New aniline-containing amino alcohols from trans-(r,r)-2-(2-nitrophenyl)-3- phenyloxirane as useful intermediates for the synthesis of chiral ligands, bases, and benzoxazine nucleus

Article abstract of DOI:10.1021/jo0617969

New enantiopure aniline-containing amino alcohols are directly derived from trans-(R,R)-2-(2-nitrophenyl)-3-phenyloxirane, by alternative regioselective double reductions. Subsequent selective alkylation procedures and derivatizations provide a rapid and

Full text of DOI:10.1021/jo0617969

New Aniline-Containing Amino Alcohols from
trans-(R,R)-2-(2-Nitrophenyl)-3-phenyloxirane as
Useful Intermediates for the Synthesis of Chiral
Ligands, Bases, and Benzoxazine Nucleus
Arlette Solladie´-Cavallo,† Paolo Lupattelli,*,‡ Carlo Bonini,‡
Valeria Ostuni,‡ and Nadia Di Blasio‡
FIGURE 1. Aniline-containing amino alcohols and 1,4-dihydro-2H-
benzo[d][1,3]oxazines.
interest for their biological activities,6 which are not yet widely
studied. Recently, novel 6-arylbenzoxazines were prepared and
examined as progesterone receptor (PR) modulators, showing
high agonist and/or antagonist activity.7 They are also used in
chiral form as stereoinductors in diastereoselective alkylation
reactions.8
Laboratoire de Ste´re´ochimie Organome´tallique associe´ au
CNRS, ECPM/UniVersite´ L. Pasteur, 25 rue Becquerel, 67087
Strasbourg, France, and Dipartimento di Chimica, UniVersita´
degli studi della Basilicata, Via N. Sauro 85, 85100 Potenza,
Italy
lupattelli@unibas.it
Although the structural simplicity of these functionalized
anilines 1 and 2, only one literature citation was found for
compound 2 (with R1 ) R2 ) R3 ) H), which was prepared
from o-methylaniline and used as an intermediate in the
synthesis of indoles.9
ReceiVed August 30, 2006
During our studies on regio- and stereoselective ring opening
of 2,3-diaryloxiranes, it was found that such epoxides were
suitable starting material for the synthesis of functionalized 1,2-
diarylethanols, and this approach has been used to prepare new
pyridyl and furyl alcohols,10 1,2-diaryl bromohydrins,11 and
acetonides12 in enantiopure form. We present here a direct
synthesis of the desired new aniline-type amino alcohols 1
and 2 from enantiopure (R,R)-2-(2-nitrophenyl)-3-phenyl
oxirane 4 and their elaboration into new ligands and benzox-
azines.
(R,R)-Epoxide 4 was prepared in good yield and >98% ee
(determined by HPLC) from the pure (R,R,R,SS)-(-)-sulfonium
salt 5,13 commercial 2-nitrobenzaldehyde, and a phosphazene
base [EtP2 ) Et-NdP(NMe2)2(NdP(NMe2)3] to generate the
sulfur ylide (Scheme 1). Numerous methods of reduction of
either nitrophenyl group or 2,3-disubstituted oxirane are known.
Although stoichiometric metal hydrides or dissolving metals are
frequently employed for the reductive ring-opening of ep-
oxides,14 the need for a practical and environmentally benign
version of this reaction has generated interest in heterogeneous
catalytic systems. In particular, much interest has been directed
New enantiopure aniline-containing amino alcohols are
directly derived from trans-(R,R)-2-(2-nitrophenyl)-3-phe-
nyloxirane, by alternative regioselective double reductions.
Subsequent selective alkylation procedures and derivatiza-
tions provide a rapid and high-yielding access to different
chiral ligands, bases, and benzoxazines, without loss of
optical purity.
Amino alcohol subunits are versatile structures, and they are
present in many natural1 and synthetic2 compounds. They are
widely used in numerous catalytic asymmetric reactions3
(hydrogenation, epoxidation, nucleophilic addition) and as chiral
bases in asymmetric desymmetrization of prochiral substrates.4
Until now, chiral amino alcohols employed as ligands in such
processes are still mostly based on a few naturally occurring
skeletons, and among these various aminoalcohols, examples
of ligands bearing an aniline group are rare.5 Among the various
products directly obtained from o-aminobenzyl alcohols of type
1, 1,4-dihydro-2H-benzo[d][1,3]oxazines 3 (Figure 1) are of
(6) (a) Kobzina, J. W. US Pat. 4030906, 1977; Chem. Abstr. 1977, 87,
79678e. (b) Imperial Chemistry Industries Ltd. Jpn. Pat. 8047665, 1980;
Chem. Abstr. 1980, 93, 204681c. Boyle, F. T.; Taylor, M. A. Span. Pat.
1980, 484472; Chem. Abstr. 1981, 94, 156956t.
(7) Zhang, P.; Terefenko, E. A.; Fensome, A.; Zhang, Z.; Zhu, Y.; Cohen,
J.; Winneker, R.; Wrobel, J.; Yardley, J. Bioorg. Med. Chem. Lett. 2002,
12, 787.
(8) Mulzer, J.; Langer, O.; Hiersermann, M.; Bats, J. W.; Buschmann,
J.; Luger, P. J. Org. Chem. 2000, 65, 6540.
(9) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957.
(10) Solladie´-Cavallo, A.; Roje, M.; Isarno, T.; Sunjic, V.; Vinkovic,
V. Eur. J. Org. Chem. 2000, 1077.
(11) (a) Solladie´-Cavallo, A.; Lupattelli, P.; Marsol, C.; Isarno, T.; Bonini,
C.; Caruso, L.; Maiorella, A. Eur. J. Org. Chem. 2002, 1439. (b) Lupattelli,
P.; Bonini, C.; Caruso, L.; Gambacorta, A. J. Org. Chem. 2003, 68, 3360.
(c) Solladie´-Cavallo, A.; Lupattelli, P.; Bonini, C. J. Org. Chem. 2005, 1605.
(12) Solladie´-Cavallo, A.; Choucair, E.; Balaz, M.; Lupattelli, P.; Bonini,
C.; Di Blasio, N. Eur. J. Org. Chem. 2006, 3007.
† ECPM/Universite´ L. Pasteur.
‡ Universita` degli studi della Basilicata.
(1) Blaser, H. U. Chem. ReV. 1992, 92, 935.
(2) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. ReV.
2000, 100, 2159.
(3) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757.
(4) Cox, P. J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2, 1.
(5) (a) Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron: Asymmetry
1997, 8, 1869. b) Philipova, I.; Dimitrov, V.; Simova, S. Tetrahedron:
Asymmetry 1999, 10, 1381.
(13) For the synthesis of 6 from (R,R,R)-oxathiane, see: Vedejs, E.;
Engler, D. A.; Mullins, M. J. J. Org. Chem. 1977, 42, 3109-3113. For the
synthesis of (R,R,R)-oxathiane, see: Eliel, E. L.; Lynch, J. E.; Kume, F.;
Frye, S. V. Org. Synth. 1987, 65, 215-221.
(14) Flaherty, T. M.; Gervay, J. Tetrahedron Lett. 1996, 37, 961.
10.1021/jo0617969 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/22/2006
J. Org. Chem. 2006, 71, 9891-9894
9891

SCHEME 1
SCHEME 2
SCHEME 3
to the use of catalysts based on Ni, Pd, and Pt in order to
improve the chemo- and regioselectivity of such reactions, even
with enantiopure epoxides.15 Different hydrogen sources, such
as HCOONH4,16 or catalysts such as Pd/C-ethylendiamine
complexes,17 have been used to improve selectivity and to
prevent further hydrogenolysis of the alcoholic C-O bond.
Nevertheless, solvolysis with methanol remains a problem,
particularly with benzylic epoxides. Recently, Pd nanoparticles,
microencapsulated in polyurea, have been described to be very
efficient in the reductive ring opening of different benzylic and
alkyl epoxides.18 Many reagents are known to perform mild
reductions of the nitroaryl group, but no examples are described
for such reactions in the presence of an oxiranyl ring.19 Thus,
we first tried LiAlH4, which had been successfully employed
with heteroaromatic epoxides,10 but the reaction led to a mixture
of several opening products in low chemical yield. The use of
a milder system, as FeCl3‚6H2O/H2NNMe2,20 also led to
degradation products, while both hydrogenation with catalytic
O-methylated products. On the other hand, using the LiH/CH3I
system, N,N-dimethyl derivatives (S)-9 and (S)-10 were obtained
in acceptable isolated yield (62-63%). Better results were
obtained using [1,8-bis(dimethylamino)naphtalene] (Proton
Sponge) as a base and trimethyloxonium tetrafluoroborate
[(CH3)3OBF4, Meerwein salt] as methylating agent, and the
target products were obtained in excellent yield (85-87%),
together with a small amount (<10%) of trimethylated com-
pound.
This remarkably high N-selective methylation in strong alkali
medium makes both of the procedures useful tools in the
derivatization of different anilino alcohols. The 99% ee for both
compounds (S)-9 and (S)-10 was determined by using chiral
HPLC, confirming the ee of the starting compounds (S)-6 and
(S)-7.
In principle, the synthesis of 1 and 2, as precursors of strong
chiral bases, requires an O-alkylation and a N-monoalkylation,
which are hardly achievable without the use of protecting
groups. Therefore, amino alcohols (S)-6 and (S)-7 were trans-
formed to N-Boc derivatives (S)-11 and (S)-12 in high yield by
using a Zn(ClO4)2‚6H2O/Boc2O system24 (Scheme 4).
The derivatives were submitted without success to different
methylation methods in alkali medium (NaH, LiH, Proton
Sponge) and with various alkylating agents (CH3I, (CH3)2SO4,
(CH3)3OBF4). In the case of (S)-11, oxazolidinone 13 was the
main reaction product in all cases, probably because of the high
tendency of the substrate to form a six-membered ring via acyl
nucleophilic substitution. In the case of (S)-12, only the (CH3)3-
OBF4/Proton Sponge system was efficient, although it afforded
dimethylated product (S)-14 in poor yield.
Ni2B21 and reduction with samarium and catalytic I2 were
22
inefficient. On the other hand, the use of procedures which
could, in principle, transform both the nitro group and the
oxiranyl ring were more successful. Catalytic hydrogenation
over Pd/C of epoxide 4 led, quantitatively, to a 86/13 mixture
of the two regioisomeric amino alcohols 6 and 7. After
chromatographic purification, amino alcohol 6 was obtained in
excellent isolated yield (80%). Alternatively, treatment of
epoxide 4 with NaBH4 and a catalytic amount of Pd/C provided
amino alcohol 7, as the only isolable product, ingood yield.
The amino alcohol (S)-6 was first used as a suitable precursor
of chiral benzoxazines. Thus, it was transformed into the
corresponding benzoxazine 8 in good yield, by ring formation
with paraformaldehyde,23 without loss of sterechemical integrity
at the benzylic carbon (Scheme 2).
The direct synthesis of ligands (S)-9 and (S)-10 (Scheme 3)
required a chemoselective bis-methylation of the nitrogen, the
hydroxyl group being untouched. Toward obtaining N,N-
dialkylanilines, classical alkaline methylation methods with NaH
or Ag2O and CH3I under various reaction conditions (THF,
Et2O, DMF, acetonitrile as solvents and at different tempera-
tures) were not selective, leading to mixtures of N- and
(15) Schultze, L. M.; Chapman, H. H.; Dubree, N. J. P.; Jones, R. J.;
Kent, K. M.; Lee, T. T.; Louie, M. S.; Postich, M. J.; Prisbe, E. J.; Rohloff,
J. C.; Yu, R. H. Tetrahedron Lett. 1998, 39, 1853.
(16) Dragovich, P. S.; Prins, T. J.; Zhou, R. J. Org. Chem. 1995, 60,
4922.
(17) Sajiki, H.; Hattori, K.; Hirota, K. Chem. Commun. 1999, 1041.
(18) Ley, S. V.; Mitchell, C.; Pears, D.; Ramarao, C.; Yu, J.-Q.; Zhou,
W. Org. Lett. 2003, 5, 4665.
To avoid competitive ring closure in alkali medium, we tried
a recent O-tert-butyl alkylation procedure with the use of the
couple (Boc)2O/Mg(ClO4)2.25 In order to optimize the synthetic
route, the study on this last and following reactions was
performed on racemic compounds.
(19) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 5th
ed.; Wiley-Interscience: New York, 2001; Chapter 19, p 1552.
(20) Kerr, M. A. Tetrahedron Lett. 1995, 36, 2411.
(21) Russel, T. W. J. Org. Chem. 1971, 36, 2081.
(22) Banik, B. K.; Becker, F. F. Tetrahedron Lett. 1998, 39, 7243.
(23) Neuvonen, K.; Pohtola, R.; Pihlaja, K. Magn. Reson. Chem. 1989,
27, 725-733.
Treatment of both racemic 11 and 12 with carefully dried
(24) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Massaccesi,
M.; Melchiorre, P.; Sambri, L. Synlett 2004, 1794.
(25) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, M.; Melchiorre,
P.; Sambri, L. Org. Lett. 2005, 7, 427-430.
9892 J. Org. Chem., Vol. 71, No. 26, 2006

SCHEME 6
FIGURE 2. Anilino tert-butyl ethers 17 and 18.
SCHEME 4
SCHEME 7
SCHEME 5
22. On the other hand, the regioisomer (S)-20 was prepared from
(S)-11, in good yield, via alkylation and subsequent reduction
(Scheme 7).
In conclusion, we have described the first examples of
efficient, alternative, and regioselective reductions of substituted
nonsymmetrical 2,3-diaryloxiranes. The opposite high regiose-
lectivity, obtained on enantiopure (R,R)-2-(2-nitrophenyl)-3-
phenyloxirane, represents a useful tool for divergent syntheses
of various 1,2-anilinoarylethanols. We have also described new
procedures for selective N- and O-alkylations, which allowed
us to prepare new potential ligands and chiral bases.
Experimental Section
Mg(ClO4)2 and (Boc)2O, at 40 °C in CH2Cl2, afforded the
corresponding O-tert butyl ethers 15 and 16 in good yield
(Scheme 5).
Interesting results, although useless for our synthetic purposes,
were obtained when the reaction was performed with wet Mg-
(ClO4)2.26 Under these conditions, both 11 and 12 underwent a
complete deprotection, together with the expected tert-butyl
alkylation, affording the corresponding anilinoethers 17 and 1827
(Figure 2). Such a transformation, if coupled with the previous
N-Boc group introduction, represents an efficient two-step
methodology for the chemoselective O-alkylation of aniline
alcohols and competes with those using different NH2 protecting
groups.
We then decided to transform the carbamate into methyl
group by reduction with LiAlH4, previously described only for
the synthesis of tertiary methylamines from the corresponding
tert-butyl carbamates.28 Since there are no examples of such
reactions on anilines, we tested the racemic N-Boc-aniline and
tert-butyl ethers 11, 12, 15, and 16 (Scheme 6). Modest to
acceptable yields of the corresponding N-methyl derivatives
were obtained in all cases. In particular, when the reaction was
performed in refluxing 1,4-dioxane, the target N-methyl-tert-
butyl ether 20 was obtained in promising yield from 15, while
for 22 the yield dropped significantly.
(1S)-1-(2-Aminophenyl)-2-phenylethanol (S)-6. A mixture of
(R,R)-4 (1 mmol) and Pd/C 10% (60 mg) in 20 mL of CH3OH/
AcOEt 9/1 was allowed to stir at room temperature under H2 (1
atm). After 1 h, the catalyst was filtered off and the mixture was
evaporated under vacuum. Chromatographic purification on silica
gel (petroleum ether/Et2O ) 3/2) of the crude product yielded 86%
of (S)-6 and 13% of (S)-7 as white crystals. (S)-6 was recrystallized
1
from Et2O. Mp: 139 °C. H NMR (500 MHz, CDCl3): δ ) 3.15
(A part of ABX system, 2JAB ) 13.5 Hz, 3JAX ) 5.0 Hz, 1H), 3.27
2
3
(B part of an ABX system, JAB ) 13.5 Hz, JBX ) 9.1 Hz, 1H),
3
3
3.30 (brs, 1H), 4.92 (X part of ABX system, JAX ) 5.0 Hz, JBX
) 9.1 Hz, 1H), 6.70 (dd, 3J ) 7.8 Hz, 4J ) 1.0 Hz, 1H), 6.74 (ddd,
3J ) J ) 7.8 Hz, J ) 1.0 Hz, 1H), 7.07 (dd, J ) 7.8 Hz, J )
3
4
3
4
3
3
4
1.0 Hz, 1H), 7.13 (ddd, J ) J ) 7.8 Hz, J ) 1.0 Hz, 1H), 7.27
(m, 3H), 7.35 (m, 2H). 13C NMR (125 MHz, CDCl3): δ ) 41.8,
75.3, 75.4, 116.9, 118.2, 126.6, 127.5, 128.5, 128.6, 129.5, 138.2,
145.0. MS (m/z): 213 [M+] (7), 195 (35), 194 (33), 122 (100).
[R]25D: +33 (c 1.3, CHCl3). Anal. Calcd for C14H15NO: C, 78.84;
H, 7.09; N, 6.57. Found: C, 78.9; H, 7.2; N, 6.5.
Higher overall yields of 22 were obtained by performing the
alkylation on 21, after the reduction of the carbamate, and this
route was used for the synthesis of enantiopure derivative (S)-
(1S)-2-(2-Aminophenyl)-1-phenylethanol (S)-7. A mixture of
NaBH4 (6 mmol, 24 equiv) in H2O (10 mL) was poured into a
suspension of Pd/C 10% (100 mg) in CH3OH (5 mL), under argon,
and the mixture was cooled to 0 °C. A solution of epoxide (R,R)-4
(1 mmol) in 10 mL of CH3OH/AcOEt 9/1 was added dropwise.
After 1 h, the catalyst was filtered off, and the reaction mixture
was poured into an ice-water mixture and extracted with EtOAc.
The organic phase was washed with brine, dried on anhydrous Na2-
(26) In a typical procedure, a MgClO4/H2O 1:10 molar ratio was used.
(27) When the reaction was performed on amino alcohols 6 and 7, an
approximately equimolar mixture of the different products 11, 12, 17, 18,
and N-Boc tert-butyl ethers was formed.
(28) Hayashi, Y.; Tamura, T.; Shoji, M. AdV. Synth. Catal. 2004, 346,
1106-1110.
J. Org. Chem, Vol. 71, No. 26, 2006 9893

SO4, and evaporated under vacuum. Chromatographic purification
on silica gel (n-hexane/Et2O ) 3/2) of the crude product yielded
64% of (S)-7 as a white crystal. Mp: 95 °C (recrystallized from
Hz, 3JAX ) 5.5 Hz, 1H), 3.04 (B part of ABX system, 2JAB ) 13.2
Hz, 3JBX ) 8.4 Hz, 1H), 4.61 (X part of ABX system, 3JAX ) 5.5
Hz, 3JBX ) 8.4 Hz, 1H), 6.90 (m, 2H), 7.20 (m, 6H), 8.07 (d, 3J )
7.9 Hz, 1H), 9.04 (s, 1H). 13C NMR (125 MHz, CDCl3): δ ) 27.8,
28.4, 44.0, 75.4, 78.2, 79.5, 120.2, 122.1, 125.8, 126.1, 127.4, 127.9,
129.9, 131.1, 137.6, 138.5, 153.2. [R]25D: -9 (c 1, CHCl3). MS
(m/z): 369 (1) [M], 278 (11), 222 (30), 166 (63), 122 (100). Anal.
Calcd for C23H31NO3: C, 74.76; H, 8.46; N, 3.79. Found: C, 74.8;
H, 8.6; N, 3.6.
(1S)-1-(2-N-Methylaminophenyl)-2-phenylethanol tert-Butyl
Ether (S)-24. Following the above procedure on compound (S)-
19 and after chromatographic purification on silica gel (petroleum
ether/Et2O ) 3:2), (S)-24 was obtained in 60% yield as an oil. 1H
NMR (500 MHz, CDCl3): δ ) 0.88 (s, 9H), 2.79 (s, 3H), 2.83 (A
prt of ABX system, 2JAB ) 13.5 Hz, 3JAX ) 5.4 Hz, 1H), 3.05 (B
part of ABX system, 2JAB ) 13.5 Hz, 3JBX ) 8.6 Hz, 1H), 4.49 (X
part of ABX system, 3JAX ) 5.4 Hz, 3JBX ) 8.6 Hz, 1H), 6.49 (dd,
3J ) 3J ) 7.3 Hz, 1H), 6.56 (d, 3J ) 7.3 Hz, 1H), 6.72 (d, 3J ) 7.3
Hz, 1H), 7.15 (m, 6H). 13C NMR (125 MHz, CDCl3): δ ) 28.1,
30.2, 42.5, 44.6, 74.7, 111.5, 116.3, 125.9, 127.5, 127.6, 127.9,
128.5, 130.0, 133.5, 139.4. [R]25D: -8.7 (c 1, CHCl3). Anal. Calcd
for C19H25NO: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.4; H,
8.9; N, 5.0.
1
Et2O). H NMR (500 MHz, CDCl3): δ ) 2.90 (A part of ABX
system, 2JAB ) 14.0 Hz, 3JAX ) 3.5 Hz, 1H), 3.03 (B part of ABX
system, 2JAB ) 14.0 Hz, 3JBX ) 9.0 Hz, 1H), 5.00 (X part of ABX
system, 3JAX ) 3.5 Hz, 3JBX ) 9.0 Hz, 1H), 6.74 (d, 3J ) 7.8 Hz,
3
3
3
1H), 6.78 (dd, J ) J ) 7.8 Hz, 1H), 7.02 (d, J ) 7.8 Hz, 1H),
7.10 (dd, J ) J ) 7.8 Hz, 1H), 7.30 (m, 5H). 13C NMR (125
MHz, CDCl3): δ ) 41.8, 75.8, 116.7, 119.7, 124.3, 125.9, 127.9,
128.5, 131.5, 144.4, 145.5. MS (m/z): 213 [M+] (11), 193 (16),
107 (100), 106 (71), 79 (22), 77 (26). [R]25D: -2.5 (c 1.6 CHCl3).
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.7; H, 7.1; N, 6.4.
3
3
(4S)-4-Benzyl-1,4-dihydro-2H-benzo[d][1,3]oxazine 8. To a
mixture of paraformaldehyde (20 mg, 2 equiv) in benzene (20 mL)
was added a solution of 60 mg (0.3 mmol) of (S)-6 in 5 mL of
benzene, and the reaction mixture was kept at reflux for 1 h. Once
cooled to room temperature, the solvent was removed, and the crude
was dissolved in diethyl ether, washed with H2O, dried with
anhydrous Na2SO4, and evaporated under vacuum. Compound 8
was obtained in 95% yield as an oil. 1H NMR (500 MHz, CDCl3):
δ ) 3.06 (A part of ABX system, 2JAB ) 14.2 Hz, 3JAX ) 8.1 Hz,
1H), 3.28 (B part of ABX system, 2JAB ) 14.2 Hz, 3JBX ) 3.4 Hz,
(1S)-2-(2-N-Methylaminophenyl)-1-phenylethanol (S)-21. To
a solution of (S)-12 (1 mmol) in 20 mL of 1,4-dioxane was added
LiAlH4 (1 mmol, 4 equiv) in one portion, and the reaction mixture
was refluxed for 3 h. The crude was then poured into ice-water
and extracted with Et2O (3 × 20 mL). The organic layers were
collected, dried with anhydrous Na2SO4, and evaporated under
vacuum. After chromatographic purification on silica gel (petroleum
2
1H), 4.24 (s, 1H), 4.57 (A part of AB system, JAB ) 10.3 Hz,
1H), 4.84 (B part of AB system, 2JAB ) 10.3 Hz, 1H), 5.22 (X part
of ABX system, 3JAX ) 8.1 Hz, 3JBX ) 3.4 Hz, 1H), 7.03 (m, 2H),
7.25 (m, 7H). 13C NMR (125 MHz, CDCl3): δ ) 42.2, 72.8, 76.2,
118.9, 120.6, 125.7, 126.4, 127.5, 128.3, 129.4, 129.6, 138.4. MS
(m/z): 225 [M+] (7), 194 (2), 134 (100), 116 (9), 106 (7), 91 (14),
77 (14). [R]25D: -27 (c 0.5 CHCl3). Anal. Calcd. for C15H15NO:
C, 79.97; H, 6.71; N, 6.22. Found: C, 79.8; H, 6.7; N, 6.3.
1
ether/Et2O ) 3:2), (S)-21 was obtained in 60% yield as oil. H
NMR (500 MHz, CDCl3): δ ) 2.82 (s, 3H), 2.90 (A part of ABX
system, 2JAB ) 14.1 Hz, 3JAX ) 4.0 Hz, 1H), 3.00 (B part of ABX
system, 2JAB ) 14.1 Hz, 3JBX ) 8.6 Hz, 1H), 4.95 (X part of ABX
system, 3JAX ) 4.0 Hz, 3JBX ) 8.6 Hz, 1H), 6.74 (m, 2H), 7.03 (d,
3J ) 6.6 Hz, 1H), 7.30 (m, 6H). 13C NMR (125 MHz, CDCl3): δ
) 30.9, 41.9, 75.4, 110.7, 117.5, 123.6, 125.6, 127.6, 128.0, 128.4,
130.9, 144.2, 148.0. [R]25D: -4.0 (c 0.5, CHCl3). MS (m/z): 227
[M+] (18), 209 (11), 132 (28), 121 (49), 120 (100), 106 (11), 91
(22), 77 (13). Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N,
6.16. Found: C, 79.4; H, 7.3; N, 6.3.
(1S)-1-(2-N,N-Dimethylaminophenyl)-2-phenylethanol (S)-9
was obtained in 87% (method A) and 62% yield (method B) from
(S)-6 after chromatographic purification on silica gel (petroleum
ether/Et2O ) 3/2). 1H NMR (300 MHz, CDCl3): δ ) 2.61 (s, 6H),
2
3
3.11 (AB part of ABX system, JAB ) 14.4 Hz, JAX ) 7.5 Hz,
3JBX ) 5.5 Hz, 2H), 5.18 (X part of ABX system, 3JAX ) 7.5 Hz,
3JBX ) 5.5 Hz, 1H), 7.10-7.31 (m, 9H). 13C NMR (75 MHz,
CDCl3): δ ) 46.2, 75.1, 122.1, 125.2, 126.0, 127.9, 128.1, 130.0,
138.2, 138.9, 152.0. MS (m/z): 241 [M+] (9), 223 (69), 150 (100),
132 (24), 120 (27), 106 (27), 91 (28) (99% ee; HPLC Chiralcel
OD, n-hexane/2-propanol 90/10, 0.5 mL/min). [R]25D: -2.0 (c 1.2,
CHCl3). Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N; 5.80.
Found: C, 79.5; H, 7.9; N 5.8.
(1S)-2-(2-N-Methylaminophenyl)-1-phenylethanol tert-Butyl
Ether (S)-22. Following the procedure described for compound
(S)-15, (S)-22 was obtained from (S)-21 in 75% yield as a colorless
oil after purification by chromatography on silica gel with a mixture
of petroleum ether/Et2O ) 4:1. 1H NMR (400 MHz, CDCl3): δ )
(1S)-2-(2-N,N-Dimethylaminophenyl)-1-phenylethanol (S)-10
was obtained in 85% (method A) and 63% yield (method B) from
(S)-7 after chromatographic purification on silica gel (petroleum
ether/Et2O ) 2/3). 1H NMR (300 MHz, CDCl3): δ ) 2.80 (s, 6H),
3.09 (A part of ABX system, 2JAB ) 14.4 Hz, 3JAX ) 2.2 Hz, 1H),
3.24 (B part of ABX system, 2JAB ) 14.4 Hz, 3JBX ) 8.5 Hz, 1H),
4.97 (X part of ABX system, 3JAX ) 2.2 Hz, 3JBX ) 8.5 Hz, 1H),
7.08 (m, 3H), 7.25-7.45 (m, 6H). 13C NMR (75 MHz, CDCl3): δ
) 43.9, 44.9, 75.8, 76.5, 120.1, 125.3, 125.6, 126.8, 127.9, 128.0,
132.0, 145.5, 151.8. MS (m/z): 241 [M+] (9), 223 (9), 207 (22),
134 (100), 118 (22), 91 (15) (99% ee; HPLC Chiralcel OD,
n-hexane/2-propanol 90/10, 0.5 mL/min). [R]25D: -73.0 (c 1.0,
CHCl3). Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N; 5.80.
Found: C, 79.7; H, 7.9; N 5.7.
2
1.26 (s, 9H), 2.82 (s, 3H), 2.84 (A part of ABX system, JAB
14.0 Hz, 3JAX ) 3.8 Hz, 1H), 2.95 (B part of ABX system, 2JAB
14.0 Hz, 3JBX ) 8.4 Hz, 1H), 4.90 (X part of ABX system, 3JAX
)
)
)
3
3
3.8 Hz, JBX ) 8.4 Hz, 1H), 6.73 (m, 2H), 6.94 (d, J ) 6.8 Hz,
1H), 7.21 (m, 6H). 13C NMR (100 MHz, CDCl3): δ ) 29.7, 31.9,
41.9, 43.6, 75.4, 112.6, 119.3, 124.7, 125.6, 127.7, 128.2, 128.5,
131.2, 143.9, 146.4. MS (m/z): 283 [M+] (26), 210 (8)163 (36),
121 (17), 120 (8), 107 (100), 91 (19), 57 (22). [R]25D: -6.0 (c 0.3,
CHCl3). Anal. Calcd for C19H25NO: C, 80.52; H, 8.89; N, 4.94.
Found: C, 80.6; H, 8.9; N, 4.8.
Acknowledgment. We thank MIUR (Ministry of Instruction,
University and Research-Rome) (Project FIRB RBNE017F8N
and PRIN 2005) and the University of Basilicata for financial
support and for an ERASMUS grant (3 months) to V.O.
(1S)-1-(2-N-Boc-aminophenyl)-2-phenylethanol tert-Butyl Ether
(S)-15. Anhydrous Mg(ClO4)2 (0.10 mmol) and (S)-11 (1 mmol)
were dissolved in 15 mL of anhydrous CH2Cl2. Then Boc2O (2.3
mmol) was added, and the mixture was stirred at reflux for 24 h.
The crude was poured into ice-water and extracted with CH2Cl2.
The tert-butyl ether (S)-15 was purified by chromatography on silica
gel with a mixture of petroleum ether/Et2O ) 4:1 and obtained in
75% yield as colorless oil. 1H NMR (500 MHz, CDCl3): δ ) 1.00
Supporting Information Available: Experimental procedures
for compounds (R,R)-4, (S)-9, (S)-10, (S)-11, (S)-12, 13, 14, 16-
1
18, and (S)-19. H and 13C NMR of compounds 6-12, 15, and
20-22. This material is available free of charge via the Internet at
http://pubs.acs.org.
2
(s, 9H), 1.57 (s, 9H), 2.86 (A part of ABX system, JAB ) 13.2
JO0617969
9894 J. Org. Chem., Vol. 71, No. 26, 2006