Synthesis of 1,3,6-Trisubstituted Azulenes Based on the 1-Acyloxyazulene Scaffold

Article abstract of DOI:10.1002/ejoc.201600962

An efficient synthetic route to 1,3,6-trisubstituted azulenes based on the 1-acyloxyazulene scaffold was developed. The 1-position in azulene was substituted in the ring-formation step with a functionalized acyloxy group. Additionally, the 3- and 6-positions of azulene were functionalized with versatile synthetic handles, a halogen atom and a formyl group.

Full text of DOI:10.1002/ejoc.201600962

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Accepted Article
Title: Synthesis of 1,3,6-trisubstituted azulenes based on the 1-acyloxyazulene scaf-
fold
Authors: Teppo O. Leino; Niklas G. Johansson; Lars Devisscher; Nina Sipari; Jari
´
Yli-Kauhaluoma; Erik A. A. Wallen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600962
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European Journal of Organic Chemistry
10.1002/ejoc.201600962
Synthesis of 1,3,6-trisubstituted azulenes based on the 1-
acyloxyazulene scaffold
Teppo O. Leino,*[a] Niklas G. Johansson,[a] Lars Devisscher,[a] Nina Sipari,[b] Jari Yli-Kauhaluoma[a]
and Erik A. A. Wallén[a]
[a] T. O. Leino, N. G. Johansson, L. Devisscher, J. Yli-Kauhaluoma, E. A. A. Wallén
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy
University of Helsinki
Viikinkaari 5 E, FI-00014 Helsinki, Finland
E-mail: teppo.leino@helsinki.fi
[b] N. Sipari
Viikki Metabolomics Unit, Department of Biosciences
University of Helsinki
Viikinkaari 5 E, FI-00014 Helsinki, Finland
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient synthetic route to access 1,3,6-trisubstituted azulenes based on the 1-acyloxyazulene scaffold was developed.
Position 1 in azulene was substituted in the ring formation step with a functionalized acyloxy group. Additionally, the 3- and 6-positions
of azulene were functionalized by versatile synthetic handles, a halogen atom and a formyl group.
Introduction
Azulene is a bicyclic nonbenzenoid aromatic structure and it has a dipole moment between its electron-rich five-membered ring
and electron deficient seven-membered ring.[1],[2] The five-membered ring readily reacts with electrophiles at its 1- and 3-
positions,[3] but the seven-membered ring is most easily substituted via a synthetic handle such as a halogen atom or a methyl
group. Azulene has not been an intensively studied ring structure in medicinal chemistry, unlike its structural isomer
naphthalene or isostere indole (aromatic molecule with a similar shape and dipole moment). The only azulene-based drug on
the market is the antiulcer agent egualen sodium.[4] In addition, azulene-based compounds have been reported to have e.g.
anticancer[5] and antidiabetic[6] activities as well as an application in erectile dysfunction.[7] General synthetic routes for multiple-
substituted azulenes will be needed to study azulene as a scaffold in medicinal chemistry.
Aiming at developing a general synthetic route to 1,3,6-trisubstituted azulenes, we have been studying different
possibilities to introduce synthetic handles on the azulene scaffold in these positions. The synthetic handles can then be used to
introduce a wide variety of substituents in the selected positions and allow a facile generation of a series of new compounds for
structure-based drug design or biological screening studies.
We have reported a general and efficient synthetic route to obtain 1,3,6-trisubstituted azulenes from 6-methylpyridine (1)
(Scheme 1).[8] However, with this procedure we did not succeed in introducing a halogen atom in position 6 by changing the
starting material from 6-methylpyridine to 6-chloropyridine. A halogen atom is highly desired as it can be exploited in many
palladium-mediated coupling reactions.[9]-[14] Unfortunately, most of the reported synthetic routes to 6-haloazulene derivatives
include multiple steps with low overall yields.[15]-[18]
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European Journal of Organic Chemistry
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Scheme 1. Two different approaches of synthesizing 1,3,6-trisubstituted azulenes.
We decided to study an alternative method to assemble the azulene ring presented by Kane et al.[19] In this method the
halogen atom at the 6-position in azulene is derived from a para-halogenated cinnamic acid 3 (Scheme 1). Furthermore, this
method gives directly an ester-linked substituent on the hydroxy group in the 1-position on the azulene scaffold. The previously
reported substituents in the 1-position are acetoxy, trimethylacetoxy and triflate.[14] The triflate group has been demonstrated to
react by a Suzuki coupling reaction. However, there is a severe selectivity problem in Pd-mediated coupling reactions with the
combination of a triflate group in the 1-position and a chlorine atom in the 6-position as both are equally reactive under Suzuki
coupling conditions.
We were interested in studying what kind of substituents could be introduced in the 1-position of azulene by a linking ester
bond and whether functional groups capable of serving as synthetic handles could also be introduced in this position. In the
other positions, a halogen atom was investigated as the synthetic handle in the 6-position and the formyl group in the 3-
position.The obtained 1,3,6-trisubstituted azulenes are in fact 1,3,6-trisubstituted azulenes based on the 1-acyloxyazulene
scaffold.
Results and Discussion
A Knoevenagel condensation between 4-chlorobenzaldehyde (4) and malonic acid gave 4-chlorocinnamic acid (5) in 92% yield
(Scheme 2). The double bond of 5 was hydrobrominated with HBr in glacial acetic acid at room temperature to give compound 6
in 98% yield. A reaction time of 4 days was needed to reach a high conversion. We replaced gaseous HBr, which was used in
the reported procedure,[19] with more practical and commercially available HBr in glacial acetic acid. Treatment of 6 with oxalyl
chloride provided the corresponding acid chloride, which was allowed to react with trimethylsilyldiazomethane to generate the
diazoketone 7 modifying a method from the literature.[20] Diazoketone 7 was obtained from 6 by this synthetic procedure in 79%
yield. Diazomethane was used previously by Kane et al.,[19] but we replaced it with the less explosive
trimethylsilyldiazomethane. In addition to the use of safer reagents compared to the reported method, the optimization of the
reaction conditions improved the yield. The overall yield from cinnamic acid 5 to diazoketone 7 was 77% with our method,
compared with the 61% yield reported in literature.[19]
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European Journal of Organic Chemistry
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Scheme 2. Synthesis of the azulene scaffold with different 1-acyloxy groups.
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European Journal of Organic Chemistry
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1-Acetoxy-6-chloroazulene (8) was synthesized from diazoketone 7 in 62% yield, which is consistent with the previously
reported yield. Different activated carboxylic acid derivatives were used as electrophiles to demonstrate possible substitutions
on the 1-position of azulene during this step. When using benzoyl chloride, nicotinoyl chloride and 2-thiophenecarbonyl chloride,
compounds 9, 10 and 11 were obtained in 40%, 33% and 40% yield, respectively. Carboxylic acid derivative 12 was
synthesized from succinic anhydride. The reaction was first carried out using the same method as in the case of 8, in which five
equivalents of the electrophile was added. However, this led to formation of an insoluble residue and the desired product could
not be isolated from the reaction mixture. The reaction was repeated with one equivalent of succinic anhydride to get 12 in 14%
yield. The result suggests that the excess of anhydride reacts further with the carboxyl group of 12 to form insoluble residue.
Compound 12 was turned out to be unstable after purification, which might also account for the low yield.
In addition to anhydrides and acid chlorides, mixed anhydrides made from pivaloyl chloride were used. Compound 13 and t-
Boc-protected glycine derivative 14 were synthesized by this method in the yields of 51% and 25%, respectively. As 13, the
methyl ester of 12, is a stable compound, it implies that the free carboxyl group causes the instability of 12. In the case of 14 the
amount of the mixed anhydride resulting from pivaloyl chloride activated N-(tert-butoxycarbonyl)glycine was reduced from five to
two equivalents, as five equivalents formed many side products and they were not separable from the desired product. The
reaction of diazoketone 7 with benzyl chloroformate as an electrophile gave the carbonate 15 in 32% yield. The use of various
activated carboxylic acid derivatives enables introduction of different ester and carbonate linked substituents in the 1-position.
These substituents can carry different functionalities to be introduced in this position of the azulene scaffold.
Introduction of the third substituent in the 3-position on the azulene scaffold was demonstrated using 1-acetoxy-6-
chloroazulene (8) as a starting material (Scheme 3). Formylation of the 3-position of azulene was optimized by changing
reaction temperatures (rt or 90 °C) or the amount of POCl3 (1.5–4 equiv), when preparing the Vilsmeier-Haack reagent from
POCl3 and DMF in situ. Yields of the trisubstituted azulene 16 varied from 31% to 59%. There was some variation in the yields
when applying the same method, which was likely caused by ester hydrolysis. To avoid this, NaHCO3 was used in the work-up
instead of NaOH. The highest yield was observed in the method, in which the reaction was carried out at room temperature
using two equivalents of POCl3. Additionally, the formylation was carried out with a commercial Vilsmeier-Haack reagent in DCM
at 0 °C providing 16 in 44% yield. The applicability of the formyl group was demonstrated by reductive amination, in which the
reaction with morpholine and sodium triacetoxyborohydride gave 17 in 53% yield. The reduction of the formyl group with
borane-THF complex to the corresponding alcohol 18 was quantitative. However, 18 is unstable and decomposes in course of a
few days at room temperature.
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European Journal of Organic Chemistry
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Scheme 3. Functionalization of the 3- and 6-positions of azulene.
Since imidazoles are important heterocycles in medicinal chemistry, we decided to introduce the moiety to the azulene
scaffold. 1-Trityl-4-vinyl-1H-imidazole (19) was synthesized following a method reported in the literature.[21] The Heck reaction
was carried out for both disubstituted azulene 8 and trisubstituted azulene 16 by heating the starting material and 19 with
microwaves at 160 °C for 30 min in the presence of palladium catalyst, phosphorous ligand and base. The reaction gave 20 and
21 in 59% and 67% yield, respectively. Trityl groups were removed with trifluoroacetic acid in DCM in yields exceeding 90%.
Conclusions
In our current work, we showed it is possible to include different functionalities at positions 1, 3 and 6 on the azulene scaffold.
The azulene ring was formed with a halogen atom in the 6-position and an acyloxy group in the 1-position. The third substituent
in the 3-position was a formyl group. The halogen atom and the formyl group are versatile synthetic handles for further
functionalization of the azulene scaffold. Additionally, we improved the reported synthetic route of the azulene scaffold and
successfully replaced the hazardous reagent diazomethane with less explosive trimethylsilyldiazomethane. We have
demonstrated the efficiency of the developed route synthesizing the 1,3,6-trisubstituted azulene derivative 23 in seven synthetic
steps in overall yield of 16%.
Experimental Section
General information. All synthesized compounds were characterized by 1H NMR and 13C NMR spectroscopy using Varian Mercury 300 MHz
spectrometer. NMR spectra are reported in chemical shifts in parts per million (ppm) relative to the residual solvents: CDCl3 7.26 and 77.16 ppm,
acetone-d6 2.05 and 29.84 ppm, DMSO-d6 2.50 and 39.52 ppm for 1H and 13C NMR, respectively. The progress of the reactions was monitored
by thin-layer chromatography on silica gel 60-F254 plates. When the product was purified by flash chromatography, silica gel (SiO2) 60 (230–400
mesh) or silica gel with a Biotage SP1 purification system (SNAP 10 g, 25 g or 50 g cartridges) was used. Microwave reactions were conducted
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European Journal of Organic Chemistry
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in sealed reaction vessels using a Biotage Initiator+ instrument equipped with an external IR-sensor to detect the reaction temperature. Mass
spectrometric analyses were executed with Waters Synapt G2 HDMS mass spectrometer with ESI. Compounds 17, 20 and 21 were ionized with
direct APPI/APCI ion source in positive, resolution ion mode, due to fragmentation and no efficient ionization during the HRMS analyses with ESI.
Compounds 17, 20 and 21 were analyzed as Na-adducts and exact masses were corrected with progesterone as a lock mass compound.
4-Chlorocinnamic acid (5). 4-Chlorobenzaldehyde (5.00 g, 35.6 mmol) and malonic acid (5.55 g, 53.4 mmol) were dissolved in pyridine (10 mL)
and piperidine (0.50 mL) was added. The reaction mixture was heated at 105 °C for 21 h and poured into a 4 M aqueous solution of HCl (40 mL).
The resulting white precipitate was filtered, washed several times with a small amount of a 0.01 M aqueous solution of HCl and evaporated under
reduced pressure to give 5 as a white, amorphous solid (5.99 g, 92%). 1H NMR (DMSO-d6) δ 12.41 (s, 1H), 7.74–7.69 (m, 2H), 7.58 (d, J = 16.2
Hz, 1H), 7.49–7.44 (m, 2H), 6.54 (d, J = 15.9 Hz, 1H). 13C NMR (DMSO-d6) δ 167.3, 142.4, 134.7, 133.2, 129.8, 128.8, 120.1. HRMS (ESI-TOF):
calcd for C9H6O2Cl [M - H]- 181.0056; found 181.0057.
3-Bromo-3-(4-chlorophenyl)propanoic acid (6). Compound 5 (2.01 g, 11.0 mmol) was suspended in a 33% solution of HBr in glacial acetic
acid (40 mL) under argon. The red-orange suspension was stirred at room temperature and after 24 h of stirring more 33% HBr in glacial acetic
acid (20 mL) was added. In total the reaction mixture was stirred at room temperature for 4 d. The solvents were evaporated and the orange
residue was dissolved in Et2O (100 mL). The organic phase was washed with a 0.05 M aqueous solution of HCl (10 × 40 mL), dried over
anhydrous Na2SO4, filtered, and evaporated to give 6 as a white, amorphous solid (2.85 g, 98%). 1H NMR (DMSO-d6) δ 7.59–7.54 (m, 2H), 7.44–
7.40 (m, 2H), 5.54–5.49 (m, 1H), 3.36–3.22 (m, 2H). 13C NMR (DMSO-d6) δ 170.6, 140.2, 133.0, 129.3, 128.6, 48.8, 43.6.
4-Bromo-4-(4-chlorophenyl)-1-diazobutan-2-one (7). Oxalyl chloride (0.57 mL, 6.6 mmol) was added to a suspension of 6 (1.5 g, 5.5 mmol) in
anhydrous benzene (20 mL) under argon. The reaction mixture was stirred at 65 °C for 18 h. The suspension turned to a clear solution after 45
min of stirring. The clear solution was allowed to cool to room temperature and the solvents were evaporated. The resulting brown oil was
dissolved in anhydrous MeCN (17 mL) under argon and it was added dropwise over 25 min to a solution of TMSCHN2 (2 M in Et2O, 5.5 mL, 11
mmol) in anhydrous MeCN (11 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h and it was allowed to react at 0–4 °C for 21 h without
stirring. The yellow solution was diluted with Et2O (80 mL) and it was extracted with a 0.5 M aqueous solution of NaHCO3 (2 × 40 mL) and water
(2 × 40 mL), dried over anhydrous Na2SO4, filtered, and evaporated to provide an orange oil. The crude product was purified by flash
chromatography (n-hexane/EtOAc 4:1) to give 7 as a yellow, amorphous solid (1.3 g, 79%). 1H NMR (CDCl3) δ 7.37–7.29 (m, 4H), 5.46–5.41 (m,
1H), 5.27 (s, 1H), 3.31–3.07 (m, 2H). 13C NMR (DMSO-d6) δ 189.8, 139.6, 134.6, 129.1, 128.7, 56.0, 50.0, 47.0. The NMR data is in accordance
with the literature.[14]
General procedure for compounds 8–15. Rhodium(II) pivalate (0.005 equiv) was dissolved in anhydrous DCM (6 mL/mmol) under argon. The
yellow solution of 7 (1 equiv) in anhydrous DCM (16 mL/mmol) was added dropwise over 1 h to the green rhodium(II) pivalate solution. The
greenish brown reaction mixture was stirred for an additional 30 min at room temperature before the appropriate electrophile (1.1–5 equiv) and 4-
DMAP (3 equiv) were added. The resulting mixture was stirred at room temperature for 5 min. In the case of 8 and 13, the reaction mixture was
treated with MeOH (1.5 mL/mmol) and stirred for additional 10 min. The reaction mixture was diluted with DCM and it was washed with a 1 M
aqueous solution of HCl (8, 9, 11, 12, 13), a 1% aqueous solution of citric acid (10, 14, 15), a saturated aqueous solution of NaHCO3 (10, 14),
water (15) and brine, dried over anhydrous Na2SO4, filtered, and evaporated to provide a crude product, which was purified by flash
chromatography.
1-Acetoxy-6-chloroazulene (8). Compound 7 (1.1 g, 4.0 mmol) and acetic anhydride (1.9 mL, 20 mmol) gave a dark blue oil, which after flash
chromatography (n-hexane/EtOAc 19:1) afforded 8 as a blue, amorphous solid (0.54 g, 62%). 1H NMR (CDCl3) δ 8.04–8.00 (m, 2H), 7.79 (d, J =
4.5 Hz, 1H), 7.29 (d, J = 4.5 Hz, 1H), 7.24–7.16 (m, 2H), 2.43 (s, 3H). 13C NMR (CDCl3) δ 169.0, 145.7, 139.8, 135.9, 134.0, 130.4, 128.2, 124.8,
122.9, 122.4, 116.2, 21.1. HRMS (ESI-TOF): calcd for C12H10O2Cl [M + H]+ 221.0369; found 221.0369. The NMR data is in accordance with the
literature.[14]
6-Chloroazulen-1-yl benzoate (9). Compound 7 (0.14 g, 0.50 mmol) and benzoyl chloride (0.064 mL, 0.55 mmol) gave a dark green oil, which
after flash chromatography (n-hexane/EtOAc 19:1) afforded 9 as a blue, amorphous solid (0.057 g, 40%). 1H NMR (CDCl3) δ 8.35–8.31 (m, 2H),
8.12 (d, J = 10.5 Hz, 1H), 8.06 (d, J = 9.9 Hz, 1H), 7.94 (d, J = 4.5 Hz, 1H), 7.71–7.64 (m, 1H), 7.60–7.54 (m, 2H), 7.35 (d, J = 4.2 Hz, 1H), 7.27–
7.18 (m, 2H). 13C NMR (CDCl3) δ 164.8, 145.8, 139.9, 136.0, 134.3, 133.8, 130.5, 130.4, 129.7, 128.8, 128.3, 125.1, 123.0, 122.6, 116.4. HRMS
(ESI-TOF): calcd for C17H12O2Cl [M + H]+ 283.0526; found 283.0525.
6-Chloroazulen-1-yl nicotinate (10). Compound 7 (0.14 g, 0.50 mmol) and nicotinoyl chloride hydrochloride (0.098 g, 0.55 mmol) gave a dark
green oil, which after flash chromatography (manual gradient of n-hexane/EtOAc 4:1  1:1) afforded 10 as a green, amorphous solid (0.047 g,
33%). 1H NMR (CDCl3) δ 9.52 (s, 1H), 8.89 (d, J = 4.2 Hz, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.09 (t, J = 10.8 Hz, 2H), 7.95 (d, J = 4.5 Hz, 1H), 7.51
(dd, J = 7.8, 3.0 Hz, 1H), 7.34 (d, J = 4.5 Hz, 1H), 7.35–7.21 (m, 2H). 13C NMR (CDCl3) δ 163.5, 154.2, 151.5, 146.1, 139.3, 137.7, 136.2, 134.2,
130.4, 128.0, 125.7, 125.0, 123.7, 123.3, 122.8, 116.4. HRMS (ESI-TOF): calcd for C16H11NO2Cl [M + H]+ 284.0478; found 284.0473.
6-Chloroazulen-1-yl thiophene-2-carboxylate (11). Compound 7 (0.14 g, 0.50 mmol) and 2-thiophenecarbonyl chloride (0.059 mL, 0.55 mmol)
gave a dark green oil, which after flash chromatography (n-hexane/EtOAc 19:1) afforded 11 as a green, amorphous solid (0.057 g, 40%). 1H
NMR (CDCl3) δ 8.13–8.03 (m, 3H), 7.92 (d, J = 4.5 Hz, 1H), 7.71 (d, J = 5.1 Hz, 1H), 7.32 (d, J = 4.2 Hz, 1H), 7.26–7.18 (m, 3H). 13C NMR
(CDCl3) δ 160.3, 145.9, 139.4, 136.1, 134.9, 134.1, 133.8, 132.7, 130.6, 128.3, 128.1, 125.0, 123.1, 122.6, 116.3. HRMS (ESI-TOF): calcd for
C15H10O2SCl [M + H]+ 289.0090; found 289.0094.
4-[(6-Chloroazulen-1-yl)oxy]-4-oxobutanoic acid (12). Compound 7 (0.14 g, 0.50 mmol) and succinic anhydride (0.050 g, 0.50 mmol) gave a
green solid, which after two flash chromatographic purifications (EtOAc/MeOH 1% + EtOAc/AcOH 1% and n-hexane/EtOAc/AcOH 80:18:2)
afforded 12 as a blue solid (0.020 g, 14%). 1H NMR (CD3CN) δ 8.16 (d, J = 9.9 Hz, 1H), 8.10 (d, J = 10.5 Hz, 1H), 7.71 (d, J = 4.5 Hz, 1H), 7.35
(d, J = 4.2 Hz, 1H), 7.31 (dd, J = 10.1, 2.3 Hz, 1H), 7.25 (dd, J = 10.5, 2.1 Hz, 1H), 2.98–2.91 (m, 2H), 2.77–2.73 (m, 2H). 13C NMR (CD3CN) δ
173.9, 172.2, 146.3, 140.8, 137.3, 135.2, 131.7, 129.5, 125.8, 123.9, 123.3, 117.3, 30.3, 29.4.
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European Journal of Organic Chemistry
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6-Chloroazulen-1-yl methyl succinate (13). Mono-methyl hydrogen succinate (0.33 g, 2.5 mmol) was suspended in DCM (8 mL) and Et3N (0.35
mL, 2.5 mmol) was added. The clear solution was cooled to 0 °C and pivaloyl chloride (0.31 mL, 2.5 mmol) was added dropwise. The resulting
white suspension was stirred at 0 °C for 1 h and then it was used as described in the General procedure. Compound 7 (0.14 g, 0.50 mmol) gave
a dark green oil, which after flash chromatography (n-hexane/EtOAc 4:1) afforded 13 as a blue oil (0.075 g, 51%). 1H NMR (CDCl3) δ 8.05–8.00
(m, 2H), 7.77 (d, J = 4.5 Hz, 1H), 7.27 (d, J = 4.5 Hz, 1H), 7.24–7.17 (m, 2H), 3.75 (s, 3H), 3.02 (t, J = 7.1 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H). 13
C
NMR (CDCl3) δ 172.7, 170.6, 145.8, 139.6, 136.0, 134.1, 130.5, 128.1, 124.9, 123.0, 122.6, 116.2, 52.1, 29.5, 29.2. HRMS (ESI-TOF): calcd for
C15H14O4Cl [M + H]+ 293.0581; found 293.0583.
6-Chloroazulen-1-yl (tert-butoxycarbonyl)glycinate (14). N-(tert-Butoxycarbonyl)glycine (0.18 g, 1.0 mmol) was suspended in DCM (3 mL)
and Et3N (0.14 mL, 1.0 mmol) was added. The clear solution was cooled to 0 °C and pivaloyl chloride (0.12 mL, 1.0 mmol) was added dropwise.
The resulting white suspension was stirred at 0 °C for 1 h and then it was used as described in the General procedure. Compound 7 (0.14 g, 0.50
mmol) gave a dark green oil, which after two flash chromatographic purifications (n-hexane/EtOAc 4:1 and toluene/MeOH 1%) afforded 14 as a
blue, amorphous solid (0.042 g, 25%). 1H NMR (acetone-d6) δ 8.22‒8.17 (m, 2H), 7.79 (d, J = 4.5 Hz, 1H), 7.37 (d, J = 4.5 Hz, 1H), 7.31 (dd, J =
10.2, 2.1 Hz, 1H), 7.24 (dd, J = 10.5, 2.1 Hz, 1H), 6.56 (s, 1H), 4.25 (d, J = 6.0 Hz, 2H), 1.46 (s, 9H). 13C NMR (acetone-d6) δ 169.7, 157.1,
146.0, 140.7, 137.1, 135.0, 131.6, 129.1, 125.6, 123.6, 122.9, 117.3, 79.7, 43.3, 28.6. HRMS (ESI-TOF): calcd for C17H19NO4Cl [M + H]+
336.1003; found 336.1007.
Benzyl (6-chloroazulen-1-yl) carbonate (15). Compound 7 (0.14 g, 0.50 mmol) and benzyl chloroformate (0.079 mL, 0.55 mmol) gave a dark
1
green oil, which after flash chromatography (n-hexane/EtOAc 9:1) afforded 15 as a blue oil (0.050 g, 32%). H NMR (acetone-d6) δ 8.25 (d, J =
10.2 Hz, 1H), 8.16 (d, J = 10.5 Hz, 1H), 7.86 (d, J = 4.2 Hz, 1H), 7.55‒7.28 (m, 8H), 5.37 (s, 2H). 13C NMR (acetone-d6) δ 154.1, 146.0, 140.9,
137.4, 136.3, 134.9, 131.4, 129.5, 129.3, 129.1, 128.6, 125.1, 123.7, 123.2, 117.1, 71.1. HRMS (ESI-TOF): calcd for C18H14O3Cl [M + H]+
313.0631; found 313.0631.
6-Chloro-3-formylazulen-1-yl acetate (16). Compound 8 (0.30 g, 1.4 mmol) was dissolved in anhydrous DMF (6 mL) under argon and POCl3
(0.25 mL, 2.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 45 min and then diluted with CHCl3 (200 mL).
The organic phase was washed with a 0.5 M aqueous solution of NaHCO3 (2 × 100 mL) and water (2 × 100 mL). The aqueous phases were
combined and extracted with CHCl3 (2 × 100 mL). All CHCl3 extracts were combined, dried over anhydrous Na2SO4, filtered, and evaporated to
provide a black oil. The crude product was purified by flash chromatography (n-hexane/EtOAc 4:1) to give 16 as a purple, amorphous solid (0.20
g, 59%). 1H NMR (acetone-d6) δ 10.36 (s, 1H), 9.30 (d, J = 10.5 Hz, 1H), 8.41 (d, J = 10.8 Hz, 1H), 8.22 (s, 1H), 7.78 (dd, J = 10.5, 2.1 Hz, 1H),
7.66 (dd, J = 10.7, 2.3 Hz, 1H), 2.44 (s, 3H). 13C NMR (acetone-d6) δ 186.6, 169.2, 148.5, 141.2, 137.0, 134.3, 134.0, 132.2, 131.7, 129.5, 128.4,
124.3, 20.9. HRMS (ESI-TOF): calcd for C13H10O3Cl [M + H]+ 249.0318; found 249.0322.
6-Chloro-3-(morpholinomethyl)azulen-1-yl acetate (17). Compound 16 (0.075 g, 0.30 mmol) and NaBH(OAc)3 (0.13 g, 0.60 mmol) were
suspended in anhydrous DCM (1.5 mL) and morpholine (0.029 mL, 0.33 mmol) was added. The purple reaction mixture was stirred at room
temperature for 2.5 h. The color of the reaction turned to green. The reaction mixture was treated with a saturated aqueous solution of NaHCO3
(10 mL) and was extracted with DCM (20 mL). Organic phase was washed with a saturated aqueous solution of NaHCO3 (10 mL) and brine (10
mL), dried over anhydrous Na2SO4, filtered, and evaporated to provide a green oil. The crude product was purified by flash chromatography
(EtOAc) to give 17 as a turquoise, amorphous solid (0.051 g, 53%). 1H NMR (acetone-d6) δ 8.47 (d, J = 10.2 Hz, 1H), 8.09 (d, J = 10.5 Hz, 1H),
7.76 (s, 1H), 7.25 (dd, J = 10.4, 2.3 Hz, 1H), 7.18 (dd, J = 10.5, 2.1 Hz, 1H), 3.92 (s, 2H), 3.61‒3.57 (m, 4H), 2.43‒2.38 (m, 7H). 13C NMR
(acetone-d6) δ 169.4, 146.0, 140.1, 134.3, 132.0, 131.3, 130.5, 126.5, 126.1, 122.7, 122.5, 67.5, 56.2, 54.6, 20.9. HRMS (APPI/APCI-TOF): calcd
for C17H18ClNO3Na [M + Na]+ 342.0873; found 342.0878.
6-Chloro-3-(hydroxymethyl)azulen-1-yl acetate (18). Borane tetrahydrofuran complex (1 M, 0.30 mL) was added dropwise to a solution of 16
(0.050 g, 0.20 mmol) in anhydrous THF (1 mL) under argon. The reaction mixture was stirred at room temperature for 20 min and the color of the
solution changed from dark purple to blue. The reaction mixture was diluted with EtOAc (15 mL), washed with saturated aqueous solution of
NaHCO3 (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give 18 as a blue, amorphous solid (0.050 g, quant). 1H NMR
(acetone-d6) δ 8.32 (d, J = 10.2 Hz, 1H), 8.08 (d, J = 10.5 Hz, 1H), 7.79 (s, 1H), 7.24 (dd, J = 10.2, 2.1 Hz, 1H), 7.17 (dd, J = 10.5, 2.1 Hz, 1H),
5.06 (d, J = 4.5 Hz, 2H), 4.14 (t, J = 5.3 Hz, 1H), 2.93 (s, 3H). 13C NMR (acetone-d6) δ 169.4, 145.8, 140.1, 134.0, 131.4, 130.9, 130.5, 129.2,
126.2, 122.7, 122.5, 57.9, 20.9.
(E)-6-[2-(1-Trityl-1H-imidazol-4-yl)vinyl]azulen-1-yl acetate (20). Compound 8 (0.10 g, 0.45 mmol), 19 (0.15 g, 0.45 mmol), Pd2(dba)3 (0.013
g, 0.014 mmol) and P(t-Bu)3HBF4 (0.016 g, 0.054 mmol) were suspended in anhydrous benzene (4.8 mL) under argon. Et3N (0.13 mL, 0.91
mmol) was added and the resulting dark blue suspension was heated with microwaves at 160 °C for 30 min. The reaction mixture was filtered
through a small pad of Celite® with EtOAc and diluted with EtOAc (30 mL). The green organic phase was washed with water (2 × 25 mL), dried
over anhydrous Na2SO4, filtered, and evaporated to provide a green solid. The crude product was purified by flash chromatography (n-
hexane/EtOAc 2:1) to give 20 as a green, amorphous solid (0.14 g, 59%). 1H NMR (acetone-d6) δ 8.19 (d, J = 9.9 Hz, 1H), 8.13 (d, J = 10.5 Hz,
1H), 7.58 (d, J = 4.2 Hz, 1H), 7.48–7.31 (m, 14H), 7.26–7.14 (m, 8H), 2.37 (s, 3H). 13C NMR (acetone-d6) δ 169.6, 149.2, 143.5, 140.5, 140.3,
139.8, 137.9, 135.2, 132.0, 131.4, 130.6, 129.1, 129.0, 127.6, 126.5, 125.7, 123.0, 122.1, 121.0, 114.9, 76.4, 20.9. HRMS (APPI/APCI-TOF):
calcd for C36H28N2O2Na [M + Na]+ 543.2048; found 543.2054.
(E)-3-Formyl-6-[2-(1-trityl-1H-imidazol-4-yl)vinyl]azulen-1-yl acetate (21). Compound 16 (0.25 g, 1.0 mmol), compound 19 (0.41 g, 1.2 mmol),
Pd2(dba)3 (0.028 g, 0.030 mmol) and P(t-Bu)3HBF4 (0.035 g, 0.12 mmol) were suspended in anhydrous benzene (12 mL) under argon. Et3N
(0.28 mL, 2.0 mmol) was added and the resulting dark blue suspension was heated with microwaves at 160 °C for 30 min. The reaction mixture
was filtered through a small pad of Celite® with EtOAc and diluted with EtOAc (100 mL). The green organic phase was washed with water (2 × 75
mL), dried over anhydrous Na2SO4, filtered, and evaporated to provide a green solid. The crude product was purified by flash chromatography (n-
hexane/EtOAc 1:1) to give 21 as a green, amorphous solid (0.37 g, 67%). 1H NMR (CDCl3) δ 10.25 (s, 1H), 9.39 (d, J = 10.2 Hz, 1H), 8.24 (d, J =
10.5 Hz, 1H), 8.02 (s, 1H), 7.69 (dd, J = 10.5, 1.5 Hz, 1H), 7.61 (dd, J = 10.7, 1.7 Hz, 1H), 7.52–7.64 (m, 2H), 7.40–7.34 (m, 9H), 7.29–7.15 (m,
7H), 7.06 (d, J = 1.2 Hz, 1H), 2.43 (s, 3H). 13C NMR (CDCl3) δ 186.1, 168.8, 151.0, 142.2, 140.4, 139.2, 138.9, 137.7, 134.5, 133.5, 131.9, 130.1,
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European Journal of Organic Chemistry
10.1002/ejoc.201600962
129.9, 128.5, 128.4, 127.6, 127.2, 126.1, 122.8, 122.1, 75.9, 21.2. HRMS (APPI/APCI-TOF): calcd for C37H28N2O3Na [M + Na]+ 571.1998; found
571.2004.
(E)-6-[2-(1H-Imidazol-4-yl)vinyl]azulen-1-yl acetate (22). Ethane-1,2-dithiol (0.1 mL) was added to a solution of 20 (0.072 g, 0.14 mmol) in
DCM (4 mL) under argon. Then trifluoroacetic acid (1 mL) was added and the resulting mixture was stirred at room temperature for 15 min. The
green reaction mixture was diluted with DCM (80 mL) and it was washed with a saturated aqueous solution of NaHCO3 (3 × 40 mL), dried over
anhydrous Na2SO4, filtered, and evaporated to provide a green oil. The crude product was purified by flash chromatography (manual gradient of
DCM  DCM/MeOH 19:1) to give 22 as a green, amorphous solid (0.035 g, 91%). 1H NMR (CD3CN) δ 8.20 (d, J = 9.9 Hz, 1H), 8.12 (d, J = 10.5
Hz, 1H), 7.64 (s, 1H), 7.54 (d, J = 4.5 Hz, 1H), 7.04–7.33 (m, 4H), 7.26–7.25 (m, 1H), 7.17 (d, J = 4.5 Hz, 1H), 2.37 (s, 3H). 13C NMR (CD3CN) δ
170.6, 149.4, 139.7, 138.2, 137.7, 135.4, 132.2, 131.7, 130.8, 128.6, 127.9, 125.8, 122.4, 121.2, 115.1, 21.2. HRMS (ESI-TOF): calcd for
C17H15N2O2 [M + H]+ 279.1133; found 279.1143.
(E)-6-[2-(1H-Imidazol-4-yl)vinyl]-3-formylazulen-1-yl acetate (23). Trifluoroacetic acid (1 mL) was added to a solution of 21 (0.080 g, 0.15
mmol) in DCM (4 mL) under argon. The reaction mixture was stirred at room temperature for 30 min and then it was diluted with DCM (100 mL).
The green organic phase was washed with a saturated aqueous solution of NaHCO3 (3 × 60 mL), dried over anhydrous Na2SO4, filtered, and
evaporated to provide a green oil. The crude product was purified by flash chromatography (manual gradient of DCM  DCM/MeOH 9:1) to give
23 as a green, amorphous solid (0.041 g, 92%). 1H NMR (DMSO-d6) δ 10.27 (s, 1H), 9.30 (d, J = 10.5 Hz, 1H), 8.35 (d, J = 10.5 Hz, 1H), 7.95 (s,
1H), 7.89–7.79 (m, 3H), 7.61 (d, J = 15.9 Hz, 1H), 7.49 (s, 1H), 7.39 (d, J = 15.9 Hz, 1H), 2.43 (s, 3H). 13C NMR (DMSO-d6) δ 185.4, 168.9,
151.4, 138.8, 137.4, 136.6, 136.4 (br), 133.9, 133.8, 130.8, 128.1, 127.9, 127.8, 127.2, 125.9, 122.1 (br), 121.4, 20.7. HRMS (ESI-TOF): calcd for
C18H15N2O3 [M + H]+ 307.1083; found 307.1088.
Acknowledgements
This study was financially supported by the Doctoral Program in Drug Research of the University of Helsinki (T.O.L.).
Keywords: synthesis design; aromatic substitution; cross-coupling; azulene; synthetic scaffold
[1] For reviews, see: a) S. Ito, T. Shoji, N. Morita, Synlett, 2011, 2279–2298; b) K. Abou-Hadeed, H-J. Hansen, Science Of Synthesis, Georg Thieme Verlag
KG, Stuttgart, 2009, 45b, 1043–1114; c) V. B. Mochalin, Y. N. Porshnev, Russ. Chem. Rev. 1977, 46, 530–547.
[2] A. G. Anderson Jr., B. M. Steckler, J. Am. Chem. Soc., 1959, 81, 4941–4946.
[3] K. Hafner, Angew. Chem. 1958, 70, 419–430.
[4] T. Yanagisawa, S. Wakabayashi, T. Tomiyama, M. Yasunami, K. Takase, Chem. Pharm. Bull. 1988, 36, 641–647.
[5] A. E. Asato, A. Peng, M. Z. Hossain, T. Mirzadegan, J. S. Bertram, J. Med. Chem. 1993, 36, 3137–3147.
[6] K. Ikegai, M. Imamura, T. Suzuki, K. Nakanishi, T. Murakami, E. Kurosaki, A. Noda, Y. Kobayashi, M. Yokota, T. Koide, K. Kosakai, Y. Ohkura, M.
Takeuchi, H. Tomiyama, M. Ohta, Bioorg. Med. Chem. 2013, 21, 3934–3948.
[7] S. Löber, H. Hübner, A. Buschauer, F. Sanna, A. Argiolas, M. R. Melis, P. Gmeiner, Bioorg. Med. Chem. Lett. 2012, 22, 7151–7154.
[8] T. O. Leino, M. Baumann, J. Yli-Kauhaluoma, I. R. Baxendale, E. A. A. Wallén, J. Org. Chem. 2015, 80, 11513–11520.
[9] S. Ito, H. Inabe, T. Okujima, N. Morita, M. Watanabe, K. Imafuku, Tetrahedron Lett. 2000, 41, 8343–8347.
[10] S. Ito, T. Okujima, N. Morita, J. Chem. Soc., Perkin Trans. 1 2002, 1896–1905.
[11] D. Balschukat, E. V. Dehmlow, Chem. Ber. 1986, 119, 2272–2288.
[12] H. Horino, T. Asao, N. Inoue, Bull. Chem. Soc. Jpn. 1991, 64, 183–190.
[13] K. Kurotobi, H. Tabata, M. Miyauchi, T. Murafuji, Y. Sugihara, Synthesis, 2002, 1013–1016.
[14] A. L. Crombie, J. L. Kane, Jr., K. M. Shea, R. L. Danheiser, J. Org. Chem. 2004, 69, 8652–8667.
[15] S. Matsumura, Chem. Pharm. Bull. 1962, 10, 1024–1028.
[16] W. Bauer, U. Müller-Westerhoff, Tetrahedron Lett. 1972, 13, 1021–1024.
[17] M. Mąkosza, R. Kuciak, K. Woijciechowski, Liebigs Ann. Chem. 1994, 615–618.
[18] Y. Hari, S. Tanaka, Y. Takuma, T. Aoyama, Synlett. 2003, 2151–2154.
[19] J. L. Kane, K. M. Shea, A. L. Crombie, R. L. Danheiser, Org. Lett. 2001, 3, 1081–1084.
[20] H. Ren, W. D. Wulff, Org. Lett. 2010, 12, 4908–4911.
[21] C. A. Faler, M. M. Joullié, Org. Lett. 2007, 9, 1987–1990.
Entry for the Table of Contents
Substituted azulenes
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European Journal of Organic Chemistry
10.1002/ejoc.201600962
Herein we describe an efficient synthetic approach for 1,3,6-trisubstituted azulenes based on the 1-acyloxyazulene
scaffold, in which the 3- and 6-positions of azulene were functionalized by versatile synthetic handles.
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