Hydroxylation and amination of azulenes by vicarious nucleophilic substitution of hydrogen

Article abstract of DOI:10.1002/(SICI)1099-0690(200001)2000:1<193::AID-EJOC193>3.0.CO;2-W

Hydroxylation of azulenes with tert-butylhydroperoxide proceeds efficiently at the 6-position when the former contain electron-withdrawing substituents in the five-membered ring. Similarly, VNS amination of azulenes proceeds with 4-amino-1,2,4-triazole; i

Full text of DOI:10.1002/(SICI)1099-0690(200001)2000:1<193::AID-EJOC193>3.0.CO;2-W

FULL PAPER
Hydroxylation and Amination of Azulenes by Vicarious Nucleophilic
Substitution of Hydrogen
[a]
[a]
ˇ
Mıeczysław Makosza,* and Renata Podraza
Keywords: Vicarious nucleophilic substitution / Azulenes / Hydroxylation / Amination
Hydroxylation of azulenes with tert-butylhydroperoxide
active nucleophile, also reacts with unsubstituted azulene. A
proceeds efficiently at the 6-position when the former variety of transformations of 6-hydroxyazulenes, such as
contain electron-withdrawing substituents in the five-
membered ring. Similarly, VNS amination of azulenes
proceeds with 4-amino-1,2,4-triazole; its anion, being an
substitution of the corresponding sulfonates with nitrogen,
oxygen, sulfur, carbon nucleophiles and halogens, and the
Claisen rearrangement of allylic ethers, is reported.
ence of potassium tert-butoxide in liquid ammonia gave
negative results. Even after prolonged stirring of a reaction
mixture containing 1a, tBuOOH and an excess of tBuOK,
the formation of hydroxyazulene was not observed and
compound 1a was recovered. It appears that due to the low
nucleophilic activity of the tBuOOϪ anion it does not form
a σH adduct with the moderately electrophilic azulene (1a)
in a concentration sufficiently high for the β-elimination,
which is the second step in the VNS reaction. On the other
hand, reaction with more electrophilic azulenes containing
electon-withdrawing substituents in the five-membered ring,
when carried out with the tBuOOH/tBuOK system in liquid
ammonia, proceeded satisfactorily (Scheme 1). The higher
electrophilicity of the 1-CN (1b), 1-NO2 (1c), 1-COPh (1d)
and 1-CHO (1e) azulene derivatives, and azulenes contain-
ing two ethoxycarbonyl or chloro substituents in positions
1 and 3 (1f and 1g) ensured a sufficiently high concentration
of the σH adduct of tBuOOϪ to azulene, and thus the sub-
sequent base-induced β-elimination of tBuOH gave the 6-
hydroxyazulenes 2b؊g in yields between 35 and 86%
(Scheme 1).
Introduction
α-Halocarbanions react with electrophilic arenes, par-
ticularly nitroarenes, by replacing the hydrogen ortho- or
para- to the nitro group with the carbanion moiety.[1] This
reaction, known as vicarious nucleophilic substitution
(VNS) proceeds via an addition-β-elimination mecha-
nism,[2][3] and is a general method for the nucleophilic alky-
lation of nitroarenes.[4]
In a previous paper we reported that azulene undergoes
the VNS reaction with α-chloroalkanesulfonamides and 4-
chlorophenoxyacetonitrile to produce the corresponding
azulenes substituted in the seven-membered ring.[5] Thus
VNS can be used for the introduction of functionalized car-
bon substituents into the azulene ring in addition to the
previously reported oxidative nucleophilic substitution reac-
tions commonly used for this purpose.[6] Contrary to the
large amount of data concerning the introduction of carbon
substituents into azulenes,[6][7] practically nothing is known
about the synthesis of hydroxyazulenes by the nucleophilic
substitution of hydrogen, and only one example of a nucleo-
philic amination giving 4-aminoazulene has been re-
ported.[8]
Since both OH and NH2 groups can be efficiently intro-
duced into nitroarene rings by VNS,[9Ϫ13] we have at-
tempted to elaborate a synthesis of hydroxy- and ami-
noazulenes using this reaction.
Results and Discussion
Hydroxylation of Azulenes
The hydroxylation of nitroarenes proceeds smoothly by
reaction with tert-butyl or cumyl hydroperoxides in the
presence of strong bases.[9][10] However, the first attempts
at hydroxylation of azulene (1a) with tBuOOH in the pres-
Scheme 1
In all these reactions we observed the formation of only
one product of the hydroxylation in the 6-position; forma-
tion of 4- or 8-hydroxyazulenes was not observed. In the
majority of cases the hydroxyazulenes are sufficiently stable
[a]
Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44, 01-224 Warsaw, Poland
E-mail: icho-s@ichf.edu.pl
Fax: (internat.) ϩ 48-22/632-6681
Eur. J. Org. Chem. 2000, 193Ϫ198
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0101Ϫ0193 $ 17.50ϩ.50/0
193

M. Makosza, R. Podraza
FULL PAPER
Scheme 2
to be isolated and purified using standard methods. 1,3- tion with the corresponding ester of trifluoromethanesul-
Dichloro-6-hydroxyazulene (2g) is relatively unstable in fonic acid 4b.
acidic media, although in the pure state it can be kept for
Of particular interest appears to be the synthesis of 6-
months. The sodium salt of 1-formyl-6-hydroxyazulene (2e) haloazulenes which otherwise are not easily available. At-
is much less stable. It was isolated as the corresponding O- tempts to react the tosylate 4a with tetraalkyl ammonium
tosyl derivative, produced by direct tosylation of the reac- halides gave negative results. However, treatment of the
tion mixture with tosyl chloride immediately after removal more active triflate 4b and nonaflate 4c of 1-cyano-6-
of the ammonia. The hydroxylation of 1-formylazulene pro- hydroxyazulene with tetraalkylammonium halides leads to
ceeds in lower yield not only because of the instability of the desired 1-cyano-6-chloro- (6a), 1-cyano-6-bromo- (6b)
the product but also due to addition of tBuOOϪ to the and 1-cyano-6-iodoazulene (6c) in excellent yields. Syn-
carbonyl group.
thesis of 1-cyano-6-fluoroazulene (6d) was, however, prob-
We had observed earlier that VNS hydroxylation of 3- lematic as the corresponding tetraalkylammonium fluorides
nitrobenzophenone proceeded much slower than other cannot be easily obtained in an anhydrous form; use of the
nitroarenes, whereas the reaction with 3-nitrobenzaldehyde hydrated salts resulted in substantial hydrolysis of the trifl-
resulted in its partial oxidation to 3-nitrobenzoic acid with- ate 4b. On the other hand the corresponding nonaflate 4c
out formation of the corresponding nitrophenol.[9b] It ap- was less sensitive to hydrolysis and even in the reaction with
pears that in these cases addition of tBuOOϪ to the car- commercial tetraethylammonium fluoride dihydrate gave
bonyl group rather than to the ring takes place preferen- the expected 1-cyano-6-fluoroazulene (6d) in 60% yield. An
tially, so the VNS proceeds slower and to a moderate extent additional 30% of the hydroxyazulene 2b was obtained due
or not at all. The carbonyl groups at the highly nucleophilic to hydrolysis of 4c (Scheme 3).
five-membered ring of azulene are less active in nucleophilic
addition so the VNS proceeds efficiently with 1-benzoylazu-
lene (1d) and in moderate yield with 1-formylazulene (1e).
All the produced hydroxyazulenes 2b؊g behave as typical
phenols, i.e. they can be dissolved in dilute aqueous alkali
and recovered upon acidification of these azulenolate solu-
tions. Under standard reaction conditions they form O-to-
syl, O-mesyl and O-trifluoromethylsulfonyl derivatives. A
facile synthesis of 6-hydroxyazulenes in which the hydroxy
group can be subsequently activated by simple conversion
into esters of sulfonic acids opens up possibilities for the
introduction of a variety of substituents at the 6-position of
the azulene ring, since 6-sulfonyloxy groups in the electro-
philic azulene ring can be readily replaced with nucleophilic
Scheme 3
The anions of the 6-hydroxyazulenes 2, similarly to phe-
agents by the addition elimination SNAr process. These pos- nolates, form the corresponding 6-alkoxyderivatives upon
sibilities were explored using 1-cyano-6-hydroxyazulene 2b treatment with alkyl halides. Particularly interesting was the
as an example which, when treated with tosyl chloride un- alkylation with allyl bromide because 6-allyloxy derivatives
der standard conditions, gave the 6-tosyloxy derivative 4a. of azulenes should undergo the Claisen rearrangement to
This, when treated with such typical N, O and S-nucleo- 6-hydroxy-5- (or 7-) allylazulenes as do allylic ethers of
philes as morpholine, 4-methoxyphenolate or 4-methoxy- phenols. This reaction sequence was performed for 1,3-di-
thiophenolate, gave the expected substitution products chloro-6-hydroxy- (2g) and 1,3-diethoxycarbonyl-6-
5a؊c in excellent yields (Scheme 2). However, when 4a was hydroxyazulenes (2f) in order to avoid problems due to pos-
treated with the carbanion of 2-phenylpropionitrile the ex- sible formation of two isomeric products of the Claisen re-
pected product of SNAr was not obtained. Substitution arangement of unsymmetrically substituted azulenes. The
with this carbanion to give 5d proceeded readily in the reac- allylation proceeded satisfactorily under typical conditions
194
Eur. J. Org. Chem. 2000, 193Ϫ198

Hydroxylation and Amination of Azulenes
FULL PAPER
for O-allylation of phenols (K2CO3 in acetone) to give 7a the reaction is carried out in DMSO in the presence of
and 7b, respectively. These allyloxyazulenes undergo a facile tBuOK. Parallel to the VNS amination, the oxidative sub-
rearrangement in boiling o-dichlorobenzene to give the cor- stitution was also underway, giving 6-aminotriazolyl deriva-
responding 5-allyl-6-hydroxyazulenes 8a and 8b in moder- tives of azulene. This side reaction could be prevented when
ate yields (Scheme 4).
the reaction system was deoxygenated and the reaction was
Scheme 4
Similarly to 1,3-dichloro-6-hydroxyazulene (2g), 1,3-di- carried out under argon. In all these cases the substitution
chloro-5-allyl-6-hydroxyazulene (7b) is relatively unstable took place at the 6-position of the azulene ring and no iso-
and decomposed during the rearrangement. When the reac- meric products of the amination in the 4- or 8- positions
tion was carried out in the presence of acetic anhydride the were observed (Scheme 5).
produced hydroxyazulene was directly acetylated and the
more stable 6-acetoxyderivative of 8b was isolated from the
reaction mixture. On the other hand the rearrangement
product of 1,3-diethoxycarbonyl-6-allyloxyazulene (8a) was
sufficiently stable to be isolated and purified in a standard
way Ϫ dissolution in dilute aqueous NaOH and acidifi-
cation of the obtained phenolate solution. The Claisen re-
arrangement of 6-allyloxyazulenes provides an efficient
pathway for the introduction of carbon substituents at the
5- or 7- positions of the azulene ring.
Amination of Azulenes
For the VNS amination of nitroarenes a variety of amin-
ating agents NH2X were used, mostly hydrazine[11] and hy-
droxylamine[12] derivatives. In our laboratory we have found
that sulfenamides (RϪSϪNH2, R ϭ 2,4,6-trichlorophenyl
or N,N-dialkylthiocarbamoyl) appear to be the most ef-
Scheme 5
ficient and versatile reactants for this purpose.[13] However
attempts at VNS amination of azulene 1a, 1-cyanoazulene
6-Aminoazulenes are of moderate stability thus they were
1b and 1,3-dichloroazulene 1g with these sulfenamides gave isolated, purified and characterized as the corresponding
negative results, the azulenes were recovered and the sulfen- acetyl derivatives 9a, 9b and 9c, produced by direct acety-
amides decomposed. Most probably there are some diffi- lation of the mixture after the reaction. Although the oxi-
culties in the β-elimination of the RS- group from the σH dative process leading to 6-triazolyloaminoazulenes was ob-
adduct of the sulfenamide anions to azulenes. We have ob- served in all three cases studied, we have isolated and
served earlier that the VNS cyanomethylation of azulene characterized only the product formed from 1,3-dichloro-
proceeds with the carbanion of ArOCH2CN but not with azulene; this was also isolated and analyzed as the acetyl
carbanions of ArSCH2CN or Me2NCSSCH2CN, appar- derivative 9d. It should be noted that the unsubstituted azu-
ently also because of difficulties in the β-elimination step.[5] lene, which was insufficiently electrophilic for the VNS hy-
These difficulties are rather unexpected because such car- droxylation with tBuOOϪ, was readily aminated with 4-am-
banions containing sulfur-based leaving groups are efficient inotriazole albeit in moderate yield.
reagents for the VNS cyanomethylation of nitroarenes.[1,4,14]
The reported results indicate that VNS is a versatile tool
On the other hand we have found that 4-aminotriazole, pro- for the introduction of a variety of oxygen, nitrogen, sulfur
posed by Katritzky for the VNS amination of nitroar- and halogen substituents directly into azulene or by further
enes,[11a] is an efficient aminating agent of azulenes when conversion of hydroxyazulenes.
Eur. J. Org. Chem. 2000, 193Ϫ198
195

M. Makosza, R. Podraza
FULL PAPER
1,3-Dichloro-6-hydroxyazulene (2g): Yield 63%, m.p. 140Ϫ142°C.
Ϫ H NMR (CDCl3): δ ϭ 6.32 (bs), 6.72 (d, J ϭ 11.0 Hz, 2 H),
Experimental Section
1
NMR spectra were recorded with a Varian Gemini (200 MHz)
spectrometer using TMS as internal standard in solvents as indi-
cated below. Mass spectra were measured with an AMP 604 In-
terctra spectrometer. Azulenes 1a؊g were prepared according to
the following literature procedures: 1a using HafnerЈs method;[15]
1b by formylation of 1a with the Vilsmeier reagent[16] and sub-
sequent dehydration of 1-formylazulene oxime; 1c via nitration of
azulene with copper nitrate;[17] 1d by a Vilsmeier-type acylation
with N,N-dimethylbenzamide and POCl3;[17] 1e by a Vilsmeier for-
mylation of azulene; 1f according to the multistep Nozoe synthesis
from tropolone[18] and 1g by chlorination of azulene with N-
chlorosuccinimide.[19]
7.35 (s), 8.14 (d, J ϭ 11.0 Hz, 2 H). Ϫ MS (EI) m/z (%) 212 (94),
178 (22), 149 (100), 115 (24). Ϫ HRMS (EI) m/z calcd. C10H6OCl2
(Mϩ): 211.9796; found 211.9793.
1-Formyl-6-tosyloxyazulene: (2e O-tosylate) Yield 35%, m.p.
151Ϫ152°C. Ϫ 1H NMR (CDCl3): δ ϭ 2.48 (s), 7.14 (dd, J ϭ 10.6,
2.5 Hz, 1 H), 7.26Ϫ7.41 (m), 7.72Ϫ7.84 (m), 8.28 (d, J ϭ 4.2 Hz,
1 H), 8.42 (d, J ϭ 10.6 Hz, 1 H), 9.42 (d, J ϭ 10.6 Hz, 1 H), 10.34
(s). Ϫ MS (EI) m/z (%) 326 (91), 155 (90), 115 (28), 91 (100), 65
(13). Ϫ HRMS (EI) m/z calcd. C18H14O4S (Mϩ): 326.0613; found
326.0610.
1-Cyano-6-tosyloxyazulene (4a): To
a solution of 1-cyano-6-
Hydroxylation of Azulene Derivatives: Azulene 1b؊g (1 mmol) in
dry THF (3 mL) was added to liquid ammonia (15 mL) and stirred
hydroxyazulene (2b) (169 mg, 1 mmol) in THF (2 mL) and Et3N
(1 mL) was added p-toluenesulfonyl chloride (210 mg, 1.1 mol) and
at Ϫ50°C. To this solution were added tert-butylhydroperoxide the mixture stirred at room temp. for 3 h. The solvent was evapo-
(250µL, 80% solution in hexane, 2 mmol) and potassium tert-bu-
toxide (560 mg, 5 mmol). The mixture was allowed to warm until
the ammonia began to reflux and stirred for 4 hours. The ammonia
was then evaporated, the residue acidified with dilute HCl (10%),
extracted several times with ethyl acetate and washed with a solu-
tion of K2S2O5 and brine. The solution was dried with MgSO4 and
the solvent was evaporated. The product was chromatographed on
silica gel (hexane/ethyl acetate 10:3 to 1:1).
rated, the residue treated with water (10 mL), the product extracted
with dichloromethane and, after evaporation of the solvent, chrom-
atographed (hexane/ethyl acetate 10:3). Yield 290 mg, 90%. Ϫ m.p.
122°C. Ϫ 1H NMR ([D6]acetone): δ ϭ 2.48 (s), 7.39 (dd, J ϭ 10.9,
2.5 Hz, 1 H), 7.52 (m), 7.57 (d, J ϭ 4.2 Hz, 1 H), 7.83 (m), 8.24
(d, J ϭ 4.2 Hz, 1 H), 8.60 (d, J ϭ 10.9 Hz, 1 H), 8.67 (d, J ϭ
10.9 Hz, 1 H). Ϫ MS (EI) m/z (%) 323 (36), 169 (11), 155 (89), 140
(12), 113 (5), 91 (100), 65 (14). HRMS (EI) m/z calcd. C18H13NO3S
(Mϩ): 323.0616; found 323.0618.
In the case of 1-formylazulene (1e) the reaction was carried out as
above. After the ammonia was evaporated THF (10 mL) Et3N·HCl
(2 g) and Et3N (1 mL) were added to the residue and then part of
the Et3N was evaporated in order to remove residues of ammonia.
To this mixture was added tosyl chloride (0.5 g, 3.2 mmol); an ex-
cess of tosyl chloride is necessary because it reacts readily with
traces of ammonia present in the mixture. The mixture was stirred
for about 12 h, quenched with water (10 mL) and extracted with
ethyl acetate. The organic layer was dried with MgSO4 and the
solvent was evaporated. The O-tosyl derivative of 2e was chromato-
graphed on silica gel (hexane/ethyl acetate 10:3).
1-Cyano-6-(trifluoromethanesulfonyloxy)azulene (4b): To a solution
of 1-cyano-6-hydroxyazulene (2b) (85 mg, 0.5 mmol) in THF
(5 mL) at Ϫ70°C was added Et3N (0.2 mL) trifluoromethanesul-
fonyl anhydride (170 mg, 0.55 mmol) and this mixture stirred for
15 min. The THF was evaporated, water (5 mL) was added and the
product was extracted with ethyl ether. Organic layer was dried
with MgSO4 and the solvent was removed. The residue was chrom-
atographed on silica gel (hexane/ethyl acetate 10:3). Yield 91%,
m.p. 98Ϫ100°C. Ϫ 1H NMR ([D6]acetone): δ ϭ 7.74 (d, J ϭ
4.3 Hz, 1 H), 7.77 (dd, J ϭ 11.0, 2.7 Hz, 1 H), 7.83 (dd, J ϭ 11.0,
2.7 Hz, 1 H), 8.37 (d, J ϭ 4.3 Hz, 1 H), 8.82 (d, J ϭ 11.0 Hz, 1 H),
8.88 (d, J ϭ 11.0 Hz, 1 H). Ϫ MS (EI) m/z (%) 3101 (48), 237 (28),
190 (2), 171 (6), 140 (100), 113 (15), 87 (3), 69 (11). Ϫ HRMS (EI)
m/z calcd. C12H6NO3F3 (Mϩ): 301.0021; found 301.0027.
1-Cyano-6-hydroxyazulene (2b): Yield 60%, m.p. 108Ϫ109°C. Ϫ 1H
NMR (CDCl3): δ ϭ 7.06 (dd, J ϭ 10.9, 2.5 Hz, 1 H), 7.11 (dd, J ϭ
10.9, 2.5 Hz, 1 H), 7.20 (d, J ϭ 4.2 Hz, 1 H), 7.80 (d, J ϭ 4.2 Hz,
1 H), 8.30 (d, J ϭ 10.9 Hz, 1 H), 8.48 (d, J ϭ 10.9 Hz, 1 H). Ϫ
MS (EI) m/z (%) 169 (100), 140 (38), 114 (25). HRMS (EI) m/z
calcd. C11H7NO (Mϩ): 169.0528; found 169.0526.
1-Cyano-6-nonafluorobutanesulfonyloxyazulene (4c): To a solution
of 1-cyano-6-hydroxyazulene (169 mg, 1 mmol) in THF (10 mL)
was added Et3N (0.5 mL) and nonafluorobutanesulfonylfluoride
(362 mg, 1.2 mmol) at room temperature and this mixture was
stirred overnight. Water (10 mL) was added and the product was
extracted with ethyl acetate. The organic layer was dried with
MgSO4 and the solvent was evaporated. The residue was chromato-
graphed on silica gel (hexane/ethyl acetate 10:3). Yield 62%, m.p.
1
1-Nitro-6-hydroxyazulene (2c): Yield 70%, m.p. 123Ϫ124°C. Ϫ H
NMR ([D6]acetone): δ ϭ 6.84 (dd, J ϭ 11.0, 2.3 Hz, 1 H), 6.87
(dd, J ϭ 11.0, 2.3 Hz, 1 H), 6.98 (d, J ϭ 4.2 Hz, 1 H), 7.69 (d, J ϭ
4.2 Hz, 1 H), 8.25 (d, J ϭ 11.0 Hz, 1 H), 8.38 (d, J ϭ 11.0 Hz, 1
H). Ϫ MS (EI) m/z (%) 189 (100), 160 (41), 143 (20), 114 (36).
HRMS (EI) m/z calcd. C10H7NO3 (Mϩ): 189.0426; found 189.0431.
1
112Ϫ113°C. Ϫ H NMR ([D6]acetone): δ ϭ 7.72 (d, J ϭ 4.2 Hz,
1 H), 7.78 (dd, J ϭ 10.9, 2.7 Hz, 1 H), 7.83 (dd, J ϭ 10.9, 2.7 Hz,
1 H), 8.35 (d, J ϭ 4.2 Hz, 1 H), 8.81 (d, J ϭ 10.9 Hz, 1 H), 8.86
(d, J ϭ 10.9 Hz, 1 H). Ϫ MS (EI) m/z (%) 451 (37), 387 (15), 219
(3), 152 (6), 140 (100), 113 (11), 69 (13). Ϫ HRMS (EI) m/z calcd.
C15H6NO3SF9 (Mϩ): 450.9925; found 450.9932.
1-Benzoyl-6-hydroxyazulene (2d): Yield 86%, m.p. 166Ϫ167°C. Ϫ
1H NMR ([D6]acetone): δ ϭ 7.19 (d, J ϭ 4.1 Hz, 1 H), 7.26 (dd,
J ϭ 11.1, 2.0 Hz, 1 H), 7.31 (dd, J ϭ 11.1, 2.0 Hz, 1 H), 7.48- 7.60
(m), 7.67 (d, J ϭ 4.1 Hz, 1 H), 7.78 7.83(m), 8.49 (d, J ϭ 11.1 Hz,
1 H), 9.54 (d, J ϭ 11.1 Hz, 1 H). Ϫ MS (EI) m/z (%) 248 (60), 231
(5), 220 (5), 189 (8), 171 (100), 143 (7), 115 (21). HRMS (EI) m/z
calcd. C17H12O2 (Mϩ): 248.0837; found 248.0833.
1-Cyano-6-N-morpholinoazulene (5a): A solution of 4a (33 mg, 0.1
mmol) and morpholine (0.5 mL) in ethanol (2 mL) was stirred at
room temp. for 10 min. The solvent and morpholine was evapo-
rated and the residue chromatographed (hexane-ethyl acetate elu-
Diethyl 6-Hydroxy-1,3-azulenedicarboxylate (2f): Yield 83%, m.p.
169Ϫ170°C (ref.[20] 171Ϫ172°C). 1H NMR ([D6]acetone): δ ϭ 7.64
(d, J ϭ 11.1 Hz, 2 H), 8.76 (1 H,s), 9.6 (d, J ϭ 11.1 Hz, 2 H). Ϫ ent). Yield of 5a, 96%, m.p. 139°C. Ϫ 1H NMR ([D6]acetone): δ ϭ
MS (EI) m/z (%) 288 (100), 259 (32), 243 (51), 215 (27), 186 (72),
141 (31), 113 (10). HRMS (EI) m/z calcd. C16H16O5 (Mϩ):
288.0998; found 288.0996
3.76Ϫ3.90 (8 H, m), 6.99 (d, J ϭ 4.0 Hz, 1 H), 7.14 (dd, J ϭ 11.4,
2.8 Hz, 1 H), 7.20 (dd, J ϭ 11.4, 2.8 Hz, 1 H), 7.48 (d, J ϭ 4.0 Hz,
1 H), 8.20 (d, J ϭ 11.4 Hz, 1 H). Ϫ MS (EI) m/z (%) 238 (100),
196
Eur. J. Org. Chem. 2000, 193Ϫ198

Hydroxylation and Amination of Azulenes
FULL PAPER
207 (12), 180 (40), 153 (95), 140 (60), 125 (12), 113 (8). Ϫ HRMS 10.8, 2.6 Hz, 1 H), 7.84 (dd, J ϭ 10.8, 2.6 Hz, 1 H), 8.37 (d, J ϭ
(EI) m/z calcd. C15H14N2O (Mϩ): 238.1106; found 238.1103.
4.2 Hz, 1 H), 8.82 (d, J ϭ 10.8 Hz, 1 H), 8.88 (d, J ϭ 10.8 Hz, 1
H). Ϫ MS (EI) m/z (%) 272 (52), 152 (100), 125 (27), 99 (10), 75
(11), 57 (12). Ϫ HRMS (EI) m/z, calcd. C11H6NI (Mϩ): 278.9545;
found 278.9543.
1-Cyano-6-p-methoxyphenoxyazulene (5b): To a solution of 4a
(33 mg, 0.1 mmol) and p-methoxy phenol ( 25 m, 0.2 mmol) in
ethanol (2 mL) was added 10% aqueous NaOH solution (0.5 mL)
and the mixture stirred at room temp. for 15 min. It was then di-
1-Cyano-6-fluoroazulene (6d): A solution of 4c (451 mg, 1 mmol)
luted with water (5 mL) and the product extracted with CH2Cl2 and Et4NϩFϪ·2H2O (1.2 mmol) in THF (5 mL) was stirred at room
(3 ϫ 10 mL). The extract was washed with water, dried with
MgSO4 and the solvent evaporated. The product was purified by
column chromatography (hexane/ethyl acetate 5:1). Yield 92%, m.p.
75°C. Ϫ 1H NMR ([D6]acetone): δ ϭ 3.87 (s), 7.07Ϫ7.21 (m), 7.24
(dd, J ϭ 10.7, 2.8 Hz, 1 H), 7.37 (d, J ϭ 4.1 Hz, 1 H), 7.91 (d, J ϭ
temp. for 15 min. Further procedure as above. Yield 60%, m.p.
132Ϫ134°C. Ϫ 1H NMR (CDCl3): δ ϭ 7.26Ϫ7.45 (m), 8.16 (d,
J ϭ 4.1 Hz, 1 H), 8.45 (dd, J ϭ 11.0, 4.4 Hz, 1 H), 8.63 (dd, J ϭ
11.0, 4.4 Hz, 1 H). Ϫ MS (EI) m/z (%) 171 (100), 153 (93), 149
(34), 144 (25), 126 (25), 100 (7), 74 (12), 63 (14). Ϫ HRMS (EI)
4.1 Hz, 1 H), 8.55 (d, J ϭ 10.7 Hz, 1 H). Ϫ MS (EI) m/z (%) 275 m/z calcd. C11H6NF (Mϩ): 171.0484; found 171.0490.
(100), 260 (7), 247 (10), 232 (26), 204 (27), 152 (25), 123 (20). Ϫ
Allylation of Hydroxyazulenes: The 6-hydroxyazulenes 2f or 2g
(1 mmol), allyl bromide (180 mg, 1.5 mmol) and anhydrous K2CO3
(0.5 g) were refluxed in acetone (10 mL) for 5 hours. The inorganic
HRMS (EI) m/z calcd. C18H13NO2 (Mϩ): 275.0946 found:
275.0942
1-Cyano-6-p-methoxyphenylthioazulene (5c): Experimental pro-
cedure as above, with p-methoxythiophenol instead of p-methoxy
salts were filtered off, washed with acetone and the solvent evapo-
rated. The residue was chromatographed on silica gel (hexane/ethyl
phenol. Yield 95%, m.p. 66°C. Ϫ 1H NMR ([D6]acetone): δ ϭ 3.92 acetate 10:3).
(s, 3 H), 7.17 (ddd, J ϭ 9.0, 2.6, 2.6 Hz, 2 H), 7.26 (dd, J ϭ
Diethyl 6-Allyloxy-1,3-azulenedicarboxylate (7a): Yield 82%, m.p.
10.5,1.8 Hz, 1 H), 7.31 (d, J ϭ 4.2 Hz, 1 H), 7.35 (dd, J ϭ
10.5,1.8 Hz, 1 H), 7.62 (ddd, J ϭ 9.0,2.6,2.6 Hz, 2 H), 7.94 (d, J ϭ
4.2 Hz, 1 H), 8.34 (d, J ϭ 10.5 Hz, 1 H), 8.36 (d, J ϭ 10.5 Hz, 1
H). Ϫ MS (EI) m/z (%) 291 (100), 276 (29), 260(21), 183 (5), 152
(18), 139 (10) 125 (17). Ϫ HRMS (EI) m/z calcd. C18H13NOS (Mϩ):
291.0718; found 291.0719.
1
191Ϫ193°C. Ϫ H NMR ([D6]acetone): δ ϭ 1.41 (t, J ϭ 7.1 Hz, 6
H), 4.38 (q, J ϭ 7.1 Hz, 4 H), 4.96 (dt, J ϭ 5.2, 1.5 Hz, 2 H), 5.39
(ddt, J ϭ 10.5, 1.5 Hz, 1 H), 5.55 (ddt, J ϭ 17.3, 1.5 Hz, 1 H), 6.19
(ddt, J ϭ 17.3, 10.5, 5.2 Hz, 1 H), 7.56 (d, J ϭ 11.6 Hz, 2 H), 8.46
(s), 9.66 (d, J ϭ 11.6 Hz, 2 H). Ϫ MS (EI) m/z (%) 328 (100), 283
(24), 181 (28), 169 (20), 153 (14), 131 (10), 113 (9), 102 (8). Ϫ
HRMS (EI) m/z calcd. C19H20O5 (Mϩ): 328.1311; found 328.1308.
1-Cyano-6-[1-(cyano-1-phenylethyl)]azulene (5d): To a solution of
potassium tert-butoxide (79 mg, 0.7 mmol) and 2-phenylpropionitr-
ile (66 mg, 0.5 mmol) in DMF (3 mL) at Ϫ30°C was added a solu-
tion of 4b (150 mg, 0.5 mmol) in DMF (3 mL). The mixture was
stirred at Ϫ30°C for 30 min, quenched with aqueous NH4Cl solu-
tion and extracted with dichloromethane. The solvent was evapo-
rated and the residue chromatographed (hexane/ethyl acetate 5:1).
Yield of 5d 78%, m.p. 136Ϫ138°C. Ϫ 1H NMR (CDCl3): δ ϭ 2.36
(s), 7.39Ϫ7.56 (m), 7.80 (dd, J ϭ 10.1, 1.9 Hz, 1 H), 7.87 (dd, J ϭ
10.1, 1.9 Hz, 1 H), 8.22 (d, J ϭ 4.2 Hz, 1 H), 8.69 (d, J ϭ 10.1 Hz,
1 H), 8.73 (d, J ϭ 10.1 Hz, 1 H). Ϫ MS (EI) m/z (%) calcd.
C20H14N2 (Mϩ): 282.1157; found 282.1154.
6-Allyloxy-1,3-dichloroazulene (7b): Yield 70%, m.p. 163Ϫ164°C. Ϫ
1H NMR ([D6]acetone): δ ϭ 4.68 (dt, J ϭ 5.1, 1.3 Hz, 2 H), 5.51
(ddt, J ϭ 10.3, 1.3, 1.3 Hz, 1 H), 5.64 (ddt, J ϭ 17.1, 1.3, 1.3 Hz,
1 H), 5.82 (ddt, J ϭ 17.1, 10.3, 5.1 Hz, 1 H), 7.19 (d, J ϭ 10.9 Hz,
2 H), 7.74 (s), 8.32 (d, J ϭ 10.9 Hz, 2 H). Ϫ MS (EI) m/z (%) 252
(100), 216 (10), 181 (36), 153 (12), 131 (9), 113 (10). Ϫ HRMS (EI)
m/z calcd. C13H10Cl2O (Mϩ): 252.0109; found 252.0106.
Claisen Rearrangement of 7a: Compound 7a (0.5 mmol) was dis-
solved in o-dichlorobenzene (5 mL) and refluxed for 2 hours. The
mixture was cooled to room temp. A 10% aqueous solution of
NaOH (5 mL) and diethyl ether (5 mL) were added. After vigorous
shaking the aqueous layer was separated, acidified with 10% HCl,
extracted with ethyl acetate, the extract dried with MgSO4 and the
solvent evaporated. The residue was chromatographed on silica gel
(hexane/ethyl acetate 1:1).
Synthesis of 1-Cyano-4-haloazulenes: A solution of 4b or 4c
(1 mmol) and the corresponding tetraalkylammonium salt
(2 mmol) in acetonitrile (10 mL) was refluxed for 4 hours (chlo-
ride), 6 hours (bromide) or 8 hours (iodide). After cooling, the solid
salts were filtered off, the solvent was evaporated and the residue
chromatographed on silica gel (hexane/ethyl acetate 10:3).
6-Chloro-1-cyanoazulene (6a): Yield 96%, m.p. 153Ϫ154°C. Ϫ 1H
NMR ([D6]acetone): δ ϭ 7.56 (d, J ϭ 4.1 Hz, 1 H), 7.81 (dd, J ϭ
10.5, 2.1 Hz, 1 H), 7.87 (dd, J ϭ 10.5, 2.1 Hz, 1 H), 8.18 (d, J ϭ
4.1 Hz, 1 H), 8.55 (d, J ϭ 10.5 Hz, 2 H), 8.63 (d, J ϭ 10.5 Hz, 2
H). Ϫ MS (EI) m/z (%) 187 (100), 152 (50), 125 (21), 99 (7), 75
(10), 62 (7), 50 (8). Ϫ HRMS (EI) m/z calcd. C11H6NCl (Mϩ):
187.0189; found 187.0185.
Diethyl 5-Allyl-6-hydroxyazulene-1,3-dicarboxylate (8a): Yield
43%, m.p. 203Ϫ205°C. Ϫ 1H NMR ([D6]acetone): δ ϭ 1.39 (t, J ϭ
7.2 Hz, 3 H), 1.4 (t, J ϭ 7.1 Hz, 3 H), 3.77 (dt, J ϭ 6.5, 1.7 Hz, 2
H), 4.36 (q, J ϭ 7.2 Hz, 2 H), 4.37 (q, J ϭ 7.1 Hz, 2 H), 5.13 (ddt,
J ϭ 11.6, 1.7, 1.7 Hz, 1 H), 5.19 (ddt, J ϭ 15.5, 1.7, 1.7 Hz, 1 H),
6.94 (ddt, J ϭ 15.5, 11.6, 6.5 Hz, 1 H), 7.58 (d, J ϭ 11.4 Hz, 1 H),
8.43 (s), 9.48 (d, J ϭ 11.4 Hz, 1 H), 9.80 (s). Ϫ MS (EI) m/z (%)
328 (100), 283 (52), 255 (47), 228 (10), 211 (12), 184 (16), 153 (6).
Ϫ -HRMS (EI) m/z calcd. C19H20O5 (Mϩ): 328.1311; found
6-Bromo-1-cyanoazulene (6b): Yield 94%, m.p. 150Ϫ152°C. Ϫ 1H 328.1315.
NMR ([D6]acetone): δ ϭ 7.54 (d, J ϭ 4.1 Hz, 1 H), 8.00 (dd, J ϭ
With compound 7b the reaction was carried out as above in the
10.0, 1.9 Hz, 1 H), 8.05 (dd, J ϭ 10.0, 1.9 Hz, 1 H), 8.22 (d, J ϭ
4.1 Hz, 1 H), 8.43 (d, J ϭ 10.0 Hz, 1 H), 8.50 (d, J ϭ 10.0 Hz, 1
H). Ϫ MS (EI) m/z (%) 231 (55), 152 (100), 125 (37), 99 (12), 75
(14), 62 (8), 44 (9). Ϫ HRMS (EI) m/z calcd. C11H6N79Br (Mϩ):
230.9684; found 230.9680, calcd. C11H6N81Br (Mϩ): 232.9663;
found 232.9643.
presence of acetic anhydride (102 mg, 1 mmol). After the reaction
most of the o-dichlorobenzene was evaporated under reduced
pressure (0.1 Torr), and the residue was treated with water (5 mL)
and extracted with ethyl acetate. The organic layer was dried with
MgSO4 and the solvent was evaporated. The residue was chromato-
graphed on silica gel (hexane/ethyl acetate 10:3). Yield of 4-acetoxy-
1-Cyano-6-iodoazulene (6c): Yield 91%, m.p. 167Ϫ168°C. Ϫ 1H
NMR ([D6]acetone): δ ϭ 7.52 (d, J ϭ 4.2 Hz, 1 H), 7.79 (dd, J ϭ Ϫ H NMR ([D6]acetone): δ ϭ 2.40 (s), 3.61 (dt, J ϭ 6.4, 1.5 Hz,
5-allyl-1,3-dichloroazulene (8b), O-acetate 28%, m.p. 179Ϫ180°C.
1
Eur. J. Org. Chem. 2000, 193Ϫ198
197

M. Makosza, R. Podraza
FULL PAPER
1
2 H), 5.13 (ddt, J ϭ 9.7, 1.5, 1.5 Hz, 1 H), 5.19 (ddt, J ϭ 17.0, 1.5, m.p. 189Ϫ191°C. Ϫ H NMR ([D6]acetone): δ ϭ 2.87 (s), 7.67 (d,
1.5 Hz, 1 H), 6.01 (ddt, J ϭ 17.0, 9.7, 6.4 Hz, 1 H), 7.19 (d, J ϭ J ϭ 10.9 Hz, 2 H), 7.92 (s), 8.43 (d, J ϭ 10.9 Hz, 2 H), 8.94 (s). Ϫ
10.8 Hz, 1 H), 7.76 (s), 8.28 (d, J ϭ 10.8 Hz, 1 H), 8.40 (s). Ϫ MS MS (EI) m/z (%) 320 (37), 278 (91), 253 (17), 211 (100), 183 (42),
(EI) m/z (%) 294 (22), 252 (100), 217 (9), 181 (115), 113 (22), 71 174 (90), 160 (19), 139 (7), 125 (6), 113 (8), 99 (4), 69 (16). Ϫ
(42), 57 (61). Ϫ HRMS (EI) m/z calcd. C15H12Cl2O2 (Mϩ): HRMS (EI) m/z calcd. C14H10Cl2N4O (Mϩ): 320.0232; found
294.0214; found 294.0219.
320.0239.
Amination of Azulenes: Azulene (1 mmol) and 4-aminotriazole
(97 mg, 1.15 mmol) were dissolved in DMSO (5 mL) and argon
was passed through the solution for 0.5 hour prior to the reaction.
To this solution tBuOK (560 mg, 5 mmol) was added in a few por-
tions keeping the temperature around 20Ϫ25°C. The mixture was
stirred for 4 hours, acidified with 10% HCl (2 mL), water (20 mL)
and CH2Cl2 (20 mL) were added and the aqueous layer containing
the aminoazulene hydrochloride was separated. It was made alka-
line with a 10% solution of NaOH and the product was extracted
with CH2Cl2, dried with MgSO4 and concentrated to a volume of
about 5 mL. After this acetic anhydride (130 mg, 1.25 mmol) and
pyridine (100 mg, 1.3 mmol) were added, the mixture was stirred
for 2 hours and treated with water (10 mL). The product was ex-
tracted with CH2Cl2, dried with MgSO4 and the solvent was evapo-
rated. The residue was chromatographed on silica gel (hexane/ethyl
acetate 2:1).
Acknowledgments
This work was partially supported by the State Committee of
Scientific Research, Grant. No T09A04911
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D. J. Gale, R. N. McDonald, R. G. Anderson, R. C. Rhodes,
6-Acetamidoazulene (9a): Yield 38%, m.p. 170Ϫ171°C (ref.
169Ϫ170°C). Ϫ 1H NMR ([D6]acetone): δ ϭ 2.59 (s), 7.70 (dd, J ϭ
9.6, 2.0 Hz, 1 H), 7.74 (dd, J ϭ 9.6, 2.0 Hz, 1 H), 7.90 (d, J ϭ
4.2 Hz, 2 H), 8.00 (t, J ϭ 4.2 Hz, 1 H), 8.67 (d, J ϭ 9.6 Hz, 2 H).
Ϫ MS (EI) m/z (%) 185 (63), 143 (100), 115 (29), 72 (14). Ϫ HRMS
(EI) m/z calcd. C12H11NO (Mϩ): 185.0841; found 185.0838.
J. Org. Chem. 1964, 29, 1373Ϫ1377.
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P. F. Pagoria, A. R.
6-Acetamido-1-cyanoazulene (9b): Yield 64%, m.p. 125Ϫ127°C. Ϫ
1H NMR ([D6]acetone): δ ϭ 2.58 (s), 7.29 (d, J ϭ 4.0 Hz, 1 H),
7.50 (d, J ϭ 4.0 Hz, 1 H), 8.11 (d, J ϭ 10.9 Hz, 1 H), 8.17 (d, J ϭ
10.9 Hz, 1 H), 8.50 (d, J ϭ 10.9 Hz, 1 H), 8.55 (d, J ϭ 10.9 Hz, 1
H). Ϫ MS (EI) m/z (%) 210 (31), 168 (82), 140 (29), 114 (14), 69
(100). Ϫ HRMS (EI) m/z calcd. C13H10N2O (Mϩ): 210.0793;
found 210.0797.
Mitchell, R. D. Schmidt, J. Org. Chem. 1996, 61, 2934Ϫ2935.
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[12]
[13]
[14]
[15]
[16]
[17]
[18]
6-Acetamido-1,3-dichloroazulene (9c): Yield 60%, m.p. 173Ϫ174°C.
Ϫ
1H NMR ([D6]acetone): δ ϭ 2.22 (s), 7.50 (s), 7.81 (d, J ϭ
11.2 Hz, 2 H), 8.24 (d, J ϭ 11.2 Hz, 2 H), 9.72 (bs). Ϫ MS (EI)
m/z (%) 253 (42), 211 (100), 183 (12), 113 (8). Ϫ HRMS (EI) m/z
calcd. C12H9Cl2NO (Mϩ): 253.0061; found 253.0056.
[19]
[20]
4-(1,3-Dichloroazulenyl-6-acetamido)-1,2,4-triazole (9d): Exper-
imental procedure as above except that oxygen was bubbled
through the reaction mixture during the amination. Yield 32%,
Received May 3, 1999
[O99246]
198
Eur. J. Org. Chem. 2000, 193Ϫ198