Efficient route to medium-ring benzo- and azabenzo-lactones

Article abstract of DOI:10.1080/00397910701845415

The synthesis of precursors of medium-ring benzo- and azabenzo-lactones is performed efficiently from simple ortho-halo aryl and heteroaryl aldehydes. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701845415

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Efficient Route to Medium‐Ring Benzo‐ and
Azabenzo‐lactones
a
a
a
Estelle Metay , Eric Léonel & Jean‐Yves Nédélec
a
Institut de Chimie et des Matériaux Paris‐Est, Equipe Electrochimie et
Synthèse Organique , Thiais, France
Published online: 22 Feb 2008.
To cite this article: Estelle Metay , Eric Léonel & Jean‐Yves Nédélec (2008) Efficient Route to Medium‐Ring
Benzo‐ and Azabenzo‐lactones, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 38:6, 889-904, DOI: 10.1080/00397910701845415
To link to this article: http://dx.doi.org/10.1080/00397910701845415
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Synthetic Communications , 38: 889–904, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845415
Efficient Route to Medium-Ring Benzo- and
Azabenzo-lactones
Estelle Metay, Eric L e´ onel, and Jean-Yves N e´ d e´ lec
Institut de Chimie et des Mat e´ riaux Paris-Est, Equipe Electrochimie et
Synth e` se Organique, Thiais, France
Abstract: The synthesis of precursors of medium-ring benzo- and azabenzo-lactones is
performed efficiently from simple ortho-halo aryl and heteroaryl aldehydes.
Keywords: electrochemical arylation, medium ring lactones, nickel catalysis
Medium-ring lactones are challenging targets of interest either as intermedi-
[
ates or as bioactive compounds. Indeed, many natural products have been
1]
[2]
described with medium- to large-ring lactones. However, they are hardly
[3]
prepared chemically, even by the most obvious ring-forming lactonization.
In addition, precursors can also be difficult to prepare. We have previously
reported our studies on the synthesis of a–v hydroxyacids to access to
[
4]
medium-ring benzolactones. Lactone precursors are characterized by two
carbon chains ortho to each other on the aromatic ring and ending with the
carboxyl for one and the alcohol group for the other. Several features have
already been investigated, such as the size of the lactone (from 7 to 11
members), the relative position of the carboxyl connection relative to the
aromatic ring (excluding conjugated carbonyls), the possible presence of
double bonds within the ring, and the number of steps. The study presented
here refers to the aromatic side of the benzolactone, considering either the
Received in Poland July 18, 2007
Address correspondence to Eric L e´ onel, Institut de Chimie et des Mat e´ riaux Paris-
Est, Equipe Electrochimie et Synth e` se Organique, UMR 7182 CNRS Universit e´ Paris
12, 2, rue Henri Dunant, F-94320 Thiais, France. E-mail: leonel@glvt-cnrs.fr
8
89

8
90
E. Metay, E. L e´ onel, and J.-Y. N e´ d e´ lec
2.
2 4 4
Figure 1. Reagents and conditions: (a) NiBr 3H O, NBu Br, NBu I, DMF/pyridine
(
9/1), 1008C, 3 h.
presence of substituents on the phenyl ring or the heteroaromatic character of
this moiety. Apart from considering the potential interest of the prepared
structures, the purpose was to take into account the specific reactivity of the
substrates in each step as a function of the aromatic ring.
Typical starting materials are aryl or heteroaryl rings featuring a
C-halogen bond and a C-C bond that are ortho to each other. In the first exper-
iment, we attempted to introduce a propionic chain alpha to the nitrogen of the
OH-protected 2-chloro-3-hydroxymethylpyridine via the nickel-catalysed
electrochemical coupling with ethyl acrylate. However, we only obtained
the bipyridine derivative instead of the addition product to the acrylic ester
(
see Fig. 1). This result was both surprising, because the reaction conditions
applied to the other substrates never gave such a dimer, and interesting,
because ortho-substituted aryl halides are hardly dimerized for steric reasons.
We then shifted to another methodology, which is detailed in Scheme 1.
For this procedure, we used the commercially available precursors, ortho-
halo aryl aldehydes or carboxylic acids, with the halogen being alpha to the
nitrogen in pyridine and quinoline derivatives. The aldehyde carbonyl is
used to introduce one carbon chain via the Wadsworth–Emmons reaction,
while the C-halogen bond is involved in the electrochemical condensation
with an activated olefin.
The starting compounds are listed in Scheme 2.
They are all commercial except the pyridine derivative, which was
obtained from 2-chloronicotinic acid via alcohol (Scheme 3).
From these aldehydes, we started introducing a carbon chain ending with
[5]
a carboxylic group via the Wadsworth–Emmons reaction (Table 1). The
propenoic chain was introduced efficiently (yields of 83% to 99%, Table 1,
entries 1–3). The yields in the pentadienoic chain (Table 1, entries 4 and 5)
were lower, between 53 and 56%, with an all (E)-geometry.
The next step was the introduction of the second carbon chain, ending
with a precursor of the alcohol group in the form of a carbonyl. The reaction
was thus the arylation of methyl-vinylketone via the electrochemical
method involving nickel complexes as catalysts. Isolated yields are good to
high (Table 2). It should be pointed out that this reaction is very selective,
because no side reaction occurred on the unsaturated carbon chain already
present on the molecule. The yield is quite medium with the fluoro derivative
(Table 2, entry 1), which indeed led more importantly to mere reduction of
the C-Br bond.

Medium-Ring Benzo- and Azabenzo-lactones
891
Scheme 1.
The two functional groups were then manipulated to generate the alcohol
by reduction of the ketone carbonyl and the carboxylic acid by saponification.
Regarding the reduction, we selected the reagent able to reduce both
the ketone carbonyl and the C 55 C double bond(s) without reducing
the ester group. This was performed by the combination of NaBH with
4
[
NiCl , as described by Narisada. The C 55 C double bonds had to be
6]
2
reduced because (E)-C,C double bonds preclude the hydroxy acid from
lactonizing.
The carboxylic group was generated from the corresponding ester by
saponification, and the hydroxy acids were obtained in high yields. The
Scheme 2.

8
92
E. Metay, E. L e´ onel, and J.-Y. N e´ d e´ lec
2 3 4
Scheme 3. Reagents and conditions: (a) 1, KOH; 2, BrCH CH , NBu Br, 308C, 4 h;
(
b) NaBH4, CaCl ethanol 08C, 2 h; (c) SOCl , reflux, 2 h; (d) NaBH , H O, 08C,
2
2
4
2
3
2 2
0 min; (e) PCC, CH Cl , rt, 2 h.
Table 1. Wadsworth–Emmons reaction
Compound
number
Isolated
yields (%)
Entry
1
Products
5
6
7
8
96
99
83
53
2
3
4
5
9
56
reactions were conducted with KOH in water/dioxane at reflux followed by
H SO hydrolysis or with NaOH in methanol at room temperature followed
2
4
by HCl treatment. The second method is more appropriate for the aza
compounds with an amount of water as low as possible, thus allowing an
easy recovery of the hydrochloride compounds (Table 3).

Medium-Ring Benzo- and Azabenzo-lactones
893
Table 2. Electrochemical arylation
Compound
number
Isolated
yield(%)
Entry
1
Product
10
11
12
43
2
3
82
66
4
5
13
14
65
63%
The final lactones were obtained by lactonization using the Yamamoto
[
method based on the use of p-nitrobenzoic anhydride and scandium triflate.
7]
All compounds obtained are new benzo- or azabenzo-lactones (Table 4).
EXPERIMENTAL
All reagents and supporting electrolytes were used as obtained commercially.
All reactions were performed under an inert atmosphere (argon) unless
otherwise indicated. An iron rod was used as the anode. The cathode was
made of nickel foam.
1
13
H and C NMR spectra were recorded on an Avance 300 (300-MHz)
spectrometer at room temperature, except for benzolactone 20, 21, and 22
1
3
at 708C. In the C data, some of aromatic signals are missing. This might
be a consequence of the overlapping of certain signals. Infrared spectra

8
94
E. Metay, E. L e´ onel, and J.-Y. N e´ d e´ lec
Table 3. Double bond and ketone reduction
Compound
number
Isolated
Yield (%)
Entry
1
Product
15
82
71
2
3
4
5
16
17
18
19
87
66
55%
were recorded on a Perkin-Elmer Spectrum BX II spectrometer. Mass spectra
electron impact) were obtained on a Thermoquest GCQ spectrometer coupled
(
to a Finnigan-GCQ chromatograph with a CPSIL5CB/MS capillary column.
High-resolution mass spectra were performed by Service Central d’Analyses
du CNRS, Lyon, France.
Compound 1, Ethyl 2-Chloropyridine-3-carboxylate
Preparation
To a solution of chloronicotinic acid (30 mmol, 4.76 g) in methanol (50 mL),
pellets of KOH (30 mmol, 1.95 g) were added. The solvent was removed

Medium-Ring Benzo- and Azabenzo-lactones
895
Table 4. Lactonization
Compound
number
Isolated
Yields (%)
Entry
1
Lactone
20
76
2
3
4
5
21
55
26
78
25
22
23
24
under pressure. The salt obtained was mixed in a flask with tetrabutylammo-
nium bromide (3 mmol, 0.967 g) and bromoethane (45 mmol, 3.44 mL). After
4 h of stirring at 308C, the reaction mixture was diluted with ether (200 mL)
and filtrated over a florisil pad.
Data
[
8]
1
RN: [1452-94-4]; 92%; H NMR (CDCl , 300 MHz) d: 8.50 (dd, J ¼ 4.8,
3
1
4
7
.9 Hz, 1H), 8.15 (dd, J ¼ 7.7, 1.9 Hz, 1H), 7.33 (dd, J ¼ 4.8, 7.7 Hz, 1H),
1
3
.41 (q, J ¼ 7.1 Hz, 2H), 1.40 (t, J ¼ 7.1 Hz, 3H); C NMR (CDCl ,
3
5 MHz) d: 164.5, 151.7, 149.9, 140.1, 127.2, 122.1, 62.1, 14.1; MS (EI) M/
Z (%): 185 (18), 159 (26), 157 (78), 150 (57), 142 (35), 140 (100), 114 (11),
13 (16), 112 (31), 76 (21); IR vmax: 3037, 2997, 2941, 2908, 1727, 1581, 1564.
1

8
96
E. Metay, E. L e´ onel, and J.-Y. N e´ d e´ lec
Compound 3, 2-Chloro-3-hydroxymethylpyridine
Method b
To a solution of ethyl-2-chloropyridine carboxylate (45 mmol, 8.4 g) in ethanol
(
150 mL), NaBH (90 mmol, 3.42 g) and CaCl (90 mmol, 9.99 g) were added
4 2
portionwise at 08C over 30 min. After 2 h of stirring at room temperature, the
reaction mixture was quenched with 1 N sodium hydroxide aqueous solution
(
50 mL), extracted with ether, dried over MgSO , filtered, and concentrated.
4
Methods c and d
Chloronicotinic acid (78.9 mmol, 12.5 g) was mixed with thionyl chloride
(
50 mL) and heat at reflux for 2 h then concentrated. The solid obtained
was added portionwise to a solution of NaBH (78.9 mmol, 12.5 g) in water
4
(
NaCl and extracted with ether, dried over MgSO , filtered, and concentrated.
100 mL) at 08C. After 30 min, the reaction mixture was saturated with
4
Data
[
9]
1
RN: [42330-59-6]; mp:62–638C;70%(a þ b); 82%(d þ e); HNMR(CDCl ,
3
3
00 MHz) d: 8.18 (dd, J ¼ 4.8, 1.9 Hz, 1H), 7.92 (dd, J ¼ 7.6, 1.9 Hz, 1H), 7.24
13
(
dd, J ¼ 4.8, 7.6 Hz, 1H), 4.73 (s, 2H); C NMR (CDCl , 75 MHz) d: 148.7,
3
1
1
47.6, 137.0, 135.8, 122.9, 60.8; EI-MS (m/z): 145 (15), 144 (14), 143 (46),
42 (28), 116 (11), 114 (30), 108 (100), 107 (13), 106 (50), 80 (16), 79 (23), 78
(70), 76 (11), 52 (15), 51 (31); IR ( max: 3605, 3350, 1583, 1570.
Compound 4, 2-Chloro-3-formylpyridine
Preparation
To a solution of 2-chloro-3-hydroxymethylpyridine (66.5 mmol, 9.61 g) in
CH Cl (100 mL), pyridinium chlorochromate (79.8 mmol, 17.2 g) was
2
2
added. After 2 h, the reaction mixture was diluted with ether, washed twice
with ether, then filtered and concentrated. Purification by column chromato-
graphy (70–200 mesh; pentane/ethyle acetate 50/50) afforded 6.89 g of the
title product.
Data
[
RN: [36404-88-3]; 73%; H NMR (CDCl , 300 MHz) d: 10.24 (s, 1H), 8.62
9]
1
3
(
m, 1H), 8.25 (m, 1H), 7.46 (dd, J ¼ 4.5, 7.5 Hz, 1H); EI-MS (m/z): 143 (28),
1
7
42 (37), 141 (80), 140 (100), 114 (11), 113 (11), 112 (34), 105 (69), 78 (12),
7 (28), 76 (36), 51 (19), 50 (16).

Medium-Ring Benzo- and Azabenzo-lactones
Compounds 5–9
897
Procedure
For general procedure, see ref. [5] for product 5 to 9.
Ethyl (E)-3-(2-bromo-5-fluorophenyl)prop-2-enoate 5
1
Yield 96%; H NMR (CDCl , 300 MHz) d: 7.96 (d, J ¼ 15.9 Hz, 1H), 7.55
3
4
3
(
dd, J ¼ 8.8 Hz,
J
¼ 5.2 Hz, 1H), 7.30 (dd, J ¼ 3.0 Hz,
J
¼
HF
HF
3
9
.4 Hz, 1H), 6.97 (ddd, J ¼ 3.0 Hz, J ¼ 8.8 Hz, J
¼ 7.7 Hz, 1H), 6.37
HF
(
1
d, J ¼ 15.9 Hz, 1H), 4.29 (q, J ¼ 7.1 Hz, 2H), 1.35 (t, J ¼ 7.1 Hz, 3H);
3
1
C NMR (CDCl , 75 MHz) d: 166.0, (d,
3
J
¼ 247.7 Hz) 161.9,
CF
4
d, J
3
3
(
¼ 2.0 Hz) 141.8, (d, J
¼ 7.8 Hz) 136.2, (d, J
¼ 8.0 Hz)
CF
CF
CF
4
34.6, 122.3, (d, J
2
1
1
¼ 3.2 Hz) 119.4, (2d, J
¼ 22.7 Hz, 23.5 Hz)
CF
CF
1
18.4 and 114.4, 60.8, 14.3; F NMR (CDCl , 188 MHz) d: 2113.8 (m);
9
3
MS (EI) M/Z (%): 273 (9), 229 (13), 227 (13), 193 (63), 166 (10), 165
100), 121 (23), 120 (38), 109 (13); IR vmax: 3074, 2980, 2938, 1713;
HRMS (ESI) m/z calcd. for C H BrFO (M þ H) 272.9926; found:
(
1
1
11
2
2
72.9940.
Ethyl (E)-3-(2-Chloro-6-methoxy-3-quinolyl)prop-2-enoate 6
1
Mp: 109.1–111.68C; quantitative; H NMR (CDCl , 300 MHz) d: 8.19
3
(
s, 1H), 8.05 (d, J ¼ 16.0 Hz, 1H), 7.85 (d, J ¼ 9.2 Hz, 1H), 7.36 (dd,
J ¼ 9.2, 2.8 Hz, 1H), 7.03 (d, J ¼ 2.8 Hz, 1H), 6.51 (d, J ¼ 16.0 Hz, 1H),
1
3
4
.32 (q, J ¼ 7.1 Hz, 2H), 3.92 (s, 3H), 1.38 (t, J ¼ 7.1 Hz, 3H); C NMR
(CDCl , 75 MHz) d: 165.9, 158.5, 147.4, 143.9, 139.3, 134.7, 129.7, 128.1,
3
1
2
2
27.4, 124.3, 122.5, 105.2, 60.9, 55.6, 14.3; MS (EI) M/Z (%): 293 (10),
91 (30), 256 (58), 229 (14), 228 (100), 200 (39), 182 (13); IR ( max: 3038,
988, 1711, 1638, 1621. HRMS (ESI) m/z calcd. for C H ClNO
3
1
5
15
(M þ H) 292.0740; found: 292.0753.
Ethyl (E)-3-(2-Chloro-3-pyridinyl)prop-2-enoate 7
[
10]
1
RN: [148247-84-1],
mp: 49.1–49.88C; 83%; H NMR (CDCl , 300 MHz)
3
d: 8.40 (dd, J ¼ 1.8 Hz, J ¼ 4.7 Hz, 1H), 7.98 (d, J ¼ 15.8 Hz, 1H), 7.94 (dd,
J ¼ 1.8 Hz, J ¼ 7.7 Hz, 1H), 7.31 (dd, J ¼ 4.7 Hz, J ¼ 7.7 Hz, 1H), 6.46
(
d, J ¼ 15.8 Hz, 1H), 4.29 (q, J ¼ 7.1 Hz, 2H), 1.36 (t, J ¼ 7.1 Hz, 3H);
1
3
C NMR (CDCl , 75 MHz) d: 165.8, 151.3, 150.5, 138.8, 136.0, 129.6,
3
(
(
2C) 123.0, 122.9, 61.0, 14.3; MS (EI) M/Z (%): 211 (,10), 176 (72), 166
27), 148 (100), 138 (12), 120 (24), 102 (16); IR vmax: 3037, 2997, 2941,
2
875, 1727, 1581, 1564.

8
98
E. Metay, E. L e´ onel, and J.-Y. N e´ d e´ lec
Ethyl (E,E)-5-(2-Bromo-4.5-methylenedioxyphenyl)penta-2.4-dienoate 8
1
Mp: 87.3–88.98C; 53%; H NMR (CDCl , 300 MHz) d: 7.46 (dd, J ¼ 11.1,
3
J ¼ 15.1 Hz, 1H), 7.18 (d. J ¼ 15.4 Hz, 1H), 7.05 (s, 1H), 7.01 (s, 1H),
6
1
7
1
.64 (dd, J ¼ 11.0, J ¼ 15.4 Hz, 1H), 6.00 (s, 2H), 5.98 (d, J ¼ 15.1 Hz,
1
3
H), 4.24 (q, J ¼ 7.1 Hz, 2H), 1.33 (t, J ¼ 7.1 Hz, 3H); C NMR (CDCl ,
3
5 MHz) d: 166.9, 149.0, 147.9, 144.3, 138.4, 129.1, 126.9, 121.6, 113.0,
16.6, 105.8, 102.1, 60.4, 14.4; MS (EI) M/Z (%): 326 (46), 324 (47), 253
(
14), 252 (27), 251 (18), 250 (25), 223 (11), 200 (23), 199 (19), 174(10),
73 (86), 172 (100), 171 (42), 144 (10), 143 (27), 115 (33), 114 (17); IR
vmax: 3054, 2984, 2904, 1705, 1614, 1505, 1475.
1
Ethyl (E,E)-5-(2-Chloro-6-methyl-3-quinolyl)penta-2.4-dienoate 9
1
Mp: 121–1248C; 56%; H NMR (CDCl , 300 MHz) d: 8.22 (s, 1H), 7.86
3
(
(
(
(
d, J ¼ 8.4 Hz, 1H), 7.57–7.48 (m, 3H), 7.32 (d, J ¼ 15.5 Hz, 1H), 6.95
dd, J ¼ 15.5 Hz, 11.1 Hz, 1H), 6.10 (d, J ¼ 15.3 Hz, 1H), 4.28
1
3
q, J ¼ 7.1 Hz, 2H), 2.54 (s, 3H), 1.36 (t, J ¼ 7.1 Hz, 3H); C NMR
CDCl , 75 MHz) d: 166.6, 149.0, 145.9, 143.5, 137.6, 134.6, 133.9, 133.2,
3
1
30.0, 128.0, 126.6, 128.6, 127.2, 123.3, 60.6, 21.6, 14.3; MS (EI) M/Z
%): 303 (15), 301 (47), 256 (13), 230 (36), 229 (21), 228 (100), 227 (23),
10 (15), 194 (12), 193 (20), 192 (53), 191 (15), 190 (12), 165 (22); IR (
(
2
max: 3025, 2992, 2928, 1707, 1629, 1602; HRMS (ESI) m/z calcd. for
C H ClNO (M þ H): 302.0948; found: 302.0941.
1
7
17
2
Preparation of Compounds 10–14
Procedure
2
Under argon, in an undivided cell equipped with a nickel grid (area 40 cm ) as
the cathode and a Fe/Ni (64/36) rod as the anode, tetrabutylammonium
bromide (0.34 mmol) and tetrabutylammonium iodide (0.21 mmol) as sup-
porting electrolytes were dissolved in a mixture of DMF (50 mL) and
pyridine (5 mL). 1,2-Dibromoethane (0.1 mmol) was introduced after a
short electrolysis run at constant current density (0.2 A) and at room tempera-
.
ture over 15 min; the olefin (30 mmol), NiBr 3H O (0.75 mmol), and the aryl
2
2
bromide (10 mmol) were added. The reaction mixture was heated at 808C. The
electrosynthesis was run at current density (0.1 A). The reaction was
monitored by gas chromatography (GC) and stopped after the aryl bromide
was consumed. The mixture was then hydrolyzed with hydrochloric acid
(6 N, 30 mL) and diluted with diethyl ether (2 ꢀ 50 mL) and the combined
organic layers were washed with water and saturated NaCl solution, then
dried over MgSO . The oil thus obtained was purified by column chromato-
4
graphy (silica gel, pentane–ether, 70/30 eluent) to give the desired product.

Medium-Ring Benzo- and Azabenzo-lactones
899
Ethyl (E)-3-[5-Fluoro-2-(3-oxobutyl)phenyl]prop-2-enoate 10
1
Yield 43%; H NMR (CDCl . 300 MHz) d: 7.94 (d, J ¼ 15.8 Hz, 1H), 7.26–
3
7
.18 (m, 2H), 7.04–6.97 (m, 1H), 6.37 (d, J ¼ 15.8 Hz, 1H), 4.29
(
q, J ¼ 7.2 Hz, 2H), 3.03–2.98 (m, 2H), 2.73–2.67 (m, 2H), 2.15 (s, 3H),
1
3
1
.36 (t, J ¼ 7.2 Hz, 3H); C NMR (CDCl , 75 MHz) d: 207.0, 166.5,
3
1
d, J
4
4
(
¼ 245.1 Hz) 161.5, (d, J
¼ 2.0 Hz) 140.4, (d, J
¼ 3.0 Hz)
CF
CF
CF
3
36.3, (d, J
3
1
2
¼ 7.5 Hz) 134.7, (d, J
¼ 7.9 Hz) 131.7, 121.2, (2d,
CF
CF
JCF ¼ 21.2, 22.1 Hz) 117.0 and 113.1, 60.7, 44.8, 30.0, 26.3, 14.3; MS
(
EI) M/Z (%): 264 (2), 190 (22), 176 (19), 175 (100), 149 (16), 148 (12),
47 (67), 146 (12), 133 (29), 127 (14); IR vmax: 3068, 2987, 2940, 1715;
1
HRMS (ESI) m/z calcd. for C H FO (M þ H): 265.1240; found: 265.1246.
1
5
18
3
Ethyl (E)-3-[6-Methoxy-2-(3-oxobutyl)-3-quinolyl]prop-2-enoate 11
1
Mp 111.3–111.78C; 82%; H NMR (CDCl , 300 MHz) d: 8.15 (s, 1H), 8.09
3
(
d, J ¼ 15.8 Hz, 1H), 7.87 (d, J ¼ 9.1 Hz, 1H), 7.36 (dd, J ¼ 9.2, 2.8 Hz, 1H),
7
.07 (d, J ¼ 2.8 Hz, 1H), 6.50 (d, J ¼ 15.8 Hz, 1H), 4.34 (q, J ¼ 7.1 Hz, 2H),
3
.95 (s, 3H), 3.39–3.35 (m, 2H), 3.11–3.06 (m, 2H), 2.36 (s, 3H), 1.38
1
3
(
t, J ¼ 7.1 Hz, 3H); C NMR (CDCl , 75 MHz) d: 208.3, 166.4, 157.7,
3
1
5
55.8, 144.1, 140.6, 132.6, 130.1, 127.8, 127.6, 123.0, 121.9, 105.2, 60.8,
5.6, 40.5, 30.5, 29.5, 14.3; MS (EI) M/Z (%): 327 (17), 312 (12), 285
(
15), 284 (100), 256 (53), 255 (14), 254 (86), 212 (29), 211 (23), 210 (57),
68 (10), 167 (18); IR vmax: 3034, 2962, 1712, 1636; HRMS (ESI) m/z
calcd. for C H NO (M þ H): 328.1549; found: 328.1556.
1
1
9
22
4
Ethyl (E)-3-[2-(3-Oxobutyl)-3-pyridinyl]prop-2-enoate 12
1
Yield 66%; H NMR (CDCl , 300 MHz) d: 8.49 (dd, J ¼ 4.8, 1.6 Hz, 1H),
3
7
.98 (d, J ¼ 15.9 Hz, 1H), 7.80 (dd, J ¼ 7.8, 1.6 Hz, 1H), 7.17 (dd, J ¼ 7.8,
.8 Hz, 1H), 6.37 (d, J ¼ 15.9 Hz, 1H), 4.30 (q, J ¼ 7.1 Hz, 2H), 3.25–3.20
4
1
3
(
m, 2H), 3.01–2.97 (m, 2H), 2.24 (s, 3H), 1.36 (t, J ¼ 7.1 Hz, 3H);
C
NMR (CDCl , 75 MHz) d: 207.9, 166.2, 158.5, 149.9, 140.1, 133.9, 128.9,
3
1
21.8, 121.6, 60.7, 40.9, 30.1, 28.6, 14.3; MS (EI) M/Z (%): 232 (57), 205
11), 204 (100), 176 (63), 174 (86), 132 (53), 131 (29), 130 (91), 117 (11);
(
IR vmax: 3069, 2977, 2939, 1713, 1637, 1583, 1566, 1433; HRMS (ESI) m/
z calcd. for C H NO (M þ H): 248.1287; found: 248.1292.
1
4
18
3
Ethyl (E,E)-5-[4,5-Methylenedioxy-2-(3-oxobutyl)phenyl]pent-2,4-
dienoate 13
1
Mp 70.5–71.38C; 65%; H NMR (CDCl , 300 MHz) d: 7.42 (dd, J ¼ 11.1,
3
J ¼ 15.3 Hz, 1H), 7.05–6.64 (m, 4H), 5.95–5.90 (m, 3H), 4.20
(
q, J ¼ 7.1 Hz, 2H), 2.90–2.85 (m, 2H), 2.66–2.61 (m, 2H), 2.12 (s, 3H),
1
3
1
.31 (t, J ¼ 7.1 Hz, 3H); C NMR (CDCl , 75 MHz) d: 207.2, 167.0,
3

9
00
E. Metay, E. L e´ onel, and J.-Y. N e´ d e´ lec
1
6
48.5, 146.7, 144.8, 136.8, 134.6, 127.8, 125.9, 120.6, 109.9, 105.3, 101.3,
0.3, 44.9, 30.0, 26.9, 14.3; MS (EI) M/Z (%): 317 (12), 316 (57), 258
(
31), 245 (21), 229 (21), 225 (13), 213 (21), 212 (24), 201 (11), 199 (19),
86 (15), 185 (100), 183 (11), 173 (26), 169 (13), 141 (12), 115 (18); IR
1
vmax: 3054, 2984, 2900, 1708, 1614, 1504, 1484; HRMS (ESI) m/z calcd.
for C H O Na (M þ Na): 339.1208; found: 339.1225.
1
8 20 5
Ethyl (E,E)-5-[6-Methyl-2-(3-oxobutyl)-3-quinolyl]penta-2.4-dienoate 14
1
Yield 63%; H NMR (CDCl , 300 MHz) d: 8.07 (s, 1H), 7.83 (d, J ¼ 8.5 Hz,
3
1
1
3
H), 7.55–7.45 (m, 3H), 7.23 (d, J ¼ 15.3 Hz, 1H), 6.87 (dd, J ¼ 15.3,
1.1 Hz, 1H), 6.05 (d, J ¼ 15.3 Hz, 1H), 4.27 (q, J ¼ 7.1 Hz, 2H), 3.52–
.45 (m, 2H), 3.31–3.27 (m, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 1.35
1
3
(
t, J ¼ 7.1 Hz, 3H); C NMR (CDCl , 75 MHz) d: 208.3, 166.8, 157.1,
3
1
1
45.9, 143.5, 136.1, 135.8, 132.0, 131.8, 129.5, 128.3, 126.5, 128.9, 126.9,
22.4, 60.5, 40.5, 30.4, 29.6, 21.5, 14.3; MS (EI) M/Z (%): 337 (26), 323
(
10), 322 (47), 308 (38), 295 (29), 294 (100), 280 (20), 266 (33), 264 (18),
48 (32), 222 (16), 221 (14), 220 (54), 207 (22), 206 (15), 194 (61), 181
14); IR vmax: 3041, 2979, 1723, 1628; HRMS (ESI) m/z calcd. for
C H NO (M þ H): 338.1756; found: 338.1757.
2
(
2
1
24
3
Ethyl 3-[5-Fluoro-2-(3-hydroxybutyl)phenyl]propanoate 15
1
Yield 82%; H NMR (CDCl , 300 MHz) d: 7.14 (dd, J ¼ 8.2, 6.3 Hz, 1H),
3
6
2
1
1
.89–6.82 (m, 2H, H ), 4.16 (q, J ¼ 7.1 Hz, 2H), 3.92–3.81 (m, 1H), 3.00–
7
.95 (m, 2H), 2.83–2.58 (m, 4H), 2.44 (se, 1H), 1.76–1.68 (m, 2H), 1.29–
¼ 243.5 Hz)
1
.24 (m, 6H); C NMR (CDCl , 75 MHz) d: 172.9, (d, J
3
1
3
CF
3
61.2, (d, J
4
3
¼ 7.0 Hz, C ) 140.3, (d. J
¼ 3.0 Hz) 135.7, (d, J
CF
6
CF
CF
2
7.9 Hz) 130.6, (2d, J
¼
¼ 21.0 Hz, 20.7 Hz) 115.3 and 113.2, 67.4,
¼ 1.3 Hz) 27.5, 23.7, 14.2; MS (EI) M/Z
CF
4
0.7, 40.6, 35.0, 28.1, (d, J
%): 268 (14), 250 (38), 205 (11), 204 (44), 189 (12), 181 (11), 178 (12),
6
CF
(
1
77 (21), 176 (70), 175 (17), 165 (11), 164 (14), 163 (22), 162 (55), 161
89), 160 (16), 159 (12), 151 (32), 150 (12), 149 (76), 148 (22), 147 (100),
46 (45), 137 (17), 136 (25), 135 (83), 134 (24), 133 (33), 123 (18), 122
12), 115 (41), 109 (22); IR vmax: 3462, 3032, 1727; HRMS (ESI) m/z
calcd. for C H FO (M þ H): 269.1553; found: 269.1561.
(
1
(
1
5
22
3
Ethyl 3-[2-(3-Hydroxybutyl)-6-methoxy-3-quinolyl]propanoate 16
1
Yield 71%; H NMR (CDCl 300 MHz) d: 7.93 (d, J ¼ 9.2 Hz, 1H), 7.84
3
(
s, 1H), 7.31 (dd, J ¼ 9.2, 2.8 Hz, 1H), 7.02 (d, J ¼ 2.8 Hz, 1H), 4.18
q, J ¼ 7.1 Hz, 2H), 3.95–3.87 (m, 4H), 3.30–3.08 (m, 4H), 2.76–2.70
m, 2H), 2.10–1.97 (m, 2H), 1.29 (d, J ¼ 6.3 Hz, 3H), 1.27 (t, J ¼ 7.1 Hz,
(
(
1
3
3
H); C NMR (CDCl , 75 MHz) d: 172.5, 158.3, 157.8, 141.8, 134.5,
3
132.3, 129.4, 128.0, 121.7, 104.7, 67.6, 60.7, 55.5, 36.7, 34.4, 31.7, 27.5,

Medium-Ring Benzo- and Azabenzo-lactones
901
2
3.7, 14.2; MS (EI) M/Z (%): 332 (2), 312 (20), 311 (100), 283 (19), 282 (13),
39 (36), 238 (73), 224 (13); IR vmax: 3602, 3037, 2931, 1728, 1643; HRMS
2
(
ESI) m/z calcd. for C H NO (M þ H): 332.1862; found: 332.1848.
1
9
25
4
Ethyl 3-[2-(3-Hydroxybutyl)-3-pyridinyl]propanoate 17
1
Yield 87%; H NMR (CDCl , 300 MHz) d: 8.34 (dd, J ¼ 4.8, 1.7 Hz, 1H),
3
7
1
2
.47 (dd, J ¼ 7.7, 1.7 Hz, 1H), 7.07 (dd, J ¼ 7.7, 4.8 Hz, 1H), 4.87 (se,
H), 4.12 (q, J ¼ 7.1 Hz, 2H), 3.76–3.88 (m, 1H), 3.08–2.83 (m, 4H),
.62–2.57 (m, 2H), 1.97–1.77 (m, 2H), 1.24 (t, J ¼ 7.1 Hz, 3H), 1.23
1
3
(
d, J ¼ 6.2 Hz, 3H); C NMR (CDCl , 75 MHz) d: 172.4, 159.6, 146.6,
3
1
37.0, 133.6, 121.4, 67.2, 60.7, 37.4, 34.5, 30.9, 27.2, 23.5, 14.2; MS (EI)
M/Z (%): 250(,10), 236 (17), 234 (17), 207 (16), 206 (75), 193 (47), 190
11), 178 (24), 164 (10), 160 (17), 144 (12), 134 (55), 132 (17), 130 (17),
(
1
22 (10), 121 (92), 120 (100), 118 (34); IR vmax: 3211, 2969, 2930, 1729,
605, 1445; HRMS (ESI) m/z calcd. for C H NO (M þ H): 252.1600;
1
found: 252.1607.
1
4
22
3
Ethyl 5-[2-(3-Hydroxybutyl)-4.5-methylenedioxyphenyl]pentanoate 18
1
Yield 66%; H NMR (CDCl , 300 MHz) d: 6.68–6.65 (m, 2H), 5.90 (s, 2H),
3
4
.15 (q, J ¼ 7.1 Hz, 2H), 3.92–3.81 (m, 1H), 2.78–2.51 (m, 4H), 2.36
(
t, J ¼ 7.1 Hz, 2H), 2.10 (se, 1H), 1.75–1.58 (m, 6H), 1.30–1.25 (m, 6H);
1
3
C NMR (CDCl , 75 MHz) d: 173.8, (2C) 145.6, 132.9, 109.3, 100.6, 67.5,
3
6
0.4, 41.0, 34.1, 32.2, 31.0, 28.7, 24.9, 23.6, 14.3; MS (EI) M/Z (%): 322
67), 304 (28), 264 (19), 205 (10), 190 (16), 189 (100), 187 (11), 175 (53),
(
1
2
73 (20), 161 (16), 159 (26), 149 (63), 145 (37), 131 (18); IR vmax: 3608,
937, 1727, 1504, 1486; HRMS (ESI) m/z calcd. for C H O Na
1
8 26 5
(M þ Na): 345.1678; found: 345.1702.
Ethyl 3-[2-(3-Hydroxybutyl)-6-methyl-3-quinolyl]pentanoate 19
1
Yield 55%; H NMR (CDCl , 300 MHz) d: 7.93 (d, J ¼ 8.5 Hz, 1H), 7.83
3
(
s, 1H), 7.52 (s, 1H), 7.48 (d, J ¼ 8.5 Hz, 1H), 4.17 (q, J ¼ 7.1 Hz, 2H),
3
2
.98–3.88 (m, 1H), 3.32–3.10 (m, 2H), 2.84–2.80 (m, 2H), 2.53 (s, 3H),
.43–2.30 (m, 2H), 2.07–1.95 (m, 2H), 1.85–1.70 (m, 5H), 1.31–1.23
1
m, 6H); C NMR (CDCl , 75 MHz) d: 173.5, 160.1, 143.9, 136.0, 135.1,
3
(
3
1
2
31.3, 127.3, 125.8, 133.6, 127.2, 67.5, 60.4, 36.8, 34.1, 32.2, 31.8, 29.7,
4.8, 23.7, 21.6, 14.3; MS (EI) M/Z (%): 343 (12), 299 (19), 283 (16), 281
(
22), 269 (10), 267 (16), 229 (10), 227 (43), 226 (17), 225 (84), 211 (31),
10 (22), 209 (100), 208 (16), 207 (78), 191 (12), 158 (14), 151 (13), 145
18), 73 (12); IR vmax: 3601, 3042, 2931, 1728, 1659; HRMS (ESI) m/z
calcd. for C H NO (M þ H): 344.2226; found: 344.2211.
2
(
2
1
30
3

9
02
E. Metay, E. L e´ onel, and J.-Y. N e´ d e´ lec
Benzolactone 20–24
General Procedure
p-Nitrobenzoic anhydride (506 mg, 1.6 mmol) was dissolved in dry aceto-
nitrile (340 mL), and a cloudy solution of scandium triflate (1.6 mL,
0
.16 mmol, 0.1 M) in acetonitrile was added to the solution at room tempera-
ture under argon. A solution of hydroxycarboxylic acid (20 mL, 0.8 mmol,
.08 M) in THF was slowly added with a syringe pump over 15 h to the
0
mixed solution at reflux under argon, and the reaction mixture was stirred
for an additional 5 h at reflux. After being cooled to room temperature, the
solution was quenched with aqueous saturated sodium hydrogen carbonate
(
8 mL). The resulting mixture was concentrated under reduced pressure and
extracted with diethyl ether twice. The organic layers were dried over
magnesium sulfate, filtered, and concentrated under vacuum. Purification
was done by flash-column chromatography on silica gel to give the desired
lactone.
3-[4-Fluoro-2-(3-hydroxybutyl)phenyl]propanoic Acid, h Lactone 20
1
Yield 76%; H NMR (DMF-d 708C, 300 MHz) d: 7.28–7.23 (m, 1H), 7.06–
7
6.95 (m, 2H), 4.88–4.65 (m, 1H), 3.27–3.15 (m, 1H), 2.96–2.84 (m, 2H),
2
.73–2.62 (m, 1H), 2.59–2.41 (m, 2H), 2.27–2.18 (m, 1H), 1.98–1.87
1
3
(
m, 1H), 1.25–1.23 (d, J ¼ 6.2 Hz, 3H); C NMR (DMF-d 708C,
3
38.3, (d, J
7
1
5 MHz) d: 173.6, (d, J
3
7
1
¼ 241.9 Hz) 161.0, (d, J
¼ 6.9 Hz) 141.1,
CF
CF
2
2
¼ 8.0 Hz) 132.0, (d, J
¼ 20.5 Hz) 116.3, (d, J
CF
CF
CF
¼
21.0 Hz) 113.6, 70.8, 38.5, 36.9, 30.4, 26.3, 20.6; MS (EI) M/Z (%): 222
10), 204 (47), 189 (10), 163 (25), 162 (74), 161 (24), 151 (27), 149 (71),
48 (12), 147 (42), 146 (25), 136 (27), 135 (100), 134 (17), 133 (24), 123
(
1
(
13), 122 (11), 115 (35), 109 (23); IR vmax: 3065, 2987, 2934, 1731; HRMS
ESI) m/z calcd. for C H FO (M þ H): 223.1134; found: 223.1148.
(
1
3
15
2
3-[2-(3-Hydroxybutyl)-6-methoxy-3-quinolyl]propanoic acid, h lactone 21
1
Yield 55%; mp: 123.4–124.68C; H NMR (DMF-d , 708C, 300 MHz) d: 8.05
7
(
s, 1H), 7.87 (d, J ¼ 9.13 Hz, 1H), 7.36 (dd, J ¼ 9.13, 2.80 Hz, 1H), 7.27
(
d, J ¼ 2.78 Hz, 1H), 5.01–4.95 (m, 1H), 3.97 (s, 3H), 3.37–3.27 (m, 1H),
3
.19–3.01 (m, 2H), 2.86–2.78 (m, 1H), 2.63–2.59 (m, 2H), 2.47–2.38
1
3
(
m, 1H), 2.28–2.17 (m, 1H), 1.21–1.18 (m, 3H); C NMR (DMF-d 708C,
7
75 MHz) d: 173.8, 161.1, 157.6, 143.2, 135.8, 133.5, 129.7, 128.1, 121.4,
105.3, 71.3, 55.4, 38.1, 37.6, 30.8, 30.3, 20.5; MS (EI) M/Z (%): 286 (13),
285 (69), 241 (17), 240 (12), 228 (25), 227 (11), 226 (46), 214 (51), 213
(
25), 212 (100), 210 (14), 200 (10), 199 (27), 198 (44), 197 (10), 187 (13),
55 (17), 154 (13); IR v max: 3024, 2986, 2939, 1721, 1643, 1627; HRMS
ESI) m/z calcd. for C H NO (M þ H): 286.1443; found: 286.1455.
1
(
1
7
20
3

Medium-Ring Benzo- and Azabenzo-lactones
903
3
-[2-(3-Hydroxybutyl)-3-pyridinyl]propanoic Acid, h Lactone 22
1
Yield 26%; H NMR (DMF-d , 708C, 300 MHz) d: 8.42 (dd, J ¼ 4.7, 1.7 Hz,
7
1
H), 7.60 (dd, J ¼ 7.6, 1.7 Hz, 1H), 7.15 (dd, J ¼ 7.6, 4.7 Hz, 1H), 4.97–4.89
(
m, 1H), 3.21–3.11 (m, 1H), 3.01–2.88 (m, 2H), 2.70–2.62 (m, 1H), 2.52–
2
3
1
.47 (m, 2H), 2.34–2.26 (m, 1H), 2.15–2.07 (m, 1H), 1.20 (d, J ¼ 6.3 Hz,
1
3
H); C NMR (DMF-d 708C, 75 MHz)d: 173.8, 162.2, 147.6, 138.0,
7
33.9, 121.3, 71.4, 37.5, 36.7, 30.5, 30.1, 20.5; MS (EI) M/Z (%): 205
(
,10), 161 (19), 160 (18), 148 (21), 146 (41), 144 (10), 134 (47), 133 (17),
32 (100), 130 (18), 119 (16), 118 (44), 117 (15); IR vmax: 3058, 2977,
1
2
found: 206.1194.
874, 1727; HRMS (ESI) m/z calcd. for C H NO (M þ H): 206.1181;
1
2
16
2
5-[2-(3-Hydroxybutyl)-4,5-methylenedioxyphenyl]pentanoic Acid,
i Lactone 23
1
Yield 78%; H NMR (CDCl , 300 MHz) d: 6.66-6.64 (m, 2H), 5.92–5.90
3
(
m, 2H), 5.15–5.07 (m, 1H), 3.02–2.89 (m, 2H), 2.58–2.35 (m, 4H), 1.95–
1
3
1
.73 (m, 5H), 1.56–1.45 (m, 1H), 1.28 (d, J ¼ 6.4 Hz, 3H); C NMR
(
CDCl , 75 MHz) d: 173.9, 145.8, 145.6, 133.5, 132.9, 109.6, 109.0, 100.6,
3
7
0.0, 36.8, 33.7, 29.2, 29.1, 26.1, 23.5, 19.0; MS (EI) M/Z (%): 277 (12),
2
76 (66), 200 (12), 190 (16), 189 (100), 175 (33), 173 (14), 162 (22), 161
10), 159 (29), 149 (16), 145 (27), 131 (24), 103 (10); IR vmax: 3053, 2936,
(
1
2
722, 1504, 1485; HRMS (ESI) m/z calcd. for C H O (M þ H):
1
6 21 4
77.1440; found: 277.1443.
5-[2-(3-Hydroxybutyl)-6-methyl-3-quinolyl]pentanoic Acid, i Lactone 24
1
Yield 25%; H NMR (CDCl , 300 MHz) d: 7.92-7.90 (m, 1H), 7.82 (s, 1H),
3
7
.50–7.46 (m, 2H), 5.21-5.16 (m, 1H), 3.37–3.28 (m, 1H), 3.14–3.06
(
(
(
m, 1H), 3.03–2.96 (m, 1H), 2.82–2.71 (m, 1H), 2.53 (s, 3H), 2.52–2.46
m, 1H), 2.42–2.33 (m, 1H), 2.25–2.14 (m, 2H), 2.08–1.66 (m, 4H), 1.32
1
3
d, J ¼ 6.4 Hz, 3H); C NMR (CDCl , 75 MHz) d: 173.7, 161.3, 145.1,
3
1
2
35.5, 135.2, 133.4, 131.0, 128.0, 127.2, 125.2, 70.5, 35.0, 34.0, 29.7, 29.2,
8.6, 23.4, 21.5, 19.1; MS (EI) M/Z (%): 297 (41), 282 (17), 224 (26), 210
(14), 199 (14), 198 (100), 197 (33), 196 (42), 195 (10), 194 (20), 184 (15),
1
2
2
83 (15), 182 (31), 181 (14), 180 (10), 171 (31), 167 (13); IR vmax: 3038,
936, 1724, 1659. HRMS (ESI) m/z Calcd for C H NO (M þ H):
1
9
24
2
98.1807; found: 298.1804.
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3
. Rousseau, G. Medium ring lactones. Tetrahedron 1995, 51, 2777–2849.
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b) Ruzicka, L.; Brugger, W. Carbon rings. V. Preparation of a nine-membered
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308–5313.
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. Ishihara, K.; Kubota, M.; Kurihara, H. Yamamoto H. Scandium trifluoromethane-
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intraamolecular 1,3-dipolar cycloaddition reaction. J. Heterocyclic Chem. 1995,
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2, 1595–1597.
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0. Kato, Y.; Niiyama, K.; Jona, H.; Okada, S.; Akao, A.; Hiraga, S.; Tsuchiya, Y.;
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