Two novel 1,2,4,5-tetrazines that participate in inverse electron demand Diels-Alder reactions with an unexpected regioselectivity

Article abstract of DOI:10.1021/jo051832o

Two new unsymmetrical 1,2,4,5-tetrazines, 3-methylsulfinyl-6-methylthio-1, 2,4,5-tetrazine (4) and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5- tetrazine (5), were prepared, and the scope of their participation in intermolecular inverse electron d

Full text of DOI:10.1021/jo051832o

Two Novel 1,2,4,5-Tetrazines that Participate in Inverse Electron
Demand Diels-Alder Reactions with an Unexpected Regioselectivity
Akiyuki Hamasaki, Richard Ducray, and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
boger@scripps.edu
ReceiVed August 30, 2005
Two new unsymmetrical 1,2,4,5-tetrazines, 3-methylsulfinyl-6-methylthio-1,2,4,5-tetrazine (4) and
3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5-tetrazine (5), were prepared, and the scope of their
participation in intermolecular inverse electron demand Diels-Alder reactions was defined. As anticipated,
sulfoxides 4 and 5 (4 > 5) display a reactivity that is substantially greater than that of their corresponding
sulfides (2 and 3), being derived from their enhanced electron-deficient character and resulting in a wider
range of potential dienophile choices or the use of milder reaction conditions. The cycloaddition reactions
were expectedly regioselective, typically producing a single cycloadduct, ensuring their synthetic utility,
but both were found to proceed with a regioselectivity opposite what would be anticipated and
complementary to that observed with 2 and 3.
Introduction
have examined a number of such tetrazines17,18 and introduced
several new useful symmetrical19 or unsymmetrical20,21 1,2,4,5-
tetrazines. Of these, dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate
Electron-deficient heterocyclic azadienes have proven to be
useful reagents that often participate in well-defined inverse
electron demand Diels-Alder reactions with electron-rich
dienophiles, providing rapid access to a range of highly
substituted heterocyclic systems.1 Of these, the substituted
1,2,4,5-tetrazines are the most reactive and most widely utilized
heterocyclic azadienes. Typically, symmetrical 1,2,4,5-tetrazines
are employed largely because of their synthetic accessibility,
and synthetic studies of their utility have necessarily focused
only on their relative reactivities.
(4) OMP: Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D. J.
Org. Chem. 1984, 49, 4405.
(5) Lavendamycin: Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M.
J. Org. Chem. 1985, 50, 5790.
(6) PDE-I and PDE-II: Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc.
1987, 109, 2717.
(7) CC-1065: Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988,
110, 1321, 4796.
(8) Prodigiosin: Boger, D. L.; Patel, M. J. Org. Chem. 1988, 53, 1405.
(9) Trikentrin A: Boger, D. L.; Zhang, M. J. Am. Chem. Soc. 1991,
113, 4230.
(10) Isochrysohermidin: Boger, D. L.; Baldino, C. M. J. Am. Chem.
Soc. 1993, 115, 11418.
(11) Ningalin A, Lamellarin O, Lukianol A, and Storniamide A: Boger,
D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem.
Soc. 1999, 121, 54.
(12) Phomazarin: Boger, D. L.; Hong, J.; Hikota, M.; Ishida, M. J. Am.
Chem. Soc. 1999, 121, 2471.
In the course of our investigations of such reagents and their
applications in complex natural products total synthesis,2-16 we
(1) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic Press: San Diego, CA, 1987.
(2) Reviews: Boger, D. L. Tetrahedron 1983, 39, 2869. Boger, D. L.
Chem. ReV. 1986, 86, 781. Boger, D. L. Chemtracts: Org. Chem. 1996, 9,
149.
(13) Ningalin B: Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick,
M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479.
(3) Streptonigrin: Boger, D. L.; Panek, J. S.; Duff, S. R. J. Am. Chem.
Soc. 1985, 107, 5745.
(14) Anhydrolycorinone and related alkaloids: Boger, D. L.; Wolkenberg,
S. E. J. Org. Chem. 2000, 65, 9120.
10.1021/jo051832o CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/30/2005
J. Org. Chem. 2006, 71, 185-193
185

Hamasaki et al.
SCHEME 1
FIGURE 1.
(1)17 and 3,6-bis(thiomethyl)-1,2,4,5-tetrazine (2)18 have been
the most widely utilized of the symmetrical tetrazines, and the
N-acyl-3-amino-6-methylthio-1,2,4,5-tetrazines (e.g., 3)21 have
proven to be the most widely explored of the unsymmetrical
tetrazines participating in well-behaved, effective, and regiose-
lective [4+2] cycloaddition reactions. Herein, we report the
preparation of two new and useful unsymmetrical 1,2,4,5-
tetrazines, 3-methylsulfinyl-6-methylthio-1,2,4,5-tetrazine (4)
and 3-(benzyloxycarbonyl)amino-6-methysulfinyl-1,2,4,5-tet-
razine (5), obtained by the S oxidation of 2 and 3, respectively,
and we describe studies defining the scope of their Diels-Alder
reactions, Figure 1. As anticipated, both 4 and 5 (4 > 5) display
a reactivity that is greater than that of either 2 or 3, being derived
from their enhanced electron-deficient character, resulting in a
wider range of potential dienophile choices and/or the use of
milder reaction conditions for the [4+2] cycloaddition reactions.
Moreover, the cycloaddition reactions were expectedly regio-
selective, typically producing a single cycloadduct, ensuring their
synthetic utility. Remarkably, this regioselectivity proved op-
posite what one would anticipate on the basis of simple
zwitterionic models or more sophisticated frontier molecular
orbital (FMO) analysis of the [4+2] cycloaddition reactions.
studies, only their intramolecular [4+2] cycloaddition reaction
with tethered unactivated alkynes was examined, and no studies
of their intermolecular Diels-Alder reactions have been dis-
closed.23 Both were prepared by the oxidation of the corre-
sponding thioether, enlisting either the DABCO-Br2 complex24
or oxone.23 The former proved effective for selective oxidation
of 2 to provide 4 as a blood red crystalline solid in good
yield (0.55 equiv of DABCO, 1.1 equiv of Br2, HOAc-H2O-
CH2Cl2, 25 °C, 20 h, 52%) along with small amounts of 2,
Scheme 1. Increasing the amount of oxidant increased the
conversion without further increasing the yield of 4, likely a
result of competing over oxidation, and the use of m-CPBA
(1.1 equiv) also provided 4 but in lower yield. In either case,
the over-oxidation led to unidentified water-soluble byproducts
that were easily removed in the workup. Tetrazine 4, like 1, is
not stable to prolonged exposure to silica gel but can be iso-
lated in pure form by washing the crude reaction product
with Et2O/hexane to remove small amounts of unreacted 2
and subsequently recrystallized from EtOAc/hexane (mp
73-74 °C).
Tetrazine 3 proved essentially unreactive toward DABCO-
Br2 under these conditions but was oxidized to the corresponding
sulfoxide with m-CPBA (1.1 equiv, CH2Cl2, 0 °C, 30 min, 85%).
Like 1 and 4, 5 was not sufficiently stable to prolonged exposure
to silica gel to permit purification by chromatography. However,
an aqueous workup of the oxidation reaction, including an
extraction with saturated aqueous NaHCO3 to remove reagent
and m-chlorobenzoic acid, provided tetrazine 5 as a blood red
oil, sufficiently pure (>95%) for [4+2] cycloaddition studies.
Results and Discussion
Preparation of 1,2,4,5-Tetrazines 4 and 5. To our knowl-
edge, there have been only two reports of the preparation of
sulfoxide-substituted 1,2,4,5-tetrazines,22,23 and only one of these
examined their [4+2] cycloaddition reactivity.23 In these latter
Diels-Alder Reactions of 4. The tetrazine 4 exhibited superb
reactivity in prototypical inverse electron demand Diels-Alder
reactions and was much more reactive than the corresponding
sulfide 2,18 Table 1. The reaction of 4 with enamines was
essentially instantaneous at 25 °C, and other electron-rich
dienophiles including ketene acetals, enol ethers, and enamides
readily react smoothly at room temperature to cleanly provide
the [4+2] cycloadducts. Notably, no problematic detection of
intermediate unaromatized product was observed, and the
Diels-Alder products were isolated in uniformly high yields.
Remarkably, even unactivated dienophiles including pheny-
lacetylene 6h and alkyne 6k reacted smoothly with 4, albeit
slowly at room temperature (ca. 24-48 h), requiring higher
reaction temperatures for a rapid reaction (100 °C, 1-9 h, 80-
(15) Roseophilin: Boger, D. L.; Hong, J. J. Am. Chem. Soc. 2001, 123,
8515.
(16) Ningalin D: Hamasaki, A.; Zimpleman, J. M.; Hwang, I.; Boger,
D. L. J. Am. Chem. Soc. 2005, 127, 10767.
(17) Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (1): Sauer, J.; Mielert,
A.; Lang, D.; Peter, D. Chem. Ber. 1965, 98, 1435. Boger, D. L.; Coleman,
R. S.; Panek, J. S.; Huber, F. X.; Sauer, J. J. Org. Chem. 1985, 50, 5377.
Boger, D. L.; Panek, J. S.; Patel, M. Org. Synth. 1991, 70, 79.
(18) 3,6-Bis(methylthio)-1,2,4,5-tetrazine (2): Sandstro¨m, J. Acta Chem.
Scand. 1961, 15, 1575. Boger, D. L.; Sakya, S. M. J. Org. Chem. 1988,
53, 1415.
(19) 3,6-Bis(3,4-dimethoxybenzoyl)-1,2,4,5-tetrazine: Soenen, D. R.;
Zimpleman, J. M.; Boger, D. L. J. Org. Chem. 2003, 68, 3593.
(20) 3-Methoxy-6-methylthio-1,2,4,5-tetrazine: Sakya, S. M.; Groskopf,
K. K.; Boger, D. L. Tetrahedron Lett. 1997, 38, 3805.
(21) N-Acyl-6-amino-3-methylthio-1,2,4,5-tetrazine (e.g., 3): Boger, D.
L.; Schaum, R. P.; Garbaccio, R. M. J. Org. Chem. 1998, 63, 6329.
(22) Johnson, J. L.; Whitney, B.; Werbel, L. M. J. Heterocycl. Chem.
1980, 17, 501.
(23) Seitz, G.; Dietrich, S.; Go¨rge, L.; Richter, J. Tetrahedron Lett. 1986,
27, 2747.
(24) Blair, L. K.; Baldwin, J.; Smith, W. C., Jr. J. Org. Chem. 1977, 42,
1817.
186 J. Org. Chem., Vol. 71, No. 1, 2006

1,2,4,5-Tetrazines in Diels-Alder Reactions
TABLE 1. [4+2] Cycloaddition Reactions of 4
90%). As such, tetrazine 4, by virtue of its enhanced electron-
deficient character, exhibits a reactivity that accommodates an
unusually wide range of potential dienophiles. Moreover, the
[4+2] cycloaddition reactions were regioselective, typically
providing a single detectable product. The only exception to
this generalization was dihydrofuran (Table 1, entry 10), where
a trace of the second regioisomer (5-11%) was detected.
Unexpectedly, this regioselectivity proved to be opposite what
one would predict from simple zwitterionic models or FMO
analysis of the [4+2] cycloaddition reaction. Although this
became apparent in assessing the spectroscopic properties of
the cycloaddition products (e.g., 1,2-diazine C4-H vs C5-H
chemical shift), single-crystal X-ray structures of 7c, 7f, and
7g unambiguously established their structures, Figure 2.25
Similarly, dienophiles 6j and 6k provided regioisomeric products
clearly distinguishable as the C4-substituted (C5-H δ 7.36) and
J. Org. Chem, Vol. 71, No. 1, 2006 187

Hamasaki et al.
SCHEME 3
FIGURE 2. ORTEP drawings of 7c, 7f, and 7g.
ceeded that of 3. Not only did 5 react with enamines, ketene
acetals, and enol ethers rapidly and effectively at room tem-
perature, but also the unactivated dienophile phenylacetylene
(6h) provided the [4+2] cycloadduct 9f in excellent conversion
(77%) at 25 °C, requiring only 24 h for complete reaction.
Although tetrazine 5 was slightly less reactive than 4, requiring
slightly longer reaction times and providing somewhat lower
conversions, it was also found to exhibit a superb [4+2]
cycloaddition reactivity. Similarly, the regioselectivity of the
[4+2] cycloaddition reactions was often excellent, although not
always as clean as that observed with 3 or 4, and, like that of
4, was found to be opposite that anticipated. This was first
evident upon examination of the spectroscopic properties of the
products and confirmed by X-ray for 9c25 or by correlation with
the alternative regioisomeric products available through S
oxidation of the analogous cycloadducts derived from tetrazine
3, Scheme 4. These latter studies not only further verified that
tetrazines 3 and 5 proceed with opposite regioselectivities in
the [4+2] cycloaddition reactions and, more surprisingly, that
it is the regioselectivity of 5 that is opposite what one might
predict, but they also illustrate that the analogous reactions of
3 require much more vigorous reaction conditions to conduct.
Reactivity and Regioselectivity. The regioselectivity of the
cycloadditions is not consistent with the expectation that the
methylsulfinyl group would control the reaction orientation by
stabilizing a partial negative charge at C3 (Table 3). The
dienophile addition does not follow an approach predicted by
this stabilization and the complementary ability of the thiomethyl
or acylamino group to stabilize a partial positive charge on C6.
These intuitive predictions are supported by the Austin model
1 (AM1) and MNDO computational studies, where C3 of both
4 and 5 bear a significant partial negative charge, while C6 is
more electropositive. Moreover, C6 bears the largest LUMO
coefficient, indicating it should dominate the regioselectivity
by preferentially combining with the dienophile C2 center, which
possesses its largest HOMO coefficient. Thus, both 4 and 5
experimentally display a [4+2] cycloaddition reaction regio-
selectivity opposite what one would predict on the basis of
simple zwitterionic models or FMO analysis of the reactions.
SCHEME 2
C5-substituted (C4-H δ 7.88) 1,2-diazines, with the latter
alkyne regioselectivity being consistent with that observed with
phenylacetylene (X-ray), Scheme 2. The structure of the
cycloadduct 7b, which lacks the distinguishing aryl CH, was
confirmed by comparison of its spectroscopic properties with
that of the two possible cycloadducts (7b vs 7l) with 7l, but
not 7b, exhibiting a characteristic diastereotopic methylene
adjacent to the sulfoxide substituent similarly observed with 7h
versus 7k, Scheme 3. As such, tetrazine 4 exhibits a very useful
Diels-Alder reactivity accommodating an unusually wide range
of potential dienophiles and proceeds with a reaction regio-
selectivity opposite what one would predict.
Diels-Alder Reactions of 5. Given the useful but unexpected
observations with tetrazine 4, an analogous but less extensive
study of the [4+2] cycloaddition reactions of tetrazine 5 was
conducted, Table 2. As anticipated, the reactivity of 5, by virtue
of its enhanced electron-deficient character, substantially ex-
(25) Atomic coordinates for 7c (CCDC 282318), 7f (CCDC 282319),
7g (CCDC 282321), and 9c (CCDC 282320) have been deposited with the
Cambridge Crystallographic Data Centre.
188 J. Org. Chem., Vol. 71, No. 1, 2006

1,2,4,5-Tetrazines in Diels-Alder Reactions
TABLE 2. [4+2] Cycloaddition Reactions of 5
TABLE 3. AM1 Computational Results (LUMO) of 1,2,4,5-Tetrazines
4
5a
1
2
3a
LUMO (EV)
-1.871
0.530
0.617
-0.571
-0.283
-1.607
0.517
0.625
-0.586
0.063
-2.149
0.591
0.591
-0.102
-0.102
-1.365
0.584
0.584
-0.277
-0.277
-1.364
0.549
0.596
-0.301
0.022
C-3 coefficient
C-6 coefficient
C-3 net charge
C-6 net charge
a Cbz group was replaced with CO2CH3 for the calculations.
Only the LUMO energy levels of the FMO analysis accurately
reflect the increased reactivity of 4 and 5 (4 > 5) relative to 2
and 3.
Consequently, the origin of the reversed regioselectivity is
not clear. It is possible that this is related to a destabilizing
steric and/or electronic interaction of the dienophile substituents
with the larger and more electronegative methylsulfinyl sub-
stituent (e.g., a destabilizing -NR2/CH3SO- interaction). In
part, this may explain the lower regioselectivity typically
observed with 5 versus 4, including the relative behavior seen
in the reaction of 5 with the terminally substituted dienophile
6b. However, it is also interesting to note that treatment of
tetrazine 4 (Et2NH, THF, 0 to 25 °C) or the cycloadducts 7c,
7d, and 7e (CH3ONa, CH3OH, 25-70 °C) with nucleophiles
only provided products derived from the displacement of the
methylsulfinyl group and not the methyl sulfide. Consequently,
J. Org. Chem, Vol. 71, No. 1, 2006 189

Hamasaki et al.
SCHEME 4
FIGURE 3. ORTEP drawing of 9c.
dition-elimination products (no cyclization) were detected, and
such a stepwise reaction course is unlikely for the unactivated
alkynes examined.
Conclusions
The unsymmetrical 1,2,4,5-tetrazines 4 and 5 participate in
well-defined and regioselective inverse electron demand Diels-
Alder reactions with a wide range of electron-rich and unacti-
vated dienophiles providing the corresponding 1,2-diazines in
excellent yields. As anticipated, their enhanced electron-deficient
character relative to 2 and 3 provides dienes that react faster
and/or under milder reaction conditions and with a wider range
of potential dienophiles. The cycloadditions are regioselective,
albeit providing products opposite what is predicted using simple
zwitterionic models or FMO analysis of the [4+2] cycloaddition
reaction.
Experimental Section
3-Methylsulfinyl-6-methylthio-1,2,4,5-tetrazine (4). 3,6-Bis-
(methylthio)tetrazine (2, 500 mg, 2.87 mmol) was dissolved in 16
mL of a 5:2:1 mixture of HOAc, H2O, and CH2Cl2. The DABCO-
2Br2 complex (681 mg, 1.58 mmol) was added, and the mixture
was stirred at room temperature for 20 h. Water was added, and
the mixture was extracted with CH2Cl2, dried (MgSO4), and
evaporated. The crude material was washed with Et2O/hexane
(1:1, 3×), providing pure tetrazine 4 (286 mg, 52% yield) as a red
solid. An analytically pure sample of 4 was obtained by recrystal-
1
lization from EtOAc/hexane: mp 73-74 °C (EtOAc/hexane); H
NMR (CDCl3, 500 MHz) δ 3.18 (s, 3H), 2.81 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 178.9, 173.0, 40.1, 13.6; IR (film) νmax 1382,
1242, 1122, 1078, 1049, 961, 892 cm-1. HRMS (MALDI-FTMS,
m/z): (M + Na+) calcd for C4H6N4OS2, 212.9875; found, 212.9878.
6-(Benzyloxycarbonyl)amino-3-(methylsulfinyl)-1,2,4,5-tetra-
zine (5). 6-(Benzyloxycarbonyl)-amino-3-methylthio-1,2,4,5-tetra-
zine (3, 100 mg, 0.36 mmol) was dissolved in 4 mL of CH2Cl2
and cooled to 0 °C. m-CPBA (68.5 mg, 0.397 mmol) was added,
and the mixture was stirred at 0 °C for 30 min. Saturated aqueous
NaHCO3 was added, and the mixture was extracted with CH2Cl2,
dried (MgSO4), and evaporated to give 90 mg (85%) of essentially
pure tetrazine 5 (> 95%) as a red foam: 1H NMR (CDCl3, 400
MHz) δ 8.91 (br s, 1H), 7.45-7.35 (m, 5H), 5.34 (s, 2H), 3.16 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 171.9, 160.7, 150.4, 134.6,
128.6, 128.5 (2C), 128.4 (2C), 68.5, 39.6; IR (film) νmax 3196, 3031,
1759, 1557, 1471, 1279, 1211, 1179, 1059, 964, 927, 742 cm-1
.
HRMS (ESI-TOF, m/z): (M + Na+) calcd for C11H11N5O3S,
316.0475; found, 316.0466.
it is also possible that the reactions proceed by stepwise
addition-cyclization reactions initiated by an analogous nu-
cleophilic addition. Although potentially reasonable for the
nucleophilic dienophiles examined, no intercepted simple ad-
General Procedure for Cycloadditions. Tetrazine 4 or 5 was
dissolved in the reaction solvent (Tables 1 and 2), the dienophile
was added at room temperature, and the mixture was stirred at the
indicated temperature for the indicated time. After completion of
190 J. Org. Chem., Vol. 71, No. 1, 2006

1,2,4,5-Tetrazines in Diels-Alder Reactions
the reaction, the solvent was removed and the crude material was
purified by chromatography on silica gel.
grown from acetone/H2O unambiguously established the structure
of 7g: mp 149-150 °C (acetone/H2O); H NMR (CDCl3, 500
1
MHz) δ 7.79 (s, 1H), 7.64 (d, J ) 8.8 Hz, 2H), 7.40 (d, J ) 8.8
Hz, 2H), 3.02 (s, 3H), 2.70 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 166.1, 163.1, 140.1, 133.0, 132.2 (2C), 130.0 (2C), 124.6, 120.6,
41.7, 14.2; IR (film) νmax 1487, 1418, 1328, 1142, 1063, 1009, 843,
821, 753 cm-1. HRMS (ESI-TOF, m/z): (M + H+) calcd for
C12H11BrN2OS2, 342.9569; found, 342.9571.
4-(2′-Hydroxyethyl)-3-(methylsulfinyl)-6-(methylthio)-
pyridazine (7h). A total of 10 mg of 4 yielded 8.5 mg of 7h (70%,
colorless oil) after chromatography (0-10% MeOH/EtOAc). The
regioisomer (7k) was isolated as a minor product (5-11%): 1H
NMR (CDCl3, 500 MHz) δ 7.36 (s, 1H), 4.04-3.98 (m, 1H), 3.87-
3.82 (m, 1H), 3.37-3.31 (m, 1H), 3.18 (s, 3H), 3.13-3.08 (m,
1H), 2.74 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.1, 161.7,
139.7, 128.4, 61.7, 38.9, 32.8, 13.3; IR (film) νmax 3383, 1415, 1353,
1193, 1057 cm-1. HRMS (MALDI-FTMS, m/z): (M + H+) calcd
for C8H12N2O2S2, 233.0413; found, 233.0412.
5-[2-(tert-Butyldimethylsilyloxy)ethyl]-3-(methylsulfinyl)-6-
(methylthio)pyridazine (7i). A total of 10 mg of 4 yielded 16 mg
of 7i (89%, colorless oil) after chromatography (40% EtOAc/
hexane): 1H NMR (CDCl3, 500 MHz) δ 7.83 (s, 1H), 3.96 (t, J )
6.2 Hz, 2H), 2.95 (s, 3H), 2.90 (t, J ) 6.2 Hz, 2H), 2.76 (s, 3H),
0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 165.5,
164.4, 139.6, 121.2, 59.6, 41.7, 35.0, 25.7, 18.1, 13.6, -5.4; IR
(film) νmax 2928, 1353, 1256, 1096, 1066, 837, 777 cm-1. HRMS
(MALDI-FTMS, m/z): (M + H+) calcd for C14H26N2O2S2Si,
347.1278; found, 347.1274.
4-[2-(tert-Butyldimethylsilyloxy)ethyl]-3-(methylsulfinyl)-6-
(methylthio)pyridazine (7j). A solution of 7h (7 mg, 0.03 mmol)
in DMF (300 µL) was treated with imidazole (3.4 mg, 0.05 mmol)
and t-butyldimethylsilyl chloride (6.7 mg, 0.045 mmol). The mixture
was stirred for 3 h at room temperature before being diluted with
EtOAc and washed with water. Preparative TLC (50% EtOAc/
hexane) afforded 8 mg (77%) of 7j as a colorless oil: 1H NMR
(CDCl3, 500 MHz) δ 7.39 (s, 1H), 3.98-3.90 (m, 2H), 3.27-3.22
(m, 1H), 3.14 (s, 3H), 3.12-3.09 (m, 1H), 2.74 (s, 3H), 0.84 (s,
9H), -0.01 (s, 3H), -0.02 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 164.7, 161.0, 139.3, 128.5, 61.6, 37.9, 33.0, 25.7 (3C), 18.1, 13.2,
-5.5 (2C); IR (film) νmax 2927, 1566, 1360, 1256, 1090, 1065,
836, 777 cm-1. HRMS (MALDI-FTMS, m/z): (M + H+) calcd
for C14H26N2O2S2Si, 347.1278; found, 347.1279.
1-(Methylsulfinyl)-4-(methylthio)-6,7-dihydro-5H-cyclopenta-
[d]pyridazine (7a). A total of 10 mg of 4 yielded 11.5 mg of 7a
(96%, white solid) after chromatography (0-5% MeOH/EtOAc):
mp 92-93 °C (EtOAc); 1H NMR (CDCl3, 400 MHz) δ 3.44-3.30
(m, 2H), 3.07 (s, 3H), 2.83 (t, J ) 7.7 Hz, 2H), 2.77 (s, 3H), 2.27-
2.16 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 161.7, 160.4, 145.3,
142.3, 39.3, 30.3, 30.1, 23.3, 12.7; IR (film) νmax 1541, 1427, 1291,
1191, 1058, 964 cm-1. HRMS (MALDI-FTMS, m/z): (M + H+)
calcd for C9H12N2OS2, 229.0464; found, 229.0466.
5-Ethyl-4-methyl-3-(methylsulfinyl)-6-(methylthio)-
pyridazine (7b). A total of 20 mg of 4 yielded 22 mg of 7b (91%,
pale yellow viscous oil) after preparative TLC (EtOAc): 1H NMR
(CDCl3, 400 MHz) δ 3.11 (s, 3H), 2.74 (q, J ) 7.5 Hz, 2H), 2.71
(s, 3H), 2.60 (s, 3H), 1.18 (t, J ) 7.6 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 164.6, 160.4, 141.3, 134.6, 37.1, 21.8, 13.7, 12.7, 11.2;
IR (film) νmax 3460, 2972, 2926, 1715, 1652, 1538, 1057 cm-1
.
HRMS (ESI-TOF, m/z): (M + H+) calcd for C9H14N2OS2,
231.0620; found, 231.0620.
5-Ethoxy-3-(methylsulfinyl)-6-(methylthio)pyridazine (7c). A
total of 10 mg of 4 yielded 10.4 mg of 7c (85%, white solid) after
chromatography (0-2% MeOH/EtOAc gradient elution). A single-
crystal X-ray structure determination25 conducted on crystals grown
from benzene unambiguously established the structure of 7c: mp
1
111.5-112.5 °C (benzene); H NMR (CDCl3, 400 MHz) δ 7.31
(s, 1H), 4.31 (q, J ) 7 Hz, 2H), 2.98 (s, 3H), 2.69 (s, 3H), 1.54 (t,
J ) 7 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.6, 157.0, 156.2,
99.5, 65.5, 41.8, 14.0, 12.6; IR (film) νmax 1556, 1353, 1193, 1058,
1033 cm-1. HRMS (MALDI-FTMS, m/z): (M + H+) calcd for
C8H12N2O2S2, 233.0413; found, 233.0412.
3-(Methylsulfinyl)-6-(methylthio)pyridazine (7d). From ethyl
vinyl ether (6d), 10 mg of 4 yielded 9.5 mg of 7d (96%, white
solid) after chromatography (EtOAc). From vinyl pyrrolidinone (6e),
10 mg of 4 afforded 6.5 mg of 7d (66%) after chromatography
(EtOAc): mp 115-117 °C (EtOAc/hexane, lit.26 mp 118-119 °C);
1H NMR (CDCl3, 500 MHz) δ 7.91 (d, J ) 8.8 Hz, 1H), 7.58 (d,
J ) 8.8 Hz, 1H), 2.98 (s, 3H), 2.76 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 166.1, 164.6, 127.4, 121.3, 41.7, 13.4; IR (film) νmax 1557,
1390, 1156, 1053, 974, 854 cm-1. HRMS (MALDI-FTMS, m/z):
(M + H+) calcd for C6H8N2OS2, 189.0151; found, 189.0153.
5-Methyl-3-(methylsulfinyl)-6-(methylthio)pyridazine (7e). A
total of 10 mg of 4 yielded 9.6 mg of 7e (91%, white solid) after
1
5-(2′-Hydroxyethyl)-3-(methylsulfinyl)-6-(methylthio)-
pyridazine (7k). A solution of 7i (5 mg) in 100 µL of THF was
treated with Bu4NF (1.0 M in THF, 30 µL, 2 equiv) at room
temperature, and the mixture was stirred at 25 °C for 1 h.
Chromatography (5% MeOH/EtOAc) afforded 3.3 mg of 7k (98%,
chromatography (EtOAc): mp 106-107 °C (EtOAc/hexane); H
NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 2.95 (s, 3H), 2.74 (s,
3H), 2.36 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 165.4, 164.8,
138.5, 121.0, 41.7, 18.5, 13.4; IR (film) νmax 1558, 1347, 1062 cm-1
.
HRMS (MALDI-FTMS, m/z): (M + H+) calcd for C7H10N2OS2,
203.0307; found, 203.0308.
1
white solid): mp 110-112 °C (EtOAc); H NMR (CDCl3, 400
MHz) δ 7.88 (s, 1H), 4.06 (t, J ) 6.2 Hz, 2H), 2.99 (s, 3H), 2.95
(t, J ) 6.2 Hz, 2H), 2.77 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
165.4, 164.7, 139.4, 120.8, 59.3, 41.6, 34.5, 13.7; IR (film) νmax
3377, 1567, 1413, 1362, 1193, 1149, 1057, 958 cm-1. HRMS
(MALDI-FTMS, m/z): (M + H+) calcd for C8H12N2O2S2,
233.0413; found, 233.0412.
4-Ethyl-5-methyl-3-(methylsulfinyl)-6-(methylthio)-
pyridazine (7l). A solution of 8 (46 mg, 0.215 mmol) in CH2Cl2
(1 mL) was treated with m-CPBA (70%, 53 mg, 0.215 mmol, 1
equiv) at 0 °C. The mixture was allowed to warm to room
temperature over 1 h before being washed with saturated aqueous
NaHCO3. The organic layer was dried over Na2SO4, and preparative
TLC (SiO2, EtOAc) afforded 7b (13 mg, 0.056 mmol, 26%, pale
yellow viscous oil) and 7l (13 mg, 0.056 mmol, 26%, white solid).
7l: mp 94-96 °C (EtOAc); 1H NMR (CDCl3, 300 MHz) δ 3.16-
2.92 (m, 2H), 3.10 (s, 3H), 2.72 (s, 3H), 2.28 (s, 3H), 1.24 (t, J )
7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.6, 159.8, 140.5,
135.5, 37.6, 20.7, 14.1, 13.8, 13.6; IR (film) νmax 3475, 2926, 1539,
1294, 1206, 1035, 952 cm-1. HRMS (ESI-TOF, m/z): (M + H+)
calcd for C9H14N2OS2, 231.0620; found, 231.0629.
3-(Methylsulfinyl)-6-(methylthio)-5-phenylpyridazine (7f). From
1-phenyl-1-(trimethylsilyloxy)ethylene (6g), 10 mg of 4 yielded 13
mg of 7f (94%, white solid) after chromatography (60% EtOAc/
hexane). From phenylacetylene (6h), 50 mg of 4 yielded 63 mg of
7f (90%) after chromatography (60% EtOAc/hexane). A single-
crystal X-ray structure determination25 conducted on crystals grown
from acetone/H2O unambiguously established the structure of 7f:
1
mp 143.2-143.8 °C (acetone/H2O); H NMR (CDCl3, 400 MHz)
δ 7.81 (s, 1H), 7.50 (s, 5H), 3.02 (s, 3H), 2.70 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 166.0, 163.5, 141.4, 134.3, 130.1, 128.9 (2C),
128.4 (2C), 120.7, 41.7, 14.3; IR (film) νmax 1344, 1193, 1059 cm-1
.
HRMS (MALDI-FTMS, m/z): (M + H+) calcd for C12H12N2OS2,
265.0464; found, 265.0466.
5-(4′-Bromophenyl)-3-(methylsulfinyl)-6-(methylthio)-
pyridazine (7g). A total of 30 mg of 427 yielded 48 mg of 7g (89%,
white solid) after chromatography (50-100% EtOAc/hexane). A
single-crystal X-ray structure determination25 conducted on crystals
(26) Sega, T.; Pollak, A.; Stanovnik, B.; Tisler, M. J. Org. Chem. 1973,
38, 3307.
J. Org. Chem, Vol. 71, No. 1, 2006 191

Hamasaki et al.
4-(Benzyloxycarbonyl)amino-1-(methylsulfinyl)-6,7-dihydro-
5H-cyclopenta[d]pyridazine (9a). A total of 54 mg of 5 yielded
47 mg of 9a (77%, orange film) after chromatography (0-1%
MeOH/EtOAc): 1H NMR (CDCl3, 400 MHz) δ 7.41-7.34 (m,
5H), 5.23 (s, 2H), 3.38 (t, J ) 7.6 Hz, 2H), 3.13-3.02 (m, 2H),
3.00 (s, 3H), 2.26-2.08 (m, 2H); 13C NMR (CDCl3, 150 MHz) δ
160.8, 153.4, 153.0, 148.0, 141.5, 135.3, 128.6 (2C), 128.5, 128.2
(2C), 67.8, 39.5, 31.6, 30.4, 24.3; IR (film) νmax 3184, 2960, 1733,
1515, 1232, 1047 cm-1. HRMS (ESI-TOF, m/z): (M + H+) calcd
for C16H17N3O3S, 332.1063; found, 332.1056.
6-(Benzyloxycarbonyl)amino-5-ethyl-4-methyl-3-(methylsul-
finyl)pyridazine (9b). A total of 29 mg of 5 yielded 9b (9.6 mg,
29%, colorless oil) after preparative TLC (SiO2, EtOAc). The
regioisomer (9j) was isolated as a minor product (3.2 mg, 10%,
colorless oil). 9b: 1H NMR (CDCl3, 400 MHz) δ 7.39-7.36 (m,
5H), 5.23 (s, 2H), 3.10 (s, 3H), 2.76 (q, J ) 7.6 Hz, 2H), 2.66 (s,
3H), 1.14 (t, J ) 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 161.9,
154.2, 153.8, 139.2, 135.3, 128.6 (2C), 128.5, 128.4 (2C), 126.9,
68.0, 37.6, 20.8, 13.3, 12.2; IR (film) νmax 3209, 2976, 1728, 1557,
1498, 1455, 1228, 1051 cm-1. HRMS (ESI-TOF, m/z): (M + H+)
calcd for C16H19N3O3S, 334.1220; found, 334.1221. Minor isomer
9j: 1H NMR (CDCl3, 400 MHz) δ 7.77 (s, 1H), 7.39-7.33 (m,
5H), 5.21 (s, 2H), 3.13-2.95 (m, 2H), 3.06 (s, 3H), 2.30 (s, 3H),
1.26 (t, J ) 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 161.3,
155.3, 153.6, 145.1, 135.3, 133.8, 128.65 (2C), 128.56, 128.3 (2C),
68.0, 38.3, 21.1, 13.9, 13.7; IR (film) νmax 3180, 2973, 1732, 1504,
1231, 1043 cm-1. HRMS (ESI-TOF, m/z): (M + H+) calcd for
C16H19N3O3S, 334.1220; found, 334.1215.
6-(Benzyloxycarbonyl)amino-5-ethoxy-3-(methylsulfinyl)-
pyridazine (9c). A total of 70 mg of 5 yielded 27 mg of 9c (34%,
white solid) after chromatography (0-10% MeOH/CH2Cl2) and
preparative TLC (SiO2, 5% MeOH/CH2Cl2). The regioisomer (9h)
was isolated as a minor product (14 mg, 17%, white solid). A single-
crystal X-ray structure determination25 conducted on crystals grown
from EtOAc/CHCl3 unambiguously established the structure of 9c.
9c: mp 119-121 °C (EtOAc/CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.48-7.38 (m, 6H), 5.30 (s, 2H), 4.29 (q, J ) 8.5 Hz, 2H), 2.96
(s, 3H), 1.52 (t, J ) 8.5 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ
165.9, 151.0, 148.8, 147.2, 135.3, 128.63 (2C), 128.58 (2C), 128.54,
102.6, 67.9, 65.9, 41.9, 14.1; IR (film) νmax 1731, 1572, 1503, 1438,
1221, 1042 cm-1. HRMS (MALDI-FTMS, m/z): (M + H+) calcd
for C15H17N3O4S, 336.1012; found, 336.1016. Minor isomer 9h:
mp 144-145 °C (EtOAc); 1H NMR (CDCl3, 400 MHz) δ 8.59 (br
s, 1H), 7.89 (s, 1H), 7.42-7.36 (m, 5H), 5.26 (s, 2H), 4.29 (q, J )
7.0 Hz, 2H), 3.00 (s, 3H), 1.53 (t, J ) 7.0 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 157.7, 157.3, 152.9, 152.1, 135.1, 128.7 (2C),
128.6, 128.2 (2C), 98.5, 67.8, 65.5, 37.3, 14.0; IR (film) νmax 1731,
1572, 1512, 1228, 1152, 1050, 1029 cm-1. HRMS (MALDI-
FTMS, m/z): (M + H+) calcd for C15H17N3O4S, 336.1012; found,
336.1017.
6-(Benzyloxycarbonyl)amino-3-(methylsulfinyl)pyridazine (9d).
A total of 16 mg of 5 yielded 12 mg of 9d (75%, white solid) after
chromatography (10% EtOAc/hexane): mp 155.5-155.8 °C (EtOAc/
hexane); 1H NMR (CDCl3, 500 MHz) δ 8.55 (d, J ) 9.4 Hz, 1H),
8.39 (br s, 1H), 8.16 (d, J ) 9.4 Hz, 1H), 7.42-7.39 (m, 5H), 5.28
(s, 2H), 2.94 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 165.2, 155.6,
152.7, 134.9, 128.78, 128.75 (2C), 128.4 (2C), 124.9, 118.6, 68.0,
41.9; IR (film) νmax 1721, 1573, 1519, 1228, 1056 cm-1. HRMS
(MALDI-FTMS, m/z): (M + H+) calcd for C13H13N3O3S,
292.0756; found, 292.0758.
m/z): (M + H+) calcd for C14H15N3O3S, 306.0907; found,
1
306.0913. Minor isomer 9i: mp 139-141 °C (EtOAc); H NMR
(CDCl3, 400 MHz) δ 8.22 (s, 1H), 8.15 (br s, 1H), 7.43-7.37 (m,
5H), 5.26 (s, 2H), 3.08 (s, 3H), 2.69 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 160.2, 155.8, 152.7, 141.6, 135.0, 128.7 (2C), 128.3
(2C), 119.1, 67.9, 37.6, 17.7; IR (film) νmax 3182, 2923, 1733, 1558,
1505, 1409, 1224, 1152, 1047, 744 cm-1. HRMS (MALDI-FTMS,
m/z): (M + H+) calcd for C14H15N3O3S, 306.0907; found,
306.0912.
6-(Benzyloxycarbonyl)amino-3-(methylsulfinyl)-5-phenyl-
pyridazine (9f). From 1-phenyl-1-(trimethylsilyloxy)ethylene (6f),
9.2 mg of 5 yielded 9.5 mg of 9f (83%, white solid) after
chromatography (60-100% EtOAc/hexane). From phenylacetylene
(6g), 10.4 mg of 5 yielded 10 mg of 9f (77%) after preparative
TLC (SiO2, EtOAc): mp 119-121 °C (EtOAc/hexane); 1H NMR
(CDCl3, 500 MHz) δ 8.07 (s, 1H), 7.52-7.49 (m, 5H), 7.35-7.33
(m, 3H), 7.28-7.27 (m, 2H), 5.07 (s, 2H), 3.03 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 166.7, 152.7, 152.0, 135.5, 135.1, 133.8,
129.9, 129.5 (2C), 128.55 (2C), 128.52, 128.4 (2C), 127.5 (2C),
124.5, 67.8, 41.9; IR (film) νmax 1731, 1495, 1213, 1045, 743, 697
cm-1. HRMS (MALDI-FTMS, m/z): (M + H+) calcd for
C19H17N3O3S, 368.1063; found, 368.1064.
6-(Benzyloxycarbonyl)amino-5-(4′-bromophenyl)-3-(methyl-
sulfinyl)pyridazine (9g). A total of 33 mg of 527 yielded 34 mg of
9g (69%, white solid) after chromatography (50-100% EtOAc/
hexane): mp 162-163 °C (toluene/CHCl3); 1H NMR (CDCl3, 500
MHz) δ 8.07 (s, 1H), 7.92 (brs, 1H), 7.57-7.55 (m, 2H), 7.40-
7.34 (m, 5H), 7.22-7.20 (m, 2H), 5.03 (s, 2H), 3.00 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 167.2, 152.7, 152.2, 135.3, 135.0, 133.4,
132.5 (2C), 128.7 (2C), 128.6, 128.5 (2C), 128.4 (2C), 124.5, 124.2,
67.9, 41.8; IR (film) νmax 3176, 2960, 1733, 1488, 1393, 1250, 1214,
1055, 751 cm-1. HRMS (MALDI-FTMS, m/z): (M + H+) calcd
for C19H16BrN3O3S, 446.0168; found, 446.0166.
6-(Benzyloxycarbonyl)amino-4-ethoxy-3-(methylthio)-
pyridazine (10a). A solution of 3 (20 mg, 0.072 mmol) in dioxane
(300 µL) was treated with ketene diethyl acetal (6c, 94 µL, 10
equiv). The mixture was heated at 100 °C in a closed vessel for 2
h. Chromatography (30% EtOAc/hexane) afforded 22 mg of 10a
1
(95%, white solid): mp 167-168 °C (EtOAc); H NMR (CDCl3,
400 MHz) δ 8.07 (br s, 1H), 7.59 (s, 1H), 7.42-7.34 (m, 5H),
5.23 (s, 2H), 4.21 (q, J ) 7.0 Hz, 2H), 2.59 (s, 3H), 1.50 (t, J )
7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 155.8, 153.6, 153.3,
150.8, 135.5, 128.6 (2C), 128.4, 128.0 (2C), 96.1, 67.3, 64.7, 14.0,
12.2; IR (film) νmax 2923, 1723, 1589, 1571, 1515, 1373, 1357,
1239, 1156, 1117, 1034, 750 cm-1. HRMS (MALDI-FTMS,
m/z): (M + H+) calcd for C15H17N3O3S, 320.1063; found,
320.1059.
6-(Benzyloxycarbonyl)amino-4-methyl-3-(methylthio)-
pyridazine (10b). A solution of 3 (20 mg, 0.072 mmol) in dioxane
(300 µL) was treated with 2-methoxypropene (6e, 69 µL, 10 equiv).
The mixture was heated in a closed vessel at 100 °C for 18 h.
Chromatography (20% EtOAc/hexane) afforded 10b (8 mg, 39%,
1
white solid): mp 151-152 °C (EtOAc); H NMR (CDCl3, 300
MHz) δ 7.96 (s, 1H), 7.82 (br s, 1H), 7.43-7.35 (m, 5H), 5.23 (s,
2H), 2.67 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
158.5, 153.0, 152.2, 138.3, 135.4, 128.6 (2C), 128.5, 128.2 (2C),
116.8, 67.5, 18.5, 13.1; IR (film) νmax 1721, 1570, 1502, 1232, 1149,
1110, 1041, 750, 695 cm-1. HRMS (MALDI-FTMS, m/z): (M +
H+) calcd for C14H15N3O2S, 290.0958; found, 290.0956.
6-(Benzyloxycarbonyl)amino-5-methyl-3-(methylthio)-
pyridazine (10c). A solution of 3 (25 mg, 0.090 mmol) in dioxane
(0.2 mL) was treated with 1-morpholinopropene28 (57 mg, 0.45
mmol, 5 equiv). The mixture was stirred at 25 °C for 1 h before
the solvent was removed. The residue was dissolved in 10% HOAc/
6-(Benzyloxycarbonyl)amino-5-methyl-3-(methylsulfinyl)-
pyridazine (9e). A total of 77 mg of 5 yielded 43 mg of 9e (54%,
colorless oil) after chromatography (0-10% EtOAc/hexane). The
regioisomer (9i) was isolated as a minor product (5.5 mg, 7%, white
solid). 9e: 1H NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.76 (br s,
1H), 7.42-7.35 (m, 5H), 5.24 (s, 2H), 2.94 (s, 3H), 2.45 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 166.8, 155.1, 153.5, 136.5, 135.1,
128.68 (2C), 128.64, 128.4 (2C), 125.8, 68.1, 41.8, 18.4; IR (film)
νmax 1732, 1506, 1234, 1049 cm-1. HRMS (MALDI-FTMS,
(27) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J.
Tetrahedron 1987, 43, 2075.
(28) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovic, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207.
192 J. Org. Chem., Vol. 71, No. 1, 2006

1,2,4,5-Tetrazines in Diels-Alder Reactions
benzene (0.2 mL) and stirred at 25 °C for 15 h. Neutralization with
saturated aqueous NaHCO3, extraction (CH2Cl2), and chromatog-
raphy (40% EtOAc/hexane) afforded 10c (24 mg, 92%, white
solid): mp 117-119 °C (EtOAc); 1H NMR (CDCl3, 400 MHz) δ
7.53 (s, 1H), 7.40-7.32 (m, 5H), 7.17 (s, 1H), 5.20 (s, 2H), 2.63
(s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 145.3, 135.6,
128.6 (2C), 128.3, 128.2 (2C), 67.6, 17.7, 13.2 (four peaks are
undetected); IR (film) νmax 3208, 2926, 1727, 1497, 1239, 1101
cm-1. HRMS (ESI-TOF, m/z): (M + H+) calcd for C14H15N3O2S,
290.0958; found, 290.0957.
3H), 1.17 (t, J ) 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
141.6, 135.8, 128.5 (2C), 128.3, 128.2 (2C), 67.6, 22.3, 13.5, 13.3,
11.5 (four peaks are undetected); IR (film) νmax 3170, 2971, 1731,
1499, 1237, 1071 cm-1. HRMS (ESI-TOF, m/z): (M + H+) calcd
for C16H19N3O2S, 318.1271; found, 318.1279.
General Procedure for the Oxidation of 8 or 10. A solution
of 8 or 10 in CH2Cl2 was treated with m-CPBA (1 equiv) at 0 °C.
The reaction mixture was allowed to warm to room temperature
over 0.5-1 h. Washing with saturated aqueous NaHCO3, drying
with Na2SO4, and chromatography afforded 7 or 9.
6-(Benzyloxycarbonyl)amino-4-ethyl-5-methyl-3-(methylthio)-
pyridazine (10d). A solution of 3 (23 mg, 0.083 mmol) in CH2Cl2
(0.17 mL) was treated with 3-morpholino-2-pentene28 (6b, 26 mg,
0.166 mmol, 2 equiv). The mixture was stirred at 25 °C for 1.5 h
before the removal of the solvent. The residue was treated with
10% HOAc/benzene (0.2 mL), and the mixture was stirred at 25
°C for 17 h. Neutralization with saturated aqueous NaHCO3,
extraction (CH2Cl2), and preparative TLC (SiO2, 33% EtOAc/
hexane) afforded 10d (21 mg, 80%, pale yellow oil): mp 124-
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA42056) and the
Skaggs Institute for Chemical Biology.
1
Supporting Information Available: H NMR spectra of all new
compounds and details of the X-ray structures of 7c, 7f, 7g, and
9c. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
126 °C (CH2Cl2); H NMR (CDCl3, 400 MHz) δ 7.41-7.32 (m,
5H), 5.20 (s, 2H), 2.70 (q, J ) 7.6 Hz, 2H), 2.64 (s, 3H), 2.23 (s,
JO051832O
J. Org. Chem, Vol. 71, No. 1, 2006 193