Lewis Acid-Directed Reactions of Quinones with Styrenyl Systems: The Case of 2-Methoxy-3-methyl-1,4-benzoquinone

Article abstract of DOI:10.1021/jo971937u

Reactions of 2-methoxy-3-methyl-1,4-benzoquinone with various (E)-1-propenylbenzenes promoted by 1 equiv of Ti(IV), as a 1:1 mixture of TiCl₄-Ti(O-i-Pr)₄, produce rel-(1S,6R,7R,8R)-8-aryl-4,7-dimethyl-3-methoxybicyclo[4.2.0]oct-3-ene-2,5- diones 3 and trans-2-aryl-3,7-dimethyl-6-methoxy-2,3-dihydro-5-benzofuranols 5 as the major products. Reactions promoted by 2 equiv of Ti(IV) as a 1:1 mixture of TiCl₄-Ti(O-i-Pr)₄ or 1 equiv of either TiCl₄, SnCl₄, or BF₃·OEt₂ give regioisomeric rel-(1R,6S,7A,8R)-7-aryl-4,8-dimethyl-3-methoxybicyclo[4.2.0]oct-3-ene-2,5- diones (4) and/or trans-2-aryl-3,6-dimethyl-7-methoxy-2,3-dihydro-5-benzofuranols (6). A mechanism involving regioselective coordination of the various Lewis acids to the quinone is used to explain the formation of the products. These reactions demonstrate the effective regiocontrol exerted over the reactions by the nature of the Lewis acid promoters. Cyclobutanes 3 and 4 cleanly undergo rearrangement to the corresponding benzofuranols 5 and 6 on treatment with protic acid. In contrast, reactions of 2-methoxy-1,4-benzoquinone promoted by either BF₃·OEt₂ or Ti(IV), as 1 equiv or excess amounts of TiCl₄ or 1:1 TiCl₄-Ti(O-i-Pr)₄, all afford the same regioisomeric products, i.e., rel-(1S,6R,7R,8R)-8-aryl-7-methyl-3-methoxybicyclo[4.2.0]oct-3-ene-2,5-dione 25 and/or trans-2-aryl-3-methyl-6-meth-oxy-2,3-dihydro-5-benzofuranol 27.

Full text of DOI:10.1021/jo971937u

J . Org. Chem. 1998, 63, 1929-1934
1929
Lew is Acid -Dir ected Rea ction s of Qu in on es w ith Styr en yl
System s: Th e Ca se of 2-Meth oxy-3-m eth yl-1,4-ben zoqu in on e
Thomas A. Engler* and Rajesh Iyengar
Department of Chemistry, 2010 Malott, University of Kansas, Lawrence, Kansas 66045
Received October 21, 1997
Reactions of 2-methoxy-3-methyl-1,4-benzoquinone with various (E)-1-propenylbenzenes promoted
by 1 equiv of Ti(IV), as a 1:1 mixture of TiCl4-Ti(O-i-Pr)4, produce rel-(1S,6R,7R,8R)-8-aryl-4,7-
dimethyl-3-methoxybicyclo[4.2.0]oct-3-ene-2,5-diones 3 and trans-2-aryl-3,7-dimethyl-6-methoxy-
2,3-dihydro-5-benzofuranols 5 as the major products. Reactions promoted by 2 equiv of Ti(IV) as
a 1:1 mixture of TiCl4-Ti(O-i-Pr)4 or 1 equiv of either TiCl4, SnCl4, or BF3‚OEt2 give regioisomeric
rel-(1R,6S,7R,8R)-7-aryl-4,8-dimethyl-3-methoxybicyclo[4.2.0]oct-3-ene-2,5-diones (4) and/or trans-
2-aryl-3,6-dimethyl-7-methoxy-2,3-dihydro-5-benzofuranols (6). A mechanism involving regiose-
lective coordination of the various Lewis acids to the quinone is used to explain the formation of
the products. These reactions demonstrate the effective regiocontrol exerted over the reactions by
the nature of the Lewis acid promoters. Cyclobutanes 3 and 4 cleanly undergo rearrangement to
the corresponding benzofuranols 5 and 6 on treatment with protic acid. In contrast, reactions of
2-methoxy-1,4-benzoquinone promoted by either BF3‚OEt2 or Ti(IV), as 1 equiv or excess amounts
of TiCl4 or 1:1 TiCl4-Ti(O-i-Pr)4, all afford the same regioisomeric products, i.e., rel-(1S,6R,7R,8R)-
8-aryl-7-methyl-3-methoxybicyclo[4.2.0]oct-3-ene-2,5-dione 25 and/or trans-2-aryl-3-methyl-6-meth-
oxy-2,3-dihydro-5-benzofuranol 27.
In tr od u ction
Previous papers have described studies involving
2-alkoxy-1,4-benzoquinone and its 5- and 6-alkyl deriva-
tives.1 We now report results of reactions involving
2-methoxy-3-methyl-1,4-benzoquinone,3 which completes
our examination of all of the possible substitution pat-
terns of monoalkyl-substituted alkoxy-1,4-benzoquinones.
These studies further demonstrate that the regioselec-
tivity of these reactions can be effectively manipulated
by the nature of the Lewis acid.
Lewis acid-promoted reactions of styrenyl systems with
alkoxy-1,4-benzoquinones and mono-/bisimide derivatives
regio- and stereoselectively give various products of
formal 2 + 2, 3 + 2, and 5 + 2 cycloadditions in good
yield.1 Of particular interest is that the regioselectivity
depends on the nature and the number of equiv of Lewis
acid used as promoters. For example, SnCl4-promoted
reactions of 2-alkoxy-5-alkyl-1,4-benzoquinones give prod-
ucts from apparent activation of the quinone through
bidentate binding of the Lewis acid to the C-1 carbonyl
and the C-2 alkoxy oxygen, whereas reactions promoted
by Ti(IV), as either TiCl4 or mixtures of TiCl4-Ti(O-i-
Pr)4, could be made to afford products from either
bidentate activation or apparent monodentate activation
through binding to the C-4 carbonyl group.1c,2 Similar
results were found with 2-alkoxy-4-N-(phenylsulfonyl)-
1,4-benzoquinone monoimine.1d
Resu lts a n d Discu ssion
The results of this study are summarized in Scheme 1
and Table 1. Reactions of various propenylbenzenes
1a -c bearing electron-donating groups with quinone 2
promoted by 1 equiv (with respect to the quinone) of
Ti(IV), as a 1:1 mixture of TiCl4-Ti(O-i-Pr)4, stereose-
lectively gave cyclobutanes 3 and dihydrobenzofurans 5
as the major products (Table 1, entries 1, 6, and 11). The
former were accompanied by small amounts of regioiso-
meric cyclobutanes 4 in some instances. However,
promotion of the same reactions with 1 equiv of SnCl4,
BF3‚OEt2 or TiCl4 or with 2 equiv of Ti(IV) as 1:1 TiCl4:
Ti(O-i-Pr)4 gave primarily cyclobutanes 4 and dihy-
drobenzofurans 6 in good yield (Table 1, entries 2-5,
7-10, and 12-15); again, in some cases, minor amounts
of cyclobutanes 3 and dihydrobenzofurans 5 were also
found. Similarly, the less activated propenylenzenes 1d /e
could also be used in the latter reactions and resulted in
4 nearly exclusively. Reactions of 1d /e promoted by
mixtures of TiCl4-Ti(O-i-Pr)4 required more than 1 equiv
* To whom correspondence should be addressed. Tel.: (785) 864-
4670. Fax: (785) 864-5396. E-mail: tengler@caco3.chem.ukans.edu.
(1) (a) Engler, T. A.; Combrink, K. D.; Ray, J . E. J . Am. Chem. Soc.
1988, 110, 7931-7933. (b) Engler, T. A.; Combrink, K. D.; Letavic, M.
A.; Lynch, K. O., J r.; Ray, J . E. J . Org. Chem. 1994, 59, 6567-6587.
(c) Engler, T. A.; Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy, J .
P. J . Org. Chem. 1994, 59, 6588-6599. (d) Engler, T. A.; Chai, W.;
LaTessa, K. O. J . Org. Chem. 1996, 61, 9297-9308. (e) Engler, T. A.;
Meduna, S. P.; LaTessa, K. O.; Chai, W. J . Org. Chem. 1996, 61, 8598-
8603. (f) Engler, T. A.; Gfesser, G. A.; Draney, B. W. J . Org. Chem.
1995, 60, 3700-3706.
(2) (a) Tou, J . S.; Reusch, W. J . Org. Chem. 1980, 45, 5012-5014.
For seminal studies on the importance of the site of Lewis acid
coordination to quinones in Diels-Alder reactions, see: (b) Dickinson,
R. A.; Kubela, R.; MacAlpine, G. A.; Stojanac, Z.; Valenta, Z. Can. J .
Chem. 1972, 50, 2377-2380. (c) Stojanac, Z.; Dickinson, R. A.; Stojanac,
N.; Woznow, R. J .; Valenta, Z. Ibid. 1975, 53, 616-618. (d) Das, J .;
Kubela, R.; MacAlpine, G. A.; Stojanac, Z.; Valenta, Z. Can J . Chem.
1979, 57, 3308-3319. For studies with other 2-methoxy-1,4-benzo-
quinones, see: (e) Hendrickson, J . B.; Singh, V. J . Chem. Soc., Chem.
Commun. 1983, 837-838. (f) Hendrickson, J . B.; Haestier, A. M.;
Stieglitz, S. G.; Foxman, B. M. New. J . Chem. 1990, 14, 689-693. (g)
Engler, T. A.; Letavic, M. A.; Lynch, K. O., J r.; Takusagawa, F. J . Org.
Chem. 1994, 59, 1179-1183.
(3) Mandell, L.; Roberts, E. C. J . Heterocycl. Chem. 1965, 2(4), 479-
480 and references therein.
(4) (a) Reactions of 1d with 1 equiv of TiCl4-Ti(O-iPr)4 produced
unusual 2:1 propenylbenzene-quinone adducts; see ref 7. (b) The
structures of these products also support the 5 + 2 cycloaddition
mechanism.
S0022-3263(97)01937-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/25/1998

1930 J . Org. Chem., Vol. 63, No. 6, 1998
Engler and Iyengar
Sch em e 1
F igu r e 1. Selected HMBC data collected on 3a and 4a .
1
F igu r e 2. Selected H-1H NOE data collected on 3a and 4a .
C-H correlation) NMR (Figures 1 and 3) and 1H-1H
NOE experiments (Figures 2 and 4). For example, in
both 3a and 4a , the protons attached to C-7 and C-8,
respectively, are clearly visible as multiplets at δ 2.95
and 2.99. HMQC experiments then establish the 13C
chemical shift of C-7 in 3a and C-8 in 4a . In 3a , the other
three methine protons appear as a triplet at δ 3.29 and
partially resolved triplets at δ 3.41 and 3.43, and the
HMQC spectrum establishes the chemical shifts of the
carbons attached to them. Correlations between the C-7
methyl hydrogen signal and two of the latter carbon
signals identify them as C-6 and C-8; they are distin-
guished from one another by an HMBC correlation
between the methine hydrogen attached to one of them
(C-8) with the aryl ring carbons. The signals for H-1 and
C-1 are then assigned by default. Thus, for 3a the
of Ti(IV) with respect to the quinone, or mixtures
enriched in TiCl4, and again gave cyclobutane 4. The
cyclobutanes 3 and 4 rearranged cleanly to dihydroben-
zofurans 5 and 6, respectively, upon treatment with
protic acid (Table 2).
The stereochemistry of the cyclobutanes and the di-
hydrobenzofurans are assigned on the basis of HMQC
(one bond C-H correlation)/HMBC (two- and three-bond
Ta ble 1. Lew is Acid -P r om oted Cycloa d d ition s of P r op en ylben zen es w ith 2-Meth oxy-3-m eth yl-1,4-ben zoqu in on ea
yieldb (%)
Lewis acid (total equiv of
Ti(IV)with respect to 2)
entry
styrene (X)
T (°C)
time (h)
3/4 (ratio)c
5
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH2O)
3,4-(OCH2O)
3,4-(OCH2O)
3,4-(OCH2O)
3,4-(OCH2O)
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
H
H
H
H
H
H
2-CH3
2-CH3
2-CH3
1:1 TiCl4-Ti(O-i-Pr)4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (2)
TiCl4 (1)
BF3‚OEt2 (1)
SnCl4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (2)
TiCl4 (1)
BF3‚OEt2 (1)
SnCl4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (2)
TiCl4 (1)
BF3‚OEt2 (1)
SnCl4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (1)
2:1 TiCl4-Ti(O-i-Pr)4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (2)
TiCl4 (1)
BF3‚OEt2 (1)
SnCl4 (1)
-78
8
5
0.5
2.5
8
8
5
0.5
2.5
8
41 (4:1)
55 (1:3.3)
16 (1:3)
4 (0:1)
15 (0:1)
36 (1:0)
39 (0:1)
4 (0:1)
16 (0:1)
43 (1:5)
31 (2:1)
48 (0:1)
8 (0:1)
59
-78
14
-78
14
32
56
24
-78
-78
-78
30
3
-78
30
32
65
15
8
48.5
35
70
31.5
-78
-78
-78
-78
3
31
5
-78
0.75
1.5
2
1.5
18
20
6
16
10
11
18
12
7
-78
-78
16 (0:1)
5 (0:1)
d
-78
11
-78 f 10
-78 f 0
-78
30 (0:1)d
51 (1:16)
76 (0:1)
42 (0:1)
29 (0:1)
see text
20 (0:1)
45 (0:1)
-78
-78
-78
2:1 TiCl4-Ti(O-i-Pr)4 (1)
4:1 TiCl4-Ti(O-i-Pr)4 (1)
1:1 TiCl4-Ti(O-i-Pr)4 (2)
-78 f -5
-78 f 10
-78
a
b
All reactions were performed in CH2Cl2 at -78 °C. Isolated yields. c When 3 and 4 were both formed, they were obtained as a
mixture after chromatography. The ratio of the two was determined by 1H NMR. Simple recrystallization of these mixtures generally
afforded the major isomer in pure form. See ref 4.
d

Lewis Acid-Directed Reactions of Quinones
J . Org. Chem., Vol. 63, No. 6, 1998 1931
Ta ble 2. Rea r r a n gem en t of Cyclobu ta n es 3/4 to
Dih yd r oben zofu r a n s 5/6a
Sch em e 2
compd
time (h)
product
yield (%)
3a
4a
3b
4b
4c
4d
4e
1.5
1.5
1
5a
6a
5b
6b
6c
6d
6e
80
78
78
74
65
76
80
2
2.5
72
96
a
All reactions conducted in CH2Cl2 at room temperature with
catalytic amounts of p-TsOH.
addition, H-4 in 6a shows a correlation with C-3, the
signal of which is easily assigned by HMQC data.
Finally, the signals for H-2, H-3, and the C-3 CH3 are
assigned by inspection, and 1H-1H NOE data firmly
secure the trans stereochemistry in both 5a and 6a
(Figure 4). As above, the structures of the other dihy-
drobenzofurans are assigned by spectral comparison to
5a and 6a .
F igu r e 3. Selected HMBC data collected on 5a and 6a .
The regioselectivity of reactions promoted by the
monodentate Lewis acid BF3‚OEt2 is consistent with
selective activation of the quinone through coordination
with the more basic ester-like C-4 carbonyl oxygen. The
resultant complex 7 undergoes a 5 + 2 (4π + 2π)
cycloaddition with the propenylbenzene affording bicyclic
carbocation 8, which proceeds on to 4 and 6 via 9 as
described previously (Scheme 2).1 The stereochemistry
of the reactions results from the preference for the aryl
group of the propenylbenzene to adopt an endo orienta-
tion with respect to the pentadienyl carbocation moiety
of 7 in the cycloaddition.
Reactions promoted by TiCl4 or SnCl4 apparently also
proceed via 7. With these Lewis acids, the expected
bidentate complexation may be overridden by steric
effects; on bidentate binding, the C-2 methoxy group is
forced into a conformation 10, incorporating a significant
CH3-CH3 A1,3 strain. To adopt the expected octahedral
coordination for Ti(IV)/Sn(IV), 2:1 quinone-Lewis acid
complexes 11 or dimeric complexes might be involved.5
1
F igu r e 4. Selected H-1H NOE data collected on 5a and 6a .
chemical shifts (ppm) are H-1, 3.41; H-6, 3.43; H-7, 2.95;
H-8, 3.29; C-1, 47.8; C-6, 43.9; C-7, 38.5; and C-8, 52.3.
In 4a , all of the methine signals are well resolved and
appear as triplets at δ 3.23, 3.35, and 3.44. Once again,
the signals of the C-7 carbon (δ 52.6) and the proton
attached to it (H-7, δ 3.23) are assigned as described
above. The most downfield methine signal correlates
(HMBC) with an aryl ring carbon (i.e., that attached to
C-7) and must be from H-6; C-6 (δ 47.6) is in turn
assigned by HMQC correlation to this proton. This
leaves the other methine proton as H-1. With assign-
ments of H-1 and H-6 through H-8 established, H-1H
1
NOE experiments (Figure 2) then clearly indicate the
relative stereochemistry about the four-membered ring
in both 3a and 4a . The stereochemistry of the other
cyclobutane products are assigned by spectral comparison
with 3a and 4a .
The substitution pattern on the enedione moiety of 3a
is assigned by an HMBC correlation between the C-4
methyl hydrogens (Figure 1) with one of the carbonyl
signals (δ 197.3) that is in turn correlated with H-7. In
4a , the C-4 methyl hydrogens are again correlated with
one of the carbonyl signals (δ 198.0), but it is the other
(δ 193.4) that is correlated to H-8.
Reactions promoted by a 1:1 mixture of TiCl4-Ti(O-i-
Pr)4 are more complex, and intriguing. The results show
that the regioselectivity is dependent upon the Ti(IV)-
quinone stoichiometry; 3/5 are formed with a 1:1 ratio,
In the case of 5a /6a , the regiochemistry is assigned on
the basis of the relative position of H-4 with respect to
the -OCH3 or the -CH3 groups on the aromatic system
of the dihydrobenzofuran. In 5a , H-4 is a singlet at δ
6.61 and shows an HMBC correlation to the C-6 signal
that is established by an HMBC correlation with the
-OCH3 group attached to it. In 6a , the H-4 (δ 6.37)
correlates to C-6, which in this case shows a correlation
with the protons of the CH3 group attached to it. In
(5) (a) Turin, E.; Nielson, R. M.; Merbach, A. E. Inorg. Chim. Acta
1987, 134, 79-85, 67-78. (b) Bachand, B.; Wuest, J . D. Organome-
tallics 1991, 10, 2015-2025. (c) Denmark, S. E.; Almstead, N. G.
Tetrahedron 1992, 48, 5565-5578. (d) Denmark, S. E.; Almstead, N.
G. J . Am. Chem. Soc. 1993, 115, 3133-3139. (e) Springer, J . B.;
DeBoard, J .; Corcoran, R. C. Tetrahedron Lett. 1995 36, 8733-8736.
For reviews, see: (f) Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
Angew. Chem., Int. Ed. Engl. 1990, 29, 256-272. (g) Shambayati, S.;
Schreiber, S. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 1, p 283.

1932 J . Org. Chem., Vol. 63, No. 6, 1998
Engler and Iyengar
Sch em e 3
Sch em e 5
Sch em e 6
Sch em e 4
whereas 4/6 are formed with a 2:1 ratio. This Lewis acid
is likely weaker than the others, and an equilibrium
between coordination to the C-1/C-2 oxygens and the C-4
carbonyl may be involved. In this scenario, Curtin-
Hammett conditions may prevail and the preferred site
of coordination may be unimportant. The regioselectivity
may depend solely on the relative rates of the cycload-
dition of the two complexes with the propenylbenzene,
and if so, the relative stabilities of the bicyclic cationic
cycloadducts may be a determining factor. Thus, we
rationalize that reactions promoted with 1 equiv of Ti-
(IV), as TiCl4-Ti(O-i-Pr)4, proceed through the thermo-
dynamically more stable oxygen-stabilized carbocationic
cycloadduct 13 (Scheme 3), which may or may not involve
bidentate coordination. The more powerful Lewis acids
TiCl4, SnCl4, and BF3‚OEt2, or mixtures of TiCl4-Ti(O-
i-Pr)4 enriched in TiCl4, sufficiently activate the quinone
to react via the less stable carbocationic cycloadduct 8.
With 2 equiv of Ti(IV) as TiCl4-Ti(O-i-Pr)4, a 1:2 quinone-
Ti(IV) complex6 of some undetermined structure may be
involved that is again reactive enough to access an
intermediate similar to 8.
Evidence supporting the 5 + 2 cycloaddition process
was found in reactions of (E)-2-methyl-1-propenylbenzene
(1e). Reactions promoted by 2 equiv of Ti(IV), again as
a 1:1 mixture of TiCl4-Ti(O-i-Pr)4, gave cyclobutane 4e
as expected, but those promoted by 1 equiv of a 2:1
mixture produced the unusual tricyclic system 15 in
7-22% yield (Scheme 4).4b The latter reactions were
quite sluggish and required the slightly stronger Lewis
acid. With a considerably more powerful 4:1 mixture of
TiCl4-Ti(O-i-Pr)4, cyclobutane 4e was again found. In
all of these reactions, considerable amounts of the pro-
penylbenzene were recovered; however, the quinone was
lost presumably due to decomposition.
nalize that it results from alkylation of bicyclic cation
13 (Scheme 5), generated stereoselectively as discussed
above, with a second equivalent of the propenylbenzene
to afford 16 followed by carbon-carbon bond formation
between the cationic center and the titanium enolate.
Indeed, the highest yields of 15 resulted from use of
excess amounts of 1e. The stereochemistry in the forma-
tion of 16 from 13 is a result of approach of the
propenylbenzene from the sterically more accessible exo
direction.
The regioselectivity of the BF3‚OEt2-promoted reac-
tions of 2 and previous reports of regioselective Lewis
acid-activation of quinones in Diels-Alder reactions2 led
us to reexamine the BF3‚OEt2-promoted reactions of
2-methoxy-1,4-benzoquinone (17) and 2-methoxy-5-meth-
yl-1,4-benzoquinone (18). We have previously reported
that Sn(IV)-promoted reactions of 17/18 with propenyl-
benzene 1a afforded bicyclo[3.2.1]adducts 23/24, cyclobu-
tanes 25/26, and/or dihydrobenzofurans 27 (Scheme 6),
apparently via complexes 19/20, respectively.1a-c Careful
examination of BF3‚OEt2-promoted reactions of 17 with
propenylbenzene 1a again revealed that only 27 was
formed in 63% yield; no evidence for other products (i.e.,
23, 25, or 28) or dihydrobenzofuran regioisomer 30 was
found. Similarly, reactions of 18 with 1a gave only
cyclobutane 26 in 23% yield with no evidence for regio-
isomer 29 or dihydrobenzofuran 31. Apparently, the
regioselectivity of these reactions is determined by the
greater stability of presumed intermediates 21/22, com-
pared to 32/33, and not on the expected site of coordina-
tion of the monodentate BF3‚OEt2 to the quinone.
Finally, reactions of quinone 17 promoted by excess
amounts of Ti(IV) have also been examined. Previous
studies on reactions of 18 and those of 2 reported herein
have demonstrated that different regioisomeric products
are obtained depending upon the quantities of Ti(IV) used
as promoter. However, reactions of 17 with propenyl-
benzene 1a promoted by 2 equiv of TiCl4, 2-5 equiv of
Of particular interest is that the tricyclic product 15
is found as a single stereoisomer; its structure was
determined by single-crystal X-ray analysis.7 We ratio-
(6) For discussions of carbonyl-(Lewis acid)2 complexes as potential
intermediates, see refs 5g and 1c and references therein.
(7) Engler, T. A.; Scheibe, C.; Iyengar, R. J . Org. Chem. 1997, 62,
8274-8275.

Lewis Acid-Directed Reactions of Quinones
J . Org. Chem., Vol. 63, No. 6, 1998 1933
20 °C over 20 h and the reaction then quenched with 3 N HCl
(ca. pH 4), extracted with Et2O, dried (Na2SO4), and concen-
trated to a red oil. Flash chromatography (20% EtOAc-
hexanes) yielded 3-methoxy-2-methylphenol (2.4 g, 55%) as a
yellow oil: Rf 0.54 (30% EtOAc-hexanes); 1H NMR (300 MHz)
6.96 (t, J ) 5, 1H), 6.45 (d, J ) 5, 1H), 6.40 (t, J ) 5, 1H), 4.78
(br s, 1H), 3.82 (s, 3H), 2.11 (s, 3H).
1:1 TiCl4-Ti(O-i-Pr)4, or 1 equiv each of TiCl4 and SnCl4
afforded only cyclobutane 25 (in 14, 50-56, 0% yields,
respectively) and/or dihydrobenzofuran 27 (69, 35-43,
53% yields, respectively). Again, no evidence for isomers
28 or 30 was found.
To a solution of this phenol (1.0 g, 7.2 mmol) in acetone (200
mL) was added a solution of Fremy’s salt (6.69 g, 25.0 mmol)
in buffered water (2.31 g of KH2PO4 in 300 mL). The reaction
mixture was stirred at room temperature for 1.5 h and
extracted with Et2O, and the extracts were dried (Na2SO4) and
concentrated to a yellow oil. Flash chromatography (10%
EtOAc-hexanes) yielded 2 (979 mg, 89%) as a yellow oil that
solidified in refrigerator: mp 21-28 °C (lit.3 mp 19-30 °C);
Rf 0.42 (30% EtOAc-hexanes); 1H NMR (300 MHz) 6.69 (d, J
) 10, 1H), 6.61 (d, J ) 10, 1H), 4.02 (s, 3H), 1.95 (s, 3H).
Rep r esen ta tive P r oced u r es for Rea ction s of P r op e-
n ylben zen es w ith 2-Meth oxy-3-m eth yl-1,4-ben zoqu in on e
(2): Rea ction s of 1a . I. P r om otion by TiCl4-Ti(O-i-P r )4.
(A) TiCl4 (20 µL, 0.18 mmol) was added to a solution of Ti(O-
i-Pr)4 (53 µL, 0.18 mmol) in CH2Cl2 (2-4 mL). After being
stirred for 20 min at room temperature, the mixture was cooled
to -78 °C and a solution of quinone 2 (50 mg, 0.33 mmol) in
CH2Cl2 (3-4 mL) added followed by propenylbenzene 1a (61
µL, 0.36 mmol), either neat or as a solution in CH2Cl2 (3 mL).
The reaction mixture was stirred for 8 h and then quenched
by the sequential addition of solid sodium bicarbonate (∼1 g)
and i-PrOH (∼3 mL). The resulting mixture was filtered
through a pad of wet (H2O) Celite, the Celite rinsed with CH2-
Cl2, and the combined filtrate and rinse extracted with CH2-
Cl2. The extracts were combined, washed with water and
brine, dried (MgSO4), and concentrated. Flash chromatogra-
phy with 20% acetone/hexanes as eluent gave a 3.6:1 mixture
of 3a /4a as a colorless oil (45 mg, 41%) and 5a (64 mg, 59%)
as a white solid. Crystallization (EtOAc-hexanes) of the
mixture of 3a /4a gave pure 3a . Physical and spectral data
for 3a : mp 131-133 °C (EtOAc-hexanes); Rf 0.21 (20%
acetone-hexanes); 1H NMR (500 MHz) 6.80-6.77 (m, 3H), 4.03
(s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 3.43 (apparent t, J ) 9.5,
1H), 3.41 (apparent t, J ) 9.5, 1H), 3.29 (apparent t, J ) 9.5,
1H), 2.95 (m, 1H), 1.98 (s, 3H), 1.13 (d, J ) 7.0, 3H); 13C NMR
(125 MHz) 197.3, 193.6, 160.0, 149.1, 148.1, 135.3, 134.0, 118.3,
111.3, 109.7, 60.0, 56.0, 55.9, 52.3, 47.8, 43.9, 38.5, 17.4, 9.5.
Anal. Calcd for C19H22O5: C, 69.08; H, 6.71. Found: C, 69.20;
H, 6.50. Physical and spectral data for 5a : mp 149-151 °C
Con clu sion s
Lewis acid-promoted reactions of 2-methoxy-3-methyl-
1,4-benzoquinone (2) and 2-methoxy-5-methyl-1,4-ben-
zoquinone (18) with various propenylbenzenes selectively
give regioisomeric 8-arylbicyclo[4.2.0]oct-3-ene-2,5-diones
and/or 2-aryl-2,3-dihydrobenzofurans depending upon the
nature and the number of equivalents of Lewis acid
promoters employed. The results demonstrate that sub-
stituent electronic and steric effects on these quinones
play a key role in the site of Lewis acid activation as
evidenced by a “regiochemical switch” in the products
obtained from reaction with different Lewis acids. On
the other hand, reactions of 2-methoxy-1,4-benzoquinone
(17) seem to be controlled more by the stability of the
cationic 5 + 2 cycloaddition intermediate.
Exp er im en ta l Section
Gen er a l Meth od s. All compounds were prepared as
racemic mixtures. Melting points were determined on a
capillary melting point apparatus and are uncorrected. All
reactions were run under an inert atmosphere of nitrogen or
argon in flame-dried glassware and stirred magnetically.
Solvents and Lewis acids were distilled under nitrogen from
appropriate drying agents just before use. Propenylbenzenes
were used as received from Aldrich Chemical Co. (1a , trans-
cis ) 23:1; 1b, trans-cis ) 7:1) or prepared using known
procedures (1e, trans-cis ) 25:1). 2-Methoxy-3-methyl-1,4-
benzoquinone was prepared using known methods.8,9 Brine
refers to saturated aqueous sodium chloride. Reactions were
monitored by thin-layer chromatography (TLC) on precoated
0.25 mm silica gel plates (Merck Kieselgel 60 F254) with
fluorescent indicator, and visualization was effected by viewing
under a UV lamp and/or by staining with p-anisaldehyde/H2-
SO4 or phosphomolybdic acid. Rf’s reported are from TLC
using the eluents indicated. Flash chromatography was
performed on silica gel (EM-Kieselgel 60, 0.04-0.063 mm
mesh) with the eluent indicated. NMR spectra were recorded
on samples dissolved in CDCl3, unless otherwise noted, and
chemical shifts are reported in δ (ppm) relative to internal
TMS or residual CHCl3. Coupling constants (J ) are reported
in Hz.
1
(EtOAc-hexanes); Rf 0.17 (20% acetone-hexanes); H NMR
(500 MHz) 6.96 (m, 2H), 6.86 (d, J ) 8.1, 1H), 6.61 (s, 1H),
5.36 (br s, 1H), 5.0 (d, J ) 9.4, 1H), 3.88 (s, 6H), 3.79 (s, 3H),
3.38 (dq, J ) 9.4, 6.5, 1H), 2.21 (s, 3H), 1.33 (d, J ) 6.5, 3H);
13C NMR (125 MHz) 151.2, 149.1, 149.0, 145.0, 143.0, 133.0,
126.6, 119.0, 113.0, 110.9, 109.3, 107.2, 92.5, 60.9, 55.9, 55.8,
45.7, 17.4, 9.4. Anal. Calcd for C19H22O5: C, 69.08; H, 6.71.
Found: C, 69.00; H, 7.00.
(B) In a similar experiment according to procedure I, a
mixture of TiCl4 (40 µL, 0.36 mmol) and Ti(O-i-Pr)4 (107 µL,
0.36 mmol) was used to promote a reaction of quinone 2 (50
mg, 0.33 mmol) with propenylbenzene 1a (61 µL, 0.36 mmol).
Workup and chromatography gave a 1:3.3 mixture of 3a /4a
as a colorless oil (60 mg, 55%) and 6a (15 mg, 14%) as a white
solid. Crystallization (EtOAc-hexanes) of the mixture of 3a /
4a gave pure 4a . Physical and spectral data for 4a : mp 113-
114 °C (EtOAc-hexanes); Rf 0.21 (20% acetone-hexanes); 1H
NMR (500 MHz) 6.79 (m, 3H), 4.04 (s, 3H), 3.88 (s, 3H), 3.85
(s, 3H), 3.43 (apparent t, J ) 9.0, 1H), 3.35 (apparent t, J )
9.0, 1H), 3.23 (apparent t, J ) 9.0, 1H), 2.99 (m, 1H), 1.97 (s,
3H), 1.19 (d, J ) 7.0, 3H); 13C NMR (125 MHz) 198.0, 193.4,
160.9, 149.0, 148.0, 134.4, 134.2, 118.1, 111.2, 109.8, 60.3, 55.9,
55.8, 52.6, 47.6, 43.1, 38.8, 17.5, 9.7. Anal. Calcd for
2-Meth oxy-3-m eth yl-1,4-ben zoqu in on e (2).8,9 NaH (1.29
g, 60% suspension in mineral oil, 32 mmol) was washed with
hexanes (3 × 5 mL), dried under a stream of argon, and
suspended in dry THF (25 mL). A solution of 2-methyl
resorcinol (4.0 g, 32 mmol) in THF (25 mL) was added, and
the mixture was stirred for 15 min at room temperature. After
being cooled to -10 °C, the mixture was treated with MeI (5.0
mL, 81 mmol). The temperature was allowed to increase to
C
19H22O5: C, 69.08; H, 6.71. Found: C, 69.00; H, 6.52.
Physical and spectral data for 6a : mp 132-133 °C (EtOAc-
hexanes); Rf 0.15 (20% acetone-hexanes); 1H NMR (500 MHz)
6.97 (m, 2H), 6.85 (d, J ) 8.1, 1H), 6.37 (s, 1H), 5.05 (d, J )
9.3, 1H), 4.71 (br s, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H),
3.35 (dq, J ) 9.3, 6.7, 1H), 2.15 (s, 3H), 1.35 (d, J ) 6.7, 3H);
(8) Cavitt, S. B.; Sarrafizadeh, R. H.; Gardner, P. D. J . Org. Chem.
1962, 27, 1211-1216.
(9) This preparation followed the procedure of Ishii, H.; Ohtake, R.;
Ohida, H.; Mitsui, H.; Ikeda, N. J . Pharm. Soc. J pn. 1970, 90, 1283-
1289.

1934 J . Org. Chem., Vol. 63, No. 6, 1998
Engler and Iyengar
13C NMR (125 MHz) 149.1, 149.0, 148.4, 143.9, 142.1, 133.2,
131.0, 118.8, 115.6, 110.9, 109.2, 104.8, 92.8, 60.0, 55.9, 55.8,
45.7, 17.5, 8.8. Anal. Calcd for C19H22O5: C, 69.08; H, 6.71.
Found: C, 68.90; H, 6.93.
(64 mg, 0.46 mmol) with propenylbenzene 1a (78 µL, 0.46
mmol) for 5 min gave after workup and chromatography (10%
EtOAc/hexanes) 27 (91 mg, 63%) as a white solid. Spectral
data matched that previously reported.1a
II. P r om otion by TiCl4, Sn Cl4, or BF 3‚OEt2. A solution
of the Lewis acid in CH2Cl2 (2-4 mL) was cooled to -78 °C,
and a solution of the quinone (0.39-0.82 mmol) in CH2Cl2 (3-4
mL) was added followed by the propenylbenzene (0.39-0.82
mmol), either neat or as a solution in CH2Cl2 (3 mL). The
reaction mixture was stirred for the times indicated in Table
1 and worked up as described above.
Rea ction of 1a w ith 18. BF3‚OEt2 (79 µL, 0.65 mmol) was
added to a solution of 18 (100 mg, 0.65 mmol) in CH2Cl2 (15
mL) maintained at -78 °C followed after 20 min by 1a (220
µL, 1.30 mmol). After being stirred for 48 h, the reaction was
worked up according to procedure II and chromatography (20%
EtOAc-hexanes) gave 26 (170 mg, 23%) as a white solid.
Spectral data matched that previously reported.1c
(C) According to procedure II, a TiCl4-promoted (43 µL, 0.39
mmol) reaction of quinone 2 (60 mg, 0.39 mmol) with prope-
nylbenzene 1a (67 µL, 0.39 mmol) gave a 1:3 mixture of 3a /4a
as a colorless oil (20 mg, 15.5%), 5a (18 mg, 14%) as a white
solid, and 6a (41 mg, 32%) as a white solid.
Gen er a l P r oced u r e for P r otic Acid -Ca ta lyzed Rea r -
r a n gem en t of Cyclobu ta n es 3/4 to Dih yd r oben zofu r a n s
5/6. p-Toluenesulfonic acid (p-TsOH, 2-10 mg) was added to
a solution of the cyclobutane (15-33 mg) in CH2Cl2 (1-5 mL)
at room temperature. The reaction was monitored by TLC and
stirred for the times indicated in Table 2, after which it was
quenched by the addition of saturated aqueous sodium bicar-
bonate. The mixture was extracted with CH2Cl2, and the
extracts were dried (MgSO4) and concentrated. Chromatog-
raphy with 10% acetone/hexanes as eluent afforded the dihy-
drobenzofurans in the yields indicated in Table 2.
Physical and spectral data for 6d : a colorless oil; Rf 0.28
(25% acetone-hexanes); 1H NMR (400 MHz) 7.24-7.42 (m,
5H), 6.35 (s, 1H), 5.12 (d, J ) 8.8, 1H), 4.59 (br s, 1H), 3.94 (s,
3H), 3.33 (dq, J ) 8.8, 6.8, 1H), 2.15 (s, 3H), 1.35 (d, J ) 6.8,
3H); 13C NMR (100 MHz) 148.4, 144.0, 142.0, 141.0, 130.8,
128.5, 128.1, 126.0, 115.6, 104.8, 92.6, 60.0, 46.0, 17.9, 8.8;
HRMS m/z 270.1279 (M+, calcd for C17H18O3 270.1256).
Physical and spectral data for 6e: colorless oil as a 10:1
mixture of trans-cis isomers; Rf 0.36 (25% acetone-hexanes);
1H NMR (400 MHz) 7.36 (d, J ) 6.9, 2H), 7.20 (m, 3H), 6.37
(s, 1H), 5.40 (d, J ) 8.0, 1H), 4.40 (br s, 1H), 3.94 (s, 3H), 3.40
(dq, J ) 8.0, 6.8, 1H), 2.40 (s, 3H), 2.15 (s, 3H), 1.38 (d, J )
6.8, 3H); 13C NMR (100 MHz) 148.3, 143.9, 142.1, 138.8, 135.5,
130.9, 130.7, 127.8, 126.4, 126.1, 115.6, 104.9, 90.2, 60.0, 45.1,
19.6, 18.2, 8.8; HRMS m/z 284.1399 (M+, calcd for C18H20O3
284.1412).
(D) According to procedure II, a SnCl4-promoted (96 µL, 0.82
mmol) reaction of quinone 2 (125 mg, 0.82 mmol) with
propenylbenzene 1a (139 µL, 0.82 mmol) gave 4a (40 mg, 15%)
as a colorless oil and 6a (65 mg, 24%) as a white solid.
(E) According to procedure II, a BF3‚OEt2-promoted (90 µL,
0.71 mmol) reaction of quinone 2 (108 mg, 0.71 mmol) with
propenylbenzene 1a (120 µL, 0.71 mmol) gave 4a (10 mg, 4%)
as a colorless oil and 6a (130 mg, 56%) as a white solid.
Rea ction of 1e w ith 2. (A) According to procedure I, a
mixture of TiCl4 (48 µL, 0.44 mmol) and Ti(O-i-Pr)4 (65 µL,
0.22 mmol) in CH2Cl2 (2 mL) was used to promote a reaction
of quinone 2 (100 mg, 0.66 mmol) with propenylbenzene 1e
(288 µL, 1.98 mmol). The reaction temperature increased to
-5 °C over 18 h, and workup and chromatography gave 15
(60 mg, 22%) as a pale yellow solid: mp 166-167 °C (CH2-
1
Cl2-hexanes); Rf 0.48 (25% acetone-hexanes); H NMR (400
MHz) 7.70 (d, J ) 8.0, 1H), 7.17-7.27 (m, 6H), 6.98 (d, J ) 7,
1H), 3.29 (d, J ) 8.0, 1H), 2.85 (d, J ) 9.8, 1H), 2.74-2.78 (m,
2H), 2.67 (s, 3H), 2.46 (d, J ) 6.4, 1H), 2.34 (s, 3H), 2.30 (s,
3H), 1.24 (s, 3H), 1.16 (d, J ) 7.1, 3H), 0.98 (d, J ) 6.4, 3H),
0.86 (m, 1H); 13C NMR (100 MHz) 213.8, 211.1, 139.5, 138.0,
136.2, 135.7, 130.6, 130.4, 129.8, 128.9, 127.2, 126.4, 126.3,
126.2, 85.0, 66.9, 55.6, 54.1, 52.6, 51.8, 48.0, 41.7, 37.7, 21.2,
21.1, 20.5, 14.7, 13.0; HRMS m/z 416.2326 (M+, calcd for
Ack n ow led gm en t. We thank Mr. Pankaj Desai for
results of experiments with 18, Dr. Martha Morton for
help with the HMQC/HMBC and NOE experiments, and
Professor J effrey Aube´’s group for use of an HPLC. This
work was supported financially by the National Science
Foundation (OSR-955223) and the KU General Re-
search Fund.
C
28H32O3, 416.2352).
(B) According to procedure I, a mixture of TiCl4 (54 µL, 0.5
mmol) and Ti(O-i-Pr)4 (148 µL, 0.5 mmol) was used to promote
a reaction of quinone 2 (75 mg, 0.49 mmol) with propenylben-
zene 1e (72 µL, 0.49 mmol). Workup and chromatography
gave 4e (62 mg, 45%) as a pale yellow solid: mp 88-90 °C
1
(EtOAc-hexanes); Rf 0.41 (25% acetone-hexanes); H NMR
(400 MHz) 7.37 (d, J ) 7.0, 1H), 7.22 (m, 1H), 7.13 (m, 2H),
4.06 (s, 3H), 3.52 (apparent t, J ) 8.6, 1H), 3.39 (apparent t,
J ) 8.6, 1H), 3.43 (apparent t, J ) 8.6, 1H), 3.01-3.11 (m,
1H), 2.22 (s, 3H), 1.99 (s, 3H), 1.14 (d, J ) 7.0, 3H); 13C NMR
(100 MHz) 198.2, 193.6, 160.8, 139.0, 136.1, 134.5, 130.4, 126.9,
126.4, 125.2, 60.3, 49.5, 48.0, 42.9, 38.9, 19.8, 17.3, 9.8. Anal.
Calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 75.68; H,
7.30.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for preparation of, and physical and spectral for, 3b/c,
4b-d , 5b/c, 6b-d ; IR and mass spectral data for all new
compounds; copies of 1H and 13C NMR spectra for all com-
pounds with HRMS (19 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Rea ction of 1a w ith 17. According to procedure II, a
BF3‚OEt2-promoted (58 µL, 0.46 mmol) reaction of quinone 17
J O971937U