Novel intramolecular cyclization of 2-(buta-1,3-dienyl)-3-methylpyrazines and 3-(buta-1,3-dienyl)-4-methyl-1,2,5-oxadiazoles into 5H-cycloheptapyrazines and 4H-cyclohepta-1,2,5-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2004.03.123

2-(Buta-1,3-dienyl)-3-methylpyrazines (5) and 3-(buta-1,3-dienyl)-4-methyl- 1,2,5-oxadiazoles (10) were synthesized starting from base-induced reaction of 2,3-dimethylpyrazine or 3,4-dimethyl-1,2,5-oxadiazole with α,β- unsaturated carbonyls. The thus obtained heteroaromatics bearing a butadienyl moiety and a methyl at the adjacent position underwent intramolecular cyclization by the action of LDA to give the corresponding heteroaromatics fused with a seven-membered ring [7 (8)] and [11 (12)] in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2004.03.123

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3895–3898
Novel intramolecular cyclization of 2-(buta-1,3-dienyl)-3-
methylpyrazines and 3-(buta-1,3-dienyl)-4-methyl-1,2,5-oxadiazoles
into 5H-cycloheptapyrazines and 4H-cyclohepta-1,2,5-oxadiazoles
Masakatsu Matsumoto,* Naoyuki Hoshiya, Ryo Isobe,
Yukie Watanabe and Nobuko Watanabe
Department of Materials Science, Kanagawa University, Tsuchiya, Hiratsuka, Kanagawa 259-1293, Japan
Received 19 February 2004; revised 10 March 2004; accepted 19 March 2004
Abstract—2-(Buta-1,3-dienyl)-3-methylpyrazines (5) and 3-(buta-1,3-dienyl)-4-methyl-1,2,5-oxadiazoles (10) were synthesized
starting from base-induced reaction of 2,3-dimethylpyrazine or 3,4-dimethyl-1,2,5-oxadiazole with a,b-unsaturated carbonyls. The
thus obtained heteroaromatics bearing a butadienyl moiety and a methyl at the adjacent position underwent intramolecular
cyclization by the action of LDA to give the corresponding heteroaromatics fused with a seven-membered ring [7 (8)] and [11 (12)] in
moderate to high yields.
ꢀ 2004Published by Elsevier Ltd.
One fundamental strategy to construct a seven-mem-
bered ring is the carbon–carbon bond formation be-
tween both termini of a C7 carbon chain, as represented
by intramolecular aldol reaction and Dieckmann con-
densation. For these types of intramolecular reaction,
both reaction centers, namely, an anionic carbon and an
electrophilic carbon, are in general separated from each
other through saturated carbons, so that they are pre-
liminarily little different from the intermolecular reac-
tion of a carbanion aside from steric factors. On the
other hand, little has been known of an intramolecular
cyclization of a C7-skeleton involving no saturated car-
bon, in which a carbanion at a terminus is conjugated
formally with a hexa-1,3,5-triene unit to construct a C7-
8p-electron system.
Precursors of the formal C7-8p-electron system now
investigated, namely, 2-(buta-1,3-dienyl)-3-methylpyr-
azines (5a–d), were synthesized from 2,3-dimethylpyr-
azine (1) and a,b-unsaturated carbonyl compounds
(3a–d) in several steps. The initial step was lithiation of
2,3-dimethylpyrazine (1) to a lithium salt of an anion
(2), which was easily attained by the use of butylli-
thium1–3 or lithium diisopropylamide (LDA)4–6 in tet-
rahydrofuran (THF) at ꢀ78 ꢁC. Coupling reaction of an
anion (2) with a,b-unsaturated carbonyl compounds
(3a–d) took place smoothly at ꢀ78 ꢁC. Aldehydes (3a,b)
afforded selectively the corresponding 1,2-adducts (4a,b)
in high yields (>90%), while ketones (3c,d) gave the
corresponding 1,2-adducts (4c,d) along with a consid-
erable amount of 1,4-adducts.7 1,2-Adducts (4a–d) were
dehydrated by the catalysis of p-toluenesulfonic acid
(TsOH) in hot toluene. The desired dienes (5a–d) were
produced as a stereoisomeric mixture of the cis,trans-
isomer and trans,trans-isomer (cis,trans/trans,trans ¼ 40/
60 for 5a and 5b, 80/20 for 5d), except the case of 4c,
which gave only cis,trans-isomer (cis,trans-5c,isolated in
83 % yield).5;8 The structures of these dienes (5) were
In the course of our investigation on homologation of
2,3-dimethylpyrazine and 3,4-dimethyl-1,2,5-oxadiazole,
we found that such a cyclization into a seven-membered
ring occurs effectively for a C7-8p-electron system
comprised of a buta-1,3-dienyl, an anionic methyl, and
two adjacent sp2-carbons of the aromatic heterocycles
joining these two substituents.
1
determined by H NMR, 13C NMR, NOE, IR, Mass,
and HRMass spectral analysis9 (Scheme 1).
As already described, lithiation of a methyl on 2,3-
dimethylpyrazine (1) with butyllithium occurs to give an
anion (2) effectively. Our initial interest was in whether
the remained methyl of a pyrazine, produced by the first
Keywords: Pyrazine; 1,2,5-Oxadiazole; Intramolecular cyclization; 5H-
Cycloheptapyrazine; 4H-Cyclohepta-1,2,5-oxadiazole.
* Corresponding author. Fax: +81-463-58-9684; e-mail: matsumo@
chem.kanagawa-u.ac.jp
0040-4039/$ - see front matter ꢀ 2004Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.03.123

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M. Matsumoto et al. / Tetrahedron Letters 45 (2004) 3895–3898
seven-membered ring product and merely a large
amount of intractable polymeric products when treated
with LDA under the conditions described above (see
Table 1). However, a potassium tert-butoxide/18-crown-
6 ether complex, ([K ꢁ (18C6)]þÆt-BuOꢀ), was found to
be effective for the cyclization. When trans,trans-5a
(2 mmol) was treated with 1.0 equiv of [K ꢁ (18C6)]þÆ
t-BuOꢀ in THF at room temperature for 1 h, a seven-
membered ring products, 7a and its isomer (8a), were
produced in 17% and 37% yield, respectively. This result
suggests that trans,trans-5a and/or its anionic form,
trans,trans-6a, should isomerize into cis,trans-5a and/or
an anion cis,trans-6a in [K ꢁ (18C6)]þÆt-BuOꢀ/THF
system prior to the cyclization.
N
N
CH3
CH3
N
N
CH2
CH3
R1
R2
O
3
2
1
HO
R1
R1
N
N
N
N
CH2
R2
CH3
CH3
cis,trans-5
R2
4
N
a: R1 = H, R2 = An [An = p-(CH3O)C6H4]
b: R1 = H, R2 = Me
R2
R1
CH3
c: R1, R2 = Ph
N
d: R1 = Ph, R2 = t-Bu
trans,trans-5
Scheme 1.
A five-membered ring heteroaromatic compound, 3,4-
dimethyl-1,2,5-oxadiazole, possesses a partial structure,
AN@C(CH3)–C(CH3)@NA, which is formally an
equivalent of diacetyl as in the case of 2,3-dimethyl-
pyrazine (1).12–14 A methyl of 3,4-dimethyl-1,2,5-oxa-
diazole has been reported also to undergo lithiation with
butyllithium similarly to the case of 2,3-dimethylpyr-
azine.15 Thus, we synthesized 3-(buta-1,3-dienyl)-4-
methyl-1,2,5-oxadiazoles (10a–d) by the use of reaction
sequences starting from a,b-unsaturated carbonyl com-
pounds similarly to the case of butadienylpyrazines (5);
cis,trans-isomer (cis,trans-10) and trans,trans-isomer
(trans,trans-10) were produced concomitantly but sepa-
rated easily from each other by column chromatography
or crystallization. When cis,trans-isomers of butadienyl-
oxadiazole (cis,trans-10a–d) were treated with LDA at
ꢀ78 ꢁC as in the case of cis,trans-5, the expected cycli-
zation took place smoothly to afford the corresponding
seven-membered ring products, 4H-cyclohepta-1,2,5-
oxadiazoles, (11a–d) in 42–85% yield as shown in Table
1. Only cis,trans-10a gave an isomeric product (12a) as a
by-product (8%) among cis,trans-10 examined here.
Furthermore, its trans,trans-isomer (trans,trans-10a) was
found to undergo LDA-induced cyclization to give 11a
in moderate yield (32%) even at ꢀ78 ꢁC. It is noteworthy
that all butadienyl-1,2,5-oxadiazoles (10) examined here
gave no detectable amount of five-membered ring
products as in the case of pyrazines (5) (Scheme 3).
homologation of 2,3-dimethylpyrazine (1), can undergo
metal–proton exchange selectively with lithium
a
reagent such as LDA. First of all, we examined a lithi-
ation of 2-[(4-methoxyphenyl)buta-1,3-dienyl]-3-methyl-
pyrazine (5a). When cis,trans-5a (2.0 mmol) was treated
with LDA in THF under N2 atmosphere at ꢀ78 ꢁC, a
deep-violet-colored intermediary anion (6a) was pro-
duced immediately and cyclized spontaneously to give a
5H-cycloheptapyrazine (7a) in 90% yield after usual
work-up and successive chromatographic purification
on silica gel.10 The structure of 7a was determined by 1H
NMR, 13C NMR, IR, Mass, and HRMass spectral
analysis.11 Similar treatment of the cis,trans-form of
dienes (5b–d) with LDA gave the corresponding seven-
membered ring products (7b–d) in 13–92% yields as
shown in Table 1. A butadienylpyrazine (5c) afforded
not only 7c but also a small amount of its isomer (8c)
(3%). It should be noted here for the LDA-induced
reaction of 5 that little cyclization into five-membered
ring products (9) occurred, though it should be formally
possible as a concurrent pathway (vide infra) (Scheme
2).
A trans,trans-isomer of diene (5) is unable to undergo
base-induced cyclization into a cycloheptene (7 or 8), if
left alone, because an anionic methylene and a terminal
carbon of a butadienyl unit are too remote from each
other for the intramolecular cyclization. In fact, a
trans,trans-isomer (trans,trans-5a) gave little of the
As described above, the LDA-induced reaction gave
little of five-membered ring product(s) for neither
Table 1. Base-induced intramolecular cyclization of 2-(buta-1,3-dienyl)-3-methylpyrazine (5) and 3-(buta-1,3-dienyl)-4-methyl-1,2,5-oxadiazole (10)a
Diene
R1
R2
Conditionsb
Product/%
cis,trans-5a
H
An
An
An
Me
Ph
A7a
B
: 90
trans,trans-5a
trans,trans-5a
cis,trans-5b
H
Polymerized
7a: 17, 8a: 37
: 13
H
C
H
A7b
A7c
A7d
A11a
A11a
A11b
A11c
A11d
cis,trans-5c
cis,trans-5d
Ph
Ph
Ph
Ph
Ph
t-Bu
t-Bu
: 92, 8c: 3
: 4 3
t-Bu
Ph
cis,trans-10a
trans,trans-10a
cis,trans-10b
cis,trans-10c
cis,trans-10d
: 80, 12a: 8
: 32
: 85
Ph
t-Bu
Ph
: 79
: 4 2
t-Bu
a Unless otherwise stated, 2.0 mmol of substrate (5 or 10) was treated with 1.0–1.2 equiv of a base in THF (15 mL).
b A: LDA as a base, at ꢀ78 ꢁC, for 1 h; B: LDA as a base, at ꢀ78 ꢁC fi 0 ꢁC, for 1 h; C: a complex of t-BuOK with 18-crown-6 ether {[K ꢁ (18C6)]þt-
BuOꢀ} as a base, at room temperature, for 30 min.

M. Matsumoto et al. / Tetrahedron Letters 45 (2004) 3895–3898
3897
R1
N
LDA
cis,trans-5
-78 °C,
N
CH2
R2
THF
cis,trans-6
R2
N
N
R1
R1
R2
N
N
N
R1
N
9
R2
7
8
N
N
An
-78
LDA / THF
-78 °C
Polymer
0 °C
CH2
trans,trans-6a
trans,trans-5a
N
[K 18C6]+t-BuO-
8a
N
CH2
THF / 0 °C
An
cis,trans-6a
Scheme 2.
R1
An
An
An
LDA
R1
N
N
N
N
N
N
N
LDA
O
An
O
X
-78 °C,
N
N
CH3
N
CH2
CH3
R2
CH3
THF
R2
R1
15
14
16
cis,trans-10
13
11
BuLi
LDA
0 °C, THF
R1, R2 = Ph
R2
N
N
N
N
O
O
Bu
R1
N
N
CH3
R2
12
trans,trans-10
a: R1, R2 = Ph
b: R1 = Ph, R2 = t-Bu
c: R1 = t-Bu, R2 = Ph
d: R1,R2 = t-Bu
Scheme 4.
The above results suggest that LDA-induced intramo-
lecular cyclization of butadienylmethylpyrazines (5) and
their 1,2,5-oxadiazole analogs (10) is most likely
regarded as an intramolecular electrocyclization of a C7-
8p-electron system rather than an intramolecular 1,6-
addition17;18 of a methyl carbanion to a butadienylimine
moiety existing in the same molecule. This idea was
supported by an AM1 MO calculation of an anion
(cis,trans -6a), which suggested that a partial bond for-
mation is already observed between an anionic methyl
and an unsaturated carbon at the 4-position of a buta-
dienyl moiety as illustrated in Figure 1.
Scheme 3.
pyrazines (5) nor 1,2,5-oxadiazoles (10). Thus, 2-[2-(4-
methoxyphenyl)ethenyl]-3-methylpyrazine (13) was
synthesized as a rather simple model for examining a
base-induced intramolecular cyclization into a five-
membered ring product. On treatment with LDA, a
styrylpyrazine (13) gave little of an expected cyclization
product (15) and was still intact even at 0 ꢁC. On the
other hand, addition of butyllithium to a styrylpyrazine
(13) took place to give a pyrazine (16) in 49% isolated
yield, when 13 was treated with butyllithium in THF at
ꢀ78 ꢁC fi room temperature for 1 h. These facts showed
that a styryl moiety should be little activated toward an
attack of a nucleophile for an anionic 2-methyl-3-styr-
ylpyrazine (14), though a styryl moiety is active enough
to allow a nucleophilic attack in a neutral form of 13.16
On similar treatment with butyllithium, both the
trans,trans-isomer of butadienylpyrazine (trans,trans-5a)
and its cis,trans-isomer (cis,trans-5a) gave only poly-
meric products (Scheme 4).
The present results show a new type of intramolecu-
lar cyclization of C7-8p-electron system comprised of a
buta-1,3-dienyl, an anionic methyl, and two adja-
cent sp2-carbons of the aromatic heterocycles, such as
pyrazine and 1,2,5-oxadiazole, joining these two sub-
stituents. We are now investigating an effective trans-
formation of seven-membered ring products 7 and 11
into the corresponding tropolones by a combination of
dehydration of the seven-membered ring and successive
hydrolysis of the heterocycles.

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M. Matsumoto et al. / Tetrahedron Letters 45 (2004) 3895–3898
J ¼ 15:6 Hz, 1H), 6.89 (d with fine coupling, J ¼ 8:7 Hz,
2H), 6.92 (ddd, J ¼ 15:6, 11.0, and 0.7 Hz, 1H), 7.42 (d
with fine coupling, J ¼ 8:7 Hz, 2H), 7.63 (dd, J ¼ 14:9 and
11.0 Hz, 1H), 8.25 (d, J ¼ 2:5 Hz, 1H), 8.35 (d, J ¼ 2:5 Hz,
1H); 13C NMR (125 MHz, CDCl3): dC 21.7, 55.3, 114.2,
125.0, 126.3, 128.1, 129.7, 136.4, 136.6, 141.4, 141.8, 149.6,
151.0, 159.8; IR (KBr) 3044, 2998, 2835, 1597, 1523,
1508 cmꢀ1; Mass (m=z, %) 252 (Mþ, 57), 251 (33), 237 (8),
145 (100); HRMS (ESI) 253.1331, calcd for C16H17N2O
(MþHþ) 253.1341; Anal. Calcd for C16H16N2O: C, 76.16;
H, 6.39; N, 11.10. Found: C, 76.31; H, 6.37; N, 11.05.
10. Typical procedure (synthesis of 7a from 5a): A solution of
cis,trans-5a (511 mg, 2.0 mmol) in THF (10 mL) was added
to a solution of LDA (2.4mmol, prepared from BuLi and
diisopropylamine) in THF (5 mL) drop by drop under N2
atmosphere at ꢀ78 ꢁC over 40 min and stirred for addi-
tional 20 min. After usual work-up, the crude product was
chromatographed on silica gel, and eluted with CH2Cl2–
AcOEt to give 7a in 90% yield.
Figure 1.
References and notes
1. Treatment of polymethylpyrazines with an alkyllithium
has been reported to lead not only to a desired lithiation of
a methyl but to a concurrent alkylation of the pyrazine
nuclei.1;2 However, a product derived from substitution of
a hydrogen on a heteroaromatic ring with a butyl group
was little observed for the case presented here.
11. Selected data for 5H-cycloheptapyrazine (7a): pale yellow
plates melted at 100.8–101.2 ꢁC (from Hexane–AcOEt); 1H
NMR (500 MHz, CDCl3): dH 3.36 (dd, J ¼ 13:3 and
4.1 Hz, 1H), 3.42 (dd, J ¼ 13:3 and 9.6 Hz, 1H), 3.64(dd
with fine coupling, J ¼ 17:0 and 6.9 Hz, 1H), 3.71–3.77 (m,
1H), 3.78 (s, 3H), 3.94(d with fine coupling, J ¼ 17:0 Hz,
1H), 5.64(d with fine coupling, J ¼ 11:9 Hz, 1H), 5.93–
6.00 (m, 1H), 6.83 (d with fine coupling, J ¼ 8:7 Hz, 2H),
7.08 (d with fine coupling, J ¼ 8:7 Hz, 2H), 8.24(d,
J ¼ 2:7 Hz, 1H), 8.26 (d, J ¼ 2:7 Hz, 1H); 13C NMR
(125 MHz, CDCl3): dC 35.2, 42.7, 43.2, 55.2, 113.9, 123.4,
128.6, 133.2, 136.1, 140.9, 141.8, 155.3, 156.7, 158.3; IR
(KBr) 3052, 3021, 2963, 2918, 2864, 2836, 1609,
1512 cmꢀ1; Mass (m=z, %) 252 (Mþ, 100), 251 (37), 237
(19), 145 (30), 144 (29), 134 (20), 131 (19), 121 (24), 108
(22); HRMS (ESI) 253.1335, calcd for C16H17N2O
(MþHþ) 253.1341; Anal. Calcd for C16H16N2O: C,
76.16; H, 6.39; N, 11.10. Found: C, 76.23; H, 6.42, N;
11.12.
2. Rizzi, G. P. J. Org. Chem. 1968, 33, 1333–1337.
3. Rizzi, G. P. J. Org. Chem. 1974, 39, 3598–3599.
4. Houminer, Y. J. Heterocycl. Chem. 1981, 18, 15–17.
5. Houminer, Y. J. Org. Chem. 1980, 45, 999–1003.
6. Bassfield, R. L.; Houminer, Y. J. Org. Chem. 1983, 48,
2130–2133.
7. Ratios of 1,2-adduct versus 1,4-adduct were as follows:
52:48 for 3c, and 71:29 for 3d.
8. The present nomenclature, ‘cis,trans’ or ‘trans,trans’ is
made to emphasize stereochemistry of a butadienyl side
chain. Dienes (5d) were produced in rather poor yield
along with a considerable amount of the starting ketone
(3d), which might be produced by retro-aldol type
reaction. A certain alcohol such as 4 has been reported
to cause retro-aldol type reaction giving a methylpyrazine
and the corresponding carbonyl through intramolecular
hydrogen bonding of an alcoholic proton to a nitrogen of
the pyrazine ring.5
9. Selected data for cis,trans-5a: yellow needles melted at
76.9–78.0 ꢁC (from MeOH); 1H NMR (500 MHz, CDCl3):
dH 2.60 (s, 3H), 3.82 (s, 3H), 6.43 (d, J ¼ 11:5 Hz, 1H),
6.66 (dd, J ¼ 11:5, and 11.2 Hz, 1H), 6.76 (d, J ¼ 15:6 Hz,
1H), 6.87 (d with fine coupling, J ¼ 8:8 Hz, 2H), 7.42 (d
with fine coupling, J ¼ 8:8 Hz, 2H), 8.01 (ddd, J ¼ 15:6,
11.2, and 0.9 Hz, 1H), 8.28 (d, J ¼ 2:5 Hz, 1H), 8.47 (d,
J ¼ 2:5 Hz, 1H); 13C NMR (125 MHz, CDCl3): dC 22.2,
55.3, 114.1, 121.8, 124.0, 128.4, 129.9, 136.7, 138.2, 140.9,
141.4, 151.2, 152.3, 159.8; IR (KBr) 3066, 3045, 3007,
2969, 2931, 2838, 1602, 1594, 1509 cmꢀ1; Mass (m=z, %)
252 (Mþ, 46), 251 (24), 237 (9), 145 (100); HRMS (ESI)
253.1331, calcd for C16H17N2O (MþHþ) 253.1341; Anal.
Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found:
C, 76.27; H, 6.62; N, 11.05. Selected data for trans,trans-
5a: yellow needles melted at 157.3–158.5 ꢁC (from
Hexane–AcOEt); 1H NMR (500 MHz, CDCl3): dH 2.63
(s, 3H), 3.83 (s, 3H), 6.80 (d, J ¼ 14:9 Hz, 1H), 6.81 (d,
12. A pyrazine ring has been known to open by treatment with
hydroiodic acid or by treatment with hydroxide ion after
its transformation into a quarternary pyrazinium salt,
though such ring opening has not been examined thor-
oughly.13 A few examples of ring-opening reaction have
been reported also for 1,2,5-oxadiazoles.14
13. Tutin, F. J. Chem. Soc. 1910, 2495.
14. Ponzio, G.; Bilietti, F. Gazz. Chim. Ital. 1933, 63, 159.
15. Boger, D. L.; Brotherton, C. E. J. Heterocycl. Chem. 1981,
18, 1247.
16. An addition of butyllithium to a solution of anion (14) in
THF gave little products.
17. Addition of a carbanion to a penta-2,4-dien-1-one or a
penta-2,4-dienoate has been known.18
18. Additions to and Substitutions at C–C p-Bonds; Semmel-
hack, M. F., Ed.; In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds. Pergamon: Oxford, 1995;
p 6, p 187.