SYNTHESIS
Papers
1178
and 3.75 (s, 3 H, OCH3), 2.33 (br s, 1 H, OH), 1.86 (m, 1 H, H-2'),
1.27 [s, 9 H, C(CH3)3], 1.05 and 0.64 (d, 3 H, J = 6.7 Hz, C2'-CH3),
0.91 and 0.78 (t, 3 H, J = 7.5 Hz, H-4'), 0.86 (m, 2 H, H-3').
13C NMR (63 MHz, CDCl3): δ = 177.0 and 176.9 (CO), 156.8 and
156.7 (C-3), 138.9 and 138.7 (C-1), 128.2 and 128.1 (C-5), 120.1 and
119.9 (C-2), 115.0 and 114.8 (C-6), 105.9 and 105.8 (C-4), 72.3 and
72.0 (C-1'), 55.6 and 55.4 (OCH3), 40.0 and 39.9 (Cα), 39.8 and 39.2
(C-2'), 27.6 [C(CH3)3], 25.8 and 25.2 (C-3'), 15.3 and 15.0 (C2'-CH3),
11.7 and 11.2 (C-4').
as representative of different methylene active com-
pounds. Their reaction with 2b following Method C af-
forded condensation and aldol products (55% of 7b and
47% of 8b, respectively), instead of the corresponding
quinolines.
In conclusion, we have developed a very efficient and
simple strategy for the synthesis of a great variety of quin-
oline derivatives from N-pivaloylanilines, with the addi-
tional advantage that deprotection of the pivaloyl group is
not necessary. We have also showed that the method is
limited by the geometry and the nature of aldol and con-
densation intermediate products.
2-tert-Butyl-5-methoxyquinazoline (5b):
This compound was obtained in the reaction of 2b with acetaldehyde
following Method B; yield 95 mg (68%); mp 61°C (hexane).
IR (KBr): ν = 1584, 1569, 1265 cm–1.
1
H NMR (250 MHz, CDCl3): δ = 9.66 (s, 1 H, H-4), 7.71 (dd, 1 H, J
= 7.9, 8.4 Hz, H-7), 7.51 (d, 1 H, J = 8.4 Hz, H-8), 6.81 (d, 1 H, J =
IR spectra were recorded on a Perkin-Elmer Paragon 1000 spectro-
photometer. NMR spectra were obtained on a Bruker AC-250
(250 MHz for 1H, 63 MHz for 13C) spectrometer; CDCl3 was used as
solvent. Elemental analyses of new compounds were determined by
the Servicio de Microanálisis, Universidad Complutense, on a Perkin-
Elmer 2400 CHN microanalyser. Melting points were measured on a
Reichert 273 hot stage microscope, and are uncorrected. Reactions
were monitored by TLC on aluminium plates coated with silica gel
with fluorescent indicator (Scharlau Cf 530). Separations by flash
chromatography were performed on silica gel (SDS 60 ACC, 230–
400 mesh and Scharlau Ge 048). All reagents were of commercial
quality (Aldrich, Fluka, Merck, SDS, Probus) and were purified fol-
lowing standard procedures. Petroleum ether refers to the fraction
boiling at 40–60°C. In the case of compounds reported in the litera-
ture only new spectroscopic data are included.
7.9 Hz, H-6), 3.99 (s, 3 H, OCH3), 1.47 [s, 9H, C(CH3)3].
C NMR (63 MHz, CDCl3): δ = 173.9 (C-2), 156.1 (C-5), 155.5 (C-
4), 151.2 (C-8a), 134.1 (C-7), 120.3 (C-8), 115.3 (C-4a), 104.7 (C-6),
13
55.9 (OCH3), 39.6 (Cα), 29.7 [C(CH3)3].
Compounds 6a, 7b and 8b:
They were the exclusive reaction products when Method C was ap-
plied to 2a and acetone as carbonyl reagent (6a); to 2b and 2-methyl-
cyclohexanone (7b) or to 2b and butyronitrile (8b). The configuration
of 7b was confirmed by NOE experiments.
2-(3-Methyl-5-oxo-3-cyclohexenyl)-N-pivaloylaniline (6a):
This compound was obtained as an oil starting from 2a; yield 25 mg
(8%).
IR (KBr): ν = 3305, 1658, 1247 cm–1.
1
H NMR (250 MHz, CDCl3): δ = 7.43 (m, 1 H, H-6), 7.31 (m, 4 H,
NH , H-3,4 and 5), 5.93 (d, 1 H, J = 1.0 Hz, H-4'), 3.37 (m, 1 H, H-
1'), 2.49 (dd, 4 H, J = 7.5, 7.7 Hz, H-2',5'), 1.97 (d, 3 H, J = 1.0 Hz,
C3'-CH3), 1.28 [s, 9 H, C(CH3)3].
3-Unsubstituted and 2,3-Disubstituted Quinoline Derivatives 3;
General Procedures:
Method A: To a solution of the suitable pivaloylaniline (2.5 mmol) in
anhyd THF (10 mL) at 0°C was added sec-BuLi (1.3 M in hexanes,
4.75 mL, 6.2 mmol). The mixture was stirred for 2 h and freshly
distilled DMF (3.71 mmol) was added dropwise. The mixture was
stirred for 1 h at 0°C and allowed to warm to r.t. for 12 h. The carbo-
nyl compound (2.5 mmol) and a 15% toluene solution of KHMDS
(6.6 mL, 4.95 mmol) were added at 0°C for 10 min and the mixture
was maintained at r.t for 2 h. Then it was quenched with a satd aq
solution of NH4Cl (5 mL) and extracted with Et2O (3 × 10 mL). The
combined organic extracts were dried (Na2SO4) and the solvent was
removed under vacuum. The residue was purified by flash chroma-
tography (silica gel, 1:1 CH2Cl2/petroleum ether) leading to the cor-
responding quinoline. Compounds 3 were derivatized to the picrates
by standard procedures.
13
C NMR (63 MHz, CDCl3): δ = 198.8 (C-5'), 177.5 (CONH), 162.1
(C-3'), 137.6 (C-1), 134.5 (C-2), 127.5, 127.0, 126.9, 126.3 and 126.1
(C-3, C-4, C-5, C-6 and C-4'), 43.3 (C-6'), 39.4 (Cα), 37.7 (C-2'),
35.5 (C-1'), 27.6 [C(CH3)3], 24.3 (C3'-CH3).
3-Methoxy-2-[(2-oxo-3-methylcyclohexylidene)methyl]-N-pivaloyl-
aniline (7b): This compound was obtained as an oil starting from 2b;
yield: 95 mg (55%).
IR (KBr): ν = 3426, 1681, 1255 cm–1.
1
H NMR (250 MHz, CDCl3): δ = 7.85 (d, 1 H, J = 8.3 Hz, H-6), 7.31
(br s, 1 H, NH), 7.21 (t, 1 H, J = 8.3 Hz, H-5), 6.98 (br s, 1 H, H-1'),
6.60 (d, 1 H, J = 8.3 Hz, H-4), 3.72 (s, 3 H, OCH3), 2.46 (m, 1 H, H-
3''), 2.14 (m, 2 H, H-6''), 1.68 (m, 4 H, H-4'' and H-5''), 1.19 [s, 9 H,
C(CH3)3], 1.14 (d, 3 H, J = 6.7, C3''-CH3).
Method B: To a solution of the suitable 2-formylpivaloylaniline
(2.5 mmol) and the carbonyl compound (2.5 mmol) in anhyd THF
(10 mL) at 0°C was added a 15% toluene solution of KHMDS
(6.6 mL, 4.95 mmol). The mixture was maintained at 0°C for 10 min
and stirred at r.t. for 2 h. Then it was quenched with a satd aq solution
of NH4Cl (5 mL) and extracted with Et2O (3 × 10 mL). The combined
organic extracts were dried (Na2SO4) and the solvent was removed
under vacuum. The residue was purified as described in Method A.
13
C NMR (63 MHz, CDCl3): δ = 204.1 (C-2''), 176.5 (CONH), 157.0
(C-3), 143.5 (C-1) ,136.8 (C-1''), 129.6 (C-5), 126.2 (C-1'), 114.8 (C-
2), 113.2 (C-6), 106.2 (C-4), 55.7 (OCH3), 45.1 (C-3''), 40.1 (Cα),
32.7 and 29.8 (C-4'' and C-6''), 27.7 [C(CH3)3], 23.2 (C-5''), 15.9
(C3''-CH3).
2-(1-Hydroxy-2-cyanobutyl)-3-methoxy-N-pivaloylaniline (8b): This
compound was obtained starting from 2b; yield: 69 mg (47%); mp
224°C (petroleum ether).
Method C: Similar to Method B; however, a 10% toluene solution of
KHMDS was used instead of 15%.
Spectroscopic data for compounds 3a to 3m are summarized in Ta-
bles 2 and 3.
IR (KBr): ν = 2240,1646, 1259 cm–1.
1
H NMR (250 MHz, DMSO-d6): δ = 10.50 (s, 1 H, NH), 8.00 (d, 1 H,
J = 8.2 Hz, H-6), 7.22 (t, 1 H, J = 8.2 Hz, H-5), 6.76 (s, 1 H, J = 8.2
Hz, H-4), 5.28 (d, 1 H, J = 5.9 Hz, H-1'), 3.77 (s, 3 H, OCH3), 3.10 (d,
1 H, J = 5.9 Hz, OH), 2.90 (m, 1 H, H-2'), 1.54 (m, 2 H, H-3'), 1.20
[s, 9 H, C(CH3)3], 0.99 (t, 3 H, J = 7.4 Hz, H-4').
2-(1-Hydroxy-2-methylbutyl)-3-methoxy-N-pivaloylaniline (4b):
yield: 275 mg (62%); mp 167°C (EtOAc/petroleum ether).
13
IR (KBr): ν = 3396 (OH), 1653 (CO), 1250 cm–1 (OCH3).
C NMR (63 MHz, DMSO-d6): δ = 175.5 (CO), 156.1 (C-3), 139.1
1H NMR (250 MHz, CDCl3): δ = 9.78 and 9.70 (s, 1 H, NH), 7.96 and
7.91 (d, 1 H, J = 8.3 Hz, H-6), 7.18 (t, 1 H, J = 8.3 Hz, H-5), 6.59 (d,
1 H, J = 8.3 Hz, H-4), 5.18 and 5.17 (d, 1 H, J = 8.3 Hz, H-1'), 3.78
(C-1), 128.8 (C-5), 120.8 (CN), 116.2 (C-2), 113.6 (C-6), 105.8 (C-
4), 66.9 (C-1'), 55.7 (OCH3), 39.7 (C-2'), 27.1 [C(CH3)3], 22.2 (C-3'),
11.3 (C-4').