Asymmetric Synthesis of Amino-Bis-Pyrazolone Derivatives via an Organocatalytic Mannich Reaction

Article abstract of DOI:10.1021/acs.joc.7b01113

A new series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in asymmetric Mannich reactions with pyrazolones. The amino-bis-pyrazolone products are obtained in excellent yields and stereoselectivities by employing a very low loading of 1 mol % of a bifunctional squaramide organocatalyst. Depending on the substitution at position 4 of the pyrazolones, the new protocol allows for the generation of one or two tetrasubstituted stereocenters, including a one-pot version combing the Mannich reaction with a base-mediated halogenation.

Full text of DOI:10.1021/acs.joc.7b01113

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Note
Asymmetric Synthesis of Amino-Bis-Pyrazolone
Derivatives via an Organocatalytic Mannich Reaction
Pankaj Chauhan, Suruchi Mahajan, Ugur Kaya, Anssi Peuronen, Kari Rissanen, and Dieter Enders
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 May 2017
Downloaded from http://pubs.acs.org on May 25, 2017
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Asymmetric Synthesis of Amino-Bis-Pyrazolone Derivatives via an
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Organocatalytic Mannich Reaction
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Pankaj Chauhan,†§ Suruchi Mahajan,†§ Uğur Kaya,† Anssi Peuronen,‡ Kari Rissanen‡ and Dieter
Enders†*
†Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
‡Department of Chemistry, Nanoscience Center, University of Jyvaskyla, 40014 JYU, Finland
ABSTRACT: A new series of N-Boc ketimines derived from pyrazolin-5-ones have been used as
electrophiles in asymmetric Mannich reactions with pyrazolones. The amino-bis-pyrazolone products
are obtained in excellent yields and stereoselectivities by employing a very low loading of 1 mol% of
a bifunctional squaramide organocatalyst. Depending on the substitution in the 4-position of the
pyrazolones the new protocol allows for the generation of one or two tetra-substituted stereocenters
including a one-pot version combing the Mannich reaction with a base mediated halogenation.
Pyrazoles and pyrazolones, are a privileged class of five-membered aza-heterocycles that find wide
applications as pharmaceuticals and agrochemicals, as well as synthetic scaffolds in combinatorial and
medicinal chemistry, photographic couplers and chelating agents in coordination chemistry.1 The
pyrazolone moiety is not a common feature of biologically active natural products, but a broad range
of synthetic pyrazolone derivatives exhibit significant pharmacological activities. For example the
pyrazolone derivatives are used as antipyretic drugs,2 neuroprotective agents3 HIV-1 integrase
inhibitors4, antibacterial agent,5 etc. Due to the wide biological and synthetic applications, the
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synthesis of these 1,2-azoles has been a major focus of interest among synthetic organic chemists. In
this context, the asymmetric synthesis of the structurally diverse pyrazole and pyrazolone derivatives,
especially employing the reactivities of pyrazolin-5-one derivatives, remain at the forefront thus
leading to the discovery of new aza-hetereocyclic compounds for further investigations.6
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With the availability of many reactive centers pyrazolin-5-ones are unique substrates with many
possibilities of modification and manipulation in order to obtain new valuable compounds (Figure 1).
The well established nucleophilic centers on pyrazolin-5-ones are available at the N-1,7 C-4 8 and 5-
OH9 positions, whereas the C-3 position is electrophilic10. The α,β-unsaturated pyrazolones bearing a
γ-hydrogen have been used as vinylogous nucleophiles11 and those derived from aldol condensation
with aldehydes, served as very good Michael acceptors12. By knowing all these reactive sites of
pyrazolin-5-one derivatives, we realized the synthesis of a new series of pyrazolin-5-one derivatives
i.e. N-Boc ketimines where the C-4 position can act as an acceptor. This new reactivity of the
pyrazolin-5-one substrates can be utilized to develop new catalytic asymmetric transformations to
generate a tetrasubstituted amino stereogenic center. To the best of our knowledge, there are only two
reports in the literature which describe the formation of pyrazolones bearing a tetrasubstituted amino
stereogenic center via the α-amination reaction of the 4-sustituted pyrazolones (Scheme 1).13
Alternatively, we herein report an enantioselective Mannich addition of pyrazolones to N-Boc
ketimines derived from pyrazolin-5-ones to provide an efficient entry to amino-bis-pyrazolones
bearing one or two tetrasubstituted stereogenic centers.
Figure 1. Reactive centers of pyrazolin-5-one derivatives.
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Scheme 1. Asymmetric synthesis of N-protected amino-pyrazolones.
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Initially, we synthesized a new series of N-Boc ketimines starting with the base catalyzed
condensation reaction of pyrazolones 1 with nitrosobenzene to afford the intermediate phenyl imines
2, which were then hydrolyzed to afford the ketones 3 (Scheme 2). The ketones 3 were subsequently
converted to the N-Boc ketimines 4 via an aza-Wittig reaction.
Scheme 2. Synthesis of pyrazolone derived N-Boc ketimines.
With the substrates in our hand, we started the optimization studies by screening various
bifunctional hydrogen-bonding organocatalysts[14] for the enantioselective addition of pyrazolone 1a to
the imine 4a in dichloromethane at room temperature to afford the desired product 5a (Table 1). It
turned out that the reactions were generally very fast with 1 mol% of squaramides C-1 to C-7. The
squaramide catalysts derived from quinine C-2 and quinidine C-5 gave the best enantioselectivities of
the products 5a and ent-5a, respectively, with an excellent yield of 99%. However, a thiourea (C-8)
and a cuperine catalyst (C-9) resulted in a slow reaction rate with poor er-values.
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Table 1. Catalyst screening.a
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a Reaction conditions: 0.24 mmol of 1a, 0.2 mmol 4a, 1 mol% of catalyst in 1.0 mL of CH2Cl2 at room temperature.
To further improve the yield and enantiomeric ratio, the optimization of the reaction
conditions was carried out by screening different solvents, additives and varying the temperature using
catalyst C-2 (Table 2). This time a one-pot addition/acylation reaction was carried out in order to
obtain the enolacetate 6a, whose enantiomers could be easily resolved by HPLC. After screening
various solvents (entries 1-9), it was found that no other solvent provide better er-values than
dichloromethane. An increase in the er-value of 6a was observed by lowering the temperature to –20
˚C (entry 10). Moreover, the presence of 4 Å molecular sieves (MS) also led to an increase in the
enantioselectivity (entry 11). Further lowering of the temperature and the reducing catalyst loading,
however, led to a lower reaction rate and hence lower yields (entries 12 and 13). Based on these
optimization studies, best reaction condition for this transformation include 1 mol% of C-2 in
dichloromethane at -48 ˚C and 4 Å MS as an additive, providing the desired product 5a with 99%
yield and 98.5:1.5 er (entry 14).
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Table 2. Optimization of the reaction conditions.a
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Entry
Solvent
Temp.
Time (h)
Yield (%) b
er c
1
CH2Cl2
ClCH2CH2Cl
CHCl3
rt
rt
rt
rt
rt
rt
rt
rt
rt
2.5
2.5
2.5
5
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95:5
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90.5:9.5
76.5:23.5
81:19
77:23
91:9
4
toluene
xylene
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Et2O
1.5
0.3
1.5
1.5
5
7
THF
8
1,4-dioxane
MTBE
80.5:19.5
79:21
96.5:3.5
97:3
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10
11d
12d,e
13d,e,f
14d,e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-20 ˚C
-20 ˚C
-78 ˚C
-48 ˚C
-48 ˚C
6
24
18
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94:6
98:2
98.5:1.5
a Reaction conditions: 0.20 mmol of 1a, 0.22 mmol of 4a, 1 mol% of C-2 in 1.0 mL
of solvent. bYield of isolated product 6a after column chromatography.
enantiomeric ratios were determined by HPLC analysis on a chiral stationary phase.
50 mg of 4 Å molecular sieves were used. e Yield of the non-acylated product 5a. f 0.5
mol% of C-2 was used.
c
The
d
After the optimization, we then focused towards the substrate scope for the squaramide C-2
catalyzed Mannich addition of the pyrazolones 1 to the imines 4 (Table 3). The variation in the N-
substituent (R1) of 1 showed that the aryl group bearing electron-withdrawing and electron-donating
group led to the formation of the corresponding adducts 5b-d in high yields and very good er-values.
A N-methyl group is also well tolerated to provide the desired product 5e in 89% yield and good er of
91:9. Various alkyl substituents (R2) at the C-3 position of the pyrazolone 1 also worked very well in
terms of er-values of the products 5f-h, but the increase in steric bulk, the yield decreased to some
extent. A pyrazolone bearing a trifluoromethyl group at the C-3 position led to the formation of the
desired product 5i in 71% yield, however, the er could not be determined by HPLC.
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Table 3. Substrate scope with catalyst C-2 and C-5.a
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a Reaction conditions: 0.20 mmol of 1, 0.22 mmol of 4, 1 mol% of C-2 or C-5, 50 mg 4 Å MS in 1.0 mL of CH2Cl2 at -48 ˚C. b
er-values of acylated product.
The imines 4 bearing an electron-withdrawing and electron-donating group (R3) at the N-1
position also reacted well to provide high enantioselectivities of the desired products 5j and 5k. It was
further observed that the imines bearing ethyl and isopropyl substituents (R4) at the C-3 position
worked well to provide very good yields and excellent enatioselectivities of 5l and 5m. However, an
increase of steric bulk (R4 = t-Bu and Ph) at this position leads to low reactivity even at room
temperature and resulted in lower er-values of 5n and 5o.
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The substrate scope was also tested with the catalyst C-5, which worked in a similar fashion to
provide the enantiomeric products ent-5a-o with the same level of yields and enantiomeric ratios.
Furthermore, we have tested the applicability of this transformation to generate two adjacent
tetrasubstituted stereocenters by using C-3 alkyl substituted pyrazolones 7 as nucleophiles (Scheme 3).
With 2 mol% of the catalysts C-2 and C-5 the corresponding bis-pyrazolone products 8 and ent-8 were
obtained with good yields and enantioselectivities as well as excellent diastereselectivities (>20:1 dr).
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Scheme 3. Asymmetric synthesis of bis-pyrazolones bearing two adjacent tetrasubstituted stereocenters.
The one-pot organocatalytic 1,2-addition and base mediated halogenation also worked
successfully leading to the formation of fluoro- and chloro- substituted amino-bis-pyrazolone products
9a and 9b bearing two contiguous tetra-substituted stereocenters (Scheme 4). In both cases, good
yields and excellent stereoselectivities were achieved.
Scheme 4. One-pot organocatalytic 1,2-addition and base mediated halogenation reaction. (NFSI: N-
fluorobenzenesulfonimide, NCS: N-chlorosuccinimide)
The absolute configuration of the products 5, 8 and 9 obtained with catalyst C-2 could be
assigned by analogy to the X-ray crystal structures of the products 6a and 8a.[15]
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CONCLUSION
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In conclusion, we have synthesized pyrazolone derived N-Boc ketimines and utilized these new
electrophiles in the organocatalytic asymmetric Mannich-type addition of pyrazolone derivatives. With
a low loading of the squaramide C-2 and C-5 both enantiomers of the corresponding amino-bis-
pyrazolones with one and two tetrasubstituted stereocenters were synthesized in good to excellent
yields and stereoselectivities for a wide range of substrates. In addition, the one-pot organocatalytic
enantioselective Mannich addition and base mediated diastereoselective α-halogenation also worked
efficiently to provide the corresponding bis-pyrazolones bearing two adjacent tetrasubstituted halo and
amino stereogenic centers.
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EXPERIMENTAL SECTION
General Method. All reactions were performed in oven-dried glassware. Analytical TLC were carried
out using SIL G-25 UV254 from Machery & Nagel and visualized with ultraviolet radiation at 254
nm. 1H and 13C NMR spectra were recorded in CDCl3 at ambient temperature on Varian Innova 400 or
Innova 600 instruments. Chemical shifts for 1H NMR and 13C NMR spectra were reported in parts per
million (ppm), with coupling constants given in Hertz (Hz). The following abbreviations are used for
spin multiplicity: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, m = multiplet
and br = broad signal. The assignment of the exact numbers of carbon atoms in the bis-amino-
pyrazolone products was not possible, hence only the number of signals seen in the 13C NMR spectra
are written. It is assumed that this problem is due to a possible keto-enol tautomerization or the
restricted rotation. Mass spectra were recorded with the spectrometer SSQ 7000 from Finnigan at 70
eV, whereas HRMS data (ESI) were collected with a ThermoFisher Scientific LTQ-Orbitrap XL
apparatus. IR spectra were taken on a PerkinElmer Spectrum 100 FT-IR spectrometer. Analytical
HPLC was carried out either on a Hewlett-Packard 1050 series instrument or Agilent 1100 instrument
using chiral stationary phases. Analytical SFC was carried out on a Thar SFC Waters Method Station
1
II instrument using chiral stationary phases. The diasteromeric ratio was determined by the H NMR
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and HPLC analysis of the isolated product. Optical rotation values were measured on a Perkin-Elmer
241 polarimeter. Melting points were measured on a LLG MPM-H2 melting point instrument.
Unless specified, the starting materials and reagents were purchased directly from the
commercial suppliers and used without further purification. The squaramides C1 to C716 and the
benzyl cuperine C-917 were synthesized using known literature procedures.
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General procedure for the synthesis of pyrazolone derived phenyl ketimines 2. Nitrosobenzene
(25.0 mmol, 1.0 equiv.) and K2CO3 (0.2 equiv.) were added to a solution of pyrazolone derivative 1
(25.0 mmol, 1.0 equiv.) in MeOH (0.6 M) at room temperature. The reaction mixture was then
refluxed for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved
in ethyl acetate. The organic layer was washed three times with water, once with brine and then dried
over anhydrous MgSO4. After evaporation of ethyl acetate under reduced pressure, the crude product
was purified by flash column chromatography (n-pentane/diethyl ether, 3:1) to afford the ketimine
product 2.
5-Methyl-2-phenyl-4-(phenylimino)-2,4-dihydro-3H-pyrazol-3-one (2a): red solid; 3.16 g, 48%; mp =
102 – 104 ˚C; IR (capillary) 3060, 2287, 2084, 1937, 1664, 1587, 1488, 1412, 1360, 1297, 1132, 998,
911, 831, 744, 687 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.88 – 7.86 (m, 2H, ArH), 7.45 – 7.23 (m, 7H,
ArH), 7.22 – 7.19 (m, 1H, ArH), 2.35 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ 152.7, 151.2,
150.8, 146.3, 137.7, 129.0 (2C), 128.7 (2C), 125.6, 121.8 (2C), 118.5 (2C), 118.4, 12.4; MS (EI) m/z:
262.9 M+; HRMS (ESI) m/z: [M + H]+ calcd for C16H14N3O 264.1131, found 264.1131.
2-(4-Chlorophenyl)-5-methyl-4-(phenylimino)-2,4-dihydro-3H-pyrazol-3-one (2b): red solid; 3.64 g,
49%; mp = 121 – 123 ˚C; IR (capillary) 3461, 2993, 2678, 2338, 2093, 1902, 1716, 1577, 1479,
1305, 1105, 994, 820 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.83 (m, 2H, ArH), 7.44 – 7.31 (m,
7H, ArH), 2.32 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 152.2, 151.2, 151.1, 146.2, 136.3, 129.1
(2C), 129.0, 128.7 (2C), 122.03, 122.01, 119.4 (2C), 118.8, 12.4; MS (EI) m/z: 296.8 M+; HRMS
(ESI) m/z: [M + H]+ calcd for C16H13N3OCl 298.0742, found 298.0742.
5-Methyl-4-(phenylimino)-2-(p-tolyl)-2,4-dihydro-3H-pyrazol-3-one (2c): red solid; 3.32 g, 48%; mp
= 75 – 77 ˚C; IR (capillary) 3354, 2934, 2702, 2339, 2092, 1907, 1690, 1497, 1306, 1129, 993, 774,
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683 cm-1; H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.5 Hz, 2H, ArH), 7.44 – 7.42 (m, 2H, ArH),
7.38 – 7.36 (m, 2H, ArH), 7.34 – 7.31 (m, 1H, ArH), 7.20 – 7.19 (m, 2H, ArH), 2.35 (s, 3H, CH3),
2.33 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ 152.8, 151.1, 150.6, 146.3, 135.3, 135.2, 129.5(2C),
129.1, 128.7 (2C), 128.6, 121.8, 118.4 (2C), 21.1, 12.4; MS (EI) m/z: 276.9 M+; HRMS (ESI) m/z: [M
+ Na]+ calcd for C17H15N3ONa 300.1107, found 300.1107.
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5-Ethyl-2-phenyl-4-(phenylimino)-2,4-dihydro-3H-pyrazol-3-one (2d): red solid; 3.19 g, 46%; mp = 94
– 96 ˚C; IR (capillary) 3460, 2970, 2663, 2336, 2094, 1912, 1728, 1589, 1479, 1341, 1225, 1117,
1037, 919, 836, 755 cm-1; 1H NMR (600 MHz, CDCl3) 7.92 – 7.90 (m, 2H, ArH), 7.45 – 7.32 (m, 6H,
ArH), 7.22 – 7.20 (m, 2H, ArH), 2.76 (q, J = 7.5 Hz, 2H, CH2CH3), 1.40 (t, J = 7.5 Hz, 3H, CH2CH3);
13C NMR (151 MHz, CDCl3) δ 154.6, 152.3, 151.3, 146.4, 137.7, 129.0 (2C), 128.7 (2C), 128.5,
125.5, 121.7, 118.4 (2C), 118.3, 20.2, 10.6; MS (EI) m/z: 276.8 M+; HRMS (ESI) m/z: [M + Na]+
calcd for C17H15N3ONa 300.1107, found 300.1109.
5-Isopropyl-2-phenyl-4-(phenylimino)-2,4-dihydro-3H-pyrazol-3-one (2e): red solid; 4.22 g, 58%; mp
= 77 – 79 ˚C; IR (capillary) 3398, 2959, 2707, 2340, 2093, 1709, 1593, 1467, 1334, 1256, 1102, 977,
835, 747, 685 cm-1; H NMR (600 MHz, CDCl3) δ 7.92 – 7.91 (m, 2H, ArH), 7.45 – 7.39 (m, 4H,
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ArH), 7.34 – 7.31 (m, 3H, ArH), 7.22 – 7.19 (m, 1H, ArH), 3.22 – 3.18 (m, 1H, CH(CH3)2), 1.42 (d, J
= 7.0 Hz, 6H, CH(CH3)2); 13C NMR (151 MHz, CDCl3) δ 157.5, 152.0, 151.3, 146.5, 137.8, 129.0
(2C), 128.7 (2C), 128.4, 125.5, 121.4 (2C), 118.4 (2C), 27.1, 20.1 (2C); MS (EI) m/z: 290.9 M+;
HRMS (ESI) m/z: [M + Na]+ calcd for C18H17N3ONa 314.1264, found 314.1264.
5-(tert-Butyl)-2-phenyl-4-(phenylimino)-2,4-dihydro-3H-pyrazol-3-one (2f): red solid; 3.74 g, 49%;
mp = 95 – 97 ˚C; IR (capillary) 2957, 2340, 2095, 1925, 1717, 1590, 1479, 1375, 1304, 1213, 1108,
963, 839, 689 cm-1; H NMR (600 MHz, CDCl3) δ 7.93 – 7.91 (m, 2H, ArH), 7.45 – 7.39 (m, 4H,
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ArH), 7.31 7.29 (m, 1H, ArH), 7.24 – 7.19 (m, 3H, ArH), 1.51 (s, 9H, C(CH3)3); 13C NMR (151 MHz,
CDCl3) δ 158.4, 152.0, 150.8, 146.7, 137.7, 128.9 (2C), 128.7 (2C), 127.8, 125.4, 120.3 (2C), 118.3
(2C), 35.1, 28.1(3C); MS (EI) m/z: 304.9 M+; HRMS (ESI) m/z: [M + H]+ calcd for C19H20N3O
306.1601, found 306.1602.
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2,5-Diphenyl-4-(phenylimino)-2,4-dihydro-3H-pyrazol-3-one (2g): red solid; 4.55 g, 56%; mp = 176 –
178 ˚C; IR (capillary) 3449, 3026, 2682, 2338, 2092, 1896, 1714, 1592, 1482, 1399, 1307, 1142, 925,
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838, 687cm-1; H NMR (600 MHz, CDCl3) δ 8.32 – 8.30 (m, 2H, ArH), 7.99 – 7.97 (m, 2H, ArH),
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7.51 – 7.42 (m, 7H, ArH), 7.35 – 7.21 (m, 3H, ArH), 7.26 – 7.23 (m, 1H, ArH); 13C NMR (151 MHz,
CDCl3) δ 152.1, 150.7, 147.1, 146.9, 137.6, 130.8, 129.0 (2C), 128.8 (3C), 128.7 (2C), 128.2, 128.1
(2C), 125.9, 120.6 (2C), 118.7 (2C); MS (EI) m/z: 324.8 M+; Anal. calcd for C21H15N3O: C, 77.52%,
H, 4.65%, N, 12.91%, found: C, 77.69%, H, 4.71%, N, 13.08%.
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General procedure for the synthesis of pyrazolone-derived ketones 3. The ketimine 2 (10 mmol)
was dissolved in THF (0.13 M) and the aqueous HCl (2.0 N) solution (25 mL) was added to it at room
temperature. The progress of the reaction was monitored on TLC. After completion of the reaction, the
mixture was diluted with water. The organic layer was extracted three times with dichloromethane and
the combined organic layers were dried over anhydrous MgSO4. The solvent was removed under
reduced pressure and the crude product was directly purified by flash column chromatography (n-
hexane/EtOAc, 1:1) to afford the desired product 3.
3-Methyl-1-phenyl-1H-pyrazole-4,5-dione (3a): red solid; 1.58g, 84%; mp = 119 – 121 ˚C; IR
(capillary) 3083, 2078, 1765, 1722, 1591, 1492, 1434, 1416, 1370, 1279, 1151, 1086, 1039, 972, 913,
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849, 763, 689 cm-1; H NMR (400 MHz, CDCl3) δ 7.84 – 7.82 (m, 2H, ArH), 7.44 – 7.40 (m, 2H,
ArH), 7.26 – 7.22 (m, 1H, ArH), 2.18 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 184.6, 149.2,
144.5, 137.0, 129.3 (2C), 126.3, 117.8 (2C), 11.1; MS (EI) m/z: 188.1 M+; HRMS (ESI) m/z: [M]+
calcd for C10H8N2O2 188.0580, found 188.0583.
1-(4-Chlorophenyl)-3-methyl-1H-pyrazole-4,5-dione (3b): red solid; 1.71 g, 77%; mp = 157 – 159 ˚C;
IR (capillary) 3106, 2060, 1772, 1714, 1591, 1491, 1432, 1402, 1369, 1309, 1284, 1166, 1090, 1048,
1006, 855, 825, 736, 687 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H, ArH), 7.41 (d,
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J = 8.4 Hz, 2H, ArH), 2.23 (s, 3H, CH3); C NMR (151 MHz, CDCl3) δ 184.3, 149.1, 144.8, 135.5,
131.6, 129.4 (2C), 118.9 (2C), 11.2; MS (EI) m/z: 222.1 M+; HRMS (ESI) m/z: [M]+ calcd for
C10H7N2O2Cl 222.0192, found 222.0191.
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1-(4-Methylphenyl)-3-methyl-1H-pyrazole-4,5-dione (3c): red solid; 1.11 g, 55%; mp = 116 – 119 ˚C;
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IR (capillary) 3192, 2349, 2099, 1703, 1507, 1368, 1220, 1117, 819, 674 cm-1; H NMR (600 MHz,
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CDCl3) δ 7.73 – 7.71 (m, 2H, ArH), 7.24 – 7.22 (m, 2H, ArH), 2.36 (s, 3H, CH3), 2.19 (s, 3H, CH3);
13C NMR (151 MHz, CDCl3) δ 184.9, 149.05, 144.4, 136.3, 134.6, 129.8 (2C), 117.9 (2C), 21.1, 11.1;
MS (EI) m/z: 202.1 M+; HRMS (ESI) m/z: [M + Na]+ calcd for C11H10N2O2Na 225.0634, found
225.0633.
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3-Ethyl-1-phenyl-1H-pyrazole-4,5-dione (3d): red solid; 1.68 g, 83%; mp = 128 – 130 ˚C; IR
(capillary) 3351, 2962, 2094, 1707, 1478, 1353, 1094, 748 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.90 –
7.87 (m, 2H, ArH), 7.47 – 7.46 (m, 2H, ArH), 7.28 – 7.26 (m, 1H, ArH), 2.62 – 2.58 (m, 2H,
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CH2CH3), 1.33 – 1.31 (m, 3H, CH2CH3); C NMR (151 MHz, CDCl3) δ 184.8, 149.4, 148.5, 137.1,
129.3 (2C), 126.4, 117.9 (2C), 19.5, 9.8; MS (EI) m/z: 202.1 M+; HRMS (ESI) m/z: [M + Na]+ calcd
for C11H10N2O2Na 225.0634, found 225.0632.
3-Isopropyl-1-phenyl-1H-pyrazole-4,5-dione (3e): red solid; 1.73, 80%; mp = 51 – 53 ˚C; IR
(capillary) 3337, 2968, 2092, 1710, 1067, 1085, 755 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.89 – 7.87
(m, 2H, ArH), 7.46 – 7.46 (m, 2H, ArH), 7.27 – 7.24 (m, 1H, ArH), 2.97– 2.92 (m, 1H, CH(CH3)2),
1.33 (d, J = 7.0 Hz, 6H, CH(CH3)2); 13C NMR (151 MHz, CDCl3) δ 184.7, 151.4, 149.3, 137.0, 129.2
(2C), 126.3, 117.8 (2C), 27.0, 19.1 (2C); MS (EI) m/z: 216.2 M+; HRMS (ESI) m/z: [M + H]+ calcd for
C12H13N2O2 217.0971, found 217.0968.
3-(tert-Butyl)-1-phenyl-1H-pyrazole-4,5-dione (3f): red solid; 1.98, 86%; mp = 80 – 82 ˚C; IR
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(capillary) 3454, 2961, 2328, 2089, 1738, 1593, 1488, 1385, 1212, 1126, 1043, 942, 753 cm-1; H
NMR (600 MHz, CDCl3) δ 7.90 – 7.88 (m, 2H, ArH), 7.46 – 7.43 (m, 2H, ArH), 7.28 – 7.25 (m, 1H,
ArH), 1.37 (s, 9H, t-Bu); 13C NMR (151 MHz, CDCl3) δ 184.3, 153.1, 148.9, 137.1, 129.2 (2C), 126.3,
117.8 (2C), 33.9, 27.1 (3C); MS (EI) m/z: 230.2 M+; HRMS (ESI) m/z: [M + Na]+ calcd for
C13H14N2O2Na 253.0947, found 253.0947.
1,3-Diphenyl-1H-pyrazole-4,5-dione (3g): red solid; 2.07 g, 83%; mp = 165 – 166 ˚C; IR (capillary)
3452, 2926, 2332, 2097, 1729, 1590, 1482, 1390, 1143, 912, 747 cm-1; 1H NMR (600 MHz, CDCl3) δ
8.19 – 8.17 (m, 2H, ArH), 7.99– 7.97 (m, 2H, ArH), 7.53 – 7.48 (m, 5H, ArH), 7.32 – 7.29 (m, 1H,
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ArH); 13C NMR (151 MHz, CDCl3) δ 184.1, 148.9, 141.2, 137.0, 132.0, 129.4 (2C), 129.3 (2C), 127.3
(2C), 126.7, 126.6, 118.1 (2C); MS (EI) m/z: 250.1 M+; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H10N2O2Na 273.0634, found 273.0634.
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General procedure for the synthesis of pyrazolone-derived N-Boc ketimine 4. The tert-
butyl(triphenylphosphoranylidene)acetate (1.1 equiv.) was added to a solution of the pyrazolone-
derived ketone 3 (0.5 mmol) in 1,4-dioxane (0.2 M) at room temperature and the mixture was refluxed
for 3-3.5 hours. After completion of the reaction, the solvent was removed under reduced pressure and
the crude product was directly purified by flash column chromatography (n-pentane/diethyl ether, 1:1)
to afford the desired N-Boc ketimine 4.
tert-Butyl (3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate (4a): orange solid;
1.09 g, 76%; 173-175 °C; IR (capillary) 2979, 2319, 2110, 1722, 1596, 1482, 1369, 1250, 1143, 843,
759 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.84-7.82 (m, 2H, ArH), 7.42-7.40 (m, 2H, ArH), 7.24-7.21
(m, 1H, ArH), 2.28 (s, 3H, Me), 1.64 (s, 9H, t-Bu); 13C NMR (151 MHz, CDCl3) δ 158.9, 153.9,
150.2, 150.0, 137.0, 129.1 (2C), 126.0, 118.3 (2C), 85.4, 28.1 (3C), 12.1; MS (EI) m/z: 286.9 M+;
HRMS (ESI) m/z: [M + Na]+ calcd for C15H17N3O3Na 310.1162, found 310.1161.
tert-Butyl (1-(4-chlorophenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)-carbamate (4b):
orange solid; 1.13 g, 70%; mp = 148 – 150 ˚C; IR (capillary) 2980, 2315, 2115, 1735, 1482, 1368,
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1239, 1145, 836, 759 cm-1; H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 2H, ArH), 7.37 (d, J =
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8.5 Hz, 2H, ArH), 2.29 (s, 3H, Me), 1.63 (s, 9H, t-Bu); C NMR (151 MHz, CDCl3) δ 158.7, 153.6,
150.6, 150.0, 135.6, 131.2, 129.2 (2C), 119.4 (2C), 85.6, 28.1 (3C), 12.1; MS (EI) m/z: 320.9 M+;
HRMS (ESI) m/z: [M + K]+ calcd for C15H16N3O3ClK 360.0512, found 360.0513.
tert-Butyl (1-(4-methylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)-carb-amate (4c):
1.13 g, 75%; orange solid; mp = 170-172 °C; IR (capillary) 2986, 1727, 1612, 1517, 1440, 1368,
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1313, 1249, 1147, 1036, 988, 880, 818, 772 cm-1; H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 8.5 Hz,
2H, ArH), 7.21 (d, J = 8.3 Hz, 2H, ArH), 2.35 (s, 3H, CH3), 2.29 (s, 3H, CH3), 1.63 (s, 9H, t-Bu); 13C
NMR (151 MHz, CDCl3) δ 158.8, 153.9, 149.9, 149.8, 135.7, 134.5, 129.6 (2C), 118.3 (2C), 85.3,
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28.0 (3C), 21.0, 12.0; MS (EI): m/z: 301.7 M+; Anal. calcd for C16H19N3O3: C, 63.77%, H, 6.36%, N,
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13.94%, found: C, 63.44%, H, 6.55%, N, 13.52%.
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tert-Butyl (3-ethyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate (4d): orange solid;
1.13 g, 75%; mp = 103 – 105 ˚C; IR (capillary) 2972, 2339, 2103, 1717, 1595, 1483, 1349, 1250,
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1141, 839, 762 cm-1; H NMR (600 MHz, CDCl3) δ 7.86 – 7.84 (m, 2H, ArH), 7.43 – 7.30 (m, 2H,
ArH), 7.24 – 7.21 (m, 1H, ArH), 2.68 (q, J = 7.5 Hz, 2H, CH2CH3), 1.64 (s, 9H, t-Bu), 1.35 (t, J = 7.5
Hz, 3H, CH2CH3); 13C NMR (151 MHz, CDCl3) δ 158.9, 154.1, 153.6, 150.3, 137.1, 129.1 (2C),
126.0, 118.4 (2C), 85.3, 28.1 (3C), 20.2, 10.2; MS (EI) m/z: 301.2 M+; HRMS (ESI) m/z: [M + Na]+
calcd for C16H19N3O3Na 324.1319, found 324.1318.
tert-Butyl (3-isopropyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate (4e): orange
solid; 1.37 g, 87%; mp = 114-116 ˚C; IR (capillary) 2975, 2306, 2115, 1728, 1597, 1497, 1369, 1251,
1150, 1045, 980, 845, 749, 684 cm-1; H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 2 H, ArH),
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7.45 – 7.40 (m, 2H, ArH), 7.23 (t, J = 7.4 Hz, 1H, ArH), 3.12 – 3.02 (m, 1H, CH(CH3)2), 1.64 (s, 9H,
t-Bu), 1.37 (d, J = 6.9 Hz, 6H, CH(CH3)2); 13C NMR (151 MHz, CDCl3) δ 158.9, 157.0, 153.0, 150.2,
137.1, 129.0 (2C), 125.8, 118.3 (2C), 85.1, 28.0 (3C), 27.4, 19.7 (2C); MS (EI) m/z: 315.7 M+; Anal.
calcd for C17H21N3O3: C, 64.74%, H, 6.71%, N, 13.32%, found: C, 64.63%, H, 6.60%, N, 13.19%.
tert-Butyl (3-(tert-butyl)-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate (4f): orange
solid; 1.39 g, 84%; mp = 111-113 ˚C; IR (capillary) 2975, 1727, 1597, 1493, 1371, 1309, 1249, 1147,
1049, 968, 845, 748, 685 cm-1; H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 2H, ArH), 7.44 –
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7.40 (m, 2H, ArH), 7.23 (t, J = 7.4 Hz, 1H, ArH), 1.64 (s, 9H, t-Bu), 1.43 (s, 9H, t-Bu); 13C NMR (151
MHz, CDCl3) δ 158.9, 158.4, 152.4, 150.0, 137.1, 129.0 (2C), 125.8, 118.2 (2C), 84.9, 34.9, 28.1
(3C), 27.8 (3 C); MS (EI) m/z: 329.7 M+; Anal. calcd for C18H23N3O3: C, 65.63%, H, 7.04%, N,
12.76%, found: C, 65.35%, H, 7.07%, N, 12.77%.
tert-Butyl (5-oxo-1,3-diphenyl-1H-pyrazol-4(5H)-ylidene)carbamate (4g): orange solid; 1.43 g, 82%;
mp = 176-178 C; IR (capillary) 2982, 2293, 2107, 1731, 1595, 1493, 1369, 1325, 1239, 1145, 1060,
984, 930, 846, 749, 684 cm-1; H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 8.3 Hz, 2H, ArH), 7.95 (d,
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NMR (151 MHz, CDCl3) δ 158.6, 152.8, 149.9, 146.8, 137.0, 131.2, 129.1 (2C), 128.8 (2 C), 128.1,
127.4 (2C), 126.2, 118.5 (2C), 85.3, 28.0 (3 C); MS (EI) m/z: 349.7 M+; Anal. calcd for C20H19N3O3:
C, 68.75%, H, 5.48%, N, 12.03%, found: C, 68.54%, H, 5.29%, N, 11.87%.
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General procedure for the synthesis of 5 and ent-5. In a 10 mL reaction tube equipped with a
magnetic stirring bar, the imine 4 (1.1 equiv., 0.22 mmol), catalyst C-2 or C-5 (2 mol%) and 4 Å
molecular sieves (50 mg) were stirred in dichloromethane (1.0 mL) at -48 °C. After 10 minutes,
pyrazolone 1 (1.0 equiv. 0.2 mmol) was added and the stirring was continued for 24 hours at the same
temperature. The reaction mixture was kept at room temperature for 1 hour and the crude product was
directly purified by flash column chromatography (n-hexane/EtOAc, 1:1) to afford the products 5 or
ent-5.
tert-Butyl (S)-(5-hydroxy-3,3'-dimethyl-5'-oxo-1,1'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'-bipyrazol]-4'-
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yl)carbamate (5a): colorless solid, 91 mg, 99%; mp = 143 – 145 ˚C; [α]D = -56.0 (c = 0.5, CHCl3);
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IR (capillary): 2974, 2322, 2093, 1730, 1473, 1366, 1210, 744 cm-1; H NMR (600 MHz, CD3OD) δ
7.99 – 7.91 (m, 2H, ArH), 7.54 – 7.52 (m, 2H, ArH), 7.47 – 7.40 (m, 4H, ArH), 7.32 (t, J = 7.4 Hz,
1H, ArH), 7.20 (t, J = 7.4 Hz, 1H, ArH), 2.15 (s, 3H, CH3), 2.10 (s, 3H, CH3), 1.43 (s, 6H, t-Bu), 1.27
(s, 3H, t-Bu); 13C NMR (151 MHz, CD3OD) δ 173.1, 162.1, 161.3, 155.9, 146.8, 139.4, 136.3, 130.4,
130.0, 129.9, 128.3, 126.3, 123.0, 120.0, 119.1, 94.9, 81.7, 66.4, 28.6, 13.5, 11.7; MS (EI) m/z: 461.0
M+; HRMS (ESI) m/z: [M + Na]+ calcd for C25H27N5O4Na 484.1955, found 484.1951.
tert-Butyl
(S)-(1-(2-chlorophenyl)-5-hydroxy-3,3'-dimethyl-5'-oxo-1'-phenyl-1',5'-dihydro-1H,4'H-
[4,4'-bipyrazol]-4'-yl)carbamate (5b): colorless solid, 90 mg, 91%; mp = 150 – 152 ˚C; [α]D24 = -38.0
(c = 0.5, CHCl3); 93.5:6.5 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 148 bar, 230
nm] tR 5.35 min (minor), tR 8.51 min (major), IR (capillary): 2976, 2927, 2099, 1713, 1598, 1483,
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1393, 1362, 1312, 1254, 1159, 1088, 1061, 1028, 938, 837, 749, 691 cm-1; H NMR (400 MHz,
CD3OD) δ 7.94 – 7.91 (br m, 2H, ArH), 7.64 – 7.61 (m, 1H, ArH), 7.55 – 7.41 (m, 5H, ArH), 7.22 (t,
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J = 7.4 Hz, 1H, ArH), 2.12 (s, 3H, CH3), 2.07 (s, 3H, CH3), 1.42 – 1.27 (br m, 9H, t-Bu); C NMR
(151 MHz, CD3OD) δ 173.1, 163.3, 162.2, 161.4, 155.9, 146.6, 139.4, 134.3, 133.4, 132.8, 131.8,
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131.7, 129.9, 129.2, 126.4, 126.1, 120.1, 119.2, 93.7, 81.7, 66.5, 28.5, 13.3, 11.6; MS (ESI): m/z:
495.2 M+; HRMS (ESI) m/z: [M + H]+ calcd for C25H27N5O4Cl 496.1746, found 496.1734.
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(S)-(1-(4-chlorophenyl)-5-hydroxy-3,3'-dimethyl-5'-oxo-1'-phenyl-1',5'-dihydro-1H,4'H-
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[4,4'-bipyrazol]-4'-yl)carbamate (5c): colorless solid, 98 mg, 99%; mp = 148 – 150 ˚C; [α]D
=
+134.0 (c = 0.5, CHCl3); 93:7 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 150 bar,
236 nm] tR 8.22 min (minor), tR 8.78 min (major); IR (capillary): 2977, 2928, 2080, 1708, 1628, 1595,
1561, 1489, 1396, 1364, 1312, 1253, 1158, 1090, 1049, 1013, 933, 887, 830, 753, 690 cm-1; 1H NMR
(400 MHz, CD3OD) δ 7.92 – 7.90 (br m, 2H, ArH), 7.59 – 7.56 (m, 2H, ArH), 7.48 – 7.39 (m, 4H,
ArH), 7.23 – 7.19 (m, 1H, ArH), 2.11 (s, 6H, 2CH3), 1.43 – 1.25 (m, 9H, t-Bu); 13C NMR (151 MHz,
CD3OD) δ 173.2, 162.5, 161.4, 156.0, 147.8, 139.4, 135.6, 133.3, 130.4, 129.9, 126.3, 124.1, 120.1,
119.2, 94.7, 81.7, 66.5, 28.5, 13.5, 11.9 MS (ESI) m/z: 495.2 M+; HRMS (ESI) m/z: [M + H]+ calcd for
C25H27N5O4Cl 496.1746, found: 496.1744.
tert-Butyl
(S)-(5-hydroxy-3,3'-dimethyl-5'-oxo-1'-phenyl-1-(p-tolyl)-1',5'-dihydro-1H,4'H-[4,4'-
bipyrazol]-4'-yl)carbamate (5d): colorless solid, 91 mg, 96%; mp = 144 – 146 ˚C; [α]D24 = –92.0 (c =
0.5, CHCl3); 95:5 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 152 bar, 209 nm] tR
16.71 min (minor), tR 19.12 min (major); IR (capillary): 2977, 2926, 2107, 1715, 1596, 1492, 1395,
1363, 1309, 1277, 1255, 1159, 1118, 1077, 1049, 1023, 970, 937, 888, 817, 755, 691 cm-1; H NMR
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(600 MHz, CD3OD) δ 7.98 – 7.91 (br m, 2H, ArH), 7.43 – 7.39 (m, 4H, ArH), 7.28 (d, J = 8.2 Hz, 2H,
ArH), 7.22 – 7.19 (m, 1H, ArH), 2.36 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.43 (s, 6H t-
Bu), 1.27 (s, 3H, t-Bu);13C NMR (151 MHz, CD3OD) δ 173.1, 162.1, 161.3, 155.9, 146.2, 139.4,
138.7, 133.7, 130.9, 129.9, 126.3, 126.1, 123.4, 120.1, 119.1, 94.7, 81.7, 66.5, 28.6, 21.1, 13.4, 11.5;
MS (ESI) m/z: 475.3 M+; HRMS (ESI) m/z: [M + H]+ calcd for C26H30N5O4 476.2292, found
476.2294.
tert-Butyl (S)-(5-hydroxy-1,3,3'-trimethyl-5'-oxo-1'-phenyl-1',5'-dihydro-1H,4'H-[4,4'-bipyrazol]-4'-
yl)carbamate (5e): colorless solid, 71 mg, 89%; mp = 207 – 209 ˚C; [α]D24 = – 90.0 (c = 0.5, CHCl3);
91:9 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 149 bar, 230 nm] tR 3.30 min
(minor), tR 3.95 min (major); IR (capillary) 3182, 2976, 2932, 2093, 1714, 1595, 1493, 1393, 1362,
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1306, 1255, 1159, 1073, 1028, 953, 885, 837, 755, 690 cm-1; H NMR (600 MHz, CD3OD) δ 7.94 –
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7.87 (m, 2H, ArH), 7.43 – 7.40 (m, 2H, ArH), 7.20 (t, J = 7.5 Hz, 1H, ArH), 3.40 (s, 3H, CH3), 2.14 –
2.02 (m, 3H, CH3), 1.98 (s, 3H, CH3), 1.43 (s, 6H, t-Bu), 1.26 (s, 3H, t-Bu);13C NMR (151 MHz,
CD3OD) δ 173.2, 162.9, 161.4, 155.9, 143.8, 139.4, 129.9, 126.3, 126.1, 120.1, 119.1, 93.9, 81.6, 66.5,
30.4, 28.5, 28.4, 13.2, 11.2; MS (EI) m/z: 399.2 M+; HRMS (ESI) m/z: [M + H]+ calcd for C20H26N5O4
400.1979, found 400.1979.
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tert-Butyl (S)-(3-ethyl-5-hydroxy-3'-methyl-5'-oxo-1,1'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'-bipyrazol]-
4'-yl)carbamate (5f): colorless solid, 90 mg, 95%; mp = 144 – 146 ˚C; [α]D24 = +24.0 (c = 0.5, CHCl3);
94.5:5.5 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 156 bar, 241 nm] tR 6.73 min
(minor), tR 7.53 min (major); IR (capillary): 2965, 1711, 1599, 1480, 1365, 1366, 1162, 7438 cm-1; 1H
NMR (600 MHz, CD3OD) δ 7.92 (br s, 2H, ArH), 7.58 – 7.56 (m, 2H, ArH), 7.51 – 7.48 (m, 2H,
ArH), 7.45 – 7.32 (m, 2H, ArH), 7.37 – 7.35 (m, 1H, ArH ), 7.22 (t, J = 7.4 Hz, 1H, ArH), 2.56 –
2.46 (m, 2H, CH2CH3), 2.12 (s, 3H, CH3), 1.43 (br s, 6H, t-Bu), 1.29 (br s, 3H, t-Bu), 1.11 (t, J = 7.6
Hz, 3H, CH2CH3); 13C NMR (151 MHz, CD3OD) δ 173.4, 162.8, 161.7, 155.9, 152.2, 139.4, 136.4,
130.4, 129.9, 128.5, 126.4, 123.6, 120.1, 119.1, 94.2, 81.7, 66.5, 28.5, 19.9, 13.4, 12.7; MS (EI) m/z:
475.2 M+; HRMS (ESI) m/z: [M + Na]+ calcd for C26H29N5O4Na 498.2098, found 498.2112.
tert-Butyl
(S)-(5-hydroxy-3'-methyl-5'-oxo-1,1'-diphenyl-3-propyl-1',5'-dihydro-1H,4'H-[4,4'-
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bipyrazol]-4'-yl)carbamate (5g): colorless solid, 94 mg, 96%; mp = 144 – 146 ˚C; [α]D = +4.0 (c =
0.5, CHCl3); 92:8. er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 148 bar, 229 nm] tR
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6.16 min (minor), tR 6.91 min (major); IR (capillary) 2965, 2087, 1709, 1471, 1170, 734 cm-1; H
NMR (400 MHz, CD3OD) δ 7.97 – 7.95 (m, 2H, ArH), 7.58 – 7.55 (m, 2H, ArH), 7.52 – 7.48 (m, 2H,
ArH), 7.46 – 7.42 (m, 2H, ArH), 7.39 – 7.35 (m, 1H, ArH), 7.22 (t, J = 7.5 Hz, 1H, ArH), 2.45 – 2.31
(m, 2H, CH2CH2CH3), 2.10 (s, 3H, CH3), 1.55 – 1.47 (m, 2H, CH2CH2CH3), 1.41 (br s, 6H, t-Bu), 2.38
(br s, 3H, t-Bu), 0.74 (t, J = 7.3 Hz, 3H, CH2CH2CH3); 13C NMR (151 MHz, CD3OD) δ 173.3, 162.9,
161.8, 155.8, 150.6, 139.4, 136.3, 130.4, 129.0, 129.9, 128.5, 126.3, 123.5, 119.8, 118.9, 94.3, 81.7,
66.7, 28.5, 28.4, 24.2, 22.7, 14.1, 13.3; MS (EI) m/z: 489.0 M+; HRMS (ESI) m/z: [M + Na]+ calcd for
C27H31N5O4Na 512.2268, found: 512.2250.
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(S)-(5-hydroxy-3-isopropyl-3'-methyl-5'-oxo-1,1'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'-
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bipyrazol]-4'-yl)carbamate (5h): colorless solid, 83 mg, 85%; mp = 151– 153 ˚C; [α]D = +8.9 (c =
0.5, CHCl3); 93:7 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 149 bar, 230 nm] tR
4.54 min (minor), tR 5.65 min (major); IR (capillary) 3230, 2960, 2281, 2286, 1723, 1580, 1356, 1165,
911, 728 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.90 (br s, 2H, ArH), 7.56 – 7.40 (m, 4H, ArH), 7.46 –
7.37 (m, 3H, ArH), 7.23 (t, J = 7.4 Hz, 1H, ArH), 3.02 – 2.98 (m, 1H, CH(CH3)2), 2.15 – 2.12 (m, 3H,
CH3), 1.42 (br s, 6H, t-Bu), 1.30 (br s, 3H, t-Bu), 1.19 (d, J = 6.9 Hz, 3H, CH(CH3)2), 1.15 (d, J = 6.9
Hz, 3H, CH(CH3)2); 13C NMR (151 MHz, CD3OD) δ 173.5, 162.7, 161.8, 156.4, 155.8, 139.4, 136.3,
130.7, 129.9, 128.8, 126.4, 124.4, 120.2, 119.1, 93.3, 81.6, 66.6, 28.5, 26.6, 21.4, 21.3, 13.4; MS (EI)
m/z: 489.0 M+; HRMS (ESI) m/z: [M + Na]+ calcd for C27H31N5O4Na 512.2268, found 512.2251.
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(S)-(5-hydroxy-3'-methyl-5'-oxo-1,1'-diphenyl-3-(trifluoromethyl)-1',5'-dihy-dro-1H,4'H-
[4,4'-bipyrazol]-4'-yl)carbamate (5i); brown solid, 73 mg, 71%; mp = 132 – 134 ˚C; [α]D24 = +114.0 (c
= 0.5, CHCl3); IR (capillary) 2976, 2926, 2097, 1700, 1597, 1563, 1494, 1367, 1305, 1231, 1153,
1121, 1057, 1029, 1006, 917, 836, 756, 728, 692 cm-1; H NMR (400 MHz, CD3OD) δ 7.87 (d, J =
1
8.1 Hz, 2H, ArH), 7.70 (d, J = 8.1 Hz, 2H,ArH), 7.47 – 7.39 (m, 4H, ArH), 7.33 – 7.29 (m, 1H, ArH),
7.21 – 7.18 (m, 1H, ArH), 2.08 (s, 3H, , CH3), 1.44 – 1.29 (m, 9H, t-Bu); 13C NMR (101 MHz, CDCl3)
δ 174.1, 160.7, 155.8, 139.9, 139.7, 138.2, 130.2, 129.9, 129.6, 127.8, 126.0, 124.4, 124.0, 122.8,
120.4, 88.2, 81.6, 30.7, 28.6, 13.2; MS (ESI) m/z: 538.2 [M + Na]+; HRMS (ESI) m/z: [M + Na]+
calcd for C25H24N5O4F3Na 538.1673, found 538.1663.
tert-Butyl
(S)-(1'-(4-chlorophenyl)-5-hydroxy-3,3'-dimethyl-5'-oxo-1-phenyl-1',5'-dihy-dro-1H,4'H-
[4,4'-bipyrazol]-4'-yl)carbamate (5j): colorless solid, 98 mg, 99%; mp = 141 – 143 ˚C; [α]D24 = –102.0
(c = 0.5, CHCl3); 94.5:5.5 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 149 bar, 219
nm] tR 9.46 min (minor), tR 10.45 min (major); IR (capillary): 2977, 2927, 2098, 1716, 1601, 1488,
1394, 1362, 1308, 1159, 1084, 1013, 968, 937, 887, 831, 757, 731, 685 cm-1; H NMR (600 MHz,
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CDCl3) δ 7.99 – 7.93 (m, 2H, ArH), 7.54 (d, J = 7.9 Hz, 2H, ArH), 7.48 – 7.45 (m, 2H, ArH), 7.42 (d,
J = 8.6 Hz, 2H, ArH), 7.34 – 7.32 (m, 1H, ArH), 2.13 (s, 3H, CH3), 2.11 (s, 3H, CH3), 1.43 (s, 6H, t-
Bu), 1.29 – 1.25 (m, 3H, t-Bu);13C NMR (151 MHz, CD3OD) δ 173.0, 152.3, 161.6, 156.0, 147.0,
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138.2, 136.4, 131.2, 130.4, 129.9, 128.3, 123.0, 121.2, 120.4, 95.0, 81.7, 66.3, 28.5, 13.6, 11.7; MS
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(EI) m/z: 495.3 M+; HRMS (ESI) m/z: [M + H]+ calcd for C25H27N5O4Cl 496.1746, found 496.1743.
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(S)-(5-hydroxy-3,3'-dimethyl-5'-oxo-1-phenyl-1'-(p-tolyl)-1',5'-dihydro-1H,
4'H-[4,4'-
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bipyrazol]-4'-yl)carbamate (5k): colorless solid, 94 mg, 99%; mp = 141 – 142 ˚C; [α]D24 = –70.0 (c =
0.5, CHCl3); >99:1 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 150 bar,254 nm] tR
11.82 min (minor), tR 12.16 min (major); IR (capillary) 2977, 2925, 2087, 1715, 1611, 1491, 1395,
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1363, 1309, 1278, 1254, 1159, 1121, 1176, 1020, 969, 937, 889, 818, 758, 729, 686 cm-1; H NMR
(600 MHz, CD3OD) δ 7.84 – 7.76 (br m, 2H, ArH), 7.57 – 7.55 (m, 2H, ArH), 7.49 – 7.47 (m, 2H,
ArH), 7.35 – 7.33 (m, 1H, ArH), 7.24 (d, J = 8.2 Hz, 2H, ArH), 2.34 (s, 3H, CH3), 2.14 – 2.10 (m, 6H,
2CH3), 1.43 (s, 6H, t-Bu), 1.23 – 1.27 (m, 3H, t-Bu); 13C NMR (151 MHz, CD3OD) δ 173.0, 162.0,
161.3, 155.9, 155.3, 146.9, 136.9, 136.4, 136.3, 130.4, 130.3, 128.3, 123.1, 120.3, 119.2, 95.0, 81.7,
66.4, 28.6, 21.0, 13.4, 11.5; MS (EI) m/z: 475.2 M+; HRMS (ESI) m/z: [M + H]+ calcd for C26H30N5O4
476.2292, found: 476.2288.
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4'-yl)carbamate (5l): colorless solid, 87 mg, 92%; mp = 136 – 138 ˚C; [α]D = –146.0 (c = 0.5,
CHCl3); IR (capillary) 2977, 2934, 2321, 2097, 1715, 1597, 1490, 1392, 1367, 1306, 1248, 1159,
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1075, 1044, 1021, 933, 888, 835, 755, 688 cm-1; H NMR (600 MHz, CDCl3) δ 10.83 (s, 1H, br s,
OH), 8.90 (s, 1H, NH), 7.89 (d, J = 8.0 Hz, 2H, ArH), 7.55 (d, J = 8.0 Hz, 2H, ArH), 7.39 – 7.31 (m,
4H, ArH), 7.19 – 7.15 (m, 2H, ArH), 2.29 – 2.27 (m, 2H, CH2CH3), 1.77 (s, 3H, CH3), 1.26 (s, 9H, t-
Bu), 1.15 – 1.14 (m, 3H, CH2CH3); 13C NMR (151 MHz, CDCl3) δ 172.3, 164.2, 162.7, 154.3, 146.1,
137.8, 135.6, 129.2, 129.1, 126.5, 125.7, 121.0, 120.5, 119.2, 118.1, 95.2, 80.4, 69.9, 28.2, 20.9, 11.5,
9.9; MS (EI) m/z: 475.3 M+; Anal. calcd for C26H29N5O4: C, 65.67%, H, 6.15%, N, 14.73%, found: C
65.54%, H, 6.17%, N, 14.43%.
tert-Butyl
(S)-(5-hydroxy-3'-isopropyl-3-methyl-5'-oxo-1,1'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'-
bipyrazol]-4'-yl)carbamate (5m): colorless solid, 93 mg, 95%; mp = 145 – 147 ˚C; [α]D24 = -186.2 (c
= 0.6, CHCl3); IR (capillary) 2974, 2931, 2107, 1715, 1597, 1490, 1369, 1305, 1249, 1160, 1078,
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1023, 979, 899, 834, 755, 689, 660 cm-1; H NMR (600 MHz, CD3OD) δ 8.02 – 7.94 (m, 2H, ArH),
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7.57 – 7.55 (m, 2H, ArH), 7.51 – 7.48 (m, 2H, ArH), 7.46 – 7.43 (m, 2H, ArH), 7.37– 7.34 (m, 1H,
ArH), 7.23 (t, J = 7.4 Hz, 1H, ArH), 2.81 – 2.78 (m, 1H, CH(CH3)2), 1.98 (s, 3H, CH3), 1.42 (s, 6H, t-
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Bu), 1.37 – 1.18 (m, 3H, t-Bu, 6H, CH(CH3)2); C NMR (151 MHz, CD3OD) δ 173.0, 167.3, 163.0,
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155.7, 146.1, 139.4, 139.4, 136.3, 130.5, 129.9, 128.4, 126.4, 123.1, 120.1, 119.1, 95.0, 81.6, 66.8,
29.6, 28.6, 28.4, 21.3, 21.2, 11.2; MS (EI) m/z: 489.3 M+; HRMS (ESI) m/z: [M + Na]+ calcd for
C27H31N5O4Na 512.2268, found 512.2256.
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(S)-(3'-(tert-butyl)-5-hydroxy-3-methyl-5'-oxo-1,1'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'-
bipyrazol]-4'-yl)carbamate (5n): colorless solid, 68 mg, 67%; mp = 165 – 158 ˚C; [α]D24 = -108.0 (c =
0.5, CHCl3); 80:20 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 151 bar, 230 nm] tR
17.83 min (minor), tR 18.94 min (major); IR (capillary) 2977, 2932, 2097, 1713, 1595, 1492, 1393,
1362, 1305, 1254, 1158, 1073, 1029, 953, 885, 838, 794, 755, 690 cm-1; 1H NMR (600 MHz, CD3OD)
δ 8.04 – 7.94 (m, 2H, ArH), 7.58 – 7.57 (m, 2H, ArH), 7.52 – 7.49 (m, 2H, ArH), 7.46 – 7.43 (m, 2H,
ArH), 7.38 – 7.36 (m, 1H, ArH), 7.24 (t, J = 7.5 Hz, 1H), 1.94 (s, 3H, CH3), 1.42 (s, 6H, t-Bu), 1.34 (s,
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3H, t-Bu), 1.31 (s, 6H, t-Bu), 1.26 (s, 3H, t-Bu); C NMR (151 MHz, CD3OD) 173.2, 167.7, 163.0,
155.6, 145.7, 139.3, 136.3, 130.5, 130.1, 129.9, 128.5, 126.4, 126.2, 123.3, 120.0, 119.0, 95.7, 81.5,
66.9, 37.0, 29.5, 29.3, 28.6, 28.4, 10.9; MS (EI) m/z: 503.3 M+; HRMS (ESI) m/z: [M + Na]+ calcd for
C28H33N5O4Na 526.2424, found 526.2419.
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yl)carbamate (5o): colorless solid, 97 mg, 93%; mp = 155 – 156 ˚C; [α]D = –8.0 (c = 0.5, CHCl3);
87:13 er; SFC [(R,R)-Whelk-O1 column, MeOH/CO2, 4.00 mL/min, 148 bar, 230 nm] tR 12.68 min
(minor), tR 13.45 min (major); IR (capillary) 2977, 2929, 2098, 1717, 1597, 1490, 1371, 1292, 1254,
1156, 1115, 1074, 1023, 949, 917, 878, 837, 796, 756, 688 cm-1; 1H NMR (600 MHz, CD3OD) δ 8.12
– 8.03 (m, 4H, ArH), 7.56 – 7.54 (m, 2H, ArH), 7.49 – 7.42 (m, 7H, ArH), 7.33 (t, J = 7.5 Hz, 1H,
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ArH), 7.28 – 7.25 (m, 1H, ArH), 1.99 (s, 3H, CH3), 1.31 (s, 6H, t-Bu), 1.14 (s, 3H, t-Bu); C NMR
(151 MHz, CD3OD) 173.5, 162.5, 157.7, 155.8, 146.1, 139.3, 136.2, 131.9, 130.4, 130.0, 129.9, 128.4,
127.7, 126.7, 123.2, 120.3, 119.4, 95.5, 81.7, 65.8, 28.5, 28.3, 11.2; MS (EI) m/z: 523.3 M+; HRMS
(ESI) m/z: [M + H]+ calcd for C30H30N5O4 524.2292, found 524.2290.
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General procedure for the acylation of product 5. In a 10 mL reaction tube equipped with a
magnetic stirring bar, the amino-bis-pyrazolone 5 (1 equiv., 0.1 mmol) was stirred in dichloromethane
(1.0 mL) at room temprature followed by the addition of Ac2O (2.0 equiv. 0.2 mmol) and
triethylamine (0.3 equiv., 0.03 mmol). The stirring was continued for 3 hours at room temperature and
the crude product was directly purified by flash column chromatography (n-hexane/EtOAc, 3:1) to
afford the enolacetate product 6.
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(S)-4'-((tert-Butoxycarbonyl)amino)-3,3'-dimethyl-5'-oxo-1,1'-diphenyl-4',5'-dihydro-1H,1'H-[4,4'-
bipyrazol]-5-yl acetate (6a): colorless solid, 49 mg, 97%; mp = 179 – 181 ˚C; 98.5:1.5 er; HPLC
[chiralpak AD column, n-heptane/i-PrOH, 8:2, 1.0 mL/min, 254 nm] tR 9.90 min (minor), tR 15.67
min (major); IR (capillary) 3294, 2929, 1656, 1530, 1446, 1367, 1241, 1051, 752, 691 cm-1; 1H NMR
(600 MHz, CDCl3) δ 7.94 – 7.93 (m, 2H, ArH), 7.42– 7.37 (m, 6H, ArH), 7.35 – 7.33 (m, 1H, ArH),
7.18 – 7.16 (m, 1H, ArH), 5.57 (br s, 1H, NH), 2.46 (s, 3H, CH3), 2.17 (s, 3H, CH3), 1.99 (s, 3H, CH3),
1.39 (s, 9H, t-Bu); 13C NMR (151 MHz, CDCl3) δ 170.7, 166.7, 159.2, 153.8, 146.8, 141.5, 138.2,
137.3, 129.4, 129.0, 128.3, 125.1, 123.5, 118.7, 101.4, 64.5, 28.2, 20.1, 15.0, 14.2; MS (EI) m/z: 503.0
M+; HRMS (ESI) m/z: [M + Na]+ calcd for C27H29N5O5Na 526.2061, found 526.2064.
(S)-4'-((tert-Butoxycarbonyl)amino)-3'-ethyl-3-methyl-5'-oxo-1,1'-diphenyl-4',5'-dihydro-1H,1'H-[4,4'-
bipyrazol]-5-yl acetate (6l): colorless wax, 50 mg, 97%; 98.5:1.5 er; HPLC [chiralpak IA column, n-
heptane/i-PrOH, 7:3, 0.5 mL/min, 254 nm] tR 13.86 min (minor), 20.54 min (major); IR (capillary)
3278, 2970. 2325, 1719, 1591, 1477, 1358, 1155, 1050, 876, 751 cm-1; 1H NMR (600 MHz, CDCl3) δ
7.98 – 7.99 (m, 2H, ArH), 7.42 – 7.38 (m, 6H, ArH), 7.34 – 7.32 (m, 1H, ArH), 7.18 – 7.16 (m, 1H,
ArH), 5.57 (s, 1H, NH), 2.51 – 2.43 (m, 2H, CH2CH3), 2.43 (s, 3H, CH3), 1.97 (s, 3H, CH3), 1.37 (br s,
9H, t-Bu), 1.31 (d, J = 7.4 Hz, 3H, CH2CH3).;13C NMR (151 MHz, CDCl3) δ 171.0, 166.7, 162.8,
146.6, 141.5, 138.4, 137.3, 129.4, 129.0, 128.3, 125.1, 101.8, 64.5, 28.4, 28.2, 21.5, 20.1, 15.0, 9.5;
MS (EI) m/z: 517.4 M+; HRMS (ESI) m/z: [M + Na]+ calcd for C28H31N5O5Na 540.2217, found
540.2211.
(S)-4'-((tert-Butoxycarbonyl)amino)-3'-isopropyl-3-methyl-5'-oxo-1,1'-diphenyl-4',5'-dihydro-1H,1'H-
[4,4'-bipyrazol]-5-yl acetate (6m): colorless wax, 51 mg, 96%; 98.5:1.5 er; HPLC [chiralpak IA
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column, n-heptane/i-PrOH, 7:3, 0.5 mL/min, 254 nm] tR 15.93 min (minor), 17.10 min (major); IR
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6
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(capillary) 3238, 2965. 2309, 1716, 1594, 1480, 1361, 1155, 871, 749 cm-1; H NMR (600 MHz,
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9
CDCl3) δ 8.01 (d, J = 8.0 Hz, 2H, ArH), 7.43 – 7.39 (m, 6H, ArH), 7.35 – 7.33 (m, 1H, ArH), 7.19 –
7.16 (m, 1H, ArH), 5.74 (s, 1H, NH), 2.83 – 2.64 (m, 1H, CH(CH3)2), 2.37 (s, 3H, CH3), 1.94 (s, 3H,
CH3), 1.41 – 1.22 (br m, 9H, t-Bu, 3H, CH(CH3)2), 1.23 – 1.22 (m, 3H, CH(CH3)2); 13C NMR (151
MHz, CDCl3) δ 170.9, 166.6, 165.4, 153.9, 146.2, 141.6, 138.3, 137.3, 129.4, 129.0, 128.3, 125.0,
123.5, 118.6, 101.8, 53.6, 28.4, 28.2, 21.0, 20.8, 20.1, 14.9; MS (EI) m/z: 531.4 M+; HRMS (ESI) m/z:
[M + Na]+ calcd for C29H33N5O5Na 554.2374, found 554.2374.
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General procedure for the synthesis of 8 and ent-8. In a 10 mL reaction tube equipped with a
magnetic stirring bar, the imine 4a (1.1 equiv., 0.22 mmol), catalyst C-2 or C-5 (2 mol%) and 4 Å
molecular sieves (50 mg) were stirred in dichloromethane (1.0 mL) at -48 °C. After 10 minutes,
pyrazolone 7 (1.0 equiv. 0.2 mmol) was added and the stirring was continued for 24 hours at the same
temperature. The reaction mixture was kept at room temperature for 1 hour and the crude product was
directly purified by flash column chromatography (n-hexane/EtOAc, 4:1) to afford the products 8 or
ent-8.
tert-Butyl
((4S,4'S)-3',4-dimethyl-5,5'-dioxo-1,1'-diphenyl-3-(phenylethynyl)-1',4,5,5'-tetrahydro-
24
1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (8a): colorless solid, 102 mg, 88%; mp = 97 – 98 ˚C; [α]D
=
–144.0 (c = 0.5, CHCl3); 96.5:3.5 er; HPLC [(S,S)-Whelk-O1 column, n-heptane/i-PrOH, 9:1, 1.0
mL/min, 230 nm] tR 12.00 min (minor), 13.93 min (major), IR (capillary) 3333, 2979, 2209, 1720,
1
1483, 1359, 1147, 878, 748 cm-1; H NMR (600 MHz, CDCl3) δ 7.84 – 7.83 (m, 2H, ArH), 7.76 –
7.74 (m, 2H, ArH), 7.61–7.59 (m, 2H, ArH), 7.48 – 7.40 (m, 5H, ArH), 7.30 – 7.25 (m, 3H, ArH),
7.13 – 7.11 (m, 2H, ArH, NH), 2.35 (s, 3H, CH3), 1.72 (s, 3H, CH3), 1.39 (s, 9H, t-Bu); 13C NMR (151
MHz, CDCl3) δ 171.8, 169.7, 155.6, 154.4, 143.6, 137.7, 136.8, 132.2, 130.4, 129.1, 128.9, 128.8,
126.7, 125.3, 120.7, 120.3, 119.3, 99.4, 79.3, 68.3, 52.9, 28.2, 16.4, 16.2; MS (ESI) m/z: 584.2 [M +
Na]+; HRMS (ESI) m/z: [M + Na]+ calcd for C33H31N5O4Na 584.2268, found 584.2266.
tert-Butyl
((4S,4'S)-3,3'-dimethyl-5,5'-dioxo-1,1'-diphenyl-4-(prop-2-yn-1-yl)-1',4,5,5'-tetrahydro-
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1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (8b): colorless solid, 86 mg, 86%; mp = 94 – 96 ˚C; [α]D
=
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+48.0 (c = 0.5, CHCl3); 94:6 er; HPLC [(S,S)-Whelk-O1 column, n-heptane/i-PrOH, 9:1, 1.0 mL/min,
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254 nm] tR 10.60 min (minor), 12.92 min (major); IR (capillary) 3296, 2975, 2190, 1718, 1470, 1355,
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8
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1163, 878, 760 cm-1; H NMR (600 MHz, CDCl3) 7.82 – 7.80 (m, 2H, ArH), 7.77 – 7.75 (m, 2H,
9
ArH), 7.43 – 7.40 (m, 2H, ArH), 7.38 – 7.35 (m, 2H, ArH), 7.26 – 7.23 (m, 1H, ArH), 7.19 – 7.17 (m,
1H, ArH), 3.21 (dd, J = 16.4, 2.6 Hz, 1H, CH2), 2.84 (dd, J = 16.4, 2.6 Hz, 1H, CH2), 2.30 (s, 3H,
CH3), 2.08 (s, 3H, CH3), 1.97 (t, J = 2.6 Hz, 1H, CH), 1.37 (s, 9H, t-Bu); 13C NMR (151 MHz, CDCl3)
δ 170.9, 169.7, 156.2, 155.4, 137.4, 136.8, 129.1, 129.0, 126.4, 125.6, 120.4, 119.1, 75.4, 72.6, 67.7,
57.2, 28.2, 20.1, 16.5, 14.7; MS (EI) m/z: 499.3 M+; HRMS (ESI) m/z: [M + Na]+ calcd for
C28H29N5O4Na 522.2109, found 522.2112.
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General procedure for the synthesis of 9. In a 10 mL reaction tube equipped with a magnetic
stirring bar, the imine 4a (1.1 equiv., 0.22 mmol), catalyst C-2 (1 mol%) and 4 Å molecular sieves (50
mg) were stirred in dichloromethane (1.0 mL) at -48 °C. After 10 minutes, pyrazolone 1a (1.0 equiv.
0.2 mmol) was added and the stirring was continued for 24 hours at the same temperature. The
reaction mixture was warmed to the room temperature. After 1 hour NFSI or NCS (1.5 equiv.) and
K2CO3 (1.5 equiv.) were added and the reaction mixture was stirred for 3.5 hours at the room
temperature. The crude product was directly purified by flash column chromatography (n-
hexane/EtOAc, 4:1) to afford the products 9a or 9b.
tert-Butyl ((4R,4'S)-4-fluoro-3,3'-dimethyl-5,5'-dioxo-1,1'-diphenyl-1',4,5,5'-tetrahydro-1H,4'H-[4,4'-
bipyrazol]-4'-yl)carbamate (9b): colorless solid, 59 mg, 62%; mp = 75 – 77 ˚C; [α]D24 = +180.0 (c =
0.5, CHCl3); 98.5:1.5 er; HPLC [chiralpak IC column, n-heptane/i-PrOH, 9:1, 1.0 mL/min, 230 nm] tR
3.72 min (major), 5.09 min (minor); IR (capillary) 3379, 2931, 2083, 1717, 1493, 1369, 1247, 1157,
908, 831, 752, 690 cm-1; 1H NMR (400 MHz, CDCl3) 7.77 (d, J = 8.1 Hz, 4H, ArH), 7.43 – 7.33 (m,
4H, ArH), 7.27 – 7.24 (m, 1H, ArH), 7.20 – 7.16 (s, 1H, ArH), 2.34 (s, 3H, CH3), 2.12 (s, 3H, CH3),
1.39 (s, 9H, t-Bu); 13C NMR (101 MHz, CDCl3) δ 167.1, 164.7, 156.7, 154.0, 152.2, 137.5, 136.2,
129.2, 129.1, 126.7, 125.9, 119.8, 119.2, 89.7, 82.0, 69.0, 28.2, 15.7, 14.0; 19F NMR (376 MHz,
CDCl3) –179.94; MS (EI) m/z: 479.0 M+; HRMS (ESI) m/z: [M + Na]+ calcd for C25H26N5O4FNa
502.1861, found 502.1862.
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tert-Butyl ((4R,4'S)-4-chloro-3,3'-dimethyl-5,5'-dioxo-1,1'-diphenyl-1',4,5,5'-tetrahydro-1H,4'H-[4,4'-
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bipyrazol]-4'-yl)carbamate (9b): colorless solid, 78 mg, 79%; mp = 83 – 85 ˚C; [α]D = –170.0 (c =
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8
9
0.5, CHCl3); 98.5:1.5 er; HPLC [chiralpak IA column, n-heptane/i-PrOH, 7:3, 0.7 mL/min, 230 nm] tR
5.24 min (minor), tR 5.70 min (major); IR (capillary) 3354, 2932, 2101, 1718, 1595, 1490, 1369, 1259,
1157, 1064, 902, 826, 745, cm-1; 1H NMR (600 MHz, CDCl3) 7.81 – 7.80 (m, 2H, ArH), 7.77 – 7.75
(m, 2H, ArH), 7.44 – 7.41 (m, 2H, ArH), 7.38 – 7.35 (m, 2H, ArH), 7.28 – 7.25 (m, 1H, ArH), 7.20 –
7.18 (m, 1H, ArH), 2.42 (s, 3H, CH3), 2.15 (s, 3H, CH3), 1.40 (s, 9H, t-Bu); 13C NMR (151 MHz,
CDCl3) δ 168.0, 166.7, 156.9, 153.2, 137.4, 136.4, 129.2, 129.1, 126.7, 125.9, 120.0, 119.2, 82.04,
68.3, 62.2, 29.8, 28.2, 16.5, 14.0; MS (EI) m/z: 494.9 M+; HRMS (ESI) m/z: [M + K]+ calcd for
C25H26N5O4ClK 534.1305, found 534.1305.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI:
xxxxxxxxxxxxxxxxxxx.
NMR spectra, HPLC data, and X-ray crystal structures of 6a and 8a (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: enders@rwth-aachen.de
Author Contributions
§P.C. and S.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank Mrs. Cornelia Vermeeren for her help with the SFC measurements.
REFERENCES
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