A convenient synthesis of functionalized azulenes via negishi cross-coupling

Article abstract of DOI:10.1055/s-0034-1379486

A mild and effective method for the synthesis of functionalized azulenes is described. Negishi cross-coupling of bromoazulenes with functionalized aromatic, heterocyclic, benzylic, and alkylic organozinc reagents affords substituted azulenes in good yields. Functional groups, including ethoxycarbonyl, cyano, methoxy, fluoro, chloro, and bromo are well tolerated. Additionally, a one-pot procedure for introducing two different substituents into positions 1 and 3 of azulene through cross-coupling reaction is described for the first time.

Full text of DOI:10.1055/s-0034-1379486

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 538–548
paper
538
J. Dubovik, A. Bredihhin
Paper
Synthesis
A Convenient Synthesis of Functionalized Azulenes via Negishi
Cross-Coupling
R1
R1
R2
R2ZnCl·LiCl
Julia Dubovik
Pd catalyst
THF, r.t.
Aleksei Bredihhin*
Br
22 examples
up to 97%
Institute of Technology, University of Tartu, Nooruse 1, 50411
Tartu, Estonia
?
aleksei.bredihhin@ut.ee
Received: 23.09.2014
Accepted after revision: 08.10.2014
Published online: 12.11.2014
another derivative was investigated as a dopamine D4 re-
ceptor agonist for the treatment of erectile dysfunction and
exhibited promising results.11 Additionally, azulene deriva-
tives have attracted attention in material science.12,13
DOI: 10.1055/s-0034-1379486; Art ID: ss-2014-z0583-op
Abstract A mild and effective method for the synthesis of functional-
ized azulenes is described. Negishi cross-coupling of bromoazulenes
with functionalized aromatic, heterocyclic, benzylic, and alkylic or-
ganozinc reagents affords substituted azulenes in good yields. Func-
tional groups, including ethoxycarbonyl, cyano, methoxy, fluoro,
chloro, and bromo are well tolerated. Additionally, a one-pot procedure
for introducing two different substituents into positions 1 and 3 of azu-
lene through cross-coupling reaction is described for the first time.
However, despite considerable interest of scientists and
recent advances in azulene chemistry, the synthesis of azu-
lene derivatives remains a difficult task. Often, it requires a
multistep synthesis or even the synthesis of an azulene
skeleton that already contains the desired substituent. Low
stability of many haloazulenes and the sensitivity of azu-
lene core towards organometallic reagents significantly
limits the use of cross-coupling reactions. To date, mainly
Suzuki14 and Stille12,15 couplings were used for the derivat-
ization of azulene, often requiring prolonged reaction times
and harsh reaction conditions. For example, the synthesis
Key words azulene, cross-coupling, halogenation, heterocycles, or-
ganometallic reagents
Azulene is an aromatic, bicyclic compound with a
unique structure, which gives azulene a deep blue color, a
strong dipole moment1 (1.08 D), and unusual chemical
properties. Azulene derivatives are common in nature (Fig-
ure 1) and are found in chamomile2 (Matricaria recutita),
trees3 (Bulnesia sarmientoi), and certain mushrooms, such
as saffron milk cap4 (Lactarius deliciosus) and indigo milk
cap5 (Lactarius indigo).
of
1,3-bis[N-(tert-butoxycarbonyl)-2-pyrrolyl]azulene
through Stille coupling required 72 hours at 110 °C15a and
the synthesis of 1,3-diphenylazulene through Suzuki cou-
pling required 2 hours at 110 °C.14a Alkynes can be success-
fully introduced into azulene core by Sonogashira
coupling.16 Also some promising results were recently re-
ported by Morita et al. using Kumada coupling.17
Taking into account the interesting properties of azu-
lenes, it would be important to develop a method for the in-
troduction of complex substituents bearing sensitive
functional groups into azulene moiety and thus to increase
availability of such derivatives for further studies. We con-
sider Negishi reaction is more suitable for this purpose than
Suzuki coupling because of much milder reaction condi-
tions. However, Negishi cross-coupling has been rarely ap-
plied for derivatization of azulenes and only few examples,
such as the alkylation of 6-bromoazulenes18 and the syn-
thesis of 1,3-di(2-pyridyl)azulene19 are reported to date.
Simple and nonfunctionalized substituents were used in
these studies. To the best of our knowledge no reports con-
azulene
guaiazulene
chamazulene
Figure 1 Azulene and its natural compounds
Azulene derivatives possess a broad range of biological
activities, including anti-inflammatory,6 antiulcer,7 and an-
ticancer8,9 properties. Also, an azulene derivative HNS-32
has attracted attention as a coronary relaxant.10 Recently,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 538–548

539
J. Dubovik, A. Bredihhin
Paper
Synthesis
CO2Et
cerning the usage of functionalized organozinc reagents for
derivatization of azulene through Negishi cross-coupling
has been published.
ClCO2Et, AlCl3
DCE,1 h, r.t.
We began our research with the synthesis of haloazu-
lenes as substrates for Negishi cross-coupling. Chlorination
and bromination of azulene (1) are usually performed in
hexane or benzene and require 24 hours to complete.14a,20
Simply changing the solvent to CH2Cl2 results in a dramatic
reduction in the reaction time and gives excellent yields
(Table 1).
1
2 42%
Scheme 1 Synthesis of ethyl azulene-1-carboxylate (2)
The influence of different ligands on the Negishi cross-
coupling reaction of 3-bromo-1-chloroazulene (3e) with
PhZnCl (Table 2) was investigated. The reaction, in which
triphenylphosphine was used as a ligand, did not proceed at
room temperature, and only traces of the desired product
were observed after 24 hours. Stirring the reaction mixture
at 50 °C for 24 hours gave 4a in 75% yield. In contrast, when
SPhos22 (2-dicyclohexylphosphino-2′,6′-dimethoxybiphe-
nyl) was used as a ligand, the reaction was complete in 45
minutes at room temperature. In both cases, PnZnCl·LiCl
was obtained through the insertion of magnesium into PhI
in the presence of LiCl and the subsequent transmetalation
with ZnCl2. It was previously reported that i-PrI can dra-
matically decrease the cross-coupling reaction time by
changing the mechanism to radical pathway.23 Therefore,
cross-coupling was performed using PhZnCl·LiCl containing
i-PrI, which was obtained through an I–Mg exchange reac-
tion of PhI with i-PrMgCl·LiCl. The cross-coupling reaction
was complete in 30 minutes, showing only a moderate de-
crease in the reaction time.
Table 1 Halogenation Experiments
R2
R1
NCS or NBS
(1.0 or 2.0 equiv)
CH2Cl2, 0 °C to r.t.
25 min
R3
1, 2, 3a
3a–f
Product
R1
R2
Cl
R3
Yield (%)
3a
3b
3c
3d
3e
3f
H
H
H
H
Cl
H
92
91
53
98
99
97
Cl
Cl
H
Br
Br
Br
Br
Br
Cl
CO2Et
CO2Et
Monohalogenation of azulene (1) can be easily achieved
by using one equivalent of NCS or NBS. Additionally, ethyl
azulene-1-carboxylate (2) and 1-chloroazulene (3a) were
easily halogenated to the corresponding bromo derivatives
3e and 3f, respectively, using NBS in excellent yields. Usage
of two equivalents of halogenating agent results selectively
in the 1,3-dihalogenated azulenes 3b and 3d, respectively.
In the case of 3c, standard halogenation procedure results
in a 1:1 mixture of starting azulene (1) and 1,3-dibromo-
azulene (3d). However, evaporation of the reaction mixture
on a rotary evaporator (40 °C, 5 min) yields 3c as the main
product.
Table 2 Optimization of Catalytic System
Cl
Cl
Br
PhZnCl (1.0 equiv)
Pd(dba)2, ligand
THF, r.t.
Ph
3e
4a
Entry Catalytic system
Conditions
Yield (%)
75
1
Pd(dba)2 (5 mol%), PPh3
(20 mol%)
24 h, 50 °C
Compounds 3a and 3c are known to be unstable.20a In
our hands, neat 3a was stable for hours at room tempera-
ture and for several months at –20 °C. In contrast, the life-
time of neat 3c may be as short as few minutes at room
temperature. To overcome the instability of 3c, it was stored
as a solution in petroleum ether. 2-Bromoazulene (3g) was
synthesized according to the reported procedure.16a
Ethyl azulene-1-carboxylate (2) was synthesized direct-
ly from 1 and ethyl chloroformate in the presence of AlCl3 in
42% yield (Scheme 1). Also 57% of the starting material 1
was recovered. This reaction does not proceed to comple-
tion even if excess of AlCl3 and ethyl chloroformate are
used. Previously, the synthesis of 2 required a multistep
procedure and proceeded via trifluoacetylation, basic hy-
drolysis, and etherification.21
2
3
Pd(dba)2 (5 mol%), SPhos 45 min, r.t.
(10 mol%)
70
76
Pd(dba)2 (5 mol%), SPhos 30 min, r.t.
(10 mol%), i-PrI
Most of the organozinc reagents were prepared from
the corresponding iodides using an I–Mg exchange reaction
with i-PrMgCl·LiCl (–20 °C, 30 min)22 and subsequent trans-
metalation with ZnCl2 because this approach is faster and
more convenient than zinc-insertion reactions.
Aromatic substituents with sensitive functional groups
were successfully introduced into azulene derivatives using
Negishi cross-coupling (Table 3 and Table 4). Many func-
tional groups, such as CO2Et, CN, Cl, F, OMe, and CF3, were
tolerated. Most of the cross-coupling reactions proceeded
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540
J. Dubovik, A. Bredihhin
Paper
Synthesis
smoothly at room temperature in 0.5 to 1 hour; however,
some reactions required up to 5 hours to reach completion
(Table 3, entries 8 and 10).
Table 3 Negishi Cross-Coupling of Monobromoazulenes with Organozinc Reagents
R2ZnCl⋅LiCl (1.1 equiv)
R1
R2
R1
Pd(dba)2 (5 mol%)
Br
SPhos (10 mol%)
THF, r.t.
R2 = aryl, hetaryl, alkyl, benzyl
R1 = Cl, H, CO2Et
Entry
Substrate
Time
Product
Entry
10
Substrate
Time
Product
5c 81%
5d 53%
CO2Et
Cl
Cl
Br
1
0.5 h
3f
5 h
S
Ph
Cl
3e
3e
4a 71%
CO2Et
2
0.5 h
11
3f
1 h
CO2Et
4b 79%
Cl
CO2Et
OMe
3
3e
0.5 h
12
3f
2 ha
OMe
OMe
5e 87%
4c 51%
Cl
CF3
Br
4
3e
1 h
13
1 h
3c
3c
CF3
6a 80%
4d 70%
Cl
CN
5
3e
1 h
14
3 h
N
6b 72%
4e 63%
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J. Dubovik, A. Bredihhin
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Synthesis
Entry
Substrate
Time
2 h
Product
Entry
Substrate
Time
4 h
Product
F3C
Cl
CF3
6
3e
15
3c
S
4f 79%
6c 65%
Cl
1 ha
5 hb
2 h
16
1 h
CO2Et
Br
7
3e
3g
7a 86%
F
OMe
4g 87%
CO2Et
CO2Et
N
8
17
3g
1 h
O
7b 76%
Br
3f
CO2Et
5a 62%
CO2Et
9
3f
18
3g
0.5 h
CF3
7c 85%
OMe
5b 83%
a 1.0 equiv of i-PrI was added.
b At 60 °C.
Reactions with aromatic substituents bearing electron-
withdrawing group in para- and meta-positions gave good
results (Table 3, entries 2, 4, 13, 14, 18). Thus, 4b was ob-
tained from 3e in 30 minutes in 79% yield. Additionally, 3-
trifluoromethylphenylzinc chloride was successfully cou-
pled with 3e to give 4d in 70% yield. Substituents with elec-
tron-donating groups and a combination of electron-
withdrawing and -donating groups were also successfully
coupled (Table 3, entries 3, 7, 9). Thus, 5b and 4g were ob-
tained in 83% and 87% yield, respectively; however, cross-
coupling with 3e resulted in 4c only in moderate yield.
Heterocyclic substituents, including furan, thiophene,
and pyridine, were successfully introduced into azulene
(Table 3, entries 5, 6, 8, 10, 17). Thus, ethyl 5-bromofuran-
2-carboxylate was treated with i-PrMgCl·LiCl, transmetalat-
ed with ZnCl2, and successfully coupled with 3f to give 5a.
Despite the presence of LiCl, which significantly improves
the solubility of the organometallic reagents, thiophenyl-
zinc chloride formed a precipitate and was used as a sus-
pension. However, 4f and 5c were successfully obtained in
79% and 81% yield, respectively. Pyridine ring was readily
introduced, resulting in 4e and 7b in good yields.
Furthermore, alkyl and functionalized benzylic substit-
uents can be easily introduced (Table 3 entries 11, 12).
Thus, isopropyl-substituted azulene 5d was obtained in
moderate yield. However, 3,5-dimethoxybenzylzinc chlo-
ride was successfully coupled to give 5e in 87% yield.
Several 1-substituted azulenes 6a–c were obtained in
good yields. Compounds of type 6 are difficult to prepare
using other methods because of the instability of 3c and the
absence of the corresponding 1-metalated azulene. Azu-
lenes 6 also have a reactive, unsubstituted position 3, which
is available for further derivatization. The solution of 3c in
THF, which was used for cross-coupling reactions, was ob-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 538–548

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J. Dubovik, A. Bredihhin
Paper
Synthesis
tained by evaporation of petroleum ether solution of 3c un-
der vacuum followed by the quick addition of anhydrous
THF.
We also managed to introduce two different substitu-
ents to 1,3-dibromoazulene (3d) in a one-pot fashion
(Scheme 2). First, 4-(ethoxycarbonyl)phenylzinc chloride
(1.0 equiv) was added, and the reaction mixture was stirred
for 1 hour. Then, 4-pyridylzinc chloride (1.0 equiv) was add-
ed and stirred overnight to give 8d in 42% yield. This proce-
Derivatization of position 2 of the azulene core was also
successfully performed. In this way, functionalized aromat-
ic and pyridine substituents were introduced to furnish
compounds 7a–c in 76–86% yields. These compounds have
the most reactive positions of the azulene core (1 and 3)
free, which gives the possibility for their subsequent deri-
vatization and synthesis of more complex structures.
Also both positions 1 and 3 of the azulene ring can be
derivatized simultaneously with good to excellent yields
using 3d as starting material and two equivalents of the or-
ganozinc reagent (Table 4). Thus, 8b was successfully ob-
tained in 97% yield. Additionally, the Negishi cross-coupling
of 3d with phenylzinc and 3-trifluorophenylzinc chloride
gave 8a and 8c in good yields.
dure allows the synthesis of
a variety of complex
substituted azulenes that are difficult to prepare or are
completely inaccessible by other methods.
CO2Et
1)
EtO2C
ZnCl
Pd(dba)2 (5 mol%)
SPhos (10 mol%)
THF, r.t. 1 h
Br
Br
2)
N
ZnCl
3d
r.t., 18 h
Table 4 Negishi Cross-Coupling of 1,3-Dibromoazulene (3d) with Or-
N
ganozinc Reagents
8d 42%
Scheme 2 One-pot introduction of two different substituents
R
Br
RZnCl⋅LiCl (2.1–2.2 equiv)
In conclusion, we have developed a mild and effective
method for the synthesis of highly functionalized azulene
derivatives from bromoazulenes. The scope of this conver-
sion was demonstrated using electron-poor and electron-
rich aromatic, heterocyclic, alkylic, and benzylic substitu-
ents. This method showed high tolerance of sensitive func-
tional groups and gave products in good yields. A variety of
monobromoazulenes and 1,3-dibromoazulene were suc-
cessfully derivatized using this method. We also provided a
procedure for the introduction of two different substituents
into positions 1 and 3 of the azulene in a one-pot fashion,
which is an unprecedented result. A simple procedure for
the synthesis of haloazulenes with excellent yields is also
described.
Pd(dba)2 (5 mol%)
SPhos (10 mol%), THF, r.t.
R
Br
3d
8a–c
Entry
1
Time
Product
Ph
0.5 h
Ph
8a 71%
CO2Et
2
0.5 h
All reactions with organometallic reagents were carried out under an
argon atmosphere in dried (using a heat gun) glassware. The syringes
that were used to transfer anhydrous solvents or reagents were
purged with argon prior to use. THF was continuously refluxed and
freshly distilled from sodium benzophenone ketyl under N2. The
ZnCl2 solution was freshly prepared and stored under argon for not
more than one week. Petroleum ether (PE) used refers to the fraction
boiling in the 40–65 °C range. NMR spectroscopy was performed on a
400 MHz spectrometer using the residual solvent peak (CDCl3, 7.26
ppm for 1H and 77.16 ppm for 13C spectra) as an internal standard.
The IR spectra were recorded on an ATR module with a ZnSe crystal.
The reactions were monitored using TLC and visualized with UV light.
The products were purified using flash chromatography and silica gel
60 (0.040–0.063 mm, 230–400 mesh ASTM).
CO2Et
8b 97%
CF3
3
0.5 h
CF3
8c 62%
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J. Dubovik, A. Bredihhin
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Synthesis
ZnCl2 Solution in THF (1 M)
1H NMR (400 MHz, CDCl3): δ = 7.16 (t, J = 9.9 Hz, 2 H), 7.60–7.65 (m, 2
H), 8.30 (d, J = 9.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 114.7, 123.5, 132.7, 133.2, 135.4,
A 100 mL flask, equipped with a magnetic stirring bar and a septum,
was charged with anhydrous ZnCl2 (6.815 g, 50 mmol) and heated
with a heatgun (350 °C, 15 min and 550 °C, 15 min) under high vacu-
um. After cooling to r.t., anhydrous THF (50 mL) was added and the
stirring was continued until the salt was completely dissolved.
140.4.
HRMS (ESI): m/z [M]+ calcd for C10H6Cl2: 195.9847; found: 195.9835.
1-Bromoazulene (3c)
Ethyl Azulene-1-carboxylate (2)
According to TP1, NBS (178 mg, 1.0 mmol) was reacted with azulene
(1; 128 mg, 1.0 mmol) to give, after purification by column chroma-
tography (eluent: PE), 3c as a blue oil; yield: 109 mg (53%).
Azulene (1; 1.282 g, 10 mmol) was dissolved in 1,2-dichloroethane
(20 mL), then ethyl chloroformate (1.085 g, 10 mmol) followed by
AlCl3 (1.333 g, 10 mmol) were added to the solution at r.t. After the
addition of AlCl3, the reaction mixture warmed up and changed the
color to red. The mixture was stirred for 1 h at r.t. Then, it was trans-
ferred to a separatory funnel, diluted with CH2Cl2 (50 mL), and
washed with HCl (100 mL, 0.5 M) and H2O (50 mL). The aqueous frac-
tions were combined and back-extracted with CH2Cl2 (2 × 30 mL). The
organic fractions were combined, dried (MgSO4), and evaporated. The
residue was purified by column chromatography (eluent: CH2Cl2) to
afford 2 as a violet oil; yield: 841 mg (42%) and the starting azulene
(727 mg).
IR (ATR, neat): 3078, 3048, 3021, 2955, 1578, 1477, 1389, 1292, 1273,
914, 856, 764, 729, 559 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.12 (t, J = 9.8 Hz, 1 H), 7.19 (t, J = 9.8
Hz, 1 H), 7.29 (d, J = 4.2 Hz, 1 H), 7.56 (t, J = 9.9 Hz, 1 H), 7.80 (d, J = 4.2
Hz, 1 H), 8.19 (d, J = 9.5 Hz, 1 H), 8.32 (d, J = 9.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 104.1, 117.1, 123.4, 123.7, 135.4,
136.1, 137.3, 137.9, 138.8, 140.1.
HRMS (ESI): m/z [M]+ calcd for C10H7Br: 205.9731; found: 205.9721.
IR (ATR, neat): 3028, 2978, 2932, 2901, 1682, 1420, 1396, 1211, 1173,
1,3-Dibromoazulene (3d)
1142, 1038, 768 cm–1
.
According to TP1, NBS (3.560 g, 20 mmol) was reacted with azulene
(1; 1.282 g, 10 mmol) to give, after purification by column chroma-
tography (eluent: PE), 3d as dark-blue crystals; yield: 2.790 g (98%);
mp 92–93 °C (Lit.20a mp 88–89 °C).
1H NMR (400 MHz, CDCl3): δ = 1.45 (t, J = 7.2 Hz, 3 H), 4.45 (q, J = 7.2
Hz, 2 H), 7.28 (d, J = 4.3 Hz, 1 H), 7.39 (t, J = 9.7 Hz, 1 H), 7.52 (t, J = 9.9
Hz, 1 H), 7.75 (t, J = 9.7 Hz, 1 H), 8.39–8.43 (m, 2 H), 9.66 (d, J = 10.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.7, 59.8, 117.2, 117.6, 126.6, 127.6,
137.8, 138.2, 138.9, 140.3, 140.7, 144.8, 165.5.
IR (ATR, neat): 3105, 3059, 2924, 2859, 1574, 1477, 1450, 1377, 1285,
930, 856, 764, 737, 590, 563 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28 (t, J = 10.0 Hz, 2 H), 7.70–7.65 (m,
1 H), 7.81 (s, 1 H), 8.27–8.31 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 102.9, 124.2, 135.9, 136.8, 138.4,
HRMS (ESI): m/z [M + H]+ calcd for C13H13O2: 201.0910; found:
201.0905.
140.2.
Haloazulenes; 1-Chloroazulene (3a); Typical Procedure 1 (TP1)
HRMS (ESI): m/z [M]+ calcd for C10H6Br2: 283.8836; found: 283.8824.
NCS (1.335 g, 10 mmol) was added to a stirred solution of azulene (1;
1.282 g, 10 mmol) in CH2Cl2 (50 mL) at 0 °C and stirred for 10 min.
Then, the cooling bath was removed, and the reaction mixture was
stirred at r.t. for another 15 min. Next, the reaction mixture was evap-
orated to a small volume (~4 mL), and the residue was diluted with PE
(30 mL). As a result, a precipitate of succinimide formed and was fil-
tered off. Then, the procedure was repeated once more. The volatiles
were evaporated, and the residue was purified by column chromatog-
raphy (eluent: PE) to afford 3a as a blue oil; yield: 1.488 g (92%).
1-Bromo-3-chloroazulene (3e)
According to TP1, NBS (1.629 g, 9.15 mmol) was reacted with 3a
(1.488 g, 9.15 mmol) to give, after purification by column chromatog-
raphy (eluent: PE), 3e as green needles; yield: 2.285 g (99%); mp 82–
83 °C (Lit.20a mp 77.5–78 °C).
IR (ATR, neat): 3098, 3048, 3021, 2990, 2955, 2924, 2870, 1694, 1578,
1485, 1385, 1296, 941, 845, 775, 725, 594 cm–1
.
IR (ATR, neat): 3078, 3048, 3024, 2959, 1578, 1481, 1389, 1281, 925,
1H NMR (400 MHz, CDCl3): δ = 7.19 (dt, J = 2.6, 9.8 Hz, 2 H), 7.63 (t,
J = 9.9 Hz, 1 H), 7.71 (s, 1 H), 8.25 (d, J = 9.7 Hz, 1 H), 8.29 (d, J = 9.7 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 101.8, 115.7, 123.7, 123.9, 134.0,
135.08, 135.11, 135.6, 137.1, 140.3.
867, 764, 729, 563, 545 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.14–7.24 (m, 2 H), 7.32 (d, J = 4.3 Hz, 1
H), 7.63 (t, J = 9.9 Hz, 1 H), 7.79 (d, J = 4.3 Hz, 1 H), 8.26 (d, J = 9.3 Hz, 1
H), 8.40 (d, J = 9.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 115.9, 116.6, 123.0, 123.5, 133.5,
134.6, 135.1, 137.7, 138.9, 139.4.
HRMS (ESI): m/z [M + H]+ calcd for C10H7BrCl: 240.9414; found:
240.9410.
HRMS (ESI): m/z [M + H]+ calcd for C10H8Cl: 163.0309; found:
163.0303.
Ethyl 3-Bromoazulene-1-carboxylate (3f)
According to TP1, NBS (747 mg, 4.2 mmol) reacted with 2 (841 mg,
4.2 mmol) to give, after purification by column chromatography (elu-
ent: CH2Cl2), 3f as black crystals; yield: 1.1407 g (97%); mp 75–76 °C.
1,3-Dichloroazulene (3b)
According to TP1, NCS (267 mg, 2.0 mmol) was reacted with azulene
(1; 128 mg, 1.0 mmol) to give, after purification by column chroma-
tography (eluent: PE), 3b as green needles; yield: 179 mg (91%); mp
91–92 °C (Lit.20a mp 87–88 °C).
IR (ATR, neat): 3028, 2982, 2913, 2870, 1694, 1578, 1501, 1458, 1420,
1385, 1331, 1288, 1196, 1165, 1099, 1042, 980, 945, 887, 864, 772,
733, 607, 563 cm–1
.
IR (ATR, neat): 3102, 3051, 3021, 2955, 2924, 2855, 1578, 1489, 1478,
1389, 1308, 1292, 1146, 1092, 941, 845, 787, 725, 613, 594, 567 cm–1
.
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1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.2 Hz, 3 H), 4.42 (q, J = 7.2
Hz, 2 H), 7.56–7.47 (m, 2 H), 7.81 (t, J = 10.0 Hz, 1 H), 8.32 (s, 1 H),
8.46 (dd, J = 1.1, 9.8 Hz, 1 H), 9.60 (dd, J = 0.9, 9.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.7, 60.1, 104.4, 116.3, 127.1, 128.3,
137.6, 138.3, 140.0, 140.2, 140.3, 140.9, 164.6.
1-Chloro-3-(4-methoxyphenyl)azulene (4c)
The organozinc reagent was prepared from 4-iodoanisole according
to TP2 with a concentration of 0.5122 M. According to TP3, 3e (242
mg, 1 mmol) was reacted with organozinc reagent (2.1 mL, 0.5122 M)
for 30 min to give, after purification by column chromatography (elu-
ent: PE), 4c as green crystals; yield: 137 mg (51%); mp 77–78 °C.
HRMS (ESI): m/z [M + H]+ calcd for C13H12BrO2: 279.0015; found:
IR (ATR, neat): 3040, 3017, 2959, 2932, 2847, 1609, 1574, 1524, 1485,
1450, 1389, 1350, 1285, 1238, 1169, 1107, 1034, 953, 941, 826, 802,
279.0011.
725, 629, 567, 529 cm–1
.
Zn Reagents; from Iodobenzene; Typical Procedure 2 (TP2)
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H), 7.03–7.10 (m, 3 H), 7.14
(t, J = 9.7 Hz, 1 H), 7.47–7.50 (m, 2 H), 7.58 (t, J = 9.8 Hz, 1 H), 7.85 (s, 1
H), 8.37 (dd, J = 1.0, 9.7 Hz, 1 H), 8.40 (dd, J = 0.7, 9.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 55.5, 114.4, 116.4, 122.8, 123.6, 128.9,
129.2, 130.9, 134.3, 134.5, 134.8, 135.0, 136.6, 139.6, 158.9.
A flask was charged with i-PrMgCl·LiCl (4.63 mL, 1.0807 M) cooled to
–20 °C, and then neat iodobenzene (1.020 g, 5 mmol) was added. The
reaction mixture was stirred for 30 min, and then, a ZnCl2 solution in
THF (5.5 mL, 1 M) was added. The mixture was stirred for 15 min and
allowed to warm to r.t. over 30 min. Titration with I2 gave a concen-
tration of 0.5226 M.
HRMS (ESI): m/z [M]+ calcd for C17H13ClO: 268.0655; found: 268.0646.
Negishi Cross-Coupling; 1-Chloro-3-phenylazulene (4a); Typical
Procedure 3 (TP3)
1-Chloro-3-[3-(trifluoromethyl)phenyl]azulene (4d)
The organozinc reagent was prepared from 3-iodobenzotrifluoride
according to TP2 with a concentration of 0.5088 M. According to TP3,
3e (242 mg, 1 mmol) was reacted with organozinc reagent (2.2 mL,
0.5088 M) for 1 h to give, after purification by column chromatogra-
phy (eluent: PE), 4d as a green solid; yield: 216 mg (70%); mp 46–
48 °C.
A flask charged with 3e (242 mg, 1 mmol), Pd(dba)2 (30 mg, 5 mol%),
and SPhos (40 mg, 10 mol%) was evacuated and back-filled with ar-
gon, and then, THF (1.5 mL) was added, and the reaction mixture was
stirred for 5 min. Next, the organozinc reagent PhZnCl (2.10 mL,
0.5226 M) was added, and the mixture was stirred for 30 min. The
mixture was quenched with aq NH4Cl (0.5 mL), diluted with Et2O (30
mL), and the organic layer was washed with sat. aq NH4Cl (2 × 30 mL)
and brine (30 mL). The organic layer was dried (MgSO4) and evaporat-
ed, and the residue was purified by column chromatography (eluent:
CH2Cl2), to afford 4a as green crystals; yield: 245 mg (79%); mp 76–
77 °C.
IR (ATR, neat): 3048, 3024, 2963, 2924, 1574, 1485, 1454, 1393, 1308,
1273, 1161, 1103, 1069, 964, 837, 799, 733, 691, 575 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.18 (t, J = 9.8 Hz, 1 H), 7.23 (t, J = 9.8
Hz, 1 H), 7.58–7.73 (m, 4 H), 7.82 (s, 1 H), 7.89 (s, 1 H), 8.39 (dd,
J = 0.5, 9.7 Hz, 1 H), 8.43 (dd, J = 0.8, 9.7 Hz, 1 H).
IR (ATR, neat): 3036, 3021, 2959, 2924, 1574, 1485, 1393, 1350, 1296,
13C NMR (100 MHz, CDCl3): δ = 116.9, 123.5 (q, J = 3.7 Hz), 123.8,
124.6, 124.8 (q, J = 272.9 Hz), 126.4 (q, J = 3.9 Hz), 127.6, 129.3, 131.3
(q, J = 32.3 Hz), 133.0 (q, J = 1.5 Hz), 134.8, 135.0, 135.5, 136.3, 137.2,
140.0.
HRMS (ESI): m/z [M]+ calcd for C17H10ClF3: 306.0423; found:
306.0411.
941, 849, 806, 764, 734, 702, 575 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.12 (t, J = 9.8 Hz, 1 H), 7.18 (t, J = 9.8
Hz, 1 H), 7.40 (tt, J = 1.5, 7.2 Hz, 1 H), 7.50–7.54 (m, 2 H), 7.57–7.63
(m, 3 H), 8.42 (dd, J = 0.7, 9.7 Hz, 1 H), 7.91 (s, 1 H), 8.47 (d, J = 9.5 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 116.6, 123.1, 123.9, 126.9, 128.8,
129.4, 129.9, 134.6, 134.76, 134.83, 135.1, 136.4, 136.6, 139.7.
4-(3-Chloroazulen-1-yl)pyridine (4e)
HRMS (ESI): m/z [M]+ calcd for C16H11Cl: 238.0549; found: 238.0540.
Organozinc reagent: A flask was charged with 4-iodopyridine (923
mg, 4.5 mmol), then THF (2 mL) was added, and the mixture was
cooled to –20 °C. After the addition of i-PrMgCl·LiCl (4.2 mL, 1.0807
M), the cooling bath was removed and the reaction mixture was
stirred for 1 h at r.t. After this, ZnCl2 solution in THF (5.0 mL, 1 M) was
added. The mixture was stirred for 15 min and titrated. Titration with
I2 gave a concentration of 0.3252 M.
Ethyl 4-(3-Chloroazulen-1-yl)benzoate (4b)
The organozinc reagent was prepared from ethyl 4-iodobenzoate ac-
cording to TP2 with a concentration of 0.3731 M. According to TP3, 3e
(242 mg, 1 mmol) was reacted with the organozinc reagent (2.95 mL,
0.3731 M) for 30 min to give, after purification by column chromatog-
raphy (eluent: CH2Cl2), 4b as green crystals; yield: 245 mg (79%); mp
107–108 °C.
Coupling reaction: A flask charged with 3e (242 mg, 1 mmol),
Pd(dba)2 (30 mg, 5 mol%), and SPhos (40 mg, 10 mol%) was evacuated
and back-filled with argon. THF (1.5 mL) was added and the reaction
mixture was stirred for 5 min. Next, the organozinc reagent (3.4 mL,
0.3252 M) was added, and the mixture was stirred for 1 h. The mix-
ture was quenched with H2O (0.5 mL) and diluted with CH2Cl2 (30
mL). The organic layer was washed with aq NH4Cl–NH3 (25% in H2O)
(1:1 mixture, 2 × 30 mL) and brine (30 mL). The organic layer was
dried (MgSO4), evaporated, and the residue was purified by chroma-
tography (eluent: Et2O) to afford 4e as a green solid; yield: 151 mg
(63%); mp 99–100 °C.
IR (ATR, neat): 3024, 2986, 2905, 2870, 1717, 1605, 1578, 1389, 1350,
1273, 1173, 1103, 1026, 845, 806, 768, 741, 706, 610, 575 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.2 Hz, 3 H), 4.43 (q, J = 7.2
Hz, 2 H), 7.15 (t, J = 9.8 Hz, 1 H), 7.21 (t, J = 9.8 Hz, 1 H), 7.60–7.65 (m,
3 H), 7.89 (s, 1 H), 8.11–8.21 (m, 2 H), 8.40 (dd, J = 0.9, 9.7 Hz, 1 H),
8.45 (d, J = 9.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.5, 61.1, 117.0, 123.8, 124.6, 128.1,
128.6, 129.5, 130.1, 134.8, 134.9, 135.2, 135.4, 136.5, 140.0, 140.9,
166.7.
IR (ATR, neat): 3051, 3024, 2990, 2959, 2924, 2851, 1597, 1578, 1489,
1420, 1389, 1354, 1292, 1215, 991, 957, 826, 733, 675, 590, 571 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C19H16ClO2: 311.0834; found:
311.0825.
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1H NMR (400 MHz, CDCl3): δ = 7.28–7.19 (m, 2 H), 7.45–7.44 (m, 2 H),
7.67 (t, J = 9.8 Hz, 1 H), 7.89 (s, 1 H), 8.42 (dd, J = 1.1, 9.8 Hz, 1 H),
8.47–8.50 (m, 1 H), 8.67 (d, J = 4.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.6, 14.7, 60.2, 60.9, 108.0, 117.2,
117.6, 119.9, 128.6, 129.0, 138.2, 138.9, 139.1, 139.3, 140.6, 142.6,
143.4, 155.7, 159.1, 165.1.
13C NMR (100 MHz, CDCl3): δ = 117.3, 124.2, 124.3, 125.1, 125.9,
HRMS (ESI): m/z [M + H]+ calcd for C20H19O5: 339.1227; found:
134.7, 135.0, 135.7, 136.2, 140.2, 143.9, 150.2.
339.1218.
HRMS (ESI): m/z [M + H]+ calcd for C15H11ClN: 240.0575; found:
240.0573.
Ethyl 3-(4-Methoxyphenyl)azulene-1-carboxylate (5b)
The organozinc reagent was prepared from 4-iodoanisole according
to TP2 with a concentration of 0.5122 M. According to TP3, 3f (279
mg, 1 mmol) was reacted with the organozinc reagent (2.2 mL, 0.5122
M) for 4 h to give, after purification by column chromatography (elu-
ent: CH2Cl2), 5b as black crystals; yield: 253 mg (83%); mp 113–
114 °C.
2-(3-Chloroazulen-1-yl)thiophene (4f)
The organozinc reagent was prepared from 2-iodothiophene accord-
ing to TP2 with a concentration of 0.5655 M. According to TP3, 3e
(242 mg, 1 mmol) was reacted with the organozinc reagent (1.95 ml,
0.5655 M) for 2 h to give, after purification by column chromatogra-
phy (eluent: PE), 4d as a green solid; yield: 194 mg (79%); mp 67–
68 °C.
IR (ATR, neat): 3040, 2978, 2932, 2905, 2835, 1686, 1528, 1504, 1427,
1389, 1246, 1207, 1173, 1030, 980, 837, 775, 745, 575 cm–1
.
IR (ATR, neat): 3105, 3071, 3021, 2974, 2862, 1574, 1493, 1454, 1393,
1H NMR (400 MHz, CDCl3): δ = 1.47 (t, J = 7.2 Hz, 3 H), 3.89 (s, 3 H),
4.46 (q, J = 7.2 Hz, 2 H), 7.03–7.07 (m, 2 H), 7.36 (t, J = 9.8 Hz, 1 H),
7.47–7.53 (m, 3 H), 7.75 (t, J = 9.8 Hz, 1 H), 8.44 (s, 1 H), 8.58 (dd,
J = 0.8, 9.8 Hz, 1 H), 9.68 (dd, J = 0.8, 9.9 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ = 14.7, 55.5, 59.9, 114.3, 116.0, 126.7,
127.5, 129.1, 130.6, 130.9, 137.0, 138.1, 139.6, 140.0, 140.2, 141.4,
158.9, 165.5.
1350, 1296, 1219, 926, 849, 826, 733, 687, 570 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.12–7.19 (m, 3 H), 7.25 (dd, J = 1.1, 3.5
Hz, 1 H), 7.37 (dd, J = 1.3, 5.1 Hz, 1 H), 7.60 (t, J = 9.9 Hz, 1 H), 7.92 (s, 1
H), 8.35 (dd, J = 0.9, 9.7 Hz, 1 H), 8.65 (d, J = 9.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 116.9, 121.7, 123.6, 124.3, 125.1,
125.3, 127.9, 134.6, 134.8, 135.2, 135.3, 136.7, 138.4, 140.1.
HRMS (ESI): m/z [M + H]+ calcd for C20H19O3: 307.1329; found:
307.1323.
HRMS (ESI): m/z [M]+ calcd for C14H9ClS: 244.0113; found: 244.0106.
1-Chloro-3-(3-fluoro-4-methoxyphenyl)azulene (4g)
Ethyl 3-(Thiophen-2-yl)azulene-1-carboxylate (5c)
The organozinc reagent was prepared by transmetalation of commer-
cial 3-fluoro-4-methoxyphenylmagnesium bromide (5.6 mL, 0.5363
M) with ZnCl2 solution in THF (3.3 mL, 1 M) in 15 min at r.t. Titration
with I2 gave a concentration of 0.3396 M. According to TP3, 3e (242
mg, 1 mmol) was reacted with the organozinc reagent (3.2 mL, 0.3396
M) and i-PrI (0.10 mL, 1 mmol) for 1 h to give, after purification by
column chromatography (eluent: PE), 4g as green crystals; yield: 249
mg (87%); mp 85–86 °C.
The organozinc reagent was prepared from 2-iodothiophene accord-
ing to TP2 with a concentration of 0.5655 M. According to TP3, 3f (279
mg, 1 mmol) was reacted with the organozinc reagent (1.95 mL,
0.5655 M) for 5 h to give, after purification by column chromatogra-
phy (eluent: PE–Et2O, 3:1), 5c as black crystals; yield: 230 mg (81%);
mp 93–95 °C.
IR (ATR, neat): 3102, 3067, 2978, 2932, 2901, 1686, 1446, 1420, 1389,
1196, 1157, 1041, 826, 775, 741, 691 cm–1
.
IR (ATR, neat): 3051, 3005, 2963, 2932, 2839, 1574, 1528, 1497, 1439,
1393, 1296, 1265, 1215, 1126, 1026, 868, 810, 737, 605, 574 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.46 (t, J = 7.2 Hz, 3 H), 4.46 (q, J = 7.2
Hz, 2 H), 7.19 (dd, J = 3.7, 5.1 Hz, 1 H), 7.28 (dd, J = 1.1, 3.5 Hz, 1 H),
7.39 (dd, J = 1.1, 5.1 Hz, 1 H), 7.44 (t, J = 9.8 Hz, 1 H), 7.52 (t, J = 9.7 Hz,
1 H), 7.79 (t, J = 9.8 Hz, 1 H), 8.51 (s, 1 H), 8.84 (d, J = 9.9 Hz, 1 H), 9.67
(d, J = 9.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.8, 60.1, 116.4, 123.1, 125.2, 125.6,
127.3, 127.8, 128.1, 137.2, 138.5, 140.0, 140.1, 140.4, 141.9, 165.3.
1H NMR (400 MHz, CDCl3): δ = 3.97 (s, 3 H), 7.06–7.26 (m, 4 H), 7.29
(dd, J = 2.1, 12.2 Hz, 1 H), 7.61 (t, J = 9.8 Hz, 1 H), 7.81 (s, 1 H), 8.39 (t,
J = 8.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 56.6, 114.0 (d, J = 2.6 Hz), 116.5, 117.4
(d, J = 18.7 Hz), 123.3, 124.0, 125.5 (d, J = 3.3 Hz), 127.9 (d, J = 1.8 Hz),
129.7 (d, J = 7.0 Hz), 134.55, 134.57, 134.8, 135.3, 136.4, 139.8, 146.8
(d, J = 11.0 Hz), 151.4, 153.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H15O2S: 283.0788; found:
283.0782.
HRMS (ESI): m/z [M]+ calcd for C17H12ClFO: 286.0561; found:
286.0552.
Ethyl 3-Isopropylazulene-1-carboxylate (5d)
The organozinc reagent was prepared by transmetalation of the com-
mercial i-PrMgCl·LiCl (5.4 mL, 1.1202 M) with ZnCl2 solution in THF
(6.6 mL, 1 M) in 15 min at r.t. Titration with I2 gave a concentration of
0.5535 M. According to TP3, 3f (279 mg, 1 mmol) was reacted with
the organozinc reagent (2.0 mL, 0.5535 M) for 1 h to give, after purifi-
cation using column chromatography (eluent: PE–Et2O, 4:1), 5d as a
violet oil; yield: 129 mg (53%).
Ethyl 5-[3-(Ethoxycarbonyl)azulen-1-yl]furan-2-carboxylate (5a)
The organozinc reagent was prepared from ethyl 5-bromofuran-2-
carboxylate according to TP2 with a concentration of 0.3467 M. Ac-
cording to TP3, 3f (279 mg, 1 mmol) was reacted with the organozinc
reagent (2.3 mL, 0.4694 M) for 30 min to give, after purification by
column chromatography (eluent: PE–Et2O, 2:1), 5a as black crystals;
yield: 210 mg (62%); mp 120–122 °C.
IR (ATR, neat): 3028, 2959, 2932, 2870, 1686, 1454, 1427, 1385, 1200,
IR (ATR, neat): 3059, 3028, 2978, 2932, 2905, 1705, 1686, 1532, 1423,
1169, 1138, 1038, 775, 745 cm–1
.
1373, 1300, 1204, 1146, 1115, 1037, 775, 748 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.41–1.48 (m, 10 H), 3.55 (sept, J = 6.8
Hz, 1 H), 4.44 (q, J = 7.2 Hz, 2 H), 7.37 (t, J = 9.9 Hz, 1 H), 7.45 (t, J = 9.9
Hz, 1 H), 7.73 (t, J = 9.9 Hz, 1 H), 8.32 (s, 1 H), 8.44 (d, J = 9.9 Hz, 1 H),
9.60 (d, J = 9.9 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.40–1.48 (m, 6 H), 4.41 (q, J = 7.2, 2
H), 4.44 (q, J = 7.2, 2 H), 6.76 (d, J = 3.6 Hz, 1 H), 7.31 (d, J = 3.6 Hz, 1
H), 7.55 (dt, J = 4.0, 9.8 Hz, 2 H), 7.83 (t, J = 9.8 Hz, 1 H), 8.65 (s, 1 H),
9.18 (d, J = 9.6 Hz, 1 H), 9.67 (d, J = 9.3 Hz, 1 H).
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13C NMR (100 MHz, CDCl3): δ = 14.8, 24.4, 26.1, 59.8, 115.6, 125.4,
127.0, 134.4, 137.1, 137.2, 137.5, 138.8, 140.0, 141.1, 165.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H19O2: 243.1380; found:
243.1373.
13C NMR (100 MHz, CDCl3): δ = 112.9, 118.0, 119.2, 124.0, 124.3,
128.5, 129.56, 129.61, 133.0, 134.0, 135.1, 135.6, 137.1, 137.9, 138.8,
138.9, 142.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H12N: 230.0964; found:
230.0956.
Ethyl 3-(3,5-Dimethoxybenzyl)azulene-1-carboxylate (5e)
1-[3,5-Bis(trifluoromethyl)phenyl]azulene (6c)
The organozinc reagent was prepared by transmetalation of commer-
cial 3,5-dimethoxybenzylmagnesium chloride solution (22.6 mL,
0.1327 M) with ZnCl2 solution in THF (3.3 mL, 1 M) in 15 min at r.t.
Titration with I2 gave a concentration of 0.1218 M. According to TP3,
3f (279 mg, 1 mmol) was reacted with the organozinc reagent (9.0
mL, 0.1218 M) for 2 h to give, after purification by column chromatog-
raphy (eluent: PE–Et2O, 4:1), 5e as dark-violet crystals; yield: 322 mg
(92%); mp 103–105 °C.
The organozinc reagent was prepared from 1,3-bis(trifluoromethyl)-
5-bromobenzene according to TP2 with a concentration of 0.5177 M.
According to TP3, a solution of 3c (207 mg, 1 mmol) in THF was react-
ed with the organozinc reagent (2.1 mL, 0.5177 M) for 5 h to give, af-
ter purification by column chromatography (eluent: PE–Et2O, 5:1), 6c
as blue crystals; yield: 221 mg (65%); mp 67–68 °C.
IR (ATR, neat): 3055, 3028, 2916, 1396, 1362, 1312, 1273, 1169, 1119,
IR (ATR, neat): 2955, 2932, 2835, 1682, 1593, 1458, 1423, 1204, 1150,
891, 845, 779, 741, 705, 682 cm–1
.
1042, 829, 775, 756, 737 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25 (dt, J = 3.7, 9.8 Hz, 2 H), 7.45 (d,
J = 4.0 Hz, 1 H), 7.66 (t, J = 9.9 Hz, 1 H), 7.82 (s, 1 H), 8.01–8.02 (m, 3
H), 8.40 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 118.2, 119.8 (quint, J = 3.7 Hz), 123.7
(q, J = 272.9 Hz), 124.5, 124.8, 127.8, 129.5 (q, J = 3.7 Hz), 132.1 (q,
J = 33.0 Hz), 134.9, 135.9, 137.3, 138.2, 139.0, 139.8, 142.5.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.2 Hz, 3 H), 3.73 (s, 6 H),
4.34 (s, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 6.31 (t, J = 2.4 Hz, 1 H), 6.36 (d,
J = 2.3 Hz, 2 H), 7.35 (t, J = 9.7 Hz, 1 H), 7.48 (t, J = 9.9 Hz, 1 H), 7.74 (t,
J = 9.8 Hz, 1 H), 8.23 (s, 1 H), 8.39 (d, J = 9.5 Hz, 1 H), 9.62 (d, J = 9.9 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 14.7, 33.8, 55.3, 59.8, 97.9, 107.0,
115.7, 126.0, 127.4, 128.0, 135.2, 137.6, 139.0, 141.1, 141.2, 141.4,
143.6, 161.0, 165.5.
HRMS (ESI): m/z [M + H]+ calcd for C18H11F6: 341.0760; found:
341.0752.
HRMS (ESI): m/z [M + H]+ calcd for C22H23O4: 351.1591; found:
351.1596.
Ethyl 4-(Azulen-2-yl)benzoate (7a)
The organozinc reagent was prepared from ethyl 4-iodobenzoate ac-
cording to TP2 with a concentration of 0.4671 M. According to TP3, 3g
(104 mg, 0.5 mmol) was reacted with the organozinc reagent (1.17
mL, 0.4671 M) for 1 h to give, after column chromatography (eluent:
CH2Cl2–PE, 4:1), 7a as light-blue crystals; yield: 119 mg (86%); mp
204–206 °C.
1-[3-(Trifluoromethyl)phenyl]azulene (6a)
The organozinc reagent was prepared from 3-iodobenzotrifluoride
according to TP2 with a concentration of 0.4498 M. According to TP3,
a solution of 3c (207 mg, 1 mmol) in THF was reacted with the or-
ganozinc reagent (2.4 mL, 0.4498 M) for 1 h to give, after purification
by column chromatography (eluent: PE), 6a as blue crystals; yield:
218 mg (80%); mp 67–68 °C.
IR (ATR, neat): 3051, 2974, 2932, 2905, 2870, 1709, 1574, 1462, 1408,
1362, 1269, 1180, 1092, 1015, 810, 772, 752, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.2 Hz, 3 H), 4.42 (q, J = 7.2
Hz, 2 H), 7.18 (t, J = 9.8 Hz, 2 H), 7.55 (t, J = 9.8 Hz, 1 H), 7.71 (s, 2 H),
8.00 – 8.03 (m, 2 H), 8.12–8.15 (m, 2 H), 8.32 (d, J = 9.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.5, 61.1, 115.0, 124.1, 127.5, 129.9,
130.3, 136.9, 137.4, 140.9, 141.5, 148.5, 166.6.
IR (ATR, neat): 3059, 3028, 2959, 2924, 1574, 1447, 1393, 1342, 1303,
1269, 1165, 1107, 1069, 799, 779, 741, 702, 683, 648 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.23 (t, J = 9.9 Hz, 2 H), 7.49 (d, J = 4.0
Hz, 1 H), 7.62–7.68 (m, 3 H), 7.80–7.83 (m, 1 H), 7.91 (s, 1 H), 8.06 (d,
J = 4.0 Hz, 1 H), 8.41 (d, J = 9.4 Hz, 1 H), 8.53 (d, J = 9.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 117.9, 122.6 (q, J = 272.2 Hz), 123.0 (q,
J = 3.9 Hz), 123.8, 124.1, 126.4 (q, J = 3.7 Hz), 129.2, 129.7, 131.2 (q,
J = 31.5 Hz), 133.0 (q, J = 1.5 Hz), 135.3, 135.6, 137.3, 137.8, 138.5,
138.6, 142.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H17O2: 277.1223; found:
277.1217.
4-(Azulen-2-yl)pyridine (7b)
The organozinc reagent was prepared as described for 4e with a con-
centration of 0.3252 M. According to TP3, 3g (104 mg, 0.5 mmol) was
reacted with the organozinc reagent (1.69 mL, 0.3252 M) for 1 h.
Then, the reaction mixture was quenched with H2O (0.5 mL), diluted
with CH2Cl2 (30 mL), and the organic layer was washed with sat. aq
NH4Cl–NH3 (25% in H2O) (1:1 mixture, 2 × 30 mL) and brine (30 mL).
The organic layer was dried (MgSO4), evaporated, and the residue was
purified using chromatography (eluent: Et2O) to afford 7b as blue
crystals; yield: 78 mg (76%); mp 254–255 °C (Lit.24 mp >200 °C).
HRMS (ESI): m/z [M]+ calcd for C17H11F3: 272.0813; found: 272.0804.
3-(Azulen-1-yl)benzonitrile (6b)
The organozinc reagent was prepared from 3-iodobenzonitrile ac-
cording to TP2 with a concentration of 0.3958 M. According to TP3, a
solution of 3c (207 mg, 1 mmol) in THF was reacted with the organo-
zinc reagent (2.8 mL, 0.3958 M) for 3 h to give, after purification by
column chromatography (eluent: PE–Et2O, 4:1, and CH2Cl2), 6b as a
blue oil; yield: 165 mg (72%).
IR (ATR, neat): 3051, 3032, 2924, 2851, 1532, 1574, 1547, 1462, 1447,
IR (ATR, neat): 3059, 3028, 2226, 1589, 1574, 1477, 1393, 895, 796,
1408, 1211, 1018, 988, 953, 880, 799, 736, 721 cm–1
.
775, 736, 691, 575 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.21 (t, J = 9.9 Hz, 2 H), 7.57–7.63 (m, 1
H), 7.72 (s, 2 H), 7.80 (dd, J = 1.7, 4.6 Hz, 2 H), 8.36 (dd, J = 1.0, 10.0 Hz,
2 H), 8.69 (dd, J = 1.7, 4.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 115.0, 122.0, 124.3, 137.8, 138.2,
141.4, 143.9, 146.4, 150.5.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.24 (m, 2 H), 7.44 (d, J = 4.0 Hz, 1
H), 7.54–7.62 (m, 2 H), 7.65 (t, J = 9.8 Hz, 1 H), 7.82 (td, J = 1.7, 7.5 Hz,
1 H), 7.87–7.88 (m, 1 H), 7.98 (d, J = 4.0 Hz, 1 H), 8.38 (d, J = 9.4 Hz, 1
H), 8.46 (d, J = 9.8 Hz, 1 H).
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547
J. Dubovik, A. Bredihhin
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C15H12N: 206.0964; found:
206.0961.
mL, 0.5088 M) for 1 h to give, after purification using column chroma-
tography (eluent: PE), 8c as a cyan solid; yield: 260 mg (62%); mp
138–139 °C.
2-[3-(Trifluoromethyl)phenyl]azulene (7c)
IR (ATR, neat): 3075, 3051, 2959, 2920, 2874, 1574, 1454, 1319, 1265,
1153, 1111, 1067, 880, 795, 737, 698, 570 cm–1
.
The organozinc reagent was prepared from 3-iodobenzotrifluoride
according to TP2 with a concentration of 0.5361 M. According to TP3,
3g (104 mg, 0.5 mmol) was reacted with the organozinc reagent (1.0
mL, 0.5361 M) for 30 min to give, after purification by column chro-
matography (eluent: CH2Cl2–PE, 4:1), 7c as blue crystals; yield: 116
mg (85%); mp 160–161 °C.
1H NMR (400 MHz, CDCl3): δ = 7.25 (t, J = 10.2 Hz, 2 H), 7.62–7.71 (m,
5 H), 7.81–7.84 (m, 2 H), 7.90–7.91 (m, 2 H), 8.14 (s, 1 H), 8.53 (d,
J = 9.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 123.4 (q, J = 3.7 Hz), 124.5 (q, J = 272.2
Hz), 124.8, 126.6 (q, J = 3.7 Hz), 129.2, 129.3, 131.4 (q, J = 32.3 Hz),
133.1 (q, J = 1.5 Hz), 136.3, 137.23, 137.26, 137.9, 139.7.
IR (ATR, neat): 3059, 3024, 2955, 2924, 1408, 1342, 1315, 1169, 1111,
1076, 802, 740, 694 cm–1
.
HRMS (ESI): m/z [M]+ calcd for C24H14F6: 416.1000; found: 416.0986.
1H NMR (400 MHz, CDCl3): δ = 7.20 (t, J = 9.9 Hz, 2 H), 7.54–7.62 (m, 3
H), 7.69 (s, 2 H), 8.11–8.13 (m, 1 H), 8.20 (s, 1 H), 8.32–8.35 (m, 2 H).
Ethyl 4-[3-(Pyridin-4-yl)azulen-1-yl]benzoate (8d)
13C NMR (100 MHz, CDCl3): δ = 114.6, 124.2, 124.4 (q, J = 4.0 Hz),
124.7 (q, J = 3.7 Hz), 125.0 (q, J = 272.2 Hz), 129.5, 130.8 (q, J = 1.5 Hz),
131.4 (q, J = 32.3 Hz), 136.9, 137.4, 137.5, 141.5, 148.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H12F3: 273.0886; found:
273.0880.
The first organozinc reagent was prepared from ethyl 4-iodobenzoate
according to TP2 with a concentration of 0.4671 M. The second or-
ganozinc reagent was prepared from 4-iodopyridine as described for
4e with a concentration of 0.3252 M. According to TP3, 3d (286 mg, 1
mmol) was reacted with the first organozinc reagent (2.14 mL, 0.4671
M) for 1 h. Then the second zinc reagent (3.1 mL, 0.3252 M) was add-
ed and reaction mixture was stirred overnight. The mixture was
quenched with H2O (0.5 mL), diluted with CH2Cl2 (30 mL), and the or-
ganic layer was washed with sat. aq NH4Cl–NH3 (25% in H2O) (1:1
mixture, 2 × 30 mL) and brine (30 mL). The organic layer was dried
(MgSO4), evaporated, and the residue was purified using column
chromatography (eluent: CH2Cl2–Et2O, 2:1) to afford 8d as a green sol-
id; yield: 150 mg (42%); mp 178–179 °C.
1,3-Diphenylazulene (8a)
The organozinc reagent was prepared from iodobenzene according to
TP2 with a concentration of 0.4694 M. According to TP3, 3d (286 mg,
1 mmol) was reacted with the organozinc reagent (4.6 mL, 0.4694 M)
for 30 min to give, after purification by column chromatography (elu-
ent: PE), 8a as green crystals; yield: 198 mg (71%); mp 104–105 °C
(Lit.25 mp 100–102 °C; Lit.14a mp 114–116 °C).
IR (ATR, neat): 3024, 2978, 2924, 2855, 1709, 1593, 1427, 1362, 1269,
IR (ATR, neat): 3051, 3036, 2955, 2924, 2855, 1593, 1566, 1481, 1427,
1176, 1099, 864, 837, 772, 710, 574 cm–1
.
1366, 876, 760, 737, 702, 640, 575 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.2 Hz, 3 H), 4.43 (q, J = 7.2
Hz, 2 H), 7.27 (dt, J = 4.0, 9.7 Hz, 2 H), 7.54–7.56 (m, 2 H), 7.67–7.72
(m, 3 H), 8.15 (s, 1 H), 8.16–8.20 (m, 2 H), 8.60 (t, J = 9.0 Hz, 2H), 8.70
(d, J = 4.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.5, 61.1, 124.4, 125.3, 127.5, 128.7,
129.6, 130.07, 130.14, 136.1, 136.7, 137.2, 137.6, 138.0, 139.9, 141.4,
144.7, 150.1, 166.7.
1H NMR (400 MHz, CDCl3): δ = 7.15 (t, J = 10.0 Hz, 2 H), 7.40–7.44 (m,
2 H), 7.54–7.63 (m, 5 H), 7.69–7.71 (m, 4 H), 8.18 (s, 1 H), 8.60 (d,
J = 9.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 123.6, 126.6, 128.8, 130.0, 130.7,
136.3, 136.8, 137.3, 137.4, 139.1.
HRMS (ESI): m/z [M]+ calcd for C22H16: 280.1252; found: 280.1242.
HRMS (ESI): m/z [M + H]+ calcd for C24H20NO2: 354.1489; found:
354.1486.
Diethyl 4,4′-(Azulene-1,3-diyl)dibenzoate (8b)
The organozinc reagent was prepared from ethyl 4-iodobenzoate ac-
cording to TP2 with a concentration of 0.3731 M. According to TP3, 3d
(286 mg, 1 mmol) was reacted with the organozinc reagent (5.6 mL,
0.3731 M) for 30 min to give, after purification by column chromatog-
raphy (eluent: CH2Cl2–PE, 4:1 and PE–Et2O, 2:1), 8b as green crystals;
yield: 411 mg (97%); mp 127–128 °C.
Acknowledgment
The authors would like to thank the Estonian Science Foundation
(grant ETF9198) and the Archimedes Foundation (Project No.
3.2.0501.10-0004) for financial support.
IR (ATR, neat): 3044, 2978, 2936, 2866, 1705, 1601, 1427, 1358, 1261,
1227, 1177, 1015, 860, 772, 741, 710, 575 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.2 Hz, 6 H), 4.44 (q, J = 7.2
Hz, 4 H), 7.22 (t, J = 10.0 Hz, 2 H), 7.66 (t, J = 9.8 Hz, 1 H), 7.72–7.63
(m, 4 H), 8.16 (s, 1 H), 8.20–8.16 (m, 4 H), 8.57 (d, J = 9.5 Hz, 2 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379486.
13C NMR (100 MHz, CDCl3): δ = 14.5, 61.1, 124.9, 128.5, 129.6, 129.8,
S
u
p
p
o
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f
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S
u
p
p
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130.1, 136.5, 137.4, 137.6, 139.7, 141.6, 166.8.
HRMS (ESI): m/z [M + H]+ calcd for C28H25O4: 425.1748; found:
425.1741.
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 538–548