An efficient preparation and selected birch reduction-alkylations of 3,4-dihydro-4,5-dialkyl-2-benzopyran-1-ones

Full text of DOI:10.1021/jo960567r

J . Org. Chem. 1996, 61, 5631-5634
5631
Notes
Sch em e 1a
An Efficien t P r ep a r a tion a n d Selected
Bir ch Red u ction -Alk yla tion s of
3,4-Dih yd r o-4,5-d ia lk yl-2-ben zop yr a n -1-on es
Arthur G. Schultz* and Steven J . Kirincich
Department of Chemistry, Rensselaer Polytechnic Institute,
Troy, New York 12180-3590
Received March 26, 1996
In connection with a study of the Birch reduction-
alkylation of chiral 3,4-dihydroisoquinolin-1-ones1 and
related heterocyclic systems, we needed convenient access
to 3,4-dihydro-4,5-dialkyl-2-benzopyran-1-ones (also called
3,4-dihydroisocoumarins); e.g., 5a -d . Dihydroisocou-
marins occur widely in plants,2 and certain 3,4-dihydro-
8-hydroxyisocoumarins are used as trail marking phero-
mones by ants.3 Although several methods for synthesis
of 3,4-dihydroisocoumarins are available,4 we desired a
reasonably general procedure that would accommodate
alkyl substitution at C(4) and C(5). We have developed
and now report a synthesis of 3,4-dihydro-4,5-dialkyl-2-
benzopyran-1-ones 5a -d starting with readily available
o-tolylacetic acid (1a ) (Scheme 1). Selected Birch reduc-
tion-alkylations of 5b and 5d leading to bridged and
fused tetracyclic lactones (Scheme 2) demonstrate the
potential utility of chiral 3,4-dihydro-4,5-dialkyl-2-ben-
zopyran-1-ones in organic synthesis.
a
Reaction conditions: (a) LiAlH4, THF, reflux; (b) MEMCl,
DIPEA, CH2Cl2; (c) TiCl4, CH2Cl2, 0 °C; (d) KMnO4, alumina,
CH2Cl2, 25 °C.
Sch em e 2
Alkylation of the dianion of o-tolylacetic acid (1a )
provided the R-substituted carboxylic acids 1b-d .5 Re-
duction of carboxylic acids 1a -d with LiAlH4 provided
alcohols 2a -d . Alcohols 2a -d were converted to the
2-(methoxyethoxy)methyl (MEM) ethers 3a -d , which
6
were cyclized in the presence of TiCl4 to give benzopy-
rans 4a -d .
There are several methods available for the oxidation
of methylene groups adjacent to aromatic rings and/or
ether oxygen atoms.7 Some7a,d,f were found to be suitable
for oxidation of the benzopyrans 4a -d , but the preferred
reagent system consisting of potassium permanganate
absorbed on alumina8 gave the desired 3,4-dihydroiso-
coumarins in excellent yields by simple filtration of the
reaction mixture and evaporation of solvent. This method
of oxidation is ideally suited to large-scale laboratory
synthesis because the use of more toxic and expensive
oxidants and aqueous extraction procedures are avoided.
(1) Schultz, A. G.; Kirincich, S. J .; Rahm, R. Tetrahedron Lett. 1995,
36, 4551-4554.
(2) Hill, R. A.; Krebs, H. C.; Verpoorte, R.; Wijnsma, R. Progress in
the Chemistry of Natural Products 49; Springer: New York, 1986.
(3) Bestmann, H. J .; Kern, F.; Scha¨fer, D.; Witschel, M. C. Angew.
Chem., Int. Ed. Engl. 1992, 31, 795-796.
(4) (a) Kanda, T.; Kato, S.; Sugino, T.; Kambe, N.; Ogawa, A.;
Sonoda, N. Synthesis 1995, 1102-1106 and references cited therein.
(b) Bhide, C. H. D.; Shah, K. K. Ind. J . Chem. 1980, 19B, 9-12.
(5) (a) Hauser, C. R.; Chambers, W. J . J . Am. Chem. Soc. 1956, 78,
4942-4944. (b) Kla¨rner, F.-G.; Band, R.; Glock, V.; Ko¨nig, W. A. Chem.
Ber. 1992, 125, 197-208. (c) Ghosh, S.; Pardo, S. N.; Salomon, R. G.
J . Org. Chem. 1982, 47, 4692-4702.
The efficiency of this procedure for 3,4-dihydroisocou-
marin construction is illustrated by comparison of the
overall yield for preparation of 5a from o-tolylacetic acid
(77% on a 17 g scale) to that for the only other reported
synthesis of 5a (19%).4b The literature method involves
nuclear metalation of N-methyl-m-toluamide and alky-
lation with ethylene epoxide.
(6) Ahmar, M.; Bloch, R. Syn. Commun. 1992, 22, 1417-1420.
(7) (a) PDC/t-BuOOH: Chidambaram, N.; Chandrasekaran, S. J .
Org. Chem. 1987, 52, 5048-5051. (b) FeCl3/H2O, hν: Barbier, M. Helv.
Chim. Acta 1984, 67, 866-869. (c) PdCl2, CuCl2, CO, O2/acetone (30
atm): Miyamoto, M.; Minami, Y.; Ukaji, Y.; Kinoshita, H.; Inomata,
K. Chem. Lett. 1994, 1149-1152. (d) Mn2O7/CCl4-acetone: Tro¨mel,
M.; Russ, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 1007-1009. (e)
Stoichiometric RuO4: Smith, A. B., III; Scarborough, R. M., J r. Synth.
Commun. 1980, 10, 205-211. (f) Catalytic RuO4, NaIO4/CH3CN, CCl4,
H2O: Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936-3938.
Box and Yiannikouros reported the Birch reduction-
(8) Zhao, D.; Lee, D. G. Synthesis 1994, 915-916.
S0022-3263(96)00567-1 CCC: $12.00 © 1996 American Chemical Society

5632 J . Org. Chem., Vol. 61, No. 16, 1996
Notes
n-butyllithium (32 mL, 0.08 mol in hexanes) over 15 min. After
20 min, methyl iodide (8.3 mL, 0.13 mol) was added in one
portion. The cold bath was left in place, and the reaction was
allowed to warm to room temperature (∼3 h) and then stirred
overnight at room temperature. The solution was acidified with
10% aqueous HCl, diluted with water (100 mL), and extracted
with CH2Cl2 (3 × 75 mL). The combined organic layers were
washed with sodium thiosulfate, dried over anhydrous MgSO4,
filtered, and evaporated to provide 1b5 as a white solid (5.4 g,
100%), which was used without further purification: 1H NMR
(CDCl3) δ 7.30 (d, J ) 7.1 Hz, 1 H), 7.17-7.22 (m, 3 H), 4.00 (q,
J ) 7.1 Hz, 1 H), 2.40 (s, 3 H), 1.50 (d, J ) 7.0 Hz, 3 H).
r-Eth yl-2-m eth ylben zen ea cetic Acid (1c). Reaction of 1a
with ethyl bromide on a 1.0 g scale provided 1c (1.14 g, 96%) as
a crystalline solid (mp 102-104 °C): 1H NMR (CDCl3) δ 7.32
(d, J ) 7.3 Hz, 1 H), 7.15-7.20 (m, 3 H), 3.76 (t, J ) 7.5 Hz, 1
H), 2.39 (s, 3 H), 2.10-2.15 (m, 1 H), 1.76-1.81 (m, 1 H), 0.92
(t, J ) 7.4 Hz, 3 H); 13C NMR (CDCl3) δ 180.45, 136.90, 136.43,
130.47, 127.12, 126.78, 126.39, 48.36, 25.79, 19.84, 12.11; IR
(film) 3500-2700 (br), 1700 cm-1; CIMS m/ z (relative intensity)
179 (M+ + 1, 100), 161 (10), 133 (75).
F igu r e 1. Most stable conformation of the enolate generated
by Birch reduction of 5b (MM2, MacroModel, Version 3.0).
alkylation of phthalides in 1990.9a We are aware of no
other report of successful Birch reduction of aromatic
lactones analogous to 5. A problem with lactones in
general is their susceptibility to ring-opening reactions
by NH3. In fact, 5a is converted to the corresponding
amido alcohol under conditions required for reduction
with lithium; a control experiment with 5b demonstrated
complete stability in NH3/THF solution at -33 °C for 1
h. The greater stability of 5b toward lactone ring
opening is attributed to the peri-effect involving the C(4)
and C(5) methyl substituents.
Selected Birch reduction-alkylations of 5b and 5d are
shown in Scheme 2. The diastereoselectivities for con-
versions to 6a -c were found to be in excess of 10:1. The
high degree of chirality transfer resulting from alkyla-
tions of enolates derived from 5b and 5d is explained by
conformational control resulting from a relief of eclipsing
interactions between the C(4) and C(5) substituents as
shown in Figure 1. Thus, the methyl substituent at C(5)
forces the substituent at C(4) to occupy a pseudoaxial
position that very effectively blocks the R-face of the
enolate.9b
These new procedures for stereoselective reductive
alkylation are expected to be useful for the construction
of complex carbocyclic frameworks. Two examples are
shown in Scheme 2. Treatment of 6b with CF3SO3H10
gave the bridged tetracyclic lactone 7. Analogous cy-
clization of 6c gave the fused tetracyclic lactone 8 with
all cis stereochemistry. Related acid-catalyzed cycliza-
tions of â-arylethylcyclohexanols or the derived cyclo-
hexenes give trans-fused or mixtures of trans- and cis-
fused perhydrophenanthrenes.10 Such cyclizations have
found utility in diterpene synthesis; e.g., podocarpic
acid.10f The availability of technology for the production
of optically active R-arylpropanoic acids (the Profen
drugs)11 suggests that the chemistry outlined in this
report should be readily adaptable to asymmetric organic
synthesis.
Anal. Calcd for C11H14O2: C, 74.13; H, 7.92. Found: C, 74.27;
H, 7.97.
r-(2-Meth ylp h en yl)ben zen ep r op ion ic Acid (1d ). Reac-
tion of 1a with benzyl bromide on a 5.0 g scale provided 1d (7.40
g, 84%): 1H NMR (CDCl3) δ 7.42 (dd, J ) 7.5, 1.2 Hz, 1 H), 7.08-
7.24 (m, 8 H), 4.12-4.15 (m, 1 H), 3.42 (dd, J ) 13.7, 8.0 Hz, 1
H), 2.98 (dd, J ) 13.7, 6.9 Hz, 1 H), 2.23 (s, 3 H); 13C NMR
(CDCl3) δ 179.90, 138.89, 136.57, 136.35, 130.35, 128.89, 128.34,
127.36, 126.89, 126.47, 126.42, 48.68, 38.90, 19.65; IR (film)
3000-2800 (br), 1705 cm-1; CIMS m/ z (relative intensity) 241
(M+ + 1, 100), 195 (16).
Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 78.93;
H, 6.76.
P r ep a r a tion of â-Alk ylben zen eeth a n ols: â,2-Dim eth yl-
ben zen eeth a n ol (2b). 1b (5.12 g, 0.03 mol) dissolved in THF
(30 mL) was added to a stirred slurry of LiAlH4 (1.50 g, 0.04
mol) in THF (100 mL). The resulting solution was stirred at
reflux for 2 h, cooled to room temperature, and then quenched
with 10% aqueous KOH and heated until a white precipitate
formed. The clear solution was filtered, and the white precipi-
tate was refluxed (10 min) with another 100 mL of THF. The
combined filtered organic phases were subjected to rotary
evaporation to provide an oil that was diluted with CH2Cl2 (150
mL), washed with brine (50 mL), and dried over anhydrous
MgSO4. Filtration and evaporation gave 2b (4.69 g, 100%) as a
clear, colorless oil: 1H NMR (CDCl3) δ 7.13-7.22 (m, 4 H), 3.74
(overlapping dd, J ) 10.7, 7.1 Hz, 1 H), 3.68 (overlapping dd, J
) 10.8, 6.6 Hz, 1 H), 3.26 (q, J ) 7.0 Hz, 1 H), 2.38 (s, 3 H), 1.25
(d, J ) 7.1 Hz, 3 H); 13C NMR (CDCl3) δ 141.75, 136.38, 130.51,
126.32, 126.22, 125.40, 67.94, 37.13, 19.56, 17.46; IR (CH2Cl2)
2970, 1490, 1465, 1385, 1080 cm-1; CIMS m/ z (relative intensity)
150 (M+ + 1, 10), 133 (100).
â-Eth yl-2-m eth ylben zen eeth a n ol (2c). Reduction of 1c
(4.9 g) provided 2c (4.42 g, 98%). Chromatographic purification
was unnecessary: 1H NMR (CDCl3) δ 7.17-7.22 (m, 3 H), 7.11-
7.14 (m, 1 H), 3.72-3.79 (m, 2 H), 3.06-3.11 (m, 1 H), 2.36 (s,
3 H), 1.76-1.81 (m, 1 H), 1.56-1.62 (m, 1 H), 0.84 (t, J ) 7.4
Hz, 3 H); 13C NMR (CDCl3) δ 140.43, 137.30, 130.45, 126.31,
126.15, 125.70, 66.94, 44.56, 44.53, 25.10, 19.97, 19.90, 11.80;
IR (film) 3350, 2940 cm-1; CIMS m/ z (relative intensity) 164
(20), 147 (100), 133 (50).
Exp er im en ta l Section
Anal. Calcd for C11H14O2: C, 80.44; H, 9.82. Found: C, 80.16;
H, 9.77.
P r ep a r a t ion of r-Alk ylb en zen ea cet ic Acid s: r,2-Di-
m eth ylben zen ea cetic a cid (1b). To a solution of 1a (5.0 g,
0.033 mol) in THF (100 mL) at -78 °C under N2 was added
â-(2-Meth ylp h en yl)ben zen ep r op a n ol (2d ). Reduction of
1d (7.40 g) provided 2d (5.26 g, 70%, two steps) after flash
chromatography (hexane/ethyl acetate, 4:1): 1H NMR (CDCl3)
δ 7.07 (m, 9 H), 3.81 (d, J ) 6.6 Hz, 2 H), 3.43 (m, J ) 6.9, 6.9,
6.9, 6.9 Hz, 1 H), 3.02 (dd, J ) 13.4, 7.3 Hz, 1 H), 2.85 (dd, J )
13.4, 7.3 Hz, 1 H), 2.18 (s, 3 H); 13C NMR (CDCl3) δ 140.03,
137.03, 130.52, 128.99, 128.21, 126.39, 126.29, 126.00, 125.98,
65.87, 44.81, 38.90, 19.64 (three missing/overlapping peaks); IR
(film) 3370 (br), 3040, 2950, 1040 cm-1; CIMS m/ z (relative
intensity) 209 (35), 131 (60), 117 (100).
Anal. Calcd for C16H18O: C, 84.91; H, 8.02. Found: C, 84.65;
H, 8.06.
P r ep a r a tion of MEM Eth er s: [1-[(2-Meth oxyeth oxy)-
m eth oxy]-2-m eth yleth yl]ben zen e (3b). To a stirred solution
(9) (a) Box, V. G. S.; Yiannikouros, G. P. Heterocycles 1990, 31, 971-
976. (b) For stereoselectivity resulting from an analogous eclipsing
interaction, see: Stork, G.; Logusch, E. W. J . Am. Chem. Soc. 1980,
102, 1218-1219.
(10) (a) Haworth, R. D.; Barker, R. L. J . Chem. Soc. 1939, 1299-
1303. (b) Stork, G.; Burgstahler, A. J . Am. Chem. Soc. 1951, 73, 3544-
3546. (c) Barnes, R. A.; Konort, M. D. J . Am. Chem. Soc. 1953, 75,
303-305. (d) Barltrop, J . A.; Rogers, N. A. J . J . Chem. Soc. 1958, 2566-
2572. (e) Mori, K.; Matsui, M. Tetrahedron 1966, 22, 879-884. (f) King,
F. E.; King, T. J .; Topliss, J . G. Chem. Ind. 1956, 113.
(11) (a) Sonawane, H. R.; Bellur, N. S.; Ahuja, J . R.; Kulkarni, D.
G. Tetrahedron: Asymmetry 1992, 3, 163. (b) Manimaran, T.; Stahly,
G. P. Tetrahedron: Asymmetry 1993, 4, 1949-1954.

Notes
J . Org. Chem., Vol. 61, No. 16, 1996 5633
of 2b (2.18 g, 0.016 mol) in CH2Cl2 (50 mL) was added N,N-
diisopropylethylamine (DIPEA, 3.60 mL, 0.02 mol) and (2-
methoxyethoxy)methyl chloride (2.2 mL, 19 mmol). The reaction
was stirred at room temperature for 8 h, diluted with CH2Cl2
(50 mL), washed with aqueous HCl, dried, filtered, and evapo-
rated. Flash chromatography (hexane-ethyl acetate, 4:1) pro-
vided 3b (2.84 g, 79%) as a pale yellow oil: 1H NMR (CDCl3) δ
7.08-7.22 (m, 4 H), 4.68-4.71 (m, 2 H), 3.71 (dd, J ) 7.8, 6.5
Hz, 1 H), 3.56-3.64 (m, 3 H), 3.49-3.53 (m, 2 H), 3.39 (s, 3 H),
3.27-3.34 (m, 1 H), 2.37 (s, 3 H), 1.28 (d, J ) 6.9 Hz, 3 H); 13C
NMR (CDCl3) δ 142.32, 135.77, 130.24, 126.04, 125.97, 125.46,
95.37, 72.85, 71.67, 66.58, 58.91, 34.84, 19.43, 18.05; IR (CH2-
Cl2) 2925, 2880, 1110, 1045 cm-1; CIMS m/ z (relative intensity)
239 (M+ + 1, 20), 163 (100), 133(35).
3,4-Dih yd r o-4-eth yl-5-m eth yl-2(1H)-ben zop yr a n (4c). 3c
(5.0 g) provided 4c (3.4 g, 97%) as a pale-yellow oil. Chromato-
graphic purification was unnecessary: 1H NMR (CDCl3) δ 7.04-
7.10 (m, 2 H), 6.81 (d, J ) 7.4 Hz, 1 H), 4.81 (d, J ) 14.9 Hz, 1
H), 4.76 (d, J ) 14.9 Hz, 1 H), 4.16 (d, J ) 11.5 Hz, 1 H), 3.67-
3.70 (dd, J ) 11.3, 2.7 Hz, 1 H), 2.46 (m, 1 H), 2.30 (s, 3 H),
1.76-1.83 (m, 1 H), 1.51-1.58 (m, 1 H), 1.06 (t, J ) 7.4 Hz, 3
H); 13C NMR (CDCl3) δ 136.93, 135.86, 133.95, 128.33, 125.78,
121.80, 67.99, 66.52, 37.28, 25.33, 18.04, 12.36; IR (film) 2950,
1460, 1120 cm-1; CIMS m/ z (relative intensity) 177 (M+ + 1,
100), 159 (10), 147 (12).
3,4-Dih yd r o-5-m eth yl-4-(p h en ylm eth yl)-2(1H)-ben zop y-
r a n (4d ). 3d (1.88 g) provided 4d (1.38 g, 98%) as a white solid
(mp 72-73 °C). Chromatographic purification was unneces-
sary: 1H NMR (CDCl3) δ 7.32 (m, 4 H), 7.24-7.30 (m, 1 H),
7.08-7.18 (m, 2 H), 6.88 (d, J ) 7.3 Hz, 1 H), 4.92 (d, J ) 15.0
Hz, 1 H), 4.81 (d, J ) 15.0 Hz, 1 H), 3.97 (d, J ) 11.5 Hz, 1 H),
3.58 (dm, J ) 11.2 Hz, 1 H), 2.85-3.01 (m, 3 H), 2.48 (s, 3 H);
13C NMR (CDCl3) δ 140.59, 136.08, 135.75, 134.33, 129.34,
128.51, 126.19, 126.18, 122.07, 68.11, 65.90, 38.31, 37.69, 18.22;
IR (film) 2850, 1450, 1110 cm-1; CIMS m/ z (relative intensity)
239 (M+ + 1, 95), 221 (100), 146 (10).
Anal. Calcd for C14H22O3: C, 70.56; H, 9.30. Found: C, 70.53;
H, 9.51.
[1-[(2-Met h oxyet h oxy)m et h oxy]-2-m et h ylp r op yl]b en -
zen e (3c). 2c (4.0 g) provided 3c (5.5 g, 89%) after flash
chromatography (hexane/ethyl acetate, 4:1): 1H NMR (CDCl3)
δ 7.13-7.17 (m, 3 H), 7.07-7.11 (m, 1 H), 4.67 (d, J ) 6.9 Hz, 1
H), 4.64 (d, J ) 6.9 Hz, 1 H), 3.66-3.69 (m, 2 H), 3.47-3.60 (m,
4 H), 3.37 (s, 3 H), 3.08-3.14 (m, 1 H), 2.34 (s, 3 H), 1.82-1.88
(m, 1 H), 1.57-1.63 (m, 1 H), 0.82 (t, J ) 7.6 Hz, 3 H); 13C NMR
(CDCl3) δ 141.05, 136.57, 130.13, 125.95, 125.84, 125.83, 95.37,
71.92, 71.68, 66.53, 58.91, 42.04, 25.45, 19.83, 11.69; IR (film)
2930, 1450, 1050 cm-1; CIMS m/ z (relative intensity) 253 (M+
+ 1, 10), 177 (100), 147 (30).
Anal. Calcd for C17H18O: C, 85.67; H, 7.61. Found: C, 85.79;
H, 7.65.
3,4-Dih yd r o-5-m eth yl-2(1H)-ben zop yr a n (4a ). 3a (11.8 g,
53 mmol) provided 4a (7.6 g, 97%). Chromatographic purifica-
tion was unnecessary: 1H NMR (CDCl3) δ 7.08 (m, 2 H), 7.05
(dd, J ) 7.3, 0.7 Hz, 1 H), 4.77 (s, 2 H), 4.02 (t, J ) 5.7 Hz, 2 H),
2.72 (d, J ) 5.7 Hz, 2 H), 2.24 (s, 3 H); 13C NMR (CDCl3) δ 136.44,
134.74, 131.68, 127.65, 125.60, 121.97, 68.27, 65.49, 26.07, 18.78;
IR (film) 2930, 2850, 1120 cm-1; CIMS m/ z (relative intensity)
163 (M+ + 15, 50), 149 (M+ + 1, 100), 119 (6).
Oxid a tion of 3,4-Dih yd r o-2(1H)-ben zop yr a n s: 3,4-Dih y-
d r o-4,5-d im eth yl 2(1H)-ben zop yr a n -1-on e (5b). A solution
of 4b (100 mg, 0.6 mmol) in methylene chloride (5 mL) was
stirred with KMnO4/Al2O3 (5 equiv) at room temperature for 6
h. The solvent was filtered through Celite, dried, filtered, and
evaporated to provide lactone 5b (99 mg, 91%) as a colorless oil
that solidified upon standing. 1H NMR (CDCl3) δ 7.97 (d, J )
7.6 Hz, 1 H), 7.40 (d, J ) 7.5 Hz, 1 H), 7.29 (t, J ) 7.8 Hz, 1 H),
4.54 (dd, J ) 11.0, 3.1 Hz, 1 H), 4.40 (d, J ) 11.2 Hz, 1 H), 3.09-
3.12 (m, 1 H), 2.37 (s, 3 H), 1.36 (d, J ) 7.0 Hz, 3 H); 13C NMR
(CDCl3) δ 165.34, 143.20, 135.43, 134.30, 128.32, 127.06, 124.12,
72.18, 29.48, 17.95, 17.18; IR (CH2Cl2) 2980, 1715, 1140, 1020
cm-1; CIMS m/ z (relative intensity) 177 (M+ + 1, 100).
Anal. Calcd for C11H12O2: C, 74.98; H, 6.86. Found: C, 74.93;
H, 6.82.
Anal. Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.41;
H, 9.57.
[3-[(2-Meth oxyeth oxy)m eth oxy]-2-(2-m eth ylph en yl)]pr o-
p yl]ben zen e (3d ). 2d (1.37 g) provided 3d (1.64 g, 86%) as a
clear, colorless oil after flash chromatography (hexane/ethyl
acetate, 4:1): 1H NMR (CDCl3) δ 7.00-7.30 (m, 9 H), 4.66 (m, 2
H), 3.71 (d, J ) 6.6 Hz, 2 H), 3.53-3.56 (m, 2 H), 3.44-3.49 (m,
3 H), 3.36 (s, 3 H), 3.09 (dd, J ) 13.7, 6.6 Hz, 1 H), 2.85 (dd, J
) 13.7, 8.1 Hz, 1 H); 13C NMR (CDCl3) δ 140.64, 140.05, 136.33,
130.12, 129.00, 128.03, 126.21, 126.02, 125.88, 125.84, 95.44,
71.64, 70.85, 66.61, 58.89, 42.41, 39.15, 19.56; IR (film) 2940,
1450, 1050 cm-1; CIMS m/ z (relative intensity) 315 (M+ + 1,
5), 239 (85), 221 (100).
Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C, 76.12;
H, 8.26.
1-[[(2-Me t h oxye t h oxy)m e t h oxy]e t h yl]-2-m e t h ylb e n -
zen e (3a ). 2a 12 (18.0 g, 0.133 mol) provided 3a (26.5 g, 89%) as
a clear, colorless oil after flash chromatography (hexane/ethyl
acetate, 4:1): 1H NMR (CDCl3) δ 7.12-7.16 (m, 4 H), 4.72 (s, 2
H), 3.76 (t, J ) 7.3 Hz, 2 H), 3.62 (m, 2 H), 3.50 (m, 2 H), 3.38
(s, 3 H), 2.91 (t, J ) 7.3 Hz, 2 H), 2.33 (s, 3 H); 13C NMR (CDCl3)
δ 136.82, 136.30, 130.11, 129.32, 126.33, 125.87, 95.29, 71.69,
67.45, 66.63, 58.92, 33.40, 19.33; IR (film) 2870, 1100 cm-1; CIMS
m/ z (relative intensity) 225 (M+ + 1, 100), 165 (90), 149 (50),
118 (24).
3,4-Dih yd r o-4-et h yl-5-m et h yl-2(1H )-b en zop yr a n -1-on e
(5c): yield 86% (mp 68-70 °C); 1H NMR (CDCl3) δ 7.94 (d, J )
7.5 Hz, 1 H), 7.40 (d, J ) 7.5 Hz, 1 H), 7.26-7.29 (m, 1 H), 4.59
(dd, J ) 11.3, 1.3 Hz, 1 H), 4.44 (dd, J ) 11.2, 2.9 Hz, 1 H),
2.79-2.82 (m, 1 H), 2.35 (s, 3 H), 1.71-1.77 (m, 1 H), 1.59-1.63
(m, 1 H), 1.08 (t, J ) 7.4 Hz, 3 H); 13C NMR (CDCl3) δ 165.56,
142.66, 135.45, 134.43, 128.25, 127.07, 124.46, 68.54, 36.24,
24.21, 18.21, 12.12; IR (KBr) 2950, 1700, 1270 cm-1; CIMS m/ z
(relative intensity) 191 (M+ + 1, 100).
Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.47;
H, 8.93.
P r ep a r a t ion of 3,4-Dih yd r o-2(1H)-b en zop yr a n s: 3,4-
Dih yd r o-4,5-d im eth yl-2(1H)-ben zop yr a n (4b). To a flame-
dried flask were added 3b (3.80 g, 0.016 mol) and CH2Cl2 (100
mL). The stirred solution was cooled to 0 °C, and TiCl4 (2.10
mL, 19 mmol) in CH2Cl2 (20 mL) was added via addition funnel.
The yellow solution was stirred for an additional 2 h at 0 °C,
whereupon the reaction was quenched with the slow addition
of water (30 mL). The two-phase system was warmed to room
temperature and allowed to stir until the organic layer was clear.
The organic phase was collected, and the aqueous layer was
washed with CH2Cl2 (50 mL). The combined organic layers were
dried, filtered, and evaporated to provide 4b6 (2.42 g, 93%) as a
pale yellow oil: 1H NMR (CDCl3) δ 7.08 (t, J ) 7.6 Hz, 1 H),
7.04 (m, 1 H), 6.82 (d, J ) 7.3 Hz, 1 H), 4.83 (d, J ) 15.2 Hz, 1
H), 4.75 (d, J ) 15.2 Hz, 1 H), 3.93 (d, J ) 11.0 Hz, 1 H), 3.81
(dd, J ) 11.0, 2.8 Hz, 1 H), 2.81-2.83 (m, 1 H), 2.32 (s, 3 H),
1.33 (d, J ) 6.8 Hz, 3 H); 13C NMR (CDCl3) δ 137.12, 135.74,
133.86, 128.28, 125.77, 121.92, 71.02, 68.02, 30.08, 19.09, 18.01;
IR (CDCl3) 2970, 1450, 1125, 920 cm-1; CIMS m/ z (relative
intensity) 163 (M+ + 1, 100).
Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.86;
H, 7.45.
3,4-Dih yd r o-5-m eth yl-4-(p h en ylm eth yl)-2(1H)-ben zop y-
1
r a n -1-on e (5d ): yield 85% (mp 101-104 °C); H NMR (CDCl3)
δ 8.01 (d, J ) 7.9 Hz, 1 H), 7.43 (d, J ) 7.6 Hz, 1 H), 7.31-7.37
(m, 3 H), 7.23-7.29 (m, 3 H), 4.33-4.40 (m, 2 H), 3.08-3.14 (m,
1 H), 2.86-2.90 (m, 2 H), 2.36 (s, 3 H); 13C NMR (CDCl3) δ
165.43, 141.73, 138.52, 135.58, 134.61, 129.16, 128.73, 128.51,
127.43, 126.77, 124.59, 68.22, 37.20, 37.06, 18.06 (two missing/
overlapping peaks); IR (KBr) 2910, 1710, 1280 cm-1; CIMS m/ z
(relative intensity) 253 (M+ + 1, 100).
Anal. Calcd for C17H16O2: C, 80.93; H, 6.39. Found: C, 80.86;
H, 6.33.
3,4-Dih ydr o-5-m eth yl-2(1H)-ben zopyr an -1-on e (5a):4b 90%
yield on a 16.68 g scale (mp 68-70 °C); 1H NMR (CDCl3) δ 7.97
(d, J ) 7.8 Hz, 1 H), 7.40 (d, J ) 7.3 Hz, 1 H), 7.29 (t, J ) 7.5
Hz, 1 H), 4.53 (t, J ) 6.0 Hz, 2 H), 2.98 (t, J ) 6.0 Hz, 2 H), 2.33
(s, 3 H).
P r ep a r a tion of 3,4,6,8a -Tetr a h yd r o-4,5,8a -tr ia lk yl-2(1H)-
ben zop yr a n -1-on es: (4R*,8a S*)-3,4,6,8a -Tetr a h yd r o-4,5,8a -
tr im eth yl-2(1H)-ben zop yr a n -1-on e (6a ). A solution of 5b (50
mg, 0.28 mmol) in THF (1.5 mL) was cooled to -78 °C, and
(12) Singh, A. K.; Bakshi, R. K.; Corey, E. J . J . Am. Chem. Soc. 1987,
109, 6187-6189.

5634 J . Org. Chem., Vol. 61, No. 16, 1996
Notes
ammonia (30 mL) and tert-butyl alcohol (27 µL, 1 equiv) were
added. Lithium (5 mg) was added to the stirred solution in small
pieces. After 15 min, piperylene (100 µL) and methyl iodide (180
µL, 10 equiv) were added, and the resulting solution was stirred
for 30 min at -78 °C. After the addition of NH4Cl (0.1 g), the
ammonia was allowed to evaporate, and water (10 mL) was
added. The mixture was extracted with methylene chloride (3
× 10 mL). The combined organic phases were washed succes-
sively with 10% aqueous sodium thiosulfate and brine. Drying,
solvent evaporation, and flash chromatography (hexane/ethyl
acetate, 4:1) provided 6a (40 mg, 73%) as a colorless oil: 1H NMR
(CDCl3) δ 6.46 (dd, J ) 9.6, 3.2 Hz, 1 H), 5.77 (m, 1 H), 4.67 (dd,
J ) 11.2, 2.9 Hz, 1 H), 4.14 (dd, J ) 11.3, 1.3 Hz, 1 H), 3.00 (m,
1 H), 2.63 (d, J ) 21.7 Hz, 1 H), 2.54 (dd, J ) 21.7, 4.9 Hz, 1 H),
1.74 (s, 3 H), 1.33 (s, 3 H), 1.10 (d, J ) 7.1 Hz, 3 H); 13C NMR
(CDCl3) δ 174.70, 131.70, 131.31, 128.82, 123.74, 70.98, 43.19,
32.31, 31.08, 27.49, 18.98, 18.50; IR (CH2Cl2) 2975, 2930, 1730,
1135 cm-1; CIMS m/ z (relative intensity) 193 (M+ + 1, 100),
177 (9), 133 (26). An acceptable analysis could not be obtained;
the 6-oxo analogue was prepared as a stable derivative.
(4R*,8a S*)-6-Oxo-3,4,6,8a -t et r a h yd r o-4,5,8a -t r im et h yl-
2(1H)-ben zop yr a n -1-on e. To a solution of 6a (100 mg, 0.52
mmol) in benzene (7 mL) was added Celite (1 g), PDC (21 mg,
0.1 equiv), and tert-butyl hydroperoxide (0.17 mL, 90% solution,
3 equiv). The reaction was stirred at room temperature for 8 h,
filtered through Celite, evaporated, and chromatographed on
silica gel (hexane-ethyl acetate, 1:1) to provide a small amount
of compound (60 mg, 56%) as a pale-yellow oil. Recrystallization
from hexane-ethyl acetate provided the analytical sample as
white crystals (mp 86-89 °C): 1H NMR (CDCl3) δ 7.57 (d, J )
10.0 Hz, 1 H), 6.19 (d, J ) 10.0 Hz, 1 H), 4.87 (dd, J ) 12.0, 3.2
Hz, 1 H), 4.26 (dd, J ) 12.0, 0.8 Hz, 1 H), 3.21-3.23 (m, 1 H),
1.91 (s, 3 H), 1.65 (s, 3 H), 1.24 (d, J ) 7.3 Hz, 3 H); 13C NMR
(CDCl3) δ 184.75, 169.67, 154.99, 149.34, 132.94, 126.44, 70.52,
46.36, 32.44, 29.62, 18.18, 12.16; IR (KBr) 2980, 2930, 1725,
1650, 1625, 1250, 1135 cm-1; CIMS m/ z (relative intensity) 207
(M+ + 1, 82), 163 (100), 143 (15).
NMR (CDCl3) δ 7.30 (m, 2 H), 7.22-7.28 (m, 3 H), 6.56 (dd, J )
9.5, 2.9 Hz, 1 H), 5.84 (ddd, J ) 9.5, 5.0, 2.2 Hz, 1 H), 4.44 (ddd,
J ) 11.7, 2.7, 1.0 Hz, 1 H), 4.13 (dd, J ) 10.7, 1.5 Hz, 1 H), 3.14
(dm, J ) 10.7 Hz, 1 H), 2.55-2.74 (m, 4 H), 1.85 (s, 3 H), 1.38
(s, 3 H); 13C NMR (CDCl3) δ 174.82, 138.70, 131.58, 130.93,
129.78, 129.30, 128.59, 126.53, 123.93, 66.20, 43.51, 38.79, 37.37,
32.65, 27.82, 19.16; IR (film) 2930, 1740, 1130 cm-1; CIMS m/ z
(relative intensity) 269 (M+ + 1, 100), 251 (16).
(4R*,7S*,12a R*)-12H-4,5-Dim eth yl-7,12a-m eth an o-3,4,6,7-
t et r a h yd r o-1H-b en zo[6,7]cyclooct a [c]p yr a n -1-on e (7).
A
solution of 6b (30 mg, 0.11 mmol) in CH2Cl2 (2 mL) was cooled
to 0 °C, trifluoromethanesulfonic acid (5 drops) was added, and
the reaction was stirred at this temperature for 50 min.
Neutralization with aqueous NaHCO3, followed by CH2Cl2
extraction, drying, filtration, evaporation, and flash chromatog-
raphy (hexane/ethyl acetate, 4:1), provided 7 (19 mg, 63%): 1H
NMR (CDCl3) δ 7.10-7.20 (m, 3 H), 7.03 (d, J ) 7.0 Hz, 1 H),
4.87 (dd, J ) 11.5, 2.9 Hz, 1 H), 4.18 (dd, J ) 11.4, 1.3 Hz, 1 H),
3.22-3.25 (m, 1 H), 3.20 (dd, J ) 16.6, 1.9 Hz, 1 H), 3.06 (d, J
) 16.4 Hz, 1 H), 2.85-2.92 (m, 1 H), 2.59 (dd, J ) 17.6, 5.9 Hz,
1 H), 2.31 (dd, J ) 12.3, 3.9 Hz, 1 H), 1.95-2.04 (m, 2 H), 1.57
(s, 3 H), 1.18 (d, J ) 7.1 Hz, 3 H); 13C NMR (CDCl3) δ 175.87,
141.27, 131.75, 129.45, 129.41, 128.76, 128.49, 126.45, 126.24,
71.02, 42.10, 42.06, 38.82, 32.81, 31.50, 31.27, 19.63, 18.79; IR
(film) 2930, 1735 cm-1; CIMS m/ z (relative intensity) 269 (M+
+ 1, 100), 177 (33).
(3a R *,6a R *,11b R *,11cR *)-3a ,11b -Dim e t h yl-3a ,6,6a ,7,
11b ,11c-h exa h yd r o-1H ,4H -p h en a n t h r o[1,10-cd ]p yr a n -4-
on e (8). To a solution of 6c (25 mg, 0.1 mmol) in methylene
chloride (2 mL) at room temperature was added trifluoromethane-
sulfonic acid (3 drops). The solution was stirred at room
temperature for 12 h, neutralized with aqueous NaHCO3, and
washed with methylene chloride (3 × 15 mL). The combined
organic phases were dried, filtered, evaporated, and flash
chromatographed (hexane/ethyl acetate, 4:1) to provide 8 (10 mg,
40%, unoptimized): 1H NMR (CDCl3) δ 7.29 (d, J ) 7.8 Hz, 1
H), 7.16 (t, J ) 7.5 Hz, 1 H), 7.09 (dd, J ) 7.6, 7.3 Hz, 1 H), 7.03
(d, J ) 7.6 Hz, 1 H), 6.11 (dd, J ) 9.8, 2.5 Hz, 1 H), 5.73 (ddd,
J ) 9.8, 6.4, 3.4 Hz, 1 H), 4.50 (dd, J ) 11.0, 2.2 Hz, 1 H), 4.39
(dd, J ) 11.1, 4.0 Hz, 1 H), 2.85 (dd, J ) 16.9, 6.7 Hz, 1 H), 2.75
(dd, J ) 16.9, 10.0 Hz, 1 H), 2.68 (dd, J ) 16.0, 6.5 Hz, 1 H),
2.59-2.64 (m, 1 H), 2.27 (d, J ) 5.8 Hz, 1 H), 2.16 (dm, J ) 16.0
Hz, 1 H), 1.51 (s, 3 H), 1.43 (s, 3 H); 13C NMR (CDCl3) δ 176.09,
141.87, 135.06, 132.79, 128.60, 126.70, 126.57, 125.94, 125.79,
71.68, 51.13, 43.67, 40.10, 35.73, 32.37, 30.62, 30.44, 28.55.
Anal. Calcd for C12H14O3: C, 69.89; H, 6.84. Found: C, 69.66;
H, 6.77.
(4R*,8a S*)-4,5-Dim eth yl-8a -(p h en ylm eth yl)-3,4,6,8a -tet-
r a h yd r o-2(1H)-ben zop yr a n -1-on e (6b). Reaction of 5b (50
mg) with benzyl bromide gave 6b (65 mg, 85%) after flash
chromatography (hexane/ethyl acetate, 4:1): 1H NMR (CDCl3)
δ 7.18-7.30 (m, 3 H), 7.00-7.02 (m, 1 H), 6.29 (dd, J ) 9.7, 3.2
Hz, 1 H), 5.76 (ddd, J ) 9.7, 5.0, 2.1 Hz, 1 H), 4.85 (dd, J )
11.6, 3.0 Hz, 1 H), 4.22 (dd, J ) 11.5, 1.2 Hz, 1 H), 3.06-3.08
(m, 1 H), 2.94 (d, J ) 13.2 Hz, 1 H), 2.84 (d, J ) 13.2 Hz, 1 H),
2.13 (dd, J ) 22.0, 5.0 Hz, 1 H), 1.63 (s, 3 H), 1.41 (dd, J ) 22.0,
1.1 Hz, 1 H), 1.16 (d, J ) 7.3 Hz, 1 H); 13C NMR (CDCl3) δ 173.52,
134.94, 132.39, 131.19, 128.22, 128.02, 127.24, 126.64, 126.28,
71.14, 49.29, 45.33, 32.56, 31.38, 19.35, 18.99; IR (film) 2930,
1725, 1255 cm-1; CIMS m/ z (relative intensity) 269 (M+ + 1,
94), 251 (85), 177 (56), 133 (100).
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 26568).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
6a -c, 7, and 8 (9 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of this journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(4R*,8a S*)-5,8a -Dim eth yl-4-(p h en ylm eth yl)-3,4,6,8a -tet-
r a h yd r o-2(1H)-ben zop yr a n -1-on e (6c). Reaction of 5d (50
mg) with methyl iodide gave 6c (33 mg, 62%) as a pale-yellow
oil after flash chromatography (hexane/ethyl acetate, 4:1): 1H
J O960567R