An easy access to 2-substituted azulenes from azulene-2-boronic acid pinacol ester

Article abstract of DOI:10.1055/s-0028-1083224

Azulene-2-boronic acid pinacol ester was conveniently transformed into 2-substituted azulenes bearing carboxyl, formyl, ester, or amino groups, which are difficult to access by conventional methods. Furthermore, the azulene-2-carboxylic acid thus synthesized was subjected to the Ugi four-component condensation to obtain a dipeptide-type product containing an azulene skeleton. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083224

PAPER
3745
An Easy Access to 2-Substituted Azulenes from Azulene-2-boronic Acid
Pinacol Ester
S
ynthesis of 2-Substitu
a
ted Azulen
s
es ayuki Fujinaga,a Kouichi Suetake,b Kazuhiro Gyoji,a Toshihiro Murafuji,*a,b Kei Kurotobi,b
Yoshikazu Sugihara*b
a
Graduate School of Medicine, Yamaguchi University, Yamaguchi City 753-8512, Japan
Department of Chemistry, Faculty of Science, Yamaguchi University, Yamaguchi City 753-8512, Japan
b
Fax +81(83)9335738; E-mail: murafuji@yamaguchi-u.ac.jp; E-mail: sugihara@yamaguchi-u.ac.jp
Received 26 June 2008; revised 13 August 2008
[IrCl(cod)]2/bpy
Abstract: Azulene-2-boronic acid pinacol ester was conveniently
transformed into 2-substituted azulenes bearing carboxyl, formyl,
ester, or amino groups, which are difficult to access by conventional
methods. Furthermore, the azulene-2-carboxylic acid thus synthe-
sized was subjected to the Ugi four-component condensation to ob-
tain a dipeptide-type product containing an azulene skeleton.
pin2B2
Bpin
cyclohexane
reflux
1 (70%)
O
O
Bpin =
bpy =
B
Key words: azulene, borylation, boronic acid ester, cross-coupling,
Ugi four-component reaction
Bpin
Owing to the p-electron polarization, azulene is prone to
electrophilic substitution at the 1- and 3-positions and nu-
cleophilic addition at the 4-, 6- and 8-positions.1 There-
fore, the synthesis of azulene derivatives bearing
substituents at the 2-, 5- or 7-positions is not trivial, and
has traditionally required a multi-step transformation in-
cluding the construction of the azulene skeleton.2 As part
of our recent efforts to overcome this problem, we report-
ed a new simple method for introducing a boryl group into
the 2-position of azulene. In this method, azulene under-
goes direct borylation preferentially at this position via the
C–H activation with an iridium-based catalyst, giving 1
together with a small quantity of 2 (Scheme 1).3a The
4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl group (Bpin) of
1 is converted into a hydroxyl group by oxidation to give
3. This ensures the easy access to 2-bromoazulene (4a)3b
and 2-iodoazulene (4b),3b which are key synthetic inter-
mediates in the production of 2-substituted azulenes, such
as 2,2¢-biazulene,4a 2-dialkylaminoazulene,4b and 2-
diphenylphosphinylazulene,5 via the organometallic
routes involving coupling or halogen–metal exchange.
Furthermore, the Miyaura–Suzuki cross-coupling of 1
with aryl halides is an efficient route to 2-arylated azu-
lenes.6 These successful transformations of 1 based on the
transition metal catalyzed reaction prompted us to explore
further their synthetic utility. In particular, there is still a
need for the development of general and simple methods
for the introduction of basic functional groups, such as
carboxyl, formyl, ester, or amino substituents, into the 2-
position of azulene. In this paper, we report a convenient
method for the synthesis of 2-substituted azulenes bearing
these functional groups based on the cross-coupling reac-
2 (10%)
N
N
H2O2
PBr3
OH
Br
1
toluene
90 °C
EtOH
r.t.
4a
3
Pd cat.
ArX
DMF
reflux
KI, CuI
Ar
I
4b
Scheme 1
tion of 1, as well as the preliminary results of the Ugi four-
component reaction using these derivatives.
Recently, Lysén and co-workers reported a new synthetic
route to aromatic amides by Pd-catalyzed coupling of
arylboronic acid esters with carbamoyl chlorides.7 When
we applied this reaction to 1, the desired amides 5 were
obtained in moderate yields and unreacted 1 (ca. 10%)
was recovered (Scheme 2). The subsequent hydrolysis of
5a gave azulene-2-carboxylic acid (6) in 60% yield.
Furthermore, morpholine amides are known to be effi-
cient precursors of aldehydes. The reduction of 5b with
DIBAL-H produced the desired 7a only in low yield, ow-
ing to the concomitant formation of the amine 7b. How-
ever, this reaction was proved to be sensitive to the
solvent effect. Thus, the use of THF8 in the place of tolu-
ene improved the yield of 7a while suppressing the forma-
tion of 7b, indicating that its coordination with the
aluminum center decreases the reducing capacity.
SYNTHESIS 2008, No. 23, pp 3745–3748
x
x.
x
x
.
2
0
0
8
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083224; Art ID: F14108SS
© Georg Thieme Verlag Stuttgart · New York
Next, we examined the conversion of 1 into ester 10
(Scheme 3). When 1 was subjected to a coupling reaction

3746
M. Fujinaga et al.
PAPER
deprotected by the addition of hydrazine14 to form 12. In
the Cu-catalyzed amination reaction, insoluble substances
due to the decomposition of 9 were formed. The attempt
to transform 1 into 11 directly was unsuccessful.
a)
b)
CONR2
CO2H
1
6 (60%)
NR2 = NMe2
5a (63%)
O
5b (66%)
The Ugi four-component condensation between an alde-
hyde, an amine, carboxylic acid, and an isocyanide allows
the rapid preparation of a-aminoacyl amide derivatives.15
The products of the Ugi reaction can participate in a wide
variety of substitution patterns, and constitute peptidomi-
metics, which have potential pharmaceutical applications.
Taking into account the versatile biological activities and
medicinal applications of azulene derivatives,16 we decid-
ed to utilize the Ugi reaction using substituted azulenes.
Thus, the condensation of 6, 6-formylazulene, benzyl-
amine, and tert-butyl isocyanide proceeded smoothly to
give the corresponding Ugi product 13 in good yield
(Scheme 4). The attempt to perform a similar condensa-
tion using 12 in the place of benzylamine was unsuccess-
ful, which is attributed to the presence of the less
nucleophilic amino group of 12.
N
O
N
c)
5b
CHO
toluene
7a (42%)
7a (62%)
7b (25%)
c)
THF
Scheme 2 Reagents and conditions: a) PdCl2(PPh3)2, ClCONR2,
CsF, THF, reflux; b) KOH (excess), 5a, EtOH–H2O, reflux; c)
DIBAL-H, 5b, –78 °C.
with ethyl chloroformate under the conditions for the syn-
thesis of 5, no reaction occurred. Duan has reported the
Pd-catalyzed coupling reaction of arylboronic acids with
ethyl chloroformate, yielding the corresponding ethyl es-
ters.9 In order to examine the applicability of this reaction
to azulene systems, we attempted to perform the conver-
sion of 1 into 9. Initially, the attempt to treat 1 with an
aqueous solution of sodium periodate containing hydro-
chloric acid10 resulted in the formation of a complex reac-
tion mixture. On the other hand, when 1 was allowed to
react with phenylboronic acid in the presence of hydro-
chloric acid, transesterification11 occurred smoothly, giv-
ing the desired 9 in 58% yield. The most prominent yield
of 9 was obtained by an alternative route via the borate 8.
OHC
6, t-BuNC
MeOH
reflux
O
CH2NH2
t-BuHN
N
O
Ph
13 (83%)
Scheme 4
12
Thus, the treatment of 1 with KHF2 produced 8, which
was subsequently hydrolyzed to 9. Furthermore, the Pd-
catalyzed coupling reaction of ethyl chloroformate with 9
thus obtained afforded 10. Although the yield of 10 is not
satisfactory, few side products are found (by TLC) in the
reaction mixture. In the presence of Cu(OAc)2,13 9 reacted
with phthalimide to give 11, whose phthaloyl group was
In summary, we have found that the azulenylboronic acid
ester 1 can be converted into useful 2-substituted azulenes
bearing carboxyl, formyl, ester, or amino groups, whose
syntheses by conventional methods are difficult. We be-
lieve that these azulene derivatives can be conveniently
utilized for the construction of new electronic systems
based on the unique electronic and pharmaceutical prop-
erties of azulene.
a)
b)
d)
1
BF3K
B(OH)2
All reactions were carried out under air, unless otherwise noted.
THF was distilled from sodium benzophenone ketyl under argon
8 (82%)
9 (85%)
1
before use. H and 13C NMR spectra were recorded in CDCl3 or
O
c)
DMSO-d6 on a Bruker Avance 400S spectrometer with TMS as an
internal standard. IR spectra were obtained as KBr pellets on a
Nicolet Avator 370 DTGS spectrophotometer.
N
O
CO2Et
10 (50%)
2-Azulenecarboxamides 5a,b; General Procedure
11 (51%)
To a flask charged with (PPh3)2PdCl2 (12.6 mg, 0.018 mmol), CsF
(182 mg, 1.2 mmol), carbamoyl chloride (1.2 mmol), and 1 (152
mg, 0.6 mmol) was added THF (5 mL) under argon. The mixture
was heated at 80 °C for 23 h. The reaction was quenched with H2O
(20 mL), and the resulting mixture was extracted with EtOAc (3 ×
10 mL). The combined extracts were dried (Na2SO4) and concen-
trated to leave a residue, which was chromatographed (silica gel;
hexane–EtOAc, 5:1) to give the corresponding amide.
e)
NH2
12 (75%)
Scheme 3
Reagents and conditions: a) KHF2, MeOH, r.t.; b)
Na2CO3, MeCN–H2O, r.t.; c) Pd(PPh3)4, K3PO4·nH2O, ClCO2Et, to-
luene, 90 °C; d) Cu(OAc)2, phthalimide, pyridine, H2O, DMF, r.t.; e)
NH2NH2, THF, r.t.
N,N-Dimethyl-2-azulenecarboxamide (5a)
Yield: 75 mg (63%); blue powder; mp 164–165 °C.
Synthesis 2008, No. 23, 3745–3748 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted Azulenes
Potassium 2-Azulenyltrifluoroborate (8)
3747
IR (KBr): 2925, 1620, 1517, 1388, 1170 cm–1.
To a solution of 1 (254 mg, 1.0 mmol) in MeOH (7 mL) was added
aq KHF2 (2.0 mL, 2.8 M, 5.6 mmol). The solution was stirred at r.t.
for 15 min and concentrated in vacuo to leave a residue, which was
dissolved in hot acetone (7 mL). The resulting mixture was filtered
off and the filtrate was concentrated in vacuo to give a crude prod-
uct, which was recrystallized from a minimum amount of hot ace-
tone–Et2O to afford 8 as a pure product; yield: 192 mg (82%); blue
powder; mp 260–265 °C (dec.).
IR (KBr): 3449, 2955, 2924, 2854, 1302 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 6.99 (2 H, t, J = 9.7 Hz), 7.30
(2 H, s), 7.40 (1 H, t, J = 9.8 Hz), 8.12 (2 H, d, J = 9.3 Hz).
1H NMR (400 MHz, CDCl3): d = 3.14 (3 H, s), 3.18 (3 H, s), 7.21
(2 H, t, J = 9.8 Hz), 7.46 (2 H, s), 7.64 (1 H, t, J = 9.9 Hz), 8.37 (2
H, d, J = 9.9 Hz).
13C NMR (100 MHz, CDCl3): d = 35.2, 39.3, 116.9, 123.8, 138.4,
138.5, 139.8, 143.6, 169.3.
Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C,
78.29; H, 6.65; N, 7.05.
Morpholino-2-azulenecarboxamide (5b)
Yield: 96 mg (66%); blue powder; mp 141–142 °C.
IR (KBr): 3442, 2965, 2856, 1634, 1431 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.64 (4 H, s), 3.81 (2 H, s), 3.87
(2 H, s), 7.23 (2 H, t, J = 9.9 Hz), 7.42 (2 H, s), 7.66 (1 H, t, J = 9.9
Hz), 8.38 (2 H, d, J = 9.6 Hz).
13C NMR (100 MHz, CDCl3): d = 42.4, 48.0, 67.0, 116.6, 124.0,
138.6, 138.8, 139.9, 142.4, 168.1.
13C NMR (100 MHz, DMSO-d6): d = 121.2, 123.2, 133.3, 134.6,
140.4. One azulene skeleton carbon signal was not observed.
Anal. Calcd for C10H7BF3K: C, 51.31; H, 3.01. Found: C, 51.10; H
2.83.
Azulene-2-boronic Acid (9)
(a) By Hydrolysis of 8: To a mixture of 8 (234 mg, 1.0 mmol) and
Na2CO3 (159 mg, 1.5 mmol) in H2O (5 mL) was added MeCN (10
mL). The resulting solution was stirred at r.t. for 4 h, acidified with
aq 1 M HCl (2 mL) followed by aq sat. NH4Cl (5 mL), and then ex-
tracted with Et2O (3 × 10 mL). The extracts were dried (Na2SO4)
and concentrated to leave a residue, which was recrystallized from
hexane–EtOAc (30:1) to afford 9 as a pure product; yield: 147 mg
(85%); blue powder; mp 256–259 °C (dec.).
Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C,
74.61; H, 6.28; N, 5.77.
Azulene-2-carboxylic Acid (6)
Amide 5a (99 mg, 0.5 mmol) was dissolved in EtOH–H2O (4:1) (5
mL), and after addition of KOH (70 mg, 0.9 mmol), the mixture was
heated at 80 °C for 23 h. The resulting solution was cooled to r.t.
and the reaction was quenched with H2O (10 mL). The resulting
mixture was washed with Et2O (3 × 10 mL). The aqueous layer was
acidified with 10% aq HCl to give a green precipitate of 6. The pre-
cipitate was extracted with Et2O (3 × 10 mL) and the extracts were
dried (Na2SO4) and concentrated to leave the pure product 6; yield:
52 mg (60%); green powder; mp 200–203 °C (dec.) (Lit.5a mp 200–
203 °C, dec.).
IR (KBr): 3404, 2924, 1499, 1458, 1359 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.13 (2 H, t, J = 9.7 Hz), 7.61
(1 H, t, J = 9.9 Hz), 7.72 (2 H, s), 8.24 (2H, s), 8.35 (2 H, d, J = 9.5
Hz).
13C NMR (100 MHz, DMSO-d6): d = 122.9, 125.2, 137.8, 138.7,
140.5, 146.1.
1H NMR (400 MHz, DMSO-d6): d = 7.30 (2 H, t, J = 9.9 Hz), 7.72
(2 H, s), 7.80 (1 H, t, J = 9.9 Hz), 8.56 (2 H, d, J = 10.0 Hz), 12.76
(1 H, br s).
Anal. Calcd for C10H9BO2: C, 69.84; H, 5.27. Found: C, 70.11; H,
5.48.
(b) By Transesterification of 1: To a solution of 1 (254 mg, 1.0
mmol) in EtOH (7 mL) was added phenylboronic acid (146 mg, 1.2
mmol) followed by a diluted aq solution of HCl (5 mL, pH 3) at r.t.,
and the mixture was stirred for 5 h. After concentration of the mix-
ture, 10% aq KOH (10 mL) was added and the resulting mixture
was washed with Et2O (3 × 10 mL). The aqueous layer was acidified
with a diluted aq solution of HCl (10 mL, pH 3) and extracted with
Et2O (3 × 10 mL). The organic layer was dried (Na2SO4) and the
solvent was evaporated to give the crude product. Purification by re-
crystallization from hexane–EtOAc (5:1) afforded the pure product
9; yield: 100 mg (58%).
Reduction of 5b to 2-Formylazulene (7a)
To a solution of 5b (121 mg, 0.5 mmol) in anhyd THF (5 mL) was
added dropwise DIBAL-H (1.0 M toluene solution, 0.9 mL, 0.9
mmol) at –78 °C under argon. The mixture was stirred at this tem-
perature for 15 min, and the reaction was quenched with aq AcOH
(50%, 1 mL). After 10 min, the resulting solution was neutralized
with aq sat. Na2CO3 and extracted with Et2O (3 × 10 mL). The com-
bined extracts were dried (Na2SO4) and concentrated to leave a res-
idue, which was chromatographed (silica gel; hexane–EtOAc, 2:1)
to give the desired 7a; yield: 49 mg (62%); green powder; mp 61–
62 °C (Lit.17 mp 62–63 °C).
1H NMR (400 MHz, CDCl3): d = 7.22 (2 H, t, J = 9.8 Hz), 7.70 (1
Ethyl 2-Azulenecarboxylate (10)
H, t, J = 9.9 Hz), 7.77 (2 H, s), 8.48 (2 H, d, J = 9.9 Hz), 10.44 (1 H,
To a flask charged with Pd(PPh3)4 (10 mg, 0.009 mmol),
K3PO4·nH2O (170 mg, 0.8 mmol), ethyl chloroformate (0.028 mL,
0.3 mmol), and 9 (52 mg, 0.3 mmol) was added toluene (5 mL) un-
der argon. The mixture was heated at 90 °C for 2 h. The reaction
was quenched with H2O (20 mL), and the resulting mixture was ex-
tracted with hexane (3 × 10 mL). The combined extracts were dried
(Na2SO4) and concentrated to leave a residue, which was chromato-
graphed (silica gel; hexane–EtOAc, 10:1) to give 10 as a pure prod-
uct; yield: 30 mg (50%); blue powder; mp 72–73 °C.
s).
A similar reduction of 5b in toluene gave 7a and 7b in 42% and 25%
yield, respectively.
2-(Morpholinomethyl)azulene (7b)
Yield: 28 mg (25%); purple oil.
1H NMR (400 MHz, CDCl3): d = 2.55 (4 H, t, J = 4.7 Hz), 3.77 (4
H, t, J = 4.7 Hz), 3.92 (2 H, s), 7.17 (2 H, t, J = 9.8 Hz), 7.35 (2 H,
s), 7.55 (1 H, t, J = 9.9 Hz), 8.26 (2 H, d, J = 9.4 Hz).
13C NMR (100 MHz, CDCl3): d = 54.0, 59.0, 67.0, 117.8, 123.1,
135.5, 136.3, 140.2, 149.8.
IR (KBr): 2977, 1697, 1320, 1227, 1202 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.44 (3 H, t, J = 7.1 Hz), 4.44 (2
H, q, J = 7.1 Hz), 7.18 (2 H, t, J = 9.8 Hz), 7.65 (1 H, t, J = 9.9 Hz),
7.80 (2 H, s), 8.41 (2 H, d, J = 9.3 Hz).
13C NMR (100 MHz, CDCl3): d = 14.4, 60.7, 118.8, 123.8, 138.6,
139.9, 140.2, 140.5, 165.7.
Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C,
78.99; H, 7.58; N, 6.25.
Synthesis 2008, No. 23, 3745–3748 © Thieme Stuttgart · New York

3748
M. Fujinaga et al.
PAPER
Anal. Calcd for C13H12O2: C, 77.98; H, 6.04. Found: C, 77.92; H,
5.89.
Acknowledgment
Support from the Japan Society for the Promotion of Science
(Grant-in-Aid for Scientific Research, No. 19550043) is gratefully
acknowledged.
2-Azulenylphthalimide (11)
To a flask charged with phthalimide (147 mg, 1.0 mmol), 9 (172
mg, 1.0 mmol), Cu(OAc)2 (9 mg, 0.1 mmol), DMF (7 mL), and H2O
(0.018 mL) was added pyridine (0.08 mL, 1.0 mmol). After stirring
the mixture at r.t. for 3 h, the reaction was quenched with H2O (10
mL). The resulting mixture was extracted with EtOAc (3 × 20 mL).
The combined extracts were dried (Na2SO4) and concentrated to
leave a residue, which was recrystallized from hot THF–hexane
(1:10) to give 11 as a pure product; yield: 140 mg (51%); purple
powder; mp 256–258 °C.
References
(1) (a) Reaction with MeLi, see: Hafner, K.; Weldes, H. Liebigs
Ann. Chem. 1957, 606, 90. (b) Reaction with NBS, see:
Anderson, A. G. Jr.; Nelson, J. A.; Tazuma, J. J. J. Am.
Chem. Soc. 1953, 75, 4980.
(2) Nozoe, T.; Seto, S.; Matsumura, S. Bull. Chem. Soc. Jpn.
1962, 35, 1990.
IR (KBr): 1721, 1491, 1474, 1377, 1282 cm–1.
(3) (a) Kurotobi, K.; Miyauchi, M.; Takakura, K.; Murafuji, T.;
Sugihara, Y. Eur. J. Org. Chem. 2003, 3663. (b) Ito, S.;
Nomura, A.; Morita, N.; Kabuto, C.; Kobayashi, H.;
Maejima, S.; Fujimori, K.; Yasunami, M. J. Org. Chem.
2002, 67, 7295.
(4) (a) Ito, S.; Okujima, T.; Morita, N. J. Chem. Soc., Perkin
Trans. 1 2002, 1896. (b) Yokoyama, R.; Ito, S.; Okujima,
T.; Kubo, T.; Yasunami, M.; Tajiri, A.; Morita, N.
Tetrahedron 2003, 59, 8191.
1H NMR (400 MHz, CDCl3): d = 7.26 (2 H, t, J = 9.8 Hz), 7.60 (1
H, t, J = 9.9 Hz), 7.80 (2 H, m), 7.99 (2 H, m), 8.03 (2 H, s), 8.39 (2
H, d, J = 9.4 Hz).
13C NMR (100 MHz, CDCl3): d = 109.5, 123.8, 124.1, 131.9, 134.6,
136.4, 136.6, 138.9, 139.4, 166.9.
Anal. Calcd for C18H11NO2: C, 79.11; H, 4.06; N, 5.13. Found: C,
79.04; H, 3.93; N, 5.11.
(5) (a) Mustafizur Rahman, A. F. M.; Murafuji, T.; Shibasaki,
T.; Suetake, K.; Kurotobi, K.; Sugihara, Y. Organometallics
2007, 26, 2971. (b) Ito, S.; Kubo, T.; Morita, N.; Matsui, Y.;
Watanabe, T.; Ohta, A.; Fujimori, K.; Murafuji, T.;
Sugihara, Y.; Tajiri, A. Tetrahedron Lett. 2004, 45, 2891.
(6) (a) Kurotobi, K.; Tabata, H.; Miyauchi, M.; Murafuji, T.;
Sugihara, Y. Synthesis 2002, 1013. (b) Ito, S.; Terazono, T.;
Kubo, T.; Okujima, T.; Morita, N.; Murafuji, T.; Sugihara,
Y.; Fujimori, K.; Kawakami, J.; Tajiri, A. Tetrahedron 2004,
60, 5357. Synthesis of 1,3-diarylazulenes by cross-coupling
reactions, see: (c) Thanh, N. C.; Ikai, M.; Kajioka, T.;
Fujikawa, H.; Taga, Y.; Zhang, Y.; Ogawa, S.; Shimada, H.;
Miyahara, Y.; Kuroda, S.; Oda, M. Tetrahedron 2006, 62,
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Nakajima, K.; Kuroda, S. Tetrahedron 2007, 63, 10608.
(7) Lysén, M.; Kelleher, S.; Begtrup, M.; Kristensen, J. L.
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2-Aminoazulene (12)
To a solution of 11 (137 mg, 0.5 mmol) in THF (7 mL) was added
hydrazine monohydrate (0.025 mL, 0.52 mmol) at r.t., and the re-
sulting solution was stirred for 24 h at this temperature. After the ad-
dition of H2O (5 mL), the mixture was extracted with Et2O (3 × 20
mL). The combined extracts were dried (Na2SO4) and concentrated
to leave a residue, which was chromatographed (silica gel; hexane–
EtOAc, 5:1) to give 12 as a pure product; yield: 54 mg (75%); red
crystals; mp 92–93 °C (Lit.18 mp 93–94 °C).
1H NMR (400 MHz, CDCl3): d = 4.54 (2 H, s), 6.68 (2 H, s), 7.19
(2 H, t, J = 9.8 Hz), 7.32 (1 H, t, J = 9.6 Hz), 7.95 (2 H, d, J = 9.2
Hz).
N-(tert-Butyl)-2-[N¢-(benzyl)azulene-2-carboxamido]-2-(6-azu-
lenyl)acetamide (13)
To a flask charged with 6-formylazulene (78 mg, 0.5 mmol) and
benzylamine (0.068 mL, 0.625 mmol) was added MeOH (3 mL).
After stirring the resulting solution at r.t. for 10 min, 6 (86 mg, 0.5
mmol) was added and the mixture was stirred at r.t. for 5 min. Then,
tert-butyl isocyanide (0.056 mL, 0.5 mmol) was added and the mix-
ture was stirred at 60 °C for 24 h. The solvent was concentrated to
leave a residue, which was recrystallized from THF–hexane (1:2) to
give 13 as a pure product; yield: 208 mg (83%); blue powder; mp
236–238 °C.
(8) Winterfeldt, E. Synthesis 1975, 617.
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346, 1679.
(14) Sasaki, T.; Minamoto, K.; Itoh, H. J. Org. Chem. 1978, 43,
2320.
The 1H NMR spectra of 13 suffered extreme peak broadening due
to rotational isomerism. This compound was characterized by vari-
1
able-temperature H NMR spectrum. Only one set of the signals
was observed at 60 °C.
(15) (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
(b) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (c) Keating, T. A.; Armstrong, R. W. J. Am. Chem.
Soc. 1996, 118, 2574.
(16) Wakabayashi, H.; Hashiba, K.; Yokoyama, K.; Hashimoto,
K.; Kikuchi, H.; Nishikawa, H.; Kurihara, T.; Satoh, K.;
Shioda, S.; Saito, S.; Kusano, S.; Nakashima, H.; Motohashi,
N.; Sakagami, H. Anticancer Res. 2003, 23, 4747; and
references cited therein.
(17) Saito, M.; Morita, T.; Takase, K. Bull. Chem. Soc. Jpn. 1980,
53, 3696.
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771.
IR (KBr): 3418, 3306, 2925, 2854, 1660, 1636 cm–1.
1H NMR (400 MHz, DMSO-d6, 60 °C): d = 1.21 (9 H, s), 4.70 (1 H,
br s), 5.12 (1 H, d, J = 16.4 Hz), 5.98 (1 H, br s), 6.94–7.00 (5 H,
m), 7.17 (2 H, br s), 7.30 (2 H, t, J = 9.9 Hz), 7.32 (2 H, d, J = 3.8
Hz), 7.45 (2 H, s), 7.68 (1 H, br s), 7.74 (1 H, t, J = 10.0 Hz), 7.84
(1 H, t, J = 3.8 Hz), 8.26 (2 H, d, J = 10.1 Hz), 8.44 (2 H, d, J = 9.5
Hz).
13C NMR (100 MHz, DMSO-d6, 60 °C): d = 28.1, 49.2 (br), 50.4,
66.9 (br), 116.0, 117.8, 123.6, 124.0, 125.8, 126.5, 127.3, 135.0,
136.9, 138.4, 138.6, 138.9, 139.0, 139.3, 143.3, 146.1 (br), 168.0,
169.9.
Anal. Calcd for C34H32N2O2: C, 81.57; H, 6.44; N, 5.60. Found: C,
81.44; H, 6.49; N, 5.55.
Synthesis 2008, No. 23, 3745–3748 © Thieme Stuttgart · New York