Synthesis of 2-aminoazulene derivatives. Nucleophilic and palladium-catalyzed amination of 2-substituted azulene

Article abstract of DOI:10.1016/j.tet.2003.08.048

Amination of 2-substituted azulene was carefully examined using several types of amines, and the scope and limitation of substrates and reagents in these direct nucleophilic aminations were found. The synthesis of 2-aminoazulenes was successfully achieved by the reaction of 2-bromoazulene with several amines via palladium-catalyzed amination.

Full text of DOI:10.1016/j.tet.2003.08.048

Tetrahedron 59 (2003) 8191–8198
Synthesis of 2-aminoazulene derivatives. Nucleophilic and
palladium-catalyzed amination of 2-substituted azulene
Ryuji Yokoyama,a Shunji Ito,a Tetsuo Okujima,a Takahiro Kubo,a Masafumi Yasunami,b
Akio Tajiric and Noboru Moritaa
,
*
aDepartment of Chemistry, Graduate School of Science, Tohoku University, Aramaki Aza Aoba, Sendai 980-8578, Japan
bDepartment of Materials Science and Engineering, College of Engineering, Nihon University, Koriyama 963-1165, Japan
cDepartment of Materials Science, Faculty of Science and Technology, Hirosaki University, Hirosaki 036-8561, Japan
Received 9 July 2003; accepted 19 August 2003
Abstract—Amination of 2-substituted azulene was carefully examined using several types of amines, and the scope and limitation of
substrates and reagents in these direct nucleophilic aminations were found. The synthesis of 2-aminoazulenes was successfully achieved by
the reaction of 2-bromoazulene with several amines via palladium-catalyzed amination.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
catalyzed aryl amination using aryl halides (or aryl triflates)
and amines.9 We previously reported the synthesis of the
parent azulene in excellent yield,10 from 2-hydroxyazu-
lene.11 In continuation of this research to explore a general
method for amination reactions of 2-hydroxyazulene and its
derivatives, we made a systematic study of nucleophilic
amination of 2-hydroxyazulene and its related compounds
(2-bromoazulene (4),12 2-azulenyl methanesulfonate (5a),
2-azulenyl p-toluenesulfonate (5b), and 2-azulenyl tri-
fluoromethanesulfonate (5c)) in order to clarify the scope
and limitation of the amination. Herein we report the direct
nucleophilic amination of 2-substituted azulenes and, in
addition, an initial application for the palladium-catalyzed
amination.
There are several kinds of known synthetic pathways for
aminoazulenes, which exhibit very interesting chemical
behavior dependent on the substituted positions,1 and are
useful for the synthesis of a higher rank of aminoazulene
derivatives,2 super-stabilized carbocations,3 azulene fused
with pyridine,4 molecules with potential applications for
non-linear optics,5 etc. On the other hand, azulene is
interpreted to be stabilized by contribution of a polarized
structure, where the negative charge is on five-membered
ring and the positive charge on the seven-membered ring.6
Therefore, nucleophilic attack on azulene is expected to
occur only at C-4, 6, and 8 of the seven-membered ring.7
Meanwhile, azulene derivatives having a leaving group at
C-2 and electron-withdrawing groups such as the alkoxy-
carbonyl and/or cyano groups at the C-1 and/or C-3 position
undergo also nucleophilic substitution at C-28 or C-6.7d But
there are few reports on the nucleophilic substitution of
azulene with a leaving group at the C-2 position and without
an electron-withdrawing group at the C-1 and C-3
position.8a There is no report about nucleophilic addition
of amino groups and dissociation of leaving groups such as
the halogen or sulfonyl groups (nucleophilic amination) in
azulenes without an electron-withdrawing group at the C-1
and C-3 positions. Moreover, to our knowledge, there is no
report of palladium-catalyzed amination to form a new
azulenyl carbon–nitrogen bond in contrast to palladium-
2. Result and discussion
2.1. Synthesis of 2-aminoazulenes from 2-hydroxy-
azulene
From cycloheptatriene, 2-hydroxyazulene (1) was con-
veniently prepared in 3 steps.11 There is the equilibrium
between 2-hydroxyazulene (1) and 2-(1H)-azulenone (2).13
If compound 2 retained the nature of a carbonyl group more
strongly than heptafulvene in solution, condensation reac-
tion by amines would be expected to easily occur. There-
fore, the first of all, the reaction of 2-hydroxyazulene with
amines in benzene was investigated. The results of the
reactions with a variety of amines are summarized in Table 1
(Scheme 1).
Keywords: 2-aminoazulene; nucleophilic amination; palladium catalyzed
amination; 2-bromoazulene.
*
Corresponding author. Tel./fax: þ81-22-217-7714;
e-mail: morita@funorg.chem.tohoku.ac.jp
The reaction of compound 1 with pyrrolidine at reflux
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.048

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R. Yokoyama et al. / Tetrahedron 59 (2003) 8191–8198
Scheme 1.
Table 1. Reaction of 1 with amines
Table 2. Reaction of 4 with amines
Entry
1
Amine
Time (h)
12
Product (%)a
Recover (%)
0
Entry
1
Amine
Time (h)
4
Product (%)a
3a (75)
3a (85)
2
3
12
12
3b (26)
3c (31)
21
18
2
3
48
5
3b (43)
3c (24)
4b
5b
6
NHMe2
NHEt2
1-Aza-15-crown
12
18
18
3d (16)
3e (5)
3i (0)
66
34
86
The reaction of 4 with amine was carried out without solvent at 1008C.
Isolated yield based on 4.
a
a
Isolated yield based on 1.
The reaction was carried out in a sealed tube.
b
in Scheme 3. On mesylation, the sulfonylation of the
hydroxy group and the electrophilic attack at the C-1
position are competitive. Compound 6a was not obtained
from compound 5a under the same reaction conditions. It
was reported that a refluxing acetonitrile solution of azulene
and methanesulfonyl chloride in the absence of a base gave
methyl-1-azulenyl sulfone in excellent yield.15 However,
the reaction of 1 with trifluoromethanesulfonyl choride gave
no clear reaction products. However, considerable difficul-
ties were found when we attempted to convert 1 to triflate
5c. We could not get 5c under a similar condition.
temperature in benzene for 12 h afforded 3a14 in 75% yield
(entry 1). However, the reaction of compound 1 with
piperidine, morpholine, dimethylamine, and diethylamine
afforded the corresponding aminoazulenes 3b,14a 3c,14a 3d
and 3e in low yields (entries 2, 3, 4, and 5). Compound 1 did
not react with 1-aza-15-crown, and the starting material 1
was recovered in 86% yield (entry 6).
2.2. Synthesis of 2-aminoazulenes from 2-bromoazulene
Conversion of the hydroxyl group in azulene into a more
reactive leaving group should be necessary for the purpose
of nucleophilic substitutions by amines.
On changing the base from triethylamine to pyridine,
prolonged reaction time was necessary (24 h), and the yields
of 5a, 6a and 5b were decreased. Furthermore, a by-product
7 was obtained in 2% yield when methanesulfonyl chloride
and p-toluenesulfonyl chloride were used. Trifluoro-
methanesulfonyl chloride did not exhibit the similar
reactivity to other sulfonyl chlorides, even in the presence
of pyridine, but underwent electrophilic substitution reac-
tion of 2-hydroxyazulene at the C-1 and C-3 position to
give 8 in 35% yield. Finally, 2-azulenyl trifluoromethane-
sulfonate (5c) was prepared by the reaction of 1 with
trifluoromethanesulfonyl anhydride in the presence of
triethylamine10 (Scheme 4).
2-Hydroxyazulene easily converted to 2-bromoazulene (4)
by the treatment with PBr3. As a next step, the nucreophilic
amination of 4 was carried out (Scheme 2). Although the
reaction of compound 4 with pyrrolidine afforded 3a in 85%
yield (Table 2, entry 1) and the reaction of compound 4 with
piperidine gave the corresponding aminoazulene in better
yield (entry 2) than previous one, in case of morpholine the
expected product 3c was only obtained (entry 3) in 24%
yield after 5 h. Futhermore, if heating was continued for
72 h until bromide 4 was disappeared, expected product 3c
could not be obtained at all.
We examined the reaction of 5a, 5b, and 5c having desirable
leaving groups (methanesulfonyl, p-toluenesulfonyl, and
trifluoromethanesulfonyl groups) with highly nucleophilic
amines without a solvent at 1008C as shown in Scheme 5.
The reaction of 5a and 5b with pyrrolidine was completed in
1 h, and afforded 3a in 66 and 65% yields, respectively. The
triflate 5c reacted with pyrrolidine to give 3a in 82% yield
after 15 min. However, similar to the reaction of 1 with
pyrrolidine, the yields of 3b and 3c, which were obtained by
the reaction of 5a and 5b with piperidine or morpholine,
2.3. Nucleophilic amination of 2-azulenylsulfonates
The direct nucleophilic substitution of substrates having a
better leaving group at the 2-position of azulene such as
mesylate 5a, tosylate 5b, and triflate 5c with amines was
next investigated. 2-Hydroxyazulene could be converted
easily to 5a, and 5b using the corresponding sulfonyl
chlorides in the presence of triethylamine as a base as shown
Scheme 2.

R. Yokoyama et al. / Tetrahedron 59 (2003) 8191–8198
8193
Scheme 3.
Scheme 4.
We found that this procedure is the most efficient coupling
procedure of 4 with secondary amines to give the
corresponding aminoazulens (3a–e, and 3i,j). In the case
of diethylamine, 15 mol% of Pd2(dba)3 was used to give
N,N-diethylaminoazulene 3e in 80% yield. If a smaller
amount of catalyst (5 mol% of Pd2(dba)3) was used, the
yield of 3e decreased (76%) and prolonged reaction time
was necessary (12 h). Similarly, the palladium-catalyzed
amination of azulene with primary amine also effectively
gave the corresponding coupling products (3f, 3g and 3h).
Moreover, the reaction of 4 with a weakly nucleophilic
indole under the same reaction conditions gave 3k in
excellent yield. It is noteworthy that the palladium-
catalyzed amination of 4 with 1-aza-15-crown-5 ether,
which is the weakest nucleophile, gave the corresponding
N-azulenyl-aza-crown ether (3l) in 66% yield.
Scheme 5.
were lower (entry 4 and 5). The reaction of 5c with
piperidine needed only 20 min to complete. From these
facts, we found that compound 5c was an excellent reagent
for the direct amination. Although the yield of 3c was
relatively low (entry 9), the reactions of 5c with pyrrolidine
and piperidine were completed within 20 min. Products 3a
and 3b were obtained in high yields (entry 3 and 6).
Similarly, the reaction of 5c with dimethylamine for 30 min
afforded 3d8 in 83% yield (entry 10). However, the 2-(N,N-
diethyl)aminoazulene or primary aminoazulene was not
obtained by the reaction of 5c with corresponding amins. On
the basis of these results, we conclude the reactivity order in
nucleophilic amination of 2-azylenyl sulphonate to be
OMsøOTs,OTf, but the reactivity of the trifluoromethane-
sulphonate is not enough for potential synthesis of a variety
of 2-aminoazulenes.
3. Conclusions
We have made clear the scope and limitation of 2-amino-
azulene synthesis by direct nucleophilic substitution.
Using a combination of Pd2(dba)3 with BINAP, a variety
of 2-substituted aminoazulenes could be conveniently
prepared through the palladium-catalyzed amination of
2-bromoazulene 4 with several amines. We are currently
investigating the physical and chemical behavior of the
obtained products.
2.4. The palladium-catalyzed amination of 2-bromo-
azulene
Therefore, we next turned our attention to an application of
efficient transition-metal-catalyzed coupling amination. In
the palladium-catalyzed amination of benzenoid aromatics,
aryl triflates are known to be good substrates,9b but attempts
to utilize compound 5c were not successful because of the
decomposition of 5c to give 1 under the reaction condition.
Successful amination was ultimately realized utilizing
compound 4 by exploiting a recent advantageous method.9a
The reactions of 4 with amines were carried out by heating a
toluene solution of the reaction mixture at 1008C for 1 h in
the presence of NaOtBu, Pd2(dba)3, and BINAP (Scheme 6).
4. Experimental
4.1. General
Melting points were determined on a Yanagimoto micro
melting point apparatus MP-S3 and are uncorrected. Mass
spectra were obtained with a JEOL HX-110 or a Hitachi
M-2500 instrument usually at 70 eV. IR and UV spectra
were measured on a Shimadzu FTIR-8100M and a Hitachi
1
U-3410 spectrophotometer, respectively. H NMR spectra
(13C NMR spectra) were recorded on JEOL LAMBDA 400
(100 MHz) and 600 (150 MHz). Elemental analyses were
performed at the Instrumental Analysis Center of Chem-
istry, Faculty of Science, Tohoku University.
Scheme 6.

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R. Yokoyama et al. / Tetrahedron 59 (2003) 8191–8198
4.2. General procedure for the reaction of 2-hydroxy-
azulene (1) with amines
d¼7.77 (2H, m, 4-H and 8-H), 7.07 (3H, m, 5-H, 6-H, and
7-H), 6.58 (2H, broad s, 1-H and 3-H), 3.50 (4H, q,
J¼7.2 Hz, N(CH2CH3)2), 1.27 (6H, t, J¼7.2 Hz,
N(CH2CH3)2; 13C NMR (100 MHz, CDCl3) d¼158.24
(C-2), 142.09 (C-3a and C-8a), 127.35 (C-6), 126.21 (C-4
and C-8), 124.55 (C-5 and C-7), 100.12 (C-1 and C-3),
45.36 (CH2CH3), and 13.20 (CH2CH3); MS (EI, 70eV) m/z
(%) 199 (Mþ, 100), 184 (81), 170 (23), 156 (33), 141 (6),
128 (38), 115 (6), 100 (6), 92 (6), and 77 (7). Anal. calcd for
C14H17N: C, 84.37; H, 8.60; N, 7.03; Found: C, 84.47; H,
8.80; N, 6.99.
A mixture of 2-hydroxyazulene (76 mg, 0.53 mmol) and
amine (1.1 mmol) in benzene (30 mL) was heated at reflux
temperature under nitrogen atmosphere. After stirring for
12 h, the solvent was removed under reduced pressure. The
residue was chromatographed by silica gel with ethyl
acetate/hexane (1:4). Yields were shown in Table 1.
4.2.1. 2-Pirrolidinoazulene (3a). Orange powder, mp
116.5–117.58C (lit.14 mp 114.0–115.08C); m/z (EI, 70 eV)
197 (Mþ, 100), 169 (7), 154 (5), 142 (11), and 128 (9).
4.3. General reaction condition of 2-bromoazulene (4)
with amines
4.2.2. 2-Piperidinoazulene (3b). Dark red needles; mp
107.5–108.08C (lit.14a 106–1078C). IR nmax (KBr) 3051,
3011, 1568, 1541, 1524, 1460, 1449, 1441, 1410, 1397,
1374, 1354, 1287, 1223, 1123, 936, 776, 720, and
660 cm21; UV–Vis (CH2Cl2) lmax (log 1) 487 sh (2.81),
427 (4.22), 408 (4.12), 364 (3.69), 339 (3.71), 307 (4.79),
A solution of 4 (52 mg, 0.25 mmol) and an amine (2 mL)
was heated at 1008C. After stirring for adequate time (shown
in Table 2), the amine was removed under reduced pressure.
The residue was purified by chromatography on silica gel
with ethyl acetate / hexane (1:4) to afford 3. Their yields
were shown in Table 2.
1
and 296 nm (4.70); H NMR (400 MHz, CDCl3) d¼7.80
(2H, d, J¼9.5 Hz, 4 and 8-H), 7.14–7.03 (30H, m, 05, 6, and
7-H), 6.67 (2H, s,01 and 3-H), 3.49 (4H, m, 2 and 6 -H), and
1.69 (6H, m, 30, 4 , and 50-H); 13C NMR (100 MHz, CDCl3)
d¼160.42 (C-2), 141.95 (C-3a and C-8a), 128.18 (C-6),
127.27 (C-4 and C-8), 124.510 (C-5 and C-7), 100.85 (C-1
and C-3), 49.01 (C-20 and C-6 ), 25.57 (C-30 and C-50), and
24.42 (C-40); MS (EI, 70 eV) m/z(%) 211 (Mþ, 100%), 196
(12), 182 (6), 155 (10), 141 (8), 128 (25), 106 (6), and 77
(8). Anal. calcd for C15H17N: C, 85.24; H, 8.11; N, 6.63;
Found: C, 85.24; H, 8.13; N, 6.58.
4.4. Synthesis of 2-azulenyl methanesulfonate (5a) from
2-hydroxyazulene
A solution of triethylamine (608 mg, 6.01 mmol) in dry
CH2Cl2 (10 mL) was added dropwise at room temperature
to a mixture of 1 (285 mg, 1.98 mmol), methanesulfonyl
chloride (494 mg, 4.31 mmol) in the same solvent (10 mL)
over a period of 5 min, and stirring the mixture at room
temperature for another 25 min. After the reaction mixture
was washed by water, the organic layer was dried over
MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel with CH2Cl2 to afford 5a (332 mg, 76%) and 6a (50 mg,
8%).
4.2.3. 2-Morpholinoazulene (3c). Orange plates; mp
170.0–170.58C (lit.14a 168–1688C); IR (KBr) nmax 3013,
2955, 2892, 2851, 1541, 1524, 1453, 1410, 1366, 1269,
1252, 1219, 1117, 988, 938, 872, 776, and 722 cm21
;
UV–Vis (CH2Cl2) lmax (log 1) 485 sh (2.59), 416 (4.04),
399 sh (3.98), 329 sh (3.70), 305 (4.69), 295 (4.61), 248 nm
(4.03); 1H NMR (400 MHz, CDCl3) d¼7.89 (2H, d,
J¼9.5 Hz, 4 and 8-H), 7.22 (1H, t, J¼9.5 Hz, 6-H), 7.12
(2H, t, J¼9.5 Hz, 5 and 70-H), 6.70 (2H, s, 1 and 3-H), 3.86
(4H, t0, J¼4.8 Hz, 30 and 5 -H), and 3.48 (4H, t, J¼4.8 Hz, 20
and 6 -H); 13C NMR (100 MHz, CDCl3) d¼159.65 (C-2),
141.60 (C-3a and C-8a), 129.66 (C-6), 128.80 (C-4 or C-8),
128.62 (C-8 or C0-4), 124.66 (C-5 and C-7), 100.78 (C0-1 and
C-3), 66.59 (C-3 and C-50), and 47.99 (C-20 and C-6 ); MS
(EI, 70 eV) m/z (%) 213 (Mþ, 100), 198 (11), 184 (7), 155
(35), 141 (7), 128 (33), 107 (5), 77 (19), and 64 (6). Anal.
calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57; Found: C,
78.56; H, 7.27; N, 6.55.
4.4.1. 2-Azulenyl methanesulfonate (5a). Purple crystals;
mp 118.0–118.58C; IR (KBr) nmax 3033, 1484, 1458, 1402,
1362, 1347, 1331, 1318, 1177, 1113, 984, 972, 835, 797,
766, 737, 579, 527, and 519 cm21; UV–Vis (CH2Cl2) lmax
(log 1) 628 sh (2.11), 577 (2.53), 338 (3.72), 326 (3.65), 283
1
(4.83), and 275 nm (4.80); H NMR (400 MHz, CDCl3)
d¼8.33 (2H, d, J¼9.8 Hz, 4 and 8-H), 7.66 (1H, t,
J¼10.5 Hz, 6-H), 7.31 (2H, dd, J¼10.5, 9.8 Hz, 5 and
7-H), 7.21 (2H, s, 1 and 3-H), and 3.20 (3H, s, CH3); 13C
NMR (100 MHz, CDCl3) d¼155.10 (C-2), 138.38 (C-3a
and C-8a), 137.15 (C-6), 137.05 (C-4 and C-8a), 124.94
(C-5 and C-7), 106.38 (C-1 and C-3), 37.42 (CH3); MS (EI,
70 eV) m/z (%) 222 (Mþ, 70), 144 (17), 143 (Mþ2CH3SO2,
7), 115 (100), and 89 (6). Anal. calcd for C11H10O3S: C,
59.44; H, 4.53; S, 14.43; Found: C, 59.09; H, 4.62; S, 14.38.
4.2.4. 2-(N,N-Dimethyl)aminoazulene (3d). Orange plates,
mp 97.5–98.08C (lit.8a, mp 98.0–99.08C); MS (EI, 70 eV)
m/z (%) 171 (Mþ, 100), 156 (24), 141 (7), 128 (46), 115 (6),
86 (9), 77 (8), and 64 (6); Anal. calcd for C12H13N: C, 84.17;
H, 7.65; N, 8.18; Found: C, 84.03; H, 7.74; N, 8.15.
4.4.2. 1-Mesylazulen-2-yl methanesulfonate (6a). Red
crystals; mp 140.0–141.08C; IR (KBr disk) nmax 3131,
3067, 3029, 3011, 1595, 1582, 1538, 1509, 1464, 1453,
1404, 1360, 1331, 1312, 1289, 1183, 1136, 1057, 980, 961,
941, 901, 858, 804, 766, 743, 735, 722, 668, 579, 567, 554,
515, 507, 471, and 424 cm21; UV–Vis (CH2Cl2) lmax
(log 1) 565 sh (2.28), 527 (2.66), 339 (3.77), 292 (4.73), and
282 nm (4.69); 1H NMR (400 MHz, CDCl3) d¼9.58 (1H, d,
J¼10.3 Hz, 8-H), 8.55 (1H, d, J¼9.5 Hz, 4-H), 7.96 (1H,
dd, J¼10.3, 10.1 Hz, 6-H), 7.73 (1H, t, J¼10.3 Hz, 7-H),
4.2.5. 2-(N,N-Diethyl)aminoazulene (3e). Red crystals; mp
59.0–60.08C; IR (KBr) nmax 3013, 2975, 2967, 2928, 1574,
1549, 1466, 1449, 1374, 1358, 1227, 1138, 1076, 770, and
723 cm21; UV–Vis (CH2Cl2) lmax (log 1) 477 sh (2.95),
428 (4.31), 406 (4.11), 387 sh (3.79), 364 (3.69), 341 (3.62),
306 (4.78), and 296 nm (4.67); 1H NMR (400 MHz, CDCl3)

R. Yokoyama et al. / Tetrahedron 59 (2003) 8191–8198
8195
7.65 (1H, dd, J¼10.1, 9.5 Hz, 5-H), 7.40 (1H, s, 3-H), 3.33
(3H, s, OSO2CH3), and 3.28 (3H, s, SO2CH3); 13C NMR
(100 MHz, CDCl3) d¼152.66 (C-2), 140.68 (C-8a), 140.03
(C-6), 139.92 (C-4), 137.44 (C-8), 136.67 (C-3a), 129.80
(C-7), 129.18 (C-5), 117.22 (C-1), 108.08 (C-3), and
46.06 (SO2CH3), and 38.49 (OSO2CH3); MS (EI, 70 eV)
m/z (%) 300 (Mþ, 100), 285 (Mþ2CH3, 9), 222
(Mþ2CH3SO2, 76), 207 (18), 193 (8), 159 (58), 130 (22),
114 (12), 102 (55), and 63 (6). Anal. calcd for C12H12O5S2:
C, 47.99; H, 4.03; S, 21.35; Found: C, 47.82; H, 3.97; S,
21.10.
4.7. Reaction of 2-hydroxyazulene with p-toluenesulfonyl
chloride in the presence of pyridine
A solution of toluene sulfonyl chloride (770.0 mg, 4 mmol)
in dichloromethane (10 mL) was added to a solution of
2-hydroxyazulene (287.2 mg, 2.0 mmol) and pyridine
(475.2 mg, 6 mmol) in dichloromethane (10 mL) for 5 min
at 08C. After it was stirring for 3.5 h, water (100 mL) was
added to the reaction mixture. Products was extracted with
dichroromethane (50 mL£4), washed with 2N hydrochloric
acid (20 mL), and dried over magnesium sulfate. Solvent
was removed under reduced pressure. Products were
separated by column chromatography on silica gel using
ethyl acetate and hexane (1:4) to give 2-chloroazulene 78a
(5.3 mg, 2%) and 2-azulenyl p-toluenesulfonate 5b
(354.3 mg, 58%).
4.5. Synthesis of 2-azulenyl p-toluenesulfonate (5b) from
2-hydroxyazulene
A solution of tosyl chloride (387 mg, 2.03 mmol) in dry
CH2Cl2 (10 mL) was added dropwise at room temperature
to a mixture of 1 (150 mg, 1.04 mmol) and triethylamine
(305 mg, 3.01 mmol) in the same solvent (10 mL) over a
period of 5 min, and stirring the mixture at room
temperature for another 25 min. After the reaction mixture
was washed with water, the organic layer was dried over
MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel with CH2Cl2 to afford 5b (240 mg, 77%).
4.8. Reaction of 2-hydroxyazulene with trifluoro-
methanesulfonyl chloride in the presence of pyridine
A solution of methanesulfonyl chloride (338.9 mg, 2 mmol)
in dichloromethane (10 mL) was added to a solution of
2-hydroxyazulene (150 mg, 1.0 mmol) and pyridine
(232 mg, 2.9 mmol) in dichloromethane (10 mL) for 5 min
at 08C. After it was stirring for 24 h, water (100 mL) was
added to the reaction mixture. Products was extracted with
dichroromethane, washed with 2N hydrochloric acid
(20 mL), and dried over magnesium sulfate. Solvent was
removed under reduced pressure. Product was separated by
GPC using chloroform to give 8 (78.7 mg, 35%).
4.5.1. 2-Azulenyl p-toluenesulphonate (5b). Purple crys-
tals; mp 153.0–153.58C; IR (KBr) nmax 1597, 1578, 1534,
1466, 1455, 1402, 1379, 1321, 1294, 1192, 1177, 1115,
1092, 1021, 978, 932, 828, 787, 720, 673, 664, 596, 579, and
550 cm21; UV–Vis (CH2Cl2) lmax (log 1) 634 sh (2.03),
576 (2.50), 340 (3.71), 327 (3.63), 284 (4.80), and 277 nm
(4.78); 1H NMR (400 MHz, CDCl3) d¼8.24 (2H, d,
J¼9.8 Hz, 4 and 8-H), 7.80 (2H, d, J¼8.3 Hz, 20 and 60-
H), 7.59 (1H, t, J¼10.0 Hz, 6-H), 7.27 (2H, d, J¼8.3 Hz, 30
and 50-H), 7.23 (2H, dd, J¼10.0, 9.8 Hz, 5 and 7-H), and
7.02 (2H, s, 1 and 3-H), 3.31 (3H, s, CH3); 103C NMR
(100 MHz, CDCl3) d¼155.45 (C-2), 145.29 (C-4 ), 138.10
(C-3a and C-8a), 136.840 (C-4 and C-8), 136.79 (C-6),
132.65 (C-10), 129.72 (C-3 and 50), 128.32 (C-20 and C-60),
124.56 (C-5 and C-7), 107.04 (C-1 and 3), 21.65 (CH3); MS
(EI, 70 eV) m/z (%) 298 (Mþ, 80), 234 (27), 206 (25), 191
(9), 159 (12), 115 (100), 91 (45), and 65 (14). Anal. calcd for
C17H14O3S: C, 68.44; H, 4.73; S, 10.75; Found: C, 68.13; H,
4.78; S, 10.99.
4.8.1. 1,3-Dichloro-2-hydroxyazulene (8). Violet crystals;
mp .3008C; IR (KBr disk) nmax 1538, 1507, and
1314 cm21; UV–Vis (CH2Cl2) lmax (log 1) 240 (4.13),
288 (4.57), 298 (4.67), 317 (3.80), 346 (3.60), 361 (3.69),
390 sh (3.34), 412 sh (3.27), 432 sh (3.10), and 490 nm
(2.77); 1H NMR (400 MHz, CDCl3) d¼8.17 (2H, dd, J¼10,
0.9 Hz, 4 and 8-H), 7.54 (1H, td, J¼10, 0.8 Hz, 6-H), 7.28
(2H, t, J¼10 Hz, 5 and 7-H), and 6.23 (1H, s, OH); 13C
NMR (100 MHz, CDCl3) d¼153.59, 135.38, 131.65,
130.67, 124.69, and 99.53; MS (70 eV) m/z (%) 216
(Mþþ4, 11), 214 (Mþþ2, 64), 212 (Mþ, 100), 178 (14),
149 (10), and 113 (19). Anal. calcd for C10H6Cl2O: C,
56.37; H, 2.84; Cl, 33.28; Found: C, 56.55; H, 3.20.
4.9. General reaction condition of 2-azulenyl sulfonates
(3a, 3b, 3c) with amines
4.6. Reaction of 2-hydroxyazulene with mthanesulfonyl
chloride in the presence of pyridine
A solution of 3 (0.25 mmol) and an amines (2 mL) was
heated at 1008C. After stirring for adequate time (shown in
Table 3), the amine was removed under reduced pressure.
The residue was purified by chromatography on silica gel
with ethyl acetate / hexane (1: 4) to afford 3. The yields were
shown in Table 3.
A solution of methanesulfonyl chloride (458.8 mg, 4 mmol)
in dichloromethane (10 mL) was added to a solution of
2-hydroxyazulene (288.3 mg, 2.0 mmol) and pyridine
(479.4 mg, 6 mmol) in dichloromethane (10 mL) for 5 min
at 08C. After it was stirring for 1.5 h, water (100 mL) was
added to the reaction mixture. Products were extracted
with dichroromethane, washed with 2N hydrochloric acid
(20 mL), and dried over magnesium sulfate. Solvent was
removed under reduced pressure. Products were separated
by column chromatography on silica gel using ethyl
acetate and hexane (1:4) to give 2-chloroazulene 78a
(5.3 mg, 2%), 2-azulenyl methanesulfonate 5a (232.1 mg,
52%), and 2-methyloxyazulen-1-yl methyl sulphone 6a
(16.6 mg, 3%).
4.10. Reaction of 2-azulenyl trifluoromethanesulfomate
(2c) with diethylamine in the presence of NaOtBu
NaOtBu (134 mg, 1.39 mmol) was added to a mixture of 3c
(271 mg, 0.981 mmol) and NHEt2 (2 mL) at room tempera-
ture. After stirring for 30 min, the reaction mixture was
poured into water. The resulting mixture was acidified with
2N hydrochloric acid and extracted with toluene. The

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R. Yokoyama et al. / Tetrahedron 59 (2003) 8191–8198
Table 3. Nucleophilic substitution of 2-substituted azulenes
with ethyl acetate/hexane (1:4) and purified by GPC with
CHCl3. Their yields were shown in Table 4.
Entry
Azulene
Amine
Time
1 h
Yield of 3 (%)a
4.11.1. 2-(N-Isopropyl)aminoazulene (3f). Red needles;
mp 56.5–57.58C; IR (KBr) nmax 3378, 2965, 1572, 1549,
1509, 1458, 1402, 1385, 1364, 1221, 1186, 781, 754, and
720 cm21; UV–Vis (CH3Cl2) lmax (log 1) 477 sh (2.65),
412 (4.19), 393 (4.07), 378 sh (3.86), 352 (3.81), 329 (3.80),
302 (4.85), 291 (4.75), and 242 nm (4.10); 1H NMR
(400 MHz, CDCl3) d¼7.80 (2H, d, J¼9.5 Hz, 4 and 8-H),
7.16–7.04 (3H, m, 5, 6, and 7-H), 6.56 (2H, s, 1 and 3-H),
4.51 (1H, broad s, NH), 3.82 (1H, hept, J¼6.4 Hz,
CH(CH3)2), and 1.30 (6H, d, J¼6.4 Hz, CH(CH3)2); 13C
NMR (100 MHz, CDCl3) d¼157.46 (C-2), 141.97 (C-3a
and C-8a), 128.37 (C-6), 127.11 (C-4 and C-8), 124.45 (C-5
and C-7), 100.94 (C-1 and C-3), 46.09 (CH(CH3)2), and
23.16 (CH(CH3)2); MS (EI, 70 eV) m/z (%) 185 (Mþ, 100),
170 (Mþ2CH3, 87), 143 (54), 128 (24), 115 (23), and 85
(6). Anal. calcd for C13H15N: C, 84.28; H, 8.16; N, 7.56;
Found: C, 84.16; H, 8.45; N, 7.45.
1
2
3
5a
5b
5c
3a (66)
3a (65)
3a (82)
1 h
15 min
4
5
6
5a
5b
5c
3 h
3 h
20 min
3b (31)
3b (23)
3b (87)
7
8
9
5a
5b
5c
5 h
5 h
2 h
3c (26)
3c (33)
3c (69)
10
5c
NHMe2
30 min
3d (83)
a
The reaction was carried out under neat condition.
organic layer was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel with ethyl acetate/hexane
(1:1) to afford 2-hydroxyazulene 1 (129 mg, 91%).
4.11. General procedure for the palladium catalyzed
reaction of 2-bromoazulene (4) with amines
4.11.2. 2-(N-Pentyl)aminoazulene (3g). Dark red crystals;
mp ,308C; IR (KBr) nmax 3399, 3042, 3013, 2953, 2926,
2857, 1576, 1516, 1462, 1399, 1374, 1350, 1219, 1181, 779,
and 722 cm21; UV–Vis (CH3Cl2) lmax (log 1) 472 (2.95),
413 (4.17), 393 (4.05), 376 sh (3.82), 351 (3.79), 328 (3.81),
302 (4.84), and 291 nm (4.74); 1H NMR (400 MHz, CDCl3)
d¼7.80 (2H, d, J¼9.8 Hz, 4 and 8-H), 7.16–7.04 (3H, m, 5,
6 and 7-H), 6.56 (2H, s, 1 and 3-H), 4.61 (1H, broad s, NH),
3.32 (2H, broad s, 10-H), 1.67 (2H, m, 20-H), 1.39 (4H, m, 30
and 40-H), and 0.92 (3H, t, J¼7.1 Hz, CH3); 13C NMR
(100 MHz, CDCl3) d¼158.52 (C-2), 141.97 (C-3a and
A mixture of 2-bromoazulene (1 mmol), Pd2(dba)3
(2 mol%), BINAP (3 mol%), NaOtBu (1.5 mmol), and
amine (2 mmol) in toluene (1 mL) or without solvents
(2–6 mL of amine) was heated at 1008C under nitrogen
atmosphere. After stirring for 1 h, the reaction mixture was
poured into water, extracted with toluene. The organic layer
was dried over with MgSO4 and concentrated under reduced
pressure. The residue was chromatographed by silica gel
Table 4. Yields of 2-aminoazulenes by palladium-catalyzed reaction
2-Aminoazulene
Yield
(%)
2-Aminoazulene
Yield
(%)
3aa
3ba
3ca
3db
3eb
94
93
93
94
80
3ga
3hc
3ic
83
77
87
78
89
3jc
3kc
3fa
85
3lc
66
a
The reaction was carried out without solvent at 1008C.
The reaction was carried out without solvent at 1008C in sealed tube.
The reaction was carried out in toluene at 1008C.
b
c

R. Yokoyama et al. / Tetrahedron 59 (2003) 8191–8198
8197
C-8a), 128.36 (C-6), 127.13 (C-4 and C-8),0124.43 (C-5 and
C-7), 100.71 (C-1 and C-3), 44.99 (C-1 ), 29.47 (C-20),
29.17 (C-30 or C-40), 22.45 (C-40 or C-30) and 14.01 (CH3);
MS (EI, 70 eV) m/z (%) 213 (Mþ, 100), 198 (8), 170 (18),
157 (85), 143 (59), 128 (35), 115 (15), and 78 (9). Anal.
calcd for C15H19N: C, 84.46; H, 8.98; N, 6.57; Found: C,
84.09; H, 9.06; N, 6.58.
m/z (%) 243 (Mþ, 100), 215 (10), and 121 (10). Anal. calcd
for C19H13N: C, 88.86; H, 5.59; N, 5.80; Found: C, 89.15; H,
5.59; N, 5.80.
4.11.7. 13-(2-Azulenyl)-1,4,7,10-tetraoxa-13-azacyclo-
pentadecane (3l). Red oil. IR (KBr) nmax 2867, 1570,
1545, 1453, 1408, 1354, 1296, 1260, 1219, 1194, 1127,
1042, 1017, 990, 970, 941, 858, 775, 727, 448, and
428 cm21; UV–Vis (CH2Cl2) lmax (log 1) 474 sh (2.48),
424 (3.90), 403 (3.71), 383 sh (3.35), 358 (3.30), 337 (3.31),
306 (4.40), 295 (4.31), and 248 nm (3.59); 1H NMR
(400 MHz, CDCl3) d¼7.79 (2H, d, J¼9.1 Hz, 4 and 8-H),
7.09 (4H, m, 5, 6, 7, and 8-H), 6.57 (2H, s, 1 and 3-H), 3.84
(4H, t,0 J¼6.2 Hz, 30 and0140-H), 3.71 (4H, t, J¼6.2 Hz, 20
and015 -H),03.64 (8H, s, 5 , 60, 110, and 120-H), and 3.59 (4H,
s, 8 and 9 -H); 13C NMR (100 MHz, CDCl3) d¼158.31
(C-2), 141.72 (C-3a and C-8a), 127.94 (C-6), 126.83 (C-4
and C-8), 124.47 (C-5 and C-7), 100.12 (C-1 and C-3),
71.11 (C-110 and C-60 or C-50 and C-120), 70.13 (C-50 and
C-120 or C-110 and C-60), 700.03 (C-80 and C-90), 68.77 (C-30
and C-140), and 53.50 (C-2 and C-150); MS (EI, 70 eV) m/z
(%) 345 (Mþ, 100), 316 (6), 302 (6), 258 (8), 214 (33), 198
(6), 184 (12), 171 (39), 156 (76), 143 (13), 128 (17), 92 (6),
and 77 (11). Anal. calcd for C20H27NO4: C, 69.54; H, 7.88;
N, 4.05; Found: C, 69.25; H, 8.02; N, 4.03.
4.11.3. N-(2-Azulenyl)aniline (3h). Red prisms, mp 142.5–
143.08C (lit.8a mp 144.0–145.08C); MS (EI, 70 eV) m/z (%)
219 (Mþ, 100), 115 (6), and 109 (10).
4.11.4. N-(2-Azulenyl)-N-methylaniline (3i). Red needles;
mp 86.0–86.58C; IR (KBr) nmax 3009, 1538, 1514, 1497,
799, and 760 cm21; UV–Vis (CH2Cl2) lmax (log 1) 492 sh
(2.76), 425 (4.28), 403 sh (4.13), 356 (3.75), 333 (3.93), 310
(4.74), and 300 sh (4.63); 1H NMR (400 MHz, CDCl3)
d¼7.83 (2H, d, J¼9.5 Hz, 4 and 8-H), 7.44–7.39 (4H, m,
o,m-Ph), 7.21 (1H, m, p-Ph), 7.20 (1H, t, J¼9.8 Hz, 6-H),
7.08 (2H, dd, J¼9.8, 9.5 Hz, 5 and 7-H), and 6.70 (2H,
broad s, 1 and 3-H), and 3.55 (3H, s, CH3); 13C NMR
(100 MHz, CDCl3) d¼157.96 (C-2), 147.36 (Ph (1C)),
141.67 (C-3a and C-8a), 129.50 (C-6), 129.38 (Ph (2C)),
128.51 (C-4 and C-8), 125.00 (Ph (1C)), 124.75 (C-5 and
C-7), 124.28 (Ph (1C)), 102.32 (C-1 and C-3), and 40.59
(CH3); MS (EI, 70 eV) m/z (%) 233 (Mþ, 100), 217 (20),
141 (17), 128 (10), 115 (8), 109 (7), and 77 (6). Anal. calcd
for C17H15N: C, 87.52; H, 6.48; N, 6.00; Found: C, 87.67; H,
6.70; N, 6.04.
References
4.11.5. N-(2-Azulenyl)-N-phenylaniline (3j). Orange
powder; mp 145.5–146.08C; IR (KBr) nmax 1588, 1534,
1497, 1456, 1402, 1368, 1260, 1229, 801, 758, 725, 698, and
509 cm21; UV–Vis (CH2Cl2) lmax (log 1) 525 sh (2.66),
431 (4.30), 359 (3.59), 338 sh (3.93), 315 (4.74), and
306 nm sh (4.66); 1H NMR (400 MHz, CDCl3) d¼7.71 (2H,
d, J¼9.5 Hz, 4 and 8-H), 7.24 (8H, m, Ph), 7.08 (3H, m, 6-H
and Ph), 6.95 (2H, dd, J¼9.8, 9.5 Hz, 5 and 7-H), and 6.69
(2H, s, 1 and 3-H); 13C NMR(100 MHz, CDCl3) d¼155.95
(C-2), 146.63 (Ph (2C)), 140.74 (C-3a and C-8a), 130.74
(C-6), 129.89 (C-4 and C-8), 129.38 (Ph (4C)), 125.61 (Ph
(4C)), 125.01 (Ph (2C)), 124.42 (C-5 and C-7), and 106.01
(C-1 and C-3); MS (EI, 70 eV) m/z (%) 295 (Mþ, 100), 217
(9), 191 (5), 148 (5), and 128 (5). Anal. calcd for C22H17N:
C, 89.46; H, 5.80; N, 4.74; Found: C, 89.60; H, 5.98; N, 4.70.
1. (a) Nozoe, T.; Matumura, S.; Murase, Y.; Seto, S. Chem. Ind.
1955, 1257. (b) Schulze, J.; Heibronner, E. Helv. Chem. Acta
1958, 165, 1492–1500. (c) Reid, D. H.; Stafford, W. H.; Ward,
J. P. J. Chem. Soc. 1958, 1100–1109. (d) Nozoe, T.; Takase,
K.; Tada, M. Bull. Chem. Soc. Jpn 1963, 36, 1006–1009.
(e) Zeller, K.-P. Azulene. 4th ed. Houben-Weyl; Methoden der
Organischen Chemie; Georg Thieme: Stuttgart, 1985; Vol. V,
pp 127–418 Part 2c.
¨
¨
2. Lohr, H.-G.; Vogtle, F. Chem. Ber. 1985, 118, 905–913.
3. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. J. Org. Chem. 1999,
64, 5815–5821.
4. (a) Jutz, C.; Schweiger, E. Chem. Ber. 1974, 107, 2383–2396.
(b) Abe, N. Bull. Chem. Soc. Jpn 1991, 64, 2393–2397.
(c) Nitta, M.; Akie, T.; Iino, Y. J. Org. Chem. 1994, 59,
1309–1314. (d) Okujima, T.; Terazono, T.; Ito, S.; Morita, N.;
Asao, T. Heterocycles 2001, 54, 667–678.
4.11.6. N-(2-Azulenyl)indole (3k). Purple prisms; mp
135.0–135.58C; IR (KBr) nmax 3141, 3048, 3019, 1538,
1528, 1514, 1491, 1455, 1408, 1198, 777, 741, and
722 cm21; UV–Vis (CH2Cl2) lmax (log 1) 625 sh (2.06),
574 (2.48), 533 (2.55), 406 (4.29), 387 sh (4.14), 318 (4.55),
311 (4.54), 270 (4.51), and 228 nm (4.37); 1H NMR
(600 MHz, CDCl3) d¼8.29 (2H, d, J¼9.9 Hz, 4 and 8-H),
8.11 (1H, dt, J¼8.4, 0.8 Hz, 70-H), 70.70 (1H, dd, J¼7.8,
1.2 Hz, 40-H), 7.68 (2H, d, J¼3.4 Hz, 2 -H), 7.56–7.52 0(3H,
m, 1, 3, and 6-H), 7.35 (1H, ddd, J¼8.4, 7.2, 1.2 Hz, 6 -H),
7.28 (2H, t, J¼9.9 Hz, 5 and 7-H), 7.24 (1H, ddd, J¼0 7.8,
7.2, 0.8 Hz, 50-H), and 6.76 (1H, dd, J¼3.4, 0.8 Hz, 3 -H);
13C NMR (125 MHz, CDCl3) d¼147.33 (C-2), 140.22
(C-3a and C-8a), 135.67 (C-70a), 134.95 (C-6), 134.53 (C-4
and C-8), 130.34 0(C-30a), 127.804 (C-2), 124.79 (C-5 and
C-7), 123.16 (C-6 ), 121.31 (C-4 and C-50), 111.74 (C-70),
107.44 (C-1 and C-3), and 105.81 (C-30); MS (EI, 70 eV)
5. Herrmann, R.; Pedersen, B.; Wagner, G.; Youn, J.-H.
J. Organomet. Chem. 1998, 571, 261–266.
6. Tilney-Bassett, J. F.; Waters, W. A. J. Chem. Soc. 1959,
3123–3129.
7. (a) Hafner, K.; Weldes, H. Liebigs Ann. Chem. 1957, 606,
90–99. (b) Hafner, K.; Patzelt, H.; Kaiser, H. Liebigs Ann.
Chem. 1962, 656, 24–33. (c) McDonald, R. N.; Petty, H. E.;
Wolfe, N. L.; Paukstelis, J. V. J. Org. Chem. 1974, 39,
1877–1886. (d) Morita, T.; Fujita, T.; Takase, K. Bull. Chem.
Soc. Jpn 1980, 53, 1647–1651. (e) Nozoe, T.; Takase, K.;
Tada, M. Bull. Chem. Soc. Jpn 1965, 38, 247–251. (f) Tada,
M. Bull. Chem. Soc. Jpn 1966, 39, 1954–1961. (g) McDonald,
R. N.; Richmond, J. M.; Curtis, J. R.; Petty, H. E.; Hoskins,
T. L. J. Org. Chem. 1976, 41, 1811. (h) Hu¨nig, S.; Hafner, K.;
Ort, B.; Mu¨ller, M. Liebigs Ann. Chem. 1986, 1222–1240.
(i) Makosza, M.; Podraza, R. Eur. J. Org. Chem. 2000,
193–198.

8198
R. Yokoyama et al. / Tetrahedron 59 (2003) 8191–8198
8. (a) Nozoe, T.; Seto, S.; Matsumura, S. Bull. Chem. Soc. Jpn
1962, 35 1990–1998. (b) McDonald, R. N.; Richmond, J. M.
J. Org. Chem. Soc. 1975, 40, 1689–1694.
11. Yokoyama, R.; Ito, S.; Watanabe, M.; Harada, N.; Kabuto, C.;
Morita, N. J. Chem. Soc., Perkin Trans. 1 2001, 2257–2261.
12. Ito, S.; Nomura, A.; Morita, N.; Kabuto, C.; Kobayashi, H.;
Maejima, S.; Fujimori, K.; Yasunami, M. J. Org. Chem. 2002,
67, 7295–7302.
9. (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62,
1264–1267. (b) Louie, J.; Driver, M. S.; Hamann, B. C.;
Hartwig, J. F. J. Org. Chem. 1997, 62, 1268–1273.
(c) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37,
2046–2067. (d) Wolfe, J. P.; Wagaw, S.; Marcous, J.-F.;
Buchwald, S. T. Acc. Chem. Res. 1998, 31, 805–815.
(e) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org.
Chem. 2001, 66, 7729–7737.
13. Takase, K.; Asao, T.; Takagi, Y.; Nozoe, T. Chem. Commun.
1968, 368–370.
14. (a) Master’s Thesis of Kikuchi, M., Tohoku University, 1980.
(b) Nitta, M.; Takayasu, T. J. J. Chem. Soc., Perkin Trans. 1
1998, 1325–1333.
15. Replogle, L. L.; Maynard, J. R. J. Org. Chem. 1967, 32,
1909–1915.
10. Ito, S.; Yokoyama, R.; Okujima, T.; Terazono, T.; Kubo, T.;
Tajiri, A.; Watanabe, M.; Morita, N. Org. Biomol. Chem.
2003, 1, 1947–1952.