Dienophilicity of imidazole in inverse electron demand Diels-Alder reactions. 4. Intermolecular reactions with 1,2,4-triazines

Article abstract of DOI:10.1021/jo030049y

Intermolecular inverse electron demand cycloadditions of 2-substituted imidazoles with various 1,2,4-triazines produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-d]pyrimid-4-ones (8-deazapteridines). The product distribution was control

Full text of DOI:10.1021/jo030049y

Dien op h ilicity of Im id a zole in In ver se Electr on Dem a n d
Diels-Ald er Rea ction s. 4. In ter m olecu la r Rea ction s w ith
1,2,4-Tr ia zin es
Brian R. Lahue, Zhao-Kui Wan, and J ohn K. Snyder*
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215
jsnyder@chem.bu.edu
Received February 7, 2003
Intermolecular inverse electron demand cycloadditions of 2-substituted imidazoles with various
1,2,4-triazines produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-d]pyrimid-
4-ones (8-deazapteridines). The product distribution was controlled by reactant substituents and
influenced by reaction temperature. A regioselective method for the preparation of 6-unsubstituted
1,2,4-triazines was also developed. By using this route to 8-deazapteridines, a new 8-deazafolate
analogue was prepared.
SCHEME 1
In tr od u ction
The ability of electron-rich heterocycles with latent
enamine functionalities to participate in inverse electron
demand Diels-Alder reactions with electron-deficient
dienes has been the focus of research for some time.1 A
prominent example is the chemistry of indole in reactions
with electron-deficient heteroaromatic azadienes, which
has been probed by several groups.2 Recently we have
become interested in utilizing imidazole as a dienophile
in such reactions with 1,2,4-triazines as a means to pre-
pare imidazo[4,5-c]pyridines (3-deazapurines, 3, Scheme
1).3 3-Deazapurines have been of long-standing interest
in drug development as purine analogues, and have been
shown to be adenosine-deaminase inhibitors,4 angiotensin
II receptor antagonists,5 antiosteoporotic agents,6 anti-
HIV 1 and antitumor agents.7 The reactivity of imidazole
in cycloaddition chemistry, however, has not been re-
ported to a great extent in the literature. Seitz first
reported successful inverse electron demand Diels-Alder
reactions of imidazoles with 1,2,4,5-tetrazines in modest
yields,8 while Horne demonstrated the condensation of
2-aminoimidazole with aldehydes by a concerted cycload-
dition route to give tetrahydropurine analogues.9 Since
then, Dang has described the concise syntheses of purine
analogues through the [4 + 2] cycloaddition of in situ
(5) (a) Mederski, W. W. K. R.; Dorsch, D.; Osswald, M.; Beier, N.;
Lues, I.; Minch, K.-O.; Schelling, P.; Ladstetter, B. J . Bioorg. Med.
Chem. 1995, 5, 2665-2670. (b) Kiyama, R.; Fuji, M.; Hara, M.;
Fujimoto, M.; Kawabata, T.; Nakamura, M.; Fuishita, T. Chem. Pharm.
Bull. J pn. 1995, 43, 450-460. (c) Bouley, R.; Gosselin, A.; Plante, H.;
Servant, G.; Peridin, J .; Arcand, M.; Guillemette, G.; Escher, E. Can.
J . Physiol. Pharm. 1997, 75, 568-575. (d) Mederski, W. W. K. R.;
Dorsch, D.; Osswald, M.; Schwartz, H.; Beier, N.; Christadler, M.;
Minch, K.-O.; Schelling, P.; Schmitges, C. J . Eur. J . Med. Chem. 1997,
32, 479-491. (e) Burrell, J . H.; Lumbers, E. R. Eur. J . Pharmacol.
1997, 330, 257-267. (f) Hashimoto, Y.; Ohashi, R.; Kurosawa, Y.;
Minami, K.; Kaji, H.; Hayashida, K.; Narita, H.; Murata, S. J .
Cardiovasc. Pharmcol. 1998, 31, 568-579.
(1) For reviews of inverse electron demand Diels-Alder reactions,
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. N. In
Hetero Diels-Alder Methodology in Organic Synthesis; Wasserman,
H. H., Ed.; Academic: New York, 1987; Vol. 47, 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.; Academic: New York, 1987; Vol. 42, pp 245-
333. (f) Boger, D. L. Chemtracts: Org. Chem. 1996, 9, 149-189. (g)
Boger, D. L. Bull. Chim. Soc. Belg. 1990, 99, 599-615. (h) Boger, D.
L. J . Heterocycl. Chem. 1996, 33, 1519-1531. (i) Boger, D. L. J .
Heterocycl. Chem. 1998, 35, 1001-1011.
(6) J iang, B. Org. Process Res. Dev. 1998, 2, 425-427.
(7) (a) Khanna, I. K.; Weier, R. M. Tetrahedron Lett. 1993, 34, 1885-
1888. (b) Gautam, R. K.; Fujii, S.; Nishida, M.; Kimoto, H.; Cohen, L.
A. J . Heterocycl. Chem. 1994, 31, 453-455.
(2) For
a review, see: Lee, L.; Snyder, J . K. In Advances in
Cycloadditions; Harmata, M., Ed.; J AI Press: Stamford, CT, 2001; Vol.
6, pp 119-171.
(3) (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. Ph.D. Disserta-
tion, Boston University, 1999.
(8) (a) Seitz, G.; Kaempchen, T. Arch. Pharm. (Weinheim) 1978, 311,
728-735. (b) Seitz, G.; Hoferichter, R.; Mohr, R. Arch. Pharm.
(Weinheim) 1989, 322, 415-417.
(9) (a) Xu, Y.-Z.; Yakushijin, K.; Horne, D. A. Tetrahedron Lett. 1993,
34, 6981-6984. (b) Braun, M.; Bu¨chi, G. J . Am. Chem. Soc. 1976, 98,
3049-3050. (c) Braun, M.; Bu¨chi, G.; Bushey, D. F. J . Am. Chem. Soc.
1978, 100, 4208-4213. (d) Xu, Y.-Z.; Yakushijin, K.; Horne, D. A. J .
Org. Chem. 1996, 61, 9569-9571.
(4) Harriman, G. C. B.; Abushanab, E.; Stoechler, J . D. J . Med.
Chem. 1994, 37, 305-308.
10.1021/jo030049y CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/30/2003
J . Org. Chem. 2003, 68, 4345-4354
4345

Lahue et al.
SCHEME 2
generated 4-aminoimidazoles with 1,3,5-triazines.10 More
recently, we have also used the inverse electron demand
Diels-Alder reaction of imidazoles with 1,2,4,5-tetrazines
to prepare the structure reported for the cytotoxic marine
natural product zarzissine.11
In preliminary work with triazines, we examined the
cycloadditions of imidazole and 2-substituted imidazoles
with several 1,2,4-triazines 2 and found that only 2-ami-
noimidazole was sufficiently reactive to participate in the
intermolecular cycloadditions (Scheme 1, R1 ) NP).3a Two
distinct reaction pathways for protected 2-aminoimida-
zoles were uncovered leading to 3-deazapurines and
pyrido[3,2-d]pyrimid-4-ones (8-deazapteridines).3a This
latter product was especially prominent with triethyl
1,2,4-triazine-3,5,6-tricarboxylate12 (2a , Scheme 2), giving
a remarkable 77% yield of the deazapteridine. We now
report full details of our earlier work and also expand
the scope of this chemistry with other 1,2,4-triazines.
quently, cycloadditions of 2-aminoimidazole, protected as
the aminoimine 1a ,13 were examined in THF (rt) with
triazine 2a , resulting in a mixture of the anticipated [4
+ 2]-cycloadduct, imidazo[4,5-c]pyridine 3a (32%), and
rearranged pyridopyrimidones 4a (55%) and 5a (<1%)
in excellent combined yield (Table 1, item 1). The latter
two products arose from rearrangements of intermediate
A formed from the initial cycloadduct following release
of N2 (Scheme 2).
Mechanistically, this rearrangement is similar to that
observed previously with indole in cycloadditions with
1,2,4,5-tetrazines,14 first noted by Acheson,15 as well as
with 1,2,4-triazines,16 and with 1,2-diazines16 albeit in
very low yields. From intermediate A, aromatization
leads to 3-deazapurine 3a while deprotonation of H3a or
H7a (pathway “a” or “b”, respectively) followed by opening
of the imidazole ring to intermediates B or C and
subsequent closure to the respective proximal ester
produces rearranged products 4a and 5a . The agent
responsible for the dehydrogenation of A, leading to
3-deazapurine 3a , is possibly the triazine 2a . However,
dihydro triazine byproducts, which would indicate the
Resu lts a n d Discu ssion
Beginning with triazine tricarboxylate 2a , one of the
most reactive 1,2,4-triazines in inverse electron demand
Diels-Alder reactions, cycloadditions were attempted
with imidazole, 2-phenylimidazole, and 2-aminoimida-
zole, but no cycloadducts were observed. While imidazole
and 2-phenylimidazole proved too unreactive and re-
turned only starting materials or decomposed under more
forcing conditions, 2-aminoimidazole gave an intractable
mixture, at or even below room temperature. Conse-
(13) (a) Greene, T. W.; Wuts, P. G. M. In Protecting Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991; pp 370-371. (b)
Zemlicka, J .; Chladek, S.; Holy, A.; Smrt, J . Collect. Czech. Chem.
Commun. 1966, 31, 3198-3212. (c) Zemlicka, J .; Holy, A. Collect.
Czech. Chem. Commun. 1967, 32, 3159-3168. (d) Taylor, E. C.;
LaMattina, J . L. J . Org. Chem. 1977, 42, 1523-1527. (e) Fitt, J . J .;
Gschwend, H. W. J . Org. Chem. 1977, 42, 2639-2641. (f) Taylor, E.
C.; Dumas, D. J . J . Org. Chem. 1980, 45, 2485-2489.
(14) (a) Seitz, G.; Kaempchen, T. Arch. Pharm. (Weinheim) 1976,
309, 679-681. (b) Li, J .-H.; Snyder, J . K. J . Org. Chem. 1993, 58, 516-
519.
(10) Dang, Q.; Liu, Y.; Erion, M. D. J . Am. Chem. Soc. 1999, 121,
5833-5834.
(15) Acheson, R. M.; Bridson, J . N.; Cecil, T. R.; Hands, A. R. J .
Chem. Soc., Perkins Trans. 1 1972, 1569-1576.
(16) (a) Benson, S. C.; Gross, J . L.; Snyder, J . K. J . Org. Chem. 1990,
55, 3257-3269. (b) Benson, S. C.; Lee, L.; Snyder, J . K. Tetrahedron
Lett. 1996, 37, 5061-5064.
(11) Wan, Z.-K.; Woo, G. H. C.; Snyder, J . K. Tetrahedron 2001, 57,
5497-5507.
(12) Boger, D. L.; Panek, J . S.; Yasuda, M. Org. Synth. 1987, 66,
142-150.
4346 J . Org. Chem., Vol. 68, No. 11, 2003

Intermolecular Reactions of Imidazoles with 1,2,4-Triazines
TABLE 1. Cycloa d d ition s of Im id a zoles (1) w ith 1,2,4-Tr ia zin es 2a a n d 2b (Sch em es 1 a n d 2)
yield (%)a
product
item
imidazole
R1
triazine
conditionsb
code
3
4
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1b
1cc
1cc
(Me)2NCHdN-
(Me)2NCHdN-
(Me)2NCHdN-
(Me)2NCHdN-
(Me)2NCHdN-
(Me)2NCHdN-
(Me)2NCHdN-
(Me)2NC(Me)dN-
(Me)2NC(Me)dN-
(Me)2N-
2a
2a
2a
2a
2a
2b
2b
2a
2a
2a
2a
THF, rt, 60 h
a
a
a
a
a
b
b
c
c
d
d
32
43
25
17
13
16
11
11
5
55
47
60
72
77
70
74
58
83
dioxane, rt, 60 h
CH2Cl2, rt, 60 h
THF, vV, 10 h
dioxane, vV, 5 h
65 °C, dioxane, 16 h
dioxane, vV, 5 h
dioxane, rt, 12 h
dioxane, vV, 3 h
dioxane, rt, 24 h
dioxane, vV, 2 h
10
11
Td
11
Td
60
(Me)2N-
a
b
d
Isolated yields. All reactions were run at 0.1-0.3 M. c Air sensitive, must be run under inert atmosphere. Trace amount detected
by 1H NMR of the crude reaction mixture.
triazine is functioning as the aromatization agent, were
not isolated. Such byproducts were detected in the
corresponding reactions of indole with 2a .16a Further-
more, running the reaction under ambient atmosphere
rather than argon also had no impact on the outcome of
the reaction. Thus, it is unlikely that adventitious oxygen
is responsible for the dehydrogenation of intermediate
A to 3a .
produce 4 since this was speculated to result from a
deprotonation/ring opening sequence (Scheme 2). How-
ever, the addition of 2,6-lutidine or triethylamine (1
equiv) to the reaction of 2a with 1a failed to alter the
distribution of products in refluxing dioxane. Reacting
2a with 1a in refluxing triethylamine produced only trace
amounts of reaction products 3a and 4a along with
decomposed starting materials.
To distinguish the regioisomeric rearrangement prod-
ucts 4a and 5a , as well as to offer evidence of this mecha-
nistic pathway, 5,6-dimethyl-3-ethyl 1,2,4-triazine-3,5,6-
tricarboxylate (2b)17 was subjected to the same reaction
with imidazole 1a (Scheme 2, Table 1, item 7). The domi-
nant rearrangement product (74%) contained no ethyl
Given the success of the cycloadditions with 1a , other
electron-rich imidazoles were prepared and subjected to
cycloadditions (Table 1, items 8-11). 2-(N′,N′-Dimethy-
lacetamidino)imidazole (1b) not only reacted faster with
triazine 2a in comparison to the reaction of 1a with 2a
(3 h vs 5 h), but also produced a slightly increased yield
of the rearranged product, 4c (83% vs 77%, items 9 and
5). 2-(Dimethylamino)imidazole (1c),18 which was ex-
pected to be the most reactive of the imidazoles investi-
gated due to the significant electron donation of the
dimethylamino group, reacted completely with triazine
2a within 2 h in refluxing dioxane producing 4d (60%,
item 11) along with aromatized 3d (11%). At room
temperature in dioxane, however, this reaction produced
only trace amounts of cycloaddition products. The air and
thermal sensitivity of imidazole 1c was presumed to be
the cause of these reduced yields of cycloadducts (items
10 and 11). As with imidazole 1a , increasing the tem-
perature of the reaction of 1b with triazine 2a also
increased the amount of 8-deazapteridine 4c at the
expense of 3-deazapurine 3c (items 8 and 9). The less
electron-rich 2-(methylthio)imidazole (1d )19 required ex-
tended reaction times as well as higher temperatures
(156 °C, refluxing bromobenzene, 69 h) to react com-
pletely with triazine 2a (Scheme 3). With 1d and this
increased reaction temperature, a significant amount
(13%) of the minor rearranged pyrido[4,3-d]pyrimidone
5e was also formed, though 4e remained the dominant
product in good yield (72%), while aromatized 3-deazapu-
rine 3e formed in only small amounts (7%). Thus in all
cases examined, the rearranged pyrido[3,2-d]pyrimidin-
4-ones 4 (8-deazapteridines) were the main products, all
produced efficiently in a single step in synthetically
useful yields.
1
resonances in the H NMR spectrum and was therefore
assigned the structure 4b; also produced were the aro-
matized product 3b (11%) and a trace amount of 5b.
The ratio of 3a :4a was strikingly dependent on the
reaction temperature, but only slightly dependent upon
the solvent (Table 1, items 1-5). As the reaction tem-
perature was raised, increasing amounts of pyrido[3,2-
d]pyrimidones 4a were produced at the expense of 3a
(compare Items 1 and 2 with 4 and 5, respectively). Thus,
when triazine 2a was heated with imidazole 1a in
refluxing dioxane (item 5), the yield of rearranged 8-dea-
zapteridine 4a reached a remarkable 77%, formed in a
6:1 ratio with 3-deazapurine 3a (13%), while at room
temperature in dioxane, 4a and 3a were produced in
yields of 47% and 43%, respectively (item 2). A similar
increase in 4a was found in refluxing THF (72%, item 4)
in comparison to the room temperature reaction, also in
THF (55%, item 1). Only a minor solvent effect was
observed, with increasing polarity (CH2Cl2-THF-diox-
ane) seemingly favoring 3a very slightly (25%, 32%, and
43%, items 1-3). The concentration at which the reaction
was run failed to have a significant effect on the product
distribution.
Analogous rearrangements following inverse electron
demand Diels-Alder cycloadditions have been noted in
the reactions of indole with both 1,2,4,5-tetrazines14-16
and 1,2,4-triazines,16 but only as minor products. Pyrrole
has also been reported to participate in inverse electron
demand cycloadditions with dimethyl 1,2,4,5-tetrazine-
3,6-dicarboxylate through a similar pathway.8a Mecha-
nistically, it seemed possible that the addition of a base
would favor the rearrangement of cycloadduct A to
Since triazine 2a reacted readily with imidazoles 1a -d
and indole,16a a competition experiment was performed
(18) Dalkafouki, A.; Ardisson, J .; Kunesch, N.; Lacombe, L.; Poisson,
J . E. Tetrahedron Lett. 1991, 32, 5325-5328.
(19) Marchwald, W. Chem. Ber. 1892, 25, 2354-2373.
(17) Martin, J . C. J . Org. Chem. 1982, 47, 3761-3763.
J . Org. Chem, Vol. 68, No. 11, 2003 4347

Lahue et al.
TABLE 2. Con d en sa tion of r-Ketoh yd r a zon es 8 w ith
Th ioa m id es To P r od u ce 1,2,4-Tr ia zin es 2
SCHEME 3
item
8
R3
R4
product
yield (%)a
1
2
3
a
b
c
CO2Et
Ph
Me
H
H
CO2Et
2c
2d
40
72
0
a
Isolated yields.
triazine-6-carboxylates,22 and ethyl 1,2,4-triazine-5-
carboxylates23 through linear methodologies. However,
no procedure has been reported for the completely
regioselective synthesis of 5,6-unsymmetrically substi-
tuted 1,2,4-triazine-3-carboxylates. Such triazines were
desirable in this work since their cycloadditions with 1a
or 1b, with subsequent rearrangement to the correspond-
ing 8-deazapteridines, would provide ready access to
8-deazafolate libraries (vide supra). To prepare such new
1,2,4-triazines while avoiding the regioselectivity prob-
lems often encountered with amidrazone condensations,
a procedure was developed from the basic protocol
reported by Mukaiyama for the synthesis of esters.24 In
this procedure, a thioamide was condensed with an
R-ketohydrazone through the intervention of the
Mukaiyama coupling reagent 2-chloro-1-methylpyridin-
ium iodide (10, Scheme 4, eq 2).24c Precedence for the use
of 10 with thioamides had been demonstrated by Lipton
in the guanylation of amines using thioureas.25 Adapting
this methodology, the previously unknown diethyl 1,2,4-
triazine-3,5-dicarboxylate (2c) was prepared in 40% yield
in one step by the coupling and concomitant cyclization
(and aromatization) of hydrazone 8a 23 and ethylthioa-
midooxalate (9a )12 in the presence of 10 (Table 2, item
1). In the absence of the pyridinium salt, no product was
formed. The outcome of this reaction was effected sig-
nificantly by the stability and reactivity of the hydrazone.
The sensitivity of hydrazone 8a to base and heat limited
the yield of triazine product 2c. The more stable hydra-
zone 8b26 produced known triazine 2d 16a in 72% yield
(item 2), while the less nucleophilic hydrazone 8c23 failed
to give any conversion (item 3), even under harsher
conditions (101 °C, dioxane) or in the presence of base
(NaHCO3, K2CO3, and Et3N).
SCHEME 4
to determine the relative reactivity of indole and pro-
tected 2-aminoimidazole 1b. When triazine 2a (1 equiv)
was refluxed in dioxane containing indole (1 equiv) and
imidazole 1b (1 equiv), the only cycloadducts detected by
1H NMR were those of 1b (3c and 4c), indicating that
1b is significantly more reactive than indole in inverse
electron demand Diels-Alder reactions with heterocyclic
azadienes.
With the new triazine 2c in hand, along with known
1,2,4-triazines 2d ,16a 2e,27 2f,16a,28 and 2g,16a,29 cycload-
ditions with 2-aminoimidazoles were examined (Table 3).
Since indole also participated in cycloadditions with
other 1,2,4-triazines, a variety of 1,2,4-triazine-3-car-
boxylates were prepared and examined in cycloadditions
with 2-aminoimidazole derivatives to expand the scope
of this chemistry. The most common method for prepar-
ing these 1,2,4-triazines was the condensation of 1,2-
dicarbonyl compounds 6 with amidrazones 7 (Scheme 4,
eq 1),12 and this strategy was used to prepare known
triazines 2a , 2b, and 2d -g (structures given in Table 3
below). While fairly general, this procedure can result
in a mixture of regioisomers when unsymmetric 1,2-
dicarbonyl compounds are involved.20
(21) (a) 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. (b) 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.
(22) Ohsumi, T.; Neunhoeffer, H. Heterocycles 1992, 33, 893-903.
(23) Ohsumi, T.; Neunhoeffer, H. Tetrahedron 1992, 48, 5227-5234.
(24) (a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett.
1975, 1045-1048. (b) Mukaiyama, T.; Toda, H.; Kobayashi, S. Chem.
Lett. 1976, 13-14. (c) Saigo, K.; Usui, M.; Kikuchi, K.; Shimada, E.;
Mukaiyama, T. Bull. Chem. Soc. J pn. 1977, 50, 1863-1866.
(25) Yong, Y. F.; Kowlaski, J . A.; Lipton, M. A. J . Org. Chem. 1997,
62, 1540-1542.
(26) Hauptmann, S.; Wilde, H. J . Prakt. Chem. 1969, 311, 604-
613.
Neunhoeffer21 has reported the regioselective prepara-
tion of a variety of trialkyl-1,2,4-triazines, ethyl 1,2,4-
(27) (a) Schmidt, P.; Druey, J . Helv. Chim. Acta 1955, 38, 1560-
1564. (b) Elix, J . A.; Wilson, W. S.; Warrener, R. N.; Calder, I. C. Aust.
J . Chem. 1972, 25, 865-874.
(28) Krass, D.; Paulder, W. W. Synthesis 1974, 5, 351-352.
(29) Seitz, G.; Dietrich, S.; Goerge, L.; Richter, J . Tetrahedron Lett.
1986, 27, 2747-2750.
(20) (a) Ohsumi, T.; Neunhoeffer, H. Tetrahedron 1992, 48, 651-
662. (b) We also encountered similar regioselectivity problems with
the condensation of amidrazones with malonates.
4348 J . Org. Chem., Vol. 68, No. 11, 2003

Intermolecular Reactions of Imidazoles with 1,2,4-Triazines
TABLE 3. [4 + 2] Cycloa d d ition s of Va r iou s 1,2,4-Tr ia zin es w ith 2-Am in oim id a zolesa
a
b
See Scheme 1. Isolated yields. c Air sensitive, must be run under an inert atmosphere.
In reaction with 1a , triazine 2c, which lacks the C6 ester
group of 2a , yielded only aromatized cycloadduct 3f
(25%), and no rearrangement products (4 or 5) were
detected (Table 3, item 1). This contrasted sharply with
the reaction of 1a with the more electron deficient 2a
that gave primarily rearranged 4a under the same
conditions (Table 1). The reactions of 2c with imidazoles
1b and 1c produced 3-deazapurines 3g and 3h in good
yields of 64% and 84% (items 2 and 3, respectively).
Higher reaction temperatures failed to produce any
detectable rearrangement products 4 or 5 and led only
to lower yields of 3-deazapurines 3 and decomposition of
triazine 2c. The relatively poor thermal stability of 2c
to the reaction conditions presumably contributed to the
lower yields in these cycloadditions, though the reaction
of 2-dimethylaminoimidazole (1c) produced 3h in excel-
lent yield (84%, item 3), since the reaction temperature
for this more reactive imidazole could be much lower (0
°C to rt). Replacement of the two electron-withdrawing
ester groups in triazine 2a at C5 and C6 with one or two
phenyl groups (2d and 2e, respectively) significantly
reduced the reactivity of the triazine such that heating
the reactants in the absence of solvent to 120-125 °C
was required to achieve the chemistry (items 4 and 5),
producing mixtures of 3-deazapurines 3 and 8-deazap-
1
F IGURE 1. Intramolecular hydrogen bonding observed in H
NMR spectra.
teridines 4 in disappointing yields and poor selectivity.
The 5,6-unsubstituted triazine 2f, as well as triazine 2g
with an electron-donating C3 thiomethyl group, failed to
give any reaction products at all with 1a -c. In all
aromatized products with a C4 ester group (3a -j), broad-
ening of the ester resonances in the 1H NMR spectra
occurred, presumably due to intramolecular hydrogen
bonding with the 3-NH (Figure 1).
While it was determined that higher temperatures
favored the rearrangement of intermediate A to produce
the 8-deazapteridine skeleton 4, the results from Table
3 indicate the C6 ester group on triazine 2a was
important to the cycloaddition and to the subsequent
rearrangement (Scheme 2) since 2c, which lacks this
ester, failed to produce any rearrangement products. The
resonance stabilization of the developing negative charge
J . Org. Chem, Vol. 68, No. 11, 2003 4349

Lahue et al.
produced 14. The use of <3 equiv of LiOH failed to give
complete conversion of 4a , which proved difficult to
separate from compounds 17 and 18 in the forthcoming
peptide coupling. The 8-deazafolic acid side chain (16)34
was prepared, protected as the acid-labile tert-butyl
esters, by peptide coupling of di-tert-butyl (S)-glutamate35
with p-nitrobenzoic acid to give 15, followed by reduction
of the nitro group to the amine 16. Amidation (EDC,
HOBt) of carboxylic acid 14 with aniline 16 under
carefully adjusted pH (3.5-4.0) yielded 18; the regiose-
lectivity of the original ester hydrolysis was then con-
firmed by a NOESY experiment. Thus, an NOE was
observed between the methylene proton resonance of the
ethyl ester with H8 of the deazapteridine core. It should
be noted that under more basic (pH 5-6) or more acidic
conditions (below pH 3) the amidation failed to produce
the desired product 18. Under more basic conditions, the
major product was imide 17 while under more acidic
conditions the poor solubility of carboxylic acid 14 in CH2-
Cl2/H2O prevents the amidation from occurring. Sequen-
tial deprotection of the tert-butyl ester and aminoimine
groups in 18 was achieved with TFA/Et3SiH36 to give the
8-deazafolic acid analogue 19.
F IGURE 2. Resonance stabilization of intermediate A, and
alternative intermediate 13c.
formed by deprotonation of H3a in intermediate A onto
this ester (11, Figure 2) may therefore direct the chem-
istry to this rearrangement pathway to 8-deazapteridines
4. In the absence of the C7 ester (12), the missing
resonance stability may be the cause for the lack of
rearrangement products 4 or 5. With triazines 2a , 2b,
2d , and 2e, the dominance of rearrangement products 4
over 5 could be attributed to additional resonance sta-
bilization of this anion onto N5 (13a ) in the pathway
leading to 4, which cannot be attained via this mecha-
nistic route (13b) leading to 5. Alternatively, tautomer-
ization of intermediate A to the 1,4-dihydro form 13c
would also favor the production of 4 over 5, though in
itself this tautomer cannot account for the lack of
imidazole-ring opened product from 2c, nor the appear-
ance of 5e in the cycloaddition of 1d with 2a as shown
in Scheme 3.30 Nevertheless, the intermediacy of 13c in
the pathway to 4 cannot be ruled out.
Con clu sion s
The inverse electron demand Diels-Alder reactions of
imidazoles with 1,2,4-triazines produce imidazo[4,5-c]-
pyridines (3-deazapteridines) and pyrido[3,2-d]pyrimid-
4-ones (8-deazapteridines). Either can be the main prod-
uct depending on the triazine substituents. The 8-deazap-
teridines can be produced in excellent yields (>76%),
particularly at higher reaction temperatures. The cy-
cloadditions require a strong electron-donating C2 sub-
stituent on the imidazole as well as strong electron-
withdrawing substituents on the triazine. The formation
of the 8-deazapteridine skeleton 4 in high yield provides
a facile route to the syntheses of 8-deazafolate analogues
such as 19.
Exp er im en ta l Section
The unprecedented high yield (maximum 83% with 1b,
Table 1, item 9) of the rearrangement products 4 provides
a novel, concise, and convergent route to the protected
8-deazapteridine skeleton. With the appropriate choice
of nitrogen protecting group, this methodology reveals a
high-yielding route to this heterocyclic core found in a
variety of dihydrofolate reductase,31 thymidylate syn-
thase,32 and tyrosine kinase33 inhibitors.
By using this chemistry, a new analogue of 8-deazafolic
acid was prepared in a four-step sequence (Scheme 5).
Selective hydrolysis of the more reactive ester of 4a
adjacent to the pyridine ring nitrogen with LiOH (3
equiv) at 0 °C in THF/H2O followed by acidification
Gen er a l P r oced u r e A: Cycloa d d ition s of Im id a zoles
w ith 1,2,4-Tr ia zin es. Imidazole 1 and 1,2,4-triazine 2 were
mixed in anhydrous solvent (CH2Cl2, THF, dioxane, or bro-
mobenzene as indicated, Tables 1 and 3, Scheme 3) under
argon. The reaction mixture was then stirred at room tem-
perature or refluxed until the limiting reagent was gone as
monitored by TLC. The solvent was removed in vacuo and the
residue was purified by flash chromatography.
Gen er a l P r oced u r e B: Cycloa d d ition s of Im id a zoles
w ith 1,2,4-tr Ia zin es. Imidazole 1 and 1,2,4-triazine 2 were
mixed under argon and heated in an oil bath in the absence
of solvent (Table 3). The residue was purified by flash
chromatography.
2-(N′,N′-Dim eth ylfor m a m id in o)im id a zole (1a ). 2-Ami-
noimidazole sulfate (539 mg, 2.0 mmol) was stirred with
(30) We thank two reviewers for this suggestion.
(31) (a) Rosowsky, A.; Forsch, R. A.; Queener, S. F. J . Med. Chem
1995, 38, 2615-2620. (b) Kunz, B. A. Mutat. Res. 1996, 355, 129-
140. (c) Gangjee, A.; Zhu, Y.; Queener, S. F.; Francom, P.; Broom, A.
D. J . Med. Chem. 1996, 39, 1836-1845.
(32) Brixner, D. I.; Ueda, T.; Cheng, Y.-C.; Hynes, J . B.; Broom, A.
D. J . Med. Chem. 1987, 30, 675-678.
(33) Rewcastle, G. W.; Palmer, B. D.; Thompson, A. M.; Bridges, A.
J .; Cody, D. R.; Zhou, H.; Fry, D. W.; McMichael, A.; Denny, W. A. J .
Med. Chem. 1996, 39, 1823-1835.
(34) (a) Hynes, J . B.; Harmon, S. J .; Floyd, G. G.; Farrington, M.;
Hart, L. D.; Gale, G. R.; Washtien, W. L.; Susten, S. S.; Freisheim, J .
H. J . Med. Chem. 1985, 28, 209-215. (b) Mann, J .; Haase-Held, M.;
Springer, C. J .; Bagshawe, K. D. Tetrahedron 1990, 46, 5377-5382.
(35) Boger, D. L.; Haynes, N.-E.; Kitos, P. A.; Warren, M. S.;
Ramacharan, J .; Marolewski, A. E.; Benkovic, S. J . Bioorg. Med. Chem.
1997, 5, 1817-1830.
(36) Mehta, A.; J aouhari, R.; Benson, T. J .; Douglas, K. T. Tetra-
hedron Lett. 1992, 33, 5441-5444.
4350 J . Org. Chem., Vol. 68, No. 11, 2003

Intermolecular Reactions of Imidazoles with 1,2,4-Triazines
SCHEME 5a
a
Key: (a) LiOH (3 equiv), THF/H2O, 0 °C, 1 h; (b) EDC, HOBt, CH2Cl2/H2O, 0 to 10 °C, 16 h; (c) H2, Pd/C, MeOH, rt, 2 h; (d) EDC,
HOBt, NaHCO3, CH2Cl2/H2O, 0 to 15 °C, 18 h; (e) TFA, Et3SiH, rt, 16 h then CH2Cl2, H2O, reflux, 1 h.
Na2CO3 (424 mg, 4.0 mmol) in water (4 mL) for 15 min, then
the solvent was removed in vacuo and the residue triturated
with anhydrous ethanol (30 mL). After filtration and evapora-
tion of the ethanol, N,N-dimethylformamide dimethyl acetal
(3 mL, 20.5 mmol) was added and the reaction mixture stirred
at room temperature for 17 h. The solvent was evaporated and
the crude product purified by flash chromatography (CH2Cl2/
Et3N, 3:1) to give 1a as a white solid (Rf 0.20, 524 mg, 95%).
Mp 140-142 °C; IR (NaCl) vmax 1627 cm-1; 1H NMR (400 MHz,
CDCl3) δ 9.80 (br s, ex, NH), 8.48 (s, 1H), 6.71 (s, 2H), 3.04 (s,
3H), 2.98 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.7 (2C),
152.5, 118.9 (br), 40.4, 34.4; HRMS (EI, 70 eV) m/z 138.0916
([M]+) 100%) calcd for C6H10N4 138.0905.
2-(N′,N′-Dim eth yla ceta m id in o)im id a zole (1b). 2-Ami-
noimidazole sulfate (550 mg, 2.03 mmol) was stirred with Na2-
CO3 (430 mg, 4.06 mmol) in water (4 mL) for 15 min, then the
solvent was removed in vacuo and the residue triturated with
anhydrous ethanol (30 mL). After filtration and evaporation
of the ethanol, N,N-dimethylaminoacetamide dimethyl acetal
(3 mL, 20.5 mmol) was added and the reaction mixture stirred
at room temperature for 17 h. The solvent was evaporated and
the crude product was purified by flash chromatography (CH2-
Cl2/Et3N, 3:1) to give 1b as a white solid (Rf 0.20, 502 mg, 86%).
Mp 125-126 °C; IR (NaCl) vmax 1600 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.78 (s, 2H), 3.05 (s, 6H), 2.32 (s, 3H), (NH not
observed); 13C NMR (75 MHz, CDCl3) δ 162.5, 152.0, 119.0
(2C), 38.2 (2C), 16.4; HRMS (CI, NH3, 140 eV) m/z 153.1130
([M + H]+, 3%), calcd for C7H13N4 153.1140.
organic fraction was collected, dried (MgSO4), and concentrated
in vacuo, and the crude reaction product was purified by flash
chromatography (hexanes/EtOAc, 2:1) to give 2c as a yellow
1
oil (Rf 0.40, 85 mg, 40%). IR (NaCl) vmax 1740, 1215 cm-1; H
NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 4.60 (q, J ) 7.2 Hz,
2H), 4.55 (q, J ) 7.2 Hz, 2H), 1.48 (t, J ) 7.2 Hz, 3H), 1.46 (t,
J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 161.8,
157.5, 148.8, 147.2, 63.8, 63.6, 14.2, 14.1; HRMS (EI, 70 eV)
m/z 225.0741 ([M]+, 49%), calcd for C9H11N3O4 225.0749.
Tr ieth yl 2-(N′,N′-Dim eth ylfor m a m id in o)-3H-im id a zo-
[4,5-c]p yr id in e-4,6,7-t r ica r b oxyla t e (3a ) a n d Diet h yl
2-(N′,N′-Dim eth ylfor m am idin o)-3H-pyr ido[3,2-d]pyr im id-
4-on e-6,7-d ica r boxyla te (4a ). Prepared following general
procedure A, optimized for 3a with imidazole 1a (402 mg, 2.90
mmol) and triazine 2a (864 mg, 2.90 mmol) in dioxane (29 mL)
at room temperature for 60 h; purified by flash chromatogra-
phy (CH2Cl2/acetone, 3:1) to give 3a as a tan solid (Rf 0.25,
507 mg, 43%) and 4a as a light yellow solid (Rf 0.20, 493 mg,
47%). Also optimized for 4a with imidazole 1a (1.40 g, 10.1
mmol) and triazine 2a (3.01 g, 10.1 mmol) by refluxing in
dioxane (90 mL) for 5 h to give 3a (532 mg, 13%) and 4a (2.82
g, 77%). 3a : mp 145-148 °C; IR (NaCl) vmax 1732, 1631, 1521
1
cm-1; H NMR (400 MHz, CDCl3) δ 9.86 (br s, ex, NH), 8.83
(s, 1H), 4.50 (q, J ) 7.3 Hz, 2H), 4.49 (q, J ) 7.3 Hz, 2H), 4.41
(q, J ) 6.9 Hz, 2H), 3.19 (s, 3H), 3.12 (s, 3H), 1.45 (t, J ) 7.3
Hz, 3H), 1.39 (t, J ) 7.3 Hz, 3H), 1.38 (t, J ) 6.9 Hz, 3H); 13
C
NMR (67.5 MHz, CDCl3) δ 165.9, 165.3, 165.1, 163.6, 160.0,
150.0, 138.9, 135.5, 128.3, 121.7, 62.2, 62.01, 61.96, 41.3, 35.0,
14.2, 14.1, 14.0; HRMS (CI, NH3, 140 eV) m/z 405.1667 ([M]+,
2%), calcd for C18H24N5O6 405.1648. 4a : mp 187-188 °C; IR
(NaCl) vmax 1731, 1705, 1635, 1551, 1529 cm-1; 1H NMR (400
MHz, CDCl3) δ 9.30 (br s, ex, NH), 8.74 (s, 1H), 8.13 (s, 1H),
4.42 (q, J ) 7.3 Hz, 2H), 4.39 (q, J ) 7.3 Hz, 2H), 3.23 (s, 3H),
3.12 (s, 3H), 1.39 (t, J ) 7.3 Hz, 3H), 1.36 (t, J ) 7.3 Hz, 3H);
13C NMR (67.5 MHz, CDCl3) δ 165.6, 165.0, 160.5, 159.0, 156.5,
147.6, 146.0, 137.1, 135.6, 131.2, 62.25, 62.21, 41.7, 35.4, 14.0
(2C); HRMS (EI, 70 eV) m/z 361.1415 ([M]+, 1%), calcd for
Dieth yl 1,2,4-Tr ia zin e-3,5-d ica r boxyla te (2c). Hydra-
zone 8a 23 (135 mg, 0.94 mmol) in CH2Cl2 (5 mL) was added
dropwise (1 min) to a stirred suspension of ethyl thioamidoox-
alate (9,12 125 mg, 0.94 mmol) and 2-chloro-1-methylpyri-
dinium iodide (10,24c 288 mg, 1.1 mmol) in CH2Cl2 (4 mL) at 0
°C. The reaction mixture was then allowed to warm slowly to
room temperature over 4 h followed by refluxing for 0.5 h. After
the mixture was cooled to room temperature, the yellow ppt
was filtered and the filtrate was diluted with additional CH2-
Cl2 (10 mL), then washed with saturated aqueous NH4Cl. The
C
16H19N5O5 361.1385.
J . Org. Chem, Vol. 68, No. 11, 2003 4351

Lahue et al.
4-Eth yl 6,7-Dim eth yl 2-(N′,N′-Dim eth ylfor m a m id in o)-
3H-im id a zo[4,5-c]p yr id in e-4,6,7-tr ica r boxyla te (9b) a n d
Dim eth yl 2-(N′,N′-Dim eth ylfor m a m id in o)-3H-p yr id o[3,2-
d ]p yr im id -4-on e-6,7-d ica r boxyla te (4b). Prepared following
general procedure A with imidazole 1a (62 mg, 0.45 mmol)
and triazine 2b (120 mg, 0.45 mmol) in refluxing dioxane (4
mL) for 5 h; purified by flash chromatography (CH2Cl2/acetone,
3:1) to give 3b as a tan solid (Rf 0.36, 19 mg, 11%) and 4a as
a pale yellow solid (Rf 0.28, 111 mg, 74%). 3b: mp 195-198
°C; IR (NaCl) vmax 1736, 1631, 1590, 1521 cm-1; 1H NMR (400
MHz, CDCl3) δ 9.85 (br s, ex, NH), 8.82 (s, 1H), 4.52 (q, J )
7.3 Hz, 2H), 4.03 (br s, 3H), 3.96 (s, 3H), 3.19 (s, 3H), 3.13 (s,
3H), 1.48 (t, J ) 7.3 Hz, 3H); 13C NMR (67.5 MHz, CDCl3) δ
168.5, 165.5, 165.0, 163.7, 160.0, 149.3, 137.7, 134.9, 128.3,
121.7, 62.3, 52.9, 52.8, 41.2, 35.0, 14.1; HRMS (EI, 70 eV) m/z
377.1317 ([M]+, 56%), calcd for C16H19N5O6 377.1335. 4b: mp
62.1, 62.0, 37.9 (2C), 14.0 (2C); HRMS (EI, 70 eV) m/z 334.1297
([M]+, 60%), calcd for C15H18N4O5 334.1277.
Tr iet h yl 2-(Met h ylt h io)-3H -im id a zo-[4,5-c]p yr id in e-
4,6,7-tr ica r boxyla te (3e), Dieth yl 2-(Meth ylth io)-3H-p y-
r id o[3,2-d ]p yr im id -4-on e-6,7-d ica r boxyla te 4e, a n d Di-
eth yl 2-(Meth ylth io)-3H-p yr id o[4,3-d ]p yr im id -4-on e-5,7-
d ica r boxyla te (5e). Prepared following general procedure A
with imidazole 1d (87 mg, 0.76 mmol) and triazine 2a (226
mg, 0.76 mmol) in refluxing bromobenzene (5 mL) for 69 h;
purified by flash chromatography (CH2Cl2/EtOAc, 3:1) to give
5e as a white solid (Rf 0.47, 33 mg, 13%), 3e as an off-white
solid (Rf 0.34, 20 mg, 7%), and 4e as a tan solid (Rf 0.27, 182
mg, 72%). 3e: mp 195-198 °C; IR (NaCl) vmax 1731, 1695, 1618
1
cm-1; H NMR (400 MHz, CDCl3) δ 10.35 (br s, ex, NH), 4.54
(br q, J ) 7.2 Hz, 2H), 4.53 (br q, J ) 7.2 Hz, 2H), 4.45 (q, J
) 7.2 Hz, 2H), 2.84 (s, 3H), 1.49 (t, J ) 7.2 Hz, 3H), 1.43 (t, J
) 7.2 Hz, 3H), 1.42 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 165.3, 165.1, 164.6, 161.1, 149.0, 138.4, 136.2, 129.5,
123.7, 62.8, 62.4, 62.3, 14.4, 14.1 (3C); HRMS (CI, NH3, 140
eV) m/z 382.1110 ([M + H]+, 22%) calcd for C16H20N3O6S
382.1073. 4e: mp 224-226 °C; IR (NaCl) vmax 1734, 1695, 1653
1
241-244 °C; IR (NaCl) vmax 1735, 1705, 1633 cm-1; H NMR
(400 MHz, CDCl3) δ 9.13 (br s, ex, NH), 8.75 (s, 1H), 8.08 (s,
1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.23 (s, 3H), 3.13 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 165.8, 165.7, 160.6, 159.1, 156.6,
147.7, 144.7, 136.9, 135.2, 131.5, 53.10, 52.96, 41.8, 35.4;
HRMS (EI, 70 eV) m/z 333.1090 ([M]+, 21%), calcd for
1
cm-1; H NMR (400 MHz, CDCl3) δ 10.54 (br s, ex, NH), 8.35
C
14H15N5O5 333.1073.
(s, 1H), 4.44 (q, J ) 7.2 Hz, 2H), 4.42 (q, J ) 7.2 Hz, 2H), 2.67
(s, 3H), 1.39 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
165.2, 164.4, 159.7, 159.6, 148.2, 146.0, 137.3, 136.5, 131.5,
62.6, 62.5, 14.00 (2C), 13.8; HRMS (EI, 70 eV) m/z 337.0734
([M]+, 6%), calcd for C14H15N3O5S 337.0732. 5e: mp 214-216
°C; IR (NaCl) vmax 1772, 1740, 1646 cm-1; 1H NMR (400 MHz,
CDCl3) δ 10.59 (br s, ex, NH), 8.23 (s, 1H), 4.51 (q, J ) 7.2 Hz,
2H), 4.49 (q, J ) 7.2 Hz, 2H), 2.70 (s, 3H), 1.43 (t, J ) 7.2 Hz,
3H), 1.39 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
165.9, 164.0, 163.1, 159.9, 155.6, 153.8, 151.4, 122.7, 114.1,
62.57 (2C), 14.3, 14.0, 13.7; HRMS (CI, NH3, 140 eV) m/z
338.0810 ([M + H]+, 27%), calcd for C14H16N3O5S 338.0810.
Tr iet h yl 2-(N′,N′-Dim et h yla cet a m id in o)-3H -im id a zo-
[4,5-c]p yr id in e-4,6,7-t r ica r b oxyla t e (3c) a n d Diet h yl
2-(N′,N′-Dim eth yla ceta m id in o)-3H-p yr id o[3,2-d ]p yr im id -
4-on e-6,7-d ica r boxyla te (4c). Prepared following general
procedure A, optimized for 3c with imidazole 1b (113 mg, 0.74
mmol) and triazine 2a (221 mg, 0.74 mmol) in 1,4-dioxane (7
mL) at room temperature for 12 h; purified by flash chroma-
tography (CH2Cl2/acetone, 3:1) to give 3c as a yellow oil (Rf
0.33, 34 mg, 11%) and 4c as a yellow oil that solidifies upon
standing (Rf 0.25, 162 mg, 58%). Also optimized for 4c with
imidazole 1b (102 mg, 0.67 mmol) and triazine 2a (200 mg,
0.67 mmol) in refluxing 1,4-dioxane (6 mL) for 3h, to give 3c
(14 mg, 5%) and 4c (210 mg, 83%). 3c: IR (NaCl) vmax 1731,
Dieth yl 2-(N′,N′-Dim eth ylfor m a m id in o)-3H-im id a zo-
[4,5-c]p yr id in e-4,6-d ica r boxyla te (3f). Prepared following
general procedure A with imidazole 1a (17 mg, 0.12 mmol)
and triazine 2c (68 mg, 0.30 mmol) in refluxing dioxane (2
mL) for 4 h; purified by flash chromatography (CH2Cl2/acetone,
3:1) to give 3f as a light yellow solid (Rf 0.33, 10 mg, 25%); mp
1
1703, 1548 cm-1; H NMR (400 MHz, CDCl3) δ 9.65 (br s, ex,
NH), 4.52 (q, J ) 7.1 Hz, 2H), 4.49 (q, J ) 7.1 Hz, 2H), 4.43
(q, J ) 7.1 Hz, 2H), 3.19 (s, 3H), 3.17 (s, 3H), 2.55 (s, 3H),
1.48 (t, J ) 7.1 Hz, 3H), 1.41 (t, J ) 7.1 Hz, 3H), 1.39 (t, J )
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 166.1, 165.5,
165.2, 161.8, 150.1, 138.1, 134.8, 127.7, 122.0, 62.3, 62.0, 61.8,
38.9, 38.4, 17.1, 14.2, 14.1 (2C); HRMS (CI, NH3, 140 eV), m/z
420.1865 ([M + H]+, 1%), calcd for C19H26N5O6 420.1883. 4c:
1
149-151 °C; IR (NaCl) vmax 1735, 1715, 1629, 1521 cm-1; H
NMR (400 MHz, CDCl3) δ 9.80 (br s, ex, NH), 8.77 (s, 1H),
8.35 (s, 1H), 4.51 (q, J ) 7.2 Hz, 2H), 4.46 (q, J ) 7.2 Hz, 2H),
3.20 (s, 3H), 3.15 (s, 3H), 1.49 (t, J ) 7.2 Hz, 3H), 1.45 (t, J )
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.6, 166.0, 161.9,
161.5, 142.6, 134.4, 130.4, 116.7, 112.3, 63.5, 63.1, 42.7, 36.3,
15.3 (2C); HRMS (EI, 70 eV) m/z 333.1455 ([M]+, 8%), calcd
for C15H19N5O4 333.1437.
mp 166-168 °C; IR (NaCl) vmax 3200, 1731, 1705, 1547 cm-1
;
1H NMR (400 MHz, CDCl3) δ 9.37 (br s, ex, NH), 8.1 (s, 1H),
4.42 (q, J ) 7.3 Hz, 2H), 4.39 (q, J ) 7.3 Hz, 2H), 3.18 (s, 3H),
3.16 (s, 3H), 2.43 (s, 3H), 1.39 (t, J ) 7.3 Hz, 3H), 1.36 (t, J )
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.8, 165.6, 165.1,
161.0, 155.3, 147.9, 145.7, 136.2, 135.3, 131.2, 62.1, 62.0, 38.8,
38.6, 17.4, 13.98 (2C); HRMS (EI, 70 eV) m/z 375.1540 ([M]+,
13%), calcd for C17H21N5O5 375.1542.
Diet h yl 2-(N′,N′-Dim et h yla cet a m id in o)-3H -im id a zo-
[4,5-c]p yr id in e-4,6-d ica r boxyla te (3g). Prepared following
general procedure A with imidazole 1b (34 mg, 0.23 mmol)
and triazine 2c (51 mg, 0.23 mmol) in refluxing dioxane (2.5
mL) for 2 h; purified by flash chromatography (CH2Cl2/acetone,
3:1) to give 3g as a yellow oil (Rf 0.35, 50 mg, 64%). IR (NaCl)
Tr ieth yl 2-(Dim eth ylam in o)-3H-im idazo[4,5-c]pyr idin e-
4,6,7-tr ica r boxyla te (3d ) a n d Dieth yl 2-(Dim eth yla m in o)-
3H-p yr id o[3,2-d ]p yr im d -4-on e-6,7-d ica r boxyla te.4d Pre-
pared following general procedure A with imidazole 1c (103
mg, 0.93 mmol) and triazine 2a (110 mg, 0.37 mmol) in
refluxing 1,4-dioxane (3 mL) for 2 h; purified by flash chro-
matography (CH2Cl2/acetone, 3:1) to give 3d (Rf 0.31, 15 mg,
11%) and 4d (Rf 0.26, 74 mg, 60%) as light yellow solids. 3d :
mp 156-158 °C; IR (NaCl) vmax 3278, 1734, 1722, 1639, 1570
v
max 1734, 1632, 1520 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.64
(br s, ex, NH), 8.38 (s, 1H), 4.51 (q, J ) 7.2 Hz, 2H), 4.45 (q,
J ) 7.2 Hz, 2H), 3.18 (s, 3H), 3.17 (s, 3H), 2.52 (s, 3H), 1.50 (t,
J ) 7.2 Hz, 3H), 1.45 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.4, 165.9, 165.3, 159.3, 149.4, 141.1, 134.0, 128.8,
116.2, 62.3, 61.8, 39.1, 38.7, 17.7, 14.3 (2C); HRMS (EI, 70 eV)
m/z 347.1577 ([M]+, 23%), calcd for C16H21N5O4 347.1593.
1
cm-1; H NMR (400 MHz, CDCl3) δ 9.45 (br s, ex, NH), 4.56
Dieth yl 2-(Dim eth yla m in o)-3H-im id a zo[4,5-c]p yr id in e-
4,6-d ica r boxyla te (3h ). Prepared following general procedure
A with imidazole 1c (72 mg, 0.64 mmol) and triazine 2c (58
mg, 0.26 mmol) in THF (2.5 mL) at 0 °C with gradual warming
(2 h) to room temperature; purified by flash chromatography
(CH2Cl2/acetone, 3:1) to give 3h as a tan solid (Rf 0.38, 66 mg,
(q, J ) 7.2 Hz, 2H), 4.51 (q, J ) 7.2 Hz, 2H), 4.44 (q, J ) 7.2
Hz, 2H), 3.34 (s, 6H), 1.49 (t, J ) 7.2 Hz, 3H), 1.41 (t, J ) 7.2
Hz, 3H), 1.40 (t, J ) 7.2 Hz, 3H); insufficient material for 13C
spectrum; HRMS (CI, NH3, 140 eV), m/z 379.1601 ([M + H]+,
3%), calcd for C17H23N4O6 379.1618. 4d : mp 192-194 °C; IR
(NaCl) vmax 3200, 3140, 1734, 1685, 1617 cm-1; 1H NMR (400
MHz, CDCl3) δ 10.68 (br s, ex, NH), 7.99 (s, 1H), 4.41 (q, J )
7.3 Hz, 2H), 4.38 (q, J ) 7.3 Hz, 2H), 3.29 (s, 6H), 1.38 (t, J )
7.3 Hz, 3H), 1.36 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 165.4 (2C), 162.0, 151.4, 148.4, 143.6, 134.1, 133.2, 132.3,
84%). Mp 164-165 °C; IR (NaCl) vmax 1733, 1700, 1684 cm-1
;
1H NMR (400 MHz, CDCl3) δ 9.42 (br s, ex, NH), 8.26 (s, 1H),
4.50 (q, J ) 7.1 Hz, 2H), 4.44 (q, J ) 7.1 Hz, 2H), 3.27 (s, 6H),
1.50 (t, J ) 7.1 Hz, 3H), 1.44 (t, J ) 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 165.4, 162.0, 151.5, 148.4, 143.6, 134.1, 133.3,
4352 J . Org. Chem., Vol. 68, No. 11, 2003

Intermolecular Reactions of Imidazoles with 1,2,4-Triazines
132.3, 62.1, 61.9, 37.9 (2C), 14.0 (2C); HRMS (EI, 70 eV) m/z
warm to 10 °C over 18 h then diluted with water and extracted
with CH2Cl2, the combined organic fractions were washed with
brine and dried (MgSO4), and the solvent was removed in
vacuo and purified by flash chromatography (hexanes/EtOAc,
3:1) to give 15 as a colorless oil that solidified upon standing
to a white solid (Rf 0.45, 976 mg, 98%): Mp 58-60 °C (lit.34b
mp 52.5-54.5 °C); [R]D +2.4 (c 1.9); IR (NaCl) vmax 1731, 1672,
306.1358 ([M]+, 3%), calcd for C14H18N4O4 306.1328.
E t h yl 2-(N′,N′-Dim et h ylfor m a m id in o)-6-p h en yl-3H -
im id a zo[4,5-c]p yr id in e-4-ca r boxyla te (3i) a n d 2-(N′,N′-
Dim eth ylfor m a m id in o)-6-p h en yl-3H-p yr id o[3,2-d ]p yr im -
id -4-on e (4i). Prepared following general procedure B with
imidazole 1a (31.3 mg, 0.227 mmol) and triazine 2d (62.4 mg,
0.272 mmol) at 120-125 °C for 2 h; purified by flash chroma-
tography (Et3N/EtOAc, 3:100) to give 3i as a tan solid (Rf 0.40,
18 mg, 24%) and 4i as a light yellow solid (Rf 0.33, 11 mg,
16%). 3i: mp 172-175 °C; IR (NaCl) vmax 3400, 1734, 1700,
1
1530, 1347 cm-1; H NMR (400 MHz, CDCl3) δ 8.27 (d, J )
8.7 Hz, 2H), 7.99 (d, J ) 8.7 Hz, 2H), 7.42 (br d, J ) 7.5 Hz,
ex, NH), 4.61 (ddd, J ) 7.5, 7.0, 4.5 Hz, 1H), 2.44 (ddd, J )
17.2, 7.1, 7.1 Hz, 1H), 2.34 (ddd, J ) 17.2, 7.1, 7.1 Hz, 1H),
2.21 (dddd, J ) 14.2, 7.1, 7.1, 4.5 Hz, 1H), 2.07 (dddd, J )
14.2, 7.1, 7.1, 7.0 Hz, 1H), 1.48 (s, 9H), 1.41 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 172.8, 170.8, 164.9, 149.7, 139.5, 128.3 (2C),
123.6 (2C), 82.6, 81.1, 53.4, 31.6, 28.0 (6C), 26.9; HRMS (CI,
NH3, 140 eV) m/z 409.2001 ([M + H]+, 2%), calcd for C20H29N2O7
409.1975.
1
1627, 1521 cm-1; H NMR (400 MHz, CDCl3) δ 9.66 (br s, ex,
NH), 8.77 (s, 1H), 8.03 (dd, J ) 7.2, 1.2 Hz, 2H), 7.93 (s, 1H),
7.44 (dd, J ) 7.3, 7.2 Hz, 2H), 7.33 (tt, J ) 7.3, 1.2 Hz, 1H),
4.52 (q, J ) 7.0 Hz, 2H), 3.17 (s, 3H), 3.13 (s, 3H), 1.49 (t, J )
7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.2, 162.0, 159.0,
151.8, 150.4, 140.2, 132.4, 130.8, 128.6 (2C), 128.0, 127.0 (2C),
111.8, 61.7, 41.1, 34.9, 14.4; HRMS (CI, NH3, 140 eV) m/z
338.1621 ([M + H]+, 0.4%), calcd for C18H20N5O2 338.1617. 4i:
Di-ter t-bu tyl (S)-N-(p-Am in oben zoyl)-glu ta m a te (16).
To 15 (976 mg, 2.39 mmol) in MeOH (20 mL) was added 10%
Pd/C (146 mg, 15 wt %), and the flask was sealed with a
septum and purged with H2, then the mixture, was stirred at
room temperature for 3 h under an H2 atmosphere (balloon).
The reaction mixture was filtered through Celite and the
solvent removed in vacuo to give 16 as a white solid (895 mg,
99%): mp 138-139 °C (lit.34b mp 138-140 °C); [R]D +7.7 (c
mp 317-320 °C; IR (NaCl) vmax 2928, 1554, 1539 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 8.88 (br s, ex, NH), 8.72 (s, 1H),
8.12 (br d, J ) 8.0 Hz, 2H), 7.99 (d, J ) 8.7 Hz, 1H), 7.82 (d,
J ) 8.7 Hz, 1H), 7.45 (br t, J ) 8.0 Hz, 2H), 7.39 (br t, J ) 8.0
Hz, 1H), 3.20 (s, 3H), 3.11 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 161.8, 158.3, 154.8, 153.9, 146.0, 138.4, 136.2, 134.5, 129.1,
128.7 (2C), 127.2 (2C), 125.7, 41.5, 35.2; HRMS (EI, 70 eV)
m/z 293.1289 ([M]+, 18%), calcd for C16H15N5O 293.1276.
0.65); IR (NaCl) vmax 1726, 1634, 1606 cm-1 1H NMR (400
;
MHz, CDCl3) δ 7.63 (d, J ) 8.5 Hz, 2H), 6.74 (d, J ) 7.7 Hz,
ex, NH), 6.64 (d, J ) 8.5 Hz, 2H), 4.64 (ddd, J ) 7.8, 7.7, 5.3
Hz, 1H), 2.39 (ddd, J ) 16.5, 8.3, 6.3 Hz, 1H), 2.27 (ddd, J )
16.5, 8.3, 6.3 Hz, 1H), 2.19 (dddd, J ) 14.2, 7.8, 6.3, 6.3 Hz,
1H), 1.99 (dddd, J ) 14.2, 8.3, 8.3, 5.3 Hz, 1H), 1.46 (s, 9H),
1.39 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 172.5, 171.6, 166.8,
149.7, 128.9 (2C), 123.6, 114.1 (2C), 82.2, 80.7, 52.7, 31.7, 28.0
(6C), 27.8; HRMS (EI, 70 eV) m/z 378.2129 ([M]+, 3%), calcd
for C20H30N2O5 378.2155.
E t h yl 2-(N′,N′-Dim et h ylfor m a m id in o)-6,7-d ip h en yl-
3H-im idazo[4,5-c]pyr idin e-4-car boxylate (3j) an d 2-(N′,N′-
Dim eth ylfor m a m id in o)-6,7-d ip h en yl-3H-p yr id o[3,2-d ]p y-
r im id -4-on e (4j). Prepared following general procedure B with
imidazole 1a (56.6 mg, 0.41 mmol) and triazine 2e (150 mg,
0.492 mmol) at 120-125 °C for 2 h; purified by flash chroma-
tography (Et3N/EtOAc, 3:100) to give 3j as a tan solid (Rf 0.40,
21 mg, 13%) and 4j as a light yellow solid (Rf 0.31, 48 mg,
31%). 3j: mp 111-113 °C; IR (NaCl) vmax 3350, 1733, 1699,
(S)-2-{4-[7-(N,N′-Dim et h ylfor m a m id in o)-1,3,5-t r ioxo-
1,3,5,6-t et r a h yd r o-2,4,6,8-t et r a a za -cyclop en t a [b]n a p h -
th a len -2-yl]-ben zoyla m in o}-p en ta n ed ioic Acid Di-ter t-
butylEster (17)and (S)-2-(4-{[2-(N,N′-Dimethylformamidino)-
7 -e t h o x y c a r b o n y l -4 -o x o -3 ,4 -d i h y d r o -p y r i d o [3 ,2 -
d ]p y r i m i d i n e -6-c a r b o n y l]-a m i n o }-b e n z o y la m i n o )-
p en ta n ed ioic Acid Di-ter t-bu tyl Ester (18). A slurry of
crude 14 (∼0.14 mmol) in CH2Cl2 (3 mL) and H2O (3 mL) was
adjusted to pH 5-6 (optimized for 17) or pH 3.5-4.0 (optimized
for 18) with NaHCO3 and cooled to 0 °C, then the following
were added in order: HOBt (19 mg, 0.14 mmol), 16 (53 mg,
0.14 mmol), and EDC (30 mg, 0.15 mmol). The reaction was
gradually warmed to 15 °C over 18 h, diluted with saturated
aqueous NaHCO3, extracted with CH2Cl2, washed with brine,
then dried (MgSO4). The solvent was removed in vacuo and
the product was purified by flash chromatography (CH2Cl2/
acetone/MeOH, 3:1:1%) to give 17 as a yellow solid (Rf 0.30,
visible with long wave UV, 10 mg, 11%) or 18 as a white solid
(Rf 0.20, visible with long wave UV, 42 mg, 44%). 17: mp 237-
239 °C; [R]D +6.6 (c 0.50); IR (NaCl) vmax 3511, 3386, 1727,
1680, 1638, 1556 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 12.25
(br s, ex, NH), 8.81 (s, 1H), 8.73 (d, J ) 7.3 Hz, ex, NH), 8.07
(s, 1H), 8.02 (d, J ) 8.2 Hz, 2H), 7.60 (d, J ) 8.2 Hz, 2H), 4.35
(m, 1H), 3.23 (s, 3H), 3.11 (s, 3H), 2.36 (dd, J ) 7.4 Hz, 2H),
2.05 (m, 1H), 1.94 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H); 13C NMR
(75 MHz, DMSO-d6) δ 171.4, 170.7, 165.93, 165.90, 164.2,
164.1, 159.2, 157.6, 144.3, 139.7, 134.2, 133.6, 130.5, 128.2,
127.9 (3C), 126.7 (2C), 80.5, 79.6, 52.5, 40.9, 34.9, 31.3, 27.64
(3C), 27.57 (3C), 25.9; HRMS (ESI) m/z 648.2794 ([M + H]+,
100%), calcd for C32H38N7O8 648.2777. 18: mp 118-120 °C;
[R]D +4.7 (c 0.55); IR (NaCl) vmax 3583, 3451, 3326, 2977, 2931,
1733, 1684, 1632, 1557, 1530 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 10.83 (s, ex, NH), 8.78 (s, 1H), 8.52 (d, J ) 7.3 Hz, ex,
NH), 8.02 (s, 1H), 7.90 (d, J ) 8.7 Hz, 2H), 7.85 (d, J ) 8.7
Hz, 2H), 4.31 (m, 1H), 4.28 (q, J ) 7.0 Hz, 2H), 3.22 (s, 3H),
3.09 (s, 3H), 2.34 (dd, J ) 7.4 Hz, 2H), 2.04 (m,1H), 1.92 (m,
1H), 1.41 (s, 9H), 1.38 (s, 9H), 1.21 (t, J ) 7.0 Hz, 3H); 13C
1
1627, 1516 cm-1; H NMR (400 MHz, CDCl3) δ 9.70 (br s, ex,
NH), 8.71 (s, 1H), 7.37-7.34 (m, 3H), 7.29-7.23 (m, 4H), 7.18-
7.15 (m, 3H), 4.53 (q, J ) 7.3 Hz, 2H), 3.13 (s, 3H), 3.10 (s,
3H), 1.47 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
166.2, 162.0, 159.3, 150.2, 149.9, 140.8, 135.9, 132.5, 131.1
(2C), 130.5 (2C), 127.8 (3C), 127.5 (3C), 127.1, 126.9, 61.7, 41.1,
34.9, 14.4; HRMS (EI, 70 eV) m/z 414.1933 ([M + H]+, 4%),
calcd for C24H24N5O2 414.1930. 4j: mp 272-275 °C; IR (NaCl)
1
vmax 3300, 1730, 1692, 1632, 1550 cm-1; H NMR (400 MHz,
CDCl3) δ 8.96 (br s, ex, NH), 8.73 (s, 1H), 7.78 (s, 1H), 7.39-
7.37 (m, 2H), 7.28-7.25 (m, 3H), 7.21-7.18 (m, 5H), 3.20 (s,
3H), 3.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 158.3,
155.3, 154.5, 145.9, 141.5, 139.4, 139.0, 135.4, 135.1, 130.1
(2C), 129.4 (2C), 128.2 (2C), 127.74, 127.66 (3C), 41.5, 35.2;
HRMS (EI, 70 eV) m/z 369.1563 ([M]+, 3%), calcd for C22H19N5O
369.1589.
2-(N,N′-Dim eth ylfor m am idin o)-3H-pyr ido[3,2-d]pyr im -
id -4-on e-6,7-d ica r boxylic Acid 7-Eth yl Ester (14). To a
solution of 4a (51 mg, 0.14 mmol) in THF (3 mL) and H2O (1
mL) at 0 °C was added LiOH (18 mg, 0.42 mmol), and the
reaction was stirred for 1 h and quenched with concentrated
HCl (to pH 2-3) and the solvent evaporated at room temper-
ature by directing a stream of air into the flask to give crude
14, which was used without further purification. 1H NMR (400
MHz, D2O) indicates a 3:1 mixture of 14 (δ 8.67 (s, 1H), 8.32
(s,1H), 4.47 (q, J ) 7.0 Hz, 2H), 3.41 (s, 3H), 3.29 (s, 3H), 1.39
(t, J ) 7.0 Hz, 3H)) and the corresponding dicarboxylic acid
(δ 8.67* (s, 1H), 8.18 (s, 1H), 3.41* (s, 3H), 3.29* (s, 3H)) [the
asterisk indicates peaks which overlap with those of 14].
Di-ter t-bu tyl (S)-N-(p-Nitr oben zoyl)-glu ta m a te (15). To
a solution of p-nitrobenzoic acid (629 mg, 2.43 mmol) in CH2-
Cl2 (24 mL) were added in order: H2O (24 mL), di-tert-butyl
(S)-glutamate35 (405 mg, 2.43 mmol), and HOBt (370 mg, 2.43
mmol). The reaction mixture was cooled to 0 °C and 1,3-
dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC,
511 mg, 2.67 mmol) was added. The reaction was allowed to
J . Org. Chem, Vol. 68, No. 11, 2003 4353

Lahue et al.
NMR (100 MHz, DMSO-d6) δ 172.1, 171.7, 166.7, 165.9, 164.5,
161.1, 159.6, 158.2, 148.2, 146.7, 142.0, 136.3, 134.8, 132.0,
129.5, 128.9 (2C), 119.4 (2C), 81.1, 80.3, 62.2, 53.0, 41.5, 35.4,
31.9, 28.25 (3C), 28.20 (3C), 26.5, 14.2; HRMS (ESI) m/z
694.3195 ([M + H]+, 55%), calcd for C34H44N7O9 694.3195.
(S)-2-{4-[(2-Am in o-7-eth oxycar bon yl-4-oxo-3,4-dih ydr o-
pyr ido[3,2-d]pyr im idin e-6-car bon yl)-am in o]-ben zoylam i-
n o}-p en ta n ed ioic Acid (19). Trifluoroacetic acid (1 mL) was
added to a mixture of Et3SiH (10 µL, 0.063 mmol) and 18 (11
mg, 0.016 mmol) and stirred at room temperature for 16 h.
The reaction mixture was diluted with CH2Cl2 (3 mL) and H2O
(0.1 mL) then was refluxed for 1 h and cooled to room
temperature, then the solvent was evaporated by directing a
stream of air into the flask to give 19 as an off-white solid
(7.5 mg, 89%); 19 could be further purified by recrystallization
from 1:1 MeOH/H2O if necessary. Mp 266-269 °C; [R]D +8.0
1H), 1.95 (m, 1H), 1.20 (t, J ) 7.0 Hz, 3H) (2 CO2H not
observed); poor solubility of 19 in DMSO-d6, D2O, 1:1 DMSO-
d6/D2O, CD3CO2H precluded obtaining adequate 13C NMR
spectra; HRMS (ESI) m/z 527.1527 ([M + H]+, 100%), calcd
for C23H23N6O9 527.1521.
Ack n ow led gm en t. The authors are grateful to the
National Science Foundation for partial financial sup-
port (grant no. CHE-9501069), to Dr. Xiaolin Zhang at
Abbott Laboratories and Mr. Michael Creech at Boston
University for obtaining HRMS spectra, and to Dr.
J onathan Lee for assistance in obtaining NOESY spec-
tra.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for previously unreported compounds and General Experi-
mental Methods. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
(H2O, c 0.25); IR (NaCl) vmax 3104, 2080, 1360; H NMR (400
MHz, DMSO-d6) δ 11.57 (br s, ex, NH), 10.78 (s, ex, NH), 8.53
(d, J ) 7.9 Hz, ex, NH), 7.89 (d, J ) 8.7 Hz, 2H), 7.85 (d, J )
8.7 Hz, 2H), 7.81 (s, 1H), 6.94 (br s, ex, NH2), 4.39 (m, 1H),
4.27 (q, J ) 7.0 Hz, 2H), 2.35 (t, J ) 7.5 Hz, 2H), 2.07 (m,
J O030049Y
4354 J . Org. Chem., Vol. 68, No. 11, 2003