Pd/Cu-catalyzed couplings of β-amino esters with aryl bromides. Synthesis of chiral 1,2,3,4-tetrahydro-4-oxo-2-alkyl-1-quinolines

Article abstract of DOI:10.1016/S0957-4166(98)00078-0

A new protocol to prepare chiral 1,2,3,4-tetrahydro-4-oxo-2-alkyl-l- quinolines has been developed. The key steps are Pd/Cu-catalyzed couplings of chiral β-amino esters and aryl bromides, and intramolecular acylation.

Full text of DOI:10.1016/S0957-4166(98)00078-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1137–1142
Pd/Cu-catalyzed couplings of β-amino esters with aryl bromides.
Synthesis of chiral 1,2,3,4-tetrahydro-4-oxo-2-alkyl-1-quinolines
Dawei Ma ∗ and Jiqing Jiang
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, PR China
Received 5 January 1998; accepted 16 February 1998
Abstract
A new protocol to prepare chiral 1,2,3,4-tetrahydro-4-oxo-2-alkyl-1-quinolines has been developed. The key
steps are Pd/Cu-catalyzed couplings of chiral β-amino esters and aryl bromides, and intramolecular acylation.
© 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The formation of a carbon–nitrogen bond by palladium-catalyzed coupling of aryl halides with amines
has been realized in the past three years. These results represent a major advance in the development of
aromatic amination methodology.1,2 However, most studies were limited to broadening aryl halides and
catalyst systems;3 little attention has been directed to seeking more complex amines4 that may expand the
synthetic applications of this new manner of carbon–nitrogen bond formation. Recently, we reported a
reasonably efficient method of coupling α-amino acids with aryl halides,5 which gave enantiomerically
pure N-aryl-α-amino acids in moderate to good yields. This is the first example of the preparation of
chiral N-aryl amines using Pd-catalyzed aromatic amination.4a After several attempts, we have extended
this method to β-amino esters. The coupling products could be further transformed to chiral 1,2,3,4-
tetrahydro-4-oxo-2-alkyl-1-quinolines 3 through intramolecular Friedel–Crafts acylations. The products
3 were envisioned to be ideal building blocks for synthesizing biologically important molecules such as
pumiliotoxin C,6 L-689,560,7 and martinellic acid8 (Scheme 1). Herein we detail our results.
∗
Corresponding author. E-mail: madw@pub.sioc.ac.cn
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00078-0

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D. Ma, J. Jiang / Tetrahedron: Asymmetry 9 (1998) 1137–1142
Scheme 1.
2. Results and discussion
β-Amino esters could be obtained in enantiomerically pure form by stereoselective conjugate addition9
of (S)- or (R)-lithium N-benzyl-N-α-methylbenzylamides to α,β-unsaturated esters followed by hy-
drogenation that provided a new class of chiral amines in a simple and efficient manner. Initially, we
hydrolyzed the esters to the corresponding amino acid salts with potassium hydroxide; the salts were
then subjected to our previously reported conditions.5 It was found that the β-amino acid salt could
couple with an aryl bromide under the catalysis of Pd/Cu to form the N-aryl-β-amino acid in moderate
yields. After some experimentation, we found that the β-amino esters, which should hydrolyze quickly
under the present reaction conditions, could be used directly in this reaction without the yield changing.
As illustrated in Table 1, this coupling method provides a general route to a variety of chiral N-aryl-β-
amino acids. Using bulky ligands gave higher yields (compare entries 3 and 4 and entries 5 and 6). These
results are consistent with those reported by Buchward3e and Hartwig.3f
Table 1
Pd/Cu-catalyzed couplings of aryl bromides and chiral β-amino esters
As shown in the following scheme, the cyclization of 2 could be achieved under the action of PPA at
120°C.10 Through this method we obtained 3c in about 60% yield, while using 2d as a starting material
produced two regioisomers 3d and 3e in a ratio of 3:1. The product 3e may serve as a suitable intermediate
for the synthesis of pumiliotoxin C6 by selective reduction. Alternatively, we could use AlCl3-catalyzed
acylation to obtain the N-protected cyclization product 5. It is worth noting that we noticed that N-
protection became very difficult to achieve after cyclization of 2 owing to the lower nucleophilicity of the
NH group in 3. Thus the latter cyclization method would give us more important synthetic intermediates.
To convert the acids 2 to their corresponding acyl chlorides, the NH group should be protected first.
Initially, we treated 2d with acyl chloride or acetic anhydride directly but no desired product was
obtained. Thus we first had to transform 2d to its methyl ester. At this time we found the NH group

D. Ma, J. Jiang / Tetrahedron: Asymmetry 9 (1998) 1137–1142
1139
could be protected in high yield by using acetic anhydride as an acylating agent.11 The protected product
was then hydrolyzed to the corresponding acid 4d in about 80% overall yield. Acid 4d was converted to
acyl chloride with PCl5 and then treated with AlCl3 to afford 5d in 89% yield.12 In a similar manner,
5b was obtained from 2b in 72% overall yield. In summary, we have established a new methodology to
prepare chiral 1,2,3,4-tetrahydro-4-oxo-2-alkyl-1-quinolines or its N-acetyl derivatives by using Pd/Cu-
catalyzed coupling and intramolecular acylation as key steps. The application of this methodology to the
synthesis of biologically important molecules is under study in our laboratory and will be reported in due
course.
3. Experimental section
3.1. General procedures
1
IR spectra were measured on a Schimadzu 440 spectrometer. H NMR spectra were recorded with
TMS as an internal standard on a Brucker AM-300 spectrometer. MS spectra were determined on a
Finnigan 4201 spectrometer. Optical rotations were obtained on a Perkin–Elmer 241 Autopol polarimeter.
THF was distilled from a deep blue ketyl prior to use. All reactions were run in flame-dried glassware
under a nitrogen atmosphere unless stated otherwise.
3.2. Typical procedure for Pd/Cu-catalyzed couplings of aryl bromides and chiral β-amino esters
To a mixture of aryl bromide (4.1 mmol), β-amino esters (4.1 mmol), potassium carbonate (12 mmol),
TEBA (0.25 mmol) in 0.1 mL of water, 5 mL of DMF were added 0.5 mL of triethylamine, CuI (0.25
mmol) and Pd(PPh3)4 (0.25 mmol). The resulting suspension was heated under argon at 110°C for 24 h.
After cooling to room temperature, the reaction mixture was acidified with 1 N HCl to pH=2, and then
extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with brine, dried
over Na2SO4 and concentrated. The residual oil was chromatographed (silica gel, ethyl acetate:petroleum
ether=1:2–1:1 as eluent) to afford the coupled product. The yield and analytical data for each compound
were as follows.
3.3. (R)-N-(40-Methoxy)phenyl-3-aminohexanoic acid 2a
65% Yield. [α]D25=−15.4 (c 1.4, CHCl3); 1H NMR δ 7.31 (br s, 1H), 6.90–6.74 (m, 4H), 3.75 (s, 3H),
3.61 (m, 1H), 2.54 (dd, J=16.5, 1.7 Hz, 1H), 2.47 (dd, J=16.5, 7.5 Hz, 1H), 1.74–1.46 (m, 2H), 1.43–1.37

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D. Ma, J. Jiang / Tetrahedron: Asymmetry 9 (1998) 1137–1142
(m, 2H), 0.91 (t, J=7.6 Hz, 3H); MS m/z 237 (M+), 194, 178, 148; HRMS calcd for C13H19NO3: 237.137,
found: 237.136.
3.4. (S)-N-Phenyl-3-aminobutanoic acid 2b
66% Yield. [α]D25=+1.3 (c 1.0, CHCl3); 1H NMR δ 7.21 (d, J=8.1 Hz, 2H), 6.78 (dd, J=8.1, 8.1 Hz,
1H), 6.68 (d, J=8.1 Hz, 2H), 6.13 (br s, 2H), 3.94 (m, 1H), 2.71 (dd, J=15.4, 5.68 Hz), 2.52 (dd, J=15.4,
6.5 Hz, 1H), 1.32 (d, J=7.2 Hz, 3H); MS m/z 179 (M+), 164, 120; HRMS calcd for C10H13NO2: 179.095,
found: 179.094.
3.5. (S)-N-(40-Methoxy)phenyl-3-aminohexanoic acid 2c
70% Yield. [α]D25=+15.6 (c 0.3, CHCl3); 1H NMR δ 7.65 (br s, 2H), 6.93 (d, J=9.0 Hz, 2H), 6.79 (d,
J=9.0 Hz, 2H), 3.75 (s, 3H), 3.61 (m, 1H), 2.54 (dd, J=16.5, 1.7 Hz, 1H), 2.47 (dd, J=16.5, 7.5 Hz, 1H),
1.74–1.46 (m, 2H), 1.43–1.37 (m, 2H), 0.91 (t, J=7.6 Hz, 3H); MS m/z 237 (M+), 194, 178, 148; HRMS
calcd for C13H19NO3: 237.137, found: 237.138.
3.6. (S)-N-(30-Methyl)phenyl-3-aminohexanoic acid 2d
55% Yield. [α]D25=+3.8 (c 0.8, CHCl3); 1H NMR δ 7.09 (dd, J=7.9, 7.9 Hz, 1H), 6.83 (br s, 2H), 6.57
(d, J=8.1 Hz, 1H), 6.51 (s, 1H), 6.50 (d, J=8.1 Hz, 1H), 3.82–3.67 (m, 1H), 2.59–2.50 (m, 2H), 2.28 (s,
3H), 1.57–1.49 (m, 2H), 1.44–1.35 (m, 2H), 0.95 (t, J=7.2 Hz, 3H); MS m/z 221 (M+), 178, 162, 132,
119, 91, 77, 43; HRMS calcd for C13H19NO2: 221.142, found: 221.142.
3.7. (R)-N-(30-Methyl)phenyl-3-aminohexanoic acid 2e
1
40% Yield. [α]D25=−3.6 (c 0.8, CHCl3); H NMR δ 7.09 (dd, J=7.9, 7.9 Hz, 1H), 6.83 (br s, 2H),
6.57 (d, J=8.1 Hz, 1H), 6.51 (s, 1H), 6.50 (d, J=8.1 Hz, 1H), 3.82–3.67 (m, 1H), 2.59–2.50 (m, 2H), 2.28
(s, 3H), 1.57–1.49 (m, 2H), 1.44–1.35 (m, 2H), 0.95 (t, J=7.2 Hz, 3H); MS m/z 221 (M+), 178, 162, 132,
119, 91, 77, 43; HRMS calcd for C13H19NO2: 221.142, found: 221.141.
3.8. (S)-6-Methoxy-1,2,3,4-tetrahydro-4-oxo-2-n-propyl-1-quinoline 3c
A mixture of 2c (510 mg, 2.2 mmol) and 7.5 g of PPA was stirred at 110–120°C for 2 h. The
cooled solution was poured into 50 mL of ice–water and then the resulting solution was neutralized
with NaHCO3 to pH=8.5. After extraction with ethyl acetate (3×40 mL), the combined organic layers
were washed with brine and dried over Na2SO4. The solvent was removed by rotavapor and the residue
was loaded onto a column of silica gel. Eluting with ethyl acetate:petroleum ether (1:3) followed by
evaporation of solvent afforded 283 mg (60% yield) of 3c. [α]D25=−157 (c 1.0, CHCl3); 1H NMR δ 7.29
(d, J=2.4 Hz, 1H), 7.00 (dd, J=8.1, 2.4 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 3.78 (s, 3H), 3.59 (m, 1H), 2.68
(dd, J=16.2, 3.5 Hz, 1H), 2.46 (dd, J=16.2, 12.8 Hz, 1H), 1.59 (m, 2H), 1.41 (m, 2H), 0.99 (t, J=7.6 Hz,
3H); HRMS calcd for C13H17NO2: 219.126, found: 219.125.
In a similar manner, 3d (60% yield) and 3e (20% yield) were obtained from the cyclization of 2d. 3d:
[α]D25=−209 (c 1.0, CHCl3); IR (KBr) 3342, 1645, 1625, 1261, 796 cm−1; 1H NMR δ 7.72 (d, J=8.0
Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 6.47 (s, 1H), 3.67–3.56 (m, 1H), 2.65 (dd, J=16.0, 3.7 Hz, 1H), 2.46
(dd, J=16.0, 13.2 Hz, 1H), 2.38 (s, 3H), 1.57–1.50 (m, 2H), 1.47–1.36 (m, 2H), 0.98 (t, J=7.6 Hz, 3H);

D. Ma, J. Jiang / Tetrahedron: Asymmetry 9 (1998) 1137–1142
1141
MS m/z 203 (M+), 160, 149, 137, 117, 99, 91, 85, 77, 44; HRMS calcd for C13H17NO: 203.131, found:
1
203.132. 3e: [α]D25=−272.6 (c 1.0, CHCl3); IR (KBr) 3342, 1645, 1625, 1261, 796 cm−1; H NMR
δ 7.12 (dd, J=7.8, 7.8 Hz, 1H), 6.56–6.49 (m, 2H), 3.67–3.56 (m, 1H), 2.63 (dd, J=15.6, 3.7 Hz, 1H),
2.58 (s, 3H), 2.47 (dd, J=15.6, 12.6 Hz, 1H), 1.63–1.54 (m, 2H), 1.47–1.38 (m, 2H), 0.97 (t, J=7.6 Hz,
3H); MS m/z 203 (M+), 160, 137, 117, 99, 91, 85, 77, 44; HRMS calcd for C13H17NO: 203.131, found:
203.130.
3.9. (S)-N-Acetyl-N-(30-methyl)phenyl-3-aminohexanoic acid 4d
To a solution of 2d (480 mg, 2.2 mmol) in 20 mL of dry methanol was added SOCl2 (0.8 mL, 10.9
mmol) dropwise at −40°C. After the addition the solution was allowed to warm gradually to room
temperature and then the stirring was continued for 2 h. Triethylamine (2 mL) was added to neutralize
the solution before it was concentrated at reduced pressure. The residue was diluted with 50 mL of
ethyl acetate and the resulting solution was washed with brine and dried over Na2SO4. After removal of
solvent, the crude ester was obtained, which was dissolved in 10 mL of acetic anhydride. The solution
was heated at 100°C for 2 h and then acetic anhydride was evaporated via rotavapor. The residual oil was
dissolved in 10 mL of methanol and 3 mL of aqueous 5% NaOH was introduced. After stirring for 5 h at
room temperature, the solution was concentrated, acidified with 1 N HCl and extracted with ethyl acetate
(2×30 mL). The combined organic layers were washed with brine, dried with Na2SO4 and concentrated
to dryness, followed by chromatography (silica gel, ethyl acetate:petroleum ether=1:1 as eluent) to afford
440 mg (76% overall yield) of the crude 4d. [α]D25=+17.8 (c 1.0, CHCl3); 1H NMR δ 7.75 (br s, 1H),
7.28 (dd, J=7.8, 7.8 Hz, 1H), 7.17 (d, J=7.8 Hz), 7.06–6.90 (m, 2H), 5.19 (m, 1H), 2.45 (d, J=6.1 Hz,
2H), 2.41 (s, 3H), 1.80 (s, 3H), 1.47–1.30 (m, 4H), 0.96 (t, J=7.1 Hz, 3H); MS m/z 263 (M+), 246, 220,
178, 162, 149, 118, 107, 91, 43; HRMS calcd for C15H21NO3: 263.152, found: 263.152.
3.10. (S)-N-Acetyl-7-methyl-1,2,3,4-tetrahydro-4-oxo-2-n-propyl-1-quinoline 5d
To an ice-cooled solution of 4d (121 mg, 0.46 mmol) in 10 mL of ether was added PCl5 (115 mg,
0.55 mmol). After stirring for 1 h, the solvent was evaporated at reduced pressure and then 10 mL of
methylene chloride was introduced. Anhydrous AlCl3 (245 mg, 1.84 mmol) was added to the resulting
solution before it was stirred for 3 h at room temperature. The mixture was poured onto 10 mL of
ice–water to quench the reaction. The organic layer was separated and the aqueous layer was extracted
with 20 mL of methylene chloride. The combined organic phase was dried over Na2SO4 and concentrated
at reduced pressure. The residue was chromatographed (silica gel, ethyl acetate:petroleum ether=1:3 as
1
eluent) to afford 100 mg (89% yield) of 5d. [α]D25=+201.5 (c 1.0, CHCl3); H NMR δ 7.91 (d, J=8.0
Hz, 1H), 7.11 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.21 (m, 1H), 2.95 (dd, J=17.9, 5.7 Hz, 1H), 2.60 (dd,
J=17.9, 1.9 Hz, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 1.51–1.20 (m, 4H), 0.83 (t, J=7.6 Hz, 3H); MS m/z 245
(M+), 202, 160; HRMS calcd for C15H19NO2: 245.141, found: 245.140.
Following the procedure for preparing 5d, 5b was obtained from 2b in 74% overall yield. [α]D25=+349
(c 1.0, CHCl3); IR (KBr) 3030, 1693, 1665, 1484, 1319 cm−1; 1H NMR δ 8.01 (d, J=7.9 Hz, 1H), 7.56
(dd, J=7.9, 7.9 Hz, 1H), 7.36 (br s, 1H), 7.28 (dd, J=7.9, 7.9 Hz, 1H), 5.38 (br s, 1H), 3.03 (dd, J=17.9,
5.9 Hz, 1H), 2.61 (dd, J=17.9, 1.5 Hz, 1H), 2.36 (s, 3H), 1.20 (d, J=7.0 Hz, 3H); MS m/z 203 (M+), 161,
146, 117, 91, 77, 43; HRMS calcd for C12H13NO2: 203.095, found: 203.095.

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D. Ma, J. Jiang / Tetrahedron: Asymmetry 9 (1998) 1137–1142
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences and the National Natural Science
Foundation of China for their financial support.
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