Asymmetric syntheses of 3,4-substituted tetrahydroquinoline derivatives by (-)-sparteine-mediated dynamic thermodynamic resolution of 2-(α- lithiobenzyl)-N-pivaloylaniline

Article abstract of DOI:10.1055/s-2006-950299

(-)-Sparteine-mediated dynamic thermodynamic resolution of 2-(α-lithiobenzyl)-N-pivaloylaniline was investigated. A temperature- and concentration-controlled epimerization-substitution sequence provides a simple protocol for the preparation of a highly en

Full text of DOI:10.1055/s-2006-950299

PAPER
3805
Asymmetric Syntheses of 3,4-Substituted Tetrahydroquinoline Derivatives
by (–)-Sparteine-Mediated Dynamic Thermodynamic Resolution of
2-(a-Lithiobenzyl)-N-pivaloylaniline
A
symmetric Synth
o
eses of Tetra
n
hydroquinol
g
ines tae Kim,a Eun-kyoung Shin,a Peter Beak,b Yong Sun Park*a
a
Department of Chemistry and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea
Fax +82(2)34365382; E-mail: parkyong@konkuk.ac.kr
b
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Received 19 May 2006; revised 4 July 2006
R
R
Abstract: (–)-Sparteine-mediated dynamic thermodynamic resolu-
tion of 2-(a-lithiobenzyl)-N-pivaloylaniline was investigated. A
temperature- and concentration-controlled epimerization–substitu-
tion sequence provides a simple protocol for the preparation of a
highly enantioenriched benzyl-substituted N-pivaloylaniline prod-
uct (up to 98:2 er). Also, application of this simple methodology to
asymmetric syntheses of 1,3,4- and 3,4-substituted tetrahydroquin-
oline derivatives is demonstrated.
n-BuLi
Li
NLiPv
NHPv
2
1
L* = (–)-sparteine (3)
R
Li/L*
Key words: asymmetric synthesis, enantiomeric resolution, alkyla-
tions, quinolines, stereoselective synthesis
NLiPv
(R)-2·3
DTR
Dynamic thermodynamic resolution (DTR) has been rec-
ognized recently as an effective synthetic method for ob-
taining highly enantioenriched products from racemic
substrates.1 The difference in the thermodynamic stabili-
ties of two diastereomeric species under the influence of a
chiral reagent is the primary source of asymmetric induc-
tion. Previous reports have demonstrated that manage-
R
R
E
E
Li/L*
NHPv
NLiPv
(S)-2·3
(R)-4
ment of experimental conditions can control the Scheme 1 (–)-Sparteine-mediated dynamic thermodynamic resolu-
tion and electrophilic substitution of dilithioaniline 2
diastereomeric equilibrations and provide significantly
improved stereoselectivities.2
of 5 to provide 6 in the presence of (–)-sparteine (3) are
summarized in Table 1. As previously reported, the enan-
tiomeric ratio (er) for the sequence is a function of temper-
ature, as shown in entries 1–3. The enantiomeric ratio of
37:63 (R:S) obtained at –78 °C (Table 1, entry 1) was im-
proved and inverted to 94:6 (R:S) when the lithiation of 5
in the presence of (–)-sparteine was carried out at –15 °C
(entry 2) or at 0 °C (entry 3) for 1 h prior to cooling to
–78 °C and addition of tert-butyl bromoacetate.4 In addi-
tion, the reactions carried out at –15 °C and 0 °C provided
6 in better yields and comparable enantioselectivities
(Table 1, entries 4 and 5).
For example, lateral lithiation reactions of 2-alkyl-N-piv-
aloylanilines 1 mediated by (–)-sparteine (3) can provide
highly enantioenriched products 4 if diastereomeric orga-
nolithium intermediates (R)-2·3 and (S)-2·3 are allowed to
reach thermodynamic equilibrium prior to electrophilic
substitution (Scheme 1).3 The successful application of
DTR of dilithioaniline 2 in electrophilic substitution
prompted us to apply this methodology to asymmetric
syntheses of various ortho-substituted aniline derivatives.
Herein we wish to report (–)-sparteine-mediated DTR of
dilithioaniline 2, in which an additional crystallization-in-
duced dynamic resolution (CIDR) participates in reinforc-
ing the asymmetric induction, as well as the application of
this to asymmetric syntheses of tetrahydroquinoline de-
rivatives.
In this work, we used a modified procedure in which lithi-
ation of 5 was carried out in the presence of (–)-sparteine.
The new procedure is operationally much simpler than the
previously reported stepwise lithiation and addition of
(–)-sparteine shown in Scheme 1. If the diastereomeric in-
termediates equilibrate rapidly under the reaction condi-
tions, the stereochemical outcome should be independent
of the method of diastereomeric complex formation. The
results shown in entry 6 (Table 1) verify the reliability of
the modified procedure.5
For asymmetric syntheses of tetrahydroquinoline deriva-
tives, tert-butyl bromoacetate was used as an electrophile
in the substitution of 2-benzyl-N-pivaloylaniline (5). The
experimental observations for the lithiation–substitution
SYNTHESIS 2006, No. 22, pp 3805–3808
x
x
.x
x
.
2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950299; Art ID: F07906SS
© Georg Thieme Verlag Stuttgart · New York

3806
Y. Kim et al.
PAPER
Table 1 Effects of Temperature and Concentration on the Lithiation
and Substitution of Aniline Derivative 5
ylation sequence at 0 °C, in which the reaction mixture
was allowed to warm to room temperature before quench-
ing. Subsequent reduction with the borane–tetrahydrofu-
ran complex completed the synthetic sequence to provide
the 1,3,4-substituted tetrahydroquinoline trans-11.7 How-
ever, if the alkylation reaction mixture was quenched at
0 °C, 3,4-substituted product 9 was obtained as the major
product instead. No epimerization at the 4-position during
the alkylation sequence was confirmed by chiral-station-
ary-phase high-performance liquid chromatography
(CSP-HPLC) analyses of 11 and 12. In addition, the lithi-
ation–benzylation of 7 at 0 °C and subsequent reduction
provided 3,4-substituted tetrahydroquinoline 13 in high
diastereoselectivity (99:1 dr). The relative configuration
of 13 was provisionally assigned by analogy to the forma-
tion of trans-11.
Ph
O
Ph
O
Br
Ot-Bu
n-BuLi
Ot-Bu
3
NHPv
NHPv
6
5
Entrya Concentration Temp
Yieldb
erc
of 5 (M)
(°C)
(%)
(R:S)
Step 1 Step 2
1
2
3
4
5
6d
7
8
0.05
0.05
0.05
0.05
0.05
0.05
0.20
0.20
–78
–15
0
–78
–78
–78
–15
0
42
87
81
93
95
87
85
81
37:63
94:6
94:6
94:6
93:7
94:6
98:2
93:7
–15
0
In summary, we have shown that dynamic thermodynam-
ic resolution of dilithioaniline can be successfully applied
to the preparation of highly enantioenriched tetrahydro-
quinoline derivatives. Significantly improved enantiose-
lectivity is obtained with concentration-controlled
thermodynamic resolution coupled with selective crystal-
lization. The methodology of the present work could also
be applicable to stereoselective syntheses and mechanistic
analyses of a number of related systems.
–15
–15
0
–15
–15
0
a All reactions were carried out in MTBE.
b Isolated yields.
c The er values were determined by CSP-HPLC.
d Lithiation of 5 was carried out for 1 h at –15 °C prior to the addition
of (–)-sparteine.
Ph
Ph
O
HCl
Ot-Bu
1,4-dioxane
In an effort to improve the enantioselectivity, we carried
out a series of reactions under selected experimental con-
ditions. Interestingly, we found that the enantioselectivity
was significantly improved at higher reactant concentra-
tion (0.20 M solution of 5 in MTBE). Addition of n-butyl-
lithium to a solution of 2-benzylaniline 5 and (–)-sparteine
(3) in methyl tert-butyl ether at –15 °C resulted in a pre-
cipitate being deposited. Subsequent stirring of the result-
ing suspension for one hour at –15 °C, followed by
alkylation with tert-butyl bromoacetate provided the
enantioenriched product 6 in 85% yield with 98:2 er
(Table 1, entry 7). This indicates that selective crystalliza-
tion in the resolution step can provide an additional oppor-
tunity to improve the asymmetric induction. The
diastereomeric intermediates have different solubilities in
methyl tert-butyl ether and the formation of solids results
in the conversion of the more soluble diastereomer into
the less soluble diastereomer.6 In the reaction at 0 °C,
however, precipitation does not occur and no improve-
ment of enantioselectivity was obtained (Table 1, entry 8).
This demonstrates the dual mechanisms of resolution by
selective formation of soluble and insoluble diastereo-
mers.
N
H
O
NHPv
6
98:2 er
7, 68%
n-BuLi, MeI
n-BuLi, E
0 °C
0 °C to r.t.
Ph
Ph
E
Me
N
H
O
N
O
Me
9 (E = Me), 77%, 96:4 dr
10 (E = Bn), 89%, 99:1 dr
8, 85%, 96:4 dr
BH3⋅THF
BH3⋅THF
Ph
E
Ph
Me
N
H
N
Me
12 (E = Me), 71%, 96:4 dr
98:2 er
13 (E = Bn), 66%, 99:1 dr
11, 70%, 96:4 dr
98:2 er
Scheme 2 Asymmetric syntheses of tetrahydroquinoline deriva-
tives
Highly enantioenriched product 6 (98:2 er), obtained by
the developed DTR method, was used for the preparation
of highly enantioenriched 3,4- and 1,3,4-substituted tet-
rahydroquinoline derivatives 11–13 (Scheme 2). Hydrol-
ysis of 6 provided cyclized product 7 in 68% yield.
Further conversion of 7 into 1,3,4-substituted 8 was ac-
complished by a highly stereoselective lithiation–meth-
Commercially available (–)-sparteine was distilled from CaH2 un-
der nitrogen. All other commercial reagents were used without fur-
ther purification. Analytical chiral-stationary-phase HPLC was
performed on a pump system coupled to an absorbance detector
(215 nm). A ChiralPak AD-H column (25 cm × 4.6 mm i.d.) with
Synthesis 2006, No. 22, 3805–3808 © Thieme Stuttgart · New York

PAPER
Asymmetric Syntheses of Tetrahydroquinolines
3807
isopropanol/hexane as mobile phase was used to determine enanti-
omeric ratios. 1H NMR and 13C NMR spectra were acquired on ei-
1H NMR (500 MHz, CDCl3): major diastereomer: d = 7.35–6.84 (m,
9 H), 3.87 (d, J = 8.5 Hz, 1 H), 3.41 (s, 3 H), 2.94 (m, 1 H), 1.16 (d,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): major diastereomer: d = 172.7, 141.5,
140.3, 129.2, 129.1, 128.9, 128.7, 128.2, 127.5, 123.3, 114.9, 49.4,
42.5, 30.3, 15.9.
1
ther U400 (400 MHz H, 100.6 MHz 13C) or U500 (500 MHz 1H,
125.7 MHz 13C) spectrometers. Mass spectrometric data were ac-
quired at University of Illinois Mass Spectrometry Laboratory by
electrospray ionization (ESI) technique.
ESI-HRMS: m/z [M + H]+ calcd for C17H18NO: 252.1388; found:
252.1379.
tert-Butyl 3-{2-[(2,2-Dimethylpropanoyl)amino]phenyl}-3-phe-
nylpropanoate (6)
To a 0.20 M soln of aniline derivative 5 (266 mg, 1.0 mmol) and
(–)-sparteine (3; 702 mg, 3.0 equiv) in MTBE (5 mL) at –15 °C was
added 1.6 M n-BuLi in hexane (1.4 mL, 2.2 equiv). After the mix-
ture had stirred at –15 °C for 1 h, tert-butyl bromoacetate (488 mg,
2.5 equiv) was added. The mixture was stirred for 10 min at –15 °C
and then quenched with excess MeOH. The resulting mixture was
extracted with EtOAc (3 × 5 mL) and the combined extracts were
washed with sat. NH4Cl (5 mL), dried (MgSO4), and concentrated
in vacuo. Chromatographic separation (silica gel, hexane–EtOAc,
5:1) afforded 6 as a colorless oil.
3-Methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (9)
To a soln of 7 (110 mg, 0.49 mmol) in THF (5 mL) was added 1.6
M n-BuLi in hexanes (2.2 equiv) at 0 °C. The brown soln was
stirred at 0 °C for 0.5 h. After MeI (2.0 equiv) had been added at
0 °C, the reaction was quenched in less than 1 min with excess
MeOH. The resulting mixture was dissolved in EtOAc (5 mL),
washed with sat. NH4Cl (5 mL), dried (MgSO4), and concentrated
in vacuo. Chromatographic separation (silica gel, hexane–EtOAc,
4:1) afforded 9 as a mixture of two diastereomers.
20
Yield: 354 mg (93%); [a]D20 +49.4 (c 0.36, CHCl3).
Colorless oil; yield: 90 mg (77%); 96:4 dr; [a]D –85.7 (c 0.10,
CHCl3).
CSP-HPLC: 98:2 er (R:S), tR (R) = 10.0 min, tR (S) = 13.9 min
(Chiralpak AD-H column; i-PrOH–hexane, 10:90; 0.5 mL/min).
IR (neat): 3222, 3069, 2976, 2928, 1681, 1594, 1488, 1376 cm–1.
1H NMR (500 MHz, CDCl3): major diastereomer: d = 8.75 (s, 1 H),
7.35–6.80 (m, 9 H), 3.92 (d, J = 9.0 Hz, 1 H), 2.91 (m, 1 H), 1.20
(d, J = 4.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): major diastereomer: d = 174.3, 141.8,
137.1, 129.4, 129.3, 128.8, 128.3, 127.6, 126.8, 123.6, 115.7, 50.0,
42.3, 15.5.
IR (neat): 3338, 2975, 1732, 1683, 1507, 1449, 1367, 1149 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.03 (s, 1 H), 7.72 (d, J = 8.0 Hz,
1 H), 7.29–7.08 (m, 8 H), 4.66 (dd, J = 6.0, 9.5 Hz, 1 H), 3.01 (m, 2
H), 1.32 (s, 9 H), 1.29 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 177.4, 172.5, 143.1, 136.2, 135.8,
129.2, 128.3, 128.1, 127.4, 127.3, 125.9, 125.8, 81.6, 42.1, 41.1,
39.9, 28.3, 28.0.
ESI-HRMS: m/z [M + H]+ calcd for C16H16NO: 238.1232; found:
238.1225.
ESI-HRMS: m/z [M + H]+ calcd for C24H32NO3: 382.2382; found:
382.2382.
3-Benzyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (10)
To a soln of 7 (120 mg, 0.54 mmol) in THF (3 mL) was added 1.6
M n-BuLi in hexanes (2.2 equiv) at 0 °C. The brown soln was
stirred at 0 °C for 0.5 h. After BnBr (2.0 equiv) had been added at
0 °C, the reaction was quenched in less than 1 min with excess
MeOH. The resulting mixture was dissolved in EtOAc (5 mL),
washed with sat. NH4Cl (5 mL), dried (MgSO4), and concentrated
in vacuo. Chromatographic separation (silica gel, hexane–EtOAc,
4:1) afforded 10 as a mixture of two diastereomers.
4-Phenyl-3,4-dihydroquinolin-2(1H)-one (7)
To a soln of 6 (303 mg, 0.79 mmol) in 1,4-dioxane (3 mL) was add-
ed H2O (3 mL) and concd HCl (3 mL). The soln was refluxed for 36
h. Upon cooling of the soln to r.t., the solvent was removed in vac-
uo. Chromatographic separation (silica gel, hexane–EtOAc, 5:1) af-
forded 7 as a white solid.
20
Yield: 120 mg (68%); mp 168–169 °C; [a]D –53.4 (c 0.12,
CHCl3).
IR (KBr): 3211, 3065, 2908, 1681, 1592, 1487, 1374 cm–1.
20
Colorless oil; yield: 150 mg (89%); 99:1 dr; [a]D –67.5 (c 0.27,
CHCl3).
1H NMR (500 MHz, CDCl3): d = 9.57 (s, 1 H), 7.36–6.91 (m, 9 H),
4.66 (t, J = 7.5 Hz, 1 H), 2.95 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 171.5, 141.9, 137.5, 129.3, 128.8,
128.4, 128.2, 127.6, 127.1, 123.8, 116.2, 42.4, 38.8.
IR (neat): 3206, 3057, 2928, 1671, 1594, 1489, 1378 cm–1.
1H NMR (400 MHz, CDCl3): major diastereomer: d = 10.00 (s, 1
H), 7.41–6.94 (m, 14 H), 3.92 (d, J = 2.8 Hz, 1 H), 3.22 (m, 2 H),
2.77 (m, 1 H).
ESI-HRMS: m/z [M + H]+ calcd for C15H14NO: 224.1075; found:
224.1072.
13C NMR (100 MHz, CDCl3): major diastereomer: d = 172.7, 142.6,
138.7, 136.9, 130.4, 129.6, 129.1, 129.0, 128.6, 127.8, 127.3, 127.1,
124.7, 124.2, 115.8, 50.7, 45.4, 36.6.
1,3-Dimethyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (8)
To a soln of 7 (80 mg, 0.36 mmol) in THF (4 mL) was added 1.6 M
n-BuLi in hexanes (2.2 equiv) at 0 °C. The brown soln was stirred
at 0 °C for 0.5 h. After MeI (3.0 equiv) had been added at 0 °C, the
soln was stirred at r.t. for 30 min. The reaction was quenched with
excess MeOH and dissolved in EtOAc (5 mL). The resulting mix-
ture was washed with sat. NH4Cl (5 mL), dried (MgSO4), and con-
centrated in vacuo. Chromatographic separation (silica gel, hexane–
EtOAc, 4:1) afforded 8 as a mixture of two diastereomers.
ESI-HRMS: m/z [M + H]+ calcd for C22H20NO: 314.1545; found:
314.1551.
1,3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline (11)
To a soln of 8 (58 mg, 0.23 mmol) in THF (3 mL) was added 1.0 M
BH3·THF (5.0 equiv), and the mixture was refluxed for 12 h. The
reaction was quenched by addition of MeOH (0.5 mL) under ice-
water cooling, and the solvents were evaporated. A 5% aq soln of
HCl (2 mL) was added to the residue, and the mixture was refluxed
for 1 h. The mixture was made basic with K2CO3, saturated with
NaCl, and extracted with CHCl3 (3 × 5 mL). The combined organic
extracts were dried (MgSO4), filtered, and concentrated in vacuo.
Chromatographic separation (silica gel, hexane–EtOAc, 4:1) af-
forded 11 as a mixture of two diastereomers.
20
Colorless oil; yield: 78 mg (85%); 96:4 dr; [a]D –63.1 (c 0.15,
CHCl3).
IR (neat): 3029, 2971, 2931, 1672, 1599, 1456, 1361 cm–1.
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3808
Y. Kim et al.
PAPER
20
Colorless oil; yield: 38 mg (70%); 96:4 dr; [a]D –55.3 (c 0.10,
1H NMR (400 MHz, CDCl3): major diastereomer: d = 7.35–6.61 (m,
14 H), 3.97 (br, 1 H), 3.92 (d, J = 8.4 Hz, 1 H), 3.21 (dd, J = 3.6,
12.0 Hz, 1 H), 2.97 (dd, J = 6.0, 11.6 Hz, 1 H), 2.82 (dd, J = 5.6,
13.6 Hz, 1 H), 2.55 (dd, J = 9.2, 13.6 Hz, 1 H), 2.33 (m, 1 H).
13C NMR (100 MHz, CDCl3): major diastereomer: d = 147.0, 145.0,
141.0, 131.8, 129.6, 129.4, 128.8, 128.7, 127.7, 126.6, 126.5, 122.6,
117.7, 114.4, 48.8, 42.7, 42.2, 39.1.
CHCl3).
CSP-HPLC: 98:2 er (3S,4R:3R,4S), tR (3R,4S) = 8.5 min, tR
(3S,4R) = 8.9 min (Chiralpak AD-H column; i-PrOH–hexane, 2:98;
0.5 mL/min).
IR (neat): 3024, 2924, 2815, 1599, 1506, 1456, 1339 cm–1.
1H NMR (400 MHz, DMSO-d6): major diastereomer: d = 7.30–6.41
(m, 9 H) 3.62 (d, J = 8.4 Hz, 1 H), 3.15 (dd, J = 3.6, 11.2 Hz, 1 H),
2.91 (m, 1 H), 2.86 (s, 3 H), 2.11 (m, 1 H), 0.81 (d, J = 6.8 Hz, 3 H).
ESI-HRMS: m/z [M + H]+ calcd for C22H22N: 300.1752; found:
300.1743.
13C NMR (100 MHz, CDCl3): major diastereomer: d = 147.0, 146.2,
130.7, 129.6, 128.7, 127.6, 126.6, 125.6, 116.8, 111.2, 57.2, 52.2,
39.8, 35.4, 18.6.
ESI-HRMS: m/z [M + H]+ calcd for C17H20N: 238.1596; found:
238.1590.
Acknowledgment
This research was supported by the Korea Research Foundation
(KRF-2004-F00019).
3-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline (12)
References
To a soln of 9 (55 mg, 0.23 mmol) in THF (2 mL) was added 1.0 M
BH3·THF (5.0 equiv), and the mixture was refluxed for 12 h. The
reaction was quenched by addition of MeOH (0.5 mL) under ice-
water cooling, and the solvents were evaporated. A 5% aq soln of
HCl (2 mL) was added to the residue, and the mixture was refluxed
for 1 h. The reaction mixture was made basic with K2CO3, saturated
with NaCl, and extracted with CHCl3 (3 × 5 mL). The combined or-
ganic extracts were dried (MgSO4), filtered, and concentrated in
vacuo. Chromatographic separation (silica gel, hexane–EtOAc, 5:1)
afforded 12 as a mixture of two diastereomers.
(1) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.;
Pippel, D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33,
715.
(2) (a) Nam, J.; Lee, S.-k.; Park, Y. S. Tetrahedron 2003, 59,
2397. (b) Laumer, J. M.; Kim, D. D.; Beak, P. J. Org. Chem.
2002, 67, 6797. (c) Coldham, I.; Dufour, S.; Haxell, T. F. N.;
Howard, S.; Vennall, G. P. Angew. Chem. Int. Ed. 2002, 41,
3887. (d) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am.
Chem. Soc. 2002, 124, 5266. (e) Nakamura, S.; Nakagawa,
R.; Watanabe, Y.; Toru, T. J. Am. Chem. Soc. 2000, 122,
11340.
(3) (a) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757.
(b) Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996,
61, 5718. (c) Park, Y. S.; Yum, E. K.; Basu, A.; Beak, P.
Org. Lett. 2006, 8, 2667.
Pale yellow oil; yield: 36 mg (71%); 96:4 dr; [a]D20 –39.3 (c 0.11,
CHCl3).
CSP-HPLC: 98:2 er (3S,4R:3R,4S), tR (3S,4R) = 14.2 min, tR
(3R,4S) = 17.7 min (Chiralpak AD-H column; i-PrOH–hexane,
5:95; 0.5 mL/min).
(4) The absolute configuration of 6 was assigned, after its
conversion into 7, by comparison of its optical rotation with
that of an authentic compound, in the following literature:
(a) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira,
E. M. Org. Lett. 2005, 7, 3821. (b) Dong, C.; Alper, H.
Tetrahedron: Asymmetry 2004, 15, 35.
(5) Reaction of 2-(1-lithioethyl)-N-pivaloylaniline with tert-
butyl bromoacetate under the same reaction conditions gave
the substituted product in lower enantioselectivity (84:16 er)
and yield (22%).
(6) (a) Kiau, S.; Discordia, R. P.; Madding, G.; Okuniewicz, F.
J.; Rosso, V.; Venit, J. J. J. Org. Chem. 2004, 69, 4256.
(b) Kosmrlj, J.; Weigel, L. O.; Evans, D. A.; Downey, C. W.;
Wu, J. J. Am. Chem. Soc. 2003, 125, 3208. (c) Lee, S.-K.;
Lee, S. Y.; Park, Y. S. Synlett 2001, 1941. (d) Heath, H.;
Wolfe, B.; Livinghouse, T.; Bae, S. K. Synthesis 2001,
2341. (e) Vedejs, E.; Chapman, R. W.; Lin, S.; Muller, M.;
Powell, D. R. J. Am. Chem. Soc. 2000, 122, 3047.
(f) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2158.
(7) The relative configuration of trans-11 was assigned by
comparison of its NMR data with that of an authentic
compound, in the following literature: (a) Beifuss, U.;
Ledderhose, S. J. Chem. Soc., Chem. Commun. 1995, 2135.
(b) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem.
1995, 60, 7631. The relative configurations of 9, 10, 12, and
13 were assigned by analogy to the formation of trans-11.
IR (neat): 3410, 3022, 2924, 1506, 1457 cm–1.
1H NMR (400 MHz, CDCl3): major diastereomer: d = 7.32–6.54 (m,
9 H), 3.94 (br s, 1 H), 3.65 (d, J = 8.4 Hz, 1 H), 3.31 (dd, J = 3.2,
11.2 Hz, 1 H), 3.04 (dd, J = 11.2, 8.8 Hz, 1 H), 2.18 (m, 1 H), 0.93
(d, J = 6.4 H, 3 H).
13C NMR (100 MHz, CDCl3): major diastereomer: d = 146.2, 145.0,
131.1, 129.6, 128.7, 127.4, 126.6, 124.4, 117.6, 114.3, 51.7, 47.5,
35.3, 18.4.
ESI-HRMS: m/z [M + H]+ calcd for C16H17N: 224.1439; found:
224.1446.
3-Benzyl-4-phenyl-1,2,3,4-tetrahydroquinoline (13)
To a soln of 10 (100 mg, 0.32 mmol) in THF (2 mL) was added 1.0
M BH3·THF (5.0 equiv), and the mixture was refluxed for 12 h. The
reaction was quenched by addition of MeOH (0.5 mL) under ice-
water cooling, and the solvents were evaporated. A 5% aq soln of
HCl (2 mL) was added to the residue, and the mixture was refluxed
for 1 h. The reaction mixture was made basic with K2CO3, saturated
with NaCl, and extracted with CHCl3 (3 × 5 mL). The combined or-
ganic extracts were dried (MgSO4), filtered, and concentrated in
vacuo. Chromatographic separation (silica gel, hexane–EtOAc, 5:1)
afforded 13 as a mixture of two diastereomers.
Pale yellow oil; yield: 63 mg (66%); 99:1 dr; [a]D20 –45.8 (c 0.30,
CHCl3).
IR (neat): 3416, 3023, 2913, 2852, 1605, 1493, 1316 cm–1.
Synthesis 2006, No. 22, 3805–3808 © Thieme Stuttgart · New York