Direct introduction of a boryl substituent into the 2-position of azulene: Application of the Miyaura and Smith methods to azulene

Article abstract of DOI:10.1002/ejoc.200300001

The 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl group was directly introduced into the 2-positions of azulenes with high selectivity by the C-H activation method with use of iridium catalysis. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300001

FULL PAPER
Direct Introduction of a Boryl Substituent into the 2-Position of Azulene:
Application of the Miyaura and Smith Methods to Azulene
Kei Kurotobi,[a] Masato Miyauchi,[a] Katsuto Takakura,[a] Toshihiro Murafuji,*[a] and
Yoshikazu Sugihara*[a]
Dedicated to Prof. Klaus Hafner on the occasion of his 75th birthday
Keywords: Azulene / Borylation / CϪH activation / Iridium
The 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl group was di-
rectly introduced into the 2-positions of azulenes with high
selectivity by the C−H activation method with use of iri-
dium catalysis.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
the 1- and 3-positions has yet been established. Here we
report the direct introduction of a boryl function into the
2-position of the azulene skeleton (Scheme 2).
Because of π-electron polarization, azulene undergoes
nucleophilic addition at its 4-, 6-, and 8-positions and elec-
trophilic substitution at its 1- and 3-positions.[1] Azulene
derivatives bearing substituents at the 2-, 5-, or 7-positions
have therefore previously been produced simply by the con-
struction of the azulene skeleton, which introduces the sub-
stituent at an early stage of each synthetic method.[2]
We have very recently reported a simple method for the
introduction of substituents into the 2-position of azulene
by making use of the ortho-coordination of halogen atoms
situated at the 1- and 3-positions; this was also the first
paper on the generation of azulenyllithium and azulenyl-
magnesium halides (Scheme 1).[3] From the viewpoint of
synthesis, however, no versatile dehalogenation method for
Scheme 2
Results and Discussion
Miyaura[4] and Smith III[5] have independently demon-
strated the CϪH activation method with iridium catalysis
to give the 4,4,5,5-tetramethyl-1,3,2-dioxaborolane deriva-
tives of benzenoid hydrocarbons. According to these papers,
the substitution should take place at the carbon processing
the more acidic hydrogen, a more crowded CϪH function
being less reactive.
Table 1 shows our results for the application of this
method to some azulene derivatives. An outstanding result
is the production of 2-(2-azulenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (1) in a good yield of 70%. Taking both
the total yields of borylated products 1 and 2 and the num-
ber of equivalents of the Bpin unit in pin2B2 into account,
both boryl groups in pin2B2 are used in the reaction.[4,5]
The other significant finding is that, in contrast to the case
Scheme 1
[a]
Department of Chemistry, Faculty of Science, Yamaguchi
University,
Yamaguchi 753-8512, Japan
Eur. J. Org. Chem. 2003, 3663Ϫ3665
DOI: 10.1002/ejoc.200300001
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3663

K. Kurotobi, M. Miyauchi, K. Takakura, T. Murafuji, Y. Sugihara
FULL PAPER
been observed in the iridium-catalyzed borylation of
haloarenes.[4,5]
Table 1. Direct borylation at the 2-positions of azulenes
The boryl function was effectively transformed into a
hydroxy function by treatment with hydrogen peroxide to
give the 2-hydroxyazulene,[8] an important compound for
the consideration of ketoϪenol tautomerism involving an
aromatic nucleus with the low aromatic energy
(Scheme 4).
[a]
Azulene derivative (2.2 equiv.), pin2B2 (1.0 equiv.) and 1/2-
[b]
[IrCl(COD)]2/bpy (10 mol %) in cyclohexane.
Yields based on
Scheme 4
[c]
the number of equivalents of the Bpin unit in pin2B2. Recovery
of the starting azulene derivative (61%). [d] Recovery of the starting
azulene derivative (89%).
In conclusion, this methodology has allowed us easy ac-
cess to 2-substituted azulenes, the syntheses of which re-
quired many reaction steps when the conventional method
was used.
of benzenoid hydrocarbons cited in the literature, the highly
acidic hydrogens on the seven-membered ring are never re-
placed. This site selectivity seems to be governed by the
formation of a π complex between the five-membered ring
and an iridium center in preference to the seven-membered
ring,[6] with the more electron-poor 2-position in the five-
membered ring being borylated. Attempted reactions with
6-formylazulene and 6-(hydroxymethyl)azulene resulted in
the recovery of the starting azulenes (74 and 93%, respec-
tively). The electron-withdrawing formyl group may be low-
ering the reactivity of the five-membered ring toward the π
complex formation. The hydroxy group seems to play an
active role in the destruction of the reactive intermediate
involving the boron atom. Steric effects should be another
Experimental Section
1H and 13C NMR spectra were recorded in CDCl3 at 25 °C with a
Bruker Avance 400S (400 MHz) spectrometer with tetramethylsil-
ane as an internal standard. Mass spectra (EI) were determined
with a Waters LCϪMS Integrity System at an ionization potential
of 70 eV. UV/Vis spectra were measured in MeCN or cyclohexane
with a Shimadzu UV-1600PC spectrophotometer.
General Procedure for Direct Borylation: Bis(pinacolato)diboron
(pin2B2; 0.5 mmol), 2,2Ј-bipyridine (0.05 mmol), and chloro(1,5-
cyclooctadiene)iridium() dimer (0.025 mmol) were added to a solu-
important factor, since substrates bearing methyl groups at tion of azulene (1.1 mmol) in dry cyclohexane (3 mL). After argon
gas had been bubbled into the mixture for 10 min, the mixture was
heated at reflux for 14 h under argon. The resulting solution was
concentrated to leave an oily residue, which was chromatographed
(silica gel; hexane/EtOAc, 5:1) to give the borylated product.
the 1- or 4-positions are converted into the 2-substituted
products 3 and 4 only in low yields. 1,3-Di-tert-butylazulene
and 1-(trifluoroacetyl)azulene did not give the borylated
products at all and the starting materials were recovered
almost intact (91% in both cases).
For comparison with the method described above, we
have also carried out the substitution of the iodine atom in
2-iodoazulene by a boryl group by use of a palladium cata-
lyst (Scheme 3).[7] Interestingly, two derivatives were
formed, one of which was identified as the desired product
1[7] while the structure of the other was tentatively assigned
as the dimeric product 5. Under the iridium-catalyzed con-
ditions, the carbonϪiodine bond in 2-iodoazulene did not
undergo borylation and only the starting azulene was reco-
vered (82%), although the 2-position of azulene is the most
reactive site under these conditions. Similar results have
2-(2-Azulenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1): Blue
solid, yield 70%; m.p. 99Ϫ101 °C (ref.[7] 99Ϫ101 °C). 1H NMR:
δ ϭ 1.40 (s, 12 H), 7.12 (t, J ϭ 9.8 Hz, 2 H), 7.58 (t, J ϭ 9.9 Hz,
1 H), 7.76 (s, 2 H), 8.35 (d, J ϭ 10.0 Hz, 2 H) ppm. 13C NMR:
δ ϭ 24.93, 83.72, 122.72, 125.07, 138.17, 138.74, 140.68 ppm. One
azulene skeleton C signal was not observed. MS: m/z (%) ϭ 128
(29) [C10H8], 154 (99) [C10H7BO], 169 (19), 181 (84), 254 (100)
[Mϩ]. UV/Vis (cyclohexane): λmax (ε) ϭ 282 (115000), 332 (9100),
347 (11400), 360 (4400), 435 (1520), 612 (1520), 665 (1490), 747 nm
(1000). C16H19BO2 (254.1): calcd. C 75.62, H 7.54; found C 75.22,
H 7.55.
2-(1-Azulenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2): Purple
solid, yield 10%; m.p. 56Ϫ57 °C. 1H NMR: δ ϭ 1.43 (s, 12 H),
7.30 (t, J ϭ 9.7 Hz, 1 H), 7.40 (t, J ϭ 9.9 Hz, 1 H), 7.43 (d, J ϭ
3.7 Hz, 1 H), 7.68 (t, J ϭ 9.9 Hz, 1 H), 8.36 (d, J ϭ 3.7 Hz, 1 H),
8.42 (d, J ϭ 9.5 Hz, 1 H), 9.20 (d, J ϭ 9.7 Hz, 1 H) ppm. 13C
NMR: δ ϭ 24.96, 82.89, 119.03, 124.64, 125.13, 136.42, 137.39,
138.24, 144.62, 145.59, 147.07 ppm. One azulene skeleton C signal
was not observed. MS: m/z (%) ϭ 128 (28) [C10H8], 154 (49)
[C10H7BO], 239 (9) [Mϩ Ϫ Me], 254 (100) [Mϩ]. UV/Vis (MeCN):
λmax (ε) ϭ 203 (18890), 229 (17530), 282 (51830), 286 (47280), 292
(50450), 336 (4460, sh), 344 (5740), 360 (5340), 551 (355), 584 (310,
sh), 648 (130, sh), 724 nm (35, sh). C16H19BO2 (254.1): calcd. C
75.62, H 7.54; found C 75.34, H 7.45.
Scheme 3
3664
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Eur. J. Org. Chem. 2003, 3663Ϫ3665

Direct Introduction of a Boryl Substituent into the 2-Position of Azulene
FULL PAPER
4,4,5,5-Tetramethyl-2-(4,6,8-trimethyl-2-azulenyl)-1,3,2-dioxa-
borolane (3): Blue solid, yield 32%; m.p. 162Ϫ163 °C. 1H NMR:
δ ϭ 1.40 (s, 12 H), 2.61 (s, 3 H), 2.88 (s, 6 H), 7.01 (s, 2 H), 7.74
(s, 2 H) ppm. 13C NMR: δ ϭ 24.90, 25.15, 28.91, 83.51, 123.22,
127.06, 136.63, 147.67, 148.17 ppm. One azulene skeleton C signal
was not observed. MS: m/z (%) ϭ 196 (28) [Mϩ Ϫ C6H12O], 223
(43) [Mϩ Ϫ C4H9O], 296 (100) [Mϩ]. UV/Vis (MeCN): λmax (ε) ϭ
Oxidation by Hydrogen Peroxide: Hydrogen peroxide (30% aqueous
solution, 10 equiv.) was added at 0 °C to a solution of 1
(0.20 mmol) in ethanol (2 mL), and the resulting solution was
stirred for 2 h at this temperature. After addition of water (5 mL),
the reaction mixture was extracted with EtOAc (3 ϫ 20 mL) and
the combined extracts were dried over Na2SO4. Concentration of
the extracts afforded an oily residue, which was chromatographed
214 (15110), 249 (30710), 291 (59700), 332 (9010), 301 (60400), 351 (silica gel; hexane/EtOAc, 5:1) to give 2-hydroxyazulene.
(5950), 366 (5200), 568 nm (610). C19H25BO2 (296.2): calcd. C
Red needles, yield 66% (based on 1); m.p. 114.5Ϫ116 °C (ref.[8]
115.5Ϫ116.5 °C).
77.04, H 8.5; found C 76.87, H 8.62.
2-(1,4-Dimethyl-7-isopropyl-2-azulenyl)-4,4,5,5-tetramethyl-1,3,2-
1
dioxaborolane (4): Blue oil, yield 5%. H NMR: δ ϭ 1.36 (d, J ϭ
6.9 Hz, 6 H), 1.40 (s, 12 H), 2.83 (s, 3 H), 2.84 (s, 3 H), 3.06 (m, 1
Acknowledgments
Acknowledgments
H), 6.94 (d, J ϭ 10.5 Hz, 1 H), 7.39 (dd, J ϭ 1.9, 10.5 Hz, 1 H),
7.61 (s, 1 H), 8.24 (d, J ϭ 1.9 Hz, 1 H) ppm. 13C NMR: δ ϭ 12.60,
24.21, 24.69, 24.95, 38.18, 83.21, 120.29, 124.81, 133.33, 134.98,
136.25, 136.90, 137.57, 139.75, 146.14 ppm. One azulene skeleton
C signal was not observed. MS: m/z (%) ϭ 209 (58) [C15H17B ϩ
H], 224 (24) [C15H17BO], 309 (87) [Mϩ Ϫ Me], 324 (100) [Mϩ].
UV/Vis (MeCN): λmax (ε) ϭ 205 (13160), 217 (13080), 248 (21550),
296 (37130), 341 (4020), 356 (5070), 635 (485), 674 (470), 750 nm
(210, sh). C21H29BO2 (324.3): calcd. C 77.78, H 9.01; found C
77.52, H 9.35.
We appreciate the financial support of Grants-in-Aid for Scientific
Research on Priority Area (A) (Nos. 12020239, 11133241 and
10146235) from the Ministry of Education, Science, Sports, and
Culture, Japan. T. M. thanks the financial support of the Nishida
Research Fund for Fundamental Organic Chemistry.
[1] [1a]
Reaction with methyllithium, see: K. Hafner, H. Weldes,
Justus Liebigs Ann. Chem. 1957, 606, 90Ϫ99. [1b] Reaction with
NBS, see: A. G. Anderson, Jr., J. A. Nelson, J. J. Tazuma, J.
Am. Chem. Soc. 1953, 75, 4980Ϫ4989.
[2]
T. Nozoe, S. Seto, S. Matsumura, Bull. Chem. Soc., Jpn. 1962,
Cross Coupling Reaction between 2-Iodoazulene and Bis(pinacolato)-
diboron: DMSO (6 mL) was added to a flask charged with
[Pd(dppf)Cl2] (0.03 mmol), KOAc (3.0 mmol), and bis(pinacolato)-
diboron (1.1 mmol), followed by 2-iodoazulene (1.0 mmol). The
mixture was stirred at 80 °C for 5 h, the reaction was quenched
with H2O (20 mL), and the resulting mixture was extracted with
benzene (3 ϫ 5 mL). The combined extracts were dried (MgSO4)
and concentrated to leave a residue, which was chromatographed
(silica gel; hexane/EtOAc, 5:1) to give the products 1 and 5 in 42
and 22% yields (based on 2-iodoazulene), respectively.
35, 1990Ϫ1998.
[3]
K. Kurotobi, H. Tabata, M. Miyauchi, Rahman, A. F. M.
Mustafizur, K. Migita, T. Murafuji, Y. Sugihara, H. Shimo-
yama, K. Fujimori, Synthesis 2003, 30Ϫ34.
[4] [4a]
T. Ishiyama, J. Takagi, J. F. Hartwig, N. Miyaura, Angew.
Chem. Int. Ed. 2002, 41, 3056Ϫ3058. [4b] T. Ishiyama, J. Takagi,
K. Ishida, N. Miyaura, N. R. Anastasi, J. F. Hartwig, J. Am.
Chem. Soc. 2002, 124, 390Ϫ391.
[5] [5a]
J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, Jr., M.
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Iverson, M. R. Smith, III, J. Am. Chem. Soc. 2000, 122,
12868Ϫ12869.
Dimeric Compound 5: Green solid, yield 22%; m.p. 103Ϫ105 °C.
1H NMR: δ ϭ 1.40 (s, 24 H), 7.12 (t, J ϭ 9.8 Hz, 4 H), 7.58 (t,
J ϭ 9.9 Hz, 2 H), 7.76 (s, 4 H), 8.35 (d, J ϭ 10.0 Hz, 4 H) ppm.
13C NMR: δ ϭ 24.93, 83.73, 122.73, 125.07, 138.18, 138.76, 140.68
ppm. Signals due to two carbon atoms in the azulene skeleton were
not observed. MS: m/z (%) ϭ 128 (17) [C10H8], 154 (55) [C10H7BO],
169 (12), 181 (83), 254 (100), 380 (16). UV/Vis (cyclohexane): λmax
(ε) ϭ 286 (130000), 336 (11400), 351 (12700), 364 (4100), 415
(1730), 438 (1990), 615 (900), 670 (910), 755 nm (450).
[6]
π-Complex formation of azulenes with transition metal center
[6a]
in the five-membered ring, see:
Chem. Ber. 1978, 111, 3001.
F. Edelmann, U. Behrrens,
[6b]
S. A. R. Knox, B. A. Sosinsky,
F. G. A. Stone, J. Chem. Soc., Dalton Trans. 1975, 1647.
K. Kurotobi, H. Tabata, M. Miyauchi, T. Murafuji, Y. Sugi-
hara, Synthesis 2002, 1013Ϫ1016.
K. Takase, T. Asao, Y. Takagi, T. Nozoe, J. Chem. Soc., Chem.
Commun. 1968, 368Ϫ370.
[7]
[8]
Received January 3, 2003
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