Efficient, "tin-free" radical cyclization to aromatic systems. Synthesis of 5,6,8,9,10,11-hexahydroindolo[2,1-a]isoquinolines

Article abstract of DOI:10.1021/jo0497048

Efficient radical cyclization of alkyl iodides to various aromatic systems including pyrrole, indole, isoquinolone, pyridone, and benzene, mediated by dicumyl peroxide, is described. The methodology was used to provide access to 5,6,8,9,10,11-hexahydroindolo[2,1-a]isoquinoline derivatives.

Full text of DOI:10.1021/jo0497048

SCHEME 1. P r op osed Mech a n ism for th e Ra d ica l
Cycliza tion to Ar om a tic System s Usin g DCP
Efficien t, “Tin -F r ee” Ra d ica l Cycliza tion to
Ar om a tic System s. Syn th esis of
5,6,8,9,10,11-
Hexa h yd r oin d olo[2,1-a ]isoqu in olin es
Martha Menes-Arzate,† Roberto Mart´ınez,*,†
Raymundo Cruz-Almanza,†,‡ J oseph M. Muchowski,§
Yazmin M. Osornio,† and Luis D. Miranda*,†
Instituto de Qu´ımica, Universidad Nacional Auto´noma de
Me´xico, Circuito Exterior, Ciudad Universitaria,
Coyoaca´n, Me´xico D. F. 04510, Mexico, and Chemistry,
Roche Palo Alto, 3431 Hillview Avenue,
Palo Alto, California 94304-1320
lmiranda@servidor.unam.mx
Received February 20, 2004
n
have been devised to effect such cyclizations, with Bu3-
SnH-mediated reactions being the most explored. This
methodology has been used to annulate five-, six-, and
seven-membered rings to various aromatic systems in-
cluding derivatives of benzene, pyrrole, indole, pyridine,
imidazole, benzimidazole, thiophene, and quinoline. Oxi-
dative intramolecular additions to aromatic systems
mediated by Mn(III),2 Fe(III),3 Cu(II),4 Ce(IV),3,4 which
proceed with varying degrees of efficiency, have also been
reported and recently Zard and co-workers5 have annu-
lated five-, six-, and seven-membered rings to an aromatic
nucleus, exploiting xanthate based radical chemistry. As
a long-term goal we have been interested in finding
efficient tin-free methods for effecting oxidative radical
cyclization to aromatic systems. In this context, we have
been exploring the possibility of effecting oxidative ho-
molytic cyclization of primary alkyl iodides to aromatic
systems using environmentally friendly organic peroxides
as the sole reagent. This paper describes the application
of such methodology to the synthesis of several poten-
tially cytotoxic indolo[2,1-a]isoquinoline derivatives.
The thermal fragmentation of dicumyl peroxide (DCP)
was of special importance for our purposes, since the very
reactive methyl radical species is produced (Scheme 1,
eq 1). Thus, on the basis of the known favorable equilib-
rium of eq 2 (Scheme 1),6 radical 6 is expected to be
generated from the methyl radical 3 and alkyl iodide 5
and then add intramolecularly to the aromatic nucleus
(Scheme 1, eq 3). Restoration of the aromatic system by
DCP would then complete the sequence (eq 4).7 Thus,
since DCP would be acting both as the initiator and the
oxidant,4 a stoichiometric amount of the peroxide would
be required to complete the reaction. In a pioneering
work, Renaud et al. reported that dilauroyl peroxide
induces a similar process; nevertheless, only an R-iodoac-
etamide derivative which produces a stabilized radical
was tested.8
Abstr a ct: Efficient radical cyclization of alkyl iodides to
various aromatic systems including pyrrole, indole, isoquino-
lone, pyridone, and benzene, mediated by dicumyl peroxide,
is described. The methodology was used to provide access
to 5,6,8,9,10,11-hexahydroindolo[2,1-a]isoquinoline deriva-
tives.
During the past several years, the addition of radicals
to aromatic nuclei followed by oxidation to restore the
aromatic systems has received considerable attention and
is frequently of preparative value.1-5 Several methods
* To whom correspondence be addressed. Phone: (+52) 55 56 22
44 40. Fax: (+52) 55 56 16 22 17.
† Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico.
‡ Deceased.
§ Chemistry, Roche Palo Alto.
(1) (a) Studer, A. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M., Eds.; Wiley VCH: Weinhem, 2001; Vol. 2, pp 62-76. (b) Beckwith,
A. L. J .; Bowry, V. W.; Bowman, W. R.; Mann E.; Parr, J .; Storey, J .
M. D. Angew. Chem., Int. Ed. 2004, 43, 95. (c) Murphy, J . A.; Sherburn,
M. S. Tetrahedron 1991, 47, 4077. (d) Suzuki, F.; Kuroda, K. J .
Heterocycl. Chem. 1993, 30, 811. (e) Antonio, Y.; de la Cruz, E.;
Galeazzi, E.; Guzman, A.; Bray, B. L.; Greenhuouse, R.; Kurz, L. J .;
Lustig, D. A.; Maddox, M. L.; Muchowski, J . M. Can. J . Chem. 1994,
72, 15. (f) Tim, C. T.; J ones, K.; Wilkinson, J . Tetrahedron Lett. 1995,
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Lett. 1997, 38, 7937. (j) Ziegler, F. E.; Belema, M. J . Org. Chem. 1997,
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1, 1997, 2639. (l) Harrowen D.; Nunn, M. I. T. Tetrahedron Lett. 1998,
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Z. Tetrahedron 1999, 55, 8111. (n) Marco-Contelles, J .; Rodr´ıguez-
Ferna´ndez, M. Tetrahedron Lett. 2000, 41, 381. (o) Bowman, W. R.;
Mann, E. J . Chem. Soc., Perkin Trans. 1 2000, 2991.
(2) (a) Mohan, R.; Kates, S. A.; Dombroski, M. A.; Snider, B. B.
Tetrahedron Lett. 1987, 28, 845. (b) Snider, B. B.; Buckman, B. O.
Tetrahedron 1989, 45, 6969 and references therein. (c) Aidhen, I. S.;
Narasimhan, N. S. Tetrahedron Lett. 1989, 30, 5323. (d) Artis, D. R.;
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56, 5328. (b) Citterio, A.; Sebastiano, R.; Caceres C. M. J . Org. Chem.
1991, 56, 5335 and references therein.
The initial experiments were carried out on the 3-acyl-
indoles 9, the oxidative radical cyclization which had been
(4) Snider, B. B.; Kown, T. J . Org. Chem. 1990, 55, 4786.
(5) (a) Gagosz, F.; Zard, S. Z. Org. Lett. 2002, 4, 4345. (b) Kaoudi,
T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem., Int. Ed. 2000,
39, 732. (c) Axon, J .; Boiteau, L.; Boivin, J .; Forbes, J . E.; Zard, S. Z.
Tetrahedron Lett. 1994, 35, 1719. (d) Liard, A.; Quiclet-Sire, B.; Saicic,
R. N.; Zard, S. Z. Tetrahedron Lett. 1997, 38, 1759. (e) Cholleton N.;
Zard, S. Z. Tetrahedron Lett. 1998, 39, 7295. (f) Ly, T.-M.; Quiclet-
Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2533.
(6) Artis, D. R.; Cho, I.-S.; J aimes, S.; Muchowski, J . M. J . Org.
Chem. 1994, 59, 2456.
(7) For a case in which DCP serves as the oxidant, see: Guerrero,
M. A.; Cruz-Almanza, R.; Miranda, L. D. Tetrahedron 2003, 59, 4953.
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10.1021/jo0497048 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/04/2004
J . Org. Chem. 2004, 69, 4001-4004
4001

TABLE 1. Oxid a tive-Ra d ica l Cycliza tion Usin g Dicu m yl
P er oxid ea
F IGURE 1. Dibenzopyrrocoline alkaloids from Cryptocarya
bowiei.
SCHEME 2a
a
Conditions: (i) 2-aminoethanol, AcOH, 60 °C; (ii) Ph3P, I2,
imidazole; (iii) dicumyl peroxide, chlorobenzene, reflux.
involving the preparation and testing of structurally
novel cytotoxic substances,12 and in this regard, it was
of interest to develop efficient synthetic strategies to
derivatives of the heterocyclic system 21.
a
Conditions: dicumyl peroxide (1.5 equiv), chlorobenzene,
reflux.
The synthesis started with the synthesis of the 1,4-
dicarbonyl compounds 23a -e according to the procedure
reported previously13 (Scheme 2). After generation of the
pyrrole nucleus by condensation of these compounds with
2-aminoethanol, followed by reaction of the hydroxyethyl
compounds so produced with triphenylphosphine and
iodine, the desired iodo compounds 26a -e were obtained
in moderate overall yields (Scheme 2). Cyclization of
these iodides under the above-described conditions gave
excellent yields of the tetracyclic compounds 26a -e with
the p-fluoro 26b compound being generated most ef-
ficiently. It is important to point out that 25d , which
bears a bromine substituent in the para position, is
converted into 26d in which the bromine atom is re-
tained. Such a process would be difficult, if not impos-
sible, to accomplish using tin-based radical chemistry.
studied previously under conditions different from those
described herein.3,1j Thus, portionwise addition of DCP
(1.5 equiv) to refluxing solutions of the indoles 9a and
9b gave the expected tricyclic products 10a and 10b in
excellent yields (Table 1) along with considerable amounts
of acetophenone and 2-phenylpropan-2-ol derived from
DCP.4 Under the same conditions, the pyrrole derivative
12, the isoquinolin-1-ones 14 and 16, and the 4-quinolone
derivative 18 were all produced in high yields from the
corresponding iodo compounds 11, 13, 15, and 17. Even
the 2-pyridone derivative 19 underwent cyclization to 20,
albeit in modest yield. It should be noted that such
cyclizations have been reported to fail in the case of
Bu3SnH/AIBN- mediated reactions.9
Indolo[2,1-a]isoquinoline 21 is the basic skeleton found
in the dibenzopyrrocoline alkaloids cryptaustoline 22a
and cryptowoline 22b isolated from the bark of Crypto-
carya bowiei (Figure 1). It has been observed that such
bases display important antileukemic and antitumor
activities.10,11 We have recently initiated a program
(10) Ewing, J .; Hughes, G. K.; Ritchie, E.; Taylor, W. C. Nature 1952,
169, 618.
(11) For a review, see: Eliot, I. W. In The Alkaloids; Brossi, A., Ed.;
Academic Press: Orlando, 1987; Vol. 31, pp 101-116.
(12) Martinez, L. R.; Zarraga, J . C.; Duran, M. A.; Apam, M. T. R.;
Can˜as, R. Bioorg. Med. Chem. Lett. 2002, 12, 1675.
(13) Maini, P. M.; Sammes, M. P.; Katritzky, A. R. J . Chem. Soc.,
Perkin Trans. 1 1988, 161.
(9) Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 40, 4073.
4002 J . Org. Chem., Vol. 69, No. 11, 2004

1516, 1475, 1342, 859; 1H NMR (300 MHz, CDCl3) δ 1.13 (s, 6H),
1.95 (s, 1H), 2.30 (s, 2H), 2.74 (s, 2H), 3.75 (t, J ) 5.7 Hz, 2H),
4.12 (t, J ) 5.7 Hz, 2H), 6.66 (s, 1H), 7.64 (d, J ) 9.0 Hz, 2H),
8.26 (d, J ) 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 28.7, 35.4,
36.8, 46.7, 51.6, 61.5, 108.0, 119.8, 124.0, 129.5, 134.1, 138.9,
146.0, 146.9, 193.9; MS (EI) m/z (rel intensity) 328 (M+, 80); 228
(100), HRMS (FAB+) calcd for C18H21O4N2 329.1501, found
329.1508.
In closing, it has been demonstrated that the intramo-
lecular oxidative radical cyclization of primary alkyl
iodides to aromatic nuclei can be efficiently effected using
DCP. Not only are these reactions conducted in the
absence of heavy metals and under tin-free conditions,
but also the well-known problem of the premature
reduction of the radical intermediate, frequently encoun-
tered in nBu3SnH-mediated reactions, is easily avoided.
The present methodology was also adapted to provide
rapid access to derivatives of the pharmacologically
important 5,6,8,9,10,11-hexahydroindolo[2,1-a]isoquino-
lines.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-(2-Iod oeth -
yl)tetr a h yd r oin d olon es (25a -e). Triphenylphosphine (1.5
equiv) and imidazole (1.5 equiv) were dissolved in dry CH2Cl2
(1.5 mL/mmol). The mixture was cooled in an ice bath, and iodine
(1.5 equiv) was added with vigorous stirring over 10 min. The
resulting slurry was warmed to room temperature, and a
solution of hydroxyethyl tetrahydroindolone (24) (1.0 equiv) in
CH2Cl2 was added dropwise over 15 min. The mixture was
stirred for 1 h under atmosphere of N2. The solvent was removed,
and the crude residue was purified by column chromatography
on neutral aluminum oxide using Hex/EtOAc as eluent.
1-(2-Iod oet h yl)-6,6-d im et h yl-2-p h en yl-1,5,6,7-t et r a h y-
d r oin d ol-4-on e (25a ): yield 85% as a white solid; mp 143-45
°C; IR (KBr, cm-1) νmax 2952, 2923, 2867, 1656, 1471, 772, 705;
1H NMR (300 MHz, CDCl3) δ 1.19 (s, 6H), 2.40 (s, 2H), 2.71 (s,
2H), 3.03 (t, J ) 8.1 Hz, 2H), 4.23 (t, J ) 8.1 Hz, 2H), 6.56 (s,
1H), 7.34-7.47 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 0.7, 28.9,
35.6, 36.4, 46.4, 51.9, 106.2, 119.7, 128.2, 128.9, 129.0, 132.0,
135.4, 143.0, 193.6; MS (EI) m/z (rel intensity) 393 (M+, 100);
HRMS (FAB+) calcd for C18H21ONI 394.0668, found 394.0666.
2-(4-F lu or op h en yl)-1-(2-iod oeth yl)-6,6-d im eth yl-1,5,6,7-
tetr a h yd r oin d ol-4-on e (25b): yield 79% as a white solid; mp
140-41 °C; IR (KBr, cm-1) νmax 2952, 2925, 2861, 1658, 1469,
851; 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 6H), 2.39 (s, 2H), 2.67
(s, 2H), 3.02 (t, J ) 7.9 Hz, 2H), 4.20 (t, J ) 7.9 Hz, 2H), 6.53 (s,
1H), 7.14 (dd, J ) 8.8, 2.9 Hz, 2H), 7.33 (dd, J ) 5.3, 2.3 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 0.5, 28.8, 35.6, 36.4, 46.3, 51.9,
106.4, 115.8, 116.1, 119.6, 130.8, 130.9, 134.2, 142.9, 193.5; MS
(EI) m/z (rel intensity) 411 (M+, 100); HRMS (FAB+) calcd for
C18H20ONFI 412.0574, found 412.0582.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of 1-(2-Hyd r oxy-
eth yl)tetr a h yd r oin d olon es (24a -e). To a vigorously stirred
suspension of triketone 19 (1 g, 3.88 mmol) in acetic acid (5 mL)
was added ethanolamine (0.36 mL, 5.82 mmol). The resulting
slurry was heated to 60 °C under an atmosphere of N2 until no
more starting material was observed by TLC, and then the
reaction mixture was allowed to warm to room temperature and
spilled over ice-water (10 mL). The solid was filtered and
washed with cooled water. The crude mixture was purified by
column chromatography on neutral aluminum oxide using a
gradient of 30-50% EtOAc in hexane as eluant. Evaporation of
the collected fractions gave 1-(2-hydroxyethyl)indolones.
1-(2-Hydr oxyeth yl)-6,6-dim eth yl-2-ph en yl-1,5,6,7-tetr ah y-
d r oin d ol-4-on e (24a ): yield 64% as a white solid; mp 172-74
°C; IR (KBr, cm-1) νmax 3325, 2955, 2883, 1624, 1475, 1061, 779,
703; 1H NMR (300 MHz, CDCl3 + DMSO) δ 1.16 (s, 6H), 2.32
(s, 2H), 2.79 (s, 2H), 3.54 (t, J ) 6.2 Hz, 2H), 4.02 (t, J ) 6.1 Hz,
3H), 6.42 (s, 1H), 7.41 (d, J ) 4.6 Hz, 5H); 13C NMR (75 MHz,
CDCl3 + DMSO) δ 28.2, 34.9, 35.9, 46.1, 51.5, 60.2, 104.6, 118.3,
127.2, 128.2, 128.8, 132.1, 135.4, 144.1, 192.4; MS (EI) m/z (rel
intensity) 283 (M+, 67), 183 (100); HRMS (FAB+) calcd for
C18H22O2N 284.1651, found 284.1642.
2-(4-F lu or op h e n yl)-1-(2-h yd r oxye t h yl)-6,6-d im e t h yl-
1,5,6,7-tetr a h yd r oin d ol-4-on e (24b): yield 60% as a white
solid; mp 161-63 °C; IR (KBr, cm-1) νmax 3340, 2954, 2879, 1629,
1481, 1058, 847; 1H NMR (300 MHz, CDCl3 + DMSO) δ 1.16 (s,
6H), 2.34 (s, 2H), 2.77 (s, 2H), 3.56 (t, J ) 6.3 Hz, 2H), 3.98 (t,
J ) 6.3 Hz, 2H), 4.36 (s, 1H), 6.43 (s, 1H), 7.11 (t, J ) 8.7 Hz,
2H), 7.41 (dd, J ) 5.4, 9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3 +
DMSO) δ 28.2, 34.8, 35.9, 45.9, 51.4, 60.3, 104.7, 114.7, 115.0,
118.3, 128.1, 130.7, 130.8, 134.3, 143.9, 160.1, 163.3, 192.8; MS
(EI) m/z (rel intensity) 301 (M+, 100), 201 (96); HRMS (FAB+)
calcd for C18H21O2NF 302.1556, found 302.1554.
2-(4-Ch lor op h e n yl)-1-(2-h yd r oxye t h yl)-6,6-d im e t h yl-
1,5,6,7-tetr a h yd r oin d ol-4-on e (24c): yield 55% as a white
solid; mp 165-66 °C; IR (KBr, cm-1) νmax 3255, 2958, 2870, 1627,
1477, 1062, 820; 1H NMR (300 MHz, CDCl3) δ 1.10 (s, 6H), 2.23
(s, 2H), 2.70 (s, 2H), 2.77 (s,1H), 3.69 (d, J ) 3.0 Hz, 2H), 4.02
(t, J ) 6.0 Hz, 2H), 6.50 (s, 1H), 7.38 (s, 4H); 13C NMR (75 MHz,
CDCl3) δ 28.7, 35.4, 36.7, 46.5, 51.5, 61.4, 106.1, 119.2, 128.9,
130.7, 130.8, 134.0, 135.1, 144.9, 194.1; MS (EI) m/z (rel
intensity) 317 (M+, 98), 217 (100); HRMS (FAB+) calcd for
C18H21O2NCl 318.1261, found 318.1251.
2-(4-Br om op h e n yl)-1-(2-h yd r oxye t h yl)-6,6-d im e t h yl-
1,5,6,7-tetr a h yd r oin d ol-4-on e (24d ): yield 40% as a white
solid; mp 159-160 °C; IR (KBr, cm-1) νmax 3258, 2953, 2872,
1628, 1475, 1063, 819; 1H NMR (300 MHz, CDCl3) δ 1.09 (s, 6H),
2.21 (s, 2H), 2.69 (s, 2H), 2.88 (s,1H), 3.71 (t, J ) 5.5 Hz, 2H),
4.02 (t, J ) 5.5 Hz, 2H), 6.49 (s, 1H), 7.32 (dd, J ) 8.6, 1.9 Hz,
2H); 7.54 (dd, J ) 8.6, 1.8 Hz, 2H,); 13C NMR (75 MHz, CDCl3)
δ 28.7, 35.4, 36.6, 46.6, 51.3, 56.9, 61.3, 106.1, 119.0, 122.2, 131.0,
131.1, 131.8, 135.2, 145.4, 194.2; MS (EI) m/z (rel intensity) 361
(M+, 100) 363 (M+ + 2, 99); HRMS (FAB+) calcd for C18H21O2-
NBr 362.0756, found 362.0742.
2-(4-Ch lor op h en yl)-1-(2-iod oeth yl)-6,6-d im eth yl-1,5,6,7-
tetr a h yd r oin d ol-4-on e (25c): yield 82% as a white solid; mp
125-26 °C; IR (KBr, cm-1) νmax 2957, 2929, 2872,1651,1472, 803;
1H NMR (300 MHz, CDCl3) δ 1.19 (s, 6H), 2.39 (s, 2H), 2.70 (s,
2H), 3.03 (t, J ) 7.9 Hz, 2H), 4.22 (t, J ) 7.9 Hz, 2H), 6.56 (s,
1H), 7.28 (d, J ) 8.7 Hz, 2H), 7.41 (d, J ) 8.7 Hz, 2H,); 13C NMR
(75 MHz, CDCl3) δ 28.8, 35.6, 36.4, 46.4, 51.9, 106.6, 119.8, 129.1,
130.1, 130.5, 134.1, 134.3, 143.2, 193.5; MS (EI) m/z (rel
intensity) 427 (M+, 100); HRMS (FAB+) calcd for C18H20ONClI
428.0278, found 428.0285.
2-(4-Br om op h en yl)-1-(2-iod oeth yl)-6,6-d im eth yl-1,5,6,7-
tetr a h yd r oin d ol-4-on e (25d ): yield 71% as a white solid; mp
119-20 °C; IR (KBr, cm-1) νmax 2955, 2871, 1654, 1466, 805; 1H
NMR (300 MHz, CDCl3) δ 1.19 (s, 6H), 2.39 (s, 2H), 2.70 (s, 2H),
3.03 (t, J ) 7.9 Hz, 2H), 4.22 (t, J ) 7.9 Hz, 2H), 6.56 (s, 1H),
7.23 (dd, J ) 9.0, 1.8 Hz, 2H), 7.57 (dd, J ) 8.5, 2.1 Hz, 2H); 13
C
NMR (75 MHz, CDCl3) δ 0.5, 28.8, 35.6, 36.4, 46.4, 51.9, 106.7,
119.8, 122.5, 130.4, 131.0, 132.1, 134.1, 143.3, 193.5; MS (EI)
m/z (rel intensity) 471 (M+, 06), 473 (M+ + 2, 07), 83 (100);
HRMS (FAB+) calcd for C18H20ONBrI 471.9773, found 471.9782.
1-(2-Iod oet h yl)-6,6-d im et h yl-2-(4-n it r op h en yl)-1,5,6,7-
tetr a h yd r oin d ol-4-on e (25e): yield 69% as a yellow solid; mp
150-51 °C; IR (KBr, cm-1) νmax 2954, 2926, 2867, 1656, 1599,
1518, 1470, 1342, 856; 1H NMR (300 MHz, CDCl3) δ 1.20 (s, 6H),
2.42 (s, 2H), 2.73 (s, 2H), 3.06 (t, J ) 7.5 Hz, 2H), 4.31 (t, J )
7.5 Hz, 2H), 6.72 (s, 1H), 7.53 (d, J ) 9.0 Hz, 2H), 8.31 (d, J )
9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 0.1, 28.8, 35.6, 36.5,
46.6, 51.9, 108.6, 120.4, 124.3, 128.9, 133.1, 138.5, 144.6, 147.1,
193.4; MS (EI) m/z (rel intensity) 438 (M+, 100); HRMS (FAB+)
calcd for C18H20O3N2I 439.0519, found 439.0521.
Gen er a l P r oced u r e for Ra d ica l Cycliza tion Usin g Di-
cu m yl P er oxid e. To a degassed solution of the corresponding
iodo derivative (1.0 equiv) in refluxing chlorobecene (7 mL/mmol)
was added dicumyl peroxide (1.5 equiv) portionwise (0.3 equiv/
1.5 h). The reaction was carried out under an atmosphere of N2
during 7.5 h. Then, the mixture was allowed to warm to room
1-(2-Hydr oxyeth yl)-6,6-dim eth yl-2-(4-n itr oph en yl)-1,5,6,7-
tetr a h yd r oin d ol-4-on e (24e): yield 60% as a yellow solid; mp
184-86 °C; IR (KBr, cm-1) νmax 3444, 2957, 2873, 1656, 1595,
J . Org. Chem, Vol. 69, No. 11, 2004 4003

temperature and evaporated to dryness. The crude residue was
purified by column chromatography on silica gel (EtOAc/Hex).
2,3,6,7,8,9-Hexa h yd r o-1H-p yr id o[1,2-a ]in d ol-4-on e (12):
yellow oil; IR (CHCl3, cm-1) νmax 2936, 2862, 1640, 1491, 1438,
1322; 1H NMR (300 MHz, CDCl3) δ 1.75-1.83 (m, 2H), 1.90-
1.97 (m, 2H), 1.99-2.07 (m, 2H), 2.50 (dd, J ) 6.4, 6.4 Hz, 2H),
2.69 (dd, J ) 6.1, 6.1 Hz, 2H), 2.78 (dd, J ) 6.4, 6.4 Hz, 2H),
4.32 (dd, J ) 6.15, 6.15 Hz, 2H), 5.77 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 19.7, 22.9, 23.0, 23.7, 23.8, 24.9, 38.14, 45.7, 105.8,
119.3, 125.4, 139.4, 140.4, 187.1; MS (EI) m/z 189 (M+, 100);
HRMS (FAB+) calcd for C12H15NO 189.1213, found 189.1231.
1,2,3,4-Tet r a h yd r op yr id o[1,2-b]isoq u in olin -6-on e (14).
Eluted with hexanes-ethyl acetate (6:4): 85% yield as a white
solid; mp 99-100 °C (lit.14 100-103 °C); IR (KBr, cm-1) νmax
2952, 2855, 1650, 1630, 1600; 1H NMR (300 MHz, CDCl3) δ
1.81-1.88 (m, 2H), 1.93-1.99 (m, 2H), 2.82 (t, J ) 6.8 Hz, 2H),
4.12 (t, J ) 6.2 Hz, 2H), 6.32 (s, 1H), 7.36-7.42 (m, 2H), 7.55-
7.60 (m, 1H), 8.40 (d, J ) 8.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 19.0, 22.4, 28.8, 41.0, 103.8, 124.9, 125.5, 125.6, 127.8, 132.0,
136.8, 140.9, 162.9; MS (EI) m/z (rel intensity) 199 (M+, 100);
HRMS (FAB+) calcd for C13H14NO 200.1075, found 200.1072.
8,9-Meth ylen ed ioxy-1,2,3,4-tetr a h yd r o-11-cya n op yr id o-
[1,2-b]isoqu in olin -6-on e (16). Eluted with hexanes-ethyl
acetate (1:1): 76% yield as a white solid; mp 277-279 °C; IR
(KBr, cm-1) νmax 2941, 2212, 1654, 1616, 1562; 1H NMR (300
MHz, CDCl3) δ 1.86-2.05 (m, 4H), 3.13 (t, J ) 6.8 Hz, 2H), 4.09
(t, J ) 6.6 Hz, 2H), 6.11 (s, 1H), 7.14 (s, 1H), 7.71 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 18.4, 21.9, 28.2, 42.4, 88.9, 101.6, 102.2,
105.8, 116.4, 118.7, 131.2, 148.2, 149.8, 153.1, 161.0; MS (EI)
m/z (rel intensity) 268 (M+, 100); HRMS (FAB+) calcd for
C15H13N2O3 269.0926, found 269.0924.
Eth yl 1,2,3,4-Tetr a h yd r op yr id o[1,2-a ]qu in olin -6-on e-5-
ca r boxyla te (18). Eluted with hexanes-ethyl acetate (1:2):
89% yield as a white solid; mp 132-133 °C (lit.15 mp 132-135
°C); IR (KBr, cm-1) νmax 2953, 1716, 1620, 1600, 1540; 1H NMR
(300 MHz, CDCl3) δ 1.39 (t, J ) 7.2 Hz, 3H), 1.83-1.92 (m, 2H),
2.06-2.15 (m, 2H), 3.01 (t, J ) 6.6 Hz, 2H), 4.10 (t, J ) 6.6 Hz,
2H), 4.39 (q, J ) 7.2 Hz, 2H), 7.37 (td, J ) 7.6, 0.9 Hz, 1H), 7.51
(d, J ) 8.4 Hz, 1H), 7.63 (td, J ) 7.2, 1.6 Hz), 8.44 (dd, J ) 8.1,
1.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 18.4, 22.5, 27.6,
46.4, 61.2, 114.7, 116.8, 124.0, 126.7, 126.8, 132.2, 140.9, 149.9,
167.5, 173.5; MS (EI) m/z (rel intensity) 271 (M+, 20), 199 (100);
HRMS (FAB+) calcd for C16H18NO3 272.1287, found 272.1275.
Eth yl 4-Oxo-6,7,8,9-tetr a h yd r o-4H-qu in olizin e-1-ca r box-
yla te (20). Eluted with hexanes-ethyl acetate (6:4): 37% yield
as a white solid; mp 54-56 °C (lit.16 52-53 °C); HRMS (FAB+)
calcd for C12H16NO3 222.1130, found 222.1123.
CDCl3) δ 28.8, 35.3, 35.6, 41.0, 52.1, 99.9, 119.8, 122.9, 126.6,
127.5, 127.9, 128.7, 130.3, 131.2, 142.1, 193.3; MS (EI) m/z (rel
intensity) 265 (M+, 81), 181 (100); HRMS (FAB+) calcd for
C
18H20ON 266.1545, found 266.1545.
3-F lu or o-9,9-d im eth yl-5,8,9,10-tetr a h yd r o-6H-in d olo[2,1-
a ]-isoqu in olin -11-on e (26b): yield 91% as a white crystalline
solid; mp 179-80 °C; IR (KBr, cm-1) νmax 2955, 2869, 1646, 1482,
826; 1H NMR (300 MHz, CDCl3) δ 1.16 (s, 6H), 2.39 (s, 2H), 2.65
(s, 2H), 3.08 (t, J ) 6.8, 2H), 3.98 (t, J ) 6.8, 2H), 6.81 (s, 1H),
6.89-7.01 (m, 2H), 7.49 (dd, J ) 5.6, 8.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 28.8, 28.9, 35.4, 35.6, 40.7, 52.1, 99.6, 114.7,
119.8, 124.6, 125.0, 130.6, 132.5, 142.1, 159.7, 163.0, 193.5; MS
(EI) m/z (rel intensity) 283 (M+, 100); HRMS (FAB+) calcd for
C
18H19ONCl 284.1451, found 284.1452.
3-Ch lor o-9,9-d im eth yl-5,8,9,10-tetr a h yd r o-6H-in d olo[2,1-
a ]-isoqu in olin -11-on e (26c): yield 85% as a white crystalline
solid; mp 199-200 °C; IR (KBr, cm-1) νmax 2955, 2868, 1647,
1481, 829; 1H NMR (300 MHz, CDCl3) δ 1.16 (s, 6H), 2.39 (s,
2H), 2.65 (s, 2H), 3.07 (t, J ) 6.7, 2H), 3.97 (t, J ) 6.7, 2H), 6.85
(s, 1H), 7.18-7.27 (m, 2H), 7.44 (d, J ) 8.28 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 28.7, 28.8, 28.8, 35.3, 35.6, 40.7, 52.1, 100.4,
119.9, 124.2, 127.2, 127.7, 127.9, 130.3, 131.8, 131.9, 142.4, 193.4;
MS (EI) m/z (rel intensity) 299 (M+, 100); HRMS (FAB+) calcd
for C18H19ONCl 300.1155, found 300.1149.
3-Br om o-9,9-d im eth yl-5,8,9,10-tetr a h yd r o-6H-in d olo[2,1-
a ]isoqu in olin -11-on e (26d ): yield 53% as a white crystalline
solid; mp 190-91 °C; IR (KBr, cm-1) νmax 2953, 2871, 1649, 1470,
825; 1H NMR (300 MHz, CDCl3) δ 1.16 (s, 6H), 2.38 (s, 2H), 2.65
(s, 2H), 3.07 (t, J ) 6.8 Hz, 2H), 3.97 (t, J ) 6.7 Hz, 2H), 6.87 (s,
1H), 7.34 (s, 1H), 7.38 (d, J ) 1.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 28.6, 28.8, 35.3, 35.6, 40.7, 52.1, 100.5, 119.8, 120.0,
124.5, 127.7, 130.4, 130.6, 130.8, 132.2, 142.4, 193.4; MS (EI)
m/z (rel intensity) 343 (M+, 76), 344 (M+ + 2, 75), 259 (100);
HRMS (FAB+) calcd for C18H19ONBr 344.0650, found 344.0661.
9,9-Dim eth yl-3-n itr o-5,8,9,10-tetr a h yd r o-6H-in d olo[2,1-
a ]isoqu in olin -11-on e (26e): yield 75% as a yellow crystalline
solid; mp 230-31 °C; IR (KBr, cm-1) νmax 2954, 2879, 1653, 1575,
1514, 1330, 807; 1H NMR (300 MHz, CDCl3) δ 1.17 (s, 6H), 2.41
(s, 2H), 2.69 (s, 2H), 3.21 (t, J ) 6.6 Hz, 2H), 4.06 (t, J ) 6.6 Hz,
2H), 7.07 (s, 1H), 7.61 (d, J ) 8.4 Hz, 1H), 8.10-8.15 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 28.8, 28.8, 35.3, 35.7, 40.9, 52.1,
103.9, 120.8, 123.2, 123.6, 129.5, 130.8, 134.8, 143.7, 145.6, 193.2;
MS (EI) m/z (rel intensity) 310 (M+, 100); HRMS (FAB+) calcd
for C18H19O3N2 311.1396, found 311.1395.
Ack n ow led gm en t . We thank DGAPA (PAPIT-
IN228103-3 and 211601) for generous financial support.
We also thank R. Patin˜o, J . Pe´rez, L. Velasco, H. Rios,
N. Zavala, E. Huerta, and A. Pen˜a for technical support.
9,9-Dim et h yl-5,8,9,10-t et r a h yd r o-6H -in d olo[2,1-a ]iso-
qu in olin -11-on e (26a ): yield 82% as a white crystalline solid;
mp 148-50 °C; IR (KBr, cm-1) νmax 2957, 2871, 1647, 1486, 762;
1H NMR (300 MHz, CDCl3) δ 1.16 (s, 6H), 2.38 (s, 2H), 2.65 (s,
2H), 3.08 (t, J ) 6.6, 2H), 3.97 (t, J ) 6.6, 2H), 6.87 (s, 1H),
7.12-7.28 (m, 3H), 7.53 (d, J ) 7.5 Hz, 1H); 13C NMR (75 MHz,
Su p p or tin g In for m a tion Ava ila ble: 1H and/or 13C spec-
tra for all compounds. Experimental details and full spectral
data for the synthesis of compounds 13, 15, 17, and 19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Coppola, G. M. J . Heterocycl. Chem. 1981, 767.
(15) Coppola, G. M.; Damon. R. E. J . Heterocycl. Chem. 1980, 17,
1729.
(16) Wang, M.-X.; Miao, W.-S.; Cheng, Y.; Huang, Z.-T. Tetrahedron
1999, 55, 14611.
J O0497048
4004 J . Org. Chem., Vol. 69, No. 11, 2004