Synthesis and reactivity of N-sugar-maleimides: An access to novel highly substituted enantiopure pyrazolines

Article abstract of DOI:10.1016/j.tetasy.2012.11.005

Two diastereomeric isoxazolines were synthesized in a stereoselective manner with 6.64-20.36% diastereoisomeric excess. The cycloaddition of N-sugar-maleimide in the presence of MgBr₂ afforded isoxazolines with high diasterioselectivities (76-8

Full text of DOI:10.1016/j.tetasy.2012.11.005

Tetrahedron: Asymmetry 23 (2012) 1689–1693
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and reactivity of N-sugar-maleimides: an access to novel highly
substituted enantiopure pyrazolines
⇑
Naoufel Ben Hamadi , Moncef Msaddek
Laboratory of Synthesis Heterocyclic and Natural Substances, Department of Chemistry, Faculty of Sciences of Monastir, Boulevard of Environment, 5000 Monastir, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 October 2012
Accepted 12 November 2012
Two diastereomeric isoxazolines were synthesized in a stereoselective manner with 6.64–20.36% diaste-
reoisomeric excess. The cycloaddition of N-sugar-maleimide in the presence of MgBr2 afforded isoxazolines
with high diasterioselectivities (76–84% de). The 1,3-dipolar cycloaddition reaction was diastereospecific
and enantiomerically pure (3R,4S,5S,6S,3aR,6aS)-pyrazolines were obtained from N-sugar-maleimides
via 1,3-proton migration.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The reaction of the resultant glycosylamine with maleic anhydride
in EtOH afforded amic acid in high yields. Cyclization of amic acid 4
It is known that oligosaccharides in glycoconjugates, such as
glycoproteins and glycolipids, play important roles in many biolog-
ical processes and consequently their biological functions have
been investigated extensively by chemists, biochemists, and biolo-
gists.1,2 Carbohydrates have been widely used as chiral templates
for introducing chirality in synthetic asymmetric processes due
to their rigid structure with a high degree of functionalization,
and the presence of several contiguous stereogenic centers.3,4
Due to the remarkable biological relevance of carbohydrates, the
synthesis of oligosaccharides or carbohydrate derivatives has long
been the goal pursued by researchers in different areas. 1,3-Dipolar
cycloaddition reactions, involving heterocyclic rings, have been
largely studied as a useful synthetic strategy to obtain various het-
erocyclic systems.5–7
Since Lewis acids are a powerful tool in organic synthesis, one of
today’s challenges in the field of 1,3-dipolar cycloadditions is Lewis
acid-induced control of the regio- and stereoselectivity in these
reactions.8 The Lewis acid-catalyzed reaction of nitrile oxide cyc-
loadditions is an important research area.9 As part of our contin-
uing interest in the chemistry of highly substituted heterocycles,
we herein report the synthesis of optically active pyrazolines from
N-sugar-maleimides containing five stereogenic centers.
with 4-dimethylaminopyridine (DMAP) in the presence of
N,N0-dicyclohexylcarbodiimide (DCC) gave the desired product 5
(Method A).
The primary alcohol 1 was converted into maleimidosugar 5 in
89% yield by a Mitsunobu reaction13 (Method B) with maleimide
in the presence of Ph3P and diethyl azodicarboxylate (DEAD)
(Scheme 1).
The reaction of maleimidosugar 5 with aromatic nitrile oxide 6
at 110 °C in toluene, without the preference of metal ions, gave a
mixture of inseparable diastereomeric cycloadducts. The mixture
of [(3R,4S,5S,6S,3aS,6aR)-7/(3R,4S,5S,6S,3aR,6aS)-8] was chromato-
graphed on silica gel. The ratio of the two NMR peaks for H1 at
5.5 ppm was approximately 50:50. These results confirmed that
the two diastereomers were responsible for signal doubling
(Table 1).
The diastereomeric ratios for all of the results shown in Table 1
were established from the 1H NMR integration of the crude mate-
rials of the isoxazolines as shown in Figure 1.
In general, maleimidosugar 5 (Table 1, entries 1–12) produced
isoxazoline products with good yields (80–95%) but with low
diastereoisomeric excess, that is, [(3R,4S,5S,6S,3aS,6aR)-7/(3R,4S,
5S,6S,3aR,6aS)-8] (6.64–20.36%). From the experimental results,
there was no obvious relationship between the electron density
of the Ar group of the nitrile oxides and the yields of the corre-
sponding isoxazoline products. Finally, the stereochemistry of the
isoxazoline products was established and assigned by a NOESY
spectrum. The cis-relationship between the H1 and H3a protons
in the minor diastereoisomers 7 was deduced from the presence
of an NOE effect as shown in Figure 2. The irradiation of H-3a in
the minor diastereoisomer 7 showed a positive NOE for H-1.
Lewis acids were successfully employed as catalysts for the 1,3-
dipolar cycloaddition reactions between aromatic nitrile oxides
and maleimidosugar 5. While the reactions proceeded in the pres-
2. Results and discussion
The synthesis of the 6-amino derivatives of galactose has been
widely investigated.10–12 Sugar 1 was converted into the corre-
sponding azido-sugar 2 by substitution of the hydroxyl group with
azide under biphasic conditions. The reduction of azide 2 was
successfully accomplished in quantitative yield with Pd/C and H2.
⇑
Corresponding author.
E-mail address: bh_naoufel@yahoo.fr (N.B. Hamadi).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.005

1690
N. B. Hamadi, M. Msaddek / Tetrahedron: Asymmetry 23 (2012) 1689–1693
OH
O
N3
O
O
O
1. pyr, TsCl
O
O
O
2. 2NaN3 ,DMF, 80°C
O
O
O
1
O
2
1.
N
H , THF
H2, Pd/C
EtOH
O
2. PPh3, DEAD, rt
O
O
NH2
O
HO2C
O
, CH2Cl2
N
O
O
O
O
HN
O
O
O
O
DMAP, DCC
O
O
O
O
O
O
O
O
O
3
5
4
Scheme 1.
Table 1
Effect of metal ion, molar concentration of nitrile oxides with 5
Ar
H
Ar
N
N
O
O
3a
H
3a
(S)
(R)
(S)
(R)
H
H
O
O
O
Ar
C
N
OH
N
N
Cl
O
N
O
O
O
O
O
Et3N, toluene
O
O
O
O
(S)
(S)
+
O
O
(R)
(R)
(R)
(R)
1
1
O
O
O
(R)
6a-c
(R)
(S)
(S)
O
O
O
a : Ar = Ph
b : Ar = p-C6H4-CH3
: Ar = p-C6H4-OCH3
c
8a-c
7a-c
5
a: Ar = Ph
b : Ar = p-C6H4-CH3
c
: Ar = p-C6H4-OCH3
Entries 7:8a
Ar
Ph
Additive (equiv)
Yieldb (%)
Diastereomeric ratio
1
3
5
7
8
9
10
12
None
None
None
MgBr2 (0.5 equiv)
MgBr2 (1 equiv)
ZnCl2 (1 equiv)
MgBr2 (1 equiv)
MgBr2 (1 equiv)
80
85
85
80
90
85
85
95
44:56
46:54
40:60
40:60
35:65
10:90
12:88
8:92
p-C6H4-CH3
p-C6H4-OCH3
Ph
Ph
Ph
p-C6H4-CH3
p-C6H4-OCH3
a
Determined by integrations of H1 signal in the 1H proton NMR spectra as discussed in the text.
Combined yield.
b
ence of a Lewis acid (0.5 equiv), the diastereoselectivities of the
reactions did not improve. Increase of the amount of MgBr2 from
0.5 equiv to 1 equiv augmented diastereoselectivity (80–95% yields
with [(3R,4S,5S,6S,3aS,6aR)-7/(3R,4S,5S,6S,3aR,6aS)-8] 40:60 to
8:92; Table 1, entry 12). We also examined the effect of the
electronic nature of the benzonitrile oxides. As can be seen in Ta-
ble 1 (entry 3), the nitrile oxides with a methoxy electron-donating
substituent showed higher diastereoselectivities (see Table 2).

N. B. Hamadi, M. Msaddek / Tetrahedron: Asymmetry 23 (2012) 1689–1693
1691
The 1,3-dipolar cycloaddition reaction of excess diazoalkanes 9
with sugar 4 at 0 °C led first to the unstable pyrazoline intermedi-
ate 10 which then underwent a prototropic shift to yield pyrazo-
lines 11. Microanalysis and FAB mass spectrometry indicated that
11 was the result of the addition of two diazoalkane equivalents.
In this case, alkylation of the carboxylic acids was carried out using
diazoalkanes (Scheme 2).14
H1-8
H1-7
The structure elucidation for stereoisomers 11a and 11b was
achieved in part with the aid of 1D NOE and 2D NMR techniques
(NOESY). In 1D NOE experiments with a CDCl3 solution of 11a,
the selective irradiation of 40-H showed a positive NOE for 4-H
and 5-H. For instance, adduct 11a displayed cross-peaks between
signal at 3.83 (40-H) and 3.15 ppm (5-H) in the two-dimensional
NOESY 1H NMR spectrum. This observation clearly indicated that
the 40-H and 3-H protons attached to the pyrazoline ring pointed
in opposite directions. From the data collected, we were able to
establish the configuration at C-40 as (S) for the cycloadducts
considered.
5.5
5.0
4.5
Figure 1. 4–6 ppm enlargement of the 1H NMR spectrum of isoxazolines 7a and 8a
in CDCl3.
ppm
0
3. Conclusion
1
2
Our studies have shown that MgBr2 catalysts are extremely
effective in affording high levels of asymmetric induction (up to
84% de) for 1,3-dipolar cycloaddition reactions between nitrile oxi-
des and N-sugar-maleimides. This synthesis allows us to obtain
one diastereoisomer of enantiomerically pure pyrazolines with
six stereogenic centers.
H1(7)-H3a(7)
3
4
5
6
4. Experimental section
Caution: Diazoalkanes are toxic and should be used in an effi-
cient fume hood.
7
8
4.1. General
ppm
8
7
6
5
4
3
2
1
0
Chemicals were of reagent-grade, purchased from commercial
suppliers, and used without further purification. CH2Cl2 and tolu-
ene used in reactions were prepared by distillation over a drying
Figure 2. NOESY spectrum of isoxazolines 7a and 8a in CDCl3.
Table 2
The characteristic peaks in the 300 MHz 1H NMR spectra (CDCl3) of 7 and 8
Ar
1H NMR (CDCl3) d
7a
7b
7c
8a
8b
8c
Ph
1.15(CH3); 1.19(CH3); 1.45(CH3); 1.47(CH3); 5.42 (H1)
p-CH3-C6H4
p-CH3O-C6H4
Ph
p-CH3-C6H4
p-CH3O-C6H4
1.17(CH3); 1.22(CH3); 1.31(CH3); 1.46(CH3); 2.38(CH3); 5.33 (H1)
1.29(CH3); 1.30(CH3); 1.43(CH3); 1.46(CH3); 3.89(OCH3); 5.35 (H1)
1.31(CH3); 1.32(CH3); 1.33(CH3); 1.46(CH3); 5.51(H1)
1.30(CH3); 1.33(CH3); 1.48(CH3); 1.51(CH3); 2.39(CH3); 5.35 (H1)
1.23(CH3); 1.37(CH3); 1.47(CH3); 1.48(CH3); 3.88(OCH3); 5.34 (H1)
H
R
R
N
R
R
N
R
R
C
R
N
N
HO
O
N
R
(S)
4'
N
C
O
C
R
H
O
O
H
HN
O
R
prototropic shift
N
H
O
O
9a,b
O
O
O
N
O
O
O
O
O
5
(R)
(R) O
O
(S)
O
O
O
O
(R)
O
3(S)
a
b
: R = Me
O
: R = Ph
4
11a,b
10a,b
a: R = Me
b: R = Ph
Scheme 2.

1692
N. B. Hamadi, M. Msaddek / Tetrahedron: Asymmetry 23 (2012) 1689–1693
H2), 4.26 (d, JH6-5 = 8.3, 1H, H6), 3.97 (d, JH6 -5 = 8.3, 1H, H60),
0
agent (CH2Cl2:CaH2; toluene:Na). TLC analysis was performed on
Merck Kieselgel 60 F254 plates. Flash chromatography was per-
formed using silica gel Merck 60 (particle size 0.040–0.063 mm).
All anhydrous reactions were performed under nitrogen using
anhydrous solvents. NMR spectra were obtained on a Bruker AC
300 spectrometer operating at 300 MHz for 1H and at 75.64 MHz
for 13C. Melting points were determined on a Buchi-510 capillary
melting point apparatus. Chemical shifts are given in parts per mil-
lion relative to tetramethylsilane (TMS) and the coupling constants
J are given in Hertz. The spectra were recorded in CDCl3 as solvent
at room temperature. Elemental analysis was recorded on a PER-
KIN–ELMER 240B microanalyzer. Mass spectra were recorded on
a Finnigan LCQ DECA XP plus.
3.88–3.79 (m, 1H, H4), 3.34–3.22 (m, 1H, H5), 1.50, 1.47, 1.36,
1.34 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) d 166.20, 164.57,
137.07, 130.38, 109.79, 109.09, 96.31, 71.81, 70.83, 70.49, 65.42,
41.15, 26.06, 25.98, 24.92, 24.28, HRMS Calcd for C16H23NO8
357.1424. Found: 357.1421; IR (KBr)
m
max/cmꢁ1 3350, 2956,
1720, 1725 cmꢁ1; Anal. Calcd for C16H23NO8: C, 53.78, H, 6.49, N,
3.92. Found: C, 53.75, H, 6.41, N, 3.89.
4.2.2. 1-(60-Deoxy-10,20:30,40-di-O-isopropylidene-
nos-60-yl)-1H-pyrrole-2,5-dione 5
a-D-glucopyra-
Yield (228 mg, 70%), white solid. Mp = 132–134 °C. ½a D22
¼ þ24
ꢀ
(c 1, CH2Cl2), Rf = 0.4 (hexane/AcOEt 3:1). 1H NMR (300 MHz,
CDCl3) d 6.42 (s, 2H, H2,4), 6.11 (d, JH1 -2 = 3.6, 1H, H10), 5.62 (dd,
0
0
JH3 -4 = 3.7, JH3 -2 = 2.3, 1H, H30), 5.21–5.10 (m, 2H, H20,40), 4.45–
4.38 (m, 1H, H50), 4.20–4.15 (m, 1H, H60), 4.02–3.90 (m, 1H, H60),
2.02, 1.98, 1.97, 1.87 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) d
169.69, 132.67, 109.52, 108.89, 96.08, 70.45, 70.36, 70.28, 68.22,
65.83, 25.95, 25.79, 24.89, 24.31, HRMS Calcd for C16H21NO7
0
0
0
0
4.2. Synthesis of sugar 4 and maleimidosugar 5
Method A: To a solution of sugar 1 (177 mg, 0.68 mmol) in dry
pyridine (2 mL) was added p-toluenesulfonyl chloride (142 mg,
0.75 mmol) and the reaction mixture was stirred at room temper-
ature for 10 h. The solvent was then removed in vacuo, after which
EtOAc was added and washed successively with 1 M HCl and satd
aq NaHCO3. The organic phase was dried (Na2SO4) and concen-
trated in vacuo. The crude product was dissolved in DMF (2 mL)
and sodium azide (110 mg, 1.7 mmol) was added. The reaction
mixture was stirred at 50 °C for 10 h after which H2O was added
and the aqueous phase was extracted with EtOAc. The organic
phase was dried over MgSO4, concentrated in vacuo, and purified
by column chromatography over silica gel using petroleum
ether–EtOAc (v/v = 7/3) as the eluent. A mixture of azido-sugar 2
(200 mg, 0.7 mmol) and 5% palladium–carbon (82 mg) in EtOH
(10 mL) was hydrogenated under an atmospheric pressure of
hydrogen using a balloon with vigorous stirring for 6 h. The mix-
ture was filtered through Celite, and the solvent removed in vacuo
to give the title compound in quantitative yield as a colorless solid.
Amino-sugar 3 (300 mg, 1.16 mmol) was dissolved in CH2Cl2
(25 mL) to which maleic anhydride (114 mg, 1 mmol) was added.
TLC control showed a quantitative reaction after which the product
was not purified further. Compound 4 (350 mg, 98%) was obtained
as a white solid. A solution of compound 4 (392 mg, 1.1 mmol), DCC
339.1318. Found: 339.1323; IR (KBr)
m
max/cmꢁ1 2954, 1710,
1715 cmꢁ1; Anal. Calcd for C16H21NO7: C, 56.63, H, 6.24, N, 4.13.
Found: C, 56.60, H, 6.27, N, 4.11.
4.2.3. 1,3-Dipolar cycloaddition of nitrile oxides with maleimido-
sugar 5
A solution of maleimidosugar 5 (1 mmol, 326 mg) and chlorox-
imes 6 (1.2 mmol) in toluene (10 mL) was stirred at 110 °C. To this
solution trimethylamine (0.2 mL), dissolved in toluene (10 mL),
was added dropwise. The precipitated triethylammonium chloride
was removed by filtration and the filtrate was concentrated in va-
cuo, which was then submitted to chromatography (SiO2; ethyl
acetate/petroleum ether, 2:1) to afford compounds 7 and 8.
4.3. Procedure for trapping 2-diazopropane 9a with sugar 4
To a solution of sugar 4 (1.0 mmol, 357 mg) in CH2Cl2, cooled at
20 °C was added portionwise a 2.6 M ether solution of diazopro-
pane. The reaction was kept at the same temperature for 2 h after
which the solvent was removed in vacuo without heating to give a
brown oil, which was subjected to flash column chromatography
(SiO2; ethyl acetate/petroleum ether, 3:1) to afford compounds 11.
(223.4 mg, 1.1 mmol), and DMAP (11.1 mg, 91 lmol) in dichloro-
methane was stirred at room temperature for 2 h and then heated
at 40 °C for a further 1 h. The crude reaction mixture was filtered
and the solvent removed in vacuo. The crude material was purified
by flash column chromatography using ethyl acetate/hexanes as
eluant to afford maleimidosugar 5 as a white solid (228 mg, 70%).
Method B: Maleimide (1.0 mmol, 97 mg) was added to a solu-
tion of alcohol 1 (1.1 mmol, 260 mg) and phosphine reagent
(1.1 mmol, 262 mg) in anhydrous CH2Cl2 under an N2 atmosphere
at 0 °C. The resulting suspension/solution was treated with diethyl
azodicarboxylate (1.1 mmol, 174 mg) and the reaction mixture
was then continued to stir at room temperature up until comple-
tion of the reaction, as indicated by TLC monitoring (the reaction
mixture was filtered to recover the reduced diethyl azodicarboxyl-
ate). The solvent was then evaporated and the residue dissolved in
cyclohexane. The triphenylphosphane oxide precipitated and then
filtered off after which the filtrate was evaporated under reduced
pressure. The product was purified by column chromatography
on silica gel to afford the pure products (302 mg, 89%).
4.3.1. 5,5-Dimethyl-3-[(2,2,7,7-tetramethyl-tetrahydro-bis[1,3]-
dioxolo[4,5-b;40,50-d]pyran-5-ylmethyl)-carbamoyl]-4,5-dihy-
dro-1H-pyrazole-4-carboxylic acid isopropyl ester 11a
Yield (375.4 mg, 83%), white solid. Mp = 189–191 °C.
½
a 2D2
ꢀ
¼ þ45 (c 1, CH2Cl2), Rf = 0.5 (hexane/AcOEt 3:1). 1H NMR
(300 MHz, CDCl3) d 5.99 (br s, 1H, NH), 5.39 (d, JH1-2 = 5.1, 1H,
H1), 4.99–5.07 (h, JHCH3-Hiso = 6.0, 1H, Hiso), 4.02 (d, JH3-2 = 6.9, 1H,
H3), 4.18–4.20 (dd, JH3-2 = 1.2, 3.9, 1H, H2), 4.10–4.06 (t, JH3-
2 = 6.3, 1H, H4), 3.83–3.60 (m, 2H, H60,H40), 3.37 (d, J = 13.2, 1H,
H6), 3.15–3.05 (m, 1H, H5), 1.58 1.46 1.44 1.41 1.37 1.29 1.22
1.19 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) d 167.99, 167.80,
162.19, 109.77, 109.11, 109.04, 72.00, 71.97, 71.13, 70.74, 69.25,
68.33, 61.18, 40.46, 26.33, 25.29, 24.66, 23.16, 23.01, 22.73,
22.29, 22.18, HRMS Calcd for
C22H35N3O8 469.2424. Found:
469.2412; IR (KBr)
m
max/cmꢁ1 3315, 2927, 1733, 1728,
1640 cmꢁ1; Anal. Calcd for C22H35N3O8: C, 56.28, H, 7.51, N, 8.95.
Found: C, 56.21, H, 7.54, N, 8.92.
4.2.1. (Z)-4-Oxo-4-(((3R,4S,5S,6S)-1,2;3,4-di-O-isopropylidene-
tetrahydro-2H-pyran-2-yl)methylamino)but-2-enoic acid 4
4.4. Procedure for trapping diphenyldiazomethane 9b with
sugar 4
White solid. Mp = 141–143 °C.
½
a 2D2
ꢀ
¼ þ86 (c 1, CH2Cl2),
Rf = 0.35 (hexane/AcOEt 3:1). 1H NMR (300 MHz, CDCl3) d 15.66
(br s, 1H, CO2H), 6.87 (br s, 1H, NH), 6.42 (d, JHeth = 13.1, 1H, Heth),
6.26 (d, JHeth = 13.1, 1H, Heth), 5.51 (d, JH1-2 = 4.9, 1H, H1), 4.63 (dd,
JH3-4 = 3.9, JH3-2 = 2.0, 1H, H3), 4.46 (dd, JH2-3 = 2.0, JH2-1 = 3.9, 1H,
To a solution of 4 (1 mmol, 357) in ethyl acetate (20 mL), diphe-
nyldiazomethane (6 mmol, 1.17 g) was added and the resulting

N. B. Hamadi, M. Msaddek / Tetrahedron: Asymmetry 23 (2012) 1689–1693
1693
solution was heated under an argon atmosphere at 40 °C for 2 h,
after which time the mixture was cooled to ambient temperature
and concentrated under reduced pressure. Pyrazoline 11b was
crystallized from ethanol.
2929, 1730, 1725, 1638 cmꢁ1; Anal. Calcd for C42H43N3O8: C,
70.28, H, 6.04, N, 5.85. Found: C, 70.26, H, 6.07, N, 5.79.
References
1. Kosuke, K.; Toshifumi, T.; Noritoshi, S.; Seiichi, N.; Hisanori, N.; Shunichi, H.
Tetrahedron 2012, 68, 5005–5017.
2. Hajime, A.; Hiroki, M.; Masahiko, I. Tetrahedron 2012, 68, 4353–4361.
3. Vikas, K.; Partha, G.; Pintu, D.; Arun, K. S. Tetrahedron: Asymmetry 2012, 23,
449–456.
4. Kavirayani, R. P.; Kamala, P. Tetrahedron: Asymmetry 2011, 22, 1400–1403.
5. BenHamadi, N.; Msaddek, M. C. R. Aldrichim. Acta 2011, 14, 891–895.
6. BenHamadi, N.; Msaddek, M. C. R. Aldrichim. Acta 2012, 15, 409–413.
7. Louhichi, N.; Houas, A.; Ben Hamadi, N.; Msaddek, M. J. Heterocycl. Chem 2012,
49, 267–271.
8. Andrei, B. G.; Peter, K. Synthesis 2010, 2207–2212.
9. Hidetoshi, Y.; Sadaka, W.; Keiko, K.; Masayuki, H.; Michihiko, N.; Shuji, K.
Tetrahedron Lett. 2000, 41, 3131–3136.
10. Freudenberg, K.; Doser, A. Chem. Ber. 1925, 294–300.
11. Cappi, M. W.; Morre, W. J.; Qiao, L.; Marron, T. G.; Weitz-Schmidt, G.; Wong, C.
H. Angew. Chem. 1996, 108, 2501–2505.
12. Carmen, L.; Romero; Zaliz, O. V. J. Carbohydr. Chem. 2001, 20, 689–701.
13. Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev.
2009, 109, 2551–2651.
4.4.1. 5,5-Diphenyl-3-[(2,2,7,7-tetramethyl-tetrahydro-bis[1,3]-
dioxolo[4,5-b;40,50-d]pyran-5-ylmethyl)-carbamoyl]-4,5-dihy-
dro-1H-pyrazole-4-carboxylic acid benzhydryl ester 11b
Yield (516.5 mg, 72%), white solid. Mp = 165–167 °C.
½
a 2D2
ꢀ
¼ þ34 (c 1, CH2Cl2), Rf = 0.45 (hexane/AcOEt 3:1). 1H NMR
(300 MHz, CDCl3) d 6.72–7.74 (m, 10H, H arom), 6.01 (br s, 1H,
NH), 5.41 (d, JH1-2 = 5.2, 1H, H1), 4.95–5.02 (h, JHCH3-Hiso = 6.0, 1H,
Hiso), 4.06 (d, JH3-2 = 6.7, 1H, H3), 4.15–4.22 (dd, JH3-2 = 1.3, 3.7,
1H, H2), 4.11–4.09 (t, JH3-2 = 6.3, 1H, H4), 3.84–3.61 (m, 2H,
H60,H40), 3.39 (d, J = 13.1, 1H, H6), 3.14–3.05 (m, 1H, H5), 1.40,
1.37, 1.28, 1.23 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) d 167.76,
166.97, 162.20, 140.10, 139.5, 139.4, 138.97, 129.2, 128.94,
128.87, 128.21, 127.43, 127.22, 126.94, 126.91, 126.21, 125.67,
125.23, 109.76, 109.14, 109.09, 72.01, 71.94, 71.16, 70.70, 69.22,
62.31, 56.19, 44.41, 25.28, 24.65, 23.00, 21.93, HRMS Calcd for
14. Black, T. H. Aldrichim. Acta 1983, 16, 3–10.
C
42H43N3O8 717.3050. Found: 717.3053; IR (KBr) m
max/cmꢁ1 3310,