Efficient synthesis of 1,4-dihydro-2H-isoquinoline-3,5,8-triones via cyclobutene ring expansion

Full text of DOI:10.1021/jo990089v

J . Org. Chem. 1999, 64, 6881-6887
6881
Efficien t Syn th esis of
1,4-Dih yd r o-2H-isoqu in olin e-3,5,8-tr ion es
via Cyclobu ten e Rin g Exp a n sion
Peter Wipf* and Corey R. Hopkins
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received J anuary 19, 1999
The thermal ring expansion and subsequent cyclization
of squaric acid derivatives has received much attention
as a valuable tool in organic synthesis over the past few
years.1,2 The versatility of this method is based on readily
available squaric acid derivatives and the plethora of
synthetic routes for alkynes.3 The squaric acid approach
has been used to construct many carbo- and heterocyclic
ring systems, such as hydroquinones, quinones, cyclo-
pentenones, piperidinoquinones, dihydrophenanthridines,
and benzophenanthridines.4 The facility of the electro-
cyclic ring opening is due to the release of strain present
in the cyclobutenone. The reaction is believed to involve
a ketene intermediate, generated by the cyclobutenone
ring opening, followed by a ring closure with the alkyne
moiety and further annulation depending on the R1 group
(Figure 1).1b The cascade of C,C-bond formations is
usually initiated at moderate temperatures (xylenes or
toluene, reflux) and occurs in satisfactory to excellent
yields.1
F igu r e 1.
F igu r e 2.
Sch em e 1
As part of our program directed toward the synthesis
of isoquinoline-containing natural products, we needed
an efficient method to construct an isoquinoline-3,5,8-
trione ring system. The squaric acid ring expansion
methodology was an attractive strategy for us since it
would allow access to this heterocycle in a convergent
manner. Xiong and Moore reported the preparation of a
related piperidinoquinone in 1996.5 However, this meth-
odology has not been extended to prepare the isoquino-
line-3,5,8-trione ring system 1 (Figure 2). Herein, we
report our studies toward the preparation of a variety of
heterocycles 1 in four steps from commercially available
carboxylic acids, 5, amines, 4, and squarates, 3.
Sch em e 2
Resu lts a n d Discu ssion
Acylation with 3,3-dimethylacrylolyl chloride- (for 6a )
or isobutyl chlorofomate-promoted coupling6 of carboxylic
acids 5b-d with propargylamine provided the R,â-
unsaturated amides 6b-d in 61-77% yield (Scheme 1).7
Amides 6a -d were N-benzylated (BnBr, NaH, THF, 0
°C) to give the tertiary amides 7a -d . The desired
cyclization precursors were subsequently obtained by
treatment of the alkynyl amides with LHMDS (-78 °C,
THF) followed by addition to a low-temperature solution
(-78 °C, THF) of the appropriate squarate 38,9 to yield
the cyclobutenones 2a -f in 47-87% yield (Scheme 2,
Table 1). R,â-Unsaturated amides with substituents R1
) H gave slightly lower yields due to product decomposi-
tion on silica gel during purification (Table 1, entries
(1) For recent reviews pertaining to this ring expansion, see: (a)
Decker, O. H. W.; Moore, H. W. Chem. Rev. 1986, 86, 821. (b) Yerxa,
B. R.; Moore, H. W. ChemTracts 1992, 273. (c) Liebeskind, L. S.
Tetrahedron 1989, 45, 3053. (d) Paquette, L. A.; Morwick, T. M.; Negri,
J . T.; Rogers R. D. Tetrahedron 1996, 52, 3075. (e) Danheiser R. L.;
Brisbois, R. G.; Kowalczyk, J . J .; Miller, R. F. J . Am. Chem. Soc. 1990,
112, 3093.
(2) For an example carried out on solid support, see: Tempest, P.
A.; Armstrong, R. W. J . Am. Chem. Soc. 1997, 119, 7607.
(3) Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J .
Org. Chem. 1988, 53, 2482.
(4) Moore, H. W.; Yerxa, B. R. In Advances in Strain in Organic
Chemistry; Halton, B., Ed.; J AI Press: London, 1995; Vol. 4, p 81.
(5) Xiong, Y.; Moore, H. W. J . Org. Chem. 1996, 61, 9168.
(6) Anderson, G. W.; Zimmerman, J . E.; Callahan, F. M. J . Am.
Chem. Soc. 1967, 89, 5012.
(8) Reed, M. W.; Pollart, D. J .; Perri, S. T.; Foland, L. D.; Moore, H.
W. J . Org. Chem. 1988, 53, 2477.
(9) Squarates 3b and 3d were prepared in two steps from the
commercially available diisopropoxy squarate according to ref 8.
(7) Amide 6a was obtained in 84% yield.
10.1021/jo990089v CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/11/1999

6882 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Ta ble 1. Ad d ition of Lith ia ted Am id e Alk yn es 7 to
Squ a r a tes 3 Accor d in g to Sch em e 2
Sch em e 4
squarate
R3
cyclobutenone
entry
no. no.
yield
(%)
R4
no. R1
R2
R3
R4
1
2
3
3a OMe
3b O-i-Pr Me
3c O-i-Pr O-i-Pr 2c
OMe
2a Me Me
OMe
O-i-Pr Me
OMe
72
61
2b
H
H
Ph
p-MeO- O-i-Pr O-i-Pr 55
C6H4
4
5
3d Me
Me
2d
H
p-Me-
C6H4
p-Me-
C6H4
2f Me Me
Me
Me
47
3e OEt
OEt
2e
H
OEt
OEt
NDa
87
6
3b O-i-Pr Me
O-i-Pr Me
a
This compound was directly used in the ring-opening cyclo-
isomerization reaction without prior purification by chromatog-
raphy.
Sch em e 3
hydrogen abstraction of the aryl radical in the putative
intermediate 9 from the benzylic carbon of the N-benzyl
substituent.5,11 In particular, this side reaction would be
of considerable concern in the trans-amide rotamer of 9
(vide infra). However, we were unable to isolate any
stable product derived from a 1,5-hydrogen atom shift,
and our further studies indicated that 1,5-hydrogen
abstraction is unlikely to be the major source of side
reactions in this cascade pathway.
To further explore the scope of this novel isoquinoline-
3,5,8-trione synthesis, we turned our attention to deriva-
tives of the heterocyclic core 1 with R5 * H, e.g., with
branching at the C(1)-position. Thus, the tosyl-protected
alcohol 11,12 derived from but-3-yn-2-ol, was converted
in 79% yield to the secondary amine 4b using benzyl-
amine in the presence of catalytic Cu(OTf)2 (Scheme
4).13,14 This amine was subsequently coupled with in situ
activated trans-cinnamic acid mixed anhydride6 to afford
the tertiary amide 7e in 61% yield. After deprotonation
of the alkyne moiety of 7e with LHMDS (-78 °C, THF),
addition to diethyl squarate 3e generated the cyclobuten-
one 2g, which was immediately subjected to the cycliza-
tion conditions. However, this compound did not undergo
the desired thermal ring expansion to the isoquinoline
trione skeleton, and only decomposition of the starting
material was observed. Since substrate 2g is likely to
favor an amide rotamer with a trans disposition between
the branched N-propargyl substituent and the styryl
moiety, a conformation suitable for annulation as shown
for 9 is energetically disfavored. The presence of the
methyl group at the crucial propargylic position in 2g is
therefore likely to promote side reactions leading to
product decomposition under the reaction conditions.
The correlation between the relative population of
favorable (cis) and unfavorable (trans) amide rotamers
in intermediates 9 derived from cyclobutenones 2, and
the ultimate success of the ring expansion strategy is
speculative but supported by our data from three sub-
sequent experiments. The N-tert-butyl-protected cycliza-
tion precursor 2h can be expected to favor the amide
2-5). In general, substrates 2a -f were stable for a few
days if kept under nitrogen in a freezer at -25 °C.
However, further conversions of these intermediates were
generally carried out shortly after preparation.
With the desired cyclization precursors 2 in hand, we
turned our attention to the thermal rearrangement
reaction.1-4 We investigated several solvents (toluene,
acetonitrile, R,R,R-trifluorotoluene, xylenes) at various
temperatures with 2a as the test substrate and deter-
mined that the optimal conditions involved the use of
degassed xylenes at reflux temperatures and moderate
dilution conditions (0.01-0.02 M concentrations). Ac-
cordingly, cyclobutenones 2a -f were dissolved in de-
gassed xylenes and slowly added (20-30 min) to refluxing
xylenes. Shortly after the addition was complete, the
reaction flask was cooled to room temperature, and
column chromatography on SiO2 provided the triones
1a -f in 45-55% yields as the only clearly identifiable
products (Scheme 3).10 It is possible that the moderate
yield of these thermal conversions is due to a 1,5-
(10) Quinone 1a was isolated along with the reduced hydroquinone
species 1a * in 58% yield. However, following Moore’s protocol,5,8 the
mixture was readily oxidized to the quinone (Ag2O, PhH, K2CO3) in
54% overall yield from 2a .
(11) However, use of an N-methyl group in place of the N-benzyl
function in 2a provided equivalent yields in the ring-opening rear-
rangement reaction.
(12) Tanabe, Y.; Yamamoto, H.; Yoshida, Y.; Miyawaki, T.; Utsumi,
N. Bull. Chem. Soc. J pn. 1995, 68, 297.
(13) Imada, Y.; Yuasa, M.; Ishin, N.; Murahashi, S. I. J . Org. Chem.
1994, 59, 2282.
(14) Wipf, P.; Uto, Y. Unpublished results.

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6883
Sch em e 5
Sch em e 6
Sch em e 7
rotamer distribution in a sense opposite to that of
substrate 2g, with the steric bulk of the N-tert-butyl
group locking the amide into a cis orientation of alkene
and alkyne substituents (Scheme 5).15 Cyclobutenone 2h
was prepared in three steps from tert-butylamine, pro-
pargyl bromide, cinnamate, and squarate 3c.16 This
substrate was then subjected to the cyclization conditions
(xylenes, reflux) to afford the trione 1h in an isolated
yield of 62%. This example illustrates that a sterically
hindered amide is well suited for ring annulation if the
amide conformation is favorable for the interconversion
of the formal diradicals 9 and 10. Since the isolated yields
with cyclobutenones 2a -f were in the 45-55% range,
whereas the conformationally strongly biased tert-butyl
amide 2h provided a slightly higher yield, we further
suggest that the cis arrangement of alkyne and alkene
moieties in the substrate is necessary for isoquinoline
formation but that there are also other decomposition
pathways for intermediates 8-10 that lead to intractable
material.
We were also interested in extending the scope of this
methodology to include readily removable protective
groups at the ring nitrogen. Since our working hypothesis
for successful cyclization demanded bulky groups at that
position, we first introduced a Boc function on amide 6a
(Scheme 6). Alkylation of cyclobutenone 3c proceeded
uneventfully, but the thermal ring expansion-cyclization
cascade stopped at an intermediate stage and provided
quinone 12 in 56% yield. We were unable to detect any
isoquinoline ring products in the crude reaction mixture.
While this novel result could be due to the unusual
conformational properties of the alkenimide moiety, we
believe that the lack of intramolecular radical addition
to the alkenimide function is due to the increased
unfavorable electronic polarization of the alkene moiety.
Even at relatively high dilution (0.015 M), intermolecular
hydrogen migration in 9 now successfully competes with
the radical annulation process.17 This mechanistically
intriguing but for us synthetically undesirable result was
readily improved upon by replacement of the Boc sub-
stituent with another acid-labile amide protective group.
The benzhydryl-protected cyclobutenone 2j was prepared
in three steps from amine 4d , cinnamoyl chloride, and
squarate 3c (Scheme 7). In this case, ring expansion-
cyclization proceeded uneventfully to give the desired
isoquinoline trione 1j, which was N-deprotected in a
mixture of trifluoroacetic acid, water, triethylsilane, and
thioanisole (92.5:2.5:2.5:2.5). The yield obtained in the
cascade step with the very bulky benzhydryl amide was
the highest (67%) observed so far, and no monocyclic
quinone derived from an intramolecular 1,5-hydrogen
abstraction5 or intermolecular migration was detected.
In conclusion, our study extends the scope of the
thermal ring expansion and cyclization of squaric acid
derived cyclobutenones toward an efficient and conver-
gent synthesis of the highly substituted 1,4-dihydro-2H-
isoquinoline-3,5,8-trione ring system. Previous routes to
these heterocycles often involve low-yielding multistep
annulations and linear arene functionalizations.18 The
cyclobutenone ring expansion proceeds in yields up to
67% from readily available precursors and tolerates
different substitution patterns on the alkene moiety (aryl
or alkyl) as well as the four-membered ring (dialkyl,
dialkoxy, monoalkyl/mono-alkoxy). Our work also pro-
vides compelling evidence that the amide conformational
preference and the electronic polarization of the acceptor
(18) For alternative preparations of related isoquinoline triones,
see: (a) Fukumi, H.; Kurihara, H.; Hata, T.; Tamura, C.; Mishima,
H.; Kubo, A.; Arai, T. Tetrahedron Lett. 1977, 3825. (b) Fukumi, H.;
Kurihara, H.; Mishima, H. Chem. Pharm. Bull. 1978, 26, 2175. (c)
Fukumi, H.; Kurihara, H. J . Heterocycl. Chem. 1978, 15, 569. (d)
Parker, K. A.; Casteel, D. A. J . Org. Chem. 1988, 53, 2847. (e)
Nakahara, S.; Tanaka, Y.; Kubo, A. Heterocycles 1996, 43, 2113.
(15) The trans-amide conformation shown for 7e is favored by ca. 2
kcal/mol over the cis conformation according to MacroModel MM2*
calculations. In contrast, the trans-amide conformation shown for 7f
is favored by ca. 9 kcal/mol.
(16) Ben-Efraim, D. A. Tetrahedron 1973, 29, 4111.
(17) Xia, H.; Moore, H. W. J . Org. Chem. 1992, 57, 3765.

6884 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
provided 857.6 mg (77%) of 6d as a colorless solid: mp 127.3-
ene can be a crucial factor in the success of the ring
expansion-cyclization cascade. Bulky R groups on cy-
clobutenones 2 are advantageous, and the benzhydryl
function allows a convenient N-deprotection under acidic
conditions.
1
128.6 °C; IR 3223, 1650, 1603, 729 cm-1; H NMR δ 7.65 (d, 1
H, J ) 15.6 Hz), 7.38 (d, 2 H, J ) 7.9 Hz), 7.14 (d, 2 H, J ) 7.8
Hz), 6.5-6.4 (m, 1 H), 6.45 (d, 1 H, J ) 15.5 Hz), 4.22-4.18 (m,
2 H), 2.35 (s, 3 H), 2.26 (t, 1 H, J ) 2.5 Hz); 13C NMR δ 166.1,
141.8, 140.2, 131.9, 129.6, 127.9, 118.9, 79.7, 71.7, 29.5, 21.5;
MS (EI) m/z (rel intensity) 199 (M+, 17), 198 ([M+ - H], 19),
156 (74), 145 (100); HRMS (EI) m/z calcd for C13H13NO 199.0997,
found 199.1000.
Exp er im en ta l Section
Gen er a l Meth od s. All moisture-sensitive reactions were
performed under an atmosphere of N2 or Ar, and all glassware
was dried in an oven at 140 °C prior to use. THF and Et2O were
dried by distillation over Na/benzophenone and LAH under a
nitrogen atmosphere, respectively. Dry CH2Cl2 and toluene were
obtained by distillation from CaH2. Unless otherwise stated,
solvents or reagents were used without further purification.
Analytical thin-layer chromatography (TLC) was performed on
precoated silica gel 60 F-254 plates (particle size 0.040-0.055
mm, 230-400 mesh). NMR spectra were recorded at either 300
MHz/75 MHz (1H/13C NMR) or 500 MHz/125 MHz (1H/13C NMR)
in CDCl3 unless stated otherwise. Chemical shifts (δ) are
reported in parts per million, and the residual solvent peak was
used as an internal standard. Data are reported as follows:
chemical shift, multiplicity (s ) singlet, d ) doublet, t ) triplet,
q ) quartet, m ) multiplet, b ) broad), integration, and coupling
constants.
N -Be n zyl-N -(1-m e t h yl-p r op -2-yn yl)-3-p h e n yla cr yla -
m id e (7e). According to general procedure A, 378.6 mg (2.556
mmol) of trans-cinnamic acid and 404.3 mg (2.548 mmol) of
propargylamine 4b provided 437.6 mg (61%) of 7e as a light
yellow oil: IR 3307, 1649, 1600, 733 cm-1; 1H NMR δ 7.76 (d, 1
H, J ) 15.3 Hz), 7.43-7.27 (m, 10 H), 6.63 (d, 1 H, J ) 15.3
Hz), 5.86-5.75 (m, 1 H), 4.91, 4.79 (AB, 2 H, J ) 17.8 Hz), 2.28
(s, 1 H), 1.39 (d, 3 H, J ) 6.9 Hz); 13C NMR δ 166.9, 143.8, 138.7,
135.2, 129.9, 128.9, 128.0, 127.5, 126.4, 118.1, 83.2, 72.5, 47.8,
42.6, 20.8; MS (EI) m/z (rel intensity) 289 (M+, 9), 236 (17), 131
(100); HRMS (EI) m/z calcd for C20H19NO 289.1467, found
289.1469.
N-ter t-Bu tyl-3-p h en yl-N-p r op -2-yn yla cr yla m id e (7f). Ac-
cording to general procedure A, 740.6 mg (5.000 mmol) of trans-
cinnamic acid and 789.4 mg (7.098 mmol) of propargylamine 4c
provided 770.5 mg (64%) of 7f as a colorless solid: mp 103.9-
1
105.5 °C; IR 3306, 2246, 1651, 1611, 732 cm-1; H NMR δ 7.60
3-Meth yl-bu t-2-en oic Acid P r op -2-yn yla m id e (6a ). A
solution of 3,3-dimethylacryloyl chloride (6.6 mL, 7.0 g, 59 mmol)
in 100 mL of Et2O was cooled to 0 °C and after 15 min treated
with propargylamine (5.0 g, 90 mmol) dropwise over a 20 min
period. After the addition was complete, the reaction mixture
was allowed to stir for 1 h at 0 °C, the precipitate was filtered,
and the Et2O solution was washed with 1 N HCl, NaHCO3
solution, and water. The organic layer was dried (MgSO4),
filtered, and concentrated in vacuo to afford 6.84 g (49.9 mmol,
84%) of amide 6a as a colorless solid: mp 87.2-88.8 °C; IR 3307,
1636, 1530, 754 cm-1; 1H NMR δ 5.71 (br. s, 1 H), 5.56 (s, 1 H),
4.1-4.03 (m, 2 H), 2.21 (t, 1 H, J ) 2.4 Hz), 2.16 (s, 3 H), 1.84
(s, 3 H); 13C NMR δ 166.9, 152.1, 117.9, 80.1, 71.2, 28.8, 27.3,
20.0; MS (EI) m/z (rel intensity) 137 (M+, 16), 83 (100), 79 (41);
HRMS (EI) m/z calcd for C8H11NO 137.0841, found 137.0845.
Gen er a l P r oced u r e A for th e Cou p lin g of Acid s w ith
P r opar gylam in e (6b-d, 7e,f). 3-P h en yl-N-pr op-2-yn ylacr yl-
a m id e (6b). A solution of trans-cinnamic acid (785.1 mg, 5.299
mmol), recrystallized from benzene, and N-methylmorpholine
(0.82 mL, 0.75 g, 7.46 mmol) in dry CH2Cl2 (50 mL) was cooled
to -20 °C and treated dropwise with 0.72 mL of isobutyl
chloroformate (0.76 g, 5.6 mmol). After 15 min, a solution of
propargylamine (0.5 mL; 401.5 mg; 7.288 mmol) in dry CH2Cl2
(10 mL) was added dropwise. The reaction mixture was warmed
to room temperature over 2 h and then washed with 1 M NaH2-
PO4, H2O, and brine. The organic layer was dried (MgSO4),
filtered, and concentrated. The resulting colorless solid was
recrystallized (hexanes/EtOAc) to afford 731.0 mg (3.950 mmol,
74%) of the desired amide 6b as a colorless solid: mp 102.1-
(d, 1 H, J ) 15.5 Hz), 7.53-7.49 (m, 2 H), 7.43-7.27 (m, 3 H),
6.94 (d, 1 H, J ) 15.4 Hz), 4.14 (d, 2 H, J ) 2.4 Hz), 2.37 (t, 1 H,
J ) 2.2 Hz), 1.55 (s, 9 H); 13C NMR δ 168.3, 141.9, 135.5, 129.6,
128.9, 127.9, 121.5, 81.3, 72.6, 58.0, 35.3, 28.8; MS (EI) m/z (rel
intensity) 241 (M+, 30), 240 ([M - H], 45), 131 (100), 103 (46);
HRMS (EI) m/z calcd for C16H18NO (M - H) 240.1388, found
240.1382.
Gen er a l P r oced u r e B for th e N-Ben zyla tion of Am id es
(7a -d ). N-Ben zyl P r op a r gyl 3,3-Dim eth yla cr yla m id e (7a ).
A solution of the amide 6a (2.875 g, 20.98 mmol) in dry THF
(30 mL) was transferred, via cannula, over a 10 min period to a
cooled (0 °C) suspension of NaH (1.078 g, 60% in oil, 26.95 mmol)
in THF (30 mL). The reaction mixture was warmed to room
temperature for 1 h and then recooled to 0 °C and treated with
neat benzyl bromide (6.2 mL, 52 mmol). The solution was stirred
overnight at room temperature and quenched by addition of H2O
(20 mL). The organic layer was washed with water and brine.
The aqueous layer was then extracted with Et2O, and the
combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on SiO2 (hexanes/EtOAc 7:3) to yield 4.42 g
(19.5 mmol, 93%) of the benzylated amide 7a as a yellow oil:
IR 3231, 1626, 1483, 953, 694 cm-1; 1H NMR δ 7.39-7.21 (m, 5
H), 5.93, 5.89 (2 s, 1 H), 4.74, 4.70 (2 s, 2 H), 4.20 (d, 1 H, J )
2 Hz), 3.97 (d, 1 H, J ) 2 Hz), 2.30, 2.21 (2 s, 1 H), 2.02, 1.99 (2
s, 3 H), 1.89, 1.84 (2 s, 3 H); 13C NMR δ 168.0, 149.2, 148.2,
137.0, 136.4, 128.9, 128.6, 128.4, 127.7, 127.5, 127.0, 117.5, 117.2,
79.1, 78.6, 73.0, 72.0, 50.5, 47.3, 36.8, 33.3, 26.5, 26.4, 20.4; MS
(EI) m/z (rel intensity) 227 (M+, 22), 91 (62), 83 (100); HRMS
(EI) m/z calcd for C15H17NO 227.1310, found 227.1309.
1
102.9 °C; IR 3307, 2360, 1662, 1625 cm-1; H NMR δ 7.68 (d, 1
H, J ) 15.6 Hz), 7.50-7.45 (m, 3 H), 7.35-7.27 (m, 3 H), 6.80-
6.70 (m, 1 H), 6.54 (d, 1 H, J ) 15.7 Hz), 4.23-4.18 (m, 2 H),
2.26 (t, 1 H, J ) 2.3 Hz); 13C NMR δ 166.1, 141.9, 134.7, 130.0,
129.0, 128.0, 120.1, 79.7, 71.8, 29.6; MS (EI) m/z (rel intensity)
185 (M+, 21), 142 (61), 131 (100), 103 (79); HRMS (EI) m/z calcd
for C12H11NO 185.0840, found 185.0849.
3-(4-Meth oxyp h en yl)-N-p r op -2-yn yla cr yla m id e (6c). Ac-
cording to general procedure A, 1.070 g (6.006 mmol) of 4-meth-
oxy-trans-cinnamic acid and 449.7 mg (8.163 mmol) of propar-
gylamine provided 789.5 mg (61%) of 6c as colorless needles:
N-Ben zyl-3-p h en yl-N-p r op -2-yn yla cr yla m id e (7b). Ac-
cording to general procedure B, 676.5 mg (3.655 mmol) of
propargyl amide 6b provided 942.5 mg (92%) of 7b as a yellow
1
oil: IR 3291, 3233, 1651, 1604, 978, 768, 694 cm-1; H NMR δ
7.82 (d, 1 H, J ) 15.4 Hz), 7.57-7.27 (m, 10 H), 6.99, 6.87 (2 d,
1 H, J ) 15.4 Hz), 4.84 (s, 1 H), 4.34, 4.09 (2 s, 2 H), 2.36, 2.26
(2 s, 1 H); 13C NMR δ 166.8, 144.3, 144.0, 136.9, 136.5, 135.1,
130.0, 129.1, 129.0, 128.6, 128.1, 126.9, 117.0, 79.0, 78.7, 73.2,
72.2, 50.4, 49.1, 36.7, 35.0; MS (EI) m/z (rel intensity) 275 (M+,
16), 184 (37), 131 (100), 91 (66), 61 (70); HRMS (EI) m/z calcd
for C19H17NO 275.1310, found 275.1304.
mp 122.6-123.5 °C; IR 3280, 3254, 2255, 1651, 1630, 1598 cm-1
;
1H NMR δ 7.62 (d, 1 H, J ) 15.6 Hz), 7.44 (d, 2 H, J ) 8.7 Hz),
6.86 (d, 2 H, J ) 8.7 Hz), 6.32 (d, 1 H, J ) 15.6 Hz), 6.25-6.15
(m, 1 H), 4.22-4.17 (m, 2 H), 3.82 (s, 3 H), 2.26 (t, 1 H, J ) 2.6
Hz); 13C NMR δ 166.4, 161.1, 141.6, 129.6, 127.5, 117.7, 114.4,
79.8, 71.8, 55.5, 29.6; MS (EI) m/z (rel intensity) 215 (M+, 11),
214 ([M-H]+, 14), 178 (76), 161 (100); HRMS (EI) m/z calcd for
C13H13NO2 215.0946, found 215.0942.
N -Be n zyl-3-(4-m e t h oxyp h e n yl)-N -p r op -2-yn yla cr yla -
m id e (7c). According to general procedure B, 667.1 mg (3.101
mmol) of propargyl amide 6c provided 868.4 mg (93%) of 7c as
a light yellow oil: IR 3291, 3233, 1730, 1646, 1604, 826, 736
cm-1; 1H NMR δ 7.78 (d, 1 H, J ) 15.3 Hz), 7.52-7.27 (m, 7 H),
6.93-6.75 (m, 3 H), 4.83 (s, 2 H), 4.33, 4.08 (2 s, 2 H), 3.82 (s, 3
H), 2.33, 2.24 (2 s, 1 H); 13C NMR δ 167.0, 161.0, 143.8, 143.6,
136.9, 136.5, 129.6, 129.0, 128.7, 128.4, 127.8, 127.7, 126.8, 114.5,
114.2, 79.0, 78.7, 73.0, 72.1, 55.3, 50.2, 49.0, 36.6, 34.8; MS (EI)
N-P r op -2-yn yl-3-p-tolyla cr yla m id e (6d ). According to gen-
eral procedure A, 902.6 mg (5.565 mmol) of 4-methyl-trans-
cinnamic acid and 417.6 mg (7.580 mmol) of propargylamine

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6885
m/z (rel intensity) 305 (M+, 27), 172 (68), 161 (100); HRMS (EI)
m/z calcd for C20H19NO2 305.1416, found 305.1404.
15.3 Hz), 7.42-7.24 (m, 7 H), 6.90-6.84 (m, 3 H), 4.89-4.76 (m,
4 H), 4.40 (d, 1 H, J ) 5.0 Hz), 4.14 (s, 1 H), 3.81 (s, 3 H), 1.4-
1.25 (m, 6 H), 1.3-1.15 (m, 6 H); 13C NMR δ 180.8, 167.2, 164.7,
161.1, 144.2, 143.9, 137.0, 136.6, 133.9, 129.7, 129.0, 128.7, 128.6,
127.8, 127.6, 126.9, 114.3, 83.8, 83.3, 79.9, 79.1, 78.5, 78.0, 74.1,
55.4, 50.4, 49.2, 37.2, 35.3, 22.8, 22.6; MS (FAB) m/z (rel
intensity) 526 ([M + Na]+, 100), 504 ([M + H]+, 22), 486 (45),
161 (97), 91 (81).
N-Ben zyl-N-p r op -2-yn yl-3-p -t olyla cr yla m id e (7d ). Ac-
cording to general procedure B, 815.7 mg (4.097 mmol) of
propargyl amide 6d provided 987.8 mg (83%) of 7d as a light
yellow oil: IR 3291, 3227, 2119, 1735, 1649, 1609, 810, 694 cm-1
;
1H NMR δ 7.80 (d, 1 H, J ) 15.3 Hz), 7.49-7.15 (m, 9 H), 6.94,
6.83 (2 d, 1 H, J ) 15.3 Hz), 4.84 (s, 2 H), 4.33, 4.09 (2 s, 2 H),
2.36-2.25 (m, 4 H); 13C NMR δ 167.0, 144.3, 144.0, 140.3, 136.5,
132.4, 129.7, 129.1, 128.8, 128.6, 128.1, 128.0, 127.8, 126.9, 126.7,
116.1, 115.8, 79.1, 73.1, 72.2, 50.4, 49.0, 36.7, 34.9, 21.6; MS (EI)
m/z (rel intensity) 289 (M+, 9), 156 (41), 145 (100); HRMS (EI)
m/z calcd for C20H19NO 289.1467, found 289.1460.
N-Ben zyl-N-[3-(1-h yd r oxy-2,3-d im eth yl-4-oxocyclobu t-2-
en yl)p r op -2-yn yl]-3-p-tolyla cr yla m id e (2d ). According to
general procedure C, 451.7 mg (1.562 mmol) of propargyl amide
7d and 226.2 mg (2.054 mmol) of squarate 3d provided 298.7
mg (47%) of 2d as a tan, waxy solid: IR 3306, 1767, 1644, 1604
cm-1; 1H NMR δ 7.77 (d, 1 H, J ) 15.3 Hz), 7.44-7.15 (m, 9 H),
6.89-6.75 (m, 1 H), 4.79, 4.73 (2 s, 2 H), 4.47-4.17 (m, 2 H),
2.36 (s, 3 H), 2.12, 2.06 (2 s, 3 H), 1.73 (s, 3 H); 13C NMR δ 177.0,
167.2, 150.8, 144.6, 144.2, 140.5, 136.5, 132.3, 131.9, 129.7, 129.3,
129.1, 128.9, 128.6, 128.2, 127.0, 126.8, 115.6, 86.0, 84.8, 79.2,
50.8, 35.6, 21.6, 10.8, 8.1; MS (FAB) m/z (rel intensity) 422 ([M
+ Na]+, 41), 400 ([M + H]+, 36), 368 (70), 154 (100), 91 (64).
3-Meth ylbu t-2-en oic Acid Ben zyl[3-(1-h yd r oxy-2-isop r o-
poxy-3-m eth yl-4-oxocyclobu t-2-en yl)pr op-2-yn yl]am ide (2f).
According to general procedure C, 564.6 mg (2.486 mmol) of
propargyl amide 7a and 343.5 mg (2.228 mmol) of squarate 3b
provided 733.7 mg (87%) of 2f as an orange oil: IR 3272, 2251,
1764, 1616 cm-1; 1H NMR δ 7.34-7.18 (m, 5 H), 5.88, 5.85 (2 s,
1 H), 5.01 (hept, 1 H, J ) 6.1 Hz), 4.7-4.65 (m, 2 H), 4.26 (s, 1
H), 4.03 (s, 1 H), 1.98, 1.96 (2 s, 3 H), 1.86, 1.82 (2 s, 3 H), 1.66,
1.64 (2 s, 3 H), 1.47-1.42 (m, 6 H); 13C NMR δ 187.8, 180.4,
168.3, 149.7, 148.7, 137.0, 136.4, 128.9, 128.7, 128.6, 127.8, 127.6,
127.1, 124.3, 117.4, 117.1, 84.9, 84.1, 83.0, 79.4, 78.5, 78.3, 50.7,
47.5, 37.4, 33.8, 26.7, 26.5, 23.0, 22.8, 20.5, 6.7, 6.6; MS (FAB)
m/z (rel intensity) 382 ([M + H]+, 100), 338 (76), 300 (77), 190
(75), 151 (85).
N-ter t-Bu tyl-N-[3-(1-h yd r oxy-2,3-d iisop r op oxy-4-oxocy-
clobu t-2-en yl)p r op -2-yn yl]-3-p h en yla cr yla m id e (2h ). Ac-
cording to general procedure C, 661.0 mg (2.743 mmol) of
propargyl amide 7f and 491.8 mg (2.481 mmol) of squarate 3c
provided 762.7 mg (69%) of 2h as a yellow sticky solid: IR 3295,
2251, 1774, 1626, 733 cm-1; 1H NMR δ 7.59-7.42 (m, 3 H), 7.39-
7.26 (m, 3 H), 6.88 (d, 1 H, J ) 15.4 Hz), 4.92, 4.82 (2 hept, 2 H,
J ) 6.1 Hz), 4.26-4.03 (m, 3 H), 1.51 (s, 9 H), 1.36 (t, 6 H, J )
6.5 Hz), 1.25 (t, 6 H, J ) 6.1 Hz); 13C NMR δ 180.8, 168.4, 164.7,
142.1, 135.4, 133.8, 129.6, 128.9, 128.0, 121.3, 85.7, 79.4, 78.6,
78.1, 74.3, 58.0, 35.8, 28.9, 22.8, 22.7, 22.6; MS (FAB) m/z (rel
intensity) 439 (M+, 20), 282 (25), 131 (100).
4-Isop r op oxy-3-m eth ylcyclobu t-3-en e-1,2-d ion e (3b).8 To
a cold (-20 °C) suspension of commercially available diisopro-
poxy squarate (1.190 g, 6.004 mmol) in dry THF (20 mL) was
added 4.4 mL of MeMgBr (1.5 M solution, 6.6 mmol, 1.1 equiv).
After 75 min, 20 mL of a saturated NH4Cl solution was added,
and the layers were separated. The aqueous layer was extracted
with Et2O. The combined organic layers were washed with brine,
dried (MgSO4), and concentrated. The resulting orange liquid
was purified by column chromatography on SiO2 (hexanes/EtOAc
7:3) to yield an inseparable mixture of the mono- and disubsti-
tuted products (961.3 mg). This mixture (1.265 g) was dissolved
in dry CH2Cl2 (26 mL) and treated with six drops of concentrated
HCl. After 1 h, TLC analysis showed product and 3d , and the
mixture was diluted with CH2Cl2, dried (K2CO3), and concen-
trated. The resulting orange liquid was purified using column
chromatography on SiO2 (hexanes/EtOAc 7:3) to afford 642.8 mg
(4.170 mmol, 69%) of the desired methyl isopropoxy squarate
3b as a yellow liquid: 1H NMR δ 5.29 (hept, 1 H, J ) 6.3 Hz),
2.12 (s, 3 H), 1.38 (d, 6 H, J ) 6.3 Hz).
Gen er a l P r oced u r e C for th e Ad d ition of th e Lith ia ted
Alk yn e to Cyclobu ten ed ion es (2a -d ,f,h -j). 3-Meth ylbu t-
2-en oic Acid Ben zyl[3-(1-h yd r oxy-2,3-d im eth oxy-4-oxocy-
clob u t -2-en yl)p r op -2-yn yl]a m id e (2a ). A solution of the
benzylated amide 7a (911.7 mg, 4.014 mmol) in 30 mL of dry
THF was cooled to -78 °C and treated dropwise with 6.0 mL of
LiHMDS (1.0 M solution in hexanes, 6.0 mmol). The resulting
alkynyllithium reagent was stirred for 10 min at -78 °C and
transferred, via cannula, to a cold (-78 °C) solution of dimethyl
squarate 3a (857.1 mg, 6.033 mmol) in 30 mL of dry THF. The
reaction mixture was allowed to stir for 2 h at -78 °C and
quenched with 50 mL of saturated NH4Cl solution. The aqueous
layer was extracted with EtOAc, and the combined organic
fractions were washed with brine, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by column chroma-
tography on SiO2 (hexanes/EtOAc; 1:1) to yield 1.06 g (2.87
mmol, 72%) of 2a as a viscous yellow oil: IR 3250, 2351, 1755,
1605, 721 cm-1; 1H NMR δ 7.36-7.19 (m, 5 H), 5.89, 5.87 (2 br.
s, 1 H), 4.71, 4.67 (2 s, 2 H), 4.28 (d, 1 H, J ) 1.7 Hz), 4.15 (2 s,
3 H), 4.07 (s, 1 H), 3.97, 3.96 (2 s, 3 H), 3.62, 3.58 (2 s, 1 H),
2.00, 1.98 (2 s, 3 H), 1.88, 1.83 (2 s, 3 H); 13C NMR δ 181.0,
168.5, 165.2, 150.1, 148.8, 136.9, 136.3, 135.4, 135.3, 128.9, 128.6,
128.5, 127.7, 127.6, 127.0, 117.3, 116.8, 84.3, 83.4, 79.2, 78.4,
60.2, 60.1, 58.7, 58.6, 50.9, 47.7, 37.4, 34.1, 26.7, 26.4, 20.5; MS
(FAB) m/z (rel intensity) 392 ([M + Na]+, 80), 369 (M+, 45), 352
(100).
[3-(1-H yd r oxy-2,3-d iisop r op oxy-4-oxocyclob u t -2-en yl)-
p r op -2-yn yl]-(3-m eth ylbu t-2-en oyl)ca r ba m ic Acid ter t-Bu -
tyl Ester (2i). According to general procedure C, 571.4 mg (2.408
mmol) of propargyl amide 7g and 601.4 mg (3.034 mmol) of
squarate 3c provided 806.2 mg (77%) of 2i as a yellow oil: IR
3411, 2981, 2253, 1776, 1736, 1632 cm-1; 1H NMR δ 6.44-6.40
(m, 1 H), 4.93, 4.85 (2 hept, 2 H, J ) 6.1 Hz), 4.52 (2s, 2 H), 2.98
(s, 1 H), 2.08 (2s, 3 H), 1.93 (2s, 3 H), 1.53 (s, 9 H), 1.40 (d, 6 H,
J ) 6.1 Hz), 1.29 (d, 3 H, J ) 6.1 Hz), 1.27 (d, 3 H, J ) 6.1 Hz);
13C NMR δ 179.9, 167.6, 163.9, 154.0, 119.6, 85.2, 83.6, 78.6,
76.7, 74.4, 33.7, 28.1, 27.6, 22.7, 22.5, 21.0; MS (FAB) m/z (rel
intensity) 435 (M+, 20), 318 (40), 276 (87), 234 (100).
N-Ben zyl-N-[(3-(1-h yd r oxy-2-isop r op oxy-3-m eth yl-4-oxo-
cyclobu t-2-en yl)p r op -2-yn yl]-3-p h en yla cr yla m id e (2b). Ac-
cording to general procedure C, 697.5 mg (2.535 mmol) of
propargyl amide 7b and 330.2 mg (2.142 mmol) of squarate 3b
provided 545.0 mg (61%) of 2b as an orange solid: mp 59.3-
N-Ben zh yd r yl-N-[3-(1-h yd r oxy-2,3-d iisop r op oxy-4-oxo-
cyclobu t-2-en yl)p r op -2-yn yl]-3-p h en yla cr yla m id e (2j). Ac-
cording to general procedure C, 654.9 mg (1.865 mmol) of
propargyl amide 7h and 499.7 mg (2.521 mmol) of squarate 3c
provided 654.7 mg (64%) of 2j as an orange amorphous solid:
1
1
60.9 °C; IR 3278, 2250, 1761, 1647, 1611 cm-1; H NMR δ 7.76
IR 3305, 3060, 2980, 2360, 1775, 1631 cm-1; H NMR δ 7.56-
(d, 1 H, J ) 15.4 Hz), 7.55-7.23 (m, 10 H), 6.93, 6.81 (2 d, 1 H,
J ) 15.3 Hz), 5.2-4.9 (m, 2 H), 4.8-4.7 (m, 2 H), 4.37, 4.13 (2
s, 2 H), 1.62 (s, 3 H), 1.44-1.26 (m, 6 H); 13C NMR δ 187.7, 180.4,
180.3, 166.9, 144.4, 144.2, 136.8, 136.4, 135.0, 130.0, 129.0, 128.9,
128.8, 128.6, 128.1, 127.9, 127.7, 126.9, 124.4, 117.0, 116.8, 84.8,
84.2, 83.0, 79.6, 78.9, 78.4, 50.4, 49.2, 37.2, 35.3, 23.0, 22.8, 6.7;
MS (FAB) m/z (rel intensity) 430 (M + H+, 10), 131 (100).
N -Be n zyl-N -[3-(1-h yd r oxy-2,3-d iisop r op oxy-4-oxocy-
clob u t -2-e n yl)p r op -2-yn yl]-3-(4-m e t h oxyp h e n yl)a cr yla -
m id e (2c). According to general procedure C, 455.2 mg (1.492
mmol) of propargyl amide 7c and 290.0 mg (1.463 mmol) of
squarate 3c provided 415.4 mg (55%) of 2c as an orange, waxy
7.02 (br. m, 18 H), 4.9-4.7 (m, 2 H), 4.21 (br. s, 2 H), 2.62 (2 br.
s, 1 H), 1.38 (d, 6 H, J ) 6.2 Hz), 1.35 (d, 3 H, J ) 6.1 Hz), 1.29
(d, 6 H, J ) 6.2 Hz); 13C NMR δ 180.0, 167.1, 164.1, 144.3, 143.8,
138.6, 135.1, 133.9, 129.9, 129.1, 128.9, 128.7, 128.1, 127.8, 117.8,
84.5, 79.3, 78.3, 76.8, 74.1, 65.7, 64.5, 61.7, 60.5, 35.4, 22.7, 22.6,
22.5; MS (FAB) m/z (rel intensity) 167 (100), 131 (21).
2-Ben zyl-4-isop r op yl-6,7-d im eth oxy-1,4-d ih yd r o-2H-iso-
qu in olin e-3,5,8-tr ion e (1a ). A solution of 2a (1.019 g, 2.762
mmol) in 15 mL of freshly degassed xylenes was added via
syringe pump over a 30 min period to 130 mL of refluxing
degassed xylenes. The solution was heated at reflux for an
additional 30 min, cooled to room temperature, and concentrated
in vacuo leaving a dark red oil. The residue was purified by
solid: IR 3295, 1774, 1631 cm-1 1H NMR δ 7.75 (d, 1 H, J )
;

6886 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
column chromatography on SiO2 (hexanes/EtOAc 1:1) to yield
599.1 mg (1.623 mmol, 58%) of a ca. 1:1 mixture of the oxidized
and reduced compounds 1a and 1a * as a red oil. A solution of
the combined mixture of 1a and 1a * (486.1 mg, 1.317 mmol),
Ag2O (1.503 g, 6.486 mmol), and potassium carbonate (906.3 mg,
6.557 mmol) in benzene (15 mL) was stirred at room temperature
overnight, passed through a small plug of SiO2, and concentrated
in vacuo to afford 447.0 mg (1.211 mmol; 93%) of the quinone
1a as a red oil. A portion of this material (100.4 mg) was further
purified by rotary chromatography on SiO2 (hexanes/EtOAc/CH2-
Cl2 7:5:3) to yield 47.2 mg (47%) of pure 1a as a red oil: IR 3053,
1672, 1657, 1623, 738 cm-1; 1H NMR δ 7.34-7.30 (m, 5 H), 4.86
(d, 1 H, J ) 14.4 Hz), 4.56 (d, 1 H, J ) 14.4 Hz), 4.24 (dd, 1 H,
J ) 19.9, 1.3 Hz), 4.06 (dd, 1 H, J ) 19.9, 2.8 Hz), 4.03 (s, 6 H),
3.66-3.62 (m, 1 H), 2.18-2.12 (m, 1 H), 1.15 (d, 3 H, J ) 6.8
Hz), 0.87 (d, 3 H, J ) 6.9 Hz); 13C NMR δ 182.1, 181.7, 168.0,
145.1, 144.6, 139.1, 136.4, 134.2, 128.9, 128.7, 128.0, 61.5, 50.3,
45.6, 45.4, 34.4, 21.4, 19.3; MS (EI) m/z (rel intensity) 367 ([M
45 min, the reaction mixture was quenched by addition to 40
mL of a saturated NH4Cl solution. The layers were separated
and the aqueous layer was extracted with EtOAc. The organic
layers were combined, washed with brine, dried (MgSO4),
filtered, and concentrated in vacuo. The resulting dark red oil
(695.9 mg) was carried on without further purification. A
solution of the crude alcohol in freshly degassed xylenes (20 mL)
was added over a 35 min period to 90 mL of degassed, refluxing
xylenes. After the addition was complete, the mixture was cooled
to room temperature and concentrated. The resulting red oil was
purified by column chromatography on SiO2 (hexanes/EtOAc/
CH2Cl2, 6:2:2) to afford 241.6 mg (0.5261 mmol, 33% based on
7d ) of the desired trione 1e as a red oil: IR 2981, 1652, 1605
1
cm-1; H NMR δ 7.34-7.21 (m, 5 H), 6.83 (d, 2 H, J ) 7.8 Hz),
6.73 (d, 2 H, J ) 8.0 Hz), 4.66 (d, 1 H, J ) 14.4 Hz), 4.37 (d, 2
H, J ) 14.3 Hz), 4.39-4.20 (m, 4 H), 4.00-3.93 (m, 1 H), 3.81
(dd, 1 H, J ) 19.7, 2.1 Hz), 3.44 (dd, 1 H, J ) 13.4, 4.7 Hz), 2.99
(dd, 1 H, J ) 13.4, 4.7 Hz), 2.78 (dd, 1 H, J ) 19.7, 3.6 Hz), 2.23
(s, 3 H), 1.42 (t, 3 H, J ) 7.1 Hz), 1.37 (t, 3 H, J ) 7.1 Hz); 13C
NMR δ 182.3, 181.6, 168.4, 144.8, 144.4, 137.3, 136.7, 135.8,
135.0, 133.2, 129.7, 129.6, 128.9, 128.8, 128.0, 70.0, 69.9, 50.2,
44.7, 41.5, 38.4, 21.2, 15.7; MS (EI) m/z (rel intensity) 459 (M+,
- H2]+, 46), 276 (52), 91 (100); HRMS (EI) m/z calcd for C21H21
NO5 (M - H2) 367.1420, found 367.1407.
-
Gen er al P r ocedu r e D for Rin g Expan sion of Cyclobu ten -
on e P r ecu r sor s (1b-d ,f,h ,j). 2,4-Diben zyl-6-isop r op oxy-7-
m eth yl-1,4-d ih yd r o-2H-isoqu in olin e-3,5,8-tr ion e (1b). A so-
lution of the alcohol 2b (306.8 mg, 0.7148 mmol) in freshly
degassed xylenes (10 mL) was added dropwise over a 20 min
period to 40 mL of refluxing, degassed xylenes. After the addition
was complete, the reaction mixture was cooled to room temper-
ature and concentrated in vacuo. The resulting red oil was
purified by column chromatography on SiO2 (hexanes/EtOAc/
CH2Cl2 6:1:3) to afford 154.6 mg (0.3602 mmol, 51%) of the
desired isoquinolinone 1b as an orange-red oil: IR 3030, 2981,
2251, 1643, 909, 734, 649 cm-1; 1H NMR δ 7.32-6.84 (m, 10 H),
4.76 (hept, 1 H, J ) 6.1 Hz), 4.68 (d, 1 H, J ) 14.3 Hz), 4.37 (d,
1 H, J ) 14.3 Hz), 4.08-4.0 (m, 1 H), 3.86 (dd, 1 H, J ) 19.8,
2.0 Hz), 3.46 (dd, 1 H, J ) 13.4, 5.0 Hz), 3.07 (dd, 1 H, J ) 13.3,
4.6 Hz), 2.84 (dd, 1 H, J ) 19.9, 3.5 Hz), 1.92 (s, 3 H), 1.34, (d,
3 H, J ) 6.1 Hz), 1.32 (d, 3 H, J ) 6.1 Hz); 13C NMR δ 185.3,
181.6, 168.7, 154.9, 137.1, 136.7, 136.5, 135.8, 130.7, 129.7, 129.0,
128.9, 128.3, 128.0, 127.2, 76.7, 50.3, 45.0, 41.4, 38.8, 23.1, 9.2;
MS (EI) m/z (rel intensity) 429 (M+, 46), 172 (86), 161 (100),
133 (39), 91 (70); HRMS (EI) m/z calcd for C27H27NO4 429.1940,
found 429.1944.
66), 356 (43), 326 (100), 91 (34); HRMS (EI) m/z calcd for C28H29
-
NO5 459.2046, found 459.2051.
2-Ben zyl-6-isopr opoxy-4-isopr opyl-7-m eth yl-1,4-dih ydr o-
2H-isoqu in olin e-3,5,8-tr ion e (1f). According to general pro-
cedure D, 299.3 mg (0.7852 mmol) of cyclobutenone 2f provided
134.7 mg (45%) of 1f as an orange oil: IR 2970, 2253, 1661, 1642,
1
909, 732 cm-1; H NMR δ 7.33-7.27 (m, 5 H), 4.83-4.78 (m, 2
H), 4.58 (d, 1 H, J ) 14.4 Hz), 4.24 (dd, 1 H, J ) 20.2, 1.6 Hz),
4.05 (dd, 1 H, J ) 20.1, 2.8 Hz), 3.64-3.60 (m, 1 H), 2.2-2.05
(m, 1 H), 1.93 (s, 3 H), 1.32 (d, 3 H, J ) 6.1 Hz), 1.29 (d, 3 H, J
) 6.2 Hz), 1.08 (d, 3 H, J ) 6.8 Hz), 0.85 (d, 3 H, J ) 7.0 Hz);
13C NMR δ 185.7, 181.8, 168.3, 155.0, 139.0, 136.5, 135.9, 130.4,
128.9, 128.7, 128.0, 76.6, 50.3, 45.7, 45.5, 34.3, 23.1, 21.4, 19.4,
9.1; MS (EI) m/z (rel intensity) 381 (M+, 100), 339 (26), 296 (65),
91 (29); HRMS (EI) m/z calcd for C23H27NO4 381.1940, found
381.1941.
2-ter t-Bu t yl-4-b en zyl-6,7-d iisop r op oxy-1,4-d ih yd r o-2H-
isoqu in olin e-3,5,8-tr ion e (1h ). According to general procedure
D, 350.7 mg (0.7984 mmol) of cyclobutenone 2h provided 218.0
mg (62%) of 1h as a red oil: IR 2979, 1653, 1603 cm-1; 1H NMR
δ 7.16-7.14 (m, 3 H), 6.94-6.91 (m, 2 H), 4.77 (hept, 2 H, J )
6.3 Hz), 4.08 (dd, 1 H, J ) 19.7, 1.6 Hz), 3.85-3.80 (m, 1 H),
3.44 (dd, 1 H, J ) 13.3, 4.6 Hz), 2.98 (dd, 1 H, J ) 13.3, 4.8 Hz),
2.76 (dd, 1 H, J ) 19.8, 3.6 Hz), 1.39 (s, 9 H), 1.35-1.29 (m, 12
H); 13C NMR δ 182.9, 182.3, 169.2, 145.9, 145.5, 137.1, 136.9,
135.6, 130.0, 128.2, 127.2, 76.5, 76.4, 58.6, 43.6, 42.1, 38.9, 28.2,
22.8, 22.7; MS (EI) m/z (rel intensity) 439 (M+, 61), 397 (35),
340 (50), 256 (90), 91 (100); HRMS (EI) m/z calcd for C26H33NO5
439.2359, found 439.2354.
2-Ben zh yd r yl-4-ben zyl-6,7-d iisop r op oxy-1,4-d ih yd r o-2H-
isoqu in olin e-3,5,8-tr ion e (1j). According to general procedure
D, 310.0 mg (0.5644 mmol) of cyclobutenone 2j provided 207.7
mg (67%) of 1j as a red oil: IR 2980, 2935, 2252, 1654 cm-1; 1H
NMR δ 7.40-7.19 (m, 10 H), 7.05-6.95 (m, 2 H), 6.85-6.72 (m,
3 H), 4.85, 4.73 (2 hept, 2 H, J ) 6.1 Hz), 4.15-4.08 (m, 1 H),
3.90 (dd, 1 H, J ) 19.7, 1.7 Hz), 3.52 (dd, 1 H, J ) 13.4, 4.3 Hz),
3.08 (dd, 1 H, J ) 13.5, 5.0), 2.47 (dd, 1 H, J ) 19.7, 3.7 Hz),
1.38 (d, 3 H, J ) 6.2 Hz), 1.35 (d, 3 H, J ) 6.1 Hz), 1.29 (d, 6 H,
J ) 6.2 Hz); 13C NMR δ 182.8, 181.9, 169.1, 146.1, 145.4, 137.7,
137.4, 137.3, 136.4, 135.6, 130.4, 129.6, 129.0, 128.9, 128.8, 128.3,
128.1, 127.6, 127.5, 127.0, 126.1, 76.6, 76.5, 59.8, 42.1, 41.2, 38.7,
23.1, 22.9, 22.8, 22.7; MS (EI) m/z (intensity) 549 (M+, 75), 437
(35), 167 (100); HRMS (EI) m/z calcd for C35H35NO5 549.2515,
found 549.2510.
2-Ben zyl-6,7-d iisop r op oxy-4-(4-m et h oxyb en zyl)-1,4-d i-
h yd r o-2H-isoqu in olin e-3,5,8-tr ion e (1c). According to general
procedure D, 292.5 mg (0.5812 mmol) of cyclobutenone 2c
provided 161.4 mg (55%) of 1c as a red oil: IR 2978, 1653, 1604
1
cm-1; H NMR δ 7.32-7.27 (m, 5 H), 6.71 (d, 2 H, J ) 8.6 Hz),
6.49 (d, 2 H, J ) 8.6 Hz), 4.81, 4.75 (2 hept, 2 H, J ) 6.1 Hz),
4.56, 4.49 (AB, 2 H, J ) 14.3 Hz), 4.0-3.9 (m, 1 H), 3.84 (dd, 1
H, J ) 19.7, 2.1 Hz), 3.69 (s, 3 H), 3.43 (dd, 1 H, J ) 13.6, 4.4
Hz), 2.96 (dd, 1 H, J ) 13.6, 4.7 Hz), 2.82 (dd, 1 H, J ) 19.7, 3.4
Hz), 1.36-1.26 (m, 12 H); 13C NMR δ 182.8, 182.0, 168.5, 158.7,
145.9, 145.4, 137.3, 135.9, 135.1, 130.7, 129.2, 128.8, 128.3, 128.0,
113.5, 76.5, 76.4, 55.3, 50.4, 44.8, 41.6, 38.0, 22.8, 22.7; MS (EI)
m/z (rel intensity) 503 (M+, 33), 121 (100), 91 (60); HRMS (EI)
m/z calcd for C30H33NO6 503.2308, found 503.2302.
2-Ben zyl-6,7-d im eth yl-4-(4-m eth yl-ben zyl)-1,4-d ih yd r o-
2H-isoqu in olin e-3,5,8-tr ion e (1d ). According to general pro-
cedure D, 249.2 mg (0.6243 mmol) of cyclobutenone 2d provided
126.6 mg (51%) of 1d as an orange-red oil: IR 2923, 1650 cm-1
;
1H NMR δ 7.36-7.20 (m, 5 H), 6.83 (d, 2 H, J ) 7.6 Hz), 6.73 (d,
2 H, J ) 7.7 Hz), 4.69 (d, 1 H, J ) 14.4 Hz), 4.34 (d, 1 H, J )
14.4 Hz), 4.02-3.95 (m, 1 H), 3.82 (d, 1 H, J ) 19.6 Hz), 3.46
(dd, 1 H, J ) 13.4, 4.6 Hz), 2.98 (dd, 1 H, J ) 13.3, 4.2 Hz), 2.77
(dd, 1 H, J ) 19.5, 3.1 Hz), 2.24 (s, 3 H), 2.08, 2.01 (2 s, 6 H);
13C NMR δ 185.2, 184.5, 168.7, 141.5, 140.8, 138.8, 136.7, 136.6,
135.9, 133.3, 129.7, 128.9, 128.8, 127.9, 50.2, 44.8, 41.7, 38.4,
21.2, 12.6, 12.3; MS (EI) m/z (rel intensity) 399 (M+, 53), 306
(58), 266 (100), 91 (68); HRMS (EI) m/z calcd for C26H25NO3
399.1834, found 399.1838.
4-Ben zyl-6,7-d iisop r op oxy-1,4-d ih yd r o-2H-isoqu in olin e-
3,5,8-tr ion e (1j′). A solution of quinone 1j (36.8 mg; 0.0670
mmol) in 2 mL of a mixture of TFA/Et3SiH/thioanisole/H2O (92.5:
2.5:2.5:2.5) was heated at 50 °C overnight. The reaction mixture
was cooled to room temperature. The red, oily residue was
purified by chromatography on SiO2 (hexanes/EtOAc 1:1) to yield
18.9 mg (0.0493 mmol, 70%) of 1j′ as a orange/red oil: IR 3410,
2-Ben zyl-6,7-d iet h oxy-4-(4-m et h ylb en zyl)-1,4-d ih yd r o-
2H-isoqu in olin e-3,5,8-tr ion e (1e). To a cooled (-78 °C) solu-
tion of the benzylated amide 7d (459.3 mg, 1.588 mmol) in dry
THF (12 mL) was added 1.8 mL of LHMDS (1.0 M solution in
THF, 1.8 mmol). After 15 min, the alkynyllithium reagent was
transferred via cannula to a cold (-78 °C) solution of the
squarate 3e (276.0 mg, 1.622 mmol) in dry THF (12 mL). After
2982, 2253, 1666 cm-1 1H NMR δ 7.22-7.10 (m, 3 H), 7.00-
;
6.95 (m, 2 H), 6.01 (br. s, 1 H), 4.80 (hept, 2 H, J ) 6.0 Hz),
4.00-3.90 (2 m, 2 H), 3.46 (dd, 1 H, J ) 13.4, 4.4 Hz), 3.06 (dd,
1 H, J ) 13.4, 5.0 Hz), 2.93 (dd, 1 H, J ) 19.5, 3.3 Hz), 1.38-

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6887
1.26 (m, 12 H); 13C NMR δ 182.7, 181.9, 170.8, 137.1, 136.4,
135.2, 129.7, 128.3, 127.2, 76.6, 76.3, 40.7, 40.2, 38.3, 22.7, 22.6;
MS (EI) m/z (intensity) 385 (M + H2, 35), 294 (21), 252 (81), 210
(100); HRMS (EI) m/z calcd for C22H27NO5 (M + H2) 385.1889,
found 385.1890.
organic layer was dried (MgSO4), and the residue was purified
by chromatography on SiO2 (hexanes/EtOAc 8:2) to yield 571.4
mg (2.408 mmol, 97%) of the desired Boc-amide 7g as a light
yellow oil: IR 3275, 2979, 1732, 1677 cm-1 1H NMR δ 6.42-
;
6.38 (m, 1 H), 4.43 (d, 2 H, J ) 2.6 Hz), 2.13 (t, 1 H, J ) 2.6 Hz),
2.08 (s, 3 H), 1.92 (s, 3 H), 1.53 (s, 9 H); 13C NMR δ 167.8, 154.0,
152.5, 119.8, 83.6, 80.0, 70.2, 33.7, 28.2, 27.7, 21.1; MS (EI) m/z
(rel intensity) 181 (M+, 21), 83 (91), 57 (100); HRMS (EI) m/z
calcd for C9H11NO3 181.0739, found 181.0736.
Ben zyl(1-m eth yl-p r op -2-yn yl)a m in e (4b).13 A solution of
Cu(OTf)2 (28.7 mg, 0.0794 mmol) in 6.0 mL of 1,4-dioxane was
cooled to 10 °C and treated with 1.2 mL of benzylamine (1.2 g,
11 mmol). After 15 min, a solution of the tosyl alcohol 11 (1.17
g, 5.22 mmol) in 1,4-dioxane (6.0 mL) was slowly added. The
reaction mixture was warmed to room temperature, stirred for
3 h, and extracted with 1 N HCl. The aqueous layer was
neutralized with NaOH and then extracted with EtOAc. The
organic extracts were dried (Na2SO4) and concentrated. The
resulting greenish oil was purified by column chromatography
on SiO2 (hexanes/EtOAc 8:2) to afford 652.8 mg (4.099 mmol,
79%) of the desired secondary amine 4b as a yellow liquid: 1H
NMR δ 7.41-7.28 (m, 5 H), 4.05 (d, 1 H, J ) 12.8 Hz), 3.84 (d,
1 H, J ) 12.8 Hz), 3.52 (dq, 1 H, J ) 6.8, 2.0 Hz), 2.36 (d, 1 H,
J ) 1.9 Hz), 1.79 (br s, 1 H), 1.42 (d, 3 H, J ) 7.0 Hz).
N-Ben zh yd r yl-3-p h en yl-N-p r op -2-yn yla cr yla m id e (7h ).
To a solution of the amine 4d (881 mg; 3.98 mmol) and Hu¨nig’s
base (0.84 mL; 620 mg; 4.8 mmol) in 6 mL of dry CH2Cl2 was
added a solution of cinnamoyl chloride (942 mg; 5.67 mmol) in
dry CH2Cl2, and the mixture was stirred overnight. After
addition of water, the organic fraction was washed with brine,
dried (MgSO4), and concentrated leaving a dark oil. The residue
was purified by chromatography on SiO2 (hexanes/EtOAc 8:2)
to afford 1.397 g (100%) of the desired amide 7h as a yellow oil:
IR 3303, 3029, 2245, 1651, 1608 cm-1; 1H NMR δ 7.82-7.27 (m,
18 H), 4.15 (d, 2 H, J ) 2.1 Hz), 2.14 (br. s, 1 H); 13C NMR δ
167.1, 144.0, 138.9, 135.2, 129.9, 129.0, 128.9, 128.7, 128.4, 128.1,
127.8, 127.5, 118.1, 79.8, 72.6, 61.9, 35.0; MS (EI) m/z (rel
intensity) 351 (M+, 65), 312 (90), 182 (86), 131 (100); HRMS (EI)
m/z calcd for C25H21NO: 351.1623, found 351.1622.
ter t-Bu tylp r op -2-yn yla m in e (4c).16 To a cold (0 °C) solution
of tert-butylamine (13.6 mL, 9.47 g; 129 mmol) in H2O (7 mL)
was added 2.4 mL of propargyl bromide (80% in PhCH3, 22
mmol) over a 40 min period. The reaction mixture was slowly
warmed to room temperature and stirred overnight. After
addition of 1 g of NaOH pellets, the mixture was extracted with
Et2O, and the organic extract was washed with brine, dried (K2-
CO3), and concentrated to afford 1.118 g (10.05 mmol, 47%) of
the desired secondary amine 4c along with the dipropargylated
tertiary amine as a 10:1 ratio of products: 1H NMR δ 3.33 (d, 2
H, J ) 2.1 Hz), 2.15 (t, 1 H, J ) 2.7 Hz), 1.08 (s, 9 H).
(4,5-Diisop r op oxy-3,6-d ioxocycloh ex-1,4-d ien ylm eth yl)-
(3-m eth ylbu t-2-en oyl)ca r ba m ic Acid ter t-Bu tyl Ester (12).
A solution of cyclobutenone 2i (339.3 mg; 0.7796 mmol) in freshly
degassed xylenes (10 mL) was added dropwise over a 20 min
period to 40 mL of refluxing, degassed xylenes. After an
additional 30 min, the reaction mixture was cooled to room
temperature and concentrated in vacuo. The resulting red oil
was purified by chromatography on SiO2 (hexanes/EtOAc 8:2)
to afford 188.4 mg (0.4329 mmol, 56%) of the monocyclized
Ben zh yd r ylp r op -2-yn yla m in e (4d ).19 A solution of diphe-
nylmethylamine (3.0 mL; 3.2 g; 17 mmol) in 40 mL of dry ether
was treated with 1.35 mL of propargyl bromide (80% in toluene;
12.2 mmol) and a catalytic amount of NaI. This mixture was
heated at reflux for 16 h, cooled to room temperature, washed
with water, and concentrated, leaving an orange oil. The residue
was purified using column chromatography on SiO2 (hexanes/
EtOAc 95:5) to afford 1.14 g (5.14 mmol; 42%) of the desired
amine 4d as a pale yellow solid: 1H NMR δ 7.47-7.21 (m, 10
H), 5.13 (s, 1 H), 3.39 (d, 2 H, J ) 2.4 Hz), 2.28 (t, 1 H, J ) 2.3
Hz), 1.80 (br s, 1 H).
product 12 as a red oil: IR 3020, 2981, 1730, 1657, 1597 cm-1
;
1H NMR δ 6.47-6.45 (m, 1 H), 6.15 (t, 1 H, J ) 1.8 Hz), 4.84,
4.75 (2 hept, 2 H, J ) 6.1 Hz), 4.68 (d, 2 H, J ) 2.0 Hz), 2.07 (d,
3 H, J ) 1.1 Hz), 1.94 (2, 3 H, J ) 0.9 Hz), 1.44 (s, 9 H), 1.29 (d,
6 H, J ) 6.2 Hz), 1.28 (d, 6 H, J ) 6.3 Hz); 13C NMR δ 184.5,
184.1, 168.1, 154.7, 152.4, 145.5, 143.4, 128.3, 119.4, 83.7, 76.2,
76.1, 42.2, 28.0, 27.6, 22.7, 21.0; MS (EI) m/z (rel intensity) 435
(M+, 7), 295 (17), 83 (100); HRMS (EI) m/z calcd for C23H33NO7
435.2257, found 435.2240.
(3-Met h ylb u t -2-en oyl)p r op -2-yn ylca r b a m ic Acid ter t-
Bu tyl Ester (7g). A solution of amide 6a (340.2 mg; 2.482 mmol)
in dry CH2Cl2 (8 mL) was treated under N2 with Boc2O (1.044
g; 4.784 mmol), DMAP (91.0 mg; 0.745 mmol), and Et3N (0.35
mL; 250 mg; 2.5 mmol). The reaction mixture was stirred at
room temperature for 6 h, diluted with ether, and washed with
aqueous HCl, saturated NaHCO3 solution, and brine. The
Ack n ow led gm en t. Financial support of this re-
search from the National Institutes of Health (GM55433
and CA78039) is gratefully acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 6a -d , 7a -h , 2a -d ,f,h -j, 1a -f,h ,j,j′, and 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Duckworth, M. D.; Wong, S. L.; Slawin, A. M. Z.; Smith, E. H.;
Williams, D. J . J . Chem. Soc. Perkins Trans. 1 1996, 815.
J O990089V