6496
T. R. Ward et al. / Tetrahedron Letters 50 (2009) 6494–6497
Table 1
Yields (%) and purity (%) of substituted quinolones 7(1–72) produced via Scheme 1
aEntry R1
=
R2 = H
R2 = Me
R2 = Ph
R2 = 4-(Me)C6H4
R2 = 4-(C5H11)C6H4
R2 = 4-(MeO)C6H4
R2 = 3-FC6H4
R2 = 2,4-(F)2C6H3
H
43/>95
64/>95
79/>95
74/>95
78/>95
38/>95
72/>95
11/>95
86/90
14/>95
36/>95
40/>95
18/>95
15/>95
Trace/n.a.
8/>95
12/>95
81/>95
88/>95
63/>95
35/>95
14/>95
5/>95
34/95
7/>95
7/>95
17/>95
9/85
3/>95
8/>95
6/95
59/95
30/80
67/>95
69/>95
73/95
20/>95
81/>95
77/>95
92/>95
93/>95
68/90
67/94
23/85
25/95
91/95
32/>95
87/>95
36/>95
31/95
7-Cl
6-Cl
6-F
6-Me
6-MeO
6,7-(MeO)2
7-F
5-F
95/>95
63/>95
86/>95
67/>95
68/>95
88/>95
74/>95
57/>95
35/>95
90/>95
60/>95
65/>95
52/>95
83/>95
31/>95
19/>95
Trace/n.a.
66/95
39/95
9/95
34/>95
Trace/n.a.
a
Table entries are yields (%)/purity (%).8
to the enolate anion in the anthranilic acid-derived case. The eno-
late anion form does not cyclize.
122.3, 121.9, 81.0, 61.8, 34.2, 28.5; MS (EI): m/z M+H 315; HRMS
14H20ClN2O4 + calcd 315.1112; found 315.1097; 6(4): R1 = 5-F:
C
In conclusion, we have developed a parallel synthesis of quino-
lones that uses much milder conditions than previously reported
methods. No strong bases or high temperatures were required.
We have obtained evidence for an addition-elimination process
to yield the apparent 6-endo-dig products, involving methanol as
the catalytic nucleophile. This expands the synthetic utility of
ynones as b-carbonyl synthons.
Yield 69%; 1H NMR (400 MHz, CDCl3) d 8.24 (s, 1H), 8.12 (dd,
J = 8.6 Hz, J = 4.8 Hz, 1H), 7.21 (dd, J = 8.8 Hz, J = 3.0 Hz, 1H), 7.11
(ddd, J = 9.1 Hz, J = 8.1 Hz, J = 3.0 Hz, 1H), 3.56 (s, 3H), 3.40 (s,
3H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) d 167.7, 158.4,
156.0, 153.2, 134.4, 122.7, 118.5, 118.3, 115.6, 115.3, 80.8, 61.8,
34.1, 28.5; MS (EI): m/z M+H 299; HRMS C14H20FN2O4 + calcd
299.1402; found 299.1383; 6(5): R1 = 5-Me: Yield 67%; 1H NMR
(400 MHz, CDCl3) d 8.15 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.25–7.17
(m, 2H), 3.58 (s, 3H), 3.38 (s, 3H), 2.32 (s, 3H), 1.50 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 169.3, 153.2, 135.5, 132.2, 131.4, 129.0,
121.8, 120.9, 80.5, 61.5, 34.8, 28.5, 20.8; MS (EI): m/z M+H 295;
HRMS C15H23N2O4 + calcd 295.1658; found 295.1656; 6(6):
R1 = 5-MeO: Yield 59%; 1H NMR (400 MHz, CDCl3) d 8.03–7.85
(m, 2H), 7.00–6.94 (m, 2H), 3.79 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H),
1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) d 168.6, 154.4, 153.4,
130.8, 123.8, 122.9, 116.9, 113.7, 80.3, 61.5, 55.8, 34.4, 28.5; MS
(EI): m/z M+H 310; HRMS C15H23N2O5 + calcd 311.1607; found
311.1600; 6(7): R1 = 4,5-(MeO)2: Yield 62%; 1H NMR (400 MHz,
CDCl3) d 8.73 (s, 1H), 7.78 (s, 1H), 6.98 (s, 1H), 3.80 (s, 3H), 3.68
(s, 3H), 3.42 (s, 3H), 3.22 (s, 3H), 1.37 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 168.8, 152.9, 151.4, 142.8, 134.0, 119.3,
111.9, 103.4, 80.0, 61.1, 56.0, 55.8, 34.1, 28.2; MS (EI): m/z M+H
340; HRMS C16H25N2O6 + calcd 341.1713; found 341.1707; 6(8):
R1 = 4-F: Yield 80%; 1H NMR (400 MHz, CDCl3) d 8.81 (s, 1H), 8.08
(dd, J = 11.9 Hz, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.7 Hz, J = 6.4 Hz, 1H),
6.68 (ddd, J = 8.7 Hz, J = 7.8 Hz, J = 2.5 Hz, 1H), 3.54 (s, 3H), 3.38
(s, 3H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) d 168.6, 165.9,
163.4, 152.8, 141.3, 141.2, 131.2, 131.1, 115.8, 108.6, 108.4,
107.4, 107.1, 81.1, 34.4, 28.5; MS (EI): m/z M+H 299; HRMS
C14H20FN2O4 + calcd 299.1402; found 299.1407; 6(9): R1 = 6-F:
Yield 59%; two isomers, ꢀ2:1: 1H NMR (400 MHz, CDCl3) d 7.75
(d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.17 (dd, J = 8.1 Hz, J = 14.9 Hz,
1H), 6.59 (dd, J = 8.8 Hz, J = 8.7 Hz, 1H), 3.70–3.31 (m, 3H), 3.22–
3.07 (m, 3H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) d 164.5,
161.2, 160.0, 159.6, 157.6, 157.2, 152.2, 138.6, 137.8, 131.9,
131.2, 115.6, 115.5, 112.1, 111.8, 109.2, 109.0, 80.6, 61.5, 60.7,
36.2, 31.9, 28.1, 27.9; MS (EI): m/z M+H 299; HRMS
C14H20FN2O4 + calcd 299.1402; found 299.1424.
Boc-protected Weinreb anthranilamides: Weinreb amide repre-
sentative procedure: To each substituted anthranilic acid 5{1–9}
(6.45 mmol) in a 100 mL round-bottomed flask with a stirring
bar was added Boc2O (1.48 g, 6.78 mmol). DMF (2.0 mL) was
added, a rubber septum cap was attached, and the mixture was
stirred. When all was dissolved, TEA (0.90 mL) or NMM (0.71 mL)
was added with a syringe, and a bubbler was attached with a nee-
dle to monitor CO2 evolution. The mixtures were stirred until all
gas evolution had ceased, between 3 and 5 days. One mixture
was warmed to 50 °C to complete the reaction (5-fluoro) (caution:
excessive heating decomposed the Boc2O). After all gas evolution
had ceased, to each flask were added HOBt (0.91 g, 6.5 mmol),
DMF (4.5 mL), CH2Cl2 (4.5 mL), and EDCI (1.33 g, 6.94 mmol), and
the mixtures were stirred for 0.5–1 h. To each flask were added
N,O-dimethyl-hydroxylamine hydrochloride (0.76 g, 7.8 mmol),
and NMM (0.85 mL) or TEA (1.08 mL), and the mixtures were stir-
red overnight. Work-up: Each reaction mixture was added to 3:1
hexanes:CH2Cl2 (100 mL) and extracted with 50% brine
(7 Â 25 mL), and brine (2 Â 25 mL). The organics were decanted
and concentrated. Crude products 6{1–9} were purified by column
chromatography on silica gel (30 mL, 60–200 mesh) using step gra-
dients in 1:1 hexanes:CH2Cl2 with ethyl acetate in proportions of
5%, 10%, and 15% as required, and collecting 10 mL fractions. The
fractions were tested by TLC and appropriate fractions were pooled
and concentrated.
Weinreb amide precursors: compound 6(1): R1 = H: Yield 75%; 1H
NMR (400 MHz, CDCl3) d 8.38 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.46
(d, J = 8.4 Hz, 1.5 Hz, 1H), 7.39 (m, 1H), 7.00 (ddd J = 7.7 Hz,
J = 7.5 Hz, J = 1.0 Hz, 1H), 3.57 (s, 3H), 3.36 (s, 3H), 1.50 (s, 9H);
13C NMR (100 MHz, CDCl3) d 169.2, 153.1, 138.3, 131.6, 128.9,
121.7, 121.2, 120.6, 80.7, 61.6, 34.7, 28.5; MS (EI): m/z M+H 281;
HRMS C14H21N2O4 + calcd 281.1496; found 281.1499; 6(2):
R1 = 4-Cl: Yield 72%; 1H NMR (400 MHz, CDCl3) d 8.65 (s, 1H),
8.34 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.97 (dd J = 2.1 Hz,
J = 8.4 Hz, 1H), 3.55 (s, 3H), 3.38 (s, 3H), 1.50 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 168.4, 152.7, 139.9, 137.9, 130.2, 122.2,
121.6, 120.1, 81.1, 61.7, 34.2, 28.5; MS (EI): m/z M+H 315; HRMS
C14H20ClN2O4 + calcd 315.1112; found 315.1113; 6(3): R1 = 5-Cl:
Yield 70%; 1H NMR (400 MHz, CDCl3) d 8.32 (s, 1H), 8.12 (d,
J = 9.0 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 2.5 Hz,
J = 9.0 Hz, 1H), 3.53 (s, 3H), 3.32 (s, 3H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 167.8, 152.9, 137.0, 131.5, 128.6, 126.8,
Quinolone library method: Boc-protected anthranilic Weinreb
amides 6{1–9} (0.150 mmol) were weighed into numbered Met-
tler–Bohdan Miniblock reaction tubes (11 Â 150 mm) and placed
into a lyophilizer overnight, one set of 6{1–9} for each metal acet-
ylide. The tubes were removed from the lyophilizer under argon,
and assembled in the Miniblock 24 tube holder with stir bars in
each tube. Empty tubes were placed in the remaining positions,
the gasket and cover were affixed, and the system was purged by
four argon/vacuum cycles and then left under argon. Into each tube
containing a Boc-protected anthranilic Weinreb amide was added
with a syringe a solution of metal acetylide. For HCCMgBr and