New Two-Step Synthesis of Azulene-1-carboxylic Esters Using Lithium Trimethylsilyldiazomethane

Article abstract of DOI:10.1055/s-2003-42064

Lithium trimethylsilyldiazomethane successfully reacted with various ethyl or tert-butyl 4-aryl-2-oxobutanoates to yield 2,3-dihydroazulene-1-carboxylic esters via alkylidene carbene intermediates, and the resulting 2,3-dihydroazulenes were easily convert

Full text of DOI:10.1055/s-2003-42064

LETTER
2151
New Two-Step Synthesis of Azulene-1-carboxylic Esters Using Lithium
Trimethylsilyldiazomethane
N
ew two-Step Syn
o
thesis of
A
zu
s
lene-1-c
a
h
rboxylic Este
i
rs yuki Hari, Shunkichi Tanaka, Yasuta Takuma, Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Fax +81(52)8363439; E-mail: aoyama@phar.nagoya-cu.ac.jp
Received 12 August 2003
Me
N
Me
Abstract: Lithium trimethylsilyldiazomethane successfully reacted
with various ethyl or tert-butyl 4-aryl-2-oxobutanoates to yield 2,3-
dihydroazulene-1-carboxylic esters via alkylidene carbene interme-
diates, and the resulting 2,3-dihydroazulenes were easily converted
to the corresponding azulene-1-carboxylic esters by oxidation with
chemical manganese dioxide.
O
R
N
TMSC(Li)N2
O
O
R
Scheme 1
Key words: alkylidene carbenes, azulenes, chemical manganese
dioxide, diazo compounds, lithium trimethylsilyldizaomethane
smoothly conduct the reaction (entries 1 and 4).9 In this
reaction, there is the possibility that the reaction of
TMSC(Li)N2 with an ester moiety of 1a competes with
that with a ketone moiety. Therefore, the ethyl ester of 1a
was replaced by the more bulky tert-butyl ester.10 As a re-
sult, tert-butyl ester 1b successfully gave the desired
dihydroazulene 2b in 60% yield though prolonged re-
action time was required (entry 5). Unfortunately, the
reaction with a methyl ketone or 2-oxoamide, such as
4-phenyl-2-oxobutane or N,N-dimethyl-4-phenyl-2-oxo-
butanamide,11 gave a complex mixture and the corre-
sponding dihydroazulenes could not be detected. These
results indicate that an ester group in 1 is essential in this
reaction.
Azulenes are the most representative nonbenzenoid aro-
matic compounds and have not only beautiful colors but
also attractive features such as pharmacological activities
and electronic properties.1 Therefore, many methods for
the synthesis of azulenes have been developed to date;2
however, few synthetic methods of azulenes via expan-
sion of an aromatic ring have been reported.3
We have already demonstrated that the lithium salt of tri-
methylsilyldiazomethane [TMSC(Li)N2], prepared from
TMSCHN2 with LDA or n-BuLi, is quite useful as a re-
agent for generating alkylidene carbenes from carbonyl
compounds.4 For instance, TMSC(Li)N2 smoothly reacts
with N-methylanilides of a-keto acids to give cyclohep-
ta[b]pyrrol-2-ones via alkylidene carbene intermediates in
good yields (Scheme 1).5 We considered that this reaction
involving the construction of a seven-membered ring by
expansion of the benzene rings would be applicable to the
synthesis of 2,3-dihydroazulenes bearing substitutents on
the seven-membered ring if 4-aryl-2-oxobutanoic esters
were used as substrates.3 We here describe a two-step syn-
thesis of azulene-1-carboxylic esters by the reaction of
various 4-aryl-2-oxobutanoic esters with TMSC(Li)N2
followed by oxidation of the resulting 2,3-dihydroazu-
lenes with chemical manganese dioxide (CMD).6
Under optimized reaction conditions (entry 5 in Table 1),
various tert-butyl 4-aryl-2-oxobutanoates (1c–f) also gave
the corresponding tert-butyl 2,3-dihydroazulene-1-car-
boxylates (2c–f) in good to moderate yields. It is worthy
of comment that the reaction was considerably affected by
substituents on the benzene ring of 1. Thus, when R2
groups were electron-donating groups such as methyl (1c)
and methoxy groups (1d), the reaction smoothly proceed-
ed to give the corresponding 2c (72%) and 2d (76%), re-
spectively (entries 6 and 7). On the contrary, substitutions
of electron-withdrawing groups such as chloro and triflu-
oromethyl groups decreased the yields (34% for 2e and
19% for 2f, entries 8 and 9). These phenomena may be ex-
plained as follows: an alkylidene carbene intermediate,
which is generated in situ by the reaction of TMSC(Li)N2
and 1, is an electron deficient species; therefore, the addi-
tion of an alkylidene carbene to a benzene ring with high
electron density smoothly proceeds to give 2 in good
yields (Scheme 2).
First, we investigated the reaction of TMSC(Li)N2 with
commercially available ethyl 4-phenyl-2-oxobutanoate
(1a) and found that TMSC(Li)N2 reacted with 1a in Et2O
to give the desired ethyl 2,3-dihydroazulene-1-carboxy-
late (2a) in 42% yield as a labile oil (entry 1 in Table 1).7
In this reaction, LDA as a base was more effective than n-
BuLi (entries 1 and 3). Et2O was found to be the solvent
of choice though THF could be used (entries 1 and 2).8
Two equivalents of TMSC(Li)N2 were required to
It is well known that alkylidene carbenes undergo the in-
tramolecular 1,5-C-H insertion reaction giving cyclopen-
tene derivatives.12,13 Therefore, the competitive reaction
of tert-butyl 4-phenyl-2-oxopentanoate 1g14 via the 1,5-
C-H insertion and the addition to a benzene ring was ex-
amined (Scheme 3). Interestingly, the reaction preferen-
tially gave the 2,3-dihydroazulene analogue 2g (47%) as
SYNLETT 2003, No. 14, pp 2151–2154
0
6
.1
1
.2
0
0
3
Advanced online publication: 07.10.2003
DOI: 10.1055/s-2003-42064; Art ID: U16303ST
© Georg Thieme Verlag Stuttgart · New York

2152
Y. Hari et al.
LETTER
Table 1 Synthesis of 2,3-Dihydroazulene by Reaction of TMSC(Li)N2 with Ethyl- or tert-Butyl 4-Aryl-2-oxobutanoates
TMSC(Li)N2
R2
Et2O
R2
O
COOR1
COOR1
1
2
Entry
Substrate
TMSC(Li)N2 (equiv)b Conditions
Yield (%)
1
2a
3
4
5
6
7
8
9
R1 = Et, R2 = H (1a)
1a
1.2
1.2
1.2c
2.0
2.0
2.0
2.0
2.0
2.0
–78 °C, 2 h → reflux, 2 h
–78 °C, 2 h → reflux, 2 h
–78 °C, 2 h → reflux, 2 h
–78 °C, 2 h → reflux, 2 h
–78 °C, 3 h → reflux, 7 h
–78 °C, 3 h → reflux, 7 h
–78 °C, 3 h → reflux, 7 h
–78 °C, 3 h → reflux, 7 h
–78 °C, 3 h → reflux, 7 h
42 (2a)
38 (2a)
32 (2a)
49 (2a)
60 (2b)
72 (2c)
76 (2d)
34 (2e)
19 (2f)
1a
1a
R1 = t-Bu, R2 = H (1b)
R1 = t-Bu, R2 = Me (1c)
R1 = t-Bu, R2 = OMe (1d)
R1 = t-Bu, R2 = Cl (1e)
R1 = t-Bu, R2 = CF3 (1f)
a THF was used as a solvent.
b TMSC(Li)N2 was prepared from LDA and TMSCHN2 (1:1)
c TMSC(Li)N2 was prepared from n-BuLi and TMSCHN2 (1:1).
Table 2 Oxidation of 2,3-Dihydroazulene-1-carboxylic Esters by CMD
R3
R3
CMD
R2
R2
CH2Cl2, r.t.
COOR1
COOR1
2
4
Entry
Substrate
CMD (equiv)
Time (h)
Yield (%)
81 (4a)
40 (4b)
52 (4b)
64 (4c)
71 (4d)
68 (4e)
49 (4f)
74 (4g)
1
2
3
4
5
6
7
8
R1 = Et, R2 = R3 = H (2a)
R1 = t-Bu, R2 = R3 = H (2b)
2b
20
20
40
40
40
40
40
40
21
21
6
R1 = t-Bu, R2 = Me, R3 = H (2c)
R1 = t-Bu, R2 = OMe, R3 = H (2d)
R1 = t-Bu, R2 = Cl, R3 = H (2e)
R1 = t-Bu, R2 = CF3, R3 = H (2f)
R1 = t-Bu, R2 = H, R3 = Me (2g)
6
6
6
6
0.2
the sole isolable product and the cyclopentene 3 could not and 3). Analogously, CMD oxidation of the other sub-
be detected.
strates 2c–g also gave the corresponding azulenes 4c–g in
good to moderate yields (entries 4–8).
Finally, oxidation of the resulting dihydroazulenes 2 to
azulenes 4 by CMD was examined.15,16 As shown in In conclusion, the two-step synthesis of azulene-1-car-
Table 2, the ethyl ester 2a was easily converted to the de- boxylic esters from 4-aryl-2-oxobutanoic esters by using
sired azulene-1-carboxylic ester 4a in 81% yield (entry 1). TMSC(Li)N2 was achieved. This route allowed us to syn-
Under the same reaction conditions, the tert-butyl ester 2b thesize azulene analogues bearing substituents on both the
also gave 4d, though the yield was low. However, the use seven- and five-membered rings, and will provide added
of large excess of CMD led to significant improvement of flexibility in the azulene synthesis.
the yield (52%) with shortened reaction time (entries 2
Synlett 2003, No. 14, 2151–2154 © Thieme Stuttgart · New York

LETTER
New Two-Step Synthesis of Azulene-1-carboxylic Esters
2153
Ley, S. V., Eds.; Georg Thieme Verlag: Stuttgart, 2001,
569. (e) See also: Shioiri, T.; Aoyama, T. J. Synth. Org.
Chem. Jpn. 1996, 54, 918.
TMSC(Li)N2
R2
O
COOR1
COOR1
R2
:C
COOR1
(5) Ogawa, H.; Aoyama, T.; Shioiri, T. Synlett 1994, 757.
(6) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.;
Anzai, M.; Aodo, A.; Shioiri, T. Synlett 1998, 35.
1
(7) Selected data for the synthesized azulene analogues 2a–g.
Compound 2a: 1H NMR (CDCl3): d = 1.27 (3 H, d, J = 7
Hz), 2.63 (4 H, s), 4.17 (2 H, q, J = 7 Hz), 5.80–6.03 (4 H,
m), 7.40 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C13H14O2:
202.0994. Found: 202.0995. Compound 2b: 1H NMR
(CDCl3): d = 1.48 (9 H, s), 2.58 (4 H, s), 5.74–5.97 (4 H, m),
7.33 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C15H18O2:
230.1307. Found: 230.1313. Compound 2c: 1H NMR
(CD2Cl2): d = 1.34 (9 H, s), 1.71 (3 H, s), 2.43 (4 H, s), 5.64–
5.71 (2 H, m), 5.76 (1 H, d, J = 12 Hz), 7.18 (1 H, d, J = 12
Hz). HRMS (EI) calcd for C16H20O2: 244.1463. Found:
244.1461. Compound 2d: 1H NMR (CD2Cl2): d = 1.37 (9 H,
s), 2.48 (4 H, s), 3.45 (3 H, s), 5.16 (1 H, d, J = 9 Hz), 5.71–
5.81 (2 H, m), 7.36 (1 H, d, J = 13 Hz). HRMS (EI) calcd for
C16H20O3: 260.1410. Found: 260.1412. Compound 2e: 1H
NMR (CD2Cl2): d = 1.28 (9 H, s), 2.38 (4 H, s), 5.48 (1 H, d,
J = 9 Hz), 5.76 (1 H, dd, J = 2, 13 Hz), 5.89 (1 H, dd, J = 2,
9 Hz), 7.09 (1 H, d, J = 13 Hz). HRMS (EI) calcd for
C15H17ClO2: 264.0917. Found: 264.0919. Compound 2f: 1H
NMR (CD2Cl2): d = 1.34 (9 H, s), 2.12 (1 H, t, J = 8 Hz),
2.59 (1 H, t, J = 8 Hz), 6.66 (1 H, d, J = 12 Hz), 7.02–7.31 (2
H, m), 11.30 (1 H, d, J = 12 Hz). HRMS (EI) calcd for
C16H17F3O2: 298.1181. Found: 298.1183. Compound 2g: 1H
NMR (CD2Cl2): d = 1.20 (3 H, d, J = 7 Hz), 1.46 (9 H, s),
2.14–2.21 (1 H, m), 2.65–2.82 (2 H, m), 5.76–5.99 (4 H, m),
7.34 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C16H20O2:
244.1463. Found: 244.1461.
R2
R2
C
COOR1
2
Scheme 2
Me
Me
O
COOBut
TMSC(Li)N2, Et2O
COOBut
2g (47 %)
–78 °C for 2 h
to reflux for 3 h
1g
COOBut
3
Scheme 3
Acknowledgment
This work was financially supported by a Grant-in-Aid for Scienti-
fic Research (KAKENHI) and a Grant-in-Aid for Research in
Nagoya City University.
(8) When 1,2-dimethoxyethane was used as a solvent, the
reaction gave a complex mixture.
(9) Typical Procedure: To a stirred solution of diisopropyl-
amine (114 mg, 1.0 mmol) in Et2O (4 mL) was added
dropwise n-BuLi (1.56 M in hexane solution, 0.64 mL, 1.0
mmol) at –78 °C under N2, and the mixture was stirred for 10
min. TMSCHN2 (1.33 M n-hexane solution, 0.75 mL, 1.0
mmol) was further added dropwise, and the mixture was
stirred for 20 min. A solution of 1b (134 mg, 0.5 mmol) in
Et2O (1 mL) was added dropwise. The mixture was stirred at
–78 °C for 3 h, then heated under reflux for 7 h. After being
quenched with H2O (3 mL) at 0 °C, the mixture was
extracted with EtOAc (30 mL × 3). The organic extracts
were washed with H2O (80 mL) and sat. brine (50 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography (n-hexane:Et2O = 20:1)
to give 2b (68 mg, 60%) as a brown wax.
References
(1) (a) Ito, S.; Nomura, A.; Morita, N.; Kabuto, C.; Kobayashi,
H.; Maejima, S.; Fujimori, K.; Yasunami, M. J. Org. Chem.
2002, 67, 7295. (b) Pham, W.; Weissleder, R.; Tung, C. H.
Angew. Chem. Int. Ed. 2002, 19, 3659. (c) Waele, V. D.;
Schmidhammer, U.; Mrozek, T.; Daub, J.; Riedle, E. J. Am.
Chem. Soc. 2002, 124, 2438. (d) Tanaka, Y.; Shigenobu, K.
Cardiovasc. Drug Rev. 2001, 19, 297; and references cited
therein. (e) Ito, S.; Inabe, H.; Okujima, T.; Morita, N.;
Watanabe, M.; Imafuku, K. Tetrahedron Lett. 2000, 40,
8343.
(2) Recent constructional methods of the azulene skeleton, see:
(a) Rekka, E.; Chrysselis, M.; Siskou, I.; Kourounakis, A.
Chem. Pharm. Bull. 2002, 50, 904. (b) Nagel, M.; Hansen,
H.-J. Synlett 2002, 692. (c) Yokoyama, R.; Ito, S.;
Watanabe, M.; Harada, N.; Kabuto, C.; Morita, N. J. Chem.
Soc., Perkin Trans. 1 2001, 2257. (d) Brown, D. G.; Hoye,
T. R.; Brisbois, R. G. J. Org. Chem. 1998, 63, 1630.
(e) Yasunami, M.; Miyoshi, S.; Kanegae, N.; Takase, K.
Bull. Chem. Soc. Jpn. 1993, 66, 892.
(3) Very recently, a synthetic method of azulenes bearing
substituents on both the five- and seven-membered rings via
rhodium-mediated carbene intermediate has been reported.
See: Kane, J. L. Jr.; Shea, K. M.; Crombie, A. L.; Danheiser,
R. L. Org. Lett. 2001, 3, 1081.
(4) (a) Miyabe, R.; Shioiri, T.; Aoyama, T. Heterocycles 2002,
57, 1313. (b) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron
Lett. 2000, 41, 6859. (c) Sakai, A.; Aoyama, T.; Shioiri, T.
Tetrahedron 1999, 55, 3687. (d) For a review, see: Shioiri,
T.; Aoyama, T. Science of Synthesis, Vol. 4; Fleming, I.;
(10) tert-Butyl 4-aryl-2-oxobutanoates 1c–f were prepared by the
reaction of 2-arylethylmagnesium bromides, prepared from
2-arylethyl bromides and magnesium, with di-tert-butyl
oxalate according to the literature on the synthesis of 1b, see:
Dao D. H., Kawai Y., Hida K., Hornes S., Nakamura K.,
Ohno A.; Bull. Chem. Soc. Jpn.; 1998, 71: 425
(11) This compound was prepared from hydrolysis of 2a
followed by condensation with dimethylamine.
(12) For reviews, see: (a) Stang, P. Chem. Rev. 1978, 78, 383.
(b) Kirmse, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164.
(13) First report on the cyclopentene synthesis by the reaction of
ketones with TMSC(Li)N2, see: Ohira, S.; Okai, K.;
Moritani, T. Chem. Commun. 1992, 721.
(14) This compound was prepared by the reaction of a Grignard
reagent, prepared from 2-phenyl-1-propyl bromide and
magnesium, with di-tert-butyl oxalate.
Synlett 2003, No. 14, 2151–2154 © Thieme Stuttgart · New York

2154
Y. Hari et al.
LETTER
(15) Typical Procedure: A mixture of 2b (59 mg, 0.26 mmol),
CMD (890 mg, 40 equiv) in CH2Cl2 (3 mL) was stirred for 6
h. The mixture was filtered through a pad of Celite® and the
filtrate was concentrated in vacuo. The residue was purified
by column chromatography (n-hexane:EtOAc = 30:1) to
give 4b (31 mg, 52%) as a violet wax.
(16) Selected data for the synthesized azulene analogues 4a–g.
Compound 4a: 1H NMR (CDCl3): d = 1.45 (3 H, t, J = 7 Hz),
4.43 (2 H, d, J = 7 Hz), 7.30 (1 H, d, J = 4 Hz), 7.44 (1 H, t,
J = 10 Hz), 7.55 (1 H, t, J = 10 Hz), 7.80 (1 H, t, J = 10 Hz),
8.38 (1 H, d, J = 4 Hz), 8.46 (1 H, d, J = 10 Hz), 9.66 (1 H,
d, J = 10 Hz). HRMS (EI) calcd for C13H12O2: 200.0837.
Found: 200.0837. Compound 4b: 1H NMR (CDCl3): d =
1.67 (9 H, s), 7.27 (1 H, d, J = 7 Hz), 7.41 (1 H, t, J = 10 Hz),
7.50 (1 H, t, J = 10 Hz), 7.76 (1 H, t, J = 10 Hz), 8.33 (1 H,
d, J = 4 Hz), 8.43 (1 H, d, J = 10 Hz), 9.63 (1 H, d, J = 10
Hz). HRMS (EI) calcd for C15H16O2: 228.1150. Found:
228.1148. Compound 4c: 1H NMR (CDCl3): d = 1.65 (9 H,
s), 2.71 (3 H, s), 7.18 (1 H, d J = 4 Hz), 7.31 (1 H, d, J = 10
Hz), 7.40 (1 H, d, J = 10 Hz), 8.20 (1 H, d, J = 4 Hz), 8.28 (1
H, d, J = 10 Hz), 18.92 (1 H, d, J = 10 Hz). HRMS (EI) calcd
for C16H18O2: 242.1307. Found: 242.1316. Compound 4d:
1H NMR (CDCl3): d = 2.07 (9 H, s), 4.00 (3 H, s), 6.81–6.87
(2 H, m), 7.00–7.15 (1 H, m), 8.04 (1 H, d, J = 4 Hz), 8.28 (1
H, d, J = 11 Hz), 9.48 (1 H, d, J = 11 Hz). HRMS (EI) calcd
for C16H18O3: 258.1256. Found: 258.1258. Compound 4e:
1H NMR (CDCl3): d = 1.65 (9 H, s), 7.28 (1 H, d J = 4 Hz),
7.51 (1 H, dd, J = 2, 10 Hz), 7.60 (1 H, dd, J = 2, 11 Hz),
8.23 (1 H, d, J = 10 Hz), 8.28 (1 H, d, J = 4 Hz), 9.43 (1 H,
d, J = 10 Hz). HRMS (EI) calcd for C15H15ClO2: 262.0761.
Found: 262.0766. Compound 4f: 1H NMR (CDCl3): d = 1.67
(9 H, s), 7.30–7.33 (1 H, m), 7.40 (1 H, d, J = 4 Hz), 7.67 (1
H, d, J = 10 Hz), 7.75 (1 H, d, J = 10 Hz), 8.48 (1 H, d, J = 4
Hz), 9.69 (1 H, d, J = 10 Hz). HRMS (EI) calcd for
C16H15F3O2: 296.1024. Found: 296.1028. Compound 4g: 1H
NMR (CDCl3): d = 1.65 (9 H, s), 2.62 (3 H, s), 7.34 (1 H, t,
J = 10 Hz), 7.38 (1 H, t, J = 10 Hz), 7.71 (1 H, t, J = 10 Hz),
8.15 (1 H, s), 8.32 (1 H, d, J = 10 Hz), 9.53 (1 H, d, J = 10
Hz). HRMS (EI) calcd for C16H18O2: 242.1307. Found:
242.1307.
Synlett 2003, No. 14, 2151–2154 © Thieme Stuttgart · New York