Thermolysis of benzannulated enyne-carbodiimides. Application in the synthesis of pyrido[1′,2′:1,2]pyrimido[4,5-b]indoles and related heteroaromatic compounds

Article abstract of DOI:10.1021/jo0204092

Several derivatives of the pyrido[1′,2′:1,2]pyrimido[4,5-b]indoles 4 and the pyrazino[1′,2′:1,2]-pyrimido[4,5-b]indoles 14 were synthesized by treatment of the benzannulated enyne-isocyanates 8 with the iminophosphoranes 9 and 13, respectively, for the aza-Wittig reaction followed by thermolysis. The reaction presumably proceeds through an initial formation of the corresponding benzannulated enyne-carbodiimides, such as 10, followed by a formal intramolecular hetero Diels-Alder reaction. Surprisingly, when the iminophosphorane 17 was used for condensation with 8, the expected pyrimido[1′,6′:1,2]pyrimido[4,5-b]indoles 16 were not obtained. Instead, the isomeric pyrimido[6′,1′:2,3]pyrimido[4,5-b]indoles 21 were isolated. Presumably, an alternative reaction pathway involving an initial [2 + 2] cycloaddition reaction to form 19 followed by ring opening could lead to 20 and, after an intramolecular radical-radical coupling, 21. Treatment of the urea derivatives 24 with dibromotriphenylphosphorane also produced in situ the benzannulated enynecarbodiimides 25, which on thermolysis gave the isoquinolino[2′,1′:1,2]pyrimido[4,5-b]indoles 26. Methylation of 4a, 14a, and 26a with methyl iodide occurred exclusively at the site of the indolo nitrogen. The planar geometry of those novel heteroaromatic compounds, resembling many DNA-binding agents, makes them potential candidates as DNA intercalators.

Full text of DOI:10.1021/jo0204092

Th er m olysis of Ben za n n u la ted En yn e-Ca r bod iim id es. Ap p lica tion
in th e Syn th esis of P yr id o[1′,2′:1,2]p yr im id o[4,5-b]in d oles a n d
Rela ted Heter oa r om a tic Com p ou n d s
Xiaoling Lu, J effrey L. Petersen,† and Kung K. Wang*
Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506-6045
kwang@wvu.edu
Received J une 13, 2002
Several derivatives of the pyrido[1′,2′:1,2]pyrimido[4,5-b]indoles 4 and the pyrazino[1′,2′:1,2]-
pyrimido[4,5-b]indoles 14 were synthesized by treatment of the benzannulated enyne-isocyanates
8 with the iminophosphoranes 9 and 13, respectively, for the aza-Wittig reaction followed by
thermolysis. The reaction presumably proceeds through an initial formation of the corresponding
benzannulated enyne-carbodiimides, such as 10, followed by a formal intramolecular hetero Diels-
Alder reaction. Surprisingly, when the iminophosphorane 17 was used for condensation with 8,
the expected pyrimido[1′,6′:1,2]pyrimido[4,5-b]indoles 16 were not obtained. Instead, the isomeric
pyrimido[6′,1′:2,3]pyrimido[4,5-b]indoles 21 were isolated. Presumably, an alternative reaction
pathway involving an initial [2 + 2] cycloaddition reaction to form 19 followed by ring opening
could lead to 20 and, after an intramolecular radical-radical coupling, 21. Treatment of the urea
derivatives 24 with dibromotriphenylphosphorane also produced in situ the benzannulated enyne-
carbodiimides 25, which on thermolysis gave the isoquinolino[2′,1′:1,2]pyrimido[4,5-b]indoles 26.
Methylation of 4a , 14a , and 26a with methyl iodide occurred exclusively at the site of the indolo
nitrogen. The planar geometry of those novel heteroaromatic compounds, resembling many DNA-
binding agents, makes them potential candidates as DNA intercalators.
In tr od u ction
We recently reported a new synthetic procedure in-
volving thermolysis of the benzannulated enyne-carbo-
diimides 1 to form the 6H-indolo[2,3-b][1,6]naphthyridines
2 (eq 1)1a as the 5-aza analogues of ellipticine (3),2a
a
naturally occurring alkaloid. Ellipticine and many of its
derivatives were found to exhibit potent antitumor
activities.2b-m Similarly, by placing a 3-pyridyl substitu-
ent at the carbodiimide terminus, 6H-indolo[2,3-b][1,5]-
naphthyridines and 10H-indolo[2,3-b][1,7]naphthyridines
were likewise synthesized.1a We now have successfully
extended this strategy to the synthesis of the pyrido[1′,2′:
1,2]pyrimido[4,5-b]indoles 4 and related heteroaromatic
compounds using the systems having a 2-pyridyl, a
pyrazinyl, a 4-pyrimidyl, or a 1-isoquinolinyl substituent.
It is worth noting that the core structure of 4 repre-
sents a new heteroaromatic system. The planar geometry
of the indoles 4, resembling those of indolo[2,3-b]quinoli-
zinium bromide (5)3 and the tetracyclic heteroaromatic
salts 6,4 makes these compounds potential candidates as
DNA intercalators. It was recently reported that 5 binds
preferentially to GC base pairs.3 Irradiation of DNA in
the presence of 5 resulted in efficient single-strand
cleavage of the nucleic acid. In addition, the indoles 4
can also be regarded as the pyridannulated derivatives
of 9H-pyrimido[4,5-b]indole (7). Many derivatives of 9H-
* To whom correspondence should be addressed. Phone: (304) 293-
3068, ext 6441. Fax: (304) 293-4904.
† To whom correspondence concerning the X-ray structure should
be addressed. Phone: (304) 293-3435, ext 6423. Fax: (304) 293-4904.
E-mail: jpeterse@wvu.edu.
(1) (a) Zhang, Q.; Shi, C.; Zhang, H.-R.; Wang, K. K. J . Org. Chem.
2000, 65, 7977-7983. For other similar studies, see: (b) Shi, C.; Zhang,
Q.; Wang, K. K. J . Org. Chem. 1999, 64, 925-932. (c) Lu, X.; Petersen,
J . L.; Wang, K. K. J . Org. Chem. 2002, 67, 5412-5415. (d) Schmittel,
M.; Steffen, J .-P.; Engels, B.; Lennartz, C.; Hanrath, M. Angew. Chem.,
Int. Ed. 1998, 37, 2371-2373. For a photochemically induced reaction,
see: (e) Schmittel, M.; Rodr´ıguez, D.; Steffen, J .-P. Angew. Chem., Int.
Ed. 2000, 39, 2152-2155.
(2) (a) Goodwin S.; Smith, A. F.; Horning, E. C. J . Am. Chem. Soc.
1959, 81, 1903-1908. (b) Dalton, L. K.; Demerac, S.; Elmes, B. C.;
Loder, J . W.; Swan, J . M.; Teitei, T. Aust. J . Chem. 1967, 20, 2715-
2727. (c) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1990; Vol. 39, p 239-351. (d) Suffness, M.; Cordell,
G. A. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York,
1985; Vol. 25, pp 89-142. (e) Kansal, V. K.; Potier, P. Tetrahedron
1986, 42, 2389-2408. (f) Gribble, G. W.; Saulnier, M. G.; Obaza-
Nutaitis, J . A.; Ketcha, D. M. J . Org. Chem. 1992, 57, 5891-5899. (g)
Ishikura, M.; Yaginuma, T.; Agata, I.; Miwa, Y.; Yanada, R.; Taga, T.
Synlett 1997, 214-216. (h) D´ıaz, M. T.; Cobas, A.; Guitia´n, E.; Castedo,
L. Synlett 1998, 157-158. (i) Ergu¨n, Y.; Patir, S.; Okay, G. J .
Heterocycl. Chem. 1998, 35, 1445-1447. (j) Ishikura, M.; Hino, A.;
Yaginuma, T.; Agata, I.; Katagiri, N. Tetrahedron 2000, 56, 193-207.
(k) Anderson, W. K.; Gopalsamy, A.; Reddy, P. S. J . Med. Chem. 1994,
37, 1955-1963. (l) Pierson, V.; Pierre, A.; Pommier, Y.; Gros, P. Cancer
Res. 1988, 48, 1404-1409. (m) Vilarem, M. J .; Riou, J . F.; Multon, E.;
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10.1021/jo0204092 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
J . Org. Chem. 2002, 67, 7797-7801
7797

Lu et al.
pyrimido[4,5-b]indole have been found to exhibit potent
biological activities,5 and there are continuing interests
in developing new synthetic methodologies for these
derivatives.5,6
through a concerted intramolecular hetero-Diels-Alder
reaction. It is interesting to note that the carbon-
nitrogen double bond of the pyridyl ring is involved in
the cyclization process to form 4 having an 18-π electron
aromatic system. The alternative process involving a
carbon-carbon double bond of the pyridyl ring did not
appear to occur, presumably because such a reaction
would disrupt the aromaticity of the pyridyl ring. A
sample of 4b was submitted to the National Cancer
Institute for evaluation against human tumor cell lines,
and it was found to exhibit activity against MCF7 (breast)
in the primary anticancer assay.
Alkylation of 4a with methyl iodide occurred exclu-
sively at the site of the indolo nitrogen, producing the
indolium iodide 12a in quantitative yield (eq 3). The
Resu lts a n d Discu ssion
The aza-Wittig reaction between the benzannulated
enyne-isocyanates 81a and the iminophosphorane 9,
derived from 2-aminopyridine and dibromotriphenylphos-
phorane in 83% yield (eq 2), produced in situ the
benzannulated enyne-carbodiimides 10, which on ther-
molysis under refluxing p-xylene at 138 °C gave the
pyrido[1′,2′:1,2]pyrimido[4,5-b]indoles 4 (Scheme 1). The
structure of 12a was unequivocally established by the
X-ray structure analysis. The close resemblance between
the core structure of 12a and 5 makes 12a a potential
DNA-binding agent. A sample of 12a was also submitted
to the National Cancer Institute for screening against
human tumor cell lines, and it was found to exhibit
activities against the three-cell line panel in the primary
anticancer assay.
SCHEME 1
The iminophosphorane 13, prepared from aminopyra-
zine in 80% yield, was also found to react with 8a and
8b, leading to the pyrazino[1′,2′:1,2]pyrimido[4,5-b]in-
doles 14a and 14b,8 respectively (Scheme 2). The core
SCHEME 2
structures of 4b and 4c were established by the X-ray
structure analysis. The transformation from 10 to 4 could
proceed either through a two-step biradical pathway via
the biradical 11 as in the enyne-allene system7 or
(5) (a) Showalter, H. D. H.; Bridges, A. J .; Zhou, H.; Sercel, A. D.;
McMichael, A.; Fry, D. W. J . Med. Chem. 1999, 42, 5464-5474. (b)
Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon,
N. J . Med. Chem. 1996, 39, 2285-2292.
(6) (a) Gangjee, A.; Chen, L. J . Heterocycl. Chem. 1999, 36, 441-
444. (b) Ple´, N.; Turck, A.; Heynderickx, A.; Que´guiner, G. J . Heterocycl.
Chem. 1994, 31, 1311-1315. (c) Molina, P.; Arques, A.; Al´ıas, A.;
Vinader, M. L. Tetrahedron Lett. 1991, 32, 4401-4404. (d) Edstrom,
E. D.; Yuan, W. Tetrahedron Lett. 1991, 32, 323-326. (e) Kondo, Y.;
Watanabe, R.; Sakamoto, T.; Yamanaka, H. Chem. Pharm. Bull. 1989,
37, 2933-2936. (f) Venugopalan B.; Desai, P. D.; de Souza, N. J . J .
Heterocycl. Chem. 1988, 25, 1633-1639. (g) Bernier, J .-L.; He´nichart,
J .-P. J . Org. Chem. 1981, 46, 4197-4198. (h) Higashino, T.; Hayashi,
E.; Matsuda, H.; Katori, T. Heterocycles 1981, 15, 483-487. (i) Wright,
G. E. J . Heterocycl. Chem. 1976, 13, 539-544. (j) Senda, S.; Hirota,
K.; Takahashi, M. J . Chem. Soc., Perkin Trans. 1 1975, 503-507. (k)
Wamhoff, H.; Wehling, B. Chem. Ber. 1975, 108, 2107-2114. (l) Hyatt,
J . A.; Swenton, J . S. J . Org. Chem. 1972, 37, 3216-3220. (m) Hyatt,
J . A.; Swenton, J . S. J . Heterocycl. Chem. 1972, 9, 409-410. (n) Schulte,
K. E.; Reisch, J .; Stoess, U. Arch. Pharm. (Weinheim, Ger.) 1972, 305,
523-533.
structure of 14 also represents a new heteroaromatic
system. Again, alkylation of 14a with methyl iodide
occurred exclusively at the site of the indolo nitrogen to
furnish 15a 8 in quantitative yield.
We have also attempted to prepare the pyrimido[1′,6′:
1,2]pyrimido[4,5-b]indoles 16 by treatment of 8a and 8b
with the iminophosphorane 17, which was prepared in
96% yield from 4-aminopyrimidine. However, we were
surprised to observe that the isomeric pyrimido[6′,1′:2,3]-
pyrimido[4,5-b]indoles 21 were obtained instead (Scheme
3). The structure of 21a was unequivocally established
by the X-ray structure analysis, and the structure of 21b
was assigned on the basis of NMR chemical shift cor-
(7) (a) Schmittel, M.; Strittmatter, M.; Kiau, S. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1843-1845. (b) Schmittel, M.; Maywald, M.;
Strittmatter, M. Synlett 1997, 165-166. (c) Musch, P. W.; Engels, B.
J . Am. Chem. Soc. 2001, 123, 5557-5562.
(8) The structure was established by the X-ray structure analysis.
7798 J . Org. Chem., Vol. 67, No. 22, 2002

Thermolysis of Benzannulated Enyne-Carbodiimides
quinoline (23) were unsuccessful. Fortunately, an alter-
native route involving condensation between 8 and 23
was successful in producing the corresponding urea
derivatives 24 as the precursors of 25 (Scheme 4).
SCHEME 4
relations with those of 21a . The indoles 21a and 21b
1
exhibited essentially identical H NMR chemical shifts
for Ha, Hb, and Hc. Because 16 and 21 could be expected
to exhibit identical number and multiplicity of NMR
signals, it was only after the X-ray structure of 21a had
been obtained that we realized that the isolated products
were not the expected indoles 16.
SCHEME 3
Subsequent treatment of 24a with dibromotriphenylphos-
phorane11 produced in situ 25a , which on heating under
refluxing p-xylene furnished 8-phenylisoquinolino[2′,1′:
1,2]pyrimido[4,5-b]indole (26a ) in 30% yield. The struc-
ture of 26a was established by the X-ray structure
analysis. In addition to 26a , a second product (24% yield)
exhibiting NMR signals very similar to those of 26a was
also isolated. Unfortunately, we were unable to obtain a
single-crystal suitable for the X-ray analysis to establish
its structure. In the case of 24b, the same reaction
condition produced 26b as the only isolated product in
48% yield.
Methylation of 26a with large excess of methyl iodide
was very sluggish at room temperature, producing only
ca. 10% of a methylated adduct after several days. It was
only after 40 days that 27a 8 was obtained in essentially
quantitative yield. Interestingly, an attempt to increase
the rate of methylation by treatment of 26a with large
excess of methyl iodide in a mixture of solvents, including
ethanol, in a sealed tube at 70 °C for 96 h afforded the
corresponding isoquinolinium triiodide 28a (eq 4). The
Presumably, an alternative reaction mechanism in-
volving an initial [2 + 2] cycloaddition reaction to form
19 became the preferred pathway. An analogous [2 + 2]
cycloaddition reaction of the benzannulated enyne-allene
system was reported previously.9 Ring opening of 19
could lead to 20, which could then undergo an intramo-
lecular radical-radical coupling to produce 21. It is worth
mentioning that the alkenyl radical center in 20 is
perhaps stabilized by the adjacent electron lone pair on
the indolo nitrogen, facilitating the ring opening of 19.
The analogous R-aminoalkyl radicals are stabilized radi-
cals having large stabilization energies due to conjugative
delocalization.10 The reason for the change of the reaction
pathway in favor of 21 over 16 is not clear at this time.
In the case of 21a , a small amount (10%) of the
guanidine derivative 22a was also isolated. Two intramo-
lecular hydrogen bondings are present in 22a as indi-
cated by the X-ray crystallographic structure. Unlike 4a
and 14a , compound 21a did not exhibit any reactivity
toward methyl iodide at room temperature for several
days.
structure of 28a was unequivocally established by the
X-ray structure analysis. Apparently, under the elevated
reaction temperature, hydrogen iodide was generated
from the reaction between methyl iodide and ethanol.12
(9) (a) Li, H.; Zhang, H.-R.; Petersen, J . L.; Wang, K. K. J . Org.
Chem. 2001, 66, 6662-6668. (b) Gillmann, T.; Hulsen, T.; Massa, W.;
Wocadlo, S. Synlett 1995, 1257-1259.
(10) Griller, D.; Lossing, F. P. J . Am. Chem. Soc. 1981, 103, 1586-
Attempts to synthesize the benzannulated enyne-
carbodiimides 25 by the aza-Wittig reaction between 8
and the iminophosphorane derived from 1-aminoiso-
1587.
(11) Palomo, C.; Mestres, R. Synthesis 1981, 373-374.
(12) Ogg, R. A., J r. J . Am. Chem. Soc. 1938, 60, 2000-2001.
J . Org. Chem, Vol. 67, No. 22, 2002 7799

Lu et al.
120.0, 119.3, 117.7, 113.6, 30.8, 20.1, 14.2; Anal. Calcd for
C17H15N3: C, 78.13; H, 5.79; N, 16.08. Found: C, 77.95; H,
5.84; N, 16.03. The structure of 4b was established by the
X-ray structure analysis.
As in methylation, protonation occurred exclusively at
the site of the indolo nitrogen of 26a . Similarly, with 26b
the same reaction condition produced the isoquinolinium
triiodide 28b.8
5-Meth yl-12-p h en yl-5H-p yr id o[1′,2′:1,2]p yr im id o[4,5-b]-
in d ol-11-iu m Iod id e (12a ). To a solution of 0.0195 g (0.066
mmol) of 4a in 15 mL of chloroform was added 13.2 mL of a
0.05 M solution of methyl iodide (0.660 mmol) in chloroform.
The reaction mixture was stirred at rt for 96 h. The organic
solvent was removed, and the remaining solid was washed
with 1 mL of chloroform (chilled at 0 °C) to afford 12a (0.0285
g, 0.065 mmol, 99%) as a yellow solid. Recrystallization from
dichloromethane afforded yellow needles: mp 312-313 °C; IR
Con clu sion s
Thermolysis of the benzannulated enyne-carbodi-
imides provides easy access to a variety of the pyrido-
[1′,2′:1,2]pyrimido[4,5-b]indoles 4 and related hetero-
aromatic compounds. The simplicity of the reaction
sequence makes the process especially attractive for the
synthesis of novel heteroaromatic compounds as potential
DNA-intercalating agents. The formation of the pyrimido-
[6′,1′:2,3]pyrimido[4,5-b]indoles 21 was unexpected and
likely involved a novel [2 + 2] cycloaddition pathway of
the benzannulated enyne-carbodiimides.
1
(KBr) 3402, 1592, 758, 710 cm-1; H δ 8.58 (1 H, d, J ) 7.4
Hz), 8.33 (1 H, dm, J ) 9.0, 1.1 Hz), 8.26 (1 H, td, J ) 9.0, 1.3
Hz), 7.98-7.94 (2 H, m), 7.86-7.81 (3 H, m), 7.73 (1 H, t, J )
7.4 Hz), 7.68 (1 H, td, J ) 6.8, 1.6 Hz), 7.62 (1 H, d, J ) 8.2
Hz), 7.24 (1 H, t, J ) 7.9 Hz), 6.91 (1 H, d, J ) 7.9 Hz), 4.12
(3 H, s); 13C δ 153.0, 148.2, 145.2, 143.8, 138.2, 132.5, 131.8,
131.5, 130.9, 129.5, 127.6, 127.1, 124.0, 123.9, 119.9, 118.2,
115.8, 111.0, 28.9. The structure of 12a was established by
X-ray structure analysis.
Exp er im en ta l Section
6-P r op ylp yr a zin o[1′,2′:1,2]p yr im id o[4,5-b]in d ole (14b).
The following procedure for the synthesis of 14b is representa-
tive. To a solution of 0.185 g (0.521 mmol) of the iminophos-
phorane 13 in 15 mL of anhydrous p-xylene was introduced
via cannula a solution of 0.096 g (0.520 mmol) of the isocyanate
8b in 10 mL of anhydrous p-xylene under a nitrogen atmo-
sphere at rt. The reaction mixture was kept at 45 °C for 12 h
and then was heated under reflux at 138 °C for an additional
12 h before it was allowed to cool to rt. The mixture was
concentrated to yield a solid residue. After three cycles of
washing the residue with 40 mL of diethyl ether followed by
centrifugation and decanting the supernatant liquid, the
remaining solid was pumped to dryness in vacuo to afford 14b
(0.076 g, 0.290 mmol, 56%) as an orange solid. Recrystalliza-
tion from chloroform afforded dark red needles: compound
turns black without melting at 170 °C; IR (KBr) 1639, 1414,
751 cm-1; 1H δ 9.19 (1 H, s), 8.03-7.93 (4 H, m), 7.63 (1 H, td,
J ) 7.9, 0.7 Hz), 7.31 (1 H, t, J ) 7.9 Hz), 3.58 (2 H, t, J ) 8.0
Hz), 1.91 (2 H, sextet, J ) 7.4 Hz), 1.20 (3 H, t, J ) 7.4 Hz);
13C δ 158.2, 154.7, 140.6, 138.6, 130.0, 129.2, 122.9, 121.3,
121.0, 119.8, 118.5, 117.6, 30.0, 20.1, 14.1. The structure of
14b was established by X-ray structure analysis.
All reactions were conducted in oven-dried (120 °C) glass-
ware under a nitrogen atmosphere. Tetrahydrofuran (THF)
and diethyl ether were distilled from benzophenone ketyl.
Triethylamine and benzene were distilled from calcium hy-
dride prior to use. The isocyanates 8 were prepared as
described previously.1a 1-Alkynes, dibromotriphenylphospho-
rane (Ph3PBr2), p-xylene (anhydrous), 2-aminopyridine, ami-
nopyrazine, 4-aminopyrimidine, and 1-aminoisoquinoline (23)
were purchased from chemical suppliers and were used as
1
received. Melting points were uncorrected. H (270 MHz) and
13C (67.9 MHz) NMR spectra were recorded in CDCl3 using
CHCl3 (1H δ 7.26) and CDCl3 (13C δ 77.00) as internal
standards unless otherwise indicated.
Im in op h osp h or a n e 9. The following procedure for the
preparation of the iminophosphorane 9 is representative. A
reaction mixture of 0.487 g (5.18 mmol) of 2-aminopyridine,
2.900 g (6.87 mmol) of Ph3PBr2, and 1.74 mL (12.5 mmol) of
anhydrous triethylamine in 40 mL of anhydrous benzene was
heated under reflux for 12 h. The triethylammonium bromide
precipitate was removed by filtration, and the filtrate was
concentrated. To the resulting viscous residue was added 30
mL of diethyl ether followed by filtration to afford 9 (1.517 g,
4.28 mmol, 83%) as a white solid: mp 140-141 °C; IR (KBr)
6-P h en ylp yr im id o[6′,1′:2,3]p yr im id o[4,5-b]in d ole (21a )
a n d th e Gu a n id in e Der iva tive 22a . The following procedure
for the synthesis of 21a is representative. To a solution of 0.177
g (0.499 mmol) of the iminophosphorane 17 in 10 mL of
anhydrous p-xylene was introduced via cannula a solution of
0.109 g (0.498 mmol) of the isocyanate 8a in 10 mL of
anhydrous p-xylene under a nitrogen atmosphere at rt. The
reaction mixture was kept at 50 °C for 12 h and then was
heated under reflux at 138 °C for an additional 24 h before it
was allowed to cool to rt. The mixture was then concentrated
to yield a solid residue. After three cycles of washing the
residue with 40 mL of diethyl ether followed by centrifugation
and decanting the supernatant liquid, the remaining solid was
pumped to dryness in vacuo to afford a golden yellow solid.
The solid was again washed three times with 1 mL of
dichloromethane and one time with 1 mL of diethyl ether to
afford 21a as a yellow solid (0.045 g, 0.152 mmol, 30%).
Recrystallization from chloroform afforded bright yellow crys-
tals. The combined solution of 3 mL of dichloromethane and 1
mL of diethyl ether was concentrated, and the residue was
purified by column chromatography (neutral alumina, 2%
absolute ethanol in dichloromethane) to yield the guanidine
derivative 22a (0.019 g, 0.049 mmol, 10%) as a pale yellow
solid. Recrystallization from chloroform afforded pale yellow
crystals. Compound 21a : compound turns brown at 265 °C
1
1584, 718, 692 cm-1; H δ 7.9-7.8 (7 H, m), 7.54-7.30 (10 H,
m), 6.92 (1 H, dt, J ) 8.4, 0.8 Hz), 6.44 (1 H, ddd, J ) 6.1, 5.0,
1.1 Hz); 13C δ 163.7 (d, J ) 6.2 Hz), 147.0, 136.5 (d, J ) 4.7
Hz), 133.1 (d, J ) 9.8 Hz), 131.4 (d, J ) 2.6 Hz), 130.4 (d, J )
99.4 Hz), 128.2 (d, J ) 11.9 Hz), 117.2 (d, J ) 24.3 Hz), 112.2.
12-P r op ylp yr id o[1′,2′:1,2]p yr im id o[4,5-b]in d ole (4b ).
The following procedure for the synthesis of 4b is representa-
tive. To a solution of 0.344 g (0.971 mmol) of the iminophos-
phorane 9 in 10 mL of anhydrous p-xylene was introduced via
cannula a solution of 0.185 g (0.100 mmol) of the isocyanate
8b in 10 mL of anhydrous p-xylene under a nitrogen atmo-
sphere at rt. After 5 h, the reaction mixture was heated under
reflux for 12 h before it was allowed to cool to rt. The mixture
was then concentrated to yield a solid residue. After three
cycles of washing the residue with 40 mL of diethyl ether
followed by centrifugation and decanting the supernatant
liquid, the remaining solid was pumped to dryness in vacuo
to afford 4b (0.147 g, 0.563 mmol, 58%) as an orange solid.
Recrystallization from methylene chloride afforded orange
flakes: compound turns black without melting at 222 °C; IR
1
(KBr) 1557, 1420, 734 cm-1; H δ 8.29 (1 H, d, J ) 7.4 Hz),
8.03 (1 H, d, J ) 7.9 Hz), 7.93 (1 H, d, J ) 7.9 Hz), 7.81 (1 H,
dm, J ) 9.2, 0.7 Hz), 7.62 (1 H, td, J ) 7.7, 1.2 Hz), 7.53 (1 H,
ddd, J ) 9.2, 6.7, 1.2 Hz), 7.28 (1 H, td, J ) 7.9, 1.0 Hz), 7.01
(1 H, ddd, J ) 8.9, 7.4, 1.5 Hz), 3.62 (2 H, t, J ) 7.9 Hz), 1.95
(2 H, sextet, J ) 7.9 Hz), 1.22 (3 H, t, J ) 7.4 Hz); 13C δ 159.3,
158.0, 146.1, 141.4, 131.2, 129.4, 127.7, 127.0, 122.7, 121.8,
1
and melts at 270 °C; IR (KBr) 1556, 1199, 761, 702 cm-1; H
δ 10.37 (1 H, d, J ) 1.1 Hz), 8.46 (1 H, d, J ) 6.3 Hz), 8.11-
8.04 (2 H, m), 8.00 (1 H, d, J ) 7.9 Hz), 7.93 (1 H, d, J ) 7.9
7800 J . Org. Chem., Vol. 67, No. 22, 2002

Thermolysis of Benzannulated Enyne-Carbodiimides
Hz), 7.79 (1 H, dd, J ) 6.3, 1.1 Hz), 7.67-7.64 (3 H, m), 7.58
(1 H, td, J ) 7.6, 1.3 Hz), 7.25 (1 H, td, J ) 7.6, 1.1 Hz); 13C
δ 157.6, 152.2, 148.2, 147.4, 143.5, 141.4, 137.6, 130.9, 129.3,
128.9, 128.2, 122.8, 121.9, 121.7, 119.6, 119.3, 115.5. The
structure of 21a was established by X-ray structure analysis.
Compound 22a : 1H δ 14.13 (1 H, br, s), 12.28 (1 H, s), 8.81 (1
H, s), 8.62 (1 H, d, J ) 8.2 Hz), 8.48 (1 H, d, J ) 5.5 Hz), 8.42
(1 H, d, J ) 5.5 Hz), 8.30 (1 H, s), 7.57 (1 H, d, J ) 7.7 Hz),
7.51-7.48 (2 H, m), 7.41-7.30 (4 H, m), 7.12 (1 H, t, J ) 7.4
Hz), 6.95 (1 H, d, J ) 5.5 Hz), 6.86 (1 H, d, J ) 5.0 Hz). The
structure of 22a was established by X-ray structure analysis.
Ur ea 24a . The following procedure for the preparation of
the urea 24a is representative. To a solution of 0.140 g (0.972
mmol) of 1-aminoisoquinoline (23) in 5 mL of anhydrous
dichloromethane was added a solution of 0.213 g (0.973 mmol)
of the isocyanate 8a in 10 mL of anhydrous dichloromethane
via cannula under a nitrogen atmosphere at rt. After 12 h, 15
mL of hexanes was added to the reaction mixture. Filtration
of the mixture afforded 0.336 g (0.926 mmol, 95%) of 24a as a
white solid: mp 234-235 °C; IR (KBr) 3250, 3128, 1673, 758
cm-1; 1H δ 12.95 (1 H, s), 8.44 (1 H, d, J ) 8.2 Hz), 8.11 (1 H,
br), 8.07 (1 H, d, J ) 8.4 Hz), 7.77-7.53 (7 H, m), 7.43-7.30
(4 H, m), 7.12-7.06 (2 H, m).
8-P h en ylisoq u in olin o[2′,1′:1,2]p yr im id o[4,5-b]in d ole
(26a ) a n d a Rela ted Com p ou n d . To a solution of 0.278 g
(0.660 mmol) of Ph3PBr2 and 0.83 mL (6.000 mmol) of
anhydrous triethylamine in 25 mL of anhydrous dichloro-
methane was added dropwise, using a pressure equalizing
addition funnel over 3 h, a solution of 0.109 g (0.300 mmol) of
the urea 24a in 50 mL of anhydrous dichloromethane. After
12 h of stirring at rt, 50 mL of anhydrous p-xylene was
introduced and dichloromethane was removed by distillation
under reduced pressure. The triethylammonium bromide
precipitate was removed by filtration under a nitrogen atmo-
sphere and washed twice with 5 mL of anhydrous p-xylene.
The combined filtrate was heated under reflux for 15 h before
it was allowed to cool to rt and concentrated to yield a solid
residue. After three cycles of washing the residue with 40 mL
of ethyl acetate followed by centrifugation and decanting the
supernatant liquid, the remaining solid was pumped to dryness
in vacuo. The solid was washed three times with 1 mL of
dichloromethane and one time with 1 mL of diethyl ether and
then pumped to dryness to yield 26a (0.031 g, 0.090 mmol,
30%) as a brown solid. The combined solution of 3 mL of
dichloromethane and 1 mL of diethyl ether was also concen-
trated to yield a second product (0.025 g, 24%) as a pale yellow
solid. Compound 26a : mp >360 °C; IR (KBr) 1599, 778, 750,
696 cm-1; 1H (6% CD3OD in CDCl3) δ 9.46 (1 H, m), 8.11 (1 H,
d, J ) 7.7 Hz), 7.99-7.84 (7 H, m), 7.68-7.62 (3 H, m), 7.59 (1
H, d, J ) 7.7 Hz), 7.17 (1 H, t, J ) 7.5 Hz), 6.84 (1 H, d, J )
7.9 Hz); 13C δ 153.1, 147.5, 146.3, 142.2, 134.5, 132.5, 132.1,
131.5, 130.9, 130.6, 128.6, 127.9, 127.8, 127.1, 125.6, 124.3,
123.6, 122.8, 119.2, 118.2, 114.6, 113.9. The structure of 26a
was established by the X-ray structure analysis. However,
during the course of refining the X-ray structure, it was
apparent that there were solvent molecules intercalated in the
crystal lattice that could not be identified. Second product: mp
>360 °C; IR (KBr) 1585, 755, 708 cm-1 1H (6% CD3OD in
;
CDCl3) δ 8.92 (1 H, d, J ) 8.4 Hz), 8.70 (1 H, d, J ) 8.4 Hz),
8.18 (1 H, d, J ) 7.7 Hz), 7.97-7.94 (3 H, m), 7.89 (1 H, t, J )
8.7 Hz), 7.84-7.74 (4 H, m), 7.73 (1 H, d, J ) 7.9 Hz), 7.64 (1
H, tt, J ) 8.4, 4.2 Hz), 7.33 (1 H, t, J ) 7.7 Hz), 6.89 (1 H, d,
J ) 7.9 Hz); 13C δ 153.3, 148.0, 147.7, 142.8, 134.7, 132.8,
132.5, 131.9, 130.9, 130.4, 129.0, 128.0, 127.9, 127.3, 125.8,
125.0, 124.6, 123.7, 120.1, 118.7, 115.5, 113.2.
8-P h en yl-13H-isoqu in olin o[2′,1′:1,2]p yr im id o[4,5-b]in -
d ol-7-iu m Tr iiod id e (28a ). To a tube were loaded 8 mg (0.023
mmol) of 26a , 1 mL of acetonitrile, 0.5 mL of chloroform, 0.5
mL of absolute ethanol, and 0.2 mL of methyl iodide. The tube
was flushed with nitrogen for 1 min and then sealed. It was
heated to 70 °C for 96 h before it was allowed to cool to rt.
The solution was concentrated to yield a solid residue. The
solid residue was washed twice with 1 mL of ethyl acetate and
then twice with 1 mL of chloroform to afford 28a as a brown
powder in quantitative yield. Recrystallization from dichlo-
romethane afforded reddish brown crystals: mp 235-236 °C;
1H (CD2Cl2) δ 10.37 (br), 9.51 (1 H, dm, J ) 8.1, 2.4 Hz), 8.25
(1 H, d, J ) 7.7 Hz), 8.15-8.03 (3 H, m), 7.98-7.86 (4 H, m),
7.80-7.70 (4 H, m), 7.32 (1 H, t, J ) 7.7 Hz), 7.00 (1 H, d, J )
8.2 Hz). The structure of 28a was established by X-ray
structure analysis.
Ack n ow led gm en t. The financial support of the
National Science Foundation (CHE-9618676) to K.K.W.
is gratefully acknowledged. J .L.P. acknowledges the
support (CHE-9120098) provided by the Chemical In-
strumentation Program of the National Science Foun-
dation for the acquisition of a Siemens P4 X-ray
diffractometer in the Department of Chemistry at West
Virginia University.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for 4a ,c, 13, 14a , 15a , 17, 21b,
1
24b, 26b, 27a , and 28b; H and/or 13C NMR spectra for 4a -
c, 9, 12a , 13, 14a ,b, 15a , 17, 21a ,b, 22a , 24a ,b, 26a ,b, a
compound related to 26a , 27a , and 28a ,b; and ORTEP
drawings and/or tables of crystallographic data for the X-ray
diffraction analyses of 4b,c, 12a , 14b, 15a , 21a , 22a , 27a , and
28a ,b. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0204092
J . Org. Chem, Vol. 67, No. 22, 2002 7801