tert-Butyl Substituent as a Regiodirecting and Novel C-H Protecting Group in Cyclobutenedione-Based Benzannulation Chemistry

Article abstract of DOI:10.1021/jo971565p

2-Unsubstituted hydroquinone monoacetates, quinones, and 3-unsubstituted quinolizinones were synthesized in moderate to high yields via tert-butyl and trimethylsilyl substituted cyclobutenediones. The addition of unsaturated carbon nucleophiles proceeded

Full text of DOI:10.1021/jo971565p

J . Org. Chem. 1998, 63, 2835-2844
2835
ter t-Bu tyl Su bstitu en t a s a Regiod ir ectin g a n d Novel C-H
P r otectin g Gr ou p in Cyclobu ten ed ion e-Ba sed Ben za n n u la tion
Ch em istr y
Fuqiang Liu and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory University, 1515 Pierce Drive, Atlanta, Georgia 30322
Received August 21, 1997
2-Unsubstituted hydroquinone monoacetates, quinones, and 3-unsubstituted quinolizinones were
synthesized in moderate to high yields via tert-butyl and trimethylsilyl substituted cyclobutene-
diones. The addition of unsaturated carbon nucleophiles proceeded regiospecifically at the carbonyl
group most distant from the tert-butyl or trimethylsilyl substituent. Thermolysis of the adducts,
followed by treatment under acidic conditions to remove the tert-butyl and trimethylsilyl groups in
good overall yields, provided access to a variety of “less-substituted” hydroquinone monoacetates,
quinones, and quinolizinones. Of the two systems, the tert-butyl-substituted cyclobutenediones
proved the most useful.
Sch em e 1
In tr od u ction
Cyclobutenediones (1, X ) O) have been widely used
in the synthesis of highly substituted aromatic molecules
including phenols, catechols, hydroquinones (and quino-
nes), and heteroaromatics (Scheme 1).1-10 One limitation
of this methodology is that, with the exception of alkoxy
and amino derivatives, monosubstituted cyclobutenedi-
ones (1, R1 or R2 ) H) are poor reaction partners. Most
monosubstituted cyclobutenediones are less stable than
their disubstituted counterparts, and the regiocontrol of
the benzannulation process is compromised by competing
1,2- and 1,4-nucleophilic addition to the cyclobutenedione.
Sch em e 2
To overcome this limitation, cyclobutenediones bearing
trimethylsilyl and tert-butyl substituents as proton sur-
rogates were studied (Scheme 2). It was anticipated that
the bulky trimethylsilyl and tert-butyl substituents would
favorably influence the regioselectivity of nucleophilic
addition. Then, after thermal rearrangement to the
corresponding hydroquinone, the trimethylsilyl or tert-
butyl groups adjacent to the phenol substituent could be
cleaved by facile protodesilylation or retro-Friedel-Crafts
alkylation, respectively. This would provide a regiocon-
trolled entry to a series of aromatic molecules at lower
levels of substitution. In practice, the tert-butyl-substi-
tuted cyclobutenediones proved the better of the two
substrates for the intended chemistry. The study docu-
mented herein revealed the tert-butyl substituent as an
effective regiodirecting and novel C-H protecting group
in the regiospecific synthesis of hydroquinone mono-
acetates, quinones, and quinolizinones.
Resu lts
Tr im et h ylsilyl-Su b st it u t ed Cyclob u t en ed ion es.
The study commenced with an exploration of the reaction
of 3-methyl-4-trimethylsilylcyclobutene-1,2-dione (2a )11
with 5-lithio-2,3-dihydrofuran, the latter of which was
generated from n-butyllithium and 5-tri-n-butylstannyl-
2,3-dihydrofuran (eq 1).12,13 Slow dropwise addition of
the lithiate to 3-methyl-4-trimethylsilylcyclobutene-1,2-
dione at -78 °C followed by an Ac2O quench and rapid
workup gave an unstable product that was not amenable
* Tel no.: (404) 727-6604. FAX no.: (404) 727-0845. E-mail:
CHEMLL1@unix.cc.emory.edu.
(1) Liebeskind, L. S. Tetrahedron Symposium in Print 1989, 45,
3053.
(2) Krysan, D. J .; Gurski, A.; Liebeskind, L. S. J . Am. Chem. Soc.
1992, 114, 1412.
(3) Moore, H. W.; Yerxa, B. R. ChemtractssOrg. Chem. 1992, 5, 273.
(4) Yerxa, B. R.; Moore, H. W. Tetrahedron Lett. 1992, 33, 7811.
(5) Edwards, J . P.; Krysan, D. J .; Liebeskind, L. S. J . Am. Chem.
Soc. 1993, 115, 9868.
(6) Gurski, A.; Liebeskind, L. S. J . Am. Chem. Soc. 1993, 115, 6101.
(7) Liebeskind, L. S.; Wang, J . J . Org. Chem. 1993, 58, 3550.
(8) Gurski-Birchler, A.; Liu, F.; Liebeskind, L. S. J . Org. Chem. 1994,
59, 7737.
(11) Allen, A. D.; Lai, W.; Ma, J .; Tidwell, T. T. J . Am. Chem. Soc.
1994, 116, 2625.
(9) Koo, S.; Liebeskind, L. S. J . Am. Chem. Soc. 1995, 117, 3389.
(10) Turnbull, P.; Moore, H. W. J . Org. Chem. 1995, 60, 3274.
(12) Boeckman, R. K.; Bruza, K. J . Tetrahedron 1981, 37, 3997.
(13) Soderquist, J . A.; Hsu, G. J .-H. Organometallics 1982, 1, 830.
S0022-3263(97)01565-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/15/1998

2836 J . Org. Chem., Vol. 63, No. 9, 1998
Liu and Liebeskind
Ta ble 1. Syn th esis of 2-Un su bstitu ted Hyd r oqu in on e
Mon oa ceta tes
F igu r e 1.
to purification by chromatography. In addition to cy-
clobutenone absorptions at 1761 and 1744 cm-1, the
entry
1
R1
Me
RunsatLi
7
R2
R3
8/%a 9/%b
5-lithio-2,3-
dihydrofuran
7a -OCH2CH2- 8a /62 9a /92
7b -OCH2CH2- 8b/71 9b/96
7c -O(CH2)3- 8c/61 9c/93
7d -O(CH2)3- 8d /55 9d /96
2
3
4
i-PrO 5-lithio-2,3-
dihydrofuran
6-lithio-2,3-
dihydropyran
i-PrO 6-lithio-2,3-
dihydropyran
â-lithiostyrene
Me
5
6
7
Me
7e
7f
7g OEt
H
H
Ph
Ph
H
8e/50 9e/74
8f/73 9f/72
8g/58 9g/94
i-PrO â-lithiostyrene
i-PrO 1-lithio-1-
ethoxyvinyl
8
Me
1-lithio-1-
ethoxyvinyl
7h OEt
H
8h /48 9h /95
unstable product showed a strong absorption in the
infrared spectrum at 2090 cm-1, which suggested the
presence of dienylketene 4, generated by a facile ring
opening of the cyclobutenone 3a at room temperature
(Figure 1). The ease with which cyclobutenone 3a opened
to the dienylketene is in accord with earlier studies by
Tidwell, who showed that trimethylsilyl-substituted cy-
clobutenediones open to the isomeric bisketenes under
mild conditions.14,11 However, the untimely ring opening
of the cyclobutenone compromised the efficiency of the
benzannulation process by exposing the reactive di-
enylketene to Ac2O/AcO- (from the reaction quench) and
to H2O/SiO2 (from the workup/purification). This prob-
lem was overcome when the crude reaction mixture
(generated by nucleophilic addition) was rapidly washed
with ice/water and then dried and heated in toluene at
90 °C for 90 min. This protocol provided the desilylated
dihydrobenzofuran 5a in 67% yield after silica gel chro-
matography, the desilylation occurring during chroma-
tography. In a similar fashion, 6-lithio-1H-2,3-dihydro-
pyran reacted with 3-methyl-4-trimethylsilylcyclobutene-
1, 2-dione to give benzodihydropyran 5b in 59% yield.
ter t-Bu tyl-Su bstitu ted Cyclobu ten ed ion es. To ex-
tend the process of benzannulation using trimethylsilyl-
substituted cyclobutenediones, a general synthesis of
3-substituted-4-trimethylsilylcyclobutene-1,2-diones is re-
quired. Some substrates can be prepared by [2 + 2]
cycloaddition of dichloroketene to 1-trimethylsilylalkynes,
followed by strong acid hydrolysis of the resulting dichlo-
rocyclobutenones to cyclobutenediones.14 Unfortunately,
this process is not general. However, a variety of 3-tert-
butyl-4-substituted cyclobutenediones can be prepared by
the sequential functionalization of diisopropylsquarate
with organolithium reagents.15 Therefore, tert-butyl-
substituted cyclobutenediones were studied in place of
the trimethylsilyl derivatives. It was anticipated that a
bulky tert-butyl substituent might favorably influence the
regioselectivity of nucleophilic addition to the cyclobutene-
dione, as did the trimethylsilyl substituent. After ther-
mal rearrangement of the cyclobutenone to the substi-
a
The yields were based on cyclobutenediones, 6, as limiting
b
reagents. Conditions: entries 1-4 and 8, HOAc/Zn(OAc)2, re-
fluxed for 1-5 h; entry 5, TFA, 130 °C, 20 h; entry 6, TFA, 110
°C, 68 h; entry 7, Zn/HOAc, reflux 45 min.
tuted phenol, the tert-butyl group ortho to the phenol
residue would be easily removed through an acid-
catalyzed retro-Friedel-Crafts alkylation reaction.16
The synthesis of 7-acetoxy-4-hydroxy-6-methyl-2,3-
dihydrobenzo[b]furan (9a ) is representative of the use of
a tert-butyl substituent as a regiodirecting, C-H protect-
ing group (Entry 1, Table 1). 5-Lithio-2,3-dihydrofuran
was slowly added to 3-tert-butyl-4-methylcyclobutene-1,2-
dione at -78 °C. Quenching with Ac2O at -78 °C yielded
7a (55%), which was unstable to purification and full
characterization. Simply on standing at room tempera-
ture, compound 7a transformed into 8a within 8 h. To
simplify the overall process, purification of the intermedi-
ate 1,2-adduct was foresaken. Instead, the reaction
mixture was subjected to rapid workup and the crude
product was heated at 120 °C for 40 min, producing 8a
in 62% yield. The tert-butyl substituent of 8a was easily
removed (3 equiv of Zn(OAc)2 in refluxing HOAc, 90 min)
giving hydroquinone monoacetate 9a in 92% yield (Table
1, entry 1).
This representative reaction revealed three significant
attributes of tert-butyl-substituted cyclobutenediones: (1)
as with the trimethylsilyl substituent, the tert-butyl
group functioned to control the regiochemistry of nucleo-
philic addition to cyclobutenediones; (2) the tert-butyl
group significantly lowered the barrier to ring opening
of the 4-acetoxy-4-substituted cyclobutenones, suggesting
that relief of steric strain is a major factor in the facility
of ring-opening of both systems;14,11 and (3) the ready
removal of the tert-butyl substituent from the thermolysis
product 8a demonstrated the potential of the tert-butyl
substituent as a novel C-H protecting group in vinyl-
ketene-based benzannulation chemistry.
To minimize untimely ring opening of the tert-butyl-
substituted cyclobutenones and secure optimum yields
of adducts 7, the lithium reagent must be added to the
(14) Zhao, D. C.; Allen, A. D.; Tidwell, T. T. J . Am. Chem. Soc. 1993,
115, 10097.
(15) Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J .
Org. Chem. 1988, 53, 2482.
(16) Tashiro, M.; Yamato, T.; Fukata, G. J . Org. Chem. 1978, 43,
1413.

Cyclobutenedione-Based Benzannulation Chemistry
J . Org. Chem., Vol. 63, No. 9, 1998 2837
cyclobutenedione 6 slowly at -78 °C. Likewise, a rapid
and cold workup of the reaction mixture was crucial,
otherwise the hydrolytically sensitive dienylketene in-
termediate (see Figure 1) would form and be quenched
by water during the workup. Using this method, a
variety of tert-butyl-substituted hydroquinone monoac-
etates were synthesized in yields ranging from 48 to 73%
(Table 1). In most cases, removal of the tert-butyl group
from 8 was achieved in near quantitative yield using 3
equiv of Zn(OAc)2 in refluxing HOAc for 1-5 h (entries
1-4, 7, 8). Compounds 8e and 8f proved resistant to
deprotection under these conditions, but removal of the
tert-butyl group was achieved by direct treatment of these
substrates with a few drops of trifluoroacetic acid (20 h
at 130 °C for the former; 3 d at 110 °C for the latter).
This protocol produced compounds 9e and 9f in 70-80%
yields (entries 5 and 6). For the purpose of full charac-
terization (in addition to 7a above), cyclobutenone inter-
mediates 7c and 7f (entries 3 and 6) were isolated and
purified (49% and 22% yields, respectively). When these
same reactions were performed without purification of
the intermediates 7, the desired products 8c and 8f were
obtained in 61% and 73% yields, respectively.
Surprisingly, with the exception of 2-lithio-1-methyl-
indole (described above), aromatic and heteroaromatic
reactants (PhLi, 5-lithio-2-methylfuran, and 2-lithio-1-
methylpyrrole) were ineffective participants in tert-butyl-
substituted cyclobutenedione-based benzannulation re-
actions. For example, addition of 5-lithio-2-methylfuran
to 3-tert-butyl-4-methoxycyclobutene-1,2-dione (6c) at
-78 °C gave 12 after quenching with 10% NH4Cl (eq 4).
P r oof of Regioch em istr y. Confirmation that the
tert-butyl group dominantly influenced the selectivity of
nucleophilic addition to tert-butylcyclobutenediones was
obtained by the addition of 2-propenyllithium to 2-tert-
butyl-3-methylcyclobutenedione (eq 2). O-Acetylation of
Upon thermolysis at 160 °C, lactone 13 was produced in
75% yield by attack of the hydroxyl group on the
transiently generated vinylketene intermediate.
In an attempt to block lactone formation and promote
benzannulation at the furan CdC bond, the methyl ether
14 was generated in 81% yield by addition of 5-lithio-2-
methylfuran to cyclobutenedione 6c followed by a MeOSO2-
CF3 quench (eq 4). This compound proved very resistant
to thermal rearrangement and survived intact without
any decomposition after 3 h at 250 °C. Slow decomposi-
tion of 14 began at 280 °C. A related attempt at
benzannulation by reaction of phenyllithium and 2-lithio-
1-methylpyrrole with cyclobutenedione 6b was similarly
unproductive. However, by carrying out the cyclobuten-
one thermolyses in xylene in the presence of Ac2O/n-
Bu3N,17 the recalcitrant reactants participated in the
desired benzannulation. Under these conditions efficient
formation of the benzannulated products was observed.
For example, 16 was obtained in 89% yield when com-
pound 15 was refluxed in xylene for 5 d in the presence
of 3.0 equiv each of Ac2O and n-Bu3N and a catalytic
amount of DMAP (Scheme 3). Depending upon the
temperature, thermolysis in the absence of the additives
gave either recycled starting material or resulted in
decomposition. Quantitative deprotection of the acetate
group (LiAlH4, 5 min, rt) gave 18 which was subjected
to tert-butyl cleavage [HOAc/Zn(OAc)2, reflux] to give
hydroquinone monomethyl ether 20 in 93% yield. Using
the modified thermolysis conditions, acamelin (22), a
natural product isolated from Australian blackwood
(Acacia melanoxylon) and previously synthesized in very
low yield,18,19 was obtained in 36% overall yield in six
steps from 3-tert-butyl-4-methoxycyclobutene-1,2-dione
(Scheme 3, 6c f 22).
the 1,2-adduct then thermolysis followed by removal of
the tert-butyl group produced hydroquinone monoacetate
1
9i in 46% overall yield. This product showed H and 13C
NMR spectra that were fully consistent with the sym-
metry of the assigned structure and confirmed selective
nucleophilic attack at the carbonyl group most distant
from the tert-butyl group (eq 1). No evidence of the
formation of isomeric products was obtained.
Reaction of 2-lithio-1-methylindole with 3-tert-butyl-
4-isopropoxycyclobutene-1,2-dione followed by an Ac2O
quench and rapid workup gave a crude product that was
heated at 120 °C for 30 min. The air-sensitive thermoly-
sis product was partially oxidized to the carbazoquinone
10 (eq 3). Intentional oxidation of the crude thermolysis
To further explore the generality of this methodology,
reactions between tert-butyl-substituted cyclobutenedi-
ones and 2-lithio azaheteroaromatics were studied. Mod-
erate to high yields of tert-butyl-substituted ring-fused
product with ceric ammonium nitrate gave the red
carbazoquinone 10 in 58% yield. Efficient removal of the
tert-butyl group was achieved by subjecting 10 to reduc-
tion with Zn in refluxing HOAc (40 min). Rapid re-
establishment of the quinone oxidation state occurred
upon SiO2 gel chromatography and produced the red
2-isopropoxy-9-methyl-9H-carbazole-1,4-dione, 11, in 82%
yield.
(17) Ishii, Y.; Gao, C.; Xu, W. X.; Iwasaki, M.; Hidai, M. J . Org.
Chem. 1993, 58, 6818.
(18) McKittrick, B. A.; Stevenson, R. J . Chem. Soc., Perkin Trans.
1 1983, 2423.
(19) Scannell, R. T.; Stevenson, R. J . Org. Chem. 1983, 48, 127.

2838 J . Org. Chem., Vol. 63, No. 9, 1998
Liu and Liebeskind
Sch em e 3
Ta ble 2. Syn th esis of Rin g-fu sed P yr id on es
entry
R1
lithiate
Z
R2
R3
23/%
24/%
1
i-PrO
Me
Et2N
i-PrO
Me
2-lithiothiazole
2-lithiothiazole
2-lithiothiazole
2-lithiobenzothiazole
2-lithiobenzothiazole
2-lithio-1-methylimidazole
2-lithio-1-methylimidazole
S
S
S
S
S
H
H
H
H
H
H
23a /63
23b/43
24a /94
24b/92
2
3a
4
23c/97a
23d /59
23e/46
23f/52
23g/66
24c/100
24d /85
24e/95
24f/99
24g/93
benzo
benzo
5
6
7
i-PrO
Me
NMe
NMe
H
H
H
H
a
The lithium reagent was added to the cyclobutenedione at -78 °C, then the reaction mixture was warmed to 0 °C. After 40 min, the
reaction was quenched with Ac2O at 0 °C. A rapid workup and thermolysis at 140 °C for 30 min produced the product.
pyridones 23 were obtained by the regiospecific addition
of lithiated azaheteroaromatics to tert-butylcyclobutene-
1,2-diones 6a , 6b, and 6d followed by an Ac2O quench
and thermolysis of the crude reaction products. Cleavage
of the tert-butyl substituent proceeded with high ef-
ficiency and gave products 24 (Table 2). Compared to
other tert-butyl-substituted cyclobutenediones, 3-diethyl-
amino-4-tert-butylcyclobutenedione, 6d , was less reactive
toward nucleophilic addition. To effect the addition, the
reaction mixture was warmed to 0 °C for 40 min.
Quenching with Ac2O at 0 °C followed by neat thermoly-
sis of the crude product at 140 °C for 30 min gave
compound 23c in 97% yield. The transformation from
23c to 24c (quantitative) in refluxing HOAc with added
Zn(OAc)2 was complete within 10 min.
dimethoxy-4-hydroxy-4-(2-furyl)cyclobutenone and 2-meth-
yl-3-methoxy-4-hydroxy-4-(2-furyl)cyclobutenone rearrange
to the corresponding furan-fused quinones with facility.1,3
But in the current study, 2-tert-butyl-3,4-dimethoxy-4-
(5-methyl-2-furyl)cyclobutenone is stable at 250 °C for 3
h, while 2-tert-butyl-3-isopropoxy-4-acetoxy-4-(2,3-dihy-
drofuran-5-yl) undergoes thermal rearrangment within
30 min at 120 °C.
The cumulative results obtained to date indicate that
an interplay between the steric nature of the cyclobuten-
one 2-substituent and the nucleophilic nature of the
4-Runsaturated substituent affects the facility with which
4-Runsaturated cyclobutenones are converted into benz-
annulated products. Since sterically encumbered cy-
clobutenones appear to open to the vinylketene at room
temperature (see above), it is unlikely that generation
of the vinylketene intermediate is the rate-determining
step in the benzannulation of these substrates; electro-
cyclization must be the slow step in the overall process.
It therefore follows that, as the central carbon of the
ketene and the π-orbital at the alkene â-carbon approach
each other for bonding (Figure 2), the reaction rate is
retarded by any nonbonded steric effects that emerge
between the vinylketene 2- and 3-substituents.
Discu ssion
Why do not 2-tert-butyl-4-aryl (and most 4-heteroaryl)
cyclobutenones undergo thermal rearrangement to the
benzannulated products under reaction conditions where
2-tert-butyl-4-alkenyl (and heteroalkenyl) cyclobutenones
do? And why, when the 2-tert-butyl substituent is
replaced with a less bulky substituent, do thermal
benzannulations proceed regardless of the nature of the
unsaturated moiety at the 4-position of the cyclobuten-
one?1,3 For example, it was previously observed that 2,3-
With 2-tert-butyl-substituted cyclobutenones, nonbond-
ed steric interactions between the tert-butyl group and

Cyclobutenedione-Based Benzannulation Chemistry
J . Org. Chem., Vol. 63, No. 9, 1998 2839
F igu r e 2. Representations of vinylketene electrocyclization
leading to benzannulation products.
F igu r e 4.
F igu r e 3.
F igu r e 5. Representation of vinylketene electrocyclization
leading to 23b.
the adjacent ketene substituent become pronounced as
the alkene substituent and the ketene central carbon
approach each other. However, those cyclobutenones
bearing nucleophilic 4-substituents (dihydrofuran, dihy-
dropyran, and indole) can attain a bonding interaction
with the ketene central carbon at distances where the
less nucleophilic π-systems fail to react. Therefore, steric
retardation of the electrocyclization by the tert-butyl
group is diminished or nullified with cyclobutenones
bearing 4-substituents with nucleophilic π-systems. Al-
ternatively, replacement of the bulky 2-tert-butyl sub-
stituent with a smaller group diminishes nonbonded
steric effects and allows closer approach of the less
nucleophilic π-systems (phenyl, substituted phenyl, fu-
ran, and N-methylpyrrole) to the ketene central carbon.
This contributes to faster rates of electrocyclization and
to a faster overall rate of reaction, thus allowing effective
benzannulation with aromatic, heteroaromatic, or vinyl
substituents at the 4-position of the cyclobutenone.1,3
ization of the phenol (eq 5). Since tautomerization of the
ring-fused pyridones is not feasible, it is presumed that
the pyridones suffer facile protonation at the tert-butyl
bearing carbon atom, which must be a consequence of
considerable stabilization of the charge by delocalization
into the adjacent heterocyclic ring (eq 6).
What is the beneficial effect of Ac2O/n-Bu3N on the
problematic electrocyclizations? Consistent with the
mechanistic arguments elaborated above, the barrier to
electrocyclization should be lowered by electrophilic
polarization of the ketene carbonyl group. At the el-
evated temperatures required to achieve an acceptable
reaction rate, ketene polarization might occur either with
catalytic quantities of n-Bu3NH+AcO- (generated by
n-Bu3N deprotonation of Ac2O) or by interaction of the
ketene with CH3CONBu3+AcO- (Figure 3). Alterna-
tively, O-acylation of the cyclobutenone carbonyl would
produce a cyclobutenyl cation; ring-expansion could then
occur by analogy with the acid-induced ring expansion
of 2-vinylcyclobutanones to cyclohexenones (Figure 4).20
Compared to 2-tert-butyl-4-arylcyclobutenones, the
facility with which 2-tert-butylcyclobutenones bearing
π-deficient 4-azaheteroaryl substituents cyclize to ring-
fused pyridones is readily explained by participation of
the in-plane, nonbonding electron pair on nitrogen in the
electrocyclization process (Figure 5). The ease with
which the tert-butyl group is lost from ring-fused pyri-
dones 23 also requires explanation. Removal of the tert-
butyl substituent from hydroquinone monoacetates 8
proceeds through protonation of the tert-butyl bearing
carbon atom, either by an acid catalyst or by tautomer-
Con clu sion s
tert-Butyl-substituted cyclobutenediones undergo re-
giospecific addition of unsaturated carbon nucleophiles
at the carbonyl group most distant from the tert-butyl
substituent. Good to high yields of 2-tert-butyl-substi-
tuted hydroquinone monoacetates, quinones, and 3-tert-
butyl-substituted quinolizinones were synthesized by
thermolysis of the O-acetylated and O-methylated ad-
ducts. Very efficient removal of the tert-butyl group is
accomplished under acidic conditions for the 2-tert-butyl-
substituted hydroquinone monoacetates and 3-tert-butyl-
substituted quinolizinones and under acidic reducing
conditions for the 2-tert-butylquinones, thus providing a
synthetic entry to 2-unsubstituted hydroquinone monoac-
etates and quinones and to 3-unsubstituted quinolizino-
nes.
(20) Matz, J . R.; Cohen, T. Tetrahedron Lett. 1981, 22, 2459.

2840 J . Org. Chem., Vol. 63, No. 9, 1998
Liu and Liebeskind
which was purified by vacuum distillation (bp 130-132 °C/
0.01 mmHg) followed by recrystallization from Et2O/hexane
(mp 54-55 °C) to give 6d as a light yellow solid (3.27 g, 15.620
mmol, 78%). TLC: silica gel, 25% ethyl acetate in hexane, Rf
) 0.18). IR (CH2Cl2, NaCl, cm-1): 2982 (m), 1775 (s), 1725
(s), 1585 (s). 1H NMR (CDCl3, 300 MHz): δ 3.66 (br s, 4 H),
1.35 (s, 9 H), 1.22 (t, J ) 7.2 Hz, 6 H). 13C NMR (CDCl3, 75.5
MHz): δ 194.4, 190.0, 180.5, 176.8, 46.0 (br s, 1 C), 44.0 (br s,
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All reactions were performed
under an atmosphere of dry prepurified nitrogen in flame-dried
glassware. Et2O was freshly distilled from sodium and ben-
zophenone under nitrogen. Prior to use, THF, toluene, and
xylene were dried with 4 Å molecular sieves and analyzed for
less than 30 ppm H2O by Karl Fischer titration. n-BuLi and
tert-BuLi solutions were purchased from Aldrich in Sure-Seal
bottles and were titrated using diphenylacetic acid as indica-
tor. Zn(OAc)2 and (1-ethoxyvinyl)tri-n-butyltin were pur-
chased from Aldrich and used as received. Thin-layer chro-
matography was performed with E. Merck silica gel 60F-245
glass plates of 0.25 mm thickness using UV light and anisal-
dehyde stain solution for visualization. Column chromatog-
raphy was carried out using flash grade silica gel 60 (EM
Science) with compressed air as the source of positive pressure.
Sta r tin g Ma ter ia ls. The following compounds were pre-
pared by literature methods: 3-methyl-4-trimethylsilyl-
cyclobut-3-ene-1, 2-dione (2a ),11 3-tert-butyl-4-isopropoxycy-
clobutene-1,2-dione (6b),15 3-tert-butyl-4-methylcyclobutene-
1,2-dione (6a ),15 5-tri-n-butylstannyl-2,3-dihydrofuran,13 6-tri-
n-butylstannyl-2,3-dihydropyran,13 â-tri-n-butylstannylstyrene,21
2-tri-n-butylstannylthiazole,22 2-tri-n-butylstannyl-1-meth-
ylimidazole,22 2-tri-n-butylstannylbenzothiazole,8 and 3,4-
dimethoxycyclobutene-1,2-dione.23
1 C), 34.0, 29.3 (3 C), 13.5 (br s, 2 C). Anal. Calcd for C12H19
-
NO2: C, 68.87; H, 9.15; N, 6.69; O, 15.29. Found: C, 68.77;
H, 9.18; N, 6.67.
Ben za n n u la tion w ith Tr im eth ylsilylcyclobu ten ed i-
on es. 7-Acetoxy-4-h yd r oxy-6-m eth yl-2,3-d ih yd r oben zo-
[b]fu r a n , 5a . 5-Tri-n-butylstannyl-2,3-dihydrofuran (485 mg,
1.350 mmol, 1.35 equiv) in THF (5 mL) at -78 °C was treated
dropwise with n-BuLi in hexane (1.11 mL, 1.25 M, 1.400 mmol,
1.40 equiv). After warming to 0 °C for 30 min, the mixture
was added very slowly dropwise to 3-methyl-4-trimethylsilyl-
cyclobut-3-ene-1,2-dione (168 mg, 0.998 mmol, 1.00 equiv) in
THF (5 mL) at -78 °C. After 2 h, Ac2O (284 mL, 3.010 mmol,
3.02 equiv) was added, and the mixture was maintained at
-78 °C for 90 min and then quickly washed with H2O,
extracted with Et2O (50 mL × 2), dried (MgSO4), and concen-
trated to a yellow oil. This crude material was dissolved in 6
mL of toluene, heated in a flame-dried flask at 90 °C (N2) for
90 min, and then purified by chromatography (flash column,
silica gel, 2 × 15 cm, 25% ethyl acetate in hexane) to yield 5a
as a yellow oil (139 mg, 0.667 mmol, 67%). TLC: silica gel,
25% ethyl acetate in hexane, Rf ) 0.13). IR (CH2Cl2, NaCl,
cm-1): 3685 (w), 3579 (s), 3467 (s), 1762 (s), 1606 (s. 1H NMR
(CDCl3, 300 MHz): δ 6.08 (s, 1 H), 5.30 (s, 1 H), 4.64 (t, J )
8.7 Hz, 2 H), 3.12 (t, J ) 8.7 Hz, 2 H), 2.31 (s, 3 H), 2.07 (s, 3
H). 13C NMR (CDCl3, 75.5 MHz): δ 169.9, 152.0, 150.0, 130.7,
126.7, 112.0, 109.3, 72.8, 27.2, 20.4, 15.7. Anal. Calcd for
N-Meth yl-2-tr i-n -bu tylsta n n ylin d ole. Under argon, 1-
methylindole (5.31 g, 40.48 mmol, 1.00 equiv) was dissolved
in 70 mL of THF and cooled to -78 °C. tert-Butyllithium
(28.57 mL, 1.70 M in pentane, 48.57 mmol, 1.20 equiv) was
added dropwise. The reaction mixture was warmed to room
temperature, stirred for 2 h, and then recooled to -78 °C. Tri-
n-butylstannyl chloride (13.18 mL, 48.59 mmol, 1.20 equiv)
was added dropwise, and the mixture was stirred for 2 h and
then quenched with 10% aqueous NH4Cl and extracted with
3 × 70 mL of Et2O. The combined organic layers were dried
with MgSO4 and concentrated to an oil. Purification by
distillation gave N-methyl-2-tri-n-butylstannylindole, a yellow
oil (14.16 g, 33.70 mmol, 83%). Bp: 163-165 °C (0.1 mmHg,
short-path distillation). IR (CH2Cl2, KCl, cm-1): 3060, 2958,
2933, 1416, 1356. 1H NMR (CDCl3, 300 MHz): δ 7.58 (d, J )
7.8 Hz, 1 H), 7.31 (d, J ) 7.8 Hz, 1 H), 7.17 (dt, J ) 7.8, 6.9
Hz, 1 H), 7.06 (dt, J ) 7.8, 6.9 Hz, 1 H), 6.59 (s, 1 H), 3.80 (s,
3 H), 1.62-1.52 (m, 6 H), 1.41-1.29 (m, 6 H), 1.18-1.12 (m, 6
C
11H12O4: C, 63.45; H, 5.81; O, 30.74. Found: C, 63.33; H,
5.83.
8-Ac e t o x y -5-h y d r o x y -7-m e t h y ld i h y d r o b e n z o [b ]-
p yr a n , 5b. 6-Tri-n-butylstannyl-2,3-dihydropyran (429 mg,
1.150 mmol, 1.15 equiv) in THF (5 mL) at -78 °C was treated
dropwise with n-BuLi in hexane (0.55 mL, 2.19 M, 1.200 mmol,
1.20 equiv). The reaction mixture was warmed to 0 °C for 30
min and then added very slowly dropwise to 3-methyl-4-
trimethylsilylcyclobut-3-ene-1,2-dione (168 mg, 0.998 mmol,
1.00 equiv) in THF (5 mL) at -78 °C. After 3 h, Ac2O (189
mL, 2.010 mmol, 2.00 equiv) was added, and the mixture was
maintained at -78 °C for 90 min and then quickly washed
with H2O, extracted with Et2O (50 mL × 2), dried (MgSO4),
and concentrated to a yellow oil. This crude material was
dissolved in 6 mL of toluene, refluxed in a flame-dried flask
for 2 h, and then purified by chromatography (flash column,
silica gel, 1 × 15 cm, 25% ethyl acetate in hexane) to yield 5b
as an orange oil (131 mg, 0.585 mmol, 59%). TLC: silica gel,
25% ethyl acetate in hexane, Rf ) 0.20). IR (CH2Cl2, NaCl,
cm-1): 3586 (s), 1758 (s), 1689 (m), 1634 (m), 1591 (m). 1H
NMR (CDCl3, 300 MHz): δ 6.02 (s, 1 H), 5.73 (br s, 1 H), 4.13
(t, J ) 4.8 Hz, 2 H), 2.57 (t, J ) 6.3 Hz, 2 H), 2.32 (s, 3 H),
2.03 (s, 3 H), 1.98 (tt, J ) 6.3, 4.8 Hz, 2 H). 13C NMR (CDCl3,
75.5 MHz): δ 170.2, 151.4, 146.8, 131.0, 128.2, 108.7, 107.5,
66.2, 21.4, 20.5, 19.0, 15.7. Anal. Calcd for C12H14O4: C, 64.85;
H, 6.35; O, 28.80. Found: C, 64.57; H, 6.30.
Isola tion of In ter m ed ia tes 7a , 7c, a n d 7f. 4-Acetoxy-
2-ter t-b u t yl-4-[5′-(2′,3′-d ih yd r ofu r a n yl)]-3-m et h yl-2-cy-
clobu ten on e, 7a . 5-Tri-n-butylstannyl-2,3-dihydrofuran (345
mg, 0.961 mmol, 1.20 equiv) in THF (6 mL) at -78 °C was
treated dropwise with n-BuLi in hexane (0.80 mL, 1.25 M,
1.000 mmol, 1.25 equiv). The reaction mixture was warmed
to 0 °C for 30 min and then added very slowly dropwise to
3-tert-butyl-4-methylcyclobutene-1,2-dione (122 mg, 0.802 mmol,
1.00 equiv) in THF (6 mL) at -78 °C. After 1 h, Ac2O (226
µL, 2.395 mmol, 2.99 equiv) was added, and the mixture was
maintained at -78 °C for 90 min and then washed with H2O,
extracted with Et2O (50 mL × 2), dried (MgSO4), filtered, and
concentrated to a yellow oil. Chromatography (flash column,
silica gel, 2 × 15 cm, 20% ethyl acetate in hexane) yielded 7a
as a yellow oil (115 mg, 0.435 mmol, 54%). TLC: silica gel,
H), 0.89 (t, J ) 7.2 Hz, 9 H). HRMS (EI) Calcd for C21H35
NSn: 421.1791. Found: 421.1791.
-
3-ter t-Bu tyl-4-m eth oxycyclobu ten e-1,2-d ion e, 6c. 3,4-
Dimethoxycyclobutene-1,2-dione (284 mg, 1.998 mmol, 1.00
equiv) in 6 mL of THF under N2 at -78 °C was treated
dropwise with tert-BuLi in pentane (1.29 mL, 1.70 M, 2.190
mmol, 1.10 equiv). After 10 min the reaction was quenched
with saturated NaHCO3 (1 mL), washed with H2O, extracted
with Et2O (30 mL × 2), dried (MgSO4), filtered, and concen-
trated. The resulting colorless oil in 5 mL of CH2Cl2 was
treated at room temperature with 3 drops of concentrated HCl.
After 15 min, the mixture was diluted with 20 mL of CH2Cl2
and dried over K2CO3. After filtration and evaporation, the
yellow oil was purified by chromatography (flash column, silica
gel, 2 × 8 cm, 15% ethyl acetate in hexane) to yield 6c as a
yellow oil (227 mg, 1.350 mmol, 68%). TLC: silica gel, 15%
ethyl acetate in hexane, Rf ) 0.25). IR (CH2Cl2, NaCl, cm-1):
2974 (s), 1792 (s), 1761 (s), 1589 (s), 1482 (s). 1H NMR (CDCl3,
300 MHz): δ 4.36 (s, 3 H), 1.25 (s, 9 H). 13C NMR (CDCl3,
75.5 MHz): δ 196.9, 194.6, 194.2, 190.8, 60.9, 34.2, 26.9 (3 C).
Anal. Calcd for C9H12O3: C, 64.27; H, 7.19; O, 28.54. Found:
C, 64.35; H, 7.24.
3-ter t-Bu tyl-4-d ieth yla m in ocyclobu ten e-1,2-d ion e, 6d .
3-tert-Butyl-4-isopropoxycyclobutene-1,2-dione (3.92 g, 19.970
mmol, 1.00 equiv) in 25 mL of THF was treated with diethyl-
amine (16.55 mL, 159.980 mmol, 8.01 equiv). After 4 d at room
temperature the solvent was evaporated, yielding a yellow oil
(21) Labadie, J . W.; Stille, J . K. J . Am. Chem. Soc. 1983, 105, 6129.
(22) J utzi, P.; Gilge, U. J . Organomet. Chem. 1983, 246, 163.
(23) Cohen, S.; Cohen, S. G. J . Am. Chem. Soc. 1966, 88, 1533.

Cyclobutenedione-Based Benzannulation Chemistry
J . Org. Chem., Vol. 63, No. 9, 1998 2841
20% ethyl acetate in hexane, Rf ) 0.30). IR (CH2Cl2, NaCl,
cm-1): 3055 (m), 2970 (s), 1769 (s), 1744 (s), 1621 (m). 1H
NMR (CDCl3, 300 MHz): δ 4.93 (t, J ) 2.4 Hz, 1 H), 4.36 (dt,
J ) 9.3, 3.0 Hz, 2 H), 2.68 (dt, J ) 9.3, 2.4 Hz, 2 H), 2.23 (s,
3 H), 2.05 (s, 3 H), 1.20 (s, 9 H).
[b]furan, 8a (91 mg, 0.344 mmol, 1.00 equiv), and anhydrous
Zn(OAc)2 (189 mg, 1.030 mmol, 2.99 equiv) were dissolved in
1 mL of HOAc and refluxed for 90 min. The liquid phase was
removed by pipet and condensed on a rotoary evaporator,
leaving a crude product that was purified by chromatography
(flash column, silica gel, 1 × 15 cm, 25% ethyl acetate in
hexane) to give 9a as a yellow oil (66 mg, 0.317 mmol, 92%).
TLC: silica gel, 25% ethyl acetate in hexane, Rf ) 0.13). IR
(CH2Cl2, NaCl, cm-1): 1762 (s), 1606 (s). 1H NMR (CDCl3, 300
MHz): δ 6.08 (s, 1 H), 5.30 (s, 1 H), 4.64 (t, J ) 8.7 Hz, 2 H),
3.12 (t, J ) 8.7 Hz, 2 H), 2.31 (s, 3 H), 2.07 (s, 3 H). 13C NMR
(CDCl3, 75.5 MHz): δ 169.9, 152.0, 150.0, 130.7, 126.7, 112.0,
109.3, 72.8, 27.2, 20.4, 15.7. Anal. Calcd for C11H12O4: C,
63.45; H, 5.81; O, 30.74. Found: C, 63.33; H, 5.83.
The experimental details and characterization data for
compounds 9b-i are found in the Supporting Information.
Syn th esis of Ca r ba zoloqu in on es 10 a n d 11 fr om N-
Met h ylin d ole. 3-ter t-Bu t yl-2-isop r op oxy-9-m et h yl-9H -
ca r ba zole-1,4-d ion e, 10. 1-Methyl-2-tri-n-butylstannylindole
(565 mg, 1.345 mmol, 1.20 equiv) in THF (6 mL) at -78 °C
was treated dropwise with n-BuLi in hexane (1.12 mL, 1.25
M, 1.400 mmol, 1.25 equiv). The reaction mixture was warmed
to 0 °C for 30 min and then added very slowly dropwise to
3-tert-butyl-4-isopropoxycyclobutene-1,2-dione (220 mg, 1.121
mmol, 1.00 equiv) in THF (6 mL) at -78 °C. After 30 min,
Ac2O (317 µL, 3.360 mmol, 3.00 equiv) was added and the
mixture was stirred at -78 °C for 20 min. The reaction
mixture was rapidly washed with H2O, extracted with Et2O
(50 mL × 2), dried (MgSO4), filtered, and concentrated to a
yellow solid that was heated neat in a flame-dried flask at 120
°C for 20 min. The crude thermolysis product was oxidized
with excess ceric ammonium nitrate in a mixture of Et2O (10
mL) and H2O (5 mL) at room temperature. The resulting red
product was purified by chromatography (flash column, silica
gel, 2 × 15 cm, 15% ethyl acetate in hexane) to yield 10 as a
red solid (211 mg, 0.648 mmol, 58%). TLC: silica gel, 15%
ethyl acetate in hexane, Rf ) 0.51. Mp: 126-128 °C (meth-
ylene chloride/hexane). IR (CH2Cl2, NaCl, cm-1): 1684 (s),
1662 (s), 1638 (m), 1614 (w). 1H NMR (CDCl3, 300 MHz): δ
8.29 (d, J ) 7.8 Hz, 1 H), 7.41-7.26 (m, 3 H), 4.87 (sept, J )
6.0 Hz, 1 H), 4.07 (s, 3 H), 1.46 (s, 9 H), 1.35 (d, J ) 6.0 Hz, 6
H). 13C NMR (CDCl3, 75.5 MHz): δ 185.4, 178.1, 154.9, 141.0,
140.0, 131.8, 126.7, 124.0, 123.7, 123.4, 118.3, 110.5, 75.6, 36.4,
32.0 (3 C), 31.5, 22.6 (2 C). Anal. Calcd for C20H23NO3: C,
73.82; H, 7.12; N, 4.30; O, 14.75. Found: C, 73.69; H, 7.22;
N, 4.05.
4-Acet oxy-2-ter t-b u t yl-4-[6′-(2′,3′-d ih yd r op yr a n yl)]-3-
m eth yl-2-cyclobu ten on e, 7c. 6-Tri-n-butylstannyl-2,3-di-
hydropyran (358 mg, 0.959 mmol, 1.20 equiv) in THF (5 mL)
at -78 °C was treated dropwise with n-BuLi in hexane (0.80
mL, 1.25 M, 1.000 mmol, 1.25 equiv). The reaction mixture
was warmed to 0 °C in a bath for 30 min and then added very
slowly dropwise to 3-tert-butyl-4-methylcyclobutene-1,2-dione
(122 mg, 0.802 mmol, 1.00 equiv) in THF (5 mL) at -78 °C.
Ac2O (226 µL, 2.395 mmol, 2.99 equiv) quench and workup as
for 7a gave a yellow oil that was purified by chromatography
(flash column, silica gel, 2 × 15 cm, 25% ethyl acetate in
hexane) to yield 7c as an orange oil (110 mg, 0.395 mmol, 49%).
TLC: silica gel, 25% ethyl acetate in hexane, Rf ) 0.36). IR
(CH2Cl2, NaCl, cm-1): 3054 (m), 2971 (s), 1767 (s), 1744 (m),
1668 (m), 1618 (w), 1588 (m). 1H NMR (CDCl3, 300 MHz): δ
4.87 (t, J ) 3.9 Hz, 1 H), 4.02 (m, 2 H), 2.22 (s, 3 H), 2.06 (s,
3 H), 2.05 (dt, J ) 6.3, 3.9 Hz, 2 H), 1.80 (tt, J ) 6.3, 5.4 Hz,
2 H), 1.21 (s, 9 H). 13C NMR (CDCl3, 75.5 MHz): δ 185.8,
169.6, 168.9, 162.8, 147.9, 98.5, 97.0, 66.5, 32.7, 27.8 (3 C),
22.0, 21.2, 19.9, 13.6. Anal. Calcd for C16H22O4: C, 69.04; H,
7.97; O, 22.99. Found: C, 68.90; H, 7.98.
(E)-4-Acetoxy-2-ter t-bu tyl-3-isop r op oxy-4-(â-styr en e)-
2-cyclobu ten on e, 7f. (E)-â-Tri-n-butylstannylstyrene (472
mg, 1.200 mmol, 1.20 equiv) in THF (5 mL) at -78 °C was
treated dropwise with n-BuLi in hexane (1.00 mL, 1.25 M,
1.250 mmol, 1.25 equiv). The reaction mixture was warmed
to 0 °C in a bath for 30 min and then added very slowly to
3-tert-butyl-4-isopropoxycyclobutene-1,2-dione (196 mg, 0.999
mmol, 1.00 equiv) in THF (5 mL) at -78 °C. Ac2O (283 µL,
2.999 mmol, 3.00 equiv) quench and workup as for 7a gave a
yellow oil that was purified by chromatography (flash column,
silica gel, 1 × 15 cm, 25% ethyl acetate in hexane) to yield 7f
as a yellow oil (76 mg, 0.222 mmol, 22%). TLC: silica gel,
25% ethyl acetate in hexane, Rf ) 0.31). 1H NMR (CDCl3, 300
MHz): δ 7.39-7.24 (m, 5 H), 6.74 (d, J ) 16.2 Hz, 1 H), 6.30
(d, J ) 16.2 Hz, 1 H), 4.66 (sept, J ) 6.0 Hz, 1 H), 2.13 (s, 3
H), 1.32 (d, J ) 6.0 Hz, 3 H), 1.31 (d, J ) 6.0 Hz, 3 H), 1.22 (s,
9 H).
Syn th esis of ter t-Bu tylp h en ols 8 w ith ou t Isola tion of
In ter m ed ia tes 7. Typ ica l P r oced u r e. 7-Acetoxy-5-ter t-
bu tyl-4-h yd r oxy-6-m eth yl-2,3-d ih yd r oben zo[b]fu r a n , 8a .
5-Tri-n-butylstannyl-2,3-dihydrofuran (517 mg, 1.440 mmol,
1.20 equiv) in THF (7 mL) at -78 °C was treated dropwise
with n-BuLi in hexane (1.20 mL, 1.25 M, 1.500 mmol, 1.25
equiv). The reaction mixture was warmed to 0 °C for 30 min
and then added very slowly dropwise to 3-tert-butyl-4-meth-
ylcyclobutene-1,2-dione (183 mg, 1.202 mmol, 1.00 equiv) in
THF (7 mL) at -78 °C. After 1 h, Ac2O (340 µL, 3.603 mmol,
3.00 equiv) was added, and the mixture was maintained at
-78 °C for 10 min and then quickly washed with H2O,
extracted with Et2O (50 mL × 2), dried (MgSO4), and concen-
trated to a yellow oil. This crude material was heated neat
under N2 in a flame-dried flask at 120 °C for 40 min and then
purified by chromatography (flash column, silica gel, 2 × 15
cm, 25% ethyl acetate in hexane) to yield 8a as a yellow oil
(195 mg, 0.738 mmol, 61%). TLC: silica gel, 25% ethyl acetate
in hexane, Rf ) 0.23). IR (CH2Cl2, NaCl, cm-1): 1760 (s), 1685
(m), 1636 (m), 1601 (m). 1H NMR (CDCl3, 300 MHz): δ 4.86
(s, 1 H), 4.61 (t, J ) 8.7 Hz, 2 H), 3.10 (t, J ) 8.7 Hz, 2 H),
2.31 (s, 3 H), 2.26 (s, 3 H), 1.53 (s, 9 H). 13C NMR (CDCl3,
75.5 MHz): δ 169.2, 149.2, 129.9, 127.6, 127.5, 126.6, 112.8,
72.3, 37.3, 32.7 (3 C), 27.6, 20.4, 15.7. Anal. Calcd for
2-Isop r op oxy-9-m et h yl-9H -ca r b a zole-1,4-d ion e,
11.
3-tert-Butyl-2-isopropoxy-9-methyl-9H-carbazole-1,4-dione, 10
(160 mg, 0.492 mmol, 1.00 equiv), and Zn powder (96.4 mg,
1.475 mmol, 3.00 equiv) were refluxed in 2 mL of HOAc for 40
min. Evaporation and chromatography (flash column, silica
gel, 1 × 15 cm, 25% ethyl acetate in hexane) provided 11 as a
red solid (108 mg, 0.401 mmol, 82%). TLC: silica gel, 25%
ethyl acetate in hexane, Rf ) 0.32. Mp: 140-142 °C (meth-
ylene chloride/hexane). IR (CH2Cl2, NaCl, cm-1): 1680 (s),
1635 (m). 1H NMR (CDCl3, 300 MHz): δ 8.24 (d, J ) 8.1 Hz,
1 H), 7.42-7.23 (m, 3 H), 5.72 (s, 1 H), 4.51 (sept, J ) 6.0 Hz,
1 H), 4.07 (s, 3 H), 1.44 (d, J ) 6.0 Hz, 6 H). 13C NMR (CDCl3,
75.5 MHz): δ 183.9, 175.7, 156.8, 139.9, 132.3, 126.9, 124.2,
123.3, 123.1, 116.9, 110.6, 108.3, 72.2, 31.6, 21.2 (2 C). Anal.
Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20; O, 17.82.
Found: C, 71.68; H, 5.63; N, 5.09.
Th er m olysis of Cyclobu ten on es 12 a n d 14. Syn th esis
of La cton e 13. 2-ter t-Bu tyl-4-h yd r oxy-3-m eth oxy-4-[5-(2-
m eth ylfu r yl)]-2-cyclobu ten on e, 12. A mixture of 2-meth-
ylfuran (119 mg, 1.449 mmol, 1.25 equiv) and TMEDA (168
mg, 1.446 mmol, 1.25 equiv) in Et2O (6 mL) at -78 °C was
treated dropwise with n-BuLi in hexane (1.04 mL, 1.40 M,
1.460 mmol, 1.25 equiv), then the reaction mixture was
warmed to room temperature. After 4 h it was added slowly
dropwise to 3-tert-butyl-4-methoxycyclobutene-1,2-dione (195
mg, 1.159 mmol, 1.00 equiv) in THF (5 mL) at -78 °C and
then 90 min later quenched with 10% aqueous NH4Cl at -78
°C for 30 min. After warming to room temperature, the
reaction mixture was washed with H2O, extracted with Et2O
C
15H20O4: C, 68.16; H, 7.63; O, 24.21. Found: C, 68.18; H,
7.66.
The experimental details and characterization data for
compounds 8b-i are found in the Supporting Information.
Syn th esis of 9 by Acid -Ca ta lyzed Rem ova l of ter t-
Bu tyl Su bstitu en ts fr om 8. Typ ica l P r oced u r e. 7-Ac-
etoxy-4-h yd r oxy-6-m eth yl-2,3-d ih yd r oben zo[b]fu r a n , 9a .
7-Acetoxy-5-tert-butyl-4-hydroxy-6-methyl-2,3-dihydrobenzo-

2842 J . Org. Chem., Vol. 63, No. 9, 1998
Liu and Liebeskind
(30 mL × 2), dried (MgSO4), filtered, and concentrated, and
the resulting yellow oil was chromatographed (flash column,
silica gel, 2 × 10 cm, 25% ethyl acetate in hexane) to yield 12
as a light yellow solid (105 mg, 0.420 mmol, 29%). TLC: silica
gel, 25% ethyl acetate in hexane, Rf ) 0.23. Mp: 69-71 °C
(Et2O/hexane). IR (CH2Cl2, NaCl, cm-1): 3564 (br, m), 1758
(s), 1618 (s). 1H NMR (CDCl3, 300 MHz): δ 6.30 (d, J ) 3.0
Hz, 1 H), 5.94 (d, J ) 3.0 Hz, 1 H), 4.92 (br s, 1 H), 3.99 (s, 3
H), 2.25 (s, 3 H), 1.20 (s, 9 H). 13C NMR (CDCl3, 75.5 MHz):
δ 188.5, 179.4, 152.3, 148.4, 137.6, 108.8, 107.0, 88.5, 59.4, 31.1,
28.0 (3 C), 13.5. Anal. Calcd for C14H18O4: C, 67.18; H, 7.25;
O, 25.57. Found: C, 67.02; H, 7.23.
2-t er t -Bu t yl-3-m e t h oxy-4-[5-(2-m e t h ylfu r yl)]-4-h y-
d r oxybu tyr ic Acid γ-La cton e, 13. 2-tert-Butyl-4-hydroxy-
3-methoxy-4-[5-(2-methylfuryl)]-2-cyclobutenone (57 mg, 0.228
mmol) was heated neat at 160 °C for 5.5 h. Chromatographic
purification (flash column, silica gel, 1 × 8 cm, 25% ethyl
acetate in hexane) yielded 13 as a yellow oil (43 mg, 0.172
mmol, 75%). TLC: silica gel, 25% ethyl acetate in hexane, Rf
) 0.37). IR (CH2Cl2, NaCl, cm-1): 1750 (s), 1653 (s). 1H NMR
(CDCl3, 300 MHz): δ 6.34 (d, J ) 3.3 Hz, 1 H), 5.99 (d, J )
3.3 Hz, 1 H), 5.72 (s, 1 H), 3.67 (s, 3 H), 2.29 (s, 3 H), 1.31 (s,
9 H). 13C NMR (CDCl3, 75.5 MHz): δ 171.8, 169.4, 154.0,
148.6, 145.2, 111.6, 107.0, 69.9, 57.3, 31.7, 28.8 (3 C), 13.6.
Anal. Calcd for C14H18O4: C, 67.18; H, 7.25; O, 25.57. Found:
C, 67.24; H, 7.30.
2-ter t-Bu tyl-3,4-d im eth oxy-4-[5-(2-m eth ylfu r yl)]-2-cy-
clobu ten on e, 14. A mixture of 2-methylfuran (133 mg, 1.620
mmol, 1.40 equiv) and TMEDA (189 mg, 1.626 mmol, 1.40
equiv) in dry Et2O (10 mL) at -78 °C was treated dropwise
with n-BuLi in hexane (1.25 mL, 1.30 M, 1.630 mmol, 1.41
equiv), then the reaction mixture was warmed to room
temperature. After 4 h it was added slowly dropwise to 3-tert-
butyl-4-methoxycyclobutene-1,2-dione (195 mg, 1.159 mmol,
1.00 equiv) in THF (6 mL) at -78 °C and then 90 min later
quenched with MeOTf (394 µL, 1.626 mmol, 3.00 equiv) at -78
°C for 30 min. After addition of H2O, the reaction mixture
was washed with H2O, extracted with Et2O (40 mL × 2), dried
(MgSO4), filtered, and concentrated to a yellow oil which was
purified by chromatography (flash column, silica gel, 2 × 8
cm, 15% ethyl acetate in hexane) to yield 14 as a yellow oil
(249 mg, 0.942 mmol, 81%). TLC: silica gel, 15% ethyl acetate
in hexane, Rf ) 0.31). IR (CH2Cl2, NaCl, cm-1): 1757 (s), 1618
(s), 1561 (w). 1H NMR (CDCl3, 300 MHz): δ 6.27 (d, J ) 3.0
Hz, 1 H), 5.92 (d, J ) 3.0 Hz, 1 H), 3.96 (s, 3 H), 3.43 (s, 3 H),
2.23 (s, 3 H), 1.18 (s, 9 H). 13C NMR (CDCl3, 75.5 MHz): δ
186.6, 178.4, 152.3, 147.3, 139.0, 109.1, 106.7, 94.1, 59.3, 52.7,
31.2, 27.9 (3 C), 13.4. Anal. Calcd for C15H20O4: C, 68.16; H,
7.63; O, 24.21. Found: C, 68.17; H, 7.59.
Electr ocycliza tion s in th e P r esen ce of n -Bu 3N/Ac2O.
2-t er t -Bu t yl-4-(2-fu r yl)-3-isop r op oxy-4-m e t h oxy-2-cy-
clobu ten on e, 15. 2-Tri-n-butylstannylfuran (429 mg, 1.201
mmol, 1.20 equiv) in THF (6 mL) at -78 °C was treated
dropwise with n-BuLi in hexane (1.05 mL, 1.14 M, 1.200 mmol,
1.20 equiv). The reaction mixture was warmed to 0 °C for 30
min and then added very slowly to 3-tert-butyl-4-isopropoxy-
cyclobutene-1,2-dione (196 mg, 0.999 mmol, 1.00 equiv) in THF
(6 mL) at -78 °C. After 20 min the reaction mixture was
quenched at -78 °C with MeOTf (340 µL, 3.004 mmol, 3.01
equiv). After addition of H2O, the reaction mixture was
washed with H2O, extracted with Et2O (30 mL × 2), dried
(MgSO4), filtered, and concentrated to a yellow oil which was
purified by chromatography (flash column, silica gel, 2 × 10
cm, 70% methylene chloride in hexane) to yield 15 as a
colorless oil (224 mg, 0.805 mmol, 81%). TLC: silica gel, 70%
methylene chloride in hexane, Rf ) 0.35). IR (CH2Cl2, NaCl,
cm-1): 1755 (s), 1612 (s). 1H NMR (CDCl3, 300 MHz): δ 7.37
(br s, 1 H), 6.42 (d, J ) 3.3 Hz, 1 H), 6.37 (dd, J ) 3.3, 1.8 Hz,
1 H), 4.72 (sept, J ) 6.0 Hz, 1 H), 3.47 (s, 3 H), 1.33 (d, J )
6.0 Hz, 3 H), 1.22 (s, 9 H), 1.02 (d, J ) 6.0 Hz, 3 H). 13C NMR
(CDCl3, 75.5 MHz): δ 186.3, 177.8, 149.6, 142.2, 139.6, 110.9,
108.2, 94.8, 77.7, 52.7, 31.4, 28.0 (3 C), 22.8, 22.5. Anal. Calcd
for C16H22O4: C, 69.04; H, 7.97; O, 22.99. Found: C, 68.96;
H, 7.94.
fu r a n , 16. 2-tert-Butyl-4-(2-furyl)-3-isopropoxy-4-methoxy-2-
cyclobutenone, 15 (115 mg, 0.413 mmol, 1.00 equiv), n-Bu3N
(295 µL, 1.238 mmol, 3.00 equiv), Ac2O (117 µL, 1.240 mmol,
3.00 equiv), and a catalytic amount of DMAP were dissolved
in 3 mL of xylene and refluxed for 5 d. The reaction mixture
was washed with 10% HCl, extracted with Et2O (30 mL × 2),
dried (MgSO4), and concentrated to a yellow oil. The crude
material was purified by chromatography (flash column, silica
gel, 2 × 10 cm, 70% methylene chloride in hexane) to yield 16
as a yellow oil (118 mg, 0.368 mmol, 89%). TLC: silica gel,
70% methylene chloride in hexane, Rf ) 0.60). IR (CH2Cl2,
NaCl, cm-1): 1758 (s), 1625 (w). 1H NMR (CDCl3, 300 MHz):
δ 7.48 (d, J ) 2.1 Hz, 1 H), 6.40 (d, J ) 2.1 Hz, 1 H), 5.05
(sept, J ) 6.3 Hz, 1 H), 4.04 (s, 3 H), 2.36 (s, 3 H), 1.50 (s, 9
H), 1.30 (d, J ) 6.3 Hz, 6 H). 13C NMR (CDCl3, 75.5 MHz): δ
169.2, 146.1, 145.5, 143.9, 136.6, 136.3, 130.1, 118.4, 104.5,
73.6, 60.3, 36.5, 32.2 (3 C), 22.1 (2 C), 21.3. HRMS (EI) Calcd
for C18H24O5: 320.1623. Found: 320.1623.
5-ter t-Bu tyl-4-h yd r oxy-6-isop r op oxy-7-m eth oxyben zo-
fu r a n , 17. 4-Acetoxy-5-tert-butyl-6-isopropoxy-7-methoxyben-
zofuran, 16 (51 mg, 0.159 mmol, 1.00 equiv), was dissolved in
5 mL of THF and cooled to 0 °C. LiAlH4 (6 mg, 0.158 mmol,
0.99 equiv) powder was introduced and the solution was
warmed to room temperature. After 5 min wet THF was
added slowly to quench the excess LiAlH4. The reaction
mixture was washed with H2O, extracted with Et2O (20 mL
× 2), dried (MgSO4), filtered, and concentrated to a yellow oil
which was purified by chromatography (flash column, silica
gel, 2 × 10 cm, 25% ethyl acetate in hexane) to yield 18 as a
yellow oil (44 mg, 0.158 mmol, 99%). TLC: silica gel, 25%
ethyl acetate in hexane, Rf ) 0.58). IR (CH2Cl2, NaCl, cm-1):
3631 (br, m), 3592 (br, s), 1629 (w). 1H NMR (CDCl3, 300
MHz): δ 7.46 (d, J ) 2.1 Hz, 1 H), 6.70 (d, J ) 2.1 Hz, 1 H),
5.06 (br s, 1 H), 4.88 (sept, J ) 6.3 Hz, 1 H), 3.98 (s, 3 H), 1.57
(s, 9 H), 1.28 (d, J ) 6.3 Hz, 6 H). 13C NMR (CDCl3, 75.5
MHz): δ 146.8, 145.8, 143.2, 142.4, 133.3, 123.4, 114.2, 103.0,
73.7, 60.5, 36.3, 32.3 (3 C), 22.1 (2 C). HRMS (EI) Calcd for
C
16H22O4: 278.1518. Found: 278.1518.
4-H yd r oxy-6-isop r op oxy-7-m et h oxyb en zofu r a n , 20.
5-tert-Butyl-4-hydroxy-6-isopropoxy-7-methoxybenzofuran, 18
(76 mg, 0.273 mmol, 1.00 equiv), and anhydrous Zn(OAc)2 (250
mg, 1.363 mmol, 4.99 equiv) were refluxed in 1.5 mL of HOAc
for 150 min. Evaporation and chromatography (flash column,
silica gel, 2 × 8 cm, 25% ethyl acetate in hexane) gave 20 as
a yellow oil (57 mg, 0.256 mmol, 94%). TLC: silica gel, 25%
ethyl acetate in hexane, Rf ) 0.32). IR (CH2Cl2, NaCl, cm-1):
3582 (s), 3380 (br, m), 1637 (m), 1505 (s). 1H NMR (CDCl3,
300 MHz): δ 7.46 (d, J ) 2.1 Hz, 1 H), 6.78 (d, J ) 2.1 Hz, 1
H), 6.35 (s, 1 H), 6.07 (s, 1 H), 4.40 (sept, J ) 6.0 Hz, 1 H),
4.00 (s, 3 H), 1.29 (d, J ) 6.0 Hz, 6 H). 13C NMR (CDCl3, 75.5
MHz): δ 148.7, 147.2, 144.0, 143.4, 130.8, 112.6, 103.6, 100.6,
73.5, 61.1, 22.2 (2 C). Anal. Calcd for C12H14O4: C, 64.85; H,
6.35; O, 28.80. Found: C, 64.64; H, 6.44.
Syn th esis of Aca m elin , 22. 4-Acetoxy-5-ter t-bu tyl-6,7-
d im et h oxy-2-m et h ylb en zofu r a n , 17. 2-tert-Butyl-3,4-di-
methoxy-4-[5-(2-methylfuryl)]-2-cyclobutenone, 14 (98 mg,
0.371 mmol, 1.00 equiv), n-Bu3N (177 µL, 0.743 mmol, 2.00
equiv), Ac2O (70 µL, 0.742 mmol, 2.00 equiv), and catalytic
amount of DMAP were dissolved in 3 mL of xylene and
refluxed for 18 h. The reaction mixture was washed with 10%
of HCl, extracted with Et2O (20 mL × 2), dried (MgSO4), and
concentrated to a yellow oil. This crude material was purified
by chromatography (flash column, silica gel, 2 × 8 cm, 15%
ethyl acetate in hexane) to yield 17 as a yellow oil (92 mg,
0.300 mmol, 81%). TLC: silica gel, 15% ethyl acetate in
hexane, Rf ) 0.31). IR (CH2Cl2, NaCl, cm-1): 1759 (s), 1607
(m). 1H NMR (CDCl3, 300 MHz): δ 6.03 (d, J ) 0.9 Hz, 1 H),
4.11 (s, 3 H), 3.90 (s, 3 H), 2.40 (d, J ) 0.9 Hz, 3 H), 2.33 (s, 3
H), 1.48 (s, 9 H). 13C NMR (CDCl3, 75.5 MHz): δ 169.4, 155.0,
148.8, 144.8, 137.0, 134.5, 129.3, 120.8, 100.3, 61.2, 60.3, 36.5,
32.0 (3 C), 21.2, 13.9. HRMS (EI) calcd for C17H22O5 306.1467,
found 306.1460.
5-ter t-Bu tyl-4-h yd r oxy-6,7-d im eth oxy-2-m eth ylben zo-
fu r a n , 19. 4-Acetoxy-5-tert-butyl-6,7-dimethoxy-2-methyl-
benzofuran, 17 (484 mg, 1.580 mmol, 1.00 equiv), was dissolved
4-Acetoxy-5-ter t-bu tyl-6-isop r op oxy-7-m eth oxyben zo-

Cyclobutenedione-Based Benzannulation Chemistry
J . Org. Chem., Vol. 63, No. 9, 1998 2843
in 30 mL of THF and cooled to 0 °C. LiAlH4 (60 mg, 1.581
mmol, 1.00 equiv) powder was introduced in and the solution
was warmed to room temperature. After 5 min wet THF was
added slowly to quench extra LiAlH4. The reaction mixture
was washed with H2O, extracted with Et2O (40 mL × 2), dried
(MgSO4), filtered, and concentrated to a yellow oil which was
purified by chromatography (flash column, silica gel, 3 × 10
cm, 15% ethyl acetate in hexane) to yield 19 as a light yellow
solid (397 mg, 1.502 mmol, 95%). TLC: silica gel, 15% ethyl
acetate in hexane, Rf ) 0.27. Mp: 120-122 °C (methylene
chloride/hexane). IR (CH2Cl2, NaCl, cm-1): 3637 (m), 3592
(s), 1603 (m). 1H NMR (CDCl3, 300 MHz): δ 6.29 (s, 1 H),
5.26 (s, 1 H), 4.04 (s, 3 H), 3.86 (s, 3 H), 2.40 (s, 3 H), 1.57 (s,
9 H). 13C NMR (CDCl3, 75.5 MHz): δ 153.9, 149.2, 145.1,
141.4, 133.2, 122.3, 116.5, 98.9, 61.5, 60.6, 36.5, 32.0 (3 C),
13.9. Anal. Calcd for C15H20O4: C, 68.16; H, 7.63; O, 24.21.
Found: C, 68.06; H, 7.63.
NSO4: C, 59.42; H, 6.54; N, 4.33; S, 9.91; O, 19.79. Found:
C, 59.65; H, 6.59; N, 4.09.
The experimental details and characterization data for
compounds 23b-g are found in the Supporting Information.
Syn th esis of 24 by Acid -Ca ta lyzed Rem ova l of ter t-
Bu t yl Su b st it u en t s fr om 23. 8-Acet oxy-7-isop r op oxy-
th ia zolo[3,2-a ]p yr id in -5-on e, 24a . 8-Acetoxy-6-tert-butyl-
7-isopropoxythiazolo[3,2-a]pyridin-5-one (58 mg, 0.179 mmol,
1.00 equiv) and anhydrous Zn(OAc)2 (165 mg, 0.899 mmol, 5.02
equiv) in 3 mL of HOAc were refluxed for 9 h. The liquid phase
was removed by a pipet and the solvent was evaporated.
Chromatographic purification (flash column, silica gel, 0.5 ×
10 cm, ethyl acetate) provided 24a as a brown oil (45 mg, 0.168
mmol, 94%). TLC: silica gel, ethyl acetate, Rf ) 0.38). IR
(CH2Cl2, NaCl, cm-1): 3124 (w), 3054 (m), 2984 (m), 1782 (s),
1662 (s), 1591 (s), 1497 (s), 1472 (m), 1464 (m), 1371 (m), 1331
(m), 1215 (m), 1185 (m), 1150 (m), 1108 (m). 1H NMR (C6D6,
300 MHz): δ 7.70 (d, J ) 4.5 Hz, 1 H), 5.85 (s, 1 H), 5.58 (d,
J ) 4.5 Hz, 1 H), 4.04 (sept, J ) 6.0 Hz, 1 H), 1.82 (s, 3 H),
0.94 (d, J ) 6.0 Hz, 6 H). 13C NMR (C6D6, 75.5 MHz): δ 167.4,
159.3, 158.5, 140.7, 124.5, 120.2, 108.6, 91.8, 71.7, 21.4 (2 C),
19.6. Anal. Calcd for C12H13NSO4: C, 53.92; H, 4.90; N, 5.24;
S, 12.00; O, 23.94. Found: C, 53.95; H, 4.99; N, 5.17.
8-Acetoxy-7-m eth ylth ia zolo[3,2-a ]p yr id in -5-on e, 24b.
8-Acetoxy-6-tert-butyl-7-methylthiazolo[3,2-a]pyridin-5-one (56
mg, 0.200 mmol, 1.00 equiv) and anhydrous Zn(OAc)2 (368 mg,
2.006 mmol, 10.03 equiv) in 3 mL of HOAc were refluxed for
10 h. Evaporation and chromatography (flash column, silica
gel, 1 × 10 cm, ethyl acetate) provided 24b as a silver gray
solid (41 mg, 0.184 mmol, 92%). TLC: silica gel, ethyl acetate,
Rf ) 0.21. Mp: 208-209 °C (methylene chloride/hexane). IR
(CH2Cl2, NaCl, cm-1): 3123 (w), 2983 (w), 1784 (s), 1671 (s),
1582 (s), 1494 (s), 1452 (m), 1373 (m), 1333 (w), 1204 (s), 1182
(s), 1127 (m). 1H NMR (CDCl3, 300 MHz): δ 8.08 (d, J ) 4.5
Hz, 1 H), 6.90 (d, J ) 4.5 Hz, 1 H), 6.23 (s, 1 H), 2.36 (s, 3 H),
2.15 (s, 3 H). 13C NMR (CDCl3, 75.5 MHz): δ 168.1, 158.0,
144.0, 140.0, 127.2, 125.0, 111.0, 109.7, 20.2, 16.7. Anal. Calcd
for C10H9NO3S: C, 53.80; H, 4.06; N, 6.27; O, 21.50; S, 14.36.
Found: C, 53.59; H, 4.11; N, 5.99.
8-Ace t oxy-7-d ie t h yla m in ot h ia zolo[3,2-a ]p yr id in -5-
on e, 24c. 8-Acetoxy-6-tert-butyl-7-diethylaminothiazolo[3,2-
a]pyridin-5-one (125 mg, 0.372 mmol, 1.00 equiv) and anhy-
drous Zn(OAc)2 (341 mg, 1.859 mmol, 5.00 equiv) in 2 mL of
HOAc were refluxed for 10 min. Evaporation and chroma-
tography (flash column, silica gel, 1 × 5 cm, ethyl acetate to
10% methanol in ethyl acetate) provided 24c as a brown oil
(104 mg, 0.371 mmol, 100%). TLC: silica gel, 25% methanol
in ethyl acetate, Rf ) 0.67). IR (CH2Cl2, NaCl, cm-1): 3125
(w), 3050 (w), 2982 (m), 1779 (s), 1650 (s), 1582 (s), 1552 (m),
1508 (m), 1465 (s), 1382 (w), 1369 (m), 1336 (w), 1188 (s), 1168
(m), 1126 (m), 1019 (w). 1H NMR (CDCl3, 300 MHz): δ 7.84
(d, J ) 4.5 Hz, 1 H), 6.64 (d, J ) 4.5 Hz, 1 H), 5.64 (s, 1 H),
3.27 (q, J ) 7.2 Hz, 4 H), 2.26 (s, 3 H), 1.11 (t, J ) 7.2 Hz, 6
H). 13C NMR (CDCl3, 75.5 MHz): δ 167.4, 157.9, 151.4, 141.9,
124.3, 119.9, 108.5, 93.2, 45.2 (2 C), 20.4, 12.6 (2 C). Anal.
Calcd for C13H16N2SO3: C, 55.70; H, 5.75; N, 9.99; S, 11.44;
O, 17.12. Found: C, 55.85; H, 5.87; N, 9.88.
4-Hyd r oxy-6,7-d im eth oxy-2-m eth ylben zofu r a n , 21. 5-
tert-Butyl-4-hydroxy-6,7-dimethoxy-2-methylbenzofuran, 19
(358 mg, 1.354 mmol, 1.00 equiv), and anhydrous Zn(OAc)2
(1.24 g, 6.770 mmol, 5.00 equiv) were refluxed in 10 mL of
HOAc for 10 h. Evaporation and chromatography (flash
column, silica gel, 3 × 10 cm, 25% ethyl acetate in hexane)
gave 21 as a white solid (247 mg, 1.186 mmol, 88%). TLC:
silica gel, 25% ethyl acetate in hexane, Rf ) 0.25. Mp: 150-
151 °C (Et2O/hexane). IR (CH2Cl2, NaCl, cm-1): 3583 (br,
s),1612 (m), 1518 (s). 1H NMR (CD3OD, 300 MHz): δ 6.36 (d,
J ) 0.9 Hz, 1 H), 6.30 (s, 1 H), 4.88 (br s, 1 H), 3.86 (s, 3 H),
3.77 (s, 3 H), 2.34 (d, J ) 0.9 Hz, 3 H). 13C NMR (CD3OD,
75.5 MHz): δ 154.6, 150.3, 149.7, 146.3, 129.3, 114.7, 100.9,
97.0, 61.7, 57.8, 13.9. Anal. Calcd for C11H12O4: C, 63.45; H,
5.81; O, 30.74. Found: C, 63.34; H, 5.85.
Aca m elin , 6-Meth oxy-2-m eth ylben zo[b]fu r a n d ion e, 22.
4-Hydroxy-6,7-dimethoxy-2-methylbenzofuran, 21 (70 mg, 0.336
mmol, 1.00 equiv), in 10 mL of CH3CN was treated with 10
mL of 0.067 N aqueous ammonium cerium(IV) nitrate solution
at room temperature. After 10 min, the reaction mixture was
extracted with Et2O (30 mL) and CHCl3 (30 mL × 2), and the
combined organic layers were dried (MgSO4), filtered, and
concentrated to an orange solid. Recrystallization from chlo-
roform-acetone gave 22 as an orange-red solid (63 mg, 0.328
mmol, 98%). TLC: silica gel, 25% ethyl acetate in hexane, Rf
) 0.29. Mp: 250-252 °C (CHCl3-acetone; lit.19 mp 253-255
°C). IR (CH2Cl2, NaCl, cm-1): 1686 (s), 1659 (s), 1607 (s), 1578
(s), 1539 (s). 1H NMR (CDCl3, 300 MHz): δ 6.42 (d, J ) 0.9
Hz, 1 H), 5.76 (s, 1 H), 3.83 (s, 3 H), 2.44 (d, J ) 0.9 Hz, 3 H).
13C NMR (CDCl3, 75.5 MHz): δ 182.2, 168.7, 161.1, 159.6,
148.6, 131.1, 106.6, 104.9, 56.9, 14.1. Anal. Calcd for
C10H8O4: C, 62.50; H, 4.20; O, 33.30. Found: C, 62.36; H, 4.28.
Spectral data matched those reported in the literature.19
Syn th esis of Rin g-fu sed P yr id on es 23. Typ ica l P r o-
ced u r e. 8-Acetoxy-6-ter t-bu tyl-7-isop r op oxyth ia zolo[3,2-
a ]p yr id in -5-on e, 23a . 2-Tri-n-butylstannylthiazole (449 mg,
1.200 mmol, 1.20 equiv) in THF (5 mL) at -78 °C was treated
dropwise with n-BuLi in hexane (1.00 mL, 1.25 M, 1.250 mmol,
1.25 equiv). After warming to 0 °C for 30 min, the solution
was added very slowly dropwise to 3-tert-butyl-4-isopropoxy-
cyclobutene-1,2-dione (196 mg, 0.999 mmol, 1.00 equiv) in dry
THF (5 mL) at -78 °C. After 40 min, the reaction was
quenched with Ac2O (283 µL, 2.999 mmol, 3.00 equiv) and held
at -78 °C for 30 min. After warming to room temperature,
the reaction mixture was rapidly washed with H2O, extracted
with Et2O (50 mL × 2), dried (MgSO4), filtered, and concen-
trated to a brown oil that was heated neat in a flame-dried
flask (120 °C, 40 min) and then purified by chromatography
(flash column, silica gel, 2 × 15 cm, 25% ethyl acetate in
hexane) to yield 23a as a yellow oil (204 mg, 0.631 mmol, 63%).
TLC: silica gel, 25% ethyl acetate in hexane, Rf ) 0.22). IR
(CH2Cl2, NaCl, cm-1): 1780 (s), 1645 (s), 1585 (s), 1477 (s). 1H
NMR (CDCl3, 300 MHz): δ 8.01 (d, J ) 4.5 Hz, 1 H), 6.76 (d,
J ) 4.5 Hz, 1 H), 4.60 (sept, J ) 6.3 Hz, 1 H), 2.31 (s, 3 H),
1.48 (s, 9 H), 1.29 (d, J ) 6.3 Hz, 6 H). 13C NMR (CDCl3, 75.5
MHz): δ 167.3, 158.5, 156.7, 137.3, 124.8, 123.1, 121.1, 109.7,
4-Acetoxy-3-isop r op oxy-1-oxop yr id o[2,1-b]ben zoth ia -
zole, 24d . 4-Acetoxy-2-tert-butyl-3-isopropoxy-1-oxopyrido-
[2,1-b]benzothiazole (90 mg, 0.241 mmol, 1.00 equiv) and
anhydrous Zn(OAc)2 (221 mg, 1.205 mmol, 5.00 equiv) in 3 mL
of HOAc were refluxed for 21 h. Evaporation and chromatog-
raphy (flash column, silica gel, 1 × 15 cm, 25% ethyl acetate
in hexane) provided 24d as a light yellow solid (65 mg, 0.205
mmol, 85%). TLC: silica gel, 25% ethyl acetate in hexane, Rf
) 0.17. Mp: 133-134 °C (methylene chloride/hexane). IR
(CH2Cl2, NaCl, cm-1): 3054 (m), 2985 (m), 1779 (s), 1667 (s),
1604 (s), 1576 (m), 1521 (s), 1473 (w), 1465 (w), 1454 (s), 1205
(m), 1179 (m), 1108 (m), 1084 (w), 1030 (m). 1H NMR (CDCl3,
300 MHz): δ 9.13 (d, J ) 8.4 Hz, 1 H), 7.53 (d, J ) 7.8 Hz, 1
H), 7.43 (app t, J ) 7.8 Hz, 1 H), 7.35 (app t, J ) 7.5 Hz, 1 H),
5.90 (s, 1 H), 4.63 (sept, J ) 6.0 Hz, 1 H), 2.32 (s, 3 H), 1.36
(d, J ) 6.0 Hz, 6 H). 13C NMR (CDCl3, 75.5 MHz): δ 167.8,
162.1, 158.4, 139.2, 138.8, 126.5, 125.9, 125.4, 121.4, 120.5,
76.2, 36.2, 30.4 (3 C), 22.2 (2 C), 20.3. Anal. Calcd for C16H21
-
119.8, 93.9, 72.1, 21.5 (2 C), 20.0. Anal. Calcd for C16H15-

2844 J . Org. Chem., Vol. 63, No. 9, 1998
Liu and Liebeskind
NSO4: C, 60.55; H, 4.76; N, 4.41; S, 10.10; O, 20.17. Found:
C, 60.62; H, 4.79; N, 4.32.
8-Acetoxy-1,7-d im eth ylim id a zo[1,2-a ]p yr id in -5-on e, 24
g. 8-Acetoxy-6-tert-butyl-1,7-dimethylimidazo[1,2-a]pyridin-
5-one (100 mg, 0.362 mmol, 1.00 equiv) and anhydrous Zn-
(OAc)2 (664 mg, 3.619 mmol, 10.00 equiv) in 2 mL of HOAc
were refluxed for 3 h. Evaporation and chromatography (flash
column, silica gel, 1 × 6 cm, 25% methanol in ethyl acetate)
provided 24g as a yellow oil (74 mg, 0.336 mmol, 93%). TLC:
silica gel, 25% methanol in ethyl acetate, Rf ) 0.42). IR (CH2-
Cl2, NaCl, cm-1): 3055 (m), 2983 (w), 1771 (s), 1669 (s), 1580
(s), 1560 (s), 1524 (s), 1430 (m), 1372 (m), 1335 (w), 1296 (w),
1274 (s), 1201 (s), 1133 (s). 1H NMR (CDCl3, 300 MHz): δ
7.70 (d, J ) 2.1 Hz, 1 H), 6.84 (d, J ) 2.1 Hz, 1 H), 5.83 (s, 1
H), 3.76 (s, 3 H), 2.36 (s, 3 H), 2.09 (s, 3 H). 13C NMR (CDCl3,
75.5 MHz): δ 170.0, 154.5, 141.8, 134.7, 122.0, 115.7, 108.9,
99.7, 34.6, 20.3, 16.4. Anal. Calcd for C11H12N2O3: C, 59.99;
H, 5.49; N, 12.72; O, 21.79. Found: C, 59.64; H, 5.89; N, 13.00.
4-Acetoxy-3-m eth yl-1-oxop yr id o[2,1-b]ben zoth ia zole,
24e. 4-Acetoxy-2-tert-butyl-3-methyl-1-oxopyrido[2,1-b]benzo-
thiazole (60 mg, 0.182 mmol, 1.00 equiv) and anhydrous Zn-
(OAc)2 (334 mg, 1.821 mmol, 10.01 equiv) in 3 mL of HOAc
were refluxed for 12 h. Evaporation and chromatography
(flash column, silica gel, 1 × 10 cm, ethyl acetate) provided
24e as a yellow solid (47 mg, 0.172 mmol, 95%). TLC: silica
gel, ethyl acetate, Rf ) 0.50. Mp: 190-191 °C (methylene
chloride/hexane). IR (CH2Cl2, NaCl, cm-1): 3052 (w), 2987 (w),
1774 (s), 1673 (s), 1598 (s), 1576 (m), 1509 (s), 1449 (m), 1372
(w), 1265 (s), 1198 (s), 1154 (m). 1H NMR (CDCl3, 300 MHz):
δ 9.24 (dd, J ) 8.4, 0.9 Hz, 1 H), 7.59 (dd, J ) 7.5, 0.9 Hz, 1
H), 7.47-7.36 (m, 2 H), 6.33 (s, 1 H), 2.37 (s, 3 H), 2.15 (s, 3
H). 13C NMR (CDCl3, 75.5 MHz): δ 168.2, 161.0, 144.1, 139.0,
138.4, 127.3, 126.5, 126.4, 125.6, 121.4, 120.3, 113.3, 20.2, 16.5.
Anal. Calcd for C14H11NO3S: C, 61.53; H, 4.06; N, 5.12; O,
17.56; S, 11.73. Found: C, 61.25; H, 4.24; N, 4.93.
8-Acetoxy-7-isopr opoxy-1-m eth ylim idazo[1,2-a ]pyr idin -
5-on e, 24f. 8-Acetoxy-6-tert-butyl-7-isopropoxy-1-methylimi-
dazo[1,2-a]pyridin-5-one (61 mg, 0.190 mmol, 1.00 equiv) and
anhydrous Zn(OAc)2 (349 mg, 1.902 mmol, 10.01 equiv) in 2
mL of HOAc were refluxed for 4 h. Evaporation and chroma-
tography (flash column, silica gel, 1 × 10 cm, 20% MeOH in
ethyl acetate) provided 24f as a brown oil (50 mg, 0.189 mmol,
99%). TLC: silica gel, 20% MeOH in ethyl acetate, Rf ) 0.25).
IR (CH2Cl2, NaCl, cm-1): 3053 (m), 2983 (m), 1774 (s), 1673
(s), 1593 (s), 1567 (s), 1530 (s), 1467 (m), 1443 (m), 1372 (m),
1332 (w), 1306 (w), 1231 (s), 1210 (m), 1194 (m), 1157 (s), 1110
(m), 1055 (m). 1H NMR (CDCl3, 300 MHz): δ 7.53 (d, J ) 2.1
Hz, 1 H), 6.71 (d, J ) 2.1 Hz, 1 H), 5.62 (s, 1 H), 4.55 (sept, J
) 6.0 Hz, 1 H), 3.67 (s, 3 H), 2.28 (s, 3 H), 1.28 (d, J ) 6.0 Hz,
6 H). 13C NMR (CDCl3, 75.5 MHz): δ 169.7, 158.2, 155.5,
135.5, 121.3, 108.2, 107.8, 85.0, 71.4, 34.4, 21.8 (2 C), 20.1.
Anal. Calcd for C13H16N2O4: C, 59.08; H, 6.10; N, 10.60; O,
24.22. Found: C, 58.99; H, 6.06; N, 10.49.
Ack n ow led gm en t . This investigation was sup-
ported by Grant No. CA40157, awarded by the National
Cancer Institute, DHHS. We acknowledge the use of a
VG 70-S mass spectrometer purchased through funding
from the National Institutes of Health, S10-RR-02478.
Su p p or tin g In for m a tion Ava ila ble: A complete descrip-
tion of the synthesis and characterization of compounds 8b-
i, 9b-i, and 23b-g and copies of the 1H NMR data for
N-methyl-2-tri-n-butylstannylindole and the unstable com-
pounds 7a and 7f, for which elemental analyses were not
1
obtained, and H and 13C NMR data for 8i, 16, 17, and 18, for
which HRMS and not elemental analyses were obtained (22
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.
J O971565P