Intramolecular inverse-electron-demand Diels-Alder reactions of imidazoles with 1,2,4-triazines: A new route to 1,2,3,4-tetrahydro-1,5-naphthyridines and related heterocycles

Article abstract of DOI:10.1021/jo040193z

The intramolecular inverse-electron-demand Diels-Alder reaction between imidazoles and 1,2,4-triazines linked by a trimethylene tether from the imidazole N1 position to the triazine C3 proceed in excellent yields to produce 1,2,3,4-tetrahydro-1,5-naphthyridines. The reaction proceeds by a cycloaddition with subsequent loss of nitrogen, followed by a presumed stepwise loss of a nitrile. The analogous intramolecular cycloadditions employing a tetramethylene tether also proceeded to give 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines in acceptable yields. The reaction to produce the tetrahydro-1,5-naphthyridines can also be promoted with microwave irradiation.

Full text of DOI:10.1021/jo040193z

In tr a m olecu la r In ver se-Electr on -Dem a n d Diels-Ald er Rea ction s
of Im id a zoles w ith 1,2,4-Tr ia zin es: A New Rou te to
1,2,3,4-Tetr a h yd r o-1,5-n a p h th yr id in es a n d Rela ted Heter ocycles
Brian R. Lahue, Sie-Mun Lo, Zhao-Kui Wan, Grace H. C. Woo, and J ohn K. Snyder*
Department of Chemistry and Center for Chemical Methodology and Library Development,
Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215
jsnyder@chem.bu.edu
Received May 7, 2004
The intramolecular inverse-electron-demand Diels-Alder reaction between imidazoles and 1,2,4-
triazines linked by a trimethylene tether from the imidazole N1 position to the triazine C3 proceed
in excellent yields to produce 1,2,3,4-tetrahydro-1,5-naphthyridines. The reaction proceeds by a
cycloaddition with subsequent loss of nitrogen, followed by a presumed stepwise loss of a nitrile.
The analogous intramolecular cycloadditions employing a tetramethylene tether also proceeded to
give 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines in acceptable yields. The reaction to produce the
tetrahydro-1,5-naphthyridines can also be promoted with microwave irradiation.
In tr od u ction
tization (Scheme 1, eq 1), the intramolecular cycloaddi-
tions of tethered triazine/imidazole pairs quite unex-
pectedly resulted in nitrile release from the intermediate
cycloadduct A leading to an efficient synthesis of 1,2,3,4-
tetrahydro-1,5-naphthyridines 1 rather than forming
annulated deazapurines 2 as originally targeted (eq 2).4b
While unintended, this facile route to 1,5-naphthyri-
dines was rather intriguing. Past syntheses of fully
aromatized 1,5-naphthyridines have relied predomi-
nantly upon annulations beginning with 3-aminopyr-
Inverse-electron-demand Diels-Alder cycloadditions
using electron-deficient heteroaromatic azadienes is well-
established chemistry for the synthesis of heterocyclic
compounds.1 We have been interested in the use of
electron-rich heteroaromatic compounds with latent enam-
ine functionalities, such as indoles,2 pyrroles,2i,3 and
imidazoles,4 as dienophiles in this chemistry for some
time. Included in this work has been investigations into
intramolecular cycloadditions with tethered 1,2,4-tria-
zines.1c,2m,5 While these reactions of indoles and pyrroles
proceeded smoothly to give the anticipated pyridoannu-
lation products following release of nitrogen and aroma-
(3) Our work: (a) Li, J .-H.; Snyder, J . K. J . Org. Chem. 1993, 58,
516-519. Others: (b) Ruccia, M.; Vivona, N.; Cusmano, G. Tetrahedron
Lett. 1972, 4703-4706. (c) Seitz, G.; Kaempchen, T. Arch. Pharm.
(Weinheim) 1978, 311, 728-735. (d) Cobb, R. L.; Vives, V. C.; Mahan,
J . E. J . Org. Chem. 1978, 43, 931-936. (e) Ruccia, M.; Vivona, N.;
Cusmano, G. J . Heterocycl. Chem. 1978, 15, 293-296. (f) Ruccia, M.;
Vivona, N.; Cusmano, G.; Macaluso, G. J . Heterocycl. Chem. 1978, 15,
1485-1488. (g) Dehaen, W.; Hassner, A. J . Org. Chem. 1991, 56, 896-
900. (g) Heine, H. W.; LaPorte, M. G.; Overbaugh, R. H.; Williams, E.
A. W. Heterocycles 1995, 40, 743-752. (h) Nair, V.; Kumar, S. Synth.
Commun. 1996, 26, 217-224.
(4) Our work: (a) Wan, Z.-K.; Snyder, J . K. Tetrahedron Lett. 1997,
38, 7495-7498. (b) Neipp, C. E.; Ranslow, P. B.; Wan, Z.-K.; Snyder,
J . K. Tetrahedron Lett. 1997, 38, 7499-7502. (c) Wan, Z.-K.; Woo, G.
H. C.; Snyder, J . K. Tetrahedron 2001, 57, 5497-5507. (d) Lahue, B.
R.; Wan, Z.-K.; Snyder, J . K. J . Org. Chem. 2003, 68, 4345-4354.
Others: see ref 3c, also (e) Seitz, G.; Hoferichter, R.; Mohr, R. Arch.
Pharm. (Weinheim) 1989, 322, 415-417. (f) Xu, Y.-Z.; Yakushijin, K.;
Horne, D. A. Tetrahedron Lett. 1993, 34, 6981-6984. (g) Xu, Y.-Z.;
Yakushijin, K.; Horne, D. A. J . Org. Chem. 1996, 61, 9569-9571. (h)
Dang, Q.; Liu, Y.; Erion, M. D. J . Am. Chem. Soc. 1999, 121, 5833-
5834.
(5) For other examples using intramolecular cycloadditions of 1,2,4-
triazines, see ref 1c, pp 333-334. Some examples since then: (a)
Taylor, E. C.; Warner, J . C.; Pont, J . L. J . Org. Chem. 1988, 53, 800-
803. (b) Taylor, E. C.; Pont, J . L.; Warner, J . C. J . Org. Chem. 1988,
53, 3568-3572. (c) Taylor, E. C.; Pont, J . L.; Van Engen, D.; Warner,
J . C. J . Org. Chem. 1988, 53, 5093-5097. (d) Taylor, E. C.; French, L.
G. J . Org. Chem. 1989, 54, 1245-1249. (e) Taylor, E. C.; Macor, J . E.
J . Org. Chem. 1989, 54, 4984-4989. (f) Rainer, J .; Seitz, G. Arch.
Pharm. (Weinheim) 1989, 322, 561-564. (g) Seitz, G.; Rainer, J . Chem.-
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H. Heterocycles 1990, 30, 1009-1021. (i) Taylor, E. C.; Macor, J . E.;
French, L. G. J . Org. Chem. 1991, 56, 1807-1812. (j) Haenel, F.;
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in heterocyclic synthesis, see: (a) Boger, D. L. Tetrahedron 1983, 39,
2869-2939. (b) Boger, D. L. Chem. Rev. 1986, 86, 781-794. (c) Boger,
D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology in Organic
Synthesis; Academic: New York, 1987; Chapters 9 and 10. (d) Boger,
D. L.; Patel, M. Prog. Heterocycl. Chem. 1989, 1, 30-64. (e) Kametani,
T.; Hibino, S. In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Acadmic Press: New York, 1987; Vol. 42, pp 245-333. (f) Boger,
D. L. Bull. Soc. Chim. Belg. 1990, 99, 599-615. (g) Boger, D. L.
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Heterocycl. Chem. 1996, 33, 1519-1531. (h) Boger, D. L. J . Heterocycl.
Chem. 1998, 35, 1003-1011.
(2) For a review, see: (a) Lee, L.; Snyder, J . K. In Advances in
Cycloaddition; Harmata, M., Ed.; J AI Press: Stamford, CT, 1999; Vol.
6, pp 119-171. For some examples of indole in cycloadditions since
then, see: (b) Pelkey, E. T.; Barden, T. C.; Gribble, G. W. Tetrahedron
Lett. 1999, 40, 7615-7619. (c) Benson, S. C.; Lee, L.; Yang, L.; Snyder,
J . K. Tetrahedron 2000, 56, 1165-1180. (d) Gribble, G. W.; Pelkey, E.
T.; Simon, W. M.; Trujillo, H. A. Tetrahedron 2001, 56, 10133-10140.
(e) Muthusamy, S.; Gunanathan, C.; Babu, S. A. Tetrahedron Lett.
2001, 42, 523-526. (f) de la Mora, M. A.; Cuevas, E.; Muchowski, J .
M.; Cruz-Almanza, R. Tetrahedron Lett. 2001, 42, 5351-5353. (g)
Chataigner, I.; Hess, E.; Toupet, L.; Piettre, S. R. Org. Lett. 2001, 3,
515-518. (h) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J .; Wolkenberg,
S. E.; Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J . Am.
Chem. Soc. 2002, 124, 11292-11294. (i) Giomi, D.; Cecchi, M.
Tetrahedron 2002, 58, 8067-8071. (j) Lynch, S. M.; Bur, S. K.; Padwa,
A. Org. Lett 2002, 4, 4643-4645. (k) Crawley, S. L.; Funk, R. L. Org.
Lett. 2003, 5, 3169-3171. (l) Chretien, A.; Chataigner, I.; L′Helias,
N.; Piettre, S. R. J . Org. Chem. 2003, 68, 7990-8002. (m) Lindsley, C.
W.; Wisnoski, D. D.; Wang, Y.; Leister, W. H.; Zhao, Z. Tetrahedron
Lett. 2003, 44, 4495-4498.
10.1021/jo040193z CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/22/2004
J . Org. Chem. 2004, 69, 7171-7182
7171

Lahue et al.
SCHEME 1
SCHEME 2
larial candidates,6b,12 ultimately evolving into large an-
timalarial programs as exemplified by the work of Barlin
and co-workers.13 Furthermore, several tetrahydronaph-
thyridines 1 prepared in our preliminary studies showed
good activity against a drug-resistant tuberculosis strain
of Mycobacterium avium.4b We therefore sought to further
develop this rather serendipitously discovered route to
1,2,3,4-tetrahydro-1,5-naphthyridines to probe its scope
and limitations, with the ultimate goal of using these
heterocycles as scaffolds in library development. We now
report full results of this work.
idines6 or 3-nitropyridines.7 These pathways have limi-
tations in developing a variety of substitution sites on
the naphthyridine core. Moreover, syntheses of 1,2,3,4-
tetrahydro-1,5-naphthyridines are quite rare,6e,k,l,8 often
relying upon reduction of one of the rings of the parent
naphthyridine.6e,9 Those that do not begin with the fully
aromatized 1,5-naphthyridine typically still begin with
a 3-amino or 3-nitropyridine6e,k,l,8 and thereby suffer the
same limitations in diversity development as preparation
of the fully aromatized naphthyridines.
As small, nitrogen-containing heterocycles, 1,5-naph-
thyridines are interesting structures since they feature
several favorable characteristics for drug development.10
The concept of fully aromatized 1,5-naphthyridines as
drug candidates is reinforced by numerous reports of
their biological activity.11 In fact, as azaquinolines, these
naphthyridines were recognized very early in the history
of small-molecule drug discovery as potential antima-
Resu lts a n d Discu ssion
Syn th esis of Tr im eth ylen e-Teth er ed Tr ia zin es.
Analogous to the indole14 and pyrrole3a studies, the
tethered triazines 7 were prepared by one of two basic
routes; the first route proceeded through an acyl hy-
drazide 6 (Scheme 2, Table 1). Nucleophilic opening of
γ-butyrolactone (4a ) and 4-methyl γ-butyrolactone (4b)
with the imidazole anions generated with KH proceeded
in good yields (94-98%) to form carboxylic acids 5a -c.
Following esterification (SOCl2/MeOH, 92-95%), the acyl
hydrazides 6, which were stable to storage under ambient
conditions but could not be chromatographed on silica
gel, were formed in nearly pure form (99%) by treatment
with anhydrous hydrazine. Adapting the procedure of
Laasko15 as used previously in the preparation of teth-
(6) Aminopyridines: (a) Bobranski, B.; Sucharda, E. Chem. Ber.
1927, 60, 1081-1083. (b) Adams, J . T.; Bradsher, C. K.; Breslow, D.
S.; Amare, S. T.; Hauser, C. R. J . Am. Chem. Soc. 1946, 68, 1317-
1319. (c) Hart, E. P. J . Chem. Soc. 1954, 1879-1882. (d) Albert, A. J .
Chem. Soc. 1960, 1790-1793. (e) Rapoport, H.; Batcho, A. D. J . Org.
Chem. 1963, 28, 1753-1759. (f) Hamada, Y.; Takeuchi, I. Chem.
Pharm. Bull. 1971, 19, 1857-1862. (g) Soufyane, M.; Mirand, C.; Levy,
J . Tetrahedron Lett. 1993, 34, 7737-7740. (h) Chen, J .-L.; Steglich,
W. J . Heterocycl. Chem. 1993, 30, 909-912. (i) Couture, A.; Deniau,
E.; Grandclaudon, P.; Simion, C. Synthesis 1993, 1227-1229. (j) Batt,
D. G.; Copeland, R. A.; Dowling, R. L.; Gardner, T. L.; J ones, E. A.;
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Bioorg. Med. Chem. Lett. 1995, 5, 1549-1554. (k) Wojciechowski, K.;
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P.; Gowan, M.; Trimble, L. A.; Lau, C. K. Synthesis 1999, 1893-1902.
(m) Phuan, P.-W.; Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3963-
3965. For an ellipticene analogue incorporating a 1,5-naphthyridine
subunit also prepared from a 3-aminopyridine, see: (n) Zhang, Q.; Shi,
C.; Zhang, H.-R.; Wang, K. K. J . Org. Chem. 2000, 65, 7977-7983.
(7) (a) Baumgarten, H. E.; Su, H. C.-F.; Barkley, R. P. J . Heterocycl.
Chem. 1966, 3, 357-358. (b) Wrobel, Z.; Makosza, M. Tetrahderon
1993, 49, 5315-5326. (c) Wrobel, Z. Tetrahedron 1998, 54, 2607-2618.
(d) Wrobel, Z. Eur. J . Org. Chem. 2000, 521-525.
(11) Angiotensin II antagonists: (a) Allott, C. P.; Bradbury, R. H.;
Dennis, M.; Fisher, E.; Luke, R. W. A.; Major, J . S.; Oldham, A. A.;
Pearce, R. J .; Reid, A. C.; Roberts, D. A.; Rudge, D. A.; Russell, S. T.
Bioorg. Med. Chem. Lett. 1993, 3, 899-904. (b) Norman, M. H.; Smith,
H. D.; Andrews, C. W.; Tang, F. L. M.; Cowan, C. L.; Steffen, R. P. J .
Med. Chem. 1995, 38, 0-4678. Other reported biological activities of
1,5-naphthyridines: (c) Takeuchi, I.; Hamada, Y. Chem. Pharm. Bull
1976, 24, 1813-1821. (d) Bisagni, E.; Landras, C.; Thirot, S.; Huel, C.
Tetrahedron 1996, 52, 10427-10441. (e) Viti, G.; Giannotti, D.;
Nannicini, R.; Balacco, G.; Pestellini, V. Tetrahedron Lett. 1994, 35,
5939-5942.
(12) (a) Price, C. C.; Roberts, R. M. J . Am. Chem. Soc. 1946, 68,
1204-1208. (b) Petrow, V.; Sturgeon, B. J . Chem. Soc. 1949, 1157-
1160.
(13) (a) McCaustland, D. J .; Cheng, C. C. J . Heterocycl. Chem. 1970,
7, 467-473. (b) Barlin, G. B.; Tan, W.-L. Aust. J . Chem. 1985, 38, 459-
465. (c) Barlin, G. B.; Tan, W.-L. Aust. J . Chem. 1985, 38, 905-911.
(d) Scott, H. V.; Tan, W.-L.; Barlin, G. B. Ann. Trop. Med. Parasit.
1988, 82, 127-131. (e) Barlin, G. B.; Ireland, S. J .; Nguyen, T. M. T.;
Kotecka, B.; Reickmann, K. H. Aust. J . Chem. 1994, 47, 1143-1154.
(14) Benson, S. C.; Li, J .-H.; Snyder, J . K. J . Org. Chem. 1992, 57,
5285-5287.
(15) (a) Laasko, P. V.; Robinson, R.; Vandrewala, H. P. Tetrahedron
1957, 1, 103-118. This one-pot procedure was adapted from a two-
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ref 2m.
(8) (a) Frydman, B.; Los, M.; Rapoport, H. J . Org. Chem. 1971, 36,
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D. K. J . Med. Chem. 2001, 44, 1313-1333.
7172 J . Org. Chem., Vol. 69, No. 21, 2004

Intramolecular Inverse-Electron-Demand Diels-Alder Reactions
TABLE 1. P r ep a r a tion of Im id a zole/Tr ia zin e Teth er ed
P a ir s 7 by Acyl Hyd r a zid e Rou te (Sch em e 2)
TABLE 2. P r ep a r a tion of Teth er ed Im id a zole/Tr ia zin e
P a ir s 5 by Am id r a zon e Rou te (Sch em e 3)
item
triazine
R1
R2
R3
R4
yielda (%)
item
triazine
R1
R3
R4
yielda (%)
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
H
H
H
Me
H
H
Ph
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Me
Me
H
76
91
80
80
30
53
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
7a
7b
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
H
Ph
Ph
Me
Me
Ph
Ph
H
Ph
95
95
87
81
98
81
96
62
61
83
80
91
82
89
91
Ph
Ph
Ph
H
Ph
Ph
H
Ph
H
Ph
Ph
H
Ph
Me
Me
Me
Ph
Ph
Ph
Me
Me
H
H
H
Ph
H
a
Isolated yields from the Laasko condensation step.
-(CH2)4-
-(CH2)4-
CO2Et
Me
Ph
Ph
p-BrPh
p-MeOPh
CO2Et
Me
Ph
H
H
H
SCHEME 3
a
Isolated yields after condensation step.
SCHEME 4
ered 1,2,4-triazines for intramolecular cycloadditions with
indoles14 and pyrroles,3a the crude acylhydrazides were
condensed with benzil or 2,3-butanedione to give the
tethered triazines 7a -d in good yields (76-91%, Table
1, items 1-4).
As previously observed with indole- and pyrrole-
tethered triazines, this acyl hydrazide route did not work
with all 1,2-dicarbonyl compounds, for example, glyoxal,
nor were the yields of 7e (30%) and 7f (53%) acceptable
(Table 1, items 5 and 6). Thus, the alternative route
through the amidrazone was probed and ultimately
became the method of choice for preparing most tethered
triazines due to its generality (Scheme 3). Imidazole-
tethered nitriles 8 were readily prepared by simple
bromide displacements on 4-bromobutyronitrile. Addition
of lithium hydrazide (NH2NH2/n-BuLi) to 8 produced
amidrazones 9, which were immediately condensed with
the R-dicarbonyl compounds to produce the tethered
triazines 7 in good to excellent overall yields (61-98%,
Table 2). The yields of 7e (81%) and 7f (98%) under these
conditions increased significantly in comparison to those
obtained via the acyl hydrazide route (30% and 53%,
respectively, Table 1). In general, derivatives from 2-
phenylimidazole were easier to monitor by TLC with
simple UV lamps as the imidazole and 2-methylimidazole
derivatives are nonquenchers.
The preparation of a few other tethered triazines not
listed in Tables 1 and 2 deserves special note. As observed
in earlier work, the regioselectivity in the condensation
of the amidrazones 9 with unsymmetric 1,2-dicarbonyl
compounds was quite variable.2m,16 With phenylglyoxal,
only a single isomer was observed (7f, 7g, and 7n , Table
2, items 5, 6, and 13), with the more nucleophilic hydra-
zinyl amino group condensing with the more electrophilic
aldehyde carbonyl.16b-e,17 Similar exclusive regioselective
was also observed in the condensation of p-bromo-18 and
p-methoxyphenyl glyoxals19 with amidrazone 9b to pro-
duce triazines 7o and 7p (Table 2, items 14 and 15). In
contrast, an analogous reaction with ethyl 2,3-dioxobu-
tanoate20 (10) with 9b led only to a 3:1 mixture of
regioisomers 7q and 7r (80% combined, Scheme 4). This
ratio proved to be insensitive to the solvent employed,
though the yield of the 7q/7r mixture was considerably
lower in benzene or THF in comparison to ethanol. The
assignment of the major regioisomer as 7q was initially
based on electronic considerations, with the more nu-
cleophilic hydrazinyl amino group assumed to add pref-
erentially to the more electophilic central carbonyl of 10.
This conclusion was confirmed following the microwave-
promoted cycloaddition as described below.
To circumvent this regioselectivity issue, a new route
to the monoester tethered triazine 7s was adapted from
a procedure we reported earlier (Scheme 5).4d Conversion
(16) (a) Neunhoeffer, H.; Hennig, H.; Fruhauf, H.-W.; Mutterer, M.
Tetrahedron Lett. 1969, 3147-3150. (b) Benson, S. C.; Gross, J . L.;
Snyder, J . K. J . Org. Chem. 1990, 55, 3257-3269. (c) Ohsumi, T.;
Neunhoeffer, H. Tetrahedron 1992, 48, 651-662. (d) Zhao, Z.; Leister,
W. H.; Strauss, K. A.; Wisnoski, D. D.; Lindsley, C. W. Tetrahedron
Lett. 2003, 44, 1123-1127. For reviews of 1,2,4-triazine preparations,
see: (e) Neunhoeffer, H. In The Chemistry of 1,2,3-Triazines and 1,2,4-
Triazines, Tetrazines, and Pentazines; Wiley-Interscience: New York,
1978; Vol. 33, pp 772-775. (f) Neunhoeffer, H. In Comprehensive
Heterocyclic Chemistry, Vol. 3, Six-Membered Rings with O, S, or Two
or More N Atoms; Boulton, A. J ., McKillop, A., Eds.; Pergamon: Oxford,
UK, 1984; pp 430-437.
(17) Taylor, E. C.; Martin, S. F. J . Org. Chem. 1972, 37, 3958-3960.
(18) Preparation of p-bromophenylglyoxal: Kornblum, N.; Frazier,
H. W. J . Am. Chem. Soc. 1966, 88, 865-866.
(19) p-Methoxyphenylglyoxal was prepared by adapting the proce-
dure in ref 18 (see the Supporting Information). For previous prepara-
tion: (a) Sisido, K.; Nozaki, H. J . Am. Chem. Soc. 1948, 70, 3326-
3329. (b) Fodor, G.; Kovacs, O. J . Am. Chem. Soc. 1949, 71, 1045-
1048.
(20) Preparation of 10: Hoffman, R. V.; Wilson, A. L.; Kim, H.-O. J .
Org. Chem. 1990, 55, 1267-1270.
J . Org. Chem, Vol. 69, No. 21, 2004 7173

Lahue et al.
SCHEME 5
SCHEME 7
SCHEME 8
SCHEME 6
of nitrile 8b to thioamide 11 with hexamethyldisi-
lathiane21 followed by condensation with hydrazone 14
(which was difficult to make)16c mediated by the Mu-
kaiyama reagent 2-chloro-1-methylpyridinium iodide (12)
produced 7s (55%), accompanied by significant amounts
(28%) of reconstituted nitrile 8b (Scheme 5). The regen-
eration of nitrile 8b presumably results from elimination
of N-methylthiopyridone (15) from intermediate 13.
Addition of HOAc to the reaction mixture failed to
suppress the formation of 8b, though it did not effect the
production of 7s. Due to the difficulty in separating 8b
from 7s, the reaction mixture was used directly in the
subsequent cycloaddition as described below, after puri-
fying small amounts of 7s for characterization purposes.
Attempts to apply this regioselective triazine prepara-
tion to the synthesis of 7q, however, were unsuccessful.
R-Diazo-â-keto ester 16 was readily prepared following
the procedure of Baum and Davies22 and then subse-
quently reduced16c,23 to hydrazone 1716c (Scheme 6). The
condensation of 17 with thioamide 11 mediated by
Mukaiyama reagent 12, or the corresponding bromopyr-
idinium reagent, failed to produce 7q, returning only
unreacted 17 (the thioamide 11 and Mukaiyama reagent
were consumed). Presumably, the reduced nucleophilicity
of the hydrazone 17, a consequence of the two adjacent
carbonyl groups, prevents the addition to the activated
thioamide 13.
SCHEME 9
and 7u could only be prepared via the acyl hydrazide
route beginning with lactone 4c24 (Scheme 7). The con-
densations of phenyl and p-bromophenyl glyoxals with
the acyl hydrazide formed from 18 were completely
regioselective, producing only tethered triazines 7t and
7u in modest yields (45% each). Attempted preparation
of 7t via the amidrazone route failed. Addition of lithium
hydrazide to nitrile 8d (Scheme 8) resulted in consider-
able deprotection of the primary alcohol with no further
reaction of the nitrile group, leading to recovery of the
primary alcohol in low yield.
Cycloa d d ition s of Tr im eth ylen e-Teth er ed Tr ia -
zin e/Im id a zole P a ir s. Inverse-electron-demand Diels-
Alder reactions of the tethered imidazole/triazine pairs
7 were initially accomplished by refluxing in triisopro-
pylbenzene (TIPB, bp 232 °C) under argon (Scheme 9)
optimizing with diphenyl triazines 7a and 7b . Rather
than the anticipated annulated deazapurines 2 (see
Scheme 1), 1,2,3,4-tetrahydro-1,5-naphthyridines 1 were
obtained along with lesser amounts of the fully aroma-
tized 1,5-naphthyridines 19 (Table 3). Apparently, the
[4 + 2] cycloaddition with immediate loss of N2 is followed
by rapid nitrile elimination rather than dehydrogenation.
Tethered triazines with a substituted central methyl-
ene were also of interest in order to examine the potential
of generating stereochemistry in the tetrahydronaphthyr-
idine ring at C3 with a substituent capable of further
diversification of the naphthyridine scaffold, such as a
hydroxymethyl group. While the amidrazone route proved
to be the preferred pathway for most tethered triazine
preparations, central methylene-substituted triazines 7t
(21) Lin, P.-Y,; Ku, W.-S.; Shiao, M.-J . Synthesis 1992, 1219-1220.
(22) Baum, J . S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709-1716.
(23) (a) Ohsumi, T.; Neunhoeffer, H. Heterocycles 1992, 33, 893-
903. (b) Ohsumi, T.; Neunhoeffer, H. Tetrahedron 1992, 48, 5227-
5234.
(24) Lactone 4c was prepared by the hydrogenation of the corre-
sponding butenolide (see the Supporting Information). For the prepa-
ration of the butenolide: Takabe, K.; Tanaka, M.; Sugimoto, M.;
Yamada, T.; Yoda, H. Tetrahedron Asymm. 1992, 3, 1385-1386.
7174 J . Org. Chem., Vol. 69, No. 21, 2004

Intramolecular Inverse-Electron-Demand Diels-Alder Reactions
TABLE 3. Cycloa d d ition s of Tr im eth ylen e Teth er ed Im id a zole/Tr ia zin e P a ir s 7
triazine
cycloadductb
item
no.
R1
R2
R3
R4
Ph
conditionsa
1
19
1
2
3
4
5
6
7
8
9
10
11d
12
13
14
15
16
17
18
19
20
21
22
23
24
25
7a
7a
7b
7b
7c
7c
7c
7d
7d
7e
7e
7f
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
Ph
H
7.5 h
a : 65
a : 92
a : 57
a : 92
0
a : 10
trace
a : 38
trace
c: 70c
c: 19
c: 6
d : 25
trace
d : 25
d : 18
f: 0
trace
h : 23
trace
trace
trace
0
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
H
3 h, BHT (1 equiv)
9 h
3 h, BHT (1 equiv)
36 h
3 h, BHT (1 equiv)
3.2 h, BHT (2 equiv)
7 h
3 h, BHT (1 equiv)
24 h
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
c: 70
c: 90
d : 60
d : 90
d : 52
d : 48
f: 75
f: 81
h : 34
h : 87
i: 89
i: 54
0h
k : 91
d : 77
a : 82
a : 91
f: 83
o: 89
p : 85
H
Ph
H
12 h, BHT (1.2 equiv)
4 h,e Ph2O
7g
7h
7h
7i
H
H
H
7 h, BHT (1.2 equiv)
42 h
Ph
Ph
Ph
H
Ph
Ph
Me
Me
Me
Me
Ph
Ph
H
3 h, BHT (1 equiv)
6 h, BHT (1 equiv)
13 h, BHT (1.2 equiv)f
1.5 h,g C6H5Br
5 h, BHT (1.2 equiv)
6 h, BHT (1.2 equiv)
1.5 h
-(CH2)4-
-(CH2)4-
7j
7k
7k
7l
7m
7m
7n
7o
7p
CO2Et
CO2Et
Me
CO2Et
CO2Et
Me
Ph
Ph
H
H
H
H
H
H
H
H
0
d : 2
a : 8
trace
trace
0
Ph
Ph
Ph
1 h, BHT (1.2 equiv)
3 h, BHT (1.2 equiv)
Ph2O, 1.3 he
p-BrPh
p-MeOPh
H
H
Ph2O, 5 he
0
a
b
All reactions performed in refluxing TIPB (232 °C) unless otherwise noted. Isolated yields. c In addition, 19a (27%) was also isolated.
Starting material (7e) also isolated (24%). e Reflux: bp ) 259 °C. Reaction in TIPB was very messy, even with BHT added. f Starting
material (7j) also isolated (24%). Reflux: bp ) 156 °C. Gave only 20k (99%); see text and Scheme 11.
d
g
h
SCHEME 10
Adventitious oxygen presumably accounts for the aro-
matization of 1 to produce the varying quantities of 19.
In support of this, resubjecting purified 1a to the cy-
cloaddition conditions (refluxing TIPB) under ambient
atmosphere resulted in a clean conversion to 19a (91%).
Conversion of the tetrahydronaphthyridines to the fully
aromatized naphthyridines could also be accomplished
by heating with selenium (e.g., 1a f 19a , 320-340 °C,
8 h, 85%). Aromatization following the cycloaddition could
be greatly reduced or eliminated by the addition of BHT
(1.0-2 equiv) to the reaction mixture, leading to the
optimal yields of the tetrahydronaphthyridines 1. Fur-
triazines with ynamines,1b,27 not a fused system as
thermore, the presence of BHT also accelerated the
cycloadditions to a degree in all cases (compare items 1
vs 2, 3 vs 4, 5 vs 6, 8 vs 9, 10 vs 11, and 14 vs 15). For
example, the cycloadditions of triazines 7a and 7b
required 7.5 and 9 h, respectively (items 1 and 3), for
completion without BHT, while only 3 h was necessary
in the presence of BHT in both cases (items 2 and 4).
Control experiments showed large amounts of 7a re-
maining after only 3 h without BHT present. Thus, BHT
could also be functioning as a general acid catalyst in
promoting the reaction by protonating or hydrogen bond-
ing to a triazinyl nitrogen and thereby lowering the diene
LUMO. Indeed, the reduced reaction times in the pres-
ence of BHT undoubtedly also helps to minimize the
aromatization. Nitrile elimination has been reported from
other cycloadducts in inverse-electron-demand Diels-
Alder reactions,1b,4h though to the best of our knowledge,
always from a bridged system such as in the cycloaddi-
tions of pyrimidines25 and 1,3,5-triazines,26 or of 1,2,4-
observed here.
Several of the cycloadditions deserve special note. The
cycloaddition of 7c without BHT resulted in the produc-
tion of significant amounts (27%) of demethylated, aro-
matized 1,5-naphthyridine 19a (R2 ) H, R3 ) R4 ) Ph)
in addition to the major product naphthyridine 19c (70%,
Table 3, item 5, Scheme 10). No tetrahydronaphthyridine
1c could be detected under these conditions. In the
presence of BHT, however, only the 4-methyl products
1c and 19c were produced, though considerably more
BHT (2 equiv) was required to suppress the aromatiza-
tion (items 6 and 7).
(26) For examples since the review (ref 1h), see ref 4h and also: (a)
Boger, D. L.; Dang, O. J . Org. Chem. 1992, 57, 1631-1633. (b) Boger,
D. L.; Menezes, R. F.; Dang, Q. J . Org. Chem. 1992, 57, 4333-4336.
(c) Boger, D. L.; Menezes, R. F.; Honda, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 273-275. (d) Boger. D. L.; Honda, T.; Menezes, R. F.; Colletti,
S. L.; Dang, Q.; Yang, W. J . Am. Chem. Soc. 1994, 116, 82-92. (e)
Boger, D. L.; Kochanny, M. J . J . Org. Chem. 1994, 59, 4950-4955. (f)
Boger, D. L.; Honda, T.; Dang, Q. J . Am. Chem. Soc. 1994, 116, 5619-
5630.
(25) For examples since the review (ref 1h), see: (a) Frissen, A. E.;
Marcelis, A. T. M.; van der Plas, H. C. Tetrahedron 1989, 45, 803-
812. (b) Frissen, A. E.; Marcelis, A. T. M.; Buurman, D. G.; Pollman,
C. A. M.; van der Plas, H. C. Tetrahedron 1989, 45, 5611-5620.
(27) Another example: Tahri, A.; Buysens, K. J .; van der Eycken,
E. V.; Vandenberghe, D. M.; Hoornaert, G. J . Tetrahedron 1998, 54,
13211-13226.
J . Org. Chem, Vol. 69, No. 21, 2004 7175

Lahue et al.
SCHEME 11
SCHEME 12
The cycloaddition of tethered triazines 7d , 7e, 7i, 7j,
and 7l (Table 3, items 8-11, 16, 17, and 20, respectively)
are also noteworthy inasmuch as these cases represent
relatively electron-rich (high LUMO) trialkyl triazines
reacting with an imidazole, thereby illustrating the
entropic advantage of intramolecular reactions.28 In
intermolecular studies,4d it was found that only more
electron-deficient 1,2,4-triazines underwent cycloaddi-
tions with imidazoles, and then only with highly electron-
rich imidazoles such as 2-aminoimidazole and, to a lesser
extent, the 2-(methylthio)imidazole. Typically, these
reactions required the presence of at least two electron-
withdrawing substituents (esters) on the triazine ring.
Less reactive imidazoles such as imidazole and 2-phenyl-
and 2-methylimidazole failed to react intermolecularly
even with the highly electron-deficient triethyl 1,2,4-
triazine-3,5,6-tricarboxylate.
converted the amidine to the desired naphthyridine 1s,
producing an 86% overall yield of 1s from 7s.
The cycloadditions of monoaryl-substituted triazines
7f, 7o, and 7p with the 2-phenylimidazole dienophilic
subunit (Table 3, items 12, 24, and 25) were successful
in refluxing diphenyl ether without added BHT. In this
solvent (bp ) 259 °C), no fully aromatized naphthyridines
were detected, so the addition of BHT was not necessary.
Indeed, under the standard conditions (refluxing TIPB
with BHT), these triazines produced profound mixtures
of products that were extremely difficult to purify and
in which only small amounts of the desired tetrahy-
dronaphthyridines could be observed in the NMR spectra.
Furthermore, when BHT was added to the reaction in
diphenyl ether, varying amounts of amidines (20f, 20o,
20p ) could be isolated.
The diester triazines 7k , and 7s with the correspond-
ingly lower triazinyl LUMO’s due to the presence of the
electron-withdrawing ester substituents underwent cy-
cloadditions at considerably lower temperatures. The
cycloaddition of 7k proceeded at 110 °C (20 h) in refluxing
toluene to give a quantitative yield of amidine 20k
(Scheme 11). Indeed, 7k slowly underwent the cycload-
dition upon storage under ambient conditions leading to
complete conversion to 20k over the course of several
days. Increasing the temperature to 156 °C (refluxing
bromobenzene) accelerated the reaction, giving a quan-
titative yield of 20k in only 1.5 h (Table 3, item 18), while
refluxing in TIPB with BHT (1 h) produced 20k (46%)
along with tetrahydronaphthyridine 1k (47%). No deaza-
purine analogue 2 (see Scheme 1) was detected at any of
the lower temperatures as initially desired. Increasing
the reaction time in TIPB to 5 h led to the sole production
of 1k (91%, Table 3, item 19). The isolation of 20k sug-
gests that the nitrile elimination proceeds through a
stepwise pathway. Indeed, refluxing 20k in TIPB in the
presence of BHT for 2 h gave 1k in 66% yield along with
21% recovered 20k and a trace amount of the fully
aromatized naphthyridine. Similar results were observed
for 7s (as the major component of the 2:1 mixture with
nitrile 8b as described previously, Scheme 5), producing
a mixture of amidine 20s and tetrahydronaphthyridine
1s upon refluxing in bromobenzene. Treatment of this
mixture with KOBut in THF (0 C, 30 min) completely
Several conditions were examined in an effort to
promote the dehydrogenation of the intermediate cy-
cloadduct A to form the annulated deazapurines 2. Thus,
7b was treated to the classic selenium melt procedure29
(Se, 320 °C, 10 h), but only naphthyridine 19a was
produced (56%, Scheme 12). Other attempts included the
addition of elemental sulfur, Pd-C, and DDQ to the
reaction of 7b (refluxing TIPB), but in these cases only
tetrahydronaphthyridine 1a was generated.
The facile loss of nitrile from the cycloadduct interme-
diate A to form the tetrahydronaphthyridines 1 led to a
reexamination of the intramolecular cycloaddition of
tethered pyrrole/triazine pairs, which in principle can
also form 1,5-naphthyridines by loss of acetylene from
the intermediate cycloadduct. As previously reported,3a
the cycloaddition of tethered triazine 21 in refluxing
TIPB produced pyrrolonaphthyridine 22 in 80% yield.
Examination of the remaining material also revealed the
presence of tetrahydronaphthyridine 1h (12%) which
presumably results from the loss of acetylene from the
intermediate cycloadduct B (Scheme 13), which is more
difficult than loss of the nitrile.
(28) (a) Ciganek, E. In Organic Reactions; Dauben, W. G., Ed.-in-
Chief; Wiley: New York, 1984; Vol. 32, Chapter 1. (b) Taylor, E. C.
Bull. Soc. Chim. Belg. 1988, 97, 599-613.
(29) Procedure adapted from: Bartlett, M. F.; Taylor, W. I. J . Am.
Chem. Soc. 1960, 82, 5941-5946.
7176 J . Org. Chem., Vol. 69, No. 21, 2004

Intramolecular Inverse-Electron-Demand Diels-Alder Reactions
TABLE 4. Micr ow a ve-P r om oted Cycloa d d ition s of Tr im eth ylen e-Teth er ed Im id a zole/Tr ia zin e P a ir s 7
triazine
cycloadduct 1b
item
no.
7o
7p
7f
7q/7r
7t
7u
R5
R3
R4
conditionsa
yield (%)
1
2
3
4
5
6
H
H
H
H
p-BrPh
p-MeOPh
Ph
CO2Et/Me
Ph
H
H
H
210 °C, 20 min
210 °C, 30 min
210 °C, 25 min
225 °C, 20 min
210 °C, 20 min
210 °C, 20 min
85 (1o)
70 (1p )
80 (1f)
56 (1q)/15 (1r )
70 (1t)
Me/CO2Et
CH2OTBS
CH2OTBS
H
H
p-BrPh
73 (1u )
a
b
All reactions performed in o-dichlorobenzene with NH4OAc as energy transfer agent. Isolated yields.
SCHEME 13
transfer agent. The use of other salts such as (n-Bu)4-
NPF6 or 1-alkyl-3-methylimidazolium ionic solvents32
were considerably less effective. Microwave irradiation
also worked well in promoting the cycloadditions of other
triazines (Table 4, items 2-6). The advantage of the
microwave-promoted chemistry was particularly note-
worthy in the reduced reaction times (from 3.5 h or more
under reflux to 20-30 min with microwave irradiation)
giving yields comparable to those observed under thermal
conditions. Microwave irradiation was not effective,
however, with triazine/imidazole pairs 7d and 7h .
The cycloaddition of the mixture of regioisomeric
triazines 7q and 7r was also successful under microwave
irradiation (Table 4, item 4). The structural distinction
of 7q and 7r originally suggested by electronic consid-
erations in the condensation of the amidrazone 9b with
the R,â-diketone 10 (Scheme 4 above) was confirmed by
NOE studies on the separable cycloadducts 1q and 1r ,
which identified the substituent adjacent to H8 as
illustrated. Also as anticipated, the naphthyridines could
also be distinguished by the chemical shifts of their
respective pyridine ring protons (H8). In 1q, this proton
was considerably deshielded (δ 7.27) in comparison to
that in 1r (δ 6.49) due to the influence of the adjacent
ester substituent in comparison to the methyl group of
1r . The H8 chemical shift in 1r was comparable to that
observed with the 6,7-dimethytetrahydronaphthyridine
1d (δ 6.55).
SCHEME 14
Micr ow a ve-P r om oted Cycloa d d ition s. Recently,
Lindsley reported that microwave irradiation signifi-
cantly accelerated the intramolecular cycloaddition of
indole/1,2,4-triazine-tethered pairs,2m chemistry we had
earlier established under relatively harsh thermal condi-
tions.14 We therefore also briefly examined the cycload-
dition of select imidazole/triazine-tethered partners under
microwave irradiation (Scheme 14).30,31 The conditions
were optimized using tethered triazine 7o to produce
naphthyridine 1o. The best conditions for the cycloaddi-
tion were found to be microwave irradiation (210 °C, 20
min, 85%, Table 4, item 1) in o-dichlorobenzene in the
presence of NH4OAc (15 equiv), which proved comparable
to refluxing in diphenyl ether in yield (89%, 1.3 h, Table
3, item 24), but in considerably less time. In the absence
of NH4OAc, only trace amounts of product 1o were
detected. Presumably, the NH4OAc serves as an energy
(30) For reviews of microwave promoted organic chemistry, see: (a)
Abramovitch, R. A. Org. Prep. Proc. Int. 1991, 23, 683-711. (b)
Caddick, S. Tetrahedron 1995, 51, 10403-10432. (c) Strauss, C. R.;
Trainor, R. W. Aust. J . Chem. 1995, 48, 1665-1692. (d) Majetich, G.;
Wheless, K. Microwave-Enhanced Chemistry; American Chemical
Society: Washington, D.C., 1997; pp 455-505. (e) Loupy, A.; Petit, A.;
Hamelin, J .; Texier-Boullet, F.; J acquault, P.; Mathe, D. Synthesis
1998, 1213-1234. (f) Strauss, C. R. Aust. J . Chem. 1999, 52, 83-96.
(g) Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J . L.; Petit, A.
Tetrahedron 1999, 55, 10851-10870. (h) Perreux, L.; Loupy, A.
Tetrahedron 2001, 57, 9199-9223. (i) Lidstrom, P.; Tierney, J .; Wathey,
B.; Westman, J . Tetrahedron 2001, 57, 9225-9283. (j) Lew, A.; Krutzik,
P. O.; Hart, M. E.; Chamberlin, A. R. J . Comb. Chem. 2002, 4, 95-
105. (k) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002,
35, 717-727. (l) Bose, A. K.; Manhas, M. S.; Ganguly, S. N.; Sharma,
A. H.; Banik, B. K. Synthesis 2002, 1578-1591.
(31) The first example of microwave-promoted cycloaddition: (a)
Giguere, R. J .; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron
Lett. 1986, 27, 4945-4948. Also, see reviews (ref 30a,d,e,i). For
examples since these reviews, see: (b) Hong, B.-C.; Shr, Y.-J .; Liao,
J .-H. Org. Lett. 2002, 4, 663-666. (c) Van der Ecken, E.; Appukkuttan,
P.; De Borggraeve, W.; Dehaen, W.; Dallinger, D.; Kappe, C. O. J . Org.
Chem. 2002, 67, 7904-7907. Also, ref 2m.
Given the success of the microwave-promoted cycload-
dition, the possibility of accomplishing the tethered
triazine preparation with subsequent cycloaddition in a
single step via the acyl hydrazide route was also exam-
ined (Scheme 15). Lindsley had reported such a strategy
in the microwave-promoted synthesis of canthines after
noting the formation of cycloadducts in the microwave-
promoted triazine formation from the condensation of
acyl hydrazides with R,â-diketones.2m In the preparation
of tethered triazines 7, no cycloadducts had been detected
under these conditions (refluxing acetic acid, see Table
1) presumably due to the higher temperature required
to effect the cycloaddition. In most cases, the one-pot
(32) (a) Fischer, T.; Sethi, A.; Welton, T.; Woolf, J . Tetrahedron Lett.
1999, 40, 793-796. (b) Leadbeater, N. E.; Torenius, H. M. J . Org.
Chem. 2002, 67, 3145-3148.
J . Org. Chem, Vol. 69, No. 21, 2004 7177

Lahue et al.
TABLE 5. On e-P ot Micr ow a ve-P r om oted Syn th esis of
1,2,3,4-Tetr a h yd r o-1,5-n a p h th yr id in es 1 fr om
Acylh yd r a zid es 9 (Sch em e 15)a
SCHEME 16
item
R2
Ar
time (min)
7 (%)
1 (%)
1
2
3
4
5
6
H
H
H
Ph
10
6
6
6
6
f: 40
o: 54
p : 68
t: 31
u : 28
v: 45
f: 14
o: 9
p : 0
t: 30
u : 32
v: 10
p-BrPh
p-MeOPh
Ph
p-BrPh
p-MeOPh
CH2OTBS
CH2OTBS
CH2OTBS
6
a
All reactions run in o-dichlorobenzene with NH4OAc (15
equiv), 190 °C.
SCHEME 15
Tetramethylene tethered imidazole/triazine pairs 24
were prepared analogously to those with trimethylene
tethers beginning with the imidazole and 5-bromovale-
ronitrile via the amidrazone route (Scheme 16, Table 6).
Interestingly, the condensation of ethyl 2,3-dioxobu-
tanoate (10) with the amidrazone derived from nitrile
23b gave a 6:1 ratio of regioisomers (24g/24h , 88%
combined yield) in favor of 24g. Thus, a slight improve-
approach to the naphthyridines beginning with the
acylhydrazide 9b or 9d resulted in the production of some
naphthyridine 1 (Table 5), though invariably in consider-
ably lower yield than resulted from the two-step prepara-
tion wherein the tethered triazine was isolated and then
subjected to microwave irradiation to promote the cy-
cloaddition. The main product in most cases was the
tethered triazine 7. With p-methoxyphenylglyoxal and
acyl hydrazide 9b, no naphthyridine at all was detected,
only the tethered triazine 7p .
In cr ea sin g t h e Tet h er Len gt h ; P r ep a r a t ion of
2,3,4,5-Tetr ah ydr o-1H-pyr ido[3,2-b]azepin es. In prior
studies of the intramolecular cycloadditions of indole and
pyrrole with 1,2,4-triazines, the tether length was ob-
served to have a significant effect. Trimethylene tethers
giving rise to six-membered annulations were optimal,
tetramethylene tethers were considerably more sluggish
with indole, and failed completely with pyrrole, while
dimethylene tethers with indole allowed for the reaction
but produced unstable products.3a,14 We therefore inves-
tigated an increase in the tether length to four methylene
units in the intramolecular reactions of imidazoles in
order to generate 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]-
azepines and thereby use ring expansion of the A-ring
as a possible diversity element for these heterocyclic
scaffolds. Earlier reports of pyrido[3,2-b]azepine prepara-
tions have relied upon nitrogen insertion chemistry with
the Schmidt reaction33 or the Beckman rearrangement34
acting upon a tetrahydroquinolone precursor. This pyri-
doazepine system also lies within the alkaloid maxonine,
which was prepared by Kelly closing the azepine ring by
an intramolecular Heck coupling.35
ment was observed in the regioselectivity in comparison
to that obtained with the trimethylene-tethered amidra-
zone 9b (see Scheme 4). Cycloadditions of 24 (Table 6)
were noticeably more sluggish than their trimethylene-
tethered counterparts (Table 3), and refluxing in diphenyl
ether could be used to decrease the reaction time and
eliminate the need for added BHT (compare items 3-5).
In the few cases where a direct comparison could be
made, the cycloadditions employing 2-methylimidazole
as the dienophile where noticeably faster than those
using the less electron rich 2-phenylimidazole (compare
items 1 and 2 with 3 and 4, also item 6 with 7). In the
case of the trimethylene-tethered imidazole/triazine pairs,
there was little distinction between the 2-methyl- and
2-phenylimidazole dienophilic subunits in reactivity.
Surprisingly, while the nitrile elimination products 25
were dominant, small yet reproducible amounts of the
aromatized deazapurine 26a were also obtained when
diphenyl triazines (24a and 24b) were employed. Micro-
wave irradiation was disappointingly unsuccessful in
promoting the reaction, returning only unreacted starting
materials, with the exception of the diester triazine 24f
(Item 11).
(33) (a) Klar, H. Arch. Pharm. (Weinheim) 1976, 309, 550-557. (b)
Gatta, F.; Del Giudice, M. R.; Pomponi, M.; Marta, M. Heterocycles
1992, 34, 991-1004.
(34) (a) J ossang-Yanagida, A.; Gansser, C. J . Heterocycl. Chem.
1978, 15, 249-251. (b) Maquestiau, van Haverbeke, Y.; Vanden Eynde,
J .-J .; de Pauw, N. Bull. Soc. Chim. Belg. 1980, 89, 45-50. (c) Albright,
J . D.; Du, X. J . Heterocycl. Chem. 2000, 37, 41-46.
As observed with the trimethylene-tethered imidazole/
triazine pair 7k with the diester substitution on the
(35) Kelly, T. R.; Xu, W.; Sundaresan, J . Tetrahedron Lett. 1993,
34, 6173-6176.
7178 J . Org. Chem., Vol. 69, No. 21, 2004

Intramolecular Inverse-Electron-Demand Diels-Alder Reactions
TABLE 6. Cycloa d d ition s of Tetr a m eth ylen e-Teth er ed Im id a zole/Tr ia zin e P a ir s 24
triazine
cycloadducta
25
item
no.
24a
R1
R3
Ph
Ph
Ph
Ph
Ph
H
H
R4
conditions
26
1
2
3
4
5
6
7
8
9
Me
Me
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
Me
CO2Et
CO2Et
CO2Et
CO2Et
TIPB, 232 °C, 7.5 h
TIPB, 232 °C, 3 h, BHT (1.2 eq)
TIPB, 232 °C, 48 h
TIPB, 232 °C, 22 h, BHT (1 eq)
Ph2O, 258 °C, 18 h
Ph2O, 258 °C, 29 h
Ph2O, 258 °C, 7 h
Ph2O, 258 °C, 20 h
PhBr, 156 °C, 30 h
a : 72
a : 41
a : 38
a : 11
a : 72
c: 59
c: 54
e: 56
traceb
f: 70
f: 63
g: 39
a : 3
a : 9
b: 4
b: 7
b; 7
c: 5
0
24a
24b
24b
24b
24c
24d
24e
24f
Me
0
0
0
0
CO2Et
CO2Et
CO2Et
Me
10
11
12
24f
24f
24g/h
Ph2O, 258 °C, 45 min
microwave, 225 °C, 25 minc
Ph2O, 258 °C, 9 h
0
a
b
Isolated yields. Gave amidine 27f as the sole product (99+%). c Reaction run in o-dichlorobenzene with NH4OAc (15 equiv).
CHART 1
triazine, 24f produced unstable amidine 27f in quantita-
tive yield upon refluxing in bromobenzene. Brief refluxing
in diphenyl ether (Table 6, item 10) or microwave-
promoted cycloaddition yielded the pyridoazepine 25f
without any amidine precursor (Table 6, item 11). In
contrast, the monoester substituted triazine regioisomeric
pair 24g/24h underwent the cycloaddition in refluxing
diphenyl ether to produce the separable pyridoazepines
25g and 25h in low yield (39%, item 12) without any
detected amidine. Microwave promotion of this reaction
was also unsuccessful.
intramolecular reactions with four carbon tethers were
also successful, though somewhat more sluggish than
those utilizing a three carbon tether, to give modest to
good yields of 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines.
This chemistry thus provides a very efficient route to both
the tetrahydronaphthyridines and the pyridoazepines,
and enables diverse substitution to be incorporated on
these heterocyclic cores. Current work is exploring the
chemistry of these heterocyclic cores for development as
scaffolds in diversity oriented library synthesis.36 The 19
scaffolds now available from this work for library syn-
thesis are shown in Chart 1 (1c, 1t, and 1u were prepared
in racemic form).
Exp er im en ta l Section
Gen er a l P r oced u r e A: P r ep a r a tion of 4-Im id a zol-1-
ylbu ta n oic Acid s 5a -d . Into a predried, thick-walled test
tube was added KH (35% suspension in mineral oil, 1.17 g).
The mineral oil was removed by washing three times with
hexanes and then adjusting the amount of KH to 0.41 g (10.2
mmol). Excess KH was quenched by transferring to hexanes
and adding acetone. (The reaction works equally well without
removing the mineral oil in most cases, with the exception
being the preparation of 5d .) Imidazole (∼10 mmol, 3a or 3b)
was added and the mixture was mechanically mixed under
argon with careful warming with a heat gun. (CAUTION:
Once the deprotonation is initiated, it is very exothermic and
warming must cease immediately!) After the imidazole potas-
sium salt was formed, the γ-butyrolactone (11 mmol, 4a , 4b,
Con clu sion s
The intramolecular inverse-electron-demand Diels-
Alder reaction of imidazoles tethered with 1,2,4-triazines
between the imidazole N1 and triazinyl C-3 positions via
tri- and tetramethylene tethers has been explored. These
linked diene/dienohile pairs are easily prepared, and the
cycloadditions with three-carbon linkers occur readily
under either thermal or microwave promotion to produce
1,2,3,4-tetrahydro-1,5-naphthyridines in good to excellent
yields. The cycloaddition is followed by immediate release
of nitrogen and then presumably a stepwise loss of a
nitrile from the original imidazole C2/N3 position. The
(36) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004,
43, 46-58.
J . Org. Chem, Vol. 69, No. 21, 2004 7179

Lahue et al.
or 4c) was added dropwise. The mixture was then heated to
160-170 °C in a sand bath with stirring for 3 h. After the
mixture was cooled to rt, water (5 mL) was added, and the
mixture was then neutralized to pH paper with 5% HCl
solution. The mixture was then extracted with ethyl acetate,
the organic layer discarded, and the solvent removed from the
aqueous layer under reduced pressure to provide the crude
product, which was purified as indicated. Due to the need to
stir this reaction in the absence of a solvent other than the
γ-butyrolactone, this reaction works best at this or larger scale.
Gen er a l P r oced u r e B: P r ep a r a tion of Meth yl 4-Im id -
a zol-1-ylb u t a n oa t e E st er s. To anhydrous MeOH (30 mL)
cooled to -78 °C was added SOCl2 (1.9-2.4 mL, 20-25 mmol)
dropwise, with stirring continued for 30 min following comple-
tion of the addition. To this solution was then added dropwise
the 4-imidazol-1-ylbutanoic acid (5a -d , 10 mmol) dissolved
in a minimum amount of anhydrous methanol. After comple-
tion of the addition, the cooling bath was removed, the
temperature was allowed to rise to rt, and stirring was
continued for 3 h. The reaction was then quenched by the
addition of saturated aq NaHCO3 (30 mL) and the reaction
mixture extracted with methylene chloride. The organic layer
was dried over Na2SO4 and then the solvent removed in vacuo.
The crude product was purified by flash chromatography as
indicated. This procedure could be scaled.
mediately in the next step. To a solution of the dicarbonyl
compound (1-1.2 mmol) in anhydrous EtOH (2 mL) was added
the freshly prepared amidrazone (∼1 mmol) as a solution in
EtOH (3-5 mL) dropwise at 0 °C under Ar. The ice bath was
removed, and the reaction mixture was stirred at rt overnight
and then refluxed for 1 h. After removal of the solvent in vacuo,
the residue was purified by flash chromatography to provide
the desired triazine.
Gen er a l P r oced u r e G: P r ep a r a tion of 1,2,3,4-Tetr a h y-
d r o-1,5-n a p h th yr id in es 1 (Ta ble 3) a n d 2,3,4,5-Tetr a h y-
d r o-1H-p yr id o[3,2-b]a zep in es 25 (Ta ble 6) by Th er m a lly
P r om oted Cycloaddition s of th e Im idazole/Tr iazin e Teth -
er ed P a ir s 7 a n d 24, Resp ectively. Triazine 7 or 24
(typically 0.5 mmol) and BHT (0-1.0 mmol, 0-2 equiv) were
suspended in an appropriate solvent (typically 20 mL). (Reac-
tions in Ph2O did not use BHT.) The reaction mixture was
slowly warmed until the starting material was completely
dissolved, and then the mixture was heated to reflux and
monitored by TLC until the starting material was gone. After
cooling, the reaction mixture was passed through a short silica
gel plug, eluting with hexanes and then hexanes/CH2Cl2 (2:1)
to remove solvent (TIPB). The crude product was eluted by
further washing with CH2Cl2/MeOH (1:1). The solvent was
removed in vacuo, and the residue was purified by flash
chromatography.
Gen er a l P r oced u r e C: P r ep a r a tion of 4-Im id a zol-1-
ylbu ta n oyl Hyd r a zid es (6a -c). To a solution of the methyl
4-imidazol-1-ylbutanoate ester in anhydrous ethanol was
added anhydrous hydrazine (2.0 equiv) at rt. The resultant
clear solution was refluxed overnight, and then the solvent
and excess hydrazine were removed in vacuo to afford acyl-
hydrazides as nearly pure white solids, which were used in
the next step without further purification.
Gen er a l P r oced u r e D: P r ep a r a tion of 3-(3-(Im id a zol-
1-yl)pr opyl)-1,2,4-tr iazin es 7 via th e Acylh ydr azide Rou te
(Ta ble 1). The crude acylhydrazide (typically 1 mmol), dicar-
bonyl compound (1-1.2 equiv), and NH4OAc (15 equiv) in
glacial acetic acid (3-5 mL) or bromobenzene (3-5 mL) were
refluxed for 6 h. After removal of most of the HOAc in vacuo,
saturated aq NaHCO3 (10 mL) was added to the cooled reaction
mixture. The aqueous layer was thoroughly extracted with
EtOAc, the combined organic layers were dried over Na2SO4,
and then the solvent was removed in vacuo to provide the
crude product. Purification by flash chromatography gave the
tethered triazines 7.
Gen er a l P r oced u r e E: P r ep a r a tion of 4-(Im id a zol-1-
yl)bu tyr o- a n d 5-(Im id a zol-1-yl)va ler on itr iles 8 a n d 23.
To a solution of the imidazole (10 mmol) in dry DMF (20 mL)
at 0 °C was added NaH (60% in mineral oil, 800 mg, 20 mmol,
mineral oil not removed), and the mixture was stirred for 15
min. To this mixture was added 4-bromobutyronitrile or
5-bromovaleronitrile (12 mmol, 1.2 equiv), and stirring was
continued overnight at rt. The reaction was quenched with
ice-water (50 mL) and then extracted with EtOAc. The
combined organic layers were washed with brine and then
dried over Na2SO4. After removal of the solvent in vacuo, the
crude product was purified by flash chromatography.
Gen er a l P r oced u r e F : P r ep a r a tion of 3-(3-Im id a zol-
1-ylp r op yl)-1,2,4-tr ia zin es 7 (Ta ble 2) a n d 3-(4-Im id a zol-
1-ylbu tyl)-1,2,4-tr ia zin es 24 via th e Am id r a zon e Rou te.
To a solution of anhydrous hydrazine (typically 4-6 mmol) in
anhydrous THF (10 mL) at 0 °C was added dropwise n-BuLi
(1.6 M in hexanes, 4-6 mmol, 1 equiv). After the suspension
was stirred at 0 °C for 20 min, a solution of the 4-imidazol-
1-ylbutyronitrile or 5-imidazol-1-ylvaleronitrile (1 mmol) in
anhydrous THF (2-4 mL) was added dropwise at 0 °C. The
resultant solution was stirred at rt for 2 h and then quenched
by adding ice-water until the mixture became translucent.
After removal of the solvent in vacuo, the oily residue was
triturated with dry EtOH. The solvent from the combined
EtOH washings was then removed in vacuo to provide the
crude amidrazone as light yellow oil, which was used im-
Gen er a l P r oced u r e H: P r ep a r a tion of 1,2,3,4-Tetr a h y-
d r o-1,5-n a p h th yr id in es 1 by Micr ow a ve-P r om oted Cy-
cloa d d ition s of Im id a zole/Tr ia zin e Teth er ed P a ir s 7
(Ta ble 4). Triazine (0.1-0.3 mmol), ammonium acetate (12-
20 equiv), and 1,2-dichlorobenzene (1-3 mL) were placed in a
10 mL microwave vessel and heated (190-225 °C) for 20-40
min (power ) 300 W, pressure ) 250 psi). After cooling, the
reaction mixture was diluted with water (5 mL) and extracted
with CH2Cl2, and the organic layer dried over Na2SO4. After
removal of the solvent in vacuo, the residue was purified by
flash chromatography.
Meth yl 3-(ter t-Bu tyldim eth ylsilyloxym eth yl)-4-(2-ph en -
ylim id a zol-1-yl)bu ta n oa te (18). A solution of 5d (45 mg,
0.12 mmol), DMAP (2 mg, 0.012 mmol), and anhydrous MeOH
(25 µL, 0.6 mmol) in CH2Cl2 (2 mL) was stirred at 0 °C for 30
min under Ar. Solid EDCI (25 mg, 0.123 mmol) was quickly
added to the reaction mixture, stirred for 2 h at 0 °C, and then
stirred for another 3 h at rt. After removal of the solvent in
vacuo, water (5 mL) was added to the residue, which was then
extracted with EtOAc. The combined organic layers were
washed with brine and dried over Na2SO4. The solvent was
removed in vacuo and the residue purified by flash chroma-
tography (eluting initially with hexanes/EtOAc, 3:1, then
EtOAc) to give 18 as a yellow oil (37 mg, 80%): IR (NaCl) νmax
1734 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.55 (dd, J ) 7.8, 1.4
Hz, 2H), 7.42-7.34 (m, 3H), 7.10 (s, 1H), 7.01 (s, 1H), 4.14
(dd, J ) 14.2, 7.8 Hz, 1H), 4.03 (dd, J ) 14.2, 6.8 Hz, 1H),
3.55 (s, 3H), 3.43 (dd, J ) 10.4, 4.0 Hz, 1H), 3.39 (dd, J )
10.4, 3.8 Hz, 1H), 2.34 (m, 1H), 2.27 (dd, J ) 16.0, 6.8 Hz,
1H), 2.08 (dd, J ) 16.0, 6.0 Hz, 1H), 0.80 (s, 9H), -0.05 (s,
3H), -0.06 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 172.5, 148.2,
131.0, 129.1 (2C), 128.9, 128.80, 128.75 (2C), 121.3, 62.0, 51.8,
47.2, 39.0, 33.3, 26.0 (3C), 18.3, -5.4, -5.6; EIMS (70 eV) m/z
389 ([M + 1]+, 36), 331 ([M]+, 100); CIHRMS (NH3, 140 eV)
m/z 389.2254 ([M + 1]+, 41), calcd for C21H32N2O3Si 389.2260.
3-(ter t-Bu tyld im eth ylsilyloxym eth yl)-4-(2-p h en ylim id -
a zol-1-yl)bu tyr on itr ile (8d ). A solution of AlMe2Cl in hex-
anes (1 M, 900 µL, 0.9 mmol) was added slowly to a suspension
of NH4Cl (50 mg, 0.9 mmol) in anhydrous CH2Cl2 (1 mL) at
0 °C with stirring. The mixture was allowed to warm to rt over
a period of 1 h. To this aluminum amide complex solution was
added a solution of methyl 3-tert-butyldimethylsilyloxymethyl-
4-(2-phenylimidazol-1-yl)butanoate (18, 50 mg, 0.12 mmol) in
CH2Cl2 (1 mL), and the mixture was refluxed for 24 h. After
cooling, the reaction mixture was diluted to pH 8 with
phosphate buffer (5 mL) and stirred at rt for 10 min. The
mixture was then passed through a Celite plug, thoroughly
7180 J . Org. Chem., Vol. 69, No. 21, 2004

Intramolecular Inverse-Electron-Demand Diels-Alder Reactions
washing with CH2Cl2. The combined CH2Cl2 washings were
extracted with water, and the organic layer was washed with
brine and then dried over Na2SO4. The solvent was removed
in vacuo and the residue purified by flash chromatographed
on (CH2Cl2/MeOH, 10:1) to give 3-(ter t-bu tyld im eth ylsilyl-
oxym eth yl)-4-(2-p h en ylim id a zol-1-yl)bu ta n a m id e as a
white solid (30 mg, 67%): IR (NaCl) νmax 3317, 3172, 1670
(CDCl3, 400 MHz) δ 7.52 (dd, J ) 7.8, 1.8 Hz, 2H), 7.41-7.36
(m, 3H), 7.11 (d, J ) 1.2 Hz, 1H), 7.05 (d, J ) 1.2 Hz, 1H),
4.51 (q, J ) 7.1 Hz, 2H), 4.17 (t, J ) 7.2 Hz, 2H), 3.06 (t, J )
7.2 Hz, 2H), 2.70 (s, 3H), 2.33 (tt, J ) 7.2, 7.2 Hz, 2H), 1.46 (t,
J ) 7.1 Hz, 3H); EIMS (70 eV) m/z 351 ([M]+, 37), 171 (100);
EIHRMS (70 eV) m/z 351.1668 ([M]+, 17), calcd for C19H21N5O2
351.1695.
1
cm-1; H NMR (CDCl3, 400 MHz) δ 7.57 (d, J ) 8.0 Hz, 2H),
4-(2-P h en ylim id a zol-1-yl)th iobu tyr a m id e (11). Hexa-
methyldisilathiane (1.64 mL, 7.8 mmol) was added dropwise
to a solution of NaOMe (442 mg, 7.8 mmol) in anhydrous DMF
(10 mL) and stirred at rt for 15 min. The dark blue solution
that resulted was then added to a solution of nitrile 8b (657
mg, 3.1 mmol) in DMF (6 mL) at rt and stirred for 80 h. The
solvent was removed by directing a stream of dry air into the
flask and the residue purified by flash chromatography
(EtOAc, followed by CH2Cl2/MeOH, 30:1) to give 11 (626 mg,
82%) as an off-white solid: mp 158-158 °C; IR (NaCl) νmax
1472, 1419 cm-1; 1H NMR (CD3OD, 400 MHz) δ 7.56 (dd, J )
7.8, 1.7 Hz, 2H), 7.52-7.46 (m, 3H), 7.27 (d, J ) 1.5 Hz, 1H),
7.06 (d, J ) 1.5 Hz, 1H), 4.10 (br t, J ) 7.3 Hz, 2H), 2.49 (t,
J ) 7.3 Hz, 2H), 2.19 (tt, J ) 7.3, 7.3 Hz, 2H); 13C NMR (CD3-
OD, 75 MHz) δ 204.0, 143.1, 125.5, 124.4, 124.3 (2C), 124.0
(2C), 122.5, 116.3, 40.8, 35.7, 25.5; EIMS (70 eV) m/z 246
([M + 1]+, 15), 245 ([M]+, 52), 102 (100); EIHRMS (70 eV) m/z
245.1006 ([M]+, 8), calcd for C13H15N3S 245.0987.
Eth yl 3-(3-(2-P h en ylim id a zol-1-yl)p r op yl)-1,2,4-tr ia -
zin e-5-ca r boxyla te (7s). Thioamide 11 (144 mg, 0.58 mmol)
and 2-chloro-1-methylpyridinium iodide39 (12, 163 mg, 0.64
mmol) were stirred in CH2Cl2 (5 mL) at rt for 10 min. A
solution of R-ketohydrazone 1416c (169 mg, 1.17 mmol) in CH2-
Cl2 (6 mL) was added, and the reaction mixture was stirred
at rt for 15 h, refluxed for 0.5 h, and then diluted with
additional CH2Cl2 (15 mL). The yellow precipitate (15, identi-
fied by HNMR40) was removed by filtration, and the solvent
removed from the filtrate in vacuo. Purification by flash
chromatography (2% MeOH in CH2Cl2) gave 7s (55%) and
nitrile 8b (28%) as an inseparable mixture (142 mg) which
was used directly in the cycloaddition. A small amount of 7s
was purified to ∼90% purity as a yellow oil by the above
conditions for characterization purposes: IR (NaCl) νmax 1749,
1728 cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.63 (s, 1H), 7.51 (dd,
J ) 7.8, 1.5 Hz, 2H), 7.40-7.36 (m, 3H), 7.10 (d, J ) 1.0 Hz,
1H), 7.05 (d, J ) 1.0 Hz, 1H), 4.52 (q, J ) 7.3 Hz, 2H), 4.19 (t,
J ) 7.1 Hz, 2H), 3.18 (t, J ) 7.3 Hz, 2H), 2.39 (tt, J ) 7.3, 7.1
Hz, 2H), 1.45 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 169.3, 162.9, 147.8, 146.3, 146.1, 130.8, 128.96 (2C), 128.88,
128.7, 128.5 (2C), 120.3, 63.4, 45.8, 33.8, 28.9, 14.1; EIMS (70
eV) m/z 337 ([M]+, 81), 171 (100); EIHRMS (70 eV) m/z
337.1522 ([M]+, 12), calcd for C18H19N5O2 337.1539.
2,3-Dip h en yl-1,5-n a p h th yr id in e (19a ): F r om 1a . A solu-
tion of 1a (33 mg, 0.115 mmol) was refluxed in TIPB (3 mL,
48 h) under air. Removal of the solvent in vacuo, and then
purification by flash chromatography (CH2Cl2/EtOAc, 6:1) gave
19a as a yellow oil (29.5 mg, 91%). Alternatively, 1a (51 mg,
0.178 mmol) and Se (1.7 g) were heated together to 320-340
°C in a sand bath for 10 h. The cooled solid was ground
carefully and then thoroughly triturated with CH2Cl2. The
combined organic layers were dried (MgSO4), the solvent
removed in vacuo, and the residue purified by flash chroma-
tography (CH2Cl2/EtOAc, 6:1) to give 19a (42.5 mg, 85%).
P r ep a r a tion of 19a fr om 7b. A mixture of 7b (65 mg, 0.156
mmol) and Se (1.5 g) was heated to 320-340 °C in a sand bath
for 10 h. Workup and purification as described in the text gave
19a (25 mg, 56%): 1H NMR (CDCl3, 400 MHz) δ 8.98 (dd, J )
4.0, 1.5 Hz, 1H), 8.47 (br d, J ) 8.2 Hz, 1H), 8.41 (s, 1H), 7.64
(dd, J ) 8.2, 4.0 Hz), 7.43 (dd, J ) 7.5, 2.0 Hz, 2H), 7.25-7.31
(m, 8H); 13C NMR (CDCl3, 67.5 MHz) δ 159.2, 151.2, 143.0,
142.6, 139.8, 139.1, 138.4, 138.0, 137.1, 129.9 (2C), 129.6 (2C),
7.43-7.37 (m, 3H), 7.11 (s, 1H), 7.05 (s, 1H), 5.33 (br s, NH),
5.20 (br s, NH), 4.17-4.06 (m, 2H), 3.48 (dd, J ) 10.2, 4.2 Hz,
1H), 3.41 (dd, J ) 10.6, 4.2 Hz, 1H), 2.40 (m, 1H), 2.15 (dd,
J ) 14.8, 7.2, 1H), 1.98 (dd, J ) 14.8, 6.2 Hz, 1H), 0.81 (s,
9H), -0.04 (s, 3H), -0.05 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ 173.3, 148.2, 130.9, 129.1 (2C), 129.0, 128.82 (2C), 128.78,
121.4, 62.0, 47.3, 39.1, 34.4, 26.0 (3C), 18.3, -5.36, -5.44;
EIMS (70 eV) m/z 374 ([M + 1]+, 15), 373 ([M]+, 6.9), 316 (100);
EIHRMS (70 eV) m/z 373.2159 ([M]+, 1) calcd for C20H31N3O2-
Si 373.2186. This amide was dehydrated to the nitrile 8d by
two different routes.
Rou te A to 8d .37 Trifluoroacetic anhydride (TFAA, 5 µL,
0.03 mmol) was added to a stirred solution of the amide (10
mg, 0.026 mmol) and pyridine (5 µL, 0.053 mmol) in anhydrous
THF (500 µL) at 0 °C. The reaction mixture was allowed to
warm to rt over 10 min and then stirred at rt for 7 h. The
reaction was quenched with water (5 mL) and then extracted
with CH2Cl2. The combined organic extracts were washed with
brine and then dried over Na2SO4. The solvent was removed
in vacuo and the residue purified by flash chromatography
(hexanes/EtOAc, 2:1, then EtOAc) to give 8d as a yellow oil
(8.4 mg, 88%): IR (NaCl) νmax 2250 cm-1 1H NMR (CDCl3,
;
400 MHz) δ 7.54 (dd, J ) 7.6, 1.4 Hz, 2H), 7.46-7.40 (m, 3H),
7.14 (s, 1H), 6.99 (s, 1H), 4.19 (dd, J ) 14.2, 7.2 Hz, 1H), 4.10
(dd, J ) 14.2, 7.2 Hz, 1H), 3.54 (dd, J ) 10.6, 3.8 Hz, 1H),
3.43 (dd, J ) 10.6, 4.2 Hz, 1H), 2.24 (dd, J ) 16.8, 8.0 Hz,
1H), 2.23-2.10 (m, 2H), 0.82 (s, 9H), -0.003 (s, 3H), -0.014
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 148.2, 130.7, 129.33,
129.26, 129.1 (2C), 128.9 (2C), 121.3, 117.7, 61.2, 46.9, 39.5,
26.0 (3C), 18.3, 17.2, -5.40, -5.48; EIMS (70 eV) m/z (%) 356
([M+1]+, 88), 298 (100); EIHRMS (70 eV) m/z 356.2180
([M + 1]+, 3), calcd for C20H30N3OSi 356.2158.
R ou t e B t o 8d .38 A solution of freshly distilled (COCl)2
(17 µL, 0.19 mmol) in anhydrous CH2Cl2 (0.5 mL) was added
to solution of amide (57 mg, 0.16 mmol) and freshly distilled
DMSO (18 µL, 0.26 mmol) in CH2Cl2 (1.0 mL) at -78 °C and
the mixture stirred for 15 min. Triethylamine (67 µL, 4.83
mmol) was added dropwise and then stirred for another 20
min at -78 °C. The reaction was quenched at -78 °C with
water (5 mL) and then allowed to warm to rt. The reaction
mixture was extracted with CH2Cl2, and the combined organic
extracts were washed with brine and then dried over Na2SO4.
The solvent was removed in vacuo and the residue purified
by flash chromatography as above give 8d as a yellow oil
(45 mg, 84%).
E t h yl 5-Met h yl-3-(3-(2-p h en ylim id a zol-1-yl)p r op yl)-
1,2,4-tr ia zin e-6-ca r boxyla te (7q) a n d Eth yl 6-Meth yl-3-
(3-(2-ph en ylim ida zol-1-yl)pr op yl)-1,2,4-tr ia zin e-5-ca r box-
yla te (7r ). A solution of ethyl dioxobutanoate20 (10) was
freshly prepared from ethyl 2-(((p-nitrophenyl)sulfonyl)oxy)-
acetoacetate (500 mg, 1.51 mmol) in anhydrous EtOH (15 mL)
with Et3N (0.5 mL, 3.6 mmol). Triazines 7q and 7r were then
prepared from nitrile 8b (240 mg, 1.1 mmol), NH2NH2 (0.175
mL, 5.5 mmol), n-BuLi (3.5 mL, 5.5 mmol), and this solution
of freshly prepared 10 according to general procedure F with
reverse addition. (The solution of 10 was cannulated into the
solution of the amidrazone.) Flash chromatography (eluting
initially with hexanes/EtOAc, 3:1, then EtOAc) gave 7q and
7r as an inseparable mixture (3:1) as a yellow oil (310 mg,
80% combined yield): IR (NaCl) νmax 1726 cm-1 1H NMR
;
(37) Campagna, F.; Carotti, A.; Casini, G. Tetrahedron Lett. 1977,
(39) Saigo, K.; Usui, M.; Kikuchi, K.; Shimada, E.; Mukaiyama, T.
Bull. Chem. Soc. J pn. 1977, 50, 1863-1866.
(40) (a) Beak, P.; Lee, J . T., J r. J . Org. Chem. 1969, 34, 2125-2128.
(b) Wang, C. H. Chem. Pharm. Bull. 1973, 21, 2760-2763.
21, 1813-1816.
(38) Nakajima, N.; Ubukata, M. Tetrahedron Lett. 1997, 38, 2099-
2102.
J . Org. Chem, Vol. 69, No. 21, 2004 7181

Lahue et al.
128.3 (3C), 128.1 (2C), 127.5, 124.4; CIMS (NH3, 140 eV) m/z
283 ([M + 1]+, 100), 282 ([M]+, 18); EIHRMS (70 eV) m/z
282.1136 ([M]+, 72), calcd for C20H14N2 282.1156; 19a was also
isolated as a minor product from the cycloadditions of 7a (10%),
7b (38%), and 7c (27%) in the absence of BHT (see Table 3).
Eth yl 1,2,3,4-Tetr a h yd r o-1,5-n a p h th yr id in e-6-ca r box-
yla te (1s). Triazine 7s (21 mg 7s, 0.062 mmol, in a 2:1 mixture
with 8b as described above) was refluxed in bromobenzene (2
mL) for 22 h, the reaction cooled to rt, and the solvent removed
by directing a stream of air into the flask. The residue was
dissolved in CH2Cl2, dried over MgSO4, and filtered, and then
the solvent was removed from the filtrate in vacuo. The residue
was redissolved in THF (3 mL) and cooled to 0 °C, KOBut (10
mg, 0.093 mmol) was added, and the solution was stirred for
30 min at 0 °C. The reaction was quenched with HCl (1 N, 0.1
mL), and then saturated aqueous NaHCO3 was added (10 mL)
and the mixture was extracted with CH2Cl2. The combined
organic layers were dried (MgSO4) and filtered, and then the
solvent was removed in vacuo. Purification by flash chroma-
tography (8% acetone in CH2Cl2) gave 1s as a colorless oil (11
prepared from ethyl 2-(((p-nitrophenyl)sulfonyl)oxy)aceto-
acetate (260 mg, 0.79 mmol) in anhydrous EtOH (7 mL) with
Et3N (2.26 mL, 1.9 mmol).20 Triazines 24g and 24h were then
prepared from nitrile 23a (225 mg, 0.75 mmol), NH2NH2 (120
µL, 3.7 mmol), and n-BuLi (2.4 mL, 3.7 mmol), and this
solution of freshly prepared 10 according to general procedure
F with reverse addition. (The solution of 10 was cannulated
into the solution of the amidrazone.) Purification by flash
chromatography (eluting initially with hexanes/EtOAc, 2:1,
then EtOAc) gave 24g and 24h as an inseparable yellow oil
mixture (240 mg, 6:1 24g/24h , 88%): IR (NaCl) νmax 1728 cm-1
;
1H NMR of 24g (CDCl3, 400 MHz) δ 7.53 (dd, J ) 8.1, 1.5 Hz,
2H), 7.45-7.35 (m, 3H), 7.10 (s, 1H), 6.99 (s, 1H), 4.51 (q, J )
7.1 Hz, 2H), 4.06-4.02 (m, 2H), 3.08-3.04 (m, 2H), 2.73 (s),
1.84-1.80 (m, 4H), 1.44 (t, J ) 7.1 Hz, 3H); EIMS (70 eV) m/z
365 ([M]+, 13), 28 (100); EIHRMS (70 eV) m/z 365.1852 ([M]+,
28), calcd for C20H23N5O2 365.1852.
Ack n ow led gm en t. We are grateful to the National
Science Foundation (Grant No. 9501069) and the Na-
tional Institutes of Health (P50 GM067041) for financial
support.We also thank Mr. Michael Creech of Boston
University for obtaining HRMS spectra and CEM Corp.
for the Discovery-Explorer microwave reactor.
mg, 86%): IR (NaCl) νmax 1701 cm-1 1H NMR (CDCl3, 400
;
MHz) δ 7.76 (d, J ) 8.3 Hz, 1H), 6.69 (d, J ) 8.3 Hz, 1H), 4.39
(q, J ) 7.1 Hz, 2H), 4.36 (br s, NH), 3.36 (t, J ) 5.6 Hz, 2H),
3.00 (t, J ) 6.3 Hz, 2H), 2.00 (tt, J ) 6.3, 5.6 Hz, 2H), 1.38 (t,
J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.8, 143.8,
142.4, 135.3, 125.1, 118.4, 61.1, 41.3, 30.6, 20.9, 14.3; EIMS
(70 eV) m/z 207 ([M + 1]+, 7), 206 ([M]+, 52), 134 (100);
EIHRMS (70 eV) m/z 206.1049 ([M]+, 56), calcd for C11H14N2O2
206.1055.
E t h yl 5-Met h yl-4-(2-p h en ylim id a zol-1-yl)b u t yl-1,2,4-
tr ia zin e-6-ca r boxyla te (24g) a n d Eth yl 6-Meth yl-4-(2-
p h en ylim id a zol-1-yl)b u t yl-1,2,4-t r ia zin e-5-ca r b oxyla t e
(24h ). A solution of ethyl dioxobutanoate (10) was freshly
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods, experimental procedures, and characterization
data for all compounds prepared following general procedures
A-H and 1H and 13C NMR spectra for all previously unre-
ported compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O040193Z
7182 J . Org. Chem., Vol. 69, No. 21, 2004