An efficient synthesis of enantiomerically pure aromatic-fused N-containing heterocycles from common chiral aziridines

Article abstract of DOI:10.1016/j.tet.2010.07.027

An efficient synthesis of enantiomerically pure aromatic-fused N-containing heterocycles was successfully achieved via Pd-catalyzed intramolecular C-N bond formation between the nitrogen originated from the aziridine and the halogen containing aromatic carbon. This reaction has a broad substrate scope to provide various enantiomerically pure (3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methanols, 2-hydroxymethyl-1,2,3,4-tetrahydroquinolines and (1,2,3,4- tetrahydroquinoxalin-2-yl)methanols from common chiral aziridines in good yields.

Full text of DOI:10.1016/j.tet.2010.07.027

Tetrahedron 66 (2010) 8108e8114
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient synthesis of enantiomerically pure aromatic-fused N-containing
heterocycles from common chiral aziridines
,
a,
*
Jong Chan Kim a, Hwan Geun Choi a, Min Suk Kim b, Hyun-Joon Ha b , Won Koo Lee
*
a Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
b Department of Chemistry, Hankuk University of Foreign Studies, Yonging, Kyunggi-Do 449-719, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2010
Received in revised form 14 July 2010
Accepted 14 July 2010
Available online 21 July 2010
An efficient synthesis of enantiomerically pure aromatic-fused N-containing heterocycles was successfully
achieved via Pd-catalyzed intramolecular CeN bond formation between the nitrogen originated from the
aziridine and the halogen containing aromatic carbon. This reaction has a broad substrate scope to provide
various enantiomerically pure (3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanols, 2-hydroxymethyl-
1,2,3,4-tetrahydroquinolines and (1,2,3,4-tetrahydroquinoxalin-2-yl)methanols from common chiral
aziridines in good yields.
Keywords:
Chiral aziridine
Ó 2010 Elsevier Ltd. All rights reserved.
Tetrahydroquinoline
Benzoxazine
Tetrahydroquinoxaline
CeN bond formation
1. Introduction
2. Results and discussion
Recently, substituted 2-hydroxymethyl-1,2,3,4-tetrahydroquino-
lines and their analogous heterocycles turned out to be agonists or
partial agonists of the 2C subtype of brain serotonin receptors.1 They
are also useful for the treatment of a variety of central nervous system
disorders.2 Moreover, their derivatives can play important roles as
promoting angiogenesis of mesenchymal stem cells3 and also as
inhibitors of apoptosis for anti-cancer drugs.4 The heterocyclic com-
pounds containing 1,4-benzoxazines,5 1,2,3,4-tetrahydroquinolines,6
and 1,2,3,4-tetrahydroquinoxalines7 have attracted increasing
interest from organic and medicinal chemists due to their various
biological activities. Therefore, we were interested in the synthesis of
enantiomerically pure substituted 2-hydroxymethyl-1,2,3,4-tetrahy-
droquinolines and their analogous heterocycles starting from com-
mon chiral aziridines. We found that chiral aziridines are valuable
synthetic building blocks for chemical bond elaborations and func-
tional group transformations.8 Herein, we would like to report an
efficient synthesis of various heterocyclic systems, such as 1,4-ben-
zoxazines,9 1,2,3,4-tetrahydroquinolines,10 and 1,2,3,4-tetrahy-
The synthesis of enantiomerically pure (3,4-dihydro-2H-benzo
[b][1,4]oxazin-3-yl)methanols commenced from commercially
available 1-a-methylbenzyl-(2R)- and (2S)-aziridine-2-methanols.
The reaction of aziridine-2-methanols and p-toluenesulfonyl
chloride with TEA in DCM at room temperature afforded the
tosylated compound,12 which was reacted with various o-hal-
ophenols and K2CO3 in DMF/acetone to give the corresponding
phenyl ethers 3aec in high yields (Scheme 1).
droquinoxalines11 from 1-
a-methylbenzyl-(2R)- and (2S)-aziridine-
2-methanols via intramolecular Pd-catalyzed CeN bond formation.
Scheme 1. Reagents and conditions: (i) p-TsCl, TEA, DMAP, DCM, 0 ꢀ
C to rt;
* Corresponding authors. Tel.: þ82 2 705 8449; fax: þ82 2 701 0967 (W.K.L.);
tel.: þ82 31 330 4369; fax: þ82 31 330 4566 (H.-J.H.); e-mail addresses: hjha@
hufs.ac.kr (H.-J. Ha), wonkoo@sognag.ac.kr (W.K. Lee).
(ii) o-halophenols, K2CO3, DMF/acetone¼1:1, reflux; (iii) corresponding phosphonium
salts, LiHMDS, THF, 0 ꢀC to rt; (iv) 2-nitrobenzenesulfonylhydrazide (NBSH), TEA, DCM,
0
ꢀC to rt; (v) 2-bromoanilines, NaBH(OAc)3, MgSO4, DCE, rt.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.027

J. Chan Kim et al. / Tetrahedron 66 (2010) 8108e8114
8109
The synthesis of enantiomerically pure 2-alkylaziridines is also
-methyl-
The synthesis of (1,2,3,4-tetrahydroquinoxalin-2-yl)methanols
started from 1- -methylbenzyl-(2R)- and (2S)-aziridine-2-carboxy-
shown in Scheme 1. We reported the preparation of 1-
a
a
benzyl-(2R)- and (2S)-aziridine-2-carboxaldehydes13 from the
corresponding (2R)- and (2S)-aziridine-2-methalols by Swern oxi-
dation.14 The 2-alkenylaziridines15 were obtained as a cis/trans
mixture (w1:1dby NMR integration and they were not separated)
from the Wittig reaction of the corresponding phosphonium salts
aldehydes, which were reacted with the corresponding 2-bromoa-
nilnes and NaBH(OAc)3 in dichloroethane (DCE)17 to obtain various 2-
aminomethyl substituted aziridines 5geh in high yields (Scheme 1).
The aziridine ring was regioselectively cleaved by AcOH in
dichloromethane (DCM) to furnish ring opening compounds in high
yields and the crude products were used for the next reaction
without further purification.18 Saponification of the acetate pro-
ceeded smoothly with lithium hydroxide in THF, methanol, and
water or potassium hydroxide in ethanol to give the corresponding
amino alcohols and the hydroxyl group was protected with TBS. The
TBS protected compounds were subsequently subjected to intra-
molecular CeN bond formation with Pd2(dba)3, X-Phos,19 and
NaOtBu in toluene at 110 ꢀC for 2e3 h. The same CeN bond forming
reaction was applied for the preparation of (3,4-dihydro-2H-benzo
[b][1,4]oxazin-3-yl)methanols, 2-hydroxymethyl-1,2,3,4-tetrahy-
droquinolines, and (1,2,3,4-tetrahydroquinoxalin-2-yl)methanols
(Scheme 2). The TBS group was deprotected by TBAF and the nitro-
gen protecting benzyl group was also cleaved by catalytic hydroge-
nation to provide the final compounds 8aef (Table 1) and 11geh
(Table 2).
and 1-a-methylbenzyl-(2R)- or (2S)-aziridine-2-carboxaldehyde in
high yields. Even though the presence of a very labile vinyl
substituted aziridine C(2)eN bond, the vinyl group was selectively
reduced to provide the corresponding alkyl substituted products
4def in 65e83% yields using o-nitrobenzenesulfonylhydrazide
(NBSH) without forming any aziridine ring C(2)eN bond reduction
product (Scheme 1).16
Table 1
Synthesis of enantiomerically pure 2-hydroxymethyl-1,2,3,4-tetrahydroquinolines
and benzoxazine derivatives
Compound
Yield (%)
Final product 8aefc
6a
7b
8
3a
3b
3c
4d
4e
88
87
48
55
61
58
92
Table 2
Synthesis of enantiomerically pure2-hydroxymethyl-1,2,3,4-tetrahydroquinoxalines
Compound
Yield (%)
Final product 11gehc
60
90
86
85
90
97
90
97
9b
10
11a
5g
63
56
72
79
5h
68
52
a
Two steps yield.
Three steps yield.
b
c
We easily obtained enantiomerically pure final heterocycles 11geh via deben-
-methylbenzyl group from single diastereomers.
zylation of
a
4f
68
59
98
3. Conclusions
a
Two steps yield.
Three steps yield
Enantiomerically pure substituted 2,3-dihydro-3-hydroxymethyl-
1,4-benzoxazines were prepared from chiral aziridine-2-methanols
and o-halophenols, 2-hydroxymethyl-1,2,3,4-tetrahydroquinolines
were synthesized from chiral aziridine-2-carboxaldeydes and o-hal-
obenzylhalides and (1,2,3,4-tetrahydroquinoxalin-2-yl)methanols
were prepared from chiral aziridine-2-carboxaldeydes and
b
c
We easily obtained enantiomerically pure final heterocycles 8aef via
-methylbenzyl group from single diastereomers.
debenzylation of
a
Scheme 2. Reagents and conditions: (i) AcOH, DCM, rt; (ii) LiOH, MeOH/THF/H2O¼1:1:1, rt or KOH, EtOH, rt; (iii) TBSCl, TEA, DMAP, DCM, 0 ꢀC to rt; (iv) Pd2(dba)3, X-Phos, NaOtBu,
toluene, 110 ꢀC; (v) TBAF, THF, rt; (vi) Pd(OH)2, H2, MeOH, rt.

8110
J. Chan Kim et al. / Tetrahedron 66 (2010) 8108e8114
o-haloanilines in good yields. The synthesis of various N-containing
heterocyclic compounds wassuccessfullyachieved fromthe common
starting compounds, aziridine-2-methanols, via a Pd-catalyzed
intramolecular CeN bond formation as the key step.
1H NMR (300 MHz, CDCl3)
d 7.39e7.25 (m, 5H), 7.00e6.87 (m, 3H),
4.19 (dd,1H, J¼3.9,10.2 Hz), 3.81 (dd,1H, J¼7.8,10.2 Hz), 2.54 (q,1H,
J¼6.6 Hz), 1.72 (d, 1H, J¼3.3 Hz), 1.58 (d, 1H, J¼2.1 Hz), 1.52 (d, 3H,
J¼6.6 Hz), 1.47 (d, 1H, J¼6.6 Hz); 13C NMR (75 MHz, CDCl3)
d 159.6,
157.7,155.8, 152.0, 144.4,128.6, 127.3,127.0,120.7,120.5,114.8,114.6,
113.9,113.8, 112.3, 112.3; HRMS m/z calcd for C17H17BrFNO [MþNa]þ
372.0375. Found 372.0375.
4. Experimental section
4.1. General method
4.1.3. (R)-2-[(3-Bromonaphthalen-2-yloxy)methyl]-1-[(R)-1-phenyl-
All reactions were carried out under an atmosphere of
nitrogen in oven-dried glasswares with magnetic stirring. Air
sensitive reagents and solutions were transferred via syringe and
were introduced to the apparatus through rubber septa. Tetrahy-
drofuran (THF) and diethyl ether (Et2O) were distilled from sodium/
benzophenone ketyl. Dichloromethane was distilled from calcium
hydride. Reactions were monitored by thin layer chromatography
(TLC) with 0.25 mm E. Merck pre-coated silica gel plates (60 F254).
Visualization was accomplished with either UV light, or by im-
mersion in solutions of ninhydrin, p-anisaldehyde, or phospho-
molybdic acid (PMA) followed by heating on a hot plate for about
10 s. Purification of reaction products was carried out by flash
chromatography using Kieselgel 60 Art 9385 (230e400 mesh). 1H
NMR and 13C NMR spectra were obtained using a Varian Gemini-
300 (300 MHz for 1H, and 75 MHz for 13C), or a Varian Inova-500
(500 MHz for 1H, and 125 MHz for 13C) spectrometer. Chemical
ethyl]aziridine (3c). Colorless oil, (90%); [
a
]
24 þ7.7 (c 0.30, CH3OH);
D
1H NMR (300 MHz, CDCl3)
d
8.04 (s, 1H), 7.68e7.64 (m, 2H),
7.40e7.16 (m, 8H), 4.31 (dd, 1H, J¼9.9, 3.6 Hz), 3.96e3.89 (m, 1H),
2.56 (q, 1H, J¼6.6 Hz), 2.13e2.11 (m, 1H), 1.77 (d, 1H, J¼2.7 Hz), 1.56
(d, 1H, J¼6.6 Hz), 1.50 (d, 1H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3)
d
153.0, 144.5, 133.6, 132.4, 129.6, 128.5, 127.2, 127.0, 126.9, 126.8,
126.7, 124.6, 113.9, 107.9, 71.7, 70.0, 38.5, 31.3, 23.5. Anal. Calcd for
C21H20BrNO: C, 65.98; H, 5.27; Br, 20.90; N, 3.66; O, 4.19. Found: C,
65.91; H, 5.37; N, 3.49.
4.1.4. (S)-2-(2-Iodophenylethyl)-1-[(R)-1-phenylethyl]aziridine
(4d). To a solution of (2-iodobenzyl)triphenylphosphonium bro-
mide (830 mg, 1.48 mmol) in THF (2.80 mL) was added 1.0 M
solution LiHMDS in THF (1.37 mL) at 0 ꢀC. After 30 min, com-
pound 2 (200 mg, 1.14 mmol) in THF (1.00 mL) was added at 0 ꢀC.
The reaction mixture was stirred for 24 h at room temperature
and then quenched with water. The aqueous layer was extracted
with DCM and the combined organic layer was dried over an-
hydrous MgSO4, filtered then concentrated in vacuo. Purification
by silica gel flash chromatography provided 403 mg of (S)-2-(2-
iodostyryl)-1-[(R)-1-phenylethyl]aziridine (cis/trans¼1:1 mixture).
To a screw-cap vial was added above Wittig compound (200 mg,
shifts are reported relative to chloroform (
d
¼7.26) for 1H NMR and
chloroform (
d
¼77.2) for 13C NMR. Data are reported as (br¼broad,
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet). Coupling
constants are given in hertz. Ambiguous assignments were re-
solved on the basis of standard one dimensional proton decoupling
experiments. Optical rotations were obtained using a Rudolph
Autopol III digital polarimeter and optical rotation data was
0.53 mmol)
in
DCM
(2.65 mL)
and
2-nitro-
reported as follows: [
a]
24 (concentration c¼g/100 mL, solvent). El-
benzenesulfonohydrazide (926 mg, 4.26 mmol) at room temper-
ature. After 10 min, TEA (1.18 mL, 2.12 mmol) was added at 0 ꢀC.
The reaction mixture was stirred for overnight at room temper-
ature and then diluted with ether (3 mL). The mixture was
quenched with satd NH4Cl solution and extracted with DCM. The
combined organic layer was dried over anhydrous Na2SO4, fil-
tered, and concentrated in vacuo. Purification by silica gel flash
D
emental analyses were performed by the Organic Chemistry Re-
search Center at Sogang University using a Carlo Erba EA 1180
elemental analyzer. High resolution mass spectra were recorded on
a 4.7 Tesla IonSpec ESI-FTMS or a Micromass LCT ESI-TOF mass
spectrometer. All commercially available compounds were used as
received unless stated otherwise.
chromatography provided 135 mg of 4d in 83% yield (yellow oil);
24
4.1.1. (R)-2-[(2-Iodophenoxy)methyl]-1-[(R)-1-phenylethyl]-aziridine
(3a). To a solution of 1 (30 mg, 0.17 mmol) in DCM (0.90 mL) were
added DMAP (2.0 mg, 0.017 mmol) and TEA (60 mL, 0.40 mmol) at
[
a
]
þ27.7 (c 0.75, CH3OH); 1H NMR (300 MHz, CDCl3)
d 7.81 (d,
D
1H, J¼7.8 Hz), 7.39e7.26 (m, 7H), 6.92e6.84 (m, 1H), 3.02e2.81
(m, 2H), 2.44 (q, 1H, J¼6.6 Hz), 1.86e1.68 (m, 2H), 1.62e1.56 (m,
1H), 1.50e1.46 (m, 4H), 1.30 (d, 1H, J¼6.6 Hz); 13C NMR (125 MHz,
0 ꢀC. After 30 min, TsCl (39 mg, 0.20 mmol) was added at room
temperature. The reaction mixture was stirred for 4 h and then
quenched with water. The mixture was extracted with DCM. The
combined organic layer was dried over MgSO4, filtered, and con-
centrated in vacuo to give a crude tosylated compound. To a solu-
tion of the crude tosylate in DMF/acetone (1:1, 0.85 mL) were added
2-iodophenol (82 mg, 0.37 mmol) and K2CO3 (117 mg, 0.84 mmol).
The reaction mixture was refluxed for 16 h and then cooled to room
temperature. The reaction mixture was quenched with water and
extracted with DCM. The combined organic layer was dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. Purification
by column silica gel chromatography provided 403 mg of 3a in 95%
CDCl3)
d 144.8, 144.5, 139.6, 129.3, 128.5, 128.4, 127.9, 127.1, 127.0,
100.9, 70.0, 40.2, 39.2, 33.8, 33.6, 23.5; HRMS m/z calcd for
C18H20IN [MþNa]þ 400.0538. Found 400.0537.
4.1.5. (S)-2-[2-(5-Bromobenzo[d][1,3]dioxol-4-yl)ethyl]-1-[(R)-1-
24
phenylethyl]aziridine (4e). Yellow oil, (68%); [
a
]
D
þ59.7 (c 1.30,
CH3OH); 1H NMR (300 MHz, CDCl3)
d
7.38e7.23 (m, 5H), 7.00 (d, 1H,
J¼8.1 Hz), 6.56 (d, 1H, J¼8.4 Hz), 5.95 (s, 2H), 2.98e2.77 (m, 2H),
2.42 (q, 1H, J¼6.6 Hz), 1.94e1.65 (m, 2H), 1.58e1.51 (m, 1H),
1.46e1.43 (m, 4H),1.25 (d,1H, J¼6.0 Hz); 13C NMR (125 MHz, CDCl3)
d
146.8, 144.9, 128.4, 127.0, 127.0, 125.3, 123.7, 116.1, 107.6, 101.5,
yield (colorless oil); [
CDCl3)
a
]
24 þ7.7 (c 0.35, CH3OH); 1H NMR (300 MHz,
70.0, 40.2, 33.4, 32.2, 28.0, 23.5; HRMS m/z calcd for C19H20BrNO2
[MþNa]þ 396.0575. Found 396.0573.
D
d
7.78 (d, 1H, J¼7.8 Hz), 7.39e7.20 (m, 6H), 6.83 (d, 1H,
J¼7.8 Hz), 6.66 (t, 1H, J¼6.9 Hz), 4.20 (dd, 1H, J¼10.2, 3.6 Hz),
3.87e3.81 (m, 1H), 2.56 (q, 1H, J¼6.6 Hz), 2.10e2.06 (m, 1H), 1.73 (d,
1H, J¼3.0 Hz), 1.57 (d, 3H, J¼6.6 Hz), 1.48 (d, 1H, J¼6.6 Hz); 13C NMR
4.1.6. (S)-2-[2-(1-Bromonaphthalen-2-yl)ethyl]-1-[(R)-1-phenyl-
24
ethyl]aziridine (4f). Yellow oil, (65%); [
a]
þ71.4 (c 1.55, CH3OH);
D
(125 MHz, CDCl3)
d
157.6, 144.6, 139.7, 129.6, 128.5, 127.2, 127.0,
1H NMR (300 MHz, CDCl3)
d
8.32 (d, 1H, J¼8.1 Hz), 7.81e7.73 (m,
122.7, 112.4, 86.7, 71.9, 70.0, 38.5, 31.2, 23.8; HRMS m/z calcd for
2H), 7.58 (t, 1H, J¼7.2 Hz), 7.48 (t, 1H, J¼7.2 Hz), 7.42e7.28 (m,
6H), 3.19 (t, 1H, J¼7.5 Hz), 2.45 (q, 1H, J¼6.3 Hz), 1.94e1.82 (m,
2H), 1.62e1.42 (m, 5H), 1.30 (d, 1H, J¼6.3 Hz); 13C NMR
C17H18INO [MþNa]þ 402.0331. Found 402.0329.
4.1.2. (R)-2-[(2-Bromo-4-fluorophenoxy)methyl]-1-[(R)-1-phenyl-
(125 MHz, CDCl3) d 144.8, 139.6, 133.4, 132.8, 128.5, 128.2, 128.1,
ethyl]aziridine (3b). Colorless oil, (95%); [
a
]
24 þ8.1 (c 0.40, CH3OH);
127.7, 127.5, 127.4, 127.1, 127.0, 126.0, 123.9, 70.0, 40.3, 35.7, 33.8,
D

J. Chan Kim et al. / Tetrahedron 66 (2010) 8108e8114
8111
33.6, 23.5; HRMS m/z calcd for C22H22BrN [MþNa]þ 402.0833.
0.50, CH3OH); 1H NMR (300 MHz, CDCl3)
d
7.37e7.22 (m, 6H), 6.98
Found 402.0833.
(td, 1H, J¼3.0, 8.7 Hz), 6.83 (dd, 1H, J¼5.1, 9.0 Hz), 4.09 (dd, 1H,
J¼4.5, 9.3 Hz), 4.00 (q, 1H, J¼6.3 Hz), 3.93 (dd, 1H, J¼4.5, 9.3 Hz),
3.59e3.50 (m, 2H), 2.97 (quintet, 1H, J¼4.8 Hz), 2.32 (s, 2H), 1.41 (d,
4.1.7. 2-Bromo-4-fluoro-N-{(S)-1-[(S)-1-phenylethylaziridin-2-yl]
methyl}aniline (5g). To
a
solution of compound
2
(509 mg,
3H, J¼6.3 Hz); 13C NMR (125 MHz, CDCl3)
d 158.0, 156.0, 151.8,
2.96 mmol) and 2-bromo-4-fluoroaniline (843 mg, 4.44 mmol) in
DCE (14.8 mL) was treated with NaBH(OAc)3 (1881 mg, 8.87 mmol)
at room temperature and in nitrogen atmosphere. To the reaction
mixture was added anhydrous MgSO4 (712 mg, 5.92 mmol). After
stirring 15 h, the reaction mixture was diluted with DCM and
quenched with distilled water. The pH of the aqueous layer was
adjusted to pH 7e8 with satd NaHCO3 solution. The organic layer
was dried over anhydrous MgSO4, filtered, and the solvent was
removed under reduced pressure to give the crude product. The
145.4, 128.8, 127.5, 126.9, 120.7, 120.5, 115.1, 114.9, 114.0, 114.0, 112.6,
112.5, 69.0, 62.5, 56.0, 55.8, 25.3. Anal. Calcd for C17H19BrFNO2: C,
55.45; H, 5.20; Br, 21.70; F, 5.16; N, 3.80; O, 8.69. Found: C, 55.32; H,
5.17; N, 3.91.
4.1.11. (R)-3-(3-Bromonaphthalen-2-yloxy)-2-[(R)-1-phenyl-
24
ethylamino]propan-1-ol (6c). Colorless oil, (90%); [
a
]
þ13.5 (c
D
0.15, CH3OH); 1H NMR (300 MHz, CDCl3)
d
8.07 (s, 1H), 7.72e7.69
(m, 2H), 7.49e7.23 (m, 7H), 7.16 (s, 1H), 4.26 (dd, 1H, J¼4.2, 9.3 Hz),
4.13e4.03 (m, 2H), 3.66e3.53 (m, 2H), 3.06 (quintet, 1H, J¼4.8 Hz),
2.21 (s, 2H), 1.43 (d, 3H, J¼6.3 Hz); 13C NMR (125 MHz, CDCl3)
crude product was purified by silica gel flash chromatography using
24
15% EtOAc/hexane to give 5g in 85% yield as a colorless oil; [a]
D
þ10.8 (c 2.213, CHCl3); Rf¼0.39 (30% EtOAc/Hex); 1H NMR
d 152.6, 145.4, 133.6, 132.4, 129.7, 128.8, 127.5, 127.0, 126.9, 126.9,
(500 MHz, CDCl3)
d
7.38e7.32 (m, 4H), 7.29e7.21 (m, 2H),
126.8, 124.9, 113.8, 107.9, 68.3, 62.7, 56.0, 55.8, 25.3. Anal. Calcd for
C21H22BrNO2: C, 63.01; H, 5.54; Br, 19.96; N, 3.50; O, 7.99. Found: C,
63.05; H, 5.59; N, 3.57.
6.96e6.92 (td, 1H, J¼8.5, 3.0 Hz), 6.66e6.64 (dd, 1H, J¼8.5, 4.5 Hz),
4.54 (br, 1H), 3.51e3.46 (m, 1H), 2.93e2.88 (m, 1H), 2.50e2.46 (q,
1H, J¼6.5 Hz),1.91e1.86 (m,1H),1.69e1.68 (d,1H, 3.5 Hz),1.47e1.45
(d, 3H, J¼6.0 Hz), 1.41e1.40 (d, 1H, J¼6.5 Hz); 13C NMR (125 MHz,
4.1.12. (S)-4-(2-Iodophenyl)-2-[(R)-1-phenylethylamino]butan-1-ol
þ4.0 (c 0.40, CH3OH); 1H NMR
24
CDCl3)
d
155.6, 153.7, 144.4, 141.9, 128.6, 127.3, 126.9, 119.7, 119.6,
(6d). Yellow oil, (86%); [
(500 MHz, CDCl3)
a]
D
115.2,114.9,111.8,111.7,109.4,109.3, 69.7, 47.0, 38.8, 32.2, 23.7; Anal.
Calcd for C17H18BrFN2: C, 58.46; H, 5.19; Br, 22.88; F, 5.44; N, 8.02.
Found: C, 58.37; H, 5.09; N, 8.11.
d
7.81 (dd, 1H, J¼7.5, 1.5 Hz), 7.33e7.23 (m, 6H),
7.17 (dd, 1H, J¼7.5, 1.5 Hz), 6.89 (td, 1H, J¼7.5, 1.5 Hz), 3.98 (q, 1H,
J¼6.5 Hz), 3.54 (dd, 1H, J¼10.5, 4.0 Hz), 3.30 (dd, 1H, J¼10.5, 7.5 Hz),
2.75e2.56 (m, 3H), 1.65e1.57 (m, 2H), 1.37 (d, 3H, J¼6.5 Hz); 13C
4.1.8. 2-Bromo-4-methyl-N-{(S)-1-[(S)-1-phenylethylaziridin-2-yl]
NMR (125 MHz, CDCl3) d 144.4, 139.8, 129.5, 128.9, 128.8, 128.7,
24
methyl}aniline (5h). Pale yellow solid, (86%); [
a
]
ꢁ3.1 (c 2.188,
128.1, 127.6, 127.0, 100.6, 64.0, 56.3, 55.7, 37.4, 31.8, 24.7; HRMS m/z
D
CHCl3); Rf¼0.48 (30% EtOAc/Hex); 1H NMR (300 MHz, CDCl3)
calcd for C18H22INO [MþNa]þ 396.0824. Found 396.0822.
d
7.39e7.30 (m, 5H), 7.24e7.22 (d, 1H, J¼7.2 Hz), 7.00e6.97 (d, 1H,
J¼8.4 Hz), 6.64e6.61 (d, 1H, J¼8.1 Hz), 4.56 (br, 1H), 3.52e3.44 (m,
1H), 2.97e2.89 (m, 1H), 2.49e2.42 (q, 1H, J¼6.3 Hz), 2.22 (s, 3H),
1.91e1.84 (m, 1H), 1.68e1.67 (d, 1H, J¼3.6 Hz), 1.47e1.45 (d, 3H,
J¼6.3 Hz), 1.39e1.37 (d, 1H, J¼6.3 Hz); 13C NMR (125 MHz, CDCl3)
4.1.13. (S)-4-(5-Bromobenzo[d][1,3]dioxol-4-yl)-2-[(R)-1-phenyl-
24
ethylamino]butan-1-ol (6e). Colorless oil, (85%); [
a]
þ6.8 (c 0.15,
D
CH3OH); 1H NMR (300 MHz, CDCl3)
d
7.33e7.22 (m, 5H), 7.02 (d, 1H,
J¼8.1 Hz), 6.58 (d, 1H, J¼8.4 Hz), 5.92 (d, 1H, J¼1.5 Hz), 5.81 (d, 1H,
J¼1.2 Hz), 3.95 (q, 1H, J¼6.6 Hz), 3.59 (dd, 1H, J¼11.1, 3.9 Hz), 3.36
(dd, 1H, J¼7.5, 10.5 Hz), 2.76e2.50 (m, 4H), 1.74e1.62 (m, 2H), 1.42
d
144.6,142.9,133.0, 129.1,128.5,127.6,127.2,126.9,111.8,110.1, 69.7,
46.8, 38.9, 32.2, 23.7, 20.2; HRMS m/z calcd for C18H21BrN2
[MþNa]þ 367.0786. Found 367.0783.
(d, 3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3)
d 146.5, 144.5, 128.6,
127.3, 126.8, 125.2, 123.1, 115.6, 107.7, 104.4, 101.4, 63.9, 56.1, 55.5,
29.7, 26.0, 24.5; HRMS m/z calcd for C19H22BrNO3 [MþH]þ
392.0861. Found 392.0863.
4.1.9. (R)-3-(2-Iodophenoxy)-2-[(R)-1-phenylethylamino]propan-1-
ol (6a). To a solution of compound 3a (370 mg, 0.98 mmol) in DCM
(2.00 mL) was added AcOH (280 mL, 4.90 mmol) at room tempera-
ture. The reaction mixture was stirred for overnight at room tem-
perature and then quenched with satd NaHCO3 solution. The
aqueous layer was extracted with DCM. The combined organic layer
was dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. Purification by silica gel flash chromatography provided
157 mg of the ring opening product. To a solution of the ring
opening product in methanol/THF co-solvent (1:1, 2.5 mL) was
added LiOH (159 mg in H2O, 1.25 mL). The reaction mixture was
stirred for 30 min at room temperature and the mixture was
quenched with satd NH4Cl solution, extracted with DCM. The
combined organic layer was dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. Purification by silica gel flash chroma-
tography provided 266 mg of 6a as a colorless oil in 88% yield (two
4.1.14. (S)-4-(1-Bromonaphthalen-2-yl)-2-[(R)-1-phenylethylamino]
butan-1-ol (6f). Colorless oil, (68%); [
NMR (500 MHz, CDCl3)
a
]
24 þ37.3 (c 0.35, CH3OH); 1H
D
d
8.33 (d, 1H, J¼8.5 Hz), 7.82 (d, 1H,
J¼8.0 Hz), 7.74 (d, 1H, J¼8.0 Hz), 7.61 (t, 1H, J¼8.0 Hz), 7.52 (t, 1H,
J¼8.0 Hz), 7.31e7.21 (m, 6H), 3.99 (q, 1H, J¼6.5 Hz), 3.63 (dd, 1H,
J¼4.0, 10.5 Hz), 3.39 (dd, 1H, J¼7.5, 10.5 Hz), 3.04e2.98 (m, 1H),
2.94e2.87 (m, 1H), 2.64e2.61 (m, 1H), 2.25 (br s, 2H), 2.02e1.96 (m,
1H), 1.82e1.75 (m, 1H), 1.40 (d, 3H, J¼6.5 Hz); 13C NMR (125 MHz,
CDCl3)
d 145.1, 139.5, 133.4, 132.8, 128.7, 128.2, 128.1, 128.0, 127.6,
127.4, 127.3, 126.9, 126.1, 123.7, 64.3, 56.1, 55.6, 34.0, 31.9, 25.0;
HRMS m/z calcd for C22H24BrNO [MþNa]þ 420.0939. Found
420.0936.
steps yield): [
a
]
24 þ19.2 (c 0.50, CH3OH); 1H NMR (300 MHz, CDCl3)
4.1.15. (S)-N1-(2-Bromo-4-fluorophenyl)-3-(tert-butyldimethylsilyl-
oxy)-N2-[(R)-1-phenylethyl]propane-1,2-diamine (9g). To a round
bottom flask was added 5g (762 mg, 2.18 mmol) in DCM (7.30 mL).
AcOH (0.75 mL, 13.10 mmol) was added to the solution at room
temperature and the mixture was stirred for 8 h. The reaction was
quenched with satd NaHCO3 solution, extracted with DCM, and
concentrated in vacuo. The crude product was dissolved in EtOH
(6.1 mL) and KOH (309 mg, 5.51 mmol) was added to the reaction
mixture. After stirring for 20 min at room temperature, the solvent
was removed under reduced pressure to give a crude product. The
crude product was diluted with DCM and added distilled water. The
D
d
7.78 (d, 1H, J¼7.2 Hz), 7.36e7.25 (m, 6H), 6.81 (d, 1H, J¼8.1 Hz),
6.74 (t, 1H, J¼7.2 Hz), 4.15e4.10 (m, 1H), 4.03e3.93 (m, 2H),
3.63e3.51 (m, 2H), 3.00e2.95 (m, 1H), 1.42 (d, 3H, J¼6.3 Hz); 13C
NMR (125 MHz, CDCl3)
d 157.1, 145.3, 139.5, 129.8, 128.8, 127.5,
127.0, 123.2, 112.3, 86.8, 68.0, 62.6, 55.8, 55.8, 25.4. Anal. Calcd for
C17H20INO2: C, 51.40; H, 5.07; I, 31.95; N, 3.53; O, 8.06. Found: C,
51.45; H, 5.13; N, 3.47.
4.1.10. (R)-3-(2-Bromo-4-fluorophenoxy)-2-[(R)-1-phenyl-
24
ethylamino]propan-1-ol (6b). Colorless oil, (60%); [
a
]
þ25.7 (c
D

8112
J. Chan Kim et al. / Tetrahedron 66 (2010) 8108e8114
aqueous layer was extracted with DCM, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was dissolved in
DCM (8.0 mL) and added TBSCl (361 mg, 2.39 mmol) at a tempera-
ture of 0 ꢀC. To the reaction mixture were added TEA (0.67 mL,
4.79 mmol) and DMAP (19 mg, 0.160 mmol) and stirred for 1.5 h at
room temperature in nitrogen atmosphere. The reaction was
quenched with distilled water and the aqueous layer was extracted
with DCM. The combined organic layer was dried over anhydrous
MgSO4 and concerted in vacuo. Purification by column chroma-
157.4, 140.3, 139.9, 134.1, 134.1, 128.8, 127.9, 127.1, 117.4, 117.3, 104.3,
104.1, 102.8, 102.6, 62.9, 61.4, 58.6, 52.0, 18.2; HRMS m/z calcd for
C
17H18FNO2 [MþNa]þ 310.1219. Found 310.1217.
4.1.19. {(R)-4-[(R)-1-Phenylethyl]-3,4-dihydro-2H-naphtho[2,3-b]
24
[1,4]oxazin-3-yl}methanol (7c). Yellow oil, (77/71%); [
a
]
D
þ86.9 (c
0.45, CH3OH); 1H NMR (300 MHz, CDCl3)
d
7.54 (t, 2H, J¼7.5 Hz),
7.28e7.10 (m, 9H), 5.26 (q, 1H, J¼6.9 Hz), 4.29 (d, 1H, J¼10.8 Hz),
3.62e3.60 (m, 2H), 3.53e3.49 (m, 1H), 3.34e3.29 (m, 1H), 2.11 (br s,
tography on silica gel using 10% EtOAc/hexane to give 9g in 63%
1H),1.71 (d, 3H, J¼6.9 Hz); 13C NMR (125 MHz, CDCl3)
d 144.5,141.0,
24
yield as a colorless oil; [
a
]
þ23.6 (c 1.147, CHCl3); Rf¼0.52 (20%
134.4, 130.5, 128.7, 127.7, 127.4, 127.1, 126.2, 125.7, 124.2, 122.9, 112.0,
108.9, 63.7, 61.3, 57.6, 51.6, 18.0; HRMS m/z calcd for C21H21NO2
[MþNa]þ 342.1470. Found 342.1471.
D
EtOAc/Hex); 1H NMR (300 MHz, CDCl3)
d 7.29e7.20 (m, 5H),
7.17e7.13 (dd, 1H, J¼8.1, 2.7 Hz), 6.87e6.80 (td, 1H, J¼8.7, 2.7 Hz),
6.45e6.40 (dd, 1H, J¼9.3, 5.4 Hz), 4.90 (br, 1H), 3.84e3.77 (q, 1H,
J¼6.6 Hz), 3.59e3.50 (m, 2H), 3.13e3.06 (m, 1H), 2.94e2.87 (m, 1H),
2.84e2.77 (m, 1H), 1.79 (br, 1H), 1.33e1.31 (d, 3H, J¼6.6 Hz), 0.83 (s,
4.1.20. {(S)-1-[(R)-1-Phenylethyl]-1,2,3,4-tetrahydroquinolin-2-yl}
24
methanol (7d). Yellow oil, (73/83%); [
a]
þ109.6 (c 4.25, CH3OH);
D
9H), ꢁ0.02 (s, 3H), ꢁ0.05 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
155.4,
1H NMR (300 MHz, CDCl3)
d 7.30e7.24 (m, 5H), 7.07 (t, 1H,
153.5, 145.9, 142.6, 128.6, 127.1, 126.6, 119.6, 119.4, 115.1, 114.9, 111.5,
111.5, 109.3, 109.3, 64.3, 55.1, 54.8, 44.5, 26.0, 24.9, 18.4, ꢁ5.3, ꢁ5.3;
HRMS m/z calcd for C23H34BrFN2OSi [MþNa]þ 503.1506. Found
503.1508.
J¼7.8 Hz), 6.98 (d, 1H, J¼7.2 Hz), 6.90 (d, 1H, J¼8.1 Hz), 6.69 (t, 1H,
J¼7.2 Hz), 5.11 (q, 1H, J¼6.6 Hz), 3.53e3.35 (m, 3H), 2.74e2.54 (m,
2H), 2.71e2.68 (m, 4H), 1.20e1.09 (m, 1H); 13C NMR (125 MHz,
CDCl3)
d 144.9, 141.9, 129.9, 128.5, 127.3, 127.1, 127.0, 123.7, 117.6,
116.7, 63.1, 59.5, 53.0, 23.5, 21.1, 18.6; HRMS m/z calcd for C18H21NO
4.1.16. (S)-N1-(2-Bromo-4-methylphenyl)-3-(tert-butyldimethylsilyl-
[MþNa]þ 290.1521. Found 290.1522.
oxy)-N2-[(R)-1-phenylethyl]propane-1,2-diamine (9h). Colorless oil,
24
(68%); [
a]
þ26.6 (c 0.948, CHCl3); Rf¼0.56 (20% EtOAc/Hex); 1H
4.1.21. {(S)-6-[(R)-1-Phenylethyl]-6,7,8,9-tetrahydro-[1,3]-dioxolo
D
NMR (300 MHz, CDCl3)
d
7.39e7.29 (m, 5H), 7.28e7.25 (m, 1H),
[4,5-f]quinolin-7-yl}methanol (7e). Brown oil, (64/90%); [
a
]
24 þ35.0
D
7.01e6.98 (d, 1H, J¼7.2 Hz), 6.54e6.51 (d, 1H, J¼8.4 Hz), 4.96 (br,
1H), 3.94e3.87 (q, 1H, J¼6.6 Hz), 3.69e3.59 (m, 2H), 3.25e3.15 (m,
1H), 3.08e3.00 (m, 1H), 2.93e2.86 (m, 1H), 2.26 (s, 3H), 1.89 (br,
1H), 1.42e1.40 (d, 3H, J¼6.6 Hz), 0.93 (s, 9H), 0.07 (s, 3H), 0.05 (s,
(c 1.30, CH3OH); 1H NMR (300 MHz, CDCl3)
d
7.30e7.18 (m, 5H),
7.64 (d, 1H, J¼8.4 Hz), 6.44 (d, 1H, J¼8.7 Hz), 5.89 (s, 2H), 5.00 (q,
1H, J¼6.9 Hz), 3.50e3.34 (m, 3H), 2.55e2.33 (m, 2H), 1.85e1.82 (m,
1H), 1.65 (d, 3H, J¼6.9 Hz), 1.54e1.48 (m, 1H), 1.01e0.92 (m, 1H);
3H); 13C NMR (125 MHz, CDCl3)
d
146.0, 143.5, 132.9, 129.0, 128.6,
13C NMR (125 MHz, CDCl3)
d 145.5, 141.9, 140.3, 139.2, 128.5, 127.4,
127.1, 127.0, 126.6, 111.7, 110.1, 64.4, 55.1, 54.9, 44.3, 26.1, 25.0, 20.2,
18.4, ꢁ5.3, ꢁ5.3; HRMS m/z calcd for C24H37BrN2OSi [MþNa]þ
499.1757. Found 499.1757.
127.1, 110.0, 108.6, 106.7, 101.0, 62.5, 61.1, 52.3, 19.6, 19.0, 17.1;
HRMS m/z calcd for C19H21NO3 [MþNa]þ 334.1419. Found
334.1420.
4.1.17. {(R)-4-[(R)-1-Phenylethyl]-3,4-dihydro-2H-benzo[b]-[1,4]ox-
4.1.22. {(S)-1-[(R)-1-Phenylethyl]-1,2,3,4-tetrahydrobenzo[h]-quino-
24
azin-3-yl}methanol (7a). To
a
screw-cap vial were added 6a
lin-2-yl}methanol (7f). Green oil, (72/82%); [
a
]
þ58.8 (c 0.30,
D
(347 mg, 0.68 mmol) and NaOtBu (163 mg, 1.69 mmol) in toluene
(6.80 mL). The reaction mixture was degassed for 10 min and
quickly added Pd2(dba)3 (37 mg, 0.041 mmol) and X-Phos (29 mg,
0.061 mmol). The reaction mixture was stirred for 30 min at 110 ꢀC.
The mixture was cooled to room temperature, filtered, and con-
centrated in vacuo. Purification by silica gel flash chromatography
provided 230 mg of cyclized product in 88% yield. To a solution of
the product (230 mg, 0.60 mmol) in THF (3.00 mL) was added
0.63 ml of 1.0 M solution of TBAF at room temperature. The reaction
mixture was stirred for 5 h at room temperature and then
quenched with water. The mixture was extracted with DCM and the
combined organic layer was dried over anhydrous MgSO4, filtered,
CH3OH); 1H NMR (300 MHz, CDCl3)
d
8.14 (d, 1H, J¼8.1 Hz), 7.84 (d,
1H, J¼7.8 Hz), 7.56e7.43 (m, 3H), 7.25e7.18 (m, 3H), 7.06 (d, 1H,
J¼8.4 Hz), 6.87e6.85 (m, 2H), 4.93 (q, 1H, J¼7.2 Hz), 3.57e3.55 (m,
1H), 3.29e3.26 (m, 2H), 2.52e2.40 (m, 2H), 2.33e2.24 (m, 1H), 1.86
(d, 3H, J¼7.2 Hz), 1.28e1.14 (m, 1H), 0.77e0.69 (m, 1H); 13C NMR
(125 MHz, CDCl3)
d 141.3, 140.1, 134.2, 129.6, 129.0, 128.3, 127.9,
127.7, 127.6, 126.6, 125.7, 125.2, 123.2, 122.8, 63.2, 61.9, 51.8, 23.7,
20.3, 18.7; HRMS m/z calcd for C22H23NO [MþNa]þ 340.1677.Found
340.1675.
4.1.23. (S)-2-[(tert-Butyldimethylsilyloxy)methyl]-7-fluoro-1-[(R)-1-
phenylethyl]-1,2,3,4-tetrahydroquinoxaline (10g). To a solution of 9g
(664 mg, 1.38 mmol) in anhydrous toluene (27.6 mL) was added
NaOtBu (332 mg, 3.45 mmol) at room temperature and in nitrogen
atmosphere. The reaction mixture was degassed for 10 min and
were added Pd2(dba)3 (76 mg, 0.08 mmol) and X-Phos (59 mg,
0.12 mmol). The reaction mixture was refluxed and stirred for 3 h in
nitrogen atmosphere. After the reaction was completed, the re-
action mixture was cooled to room temperature, filtered with glass
filter on a pad of Celite. The residue was concentrated in vacuo to
give a crude product. Purification by column chromatography on
silica gel using 5% EtOAc/hexane to give of 10g in 56% yield as a dark
and concentrated in vacuo. Purification by silica gel flash chroma-
24
tography provided 159 mg of 7a as a colorless oil in 99% yield: [a]
D
þ66.1 (c 0.50, CH3OH); 1H NMR (300 MHz, CDCl3)
d 7.30e7.22 (m,
5H), 7.00 (d, 1H, J¼7.5 Hz), 6.88 (t, 1H, J¼7.5 Hz), 6.80 (d, 1H,
J¼7.5 Hz), 6.69 (t, 1H, J¼7.5 Hz), 5.12 (q, 1H, J¼6.6 Hz), 4.05 (d, 1H,
J¼10.5 Hz), 3.52 (d, 2H, J¼7.2 Hz), 3.33e3.30 (m, 1H), 3.05 (d, 1H,
J¼10.5 Hz), 1.89 (br s, 1H), 1.69 (d, 3H, J¼6.6 Hz); 13C NMR
(125 MHz, CDCl3) d 144.0,140.5,133.1,128.6,127.7,127.1,121.9,118.7,
117.1, 117.0, 62.6, 61.1, 58.9, 52.0, 18.4; HRMS m/z calcd for
C17H19NO2 [MþNa]þ 292.1314. Found 292.1311.
brown oil; [
a
]
24 ꢁ4.9 (c 0.500, CHCl3); Rf¼0.46 (10% EtOAc/Hex); 1H
D
4.1.18. {(R)-6-Fluoro-4-[(R)-1-phenylethyl]-3,4-dihydro-2H-benzo[b]
NMR (300 MHz, CDCl3) d 7.33e7.21 (m, 5H), 6.48e6.40 (m, 2H),
24
[1,4]oxazin-3-yl}methanol (7b). Yellow oil, (60/80%); [
a]
þ5.5 (c
6.28e6.22 (td, 1H, J¼8.4, 2.4 Hz), 5.02e4.95 (q, 1H, J¼6.9 Hz),
3.61e3.55 (t, 1H, J¼9.6 Hz), 3.49e3.44 (m, 2H), 3.31e3.23 (m, 2H),
2.56e2.51 (dd, 1H, J¼11.1, 3.3 Hz), 1.68e1.65 (d, 3H, J¼7.2 Hz), 0.86
D
0.85, CH3OH); 1H NMR (300 MHz, CDCl3)
d
7.30e7.25 (m, 5H),
6.74e6.63 (m, 2H), 6.36 (m, 1H), 5.05 (q, 1H, J¼7.5 Hz), 4.12 (d, 1H,
J¼6.6 Hz), 3.57e3.54 (m, 2H), 3.35e3.29 (m, 1H), 3.12 (d, 1H,
(s, 9H), 0.02 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 158.2, 156.3, 141.4,
J¼6.0 Hz), 1.69 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3)
d
159.2,
134.6, 134.5, 429.5, 128.6, 127.4, 127.1, 114.7, 114.6, 102.9, 102.7, 101.3,

J. Chan Kim et al. / Tetrahedron 66 (2010) 8108e8114
8113
101.0, 62.7, 57.9, 52.9, 39.1, 26.1,18.2, ꢁ5.2, ꢁ5.2; HRMS m/z calcd for
(300 MHz, CDCl3)
d
7.77e7.72 (m, 2H), 7.43e7.38 (m, 2H), 7.24e7.10
C23H33FN2OSi [MþNa]þ 423.2244. Found 423.2248.
(m, 2H), 3.84 (dd, 1H, J¼3.6, 10.2 Hz), 3.70e3.64 (m, 1H), 3.59e3.48
(m, 1H), 3.06e2.81 (m, 2H), 2.00e1.94 (m, 1H), 1.87e1.75 (m, 1H);
4.1.24. (S)-2-[(tert-Butyldimethylsilyloxy)methyl]-7-methyl-1-[(R)-
13C NMR (125 MHz, CDCl3)
d 138.4, 133.2, 128.7, 128.3, 125.2, 125.0,
1-phenylethyl]-1,2,3,4-tetrahydroquinoxaline
(10h). Brown
oil,
123.4, 119.7, 117.6, 115.9, 66.8,53.3, 26.5, 24.4; HRMS m/z calcd for
(72%); [
a
]
24 ꢁ42.8 (c 1.160, CHCl3); Rf¼0.58 (10% EtOAc/Hex); 1H NMR
C14H15NO [MþNa]þ 236.1051. Found 236.1052.
D
(300 MHz, CDCl3) d 7.34e7.26 (m, 5H), 6.68 (s, 1H), 6.52e6.49 (d, 1H,
J¼7.8 Hz), 6.46e6.44 (d, 1H, J¼7.5 Hz), 5.20e5.13 (q, 1H, J¼6.9 Hz),
3.66e3.59 (t, 1H, J¼9.9 Hz), 3.54 (br, 1H), 3.52e3.47 (dd, 1H, J¼9.6,
4.8 Hz), 3.31e3.21 (m, 2H), 2.54e2.49 (dd,1H, J¼10.5, 2.7 Hz), 2.28 (s,
3H), 1.73e1.71 (d, 3H, J¼6.9 Hz), 0.91 (s, 9H), 0.06 (s, 6H); 13C NMR
4.1.31. (S)-(7-Fluoro-1,2,3,4-tetrahydroquinoxalin-2-yl)methanol
(11g). To a solution of 10g (239 mg, 0.50 mmol) in anhydrous THF
(2.5 mL) was added 0.52 ml of 1.0 M solution of TBAF at room
temperature in nitrogen atmosphere. The reaction mixture was
stirred for 2 h and then diluted with EtOAc. The reaction was
quenched with distilled water and the aqueous layer was extracted
with DCM, dried over MgSO4, and filtered. The solvent was re-
moved under reduced pressure to give a crude product. The crude
product was purified by column chromatography on silica gel using
40% EtOAc/hexane. A mixture of the desilylated product and Pd
(OH)2 (80 mg) in MeOH (2.5 mL) was stirred at room temperature
under H2 atmosphere for 2 h. After the reaction was completed the
reaction mixture was filtered to remove Pd(OH)2, concentrated in
vacuo. Purification by column chromatography to give of 11g as
(125 MHz, CDCl3) d 133.5, 131.2, 128.4, 128.1, 127.3, 127.2, 117.9, 115.0,
114.8, 62.8, 57.6, 52.5, 38.7, 26.1, 21.3,18.3, ꢁ5.1, ꢁ5.2; HRMS m/z calcd
for C24H36N2OSi [MþNa]þ 419.2495. Found 419.2496.
4.1.25. (R)-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanol
(8a). To a solution of 7a (53 mg, 0.20 mmol) in methanol (0.70 mL)
was added Pd(OH)2 (30 wt %) at room temperature under 100 psi of
H2 (g). The reaction mixture was filtered and the filtrate was con-
centrated in vacuo. Purification by silica gel flash column chroma-
24
tography provided 30 mg of 8a as a white solid in 92% yield: [a]
D
þ9.4 (c 0.30, CH3OH); 1H NMR (300 MHz, CDCl3)
d
6.81e6.62 (m,
a brown oil in 79% yield; [
a
]
24 þ20.5 (c 0.705, CHCl3); Rf¼0.37 (100%
D
5H), 4.19 (dd, 1H, J¼2.7, 10.8 Hz), 4.06 (dd, 1H, J¼5.7, 10.8 Hz), 3.72
EtOAc); 1H NMR (300 MHz, CDCl3)
d
6.45e6.40 (m, 1H), 6.31e6.25
(dd, 1H, J¼5.1, 10.2 Hz), 3.63 (dd, 1H, J¼6.9, 10.2 Hz), 3.57e3.50 (m,
(m, 2H), 3.74e3.69 (dd, 1H, J¼10.5, 4.5 Hz), 3.64e3.57 (m, 1H),
1H); 13C NMR (125 MHz, CDCl3)
d 144.0, 132.8, 121.8, 119.2, 116.9,
3.56e3.51 (m, 1H), 3.31e3.26 (dd, 1H, J¼11.1, 3.0 Hz), 3.20e3.14 (dd,
116.1, 66.0, 62.9, 51.3; HRMS m/z calcd for C9H11NO2 [MþNa]þ
1H, J¼10.8, 5.4 Hz); 13C NMR (125 MHz, CDCl3)
d 158.3, 156.4, 134.4,
188.0688. Found 188.0689.
134.3, 128.9, 128.9, 115.3, 115.2, 104.2, 104.1, 101.7, 101.4, 65.1, 51.7,
42.9; HRMS calcd for C9H11FN2O [MþNa]þ 205.0753. Found
205.0753.
4.1.26. (R)-(6-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)
methanol (8b). Red solid, (90%); [
(500 MHz, CDCl3)
a
]
24 þ7.1 (c 0.40, CH3OH); 1H NMR
D
d
6.72e6.67 (m, 1H), 6.36e6.30 (m, 2H), 4.14 (dd,
4.1.32. (S)-(7-Methyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methanol
24
1H, J¼3.0, 10.8 Hz), 4.03 (dd, 1H, J¼5.1, 10.8 Hz), 3.73 (dd, 1H, J¼5.1,
(11h). Dark brown oil, (52%); [
a
]
þ40.2 (c 1.800, CHCl3); Rf¼0.33
D
10.8 Hz), 3.66e3.60 (m, 1H), 3.58e3.51 (m, 1H), 2.98 (br s, 2H); 13C
(100% EtOAc); 1H NMR (300 MHz, CDCl3)
d 6.45e6.40 (m, 2H), 6.38 (s,
NMR (125 MHz, CDCl3)
d
159.0, 157.1, 139.8, 139.7, 133.7, 133.6, 117.2,
1H), 3.72e3.69 (dd, 1H, J¼10.5, 5.0 Hz), 3.64e3.60 (dd, 1H, J¼11.0,
117.2, 104.8, 104.7, 102.4, 102.2, 65.7, 62.9, 51.1; HRMS m/z calcd for
7.0 Hz), 3.54 (br, 1H), 3.29 (br, 1H), 3.21 (br, 3H), 2.18 (s, 3H); 13C NMR
C9H10FNO2 [MþNa]þ 206.0593. Found 206.0597.
(125 MHz, CDCl3) d133.1,130.7,129.1,119.3,115.8,115.1, 65.0, 51.9, 43.1,
20.8; HRMS calcd for C10H14N2O [MþNa]þ 201.1004. Found 201.1003.
4.1.27. (R)-(3,4-Dihydro-2H-naphtho[2,3-b][1,4]oxazin-3-yl)metha-
24
nol (8c). Yellow solid, (97%); [
(300 MHz, CD3OD)
a]
þ9.5 (c 0.35, CH3OH); 1H NMR
D
Acknowledgements
d
7.50e7.44 (m, 2H), 7.17e7.06 (m,3H), 6.90 (s,
1H), 4.26 (dd, 1H, J¼3.0, 10.8 Hz), 4.10 (dd, 1H, J¼5.7, 10.8 Hz),
The authors are grateful for the financial support from (NRF-
2010-0005538 and NRF-2009-0081956) for W.K.L. and KOSEF (R01-
2007-000-20037-0) for H.J.H.
3.62e3.60 (m, 2H), 3.55e3.47 (m, 1H); 13C NMR (125 MHz, CD3OD)
d
146.2,136.1,132.0,129.4,127.3,126.1,124.7,123.1,112.2,109.5, 67.4,
63.1, 52.4; HRMS m/z calcd for C13H13NO2 [MþNa]þ 238.0844.
Found 238.0844.
References and notes
4.1. 28. (S)-(1, 2, 3, 4-Tetrahydroquinolin-2-yl)methanol
24
(8d)10,20. Yellow oil, (90%); [
a]
þ54.0 (c 0.85, CH3OH); 1H NMR
1. Stack, G.P.; Hatzenbuhler, N.T.; Zhou, D.; (Wyeth, USA). Application: WO 2008/
052075 A2.
2. Shoemaker, J. L.; Seely, K. A.; Reed, R. L.; Crow, J. P.; Prather, P. L. J. Neurochem.
D
(300 MHz, CDCl3)
d
7.00e6.95 (m, 2H), 6.63 (t, 1H, J¼6.9 Hz), 6.53
(d, 1H, J¼7.8 Hz), 3.73 (dd, 1H, J¼3.6, 10.2 Hz), 3.57e3.51 (m, 1H),
3.48e3.40 (m, 1H), 2.89e2.70 (m, 2H), 1.92e1.87 (m, 1H), 1.76e1.63
2007, 101, 87.
3. Scutt, A.; Williamson, E. M. Calcif. Tissue Int. 2007, 80, 50.
4. Zhao, J.; He, Q.; Cheng, Y.; Zhao, B.; Zhang, Y.; Zhang, S.; Miao, J. Toxicol. in Vitro
2009, 23, 1039.
(m,1H); 13C NMR (125 MHz, CDCl3)
d 144.3,129.4, 127.0,121.6,117.6,
114.7, 66.9, 52.9, 26.0, 24.5; HRMS m/z calcd for C10H13NO [MþNa]þ
5. (a) Liu, X.; Zhao, J.; Xu, J.; Zhao, B.; Zhang, Y.; Zhang, S.; Miao, J. Bioorg. Med.
Chem. Lett. 2009, 19, 2896; (b) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009,
11, 1923; (c) Bourlot, A.-S.; Sanchez, I.; Dureng, G.; Guillaumet, G.; Massingham,
R.; Monteil, A.; Winslow, E.; Pujol, M. D.; Merour, J.-Y. J. Med. Chem. 1998, 41,
3142; (d) Largeron, M.; Dupuy, H.; Fleury, M.-B. Tetrahedron 1995, 51, 4953; (e)
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Haycock, D. A.; Baizman, E. R.; Casiano, F. M. J. Med. Chem. 1992, 35, 124; (f)
Combs, D. W.; Rampulla, M. S.; Bell, S. C.; Klaubert, D. H.; Tobia, A. J.; Falotico, R.;
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Varady, J.; Yang, C.-Y.; Lu, Y.; Deschamps, J. R.; Levant, B.; Wang, S. J. Med. Chem.
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T. A.; Al-awar, R. S.; Brooks, H. B.; Watkins, S. A.; Spencer, C. D.; Schultz, R. M.;
Dempsey, J. A.; Considine, E. L.; Patel, B. R.; Ogg, C. A.; Vasudevan, V.; Lytle, M. L.
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186.0895. Found 186.0896.
4.1.29. (S)-(6,7,8,9-Tetrahydro-[1,3]dioxolo[4,5-f]quinolin-7-yl)meth-
24
anol (8e). Brown oil, (97%); [
a
]
þ71.2 (c 1.10, CH3OH); 1H NMR
D
(300 MHz, CDCl3)
d
6.51 (d, 1H, J¼8.1 Hz), 6.03 (d, 1H, J¼8.1 Hz), 5.85
(d, 2H, J¼3.9 Hz), 3.74 (dd, 1H, J¼3.9, 10.5 Hz), 3.55 (dd, 1H, J¼7.8,
10.5 Hz), 3.35 (br s, 1H), 2.86 (br s, 1H), 2.80e2.58 (m, 3H), 1.93e1.86
(m, 1H), 1.73e1.59 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 145.6, 140.0,
139.2, 106.7, 106.1, 106.0,100.8, 66.7, 53.0, 23.9, 20.0; HRMS m/z calcd
for C11H13NO3 [MþNa]þ 230.0793. Found 230.0795.
4.1.30. (S)-(1,2,3,4-Tetrahydrobenzo[h]quinolin-2-yl)methanol
24
(8f). Green oil, (98%); [
a
]
þ104.0 (c 1.00, CH3OH); 1H NMR
D

8114
J. Chan Kim et al. / Tetrahedron 66 (2010) 8108e8114
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