Quantitating the effect of an ortho substituent on cyclization and intramolecular hydrogen-transfer reactions of aryl radicals

Article abstract of DOI:10.1021/jo0268759

Reduction of allyl 2-iodobenzyl malonates with triphenyltin hydrides generates aryl radicals that partition between 6-exo cyclization, 7-endo cyclization, and 1,5-hydrogen atom transfer. Rate constants for all of these processes are high (> 10⁸ M^-1 s^-1), and the rates are only marginally reduced (<33%) by the introduction of methyl group ortho to the reacting radical.

Full text of DOI:10.1021/jo0268759

Quantitating the Effect of an Ortho Substituent on Cyclization and Intramolecular
Hydrogen Transfer Reactions of Aryl Radicals
Dennis P. Curran* and Neil Fairweather
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260
email: curran@pitt.edu
Supporting Information
Purities of all authentic samples and isolated products were excellent (>95%, typically >98%) as
assessed by GC (see Appendix A below for column and conditions).
(2-Iodo-3-methylphenyl)methanol:1 To a stirred solution of 2-iodo-3-methyl benzoic acid
(4.57 g, 17.4 mmol) and triethylamine (2.70 mL, 19.4 mmol) in THF (12 mL) at 0 °C was added
dropwise ethyl chloroformate (1.90 mL, 19.9 mmol) over 30 min. The reaction mixture was
stirred for 30 min followed by filtration to remove the solid precipitate. The precipitate was
washed with additional THF (2 x 10 mL). Sodium borohydride (2.57 g, 67.8 mmol) was then
added to the filtrate in one portion followed by the dropwise addition of methanol (30 mL) over
45 min at 0 °C. The mixture was stirred for an additional 40 min followed by quenching with 6
N HCl. The layers were separated and the aqueous layer was extracted with Et2O (2 x 40 mL).
The combined organic layers were dried over MgSO4 and concentrated on a rotary evaporator.
The residue was purified by silica gel chromatography (20% EtOAc in hexanes) to provide the
1
product as a white solid: (7.19 g, 74%) mp 75-76 °C; H NMR (CDCl3, 300 MHz) δ 7.17-7.22
(m, 3 H), 4.73 (d, 1 H, J = 6.5 Hz), 2.48 (s, 3 H), 2.12 (t, J = 6.5 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 143.3, 142.2, 129.1, 128.2, 125.8, 104.8, 70.4, 29.2; IR (KBr) 3275, 2899, 2839, 1583,
1447, 1403, 1314, 1169, 1059, 1002, 765 cm-1; EIMS 248 (M+, 100), 231 (7), 127 (14), 119

(119), 103 (20), 91 (59), 77 (61), 65 (30), 54 (18); HRMS calcd for C8H9OI (M+) 247.9698,
found 247.9696.
2-Iodo-3-methylbenzyl bromide:2 To a stirred solution of (2-iodo-3-methylphenyl)methanol
(0.84 g, 3.41 mmol) in CH2Cl2 (15 mL) was added PPh3 (0.98 g, 3.74 mmol) in one portion. The
mixture was stirred for 45 min prior to the portionwise addition of NBS (0.67 g, 3.75 mmol).
The mixture was stirred for 3 h followed by quenching with sat. NaHCO3. The layers were
separated and the aqueous layer was extracted with Et2O (2 x 20 mL). The combined organic
layers were washed with sat. NaHCO3 (20 mL), H2O (30 mL) and brine (30 mL), dried over
MgSO4 and concentrated on a rotary evaporator. The residue was purified by silica gel
chromatography (hexanes) to provide the product as a clear oil (0.84 g, 79%). Data from the
1
obtained product was in direct agreement to published characterization data3: H NMR (CDCl3,
300 MHz) δ 7.29-7.18 (m, 3 H), 4.65 (s, 2 H), 2.44 (s, 3 H); HRMS calcd for C8H8Br2 (M+)
261.8993, found 261.9002.
2-Allylmalonic acid dimethyl ester (CAS # 40637-57-7). (General Procedure for
Alkylations of Malonates): To a stirred suspension of NaH (0.21 g, 8.5 mmol) in THF (15.0
o
mL) at 25 C was added dropwise dimethyl malonate (1.3 mL, 11.4 mmol). The mixture was
stirred for 30 min prior to the dropwise addition of allyl bromide (0.95 g, 7.9 mmol) in THF (3.0
mL). The solution was stirred at room temperature for 14 h followed by quenching with H2O.
The layers were separated and the aqueous layer was extracted with Et2O (3 x 10 mL). The
combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried over MgSO4
and concentrated on a rotary evaporator. The residue was purified by silica gel chromatography
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1
(15% EtOAc in hexanes) to provide the product as a clear oil (0.95 g, 49%): H NMR (CDCl3,
300 MHz) δ 5.77 (ddt, 1 H, J = 17.0, 10.3, 7.0 Hz), 5.12 (dq, 1 H, J = 17.0, 1.3 Hz), 5.06 (dq, 1
H, J = 10.3, 1.1 Hz), 3.74 (s, 6 H), 3.47 (t, 1 H, J = 7.3 Hz), 2.65 (t, 2 H, J = 7.3 Hz); 13C NMR
(CDCl3, 75 MHz) δ 169.2, 133.9, 117.6, 52.5, 51.4, 32.8; IR 3083, 3004, 2956, 2847, 1746,
1643, 1438, 1347, 1201 cm-1; LRMS 172 (M+, 20), 157 (10), 141 (10), 112 (100), 81 (100), 59
(65), 53 (30); EIMS calcd for C8H12O4 (M+) 172.0736, found 172.0730.
2-Allyl-2-(2-iodobenzyl)malonic acid dimethyl ester (1a): The reaction was carried out as
above with NaH (0.088 g, 3.7 mmol), 2-allyldimethyl malonate (0.57 g, 3.3 mmol) and 2-
iodobenzyl bromide (1.08 g, 3.7 mmol) in THF (9.0 mL). Purification by silica gel
1
chromatography (20% EtOAc in hexanes) provided the product as a clear oil (1.13 g, 88%): H
NMR (CDCl3, 300 MHz) δ 7.82 (d, 1 H, J = 7.9 Hz), 7.27-7.19 (m, 2 H), 6.92-6.87 (m, 1 H),
5.83 (ddt, 1 H, J = 19.6, 9.6, 7.2 Hz), 5.14-5.07 (m, 2 H), 3.70 (s, 6 H), 3.51 (s, 2 H), 2.67 (d, 2
13
H, J = 7.2 Hz); C NMR (CDCl3, 75 MHz) δ 170.7, 139.6, 139.3, 132.6, 129.8, 127.8, 118.7,
102.5, 58.8, 52.2, 42.3, 37.8; IR 3077, 2951, 2841, 1740, 1640, 1562, 1434 cm-1; LRMS 388
(M+, 20), 357 (25), 315 (20), 261 (100), 217 (65), 201 (30), 139 (30), 128 (20), 115 (25); EIMS
calcd for C15H17O3I (M+) 388.0172, found 388.0165.
2-Allyl-2-(2-iodo-3-methylbenzyl)malonic acid dimethyl ester (1b): The reaction was carried
out as above with NaH (0.027 g, 1.8 mmol), 2-allyl-dimethyl malonate (0.17 g, 1.0 mmol) in
THF (0.5 mL) and 2-iodo-3-methylbenzyl bromide (0.36 g, 1.2 mmol) in THF (3.5 mL).
Purification by silica gel chromatography (20% EtOAc in hexanes) provided the product as a
1
clear oil (0.32 g, 80%): H NMR (CDCl3, 300 MHz) δ 7.12-7.10 (m, 2 H), 7.00-6.97 (m, 1 H),
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5.43 (ddt, 1 H, J = 17.5, 9.6, 7.3 Hz), 5.12-5.06 (m, 2 H), 3.69 (s, 6 H), 3.62 (s, 2 H), 2.67 (d, 2
13
H, J = 7.3 Hz), 2.48 (s, 3 H); C NMR (CDCl3, 75 MHz) δ 171.2, 142.6, 140.3, 133.1, 128.2,
127.5, 127.0, 118.9, 110.3, 59.4, 52.4, 43.7, 38.1, 30.7; IR 3082, 2953, 2839, 1731, 1632, 1575,
1451 cm-1; LRMS 402 (M+, 5), 371 (10), 339 (40), 329 (75), 275 (100), 231 (55), 215 (20), 155
(20), 139 (20), 115 (25), 104 (30), 59 (25); EIMS calcd for C16H19O4I (M+) 402.0328, found
402.0337.
Representative Procedure for Kinetic Experiments with Ph3SnH: To a stirred solution of 2-
allyl-2-(2-iodo-3-methylbenzyl)malonic acid dimethyl ester 1b (0.11 g, 0.27 mmol) in benzene
(11 mL) was added Ph3SnH (0.19 g, 0.55 mmol) and a catalytic amount of AIBN. The mixture
was heated to reflux for 3 h followed by cooling to room temperature and concentration on a
rotary evaporator to yield a crude oil. An aliquot from the crude reaction mixture was then
diluted in CH2Cl2 for analysis by GC/MS and GC. A mixture of four products (2b, 3b, 4b and
5b) with m/e = 276 (GC/MS) was obtained. GC product ratios as a function of concentration are
listed in Table 1. A representative chromatogram is shown in Appendix A.
2-Allyl-2-(3-methylbenzyl)malonic acid dimethyl ester (2b): The reaction was carried out as
above with NaH (0.031 g, 1.3 mmol), 2-allyl dimethyl malonate (0.20 g, 1.2 mmol) and 3-
methylbenzyl bromide (0.17 mL, 1.3 mmol) in THF (6.0 mL). Purification by silica gel
1
chromatography (20% EtOAc in hexanes) provided the product as a clear oil (0.28 g, 88%): H
NMR (CDCl3, 300 MHz) δ 7.16 (t, 1 H, J = 7.6 Hz), 7.03 (d, 1 H, J = 7.7 Hz), 6.88 (d, 2 H, J =
7.5 Hz), 5.77 (ddt, 1 H, J = 14.9, 11.1, 7.3 Hz), 5.16 (bd, 1 H, J = 10.6 Hz), 5.13 (bd, 1 H, J = 5.7
Hz), 3.73 (s, 6 H), 3.21 (s, 2 H), 2.55 (d, 2 H, J = 7.2 Hz), 2.31 (s, 3 H); 13C NMR (CDCl3, 75
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MHz) δ 171.1, 137.7, 135.7, 132.7, 130.7, 128.1, 127.7, 126.9, 119.1, 59.1, 52.2, 38.1, 36.5,
21.3; IR 3078, 3025, 2952, 2359, 2342, 1738, 1641, 1608, 1435 cm-1; EIMS 276 (M+, 35), 244
(45), 235 (65), 203 (70), 157 (45), 105 (100), 59 (10); HRMS calcd for C16H20O4 (M+) 276.1362,
found 276.1363.
Product 2b was injected into the GC and it coeluted the second peak from the radical cyclizations
of 1b.
2-(3-Methylbenzyl)-2-propenylmalonic acid dimethyl ester (3b):3 To a stirred solution of 2-
allyl-2-(3-methylbenzyl)malonic acid dimethyl ester 2b (0.102 g, 0.37 mmol) in EtOH (3.5 mL)
was added a catalytic amount of RhCl3. This mixture was heated to reflux for 20 h followed by
cooling to room temperature. The crude reaction mixture was filtered through a plug of Celite
(1:1 CH2Cl2:hexanes) and concentrated on a rotary evaporator. The residue was purified by
column chromatography (20% EtOAc in hexanes) to yield the product as a clear oil (0.078 g,
1
77%): H NMR (CDCl3, 300 MHz) δ 7.36-7.21 (m, 1 H), 7.18-7.15 (m, 1 H), 7.03-7.01 (m, 2
H), 5.96 (dq, 1 H, J = 16.1, 1.6 Hz), 5.73 (dq, 1 H, J = 16.1, 6.3 Hz), 3.87 (s, 6 H), 3.46 (s, 2 H),
2.44 (s, 3 H), 1.90 (dd, 3 H, J = 6.4, 1.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 171.1137.2, 135.6,
130.9, 128.2, 128.1, 127.9, 127.8, 127.1, 60.7, 52.4, 42.3, 21.3, 18.1; IR 3010, 2952, 2703,
2342, 1730, 1606, 1434, 1274, 1194, 966, 806, 778, 705 cm-1; EIMS 276 (M+, 20), 244 (35),
216 (90), 203 (80), 185 (65), 171 (80), 157 (100), 141(70), 106 (80), 77 (95), 59 (65); HRMS
calcd for C16H20O4 (M+) 276.1362, found 276.1356.
Product 3b was injected into the GC and it coeluted with the first peak from the radical
cyclizations of 1b.
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4,5-Dimethyl-3,4-dihydro-1H-napthalene-2,2-dicarboxylic acid dimethyl ester (4b) and 1-
Methyl-8,9-dihydro-5H,7H-benzocycloheptene-6,6-dicarboxylic acid dimethyl ester (5b):
To a stirred solution of 2-allyl-2-(2-iodo-3-methylbenzyl)malonic acid dimethyl ester 1b (0.19 g,
0.41 mmol) in benzene (9.0 mL) was added Ph3SnH (0.22 g, 0.62 mmol) and a catalytic amount
of AIBN. The mixture was heated to reflux for 3 h followed by cooling to room temperature and
concentration on a rotary evaporator to yield a crude oil. The crude oil was dissolved in Et2O
followed by the addition of DBU. A saturated solution of I2 in Et2O was then added until a dark
brown color persisted. The mixture was then filtered through a plug of silica eluting with Et2O
followed by concentration on a rotary evaporator. Ozone was bubbled for 30 min through a
o
stirred solution of the crude products in MeOH:CH2Cl2 (15 mL : 11 mL) at –78 C. Pyridine
(0.10 mL, 1.2 mmol) and Me2S (1.2 mL, 16.3 mmol) were added followed by warming the
mixture to room temperature. The mixture was stirred for 16 h followed by concentration on a
rotary evaporator. The residue was purified by column chromatography (15% EtOAc in
hexanes) to yield the products as an inseparable mixture in approximately a 5:1 ratio in favor of
the 6-exo product 4b over 5b (0.023 g, 18% from 1b). 4,5-Dimethyl-3,4-dihydro-1H-
1
napthalene-2,2-dicarboxylic acid dimethyl ester (4b): H NMR (CDCl3, 300 MHz) δ 7.09-
6.94 (m, 3 H), 3.75 (s, 3 H), 3.57 (s, 3 H), 3.19-3.12 (m, 2 H), 2.69 (ddd, 1 H, J = 14.0, 7.8, 1.8
Hz), 2.29 (s, 3 H), 2.05 (dd, 2 H, J = 14.0, 4.9 Hz), 1.17 (d, 3 H, J = 7.1 Hz); 13C NMR (CDCl3,
75 MHz) δ 172.7, 171.6, 138.8, 135.5, 133.1, 129.0, 126.8, 53.7, 52.2, 36.9, 35.5, 28.8, 21.9,
19.3; 1-Methyl-8,9-dihydro-5H,7H-benzocycloheptene-6,6-dicarboxylic acid dimethyl ester
1
(5b): H NMR (CDCl3, 300 MHz) δ 7.09-6.94 (m, 3 H), 3.64 (s, 6 H), 3.35 (s, 2 H), 2.83-2.79
13
(m, 2 H), 2.16 (t, 2 H, J = 6.5 Hz), 1.88-1.80 (m, 2 H); C NMR (CDCl3, 75 MHz) δ 171.8,
141.2, 135.9, 134.5, 129.1, 128.9, 125.3, 55.5, 52.6, 39.4, 36.0, 28.2, 22.6, 20.3; Mixture, IR
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3142, 2992, 2953, 2863, 2356, 2340, 1735, 1435, 1257, 1204, 1105, 957, 774 cm-1; EIMS 276
(M+, 40), 216 (85), 201 (60), 157 (100), 142 (60), 128 (35), 115 (35), 59 (25); HRMS calcd for
C16H20O4 (M+) 276.1362, found 276.1362.
Products 4b and 5b were injected into the GC and coeluted with the third and fourth peaks from
the radical cyclizations of 1b.
2-Allyl-2-benzylmalonic acid dimethyl ester (2a):4 The reaction was carried out as above with
NaH (0.011 g, 0.46 mmol), 2-allyldimethyl malonate (0.069 g, 0.40 mmol) and benzyl bromide
(0.060 mL, 0.44 mmol) in THF (1.5 mL). Purification by silica gel chromatography (20%
1
EtOAc in hexanes) provided the product as a clear oil (0.078 g, 75%): H NMR (CDCl3, 300
MHz) δ 7.27-7.25 (m, 3 H), 7.10-7.08 (m, 2 H), 5.76 (ddt, 1 H, J = 18.7, 11.4, 7.1 Hz), 5.16 (bd,
1 H, J = 10.2 Hz), 5.13 (bd, 1 H, J = 5.9 Hz), 3.71 (s, 6 H), 3.24 (s, 3 H), 2.55 (d, 2 H, J = 7.2
Hz); 13C NMR (CDCl3, 75 MHz) δ 171.1, 135.8, 132.6, 130.0, 128.3, 127.0, 119.2, 51.1, 52.2,
38.2, 36.5; IR 3405, 3288, 3181, 3029, 2953, 2358, 2340, 1733, 1640, 1436 cm-1; EIMS 262
(M+, 30), 231 (25), 221 (35), 189 (65), 143 (40), 91 (100); HRMS calcd for C15H18O4 (M+)
262.1205, found 262.1208.
Product 2a was injected into the GC and coeluted with the second peak from the radical
cyclizations of 1a.
2-Benzyl-2-propenylmalonic acid dimethyl ester (3a): To a stirred solution of 2-allyl-2-
benzylmalonic acid dimethyl ester 2a (0.063 g, 0.24 mmol) in EtOH (2.0 mL) was added a
catalytic amount of RhCl3. This mixture was heated to reflux for 21 h followed by cooling to
room temperature. The crude reaction mixture was filtered through a plug of Celite (1:1 CH2Cl2
: hexanes) and concentrated on a rotary evaporator. The residue was purified by column
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1
chromatography (20% EtOAc in hexanes) to yield the product as a clear oil (0.048 g, 77%): H
NMR (CDCl3, 300 MHz) δ 7.26-7.22 (m, 3 H), 7.10-7.02 (m, 2 H), 5.82 (dq, 1 H, J = 16.1, 1.6
Hz), 5.60 (dq, 1 H, J = 16.1, 6.4 Hz), 3.72 (s, 3 H), 3.71 (s, 3 H), 3.36 (s, 2 H), 1.75 (dd, 3 H, J =
6.5, 1.4 Hz) 13C NMR (CDCl3, 75 MHz) δ 171.1, 135.8, 130.1, 129.9, 128.3, 128.0, 127.8,
127.7, 126.8, 60.7, 52.5, 42.4, 18.2; IR 3031, 2952, 2855, 1738, 1604, 1444, 1224, 967, 744,
702 cm-1; EIMS 262 (M+, 35), 171 (30), 143(25), 91 (100), 65 (20); HRMS calcd for C15H18O4
(M+) 262.1205, found 262.1207.
Product 3a was injected into the GC and coeluted with the first peak from the radical cyclizations
of 1a.
4-Methyl-3,4-dihydro-1H-napthalene-2,2-dicarboxylic acid dimethyl ester (4a) and 5,7,8,9-
Tetrahydrobenzocycloheptene-6,6-dicarboxylic acid dimethyl ester (5a): To a stirred
solution of 2-allyl-2-(2-iodobenzyl)malonic acid dimethyl ester (0.28 g, 0.73 mmol) in benzene
(14.0 mL) was added Ph3SnH (0.51 g, 1.5 mmol) and a catalytic amount of AIBN. The mixture
was heated to reflux for 3 h followed by cooling to room temperature and concentration on a
rotary evaporator to yield a crude oil. The crude oil was dissolved in Et2O followed by the
addition of DBU. A saturated solution of I2 in Et2O was then added until a dark brown color
persists. The mixture was then filtered through a plug of silica eluting with Et2O followed by
concentration on a rotary evaporator. Ozone was bubbled for 30 min through a stirred solution
o
of the crude products in MeOH:CH2Cl2 (20 mL : 15 mL) at –78 C. Pyridine (0.20 mL, 2.5
mmol) and Me2S (2.5 mL, 34.0 mmol) were added followed by warming the mixture to room
temperature. The mixture was stirred for 16 h followed by concentration on a rotary evaporator.
The residue was purified by column chromatography (15% EtOAc in hexanes) to yield the
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products as an inseparable mixture along with benzyl dimethylmalonate. The mixture of three
products was dissolved in DMF (2.5 mL) and heated to 180 ºC in a microwave for 30 min. This
converted benzyl dimethylmalonate to PhCH2CH2CO2 Me without reacting the cyclized
(disubstituted) malonates. Purification by column chromatography (10% EtOAc in hexanes)
yielded the cyclized products as an inseparable mixture in approximately a 3:1 ratio in favor of
the 6-exo product (4a over 5a) (0.044 g, 23% from 1a). 4,5-Dimethyl-3,4-dihydro-1H-
napthalene-2,2-4-Methyl-3,4-dihydro-1H-napthalene-2,2-dicarboxylic acid dimethyl ester
(4a): 1H NMR (CDCl3, 300 MHz) δ 7.25-7.05 (m, 4 H), 3.75 (s, 3 H), 3.67 (s, 3 H), 3.38 (d, 1 H,
J = 16.3 Hz), 3.17 (d, 1 H, J = 16.3 Hz), 2.59 (ddd, 1 H, J = 13.6, 5.9, 2.2 Hz), 1.83 (dd, 2 H, J =
13.5, 11.3 Hz), 1.36 (d, 3 H, J = 6.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 172.3, 171.4, 139.7,
133.3, 128.6, 126.5, 125.9, 55.7, 52.8, 37.3, 35.3, 29.9, 21.3; 5 , 7 , 8 , 9 -
1
Tetrahydrobenzocycloheptene-6,6-dicarboxylic acid dimethyl ester (5a): H NMR (CDCl3,
300 MHz) δ 7.25-7.05 (m, 4 H), 3.64 (s, 6 H), 3.34 (s, 2 H), 2.79 (t, 2 H, J = 5.5 Hz), 2.21 (t, 2
H, J = 5.6 Hz), 1.92-1.86 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 171.7, 143.1, 135.8, 131.0,
128.5, 127.0, 53.8, 52.6, 52.3, 35.3, 29.9; Mixture: IR 3023, 2953, 2852, 1737, 1449, 1263,
1210, 755 cm-1; LRMS 262 (M+, 25), 202 (55), 187 (25), 143 (100), 128 (55), 115 (30), 91 (15),
59 (30); HRMS calcd for C15H18O4 (M+) 262.1205, found 262.1197.
Products 4a and 4b were injected into the GC and coeluted with the third and fourth peaks from
the radical cyclizations of 1a.
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Appendix A. A Representative GC Chromatogram from the
Radical Cyclization of 1b.
CO Me
2
CO Me
CO Me
CO Me
2
2
2
MeO C
MeO C CO Me
2
2
2
Ph SnH, AIBN
MeO C
3
2
MeO C
MeO C
2
2
I
Benzene
2b
4b
1b
3b
5b
GC Parameters:
Column: Agilent 190091Z-413E, Crosslinked Methyl Siloxane Stationary Phase
30 m x 0.320 mm x 0.25 µm
Initial Temp: 60 ˚C
Ramp Temp: 12 ˚C/min
Final Temp: 300 ˚C
Detector: FID
Gas Flow Rate: 34 cm/s
1 Kanohi, S.; Muramoto, H.; Kobayashi, N.; Motoi, M.; Suda, H. Bull. Chem. Soc. Jpn. 1987, 60,
3659-3662.
2 Yokohama, S.; Mochida, K. Synthesis, 1987, 647.
3 Grieco, P. A. Nishizawa, M.; Mariovic, N.; Ehmann, W. J. J. Am. Chem. Soc. 1976, 98, 7102-
7104.
4
2-Allyl-2-benzylmalonic acid dimethyl ester 104 has been reported in the literature without
spectral data. Please see: a) Wang, S. F.; Chuang, C. P.; Lee, J. H.; Liu, S. T. Tetrahedron 1999,
55, 2273-2288. b) Chuang, C. P. Tetrahedron Lett. 1992, 33, 6311-6314.
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