Asymmetric Syntheses of 3,4-Disubstituted Tetrahydroquinoline Derivatives Using (+)-Sparteine-mediated Electrophilic Substitution

Full text of DOI:10.1002/bkcs.10256

Note
DOI: 10.1002/bkcs.10256
BULLETIN OF THE
Y. S. Choi et al.
KOREAN CHEMICAL SOCIETY
Asymmetric Syntheses of 3,4-Disubstituted Tetrahydroquinoline
Derivatives Using (+)-Sparteine-mediated Electrophilic Substitution
*
Yun Soo Choi, Kyoung Hee Kang, and Yong Sun Park
Department of Chemistry, Konkuk University, Seoul 143-701, Korea. *E-mail: parkyong@konkuk.ac.kr
Received December 19, 2014, Accepted January 5, 2015, Published online April 28, 2015
Keywords: Heterocycles, Dynamic resolution, Chiral ligand, Asymmetric synthesis, Substitution
Tetrahydroquinolines bearing substituents are frequently found
as a substructure ina numberofalkaloids and natural products.1
Since their individual stereoisomers displays different biologi-
cal activities, it is desirable to develop a highly stereoselective
synthetic method for tetrahydroquinolines. While some prog-
ress has recently been made toward the development of asym-
metric synthetic methods for tetrahydroquinolines, it is still a
challenging topic in organic synthesis.2 In the course of our
studies onasymmetricsubstitution of 2-substituted aniline deri-
vatives, we envisaged a simple and straightforward synthetic
method for 3,4-disubstituted tetrahydroquinolines.
The strategy, as shown in Figure 1, involves an asymmetric
electrophilic substitution of 2-alkyl aniline with epoxide (step
1) to afford amino alcohol and the subsequent intramolecular
cyclization of the amino alcohol (step 2). While epoxides are
frequently used in a wide range of nucleophilic ring-opening
reactions, the kinetic resolution of racemic epoxide with
organolithium species has rarely been reported.3 Here we
report a novel asymmetric synthetic method for trans-3,4-
disubstituted tetrahydroquinolines via (+)-sparteine-mediated
electrophilic substitution of 2-benzyl-N-pivaloylanilines,
kinetic resolution of racemic epoxide, and Mitsunobu intra-
molecular cyclization.
electrophile can afford highly enantioenriched amino alcohols
suitable for the preparation of tetrahydroquinolines by intra-
molecular cyclization.
Our first attempt to test the synthetic approach involved the
use of phenyloxirane as an electrophile. Lithiation of 1 in the
presence of (+)-sparteine in methyl tert-butyl ether (MTBE) at
−20 ꢀC can provide the highly diastereoenriched lithium inter-
mediate 2bydynamic thermodynamicresolution.4d After add-
ing phenyloxirane (2.5 equiv) at −78 ꢀC, regioselective ring
opening occurred at the benzylic position and amino alcohol
3 was obtained in 80% yield as a 90:10 mixture of two insep-
arable diastereomers. The enantiomeric ratio (er) of the major
diastereomer was 87:13, as shown in Scheme 1, and that of the
minor diastereomer was 99:1.5
When the 90:10 diastereomeric mixture of 3 was treated
with PPh3 and diethyl azodicarboxylate (DEAD) in tetrahy-
drofuran (THF) at room temperature, the nucleophilic attack
by N-pivaloyl amide nucleophile provided trans-3,4-
disubstituted tetrahydroquinoline 4 with 87:13 er; no cis prod-
uctwasdetected. The transrelationshipof thetwosubstituents
was established after converting 4 to N-methyl-substituted tet-
rahydroquinoline 5.6 The results indicated that trans-4 was
produced in 82% yield from the major diastereomer of 3
(87:13 er); the minor diastereomer did not cyclize to afford tet-
rahydroquinoline 4. We reasoned that the repulsion between
two phenyl groups in the transition state formed during the
cyclization of the minor diastereomer of 3 prevents the forma-
tion of the cis product.
In order to investigate the source of diastereoselection
attained in the substitution reaction with a racemic epoxide,
we examined the substitution of 2 with an excess amount of
racemic p-chlorophenyl-substituted oxirane, as shown in
Scheme 2. When racemic p-chlorophenyloxirane (4.0 equiv)
was treated with 2-(α-lithiobenzyl)-N-pivaloylaniline (αR)-
2, the reaction of the epoxide proceeded to provide a diaster-
eomeric mixture (84:16 dr) of amino alcohol 6; the er of the
recovered epoxide was 66:34 (S:R) with 32% conversion.
The kinetic resolution in the substitution favoring (R)-epoxide
proceeded with a selectivity factor (s) of 7, as shown in
Scheme 2.7 Based on the trans relationship of the two substi-
tuents of tetrahydroquinoline 4 and the (S)-enantiomer-
enriched recovered epoxide, the absolute configurations of
the major enantiomer of 6 are assigned as (S,S).8 The
We have recently reported (−) or (+)-sparteine-mediated
asymmetric lateral substitutions of 2-benzyl-N-pivaloyl ani-
line 1 with various electrophiles.4 Substitution with ketones,
aldehydes, alkyl halides, and α,β-unsaturated esters afforded
diverse 2-alkyl-substituted aniline derivatives with high enan-
tioselectivities. We envisioned that the use of epoxide as an
Figure 1. Retrosynthetic analysis for tetrahydroquinoline.
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Scheme 2. Kinetic resolution of p-chlorophenyloxirane.
Scheme 1. Asymmetric synthesis of tetrahydroquinoline.
Scheme 3. Reactions with aliphatic epoxides.
MTBE, followed by the addition of 4-fluorophenyl oxirane
at −78 ꢀC, provided an amino alcohol as an 85:15 mixture
of two inseparable diastereomers. Since the minor diastereo-
mer did not provide the cyclized product, separation of the
major diastereomer was not required. Therefore, the crude
mixture of diastereomers was directly subjected to the Mitsu-
nobu cyclodehydration condition, which afforded trans-
tetrahydroquinoline 10 with 81:19 er in 63% overall yield
(entry1, Table1). Asshowninentries 2–5, thesameprocedure
with 4-chlorophenyloxirane, 4-methylphenyl oxirane, 1-
naphthyloxirane, and 2-naphthyloxirane provided 3,4-
disubstituted tetrahydroquinolines 11–14 with a high level
of asymmetric induction in 40–68% overall yields. With a
practical procedure in hand, we examined the scope of the
methodology with 2-(p-bromobenzyl)-N-pivaloylaniline 9.
Under identical reaction conditions, this simple two-step pro-
cedure is also efficient for the asymmetric preparation of 4-(p-
bromophenyl)-substituted tetrahydroquinolines 15–18 with
enantiomeric ratios ranging from 94:6 to 73:27 (entries 6–9).
In summary, we have developed a novel method for the
asymmetric synthesis of trans-3,4-diaryl-substituted tetrahy-
droquinolines from ortho-substituted N-pivaloyl anilines.
The enantioselective process includes (+)-sparteine-mediated
stereoselective lithiation, kinetic resolution of epoxides in
formation of (S,S)-amino alcohol 6 can be explained by the
invertive electrophilic substitution of lithium intermediate
(αR)-2 and the backside approach to (R)-epoxide coordinated
to the Li cation, as depicted in Scheme 2.
To expand the scope of this methodology to 3-alkyl substi-
tuted tetrahydroquinoline, we conducted electrophilic substi-
tutions of1 withmethyloxirane and benzyloxiraneasshown in
Scheme 3. Lithiation of 1 in the presence of (+)-sparteine at
−20 ꢀC in MTBE, followed by the addition of methyloxirane
at −78 ꢀC, provided the corresponding amino alcohol 7 in 77%
yield as a 60:40 mixture of two inseparable diastereomers with
82:18 and 80:20 er, respectively. In contrast to the reactions
with aryl-substituted oxiranes, the substitution showed a dif-
ferent regioselectivity to attack the sterically favored position
of oxirane. Under the same reaction conditions, the electro-
philic substitution of benzyloxirane showed the same regios-
electivity to afford amino alcohol 8 in 80% yield as a 52:48
mixture of two diastereomers with 90:10 and 66:34 er, respec-
tively. No sign of any regioisomer was detected by NMR anal-
ysis. The reversal ofregioselectivitymeansthatinthealiphatic
epoxides, theonly governingfactor wouldbethesteric factor.9
Next, we initiated investigations into the reaction scope
with various aryl-substituted oxiranes, as shown in Table 1.
Lithiation of 1 in the presence of (+)-sparteine at −20 ꢀC in
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Table 1. Asymmetric synthesis of tetrahydroquinolines 10–18
400 MHz) δ 7.55 (d, 1H), 7.29–6.90 (m, 13H), 4.38 (m, 1H),
4.28 (d, J = 10.0 Hz, 1H), 3.74 (dd, J = 13.2 and 10.8 Hz,
1H), 3.15 (m, 1H), 1.33 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 177.9, 144.4, 141.5, 140.5, 133.0, 130.2, 128.8,
128.7, 128.3, 127.7, 127.2, 126.5, 125.9, 125.8, 124.8, 52.1,
51.8, 51.3, 40.2, 28.7; HRMS (FAB) calcd for C26H28NO
(M+ + 1): 370.2173. Found 370.2171; CSP-HPLC (Chiralcel
OD column; 1% 2-propanol in hexane; 0.5 mL/min; 217 nm)
87:13 er, 18.2 min (major), 21.6 min (minor).
N-Pivaloyl-(3S,4S)-3-(p-fluorophenyl)-4-phenyl tetra-
hydroquinoline (10). A colorless oil, 122 mg, 63% overall
yield: 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, 1H),
7.54–6.89 (m, 12H), 4.34 (m, 1H), 4.20 (d, J = 9.6 Hz, 1H),
3.73 (dd, J = 13.2 and 10.8 Hz, 1H), 3.14 (m, 1H), 1.33 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 177.9, 144.0, 140.4,
137.3, 135.1, 132.8, 130.1, 129.1, 129.0, 128.8, 128.4,
126.6, 126.0, 125.8, 124.9, 115.7, 115.5, 53.4, 52.4, 51.2,
50.9, 40.2, 28.7; HRMS (FAB) calcd for C26H27FNO (M+ +
1): 388.2077. Found 388.2077; CSP-HPLC (Chiralcel OD
column; 1% 2-propanol in hexane; 0.5 mL/min; 217 nm)
81:19 er, 14.9 min (major), 18.9 min (minor).
N-Pivaloyl-(3S,4S)-3-(p-chlorohenyl)-4-phenyltetrahydro
quinoline (11). A colorless oil, 138 mg, 68% overall yield: 1H
NMR (CDCl3, 400 MHz) δ 7.55 (d, 1H), 7.54–6.88 (m, 12H),
4.34 (m, 1H), 4.20 (d, J = 10.0 Hz, 1H), 3.73 (dd, J = 13.2 and
10.4 Hz, 1H), 3.12 (m, 1H), 1.33 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ 177.9, 143.8, 140.3, 140.0, 132.9, 132.7, 130.1,
129.0, 128.9, 128.8, 128.4, 126.6, 126.0, 125.8, 124.9, 52.2,
51.1, 51.0, 40.2, 28.7; HRMS (FAB) calcd for C26H27ClNO
(M+ + 1): 404.1780. Found 404.1781; CSP-HPLC (Chiralcel
OD column; 2% 2-propanol in hexane; 0.5 mL/min; 217 nm)
93:7 er, 14.1 min (major), 18.3 min (minor).
.
Overall
Entry
R1
R2
dr
yielda (%)
erb
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
p-Br-Ph
p-Br-Ph
p-Br-Ph
p-Br-Ph
p-F-Ph
p-Cl-Ph
p-CH3-Ph
1-Naph
2-Naph
Ph
1-Naph
p-Cl-Ph
2-Naph
79:21
80:20
75:25
82:18
73:27
71:29
75:25
73:27
74:26
63 (10)
68 (11)
67 (12)
68 (13)
40 (14)
55 (15)
51 (16)
54 (17)
45 (18)
81:19
93:7
87:13
96:4
88:12
79:21
94:6
73:27
77:23
a Isolated overall yields after two steps.
b The enantiomeric ratios were determined by chiral stationary phase
high-performance liquid chromatography using racemic material as the
standard.
substitution, and stereospecific Mitsunobu cyclization as
the key reactions. The simple protocol can provide highly
functionalized tetrahydroquinoline rings and would allow
their further functionalization to access more complex target
molecules.
N-Pivaloyl-(3S,4S)-3-(p-methylphenyl)-4-phenyl tetra-
hydroquinoline (12). A colorless oil, 129 mg, 67% overall
yield: 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, 1H),
7.19–6.90 (m, 12H), 4.37 (m, 1H), 4.26 (d, J = 9.6 Hz, 1H),
3.70 (dd, J = 13.2 and 10.8 Hz, 1H), 3.12 (m, 1H), 2.31 (s,
3H), 1.33 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.8,
144.5, 140.5, 138.5, 136.7, 133.1, 130.2, 129.4, 128.8,
128.3, 127.5, 126.4, 125.8, 124.8, 52.2, 51.5, 51.4, 40.1,
28.7, 21.1; HRMS (FAB) calcd for C27H30NO (M+ + 1):
384.2324. Found 384.2327; CSP-HPLC (Chiralpak AD-H
column; 1% 2-propanol in hexane; 0.5 mL/min; 217 nm)
87:13 er, 19.7 min (minor), 21.2 min (major).
N-Pivaloyl-(3S,4S)-3-(1-naphtyl)-4-phenyltetrahydro
quinoline (13). A yellow oil, 143 mg, 68% overall yield:
1H NMR (CDCl3, 400 MHz) δ 7.76–6.92 (m, 16H),
4.49 (m, 1H), 4.38 (m, 1H), 4.11 (m, 1H), 3.91 (m, 1H),
1.23 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 178.3, 144.7,
140.6, 130.2, 128.8, 128.5, 128.4, 127.6, 127.2, 126.4,
126.0, 125.9, 125.8, 125.6, 125.5, 125.0, 124.8, 52.2, 51.0,
44.5, 40.2, 28.7; HRMS (FAB) calcd for C30H30NO
(M++1): 420.2327. Found 420.2325; CSP-HPLC
(Chiralpak AD-H column; 2% 2-propanol in hexane;
0.5 mL/min; 217 nm) 96:4 er, 25.8 min (minor), 28.8
min (major).
Experimental
General Procedure for the Asymmetric Preparation of
Tetrahydroquinolines 4 and 10–18. To a solution of N-
pivaloylanilines 1 or 9 (0.5 mmol) and (+)-sparteine (258
mg, 2.2 equiv) in 3 mL of MTBE at −20 ꢀC was added n-BuLi
(0.7 mL, 1.6 M in hexane, 2.2 equiv). After the mixture was
stirred at −20 ꢀC for 1 h, an epoxide (2.5 equiv) was added
at −78 ꢀC. The mixture was stirred for 20 min at −78 ꢀC and
then quenched with excess methanol. The resulting mixture
was dissolved in EtOAc, washed with saturated NH4Cl, dried
with MgSO4, and concentrated in vacuo. The resulting residue
was purified by passing through a short silica gel column
(EtOAc/hexanes solvents) to afford the amino alcohol as an
inseparable mixture of two diastereomers. To a solution of
the products in CH3CN (2 mL) was added PBu3 (2.5 equiv)
and DEAD (2.5 equiv), and the mixture was stirred at room
temperature for 6 h. After the solvent was removed in vacuo,
chromatographic separation of the crude mixture on silica gel
(EtOAc/hexanes solvents) afforded tetrahydroquinolines 4
and 10–18 in 68–40% overall yields.
N-Pivaloyl-(3S,4S)-3,4-diphenyltetrahydroquinoline (4).
A colorless oil, 121 mg, 66% overall yield: 1H NMR (CDCl3,
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N-Pivaloyl-(3S,4S)-3-(2-naphtyl)-4-phenyltetrahydro
(Chiralcel ODcolumn;2%2-propanolinhexane; 0.5 mL/min;
217 nm) 77:23 er, 18.0 min (major), 25.4 min (minor).
quinoline (14). A pale yellow oil, 84 mg, 40% overall yield:
1H NMR (CDCl3, 400 MHz) δ 7.57-6.90 (m, 16H), 4.48–4.40
(m, 2H), 3.84 (dd, J = 13.2 and 10.8 Hz, 1H), 3.32 (m, 1H),
1.34 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.9, 144.3,
140.6, 139.0, 133.5, 133.1, 132.6, 130.2, 128.8, 128.6,
128.4, 127.7, 127.6, 126.5, 126.4, 126.2, 125.9, 125.8,
125.7, 125.6, 125.5, 52.1, 52.0, 51.6, 40.2, 28.7; CSP-HPLC
(Chiralcel ODcolumn;1%2-propanolinhexane;0.5 mL/min;
217 nm) 88:12 er, 23.6 min (major), 31.7 min (minor).
N-Pivaloyl-(3S,4S)-4-(p-bromophenyl)-3-phenyl tetra-
hydroquinoline (15). A colorless oil, 123 mg, 55% overall
yield: 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, 1H),
7.31–6.76 (m, 12H), 4.39 (dd, J = 13.6 and 4.0 Hz, 1H),
4.26 (d, J = 9.6 Hz, 1H), 3.72 (dd, J = 13.2 and 11.2 Hz,
1H), 3.06 (m, 1H), 1.34 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 178.0, 143.4, 141.1, 140.5, 132.3, 131.5, 130.5,
130.0, 128.9, 127.6, 127.4, 126.1, 126.0, 124.9, 120.4,
51.8, 51.7, 51.3, 40.2, 28.7; CSP-HPLC (Chiralcel OD col-
umn; 1% 2-propanol in hexane; 0.5 mL/min; 217 nm) 79:21
er, 17.7 min (major), 25.7 min (minor).
Acknowledgment. This workwassupportedbyKonkukUni-
versity in 2014.
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
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5. When the reaction of 1 was carried out in toluene, ether, or n-hex-
ane, the asymmetric lithiation substitution reactions gave
lower diastereoselectivities of 81:19, 84:16, and 83:17 dr, respec-
tively. Among the solvents examined, n-hexane was found to give
a slightly higher enantioselectivity (89:11 er of major diastereo-
mer) than t-BuOMe and significant decrease in enantioselectivity
was observed in the reactions in toluene (72:28 er) and ether
(77:23 er).
N-Pivaloyl-(3S,4S)-4-(p-bromophenyl)-3-(1-naphtyl)
tetrahydroquinoline(16). Acolorless oil, 127 mg, 51%over-
all yield: 1H NMR (CDCl3, 400 MHz) δ 7.83–6.77 (m, 15H),
4.46(m, 1H), 4.36 (m, 1H), 4.05 (m, 1H), 3.86 (m, 1H), 1.24 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 178.3, 143.7, 140.6,
133.7, 132.5, 131.5, 130.2, 130.1, 128.9, 128.5, 128.4,
127.7, 126.3, 126.2, 126.0, 125.7, 125.6, 125.0, 124.0,
122.1, 120.4, 51.9, 51.1, 44.3, 40.2, 28.7; CSP-HPLC
(Chiralcel OD column; 2% 2-propanol in hexane; 0.5 mL/
min; 217 nm) 94:6 er, 28.2 min (major), 38.4 min (minor).
N-Pivaloyl-(3S,4S)-4-(p-bromophenyl)-3-(p-chlorophe-
nyl)tetrahydroquinoline (17). A colorless oil, 130 mg, 54%
1
overall yield: H NMR (CDCl3, 400 MHz) δ 7.54 (d, 1H),
7.31–6.76 (m, 11H), 4.34 (dd, J = 13.2 and 3.6 Hz, 1H),
4.18 (d, J = 9.6 Hz, 1H), 3.71 (dd, J = 13.2 and 10.8 Hz,
1H), 3.05 (m, 1H), 1.33 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 178.0, 142.9, 140.4, 139.6, 133.2, 132.0, 131.6,
130.5, 129.9, 129.1, 128.9, 126.3, 125.9, 125.0, 120.6,
51.7, 51.2, 51.0, 40.2, 28.7; CSP-HPLC (Chiralcel OD col-
umn; 1% 2-propanol in hexane; 0.5 mL/min; 217 nm) 73:27
er, 18.6 min (major), 26.6 min (minor).
6. The relative configuration of trans-5 is assigned by comparison to
the NMR of the authentic compound in the following literature.
We assume the same stereochemical assignments for all tetrahy-
droquinolines 10–18. b A. R. Katrizky, B. Rachwal, S. Rachwal,
J. Org. Chem. 1995, 60, 7631.
7. The selectivity factor (s) was estimated using the equation, s = kR/
kS = ln[(1 – C)(1 – ee)]/ln[(1 – C)(1 + ee)], where ee is the enan-
tiomeric excess of unconverted epoxide and the conversion (C)
1
determined by H NMR of reaction mixture. The selectivity (s
N-Pivaloyl-(3S,4S)-4-(p-bromophenyl)-3-(2-naphtyl)
tetrahydroquinoline (18). A yellow oil, 112 mg, 45% overall
= 7) is an average of three experiments, while conversion and er
are for a specific case.
1
yield: H NMR (CDCl3, 400 MHz) δ 7.82–6.76 (m, 15H),
8. The (S)-configuration at benzylic position of 6 is consistent with
thepreviouslyestablishedresultsinthesubstitutionof 1withother
electrophiles.4
9. (a) R.-H. Fan, X.-L. Hou, J. Org. Chem. 2003, 68, 726; (b) M. Taj-
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4.46 (dd, J = 13.2 and 3.6 Hz, 1H), 4.38 (d, J = 10.0 Hz,
1H), 3.82 (dd, J = 13.2 and 11.2 Hz, 1H), 3.25 (m, 1H),
1.35 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.8, 143.3,
140.5, 138.4, 133.4, 132.6, 132.4, 131.4, 130.4, 130.0,
128.7, 127.7, 127.6, 126.4, 126.3, 126.1, 125.9, 125.8,
125.4, 124.9, 120.4, 52.0, 51.6, 51.4, 40.1, 28.6; CSP-HPLC
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