Ruthenium tetroxide oxidation of N,N'-Diboc hexahydropyridazines

Article abstract of DOI:10.3987/COM-08-S(D)31

The ruthenium tetroxide (RuO₄) oxidation of the 3-substituted N,N'-diBochexahydropyridazines gave the 6-oxohexahydropyridazines in good to high yields, whereas the oxidation of the unsubstituted ones also gave the 3,6-dioxo derivatives. The 3,6

Full text of DOI:10.3987/COM-08-S(D)31

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HETEROCYCLES, Vol. 79, 2009
647
HETEROCYCLES, Vol. 79, 2009, pp. 647 - 658. © The Japan Institute of Heterocyclic Chemistry
Received, 25th September, 2008, Accepted, 28th November, 2008, Published online, 28th November, 2008.
DOI: 10.3987/COM-08-S(D)31
RUTHENIUM
TETROXIDE
OXIDATION
OF
N,N’-DIBOC
HEXAHYDROPYRIDAZINES
Mamoru Kaname, Shigeyuki Yoshifuji, and Haruki Sashida*
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi,
Kanazawa 920-1181, Japan
h-sashida@hokuriku-u.ac.jp
Abstract - The ruthenium tetroxide (RuO4) oxidation of the 3-substituted
N,N’-diBochexahydropyridazines gave the 6-oxohexahydropyridazines in good to
high yields, whereas the oxidation of the unsubstituted ones also gave the
3,6-dioxo derivatives. The 3,6-cis-disubstituted pyridazines were essentially
oxidized to give the 3-hydroxypyridazines; no oxidation of the trans-derivative
occurred.
INTRODUCTION
RuO4 is an effective multipurpose oxidant1 and has been widely used for the oxidation of various amines,
alcohols, olefins and aromatic compounds in recent years. In the RuO4 oxidation of the N-acyl amines,
only the methylene moiety adjacent to the nitrogen atom is generally oxidized to afford the imides; the
second and higher stages of oxidation never occur (eq. 1). There are many reports concerning both the
(CH2)n
(CH2)n
(CH2)n
RuO4
RuO4
(eq. 1)
N
O
N
O
O
N
O
R
O
R
R
O
2
1
3
Ac
N
Ac
N
Ac
N
O
O
RuO4
RuO4
(eq. 2)
O
N
N
N
O
Ac
Ac
Ac
4
6
5
Scheme 1

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HETEROCYCLES, Vol. 79, 2009
transformation of cyclic and acyclic N-acyl amines into the corresponding lactams2,3 and imides4
including natural products5 using a catalytic amount of RuO2 hydrate and an appropriate co-oxidant by
us6 and other workers7 in this field. However, to the best of our knowledge, only a few papers8,9 have
described the RuO4 oxidation of the heterocycles containing two nitrogen atoms; the RuO4 oxidation of
N,N’-diacethylhexahydropyrazine (4)8 gives the pyrazi-2,3-dione 5, not pyrazi-2,5-dione 6 (eq. 2). We
now report the result of the RuO4 oxidation of the N-acylhexahydropyridazines, six-membered
heterocycles containing two nitrogen atoms.
RESULTS AND DISCUSSION
In order to obtain the hexahydropyridazines, which are the substrates for the RuO4 oxidation, the
Diels-Alder (DA) reaction using the 1,3-dienes and azodicarboxylate was carried out. The hetero DA
reaction between the 1,3-dienes 7a-h and di-tert-butyl azodicarboxylate (8)3 produced the corresponding
adducts, the 6-unsubstituted 1,2-di-tert-butyl 1,2,3,6-tetrahydropyrydazine-1,2-carboxylates (9) in good to
excellent yields except for the 1-methoxycarbonyl-1,3-diene (7d) having an electron withdrawing group
(Scheme 2). Similarly, the reaction of 2,4-hexadiene (7i) and methyl hexa-2,4-dienate (7j) with 8 gave the
3,6-disubstituted cis-tetrahydropyrydazines 9i, j in almost quantitative yields. The olefin moiety in 9 was
hydrogenated by Pd-C in EtOH to give the hexahyropyridazine derivatives 10 in high yields as shown in
Schemes 2 and 3. The methyl cis-ester 10j was epimerized into the trans-ester 10k by treatment with
NaOMe in refluxing MeOH in 94% yield.
R3
R2
R3
R2
R3
R2
H2 / Pd-C
Boc
R1
Boc
R1
Boc
N N
+
R1
Boc
N N
N N
Boc
Boc
8
7
10
9
a: R1 = R2 = R3 = H
b: R1 = Me, R2 = R3 = H
c: R1 = Et, R2 = R3 = H
d: R1 = CO2Me, R2 = R3 = H
e: R1 =H, R2 = Me, R3 = H
f: R1 =H, R2 = R3 = Me
a: 95%
b: 100%
c: 98%
d: 47%
e: 95%
f: 84%
a: 100%
b: 100%
c: 81%
d: 92%
e: 87%
f: 93%
g: R1 = R2 = Me, R3 = H
h: R1 = Me, R2 = H, R3 = Me
g: 68%
h: 89%
g: 77%
h: 83%
Scheme 2

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HETEROCYCLES, Vol. 79, 2009
649
H2 / Pd-C
Boc
Me
Boc
R
N
N
Me
Boc
R
Me
R
Boc
N
N
N
N
+
Boc
Boc
7
9
8
10
i: 92% (cis)
j: 81% (cis)
k: 94% (trans)
i: 99%
j: 96%
i: R = Me
j: R = CO2Me
NaOMe
Scheme 3
Next, the RuO4 oxidation of the hexahyropyridazines 10a-h was carried out at room temperature
according to our standard method3 using a catalytic amount of RuO2 hydrate and excess of 10% NaIO4 in
a double layer system of ethyl acetate-water. When the 3-substituted 6-unsubstituted pyridazines 10b-d, g,
h were oxidazed, the reaction smoothly proceeded to give the desired pyridazinones 11b-d, g, h in good
to excellent yields as the sole product. The oxidation of the pyridazines 10a, e, f having no substituted at
the C-3 and -6 positions in spite of the existence or absence of the functional groups at the C-4 and -5
positions, gave both the pyridazin-3-ones 11a, e, f and 3,6-dioxo derivatives 12a, e, f as shown in Scheme 4.
R3
R2
R3
R2
R3
R2
RuO4
R1
Boc
R1
Boc
O
O
O
+
N
N
N
N
N
N
Boc
Boc
Boc
Boc
10
11
12
a: R1 = R2 = R3 = H
b: R1 = Me, R2 = R3 = H
c: R1 = Et, R2 = R3 = H
d: R1 = CO2Me, R2 = R3 = H
e: R1 =H, R2 = Me, R3 = H
f: R1 =H, R2 = R3 = Me
g: R1 = R2 = Me, R3 = H
h: R1 = Me, R2 = H, R3 = Me
a: 17%
b: 0%
c: 0%
d: 0%
e: 32%
f: 27%
g: 0%
h: 0%
a: 46%
b: 98%
c: 85%
d: 83%
e: 33%
f: 42%
g: 91%
h: 78%
Scheme 4
On the other hand, the behavior of the 3,6-disubstituted pyridazines 10i-k under the RuO4 oxidation was
different. The hemiaminal 13 was produced by the RuO4 oxidation of cis-dimethylpyridazine 10i in 87%
yield as the sole product. In contrast, the oxidation of the methyl cis-ester 10j under similar conditions
resulted in the ring-opening reaction to give the hydrazine derivative 14 in 81% yield via the hemiaminal
intermediate 15, which is essentially the same type of oxidation product as 13. However, the RuO4

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HETEROCYCLES, Vol. 79, 2009
oxidation of the methyl trans-ester 10k did not occur; the starting material was recovered. This distinction
between the cis and trans carbon functionalities at the C-3 and C-6 positions of the chair-form
conformation having two axial N-Boc groups with respect to the reactivity of the hexahyropyridazines 10i,
j towards the RuO4 is explained in Scheme 5. During the RuO4 oxidation of the methyl cis-ester 10j, the
reagent could slightly attack the nitrogen atom from the back side of the axial N-Boc group to oxidize the
methyne carbon giving the hydroxypyridazine intermediate 15 as illustrated in 10j’. However, RuO4
could not approach the nitrogen atom of the methyl trans-ester 10k’ from any direction due to the steric
hindrance of the two bulky Bocs, methyl and methoxycarbonyl groups, which are all axial. For that
reason, no oxidized products were obtained.
Me
HO
Me
HO
j
i
Me
Me
Boc
R
CO2Me
N N
N N
N N
R = CO2Me
87%
R = Me
Boc
Boc
Boc
Boc
Boc
10
15
13
k
i: R = Me (cis)
j: R = CO2Me (cis)
CO2Me
H
k: R = CO2Me (trans)
Me
N
N
Boc
O
Boc
14
81% from 10j
CO2Me
CO2Me
Boc
Boc
N
Me
N
N
N
Boc
Me
Boc
RuO4
10k'
10j'
Scheme 5
CONCLUSION
In summary, we have developed the RuO4 oxidation of the N,N’-diacyl hexahydropyridazines. The results
mentioned in this paper suggest that the RuO4 oxidation of the six-membered species containing two
nitrogen atoms smoothly proceeded, and is synthetically very useful for the preparation of the
hexahydropyridazin-ones and -diones. A distinction between the oxidation of the cis and trans
1,2,3,6-tetrasubstituted hexahydropyridazines was also examined.