Synthesis and highly enantioselective hydrogenation of exocyclic enamides: (Z)-3-arylidene-4-acetyl-3,4-dihydro-2H-1,4-benzoxazines

Article abstract of DOI:10.1021/jo048212s

(Chemical Equation Presented) Highly enantioselective hydrogenation of exocyclic enamides, (Z)-3-arylidene-4-acyl-3,4-dihydro-2H-benzoxazines, was achieved in up to 98.6% ee by using Rh/(R,R)-Me-Duphos complex as the catalytic system. The absolute configu

Full text of DOI:10.1021/jo048212s

Synthesis and Highly Enantioselective Hydrogenation of Exocyclic
Enamides: (Z)-3-Arylidene-4-acetyl-3,4-dihydro-2H-
1,4-benzoxazines
Yong-Gui Zhou,* Peng-Yu Yang, and Xiu-Wen Han
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road,
Dalian 116023, The People’s Republic of China
ygzhou@dicp.ac.cn
Received October 11, 2004
Highly enantioselective hydrogenation of exocyclic enamides, (Z)-3-arylidene-4-acyl-3,4-dihydro-
2H-benzoxazines, was achieved in up to 98.6% ee by using Rh/(R,R)-Me-Duphos complex as the
catalytic system. The absolute configuration of the product was assigned as R by chemical
interrelations.
Optically active 3-substituted-3,4-dihydro-2H-1,4-ben-
zoxazines represent the structure motifs of many natu-
rally occurring substances and chiral drugs. They can
also be employed as building blocks in the synthesis of a
wide range of biologically active molecules.1 As shown
in Figure 1, levofloxacin, a potent antibacterial agent on
the market, possesses the structural unit of 3-substituted-
3,4-dihydro-2H-1,4-benzoxazines. It exhibits excellent
activities against Gram-positive and -negative bacteria.
In addition, some natural aspidosperma-type alkloids
also have this structural unit.1a The stereoconfiguration
at the C-3 position of the 1,4-benzoxazine ring plays an
important role for its pharmacological properties.1e For
example, it is found that levofloxacin is less toxic than
its enantiomer.1e To get enantiopure compounds, chiral
FIGURE 1. Design of cyclic enamides containing 1,4-benzox-
azines.
acids2 and acyl chlorides3 were employed in the kinetic
resolution of racemic products. Furthermore, several
a key intermediate for the synthesis of levofloxacin.4e
However, the search for an efficient catalytic synthesis
of 3-substituted-3,4-dihydro-2H-1,4-benzoxazines is still
highly desirable. Recently, catalytic asymmetric hydro-
genation of prochiral enamides with Ru- or Rh-complexes
stoichiometric and catalytic methods have been developed
for the synthesis of this type of building blocks.4 Elegant
examples include Ir/BPPM/BiI3-catalyzed asymmetric
hydrogenation of prochiral imine with 90% ee,4f and Ru-
BINAP-catalyzed asymmetric hydrogenation of acetol as
(1) (a) Brown, K. S.; Djerassi, C. J. Am. Chem. Soc. 1964, 86, 2451.
(b) Belattar, A.; Saxton, J. E. J. Chem. Soc., Perkin Trans. 1 1992,
679. (c) Daiichi, S. Drugs Future 1992, 17, 559. (d) McAllister, S. D.;
Rizvi, G.; Anavi-Goffer, S.; Hurst, D. P.; Barnett-Norris, J.; Lynch, D.
L.; Reggio, P. H.; Abood, M. E. J. Med. Chem. 2003, 46, 5139. (e)
Bouzard, D. In Antibiotics and Antiviral Compounds; Korhn, K., Rirst,
H. A., Maag, H., Eds.; VCH: Weinheim, Germany, 1993. (f) Shim, J.
Y.; Collantes, E. R.; Welsh, W. J. J. Med. Chem. 1998, 41, 4521.
(2) (a) Fujiwara, T.; Tsurumi, H.; Sato, Y. T. EP 1989, 304, 684. (b)
Hayakawa, J.; Atarashi, S.; Yokohama, S.; Imamura, M.; Higashihashi,
N.; Oshima, M. EP 1986, 206, 283.
(3) (a) Charushin, V. N.; Krasnov, V. P.; Levit, G. L.; Korolyova, M.
A.; Kodess, M. I.; Chupakhin, O. N.; Kim, M. H.; Lee, H. S.; Park, Y.
J.; Kim, K. C. Tetrahedron: Asymmetry 1999, 10, 2691. (b) Krasnov,
V. P.; Levit, G. L.; Bukrina, I. M.; Andreeva, I. N.; Sadretdinova, L.
S.; Korolyova, M. A.; Kodess, M. I.; Charushin, V. N.; Chupakhin, O.
N. Tetrahedron: Asymmetry 2003, 14, 1985. (c) Krasnov, V. P.; Levit,
G. L.; Kodess, M. I.; Charushin, V. N.; Chupakhin, O. N. Tetrahedron:
Asymmetry 2004, 15, 859. (d) Potemkin, V. A.; Krasnov, V. P.; Levit,
G. L.; Bartashevich, E. V.; Andreeva, I. N.; Kuzminsky, M. B.; Anikin,
N. A.; Charushin, V. N.; Chupakhin, O. N. Mendeleev Commun. 2004,
14, 69.
10.1021/jo048212s CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/08/2005
J. Org. Chem. 2005, 70, 1679-1683
1679

Zhou et al.
SCHEME 1. Synthesis of Exocyclic Enamides 5
together with chiral bisphosphine ligands,5 such as
BINAP, BICP, PennPhos, Binapine, DIOP*, o-Ph-hex-
aMeO-BIPHEP, TangPhos, BPE, BisP, BDPMI, BDPAB,
or some monodentate phosphorus ligands,6 has attracted
much attention as an efficient method for the synthesis
of the corresponding chiral amines. The presence of a
secondary donor acyl group in the substrate, which will
allow the chelation of the substrate to the central metal,
is crucial for the reactivity and enantioselectivity.7 Ac-
cording to retrosynthetic analysis, we envisioned that
direct asymmetric hydrogenation of exocyclic enamides,
3-arylidene-4-acetyl-3,4-dihydro-2H-1,4-benzoxazines,
should be a convenient and efficient route to the corre-
sponding chiral saturates. Herein, we report the synthe-
sis and highly enantioselective hydrogenation of (Z)-3-
arylidene-4-acyl-3,4-dihydro-2H-benzoxazines.
All enamide substrates in this study were synthesized
by a modification of a published procedure.8 As shown
in Scheme 1, the treatment of o-nitrophenol derivatives
1 with propargyl bromide in the presence of K2CO3 in
acetone afforded 2 in 70-85% yield, and then 2 was
reduced with iron powder in acetic acid to give 2-(prop-
2′-ynyloxy)aniline derivatives 3. Compound 3 underwent
palladium-catalyzed C-arylation with aryl iodides in the
present of Cu(I) and triethylamine to provide the disub-
stituted alkynes, which were directly converted to the
corresponding acetamides with acetic anhydride under
base condition in dichloromethane. The acetamides 4
could then be cyclized with CuI in the presence of K2-
CO3 and tetrabutylammonium bromide in acetonitrile at
80 °C to produce the corresponding hydrogenation sub-
strates 5 with low to moderate yields.8 Instead of acetic
anhydride, benzoyl chloride and tosyl chloride were
employed to synthesize compounds 5k and 5l, respec-
tively, under the same conditions. It is noted if the aryl
group at the carbon-carbon triple bond was replaced
with alkyl group, the Cu-catalyzed cyclization (N-(2-hept-
2-ynyloxyphenyl)acetamide) could not occur under the
above reaction conditions. The Z-sterochemistry of the
exocyclic double bond of the substrate 5a was assigned
according to NOE experiments. When methylenic protons
of the heterocyclic ring of compound 5a were irradiated,
a strong enhancement of the vinylic proton signal of the
exocyclic double bond was observed.
(4) (a) Atarashi, S.; Tsurumi, H.; Fujiwara, T.; Hayakawa, I. J.
Heterocycl. Chem. 1991, 28, 329. (b) Kang, S. B.; Ahn, E. J.; Kim, Y.
Tetrahedron Lett. 1996, 37, 9317. (c) Xie, L. J. Chin. Chem. Lett. 1995,
6, 857. (d) Adrio, J.; Carretero, J. C.; Ruano, J. L. G.; Pallare´s, A.;
Vicioso, M. Heterocycles 1999, 51, 1563. (e) Noroyi, R. Acta Chem.
Scand. 1996, 50, 380. (f) Satoh, K.; Inenaga, M.; Kanai, K. Tetrahe-
dron: Asymmetry 1998, 9, 2657. (g) Miyadera, A.; Imura, A. Tetrahe-
dron: Asymmetry 1999, 10, 119. (h) Sakano, K.; Yokohama, S.;
Hayakawa, I.; Atarashi, S.; Kadoya, S. Agric. Biol. Chem. 1987, 51,
1265. (i) Imamura, M.; Hayakawa, I. Chem. Pharm. Bull. 1987, 35,
1896.
(5) (a) Sinou, D.; Kagan, H. B. J. Organomet. Chem. 1976, 114, 325.
(b) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya,
H. J. Am. Chem. Soc. 1986, 108, 7117. (c) Kitamura, M.; Hsiao, Y.;
Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J. Org.
Chem. 1994, 59, 297. (d) Tschaen, D. M.; Abramson, L.; Cai, D.;
Desmond, R.; Dolling, U. F.; Frey, L.; Karady, S.; Shi, Y. J.; Verhoeven,
T. R. J. Org. Chem. 1995, 60, 4324. (e) Burk, M. J.; Wang, Y. M.; Lee,
J. R. J. Am. Chem. Soc. 1996, 118, 5142. (f) Burk, M. J.; Casy, G.;
Johnson, N. B. J. Org. Chem. 1998, 63, 6084. (g) Zhang, F. Y.; Pai, C.
C.; Chan, A. S. C. J. Am. Chem. Soc. 1998, 120, 5808. (h) Zhu, G.;
Casalnuovo, A. L.; Zhang, X. J. Org. Chem. 1998, 63, 8100. (i) Zhang,
Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org. Chem. 1999, 64, 1774.
(j) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679. (k) Dupau,
P.; Bruneau, C.; Dixneuf, P. H. Adv. Synth. Catal. 2001, 343, 331. (l)
Li, W.; Waldkirch, J. P.; Zhang, X. J. Org. Chem. 2002, 67, 7618. (m)
Tang, W.; Chi, Y.; Zhang, X. Org. Lett. 2002, 4, 1695. (n) Renaud, J.
L.; Dupau, P.; Hay, A.-E.; Guingouain, M.; Dixneuf, P. H.; Bruneau,
C. Adv. Synth. Catal. 2003, 345, 230 (o) Tang, W.; Zhang, X. Angew.
Chem., Int. Ed. 2002, 41, 1612. (p) Lee, S.-G.; Zhang, Y. J.; Song, C.
E.; Lee, J. K.; Choi, J. H. Angew. Chem., Int. Ed. 2002, 41, 847.
(6) (a) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou,
Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348. (b) van den Berg, M.;
Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de vries, A. H. M.; de
Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539. (c)
Reetz, M. T.; Mehler, G.; Meiswinkel, A.; Sell, T. Tetrahedron Lett.
2002, 43, 7941. (d) Huang, H.; Zheng, Z.; Luo, H.; Bai, C.; Hu, X.; Chen,
H. Org. Lett. 2003, 5, 4137. (e) Jia, X.; Li, X.; Xu, L.; Shi, Q.; Yao, X.;
Chan, A. S. C. J. Org. Chem. 2003, 68, 4539. (f) Huang, H.; Zheng, Z.;
Luo, H.; Bai, C.; Hu, X.; Chen, H. J. Org. Chem. 2004, 69, 2355. (g)
Hoen, R.; van den Berg, M.; Bernsmann, H.; Minnaard, A. J.; de Vries,
J. G.; Feringa, B. L. Org. Lett. 2004, 6, 1433.
Since Rh/Me-DuPhos has been successfully applied
to asymmetric hydrogenation of acyclic and cyclic
enamides,5e,f we initially examined the [Rh(COD)2]BF4/
(R,R)-Me-DuPhos complex for hydrogenation of the ena-
mide substrate 5a. The reaction was carried out under
60 psi of H2 at room temperature with a ratio of
(7) (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-
VCH: New York, 2000. (b) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994. (c) Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H. Comprehensive Asymmetric Catalysis; Springer; Berlin,
Germany, 1999; Vol. 1. (d) Tang, W.; Zhang, X. Chem. Rev. 2003, 103,
3029.
(8) (a) Kundu, N. G.; Chaudhuri, G.; Upadhyay, A. J. Org. Chem.
2001, 66, 20. (b) Kundu, N. G.; Nandi, B. J. Org. Chem. 2001, 66, 4563.
(c) Chowdhury, C.; Chaudhuri, G.; Guha, S.; Mukherjee, A. K.; Kundu,
N. G. J. Org. Chem. 1998, 63, 1863.
1680 J. Org. Chem., Vol. 70, No. 5, 2005

(Z)-3-Arylidene-4-acetyl-3,4-dihydro-2H-1,4-benzoxazines
TABLE 1. Rh-Catalyzed Asymmetric Hydrogenation of
Exocyclic Enamide 5aa
TABLE 2. Rh/(R,R)-Me-DuPhos-Catalyzed Asymmetric
Hydrogenation of 5a
entry
R in 5
H (5a)
6-Me (5b)
Ar in 5
Ph
Ph
R′ in 5 eeb(%) configc
1
2
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Bz
Ts
97.2
98.0
97.2
98.2
97.2
98.6
96.4
98.2
90.6
92.2
90.5
R
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
N/A
3
6-MeO (5c) Ph
4
6-Cl (5d)
7-Me (5e)
H (5f)
H (5g)
H (5h)
H (5i)
H (5j)
H (5k)
H (5l)
Ph
Ph
5
6
p-MeOC6H4
2-MeOC6H4
p-MeC6H4
2-MeC6H4
1-naphthyl
Ph
7
P
yieldb eec
8
entry Rh precursor
ligand
solvent (psi) (%)
(%)
9
10
11d
12e
1
2
3
4
5
6
7
8
9
Rh(COD)2BF4 (R,R)-Me-DuPhos CH2Cl2
Rh(COD)2BF4 (R,R)-Me-DuPhos toluene
Rh(COD)2BF4 (R,R)-Me-DuPhos THF
Rh(COD)2BF4 (R,R)-Me-DuPhos MeOH
Rh(COD)2BF4 (R,R)-Me-DuPhos i-PrOH
Rh(COD)2BF4 (R,R)-Me-DuPhos MeOH
60
60
60
60
60
30
98
45
75
97
96
97
97
90
96
94
24
39.0
76.3
96.7
97.2
72.0
96.8
93.8
83.2
96.3
80.8
66.8
Ph
N/A
a The reaction was run in methanol under hydrogen pressure
of 60 psi for 16 h, subtrate/[Rh(COD)2]BF4/(R,R)-Me-DuPhos )
1/0.01/0.011. b Enantiomeric excess was determined by HPLC with
chiral column. c Absolute configurations of these products were
assigned by analogy. d (S)-MeO-Biphep was used. e No reaction.
Rh(COD)2BF4 (R,R)-Me-DuPhos MeOH 200
[Rh(COD)Cl]2 (R,R)-Me-DuPhos MeOH
Rh(NBD)2BF4 (R,R)-Me-DuPhos MeOH
60
60
60
60
10 Rh(COD)2BF4 (S)-MeO-Biphep MeOH
11 Rh(COD)2BF4 (S)-BINAP MeOH
double bond, a slightly low enantioselectivity was ob-
tained (90.6% ee, entry 9 and 92.2% ee, entry 10).
Replacement of the N-Ac of (Z)-5a with an N-Bz group
led to a significant drop in the enantioselectivity (90.5%
ee, entry 11 vs 97.2% ee, entry 4). No reduction was
observed with (Z)-3-benzylidene-4-tosyl-3,4-dihydro-2H-
benzoxazine as the hydrogenation substrate under stan-
dard condition, and the reason is not clear.
a Reactions were carried out at room temperature for 16 h. The
catalysts were made in situ by stirring a solution of Rh precursor
and bisphosphine ligand in MeOH for 10 min. Substrate/Rh/ligand
) 1/0.01/0.011. b Isolated yields based on substrate 5a. c Enantio-
meric excess was determined by chiral HPLC using a Chiralcel
OD-H column.
substrate/Rh/(R,R)-Me-DuPhos of 100:1:1.1. The results
are summarized in Table 1. It was observed that the
reaction was dependent on solvent. The catalytic hydro-
genation goes to completion in dichloromethane, metha-
nol, and 2-propanol under 60 psi of H2 in 16 h (entries 1,
4, and 5), while only 45% yield was achieved in toluene
(entry 2). Enantioselectivities dropped to 39% and 72%
when dichloromethane and 2-propanol were used as
solvents, respectively (entries 1 and 5). Systematic
investigation showed that methanol was the best solvent
for this transformation. Increasing the pressure of H2
resulted in a slight decrease of enantioselectivity. For
example, 93.8% ee was obtained under 200 psi of H2 while
96.8% ee was achieved under 30 psi of H2 (entries 6 and
7). Different catalyst precursors and chiral bisphosphine
ligands were also examined for hydrogenation of 5a
under the above optimized conditions, and it was found
that a cationic Rh(I) species gave better results than a
neutral Rh(I) complex (97.2% ee, entry 4 vs 83.2% ee,
entry 8). On the basis of the result shown in entry 4, other
chiral bisphosphines were tried for asymmetric hydro-
genation of 5a. It could be concluded that hydrogenation
of 5a with Rh/BINAP (66.8% ee, entry 11) and Rh/MeO-
Biphep species (80.8% ee, entry 10) gave lower ee values
than the reaction with Rh/(R,R)-Me-Duphos complex
(97.2% ee, entry 4) did.
1
It was noted that the resolution of H and 13C NMR
was dependent on the temperature. The 1H and 13C NMR
spectra of the hydrogenation products measured at room
temperature are broadening (see the Supporting Infor-
mation), while the spectral lines become narrow with
1
increasing temperature. The best resolution H and 13C
NMR spectra were obtained in DMSO-d6 at 100 °C. This
phenomenon was also observed in other acyl-protected
2-methyl-1,2,3,4-tetrahydroquinolines, 2-methylindoles,
and 3-methyl-3,4-dihydro-2H-1,4-benzoxazines in recent
publications.3
The absolute configuration of chiral products was
figured out by chemical interrelation comparing with the
known absolute configuration of (S)-naproxen acyl chlo-
ride, and was comfirmed by X-ray crystallographic analy-
sis (Scheme 2). Racemic product 6a was hydrolyzed with
KOH/MeOH to give amine 7, which then reacted with
(S)-naproxen acyl choride9 to afford the amide 8 with a
known absolute configuration in 88% yield, using Chu-
pakhin’s condition3c (benzene, room temperature). Re-
crystallization from DCM/hexane gave amide 8 (>99%
ee) as a colorless crystal, and its absolute configuration
was assigned as (S,S)-(+)-8 by X-ray diffraction analysis
(see the Supporting Information). The (S,S)-amide 8 was
hydrolyzed by heating in a mixture of concentrated
hydrochloric and acetic acids to afford (S)-(-)-7 in 88%
yield with high enantiomeric purity (>99% ee). The chiral
hydrogenation product (-)-6a (96.8% ee) was hydrolyzed
Under the optimal conditions, several (Z)-3-arylidene-
4-acyl-3,4-dihydro-2H-1,4-benzoxazines 5a-k were in-
vestigated (Table 2). Hydrogenation gives high enanti-
oselectivities (>97% ee) regardless of the substituents on
the aromatic ring of 1,4-benzoxazines. In the case of the
compounds with an ortho substituent of aryl on exocyclic
(9) Wang, C. P.; Howell, S. R.; Scatina, J.; Sisenwine, S. F. Chirality
1992, 4, 84.
J. Org. Chem, Vol. 70, No. 5, 2005 1681

Zhou et al.
SCHEME 2 The Determination of the Absolute Configuration of 6a
General Procedure for Sonogashira Coupling and
Acylation. A mixture of iodobenzene (5.10 g, 25 mmol),
(PPh3)2PdCl2 (0.526 g, 0.75 mmol), and CuI (0.238 g, 1.25
mmol) in triethylamine (50 mL) was stirred under nitrogen
atmosphere for 40 min, and then aniline derivative 3a (4.413
g, 30 mmol) in triethylamine (40 mL) was added slowly. The
resulting reaction mixture was stirred at room temperature
for 16 h under nitrogen atmosphere. After removal of triethy-
lamine under reduced pressure, the reaction mixture was
poured into water (150 mL) and extracted with ethyl acetate
(3 × 50 mL). The combined organic layer was washed succes-
sively with water and brine and dried over anhydrous Na2-
SO4. After removal of solvent, the residue was used in the next
step without further purification. The residue was dissolved
in dry dichloromethane (50 mL). Then under ice-cold condi-
tions, pyridine (2.43 mL, 30 mmol) and acetic anhydride (2.64
mL, 28 mmol) were added. After being stirred at room
temperature for about 2 h under nitrogen atmosphere, the
reaction was quenched with brine (50 mL). The separated
aqueous layer was then extracted with dichloromethane (3 ×
50 mL). The combined organic layer was washed successively
with hydrochloric acid (3%), water, and brine and dried over
anhydrous Na2SO4. After removal of solvent, the residue was
purified by recrystallization from hexane-dichloromethane to
give the desired product 4a (4.438 g, 67%). N-[2-(3′-Phenyl-
prop-2′-ynyloxy)phenyl]acetamide (4a): 1H NMR (400
MHz, CDCl3) δ 8.39 (d, J ) 7.6 Hz, 1H), 7.82 (s, 1H), 7.43-
7.41 (m, 2H), 7.34-7.30 (m, 2H), 7.06-7.00 (m, 3H), 4.97 (s,
2H), 2.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 24.9, 57.5,
83.6, 87.8, 112.0, 120.2, 121.9, 122.0, 123.6, 128.4, 128.9, 131.8,
146.0, 168.2; HRMS calcd for C17H16NO2 (M + 1) 266.1176,
found 266.1161.
General Procedure for Cyclization to Benzoxazines.
A mixture of the acetamide 4a (5.30 g, 20 mmol), CuI (761
mg, 4.0 mmol), anhydrous K2CO3 (6.91 g, 50 mmol), and n-Bu4-
NBr (6.447 g, 20 mmol) in dry acetonitrile (150 mL) was stirred
for about 20 min under nitrogen atmosphere, and the resulting
mixture was refluxed for 12 h under nitrogen atmosphere.
After removal of acetonitrile under reduced pressure, the
reaction mixture was poured into water (150 mL) and ex-
tracted with ethyl acetate (3 × 50 mL). The combined organic
layer was washed successively with water, saturated NH4Cl
aqueous solution, and brine and dried over anhydrous Na2-
SO4. After removal of solvent, the residue was subjected to
column chromatography to give the desired product and the
recovered material. The product was finally recrystallized from
hexane-dichloromethane to give the desired enamide 5a as a
white solid (1.59 g, 30%) and recovered 4a (3.18 g, 60%). (Z)-
3-Benzylidene-4-acetyl-3,4-dihydro-2H-1,4-benzoxazine
(5a): mp 119-120 °C; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J
) 7.9 Hz, 1H), 7.45-7.33 (m, 5H), 7.11-7.09 (m, 1H), 7.03-
6.99 (m, 1H), 6.93 (dd, J1 ) 0.8 Hz, J2 ) 8.2 Hz, 1H), 6.63 (s,
1H), 4.81 (s, 2H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
in a mixture of KOH/MeOH to give (+)-7 (96.6% ee)
without loss of optical purity. By comparison of the sign
of optical rotation, it was found that the absolute con-
figuration of the product (+)-7 was R. Thus the absolute
configuration of the product (-)-6a was unambiguously
assigned as the R configuration. The configurations of
other compounds 6 are deduced based on the signs of the
optical rotations because of the structure similarity.
In summary, we have designed and synthesized a new
type of cyclic enamide from the cheap starting material
o-nitrophenol derivatives, which can be hydrogenated
with high enantioselectivity by using commercially avail-
able Rh/(R,R)-Me-DuPhos complex as the catalyst. The
absolute configuration of the hydrogenation product was
also assigned by chemical interrelation. This method
provides an efficient access to a variety of optically active
3-substituted-3,4-dihydro-2H-1,4-benzoxazines.
Experimental Section
General Procedure for Propargylation of 2-Nitro-
phenol Derivatives. A mixture of 2-nitrophenol 1a (6.95 g,
50 mmol) and anhydrous K2CO3 (7.05 g, 51 mmol) in dry
acetone (50 mL) was stirred for 3 h at room temperature.
Propargyl bromide (7.14 g, 60 mmol) in acetone (15 mL) was
then added during 1 h. The mixture was then refluxed for 16
h with constant stirring under nitrogen atmosphere, and TLC
analysis indicated all the starting materials had been con-
sumed. After removal of acetone under reduced pressure, the
reaction mixture was poured into water (50 mL) and extracted
with ethyl acetate (3 × 50 mL). The combined organic layer
was washed successively with hydrochloric acid (3%), water,
and brine and dried over anhydrous Na2SO4. After removal of
solvent, the residue was purified by recrystallization from
hexane-dichloromethane to give the desired product 2a as a
light yellow to yellow solid (6.64 g, 75%). 2-(Prop-2′-ynyloxy)-
nitrobenzene (2a):8 1H NMR (400 MHz, CDCl3) δ 7.84 (dd,
J1 ) 1.6 Hz, J2 ) 8.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.26(d, J )
8.4 Hz, 1H), 7.11-7.08 (m, 1H), 4.85 (d, J ) 2.4 Hz, 2H), 2.60
(t, J ) 2.4 Hz, 1H).
General Procedure for Reduction of Nitro Com-
pounds 2 with Fe/Ac2O. 3a-e were prepared by the reduc-
tion of 2a-e with Fe/AcOH following the known procedure.10
8
1
2-(Prop-2′-ynyloxy)aniline (3a): yield 80%; H NMR (400
MHz, CDCl3) δ 6.96-6.92 (m, 1H), 6.88-6.81 (m, 1H), 6.74 (t,
J ) 8.2 Hz, 2H), 4.73 (d, J ) 2.3 Hz, 2H), 2.53 (t, J ) 2.2 Hz,
1H).
(10) Vogel, A. I. A Text Book of Practical Organic Chemistry, 4th
ed.; ELBS, Longman Group Limited; London, UK, 1978; p 658.
1682 J. Org. Chem., Vol. 70, No. 5, 2005

(Z)-3-Arylidene-4-acetyl-3,4-dihydro-2H-1,4-benzoxazines
22.1, 70.9, 116.7, 120.5, 124.4, 126.0, 126.6, 128.5, 128.9, 129.0,
130.5, 133.7, 146.7, 168.2; HRMS calcd for C17H16NO2 (M +
1) 266.1176, found 266.1162.
N-[(2S)-2-(6-Methoxynaphthyl-2)propionyl]-(3S)-2,3-di-
hydro-3-benzyl-4H-1,4-benzoxazine (8). To a stirred solu-
tion of racemate 7 (112 mg, 0.5 mmol) in anhydrous benzene
(1.0 mL) was added a solution of (S)-naproxen acyl chloride9
(62 mg, 0.25 mmol) in benzene (2.0 mL) at 5 °C. The mixture
was stirred at room temperature for 5 h, then 2 mL of 1 N
HCl was added to the reaction mixture at 5 °C followed by
extraction with benzene. The combined organic layer was
washed successively with water, 5% aqueous NaHCO3 solution,
and brine and dried over anhydrous Na2SO4. After removal of
solvent, the residue was subjected to column chromatography
to give the desired white solid 8 (98 mg, yield based on (S)-
naproxen acyl chloride: 88%). The product was finally recrys-
tallized from hexane-dichloromethane to give the colorless
crystals. Mp 143-144 °C; [R]25D +36.7 (c 1.0, CHCl3); 1H NMR
(400 MHz, DMSO-d6, 100 °C) δ 7.66 (d, J ) 8.8 Hz, 2H), 7.60
(d, J ) 8.8 Hz, 1H), 7.39 (s, 1H), 7.23-7.10 (m, 7H), 6.98 (t, J
) 7.2 Hz, 3H), 6.83 (dd, J1 ) 1.0 Hz, J2 ) 8.2 Hz, 1H), 4.92 (t,
J ) 7.0 Hz, 1H), 4.52 (q, J ) 6.8 Hz, 1H), 4.11 (d, J ) 11.2 Hz,
1H), 3.89 (d, J ) 2.8 Hz, 1H), 3.87 (s, 3H), 2.60 (dd, J1 ) 7.6
Hz, J2 ) 13.6 Hz, 1H), 2.36 (dd, J1 ) 8.0 Hz, J2 ) 13.6 Hz,
1H), 1.47 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, DMSO-d6,
100 °C) δ 18.6, 34.2, 41.5, 49.9, 45.7, 66.8, 105.9, 115.7, 117.8,
119.4, 123.5, 125.0, 125.4, 125.7, 126.2, 127.5, 128.0, 128.3,
132.7, 135.8, 136.7, 146.1, 156.8, 172.2; HRMS calcd for C29H27-
NO3 (M + 1) 438.2064, found 438.2045.
General Procedure for Asymmetric Hydrogenation of
5. In a glovebox, the Rh-(R,R)-Me-DuPhos complex was made
in situ by mixing [Rh(COD)2]BF4 (2.0 mg, 0.005 mmol) and
(R,R)-Me-DuPhos (1.7 mg, 0.0055 mmol) in MeOH (2.0 mL).
After the mixture was stirred at room temperature for 10 min,
substrate 5a (133 mg, 0.5 mmol) in MeOH (2.0 mL) was added
via a syringe. The hydrogenation was performed at room
temperature under 60 psi of H2 for 16 h. After the hydrogen
was carefully released, the reaction mixture was passed
through a short silica gel column to remove the catalyst.
Purification was performed by a silica gel column eluted with
hexanes/EtOAc to give pure products 6a (129 mg, 97%). (R)-
3-Benzyl-4-acetyl-3,4-dihydro-2H-1,4-benzoxazine(6a): 97.2%
1
ee; [R]20 -90.8 (c 0.80, CHCl3); H NMR (400 MHz, DMSO-
D
d6, 100 °C) δ 7.67 (d, J ) 8.0 Hz, 1H), 7.31-7.21(m, 3H), 7.14-
7.07 (m, 3H), 6.95-6.92 (t, J ) 7.5 Hz, 2H), 4.77 (s, 1H), 4.29
(t, J ) 5.5 Hz, 1H), 4.15 (dd, J1 ) 2.9 Hz, J2 ) 11.0 Hz, 1H),
2.81 (dd, J1 ) 6.3 Hz, J2 ) 13.8 Hz, 1H), 2.68 (dd, J1 ) 8.9 Hz,
J2 ) 13.7 Hz, 1H), 1.99 (s, 3H); 13C NMR (100 MHz, DMSO-
d6, 100 °C) δ 22.3, 35.0, 50.9, 67.7, 116.2, 119.9, 124.1, 124.9,
125.1, 126.2, 128.1, 128.8, 137.6, 145.8, 168.2; HRMS calcd
for C17H17NO2 (M + 1) 268.1332, found 268.1325; HPLC, UV
254 nm, Chiralcel OD-H, 1.0 mL/min, 30% 2-propanol/70%
hexane, (R) t1 ) 5.89 min; (S) t2 ) 7.34 min.
(S)-(-)-3-Benzyl-3,4-dihydro-2H-1,4-benzoxazine (7).
(S,S)-(+)-8 (24 mg, 0.055 mmol) was refluxed in a mixture of
1 mL of acetic acid and 1.0 mL of hydrochloric acid for 5 h
under nitrogen atmosphere. The reaction mixture was evapo-
rated to dryness in vacuo. Water (10 mL) was then added and
the resulting mixture was cooled in an ice bath. The precipitate
was filtered off and washed with water. The combined filtrates
were alkalized by 10 N NaOH up to pH 8-9 under ice-cooling,
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
layer was washed successively with water and brine and dried
over anhydrous Na2SO4. After removal of solvent, the residue
was subjected to column chromatography to give the desired
The Determination of the Absolute Configuration: (()-
3-Benzyl-3,4-dihydro-2H-1,4-benzoxazine (7). A mixture
of (()-6a (905 mg, 3.4 mmol), potassium hydroxide (1.28 g,
22.8 mmol), water (1.2 mL), and methanol (5 mL) was stirred
at 50-60 °C under nitrogen atmosphere for 12 h. The mixture
was then poured into water and extracted with ether. The
combined organic layer was washed successively with water
and brine and dried over anhydrous Na2SO4. After removal of
solvent, the residue was subjected to column chromatography
to give the desired product (()-7 (612 mg). Yield 80%: mp 71-
72 °C [lit.11mp 63 °C (n-pentane)]; 1H NMR (400 MHz, DMSO-
d6) δ 7.32 (t, J ) 7.4 Hz, 2H), 7.24 (dd, J1 ) 7.2 Hz, J2 ) 11.2
Hz, 3H), 6.68-6.59 (m, 3H), 6.46 (t, J ) 7.4 Hz, 1H), 5.76 (s,
1H), 3.97 (d, J ) 10.4 Hz, 1H), 3.74 (dd, J1 ) 6.6 Hz, J2 ) 10.6
Hz,1H), 3.52 (d, J ) 6.0 Hz, 1H), 2.81 (dd, J1 ) 6.0 Hz, J2 )
13.6 Hz, 1H), 2.70 (dd, J1 ) 7.8 Hz, J2 ) 13.4 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 38.1, 50.1, 67.5, 114.8, 115.8,
116.7, 121.2, 126.3, 128.4, 129.3, 134.2, 137.8, 142.8; HRMS
calcd for C15H16NO (M + 1) 226.1226, found 226.1238.
white solid (S)-(-)-7 (9 mg, 75%); [R]25 -39.8 (c 0.1, CHCl3);
D
>99.5% ee. The HPLC analysis showed only a single peak,
and the minor enantiomer could not be detected. HPLC
(Chiralcel OD-H, elute: 5% 2-propanol/95% hexane, flow
rate: 1.0 mL/min, detector: UV 254 nm), tS ) 12.63 min.
Acknowledgment. We are grateful for the financial
support from National Science Foundation of China
(20302005) and Talent Scientist Program, the Chinese
Academy of Sciences.
Similar Condition for the Synthesis of (R)-(+)-3-Ben-
zyl-3,4-dihydro-2H-1,4-benzoxazine (7). Yield 89%; 96.6%
ee, [R]20 +46.1 (c 0.46, CHCl3), HPLC (Chiralcel OD-H,
Supporting Information Available: X-ray crystal struc-
ture of 8, spectroscopic characterization of the unknown
compounds, and HPLC data. This material is available free
of charge via the Internet at http://pubs.acs.org.
D
elute: 5% 2-propanol/95% hexane, flow rate: 1.0 mL/min,
detector: UV 254 nm), (R) t1 ) 11.67 min; (S) t2 ) 12.87 min.
(11) Fusco, R.; Garanti, L.; Zecchi, G. J. Org. Chem. 1975, 40, 1906.
JO048212S
J. Org. Chem, Vol. 70, No. 5, 2005 1683