Ring expansion of 4-alkynylcyclobutenones. Synthesis of piperidinoquinones, highly substituted dihydrophenanthridines, benzophenanthridines, and the naturally occurring pyrrolophenanthridine, assoanine

Article abstract of DOI:10.1021/jo9613803

New synthetic routes to a variety of N-heterocyclic quinones and hydroquinones are described. These include thermolyses of 4-hydroxy-4-[4-N-(benzenesulfonyl)-4-aza-1,6-dialkynyl]cyclobutenones to piperidinoquinones and 4-hydroxy-4-[3-(N-phenylamino)-1-propynyl]cyclobutenones to dihydrophenanthridinediols. Included in the array of products available by this method are benzophenanthridines, indolophenanthridines, isoindoloindoles, and pyrrolophenanthridines. The methodology was employed in a five-step synthesis of the alkaloid assoanine starting with dimethyl squarate and indoline. The key step in all of these transformations is the ring expansion of appropriately substituted 4-hydroxy-4-alkynylcyclobutenones. These are envisaged to undergo electrocyclic ring opening to the corresponding enynylketenes which ring close to diradical intermediates that then lead to products via either radical additions to proximal alkyne moieties or undergo homolytic aromatic substitution to appropriately placed aryl groups. The synthetic scope and mechanism of the ring expansion reactions are discussed.

Full text of DOI:10.1021/jo9613803

9168
J . Org. Chem. 1996, 61, 9168-9177
Rin g Exp a n sion of 4-Alk yn ylcyclobu ten on es. Syn th esis of
P ip er id in oqu in on es, High ly Su bstitu ted Dih yd r op h en a n th r id in es,
Ben zop h en a n th r id in es, a n d th e Na tu r a lly Occu r r in g
P yr r olop h en a n th r id in e, Assoa n in e
Yifeng Xiong and Harold W. Moore*
Department of Chemistry, University of California-Irvine, Irvine, California 92717
Received J uly 22, 1996X
New synthetic routes to a variety of N-heterocyclic quinones and hydroquinones are described.
These include thermolyses of 4-hydroxy-4-[4-N-(benzenesulfonyl)-4-aza-1,6-dialkynyl]cyclobutenones
to piperidinoquinones and 4-hydroxy-4-[3-(N-phenylamino)-1-propynyl]cyclobutenones to dihydro-
phenanthridinediols. Included in the array of products available by this method are benzophenan-
thridines, indolophenanthridines, isoindoloindoles, and pyrrolophenanthridines. The methodology
was employed in a five-step synthesis of the alkaloid assoanine starting with dimethyl squarate
and indoline. The key step in all of these transformations is the ring expansion of appropriately
substituted 4-hydroxy-4-alkynylcyclobutenones. These are envisaged to undergo electrocyclic ring
opening to the corresponding enynylketenes which ring close to diradical intermediates that then
lead to products via either radical additions to proximal alkyne moieties or undergo homolytic
aromatic substitution to appropriately placed aryl groups. The synthetic scope and mechanism of
the ring expansion reactions are discussed.
In tr od u ction a n d Over view
number of applications of this rearrangement have been
reported, its scope and limitations are still incompletely
defined.3-6 Selected previously reported examples that
directly relate to the syntheses described herein are given
in Scheme 1. Specifically, thermolysis of 4-(1,5-dialky-
nyl)-4-hydroxycyclobutenones 1 was shown to give car-
bocyclic annulated quinones 5.4 This is considered to
involve initial electrocyclic ring opening of 1 to enyn-
ylketene 2 followed by subsequent ring closure to diradi-
cal 3. The more reactive ring-based radical center in 3
then adds to the proximal alkyne group to give 4 which
undergoes intramolecular H-atom abstraction from the
neighboring hydroxyl group to provide the annulated
quinone 5. In an analogous reaction, aryl radical addi-
tions to alkene groups were realized as evidenced by the
formation of pyranoquinones from the corresponding
4-enynylcyclobutenones, e.g., 6 f 7.3 Finally, it is noted
that arylations involving intermediates generally repre-
sented by diradical 8 have also been reported.5 Ad-
ditional examples of the above reaction types as they
apply to the syntheses of selected N-heterocyclic systems
are provided below.
Reported here is a highly convergent route to a variety
of N-heterocyclic ring systems, including piperidino-
quinones, benzophenanthridines, indolophenanthridines,
isoindoloindoles, and pyrrolophenanthridines. The method
entails the thermal rearrangements of selected 4-hy-
droxy-4-[4-N-(benzenesulfonyl)-4-aza-1,6-alkadiynyl]cy-
clobutenones and 4-hydroxy-4-(4-N-aryl-4-aza-1,6-alkadi-
ynyl)cyclobutenones to piperidinoquinones 17 (Scheme
3) and highly substituted phenanthridines 22 (Scheme
4), respectively. Although rare, the piperidinoquinone
skeleton is found as a subunit in naturally occurring
N-heterocyclic quinones such as the cyanocycline and
saframycin families.1,2 In contrast, phenanthridines are
quite common, but available methods are limited for
regiospecific syntheses of highly substituted derivatives.
This is particularly true for heterocyclic quinones in this
series. That drawback is circumvented by the method
outlined here which allows construction of highly con-
densed polycyclic analogs from readily available starting
materials. Particularly noteworthy is the utility of these
ring expansions as key steps in the synthesis the 39
(Scheme 9) and 43 (Scheme 10). The former is an
example of the ring system found in the benzophenan-
thridine alkaloid family. The latter is an intermediate
in the synthesis of assoanine (40), a naturally occurring
pyrrolophenanthridine.
Syn th esis of P ip er id in oqu in on es
Synthesis of piperidinoquinones, as described here,
depends upon the availability of the previously unknown
4-hydroxy-4-[4-N-(benzenesulfonyl)-4-aza-1,6-alkadiynyl]-
cyclobutenolnes 14 (Scheme 3). These are now available
as outlined here and araise from 4-aza-1,6-diynes which
were prepared by two methods (Scheme 2). The first
The synthetic methodology presented here stems from
the thermal rearrangement of 4-alkynyl-4-hydroxycy-
clobutenones, a reaction that is envisaged to lead to
products via a mechanism involving the formation of
enynylketenes and diradical intermediates. Although a
(3) Xiong, Y., Moore, H. W. J . Org. Chem. 1995, 60, 6460.
(4) Xia, H.; Moore, H. W. J . Org. Chem. 1992, 57, 3765.
(5) For a recent review on the synthetic utility of cyclobutenones
see: Moore, H. W.; Yerxa, B. R. Adv. Strain Org. Chem. 1995, 4, 81-
162.
(6) For an excellent review on the generation of diradicals from
enediynes, enynylallenes, and enynylketenes see: (a) Wang, K. W.
Chem. Rev. 1996, 96, 207. (b) Grissom, J . W.; Gunawardena, G. U.;
Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453.
(7) Padwa, A.; Nimmesgern, H.; Wong, G. S. K. J . Org. Chem. 1985,
50, 5620.
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) Thomson, R. H. Naturally Occurring Quinones III--Recent Ad-
vances; Chapman Hall: London, New York, 1987; pp 633-666.
(2) (a) Park, A.; Schmitz, F. J . Tetrahedron Lett. 1993, 34, 3983. (b)
Davidson, B. S. Tetrahedron Lett. 1992, 33, 3721. (c) McKee, T. C.;
Ireland, C. M. J . Nat. Prod. 1987, 50, 754. (d) McKillop, A.; Brown, S.
P. Syn. Commun. 1987, 17(6), 657. (e) Kobayashi, M.; Rao, S. R.;
Chavakula, R.; Sarma, N. S. J . Chem. Res. (S) 1994, 282.
S0022-3263(96)01380-1 CCC: $12.00 © 1996 American Chemical Society

Ring Expansion of 4-Alkynylcyclobutenones
J . Org. Chem., Vol. 61, No. 26, 1996 9169
Sch em e 1
Sch em e 3
10a -c. In order to eliminate undesired disubstitution
pathways, a second method was developed in which the
sulfonamide 118 was subjected to Mitsunobu conditions9
using substituted propargyl alcohols to afford the diynes
12a ,b in good to excellent yields.
Addition of the lithium salt of the diynes to the
cyclobutenediones 13 in THF at -78 °C provided the
cyclobutenones 14 (Scheme 3). These were not purified,
but thermolyzed directly (toluene, 110 °C) to give the
desired piperidinoquinones 17 in 40-60% overall yield.
In analogy to the discussion presented above, these
transformations are envisaged to occur via the interme-
diate diradicals 15 and 16.
Sch em e 2
The structures of the piperidinoquinones 17 were
assigned on the basis of their spectral data (1H NMR and
13C NMR) as well as a single crystal X-ray analysis of
3,4-dimethoxy-2,5-dioxo-7-benzylidene-9-N-(benzene-
sulfonyl)bicyclo[4.4.0]deca-1,3-diene (17e).25 The ob-
served E-stereochemistry of the exocyclic double bond is
in agreement with the proposed configuration of the
ultimate diradical intermediate 16. Since the barrier of
inversion for vinyl radicals is low (approximately 2 kcal/
mol),10 this intermediate may actually be in configura-
tional equilibrium, but intramolecular H-atom abstrac-
tion provides a direct productive pathway to 17.
involves treatment of N,N-dipropynylbenzenesulfona-
mide 97 with n-butyllithium followed by addition of
selected electrophiles (trimethylsilyl chloride, acetone,
and benzaldehyde) to provide the functionalized diynes
(9) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Comins, D. L.; Gao, J .
Tetrahedron Lett. 1994, 35, 2819.
(8) This compound was obtained in 98% yield from benzenesulfonyl
chloride and propargylamine. For an alternate method see: Fr
1,438,772 (C1. C 07c), May 13, 1966.
(10) Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry, Part
A, 3rd ed.; Plenum Press: New York, 1990; Part A, Chapt. 12, pp 651-
719.

9170 J . Org. Chem., Vol. 61, No. 26, 1996
Xiong and Moore
Sch em e 4
Sch em e 5
to form a new diradical 23. This leads to aminal 24 upon
radical-radical coupling. Standard workup then results
in hydrolysis to give hydroquinone 25 (Scheme 5).
The structures of dihydrophenanthridinediols 22a -f
were assigned on the basis of their spectral data. Par-
1
ticularly revealing are their H NMR spectra which show
a characteristic low field aromatic proton (Ha) absorption
due to the deshielding effect of the proximal aromatic ring
as well as the hydroxy group.13 As an illustration, this
absorption for 22f appears at δ 8.37 ppm (dd, J ) 1.4,
7.7 Hz, 1H). The remaining three aromatic protons
absorb at 6.76 ppm (d, J ) 8.2 Hz), 6.84 ppm (t, J ) 7.5
Hz), and 7.17 ppm (dt, J ) 1.4, 8.2 Hz). The two hydroxy
groups were observed as singlets at 5.45 ppm and 5.97
ppm. On the basis of these data analogous structure
assignments are assumed for the other members of the
family.
In spite of the spectral data which are in agreement
with the assigned structure, the colors of these com-
pounds are unusual. Most of the hydroquinones 22a -f
are deep purple in color. An exception is 22e which is
light yellow. It is assumed that 22a -f, all having a more
basic nitrogen than 22e, exist either as highly colored
zwitterions or are in equilibrium with such species, i.e.,
zwitterions formed by protonation of the amine nitrogen
by one of the phenolic hydroxyl groups. Analogies for
this are not readily apparent since, to our knowledge,
phenanthridine diols such as 22 are not known.
Syn th esis of P h en a n th r id in ed iols
As an extension of the synthetic scope, cyclobutendi-
ones 18a ,d were treated with lithium salts of N-arylpro-
pargylamines 1911 to give 4-(3-N-phenyl-1-propynyl)-4-
hydroxycyclobutenones 20a -f in excellent yields (82-
94%) (Scheme 4). Thermolyses of these in refluxing
toluene or p-xylene resulted in the dihydrophenan-
thridinediols 22a -f (42-70%). In two cases, the crude
cyclobutenones 20b and 20d were thermolyzed without
purification to give dihydrophenanthridinediols 22b and
22d in 42% and 48% overall yield from the cyclobutene-
diones 18b and 18d , respectively.
The formation of the dihydrophenanthridinediols 22
is envisaged to involve initial electrocyclic ring opening
to the corresponding ketene followed by ring closure to
the diradical 21. The more reactive ring-based radical
then undergoes homolytic aromatic substitution to give
22.12
In three cases (20a ,c,f), the hydroquinone 25 was also
isolated as a minor product (approximately 10% yield).
Its formation is also envisaged to arise from the corre-
sponding diradical intermediate. That is, 20c gives 21c,
which, in addition to the arylation pathway, suffers
intramolecular H-atom abstraction from the N-allyl group
In attempts to obtain supportive chemical evidence for
the structure of hydroquinones 22, selected examples
were subjected to oxidizing conditions in anticipation of
obtaining the corresponding quinones. Indeed, treatment
of 22e with silver oxide (Ag2O) provided a nearly quan-
titative yield of the corresponding quinone 26 (Scheme
6); the hydroquinone 22e was efficiently regenerated
upon treatment of 26 with sodium dithionite.
In contrast to the above, unanticipated results were
obtained when other members of the 22 series were
subjected to the same oxidizing conditions. For example,
N-allylphenanthridinediol 22c resulted in oxidative
dealkylation to give quinone 27 in 60% isolated yield.
Although the dealkylation was unexpected, the overall
transformation is consistent with the assigned structure
of 22c. Under similar reaction conditions the N-alkyl
(11) (a) Onaka, M.; Umezono, A.; Kawai, M.; Izumi, Y. J . Chem. Soc.,
Chem. Commun. 1985, 1202. (b) Onaka, M.; Ishikawa, K.; Izumi, Y.
Chem. lett. 1982, 1783. (c) Nasimov, E.; Kurbanov, F. K.; Murtazaeva,
G. A.; Kuchkarov, A. B. Uzb. Khim. Zh. 1982, 2, 5. (d) Trost, B. M.;
Chen, S. J . Am. Chem. Soc. 1986, 108, 6053.
(12) For a review on homolytic aromatic substitutions, see: Waters,
W. A. Free Radical Reactions; Butterworth: London, 1987; Chapter
3, pp 25-45.
(13) Krane, B. D.; Fagbule, M. O.; Shamma, M. J . Nat. Prod. 1984,
47, 1.

Ring Expansion of 4-Alkynylcyclobutenones
J . Org. Chem., Vol. 61, No. 26, 1996 9171
Sch em e 6
Sch em e 7
Sch em e 8
examples, 22a and 22f, gave complex reaction mixtures
from which 27 (5-14%) and 2,3-dimethoxy-5-methyl-1,4-
benzoquinone (28) (10-16%) were the only isolable
products. The formation of 28 is particularly intriguing
and remains a mechanistic puzzle.
The scope of the phenanthridine synthesis was ex-
panded to include the preparation of selected examples
having highly condensed ring systems, e.g., indolophenan-
thridines, isoindoloindoles, and benzophenanthridines.
Thus, treatment of dimethyl squarate with the N-
propargylcarbazole lithium reagent 2914 provided cy-
clobutenone 30 in 85% yield (Scheme 7). Thermolysis of
this in refluxing chlorobenzene for 1.75 h gave the
pentacyclic indolophenanthridine 31 as a light blue
crystalline solid in good yield (83%).
Pyrrolophenanthridinediol 35 is envisaged to arise in
a manner similar to that of the other phenanthridinediols,
i.e. intramolecular homolytic aromatic substitution at the
intermediate diradical stage. Isoindoloindole 34 is formed
analogously except radical attack takes place on the
pyrrole ring. The hydroquinone 36 presumably arises
from H-atom abstractions from unspecified sources by the
diradical intermediate.
The 1H NMR spectrum of 31 provides characteristic
structure information; the characteristic low field aro-
matic absorption appears at d, 8.50 ppm (dd, J ) 0.7,
7.7 Hz); the two hydroxy groups absorb as singlets at 5.54
and 6.15 ppm, and the absorption for the other six
aromatic protons appear at 7.19-8.10 ppm.
Synthesis of an isoindoloindole as well as a pyrrol-
ophenanthridinediol stems from treatment of dimethyl
squarate with the lithium salt of N-propargylindole (32)14
to provided cyclobutenone 33 in 83% yield. Subsequent
thermolysis (2 h, refluxing chlorobenzene) of this gave
the tetracyclic isoindoloindole 34 (57%) and pyrrol-
ophenanthridinediol 35 (12%) along with a nonannulated
hydroquinone 36 (8%) (Scheme 8).
1
The H NMR spectral data for 34-36 are consistent
with their assigned structures. Both 34 and 35 show
absorption for five aromatic protons. The proton Ha in
34 appears at 6.63 ppm as a singlet, while the low field
absorption for proton Hb in 35 appears at 8.20 ppm as a
doublet (J ) 7.7 Hz). The spectrum of compound 36
shows absorption for seven aromatic protons with the
characteristic proton Hc showing its absorption at 6.27
ppm as a singlet.
A new synthetic route to benzophenanthridine (Scheme
9) is particularly noteworthy since this ring system is the
framework for a large class of alkaloids.13,15 Addition of
(14) The synthesis of this compound differs slightly from that
reported by Broggini, G.; Bruche, L.; Zecchi, G. J . Chem. Soc., Perkin.
Trans. 1 1990, 533.

9172 J . Org. Chem., Vol. 61, No. 26, 1996
Xiong and Moore
Sch em e 9
Sch em e 10
the lithium salt of N-methyl-N-propargyl-1-naphthyl-
amine (37)16 to dimethyl squarate in THF at -78 °C
provided cyclobutenone 38 in 87% yield, thermolysis
(chlorobenzene, 2 h) of which gave benzophenanthridine
39 in 68% yield. The characteristic low field aromatic
absorption for Ha appears at 8.55 ppm (d, J ) 8.7 Hz),
and the two hydroxy groups appear as singlets at 5.46
ppm and 6.04 ppm.
for 2 h to afford the desired pyrrolophenanthridine 43
(40%) along with a nonannulated hydroquinone 36 (50%).
Formation of the former is in analogy to the above
described arylation reactions. The latter apparently
arises via an intramolecular H-atom abstraction from the
indoline moiety at the diradical stage, thus providing the
nonannulated hydroquinone bearing the indole group.
This product was shown to be identical to the minor
product previously noted as arising in the thermolysis
of 33.
The 1H NMR spectrum of 43 shows the previously
noted characteristic aromatic proton Ha at 8.06 ppm (d,
J ) 7.7 Hz). The two hydroxy groups appear as singlets
at 5.56 and 5.97 ppm, and the two pyrrolidinyl methylene
groups appear as triplets at 3.00 ppm and 3.31 ppm while
the benzylic protons appear at 4.10 ppm as a singlet.
A variety of conditions were employed to remove the
phenolic hydroxy groups from 43 and thus obtain the
natural product.23 The best method, although still inef-
ficient, involved reductive cleavage of diethyl phosphate
ester 44. This derivative was formed in 72% yield upon
treatment of 43 with sodium hydride in THF followed
by addition of diethyl chlorophosphonate. Reductive
removal of the phosphate ester groups using sodium in
liquid ammonia provided the natural product assoanine
(40) in 25% yield. The structure of assoanine is based
on comparison of its spectral data to those reported in
the literature.17,18 Particularly revealing is the compari-
son of the 13C NMR spectra where all 16 chemical shifts
in the observed carbon-13 spectrum matched to within
Syn th esis of Assoa n in e
Finally, the 4-alkynyl-4-hydroxycyclobutenone ring
expansion reaction was applied in a total synthesis of
assoanine (40), a member of a series of biologically active
pyrrolophenanthridine alkaloids isolated from various
Crinum species (Amaryllidaceae).17-21 The synthesis
(Scheme 10) begins by treating indoline with sodium
hydride and propargyl bromide in DMF to provide
N-propargyl indoline in 93% yield.22 Addition of the
lithium salt of this compound to dimethyl squarate in
THF at -78 °C gave cyclobutenone 42 in 87% yield. This
adduct was subjected to thermolysis in refluxing p-xylene
(15) (a) For a review prior to 1984 on this subject, see: Simanek, V.
The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando, 1985; Vol.
26, p 185. (b) Ishii, H.; Ichikawa, Y.; Kawanabe, E.; Ishikawa, M.;
Ishikawa, T.; Kuretani, K.; Inomata, M.; Hoshi, A. Chem. Pharm. Bull.
1985, 33, 4139. (c) Carty, A.; Elliott, W.; Lenior, G. M. Can. J . Chem.,
1984, 2435. (d) Kessar, S. V.; Gupta, Y. P.; Dhingra, K.; Sharma, G.
S.; Narula, S. Tetrahedron Lett. 1977, 17, 1459. (e) Ishii, H.; Ishikawa,
T.; Watanabe, T.; Ichikawa, Y.; Kawanabe, E. J . Chem. Soc., Perkin
Trans. 1 1984, 2283. (f) Hanaoka, M.; Kobayashi, N.; Shimada, K.;
Mukai, C. J . Chem. Soc., Perkin Trans. 1 1987, 677. (g) Olugbade, T.
A.; Waigh, R. D.; Mackay, S. P. J . Chem. Soc., Perkin Trans. 1 1990,
2657. (h) Sotomayor, N.; Dominguez, E.; Lete, E. Tetrahedron, Lett.
1994, 35, 2973. (i) Seraphin, D.; Lynch, M.; Duval. O. Tetrahedron Lett.
1995, 36, 5731.
(16) (a) Katritzky, A. R.; Balck, M.; Fan, W. J . Org. Chem. 1991,
56, 5045. (b) Scheurer, H.; Zsindely, J .; Schmid, H. Helv. Chim. Acta
1973, 56, 478.
(17) Liabres, J . M.; Viladomat, F.; Bastida, J .; Codina, C.; Rubiralta,
M. Phytochemistry 1986, 25, 2637.
(18) Parnes, J . S.; Carter, D. S.; Kurz, L. J .; Flippin, L. A. J . Org.
Chem. 1994, 59, 3497.
(19) (a) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar, Y.; Frahm,
A. W. Phytochemistry 1981, 20, 2003. (b) Ghosal, S.; Saini, K. S.;
Frahm, A. W. Ibid. 1983, 22, 2305.
(23) For deoxygenation of phenols, see: (a) Rossi, R. A.; Bunnett, J .
F. J . Org. Chem. 1973, 38, 2314. (b) Sebok, P.; Timar, T.; Eszenyi, T.
J . Org. Chem. 1994, 59, 6318. (c) Subramanian, L. R. Synthesis 1984,
481. (d) Hussey, B. J .; J ohnstone, R. A. W. Tetrahedron 1982, 38, 3775.
(e) Cabri, W.; Bernardinis, S. D.; Francalanci, F.; Penco, S.; Santi, R.
J . Org. Chem. 1990, 55, 350. (f) Clauss, K.; J ensen, H. Angew. Chem.,
Int. Ed. Engl. 1973, 12, 918. (g) Welch, S. C.; Walters, M. E. J . Org.
Chem. 1978, 43, 4797.
(20) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 79.
(21) (a) Chattopadhyay, S. C.; Chattopadhyay, U.; Mathur, P. P.;
Saini, K. S.; Ghosal, S. Planta Med. 1983,49, 252. (b) Cheng, R. K. Y.;
Yan, S. J .; Chen, C. C. J . Med. Chem. 1978, 21, 199.
(22) Torregrosa, J .; Baboulene, M.; Speziale, V.; Lattes, A. J .
Organomet. Chem. 1983, 244, 311.

Ring Expansion of 4-Alkynylcyclobutenones
J . Org. Chem., Vol. 61, No. 26, 1996 9173
NMR (125 MHz, CDCl3) δ 139.9, 138.1, 133.0, 128.9, 128.5,
128.4, 127.7, 126.4, 85.6, 78.8, 76.1, 74.2, 64.2, 36.6, 36.5; exact
mass calcd for C19H18NO3S (MH)+: 340.1007, found 340.1023.
N-(2-P r op yn yl)-N-(3-p h en yl-2-p r op yn yl)b en zen esu l-
fon a m id e (12a ). To a solution of 118 (1.40 g, 7.18 mmol),
triphenylphosphine (1.88 g, 7.18 mmol), and 3-phenyl-2-
propyn-1-ol (1.42 g, 10.77 mmol) in THF (70 mL) was added a
solution of diethyl azodicarboxylate (1.25 g, 7.18 mmol) in THF
(10 mL) at 0 °C in 15 min. The mixture was stirred at room
temperature overnight and then concentrated in vacuo. Chro-
matography (hexanes/EtOAc ) 3:1) gave product 12a (2 g,
90%) as a yellow oil: IR (neat) 3425, 3291, 2245 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 2.16 (t, J ) 2.2 Hz, 1H), 4.22 (d, J ) 2.2
Hz, 2H), 4.43 (s, 2H), 7.19-7.21 (m, 2H), 7.23-7.30 (m, 3H),
0.3 ppm (average deviation ( 0.1 ppm) the published
spectrum obtained for the natural product.
Con clu sion s
In conclusion, the following significant points arising
from the study outlined here are noted: (1) ring expan-
sions of 4-hydroxy-4-[4-N-(benzenesulfonyl)-4-aza-1,6-
alkadiynyl]cyclobutenones provide a general route to
piperidinoquinones; (2) dihydrophenanthridinediols are
formed from the thermolysis of 4-hydroxy-4-(3-N-phenyl-
1-propynylamino)cyclobutenones, and these hydroquino-
nes are members of a previously unknown class of
compounds; (3) a benzophenanthridine was synthesized
from 4-(3-N-naphthalenyl-1-propynylamino)cyclobuten-
one in only four steps and thus provided a potentially
general route to the ring system found in a large family
of alkaloids; (4) assoanine was synthesized from dimethyl
squarate and indoline in five steps. Although the overall
yield is low (5%), the route is direct and provides
methodology that is potentially useful for the construction
of a variety of related alkaloids and analogs.
7.47-7.51 (m, 2H), 7.54-7.57 (m, 1H), 7.87-7.89 (m, 2H); 13
C
NMR (CDCl3, 125 MHz) δ 138.3, 133.0, 131.6, 128.9, 128.6,
128.2, 127.8, 122.0, 85.9, 81.2, 76.3, 74.0, 37.2, 36.4; exact mass
calcd for C18H15NO2S: 309.0823, found 309.0813.
N-(2-P r opyn yl)-N-(2-bu tyn yl)ben zen esu lfon am ide (12b).
In analogy to the above procedure for 12a , compound 12b (800
mg, 64%) was obtained as a light yellow solid from 11 (1.40 g,
7.18 mmol): mp 57-58 °C; IR (CDCl3) 3307, 3070, 1447, 1095
1
cm-1; H NMR (CDCl3, 500 MHz) δ 1.61 (t, J ) 2.3 Hz, 3H),
2.12 (t, J ) 2.3 Hz, 1H), 4.10 (d, J ) 2.3 Hz, 2H), 4.12 (d, J )
2.4 Hz, 2H), 7.46-7.57 (m, 2H), 7.80-7.83 (m, 3H); 13C NMR
(CDCl3, 125 MHz) δ 138.1, 132.8, 128.7, 127.7, 82.1, 76.7, 76.3,
73.7, 36.6, 36.1, 3.3; exact mass calcd for C13H12NO2S (M -
H)+: 246.0589, found 246.0599.
Exp er im en ta l Section
Gen er a l P r oced u r e. All air or water sensitive reactions
were run in flame dried glassware under an atmosphere of
dry (Drierite) nitrogen. Tetrahydrofuran was freshly distilled
from calcium hydride then sodium/benzophenone. Other
anhydrous solvents (benzene, toluene, and p-xylene) were
freshly distilled from calcium hydride. Commercial reagents
were used without any further purification unless otherwise
noted.
Gen er a l P r oced u r e for th e Syn th esis of Cyclobu ten -
on es 14a -f. 2-P h en yl-3-isop r op oxy-4-[4-N-(ben zen esu l-
fon yl)-4-a za -7-(tr im eth ylsilyl)-1,6-h ep td iyn yl]-4-h yd r oxy-
2-cyclobu ten -1-on e (14a ). To a solution of 10a (122 mg, 0.4
mmol) in THF (5 mL) at -78 °C was added nBuLi (0.25 mL,
1.6 M in hexanes, 0.4 mmol), and the solution was stirred for
30 min at the same temperature and was transferred to a
solution of 2-phenyl-3-isopropoxycyclobutenedione (87 mg, 0.4
mmol) in THF (5 mL) via cannula. The resulting solution was
stirred for 40 min at -78 °C, quenched with saturated
ammonium chloride (10 mL), and extracted with diethyl ether
(2 × 10 mL). The combined organic portion was washed with
brine (15 mL), dried over magnesium sulfate, and concentrated
in vacuo. The crude product (predominantly one spot by thin
layer chromatography) was subjected to thermolysis without
further purification.
N-(2-P r op yn yl)-N-[3-(t r im et h ylsilyl)-2-p r op yn yl]b en -
zen esu lfon a m id e (10a ). A solution of nBuLi (0.687 mL, 1.6
M in hexanes, 1.1 mmol) in THF (10 mL) was cooled to -78
°C. This was then added via cannula to a solution of N,N-
bis(2-propynyl)benzenesulfonamide (9) (233 mg, 1.0 mmol) in
THF (10 mL) at -78 °C. The resulting alkynyllithium solution
was stirred at -78 °C for 30 min, and chlorotrimethylsilane
(163 mg, 1.5 mmol) was added. The resulting solution was
stirred at -78 °C for 1 h. The mixture was then quenched
with ammonium chloride (10%, 20 mL), and the aqueous layer
was extracted with EtOAc (2 × 15 mL). The combined organic
portion was dried over magnesium sulfate and concentrated
in vacuo. Chromatography (hexanes/EtOAc ) 8:1) gave
product 10a (152 mg, 50%) as a light yellow solid: mp 66-67
3-P h en yl-4-isop r op oxy-2,5-d ioxo-7-[(E)-2-(tr im eth ylsi-
lyl)eth ylid en e]-9-N-(ben zen esu lfon yl)bicyclo[4.4.0]d eca -
1,3-d ien e (17a ). The crude cyclobutenone 14a in toluene (25
mL) was added dropwise (40 min) under nitrogen to refluxing
toluene (150 mL), and the resulting solution was refluxed for
an additional 20 min. The solution was cooled to room
temperature and concentrated in vacuo. Chromatography
(hexanes/ethyl acetate ) 4:1) gave 17a [91 mg, 44% overall
yield from 13a (87 mg, 0.4 mmol)] as a brown oil: IR (CDCl3)
°C; IR (CDCl3) 2256, 1479, 1165 cm-1
;
1H NMR (500 MHz,
CDCl3) δ 0.047 (s, 9H), 2.13 (t, J ) 2.5 Hz, 1H), 4.14 (d, J )
2.5 Hz, 2H), 4.20 (s, 2H), 7.48-7.52 (m, 2H), 7.57-7.59 (m,
1H), 7.83-7.85 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 138.1,
132.9, 128.8, 127.6, 97.1, 91.2, 76.1, 73.8, 37.1, 36.1, -0.485;
exact mass calcd for C15H20NO2SiS (MH)+: 306.0984, found
306.0987.
N-(2-P r opyn yl)-N-(4-m eth yl-4-h ydr oxy-2-pen tyn yl)ben -
zen esu lfon a m id e (10b). Using acetone as the trap and in
analogy to the above procedure for 10a , compound 10b (1.33
g, 62%) was obtained as a light yellow oil from 9 (1.72 g, 7.38
mmol): IR (neat) 3509, 3288, 2122 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.32 (s, 6H), 1.96 (s, 1H), 2.14 (t, J ) 2.4 Hz, 1H),
4.12 (d, J ) 2.4 Hz, 2H), 4.19 (s, 2H), 7.48-7.51 (m, 2H), 7.53-
7.59 (m, 1H), 7.81-7.84 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 138.2, 133.0, 128.9, 127.8, 90.6, 76.2, 74.1, 73.9, 64.7, 36.5,
36.3, 31.0; exact mass calcd for C15H18NO3S (MH)+: 292.1007,
found 292.1013.
1
1668, 1640 cm-1; H NMR (CDCl3, 500 MHz) δ 0.30 (s, 9H),
1.08 (d, J ) 6.2Hz, 6H), 3.96 (s, 2H), 4.16 (s, 2H), 4.43 (heptet,
J ) 6.2 Hz, 1H), 7.08 (s, 1H), 7.25-7.27 (m, 2H), 7.37-7.40
(m, 3H), 7.50-7.53 (m, 2H), 7.57-7.59 (m, 1H), 7.79-7.81 (m,
2H); 13C NMR (CDCl3, 125 MHz) δ 185.8, 183.0, 154.7, 143.2,
137.3, 136.3, 135.5, 133.6, 133.4, 130.5, 130.2, 129.9, 129.4,
128.8, 128.0, 127.9, 76.7, 49.0, 44.0, 22.7, 0.071; exact mass
calcd for C28H32O5SiS (MH)+: 522.1770, found 522.1766.
3,4-Dim et h oxy-2,5-d ioxo-7-[(E)-2-(t r im et h ylsilyl)et h -
ylid en e]-9-N-(ben zen esu lfon yl)bicyclo[4.4.0]d eca -1,3-d i-
en e (17b). In analogy to the above procedure, compound 17b
[71 mg, 40% overall yield from 13b (57 mg, 0.4 mmol)] was
obtained as a red-orange oil: IR (CDCl3) 1659 cm -1; 1H NMR
(CDCl3, 300 MHz) δ 0.26 (s, 9H), 3.88 (s, 2H), 3.96 (s, 3H),
3.97 (s, 3H), 4.08 (s, 2H), 7.08 (s, 1H), 7.53-7.60 (m, 3H), 7.77-
7.80 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 182.6, 182.4, 144.9,
144.1, 143.7, 136.8, 135.9, 133.5, 133.2, 132.5, 129.2, 127.6,
61.2, 61.1, 48.7, 43.3, -0.304; exact mass calcd for C21H25NO6-
SiS: 447.1172, found 447.1179.
N-(2-P r op yn yl)-N-(4-p h en yl-4-h yd r oxy-2-bu tyn yl)ben -
zen esu lfon a m id e (10c). Using benzaldehyde as the trap and
in analogy to the above 10c (1.22 g, 49%) was obtained as a
light-yellow oil from 9 (1.72 g, 7.38 mmol): IR (neat) 3498,
1
3288, 2360, 2122 cm-1; H NMR (300 MHz, CDCl3) δ 2.14 (t,
3-Bu t yl-4-isop r op oxy-2,5-d ioxo-7-[(E)-2-(t r im et h ylsil-
yl)eth ylid en e]-9-N-(ben zen esu lfon yl)bicyclo[4.4.0]d eca -
1,3-d ien e (17c). In analogy to the above procedure, compound
17c [120 mg, 60% overall yield from 13c (78.4 mg, 0.4 mmol)]
J ) 2.5 Hz, 1H), 2.18 (s, 1H), 4.14 (d, J ) 2.5 Hz, 2H), 4.27 (d,
J ) 1.8 Hz, 2H), 5.26 (d, J ) 1.5 Hz, 1H), 7.31-7.37 (m, 5H),
7.42-7.46 (m, 2H), 7.52-7.55 (m, 1H), 7.81-7.83 (m, 2H); 13
C

9174 J . Org. Chem., Vol. 61, No. 26, 1996
Xiong and Moore
was obtained as a red oil: IR (CDCl3) 1669, 1636 cm-1
;
1H
chloride (70 mL), and extracted with diethyl ether (2 × 40 mL).
The organic layer was washed with brine, dried, and concen-
trated in vacuo. Chromatography (hexanes/ethyl acetate )
8:1) gave 19e (3.97 g, 86%) as a yellow oil: IR (neat) 2360,
2120 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.49 (s, 9H), 2.28 (t,
J ) 2.4 Hz, 1H), 4.40 (d, J ) 3.4 Hz, 2H), 7.24-7.30 (m, 5H);
13C NMR (125 MHz, CDCl3) δ 153.7, 141.9, 128.5, 126.0, 80.7,
79.8, 71.7, 39.5, 28.1; exact mass calcd for C14H17NO2: 231.1259,
found 231.1257.
NMR (CDCl3, 500 MHz) δ 0.26(s, 9H), 0.89 (t, J ) 7.0 Hz, 3H),
1.26-1.36 (m, 10H), 2.37 (t, J ) 7.3 Hz, 2H), 3.89 (s, 2H), 4.09
(s, 2H), 4.73 (heptet, J ) 6.2 Hz, 1H), 6.96 (s, 1H), 7.48-7.58
(m, 3H), 7.76-7.79 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
186.3, 182.3, 155.3, 142.4, 137.3, 135.9, 135.2, 133.1, 132.9,
129.2, 127.7, 75.6, 48.8, 43.7, 30.7, 22.9, 22.8, 22.7, 13.8, -0.16;
exact mass calcd for C26H35NO5SiS: 501.2005, found 501.2010.
3,4-Dim eth oxy-2,5-d ioxo-7-[(E)-3-m eth yl-3-h yd r oxy-1-
bu tylid en e]-9-N-(ben zen esu lfon yl)bicyclo[4.4.0]d eca -1,3-
d ien e (17d ). In analogy to the above procedure, compound
17d [150 mg, 50% overall yield from 13b (100 mg, 0.7 mmol)]
was obtained as an orange-red solid: mp 139-140 °C; IR
N-(4-P en ten yl)-N-p r op a r gyla n ilin e (19f). In analogy to
the above procedure, 19f (1.96 g, 90%) was obtained as a yellow
oil starting with N-(4-pentenyl)aniline (1.77 g, 11 mmol): IR
(neat) 2934 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.80 (quintet,
J ) 7.3 Hz, 2H), 2.16-2.21 (m, 2H), 2.23 (t, J ) 2.2 Hz, 1H),
3.41 (t, J ) 7.3 Hz, 2H), 4.06 (bs, 2H), 5.06-5.14 (m, 2H), 5.88-
5.94 (m, 1H), 6.82-6.84 (m, 1H), 6.88 (d, J ) 7.7 Hz, 2H),
7.29-7.33 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 148.0, 137.9,
129.0, 117.5, 115.0, 113.6, 80.1, 71.6, 50.7, 40.1, 31.1, 26.4;
exact mass calcd for C14H17N: 199.1361, found 199.1361.
2,3-Dim eth oxy-4-h ydr oxy-4-[3-(N-n -bu tyl-N-ph en ylam i-
n o)-1-p r op yn yl]-2-cyclobu ten -1-on e (20a ). To a solution
of 19a (449 mg, 2.4 mmol) in THF (20 mL) at -78 °C was
added nBuLi (1.5 mL, 1.6 M in hexanes, 2.4 mmol), and the
solution was stirred for 15 min and then transferred to a
solution of dimethyl squarate (284 mg, 2.0 mmol) in THF (20
mL) via cannula. The resulting solution was stirred for 30
min at -78 °C, quenched with saturated ammonium chloride
(40 mL), and extracted with diethyl ether (2 × 25 mL). The
combined organic portion was washed with brine (30 mL),
dried over magnesium sulfate, and concentrated in vacuo.
Chromatography (hexanes/ethyl acetate ) 4:1) gave 20a (584
mg, 89%) as a brown viscous oil: IR (neat) 3373, 2359, 2249,
1780, 1633 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J ) 7.3
Hz, 3H), 1.35 (hextet, J ) 7.5 Hz, 2H), 1.58 (quintet, J ) 7.6
Hz, 2H), 3.30 (t, J ) 7.5 Hz, 2H), 3.89 (s, 3H), 4.03 (s, 3H),
4.06 (d, J ) 3.0 Hz, 2H), 4.28 (s, 1H), 6.72-6.75 (m, 1H), 6.78-
6.80 (m, 2H), 7.20-7.23 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 180.9, 164.9, 147.9, 135.1, 128.9, 117.5, 113.7, 85.9, 78.2, 77.9,
59.7, 58.3, 51.0, 40.5, 29.3, 20.3, 13.8; exact mass calcd for
C19H23NO4: 329.1627, found 329.1612.
1
(CDCl3) 1669, 1636 cm -1; H NMR (CDCl3, 500 MHz) δ 1.47
(s, 6H), 1.95 (s, 1H), 3.95 (s, 3H), 3.97 (s, 3H), 4.09 (s, 2H),
4.33 (s, 2H), 6.86 (s, 1H), 7.50-7.53 (m, 2H), 7.56-7.58 (m,
1H), 7.82-7.83 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 182.4,
146.4, 146.3, 145.0, 143.8, 136.6, 134.4, 133.9, 133.0, 129.2,
127.6, 123.6, 72.3, 61.3, 61.2, 43.8, 43.2, 31.1, 31.0; exact mass
calcd for C21H23NO7S (MH)+: 434.1273, found 434.1237.
3,4-Dim et h oxy-2,5-d ioxo-7-(E)-b en zylid en e-9-N-(b en -
zen esu lfon yl)bicyclo[4.4.0]d eca -1,3-d ien e (17e). In anal-
ogy to the above procedure, compound 17e [123 mg, 55%
overall yield from 13b (71 mg, 0.5 mmol)] was obtained as an
orange-red solid: mp 155-156 °C; IR (CDCl3) 1649, 1593 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 3.97 (s, 3H), 4.00 (s, 3H), 4.20
(s, 2H), 4.24 (s, 2H), 7.25-7.27 (m, 2H), 7.36-7.38 (m, 1H),
7.42-7.47 (m, 4H), 7.54-7.56 (m, 1H), 7.65-7.67 (m, 2H), 7.82
(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 182.4, 182.2, 145.0,
143.9, 139.5, 136.7, 135.8, 133.8, 133.6, 133.0, 129.3, 129.1,
128.7, 128.6, 127.5, 123.8, 61.3, 61.2, 45.0, 43.3; exact mass
calcd for C24H21NO6S: 451.1089, found 451.1098.
3-Bu t yl-4-isop r op oxy-2,5-d ioxo-7-b e n zylid e n e -9-N -
(ben zen esu lfon yl)b icyclo[4.4.0]d eca -1,3-d ien e (17f). In
analogy to the above procedure, compound 17f [200 mg, 57%
overall yield from 13c (137 mg, 0.7 mmol)] was obtained as a
red oil: IR (CDCl3) 1665, 1635 cm-1 1H NMR (CDCl3, 500
;
MHz) δ 0.92 (t, J ) 7.3 Hz, 3H), 1.28 (d, J ) 6.2 Hz, 6H), 1.31-
1.41 (m, 4H), 2.40 (t, J ) 7.3 Hz, 2H), 4.20 (d, J ) 1.1 Hz,
2H), 4.25 (s, 2H), 4.73 (heptet, J ) 6.2 Hz, 1H), 7.25-7.28 (m,
2H), 7.34-7.38 (m, 1H), 7.42-7.47 (m, 4H), 7.52-7.56 (m, 1H),
7.65-7.67 (m, 2H), 7.73 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ
185.8, 182.3, 155.3, 138.3, 136.7, 135.8, 135.2, 134.1, 133.2,
133.0, 129.3, 129.1, 128.6, 128.4, 127.6, 124.1, 75.7, 45.0, 43.6,
30.7, 22.9, 22.8, 13.8; exact mass calcd for C29H31NO5S:
505.1923, found 505.1944.
2,3-Dim et h oxy-4-h yd r oxy-4-[3-[N-n -b u t yl-N-(4-m et h -
oxyp h en yl)a m in o]-1-p r op yn yl]-2-cyclobu ten -1-on e (20b).
In analogy to the above, 19b (238 mg, 1.1 mmol) was converted
to the cyclobutenone 20b. The crude product (approximately
1
70% pure by H NMR analysis) was subjected to thermolysis
without further purification.
2,3-Dim eth oxy-4-h ydr oxy-4-[3-(N-allyl-N-ph en ylam in o)-
1-p r op yn yl]-2-cyclobu ten -1-on e (20c). In analogy to the
above procedure, 20c (564 mg, 90%) was obtained as a yellow
solid starting with 18c (284 mg, 2.0 mmol): mp 75-78 °C; IR
(CDCl3) 3577, 3359, 2245, 1781, 1626 cm-1; 1H NMR (300 MHz,
CDCl3) δ 3.81 (s, 1H), 3.93 (m, 5H), 4.07 (s, 3H), 4.08 (bs, 2H),
5.15-5.28 (m, 2H), 5.86 (dddd, J ) 5.1, 10.2, 15.3, 17.0 Hz,
1H), 6.75-6.84 (m, 3H), 7.20-7.26 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 180.7, 164.7, 148.2, 135.4, 133.8, 129.0, 118.1,
116.8, 114.2, 85.8, 78.3, 78.0, 59.9, 58.5, 53.7, 40.1; exact mass
calcd for C18H19NO4: 313.1314, found 313.1314.
2-P h en yl-3-m et h oxy-4-h yd r oxy-4-[3-(N-a llyl-N-p h en -
yla m in o)-1-p r op yn yl]-2-cyclobu ten -1-on e (20d ). In anal-
ogy to the above, 19c (157 mg, 0.92 mmol) was converted to
20d . The crude product (predominantly one spot by thin layer
chromatography) was subjected to thermolysis without further
purification.
N-n -Bu tyl-N-p r op a r gyl-p-a n isid in e (19b). A mixture of
N-n-butyl-p-anisidine (1.03 g, 5.75 mmol), propargyl bromide
(1.71 g, 80% in toluene, 11.5 mmol), and potassium carbonate
(952 mg, 6.9 mmol) in acetone (120 mL) was refluxed for 21 h.
The mixture was diluted with diethyl ether (50 mL), washed
with water (30 mL), and extracted with diethyl ether (3 × 40
mL). The combined organic portion was washed with water
(40 mL) and brine (50 mL), dried, and concentrated in vacuo.
Chromatography (hexanes/EtOAc ) 8:1) gave product 19b
1
(1.13 g, 91%) as a yellow oil: IR (neat) 2054 cm-1; H NMR
(300 MHz, CDCl3) δ 0.94 (t, J ) 7.3 Hz, 3H), 1.38 (hextet, J )
7.6 Hz, 2H), 1.53-1.59 (m, 2H), 2.17 (t, J ) 2.3 Hz, 1H), 3.23
(t, J ) 7.4 Hz, 2H), 3.75 (s, 3H), 3.93 (d, J ) 2.4 Hz ,2H), 6.85
(s, 4H); 13C NMR (125 MHz, CDCl3) δ 152.6, 142.8, 116.8,
114.3, 80.0, 71.8, 55.3, 51.5, 41.1, 29.4, 20.2, 13.8; exact mass
calcd for C14H19NO: 217.1467, found 217.1472.
N-(ter t-Bu toxyca r bon yl)-N-p r op a r gyla n ilin e (19e). To
a solution of aniline (1.86 g, 20 mmol) and triethylamine (3.03
g, 30 mmol) in chloroform (40 mmol) was added di-tert-butyl
dicarboxylate (6.55 g, 30 mmol) at 0 °C. The mixture was
stirred at room temperature for a few hours and then washed
with 3 N NaOH. The aqueous layer was extracted with
methylene chloride (3 × 40 mL). The combined organic layer
was washed with brine, dried, and concentrated in vacuo. The
crude product was dissolved in THF-DMSO (120 mL, 1:1),
and sodium hydride (1.44 g, 50% oil suspension, 30 mmol) was
added. The resulting solution was stirred at room temperature
for 3 h and propargyl bromide (4.46 g, 80% in toluene, 30
mmol) was added at 0 °C. The mixture was stirred at room
temperature overnight, quenched with saturated ammonium
2,3-Dim eth oxy-4-h ydr oxy-4-[3-[N-(ter t-bu toxycar bon yl)-
N-p h en yla m in o]-1-p r op yn yl]-2-cyclobu ten -1-on e (20e). In
analogy to the above procedure, 20e (610 mg, 82%) was
obtained as a viscous dark red oil starting with 18e (284 mg,
1
2.0 mmol): IR (neat) 3378, 1781, 1697, 1645 cm-1; H NMR
(300 MHz, CDCl3) δ 1.44 (s, 9H), 3.33 (s, 1H), 3.95 (s, 3H),
4.10 (s, 3H), 4.44 (s, 2H), 7.26-7.34 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 180.5, 164.8, 153.9, 141.6, 135.1, 128.5, 126.3,
126.2, 85.2, 81.1, 78.3, 59.7, 58.4, 39.9, 28.0; exact mass calcd
for C20H23NO6: 373.1525, found 373.1525.
2,3-D im e t h o x y -4-h y d r o x y -4-[3-[N -(4-p e n t e n y l)-N -
p h en yla m in o]-1-p r op yn yl]-2-cyclobu ten -1-on e (20f). In
analogy to the above procedure, 20f (963 mg, 94%) was

Ring Expansion of 4-Alkynylcyclobutenones
J . Org. Chem., Vol. 61, No. 26, 1996 9175
obtained as a yellow oil starting with 18f (426 mg, 3.0 mmol):
solution (50 mL). The organic layer was dried and concen-
trated in vacuo. Chromatography (hexanes/ethyl acetate )
3:1) gave product 22e (320 mg, 70%) as a light yellow solid:
mp 196-198°; IR (CDCl3) 3520,1691 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.49 (s, 9H), 3.94 (s, 3H), 3.95 (s, 3H), 4.77 (s, 2H),
5.51 (s, 1H), 5.97 (s, 1H), 7.18 (dt, J ) 1.5, 7.7 Hz, 1H), 7.24
(dt, J ) 1.5, 7.7 Hz, 1H), 7.54-7.56 (m, 1H), 8.35 (dd, J ) 1.5,
7.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 152.8, 140.0, 138.6,
137.6, 137.5, 127.9, 127.0, 126.7, 124.6, 124.2, 117.7, 114.2,
80.9, 60.9, 60.8, 40.6, 28.3; exact mass calcd for C20H23NO6:
373.1525, found 373.1528.
1
IR (CDCl3) 3378, 1779, 1651, 1633 cm-1; H NMR (300 MHz,
CDCl3) δ 1.74 (quintet, J ) 7.3 Hz, 2H), 2.11 (q, J ) 7.1 Hz,
2H), 3.34 (t, J ) 7.3 Hz, 2H), 3.65-3.68 (m, 1H), 3.93 (s, 3H),
4.06 (s, 3H), 4.09 (s, 2H), 5.02-5.08 (m, 2H), 5.77-5.91 (m,
1H), 6.74-6.82 (m, 3H), 7.24-7.26 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 180.7, 164.8, 147.9, 137.9, 135.2, 129.0, 117.6,
114.9, 113.8, 85.9, 78.2, 78.0, 59.8, 58.4, 50.7, 40.6, 31.0, 26.2;
exact mass calcd for C20H23NO4: 341.1627, found 341.1617.
5-B u t y l-5,6-d i h y d r o -8,9-d i m e t h o x y -7,10-p h e n a n -
th r id in ed iol (22a ). A solution of 20a (395 mg, 1.20 mmol)
in toluene (120 mL) was added dropwise to a refluxing toluene
(250 mL, under N2) during a 1 h 40 min period. The solution
was refluxed for an additional 20 min and cooled to room
temperature, and the solvent was removed in vacuo. Chro-
matography (hexanes/ethyl acetate ) 3:1) gave product 22a
(255 mg, 65%) as a purple oil: IR (CDCl3) 3520,1633, 1599
5-(4-P en ten yl)-5,6-d ih ydr o-8,9-d im eth oxy-7,10-p h en a n -
th r id in ed iol (22f). In analogy to the above procedure, 22f
(340 mg, 70%) was obtained as a purple oil starting with 20f
1
(489 mg, 1.43 mmol): IR (CDCl3) 3522, 1637 cm-1; H NMR
(500 MHz, CDCl3) δ 1.81 (quintet, J ) 7.3 Hz, 2H), 2.16
(hextet, J ) 7.3 Hz, 2H), 3.3 (t, J ) 7.7 Hz, 2H), 3.93 (s, 3H),
3.95 (s, 3H), 4.20 (s, 2H), 5.05 (dddd, J ) 1.1, 1.5, 10.2, 17.2
Hz, 2H), 5.45 (s, br, 1H), 5.83-5.91 (m, 1H), 5.97 (s, br, 1H),
6.76 (d, J ) 8.2 Hz, 1H), 6.84 (t, J ) 7.5 Hz, 1H), 7.17 (dt, J
) 1.4, 8.2 Hz, 1H), 8.37 (dd, J ) 1.4, 7.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 146.1, 139.6, 138.2, 138.0, 137.9, 136.8,
128.5, 128.0, 122.1, 117.6, 116.7, 115.0, 114.5, 112.0, 60.8, 60.8,
50.3, 45.9, 31.3, 24.4; exact mass calcd for C20H23NO4: 341.1627,
found 341.1637.
1
cm-1; H NMR (500 MHz, CDCl3) δ 0.97 (t, J ) 7.3 Hz, 3H),
1.41 (hextet, J ) 7.7 Hz, 2H), 1.69 (quintet, J ) 7.3 Hz, 2H),
3.28 (t, J ) 7.7 Hz, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 4.19 (s, 2H),
5.40 (s, br, 1H), 5.93 (s, br, 1H), 6.76 (d, J ) 8.01 Hz, 1H),
6.82 (dt, J ) 1.1, 7.7 Hz, 1H), 7.17 (dt, J ) 1.5, 8.0 Hz, 1H),
8.37 (dd, J ) 1.4, 7.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
146.2, 139.6, 138.3, 137.9, 136.8, 128.5, 127.9, 122.0, 117.4,
116.7, 114.6, 112.6, 60.9, 60.8, 50.7, 45.7, 27.4, 20.6, 13.9; exact
mass calcd for C19H23NO4: 329.1627, found 329.1634.
5-(An ilin om eth yl)-2,3-d im eth oxy-1,4-ben zen ed iol (25).
In analogy to the above procedure, 25 (27 mg, 12%) was
obtained as a light yellow oil from the thermolysis of 20c (250
5-Bu t yl-5,6-d ih yd r o-2,8,9-t r im e t h oxy-7,10-p h e n a n -
th r id in ed iol (22b). The crude cyclobutenone 20b in toluene
(50 mL) was added dropwise to a refluxing toluene (150 mL)
in 1 h 20 min under nitrogen, and the solution was refluxed
for an additional 20 min. The solution was cooled to room
temperature and concentrated in vacuo. Chromatography
(hexanes/ethyl acetate ) 2:1) gave 22b (150 mg, 42% overall
yield from 18b) as a purple oil: IR (CDCl3) 3520, 2942, 1611,
1
mg, 0.80 mmol): IR (CDCl3) 3540 cm-1; H NMR (500 MHz,
CDCl3) δ 3.93 (s, 3H), 3.95 (s, 3H), 4.30 (s, 2H), 5.25 (s, 1H,
OH), 6.48 (s, 1H, NH), 6.62 (s, 1H), 6.74 (d, J ) 7.7 Hz, 2H),
6.78 (t, J ) 7.3 Hz, 1H), 7.18-7.21 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 147.9, 142.0, 141.6, 139.9, 138.9, 129.3, 119.9,
118.8, 114.2, 109.4, 61.1, 60.9, 45.1; exact mass calcd for
C15H17NO4: 275.1157, found 275.1171.
1
1573 cm-1; H NMR (CDCl3, 500 MHz) δ 0.96 (t, J ) 7.3 Hz,
5-(t er t -Bu t oxyca r b on yl)-5,6-d ih yd r o-8,9-d im et h oxy-
7,10-d ioxop h en a n th r id in e (26). A mixture of 22e (60 mg,
0.16 mmol), silver oxide (186 mg, 0.80 mmol), and potassium
carbonate (110 mg, 0.80 mmol) in benzene (10 mL) was stirred
at room temperature overnight. The mixture was filtered
through a short silica gel plug and concentrated in vacuo to
give product 26 (57 mg, 95%) as a red solid: mp 134-135 °C;
IR (CDCl3) 1698, 1650 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.50
(s, 9H), 4.03 (s, 3H), 4.06 (s, 3H), 4.65 (s, 2H), 7.19 (t, J ) 7.3
Hz, 1H), 7.37 (t, J ) 7.0 Hz, 1H), 7.60 (d, J ) 8.4 Hz, 1H),
8.10 (dd, J ) 8.1, 1.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
182.5, 181.5, 152.2, 144.7, 144.5, 139.5, 134.9, 132.3, 130.1,
129.1, 124.5, 124.4, 123.2, 82.0, 61.4, 61.2, 39.8, 28.2; exact
mass calcd for C20H23NO6 (M + 2H)+: 373.1525, found
373.1538.
8,9-Dim eth oxy-7,10-d ioxop h en a n th r id in e (27). A mix-
ture of 22c (80 mg, 0.27 mmol), silver oxide (312 mg, 1.35
mmol), and potassium carbonate (186 mg, 1.347 mmol) in
benzene (20 mL) was stirred at room temperature overnight.
The mixture was filtered through a short silica gel plug and
concentrated in vacuo. Chromatography (hexanes/EtOAc )
3:1) gave product 27 (43 mg, 60%) as a yellow solid: mp 90-
91 °C; IR (CDCl3) 1664, 1619 cm-1; 1H NMR (500 MHz, CDCl3)
δ 4.16 (s, 3H), 4.18 (s, 3H), 7.78 (t, J ) 7.0 Hz, 1H), 7.87 (t, J
) 7.0 Hz, 1H), 8.18 (dd, J ) 0.7, 8.5 Hz, 1H), 9.39 (dd, J )
0.7, 8.5 Hz, 1H), 9.60 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
184.4, 182.3, 152.0, 147.7, 147.0, 145.2, 131.9, 131.0, 130.5,
130.3, 127.6, 122.0, 121.8, 61.5, 61.5; exact mass calcd for
C15H11NO4: 269.0688, found 269.0691.
3H), 1.38 (sextet, J ) 7.7 Hz, 2H), 1.67 (quintet, J ) 7.7 Hz,
2H), 3.20 (t, J ) 7.7 Hz, 2H), 3.81 (s, 3H), 3.91 (s, 3H), 3.94 (s,
3H), 4.11 (s, 2H), 5.42 (s, br, 1H), 5.95 (s, 1H), 6.73-6.80 (m,
2H), 8.05 (d, J ) 2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
152.0, 140.7, 139.7, 138.2, 138.1, 137.0, 123.6, 117.2, 114.4,
113.5, 113.4, 111.2, 60.9, 60.8, 55.6, 51.1, 45.9, 27.5, 20.5, 13.9;
exact mass calcd for C20H25NO5: 359.1733, found 359.1723.
5-Ally l-5,6-d i h y d r o -8,9-d i m e t h o x y -7,10-p h e n a n -
th r id in ed iol (22c). In analogy to the above procedure, 22c
(157 mg, 63%) was obtained as a purple oil starting with 20c
1
(250 mg, 0.80 mmol): IR (CDCl3) 3523, 1599 cm-1; H NMR
(500 MHz, CDCl3) δ 3.92 -3.95 (m, 8H), 4.16 (s, 2H), 5.26-
5.35 (m, 2H), 5.36 (d, J ) 1.47 Hz, 1H), 5.95 (s, 1H), 5.96-
6.02 (m, 1H), 6.82 (d, J ) 8.07 Hz, 1H), 6.87 (dt, J ) 1.4, 8.07
Hz, 1H), 7.17 (dt, J ) 1.4, 7.3 Hz, 1H), 8.38 (dd, J ) 1.5, 7.7
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 146.1, 139.6, 138.3,
137.9, 136.9, 133.4, 128.4, 127.9, 122.3, 118.1, 117.9, 116.8,
114.5, 112.7, 60.9, 53.6, 45.7; exact mass calcd for C18H19NO4:
313.1314, found 313.1328.
5-Allyl-5,6-d ih yd r o-8-p h en yl-9-m et h oxy-7,10-p h en a n -
th r id in ed iol (22d ). In analogy to the procedure used for the
synthesis of 22b the phenanthridinediol 22d [138 mg, 48%
overall yield from 18d (150 mg, 0.8 mmol)] was obtained as a
purple-brown oil: IR (CDCl3) 3557, 3510, 1600 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 3.35 (s, 3H), 3.95 (d, J ) 5.87 Hz, 2H),
4.22 (s, 2H), 4.77 (s, br, 1H), 5.28 (dd, J ) 1.4, 10.2 Hz, 1H),
5.35 (dd, J ) 1.8, 17.2 Hz, 1H), 5.99 (ddd, J ) 1.8, 5.8, 10.6
Hz, 1H), 6.08 (s, 1H), 6.85 (d, J ) 8.0 Hz, 1H), 6.89 (dt, J )
1.1, 7.7 Hz, 1H), 7.21 (dt, J ) 1.4, 8.0 Hz, 1H), 7.44-7.48 (m,
3H), 7.53-7.55 (m, 2H), 8.47 (dd, J ) 1.5, 7.7 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ 146.6, 143.3, 140.5, 139.7, 133.3,
132.0, 130.2, 129.5, 128.8, 128.5, 128.4, 122.3, 119.4, 119.2,
118.0, 117.9, 117.7, 112.6, 60.7, 53.6, 46.0; exact mass calcd
for C23H21NO3: 359.1521, found 359.1510.
2,3-Dim eth oxy-5-m eth yl-1,4-ben zoqu in on e (28). A de-
gassed solution of 22a (88 mg, 0.27 mmol) and potassium
carbonate (158 mg, 1.07 mmol) in benzene (5 mL) was charged
with nitrogen. To this was added silver oxide (266 mg, 1.07
mmol). The mixture was stirred for 10 min at room temper-
ature, filtered through a short Celite plug, and concentrated
in vacuo. Chromatography (hexanes/EtOAc ) 3:1) gave
product 27 (10 mg, 14%) and 28 (8 mg, 16%) both as yellow
solid. 28: mp 53-55 °C (lit.:24 57-58 °C)
5-(ter t-Bu t oxyca r b on yl)-5,6-d ih yd r o-8,9-d im et h oxy-
7,10-p h en a n th r id in ed iol (22e). The solution of 20e (460
mg, 1.23 mmol) in freshly distilled toluene (300 mL, 4.11 ×
10-3 M) was refluxed under nitrogen for 3 h. The mixture was
cooled to room temperature and the solvent removed in vacuo.
The residue was dissolved in ethyl acetate (40 mL) and poured
into a separatory funnel containing aqueous sodium dithionite
(24) Sato, K.; Inoue, S.; Sato, H. Bull. Chem. Soc. J pn. 1972, 45,
3455.

9176 J . Org. Chem., Vol. 61, No. 26, 1996
Xiong and Moore
2,3-Dim eth oxy-4-h yd r oxy-4-(3-ca r ba zolyl-1-p r op yn yl)-
2-cyclobu ten -1-on e (30). To a solution of N-propargylcar-
bazole (472 mg, 2.3 mmol) in THF (15 mL) at -78 °C was
added nBuLi (1.44 mL, 1.6 M in hexanes, 2.3 mmol). The
solution was stirred for 20 min and then transferred to a
solution of dimethyl squarate (326 mg, 2.3 mmol) in THF (20
mL) via cannula. The resulting solution was stirred for 35
min at -78 °C, quenched with saturated ammonium chloride
(30 mL), and extracted with diethyl ether (2 × 15 mL). The
combined organic portion was washed with brine (30 mL),
dried over magnesium sulfate, and concentrated in vacuo.
Chromatography (hexanes/ethyl acetate ) 2:1) gave 30 (680
mg, 85%) as a light-brown solid: mp 99-100 °C; IR (CDCl3)
1H), 7.12 (d, J ) 3.3 Hz, 1H), 7.44 (d, J ) 7.7 Hz, 1H), 8.20 (d,
J ) 7.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 141.3, 138.6,
138.2, 138.0, 132.9, 125.4, 120.4, 120.0, 119.6, 117.2, 112.7,
112.6, 102.3, 60.9, 60.8, 43.2; exact mass calcd for C17H15NO4:
297.1001, found 297.1012.
2,3-Dim eth oxy-5-(in d olylm eth yl)-1,4-ben zen ed iol (36).
In analogy to the above procedure, product 36 (9 mg, 8%) was
obtained as a brown oil starting with 33 (110 mg, 0.37 mmol):
1
IR (neat) 3538, 2945, 1611 cm-1; H NMR (CDCl3, 500 MHz)
δ 3.87 (s, 3H), 3.92 (s, 3H), 5.28 (s, 2H), 5.38 (s, br, 1H), 5.63
(s, br, 1H), 6.27 (s, 1H), 6.54 (d, J ) 2.9 Hz, 1H), 7.12 (t, J )
7.7 Hz, 1H), 7.20-7.22 (m, 2H), 7.43 (d, J ) 8.0 Hz, 1H), 7.65
(d, J ) 7.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 142.0, 139.8,
139.1, 138.6, 136.0, 128.4, 128.3, 121.3, 120.7, 119.2, 118.9,
109.6, 109.2, 101.1, 60.7, 60.6, 44.2; exact mass calcd for
C17H17NO4: 299.1157, found 299.1170.
1
3387, 1778, 1632 cm-1; H NMR (CDCl3, 500 MHz) δ 3.03 (s,
1H), 3.90 (s, 3H), 3.97 (s, 3H), 5.09 (s, 2H), 7.25-7.27 (m, 2H),
7.45-7.47 (m, 4H), 8.08 (d, J ) 7.7 Hz, 2H); 13C NMR (CDCl3,
125 MHz) δ 179.8, 164.1, 139.8, 135.6, 125.9, 123.2, 120.4,
119.6, 108.7, 83.6, 78.4, 78.2, 60.0, 58.6, 32.6; exact mass calcd
for C21H19NO4 (M + 2H)+: 349.1313, found 349.1312.
2,3-Dim et h oxy-4-h yd r oxy-4-[3-[N-m et h yl-N-(1-n a p h -
th yl)a m in o]-1-p r op yn yl]-2-cyclobu ten -1-on e (38). To a
solution of N-methyl-N-propargyl-1-aminonaphthalene (552
mg, 2.83 mmol) in THF (15 mL) at -78 °C was added nBuLi
(2.02 mL, 1.4 M in hexanes, 2.83 mmol), and the resulting
reaction mixture was stirred for 25 min. It was then trans-
ferred to a solution of dimethyl squarate (402 mg, 2.83 mmol)
in THF (30 mL) via cannula. The resulting mixture was
stirred for 30 min at -78 °C, quenched with saturated
ammonium chloride (30 mL), and extracted with diethyl ether
(2 × 15 mL). The combined organic portion was washed with
brine (30 mL), dried over magnesium sulfate, and concentrated
in vacuo. Chromatography (hexanes/ethyl acetate ) 1:1) gave
38 (829 mg, 87%) as a viscous yellow oil: IR (neat) 3384, 1780,
1635 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.97 (s, 3H), 3.93 (s,
3H), 4.01 (s, 2H), 4.08 (s, 3H), 4.36 (s, 1H), 7.21 (dd, J ) 0.8,
7.6 Hz, 1H), 7.40 (t, J ) 7.6 Hz, 1H), 7.47-7.54 (m, 2H), 7.57
(d, J ) 8.0 Hz, 1H), 7.82-7.84 (m, 1H), 8.18 (dd, J ) 0.8, 8.0
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 181.0, 164.9, 147.7,
135.1, 134.6, 128.7, 125.7, 125.5, 125.4, 123.9, 123.4, 116.5,
85.2, 79.8, 78.2, 59.8, 58.4, 46.8, 40.8; exact mass calcd for
C20H19NO4: 337.1314, found 337.1315.
10,11-Dim eth oxy-N-m eth yl-7,8-d ih yd r oben zop h en a n -
th r id in e-9,12-d iol (39). A solution of 38 (150 mg, 0.455
mmol) in chlorobenzene (25 mL, N2) was added dropwise to
refluxing chlorobenzene (125 mL) during a period of 1.5 h. The
reaction solution was refluxed for an additional 20 min, cooled
to room temperature, and concentrated in vacuo. Chroma-
tography (hexanes/ethyl acetate ) 3:1) gave 39 (102 mg, 68%)
as a light purple solid: mp 50-52 °C; IR (neat) 3503 cm-1; 1H
NMR (CDCl3, 500 MHz) δ 2.70 (s, 3H), 3.98 (s, 3H), 4.00 (s,
3H), 4.27 (s, 2H), 5.46 (s, 1H), 6.04 (s, 1H), 7.47 (t, J ) 7.2 Hz,
1H), 7.53 (t, J ) 7.1 Hz, 1H), 7.67 (d, J ) 8.7 Hz, 1H), 7.83 (d,
J ) 8.0 Hz, 1H), 8.40 (d, J ) 8.3 Hz, 1H), 8.55 (d, J ) 8.7 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 144.0, 139.7, 138.7, 138.2,
133.5, 129.2, 127.8, 126.1, 125.6, 125.5, 124.3, 123.9, 123.5,
11,12-Dim eth oxy-9H-in d olo[3,2,1-d e]p h en a n th r id in e-
10,13-d iol (31). A solution of 30 (80 mg, 0.23 mmol) in
chlorobenzene (50 mL, N2) was added dropwise to a refluxing
chlorobenzene (100 mL) during a 1.5 h period, and the
resulting solution was refluxed for an additional 15 min. The
solution was cooled to room temperature and concentrated in
vacuo. Chromatography (methylene chloride) gave product 31
(66 mg, 83%) as a light blue solid: mp 73-74 °C; IR (CDCl3)
1
3521,1604, 1460 cm-1; H NMR (CDCl3, 500 MHz) δ 3.98 (s,
3H), 4.00 (s, 3H), 5.49 (s, 2H), 5.54 (s, 1H), 6.15 (s, 1H), 7.19
(t, J ) 7.7 Hz, 1H), 7.26-7.29 (m, 1H), 7.48-7.50 (m, 2H),
7.89 (dd, J ) 0.7, 7.7 Hz, 1H), 8.10 (d, J ) 7.7 Hz, 1H), 8.50
(dd, J ) 0.7, 7.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 141.3,
139.6, 138.8, 138.4, 138.1, 136.7, 125.2, 123.6, 123.4, 120.6,
120.5, 119.7, 119.5, 119.3, 116.6, 112.7, 112.5, 108.7, 60.9, 60.9,
41.0; exact mass calcd for C21H17NO4: 347.1157, found 347.1153.
2,3-Dim et h oxy-4-h yd r oxy-4-(3-in d olyl-1-p r op yn yl)-2-
cyclobu ten -1-on e (33). To a solution of N-propargylindole
(730 mg, 4.71 mmol) in THF (20 mL) at -78 °C was added
nBuLi (2.94 mL, 1.6 M in hexanes, 4.71 mmol). The solution
was stirred for 20 min and then transferred via cannula to a
solution of dimethyl squarate (608 mg, 4.28 mmol) in THF (40
mL). The resulting solution was stirred for 35 min at -78
°C, quenched with saturated ammonium chloride (30 mL), and
extracted with diethyl ether (2 × 15 mL). The combined
organic portion was washed with brine (30 mL), dried over
magnesium sulfate, and concentrated in vacuo. Chromatog-
raphy (hexanes/ethyl acetate ) 2:1) gave 33 (1.06 g, 83%) as
1
a brown oil: IR (neat) 3381, 2247, 1778, 1641 cm-1; H NMR
(CDCl3, 500 MHz) δ 3.90 (s, 1H), 3.91 (s, 3H), 4.07 (s, 3H),
4.90 (s, 2H), 6.50 (d, J ) 2.6 Hz, 1H), 7.12 (t, J ) 7.0 Hz, 1H),
7.15 (d, J ) 3.3 Hz, 1H), 7.21-7.23 (m, 1H), 7.35 (d, J ) 8.0
Hz, 1H), 7.61 (d, J ) 7.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
δ 180.3, 164.5, 135.7, 135.5, 128.7, 127.3, 121.8, 121.0, 119.8,
109.2, 102.0, 83.4, 79.3, 78.3, 60.1, 58.6, 36.0; exact mass calcd
for C17H15NO4: 297.1001, found 297.1009.
115.0, 114.4, 60.8, 60.8, 48.1, 41.1; exact mass calcd for C20H19
NO4: 337.1314, found 337.1314.
-
2,3-Dim eth oxy-4-h yd r oxy-4-(3-in d olin yl-1-p r op yn yl)-2-
cyclobu ten -1-on e (42). To a solution of N-propargylindoline
(3.03 g, 19.3 mmol) in THF (60 mL) at -78 °C was added
nBuLi (12.1 mL, 1.6 M in hexanes, 19.3 mmol), and the
mixture was stirred for 25 min. It was transferred to a
solution of dimethyl squarate (2.50 g, 17.6 mmol) in THF (90
mL) via cannula. The resulting solution was stirred for 35
min at -78 °C, quenched with saturated ammonium chloride
(50 mL), and extracted with ethyl acetate (2 × 35 mL). The
combined organic portion was washed with brine (40 mL),
dried over magnesium sulfate, and concentrated in vacuo.
Chromatography (hexanes/ethyl acetate ) 2:1) gave 42 (4.60
g, 87%) as a yellow solid: mp 104-105 °C; IR (CDCl3) 3380,
1781, 1647 cm-1, 1H NMR (CDCl3, 300 MHz) δ 2.95 (t, J ) 8.1
Hz, 2H), 3.37 (dt, J ) 2.2, 8.1 Hz, 2H), 3.61-3.62 (m, 1H),
3.92 (s, 3H), 3.97 (s, 2H), 3.98 (s, 3H), 6.56 (d, J ) 7.7 Hz,
1H), 6.73 (dt, J ) 0.9, 7.7 Hz, 1H), 7.07-7.10 (m, 2H); 13C NMR
8,9-Dim eth oxy-5,6-dih ydr oisoin doloin dole-7,10-diol (34).
A solution of 33 (110 mg, 0.37 mmol) in chlorobenzene (50 mL)-
was added dropwise to a refluxing chlorobenzene (250 mL, N2)
during a period of 1.5 h, and the solution was refluxed for an
additional 20 min. The solution was cooled to room temper-
ature and concentrated in vacuo. Chromatography (hexanes/
ethyl acetate ) 2:1) gave product 34 (63 mg, 57%) as a green-
yellowish solid: mp 160 °C dec; IR (CDCl3) 3539 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 3.96 (s, 3H), 3.97 (s, 3H), 5.03 (s, 2H),
5.47 (s, 1H), 5.63 (s, 1H), 6.63 (s, 1H), 7.08 (t, J ) 7.1 Hz, 1H),
7.18 (t, J ) 7.2 Hz, 1H), 7.33 (d, J ) 7.8 Hz, 1H), 7.65 (d, J )
7.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 141.6, 139.6, 139.1,
137.8, 137.1, 133.8, 133.0, 121.7, 121.5, 121.2, 119.2, 115.3,
108.9, 93.0, 61.1, 61.0, 46.2; exact mass calcd for C17H15NO4:
297.1001, found 297.0987.
9,10-Dim et h oxy-6,7-d ih yd r op yr r olop h en a n t h r id in e-
8,11-d iol (35). In analogy to the above procedure, product
35 (13 mg, 12%) was obtained as a blue oil starting with 33
(110 mg, 0.37 mmol): IR (CDCl3) 3532 cm-1; 1H NMR (CDCl3,
500 MHz) δ 3.96 (s, 3H), 3.97 (s, 3H), 5.44 (s, 1H), 5.46 (s,
2H), 6.08 (s, 1H), 6.52 (d, J ) 2.9 Hz, 1H), 7.07 (t, J ) 7.7 Hz,
(25) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Ring Expansion of 4-Alkynylcyclobutenones
J . Org. Chem., Vol. 61, No. 26, 1996 9177
(CDCl3, 125 MHz) δ 180.4, 164.6, 150.7, 135.4, 130.7, 127.1,
124.4, 119.0, 108.5, 84.7, 78.5, 78.3, 59.7, 58.5, 53.1, 38.6, 28.4;
exact mass calcd for C17H18NO4 (MH)+: 300.1235, found
300.1230.
8.1 Hz, 2H), 3.28 (t, J ) 8.1 Hz, 2H), 3.95 (s, 3H), 3.96 (s, 3H),
4.02-4.14 (m, 6H), 4.20-4.25 (m, 4H), 6.74 (t, J ) 7.3 Hz, 1H),
7.00 (dt, J ) 0.9, 7.3 Hz, 1H), 7.90 (d, J ) 8.1 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 150.9, 145.0, 144.3, 139.3, 137.9,
128.3, 125.2, 124.2, 122.3, 120.4, 119.3, 116.2, 64.6, 64.5, 64.3,
64.3, 61.0, 55.4, 47.9, 28.8, 16.0, 16.0, 15.9, 15.8; exact mass
calcd for C25H35NO10P2: 571.1736, found 571.1734.
Assoa n in e (40). Ammonia was condensed in a three-neck
round-bottom flask (500 mL) under nitrogen at -78 °C; the
flask was provided with a cold-finger condenser containing dry
ice and acetone. Compound 44 (270 mg, 0.47 mmol) in dry
ether (18 mL) was added followed by sodium (76 mg, 3.3 mmol)
in small pieces. The mixture was stirred at -78 °C for 1 h
and then stirred at room temperature overnight to allow
ammonia to evaporate. The reaction was quenched with
methanol (20 mL) and saturated ammonium chloride (30 mL)
and extracted with ethyl acetate (3 × 20 mL). The combined
organic layer was dried over magnesium sulfate, and concen-
trated in vacuo. Chromatography (hexanes/EtOAc ) 4:1) gave
assoanine (40) (31 mg, 25%) as a light brown solid: mp 166-
168 °C (lit.,18 mp 175-176 °C). The 1H NMR and 13C NMR
data observed for this product are identical to those reported
in the literature for the natural product.17,18
9,10-Dim eth oxy-4,5,6,7-tetr a h yd r op yr r olop h en a n th r i-
d in e-8,11-d iol (43). A solution of 42 (250 mg, 0.84 mmol) in
p-xylene (150 mL) was added dropwise to a refluxing p-xylene
solution (200 mL, N2) during a 1 h and 45 min period, and the
mixture was refluxed for an additional 5 min. The solution
was cooled to room temperature and concentrated in vacuo.
Chromatography (methylene chloride/ethyl acetate ) 20:1)
gave product 43 (100 mg, 40%) as a purple solid: mp 130-
1
132 °C; IR (CDCl3) 3527 cm-1; H NMR (CDCl3, 300 MHz) δ
3.00 (t, J ) 8.1 Hz, 2H), 3.31 (t, J ) 8.1 Hz, 2H), 3.88 (s, 6H),
4.10 (s, 2H), 5.56 (s, 1H), 5.97 (s, 1H), 6.76 (t, J ) 7.4 Hz, 1H),
7.00 (dt, J ) 0.7, 7.3 Hz, 1H), 8.06 (d, J ) 7.7 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 149.8, 140.1, 138.3, 138.1, 138.0,
128.0, 125.2, 123.3, 119.3, 117.8, 114.8, 113.8, 60.8, 60.7, 55.4,
46.8, 29.0; exact mass calcd for C17H17NO4: 299.1157, found
299.1149.
In addition to 43, the hydroquinone 36 (125 mg 50%) was
also isolated from the chromatographic purification step. The
spectral data obtained for this compound were shown to be
identical to those realized from the minor (8%) product
obtained in the thermolysis of 33.
Ack n ow led gm en t. The authors thank the National
Institutes of Health (GM-36312) for financial support
of this work. We are also grateful to Catherine A.
Moore, J ohn Greaves, and J ohn A. Mudd for technical
assistance in obtaining high resolution mass spectral
data and to Dr. J oseph Ziller for X-ray crystallographic
analysis of 17e.
9,10-Dim et h oxy-4,5,6,7-t et r a h yd r o-8,11-b is[d iet h oxy-
p h osp h in yl)oxy]p yr r olop h en a n th r id in e (44). Sodium hy-
dride (313 mg, 50% in oil suspension, 6.52 mmol) was washed
with pentane (2 × 10 mL) and covered with THF (10 mL). To
the cooled (0 °C) solution of sodium hydride was added a
solution of 43 (650 mg, 2.17 mmol) in THF (20 mL). The
mixture was stirred at room temperature for 3 h, cooled to 0
°C, and diethyl chlorophosphonate (1.13 g, 6.52 mmol) was
added. The resulting solution was stirred at room temperature
overnight and then washed with saturated aqueous sodium
bicarbonate (40 mL). The aqueous layer was extracted with
ethyl acetate (3 × 30 mL), the combined organic layer was
washed with brine, dried over magnesium sulfate, and con-
centrated in vacuo. Chromatography (chloroform/methanol )
30:1) gave product 44 (890 mg, 72%) as a red oil: IR (neat)
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds 10a -c, 11, 12a ,b, 17a -f, 19a -f, 20a , 20c, 20e, 20f,
22a -f, 25-27, 31, 33-36, 38, 39, and 42-45 (43 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.
1632, 1426, 1280, 1084 cm-1
1.24 (t, J ) 5.9 Hz, 6H), 1.34(t, J ) 5.9 Hz, 6H), 3.00 (t, J )
,
1H NMR (CDCl3, 500 MHz) δ
J O9613803