Regioselective coupling reaction of azulene with α,β-unsaturated ketones by Mg-promoted reduction

Article abstract of DOI:10.1016/j.tetlet.2012.09.080

Mg-Promoted reductive coupling of azulene with various α,β- unsaturated ketones in the presence of chlorotrimethylsilane in 1-methyl-2-pyrrolidinone brought about regioselective formation of the corresponding 6-substituted dihydroazulenes, which were easi

Full text of DOI:10.1016/j.tetlet.2012.09.080

Tetrahedron Letters 53 (2012) 6519–6522
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Regioselective coupling reaction of azulene with
Mg-promoted reduction
a,b-unsaturated ketones by
Hirofumi Maekawa a, , Junya Honda a, Ryoichi Akaba b
⇑
a Department of Materials Science and Technology, Nagaoka University of Technology, 1603-1, Kamitomioka-cho, Nagaoka, Niigata 940-2188, Japan
b Department of Chemistry, Gunma College of Technology, 580, Toriba-machi, Maebashi, Gunma 371-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2012
Revised 10 September 2012
Accepted 19 September 2012
Available online 26 September 2012
Mg-Promoted reductive coupling of azulene with various
a,b-unsaturated ketones in the presence of
chlorotrimethylsilane in 1-methyl-2-pyrrolidinone brought about regioselective formation of the corre-
sponding 6-substituted dihydroazulenes, which were easily oxidized to the corresponding 6-substituted
azulenes by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in good yields. This new regioselective method
enabled us to synthesize various 6-substituted azulenes from azulene in only two steps.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Electron transfer
Magnesium
Reductive coupling
Azulene
Regioselective reaction
Azulene, an isomer of naphthalene is well-known as a blue-
coloured non-benzenoid aromatic compound and many scientists
have been concentrating much attention in view of physical organ-
ic and pharmaceutical chemistry.1 Guaiazulene easily derived from
a natural compound has been studied for a long time2 and its
derivative is used as a potent pharmaceutical drug.3 Furthermore,
azulene derivatives have been recently also focused as photo-
reactive materials.4–6
to azulene with an electron-withdrawing group in the five-
membered ring led to a mixture of 4- and 6-ethynylazulenes.14–16
Namely, ring attacked by a reagent depends on the nature of the
reagent, and regiochemistry is also controlled by resonance and
conjugation of azulene ring. Therefore, it has been an important
theme to control positional regioselectivity and direction of nucle-
ophilic or electrophilic attack. Recently, Sugihara and co-workers
reported the regioselective synthesis of 6-azulenethiocarboxylic
acid derivatives through addition of tris(methylthio)methyllithium
to azulene, which was one of the few examples of selective synthe-
sis of 6-substituted azulenes in several steps from azulene.17,18
Introduction of a hydroxyl group was also explored to give 6-
hydroxyazulene derivatives by Makosza et al.19 Reductive carbox-
ylation of azulene by sodium was already reported,20 which
suggested reductive coupling would be possible. However,
1-azulenecarboxylic acid was obtained in low yield by this
carboxylation.
In spite of such characteristics and much importance7,8 of azu-
lene derivatives, synthetic chemistry of azulenes has not been
wide-spread sufficiently because of much difficulty in regioselec-
tive synthesis. Although in general, electrophiles may exclusively
attack the five-membered ring, and nucleophilic attack may take
place selectively to the seven-membered ring due to the polarity
of azulene ring,1 their detailed positional regioselectivity on both
of nucleo- and electro-substitutions has been rather poor.
For example, electrophiles react at C1- or C3-position of azulene
ring and Vilsmeier–Haack formylation of azulene brought about
formation of 1-formylazulene.9–12 On the other hand, alkyllithium
reagents add to C4- or C8-position of azulene ring. A reaction of
azulene with methyllithium followed by oxidation afforded 4-
methylazulene as a single product.13 Addition of lithium acetylide
We have already reported coupling reactions of a,b-unsaturated
carbonyl compounds, anthracene, and stilbenes with carbonyl
compounds by electron transfer, in which Mg turnings for Grignard
reaction in the presence of chlorotrimethylsilane was found to be a
superior electron transfer agent for those coupling reactions be-
cause of high reactivity, easy handling, low toxicity and easy avail-
ability with no pre-treatment.21–23
In this study, we have developed the regioselective coupling of
azulene with a,b-unsaturated ketones through umpolung by mag-
nesium metal followed by oxidation to establish regioselective for-
mation of 6-substituted azulenes in good yields.
⇑
Corresponding author. Tel.: +81 258 47 9320; fax: +81 258 47 9300.
E-mail address: maekawa@vos.nagaokaut.ac.jp (H. Maekawa).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.080

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H. Maekawa et al. / Tetrahedron Letters 53 (2012) 6519–6522
Table 1
Table 3
Mg-Promoted coupling reaction of azulene (1) and mesityl oxide (2a)
Dehydrogenation of dihydroazulene 3a
Mg / TMSCl
+
Dehydrogenation
NMP
O
3a
3a
2a
5a
1
O
O
O
Entry Mg
TMSCI
(equiv)
2a
(equiv)
Temperature
(°C)
GC Yield
(%)
Entry
Method
Isolated Yield 5a (%)
(equiv)
1a
2b
3c
4d
5e
DDQ/CH2Cl2
DDQ/benzene
p-Chloranil/Et2O
Air oxidation(bubbling)/benzene
Pd/C/toluene(reflux)
21
70
20
-
1
2
3
4
5
6
7
8
9
10
2
3
4
3
3
3
3
3
4
4
6
6
6
3
5
7
6
6
6
6
8
8
8
8
8
8
4
12
8
8
À15
À15
À15
À15
À15
À15
À15
À15
À5
46
64
45
43
44
48
60
56
25
35
-
a
b
c
0 °C to rt, 1 day.
Substrate 0.88 mmol, DDQ 1.2 equiv, benzene 50 ml, 7 °C, 20 min.
0 °C to rt, 1 day.
rt, 1 day.
d
e
À10
rt, 12 h.
Reaction conditions: azulene (3.9 mmol), NMP (25 mL), under N2 atmosphere.
Table 4
Synthesis of azulene 5 by dehydrogenation
Table 2
Mg-promoted regioselective coupling of azulene (1) and
compounds 2
a,b-unsaturated carbonyl
DDQ
R1
R1
Benzene
Z
Z
R2
R1
R2
R3
R2
5
R3
3
R3
Mg / TMSCl
NMP
Z
R1
+
Z
Entry
R1
R2
R3
Z
Isolated yield 5 (%)
R2
3
2
1
R3
1
2
3
4
5
H
CH3
H
H
H
CH3
H
CH3
CH3
CH3CO
CH3CO
5a
5b
5c
5d
5e
70
41a
52
78
82
CH3
H
CH3
–CH2C(CH3)2CH2CO–
–CH2CH2CH2CO–
–CH2CH2CO–
Entry
1
2
Isolated yield 3a (%)
a
A mixture of diastereomers (9:1).
2b
3b
43b
O
2
3
4
0
0
0
O
and this reaction is not applicable to aliphatic esters or nitriles in-
stead of ketones because of easy polymerization of the starting
materials (entries 2–4). Cyclic ketones also reacted with azulene
to give the corresponding 6-substituted dihydroazulenes in spite
of steric hinderance (entries 5–7). Interestingly, only the reaction
of 2-cyclopenten-1-one (2f) afforded a mixture of 4- and 6-regioi-
somers probably because three-dimensionally small size of 2f
minimized the steric effect between 2f and hydrogen atom at
C1-position of the azulene ring (entry 8).
O
O
NC
O
5
2c
3c
41b
6
7
8
2d
2e
2f
O
3d
3e
49b
54b
O
O
Oxidation
by
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in benzene turned out to be an efficient route to azulene
5a from 3a while neither air oxidation nor dehydrogenation by pal-
ladium–carbon afforded the corresponding azulene (Table 3). The
results of dehydrogenation of 3a–e are summarized in Table 4
and most of the dihydroazulenes were transformed into the corre-
sponding azulenes in good to moderate yields.
3f and 4
21b,c
a
Neither significant regioisomer nor by-product was detected except entry 8.
Olefinic position could not be examined in detail.
b
A mixture of diastereomers.
A mixture of 4- and 6- regioisomers. (4 and 3f, respectively).
c
The mixture of isomers 3f and 4 was also oxidized under the
similar reaction conditions to give the corresponding mixture of
regioisomers 5f and 6 in 53% yield. The 6-substituted isomer 5f
turned out to be a predominant product by isolation and analysis
of the products (Scheme 1).
Thus, Mg-promoted reduction of azulene (1) in the presence of
8 equiv of mesityl oxide (2a) and 6 equiv of chlorotrimethylsilane
in 1-methyl-2-pyrrolidinone at À15 °C gave a single cross-coupling
compound 3a at the C6-position of 1 as shown in Table 1. The re-
sults of reductive coupling of 1 with various kinds of
a,b-unsatu-
rated carbonyl compounds under the similar reaction conditions
are summarized in Table 2.
DDQ
The structure of 3a was determined by 1H and 13C NMR spectra.
Coupling pattern and chemical shift of the signals of 3a are quite
similar to those of dihydroazulene given by Birch reduction of azu-
lene.24,25 Existence of alkyl group at the b-carbon atom towards the
carbonyl carbon atom is essential to proceed this coupling reaction,
3f and 4
+
O
Benzene
5f
6
O
53% (5f : 6 = 5 : 4)
Scheme 1.

H. Maekawa et al. / Tetrahedron Letters 53 (2012) 6519–6522
6521
C16A
C16
C8
C1
C9
C7
C2
C3
C12
C12A
C13
C6
C10
C11
C4
C13A
C11A
C5
O1A
C15
C15A
C14
C14A
O1
Figure 1. Chemical structure of 5e by X-ray crystalline analysis.
Table 5
O
O
Reduction potential of substrates by cyclic voltammetry
Mg, TMSCl
NMP
DDQ
+
Substrate Potential/V versus Ag/
AgCl
Substrate
Potential/V versus Ag/
benzene
AgCl
8
7
1
Total Yield 39%
O
O
À1.58
À1.77
Scheme 2.
9
1
O
À2.18
2a
TMSCI
No wave (À3.0–0)
Mg, TMSCl
NMP
Conversion Yield 51%
DDQ
+
O
O
9
benzene
Working electrode, counter electrode: Pt, reference Electrode: Ag/AgCl, solvent:
NMP, supporting electrolyte: Bu4NCIO4, sweep rate: 100 mV/s.
10
1
(Conversion of 1, 21%)
O
O
Scheme 3.
CH3
O
H3C
H
CH3
TMSCl
Mg (+e)
2a
Mg (+e)
The NMR spectra clearly supported symmetrical structure of
those obtained azulene derivatives 5a–f, which suggested regiose-
lective synthesis of 2- or 6-substituted azulene. Finally, the struc-
ture of azulene racemate 5e was confirmed by X-ray crystalline
analysis, as shown in Figure 1.
H3C
H
CH3
O-
11
1
CH3
H+
DDQ
Similarly, the coupling reaction of b-ionone, a,b,c,d-conjugated
dienone (7), with azulene also regioselectively proceeded at the d-
carbon atom towards the carbonyl group among the three possible
carbon atoms of 7. Regioselective addition of conjugated dienone 7
to the C6-position of the azulene ring, followed by oxidation, also
occurred to give a single product 8 (Scheme 2). In this case, isola-
tion of dihydroazulene was quite difficult and the dihydroazulene
was oxidized to the corresponding azulene promptly.
H3C
H
H3C
H3C
CH3
OTMS
CH3
O
CH3
O
CH3
3a
H
H
CH3
CH3
5a
Scheme 4.
Furthermore, a coupling compound 10 was obtained in the sim-
ilar reaction of 1 with coumarin (9), a typical aromatic
rated ester, while the conversion of 1 was quite low, compared
with the reactions of aliphatic ,b-unsaturated compound
(Scheme 3). The yield of 10 was calculated on the basis of the con-
verted amount of 1. It may be interesting to obtain different results
a,b-unsatu-
by single electron transfer from magnesium to azulene. On the
other hand, the difference of reduction potential between azulene
1 and coumarin 9 is not so large, and the reduction of 1 and 9 may
occur competitively, therefore, the reaction is thought to proceed
less selectively and ineffectively.
a
between aliphatic
a,b-unsaturated ester and aromatic one in the
coupling with 1.
The plausible reaction mechanism is shown in Scheme 4. An an-
ion radical species 11 derived from single electron transfer from
Application of guaiazulene instead of azulene to this coupling
reaction with mesityl oxide gave no coupling compound probably
because of the steric hindrance of alkyl groups of guaiazulene.
To clarify the reaction mechanism, reduction potential of the
substrates was measured by cyclic voltammetry as shown in Ta-
ble 5, indicating that azulene is much easily reduced than 2a.
Therefore, it may be reasonably postulated that the reaction be-
magnesium to azulene attacks
a,b-unsaturated ketone 2a to give
a coupling compound which is reduced by the second electron
transfer from magnesium immediately. Azulene radical anion can
be represented as a structure of 11 in which the negative charge
is delocalized mainly in the five-membered ring and the unpaired
electron is delocalized mainly in the seven-membered ring. Since
the C4 or C8 position may be sterically influenced by the hydrogen
tween azulene and aliphatic
a,b-unsaturated ketone is initiated

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H. Maekawa et al. / Tetrahedron Letters 53 (2012) 6519–6522
7. Estdale, S. E.; Brettle, R.; Dunmur, D. A.; Marson, C. M. J. Mater. Chem. 1997, 7,
391–401.
8. Hänig, S.; Ort, B. Liebigs Ann. Chem. 1984, 1905–1935.
atom at the C1 or C3 position, respectively, 11 would undergo
Michael addition to 2a at C6-position in a selective manner. After
silylation by chlorotrimethylsilane, followed by usual work-up,
dihydroazulene 3a was isolated and azulene 5a was obtained
through dehydrogenation by DDQ.
As a summary, Mg-promoted reduction of azulene in the pres-
ence of a,b-unsaturated ketone and chlorotrimethylsilane afforded
9. Hafner, K.; Bernhard, C. Angew. Chem. 1957, 69, 533.
10. Hafner, K.; Bernhard, C. Liebigs Ann. Chem. 1959, 625, 108–123.
11. Nefedov, V. A.; Tarygina, L. K. Russ. J. Org. Chem. 1994, 30, 1724–1728.
12. Shoji, T.; Inoue, Y.; Ito, S. Tetrahedron Lett. 2012, 53, 1493–1496.
13. Hafner, K.; Weldes, H. Liebigs Ann. Chem. 1957, 606, 90–99.
14. Fujita, T.; Morita, T.; Takase, K. Tetrahedron Lett. 1974, 15, 2585–2586.
15. Morita, T.; Fujita, T.; Takase, K. Bull. Chem. Soc. Jpn. 1980, 53, 1647–1651.
16. Hänig, S.; Hafner, K.; Ort, B.; Müller, M. Liebigs Ann. Chem. 1986, 1222–1240.
17. Kurotobi, K.; Takakura, K.; Murafuji, T.; Sugihara, Y. Synthesis 2001, 1346–1350.
18. Shibasaki, K.; Ooishi, T.; Yamanouchi, N.; Murafuji, T.; Kurotobi, K.; Sugihara, Y.
J. Org. Chem. 2008, 73, 7971–7977.
19. Makosza, M.; Podraza, R. Eur. J. Org. Chem. 2000, 193–198.
20. Anderson, A. G.; Gale, D. J.; McDonald, R. N.; Anderson, R. G.; Rhodes, R. C. J. Org.
Chem. 1964, 29, 1373–1377.
21. Ohno, T.; Sakai, M.; Ishino, Y.; Shibata, T.; Maekawa, H.; Nishiguchi, I. Org. Lett.
2001, 3, 3439–3442.
6-substituted dihydroazulenes in good yield26 and the dihydroazu-
lenes can be easily converted into the corresponding azulenes in
good to moderate yields. This coupling reaction is a novel method
for the regioselective synthesis of 6-substituted azulenes through
electron transfer only in two steps, and also a novel carbon–carbon
bond formation between electron-deficient carbon atoms at the
same time. Further investigations on synthetic and mechanistic as-
pects of these reductive coupling reactions are now in progress.
22. Matsunami, M.; Sakai, N.; Morimoto, T.; Maekawa, H.; Nishiguchi, I. Synlett
2007, 769–774.
23. Yamamoto, Y.; Maekawa, H.; Goda, S.; Nishiguchi, I. Org. Lett. 2003, 5, 2755–
2758.
Acknowledgments
24. Kuroda, S.; Asao, T. Tetrahedron Lett. 1977, 18, 285–288.
Authors thank Mr. Hiroyasu Sato, Rigaku Cooperation for X-ray
crystalline analysis of our product 5e.27 This work was supported
in part by Grant-in-Aid for Scientific Research, No. 22605003 from
Japan Society for the Promotion of Science (JSPS) and The Uchida
Energy Science Promotion Foundation.
25. Oda, M.; Kajioka, T.; Uchiyama, T.; Nagara, K.; Okujima, T.; Ito, S.; Morita, N.;
Sato, T.; Miyatake, R.; Kuroda, S. Tetrahedron 1999, 55, 6081–6096.
26. General procedure for the coupling reaction of azulene and mesityl oxide. A general
procedure is as follows. Magnesium turnings (0.28 g, 11.5 mmol) for Grignard
reagent with no pre-treatment in dry 1-methyl-2-pyrrolidinone (NMP) (20 ml)
was placed in a 100 mL-four-necked flask and TMSCl (2.54 g, 23.4 mmol) was
added dropwise. After activation of magnesium for 30 min, the mixture was
cooled to À15 °C and a mixture of azulene (0.5 g, 3.9 mmol) and mesityl oxide
(3.06 g, 31.2 mmol) in dry NMP (5 ml) was added dropwise and stirring was
continued until azulene was consumed completely. Then the reaction mixture
was poured into a mixture of water (10 ml), THF (50 ml) and p-toluenesulfonic
acid mono-hydrate (1.2 g, 6.3 mmol) was added to the flask and the mixture
was stirred for 30 minutes. The reaction mixture was extracted with ether
three times. The combined organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified by column chromatography to give 3a. 4-
(1,6-Dihydroazulenyl)-4-methylpentan-2-one (3a): 1H NMR (400 MHz, CDCl3) d
(ppm): 1.17 (6H, s), 1.38–1.41 (1H, m), 2.16 (3H, s), 2.53 (2H, s), 3.30–3.31 (2H,
m), 5.17 (1H, dd, J = 6.4 Hz, 9.6 Hz), 5.28 (1H, dd, J = 6.4 Hz, 9.6 Hz), 6.38–6.40
(1H, m), 6.50–6.55 (2H, m), 6.64–6.63 (1H, m). 13C NMR (100 MHz, CDCl3) d
(ppm): 24.07, 32.75, 34.54, 43.68, 48.51, 52.45, 117.37, 119.41, 122.90, 124.08,
131.95, 134.66, 143.96, 144.32, 208.85. IR (Neat): 3054, 2985, 2305, 1703,
1421, 1360, 1265, 1018, 956, 987, 735, 705 cmÀ1. LRMS (EI) m/z: 228 [M+].
HRMS (EI): Calculated for C16H20O, 228.1514, Found 228.1513.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.080.
References and notes
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Stuttgart, 1985; Vol. 5/2C, p. 127 and reference cited therein.
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3. Treibs, W.; Schroth, W. Liebigs Ann. Chem. 1954, 586, 202–212.
4. Farrand, L.; Findlater, M.; Giles, M.; Heeney, M.; Tierney, S.; Thompson, M.;
Shkunov, M.; Sparrowe, D.; McCulloch, I. Eur. Pat. 2003, EP 1,318,183.
5. Tanabe, J.; Shinkai, M.; Tsuchiya, M. Jpn. Kokai Tokkyo Koho 2008, JP 2008-
101065.
27. Crystallographic data for the structural analyses of 5e have been deposited
with the Cambridge Crystallographic Data Centre (CCDC No. 883613). Copy of
this information can be obtained free of charge via www.ccdc.cam.ac.uk.
6. Yamaguchi, Y.; Maruya, Y.; Katagiri, H.; Nakayama, K.; Ohba, Y. Org. Lett. 2012,
14, 2316–2319.