Free radical reactions for heterocycle synthesis. Part 7: 2-Bromobenzoic acids as building blocks in the construction of spirobenzolactones and spirobenzolactams

Article abstract of DOI:10.1016/S0040-4020(03)00655-0

A straightforward 2-step parallel synthesis for structurally diversified spiro compounds is developed. 2-Bromobenzoic acids are used as common building blocks to couple with a series of conjugated enoles or enamines. Sequential intramolecular free radical

Full text of DOI:10.1016/S0040-4020(03)00655-0

Tetrahedron 59 (2003) 4237–4247
Free radical reactions for heterocycle synthesis. Part 7:
2-Bromobenzoic acids as building blocks in the construction of
spirobenzolactones and spirobenzolactams
*
Wei Zhang and Georgia Pugh
Lead Discovery, DuPont Crop Protection, Stine-Haskell Research Center, Newark, DE 19714, USA
Received 8 April 2003; revised 17 April 2003; accepted 17 April 2003
Abstract—A straightforward 2-step parallel synthesis for structurally diversified spiro compounds is developed. 2-Bromobenzoic acids are
used as common building blocks to couple with a series of conjugated enoles or enamines. Sequential intramolecular free radical Michael
additions lead to formation of spirobenzolactones, spirobenzolactams, spirobenzolactone-lactams, spiorbenzolactone-thiolactones,
spiordilactones, and bridged-spirolactones. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
lactam, and related compounds (Scheme 3).5 This paper
describes the scope and limitation of free radical spiro-
cyclization reactions.
Spirolactones and spirolactams are frequently occurring
motifs in biologically active molecules.1 Synthesis of
spirolactones, for example, can be achieved by carbon–
oxygen bond formation via lactonization (Scheme 1, path a)
or carbon–carbon bond formation via cyclization of esters
(Scheme 1, path b).2,3 We recently developed an intra-
molecular free radical conjugate addition method to
synthesize nitrogen heterocycles.4 The cyclization strategy
is now extended to the construction of spiro quaternary
carbon–carbon bond (Scheme 2) of spirolactone, spiro-
2. Results and discussion
2.1. Synthesis of spirobenzolactones and
spirobenzolactams
The synthesis of spirobenzolactones 2 proceeded through a
straightforward two-step reaction sequence (Scheme 4).5c
At the first step, 2-bromobenzoic acids were reacted with
cyclic 1,3-diones using the Mukaiyama coupling agent
(N-methyl-2-chloropridinum iodide).6 The enol esters 1 are
well-known intermediates in the preparation of the triketone
inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD)
which have important pharmaceutical7 and agricultural8
utilities. In this work, the enol esters were used as aryl
radical precursors for spirocyclizations.9 Tris(trimethyl-
silyl)silane (1.5 equiv.) and catalytic amount of 2,20-
azobis(2-methylpropisonitrile) (AIBN) in refluxing benzene
promoted the radical spirocyclization of 1. The initial
radical 3 equilibrated between the cis and trans conformations
by rotation of the C–O bond. The trans-3 conformer
underwent cyclization to afford product 2 via a-acyl stabilized
radical 4 (Scheme 4). The a,b-unsaturated ketone served as a
conjugate radical acceptor to facilitate the cyclization and
control the regioselective 5-exo cyclization.10
Scheme 1. Synthesis of spirolactone.
Scheme 2. Free radical spirocyclization.
Keywords: free radical; spirolactone; 2-bromobenzoic acid; Michael
addition; tris(trimethylsilyl)silane.
A series of spirobenzolactones were prepared from readily
available 1,3-cyclic diones (Table 1). Cyclizations of
5-phenyl substituted 1,3-cyclohexanediones could generate
two diastereomers. Under a general reaction condition,
*
Corresponding author. Address: Fluorous Technologies, Inc., 970
William Pitt Way, Pittsburgh, PA 15238, USA. Tel.: þ1-412-826-3062;
fax: þ1-412-826-3053; e-mail: w.zhang@fluorous.com
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00655-0

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Scheme 3. 2-Bromobenzoic acid-based free radical reactions for spiro compounds.
products 18 and 20 were produced as diastereomeric
mixtures, while 10, 12, 14, and 16 were generated in higher
diaostereoselectivity. Stereostructures of 10 and 16 were
determined by X-ray analyses (Fig. 1).
Spirocyclization reactions were also used to prepare
spirobenzolactams 29 by coupling amines 27 with 2-bromo-
benzoyl chlorides followed by free radical cyclizations of 28
(Scheme 6). Details for this kind of reactions have been
disclosed in a recent paper from our group.4
Scheme 5 shows the synthesis of a spirolactone ester by
coupling of 2-bromobenzoic acid with a b-keto ester 23
followed by the radical cyclization of 24. The reduction of
cyclized radical 25 gave product 26 as a mixture of two
diastereomers.
2.2. Synthesis of spirodilactones
Scheme 7 outlines the synthesis of spirodilactones by
cyclization of tetronic acid derivatives.5b The intermediate
Scheme 4. Intramolecular aryl radical cyclizations for spirobenzolactones.

Table 1. Preparation of spirobenzolactones
Entry
1
Enol estera
Productb
Entry
5
Enol ester
Product
2
3
4
6
7
8
a1.0 equiv. of bromobenzoic acid, 1.1 equiv. of 1,3-diketone, 1.2 equiv. of 2-chloro-1-methylpyridinium iodide, 2.7 equiv. of Et3N, THF, rt, b1.5 equiv. of (Me3Si)3SiH, cat. AIBN, benzene, 808C, cThe diastereomer
ratio was determined by H NMR.

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preparation of spirodilactones having substituents on the
benzene ring. Purifications of enol ester intermediates 32,
34, and 36 and corresponding cyclization products 33, 35
and 37 were straightforward; all these compounds were
simply precipitated out from the concentrated reaction
mixture at room temperature. Successful extension of this
method to a reaction of 1-bromo-2-naphthoic acid
derivative 38 resulted tetracyclic spirodi-g-lactone 39. The
use of 5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one
instead of tetronic acid as a starting material led to
formation of spiro-g/d-dilactone 41 as a mixture of
diastereomers (entry 3). Entry 4 provides another example
for the synthesis of tetracyclic spiro-g/d-dilactone 43. The
synthesis of dispiro-g/d-dilactone 45 using readily available
spirodihydropyranon15 as a starting material is shown in
Scheme 8.
To further investigate the reaction scope, cyclization of
enol ester 46 containing a phenyl group at 3-position of
tetronic acid was carried out (Scheme 9). No cyclization
product 49 was observed. Surprisingly, three intermolecular
coupling products 50a–50c were isolated from a
complex reaction mixture. It is believed that the initial
radical 47 was involved in a reversible 5-exo cyclization to
form a highly unreactive and persistent tertiary benzylic
radical 48. This could provide a safe ‘sink’ for transient
radical 47 to allow it to be continually re-generated in low
but stable concentration so that it eventually coupled with
solvent benzene, transient isopropionnitrile radical, or
tris(trimethylsilyl)silyl radical to generate 50a–50c,
respectively.16 The structure of 50a was confirmed by
X-ray analysis (Fig. 2).
Figure 1. X-Ray structures of compounds 10 (top) and 16 (bottom).
enol esters 30 were reported having antifungal activity.11
Cyclized spirodilactones 31 possess a unique heterocyclic
system that was also found in natural product altenuic acid
II.12 There are more examples of natural products contain-
ing spirotetronic acid units.13 To the best of our knowledge,
no synthetic method for spirodilactones such as 31 has been
reported.14
The scope of spirodilactone synthesis is demonstrated by the
examples listed in Table 2. Entry 1 demonstrated the
Scheme 5.
Scheme 6. Synthesis of spirolactams.
Scheme 7. Synthesis of spirodilactones.

W. Zhang, G. Pugh / Tetrahedron 59 (2003) 4237–4247
4241
Table 2. Preparation of spirodilactones
Entry
1
Enol estera
Productb
2
Figure 2. X-Ray structure of compound 50a.
3
2.3. Synthesis of spirolactone-lactams and spirolactone-
thiolactones
Free radical spirocyclizations have been applied in the
synthesis of spirolactone-lactams using readily available
lactams 51 and 5417 as starting materials (Scheme 10). Both
products 53 and 56 contain attractive functionalized
polycyclic systems. The structure of product 53 was
confirmed by X-ray crystal analysis (Fig. 3).
4
The radical spirocyclization has been further employed in
the synthesis of spirolactone-thiolactone 59 using com-
mercially available thiotetronic acid 57 as the starting
material (Scheme 11).
a
1.0 equiv. of carboxylic acid, 1.1 equiv. of keto lactone, 1.2 equiv. of
2-chloro-1-methylpyridinium iodide, 2.7 equiv. of Et3N, THF, rt.
1.5 equiv. of (Me3Si)3SiH, cat. of AIBN, benzene, 808C.
b
Scheme 8. Synthesis of a dispirodilactone.
Scheme 9. Radical reaction of 46.

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W. Zhang, G. Pugh / Tetrahedron 59 (2003) 4237–4247
Scheme 10. Synthesis of spirolactone-lactams 53 and 56.
chromatography. When 61a was treated with tris(timethyl-
silyl)silane, the initial radical underwent double cyclizations
(Scheme 13): an intramolecular conjugate addition was
followed by a 5-exo cyclization to give bridged spiro-
lactones 64 as a mixture of two diastereomers. A small
amount of monocyclization product 65 was also observed.
The formation of 64 suggested that the spirocyclization (66
to 67) was processed through an equatorial attack of 66 to
form a carbon–carbon bond trans to the vinyl group. The
sequential 5-exo cyclization (67 to 68) gave a mixture of
diastereomers 64 due to the free rotation of allylic carbon–
carbon single bond.
Reactions using substrates 61b containing a 2-methylallyl
side chain afforded a dicyclization product 69. In this
case, the spirocyclization was followed by a cyclization of
6-endo instead of 5-exo. The bridged spirolactones 69
was generated as a single diastereomer (Scheme 14).
The reaction of enol ester 62a produced only a 5-exo
monocyclization product. No dicyclization product
was observed. Similar results were observed by
Simpkins and co-workers in the synthesis of spiroethers.19
Radical precursor 62b which has a methyl group on the
allyl side chain induced the second 6-endo cyclization
(Scheme 15). In this case, adequate amount of dicyclization
product 72 was generated as a single diastereomer
together with the monocyclization product 73. The
structure of 72 was confirmed by X-ray structure analysis
(Fig. 4).
Figure 3. X-Ray structure of compound 53.
2.4. Synthesis of bridged-lactones by tandem cyclizations
Tandem, or cascade, cyclizations have a high synthetic
efficiency, and are widely used in the construction of fused
polycyclic compounds.18 We designed a double cyclization
sequence in the preparation of complex heterocyclic
systems containing spiro and bridged rings.5a
In summary, a general synthetic method to construct
a variety of spiro compounds has been developed.
The formation of spiro-quaternary carbon–carbon bonds
by intramolecular free radical conjugate addition of
Aryl bromides with allyl groups at different positions of
keto enol esters were prepared (Scheme 12). The regio-
isomers of 61 and 62 were separated by flash column
Scheme 11. Synthesis of spirolactone-thiolactone 59.

W. Zhang, G. Pugh / Tetrahedron 59 (2003) 4237–4247
4243
Scheme 12. Synthesis of radical precursors 61 and 62.
Scheme 13. Synthesis of bridged-spirolactone 64.
Scheme 14. Synthesis of bridged-spirolactone 69.
Scheme 15. Synthesis of bridged-spirolactone 72.

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was washed with aqueous NH4Cl and brine, dried over
MgSO4, and concentrated in vacuo to afford the enol ester.
3.4. General procedure for radical spirocyclization
To a refluxing solution of radical precursor (1.0 equiv.) in
dry benzene (20 mL per mmol of radical precursor) was
added (CH3Si)3SiH (1.5 equiv.) and AIBN (0.05–
0.1 equiv.). After 2 h, a second portion of AIBN
(0.05 equiv.) was added and the reaction mixture was
refluxed for an additional 5–25 h. The concentrated reaction
mixture was triturated with BuCl or further purified by flash
chromatography to give a cyclization product.
3.4.1. Compound 6. 0.27 g, 83% yield after chromato-
graphy as a clear oil; IR nmax (neat) 2954, 1765, 1721, 1467,
1362, 1289, 1253, 1200, 1120, 1072, 931, 764, 694, 628,
600, 554 cm21; H NMR (300 MHz, CDCl3) d 2.00–2.70
1
Figure 4. X-Ray structure of compound 72.
(6H), 2.84 (d, J¼15.2 Hz, 1H), 7.43 (d, J¼7.7 Hz, 1H), 7.57
(t, J¼7.7 Hz, 1H), 7.72 (t, J¼7.5 Hz, 1H), 7.92 (d,
J¼7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 20.0, 33.8,
38.4, 49.2, 87.0, 119.8, 123.7, 124.3, 128.1, 133.3, 150.1,
167.2, 204.3; LRMS (APþ) m/z (rel. intensity) 217 (MþþH,
100), 176 (10), 150 (12); HRMS calcd for C13H12O3
216.0786, found 216.0797.
2-bromobenzoic acid derivatives provided an easy access to
some novel benzolactone and benzolactam systems.
3. Experimental
3.1. General
3.4.2. Compound 8. 0.27 g, 68% yield after chromato-
graphy as a white solid. Mp 133–1358C; IR nmax (neat)
2954, 1769, 1723, 1626, 1483, 1362, 1249, 1122, 1023, 945,
1
814, 686 cm21; H NMR (300 MHz, CDCl3) d 2.18–2.62
Bromobenzoic acids and cyclic 1,3-diketone compounds
were obtained from commercial sources unless otherwise
indicated. The coupling reagent N-methyl-2-chloro-
pridinium iodide and radical initiator 2,20-azobis(2-methyl-
propisonitrile) (AIBN) were purchased from Aldrich.
Tris(trimethylsilyl)silane for radical reactions was
purchased from Fluka. Anhydrous benzene obtained from
Fluka was used without further purification.
(m, 7H), 2.82 (d, J¼15.2 Hz, 1H), 7.21 (m, 2H), 7.74 (m,
1H); 13C NMR (75 MHz, CDCl3) d 19.8, 33.6, 38.5, 49.0,
84.9, 86.6, 115.2, 115.5, 135.7, 152.8, 156.4, 159.9, 203.9;
LRMS (APþ) m/z (rel. intensity) 235 (MþþH, 100), 217
(47), 191 (23); HRMS calcd for C13H11FO3 234.0692, found
234.0692.
3.4.3. Compound 10. 0.56 g, 68% yield after chromato-
graphy as white solid. Mp 177–1788C; IR nmax (neat) 1760,
1724, 1475, 1286, 1262, 1066, 1047, 960, 897, 818, 764,
3.2. General procedure for allylation of 1,3-
cyclohexanedione
1
737, 694 cm21; H NMR (300 MHz, CDCl3) d 2.15 (m,
1H), 2.45 (t, J¼13.5 Hz, 1H), 2.65 (t, J¼13.7 Hz, 2H), 2.84
(m, 1H), 2.95 (d, J¼15.5 Hz, 1H), 4.15 (m, 1H), 7.24 (m,
2H), 7.41 (s, 1H), 7.51 (d, J¼7.7 Hz, 1H), 7.60 (t, J¼7.7 Hz,
1H), 7.78 (t, J¼7.7 Hz, 1H), 7.91 (d, J¼7.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 34.1, 39.4, 44.2, 48.6, 85.9,
119.5, 123.6, 124.7, 126.1, 126.4, 128.1, 128.5, 131.9,
132.8, 133.3, 136.6, 146.9, 167.1, 202.7; LRMS (APþ) m/z
(rel. intensity) 361 (MþþH, 100); HRMS calcd for
C19H14Cl2O3 360.0320, found 360.0323.
To a solution of 1,3-cyclohexanedione (89.3 mmol) in
200 mL of anhydrous THF and 50 mL of HMPA was added
2 M of lithium diisopropylamine (in hexane, 98.2 mL,
196.4 mmol) at 2788C. After 1 h, the reaction temperature
was raised to 2408C and 2-methylallyl bromide
(98.2 mmol) was added quickly. The mixture was slowly
warmed up to room temperature and stirred for an additional
10 h. The concentrated reaction mixture was diluted with
5% HCl, extracted with diethyl ether. The organic layer was
washed with 3% aqueous HCl and brine, dried over MgSO4,
and concentrated in vacuo. The crude product was purified
by flash column chromatography with hex/EtOAc (50:50) to
afford allylation product 60.
3.4.4. Compound 12. 0.62 g, 76% yield after chromato-
graphy (two diastereomers in a ratio of 1:5). The major
isomer as a white solid. Mp 206–2088C; IR nmax (neat)
1754, 1723, 1466, 1260, 1062, 961, 918, 764, 692 cm21; 1H
NMR (300 MHz, CDCl3) d 2.12 (m, 1H), 2.42–2.75 (m,
3H), 2.85 (m, 1H), 3.00 (d, J¼15.3 Hz, 1H), 3.68 (m, 1H),
7.15 (m, 1H), 7.24 (m, 3H), 7.27 (d, J¼7.7 Hz, 1H), 7.61 (t,
J¼7.7 Hz, 1H), 7.74 (t, J¼7.5 Hz, 1H), 7.95 (d, J¼7.5 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 37.6, 41.1, 45.7, 48.5,
85.8, 119.3, 123.6 (2C), 124.8, 125.1, 125.9, 128.4, 128.7,
133.2 (2C), 142.9, 149.8, 167.0, 202.7; LRMS (APþ) m/z
(rel. intensity) 327 (MþþH, 92), 264 (39), 223 (51), 181
3.3. General procedure for preparation of radical
precursors, enol esters
A mixture of 2-bromobenzoic acid (5.0 mmol), 1,3-
2-chloro-1-methyl-
cyclohexanedione
(5.5 mmol),
pyridinium iodide (5.8 mmol), and triethylamine
(13.5 mmol) in 100 mL of anhydrous THF was stirred at
room for 10 h. After ethyl acetate workup, the organic layer

W. Zhang, G. Pugh / Tetrahedron 59 (2003) 4237–4247
4245
(100); LRMS (APþ) m/z (rel. intensity) 327 (MþþH, 100),
309 (7), 278 (9); HRMS calcd for C19H15ClO3 362.0710,
found 362.0713.
37.7, 41.8, 46.4, 48.7, 55.3, 85.9, 99.6, 105.4, 106.5, 107.0,
118.2, 120.2, 121.9, 125.1, 135.0, 142.6, 145.1, 146.5,
159.6, 167.1, 203.4; LRMS (APþ) m/z (rel. intensity) 367
(MþþH, 100); HRMS calcd for C21H18O6 366.1103, found
366.1133.
3.4.5. Compound 14. 0.80 g, 64% yield after chromato-
graphy (two diastereomers in a ratio of 1:6). The major
isomer; IR nmax (neat) 1763, 1722, 1498, 1330, 1288, 1164,
1122, 1076, 1027, 961, 924, 803, 749, 702 cm21; 1H NMR
(300 MHz, CDCl3) d 2.13 (m, 1H), 2.40–2.72 (m, 3H), 2.84
(m, 1H), 2.98 (d, J¼15.4 Hz, 1H), 3.75 (m, 1H), 3.88 (s,
3H), 7.26–7.50 (m, 6H); 13C NMR (75 MHz, CDCl3) d
37.9, 41.1, 45.7, 48.7, 54.3, 85.9, 106.6, 120.4, 121.6, 121.9,
122.6, 124.3, 125.0, 128.0, 128.9, 129.7, 142.0, 142.4,
159.7, 167.1, 203.1; LRMS (APþ) m/z (rel. intensity) 391
(MþþH, 100), 313 (19), 300 (8); HRMS calcd for
C21H17F3O4 390.1079, found 390.1099.
3.4.9. Compound 22. 0.75 g, 76% yield after chromato-
graphy as a white solid. Mp 126–1278C; IR nmax (neat)
2937, 1767, 1702, 1624, 1497, 1435, 1334, 1291, 1263,
1179, 1112, 1076, 1029, 1015, 990, 953, 928, 885, 840, 786,
1
750, 574 cm21; H NMR (300 MHz, CDCl3) d 1.79 (m,
1H), 1.90–2.20 (m, 5H), 2.60–2.96 (m, 3H), 3.18 (d,
J¼15.4 Hz, 1H), 3.87 (s, 3H), 7.20–7.38 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 21.9, 23.7, 39.5, 42.5, 51.4, 54.3, 83.4,
106.3, 120.0, 121.7, 123.9, 145.8, 159.2, 167.7, 206.8;
LRMS (APþ) m/z (rel. intensity) 261 (MþþH, 100); 243
(62); HRMS calcd for C15H16O4 260.1049, found 260.1049.
3.4.6. Compound 16. 0.28 g, 42% yield after chromato-
graphy as white solid. Mp 75–768C; IR nmax (neat) 2959,
1765, 1722, 1612, 1514, 1498, 1466, 1336, 1289, 1254,
3.4.10. Compound 26. 0.20 g, 77% yield after chromato-
graphy as a mixture of two diastereomers 26a and 26b (1:1);
IR nmax (neat) 2979, 1769, 1733, 1466, 1372, 1348, 1286,
1
1181, 1068, 1026, 959, 834 cm21; H NMR (300 MHz,
CDCl3) d 2.06 (m, 1H), 2.38–2.70 (m, 3H), 2.80 (m, 1H),
2.94 (d, J¼15.3 Hz, 1H), 3.61 (m, 1H), 3.79 (s, 3H), 3.88 (s,
3H), 6.87 (d, J¼8.7 Hz, 2H), 7.19 (d, J¼8.7 Hz, 2H), 7.27
(m, 1H), 7.34 (m, 2H); 13C NMR (75 MHz, CDCl3) d 37.2,
41.8, 46.3, 48.8, 53.8, 45.4, 86.1, 106.5, 112.7 (2C), 120.3,
121.9, 125.1, 126.1 (2C), 133.2, 142.7, 157.1, 159.6, 167.2,
203.8; LRMS (APþ) m/z (rel. intensity) 353 (MþþH, 95),
309 (16), 263 (10), 234 (17), 222 (100), 208 (57), 171 (14);
HRMS calcd for C21H20F3O5 352.1311, found 352.1317.
1197, 1063, 957, 758, 693 cm21 1H NMR (300 MHz,
;
CDCl3) d 0.84 (t, J¼7.2 Hz, 3H), 2.10 (m, 2H), 2.27 (m,
4H), 3.32 (m, 1H), 3.80 (m, 2H), 7.39 (d, J¼7.6 Hz, 1H),
7.52 (t, J¼7.6 Hz, 1H), 7.62 (t, J¼7.5 Hz, 1H), 7.86 (d,
J¼7.5 Hz, 1H); LRMS (AP2) m/z (rel. intensity) 259
(Mþ2H, 100), 197 (47), 180 (63); HRMS calcd for
C15H16O4 260.1049, found 260.1077.
3.4.11. Compound 33. 0.76 g, 75% yield after BuCl
trituration as a yellow solid. Mp 207–2088C; IR nmax
1
3.4.7. Compound 18. 0.54 g, 70% yield after chromato-
graphy as a mixture of two diastereomers (1:1); IR nmax
(neat) 1744, 1718, 1604, 1514, 1300, 1251, 1222, 1099,
1012, 934, 840 cm21; 1H NMR (300 MHz, CDCl3) d 2.00–
2.80 (m), 2.93 (d, J¼15.0 Hz), 3.10 (d, J¼14.5 Hz), 3.32
(m, 1Ha), 3.63 (m, 1H), 3.79 (s, 3H), 3.94 (s, 3H), 3.98 (s,
3H), 4.01 (s, 3H), 6.73 (s), 6.87 (m), 7.18 (t, J¼6.2 Hz), 7.28
(m), 7.36 (s); 13C NMR (75 MHz, CDCl3) d 35.5, 37.1, 41.7,
45.9, 46.2, 48.7, 53.8, 54.8, 55.0, 83.9, 85.3, 100.6, 101.7,
104.9, 105.1, 112.7, 112.8, 115.6, 115.8, 126.0, 126.1,
126.8, 132.5, 133.2, 144.7, 144.8, 149.4, 153.3, 153.6,
157.1, 157.2, 167.3, 203.6, 204.9; LRMS (APþ) m/z (rel.
intensity) 383 (MþþH, 100); HRMS calcd for C22H22O6
382.1416, found 382.1410.
(neat) 1771, 1230, 1024, 762 cm21; H NMR (300 MHz,
CDCl3) d 3.06 (d, J¼18.2 Hz, 1H), 3.14 (d, J¼18.2 Hz, 1H),
4.60 (s, 2H), 7.57 (d, J¼7.7 Hz, 1H), 7.67 (t, J¼7.7 Hz, 1H),
7.81 (t, J¼7.5 Hz, 1H), 7.93 (d, J¼7.5 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) d 38.6, 74.5, 82.8, 119.7, 124.9, 127.5,
129.0, 129.3, 133.7, 142.2, 165.3; LRMS (APþ) m/z (rel.
intensity) 205 (MþþH, 100), 195 (70), 157 (27), 150 (33);
HRMS calcd for C11H8O4 204.0423, found 204.0453.
3.4.12. Compound 35. 0.63 g, 50% yield after BuCl
trituration as a white solid. Mp 170–1718C; IR nmax (neat)
1774, 1020, 749 cm21; 1H NMR (300 MHz, CDCl3) d 3.01
(d, J¼18.2 Hz, 1H), 3.08 (d, J¼18.2 Hz, 1H), 3.90 (s, 3H),
4.56 (s, 2H), 7.30–7.46 (3H); 13C NMR (75 MHz, DMSO-
d6) d 38.9, 54.6, 74.1, 86.9, 106.3, 121.7, 122.6, 126.0,
136.2, 160.0, 166.1, 172.6; LRMS (APþ) m/z (rel. intensity)
235 (MþþH, 100), 211 (27), 191 (7); HRMS calcd for
C12H10O5 234.0528, found 234.0528.
3.4.8. Compounds 20a and 20b. Diastereomers 20a and
20b were separated by chromatography. Diastereomer 20a,
0.15 g, 26% yield as a yellow semisolid; IR nmax (neat)
1
1765, 1722, 1492, 1442, 1285, 1037, 934, 742 cm21; H
NMR (300 MHz, CDCl3) d 2.21 (m, 1H), 2.58–2.77 (m,
4H), 3.15 (d, J¼13.9 Hz, 1H), 3.25 (m, 1H), 3.87 (s, 3H),
5.94 (s, 2H), 6.73 (m, 3H), 7.25 (m, 2H), 7.38 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 35.9, 41.8, 46.1, 49.0, 54.3, 48.3,
99.7, 105.4, 106.9, 107.0, 118.2, 121.1, 121.2, 125.5, 134.4,
142.6, 145.2, 146.6, 159.6, 167.0, 204.3; LRMS (APþ) m/z
(rel. intensity) 367 (MþþH, 100), 346 (13), 273 (18), 208
(17). Diastereomer 20b, 0.30 g, 51% yield as an reddish oil;
IR nmax (neat) 1764, 1722, 1492, 1442, 1336, 1287, 1037,
3.4.13. Compound 37. 0.76 g, 76% yield after BuCl
trituration as a white solid. Mp 72–748C; IR nmax (neat)
1789, 1764, 1604, 1502, 1474, 1377, 1331, 1281, 1228,
1
1154, 1100, 1025, 913, 743 cm21; H NMR (300 MHz,
CDCl3) d 3.03 (d, J¼18.2 Hz, 1H), 3.12 (d, J¼18.2 Hz, 1H),
3.97 (s, 3H), 4.02 (s, 3H), 4.58 (s, 2H), 6.92 (s, 1H), 7.30 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d 38.9, 54.7, 54.8,
74.2, 86.1, 103.6, 104.5, 116.0, 138.7, 149.6, 153.5, 166.4,
172.7; LRMS (APþ) m/z (rel. intensity) 265 (MþþH, 100),
247 (11), 205 (6); HRMS calcd for C13H12O6 264.0634,
found 264.0644.
1
930, 748 cm21; H NMR (300 MHz, CDCl3) d 2.06 (m,
1H), 2.35–2.62 (m, 3H), 2.79 (m, 1H), 2.99 (d, J¼15.2 Hz,
1H), 3.53 (m, 1H), 3.88 (s, 3H), 5.93 (s, 2H), 6.72 (m, 3H),
7.32 (m, 2H), 7.39 (m, 1H); 13C NMR (75 MHz, CDCl3) d
3.4.14. Compound 39. 0.31 g, 87% yield after BuCl

4246
W. Zhang, G. Pugh / Tetrahedron 59 (2003) 4237–4247
trituration as white solid. Mp 2208C (decomposed); IR nmax
(neat) 1767, 913, 744 cm21; 1H NMR (300 MHz, CDCl3) d
3.19 (d, J¼18.8 Hz, 1H), 3.53 (d, J¼18.8 Hz, 1H), 4.73 (d,
1H), 5.00 (d, J¼10.8 Hz, 1H), 7.77–7.90 (3H), 7.90 (d,
J¼8.4 Hz, 1H), 8.10 (d, J¼8.4 Hz, 1H), 8.13 (m, 1H); 13C
NMR (75 MHz, DMSO-d6) d 38.9, 73.4, 87.6, 118.5, 123.1,
123.3, 124.5, 127.2, 127.9, 128.3, 130.7, 134.7, 141.9,
166.5, 172.4; LRMS (APþ) m/z (rel. intensity) 255 (MþþH,
100), 237 (26), 195 (26), 155 (19); HRMS calcd for
C15H10O4 254.0579, found 254.0577.
(s, 2CH3), 3.89 (s, 3H), 5.05 (s, 2H), 7.00–7.15 (2H), 7.20–
7.40 (5H), 7.45 (m, 2H); 13C NMR (75 MHz, CDCl3) d 25.4
(2C), 45.3, 54.0, 70.6, 112.6, 114.9, 119.0, 121.8, 124.9,
126.7 (2C), 126.9, 127.5 (2C), 128.0, 129.6, 134.0, 147.5,
148.7, 165.8, 171.7; LRMS (APþ) m/z (rel. intensity) 377
(Mþ, 100), 350 (64), 293 (30), 386.
3.4.20. Compound 50c. 0.28 g, 25% yield after chroma-
tography; IR nmax (neat) 2959, 1752, 1605, 1245, 1055,
1
1025, 841 cm21; H NMR (300 MHz, CDCl3) d 0.20 (s,
9CH3), 3.85 (s, 3H), 4.98 (s, 2H), 6.99–7.35 (m, 7H), 7.58
(br s, 1H); 13C NMR (75 MHz, CDCl3) d 2.11 (9CH3), 23.4,
39.3, 42.0, 55.7, 72.3, 117.9, 120.1, 121.4, 126.1, 128.3
(2C), 128.8 (2C), 129.5, 130.8, 160.1, 160.2, 170.2, 173.5;
LRMS (APþ) m/z (rel. intensity) 557 (MþþH, 66), 383 (8),
352 (15), 311 (Mþ2Si(SiMe3)3, 100), 265 (26).
3.4.15. Compound 41. 0.67 g, 70% yield after BuCl
trituration as a mixture of two diastereomers (a/b¼1:1.2).
Mp 172–1738C; IR nmax (neat) 1769, 1467, 1387, 1288,
1256, 1083, 962, 913, 725, 964 cm21; 1H NMR (300 MHz,
CDCl3) d 1.49 (d, J¼6.4 Hz, 3Ha), 1.55 (d, J¼6.4 Hz, 3Hb),
2.00–2.20 (m, 1H), 2.33 (m, 1H), 2.96 (m, 2H), 4.70 (m,
1Hb), 5.00 (m, 1Ha), 7.42 (m, 1H), 7.62 (t, J¼7.5 Hz, 1H),
7.75 (m, 1H), 7.93 (d, J¼7.5 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) d 18.9, 19.8, 38.7, 38.9 (2C), 70.9, 72.4, 82.2,
82.8, 120.7, 120.8, 123.1, 123.3, 123.7, 123.8, 128.5, 128.6,
133.6, 133.7, 149.5, 150.3, 166.7 (2C), 167.8; LRMS (APþ)
m/z (rel. intensity) 233 (MþþH, 100), 215 (33), 189 (42),
171 (13), 145 (38); HRMS calcd for C13H12O4 232.0736,
found 232.0776.
3.4.21. Compound 53. 0.096 g, 54% yield after chroma-
tography as a white solid. Mp.2508C; IR nmax (neat) 1749,
1676, 1603, 1495, 1466, 1364, 1332, 1274, 1100, 1021, 986,
1
918, 764 cm21; H NMR (300 MHz, CDCl3) d 3.10 (d,
J¼16.5 Hz, 1H), 3.20 (d, J¼16.5 Hz, 1H), 3.49 (s, 3H), 3.91
(s, 3H), 6.82 (d, J¼7.5 Hz, 1H), 6.97 (t, J¼7.5 Hz, 1H), 7.18
(d, J¼7.5 Hz, 1H), 7.26–7.50 (m, 4H); 13C NMR (75 MHz,
CDCl3) d 28.1, 41.9, 54.4, 82.4, 106.5, 114.0, 121.6, 121.8,
122.0, 122.6, 124.4, 126.3, 129.4, 139.1, 140.2, 159.9,
164.2, 167.1; LRMS (APþ) m/z (rel. intensity) 310 (MþþH,
100); HRMS calcd for C18H15NO4 309.1001, found
309.1010.
3.4.16. Compound 43. 0.58 g, 74% yield after BuCl
trituration as a yellow solid. Mp 250–2528C; IR nmax
(neat) 1776, 1480, 1335, 1286, 1200, 1091, 913, 743 cm21
;
1H NMR (300 MHz, CDCl3) d 3.26 (s, 2H), 3.93 (s, 3H),
6.83 (s, 1H), 7.18 (d, J¼8.7 Hz, 1H), 7.28–7.53 (m, 4H);
13C NMR (75 MHz, CDCl3) d 39.3, 54.5, 80.2, 106.9, 117.7,
121.9, 122.5, 124.1, 125.8, 128.9, 130.2, 138.5, 148.6,
160.4, 161.8, 166.1; LRMS (APþ) m/z (rel. intensity) 331
(MþþH, 100), 297 (9); HRMS calcd for C17H11ClO5
330.0295, found 330.0311.
3.4.22. Compound 56. 0.37 g, 52% yield after chromato-
graphy as a mixture of two diastereomers (1:1.5); IR nmax
(neat) 1765, 1644, 1516, 1496, 1464, 1362, 1335, 1285,
1
1257, 1223, 1095, 914, 731 cm21; H NMR (300 MHz,
CDCl3) d 2.20–3.15 (7H), 3.80 (s, 3H), 3.87 (s, 3H), 3.90 (s,
3H), 4.89–5.20 (m, 2H), 6.57 (d, J¼10.7 Hz, 1H), 6.66 (s,
1H), 7.26–7.40 (3H); 13C NMR (75 MHz, CDCl3) d 26.7,
27.0, 38.5, 39.1, 39.5, 40.4, 40.8, 51.6, 51.8, 54.4, 54.5,
80.7, 81.3, 106.0, 106.4, 106.5, 106.9, 110.1, 120.4, 121.1,
121.7, 122.0, 125.2, 125.3, 125.5, 125.7, 125.8, 125.9,
141.6, 142.2, 146.4, 146.5, 146.7, 159.8, 163.9, 164.1,
167.1, 167.4; LRMS (APþ) m/z (rel. intensity) 410 (MþþH,
100), 408 (50), 390 (18), 364 (21); HRMS calcd for
C23H23NO6 409.1525, found 409.1523.
3.4.17. Compound 45. 0.58 g, 67% yield after BuCl
trituration as yellow solid. Mp 154–1578C; IR nmax (neat)
1
2938, 1766, 1727, 1374, 1286, 913, 742, 695 cm21; H
NMR (300 MHz, CDCl3) d 1.20–2.40 (12H), 2.90 (d,
J¼18.0 Hz, 1H), 3.03 (d, J¼18.0 Hz, 1H), 7.44 (d,
J¼7.7 Hz, 1H), 7.63 (t, J¼7.7 Hz, 1H), 7.76 (t, J¼7.5 Hz,
1H), 7.93 (d, J¼7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d
20.1, 20.2, 23.3, 35.7, 38.4, 38.5, 41.7, 81.4, 81.9, 119.6,
123.6, 124.6, 128.6, 133.5, 149.9, 165.8, 166.8; LRMS
(APþ) m/z (rel. intensity) 287 (MþþH, 87), 269 (100), 251
(66), 223 (13), 198 (7), 147 (22); HRMS calcd for C17H18O4
274.1205, found 286.1209.
3.4.23. Compound 59. 0.36 g, 67% yield after BuCl
trituration as a yellow solid. Mp 181–1838C; IR nmax
(neat) 1765, 1710, 1497, 1286, 1286, 1984, 913, 744 cm21
;
1H NMR (300 MHz, CDCl3) d 2.99 (d, J¼15.3 Hz, 1H),
3.13 (d, J¼15.3 Hz, 1H), 3.63 (d, J¼12.4 Hz, 1H), 3.90 (s,
3H), 3.90 (d, J¼12.4 Hz, 1H), 7.30–7.40 (2H), 7.48 (d,
J¼7.5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d 41.0,
49.6, 54.6, 87.9, 106.4, 121.5, 122.3, 125.9, 138.7, 159.7,
166.3, 202.4; LRMS (APþ) m/z (rel. intensity) 251 (MþþH,
100), 233 (40), 207 (32), 193 (27), 175 (16), 152 (47);
HRMS calcd for C12H10O4S 250.0300, found 250.0318.
3.4.18. Compound 50a. 0.12 g, 15% yield after chroma-
tography as a white solid. Mp 132–1338C; IR nmax (neat)
3058, 3027, 2935, 2359, 1757, 1683, 1607, 1483, 1366,
1271, 1199, 1037 cm21; 1H NMR (300 MHz, CDCl3) d 3.87
(s, 3H), 5.45 (s, 2H), 7.10–7.55 (m, 9H), 7.63 (br s, 1H),
7.75 (d, J¼7.7 Hz, 1H), 7.90 (d, J¼7.5 Hz, 2H); LRMS
(APþ) m/z (rel. intensity) 387 (MþþH, 17), 311 (40), 211
(100), 177 (39); HRMS calcd for C24H18O5 386.1154, found
386.1154.
3.4.24. Compound 64. 0.020 g, 55% yield after chroma-
tography as a mixture of two diastereomers (a/b¼1:2); IR
n
max (neat) 2956, 1766, 1713, 1466, 1278, 1121, 1025, 994,
3.4.19. Compound 50b. 0.076 g, 10% yield after chroma-
tography; IR nmax (neat) 3304, 1740, 1667, 1603, 1527,
1301, 1061, 1032 cm21; 1H NMR (300 MHz, CDCl3) d 1.55
975, 759, 695 cm21; 1H NMR (300 MHz, CDCl3) d 1.09 (d,
J¼7.3 Hz, 3Ha), 1.38 (d, J¼7.3 Hz, 3Hb), 1.80–2.80 (9H),
7.10 (d, J¼7.7 Hz, 1H), 7.50–7.64 (m, 2H), 7.95 (m, 1H);

W. Zhang, G. Pugh / Tetrahedron 59 (2003) 4237–4247
4247
LRMS (APþ) m/z (rel. intensity) 257 (MþþH, 100), 239
4. Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 3009.
5. Preliminary communications: (a) Zhang, W.; Pugh, G.
Tetrahedron Lett. 2001, 42, 5617. (b) Zhang, W. Tetrahedron
Lett. 2000, 41, 2523. (c) Zhang, W.; Pugh, G. Tetrahedron
Lett. 1999, 40, 7595.
(25); HRMS calcd for C16H16O3 256.1099, found 256.1079.
3.4.25. Compound 69. 0.025 g, 58% yield after chroma-
tography as a clear oil; IR nmax (neat) 1767, 1713, 1260,
750 cm21
;
1H NMR (300 MHz, CDCl3) d 1.02 (d,
6. Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707.
7. (a) Wu, C.-S.; Huang, J.-L.; Sun, Y.-S.; Yang, D.-Y. J. Med.
Chem. 2002, 45, 2222. (b) Lin, Y.-L.; Wu, C.-S.; Lin, S.-W.;
Huang, J.-L.; Sun, Y.-S.; Yang, D.-Y. Bioorg. Med. Chem.
2002, 10, 685. (c) Meazza, G.; Scheffler, B. E.; Tellez, M. R.;
Rimando, A. M.; Romagni, J. G.; Duke, S. O.; Nanayakkara,
D.; Khan, I. A.; Abourashed, E. A.; Dayan, F. E. Phyto-
chemistry 2002, 60, 281.
J¼6.0 Hz, 3H), 1.70–2.60 (7H), 3.03 (m, 1H), 3.58 (br d,
1H), 7.24–7.50 (m, 3H), 7.92 (d, J¼7.5 Hz, 1H); LRMS
(APþ) m/z (rel. intensity) 271 (MþþH, 100), 253 (40), 197
(9), 159 (7); HRMS calcd for C17H18O3 270.1256, found
270.1256.
3.4.26. Compound 72. 0.045 g, 34% yield after chroma-
tography as a clear oil; IR nmax (neat) 1766, 1723, 1465,
1289, 1262, 1122, 1021, 768, 732, 692, 554 cm21; 1H NMR
(300 MHz, CDCl3) d 1.01 (d, J¼5.3 Hz, 3H), 1.50–2.40 (m,
8H), 2.60 (m, 1H), 2.78 (m, 1H), 2.97 (m, 1H), 7.22 (d,
J¼7.5 Hz, 1H), 7.50–7.62 (m, 2H), 7.90 (d, J¼7.6 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 19.4, 25.0 (2C), 25.4, 34.6,
37.6, 41.4, 52.5, 88.2, 120.7, 123.7, 124.6, 128.0, 132.6,
150.2, 167.3, 214.6; LRMS (APþ) m/z (rel. intensity) 271
(MþþH, 100), 251 (60); HRMS calcd for C17H18O3
270.1256, found 270.1251.
8. Lee, D. L.; Knudsen, C. G.; Michaely, W. J.; Chin, H.-L.;
Nguyen, N. H.; Carter, C. G.; Cromartie, T. H.; Lake, B. H.;
Shribbs, J. M.; Fraser, T. Pestic. Sci. 1998, 54, 377.
9. For a review on aryl radical cyclizations, see: Banik, B. K.
Curr. Org. Chem. 1999, 3, 469.
10. Zhang, W. Tetrahedron 2001, 57, 7237.
11. Kennosuke, S.; Hiroichi, M.; Jun, A. Yakugaku Zasshi 1968,
88, 919.
12. Williams, D. Tetrahedron Lett. 1973, 639.
13. Isolation: (a) Kusumi, T.; Ichikawa, A.; Kakisawa, H.;
Tsunakawa, M.; Konishi, M.; Oki, T. J. Am. Chem. Soc.
1991, 113, 8947. Synthesis: (b) Roush, W. R.; Barda, D. A.;
Limberakis, C.; Kunz, R. K. Tetrahedron 2002, 58, 6433.
14. For synthesis of related spirodilactones, see: (a) Naito, S.;
Escobar, M.; Kym, P. R.; Liras, S.; Martin, S. F. J. Org. Chem.
2002, 67, 4200. (b) Liddell, J. R.; Whiteley, C. G. S. Afr. J.
Chem. 1991, 44, 35. (c) Jaroszewski, J. W.; Ettlinger, M. G.
J. Org. Chem. 1989, 54, 1506.
Acknowledgements
We thank William Marshall for the X-ray structural
analysis.
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