Reaction between hydrazines and chiral α-acetylenic ketones: Synthesis of novel enantiomerically pure pyrazolyl-β-amino alcohols

Article abstract of DOI:10.1016/S0957-4166(00)00204-4

A simple and efficient methodology toward the stereoselective synthesis of novel, enantiomerically pure, pyrazolyl-β-amino alcohols is presented. Thus, when hydrazines 4a,b were allowed to react at 0°C with chiral α-acetylenic ketones of type 3, pyrazolyl

Full text of DOI:10.1016/S0957-4166(00)00204-4

Tetrahedron: Asymmetry 11 (2000) 2483±2493
Reaction between hydrazines and chiral a-acetylenic ketones:
synthesis of novel enantiomerically pure
pyrazolyl-b-amino alcoholsy
Gemma Cabarrocas,a Montserrat Ventura,a Miguel Maestro,b Jose Mahõab and
Jose M. Villalgordoa,*
a
Â
Departament de Quõmica, Facultat de Ciencies, Universitat de Girona, Campus de Montilivi, E-17071 Girona, Spain
Á
Servicios Xerais de Apoio a Investigacion, Universidade da CorunÄa, Campus da Zapateira s/n, E-15071 A CorunÄa, Spain
b
Â
Â
Received 13 April 2000; accepted 23 May 2000
Abstract
A simple and ecient methodology toward the stereoselective synthesis of novel, enantiomerically pure,
pyrazolyl-b-amino alcohols is presented. Thus, when hydrazines 4a,b were allowed to react at 0ꢀC with
chiral a-acetylenic ketones of type 3, pyrazolyl oxazolidine derivatives 5a±d were formed with total
regioselectivity in 92±97% yield. Subsequent oxazolidine ring opening by means of TFA, and re-protection
of the amino group as the N-Boc derivatives, a€orded enantiopure amino alcohols 7a±d. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
The stereoselective synthesis of b-amino alcohols is a topic of current interest. In recent years,
members of this group of compounds have been used in pharmacological applications such as
modulators of the potassium channel in cells1 or as a core moieties of a number of biologically
important compounds.2 5 In addition, b-amino alcohols bearing heterocyclic residues are of
particular interest, since they can serve as novel building-blocks for biologically active molecules.6 10
On the other hand, it is well known that enantiomerically pure b-amino alcohols are ®nding
extensive use in asymmetric synthesis.11,12 They are frequently used as chiral synthons,13 and as
precursors of chiral auxiliaries.14 16 They have been used as well as ecient chiral ligands in
many asymmetric reactions involving achiral reagents such as Lewis acids,17,18 organometallic
reagents19 or metallic hydrides.20,21 In this particular ®eld, it is often possible to achieve high levels
of asymmetric induction by modulating the steric and electronic properties of the intervening
* Corresponding author. Fax +34-972418150; e-mail: dqjvs@xamba.udg.es
y
Taken in part from the PhD Thesis of G.C. (Universitat de Girona, 1999).
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00204-4

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G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
chiral ligands. In this sense, there is a constant need for the development of new synthetic reper-
toires toward the preparation of novel enantiopure ligands.
Despite the numerous synthetic methods available for the preparation of chiral 1,2-amino
alcohols, only a few stereoselective preparations have been reported.22 The most direct synthesis
of optically active 1,2-amino alcohols is the reduction of a-amino acids;23 26 however, this
method is limited by the nature of lateral chains.
On the other hand, a-acetylenic ketones of type 1 have been shown to be highly versatile
building blocks. These conjugated ynones have proven to be very suitable substrates for the
synthesis of a wide range of heterocyclic systems.27 34 In addition, when properly functionalised,
compounds of type 1 have also proven to be valuable substrates for the combinatorial and parallel
synthesis on solid support of highly molecular diverse 2,4,6-trisubstituted pyrimidines.35,36 In
view of the strong synthetic potential of these conjugated ynones 1, we recently described37 a very
ecient and straightforward synthesis of novel chiral a-acetylenic ketones of type 3 (Fig. 1).
These compounds bear a protected b-amino alcohol functionality as a special structural feature.
This chiral moiety should be readily incorporated into a variety of relevant core structures.
Figure 1.
With the aim of validating our working hypothesis and in order to check the utility of such
chiral building blocks 3 for the preparation of novel optically active 1,2-amino alcohols containing
heterocyclic residues on the lateral chain, we focused our interest on the pyrazole nucleus.
2. Results and discussion
When hydrazine 4a or phenyl hydrazine hydrochloride 4b were allowed to react in DMF (in the
presence of K2CO3 for 4b) at 0ꢀC with chiral ynones 3a±b for a period of 16±22 h, the corre-
sponding pyrazolyl oxazolidines 5a±d were isolated almost quantitatively (92±97% yields). In
marked contrast with a previous report,38 under our reaction conditions, only one regioisomer
5c±d was detected (Scheme 1, Table 1). Although under these reaction conditions we did not
expect that the stereogenic centre at the oxazolidine ring could be a€ected,{ we checked the
{
In another set of experiments using chiral conjugated ynones of type 3, their cyclocondensation reaction with other
more basic bidentated nucleophiles (e.g. amidines) produced the expected compounds (e.g pyrimidines) but with high
levels of epimerisation.39

G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
2485
Scheme 1.
Table 1
Prepared pyrazolyl oxazolidine derivatives 5a±d
enantiomeric excess of the recovered pyrazoles 5 and these were found to be enantiomerically
pure (ꢁ95%, 1H NMR analysis, 200 MHz in the presence of varying amounts of Eu(hfc)3).
Next, treatment of 5a±d with TFA in MeOH at 0ꢀC a€orded the corresponding amino alcohol
derivatives 6a±d that were not isolated, but re-protected in situ leading to N-Boc protected chiral
b-amino alcohol derivatives 7a±d in good overall yields. Again, in the case of 7c the correspond-
ing Mosher's ester derivative 8 was prepared from the crude reaction mixture and the enantio-
1
meric excess of this derivative assessed by H NMR and found to be diastereoisomerically pure
(Scheme 2, Table 2).
In addition, also for 7c, we were able to grow crystals that were suitable for an X-ray crystal
structure determination that on one side con®rmed the structure of the proposed regioisomer and
additionally that the crystals were enantiomerically pure. It was then assumed that they had the
expected absolute con®guration. This assumption was extended to the complete series of synthe-
sised compounds 7a±d (Fig. 2).

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G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
Scheme 2.
Table 2
Prepared chiral pyrazolyl 1,2-amino alcohols 7a±d
In summary, we have developed a short and ecient procedure for the stereoselective synthesis
of novel optically active pyrazolyl-1,2-amino alcohols. The key step in this strategy was the total
regioselectivity exhibited by conjugated ynones 3a±b in their tandem Michael addition±cyclo-
condensation reaction with hydrazines 4a±b under the very mild conditions employed. The
obtained pyrazolyl amino alcohols can serve as useful ligands in a variety of asymmetric trans-

G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
2487
Figure 2. Ortep plot40 of the molecular structure of 7c with 50% probability ellipsoids
formations. Their further elaboration into chiral oxazolines and their application in asymmetric
synthesis is the subject of current e€orts in our laboratory and the results will be published in due
course.
3. Experimental
3.1. General methods
All commercially available chemicals were used as purchased. Melting points (capillary tube)
were measured with a Gallenkamp apparatus and are uncorrected. IR spectra were recorded on a
1
Mattson±Galaxy Satellite FT-IR. H and 13C NMR spectra were recorded at 200 and 50 MHz,
respectively, on a Bruker DPX200 Advance instrument with TMS as internal standard. MS
spectra were recorded on a VG Quattro instrument in the positive ionisation FAB mode, using
3-NBA or 1-thioglycerol as the matrix. Elemental analyses were performed on an apparatus from

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G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
Thermo instruments, model EA1110-CHNS. Optical rotation measurements were performed on a
Perkin±Elmer 241 polarimeter. Analytical TLC was performed on precoated TLC plates, silica
gel 60 F254 (Merck). Flash-chromatography puri®cations were performed on silica gel 60 (230±
400 mesh, Merck).
3.2. Synthesis of pyrazolyl oxazoline derivatives 5a±d. General procedure
To a cooled (0ꢀC) solution of acetylenic ketones 3a±b (300 mg) in DMF (2.5 mL), 1.1 equiv. of
aqueous hydrazine 4a were added. Alternatively, addition of phenyl hydrazine hydrochloride
4b was followed by addition of 1.3 equiv. of K2CO3. The reaction mixture was stirred at 0ꢀC for 2 h
and 16±18 h at rt (TLC monitoring). DMF was eliminated under reduced pressure, and the residue
partitioned between CH2Cl2 (15 mL) and H2O (10 mL). The layers were separated, and the aqueous
one extracted with CH2Cl2 (2Â15 mL). The combined organic layers were dried over MgSO4. The
solvent was evaporated and the resulting residue puri®ed by ¯ash-chromatography (hexanes/
AcOEt as eluent) to a€ord pure 5a±d (Table 1).
3.3. tert-Butyl (4R)-4-[5-(1,3-benzodioxol-5-yl)-1H-3-pyrazolyl]-2,2-dimethyl-1,3-oxazolane-3-
carboxylate 5a
According to the general procedure described in Section 3.2, reaction between 3a and 4a
20
a€orded 302 mg (97%) of 5a as a colourless oil. ‰ꢀŠ ^97.9 (c 2.15, MeOH). IR (®lm, ꢁ): 3400 br.,
D
3289 m, 3144 w, 2973 m, 2958 m, 2925 m, 2876 m, 2780 w, 1697s, 1611 w, 1575 w, 1496 m, 1464
1
m, 1385 m, 1237 m, 1170 m, 1100 m, 1041 m, 976 w, 937 m, 851 m, 809 m, 771 w, 724 w. H
NMR (DMSO-d6, T=60ꢀC), ꢂ=12.65 (s, br., 1H, NH), 7.4±7.25 (m, 2H, CH arom.), 7.01 (d,
J=8.0 Hz, 1H, CH arom.), 6.47 (s, 1H, CH arom.), 6.11 (s, 2H, OCH2O), 5.05 (dd, J=6.4 Hz,
J0=3.0 Hz, 1H, CH), 4.31 (dd, J=8.8 Hz, J0=6.4 Hz, 1H, syst. AB, CH2O), 4.06 (dd, J=8.8 Hz,
J0=3.0 Hz, 1H, syst. AB, CH2O), 1.74 (s, 3H, C(CH3)2), 1.63 (s, 3H, C(CH3)2), 1.44 (s, 9H,
C(CH3)3). 13C NMR (DMSO-d6, T=60ꢀC), ꢂ=151.1 (s, NCO), 150.0, 147.5, 146.6, 145.3, 125.4
(5s, C arom.), 118.6, 108.2, 105.3 (3d, CH arom.), 100.7, (t, OCH2O), 99.0 (d, CH arom.), 93.2 (s,
C(CH3)2), 78.8 (s, C(CH3)3), 68.3 (t, CH2O), 54.2 (d, CH), 27.7 (q, C(CH3)3), 25.9 (q, C(CH3)2),
23.9 (q, C(CH3)2). MS (FAB+) m/e: 388 ([M+1], 100), 387 (M+, 93), 332 (51), 274 (60), 272 (54),
231 (50), 230 (79). Anal. calcd for C20H25N3O5 (387.43): C, 62.00%; H, 6.50%; N, 10.85%.
Found: C, 62.30%; H, 6.26%; N, 10.74%.
3.4. tert-Butyl (4R)-2,2-dimethyl-4-[5-(2-thienyl)-1H-3-pyrazolyl]-1,3-oxazolane-3-carboxylate
5b
According to the general procedure described in Section 3.2, reaction between 3b and 4a
20
a€orded 290 mg (93%) of 5b as a colourless solid. M.p. 135±136ꢀC. ‰ꢀŠ ^125.5 (c 0.80, MeOH).
D
IR (KBr, ꢁ): 3450 br., 3282 m, 3156 w, 2983 m, 2935 w, 2873 w, 1660 s, 1579 w, 1473 w, 1456 w,
1407 m, 1366 m, 1258 m, 1202 w, 1167 m, 1137 m, 1100 m, 1063 m, 946 w, 919 w, 848 m, 809 w,
791 w, 732 w, 701 w. 1H NMR (DMSO-d6, T=60ꢀC), ꢂ=12.65 (s, br. 1H, NH), 7.55±7.4 (m, 2H,
CH arom.), 7.2±7.15 (m, 1H, CH arom.), 6.43 (s, 1H, arom.), 5.07 (dd, J=6.3 Hz, J0=2.8 Hz, 1H,
CH), 4.32 (dd, J=8.8 Hz, J0=6.3 Hz, 1H, Sist. AB, CH2O), 4.06 (dd, J=8.8 Hz, J0=2.8 Hz, 1H,
Sist. AB, CH2O), 1.74 (s, 3H, C(CH3)2), 1.63 (s, 3H, C(CH3)2), 1.45 (s, 9H, C(CH3)3). 13C NMR
(DMSO-d6, T=60ꢀC), ꢂ=151.0 (s, NCO), 127.3 (d, CH arom.) 127.2 (s, C arom.), 124.4 (d, CH

G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
2489
arom.), 124.3 (s, C arom.), 123.3 (d, CH arom.), 123.2 (s, C arom.), 99.5 (d, CH arom.), 93.2 (s,
C(CH3)2), 79.0 (s, C(CH3)3), 68.2 (t, CH2O), 53.6 (d, CH), 27.7 (q, C(CH3)2), 26.0 (q, C(CH3)2),
23.8 (q, C(CH3)3). MS (FAB+) m/e: 351 ([M+2]+, 11), 350 ([M+1]+, 45), 349 (M+, 40), 294 (57),
250 (66), 236 (96), 193 (63), 192 (100). Anal. calcd for C17H23N3O3S (349.44): C, 58.43%; H,
6.63%; N, 12.02%; S, 9.17%. Found: C, 58.38%; H, 6.55%; N, 12.02%; S, 8.91%.
3.5. tert-Butyl (4R)-4-[5-(1,3-benzodioxol-5-yl)-1-phenyl-1H-3-pyrazolyl]-2,2-dimethyl-1,3-oxa-
zolane-3-carboxylate 5c
According to the general procedure described in Section 3.2, reaction between 3a and 4b
20
a€orded 342 mg (92%) of 5c as a yellowish oil. ‰ꢀŠ ^69.2 (c 1.89 MeOH). IR (KBr, ꢁ): 2975 m,
D
2928 m, 2875 m, 1697 s, 1598 m, 1503 m, 1487 m, 1457 m, 1382 m, 1236 m, 1171 m, 1134 w, 1095
ꢀ
1
m, 1040 m, 936 m, 852 m, 809 m, 766 m, 695 m. H NMR (DMSO-d6, T=60 C), ꢂ=7.50±7.35
(m, 5H, CH arom.) 7.0±6.80 (m, 3H, CH arom.), 6.48 (s, 1H, CH arom.), 6.11 (s, 2H, OCH2O),
5.10 (dd, J=6.3 Hz, J0=3.0 Hz, 1H, CH), 4.36 (dd, J=8.7 Hz, J0=6.3 Hz, 1H sist. AB, CH2O),
4.15 (dd, J=8.7 Hz, J0=3.0 Hz, 1H, sist. AB, CH2O), 1.75 (s, 3H, C(CH3)2), 1.65 (s, 3H,
C(CH3)2), 1.46 (s, 9H, C(CH3)3). 13C NMR (DMSO-d6, T=60ꢀC), ꢂ=153.3 (s, C arom.), 151, (s,
NCO), 147.1, 147.0, 142.6, 139.6 (4 s, C arom.), 128.5, 126.9, 124.5 (3d, CH arom.), 123.6 (s, C
arom.), 122.2, 108.3, 108.0, 105.0 (4d, CH arom.), 101.0 (t, OCH2O), 93.2 (s, C(CH3)2), 78.8 (s,
C(CH3)3), 68.3 (t, CH2O), 55.0 (d, CH), 27.7 (q, C(CH3)3), 25.8, 23.9 (2 q, C(CH3)2). MS (FAB+)
m/e: 464 ([M+1]+, 100), 463 (M+, 29), 348 (70), 306 (66). Anal. calcd for C26H29N3O5 (463.53): C,
67.37%; H, 6.31%; N, 9.07%. Found: C, 67.58%; H, 6.42%; N, 9.15%.
3.6. tert-Butyl (4R)-2,2-dimethyl-4-[1-phenyl-5-(2-thienyl)-1H-3-pyrazolyl]-1,3-oxazolane-3-carb-
oxylate 5d
According to the general procedure described in Section 3.2, reaction between 3b and 4b
20
a€orded 366 mg (96%) of 5d as a yellowish oil. ‰ꢀŠ ^82.96 (c 1.73 MeOH). IR (®lm, ꢁ): 3103 w,
D
3073 w, 2977 m, 2932 m, 2873 m, 1698 s, 1597 m, 1504 m, 1477 w, 1456 m, 1382 m, 1314 w, 1256
1
m, 1205 w, 1171 m, 1133 w, 1093 m, 1059 m, 926 d, 849 m, 791 d, 766 m, 697 m. H NMR
(DMSO-d6, T=60ꢀC), ꢂ=7.62 (dd, J=5.0 Hz, J0=1.2 Hz, 1H, CH arom.), 7.6±7.4 (m, 5H, CH
arom.), 7.11 (dd, J=5.0 Hz, J0=3.6 Hz, 1H, CH arom.), 7.03 (dd, J=3.6 Hz, J0=1.2 Hz, 1H, CH
arom.), 6.60 (s, 1H, CH arom.), 5.09 (dd, J=6.4 Hz, J0=3.0 Hz, 1H, CH), 4.36 (dd, J=8.7 Hz,
J0=6.4 Hz, 1H, sist. AB, CH2O), 4.15 (dd, J=8.7 Hz, J0=3.0 Hz, 1H, sist. AB, CH2O), 1.75 (s,
3H, C(CH3)2), 1.65 (s, 3H, C(CH3)2), 1.47 (s, 9H, C(CH3)3). 13C NMR (DMSO-d6, T=60ꢀC), ꢂ
=153.4 (s, C arom.), 151.0 (s, NCO), 139.3, 136.7, 130.3 (3s, C arom.), 128.7, 127.9, 127.2, 127.1,
127.0, 125.5, 105.1 (5d, CH arom.), 93.2 (s, C(CH3)2), 78.8 (s, C(CH3)3), 68.2 (t, CH2O), 54.9 (d,
CH), 27.7 (q, C(CH3)3), 25.9 (q, C(CH3)2), 23.9 (q, C(CH3)2). MS (FAB+) m/e: 427 ([M+2]+, 29),
426 ([M+1]+, 100), 425 (M+, 20), 370 (41), 326 (44), 312 (60), 310 (98), 269 (70), 268 (96). Anal.
calcd for C23H27N3O3S (425.54): C, 64.92%; H, 6.40%; N, 9.87%; S, 7.54%. Found: C, 65.09%;
H, 6.22%; N, 9.59%; S, 7.74%.
3.7. Synthesis of pyrazolyl 1,2-aminoalcohol derivatives 7a±d. General procedure
To a cooled (0ꢀC) solution of pyrazole derivatives 5a±d in MeOH (0.7 mL/mmol), TFA (3 mL/
mmol) was added dropwise. After stirring 2 h at 0ꢀC and overnight at rt, TFA was removed

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G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
under gentle Ar stream. The resulting residue was re-dissolved in 1:1 mixture dioxane:NaHCO3
(sat.) (12 mL/mmol), cooled to 0ꢀC and 3.3 equiv. of (Boc)2O added in one portion. The reaction
mixture was stirred at 0ꢀC for 4 h and overnight at rt. The mixture was partitioned between H2O
and AcOEt, the organic layer separated and dried over MgSO4 (anh.). Filtration, removal of the
solvent and puri®cation of the resulting residue by ¯ash chromatography (hexanes/AcOEt as
eluent) a€orded pure 7a±d (Table 2).
3.8. Synthesis of (2R)-2-(3-Benzo[d][1,3]dioxol-5-yl-1H-5-pyrazolyl)-2-[(1,1-dimethylethoxy)
carbonylamino]ethan-1-ol 7a
According to the general procedure described in Section 3.7, reaction of 5a (267 mg, 0.69
20
mmol) a€orded 149 mg (62%) of 7a as a colourless solid. M.p. 142±143ꢀC. ‰ꢀŠ ^36.6 (c 1.54,
D
MeOH). IR (KBr, ꢁ): 3550 br., 3400 m, 3278 m, 2974 m, 2926 m, 2779 w, 1687 s, 1499 m, 1465 m,
1392 m, 1367 m, 1331 w, 1241 s, 1167 m, 1108 w, 1038 m, 976 w, 934 m, 875 m, 859 m, 809 m, 728
1
w, 606 w. H NMR (DMSO-d6), ꢂ=13.10±12.40 (s, br., 1H, NH), 7.35±6.95 (m, 4H, 3 CH
arom.+CONH), 6.54 (s, 1H, CH arom.), 6.13 (s, 2H, OCH2O), 4.9 (s, br., 1H, OH), 4.75±4.65 (m,
1H, CH), 3.70±3.50 (m, 2H, CH2OH), 1.49 (s, 9H, C(CH3)3). 13C NMR (CDCl3), ꢂ =156.1 (s, C
arom.), 149.1 (s, NCO), 147.9, 147.6, 146.8, 124.9 (4s, C arom.), 119.3, 108.5, 106.2 (3d, CH
arom.), 101.1 (t, OCH2O), 100.5 (d, CH arom.), 80.1 (s, C(CH3)3), 64.8 (t, CH2OH), 50.2 (d, CH),
28.3 (q, C(CH3)3).). MS (FAB+) m/e: 348 ([M+1]+, 66), 347 (M+, 48), 292 (74), 231 (100), 216 (50).
Anal. calcd for C17H21N3O5 (347.37): C, 58.68%; H, 6.09%; N, 12.10. Found: C, 58.68%; H,
6.21%; N, 12.35%.
3.9. (2R)-2-[(1,1-Dimethylethoxy)carbonylamino]-2-[3-(2-thienyl)-1H-5-pyrazolyl]ethan-1-ol 7b
According to the general procedure described in Section 3.7, reaction of 5b (174 mg, 0.50
20
mmol) a€orded 140 mg (91%) of 7b as a colourless solid. M.p. 75±76ꢀC. ‰ꢀŠ ^74.7 (c 0.58,
D
MeOH). IR (KBr, ꢁ): 3600 br., 3417 s, 2975 m, 2930 m, 2873 w, 1688 s, 1515 m, 1474 w, 1456 w,
1393 m, 1367 m, 1279 w, 1251 m, 1167 m, 1057 m, 1026 m, 925 w, 850 m, 800 w, 698 m. 1H NMR
(DMSO-d6), ꢂ=1360±11.80 (s, br. 1H, NH), 7.55±6.90 (m, 4H, 3 CH arom.+NHCO), 6.51 (s, 1H,
CH arom.), 4.90±4.60 (m, 1H, CH), 4.30±3.70 (s, br., OH), 3.66 (d, J=6.0 Hz, 2H, CH2OH), 1.49
(s, 9H, C(CH3)3). 13C NMR (CDCl3), ꢂ =156.1 (s, C arom.), 148.2 (s, NCO), 142.9, 133.8 (2s, 2
C arom.), 127.6, 125.1, 124.2, 101.2 (4d, 4CH arom.), 80.3 (s, C(CH3)3), 64.8 (t, CH2OH), 49.7 (d,
CH), 28.3 (q, C(CH3)3). MS (FAB+) m/e: 311 ([M+2]+, 10), 310 ([M+1]+, 46), 309 (M+, 44), 254
(87), 193 (100). Anal. calcd for C14H19N3O3S (309.39): C, 54.35%; H, 6.19%; N, 13.58; S, 10.36.
Found: C, 54.10%; H, 6.08%; N, 13.78%; S, 10.33%.
3.10. (2R)-2-(5-Benzo[d][1,3]dioxol-5-yl-1-phenyl-1H-3-pyrazolyl)-2-[(1,1-dimethylethoxy)-
carbonylamino]ethan-1-ol 7c
According to the general procedure described in Section 3.7, reaction of 5c (207 mg, 0.45
20
mmol) a€orded 122 mg (65%) of pure 7c as a colourless solid. M.p. 108±109ꢀC. ‰ꢀŠ ^71.6 (c
D
0.57, MeOH). IR (KBr, ꢁ): 3500 br., 3368 m, 3276 m, 3063 w, 2979 w, 2931 w, 2884 w, 2764 w,
1668 s, 1600 w, 1541 m, 1503 s, 1485 m, 1455 m, 1369 m, 1337 m, 1293 m, 1275 m, 1235 m, 1170
m, 1103 w, 1057 m, 1037 m, 981 w, 932 m, 882 w, 860 w, 809 m, 757 m, 693 m, 632 w. 1H NMR
(CDCl3), ꢂ=7.40±7.25 (m, 5H, CH arom.), 6.80±6.55 (m, 3H, CH arom.), 6.45 (s, 1H, CH

G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
2491
arom.), 5.99 (s, 2H, OCH2O), 5.57 (s, br., 1H, NH), 5.10±4.90 (m, 1H, CH), 4.12 (dd, J=11.2 Hz,
J0=4.4 Hz, 1H, CH2O), 3.96 (dd, J=11.2 Hz, J0=4.2 Hz, 1H, CH2O), 2.50±1.90 (s, br., 1H, OH),
1.51 (s, 9H, C(CH3)3). 13C NMR (CDCl3), ꢂ =156.0 (s, CˆN), 151.8 (s, NCO), 147.8, 147.7,
143.8, 139.7 (4s, C arom.), 128.9, 127.6, 125.1 (3d, CH arom.), 123.9 (s, C arom.), 122.8, 109.1,
108.4, 106.3 (4d, CH arom.), 101.3 (t, OCH2O), 79.8 (s, C(CH3)3), 65.9 (t, CH2O), 50.7 (d, CH),
28.4 (q, C(CH3)3). MS (FAB+) m/e: 424 ([M+1]+, 71), 423 (M+, 10), 369 (52), 336 (26), 307 (100),
292 (69). Anal. calcd for C23H25N3O5 (423.46): C, 62.24%; H, 5.95%; N, 9.92. Found: C,
62.02%; H, 6.22%; N, 10.06%.
3.11. (2R)-2-[(1,1-Dimethylethoxy)carbonylamino]-2-[1-phenyl-5-(2-thienyl)-1H-3-pyrazolyl]-
ethan-1-ol 7d
According to the general procedure described in Section 3.7, reaction of 5d (286 mg, 0.67
20
mmol) a€orded 215 mg (83%) of pure 7d as a yellowish oil. ‰ꢀŠ ^46.9 (c 0.55, MeOH). IR (®lm,
D
ꢁ): 3500 br., 3423 m, 3103 w, 3071 w, 2972 m, 2926 m, 2871 m, 2857 m, 1706 s, 1597 m, 1501 s,
1455 m, 1369 m, 1323 w, 1275 m, 1249 m, 1166 s, 1055 m, 1024 m, 964 w, 929 m, 851 m, 794 w,
0
1
766 m, 697 m. H NMR (CDCl3), ꢂ=7.45±7.35 (m 5H, CH arom.), 7.32 (dd, J=5.2 Hz, J =1.2
Hz, 1H, CH arom.), 6.97 (dd, J=5.2 Hz, J0=3.6 Hz, 1H, CH arom.), 6.85 (dd, J=3.6 Hz, J0=1.2
Hz, 1H, CH arom.), 6.58 (s, 1H, CH arom.), 5.55 (s, br., 1H, NH), 5.10-4.90 (m, 1H, CH), 4.12
(dd, J=11.2 Hz, J0=4.2 Hz, 1H, CH2O), 2.40±1.80 (s, br., 1H, OH), 1.51 (s, 9H, C(CH3)3). 13C
NMR (CDCl3), ꢂ=156.0 (s, CˆN), 151.8 (s, NCO), 139.5, 137.9, 130.9 (3s, C arom.), 129.0,
128.4, 127.4, 127.3, 126.7, 126.1, 106.5 (7d, CH arom.), 79.8 (s, C(CH3)3), 65.8 (t, CH2O), 50.7 (d,
CH), 28.3 (q, C(CH3)3). MS (FAB+) m/e: 387 ([M+2]+, 25), 386 ([M+1]+, 97), 385 (M+, 4), 354
(22), 330 (69), 298 (25), 269 (100), 254 (59). Anal. calcd for C20H23N3O3S (385.48): C, 62.32%; H,
6.01%; N, 10.90; S, 8.32%. Found: C, 62.54%; H, 6.18%; N, 11.07%; S, 8.08%.
3.12. Synthesis of the Mosher's ester derivative 8
To a solution of the amino alcohol derivative 7c (25 mg, 0.058 mmol) in anhydrous CCl4 (0.29
mL), dry pyridine (0.17 mL) was added. After stirring for 5 min until homogenisation, (R)-(^)-
MPTA±Cl (15.2 mL, 0.082 mmol) was added. The reaction mixture was stirred at rt under N2 for
1 h. The mixture was diluted with CH2Cl2, and washed successively with sat. NaHCO3 and brine.
The organic layer dried over MgSO4, and ®ltered and the solvent eliminated under reduced
pressure to a€ord quantitatively 8 which was dried under H.V. and analysed without further
puri®cation. IR (KBr, ꢁ): 3362 br., 3064 w, 2956 m, 2923 m, 2853 m, 1751 s, 1712 s, 1599 m, 1500
s, 1487 s, 1454 m, 1371 m, 1333 w, 1238 s, 1167 s, 1123 m, 1078 w, 1035 w, 935 w, 864 w, 806 m,
1
765 m, 721 m, 697 m. H NMR (CDCl3), ꢂ=8.65 (s, br., 1H, NHCO), 7.60±7.25 (m, 10H, CH
arom.), 6.80±6.60 (m, 3H, CH arom.), 6.29 (s, 1H, CH arom.), 6.0 (s, 2H, OCH2O), 5.25 (s, br.,
1H, CH), 4.80±4.65 (m, 2H, CH2O), 3.52 (s, 3H, OCH3), 1.49 (s, 9H, C(CH3)3). 13C NMR
(CDCl3), ꢂ =166.3 (s, CO), 155.1 (s, CˆN), 149.9 (s, NCO), 149.7 (s, C arom.), 147.8, 147.6,
143.8, 139.8, 132.1 (1s, C arom.+CF3), 129.5, 128.9, 128.3, 127.6, 127.4, 125.1 (6s, CH arom.),
123.9 (s, C arom.), 122.8, 109.0, 108.4, 105.9 (4d, CH arom.), 101.3 (t, OCH2O), 79.9 (s,
C(CH3)3), 67.4 (t, CH2O), 55.4 (q, OCH3), 48.3 (d, CH), 28.32 (q, C(CH3)3). Anal. calcd for
C33H32F3N3O7 (639.62): C, 61.97%; H, 5.04%; N, 6.57. Found: C, 62.26%; H, 5.28.18%; N,
6.29%.

2492
G. Cabarrocas et al. / Tetrahedron: Asymmetry 11 (2000) 2483±2493
Acknowledgements
Generous ®nancial support from the Direccion General de Ensenanza Superior (DGESIC,
Spain) through project PB94-0509, Universitat de Girona through project UdG98-452, Medichem
S.A. (Barcelona) and Roviall Quõmica S.L. (Murcia) is gratefully acknowledged. Thanks are also
due to Dr. Lluisa Matas (Servei d'Analisi, Universitat de Girona) for recording the NMR spectra
and performing the microanalyses. One of us (G.C.) wishes to thank the Ministerio de Educacion
y Ciencia (Spain) for a pre-doctoral fellowship.
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