[3 + 2] Cycloaddition Reactions of 4-Alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium Inner Salts

Article abstract of DOI:10.1021/jo034160f

Heating dipolarophiles with 4-alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide inner salts results in [3 + 2] cycloaddition across positions 3a and 5 of the aromatic system to give the [3 + 2] cycloadducts in good yield. When the 4-alkyl substit

Full text of DOI:10.1021/jo034160f

[3 + 2] Cycloa d d ition Rea ction s of
4-Alk yl-3-h yd r oxy-2H-p yr a zolo[4,3-c]iso-
qu in olin iu m In n er Sa lts
Eifion D. Phillips,* Simon C. Hirst,†
Matthew W. D. Perry, and J ane Withnall
Department of Medicinal Chemistry, AstraZeneca R&D
Charnwood, Bakewell Road, Loughborough, Leicestershire
LE11 5RH, United Kingdom
F IGURE 1. Compounds 1-3.
cerned with the investigation of the properties of com-
pounds related to 1 and 2.
eifion.phillips@astrazeneca.com
Received February 5, 2003
The inner salt 5 was prepared by the route6 shown in
Scheme 1 (PMB ) 4-methoxybenzyl), analogous to the
procedure described by Cook and co-workers for related
compounds.7 The condensation of keto-ester 4 with 4-tri-
fluoromethylphenylhydrazine proceeded with concomi-
tant oxidation of the isoquinoline ring to produce the fully
aromatic, intensely purple, formally zwitterionic com-
pound 5 directly. Compound 5 then underwent loss of
the PMB group upon heating in trifluoroacetic acid to
give the acidic (pKa ∼6) phenolic compound 6. The
alkoxide anion resulting from deprotonation of the hy-
droxy compound 6 could, as a result of delocalization of
the negative charge, in principle undergo electrophilic
attack at any of three positions: N-1, N-4, or the alkoxide
oxygen. We observed, however, that upon treatment with
potassium carbonate and appropriate alkyl halides in
DMF, alkylation occurred predominantly at N-4 to give
compounds 7 and 8 as the only isolated products,
although the formation of minor amounts of byproducts
resulting from alkylation at the alternative alkylation
positions is a possibility.
Abstr a ct: Heating dipolarophiles with 4-alkyl-3-hydroxy-
2H-pyrazolo[4,3-c]isoquinolinium hydroxide inner salts re-
sults in [3 + 2] cycloaddition across positions 3a and 5 of
the aromatic system to give the [3 + 2] cycloadducts in good
yield. When the 4-alkyl substituent is a 2-acetate ester and
the methylene group can be deprotonated, a second mode of
[3 + 2] cycloaddition becomes available for the resulting
anion (across the side chain methine group and position 5
of the aromatic system) and occurs under basic conditions,
allowing either of two modes of [3 + 2] cycloaddition to be
selected by appropriate choice of reaction conditions.
Benzodiazepine receptor ligands have been of long
standing interest in medicinal chemistry due to the wide
range of pharmacological actions they mediate.1 Cook and
co-workers2 reported the investigation of 2-aryl-2H-
pyrazolo[4,3-c]isoquinolinium-3-ols 1 and corresponding
inner salts 2 (R ) Bn), bearing a benzyl group at the
4-position, as potential ligands at benzodiazepine recep-
tors (Figure 1).3 The compounds showed low affinity at
the benzodiazepine receptors, consistent with a pharma-
cophore model for binding to the benzodiazepine receptor
proposed by the authors. Related 2-arylpyrazolo[4,3-c]-
quinolin-3-ones 3, however, show nanomolar binding to
benzodiazepine receptors, with a range of activity from
full agonists to antagonists,4 while other derivatives of
the same class show potent antitumor activity associated
with inhibition of mammalian topoisomerase II.5 As part
of a pharmaceutical discovery program we became con-
The valence bond structure by which the inner salts 2
are represented suggested that these compounds might
undergo [3 + 2] cycloaddition reactions of the type
observed with azomethine ylides8 across positions 3a and
5, as shown in Scheme 2, to give compounds containing
the novel 6,7-benzo-3,4,11-triazatricyclo[6.2.1.01,5]undeca-
4,6,9-triene (or -4,6-diene) heterocyclic ring system. The
azomethine ylide motif here is part of an extended
aromatic system, and the ready oxidation that occurs
during the formation of 5 suggests a significant degree
of aromatic stabilization of the inner salt structure.
Furthermore, the [3 + 2] cycloaddition requires the
disruption of two aromatic rings. We therefore decided
to investigate the possibility of a [3 + 2] cycloaddition in
* To whom correspondence should be addressed. Current address:
AstraZeneca R&D Wilmington, 1800 Concord Pike, Wilmington, DE
19850. Tel: +1-302-886-2423. Fax: +1-302-886-5382.
† Current address: CombiPure Ltd., The Cornerstone, Market Place,
Kegworth, Leicestershire DE74 2EE, United Kingdom.
(1) (a) Teuber, L.; Watjen, F.; J ensen, L. H. Curr. Pharm. Des. 1999,
5, 317. (b) Sigel, E.; Buhr, A. Trends Pharmacol. Sci. 1997, 18, 425.
(c) Wang, Q.; Han, Y.; Xue, H. CNS Drug Rev. 1999, 5, 125.
(2) Allen, M. S.; Skolnik, P.; Cook, J . M. J . Med. Chem. 1992, 38,
368.
(5) Wentland, M. P.; Aldous, S. C.; Gruett, M. D.; Perni, R. B.;
Powles, R. G.; Danz, D. W.; Klingbeil, K. M.; Peverly, A. D.; Robinson,
R. G.; Corbett, T. H.; Rake, J . B.; Coughlin, S. A. Bioorg. Med. Chem.
Lett. 1995, 5, 905.
(6) Bantick, J .; Bonnert, R.; Cage, P.; Donald, D.; Furber, M.; Hirst,
S.; Phillips, E. PCT Int. Appl. WO-9734893-A1, 25 September 1997;
Chem. Abstr. 127, 307393.
(7) See ref 2 and also: (a) Hinton, I. G.; Mann, F. G. J . Chem. Soc.
1959, 599. (b) Grethe, G.; Lee, H. L.; Uskokovic, M.; Brossi, A. J . Org.
Chem. 1968, 33, 494.
(8) (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; Vols. 1 and 2. (b) Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Wiley: New York, 2002. Cycloaddition
reactions of 4-hydroxyisoquinolinium inner salts are precedented.
See: (c) Padwa, A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.;
Semones, M. A. J . Org. Chem. 1994, 59, 5347. (d) Edmunds, J . J .;
Cheng, X.-M.; Tobias, B. J . Chem. Soc., Perkin Trans. 1 1996, 2005.
(3) CAUTION: Planar polycyclic halogenated compounds containing
6,6,5 systems similar to those of the present study have been described
as potent chloracnegens; because of this potential health hazard,
appropriate precautions should be taken in the handling of such
compounds. See: MacKenzie, A. R.; Brooks, S. Chem. Eng. News 1998,
76 (47), 8.
(4) (a) Yokoyama, N.; Ritter, B.; Neubert, A. D. J . Med. Chem. 1982,
25, 337. (b) Savini, L.; Massarelli, P.; Nencini, C.; Pellerano, C.; Biggio,
G.; Maciocco, A.; Tuligi, G.; Carrieri, A.; Cinone, N.; Carotti, A. Bioorg.
Med. Chem. 1998, 6, 389. (c) Savini, L.; Chiasserini, L.; Pellerano, C.;
Biggio, G.; Maciocco, E.; Serra, M.; Cinone, N.; Carrieri, A.; Altomare,
C.; Carotti, A. Bioorg. Med. Chem. 2001, 9, 431.
10.1021/jo034160f CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/27/2003
8700
J . Org. Chem. 2003, 68, 8700-8703

SCHEME 1. Syn th esis of 4-Alk yl-3-h yd r oxy-2H-p yr a zolo[4,3-c]isoqu in olin iu m In n er Sa lts
SCHEME 2. 1,3-Cycloa d d ition Rea ction s of 4-Alk yl-3-h yd r oxy-2H-p yr a zolo[4,3-c]isoqu in olin iu m In n er Sa lts
this type of aromatic system. To test the feasibility of a
dipolar cycloaddition, we first heated a solution of
compound 5 in toluene with dimethyl acetylenedicar-
boxylate (DMAD) as a dipolarophile. After 1 h, the deep
purple color of the solution had disappeared, and the
cycloadduct 9 was isolated in 89% yield. Compound 7
underwent a similar reaction to give the cycloadduct 10
in 86% yield. The reaction of compound 6 with DMAD
was also investigated. Upon treatment with a 4-fold
excess of DMAD in toluene a cycloaddition addition
product 11 (52% yield) was indeed produced. The E-
stereochemistry of the side chain CdC bond was assigned
on the basis of the observation of NOEs between the
singlets in the 1H NMR spectrum assigned to the
bridgehead and olefinic CH groups. Potentially, formation
of 11 could occur through alkylation of N-4 by conjugate
addition to the DMAD to form the 1,3-dipole species for
this cycloaddition, although dipole formation via tau-
tomerization in which the C-3 hydroxyl proton is trans-
ferred to N-4 (i.e., to give a structure 2 with R ) H),
cycloaddition, and a subsequent conjugate addition is also
possible.
The reactions of 5 with maleimide and with methyl
propiolate were investigated to probe the stereo- and
regiochemistry of the cycloaddition reaction. Treatment
of 5 with excess maleimide in toluene gave, after chro-
matography, a 2:1 mixture of compounds, tentatively
assigned as a mixture of 15 and 16, respectively the exo
and endo cycloaddition products, from which the major
isomer 15 could be isolated by recrystallization (ethyl
acetate/isohexane). When a solution of 15 in DMSO-d6
was heated at 100 °C for 24 h, the solution became
purple, and 1H NMR examination showed that the
cycloadduct had largely decomposed to reform the inner
salt 5. Equilibration of the isomers 15 and 16 had also
occurred (the ratio of 5:15:16 was approximately 8:2:1).
J . Org. Chem, Vol. 68, No. 22, 2003 8701

tinued for 12 h. The mixture was allowed to cool to room
temperature, then poured onto saturated ammonium chloride
solution, and extracted three times with ethyl acetate. The
combined organic extract was washed with brine and dried (Na2-
SO4). Filtration and evaporation followed by purification by
column chromatography, eluting with diethyl ether/isohexane
(1:4), gave the subtitle compound as an oil (20.41 g. 62.7 mmol,
81%): 1H NMR (400 MHz, CDCl3) (major component, enol
tautomer) δ 3.60 (2H, s), 3.81 (3H, s), 3.91 (5H, s), 6.86 (2H, d,
J ) 8.7 Hz), 7.09 (1H, d, J ) 8.7 Hz), 7.25 (2H, d, J ) 7.4 Hz),
7.35-7.43 (2H, m), 7.77 (1H, d, J ) 8.8 Hz), 11.58 (1H, s).
3-Hyd r oxy-4-[(4-m eth oxyp h en yl)m eth yl]-2-(4-tr iflu or o-
m eth ylph en yl)-2H-pyr azolo[4,3-c]isoqu in olin iu m In n er Salt
(5). Compound 4 (30.14 g, 92.9 mmol), 4-(trifluoromethyl)-
phenylhydrazine (20.55 g, 128.3 mmol), and 4-toluenesulfonic
acid hydrate (0.56 g, 2.94 mmol) in ethanol was heated under
reflux for 18 h, and then the solution was allowed to cool. The
precipitated solid was collected by filtration, washed with ether,
and then dried under vacuum to give compound 5 as a dark
purple solid (15.49 g, 34.5 mmol, 37%), mp 220-221 °C: 1H NMR
(300 MHz, DMSO-d6) δ 3.72 (3H, s), 6.08 (2H, s), 6.95 (2H, m),
7.71 (2H, m), 7.79 (1H, td, J ) 7.8 Hz, 1.2 Hz), 7.81 (2H, d, J )
9.0 Hz), 7.95 (1H, td, J ) 7.7 Hz, 1.2 Hz), 8.15 (1H, d, J ) 7.7
Hz), 8.35 (1H, d, J ) 8.1 Hz), 8.6 (2H, d, J ) 8.1 Hz), 8.96 (1H,
s); MS (APCI) m/z 450 [(MH)+]. Anal. Calcd for C25H18F3N3O2:
C, 66.81; H, 4.04; N, 9.35; Found: C, 66.69; H, 4.26; N, 9.31.
The solution was evaporated, and the residue was triturated
with ether. The resulting solid was collected by filtration, washed
with ether, and dried under vacuum to give further recovery of
compound 5 (4.43 g, 9.9 mmol, 11%).
3-Hyd r oxy-2-(4-tr iflu or om eth ylp h en yl)-2H-p yr a zolo[4,3-
c]isoqu in olin e (6). Compound 5 (5.20 g, 11.6 mmol) in trifluo-
roacetic acid (100 mL) was heated under reflux for 8 h. The
solution was evaporated, and the residue was coevaporated twice
with toluene and then with methanol. The residue was triturated
with ether to give a red solid (3.64 g, 11.1 mmol, 96%), mp >250
°C: 1H NMR (300 MHz, DMSO-d6) δ 7.98 (4H, m), 8.33 (4H,
m), 9.06 (1H, broad s), 11.96 (1H, broad s). MS (APCI) m/z 330
(MH+). Anal. Calcd for C17H10F3N3O: C, 62.01; H, 3.06; N, 12.76;
Found: C, 61.73; H, 3.29; N, 12.65.
3-Hyd r oxy-4-eth yl-2-(4-tr iflu or om eth ylp h en yl)-2H-p yr a -
zolo-[4,3-c]isoqu in olin iu m In n er Sa lt (7). Compound 6 (950
mg, 2.89 mmol) and potassium carbonate (2.6 g, 18.8 mmol) were
stirred in DMF (50 mL), and then iodoethane (1.0 mL, 1.95 g,
12.5 mmol) was added. After 1 h of stirring at 25 °C, the solution
was diluted with ethyl acetate, washed with water and then
brine, dried (MgSO4), filtered, and evaporated. Flash chroma-
tography with methanol (2.5-5%) in dichloromethane followed
by recrystallization from ethyl acetate/isohexane gave compound
7 (561 mg, 1.57 mmol, 54%) as a purple solid, mp 192-198 °C:
1H NMR (300 MHz, DMSO-d6) δ 1.63 (3H, t, J ) 7.1 Hz), 4.89
(2H, q, J ) 7.1 Hz), 7.78 (3H, m), 7.96 (1H, t, J ) 7.5 Hz), 8.10
(1H, d, J ) 8.1 Hz), 8.35 (1H, d, J ) 7.8 Hz), 8.60 (2H, d, J )
8.4 Hz), 8.76 (1H, s). MS (APCI) m/z 358 (MH+). Anal. Calc. for
The cycloaddition is therefore reversible, and the ob-
served exo/endo ratio for the reaction of 5 with maleimide
probably represents the thermodynamic ratio. Treatment
of 5 with excess methyl propiolate in toluene gave a
mixture of regioisomers, which were separable by chro-
matography: 12 (32% yield) and 13 (59% yield). These
regioisomers could be distinguished by the observation
1
in the H NMR spectrum of 13 of coupling between the
bridgehead and olefinic H atoms, whereas the corre-
1
sponding signals are singlets in the H NMR spectrum
of 12.
Finally, we investigated the cycloaddition reactions of
compound 8. The methylene group of the C-4 substituent
in 8 was anticipated to be sufficiently acidic to enable
facile deprotonation. Two modes of [3 + 2] cycloaddition
could be envisaged for the resulting anion 17: first,
across positions 3a and 5 of the aromatic system or
second, across the side chain methine group and position
5. The second mode was expected to be preferred, since
only one aromatic ring is disrupted by the cycloaddition.
Treatment of compound 8 with DMAD in the presence
of triethylamine (4 equiv) at room temperature, for 20
h, afforded compound 18 in 44% yield. Formation of 18
can be rationalized as the product of the expected mode
[3 + 2] cycloaddition of DMAD across the side chain
methine group of anion 17 and C-5, followed by oxidative
aromatization of the resulting cycloadduct. In contrast,
if the side chain deprotonation is suppressed, addition
should occur as above, resulting in cycloaddition across
positions 3a and 5. Indeed, treatment of compound 8 with
DMAD in the presence of acetic acid, added to suppress
possible deprotonation of the side chain by the tertiary
amine of the product, gave compound 14 in 86% yield.
Thus, 4-alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolin-
ium inner salts were found to undergo cycloaddition with
dipolarophiles to give cycloadducts containing the
novel 6,7-benzo-3,4,11-triazatricyclo[6.2.1.01,5]undeca-
4,6,9-triene (or -4,6-diene) heterocyclic ring system. In
the cycloaddition of compound 8, with DMAD, alternative
modes of [3 + 2] cycloaddition could be selected by
appropriate choice of reaction conditions.
Exp er im en ta l Section
Meth yl 1,2,3,4-Tetr a h yd r o-2-(4-m eth oxyp h en yl)m eth yl-
4-oxo-3-isoqu in olin eca r boxyla te (4). Methyl 2-bromometh-
ylbenzoate9 (23.47 g, 102 mmol) and triethylamine (15.7 mL,
11.4 g, 112 mmol) were dissolved in dry diethyl ether (200 mL)
under a nitrogen atmosphere. Methyl N-[(4-methoxyphenyI)-
methyl]glycinate10 (23.6 g, 112 mmol) was added dropwise. The
mixture was heated under reflux for 16 h and allowed to cool to
room temperature. Water was added, and the organic phase was
separated. The aqueous phase was then extracted three times
with ethyl acetate. The combined organic extract was washed
with brine and dried (Na2SO4). Filtration and evaporation of the
solution followed by further purification of the residues by
column chromatography, eluting with ethyl acetate/isohexane
(1:9), gave methyl 2-{N-(methoxycarbonylmethyl)-N-[(4-meth-
oxyphenyl)methyl]aminomethyl}benzoate as an oil (27.85 g, 77.9
mmol, 76%). The oil was dissolved in dry toluene (150 mL) and
added dropwise to a refluxing suspension of oil-free sodium
hydride (from 4.37 g of 60% sodium hydride) in dry toluene (300
mL) and 2-methylpropan-2-ol (2.0 mL). The heating was con-
C
19H14F3N3O: C, 63.86; H, 3.95.N, 11.76; Found: C, 63.92; H,
3.90; N, 11.90.
3-H yd r oxy-4-m e t h oxyca r b on ylm e t h yl-2-(4-t r iflu or o-
m eth ylp h en yl)-2H-p yr a zolo-[4,3-c]isoqu in olin iu m In n er
Sa lt (8). Prepared by a method analogous to that described for
compound 7 by alkylation of compound 6 with methyl bromoac-
etate. Purification by flash chromatography with methanol (3%)
in dichloromethane gave compound 8 (46%) as a purple solid,
mp 149-152 °C: 1H NMR (DMSO-d6) δ 3.79 (3H, s), 5.84 (2H,
s), 7.82 (3H, m), 8.04 (1H, t, J ) 7.2 Hz), 8.19 (1H, d, J ) 8.1
Hz), 8.41 (1H, d, J ) 7.8 Hz), 8.56 (2H, d, J ) 8.4 Hz), 8.71 (1H,
s); MS (APCI) m/z 402 (MH+).
6,7-Ben zo-11-[(4-m eth oxyp h en yl)m eth yl]-2-oxo-3-(4-tr i-
flu or om eth ylph en yl)-3,4,11-tr iazatr icyclo[6.2.1.01,5]u n deca-
4,6,9-tr ien e-9,10-d ica r boxylic Acid Dim eth yl Ester (9). A
solution containing compound 5 (236 mg, 0.53 mmol), 2,6-di-
tert-butyl-4-methylphenol (1 crystal), and dimethyl acetylene-
dicarboxylate (0.2 mL, 0.23 g, 1.63 mmol) in toluene (5 mL) was
heated under reflux under a nitrogen atmosphere for 1 h. The
solution was evaporated, and the residue was purified by
(9) Miknis, G. F.; Williams, R. M. J . Am. Chem. Soc. 1993, 116, 536.
(10) Hanna, P. E.; Grund, V. R.; Anders, M. W. J . Med. Chem. 1974,
17, 1020.
8702 J . Org. Chem., Vol. 68, No. 22, 2003

chromatography using ethyl acetate/isohexane as the eluant to
give cycloadduct 9 (276 mg, 0.47 mmol, 89%) as a colorless solid,
mp 205-208 °C: 1H NMR (400 MHz, DMSO) δ 3.52 (1H, d, J )
12.8 Hz), 3.62 (3H, s), 3.67 (3H, s), 3.70 (1H, d, J ) 12.8 Hz),
3.74 (3H, s), 4.98 (1H, s), 6.77 (2H, d, J ) 8.4 Hz), 7.06 (2H, d,
J ) 8.4 Hz), 7.40 (1H, m), 7.57 (2H, m), 7.89 (2H, d, J ) 8.8 Hz),
8.01 (1H, m), 8.05 (2H, d, J ) 8.8 Hz). MS (APCI+) m/z 592
(100%, MH+). Anal. Calcd for C31H24F3N3O6: C, 62.94; H, 4.09;
N, 7.10. Found: C, 62.67; H, 4.18; N, 7.03.
6,7-Benzo-11-[(4-methoxyphenyl)methyl]-2-oxo-3-(4-trifluoro-
m eth ylp h en yl)-3,4,11-tr ia za tr icyclo[6.2.1.01,5]u n d eca -4,6,9-
tr ien e-9-ca r boxylic Acid Meth yl Ester (13). Prepared by a
method similar to that described for compound 9 from the
reaction of compound 5 with methyl propiolate. The crude
product was purified by chromatography using ether/isohexane
to give two compounds: compound 12 obtained as a colorless
solid in 32% yield, and compound 13 obtained as an oil in 59%
1
yield. Compound 12: mp 197 °C, H NMR (400 MHz, DMSO) δ
6,7-Ben zo-11-et h yl-2-oxo-3-(4-t r iflu or om et h ylp h en yl)-
3,4,11-tr ia za tr icyclo[6.2.1.01,5]u n d eca -4,6,9-tr ien e-9,10-d i-
ca r boxylic Acid Dim eth yl Ester (10). Prepared by a method
similar to that described for compound 9 from the reaction of
compound 7 with dimethyl acetylenedicarboxylate and obtained
as a colorless solid in 86% yield, mp 158-160 °C: 1H NMR (400
MHz, CDCl3) δ 1.10 (3H, t, J ) 7.2 Hz), 2.64 (2H, m), 3.68 (3H,
s), 3.82 (3H, s), 5.02 (1H, s), 7.33 (1H, m), 7.46 (2H, m), 7.70
(2H, d, J ) 8.6 Hz), 8.00 (1H, m), 8.19 (2H, d, J ) 8.6 Hz). MS
(APCI+) m/z 500 (100%, MH+). Anal. Calcd for C25H20F3N3O5:
C, 60.12; H, 4.04; N, 8.41. Found: C, 59.75; H, 4.18; N, 8.34.
6,7-Ben zo-11-[E-1,2-bis(m eth oxycar bon yl)eth en yl]-2-oxo-
3-(4-tr iflu or om eth ylp h en yl)-3,4,11-tr ia za tr icyclo[6.2.1.01,5]-
u n d eca -4,6,9-tr ien e-9,10-d ica r boxylic Acid Dim eth yl Ester
(11). Prepared by a method similar to that described for
compound 9 from the reaction of compound 6 with dimethyl
acetylenedicarboxylate and obtained as a colorless solid in 52%
yield, mp 229-231 °C: 1H NMR (300 MHz, DMSO) δ 3.47 (3H,
s), 3.56 (3H, s), 3.65 (3H, s), 3.80 (3H, s), 5.06 (1H, s), 6.14 (1H,
s), 7.57-7.71 (3H, m), 7.94 (2H, d, J ) 8.9 Hz), 8.03 (1H, m),
8.12 (2H, d, J ) 8.9 Hz). MS (APCI+) m/z 614 (100%, MH+). Anal.
Calcd for C29H22F3N3O9: C, 56.78; H, 3.61; N, 6.85. Found: C,
56.51; H, 3.58; N, 7.12. The E-stereochemistry of the side chain
CdC bond was assigned on the basis of the observation of NOEs
between the singlets at 5.06 and 6.14.
[3 + 2] Cycloa d d ition of Com p ou n d 5 a n d Ma leim id e. A
solution containing compound 5 (203 mg, 0.45 mmol), 2,6-di-
tert-butyl-4-methylphenol (1 crystal), and maleimide (193 mg,
1.99 mmol) in toluene (5 mL) was heated under reflux under a
nitrogen atmosphere for 2 h. The solution was evaporated, and
the residue was purified by chromatography using ether/
isohexane as the eluant to give a colorless solid that was
tentatively assigned as a 2:1 mixture of the exo (1R,8S,9R,13S)
and endo (1R,8S,9S,13S) isomers (compounds 15 and 16) of
6,7-benzo-14-[(4-methoxyphenyl)methyl]-2,10,12-trioxo-3-(4-tri-
fluoromethylphenyl)-3,4,11,14-tetrazatetracyclo[6.5.1.0.1,509,13]-
tetradeca-4,6-diene (252 mg, approximately quantitative yield).
The major product 15 crystallized from ethyl acetate/isohexane,
mp 220 °C (dec): 1H NMR (300 MHz, CDCl3) δ 3.19 (1H, d, J )
12.3 Hz), 3.30 (2H, AB quartet), 3.66 (1H, d, J ) 12.3 Hz), 3.77
(3H, s), 4.52 (1H, s), 6.76 (2H, d, J ) 8.7 Hz), 6.98 (2H, d, J )
8.7 Hz), 7.53 (2H, m), 7.70 (2H, d, J ) 8.6 Hz), 8.09 (1H, m),
8.17 (2H, d, J ) 8.6 Hz), 8.23 (1H, m), 10.88 (1H, broad). MS
(APCI-) m/z 545 (M - H+). Anal. Calcd for C29H21F3N4O4: C,
63.74; H, 3.87; N, 10.25. Found: C, 63.86; H, 3.81; N, 10.32. The
stereochemical assignment was based the coupling pattern
observed for the 1H NMR signal assigned to the bridgehead
hydrogen, which in compound 15 appears as a singlet (dihedral
angle to neighboring proton ∼90° for the exo isomer based on
examination of a molecular model), whereas in the spectrum of
the mixture the signal tentatively assigned to the corresponding
hydrogen of the minor component 16 was a doublet (J ) 6.9 Hz)
(dihedral angle to neighboring proton ∼0° for the endo isomer).
6,7-Ben zo-11-[(4-m eth oxyp h en yl)m eth yl]-2-oxo-3-(4-tr i-
flu or om eth ylph en yl)-3,4,11-tr iazatr icyclo[6.2.1.01,5]u n deca-
4,6,9-t r ien e-9-ca r b oxylic Acid Met h yl E st er (12) a n d
3.47 (1H, d, J ) 12.8 Hz), 3.64 (1H, d, J ) 12.8 Hz), 3.66 (3H,
s), 3.69 (3H, s), 4.73 (1H, s), 6.74 (2H, d, J ) 8.4 Hz), 7.03 (2H,
d, J ) 8.4 Hz), 7.31 (1H, s), 7.33 (1H, m), 7.53 (2H, m), 7.87
(2H, d, J ) 8.8 Hz), 7.98 (1H, m), 8.05 (2H, d, J ) 8.8 Hz). MS
(APCI+) m/z 534 (100%, MH+). Anal. Calcd for C29H22F3N3O4:
C, 65.29; H, 4.16; N, 7.88. Found: C, 64.94; H, 4.23; N, 7.83.
Compound 13: 1H NMR (400 MHz, DMSO) δ 3.50 (1H, d, J )
13.2 Hz), 3.60 (4H, m), 3.67 (3H, s), 4.78 (1H, d, J ) 3.0 Hz),
6.76 (2H, d, J ) 8.8 Hz), 7.05 (2H, d, J ) 8.8 Hz), 7.37 (1H, m),
7.54 (2H, m), 7.77 (1H, d, J ) 3.0 Hz), 7.88 (2H, J ) 8.8 Hz),
7.98 (1H, m), 8.07 (2H, J ) 8.8 Hz); MS (APCI+) m/z 534 (100%,
MH+).
6,7-Ben zo-11-(m et h oxyca r b on yl)m et h yl-2-oxo-3-(4-t r i-
flu or om eth ylph en yl)-3,4,11-tr iazatr icyclo[6.2.1.01,5]u n deca-
4,6,9-tr ien e-9,10-d ica r boxylic a cid d im eth yl Ester (14). A
solution containing compound 8 (151 mg, 0.38 mmol), 2,6-di-
tert-butyl-4-methylphenol (1 crystal), dimethyl acetylenedicar-
boxylate (0.3 mL, 0.35 g, 2.45 mmol), and acetic acid (0.15 mL)
in toluene (5 mL) was heated under reflux under a nitrogen
atmosphere for 1 h. The solution was partitioned between
aqueous sodium bicarbonate and dichloromethane, the organic
layer was separated, dried (MgSO4), filtered, and evaporated,
and the residue was purified by chromatography using ether/
isohexane as the eluant to give cycloadduct 14 (176 mg, 0.32
mmol, 86%) as a colorless solid, mp 164-166 °C: 1H NMR (300
MHz, DMSO) δ 3.57 (3H, s), 3.63 (5H, m), 3.77 (3H, s), 5.38 (1H,
s), 7.48 (1H, m), 7.57 (2H, m), 7.92 (2H, d, J ) 8.6 Hz), 8.00
(1H, m), 8.13 (2H, d, J ) 8.6 Hz); MS (APCI+) m/z 544 (100%,
MH+). Anal. Calcd for C26H20F3N3O7: C, 57.46; H, 3.71; N, 7.73.
Found: C, 57.10; H, 3.77; N, 7.64.
3-Hyd r oxy-2-(4-tr iflu or om eth ylp h en yl)-2H-p yr a zolo[4,3-
c]p yr r olo[2,1-a ]isoqu in olin e-4,5,6-tr ica r boxylic Acid Tr i-
m eth yl Ester (18). A solution containing compound 8 (16 mg,
0.040 mmol), dimethyl acetylenedicarboxylate (5.7 mg, 0.040
mmol), and triethylamine (0.021 mL, 15 mg, 0.15 mmol) in
dichloromethane (10 mL) was stirred at room temperature for
20 h. The solution was evaporated, and the residue was purified
by chromatography using ethanol (3%) in dichloromethane as
the eluant to give cycloadduct 18 (9.6 mg, 0.017 mmol, 44%) as
a pale yellow solid, mp 246-248 °C (dec): 1H NMR (300 MHz,
DMSO) δ 3.81 (3H, s), 3.90 (3H, s), 3.95 (3H, s), 7.77 (2H, m),
7.93 (2H, d, J ) 8.7 Hz), 8.18 (2H, d, J ) 8.7 Hz), 8.21 (1H, m),
8.28 (1H, m); MS (APCI+) m/z 542 (100%, MH+). Anal. Calcd
for C26H18F3N3O7: C, 57.66; H, 3.11; N, 7.60. Found: C, 57.68;
H, 3.35; N, 7.76.
Ack n ow led gm en t. We thank Drs. Roger Bonnert
and Dave Donald for helpful discussions. We also thank
Drs. Mike Bernstein, Mark Dixon, and Richard Lewis
for NMR spectra.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all the compounds described. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034160F
J . Org. Chem, Vol. 68, No. 22, 2003 8703