Synthesis of 2-Iodoazulenes by the Iododeboronation of Azulen-2-ylboronic Acid Pinacol Esters with Copper(I) Iodide

Article abstract of DOI:10.1021/acs.joc.7b02820

Azulen-2-ylboronic acid pinacol ester, prepared by iridium-catalyzed C-H borylation of azulene, efficiently underwent iododeboronation with a stoichiometric amount of copper(I) iodide. This reaction allowed the synthesis of 2-iodoazulene in only two steps starting from azulene. This methodology was successfully applied to analogous azulenes.

Full text of DOI:10.1021/acs.joc.7b02820

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Article
Synthesis of 2-Iodoazulenes by the Iododeboronation of
Azulen-2-ylboronic Acid Pinacol Esters with Copper(I) Iodide
Masahiro Narita, Toshihiro Murafuji, Saki Yamashita, Masayuki Fujinaga,
Kumiko Hiyama, Yurie Oka, Fumito Tani, Shin Kamijo, and Katsuya Ishiguro
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02820 • Publication Date (Web): 04 Jan 2018
Downloaded from http://pubs.acs.org on January 4, 2018
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Synthesis of 2-Iodoazulenes by the Iododeboronation of Azulen-2-ylboronic Acid
Pinacol Esters with Copper(I) Iodide
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†
†‡§
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Masahiro Narita, Toshihiro Murafuji,* Saki Yamashita, Masayuki Fujinaga, Kumiko Hiyama,
§
||
†‡
†‡
Yurie Oka, Fumito Tani,* Shin Kamijo, Katsuya Ishiguro
†
Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Yamaguchi
753ꢀ8512, Japan
‡
§
Department of Chemistry, Faculty of Science, Yamaguchi University, Yamaguchi 753ꢀ8512, Japan
Graduate School of Medicine, Yamaguchi University, Yamaguchi 753ꢀ8512, Japan
Eꢀmail: murafuji@yamaguchiꢀu.ac.jp
||
Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka 819ꢀ0395, Japan
Eꢀmail: tanif@ms.ifoc.kyushuꢀu.ac.jp
ABSTRACT
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Azulenꢀ2ꢀylboronic acid pinacol ester, prepared by iridiumꢀcatalyzed C–H borylation of azulene,
efficiently underwent iododeboronation with a stoichiometric amount of copper(I) iodide. This
reaction allowed the synthesis of 2ꢀiodoazulene in only two steps starting from azulene. This
methodology was successfully applied to analogous azulenes.
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INTRODUCTION
Azulene, a nonꢀalternant and nonꢀbenzenoid hydrocarbon, has recently attracted much attention in
1–3
the wide field of advanced organic molecular materials because its unique electronic structure
endows rationally designed derivatives with distinctive physicochemical properties currently
4
unattainable by benzenoid systems. Haloazulenes are key synthetic intermediates in constructing
2
such organic molecular materials by crossꢀcoupling reactions. In particular, there is increasing
3
demand for 2ꢀhaloazulenes. An azulenꢀ2ꢀyl group has polarized πꢀelectrons, which are delocalized
5
along the direction of the dipolar C2v axis, leading to an increased dipole moment.
The synthetic pathway to haloazulenes strongly depends on the intended position of the
halogen substituent. Due to its πꢀpolarization, azulene undergoes electrophilic substitution at the 1ꢀ
and 3ꢀpositions of the fiveꢀmembered ring and nucleophilic addition at the 4ꢀ, 6ꢀ and 8ꢀpositions of
the sevenꢀmembered ring. 1ꢀHalo and 1,3ꢀdihaloazulene are synthesized by the halogenation of
6
azulene through electrophilic substitution. In this reaction, the 2ꢀposition is inert and the synthesis
of 2ꢀhaloazulenes 1 and 2 has traditionally required an alternative multistep transformation,
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including construction of the azulene skeleton (Scheme 1).
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Scheme 1. Traditional synthetic route to 2-haloazulenes
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To access 2ꢀsubstituted azulenes more conveniently, we previously established an efficient
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method to introduce a boryl substituent at the 2ꢀposition of azulene (Scheme 2). The borylation
reaction proceeds at the 2ꢀposition to give predominantly 3, along with 1ꢀborylated 4 as a minor
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a
product. The boryl substituent of 3 is converted into a hydroxyl group by oxidation to give 5,
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which opens a route to 2. However, 5 is susceptible to decomposition through ketoꢀenol
tautomerization. Furthermore, the halogen exchange reaction of 6 requires a large excess of iodide.
Hence, a more efficient route still remains to be developed.
Scheme 2. Synthetic route to 2-haloazulenes from azulene
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We previously reported the copperꢀcatalyzed ipsoꢀamination of azulenꢀ2ꢀyl boronic acid
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derived from 3. Transformation of arylboronic compounds by copperꢀmediated or ꢀcatalyzed
ipsoꢀsubstitution is useful for introducing heteroatom functionality into an arene at the desired
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position. In this context, the ipsoꢀhalogenation of arylboronic acids and esters is also a reliable
synthetic method for aryl halides. Therefore, the development of a more convenient synthetic route
to 2ꢀhaloazulenes would provide practical benefits. In this paper, we describe the direct conversion
of 3 and its related pinacol esters into 2ꢀiodoazulenes by copperꢀmediated ipsoꢀiodination.
RESULTS AND DISCUSSION
12c,13b
In our plan for applying ipsoꢀiodination to 3, we excluded the use of Nꢀiodosuccinimide,
which is expected to iodinate the 1,3ꢀpositions. Rather, we focused on the method reported by
Hartwig and coꢀworkers, who developed the CuIꢀcatalyzed iodination of arylboronic acid pinacol
13d
esters with KI in the presence of 1,10ꢀphenanthroline by heating under air. Initially, when we
applied this method to 3, the yield of 2 was only 11% and most of 3 was recovered, along with
azulenꢀ2ꢀylꢀboronic acid formed by the hydrolysis of 3 (Table 1, entry 1). From this result, we
inferred that CuI would directly iodinate 3 rather than act as a catalyst because the yield of 2 was
comparable with the loading amount of CuI (0.1 equiv). Consequently, when 3 was allowed to react
with a stoichiometric amount of CuI in the presence of 1,10ꢀphenanthroline, the yield of 2 was
dramatically increased (entry 2). Interestingly, the yield was increased more by simply reacting 3
with CuI without the addition of 1,10ꢀphenanthroline (entry 3). As the reaction progressed, the
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reaction mixture suspension, which was initially blue due to 3, turned to a clear green solution. Next,
in order to determine the effect of oxygen, the reaction described in entry 3 was conducted under
argon (entry 4). The color change observed in entry 3 did not appear and a very small amount of 2
was obtained (only 2% yield). This suggests that the oxidation process of the copper salt is essential
for this reaction. Although the detailed mechanism underlying ipsoꢀiodination is unclear, many
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11aꢀh,12b,13d
papers have revealed that air works effectively as an oxidant in the ipsoꢀsubstitution.
11aꢀd, g.h
Furthermore, it has been reported that Cu(II) or Cu(III) species are generated.
In this context,
when we heated a mixture of CuI and DMF at 90 °C in air or under argon, the color of the
suspension turned from brown to yellowish ocher within 5 minutes in air but remained unchanged
under argon. The addition of 3 into the yellowish ocher suspension at the same temperature in air
gave 2 immediately (detected by thin layer chromatography) but little reaction was seen under
argon. Hence, we infer that this color change shows the generation of an active copper species
possessing a higher oxidation state. In entry 5, to examine whether radical species were involved,
we added TEMPO to decrease the yield of 2, but only a mild inhibition effect was observed. Next,
this iodination in entry 3 was extended to the chlorination and bromination of 3. Hartwig and
coꢀworkers have succeeded in the ipsoꢀchlorination and bromination of arylboronic esters by using
1
3f
2 2
the Cu(II) halides CuCl and CuBr , respectively. Nevertheless, we persisted in using the Cu(I)
halides CuCl and CuBr because azulene undergoes halogenation with copper(II) halides to give
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1,3ꢀdichloroazulene and 1,3ꢀdibromoazulene, respectively.
The reactions of 3 with a
stoichiometric amount of CuCl or CuBr gave 1 and 6, respectively, in acceptable yields (entries 6
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and 7). For comparison, although we attempted the reaction of 3 with CuCl , we could not detect
2
either 1 or 1ꢀ or 3ꢀchlorinatedꢀ2ꢀBpin azulene. Only azulenꢀ2ꢀyl boronic acid was obtained in 90%
yield, along with azulene and 1ꢀchloroazulene in 1% and 3% yields, respectively.
Table 1. Halogenation of 3
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entry
CuX
n
(equiv)
additive
Yield (%)
2 (11)
2 (59)
2 (79)
2 (2)
a
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2
3
CuI (0.1)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuCl (1.0)
CuBr (1.0)
phen (0.2 equiv), KI (1.5 equiv)
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phen (0.2 equiv)
no
no
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5
6
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TEMPO (1.0 equiv)
2 (50)
1 (57)
6 (70)
1 (0)
no
no
no
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CuCl (1.0)
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,10ꢀPhenanthroline. Under argon. 2,2,6,6ꢀTetramethylpiperidine 1ꢀoxyl.
Next, this easy access to 2 was utilized in the synthesis of 2,2’ꢀbiazulene (7) (Scheme 3). The
SuzukiꢀMiyaura crossꢀcoupling reaction of 2 with 3 gave 7 in high yield. Although we previously
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reported the synthesis of 7 based on sulfonyl groupꢀdirected lithiation, this previous method
reqires the following multistep reaction sequence starting from azulene: sulfonylation, directed
lithiation and subsequent iodination, crossꢀcoupling with azulenꢀ2ꢀylꢀboronic acid, and
desulfonylation. Hence, it should be emphasized that 7 can be synthesized in only three steps
starting from azulene.
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Scheme 3. Synthesis of 7
The functionalization of guaiazulene has attracted much interest due to the versatile biological
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activities of its derivatives. We previously reported the Irꢀcatalyzed borylation of guaiazulene, but
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a
the yield of 8 was very poor (5%). Recently, we were successful in remarkably improving the
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yield of 8 up to 84% by using an active Irꢀcatalyst and a phenanthroline ligand at a higher reaction
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temperature (Scheme 4). This made it possible to attempt the iodination of 8 and the iodinated
product 9 was obtained in 65% yield. However, the chlorination and bromination of 8 afforded 10
and 11 in lower yields (48% and 55%, respectively). The efficiency of each halogenation of 3 and 8
is reflected in the yield of the haloazulene, which decreased in the order I > Br > Cl. It is known that
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ꢀhaloazulenes are generally less stable. In this context, 3ꢀbromoguaiazulene changes to
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sideꢀchain brominated derivatives and 3,3’ꢀbiguaiazulene upon dissolution in benzene. This is in
contrast to stable 2ꢀbromoguaiazulene (11), which guarantees the identification.
Scheme 4. Halogenation of 8
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Next, we synthesized pinacol esters 12 and 13 derived from 4,6,8ꢀtrimethylazulene and
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tertꢀbutylazulene, respectively, and applied this iodination strategy to these esters (Scheme 5). We
previously reported that the Irꢀcatalyzed borylation of 4,6,8ꢀtrimethylazulene using bpy ligand gives
8
a
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2 in low yield (32%). This low yield was addressed by changing the ligand from bpy to dtbpy.
Thus, the yield of 12 was improved up to 76% and this method was applicable to the borylation of
tertꢀbutylazulene possessing a bulky alkyl substituent. The iodination of 8, 12 and 13 with CuI
revealed that the yields of 9 and 14 was lower than the yields of 2 and 15, likely due to either the
6
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1
1h,22
high reactivity of alkylꢀsubstituted azulenes toward oxidation, deprotonation by base
or
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transitionꢀmetalꢀcatalyzed C–H activation. In particular, 12 possesses three reactive methyl groups
at the electronꢀdeficient 4,6,8ꢀpositions on the positively polarized sevenꢀmembered ring.
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Scheme 5. Iodination of 12 and 13
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We previously reported that 3 undergoes Irꢀcatalyzed borylation to give an isomeric mixture of
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6 and 17 containing a small amount of 2,5,7ꢀtriborylated azulene (Scheme 6). Compounds 16
and 17 are separable by fractional recrystallization. Their defining structural feature is that the boryl
substituents of 16 at the 2ꢀ and 6ꢀpositions are present on the 2v axis, while those of 17 at the 2ꢀ
and 5ꢀpositions are in a bent orientation. In particular, the need for 2,6ꢀdisubstituted azulenes has
C
3
c,3e,24
been increasing in the field of molecular materials.
The iodination of 16 and 17 is expected to
attract much interest because the resulting diiodoazulenes can be used as building blocks for linear
or bent conjugated molecules having an azulene unit as the central core. When 16 was reacted with
CuI, 18 was obtained in only 26% yield. Similar iodination of 17 resulted in a modest yield of 19.
These low yields may be due to loss of 16 and 17 caused by formation of a large amount of
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insoluble black deposits. Such deposits were not formed in the iodination of 3. Hence, the boryl
substituents at the 5ꢀ and 6ꢀpositions of the sevenꢀmembered rings appear to be very reactive
compared with those at the 2ꢀposition of the fiveꢀmembered rings. Although the yields of the
iodination reaction are not satisfactory, it should be emphasized that 18 and 19 are accessible in
only three steps starting from azulene, and their synthesis by typical electrophilic substitution is
difficult. Based on the yields of the iodination of 3, 16, and 17, the efficiency of the iodination
reaction decreases in the order: 2ꢀposition >> 5ꢀposition > 6ꢀposition. This suggests that the
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iodination reaction is governed by the
πꢀpolarization of the azulene core. In this context, we
previously revealed that the oxidation of 16 with hydrogen peroxide is governed by the
πꢀpolarization of 16 and the boryl substituent at the sevenꢀmembered ring is the predominant
8b
reactive group.
Scheme 6. Iodination of 16 and 17
In summary, we developed a simple and convenient synthetic method for 2ꢀiodoazulenes from
azulenꢀ2ꢀyl boronic acid pinacol esters by direct iodination. We believe that this method will
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contribute to the development of novel extended
πꢀelectron systems containing the azulene
skeleton.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
1
13
1
3 6
H and C{ H} NMR spectra were recorded of samples prepared in CDCl or DMSOꢀd on a
Bruker Avance IIIꢀ400 (400 MHz) spectrometer. Chemical shifts were referenced to residual solvent
peak: chloroform (7.26 ppm, 77.0 ppm) and DMSO (2.50 ppm, 40.45 ppm). The signal
corresponding to the carbon ipso to the boron atom was not observed due to the quadrupolar
relaxation of the boron atom. IR spectra were recorded on a JASCO FT/IRꢀ4100 (ATR)
spectrophotometer. HRMS was carried out on a Bruker Daltonics micrOTOF II (APCI) instrument.
Analytical TLC was carried out by using aluminumꢀbacked plates preꢀcoated (0.25 mm) with
Merck Silica Gel 60 F254. Boronic esters 3, 16 and 17 were prepared from azulene by using our
8
25
26
27
reported method. Azulene, 4,6,8ꢀtrimethylazulene and 6ꢀtertꢀbutylazulene were synthesized in
accordance with the reported methods. In the synthesis of 4,6,8ꢀtrimethylazulene,
2,4,6ꢀtrimethylpyrylium tetrafluoroborate was purchased from Tokyo Chemical Industry Co., Ltd.
and substituted for its perchlorate. Sodium cyclopentadienide was prepared by using the reported
2
7
method. Guaiazulene was purchased from Wako Pure Chemical Industries, Ltd. Copper(I) salts
were commercial grades and used without purification.
2-(1,4-Dimethyl-7-isopropylazulen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8). The
reaction was carried out under argon. To a roundꢀbottomed flask (50 mL) equipped with a magnetic
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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6
stir
bar
were
added
bis(pinacolato)diboron
(pin
2
B
2
;
1.27
g,
5.0
mmol),
4,7ꢀdimethylꢀ1,10ꢀphenanthroline (dmphen; 10 mg, 0.05 mmol), [Ir(OMe)(cod)]
2
(17 mg, 0.025
mmol) and guaiazulene (992 mg, 5.0 mmol). After dry ꢀheptane (15 mL) was added to the flask,
n
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the mixture was heated at 110 °C for 2 h. The reaction was quenched with water (5 mL) at room
temperature and the resulting mixture was extracted with hexane (30 mL × 3). The organic layer
2 4
was dried (Na SO ) and concentrated to leave a residue, which was chromatographed on silica gel
8a
1
with hexane–AcOEt (20:1) to afford 8. Yield: 1.36g, 84%; blue solid; mp 71–74 °C (lit. oil); H
NMR (400 MHz, CDCl3) 1.35 (d, = 6.8 Hz, 6H), 1.40 (s, 12H), 2.82 (s, 3H), 2.83 (s, 3H), 3.06
m, 1H, CH), 6.94 (d, = 10.4 Hz, 1H), 7.38 (dd, = 10.4, 1.6 Hz, 1H), 7.61 (brꢀs, 1H), 8.23 (d,
12.6, 24.2, 24.7, 25.0, 38.2, 83.2, 120.3, 124.8, 133.4,
δ
J
(
J
J
J =
1
3
1.6 Hz, 1H); C NMR (100 MHz, CDCl )
δ
3
135.0, 136.2, 136.9, 137.6, 139.8, 146.1; One azulene skeleton carbon signal was not observed; IR
+
(ATR)
ν
2953, 1497, 1355, 1258, 1141; HRMS (APCI) m/z [M + H] calcd for C H BO
21 30 2
3
25.2333, found 325.2329.
-(4,6,8-Trimethylazulen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12). The reaction
was carried out under argon. To a roundꢀbottomed flask (50 mL) equipped with a magnetic stir bar
2
were added bis(pinacolato)diboron (pin
2
B
2
; 1.27 g, 5.0 mmol), 4,4’ꢀdi(tertꢀbutyl)ꢀ2,2’ꢀbipyridine
(dtbpy; 45 mg, 0.125 mmol), [Ir(Cl)(cod)]
2
(42 mg, 0.0625 mmol) and 4,6,8ꢀtrimethylazulene (851
mg, 5 mmol). After dry cyclohexane (15 mL) was added to the flask, the mixture was refluxed for
4 h. The reaction was quenched with water (5 mL) at room temperature and the resulting mixture
was extracted with hexane (30 mL × 3). The organic layer was dried (Na SO ) and concentrated to
2
2
4
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leave a residue, which was chromatographed on silica gel with hexane–AcOEt (20:1) to afford 12.
8a
1
Yield: 1.13 g, 76%; bluish purple solid; mp 162–163 °C (lit. mp 162–163 °C); H NMR (400 MHz,
1
3
CDCl3)
CDCl3)
δ
δ
1.42 (s, 12H), 2.62 (s, 3H), 2.89 (s, 6H), 7.02 (s, 2H), 7.76 (s, 2H); C NMR (100 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
24.9, 25.1, 28.9, 83.5, 123.2, 127.0, 136.6, 147.6, 148.1; One azulene skeleton carbon
+
signal was not observed; IR (ATR)
ν 2984, 1509, 1320, 1254, 1140; HRMS (APCI) m/z [M + H]
calcd for C19 297.2020, found 297.2029.
H
26BO
2
2-(6-tert-Butylazulen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13). The reaction was
carried out under argon. To a roundꢀbottomed flask (50 mL) equipped with a magnetic stir bar were
added bis(pinacolato)diboron (pin
2
B
2
; 1.27 g, 5.0 mmol), 4,4’ꢀdi(tertꢀbutyl)ꢀ2,2’ꢀbipyridine (dtbpy;
45 mg, 0.125 mmol), [Ir(Cl)(cod)]
2
(42 mg, 0.0625 mmol) and 6ꢀtertꢀbutylazulene (921 mg, 5
mmol). After dry cyclohexane (15 mL) was added to the flask, the mixture was refluxed for 19 h.
The reaction was quenched with water (5 mL) at room temperature and the resulting mixture was
extracted with hexane (30 mL × 3). The organic layer was dried (Na SO ) and concentrated to leave
2
4
a residue, which was chromatographed on silica gel with hexane–AcOEt (20:1) to afford 13. Yield:
1
965 mg, 62%; blue solid; mp 180–181 °C; H NMR (400 MHz, CDCl )
δ 1.40 (s, 12H), 1.45 (s,
3
1
3
9H), 7.29 (d,
CDCl3)
J = 10.8 Hz, 2H), 7.68 (s, 2H), 8.29 (d, J = 10.8 Hz, 2H); C NMR (100 MHz,
δ
24.9, 31.8, 38.7, 83.6, 120.9, 124.6, 137.2, 139.5, 162.8; One azulene skeleton carbon
+
signal was not observed; IR (ATR)
ν 2967, 1509, 1345, 1244, 1137; HRMS (APCI) m/z [M + H]
calcd for C20 311.2177, found 311.2176.
H
28BO
2
Reaction with copper(I) salt; General procedure. All reactions were carried out under air. A
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6
typical example is exemplified by the synthesis of 2. To a roundꢀbottomed flask (50 mL) equipped
with a magnetic stir bar were added DMF (10 mL) and CuI (1.0 mmol), and the resulting
suspension was heated at 90 °C for 5 min. The color of the suspension turned yellowish ocher from
brown by heating. To this suspension was added a solution of 3 (1.0 mmol) in DMF (10 mL) at the
same temperature and the resulting mixture was stirred at this temperature for 3 h. The reaction was
quenched with water (20 mL) at room temperature, and the resulting mixture was extracted with
0
1
2
3
4
5
6
7
8
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0
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7
8
9
0
hexane (10 mL
× 3). The combined extracts were dried (Na SO ) and concentrated to leave a
2 4
residue, which was chromatographed (silica gel; hexane) to give the corresponding product.
7
2
-Chloroazulene (1). Yield: 46 mg, 57%; bluish purple solid; mp 91–92 °C (lit. mp 91–92 °C);
1
H NMR (400 MHz, CDCl3)
δ
7.26 (s, 2 H), 7.26 (t,
J
= 10.0 Hz, 2H), 7.61 (t,
J = 10.0 Hz, 1H),
1
3
8.24 (d,
J
= 9.6 Hz, 2H); C NMR (100 MHz, CDCl ) δ
115.9, 124.6, 135.4, 136.9, 139.5, 140.0;
3
+
IR (ATR)
ν
1570, 1530, 1446, 1392, 1295, 1214, 1080; HRMS (APCI)(Clꢀ35)
m
/z [M + H] calcd
8
for C10H Cl 163.0309, found 163.0309.
7
2
-Iodoazulene (2). Yield: 200 mg, 79%; bluish purple solid; mp 125–126 °C (lit. mp
1
125–126 °C); H NMR (400 MHz, CDCl )
δ
7.22 (t,
J = 10.0 Hz, 2H), 7.51 (s, 2H), 7.65 (t, J = 10.0
3
1
3
Hz, 1H), 8.27 (d,
40.5; IR (ATR)
found 254.9669.
J
= 9.2 Hz, 2H); C NMR (100 MHz, CDCl )
δ
98.5, 124.3, 124.8, 134.7, 137.7,
3
+
1
ν
1469, 1387, 1197; HRMS (APCI)
m
/z [M + H] calcd for C H I 254.9665,
10
8
9
2
-Bromoazulene (6). Yield: 72 mg, 70%; bluish purple solid; mp 106–107 °C (lit. mp
1
1
06.8–107.2 °C); H NMR (400 MHz, CDCl )
δ
7.25 (t,
J
= 10.0 Hz, 2H), 7.36 (s, 2H), 7.64 (t,
J
=
3
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0.0 Hz, 1 H), 8.26 (d,
37.3, 139.9; IR (ATR)
J
= 9.6 Hz, 2H); C NMR (100 MHz, CDCl )
δ
118.8, 124.6, 127.5, 135.2,
3
+
1
ν
1568, 1526, 1436, 1392, 1197; HRMS (APCI)(Brꢀ79)
m
/z [M + H] calcd
8
for C10H Br 206.9804, found 206.9804.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of 2,2’-biazulene (7). The reaction was carried out under argon. To a roundꢀbottomed
flask (10 mL) equipped with a magnetic stir bar were added 2 (29 mg, 0.11 mmol), 3 (29 mg, 0.11
2 2 2
mmol), Pd(dppf)Cl ·CH Cl (5 mg, 0.007 mmol), cesium carbonate (115 mg, 0.35 mmol),
cyclohexane (5 mL) and water (1 mL). After the resulting mixture was refluxed for 24 h, the
reaction was quenched with water (10 mL) at room temperature and ethyl acetate (10 mL) was
added. The resulting mixture was washed with water (10 mL
× 3) and the organic layer was dried
over anhydrous sodium sulfite. Concentration of the organic layer gave a solid residue, which was
purified by recrystallization from hexane to give 7. Yield: 27 mg, 93%; green powder; mp > 300 °C
28
1
(
lit. mp > 300 °C); H NMR (400 MHz, DMSOꢀd6
)
δ
7.22 (t,
J
= 9.6 Hz, 4H), 7.59 (t,
J
= 9.6 Hz,
13
2
H), 7.95 (s, 4H), 8.38 (d,
38.3, 142.1, 146.3.
J
= 9.6 Hz, 4H); C NMR (100 MHz, DMSOꢀd6
)
δ
117.1, 125.1, 137.6,
1
1
2-Iodoguaiazulene (9). Yield: 212 mg, 65%; blue oil; H NMR (400 MHz, CDCl )
δ
1.37 (d,
= 10.4 Hz, 1H), 7.44 (s, 1H), 7.47
= 1.6 Hz, 1H); C NMR (100 MHz, CDCl ) 14.6, 24.1, 24.7,
8.3, 103.1, 120.1, 126.5, 127.5, 132.9, 134.8, 135.2, 137.3, 141.7, 142.9; IR (ATR) 2957, 2922,
18I 325.0448, found 325.0444.
J =
3
7.2 Hz, 6H), 2.63 (s, 3H), 2.77 (s, 3H), 3.10 (m, 1H), 7.07 (d,
J
1
3
(dd,
J
= 10.4, 1.6 Hz, 1H), 8.20 (d,
J
δ
3
3
1
ν
+
556, 1402, 1367; HRMS (APCI)
m/z [M + H] calcd for C15H
1
2
-Chloroguaiazulene (10). Yield: 56 mg, 48%; blue oil; H NMR (400 MHz, CDCl )
δ 1.40 (d,
3
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
J
7
2
= 6.8 Hz, 6H), 2.62 (s, 3H), 2.81 (s, 3H), 3.12 (m, 1H), 7.10 (d,
J
= 10.8 Hz, 1H), 7.18 (s, 1H),
10.1, 24.0,
2959,
13
.44 (dd,
J
= 10.4, 2.0 Hz, 1H), 8.16 (d,
J
= 2.0 Hz, 1H); C NMR (100 MHz, CDCl )
δ
3
4.7, 38.3, 111.5, 120.8, 126.7, 132.7, 134.5, 135.4, 135.6, 138.3, 141.8, 143.2; IR (ATR)
ν
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
2925, 1557, 1528, 1415, 1386; HRMS (APCI)(Clꢀ35)
found 233.1083.
m
/z [M + H] calcd for C15
H18Cl 233.1092,
1
2
-Bromoguaiazulene (11). Yield: 76 mg, 55%; blue oil; H NMR (400 MHz, CDCl )
δ
1.37 (d,
= 10.8 Hz, 1H), 7.27 (s, 1H), 7.46
11.7, 24.1, 24.8,
2958, 2924,
J
3
=
6.8 Hz, 6H), 2.60 (s, 3H), 2.78 (s, 3H), 3.10 (m, 1H), 7.09 (d, J
13
(dd,
J
= 10.8, 2.0 Hz, 1H), 8.17 (d,
J
= 2.0 Hz, 1H); C NMR (100 MHz, CDCl )
δ
3
38.3, 114.3, 123.1, 126.7, 128.1, 132.9, 134.8, 135.4, 136.2, 141.9, 143.2; IR (ATR) ν
+
1556, 1408, 1368; HRMS (APCI)(Brꢀ79):
m
/z [M + H] calcd for C15
H18Br 277.0586, found
277.0597.
2-Iodo-4,6,8-trimethylazulene (14). Yield: 55 mg, 62%; reddish purple solid; mp 138–139 °C;
1
13
H NMR (400 MHz, CDCl3)
δ
2.60 (s, 3H), 2.80 (s, 6H), 7.08 (s, 2H), 7.43 (s, 2H); C NMR (100
MHz, CDCl3)
δ
25.1, 28.8, 93.4, 123.1, 128.5, 136.8, 144.2, 146.9; IR (ATR) ν 2924, 1568, 1412,
+
1325, 1213; HRMS (APCI)
m
/z [M + H] calcd for C13
H14I 297.0135, found 297.0123.
1
6-tert-Butyl-2-iodoazulene (15). Yield: 70 mg, 75%; blue solid; mp 135–136 °C (dec); H NMR
(400 MHz, CDCl3) δ 1.46 (s, 9H) 7.39 (d, J = 10.8 Hz, 2H), 7.42 (s, 2H), 8.20 (d, J = 10.8 Hz, 2H);
1
3
C NMR (100 MHz, CDCl3)
δ
31.8, 38.8, 97.0, 122.5, 124.0, 133.8, 139.3, 161.7; IR (ATR) ν 2958,
+
1576, 1389; HRMS (APCI)
m
/z [M + H] calcd for C14
H16I 311.0291, found 311.0289.
1
2,6-Diiodoazulene (18). Yield: 28 mg, 26%; bluish solid; mp 207–208 °C (dec); H NMR (400
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3
MHz, CDCl3)
MHz, CDCl3)
δ
δ
7.49 (s, 2H), 7.74 (d, J = 10.8 Hz, 2H), 7.79 (d, J = 10.8 Hz, 2H); C NMR (100
99.8, 110.8, 126.5, 132.7, 134.4, 139.5; IR (ATR)
ν
1557, 1509, 1381, 957; HRMS
+
(APCI)
m/z [M + H] calcd for C10
H
7
I
2
380.8632, found 380.8625.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2,5-Diiodoazulene (19). Yield: 15 mg, 40%; bluish solid; mp 101–102 °C; H NMR (400 MHz,
CDCl3)
d, = 9.6 Hz, 1H), 8.69 (d,
25.3, 125.8, 133.9, 139.3, 140.6, 143.5, 146.6; IR (ATR)
δ
6.79 (t,
J
= 10.4 Hz, 1H), 7.41 (s, 1H), 7.49 (s, 1H), 8.13 (dd,
J
= 10.4, 1.2 Hz, 1H), 8.38
= 1.2 Hz, 1H); C NMR (100 MHz, CDCl ) 92.1, 100.7, 124.3,
1434, 1389; HRMS (APCI) /z [M +
13
(
J
J
δ
3
1
ν
m
+
7 2
H] calcd for C10H I 380.8632, found 380.8632.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
13
[
H and C NMR spectra of compounds 1, 2, 6–15, 18 and 19 (PDF)]
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: murafuji@yamaguchiꢀu.ac.jp
*Eꢀmail: tanif@ms.ifoc.kyushuꢀu.ac.jp
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Number 16K05697 to T.M. We are grateful to
the Center of Instrumental Analysis, Yamaguchi University. This work was performed under the
Cooperative Research Program of "Network Joint Research Center for Materials and Devices"
(Institute for Materials Chemistry and Engineering, Kyushu University).
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