 83:17 dr, 97% eemajor, 95%
eeminor. The dr and ee values were determined by HPLC
[Daicel Chiralpak AD-H with hexane/i-PrOH (80:20) as the
eluent, flow: 1.0 mLminÀ1, l=254 nm]: major diastereoiso-
mer tmajor =12.675 min, tminor =13.712 min; minor diastereo-
isomer tmajor =14.454 min, tminor =11.559 min; [a]2D5: +92.7 (c
13.634 min,
t
minor =18.818 min; [a]2D5: +57.3 (c 0.41 in
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.51 (d, J=8 Hz,
2H), 7.34–7.30 (m, 2H), 7.19–7.13 (m, 2H), 7.05–7.00 (m,
3H), 6.36 (s, 1H), 6.25 (s, 1H), 6.25 (s, 1H), 3.88–3.80 (m,
2H), 3.64 (s, 6H), 3.56–3.50 (m, 1H), 3.27 (dd, J=16.6,
4.6 Hz, 1H), 2.98 (dd, J=16.4, 10.4 Hz, 1H), 2.62 (dd, J=
16.4, 2.4 Hz, 1H), 2.21 (s, 3H), 1.83 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=209.5, 175.1, 161.1, 140.7, 137.9,
137.3, 133.4, 129.3, 128.8, 128.0, 127.7, 125.6, 119.7, 109.9,
105.7, 99.6, 62.1, 55.3, 44.1, 42.3, 41.3, 40.5, 21.0, 15.8; IR
(KBr): nmax =1710, 1600, 1496, 1205, 1152, 1057, 834., 758,
1
0.36 in CHCl3); H NMR (400 MHz, CDCl3): d=7.48 (d, J=
8 Hz, 2H), 7.36–7.28 (m, 4H), 7.20–7.13 (m, 4H), 7.07–7.05
(m, 3H), 3.95–3.79 (m, 2H), 3.62–3.58 (m, 1H), 3.29 (dd, J=
16.4, 4.4 Hz, 1H), 2.98 (dd, J=16.4, 10.4 Hz, 1H), 2.64 (dd,
J=16.4, 2.4 Hz, 1H), 1.77 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=208.5, 174.6, 160.1, 138.4, 137.0, 136.8, 134.6,
134.3, 130.2, 129.4, 129.0, 128.7, 128.2, 126.1, 126.1, 120.2,
120.0, 61.9, 43.4, 42.3, 40.9, 40.5, 16.0; IR (KBr): nmax: 1710,
1597, 1494, 1406, 1094, 834, 759, 692 cmÀ1; ESI-MS (%): m/
z=477.1 [M+H]+; HR-MS (ESI): m/z=477.1110 [M+H]+,
calcd. for C27H23Cl2N2O2: 477.1137.
693 cmÀ1
;
ESI-MS (%): m/z=483.2 [M+H]+; HR-MS
(ESI): m/z=483.2275 [M+H]+, calcd. for C30H31N2O4:
483.2284.
6-(4-Chlorophenyl)-4-methyl-2-phenyl-10-p-tolyl-2,3-
diazaspiroACTHNUTRGNEUG[N 4.5]dec-3-ene-1,8-dione (3s): white solid; yield:
80.4 mg (88%), 68:32 dr, 94% eemajor, 94% eeminor. The dr and
6-(3-Chlorophenyl)-4-methyl-2-phenyl-10-m-tolyl-2,3-
ee values were determined by HPLC [Daicel Chiralpak AD-
diazaspiro
G
H with hexane/i-PrOH (80:20) as the eluent, flow:
81.3 mg (89%), 86:14 dr, 94% eemajor, 99% eeminor. The dr and
ee values were determined by HPLC [Daicel Chiralpak AD-
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
18.058 min, tminor =14.880 min; minor diastereoisomer tmajor
=
=
H
with hexane/i-PrOH (95:5) as the eluent, flow:
32.081 min,
t
minor =13.885 min; [a]2D5: +84.4 (c 0.44 in
0.6 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
36.687 min, tminor =52.714 min; minor diastereoisomer tmajor
CHCl3); H NMR (400 MHz, CDCl3): d=7.48 (d, J=7.9 Hz,
2H), 7.36–7.34 (m, 2H), 7.31–7.29 (m, 2H), 7.20–7.18 (m,
2H), 7.08–7.06 (m, 1H), 7.02 (m, 4H), 3.92–3.82 (m, 2H),
3.60 (d, J=14.4 Hz, 1H), 3.31 (dd, J=16.4, 4.8 Hz, 1H),
2.97 (dd, J=16.6, 10.6 Hz, 1H), 2.64 (d, J=16.4 Hz, 1H),
2.21 (s, 3H), 1.75 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
209.2, 174.8, 160.4, 138.0, 137.1, 135.4, 134.1, 133.2, 129.4,
129.2, 129.0, 128.8, 127.6, 125.8, 119.9, 62.0, 43.5, 42.2, 41.3,
40.5, 21.0, 15.9; IR (KBr): nmax: 1708, 1598, 1498, 1404, 1103,
1014, 828, 755, 646 cmÀ1; ESI-MS (%): m/z=457.2 [M+H]+;
HR-MS (ESI): m/z=457.1672 [M+H]+, calcd. for
C28H26ClN2O2: 457.1683.
1
35.199 min,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.52 (d, J=8 Hz,
2H), 7.35 (t, J=7.6 Hz, 2H), 7.24–7.06 (m, 7H), 6.94–6.90
(m, 2H), 3.89–3.81 (m, 2H), 3.67–3.62 (m, 1H), 3.38 (dd, J=
16.6, 5.0 Hz, 1H), 2.96 (dd, J=16.4, 9.2 Hz, 1H), 2.65 (d, J=
16.0 Hz, 1H), 2.29 (s, 3H), 1.67 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=209.4, 174.9, 160.6, 138.0, 137.1,
135.3, 133.4, 129.7, 129.4, 128.8, 127.6, 125.8, 119.9, 116.1,
115.9, 62.0, 43.5, 42.1, 41.4, 40.7, 21.0, 15.8; IR (KBr): nmax
1708, 1595, 1495, 1404, 1096, 763, 694 cmÀ1; ESI-MS (%): m/
z=457.2 [M+H]+; HR-MS (ESI): m/z=457.1655 [M+H]+,
calcd. for C28H26ClN2O2: 457.1683.
4-Methyl-2-phenyl-6-m-tolyl-10-p-tolyl-2,3-diazaspiro-
AHCTUNGTREG[NNUN 4.5]dec-3-ene-1,8-dione (3t): white solid; yield: 73.4 mg
6-(4-Fluorophenyl)-4-methyl-2-phenyl-10-p-tolyl-2,3-
diazaspiroACHTUNGTRENNUNG[4.5]dec-3-ene-1,8-dione (3q): white solid; yield:
73.2 mg (83%), 72:28 dr, 92% eemajor, 99% eeminor. The dr and
ee values were determined by HPLC [Daicel Chiralpak AD-
(84%), 78:22 dr, 98% eemajor. The dr and ee values were de-
termined by HPLC [Daicel Chiralpak IA with hexane/i-
PrOH (90:10) as the eluent, flow: 1.0 mLminÀ1, l=254 nm]:
major diastereoisomer tmajor =12.616 min. tminor =13.611 min;
1
H
with hexane/i-PrOH (80:20) as the eluent, flow:
[a]2D5: +45.0 (c 0.46 in CHCl3); H NMR (400 MHz, CDCl3):
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
21.591 min, tminor =17.550 min; minor diastereoisomer tmajor
=
=
d=7.53–7.51 (m, 2H), 7.37–7.33 (m, 2H), 7.22–7.18 (m,
2H), 7.07–7.00 (m, 5H), 6.98–6.92 (m, 2H), 3.91–3.84 (m,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
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Jin-Xin Zhang et al.
UPDATES
2H), 3.65 (dd, J=14.4, 2.8 Hz, 1H), 3.39 (dd, J=16.4,
5.2 Hz, 1H), 2.96 (dd, J=16.4, 9.2 Hz, 1H), 2.65 (d, J=
16.0 Hz, 1H), 2.29 (s, 3H), 2.22 (s, 3H), 1.66 (s, 3H);
13C NMR (100 MHz, CDCl3): d=209.8, 175.1, 161.0, 138.7,
138.6, 137.9, 137.3, 136.8, 133.7, 129.4, 128.9, 128.8, 128.6,
127.6, 125.7, 124.6, 120.0, 61.9, 44.4, 42.1, 41.6, 40.7, 21.5,
21.0, 15.8; IR (KBr): nmax =1708, 1599, 1499, 1401, 1118, 829,
757, 696 cmÀ1; ESI-MS (%): m/z=437.2 [M+H]+; HR-MS
(ESI): m/z=437.2207 [M+H]+, calcd. for C29H29N2O2:
437.2229.
d=208.6, 174.8, 161.0, 140.4, 138.7, 138.4, 136.1, 134.7, 130.2,
130.1, 129.3, 128.9, 128.7, 128.5, 127.8, 126.0, 125.8, 119.5,
117.4, 62.0, 44.3, 42.4, 41.2, 40.7, 15.9; IR (KBr): nmax =1721,
1704, 1594, 1575, 1482, 1368, 1329, 1087, 872, 785, 702,
686 cmÀ1
;
ESI-MS (%): m/z=477.1 [M+H]+; HR-MS
(ESI): m/z=477.1121 [M+H]+, calcd. for C27H23Cl2N2O2:
477.1131.
6-(3-Chlorophenyl)-4-methyl-10-phenyl-2-p-tolyl-2,3-
diazaspiroACTHNUTRGNEUG[N 4.5]dec-3-ene-1,8-dione (3x): white solid; yield:
80.0 mg (88%), 84:16 dr, 99% eemajor, 99% eeminor. The dr and
ee values were determined by HPLC [Daicel Chiralpak AD-
6-(3-Chlorophenyl)-2,4,10-triphenyl-2,3-diazaspiro-
ACHTUNGTRENNUNG[4.5]dec-3-ene-1,8-dione (3u): white solid; yield: 60.5 mg
H
with hexane/i-PrOH (80:20) as the eluent, flow:
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
11.572 min. tminor =15.736 min; minor diastereoisomer tmajor
=
=
(60%), 11:43:46 dr, 99% ee on the 43% diastereoisomer,
99% ee on the 46% diastereoisomer. The dr and ee values
were determined by HPLC [Daicel Chiralpak AD-H with
hexane/i-PrOH (80:20) as the eluent, flow: 1.0 mLminÀ1, l=
254 nm]: 43% diastereoisomer tmajor =14.021 min; 46% dia-
stereoisomer tmajor =18.374 min; [a]2D5: +141.8 (c 0.29 in
14.209 min; [a]D25: +41.4 (c 0.58 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.34–7.24 (m, 4H), 7.20–7.02 (m,
9H), 3.88–3.79 (m, 2H), 3.61 (d, J=12.0 Hz, 1H), 3.36 (d,
J=13.6 Hz, 1H), 2.96–2.94 (m, 1H), 2.60 (d, J=14.8 Hz,
1H), 2.30 (s, 3H), 1.62 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=209.0, 174.6, 160.4, 138.9, 138.6, 135.8, 134.7,
134.6, 130.2, 129.6, 129.2, 128.6, 128.4, 128.3, 127.9, 126.1,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.46–7.41 (m, 4H),
7.37–7.29 (m, 4H), 7.25–7.14 (m, 10H), 7.06–6.90 (m, 10H),
6.88–6.76 (m, 6H), 6.64–6.50 (m, 4H), 4.19–4.04 (m, 4H),
3.97–3.82 (m, 2H), 3.33–3.21 (m, 2H), 2.92 (dd, J=17.6,
3.6 Hz, 1H), 2.82 (dd, J=17.2, 3.2 Hz, 1H), 2.56–2.48 (m,
2H); 13C NMR (100 MHz, CDCl3): d=209.2, 175.4, 159.0,
139.4, 137.2, 135.6, 134.4, 132.6, 130.6, 129.7, 129.0, 128.9,
128.5, 128.2, 127.8, 127.6, 127.2, 126.5, 126.3, 125.5, 120.2,
63.4, 43.3, 42.8, 41.1, 39.9; IR (KBr): nmax =1717, 1680, 1597,
1497, 1397, 1331, 1288, 1140, 764., 696, 674 cmÀ1; ESI-MS
(%): m/z=505.2 [M+H]+; HR-MS (ESI): m/z=505.1662
[M+H]+, calcd. for C32H26ClN2O2: 505.1677.
120.1, 61.6, 44.4, 42.3, 41.3, 40.7, 21.3, 15.9; IR (KBr): nmax
=
1721, 1700, 1596, 1573, 1514, 1369, 1330, 1087, 819, 788,
703 cmÀ1
;
ESI-MS (%): m/z=457.2 [M+H]+; HR-MS
(ESI): m/z=457.1678 [M+H]+, calcd. for C28H26ClN2O2:
457.1677.
6-(3-Chlorophenyl)-2-(4-methoxyphenyl)-4-methyl-10-
phenyl-2,3-diazaspiroACHTUNTGRNEUNG[4.5]dec-3-ene-1,8-dione (3y): white
solid; yield: 85.6 mg (93%), 88:12 dr, 91% eemajor, 99%
eeminor. The dr and ee values were determined by HPLC
[Daicel Chiralpak AD-H with hexane/i-PrOH (80:20) as the
eluent, flow: 1.0 mLminÀ1, l=254 nm]: major diastereoiso-
mer tmajor =18.874 min. tminor =22.311 min; minor diastereo-
isomer tmajor =24.189 min; [a]2D5: +42.4 (c 0.5 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.33–7.28 (m, 5H), 7.13–
7.10 (m, 5H), 7.02–7.00 (m, 1H), 6.84 (d, J=8.8 Hz, 2H),
3.89–3.81 (m, 2H), 3.76 (s, 3H), 3.62–3.59 (m, 1H), 3.35 (dd,
J=16.4, 4.8 Hz, 1H), 2.93 (dd, J=16.2, 9.4 Hz, 1H), 2.60 (d,
J=14.6 Hz, 1H), 1.62 (s, 3H); 13C NMR (100 MHz, CDCl3):
d=209.1, 174.5, 160.4, 157.8, 138.9, 138.5, 134.6, 130.3, 130.1,
129.2, 128.6, 128.4, 128.2, 127.9, 126.2, 122.1, 114.2, 61.5,
55.7, 44.3, 42.2, 41.2, 40.7, 15.9; IR (KBr): nmax =1721, 1699,
1596, 1512, 1372, 1298, 1249, 1031, 832, 702, 657 cmÀ1; ESI-
MS (%): m/z=473.2 [M+H]+; HR-MS (ESI): m/z=
473.1631 [M+H]+, calcd. for C28H26ClN2O3: 473.1626.
2-(4-Bromophenyl)-6-(3-chlorophenyl)-4-methyl-10-
phenyl-2,3-diazaspiroACHTUNTGRNEUNG[4.5]dec-3-ene-1,8-dione (3v): white
solid; yield: 92.9 mg (90%), 74:26 dr, 99% eemajor, 99%
eeminor. The dr and ee values were determined by HPLC
[Daicel Chiralpak AD-H with hexane/i-PrOH (85:15) as the
eluent, flow: 1.0 mLminÀ1, l=254 nm]: major diastereoiso-
mer tmajor =15.283 min. tminor =19.106 min; minor diastereo-
isomer tmajor =19.973 min; [a]2D5: +23.9 (c 0.36 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.43–7.34 (m, 5H), 7.17–
7.09 (m, 7H), 6.99–6.97 (m, 1H), 3.88–3.73 (m, 2H), 3.62–
3.59 (m, 1H), 3.33 (d, J=14.8 Hz, 1H), 2.97–2.91 (m, 1H),
2.60 (d, J=15.6 Hz, 1H), 1.64 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=208.7, 174.7, 160.9, 140.4, 138.7, 138.4, 136.3,
135.1, 134.6, 132.0, 130.5, 130.2, 129.3, 128.8, 128.7, 128.5,
128.2, 127.8, 126.0, 121.0, 118.8, 62.0, 44.2, 42.3, 41.1, 40.7,
15.9; IR (KBr): nmax =1721, 1703, 1590, 1490, 1368, 1329,
1008, 826, 702, 656 cmÀ1; ESI-MS (%): m/z=523.1 [M+H]+;
HR-MS (ESI): m/z=523.0571 [M+H]+, calcd. for
C27H23Br81ClN2O2: 523.0611.
Acknowledgements
We are grateful for financial support of the National Natural
Science Foundation of China (21072145, 21272166), Founda-
tion for the Author of National Excellent Doctoral Disserta-
tion of PR China (200931). Scientific Research Foundation
for Returned Scholars, and Ministry of Education of China (-
AHCTUNGTREG[NNNU 2010]1174). This project was also funded by the Priority
Academic Program Development of Jiangsu Higher Educa-
tion Institutions (PAPD).
2,6-Bis(3-chlorophenyl)-4-methyl-10-phenyl-2,3-diaza-
spiroACHTUNGTRENNUNG[4.5]dec-3-ene-1,8-dione (3w): white solid; yield:
85.9 mg (90%), 70:30 dr, 98% eemajor, 99% eeminor. The dr and
ee values were determined by HPLC [Daicel Chiralpak AD-
H
with hexane/i-PrOH (85:15) as the eluent; flow:
1.0 mLminÀ1, l=254 nm]: major diastereoisomer tmajor
10.257 min. tminor =11.998 min; minor diastereoisomer tmajor
=
=
11.041 min; [a]D25: +34.0 (c 0.44 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.59 (s, 1H), 7.52–7.49 (m, 1H),
7.28–7.20 (m, 4H), 7.10–7.08 (m, 6H), 6.99–6.97 (m, 1H),
3.89–3.74 (m, 2H), 3.63–3.59 (m, 1H), 3.35 (dd, J=16.4,
4.8 Hz, 1H), 2.93 (dd, J=16.0, 9.6 Hz, 1H), 2.61 (d, J=
14.4 Hz, 1H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3):
10
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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Enantioselective Synthesis of Unsymmetrical Diaryl-Substituted Spirocyclohexanonepyrazolones
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UPDATES
Enantioselective Synthesis of Unsymmetrical Diaryl-
Substituted Spirocyclohexanonepyrazolones through
a Cascade [4+2]Double Michael Addition
13
Adv. Synth. Catal. 2013, 355, 1 – 13
Jin-Xin Zhang, Nai-Kai Li, Zhao-Min Liu, Xiao-Fei Huang,
Zhi-Cong Geng, Xing-Wang Wang*
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!