Isoxazolinoisoquinoline Heterocycles via Solid-Phase Reinsert and Suzuki Reactions

Article abstract of DOI:10.1021/jo9720142

A traceless solid-phase synthesis strategy has been developed that delivers novel isoxazolinoisoquinoline heterocycles. The process consists of solid-phase Reissert formation (isoquinoline → I), Suzuki coupling lithiation, and subsequent C1-alkylation (I → II), and exo-olefin selective 1,3-dipolar nitrile oxide cycloaddition followed by Reissert hydrolysis (II → III) to liberate the targeted heterocycle.

Full text of DOI:10.1021/jo9720142

2244
J . Org. Chem. 1998, 63, 2244-2250
Isoxa zolin oisoqu in olin e Heter ocycles via Solid -P h a se Reisser t a n d
Su zu k i Rea ction s
Beth A. Lorsbach, J effrey T. Bagdanoff, R. Bryan Miller,* and Mark J . Kurth*
Department of Chemistry, University of California, Davis, California 95616
Received November 3, 1997
A traceless solid-phase synthesis strategy has been developed that delivers novel isoxazolinoiso-
quinoline heterocycles. The process consists of solid-phase Reissert formation (isoquinoline f I),
Suzuki coupling lithiation, and subsequent C1-alkylation (I f II), and exo-olefin selective 1,3-
dipolar nitrile oxide cycloaddition followed by Reissert hydrolysis (II f III) to liberate the targeted
heterocycle.
In tr od u ction
the incorporation of a polymer-bound Suzuki coupling
reaction to further enhance compound diversity.10
There are numerous examples of the Suzuki coupling
reactions both in solution as well as on a solid support.11,12
Typically, Suzuki coupling involves the palladium-
catalyzed coupling of an aryl or alkenyl halide with an
aryl- or alkenyl boronic acid. The catalytic cycle proceeds
via oxidative addition, transmetalation, and reductive
elimination.13 While Suzuki coupling strategies provide
an effective method for C-C formation, to our knowledge
there has been no report of Suzuki couplings performed
on Reissert intermediates. We report herein the solution-
and solid-phase Suzuki coupling of a Reissert halide with
aryl boronic acids as well as incorporation of Suzuki
couplings in the synthesis of isoxazolinoisoquinoline
derivatives.
In a recent paper, we reported the Reissert-based solid-
phase synthesis of several isoxazolinoisoquinoline het-
erocycles.1 Our interest in the novel combination of these
two structural features within a single framework
stemmed from the observation that isoquinoline and
isoxazoline substructures both exhibit significant biologi-
cal activities: isoquinolines, substituted at C1 with basic-
containing substituents including N and O heterocycles,
have shown a wide variety of bioactivity,2 and the
isoxazoline heterocycle has been used extensively to
modify a variety of other biologically active systems.3 An
efficient method for incorporating substitution at the
isoquinoline C1 position is through use of Reissert
intermediates that take advantage of the increased C1-
acidity of the 2-acyl-1,2-dihydroisoquinaldonitriles.4,5 This
type of chemistry has been used in the polymer area for
both production of monomers for subsequent polymeri-
zation and polymerization of Reissert compounds them-
selves.6 These observations, plus the importance of
methodological developments in solid-phase7 and combi-
natorial strategies,8 led us9 to investigate a “traceless”
solid-phase approach for construction of the isoxazoli-
noisoquinoline heterocyclic system. The success of our
preliminary studies with the Reissert-based solid-phase
synthesis of these heterocycles1 encouraged us to pursue
Resu lts a n d Discu ssion
In our preliminary paper,1 we validated the solid-phase
synthetic strategy outlined in Figure 1. The hallmarks
of this study were that (i) solid-phase Reissert formation
can be effected such that the resulting Reissert interme-
diate provides coincident substrate-resin linkage (iso-
quinoline f I), (ii) the resulting solid-phase Reissert
complex can be C1-allylated (I f II), and (iii) nitrile oxide
reagents undergo chemoselective exo-olefin 1,3-dipolar
cycloaddition (vs endo-enamide 1,3-dipolar cycloaddition;
see II). Once the Reissert complex had been successfully
exploited for linker, activation (C1), and nitrile oxide
chemoselection, hydrolysis deconvoluted the Reissert
complex delivering the targeted heterocycle III and thus
constituted a “traceless”14 solid-phase route to isoxazoli-
noisoquinoline heterocycles (III).
(1) Lorsbach, B. A.; Miller, R. B.; Kurth, M. J . J . Org. Chem. 1996,
61, 8716-17.
(2) (a) Brossi, A. Heterocycles 1978, 11, 521-47. (b) Shuster, H. F.;
Kathawala, F. Chem. Heterocycl. Comp. 1995, 38, 1-224.
(3) (a) Khalil, M. A.; Mapaonya, M. F.; Ko, D.-H.; You, Z.; Oriaku,
E. T.; Lee, H. J . Med. Chem. Res. 1996, 6, 52-60. (b) Groutas, W. C.;
Venkataraman, R.; Chong, L. S.; Yoder, J . E.; Epp, J . B.; Stanga, M.
A.; Kim, E.-H. Bioorg. Med. Chem. 1995, 3, 125-8.
(4) Reissert, A. Chem. Ber. 1905, 38, 1603.
(5) Reviews: (a) Popp, F. D. In Quinolines; J ones, G., Ed.; J . Wiley
and Sons: New York, 1982; Part II, pp 353-375. (b) Popp, F. D. Bull.
Soc. Chim. Belg. 1981, 90, 609-13.
(10) Stavenuiter, J .; Hamzink, M.; van der Hulst, R.; Zomer, G.;
Westra, G. Kriek, E. Heterocycles 1987, 26, 2711-16.
(6) (a) Gibson, H. W.; Guilani, B. Polym. Commun. 1991, 32, 324-
8. (b) Gibson, H. W.; Pandya, A.; Guilani, B. Polym. Prepr. 1988, 29,
154-4.
(11) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981
11, 513. (b) Sato, M.; Miyaura, N. Suzuki, A. Chem. Lett. 1989, 1405.
(c) Takayuki, O.; Miyaura, N.; Suzuki, A. J . Org. Chem. 1993, 58, 2201.
(d) Miyaura, N.; Suzuki, A. Terahedron Lett. 1979, 3437. (e) Miyaura,
N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 2865. (c) Miyaura,
N.; Suzuki, A. J . Chem. Soc., Chem. Commun. 1979, 866. (f) Negishi,
E.; King, A. O.; Okukado, N. J . Org. Chem. 1977, 42, 1821.
(12) (a) Frenette, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35,
9177-9180. (b) Backes, J . A.; Ellman, J . A. J . Am. Soc. Chem. 1994,
116, 11171-11172. (c) Guile, J . W.; J ohnson, S. G.; Murray, W. V.
Abstracts of Papers, 211th Nathional Meeting of the American Chemi-
cal Society, New Orleans, Spring 1996; American Chemical Society:
Washington, DC, 1996; Abstract 126.
(7) (a) Crowley, J . I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-
44. (b) Leznoff, C. C. Chem. Soc. Rev. 1974, 3, 65-85. (c) Leznoff, C.
C. Acc. Chem. Res. 1978, 11, 327-33.
(8) (a) Ellman, J . A.; Acc. Chem. Res. 1996, 29, 132-43. (b) Gordon,
E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144-54.
(c) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555-600.
(9) (a) Chen, C.; Ahlberg Randall, L. A.; Miller, R. B.; J ones, A. D.;
Kurth, M. J . J . Am. Chem. Soc. 1994, 116, 2661-2. (b) Kurth, M. J .;
Ahlberg Randall, L. A.; Chen, C.; Melander, C.; Miller, R. B.; McAlister,
K.; Reitz, G.; Kang, R.; Nakatsu, T.; Green, C. J . Org. Chem. 1994,
59, 5862-4.
(13) Miyaura, N.; Suzuki, A. Chem. Rev. 1995 95, 2457-2483.
S0022-3263(97)02014-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/11/1998

Isoxazolinoisoquinoline Heterocycles
J . Org. Chem., Vol. 63, No. 7, 1998 2245
the 1,3-dipolar cycloaddition step became our next prob-
lem. Our previous experience with both solution-16 and
solid-phase17 nitrile oxide cycloaddition reactions18 es-
tablished that steric and electronic factors influence olefin
selectivity in 1,3-dipolar cycloadditions,19 suggesting that
C1-allylated Reissert compound II was a good candidate
for olefin-selective cycloaddition. In our first test of this
exo-olefin versus endo-enamide competition in the Reis-
sert series, we felt it was prudent to bias the system
toward exo-addition by placing a bulky substituent at the
isoquinoline C4-position. Thus, 4-phenylisoquinoline20
was selected and Reissert formation (®4) followed by
LDA-mediated C1-allylation delivered ®5a . We found
that in situ generation of CH3CH2CtN+O- (nitropropane
+ PhNCO + Et3N) resulted in concomitant 1,3-dipolar
cycloaddition with complete exo-selectivity based on
analysis of the crude hydrolysis product.1 That is, only
isoxazolinoisoquinoline 6a was obtained (27% overall
yield from ®C6H4CO2H).21 This was impressive given
that 5 equiv of CH3CH2CN+O- were employed! More-
over, alkylation of ®4 with methallyl bromide delivered
®5b, which, despite increased steric hindrance at the exo-
olefin, also underwent only exo-1,3-dipolar cycloaddi-
tion, giving 6c on hydrolysis (24% overall yield from
®C6H4CO2H) (Scheme 2). Finally, the exo-olefin selectiv-
ity found in the reaction of CH3CH2CtN+sO- with ®5a
was also observed in the reaction C6H5CtN+O- with
®5a ; again, only exo-cycloadduct 6b was obtained (23%
overall yield from ®C6H4CO2H).21b
F igu r e 1. Solid-phase Reissert approach to isoxazolinoiso-
quinoline heterocycles (® ) 2% DVB-polystyrene).
Sch em e 1. C1-Alk yla tion of th e Solid -P h a se
Reisser t Com p lex (® ) 2% DVB-P olystyr en e)
We returned to resin ®1, encouraged by the exo-olefin
selectivity in the 1,3-dipolar cycloaddition step, and C1-
alkylated it with allyl bromide to give resin ®2e (see
Scheme 3).22 Thus, the 1,3-dipolar cycloaddition con-
fronted
a much less hindered enamide CdC and
brought to the fore the question of whether exo-selectivity
would still prevail. Treating resin ®2e with excess
CH3CH2CtN+O- or excess C6H5CtN+O- followed by
Reissert hydrolysis delivered only the exo-cycload-
ducts 7a and 7b (25% and 26% overall yield from
®C6H4CO2H)!21b The resin does not mediate endo-/exo-
olefin selectivity as the solution-phase variant of this
reaction also gives only exo-cycloaddion (2e f 2e′; 1.9:1
ratio of diastereomers; 82% unoptimized) leading to 7a
upon Reissert hydrolysis. One final probe of the exo-
selectivity was to alkylate ®1 with methallyl bromide,
thus adding steric hindrance to the exo-olefin. Again,
when resin ®2f was treated with excess CH3CH2CtN+O-,
only exo-cycloadduct 7c (21% overall yield) was obtained.
While solution-phase Reissert alkylations traditionally
use NaH for activation,15 solid-phase Reissert ®1 (®1
denotes Reissert substrate 1 supported on 2% DVB-
polystyrene) formed by treating polymer-bound benzoyl
chloride [®C6H4C(dO)Cl]7b,c with isoquinoline and trim-
ethylsilyl cyanide (TMSCN) required the soluble base
LDA for C1-alkylation. Addition of methyl iodide at -78
°C followed by warming to ambient temperature (48 h)
gave resin ®2a (Scheme 1). This resin, having been
exposed to four synthetic transformations (carbonylation,
acid chloride formation, Reissert condensation, and C1-
alkylation), was swollen in THF and treated with aque-
ous KOH to effect Reissert hydrolysis. Subsequent
filtration and ether wash followed by normal aqueous
workup of the organic layer delivered 1-methylisoquino-
line (3a ; 56% overall yield from ®C6H4CO2H). In a
similar fashion, C1-substituted isoquinolines 3b and 3c
were prepared from ethyl iodide (59% overall yield) and
benzyl bromide (50% overall yield), respectively. GC
analysis of each crude Reissert/C1-alkylation/hydrolysis
reaction mixture showed nearly complete C1-alkylation;
in all cases, only a trace (<5%) of unalkylated isoquino-
line could be detected.
(16) (a) Beebe, X.; Chiappari, C. L.; Kurth, M. J .; Schore, N. E. J .
Org. Chem. 1993, 58, 7320-1. (b) Kim, H. R.; Kim, H. J .; Duffy, J . L.;
Ruhlandt-Senge, K.; Kurth, M. J . Tetrahedron Lett. 1991, 32, 4259-
62. (c) Kurth, M. J .; Olmstead, M. M.; Rodriguez, M. J . J . Org. Chem.
1990, 55, 283-8. (d) Kurth, M. J .; Rodriguez, M. J . Tetrahedron 1989,
45, 6963-8. (e) Kurth, M. J .; Rodriguez, M. J . J . Am. Chem. Soc. 1987,
109, 7577-8.
(17) (a) Beebe, X.; Chiappari, C. L.; Olmstead, M. M.; Kurth, M. J .;
Schore, N. E. J . Org. Chem. 1995, 60, 4204-12. (b) Beebe, X.; Schore,
N. E.; Kurth, M. J . J . Org. Chem. 1995, 60, 4196-203. (c) Beebe, X.;
Schore, N. E.; Kurth, M. J . J . Am. Chem. Soc. 1992, 114, 10061-2.
(18) Easton, C. J .; Hughes, C. M. M.; Savage, G. P.; Simpson, G. W.
Adv. Heterocycl. Chem. 1994, 60, 261-327.
(19) Rodriguez, M. J . Ph.D. Thesis, UCD, 1989 (Avail.: University
Microfilms Int., Order No. DA8903740).
(20) Miller, R. B.; Svoboda, J . J . Synth. Commun. 1994, 24, 1187-
Once we verified that we could form and alkylate solid-
phase Reissert ®1, the question of olefin selectivity in
93.
(14) (a) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006-
7. (b) Chenera, B.; Finkelstein, J . A.; Veber, D. F. J . Am. Chem. Soc.
1995, 117, 11999-12000. (c) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703-6.
(15) Boekelheide, V.; Weinstock, J . J . Am. Chem. Soc. 1952, 74, 660-
3.
(21) (a) The crude 1H NMR show no evidenced of a second isoxazo-
line-containing product. (b) The purity of the crude product was judged
to be 90% by 1H NMR analysis.
(22) Hydrolysis of this Reissert compound is complicated by the fact
that a fair degree of olefin isomerization occurs, leading to a 1:4 mixture
of 1-(2-propenyl)isoquinoline and 1-(1-propenyl)isoquinoline.

2246 J . Org. Chem., Vol. 63, No. 7, 1998
Lorsbach et al.
Sch em e 4. C4-Br om o Su bstitu ted
Sch em e 2. P r ep a r a tion of C4-Su bstitu ted
Isoxa zolin oisoqu in olin e Heter ocycles (® ) 2%
DVB-P olystyr en e)
Isoxa zolin oisoqu in olin es
(® ) 2% DVB-P olystyr en e)
Sch em e 5. Su zu k i Cou p lin g of a Reisser t-Der ived
En a m id e Br om id e (8)
Sch em e 3. P r ep a r a tion of C4-Un su bstitu ted
Isoxa zolin oisoqu in olin e Heter ocycles (® ) 2%
DVB-P olystyr en e in ®2e a n d ®2f;
® ) H in 2e a n d 2e′)
tion f hydrolysis sequence, isoxazolinoisoquinolines 9a ,
9b, and 9c were obtained in 26%, 24%, and 23% overall
yield, respectively, from ®C6H4CO2H (Scheme 4).21b Since
these results were as expected, we set out to use com-
mercially available 4-bromoisoquinoline in our investiga-
tion of the Suzuki coupling reaction, which is well
established as an active halide for Suzuki couplings.24
4-Bromoisoquinoline readily undergoes solution-phase
Reissert formation when treated with TMSCN and ben-
zoyl chloride (Scheme 5). However, Suzuki coupling of
the vinyl bromide in 8 with phenylboronic acid fails to
deliver the desired product (starting material recovered),
suggesting that this electron-rich enamide bromide is not
conducive to the Suzuki coupling protocol.
In light of this failure, we next prepared 6-bromo-5,8-
dimethylisoquinoline (10)25 in the hope that the corre-
sponding Reissert intermediate, now possessing a fully
aromatic halide, would retain normal Suzuki reactivity.
As an initial foray, we carried out the solution-phase
Suzuki coupling of 10 with phenylboronic acid [catalytic
Pd(PPh3)4 in 2 M aqueous Na2CO3 plus DME] (Scheme
6; ® ) H).
These results, especially with excess nitrile oxide, suggest
that the Reissert enamide CdC is electronically deacti-
vated for 1,3-dipolar cycloaddition. AM1 semiempirical
calculations support this conclusion.23
When 4-bromoisoquinoline was put through the solid-
phase Reissert f C1-allylation f 1,3-dipolar cycloaddi-
After heating at 80 °C for 12 h, the reaction was
quenched with aqueous NH4OAc and yielded 5,8-dim-
ethyl-6-phenylisoquinoline (13a ) in 89% yield. Having
thus prepared an authentic product sample, we next
synthesized Reissert derivative 11 (93% yield) and sub-
jected this to Suzuki coupling conditions. To our delight,
Suzuki coupling proceeded nicely, delivering Reissert 12a
(23) Mulliken population analysis, obtained by AM1 semiempirical
calculations comparing 2e/f and hypothetical compound 2g, indicates
that the exo-olefin is unaffected by the amide moiety whereas the endo-
olefin is deactivated.
(24) Miller, R. B.; Dugar, S. Tetrahedron Lett. 1989, 30, 297-300.
(25) Miller, R. B.; Moock, T. Tetrahdedron Lett. 1980, 21, 3319-22.

Isoxazolinoisoquinoline Heterocycles
J . Org. Chem., Vol. 63, No. 7, 1998 2247
Sch em e 6. Solu tion - a n d Solid -P h a se Su zu k i
Cou p lin g of a Reisser t In ter m ed ia te (® ) H for
Solu tion -P h a se Stu d ies; ® ) 2% DVB-P olystyr en e
for Solid -P h a se Stu d ies)
Sch em e 7. C6-Su bstitu ted
Isoxa zolin oisoqu in olin es via Su zu k i Cou p lin g
(® ) 2% DVB-P olystyr en e)
in 75% yield overall from 10. Subsequent treatment of
12a with aqueous KOH (100 °C, 12 h, solvent) effected
Reissert hydrolysis and produced 5,8-dimethyl-6-phenyl-
isoquinoline (13a ; 89% overall yield from 10), identical
to the authentic sample prepared by direct Suzuki
coupling of 10.
treated with LDA and alkylated at C1 with allyl bromide
(see Scheme 7). Alkylated resins ®13a and ®13b were
in turn treated with excess CH3CH2CtN+O- to deliver
only the exo-cycloadducts 14a and 14b in 19% and 17%
yield, respectively, after Reissert hydrolysis.
Having established that the aryl bromide of Reissert
11, unlike the enamide bromide of Reissert 8, participates
in the Suzuki coupling reaction, we next explored using
a heteroaromatic boronic acid in place of phenylboronic
acid. Indeed, palladium-mediated coupling of solution-
phase Reissert intermediate 11 with 3-thiopheneboronic
acid delivered Reissert 12b in 77% overall yield from 10.
Subsequent Reissert hydrolysis gave 5,8-dimethyl-6-(3-
thiophene)isoquinoline (13b; 69% overall yield), which
was identical to the product obtained by direct Suzuki
coupling of isoquinoline 10 with 3-thiopheneboronic acid
(10 f 13b). These solution results with Reissert 11 f
13a /13b set the stage for exploring the solid-phase
variant.
Con clu sion
In summary, we have developed a traceless solid-phase
strategy for the synthesis of novel isoxazolinoisoquinoline
heterocycles. We have established the viability of the
solid-supported Reissert reaction, demonstrated that the
polymer-bound Reissert compound can be C1-alkylated,
and determined that the 1,3-dipolar cycloaddition reac-
tion of nitrile oxides is selective for the exo-olefin.
Finally, we have shown that Reissert intermediates can
accommodate a Suzuki coupling reaction to give an
additional pathway for diversity. Currently, we are
looking to extend this methodology to other heterocycles.
Solid-phase Reissert ®11 was subjected to Suzuki
coupling as follows (Scheme 6; ® ) 2% DVB-polystyrene).
First, ®11 was swollen in DME, and a catalytic amount
of Pd(PPh3)4 was added and the mixture stirred gently
at ambient temperature for 30 min. Phenylboronic acid
and 2 M aqueous Na2CO3 were added, and the solution
was heated to 80 °C for 36 h (monitoring this reaction
proved unworkable by FT-IR). The cooled reaction
mixture, which was filtered and washed with DME/H2O
[(1:1), 40 mL], H2O (2 × 20 mL), 1 M HCl (2 × 15 mL),
H2O (2 × 30 mL), DME (2 × 20 mL), THF (2 × 40 mL),
and Et2O (2 × 25 mL), gave solid-phase ®12a , which was
treated with aqueous KOH to effect Reissert hydrolysis
with concomitant cleavage of 13a from the polymer (19%
overall yield in four steps from ®C6H5CO2H; ∼66% yield
per solid-phase step). In a similar manner, 13b was
prepared in a 17% overall yield using 3-thiopheneboronic
acid in the coupling reaction with ®11. With these
results, we were poised to incorporate the Suzuki cou-
pling reaction in the synthesis of isoxazolinoisoquinolines
derivatives.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. All reactions were
run under a N2 atmosphere. Reagents and solvents were
purified as follows: dichloromethane was distilled from P2O5,
benzene and THF were distilled from sodium/benzophenone,
cyclohexane was distilled from CaH2, and diisopropylamine
was distilled from KOH. All other reagents were used as
received. Infrared spectra were determined on a Galaxy 3000
series Mattson FT-IR. NMR spectra were run using a General
Electric QE-300 spectrometer (1H at 300 MHz and 13C at 75
MHz). Elemental analyses were performed at Midwest Mi-
croLabs.
For reactions involving a polymer support, the polymer was
swollen in the reaction solvent for 30 min prior to addition of
other reagents. The reaction workup for the polymer substrate
included suction filtration using a sintered glass funnel and
washing with solvents of varying polarity, usually three times
each with water, THF, and hexane. The polymer was then
dried overnight under vacuum and an IR spectrum obtained
of a KBr pellet of a crushed sample of the polymer. IR bands
that are assigned to the polymer support are 3026, 2922, 1601,
1493, 1453, 759, and 698 cm-1. All other bands reported are
indicative of the new functionality attached to the polymer.
Reactions were monitored by the appearance and/or disap-
pearance of absorbances ascribed to functional group trans-
formations occurring where possible. In the case where the
To incorporate the Suzuki coupling reaction in our
solid-phase synthesis of isoxazolinoisoquinoline deriva-
tives, resin ®11 was subjected to Suzuki coupling condi-
tions to deliver resins ®12a and ®12b which were then

2248 J . Org. Chem., Vol. 63, No. 7, 1998
Lorsbach et al.
new functionality is indistinguishable from the previous IR
spectrum, a small amount of the polymer was subjected to
appropriate cleavage conditions and an 1H NMR spectrum
taken.
MHz, CDCl3) δ 14.02, 28.90, 119.57, 125.64, 127.36, 127.80,
130.27, 135.27, 142.33, 163.56, 183.79; 59% yield; trace un-
alkylated isoquinoline by GC.
1-Ben zylisoqu in olin e (3c):15 1H NMR (300 MHz, CDCl3)
δ 4,21 (s, 3H), 7.15 (m, 5H), 7.46 (m, 3H), 7.63 (d, J ) 8.90
Hz, 1H), 7.99 (d, J ) 7.60 Hz, 1H), 8.36 (d, J ) 5.75 Hz, 1H);
13C NMR (300 MHz, CDCl3) δ 42.05, 119.76, 125.79, 126.21,
127.16, 127.32, 128.48, 128.57, 128.59, 129.80, 136.58, 139.44,
142.01, 160.13; 50% yield; trace unalkylated isoquinoline by
GC.
Gen er a l P olym er -Su p p or ted 1,3-Dip ola r Cycloa d d i-
tion P r oced u r e. The alkylated resin (1.5 g, 1.5 mequiv/g)
was placed in two-necked flask (100 mL) with dry benzene (40
mL). Nitropropane (844 mg, 11.3 mmol) and PhNCO (2.67 g,
22.5 mmol) were added followed by a catalytic amount of Et3N
(22.7 mg, 0.2 mmol). The mixture was heated to reflux for 36
h and cooled to ambient temperature, water (10 mL) was
added, and the resulting mixture was stirred for 10 min. The
resin was collected by filtration and washed with THF (2 ×
50 mL), water (8 × 50 mL), and THF (4 × 50 mL). The resin
was dried in a desiccator for 5 h.
1-[(3-Eth yl-4,5-d ih yd r o-5-isoxa zolyl)m eth yl]isoqu in o-
lin e (7a ): 1H NMR (300 MHz, CDCl3) δ 1.04 (t, J ) 7.59 Hz,
3H), 2.25 (q, J ) 7.49 Hz, 2H), 2.80 (ddd, J ) 7.03 Hz, 1H),
2.87, (ddd, J ) 9.92 Hz, 1H), 3.32 (ddd, J ) 8.14 Hz, 1H), 3.73
(ddd, J ) 5.26 Hz, 1H), 5.12 (m, 1H), 7.47, (d, J ) 5.75 Hz,
1H), 7.53 (m, 2H), 7.74, (d, J ) 7.70 Hz, 1H), 8.12 (d, J ) 7.93
Hz, 1H), 8.36 (d, J ) 5.71 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 11.19, 21.63, 40.16, 42.27, 79.47, 120.14, 125.56, 127.54,
127.73, 127.86, 130.39, 136.43, 141.85, 157.75, 160.72; FTIR
(CDCl3) 3060, 2975, 2939, 1623, 1586, 1561, 1502, 1434, 1384,
1367, 1297, 908 cm-1; 25% yield; pale yellow oil.
P olym er -Su ppor ted Ben zoic Acid.7b,c Following Leznoff’s
procedure, unfuctionalized polystyrene-2% divinylbenzene
copolymer (20 g) was suspended in cyclohexane (80 mL) and
n-BuLi (1.6 M, 150 mL) at ambient temperature over 1 h. The
orange mixture was heated to 60 °C, allowed to stir at this
temperature for 12 h, and cooled, and the cyclohexane was
cannulated out, and the resin was washed three times with
dry THF (150 mL). The lithiated polymer was swollen in THF
(150 mL), and dry CO2 was bubbled in for 2-3 h. As CO2
addition proceeded, the resin changed color from orange to
yellow and finally back to orange. The resulting polymer was
collected by filtration, washed and dried as described in the
general experimental procedures. Polymer loading was de-
termined by titration to be 1.5 mequiv/g: FTIR (KBR) 1698
cm-1
.
P olym er -Su p p or ted Ben zoyl Ch lor id e.7b,c Polymer-sup-
ported benzoic acid (15 g) was swollen in SOCl2 (200 mL) at
ambient temperature for 30 min. A catalytic amount of DMF
(1 mL) was added, and the mixture was refluxed for 2-3 h.
The polymer was filtered and washed with CHCl3, CH2Cl2,
THF, and Et2O. The polymer was dried in a vacuum desiccator
overnight: FTIR (KBR) 1760 cm-1
.
Gen er a l P olym er -Su p p or ted Reisser t P r oced u r e. To
a mixture of the acid chloride resin 1 (1.5 g, loading 1.5 mmol/
g) in CH2Cl2 (30 mL) was added isoquinoline (1.45 g, 11.2
mmol). The mixture was allowed to stir at ambient temper-
ature for 20 min, at which time TMSCN (1.12 g, 10.1 mmol)
was added. The resulting mixture was stirred for an ad-
ditional 48 h, filtered, and washed with CH2Cl2 (1 × 50 mL),
aqueous HCl (1 × 75 mL), water (1 × 75), aqueous NaHCO3,
(1 × 75 mL), water (1 × 75 mL), and THF (2 × 50 mL). The
resin was dried in a desiccator for 5 h. All polymer-supported
Reissert compounds were made in this fashion from the
1-[(4,5-Dih yd r o-3-p h en yl-5-isoxa zolyl)m eth yl]isoqu in -
1
olin e (7b): mp 131-132 °C (recrystallized from EtOAc); H
NMR (300 MHz, CDCl3) δ 3.21 (ddd, J ) 7.34 Hz, 1H), 3.41
(m, 2H), 3.83 (ddd, J ) 5.27 Hz, 1H), 5.37 (m, 1H), 7.30 (m,
3H), 7.50 (d, J ) 5.87 Hz, 1H), 7.58 (m, 4H), 7.75 (d, J ) 7.59
Hz, 1H), 8.12 (d, J ) 8.48 Hz, 1H), 8.37 (d, J ) 5.74 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 39.75, 40.14, 80.42, 119.82,
125.07, 126.63, 127.26, 127.43, 127.52, 128.54, 129.64, 129.88,
130.05, 136.09, 141.60, 156.89, 157.20; FTIR (CDCl3) 3053,
2953, 2926, 1623, 1586, 1563, 1502, 1447, 1391, 1355, 909
cm-1; 26% yield. Anal. Calcd for C19H16N2O: C, 79.14; H, 5.59;
N, 9.71. Found: C, 79.04; H, 5.66; N, 9.94.
appropriate isoquinolines: FTIR (KBR) 1680 cm-1
.
Gen er a l P olym er -Su p p or ted Alk yla tion P r oced u r e.
The resin obtained from the Reissert reaction was placed in a
round-bottom flask (100 mL) with dry THF (20 mL) and cooled
to -78 °C. LDA (1.20 g, 11.12 mmol) was added, and the
mixture was stirred for 30 min. Methyl iodide (0.90 mL, 84.0
mmol) was added dropwise, and the mixture was allowed to
warm to ambient temperature, stirred for 48 h, and collected
by filtration. The resin was washed with THF (1 × 50 mL),
aqueous HCl/THF (1:1; 2 × 50 mL), water (2 × 50 mL), and
THF (2 × 50 mL). The resin was dried in a desiccator for 8 h.
Since FTIR could not establish the completeness of the
alkylation, the Reissert was hydrolyzed to determine alkyla-
1-[(3-E t h yl-5-m et h yl-5-oxa zolyl)m et h yl]isoq u in olin e
(7c): 1H NMR (300 MHz, CDCl3): δ 0.87t, J ) 7.54 Hz, 3H),
1.30 (s, 3H), 2.05 (q, J ) 7.48 Hz, 2H), 2.63 (dd, J ) 17.13 Hz,
1H), 3.39 (dd, J ) 17.08 Hz, 1H), 3.49 (dd, J ) 13.915, 1H),
3.64 (dd, J ) 13.91 Hz, 1H), 7.45, (d, J ) 5.75 Hz, 1H), 7.57
(m, 2H), 7.70, (d, J ) 7.61 Hz, 1H), 8.26 (d, J ) 8.12 Hz, 1H),
8.35 (d, J ) 3.23 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 10.38,
20.98, 26.16, 43.74, 46.06, 85.86, 119.24, 126.25, 126.24,
126.80, 128.00, 129.62, 135.95, 140.80, 157.75, 160.72; FTIR
(CDCl3) 3154, 2977, 1793, 1560, 1463, 1380, 1097 cm-1; 21%
yield; light brown oil.
1-[(3-Eth yl-4,5-d ih yd r o-5-isoxa zolyl)m eth yl]-4-p h en yl-
isoqu in olin e (6a ): 1H NMR (300 MHz, CDCl3) δ 1.05 (t, J )
4.80 Hz, 3H), 2.26 (q, J ) 7.55 Hz, 2H), 2.84 (ddd, J ) 7.10
Hz, 1H), 3.01 (ddd, J ) 9.95 Hz, 1H), 3.34 (ddd, J ) 8.05, 1H),
3.77 (ddd, J ) 5.33 Hz, 1H), 5.16 (m, 1H), 7.36, (m, 5H), 7.55
(m, 2H), 7.81, (d, J ) 7.73 Hz, 1H), 8.17 (d, J ) 7.96 Hz, 1H),
8.36 (s, 1H); 13C NMR (75 MHz, CDCl3)_δ 11.36, 21.81, 40.45,
42.55, 79.69, 125.91, 125.98, 127.66, 127.70, 128.27, 128.97,
130.56, 130.60, 132.89, 135.03, 137.55, 141.78, 157.24, 160.92;
FTIR (CDCl3) 3058, 3024, 2972, 2918, 2879, 2850, 1678, 1638,
1599, 1492, 1451, 1340, 1263, 1242, 1065 cm-1; 27% yield; light
brown oil.
1
tion efficiency by H NMR of the crude isoquinoline reaction
mixture (>95% C1-alkylated).
Gen er al P olym er -Su ppor ted Cleavage P r ocedu r e. The
alkylated resin was placed in a round-bottom flask (25 mL),
and THF (10 mL) plus 1 M KOH (10 mL) were added. The
mixture was refluxed for 12 h, cooled to ambient temperature,
filtered, and washed with Et2O (2 × 25 mL). The filtrate was
placed in a separatory funnel and the aqueous layer discarded.
The organic layer was washed with water (2 × 50 mL) and
dried over MgSO4. The solvent was removed in vacuo, and
the residue was purified by silica gel chromatography (90:10
hexane/EtOAc to 25:75 hexane/EtOAc) to give the alkylated
isoquinoline. Note: this cleavage procedure was also used to
liberate isoxazolinoisoquinoline derivatives.
1-Meth ylisoqu in olin e (3a ):15 1H NMR (300 MHz, CDCl3)
δ 2.97 (s, 3H), 7.50 (d, J ) 5.76 Hz, 1H), 7.60 (m, 2H), 7.80 (d,
J ) 7.79 Hz, 1H), 8.11 (d, J ) 7.62 Hz, 1H), 8.38 (d, J ) 5.79
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.42, 119.25, 125.62,
127.01, 127.19, 129.91, 134.85, 141.81, 158.59; 56% yield; trace
unalkylated isoquinoline by GC.
1-[(4,5-Dih yd r o-3-p h en yl-5-isoxa zolyl)m et h yl]-4-p h e-
n ylisoqu in olin e (6b): 1H NMR (300 MHz, CDCl3) δ 3.26
(ddd, J ) 7.52 Hz, 1H), 3.46 (m, 2H), 3.88 (ddd, J ) 5.43 Hz,
1H), 5.37 (m, 1H), 7.30 (m, 3H), 7.42 (m, 5H), 7.60 (m, 4H),
7.85 (d, J ) 3.21 Hz, 1H), 8.19 (d, J ) 4.34 Hz, 1H), 8.21 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 39.81, 40.38, 80.60, 125.48,
125.66, 126.58, 126.91, 127.14, 127.31, 126.76, 127.39, 127.91,
1-Eth ylisoqu in olin e (3b):15 1H NMR (300 MHz, CDCl3)
δ 1.42 (t, J ) 7.53 Hz, 3H), 3.30 (q, J ) 7.56 Hz, 2H), 7.49 (d,
J ) 5.76 Hz, 1H), 7.59 (m, 2H), 7.81 (d, J ) 7.93 Hz, 1H), 8.15
(d, J ) 8.39 Hz, 1H), 8.43 (d, J ) 5.71 Hz, 1H); 13C NMR (75

Isoxazolinoisoquinoline Heterocycles
J . Org. Chem., Vol. 63, No. 7, 1998 2249
127.96, 128.56, 128.64, 130.16, 131.34, 135.39, 137.07, 141.12,
156.61; FTIR (CDCl3) 3058, 3031, 2962, 2917, 1615, 1556,
1507, 1498, 1445, 1392, 1355, 1260, 1074, 1029, 909 cm-1; 23%
yield; pale yellow oil.
solvent was removed in vacuo. This procedure was followed
for all solution Reissert hydrolysis reactions.
2-Ben zoyl-6-br om o-1-cyan o-5,8-dim eth yl-1,2-dih ydr oiso-
qu in olin e (11): mp 175-177 °C (recrystallized from EtOAc);
1H NMR (300 MHz, CDCl3) δ 2.44 (s, 6H), 6.21 (d, J ) 7.96
Hz, 1H), 6.59 (s, 1H), 6.70 (d, J ) 1.53 Hz, 1H), 7.41 (s, 1H),
7.41-7.61 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 18.06, 18.46,
42.39, 107.86, 115.49, 122.89, 126.69, 126.98, 128.63, 129.20,
129.39, 130.18, 130.84, 130.91, 132.09, 132.21, 133.61, 133.69,
168.59; FTIR (CDCl3) 2951, 1667, 1631, 1452, 1348, 1270, 908
cm-1; 93% yield. Anal. Calcd for C19H15N2OBr: C, 62.14; H,
4.12; N, 7.63. Found: C, 62.08; H, 4.12; N, 7.66.
2-Be n zoyl-1-cya n o-5,8-d im e t h yl-6-p h e n yl-1,2-d ih y-
d r oisoqu in olin e (12a ): 1H NMR (300 MHz, CDCl3) δ 2.16
(s, 3H), 2.41 (s, 3H), 6.20 (d, J ) 7.72 Hz, 1H), 6.63 (m, 2H),
7.00 (s, 1H), 7.21-7.67 (m, 10H); 13C NMR (75 MHz, CDCl3) δ
16.42, 18.69, 43.20, 108.88, 116.46, 123.41, 126.29, 127.65,
128.66, 129.09, 129.13, 129.32, 129.56, 129.61, 129.71, 130.04,
132.21, 132.24, 132.32, 132.98, 141.84, 144.46, 169.12; FTIR
(CDCl3) 2957, 1669, 1632, 1468, 1378, 1271, 1154, 1042, 908
cm-1; 75% yield; pale yellow oil.
2-Ben zoyl-1-cya n o-5,8-d im eth yl-6-(3-th iop h en e)-1,2-d i-
h yd r oisoqu in olin e (12b): 1H NMR (300 MHz, CDCl3) δ 2.20
(s, 3H), 2.38 (s, 3H), 6.17 (d, J ) 7.76 Hz, 1H), 6.60 (s, 1H),
7.04 (m, 2H), 7.38 (m, 1H), 7.41-7.55 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 15.95, 18.16, 42.59, 108.23, 115.90, 122.88,
122.98, 125.26, 125.80, 128.56, 128.77, 129.10, 129.19, 131.65,
131.75, 131.86, 132.27, 138.59, 141.43, 168.58; FTIR (CDCl3)
2957, 1669, 1632, 1468, 1378, 1271, 1154, 1042, 908 cm-1; 77%
yield; pale yellow oil.
1-[(3-E t h yl-5-m et h yl-5-oxa zolyl)m et h yl]-4-p h en yliso-
qu in olin e (6c): 1H NMR (300 MHz, CDCl3) δ 0.87 (t, J )
7.54 Hz, 3H), 1.51 (s, 3H), 2.10 (q, J ) 7.48 Hz, 2H), 2.63 (dd,
J ) 17.13 Hz, 1H), 3.39 (dd, J ) 17.08 Hz, 1H), 3.49 (dd, J )
13.915, 1H), 3.64 (dd, J ) 13.91 Hz, 1H), 7.39, (m, 5H), 7.54
(m, 2H), 7.78, (d, J ) 3.67 Hz, 1H), 8.30 (s, 1H), 8.34 (d, J )
3.18 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 10.84, 21.40, 26.57,
44.24, 46.40, 86.34 125.14, 126.80, 126.97, 127.76, 127.96,
128.50, 130.04, 130.13, 132.38, 134.61, 137.28, 141.08, 157.15,
160.73; FTIR (CDCl3) 3058, 3031, 2962, 2917, 1617, 1556,
1507, 1498, 1445, 1392, 1355, 1260, 1074, 1029, 1020, 909
cm-1; 24% yield; brown oil.
4-Br om o-1-[(3-et h yl-4,5-d ih yd r o-5-isoxa zolyl)m et h yl-
]isoqu in olin e (9a ): 1H NMR (300 MHz, CDCl3) δ 1.05 (t, J
) 4.33 Hz, 3H), 2.23 (q, J ) 7.60 Hz, 2H), 2.76 (ddd, J ) 7.66
Hz, 1H), 3.01 (ddd, J ) 6.99 Hz, 1H), 3.35 (ddd, J ) 5.31, 1H),
3.71 (ddd, J ) 5.35 Hz, 1H), 5.11 (m, 1H), 7.46, (m, 2H), 8.12,
(d, J ) 4.44 Hz, 1H), 8.34 (d, J ) 5.75 Hz, 1H), 8.54 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 10.90, 21.35, 39.76, 42.05, 78.92,
118.62, 125.73, 126.64, 128.33, 128.83, 131.31, 134.79, 143.40,
157.12, 160.42; FTIR (CDCl3) 3082, 3058, 3023, 3000, 2970,
2920, 2848, 1716, 1683, 1675, 1635, 1600, 1309, 1288, 1261,
1241, 1208, 1179, 1113, 1064 cm-1; 26% yield; brown oil.
4-Br om o-1-[(4,5-d ih yd r o-3-p h en yl-5-isoxa zolyl)m eth yl-
]isoqu in iolin e (9b): 1H NMR (300 MHz, CDCl3) δ 3.22 (ddd,
J ) 7.28 Hz, 1H), 3.46 (m, 2H), 3.89 (ddd, J ) 5.39 Hz, 1H),
5.38 (m, 1H), 7.33 (m, 3H), 7.51 (m, 5H), 7.58 (m, 4H), 7.85 (d,
J ) 3.21 Hz, 1H), 8.19 (d, J ) 4.34 Hz, 1H), 8.21 (s, 1H); 13C
NMR (75 MHz, CDCl3) 29.66, 40.25, 80.48, 119.93, 125.19,
125.47, 126.60, 127.23, 127.52, 128.16, 128.29, 128.41, 128.51,
129.87, 129.92, 130.22, 143.35, 156.89, 157.17; FTIR (CDCl3)
3154, 2960, 2901, 1617, 1567, 1469, 1382 cm-1; 24% yield; light
brown oil.
4-Br om o-1-[(3-et h yl-5-m et h yl-5-oxa zolyl)m et h yl]iso-
qu in olin e (9c): 1H NMR (300 MHz, CDCl3) δ 1.13 (t, J )
6.79 Hz, 3H), 1.45 (s, 3H), 2.11 (q, J ) 7.54 Hz, 2H), 2.60 (dd,
J ) 17.17 Hz, 1H), 3.29 (dd, J ) 17.14 Hz, 1H), 3.41 (dd, J )
14.01, 1H), 3.55 (dd, J ) 14.01 Hz, 1H), 7.60, (t, J ) 1.23 Hz,
1H), 7.68, (t, J ) 1.12 Hz, 1H), 8.07 (d, J ) 7.97 Hz, 1H), 8.25
(d, J ) 8.48 Hz, 1H), 8.55 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 11.21, 21.81, 26.93, 44.45, 46.88, 86.42, 119.11, 126.69,
127.55, 128.51, 130.04, 131.68, 135.30, 143.45, 157.88, 161.08;
FTIR (CDCl3) 3154, 2977, 2938, 1816, 1617, 1567, 1461, 1380,
1097 cm-1; 23% yield; yellow oil.
Gen er a l Solu tion Su zu k i Cou p lin g P r oced u r e. Pd-
(PPh3)4 (115.5 mg, 0.133 mmol) was added to 2-benzoyl-6-
bromo-1-cyano-5,8-dimethyl-1,2-dihydroisoquinoline (11; 1.0 g,
2.66 mmol) in benzene (20 mL), and the solution was stirred
for 30 min. Phenylboronic acid (0.649 g, 5.32 mmol) and 2 M
aqueous Na2CO3 (3.0 mL, 5.85 mmol) were added, and the
mixture was heated to 80 °C for 20 h. The solution was cooled
to ambient temperature, diluted with 25% aqueous NH4OAc
(10 mL) and stirred for 5 min. The organic layer was
separated from the aqueous layer. The aqueous layer was
washed with EtOAc (2 × 10 mL), and the washings were
combined with the organic layer. The combined organic layers
were washed with DME/H2O (1:1, 10 mL), water (2 × 10 mL),
1 M HCl (2 × 5 mL), and water (2 × 15 mL) and then dried
with MgSO4. The solvent was removed in vacuo. This
procedure was followed for all solution Suzuki coupling reac-
tions.
Gen er a l Solu tion Reisser t Hyd r olysis P r oced u r e. A
THF (10 mL) solution of 2-benzoyl-6-phenyl-1-cyano-5,8-dim-
ethyl-1,2-dihydroisoquinoline (12; 0.50 g, 1.33 mmol) was
treated with 1 M aqueous KOH (10 mL, 0.01 mol). The
solution was refluxed for 12 h and cooled to ambient temper-
ature, and the organic layer was separated from the aqueous
layer. The aqueous layer was washed with CH2Cl2 (3 × 10
mL), and the washings were combined with the organic layer.
The combined organic layers were dried with MgSO4, and the
5,8-Dim eth yl-6-p h en yl-1-isoqu in olin e (13a ): 1H NMR
(300 MHz, CDCl3) 2.53 (s, 3H), 2.78(s, 3H), 7.41-7.50 (m, 6H),
7.84 (d, J ) 5.35 Hz, 1H), 8.61 (d, J ) 5.96 Hz, 1H), 9.47 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 15.34, 18.24, 117.67, 126.86,
127.18, 127.99, 128.15, 129.35, 130.36, 132.54, 136.09, 141.71,
142.79, 143.26, 149.57; FTIR (CDCl3) 2951, 2924, 1613, 1602,
1465, 1389, 1036, 907 cm-1; 89% yield; pale yellow oil.
5,8-Dim eth yl-6-(3-th iop h en e)-1-isoqu in olin e (13b): 1H
NMR (300 MHz, CDCl3) δ 2.59, (s, 3H), 2.76 (s, 3H), 7.18 (m,
1H), 7.28 (m, 1H), 7.35 (s, 1H), 7.43 (m, 1H), 7.81 (d, J ) 5.10
Hz, 1H), 8.60 (d, J ) 5.97 Hz, 1H), 9.44 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 15.37, 18.18, 117.60, 123.55, 125.30, 126.80,
128.35, 129.02, 130.20, 132.56, 136.09, 137.44, 141.91, 143.23,
149.47; FTIR (CDCl3) 2949, 2918, 1614, 1587, 1481, 1465,
1444, 1411, 1384, 1247, 1035, 907 cm-1; 69% yield; pale yellow
oil.
Gen er a l P olym er -Su p p or t ed Su zu k i Cou p lin g P r o-
ced u r e.11a Polymer-supported Reissert resin (1.5 g, 1.5
mequiv/g) was swollen in CH2Cl2 (30 mL) and treated with
Pd(PPh3)4 (173.3 mg, 0.15 mmol). After 30 min, phenylboronic
acid (731.5 mg, 6.0 mmol) and 2 M aqueous Na2CO3 (1.65 mL,
6.6 mmol, 4.4 equiv) were added, and the mixture was heated
to 80 °C for 72 h. The mixture was cooled to ambient
temperature, diluted with 25% aqueous NH4OAc (10 mL),
stirred for 5 min, and filtered. The resin was washed with
CH2Cl2/H2O (1:1, 40 mL), water (2 × 20 mL), 1 M aqueous
HCl (2 × 15 mL), water (2 × 30 mL), CH2Cl2 (2 × 20 mL),
THF (2 × 40 mL), and Et2O (2 × 25 mL) and dried in a
desiccator for 8 h.
5,8-Dim et h yl-1-[(3-et h yl-4,5-d ih yd r o-5-isoxa zolyl)m e-
th yl]-6-p h en yl-1-isoqu in olin e (14a ): 1H NMR (300 MHz,
CDCl3) δ 1.08 (t, J ) 3.55, 3H), 2.28 (q, J ) 7.43 Hz, 2H), 2.45
(s, 3H), 2.65 (ddd, J ) 9.18 Hz, 1H), 2.70 (s, 3H), 3.11, (ddd, J
) 7.0 Hz, 1H), 3.50 (ddd, J ) 7.32 Hz, 1H), 4.07 (ddd, J )
4.39 Hz, 1H), 5.18 (m, 1H), 7.29 (m, 5H), 7.76 (d, J ) 5.98 Hz,
1H), 8.54 (d, J ) 5.82 Hz, 1H), 9.39 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 10.96, 15.37, 18.27, 21.45, 26.05, 42.69, 44.86, 80.04,
117.70, 127.24, 128.04, 128.20, 129.40, 130.40, 132.59, 132.62,
133.29, 137.95, 141.19, 141.78, 143.35, 149.65, 158.12, 160.64;
23% yield; pale yellow oil.
5,8-Dim et h yl-1-[(3-et h yl-4,5-d ih yd r o-5-isoxa zolyl)m e-
th yl]-6-(3-th iop h en e)-1-isoqu in olin e (14b): 1H NMR (300
MHz, CDCl3) δ 1.13 (t, J ) 7.52, 3H), 2.36 (q, J ) 7.60 Hz,
2H), 2.59 (s, 3H), 2.76 (ddd, J ) 7.60 Hz, 1H), 2.87, (ddd, J )
9.92 Hz, 1H), 2.94 (s, 3H), 3.32 (ddd, J ) 8.14 Hz, 1H), 3.73

2250 J . Org. Chem., Vol. 63, No. 7, 1998
Lorsbach et al.
(ddd, J ) 5.26 Hz, 1H), 5.12 (m, 1H), 7.18 (d, J ) 3.73, 1H),
7.29 (m, 1H), 7.38 (s, 1H), 7.44, (m, 1H), 7.76 (d, J ) 5.92,
1H), 8.42 (d, J ) 5.92 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
11.32, 16.65, 21.82, 26.35, 43.07, 45.22, 80.44, 117.10, 123.97,
125.76, 129.47, 129.66, 133.07, 133.57, 141.59, 158.49; 25%
yield; pale yellow oil.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
3a -c, 6a -c, 7a -c, 9a -c, 11, 12a ,b, 13a ,b, and 14a ,b; 13C
NMR spectra for 3a -c, 6a -c, 7a -c, 9a -c, 11, 12a ,b, 13a ,b,
and 14a ,b (38 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.
Ack n ow led gm en t. We are grateful to the National
Science Foundation and the DuPont Educational Aid
Program for financial support of this research.
J O9720142