Bifunctional squaramide-catalyzed one-pot sequential Michael addition/dearomative bromination: Convenient access to optically active brominated pyrazol-5(4H)-ones with adjacent quaternary and tertiary stereocenters

Article abstract of DOI:10.1002/ejoc.201300460

The organocatalytic asymmetric, one-pot, sequential Michael addition/dearomative bromination reaction of pyrazol-5-ones to nitro olefins and N-bromosuccinimide (NBS) has been developed. Under the catalysis of a chiral bifunctional squaramide, a wide variety of chiral brominated pyrazol-5-one derivatives with contiguous quaternary and tertiary stereocenters was obtained in high yields (up to >99 %) with good to excellent diastereoselectivities (62:38-99:1 dr) and uniformly high levels of enantioselectivity (92 to >99 % ee). This experimentally simple process facilitates access to various enantioenriched, multiply substituted pyrazolin-5-one derivatives, potential biologically active molecules, starting from readily available starting materials. Copyright

Full text of DOI:10.1002/ejoc.201300460

Job/Unit: O30460
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FULL PAPER
Asymmetric Synthesis
A one-pot synthesis of optically active
brominated pyrazol-5-one derivatives
H. Wang, Y. Wang,* H. Song, Z. Zhou,*
C. Tang ............................................. 1–9
bearing contiguous quaternary and tertiary
stereocenters has been developed. The
asymmetric, sequential Michael addition/
dearomative bromination reaction of pyr-
azol-5-ones and nitro olefins is catalyzed by
a bifunctional squaramide.
Bifunctional Squaramide-Catalyzed One-
Pot Sequential Michael Addition/Dearom-
ative Bromination: Convenient Access to
Optically Active Brominated Pyrazol-
5(4H)-ones with Adjacent Quaternary and
Tertiary Stereocenters
Keywords: Organocatalysis / Michael ad-
dition / Nitrogen heterocycles / Nitro olef-
ins
0000, 0–0
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Job/Unit: O30460
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Date: 17-06-13 16:47:43
Pages: 9
H. Wang, Y. Wang, H. Song, Z. Zhou, C. Tang
FULL PAPER
DOI: 10.1002/ejoc.201300460
Bifunctional Squaramide-Catalyzed One-Pot Sequential Michael Addition/
Dearomative Bromination: Convenient Access to Optically Active Brominated
Pyrazol-5(4H)-ones with Adjacent Quaternary and Tertiary Stereocenters
Huanxia Wang,[a] Youming Wang,*[a] Haibin Song,[a] Zhenghong Zhou,*[a] and
Chuchi Tang[a]
Keywords: Organocatalysis / Michael addition / Nitrogen heterocycles / Nitro olefins
The organocatalytic asymmetric, one-pot, sequential Michael
addition/dearomative bromination reaction of pyrazol-5-ones
to nitro olefins and N-bromosuccinimide (NBS) has been de-
veloped. Under the catalysis of a chiral bifunctional squar-
amide, a wide variety of chiral brominated pyrazol-5-one de-
rivatives with contiguous quaternary and tertiary stereocen-
ters was obtained in high yields (up to Ͼ99%) with good to
excellent diastereoselectivities (62:38–99:1dr) and uniformly
high levels of enantioselectivity (92 to Ͼ99%ee). This experi-
mentally simple process facilitates access to various enanti-
oenriched, multiply substituted pyrazolin-5-one derivatives,
potential biologically active molecules, starting from readily
available starting materials.
the organocatalytic diastereo- and enantioselective Michael
addition of 4-substituted pyrazolin-5-ones to nitro olefins,[6]
a highly enantioselective Michael addition of 4-substituted
pyrazolones and 4-oxo-4-arylbutenoates catalyzed by chiral
metal/N,NЈ-dioxide complexes,[7] the synthesis of chiral spi-
ropyrazol-3-ones through an organocatalyzed Michael/
Michael/aldol cascade reaction,[8] the amination of pyrazol-
3-ones through nucleophilic attack of diazodicarboxylates
catalyzed by Gd salts,[9] the asymmetric Michael addition
of pyrazolones to maleimides catalyzed by bifunctional
thiourea catalysts,[10] and the one-pot asymmetric synthesis
of tetrahydropyrano[2,3-c]pyrazoles through a secondary
amine catalyzed asymmetric Michael/Wittig/oxa-Michael
reaction sequence.[11] Despite this promising progress, it is
still highly desirable to broaden the diversity of function-
alized pyrazolones and to develop new efficient catalytic
asymmetric methods to access chiral multifunctionalized
pyrazolone species. In addition, the stereocontrolled con-
struction of contiguous quaternary and tertiary stereocen-
ters, which are common structural motifs in complex natu-
ral products, has proven to be a formidable challenge in
asymmetric organic synthesis.[12] Consequently, exploring
highly efficient approaches to optically active building
blocks containing such contiguous quaternary and tertiary
stereocenters has been a hot point of research in catalytic
asymmetric transformations. Herein, we wish to report the
first highly enantioselective one-pot sequential Michael ad-
dition/dearomative bromination of 4-substituted pyrazol-5-
ones by using a chiral bifunctional squaramide as the cata-
lyst to generate optically active brominated pyrazol-5(4H)-
ones with adjacent quaternary and tertiary stereocen-
ters.[13,14] High yields (up to 99%), good to excellent dia-
Introduction
Pyrazolone derivatives, an important class of five-mem-
bered, lactam-containing ring with two contiguous nitrogen
atoms, can be used as pharmaceutical candidates and as
biologically important structural components.[1] For exam-
ple, edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, also
known as MCI-186) has been developed as a medical drug
for brain ischemia[2] and has also been reported to be effec-
tive for myocardial ischemia.[3] Because of their biological
significance, the development of asymmetric methods to ac-
cess optically active pyrazolone derivatives is therefore of
considerable interest. The most convenient access to chiral
pyrazolone derivatives is the catalytic asymmetric direct
functionalization of achiral pyrazolones. However, rela-
tively few examples have been documented for catalytic
asymmetric transformations by using pyrazolone as a nu-
cleophile. These methods involve a cinchona alkaloid cata-
lyzed tandem Michael addition/cyclization between 2-pyr-
azolin-5-ones and benzylidenemalononitriles to generate 6-
amino-5-cyanodihydropyrano[2,3-c]pyrazoles,[4] the enan-
tioselective synthesis of β-(3-hydroxypyrazol-1-yl) ketones
through an organocatalyzed aza-Michael addition of 2-pyr-
azolin-5-ones to acyclic aliphatic α,β-unsaturated ketones,[5]
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
Homepage: http://skleoc.nankai.edu.cn/professors/zhouzh/
index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300460.
2
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Synthesis of Optically Active Brominated Pyrazol-5-ones
stereoselectivities (up to 99:1dr), and excellent enantio- Table 1. Catalyst evaluation.[a]
selectivities (up to Ͼ99%ee) were achieved for a wide range
of nitro olefins at 5 mol-% catalyst loading.
Results and Discussion
Bifunctional tertiary amine squaramide catalysts[15] I–V
Entry Catalyst Time [h] Yield [%][b]
dr[c]
ee [%][d]
(Figure 1) were evaluated for the Michael addition of 3-
methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a, 1.0 equiv.) to
trans-β-nitrostyrene (2a, 1.1 equiv.) in chloroform at 20 °C,
and the results are summarized in Table 1.
1
2
3
4
5
6
7
I
1
0.33
16
47
6
5
1.5
94
97
98
90
99
99
99
80:20
81:19
90:10
80:20
82:18
80:20
83:17
76
77
43
18
81
93
98
II
II
IV
Va
Vb
Vc
[a] All reactions were carried out with pyrazol-5-one (1a,
0.20 mmol), nitrostyrene (2a, 0.22 mmol), and the squaramide cata-
lyst (10 mol-%) in chloroform (1 mL) at 20 °C for the time indi-
cated. Then, N-bromosuccinimide (NBS, 0.3 mmol) and Na2CO3
(0.24 mmol) were added at the same temperature, and the resulting
mixture was stirred for 5 min. [b] Yield of the isolated product after
chromatography on silica gel. [c] Determined by 1H NMR spec-
troscopy or HPLC analysis. [d] Determined by chiral HPLC analy-
sis.
squaramides derived from chiral 1,2-diphenylethane-1,2-di-
amine. It was gratifying that a slightly better enantio-
selectivity was obtained if catalyst Va was employed
(81%ee; Table 1, entry 5). To investigate the effect of the
tertiary amino group, squaramide-based catalysts Vb, and
Vc containing a dipropylamino and a piperidinyl group,
respectively, were prepared and screened. Satisfactorily,
squaramides Vb and Vc gave access to the desired products
with excellent enantioselectivities (93 and 98%ee, respec-
tively; Table 1, entries 6 and 7). Catalyst Vc afforded the
highest enantioselectivity of 98%ee and was selected as the
best catalyst for further optimization.
Figure 1. Catalyst candidates.
Indeed, the model reaction ran smoothly to give the cor-
With promising catalyst Vc in hand, other reaction pa-
responding conjugate addition intermediate in the presence rameters, such as solvent, catalyst loading, and reaction
of quinine-based squaramide catalyst I (10 mol-%). Al- temperature (Table 2, entries 1–11), were further optimized,
though analysis by NMR spectroscopy indicated that the and the results are summarized in Table 2.
addition intermediate was a mixture of tautomers, to our
Variation of the solvent had a significant effect on the
delight, this mixture could be further brominated with N- enantioselectivity of the reaction. The common solvents,
bromosuccinimide (NBS) to afford brominated chiral pyr- such as CHCl3, CH2Cl2, THF, and ethyl acetate, gave excel-
azo-5(4H)-one 3a in high yield with good diastereo- lent enantioselectivities (92–98%ee; Table 2, entries 1–3, 6).
(80:20dr) and enantioselectivity (76%ee) within 5 min Performing the reaction in either nonpolar toluene or polar
(Table 1, entry 1). Screening of other squaramide catalysts acetonitrile led to clearly decreased ee values (Table 2, en-
demonstrated that the chiral diamine backbone signifi- tries 4 and 5). As expected, EtOH resulted in a dramatic
cantly affected the enantioselectivity of the reaction. A sim- decrease in the enantioselectivity (51%ee; Table 2, entry 7)
ilar stereochemical outcome was observed for cinchonine- because it is often a poor solvent in hydrogen-bond-con-
derived squaramide catalyst II (Table 1, entry 2). The use of trolled organocatalysis. Finally, by decreasing the tempera-
catalyst III, incorporating (1R,2R)-1,2-cyclohexanediamine, ture to –20 °C and by adjusting the catalyst loading to
resulted in a clearly decreased ee value (Table 1, entry 3). 5 mol-%, we achieved excellent yields and almost perfect
Squaramide catalyst IV bearing a structurally rigid 9,10- enantioselectivity in this reaction (Table 2, entry 11).
ethylene-9,10-dihydroanthracene skeleton, which had pre-
After having established the optimal reaction conditions
viously been successfully employed for the Michael addition (5 mol-% Vc in CHCl3 at –20 °C), the scope and limitations
of 4-hydroxycoumarins to β,γ-unsaturated α-ketophos- of this enantioselective synthesis were next examined, and
phonates, demonstrated much lower catalytic activity, and the results are collected in Table 3.
it gave product 3a in 47 h with quite low enantioselectivity
As shown in Table 3, this asymmetric one-pot multistep
(18%ee; Table 1, entry 4). We then turned our attention to reaction is compatible with a wide range of nitro olefin sub-
Eur. J. Org. Chem. 0000, 0–0
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H. Wang, Y. Wang, H. Song, Z. Zhou, C. Tang
FULL PAPER
Table 2. Optimization of the reaction conditions.[a]
Table 3. Vc-catalyzed cascade Michael addition/dearomative bro-
mination reaction of pyrazolones 1 and nitro olefins 2.[a]
Entry
Solvent
Time [h] Yield [%][b]
dr[c]
ee [%][d]
Entry
3 (R, R1)
Time Yield
[h]
dr[c]
ee
1
2
3
4
5
6
7
CHCl3
CH2Cl2
THF
PhCH3
CH3CN
AcOEt
EtOH
CHCl3
CHCl3
CHCl3
CHCl3
1.5
2
99
99
90
87
92
90
77
99
99
99
99
80:20
81:19
80:20
80:20
82:18
78:22
75:25
80:20
82:18
82:18
83:17
98
96
95
80
87
92
51
98
98
[%][b]
[%][d]
4
1
2
3
4
5
6
7
8
3a (CH3, Ph)
8
5.5
99 83:17
99 85:15
Ͼ99
99
Ͼ99
Ͼ99
99
96
99
99
Ͼ99
97
10
10
17
17
2
3b (CH3, 4-FC6H4)
3c (CH3, 2-ClC6H4)
3d (CH3, 3-ClC6H4)
3e (CH3, 4-ClC6H4)
3f (CH3, 2,4-Cl2C6H3)
3g (CH3, 2-BrC6H4)
3h (CH3, 4-NO2C6H4)
3i (CH3, 4-CF3C6H4)
3j (CH3, 4-MeC6H4)
3k (CH3, 2,4,6-
5.5 Ͼ99
97:3
5
94 86:14
97 84:16
82
Ͼ99
93
11
72
5
72
32
8[e]
9[f]
10[g]
11[h]
93:7
94:6
94:6
8
3
8
99
Ͼ99
9
10
11
98 82:18
6.5 Ͼ99 85:15
[a] Unless otherwise noted, all reactions were carried out with pyr-
azol-5-one (1a, 0.20 mmol), nitrostyrene (2a, 0.22 mmol), and
squaramide catalyst Vc (10 mol-%) in solvent (1 mL) at 20 °C for
the time indicated. Then, NBS (0.30 mmol) and Na2CO3
(0.24 mmol) were added at the same temperature, and the resulting
mixture was stirred for 5 min. [b] Yield of the isolated product after
chromatography on silica gel. [c] Determined by 1H NMR spec-
troscopy or HPLC analysis. [d] Determined by chiral HPLC analy-
sis. [e] With a catalyst loading of 5 mol-%. [f] With a catalyst load-
ing of 2 mol-%. [g] Reaction was performed at 0 °C with a catalyst
loading of 5 mol-%. [h] Reaction was performed at –20 °C with a
catalyst loading of 5 mol-%.
120
96
95:5
96
Me3C6H2)
12
13
3l (CH3, 3-MeOC6H4)
3m (CH3, 4-Me-
OC6H4)
3n (CH3, 1-naphthyl)
3o (CH3, 2-furyl)
3p (CH3, 2-thienyl)
3q (CH3, Et)
3r (CH3, iBu)
3s (CF3, Ph)
3t (Ph, Ph)
17
26
Ͼ99 88:12
91 88:12
98
98
14
15
16
17
18
19
20
86
12
Ͼ99 82:18
89 80:20
Ͼ99
99
Ͼ99
95
98
92
12.5
168
48
82
97:3
86 84:16
90 62:38
144
87
99:1
97:3
2.5 Ͼ99
99
[a] All reactions were carried out with pyrazol-5-one (1a,
0.20 mmol), nitrostyrene (2a, 0.22 mmol), and squaramide catalyst
(5 mol-%) in chloroform (1 mL) at –20 °C for the time indicated.
Then, NBS (0.30 mmol) and Na2CO3 (0.24 mmol) were added at
20 °C, and the resulting mixture was stirred for 5 min. [b] Yield of
the isolated product after chromatography on silica gel. [c] Deter-
mined by 1H NMR spectroscopy or HPLC analysis. [d] Deter-
mined by chiral HPLC analysis.
strates, as brominated pyrazol-5-ones 3a–r were generated
in 82 to Ͼ99% yields with 95 to Ͼ99% enantioselectivities
and good to excellent diastereoselectivities (Table 3, en-
tries 1–18). It appeared that the electronic properties of the
substituents on the aromatic rings had a very limited influ-
ence on the stereoselectivities of the reactions (Table 3, en-
tries 2–14). Substrates with electron-withdrawing (Table 3,
entries 2–9), electron-donating (Table 3, entries 10–13), and
electron-neutral (Table 3, entries 1 and 14) groups partici-
pated in this reaction efficiently to deliver the brominated
pyrazolin-5-ones bearing contiguous quaternary and terti-
ary stereocenters with uniformly high enantioselectivities
(ee values ranging from 96 to Ͼ99%) regardless of the sub-
stitution pattern. For example, the most sterically de-
manding substrate, β-mesityl-substituted nitroethylene 2k,
worked well to give product 3k in 96% yield with 95:5dr
and 96%ee (Table 3, entry 11). Not only aromatic groups
but also heteroaromatic groups such as furyl and thienyl
azolone 1a was replaced with either 1b or 1c (Table 3, en-
tries 19 and 20).
The relative and absolute configuration of product 3d
was unequivocally established by X-ray analysis (Figure 2),
and the remaining configurations were assumed by anal-
ogy.[16]
Conclusions
In conclusion, we have developed a facile organocata-
could be successfully employed to afford the respective chi- lytic, enantioselective synthesis of highly functionalized chi-
ral pyrazol-5-one derivatives with excellent enantio- ral pyrazol-5(4H)-ones with contiguous quaternary and ter-
selectivities (Table 3, entries 15 and 16). Notably, less reac- tiary stereocenters by a one-pot sequential Michael ad-
tive aliphatic nitro olefins, such as (E)-1-nitrobut-1-ene (2q) dition/dearomative bromination strategy. Under the cataly-
and (E)-4-methyl-1-nitropent-1-ene (2r), were also tolerated sis of a bifunctional tertiary amine squaramide, a series of
in this reaction, and they afforded the desired products with optically active brominated pyrazol-5-ones bearing adjacent
almost the same high level of enantioselectivities at the ex- quaternary and tertiary stereocenters were obtained in high
pense of reaction time (Table 3, entries 17 and 18). Further- yields (82 to Ͼ99%) and good to excellent diastereoselectiv-
more, by using nitro olefin 2a as the reaction partner, the ities (62:38–99:1dr) with high levels of enantioselectivity (92
one-pot sequential reaction also proceeded smoothly if pyr- to Ͼ99%ee).
4
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Synthesis of Optically Active Brominated Pyrazol-5-ones
Na2CO3 (0.24 mmol) were added at 20 °C, and the resulting mix-
ture was stirred at the same temperature for 5 min. The reaction
mixture was concentrated under reduced pressure, and the crude
product was purified by column chromatography on silica gel [200–
300 mesh, petroleum ether (PE)/EtOAc = 20:1] to afford chiral bro-
minated pyrazol-5-one 3. The title compounds were fully charac-
terized by 1H NMR and 13C NMR spectroscopy, HRMS, and spe-
cific rotation. Diastereomeric ratios and enantiomeric excess values
of the products were determined by chiral HPLC analysis.
(R)-4-Bromo-3-methyl-4-[(R)-2-nitro-1-phenylethyl]-1-phenyl-1H-
pyrazol-5(4H)-one (3a): Yellow solid, 98 % yield, m.p. 45–47 °C,
[α]2D0 = +90.2 (c = 1.0, CHCl3), 83:17dr, Ͼ99%ee for the major
Figure 2. X-ray crystal structure of (4R,1ЈR)-3d. Most of the hydro-
1
isomer. H NMR (400 MHz, CDCl3): δ = 2.06 (s, 0.51 H), 2.14 (s,
gen atoms are omitted for clarity.
2.49 H), 4.06 (dd, J = 5.2, 9.6 Hz, 0.83 H), 4.22 (dd, J = 3.2,
11.6 Hz, 0.17 H), 4.96 (dd, J = 11.6, 13.2 Hz, 0.17 H), 5.34–5.44
(m, 1.83 H), 7.10–7.24 (m, 6 Harom), 7.31 (t, J = 8.0 Hz, 2 Harom),
7.54 (d, J = 8.4 Hz, 0.34 Harom), 7.61 ppm (d, J = 8.0 Hz, 1.66
Experimental Section
General Methods: All reagents and solvents were commercial grade
and were purified prior to use if necessary. NMR spectra were ac-
quired with a Varian 400 MHz instrument. Chemical shifts are
measured relative to residual solvent peaks as an internal standard
set to δ = 7.26 ppm and δ = 77.0 ppm (CDCl3) or δ = 2.50 ppm
and δ = 39.43 ppm ([D6]DMSO). Specific rotations were measured
with a Perkin–Elmer 341MC polarimeter. Enantiomeric excesses
were determined with an HP-1100 instrument (chiral column, mo-
bile phase = hexane/iPrOH). HRMS was performed with a Varian
QFT-ESI instrument. Melting points were determined with a Taike
X-4 melting point apparatus.
H
arom). 13C NMR (100.6 MHz, CDCl3): δ = 13.6 (major isomer),
15.8 (minor isomer), 48.0 (minor isomer), 48.8 (major isomer), 56.4
(major isomer), 57.7 (minor isomer), 75.9 (major isomer), 76.0
(minor isomer), 119.1 (minor isomer), 119.2 (major isomer), 126.0
(minor isomer), 126.1 (major isomer), 127.8 (major isomer), 128.6
(minor isomer), 128.9 (minor isomer), 129.0 (major isomer), 129.1
(minor isomer), 129.4 (major isomer), 129.5 (minor isomer), 129.6
(major isomer), 131.9 (minor isomer), 132.2 (major isomer), 136.7
(minor isomer), 136.8 (major isomer), 155.7 (minor isomer), 156.8
(major isomer), 168.3 (minor isomer), 168.7 ppm (major isomer).
HRMS (ESI): calcd. for C18H16BrN3NaO3 [M + Na]+ 424.0627;
found 424.0624. HPLC (Chiralpak AD-H, hexane/2-propanol =
95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR = 12.03 (minor,
major isomer), 15.53 (major, major isomer), 18.48 (major, minor
isomer), 19.66 min (minor, minor isomer).
Synthesis of Squaramide Catalyst Vb and Vc: To a solution of the
corresponding (1R,2R)-1,2-diphenylethane-1,2-diamine (4.8 mmol)
in CH2Cl2 (40 mL) was added 3-[3,5-bis(trifluoromethyl)phen-
ylamino]-4-methoxycyclobut-3-ene-1,2-dione (4.0 mmol) in one
portion. The resulting mixture was stirred at room temperature un-
til completion of the reaction (monitored by TLC). The precipitate
was filtered and dried in the vacuum to obtain the product.
(R)-4-Bromo-4-[(R)-1-(4-fluorophenyl)-2-nitroethyl]-3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one (3b): Yellow solid, 99% yield, m.p.
56–58 °C, [α]2D0 = +110.6 (c = 1.0, CHCl3), 85:15dr, 99%ee. 1H
NMR (400 MHz, CDCl3): δ = 2.18 (s, 0.45 H), 2.23 (s, 2.55 H),
4.15 (t, J = 7.2 Hz, 0.85 H), 4.31 (d, J = 11.2 Hz, 0.15 H), 4.99 (t,
J = 12.4 Hz, 0.15 H), 5.42–5.49 (m, 1.85 H), 6.96 (d, J = 8.0 Hz,
1.70 Harom), 7.02 (d, J = 8.0 Hz, 1.70 Harom), 7.19–7.26 (m, 3
Vb: White solid, 63% yield, m.p. 204–206 °C, [α]2D0 = –216 (c = 0.2,
1
DMSO). H NMR (400 MHz, CDCl3): δ = 0.80 (t, J = 7.2 Hz, 6
H), 1.30–1.39 (m, 2 H), 1.45–1.53 (m, 2 H), 1.99–2.06 (m, 2 H),
2.52–2.59 (m, 2 H), 4.31 (d, J = 11.6 Hz, 1 H), 5.86 (br. s, 1 H),
7.10–7.24 (m, 8 Harom), 7.31 (d, J = 7.6 Hz, 2 Harom), 7.67 (s, 1
Harom), 7.41 (t, J = 7.6 Hz, 2 Harom), 7.65 (d, J = 7.6 Hz, 0.30
Harom), 7.71 ppm (d, J = 8.0 Hz, 1.70 Har om ). 13 C NMR
(100.6 MHz, CDCl3): δ = 13.6 (major isomer), 15.7 (minor isomer),
47.4 (minor isomer), 48.0 (major isomer), 56.2 (major isomer), 57.4
(minor isomer), 75.8 (major isomer), 76.0 (minor isomer), 116.3 (d,
J = 21.8 Hz, minor isomer), 116.7 (d, J = 21.7 Hz, major isomer),
119.0 (minor isomer), 119.1 (major isomer), 126.1 (minor isomer),
126.2 (major isomer), 127.8 (d, J = 3.7 Hz, minor isomer), 128.0
(d, J = 3.3 Hz, major isomer), 128.9 (minor isomer), 129.0 (major
isomer), 129.7 (d, J = 8.6 Hz, major isomer), 130.6 (d, J = 8.3 Hz,
minor isomer), 136.6 (minor isomer), 136.7 (major isomer), 155.5
(minor isomer), 156.6 (major isomer), 163.1 (d, J = 250.5 Hz),
168.2 (minor isomer), 168.6 ppm (major isomer). HRMS (ESI):
calcd. for C18H15BrN3NaO3 [M + Na]+ 442.0173; found 442.0175.
HPLC (Chiralpak AD-H, hexane/2-propanol = 98:2, flow rate =
1.0 mLmin–1, λ = 254 nm): tR = 21.72 (minor, major isomer), 24.19
(major, major isomer), 38.35 min (major, minor isomer).
H
arom), 8.08 (s, 2 Harom), 8.22 (br. s, 1 H), 10.21 (br. s, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 11.5, 21.0, 51.2, 58.1, 67.1,
114.7, 118.0, 121.7, 124.4, 126.9, 127.4, 127.6, 128.4, 129.1, 131.3
(q,
J = 32.8 Hz), 134.7, 140.0, 140.9, 162.0, 168.9, 179.6,
184.6 ppm. HRMS (ESI): calcd. for C32H32F6N3O2 [M + H]+
604.2393; found 604.2395.
For Vc: Yellow solid, 66% yield, m.p. 228–206 °C, [α]2D0 = –136 (c
1
= 0.1, DMSO). H NMR (400 MHz, CDCl3): δ = 1.21 (br. s, 2 H),
1.39 (br. s, 2 H), 1.47 (br. s, 2 H), 2.21 (br. s, 2 H), 2.50 (br. s, 2
H), 4.18 (d, J = 15.2 Hz, 1 H), 5.81 (br. s, 1 H), 7.09–7.31 (m, 10
Harom), 7.67 (s, 1 Harom), 8.08 (s, 2 Harom), 8.33 (br. s, 1 H), 10.32
(br. s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 24.0, 25.9,
26.0, 49.8, 57.4, 72.1, 114.7, 118.1, 121.7, 124.4, 127.0, 127.4, 127.5,
127.6, 128.3, 129.2, 131.2 (q, J = 33.1 Hz), 133.2, 139.9, 141.0,
162.2, 169.3, 180.0, 184.5 ppm. HRMS (ESI): calcd. for
C31H28F6N3O2 [M + H]+ 588.2080; found 588.2085.
General Procedure for Bifunctional Squaramide Vc-Catalyzed (R)-4-Bromo-4-[(R)-1-(2-chlorophenyl)-2-nitroethyl]-3-methyl-1-
Asymmetric One-Pot Sequential Michael Addition/Dearomative
Bromination Reactions: To a stirring mixture of catalyst Vc
(0.010 mmol) and nitro olefin 2 (0.22 mmol) in chloroform (1 mL)
was added pyrazol-5-one 1 (0.20 mmol) at –20 °C. Upon comple-
tion of the reaction (monitored by TLC), NBS (0.30 mmol) and
phenyl-1H-pyrazol-5(4H)-one (3c): Yellow solid, 91 % yield, m.p.
36–38 °C, [α]2D0 = +117.2 (c = 1.0, CHCl3), 97:3dr, Ͼ99%ee. 1H
NMR (400 MHz, CDCl3): δ = 2.30 (s, 3 H), 4.97 (dd, J = 3.2,
10.8 Hz, 1 H), 5.37 (dd, J = 10.8, 13.6 Hz, 1 H), 5.53 (dd, J = 3.2,
13.6 Hz, 1 H), 7.11 (dt, J = 1.2, 7.6 Hz, 1 Harom), 7.19–7.26 (m, 3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O30460
/KAP1
Date: 17-06-13 16:47:43
Pages: 9
H. Wang, Y. Wang, H. Song, Z. Zhou, C. Tang
FULL PAPER
Harom), 7.41 (t, J = 7.6 Hz, 3 Harom), 7.73 ppm (d, J = 7.6 Hz, 2
Harom). 13C NMR (100.6 MHz, CDCl3): δ = 13.7, 43.7, 56.4, 76.0,
119.1, 126.2, 127.0, 128.1, 129.0, 130.6, 130.9, 131.0, 134.4, 136.7,
(R)-4-Bromo-4-[(R)-1-(2-bromophenyl)-2-nitroethyl]-3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one (3g): Yellow solid, 91% yield, m.p.
48–49 °C, [α]2D0 = +132.0 (c = 0.5, CHCl3), 94:6dr, 99%ee. 1H
157.1, 168.7 ppm. HRMS (ESI): calcd. for C18H15BrClN3NaO3 [M NMR (400 MHz, CDCl3): δ = 2.33 (s, 3 H), 4.97 (dd, J = 3.2,
+ Na]+ 457.9878; found 457.9874. HPLC (Chiralpak AD-H, hex-
ane/2-propanol = 95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR
= 11.79 (minor, major isomer), 18.26 (major, major isomer),
30.77 min (major, minor isomer).
10.8 Hz, 1 H), 5.33 (dd, J = 10.8, 13.2 Hz, 1 H), 5.55 (dd, J = 3.2,
13.2 Hz, 1 H), 7.13–7.19 (m, 2 Harom), 7.21–7.27 (m, 2 Harom), 7.42
(t, J = 8.0 Hz, 2 Harom), 7.60 (dd, J = 1.6, 7.6 Hz, 1 Harom),
7.75 ppm (d, J = 8.0 Hz, 2 Harom). 13C NMR (100.6 MHz, CDCl3):
δ = 14.2, 46.7, 56.3, 76.2, 119.2, 125.2, 126.2, 127.0, 128.8, 129.0,
130.9, 133.1, 134.4, 136.8, 157.2, 168.8 ppm. HRMS (ESI): calcd.
for C18H15Br2N3NaO3 [M + Na]+ 501.9372; found 501.9370.
HPLC (Chiralpak AD-H, hexane/2-propanol = 95:5, flow rate =
1.0 mLmin–1, λ = 254 nm): tR = 12.70 (minor, major isomer), 23.85
(major, major isomer), 32.28 min (major, minor isomer).
(R)-4-Bromo-4-[(R)-1-(3-chlorophenyl)-2-nitroethyl]-3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one (3d): Yellow solid, 94% yield, m.p.
1
118–119 °C, [α]2D0 = +90.8 (c = 1.0, CHCl3), 86:14dr, Ͼ99%ee. H
NMR (400 MHz, CDCl3): δ = 2.13 (s, 0.42 H), 2.22 (s, 2.58 H),
4.10 (t, J = 7.2 Hz, 0.86 H), 4.23 (d, J = 10.8 Hz, 0.14 H), 4.98 (t,
J = 7.6 Hz, 0.14 H), 5.42 (d, J = 7.2 Hz, 1.86 H), 7.08 (d, J =
7.2 Hz, 1 Harom), 7.18–7.26 (m, 4 Harom), 7.39 (t, J = 7.6 Hz, 2
(R)-4-Bromo-3-methyl-4-[(R)-2-nitro-1-(4-nitrophenyl)ethyl]-1-
phenyl-1H-pyrazol-5(4H)-one (3h): Yellow solid, 93% yield, m.p.
66–68 °C, [α]2D0 = +85.0 (c = 1.0, CHCl3), 92:8dr, Ͼ99%ee. 1H
NMR (400 MHz, CDCl3): δ = 2.23 (s, 0.24 H), 2.25 (s, 2.76 H),
4.12 (dd, J = 7.2, 14.4 Hz, 0.08 H), 4.28 (dd, J = 5.2, 8.8 Hz, 1 H),
5.42–5.55 (m, 2 H), 7.26 (t, J = 7.6 Hz, 1 Harom), 7.39–7.44 (m, 4
Harom), 7.66 (d, J = 7.6 Hz, 0.16 Harom), 7.70 (d, J = 8.0 Hz, 1.84
H
arom), 7.67 ppm (d, J = 8.0 Hz, 2 Harom). 13C NMR (100.6 MHz,
CDCl3): δ = 13.6 (major isomer), 15.7 (minor isomer), 47.5 (minor
isomer), 48.4 (major isomer), 56.0, 75.6 (major isomer), 75.7
(minor isomer), 119.4, 125.7, 126.4, 128.3, 129.0, 130.0, 130.8,
134.3, 135.4, 136.6, 156.5, 168.5 ppm. HRMS (ESI): calcd. for
C18H15BrClN3NaO3 [M + Na]+ 457.9878; found 457.9875. HPLC
(Chiralpak AD-H, hexane/2-propanol = 97:3, flow rate =
1.0 mLmin–1, λ = 254 nm): tR = 15.74 (minor, major isomer), 19.00
(major, major isomer), 23.55 (major, minor isomer), 26.14 min
(minor, minor isomer).
Harom), 8.12 (d, J = 8.8 Hz, 1.84 Harom), 8.19 ppm (d, J = 8.8 Hz,
0.16 Harom). 13C NMR (100.6 MHz, CDCl3): δ = 13.6, 48.3, 55.5,
75.4, 119.0, 124.6, 126.4, 129.0, 129.1, 136.5, 139.5, 148.4, 156.2,
168.2 ppm. HRMS (ESI): calcd. for C18H15BrN4NaO5 [M +
Na]+ 469.0118; found 469.0114. HPLC (Chiralpak AD-H, hexane/
(R)-4-Bromo-4-[(R)-1-(4-chlorophenyl)-2-nitroethyl]-3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one (3e): Yellow solid, 97% yield, m.p.
50–51 °C, [α]2D0 = +101.4 (c = 1.0, CHCl3), 84:16dr, 99%ee. 1H
NMR (400 MHz, CDCl3): δ = 2.18 (s, 0.48 H), 2.24 (s, 2.52 H),
4.14 (t, J = 7.2 Hz, 0.84 H), 4.29 (d, J = 11.6 Hz, 0.16 H), 5.00 (t,
J = 12.4 Hz, 0.16 H), 5.45 (d, J = 7.2 Hz, 1.84 H), 7.16 (d, J =
8.0 Hz, 1.68 Harom), 7.24–7.32 (m, 3.32 Harom), 7.42 (t, J = 7.6 Hz,
2 Harom), 7.67 (d, J = 7.6 Hz, 0.32 Harom), 7.72 ppm (d, J = 8.0 Hz,
1.68 Harom). 13C NMR (100.6 MHz, CDCl3): δ = 13.6 (major iso-
mer), 15.7 (minor isomer), 47.4 (minor isomer), 48.1 (major iso-
mer), 56.0 (major isomer), 57.2 (minor isomer), 75.7 (major iso-
mer), 75.8 (minor isomer), 119.1 (major isomer), 119.4 (minor iso-
mer), 126.1 (minor isomer), 126.2 (major isomer), 128.9 (minor iso-
mer), 129.0 (major isomer), 129.2 (major isomer), 129.4 (minor iso-
mer), 129.8 (major isomer), 130.1 (minor isomer), 130.6 (minor iso-
mer), 130.7 (major isomer), 135.7 (minor isomer), 135.8 (major iso-
mer), 136.6 (minor isomer), 136.7 (major isomer), 155.4 (minor
isomer), 156.5 (major isomer), 168.1 (minor isomer), 168.5 ppm
(major isomer). HRMS (ESI): calcd. for C18H15BrClN3NaO3 [M
+ Na]+ 457.9878; found 457.9873. HPLC (Chiralpak AD-H, hex-
ane/2-propanol = 95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR
= 11.39 (major, major isomer), 14.28 (minor, major isomer), 21.31
(major, minor isomer), 23.11 min (minor, minor isomer).
2-propanol = 95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR
=
23.82 (major, major isomer), 44.62 (minor, major isomer), 52.16
(minor, minor isomer), 57.12 min (major, minor isomer).
(R)-4-Bromo-4-{(R)-1-[4-(trifluoromethyl)phenyl]-2-nitroethyl}-3-
methyl-1-phenyl-1H-pyrazol-5(4H)-one (3i): Yellow solid, 98 %
yield, m.p. 46–48 °C, [α]2D0 = +75.6 (c = 0.5, CHCl3), 82:18dr,
1
Ͼ99%ee. H NMR (400 MHz, CDCl3): δ = 2.18 (s, 0.54 H), 2.24
(s, 2.46 H), 4.23 (t, J = 7.2 Hz, 0.82 H), 4.36 (d, J = 10.8 Hz, 0.18
H), 5.00–5.12 (m, 0.18 H), 5.48 (d, J = 7.2 Hz, 1.82 H), 7.26 (t, J
= 7.6 Hz, 1 Harom), 7.35 (d, J = 7.6 Hz, 2 Harom), 7.41 (d, J =
8.0 Hz, 2 Harom), 7.54 (d, J = 8.0 Hz, 2 Harom), 7.70 ppm (d, J =
8.0 Hz, 2 Harom). 13C NMR (100.6 MHz, CDCl3): δ = 13.6, 48.5,
55.9, 75.6 119.2, 126.4, 126.5 (q, J = 3.6 Hz), 128.4, 129.0, 129.1,
129.3, 136.5, 136.6, 156.4, 168.5 ppm. HRMS (ESI): calcd. for
C19H15BrF3N3NaO3 [M + Na]+ 492.0141; found 492.0139. HPLC
(Chiralpak AD-H, hexane/2-propanol = 95:5, flow rate =
1.0 mLmin–1, λ = 220 nm): tR = 7.97 (major, major isomer), 13.57
(minor, major isomer), 18.29 (minor, minor isomer), 20.65 min
(major, minor isomer).
(R)-4-Bromo-3-methyl-4-[(R)-2-nitro-1-p-tolylethyl]-1-phenyl-1H-
pyrazol-5(4H)-one (3j): Yellow solid, Ͼ99% yield, m.p. 50–51 °C,
[α]2D0 = +84.4 (c = 1.0, CHCl3), 85:15dr, 97%ee. 1H NMR
(400 MHz, CDCl3): δ = 2.16 (s, 0.45 H), 2.23 (s, 2.55 H), 2.25 (s,
2.55 H), 2.27 (s, 0.45 H), 4.11 (dd, J = 4.4, 9.6 Hz, 0.85 H), 4.27
(t, J = 3.6, 12.0 Hz, 0.15 H), 5.40–5.52 (m, 2 H), 7.04 (d, J =
8.0 Hz, 1.70 Harom), 7.08 (d, J = 8.4 Hz, 1.70 Harom), 7.11 (d, J =
8.4 Hz, 0.30 Harom), 7.19 (d, J = 8.0 Hz, 0.30 Harom), 7.24 (t, J =
7.6 Hz, 1 Harom), 7.41 (t, J = 8.0 Hz, 2 Harom), 7.66 (d, J = 8.0 Hz,
(R)-4-Bromo-4-[(R)-1-(2,4-dichlorophenyl)-2-nitroethyl]-3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one (3f): Yellow solid, 72% yield, m.p.
140–142 °C, [α]2D0 = +120.0 (c = 1.0, CHCl3), 93:7dr, 96%ee. 1H
NMR (400 MHz, CDCl3): δ = 2.31 (s, 3 H), 4.91 (dd, J = 3.2,
10.8 Hz, 1 H), 5.37 (dd, J = 10.8, 13.6 Hz, 1 H), 5.52 (dd, J = 3.2,
13.6 Hz, 1 H), 7.11 (dd, J = 2.0, 8.8 Hz, 1 Harom), 7.19 (d, J =
8.4 Hz, 1 Harom), 7.27 (t, J = 7.6 Hz, 1 Harom), 7.41–7.45 (m, 3
Harom), 7.75 ppm (d, J = 7.6 Hz, 2 Harom). 13C NMR (100.6 MHz, 0.30 Harom), 7.72 ppm (d, J = 8.4 Hz, 1.70 Harom). 13C NMR
CDCl3): δ = 13.7, 43.2, 56.0, 75.8, 119.1, 126.3, 127.9, 128.5, 129.1,
129.6, 130.8, 135.2, 136.1, 136.6, 156.9, 168.5 ppm. HRMS (ESI):
calcd. for C18H14BrClN3NaO3 [M + Na]+ 491.9488; found
491.9495. HPLC (Chiralpak AD-H, hexane/2-propanol = 95:5,
(100.6 MHz, CDCl3): δ = 13.5 (major isomer), 15.8 (minor isomer),
21.1, 47.7 (minor isomer), 48.5 (major isomer), 56.5, 76.0 (major
isomer), 76.1 (minor isomer), 119.1 (minor isomer), 119.2 (major
isomer), 125.9 (minor isomer), 126.1 (major isomer), 127.6 (major
flow rate = 1.0 mLmin–1, λ = 254 nm): tR = 7.20 (major, major isomer), 128.0 (minor isomer), 128.5 (major isomer), 128.7 (minor
isomer), 8.29 (minor, major isomer), 14.41 (minor, minor isomer),
15.88 min (major, minor isomer).
isomer), 128.9 (minor isomer), 129.0 (major isomer), 129.9 (minor
isomer), 130.2 (major isomer), 136.8 (minor isomer), 136.9 (major
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30460
/KAP1
Date: 17-06-13 16:47:43
Pages: 9
Synthesis of Optically Active Brominated Pyrazol-5-ones
isomer), 139.6 (minor isomer), 139.7 (major isomer), 155.8 (minor
57–58 °C, [α]2D0 = +190.0 (c = 1.0, CHCl3), 82:18dr, Ͼ99%ee. 1H
isomer), 156.9 (major isomer), 168.4 (minor isomer), 168.8 ppm NMR (400 MHz, CDCl3): δ = 1.69 (s, 0.54 H), 1.91 (s, 2.46 H),
(major isomer). HRMS (ESI): calcd. for C19H18BrN3NaO3 [M + 5.15 (dd, J = 10.4, 12.8 Hz, 0.18 H), 5.23 (dd, J = 3.2, 10.8 Hz,
Na]+ 438.0424; found 438.0424. HPLC (Chiralpak AD-H, hexane/
0.82 H), 5.28 (s, 0.18 H), 5.54 (dd, J = 10.4, 14.0 Hz, 0.82 H), 5.69
(dd, J = 3.2, 14.0 Hz, 0.82 H), 5.81 (dd, J = 3.2, 13.2 Hz, 0.18 H),
7.23–7.28 (m, 2 Harom), 7.33 (t, J = 8.0 Hz, 0.54 Harom), 7.41 (t, J
= 8.0 Hz, 2.46 Harom), 7.52 (t, J = 8.0 Hz, 1 Harom), 7.64 (t, J =
8.4 Hz, 1 Harom), 7.69–7.77 (m, 3 Harom), 7.83 (d, J = 8.0 Hz, 1
Harom), 8.14 (d, J = 8.8 Hz, 0.18 Harom), 8.25 ppm (d, J = 8.8 Hz,
0.82 Harom). 13C NMR (100.6 MHz, CDCl3): δ = 13.7 (major iso-
mer), 15.4 (minor isomer), 40.1 (minor isomer), 42.0 (major iso-
mer), 56.9 (major isomer), 58.4 (minor isomer), 76.8, 119.0 (minor
isomer), 119.2 (major isomer), 122.3 (minor isomer), 122.4 (major
isomer), 124.0 (major isomer), 124.9 (minor isomer), 125.4 (major
isomer), 125.9 (minor isomer), 126.2 (major isomer), 126.4 (major
isomer), 12126.5 (minor isomer), 127.3 (major isomer), 127.5
(minor isomer), 128.9 (minor isomer), 129.0 (major isomer), 129.4,
129.6, 130.3, 131.1 (major isomer), 132.0 (minor isomer), 133.8
(minor isomer), 134.1 (major isomer), 136.8 (minor isomer), 136.9
(major isomer), 156.4 (minor isomer), 156.9 (major isomer), 168.5
(minor isomer), 169.0 ppm (major isomer). HRMS (ESI): calcd.
for C22H18BrN3NaO3 [M + Na]+ 474.0424; found 474.0421. HPLC
(Chiralpak AS-H, hexane/2-propanol = 90:10, flow rate =
1.0 mLmin–1, λ = 254 nm): tR = 11.21 (minor, major isomer), 14.56
(major, minor isomer), 16.72 min (major, major isomer).
2-propanol = 95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR
=
15.25 (minor, major isomer), 17.65 (major, major isomer), 24.11
(major, minor isomer), 28.45 min (minor, minor isomer).
(R)-4-Bromo-4-[(R)-1-mesityl-2-nitroethyl]-3-methyl-1-phenyl-1H-
pyrazol-5(4H)-one (3k): Yellow solid, 96% yield, m.p. 114–115 °C,
[α]2D0 = +104.9 (c = 0.89, CHCl3), 95:5dr, 96%ee for major isomer.
1H NMR (400 MHz, CDCl3): δ = 1.94 (s, 3 H), 2.07 (s, 3 H), 2.20
(s, 3 H), 2.46 (s, 3 H), 5.03 (dd, J = 10.8, 4.0 Hz, 1 H), 5.27 (dd, J
= 12.8, 11.2 Hz, 1 H), 5.75 (dd, J = 12.8, 4.0 Hz, 1 H), 6.74 (s, 1
Harom), 6.84 (s, 1 Harom), 7.26 (t, J = 7.6 Hz, 1 Harom), 7.44 (t, J =
8.0 Hz, 2 Harom), 7.83 ppm (d, J = 8.0 Hz, 2 Harom). 13C NMR
(100.6 MHz, CDCl3): δ = 14.0, 20.0, 20.6, 21.9, 46.3, 56.3, 74.1,
118.9, 126.0, 127.7, 129.1, 130.4, 131.9, 136.0, 137.0, 138.4, 138.7,
157.4, 169.5 ppm. HRMS (ESI): calcd. for C21H22BrN3NaO3 [M +
Na]+ 466.0737; found 466.0732. HPLC (Chiralpak AS-H, hexane/
2-propanol = 98:2, flow rate = 1.0 mLmin–1, λ = 254 nm): tR
=
8.78 (minor, major isomer), 10.01 (major, minor isomer), 11.40
(minor, minor isomer), 13.00 min (major, major isomer).
(R)-4-Bromo-4-[(R)-1-(3-methoxyphenyl)-2-nitroethyl]-3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one (3l): Yellow solid, Ͼ99% yield, m.p.
103–105 °C, [α]2D0 = +85.2 (c = 0.5, CHCl3), 88:12dr, 98% ee. 1H
NMR (400 MHz, CDCl3): δ = 2.24 (s, 3 H), 3.60 (s, 3 H), 4.12 (dd,
J = 6.8, 7.6 Hz, 1 H), 5.43–5.45 (m, 2 H), 6.70 (s, 1 Harom), 6.76–
6.82 (m, 2 Harom), 7.16 (t, J = 8.0 Hz, 1 Harom), 7.24 (t, J = 6.4 Hz,
1 Harom), 7.40 (t, J = 8.0 Hz, 2 Harom), 7.72 ppm (d, J = 8.4 Hz, 1
(R)-4-Bromo-4-[(R)-1-(furan-2-yl)-2-nitroethyl]-1,3-diphenyl-1H-pyr-
azol-5(4H)-one (3o): Brown oil, 89% yield, m.p. 38–40 °C, [α]2D0
=
+57.4 (c = 1.0, CHCl3), 80:20 dr, 99 % ee. 1H NMR (400 MHz,
CDCl3): δ = 2.16 (s, 0.60 H), 2.23 (s, 2.40 H), 4.29 (d, J = 10.8 Hz,
0.80 H), 4.44 (d, J = 10.8 Hz, 0.20 H), 5.06 (t, J = 12.4 Hz, 0.20
H), 5.27–5.41 (m, 1.80 H), 6.18–6.28 (m, 2 Harom), 7.16 (t, J =
7.2 Hz, 1 Harom), 7.19 (s, 1 Harom), 7.33 (t, J = 7.2 Hz, 2 Harom),
7.66 ppm (d, J = 7.2 Hz, 2 Harom). 13C NMR (100.6 MHz, CDCl3):
δ = 13.2 (major isomer), 15.0 (minor isomer), 41.8 (minor isomer),
42.4 (major isomer), 54.5 (major isomer), 55.8 (minor isomer), 73.8
(major isomer), 74.2 (minor isomer), 109.9 (major isomer), 111.0
(major isomer), 111.2 (minor isomer), 111.5 (minor isomer), 119.0
(minor isomer), 119.1 (major isomer), 126.0, 128.9, 136.8 (minor
isomer), 136.9 (major isomer), 143.5 (minor isomer), 143.7 (major
isomer), 145.0 (minor isomer), 145.5 (major isomer), 156.2 (minor
isomer), 156.6 (major isomer), 168.3 ppm. HRMS (ESI): calcd. for
H
arom). 13C NMR (100.6 MHz, CDCl3): δ = 13.7 (major isomer),
15.8 (minor isomer), 47.8 (minor isomer), 49.0 (major isomer),
55.1, 56.4, 75.9, 113.0, 115.4, 119.2, 120.0, 126.1, 129.0, 130.6,
133.6, 136.9, 156.9, 160.2, 168.9 ppm. HRMS (ESI): calcd. for
C
19H18BrN3NaO4 [M + Na]+ 454.0373; found 454.0374. HPLC
(Chiralpak AD-H, hexane/2-propanol = 95:5, flow rate =
1.0 mLmin–1, λ = 254 nm): tR = 13.48 (minor, major isomer), 16.56
(major, major isomer), 21.13 (major, minor isomer), 22.60 min
(minor, minor isomer).
(R)-4-Bromo-4-[(R)-1-(4-methoxyphenyl)-2-nitroethyl]-3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one (3m): Yellow solid, 91% yield, m.p.
63–64 °C, [α]2D0 = +123.2 (c = 0.5, CHCl3), 88:12dr, 98%ee. 1H
NMR (400 MHz, CDCl3): δ = 2.17 (s, 0.36 H), 2.23 (s, 2.64 H),
C
16H14BrN3NaO4 [M + Na]+ 414.0060; found 414.0058. HPLC
3.72 (s, 2.64 H), 3.74 (s, 0.36 H), 4.09 (dd, J = 4.8, 10.0 Hz, 0.88 (Chiralpak AD-H, hexane/2-propanol = 95:5, flow rate =
H), 4.26 (dd, J = 3.6, 11.6 Hz, 0.12 H), 5.00 (dd, J = 11.6, 13.2 Hz,
0.12 H), 5.39–5.50 (m, 1.88 H), 6.76 (d, J = 8.4 Hz, 1.76 Harom),
6.82 (d, J = 8.4 Hz, 0.24 Harom), 7.12 (d, J = 8.8 Hz, 2 Harom), 7.24
(t, J = 7.6 Hz, 1 Harom), 7.40 (t, J = 7.6 Hz, 2 Harom), 7.66 (d, J =
8.4 Hz, 0.24 H), 7.72 ppm (d, J = 8.4 Hz, 1.76 Harom). 13C NMR
(100.6 MHz, CDCl3): δ = 13.6 (major isomer), 15.9 (minor isomer),
47.4 (minor isomer), 48.1 (major isomer), 55.2, 56.4, 76.0 (major
isomer), 76.2 (minor isomer), 114.5 (minor isomer), 114.9 (major
isomer), 119.1 (minor isomer), 119.2 (major isomer), 123.5 (minor
isomer), 123.7 (major isomer), 126.0 (minor isomer), 126.1 (major
isomer), 128.9 (minor isomer), 129.0 (major isomer), 129.1 (major
isomer), 129.9 (minor isomer), 136.8 (minor isomer), 136.9 (major
isomer), 156.9, 160.3, 168.8 ppm. HRMS (ESI): calcd. for
C19H18BrN3NaO4 [M + Na]+ 454.0373; found 454.0378. HPLC
(Chiralpak AD-H, hexane/2-propanol = 95:5, flow rate =
1.0 mLmin–1, λ = 254 nm): tR = 14.02 (major, major isomer), 17.34
(minor, major isomer), 25.12 (minor, minor isomer), 27.48 min
(major, minor isomer).
1.0 mLmin–1, λ = 254 nm): tR = 18.04 (minor, major isomer), 23.93
(major, minor isomer), 25.77 (major, major isomer), 33.78 min
(minor, minor isomer).
(R)-4-Bromo-4-[(R)-2-nitro-1-(thiophen-2-yl)ethyl]-1,3-diphenyl-1H-
pyrazol-5(4H)-one (3p): Brown solid, 82 % yield, m.p. 38–40 °C,
[α]2D0 = +87.6 (c = 1.0, CHCl3), 97:3dr, Ͼ99%ee. 1H NMR
(400 MHz, CDCl3): δ = 2.30 (s, 3 H), 4.47 (t, J = 7.2 Hz, 1 H),
5.46 (d, J = 7.2 Hz, 2 H), 6.88 (t, J = 3.6 Hz, 1 Harom), 6.98 (d, J
= 3.6 Hz, 1 Harom), 7.21 (d, J = 5.2 Hz, 1 Harom), 7.25 (t, J =
7.6 Hz, 1 Harom), 7.41 (t, J = 7.6 Hz, 2 Harom), 7.75 ppm (d, J =
8.4 Hz, 2 Harom). 13C NMR (100.6 MHz, CDCl3): δ = 13.5, 43.7,
55.5, 76.7, 119.1, 126.1, 127.0, 127.5, 127.8, 129.0, 133.1, 136.9,
156.6, 168.4 ppm. HRMS (ESI): calcd. for C16H14BrN3NaO3S [M
+ Na]+ 429.9831; found 429.9830. HPLC (Chiralpak AD-H, hex-
ane/2-propanol = 95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR
= 13.52 (minor, major isomer), 15.59 (major, major isomer), 28.32
(major, minor isomer), 29.84 min (minor, minor isomer).
(R)-4-Bromo-3-methyl-4-[(R)-1-(naphthalen-1-yl)-2-nitroethyl]-1-
phenyl-1H-pyrazol-5(4H)-one (3n): Yellow solid, Ͼ99% yield, m.p.
(R)-4-Bromo-3-methyl-4-[(R)-1-nitrobutan-2-yl]-1-phenyl-1H-pyr-
azol-5(4H)-one (3q): Pale yellow oil, 86% yield, [α]2D0 = –45.6 (c =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O30460
/KAP1
Date: 17-06-13 16:47:43
Pages: 9
H. Wang, Y. Wang, H. Song, Z. Zhou, C. Tang
FULL PAPER
0.5, CHCl3), 70:30dr, 95%ee. 1H NMR (400 MHz, CDCl3): δ =
0.93–1.00 (m, 3 H), 1.36–1.74 (m, 2 H), 2.27 (s, 0.90 H), 2.34 (s,
2.10 H), 3.02 (br. s, 0.70 H), 3.11 (br. s, 0.30 H), 4.46 (dd, J = 7.6,
13.6 Hz, 0.30 H), 4.75 (dd, J = 7.6, 14.8 Hz, 0.70 H), 4.82 (d, J =
13.6 Hz, 0.30 H), 5.37 (d, J = 14.8 Hz, 0.70 H), 7.24 (t, J = 8.0 Hz,
1 Harom), 7.42 (t, J = 7.6 Hz, 2 Harom), 7.84 ppm (d, J = 8.0 Hz, 2
Harom). 13C NMR (100.6 MHz, CDCl3): δ = 10.9 (major isomer),
11.5 (minor isomer), 13.3 (major isomer), 14.9 (minor isomer), 22.7
(major isomer), 22.8 (minor isomer), 42.7 (major isomer), 43.0
(minor isomer), 57.5 (major isomer), 58.3 (minor isomer), 75.2
(major isomer), 76.0 (minor isomer), 118.8 (major isomer), 118.9
(minor isomer), 125.9, 129.0, 137.1, 156.3 (minor isomer), 157.4
(major isomer), 168.6 (minor isomer), 168.7 ppm (major isomer).
HRMS (ESI): calcd. for C14H16BrN3NaO3 [M + Na]+ 376.0267;
found 376.0266. HPLC (Chiralpak AS-H, hexane/2-propanol =
95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR = 8.94 (minor,
major isomer), 11.48 (major, major isomer), 13.37 (major, minor
isomer), 15.71 min (minor, minor isomer).
169.2 ppm. HRMS (ESI): calcd. for C23H18BrN3NaO3 [M +
Na]+ 486.0424; found 486.0417. HPLC (Chiralpak AD-H, hexane/
2-propanol = 95:5, flow rate = 1.0 mLmin–1, λ = 254 nm): tR
=
12.26 (minor, major isomer), 15.06 (major, major isomer), 19.86
(minor, minor isomer), 21.88 min (major, minor isomer).
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR and HRMS spectra as well as chiral
HPLC traces for the prepared optically active pyrazol-5-ones.
Acknowledgments
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (grant numbers 20972070, 21121002), the
National Basic Research Program of China (973 program, grant
number 2010CB833300), the Program for New Century Excellent
Talents in University (grant number NCET-11-0265), and the Key
Laboratory of Elemento-Organic Chemistry for generous financial
support of our programs.
(R)-4-Bromo-3-methyl-4-[(R)-4-methyl-1-nitropentan-2-yl]-1-phenyl-
1H-pyrazol-5(4H)-one (3r): Pale yellow oil, 90% yield, [α]2D0 = –42.0
1
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Curr. Org. Chem. 2012, 16, 373; c) G. Mariappan, B. P. Sana,
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Yuki, M. Egawa, H. Nishi, J. Pharmacol. Exp. Ther. 1994, 268,
1597.
(c = 0.5, CHCl3), 62:38dr, 98%ee. H NMR (400 MHz, CDCl3): δ
= 0.87–0.94 (m, 6 H), 1.26–1.56 (m, 3 H), 2.28 (s, 1.14 H), 2.33 (s,
1.86 H), 3.16 (br. s, 0.62 H), 3.24 (br. s, 0.38 H), 4.40 (dd, J = 6.4,
13.6 Hz, 0.38 H), 4.53 (dd, J = 5.6, 15.2 Hz, 0.62 H), 4.80 (dd, J =
4.4, 13.6 Hz, 0.37 H), 5.48 (dd, J = 3.6, 15.2 Hz, 0.60 H), 7.24 (t,
J = 7.2 Hz, 1 Harom), 7.43 (t, J = 7.6 Hz, 2 Harom), 7.86 ppm (d, J =
7.6 Hz, 2 Harom). 13C NMR (100.6 MHz, CDCl3): δ = 13.2 (major
isomer), 14.8 (minor isomer), 21.1 (minor isomer), 21.2 (major iso-
mer), 23.4 (minor isomer), 23.7 (major isomer), 25.5 (major iso-
mer), 25.9 (minor isomer), 38.7 (minor isomer), 39.0 (major iso-
mer), 39.1 (major isomer), 39.5 (minor isomer), 57.5 (major iso-
mer), 58.5 (minor isomer), 75.9 (major isomer), 76.7 (minor iso-
mer), 118.8 (major isomer), 118.9 (minor isomer), 125.9, 129.0,
137.1, 156.2 (minor isomer), 157.3 (major isomer), 168.6 ppm.
HRMS (ESI): calcd. for C16H20BrN3NaO3 [M + Na]+ 404.0580;
found 404.0586. HPLC (Chiralpak AS-H, hexane/2-propanol =
90:10, flow rate = 1.0 mLmin–1, λ = 254 nm): tR = 5.67 (minor,
major isomer), 6.47 (major, major isomer), 7.44 min (inseparable
minor isomer).
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ano, R. Rios, Org. Biomol. Chem. 2011, 9, 6519.
(R)-4-Bromo-3-trifluoromethyl-4-[(R)-2-nitro-1-phenylethyl]-1-
phenyl-1H-pyrazol-5(4H)-one (3s): Pale yellow oil, 87% yield, [α]2D0
= +18.0 (c = 0.5, CHCl3), 99:1dr, 92%ee. 1H NMR (400 MHz,
CDCl3): δ = 4.46 (dd, J = 6.4, 8.4 Hz, 1 H), 5.45 (s, 1 H), 5.46 (d,
J = 2.0 Hz, 1 H), 7.22 (d, J = 7.2 Hz, 2 Harom), 7.30 (t, J = 7.2 Hz,
3 Harom), 7.44 (t, J = 8.0 Hz, 3 Harom), 7.59 ppm (d, J = 8.4 Hz, 2
Harom). 13C NMR (100.6 MHz, CDCl3): δ = 48.3, 51.0, 75.0, 119.8,
127.5, 127.9, 129.3, 129.6, 130.1, 131.4, 135.7, 168.0 ppm. HRMS
(ESI): calcd. for C23H18BrN3NaO3 [M + Na]+ 486.0424; found
486.0417. HPLC (Chiralpak AS-H, hexane/2-propanol = 80:20,
flow rate = 1.0 mLmin–1, λ = 254 nm): tR = 6.08 (minor, major
isomer), 7.63 (major, major isomer), 9.39 min (inseparable minor
isomer).
[9] Z. Yang, Z. Wang, S. Bai, X. Liu, L. Lin, X. Feng, Org. Lett.
2011, 13, 596.
[10] A. Mazzanti, T. Calbet, M. Font-Bardia, A. Moyano, R. Rios,
Org. Biomol. Chem. 2012, 10, 1645.
[11] D. Enders, A. Grossmann, B. Gieraths, M. Düzdemir, C. Merk-
ens, Org. Lett. 2012, 14, 4254.
[12] For selected recent examples on the stereocontrolled construc-
tion of contiguous quaternary and tertiary stereocenters, see:
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M. Shiro, N. Shibata, Angew. Chem. 2013, 125, 2277; Angew.
Chem. Int. Ed. 2013, 52, 2221; b) W. Chen, J. F. Hartwig, J.
Am. Chem. Soc. 2013, 135, 2068; c) W. Zhang, D. Tan, R. Lee,
G. Tong, W. Chen, B. Qi, K.-W. Huang, C.-H. Tan, Z. Jiang,
Angew. Chem. 2012, 124, 10216; Angew. Chem. Int. Ed. 2012,
51, 10069; d) X. Chen, W. Zhu, W. Qian, E. Feng, Y. Zhou, J.
Wang, H. Jiang, Z.-J. Yao, H. Liu, Adv. Synth. Catal. 2012,
354, 2151; e) D. Mailhol, M. M. Sanchez Duque, W. Raimondi,
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Chi, Org. Lett. 2012, 14, 5412; h) A. Noole, I. Jarving, F. Wer-
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i) A. W. Schammel, G. Chiou, N. K. Garg, Org. Lett. 2012, 14,
4556; j) M. Jörres, I. Schiffers, I. Atodiresei, C. Bolm, Org.
Lett. 2012, 14, 4518; k) M. Weber, S. Jautze, W. Frey, R. Peters,
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(R)-4-Bromo-4-[(R)-2-nitro-1-phenylethyl]-1,3-diphenyl-1H-pyrazol-
5(4H)-one (3t): Yellow solid, Ͼ99% yield, m.p. 55–57 °C, [α]2D0
=
+102.4 (c = 0.5, CHCl3), 98:2dr, 99%ee for major isomer. 1H
NMR (400 MHz, CDCl3): δ = 4.56 (dd, J = 4.8, 10.0 Hz, 1 H),
5.54–5.65 (m, 2 H), 6.81 (d, J = 7.6 Hz, 2 Harom), 7.05 (t, J =
7.6 Hz, 2 Harom), 7.16 (t, J = 7.6 Hz, 1 Harom), 7.27 (t, J = 7.6 Hz,
1 Harom), 7.44 (t, J = 7.6 Hz, 2 Harom), 7.49–7.56 (m, 3 Harom), 7.78
(d, J = 8.0 Hz, 2 Harom), 7.96 ppm (d, J = 7.2 Hz, 2 Harom). 13C
NMR (100.6 MHz, CDCl3): δ = 48.8, 53.9, 75.4, 119.5, 126.4,
126.9, 128.2, 128.9, 129.0, 129.3, 131.3, 131.4, 136.8, 154.7,
8
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Date: 17-06-13 16:47:43
Pages: 9
Synthesis of Optically Active Brominated Pyrazol-5-ones
[13] For a recent review on catalytic asymmetric dearomatization
reactions, see: C.-X. Zhuo, W. Zhang, S.-L. You, Angew. Chem.
2012, 124, 12834; Angew. Chem. Int. Ed. 2012, 51, 12662.
[14] Over course of this study, Ma reported a bifunctional thiourea
catalyzed Michael addition/dearomative fluorination reaction
of pyrazol-5-ones and nitro olefins to generate fluorinated pyr-
zol-5-one derivatives with ee values ranging from 87–98%. F.
Li, L. Sun, Y. Teng, P. Yu, J. C.-G. Zhao, J.-A. Ma, Chem. Eur.
J. 2012, 18, 14255.
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Alemán, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J.
2011, 17, 6890.
[16] CCDC-937703 [for (4R,1ЈR)-3d] contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: March 29, 2013
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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