2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-carboxylic acid ethyl ester - A novel precursor for a new class of liquid crystalline materials

Article abstract of DOI:10.1080/00397910500406393

A novel approach for the syntheses of carbene adduct 4 is reported. A ring-enlargement strategy was employed for the synthesis of precursors 5 and 6 and established the mechanism of the formation of azulene derivative 6. Synthesis of target precursor 13, a novel precursor for the synthesis of new mesogenic materials, and its various halogenated derivatives (14-16) was carried out. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500406393

Synthetic Communicationsw, 36: 559–571, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500406393
2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-
carboxylic Acid Ethyl Ester—A Novel
Precursor for a New Class of Liquid
Crystalline Materials
Zakir Hussain
Institut fu¨r Organische Chemie, Braunschweig, Germany and
Max-Planck-Institut fu¨r Bioanorganische Chemie,
Mu¨lheim an der Ruhr, Germany
Henning Hopf, Ludwig Pohl, and Toni Rantanen
Institut fu¨r Organische Chemie, Braunschweig, Germany
Abstract: A novel approach for the syntheses of carbene adduct 4 is reported. A ring-
enlargement strategy was employed for the synthesis of precursors 5 and 6 and estab-
lished the mechanism of the formation of azulene derivative 6. Synthesis of target
precursor 13, a novel precursor for the synthesis of new mesogenic materials, and its
various halogenated derivatives (14–16) was carried out.
Keywords: Birch reduction, carbene addition, liquid crystals, ring enlargement
INTRODUCTION
A wide range of property changes affecting the liquid crystal (LC) behavior of
the materials can be produced by simply modifying the basic structure of the
core units. The core unit presently used in most of the calamitic LC is cyclo-
hexane and phenylcyclohexane, and various modifications in the basic
Received in Poland July 28, 2005
Address correspondence to Zakir Hussain, Max-plank-Institut fu¨r Organische
Chemie, Postfoch 101365, 5470 Mu¨lheim ander Ruhr, Germany. Fax: þ49-208-306-
3951; E-mail: zakir@mpi-muelheim.mpg.de
559

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Z. Hussain et al.
cyclohexyl, bicyclohexyl, and phenyl bicyclohexyl structures have been made
recently to overcome problems of electrooptic and viscoelastic parameters.[1,2]
We developed a completely new core unit—the perhydroazulene unit.[3]
It is flat and allows introduction of numerous substituents. Its stereochemistry
can be affected by the central junction as well as the relative orientation of
the substituents. Our experience on the synthesis of a variety of similar
materials showed the novelty of such core units for mesogenic materials.
However, previous synthetic approaches lead to the core units with the
possibility of extending the system in only one side. Therefore, a new
approach that could result in precursors with the possibility of extending the
core units in both directions was desirable. We here report the first
synthesis of a core unit (13) as a novel precursor for a variety of new
mesogenic materials.
RESULTS AND DISCUSSION
To get a partially reduced azulene system with the possibility of derivatizable
or replaceable group such as OH or any halogen at position 2, the new
synthetic route outlined in Scheme 1 was developed. This new strategy
resulted in compounds such as 5, which is a potential intermediate for a
large variety of new materials, and 6, which is a new azulene derivative
formed during the course of the reaction. Starting from inexpensive and
readily available 2-indanol 1 it was possible to prepare 4,7-dihydro-2-
indanol 2 by Birch reduction in almost quantitative yield. The hydroxy
function of 1 was protected by tertiary butyl diphenyl silyl chloride in the
Scheme 1. Synthesis of 1,3-dibromo azulene derivative 6 and a 2,6-disubstituted
tetrahydroazulene derivative 5.

2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid Ethyl Ester
561
presence of dimethyl amino pyridine and imidazole[4] at room temperature,
also in quantitative yield. The protection of the hydroxy function was
carried out to direct the carbene addition to the external double bond in the
next step. The protected 4,7-dihydro-2-indanol 3 was subjected to carbene
addition in the presence of ethyldiazoacetate and dried copper sulfate in
dried cyclohexane to yield the carbene adduct 4 in 75% yield while some of
the diethyl fumarate, which was formed during the reaction, was also
isolated as well as some unreacted starting material. The yield in this
reaction was improved by increasing the carbene addition time and using
thoroughly dried copper sulfate and cyclohexane as the solvents. Ring
expansion of compound 4 was performed in the presence of bromine and
triethyl amine with carbon tetrachloride as solvent. In this reaction bromine
was added first to the double bond and later removed as a hydrobromide
salt by adding triethylamine and refluxing the mixture for several hours.
This resulted in cyclopropane ring opening to provide 5 as the major
product in 52% yield and 6 as a minor component in 10% yield. The
formation of 5 was expected during the reaction, and 6 formed by rearrange-
ment and bromination of 5. It is important to note that the yield of 6 can be
increased by merely prolonging the reflux time, which might be due to the
rearrangement of 6, which forms first. The new adducts were characterized
by the usual spectroscopic data, which are summarized in the experimental
section.
A triplet at 1.40 ppm in 1H NMR for 4 with coupling constants of 4.3 Hz
between the protons on the cyclopropyl ring indicates a trans configuration
between the carbethoxy group and the cyclohexene ring. Furthermore, a
triplet at 2.53 ppm (3J ¼ 5.6 Hz) in the 1H NMR for 6-H in 5 and the
presence of two doublets at 6.04 (3J ¼ 9.4 Hz) for 4/8-H in 5 indicates the
formation of a seven-membered skeleton in compound 5. The formation of
compound 6 was confirmed by the presence of an AB quartet at 8.01 ppm
1
in H NMR (3J ¼ 10.3 Hz) for 4,8/5,7-H and further confirmation of the
skeleton from its single-crystal X-ray structure.
A plausible mechanism for the formation of 6 could involve the following
steps (Scheme 2). On refluxing the mixture for a longer time, the side chain
from the rearranged 5, which is too bulky, can be cleaved off, leaving
behind a secondary carbocation 7, which can be stabilized by a proton abstrac-
tion with a negatively charged oxygen atom of the leaving group or triethyl-
amine present in the mixture.
Very likely the driving force of the transformation is the formation of
more stable aromatic azulene nucleus. Positions 1 and 3 of azulene are
more susceptible to electrophilic attack,[5] and the presence of bromine
results in the formation of brominated product 6. First bromine adds to the
double bond at 1 and 8a, which results in the formation of bromonium 9,
while the bromide ion abstracts a proton, resulting the formation of the
mono-substituted product 10 instead of the addition product, thus restoring
the aromaticity of the molecule. The abstraction of a proton from 11,

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Z. Hussain et al.
Scheme 2. Mechanism of formation of dibromide 6.
when a second bromine molecule adds at the double bond between position 2
and 3, is more likely to take place from position 3, which is more accessable to
bromide. This results in the formation of 6.
Compound 6 was obtained as a dark blue solid, which was recrystallized
from dichloromethane and hexane to yield dark green needles suitable for
X-ray analysis. X-ray data[6] showed the presence of two crystallographically
independent molecules in the asymmetric unit. The azulene frameworks of
˚
both the molecules were planar with mean deviations of 0.01 and 0.02 A
out of the calculated ring planes. Planes defined by the atoms of the ethyl
ester groups were twisted from the ring planes by 4.3(4)8 and 3.3(4)8. The
˚
˚
bond lengths of the azulene systems, from 1.374(8) A to 1.410(8) A, did
not show significant differences within their standard deviations in both the
molecules. This is the same order of magnitudes as found by Kaftory
et al.[7] for other substituted azulene derivatives.
Considering compound 13 as an intermediate for further coupling
reactions, it was thought desirable to remove the TBDPS group without
damaging the rest of the molecule. After trying various approaches,[8] the
method reported by Overman and Rishton[9] was found to be the method of
choice where a more expensive but effective commercially available
catalyst, tetrabutylammonium fluoride (TBAF) in THF, was used, resulting
in acceptable to good yield (62–65%) of 13 from 5. The disappearance of
aromatic signals at 7.69–7.41 ppm and signals at 1.07 ppm due to t-butyl
1
protons in H NMR spectrum indicates the formation of 13 (Scheme 3).

2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid Ethyl Ester
563
Scheme 3. Synthetic route to cycloheptatriene 13.
Compound 13 is a novel precursor for the synthesis of a variety of
new materials. It gives the possibility to extend the system in both 2 and
6 positions. It further allows getting the fully reduced core unit—a perhydr-
oazulene system—which could be an alternate to cyclohexyl or phenyl
cyclohexyl core units for the synthesis of novel materials as calamitic liquid
crystals.
Derivative 13 is therefore, in principle an important candidate for various
coupling reactions. However, most of such reactions are successful only for
activated molecules,[10] and the most promising results were obtained with
an intermediate that had halogen substituents. Therefore, halogen derivatives
of 13 are more important intermediates, and the method of choice for the
conversion of the alcohol to halogen derivatives utilizes Ph3P and corres-
ponding halogen.[11] Alcohol 13 was converted to the halogenated derivatives
14–16 (Scheme 4). It is important to note that the reaction in the cases of
chloride and iodide resulted in ꢀ60% yield but in the case of bromide only
ꢀ30% of the purified product 15 could be isolated. Direct conversion[12] of
the protected alcohol 5 to bromide derivative 15 did not yield any product
at all. All of these derivatives showed similar 13C NMR spectra; however,
signals corresponding to 2-H in the 1H NMR spectra appeared to have
slightly different ppm values (d ¼ 4.57 ppm for the bromo derivative,
d ¼ 4.60 ppm for the chloro derivative, and d ¼ 4.76 ppm for 16). All of
these derivatives were fully characterized further by their usual mass
spectrometric and other analytical data, which are given separately in the
experimental section.
Scheme 4. Halogenation reactions of the alcohol 13.

564
Z. Hussain et al.
EXPERIMENTAL
Thin-layer chromatography was performed by using precoated plastic
plates, PolyGram Sil G/UV254. Column chromatography was performed
on silica gel 60 (70–230 mesh) from Merck (Darmstadt). Measurements
below 2008C were determined on a Bu¨chi 510 melting-point apparatus
and above 2008C were carried out on a Kofler-Heiztischmikroskop
1
apparatus. They are uncorrected. H and 13C NMR spectra were recorded
on the following spectrometers: Bruker AC 200, 1H NMR (200.1 MHz)
1
and 13C NMR (50.3 MHz); Bruker DRX-400, H NMR (400.1 MHz) and
13C NMR (100.6 MHz). Chemical shifts (d) are expressed in parts per
million (ppm) downfield from tetramethylsilane or using the residual non-
deuterated solvent as internal standard (CDCl3: 1H: d ¼ 7.26; 13C:
d ¼ 77.00). Coupling constants are expressed in Hertz. IR spectra were
recorded using a Nicolet 320 FT-IR and a Bruker Tensor 27 spectrometer.
Samples were prepared either as KBr pellets or as thin films. UV spectra
were recorded in acetonitrile and methanol using a Beckman UV 5230
and HP 8452 A diode array spectrophotometer. Mass spectra were
recorded using a Finnigan MAT 8430 spectrometer using the electron ion-
ization method (EI, 70 eV). GC/MS spectra were recorded on a Finnigan
MAT 4515 (EI, 40 eV) mass spectrometer attached to a Carlo-Erba
HRGC 5160 (DB 1–0.25 mm fused silica capillary column;
30 m ꢀ 0.31 mm ID; carrier gas Argon) gas chromatograph. Elemental
analyses were carried out at the Institut fu¨r Pharmazeutische Chemie, TU
Braunschweig. CH2Cl2 and Et3N were distilled from CaH2 under nitrogen
prior to use, and THF and Et2O were distilled from Na and benzophenone
under nitrogen prior to use. All other chemicals were of reagent quality and
used as obtained from the manufacturers. Reactions were carried out in dry
N2 when necessary.
Synthesis of 4-7-Dihydro-2-indanol (2)
2-Indanol (1, 5.0 g; 37.26 mmol), liquid NH3 (30 mL), EtOH (30 mL), and
THF (20 mL, anhydrous) were placed in a 500-mL, three-necked flask fitted
with a mechanical stirrer, and the temperature was maintained at 2758C
with a methanol–liquid nitrogen bath. Sodium metal was added until the
blue color persisted for 20 min. The NH3 was allowed to evaporate
overnight. The remaining residue was partitioned between ether and water.
The ether layer was evaporated, and the resulting liquid was again partitioned
between ether and water. The ether layer was dried with MgSO4 and the ether
evaporated to give crude 4,7-dihydro-2-indanol (4.91 g, 97%) as a colorless
solid, which melted above room temperature. The product was rather
unstable and on standing slowly reoxidized to 2-indanol; it was thus readily
used for further reaction.

2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid Ethyl Ester
565
RF (SiO2; ether/pentane, 1 : 2) ¼ 0.3; mp ¼ 368C (lit.[13]); 1H NMR
(400.1 MHz, CDCl3): d ¼ 2.23–2.64 (m, 4H, 1/3-H), 2.64–2.75 (m, 4H, 4/
7-H), 4.51–4.55 (m, 1H, 2-H), 5.77 (s, 2H, 5/6-H); 13C NMR (100.6 MHz,
CDCl3): d ¼ 27.57 (t, C-4/7), 46.02 (t, C-1/3), 70.83 (d, C-2), 124.75
(d, C-5/6), 129.77 (s, C-3a/7a); IR (film): n ¼ 3330 cm21 (s, OH), 2912,
˜
2818 (s, CH-stretching), 1430, 1291 (m); UV/Vis (CH3CN): lmax (lg
1) ¼ 194 nm (4.06), 204 (3.65), 212 (3.48), 218 (3.31), 224 (2.90), 266
(2.50), 274 (2.49); MS (EI, 70 eV): m/z (%) ¼ 136 [Mþ] (35), 119
[Mþ-OH] (5), 117 [119-H2] (77), 92 [Mþ-C2H4O] (70), 91[92-H] (100), 79
[92-CH] (30), 77 [91-CH2] (23); Anal. calcd. for C9H12O (136.19): C,
79.37%; H, 8.88%; O, 11.75%. Found C, 79.57%; H, 9.02%.
Synthesis of 2-(tert-Butyl-diphenyl-silanyloxy)-4,7-dihydro-
indane (3)
4,7-Dihydro-2-indanol (2, 4 g; 29.41 mmol) in anhydrous dichloromethan
(100 mL) was added in a flame-dried flask kept under a stream of nitrogen,
and the mixture was stirred for a few min. DMAP (359mg, 2.94mmol) and
imidazole (4.40 g, 64.70 mmol) were added, and the mixture cooled to 08C
with an ice bath. TBDPSCl (8.892g, 32.35 mmol) dissolved in dichloromethan
(10mL) was then added dropwise at 08C with stirring. After complete addition,
the mixture was stirred further for 3 h at room temperature, the solvent evapor-
ated, and the product purified by passing through a small column of silica gel
with pentane to provide 10g (90%) of pure 3 as colorless viscous oil.
1
RF (SiO2; pentane) ¼ 0.2; H NMR (400.1 MHz, CDCl3): d ¼ 1.11 (s, 9 H,
tert-butyl-H), 2.43–2.45 (m, 4H, 1/3-H), 2.60-2.67 (m, 4H, 4/7-H), 4.61–
4.64 (m, 1H, 2-H), 5.77 (s, 2H, 5/6-H), 7.42–7.47 (m, 6H, 10-12/10a-12a-
3
4
H), 7.73–7.75 (dd, J1 ¼ 7.85 Hz, J2 ¼ 1.57 Hz, 4H, 9, 13/9a-13a-H); 13C
NMR (100.6 MHz, CDCl3): d ¼ 19.11 (s, tert-butyl), 26.91 (q, tert-butyl),
27.18 (t, C-4/7), 45.45 (t, C-1/3), 72.32 (d, C-2), 124.56 (d, C-5/6), 127.49
(d, C-10, 12/10a, 12a), 129.39 (s, C-3a/7a), 129.44 (d, C-11/11a), 134.59
(s, C-8/8a), 135.71 (d, C-9, 13/9a, 13a); IR (film): n ¼ 2930 cm21, 2885,
˜
2856 (s, CH-stretching), 1428 (m), 111 (m), 1074 (m); UV/Vis (CH3CN):
lmax (lg 1) ¼ 196 nm (4.73), 204 (4.44), 214 (4.24), 224 (4.09), 256 (2.92),
266 (2.99); MS (EI, 70 eV): m/z (%) ¼ 317 [Mþ-tert-butyl] (91), 240 [317-
C6H5] (10), 239 [240-H] (52), 227 [240-CH] (99), 199 [239-C3H4] (100),
135 [Mþ-TBDPS] (10).
Synthesis of 4-(tert-Butyl-diphenyl-silanyloxy)-1,1a,2,3,4,5,6,6a-
octahydrocyclopropa [ f ] indene-1-carboxylic Acid Ethyl Ester (4)
A solution of ethyl diazoacetate (6.73 g, 58.99 mmol) in 30 mL of anhydrous
cyclohexane was added dropwise with stirring over a 5 h period, with a

566
Z. Hussain et al.
dropping funnel to a refluxing mixture of 3 (6.5 g, 17.37 mmol), CuSO4
(anhydrous, 1.45 g), and cyclohexane (anhydrous, 60 mL). The mixture was
refluxed for another 60 min and filtered to remove CuSO4. The solution was
concentrated, and the product was separated by column chromatography on
silica gel using pentane as the solvent, increasing its polarity with dichloro-
methane (1–10%). Some unreacted starting material was recovered as it
eluted from the column first, followed by the product (6.0 g, 75%) and by
diethyl fumarate as a side product. The product was obtained as colorless
1
viscous oil. RF (SiO2; pentane/CH2Cl2; 3 : 2) ¼ 0.6; H NMR (200.1 MHz,
CDCl3): d ¼ 1.07 (s, 9H, tert-butyl), 1.22–1.24 (t, 3J ¼ 7.1 Hz, 3H,
9-H), 2.26–2.35 (m, 4H, 3/5-H), 1.33–1.38 (m, 2H, 1a, 6a-H), 1.40
3
3
(t, J ¼ 4.3 Hz, 1H, 1-H), 2.40 (br. s, 4H, 2/6-H), 4.16-4.19 (q, J ¼ 7.0 Hz,
2H, 8-H), 4.50–4.52 (m, 1H, 4-H), 7.69–7.41 (m, 10H, aromatic rings
protons); 13C NMR (50.3 MHz, CDCl3): d ¼ 14.26 (q, C-9), 19.06 (s, tert-
butyl), 26.89 [q, (-CH3)3], 21.88 (d, C-1a/6a), 23.44 (d, C-1), 23.78 (t, C-2/
6), 45.68 (t, C-3/5), 60.26 (t, C-8), 71.90 (d, C-4), 127.50 (d, C-12, 14/12a,
14a), 127.53 (d, C-13/13a), 135.65 (d, C-11, 15/11a, 15a), 135.58
(s, C-10/10a), 129.45 (s, C-2a/5a), 175.02 (s, C-7); IR (film):
n ¼ 3071 cm21, 3049 (m, CH-stretching), 2959, 2930, 2898, 2875, 2858
˜
(s, CH-aromatic), 1723 (s, C55O), 1463, 1428 (m), 1287, 1173, 112, 1076
(s), 1063 (s); UV/Vis (CH3CN): lmax (lg 1) ¼ 194 nm (4.96), 208 (4.46),
214 (4.33), 222 (4.22), 228 (3.92), 266 (2.86); MS (EI, 70 eV):
m/z (%) ¼ 460 [Mþ] (25), 459 [Mþ-H] (36), 445 [Mþ-CH3] (95), 403
[Mþ-tert-butyl] (8), 326 [403-C6H5] (1), 297 [326-C2H5] (2), 199
[C13H11O2] (100), 183 [199-O] (29); Anal. calcd. for C29H36O3Si (460.24):
C, 75.61%; H, 7.88%; found C, 75.48%; H, 8.09%.
Synthesis of Ethyl 2-(tert-Butyl-diphenyl-silanyloxy)-1, 2, 3,
6-tetrahydro-6-azulen-carboxylate (5)
Reactant 4 (6.0 g, 13.39 mmol) was dissolved in CCl4 (300 mL) and the
mixture cooled with an ice bath under stirring. Bromine (2.139 g,
13.39 mmol) dissolved in CCl4 (20 mL) was added dropwise with stirring.
When the addition was complete, triethylamine (6.62 g, 65.64 mmol) was
added. Triethylamine hydrobromide began to form immediately. The
mixture was refluxed for 18 h. The HBr salt was filtered off, and the solvent
was evaporated. The resulting oil was washed with water, dried with
MgSO4, and filtered to get the crude product (5 g) containing ethyl 1,3-
dibromo-6-azulenecarboxylate and ethyl 2-(tert-butyl-diphenyl-silanyloxy)-
1,2,3,6-tetrahydro-6-azulenecarboxylate. The mixture was purified by
column chromatography on silica gel using pentane as an eluent, increasing
its polarity with dichloromethan (1–10%). Ethyl 1,3-dibromo-6-azulenecar-
boxylate 6 (0.5 g, 10%), being less polar, eluted first (dark blue material)
followed by ethyl 2-(tert-butyl-diphenyl-silanyloxy)-1,2,3,6-tetrahydro-6-
azulenecarboxylate.

2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid Ethyl Ester
567
Compound 5: 3.2 g, 52%, bluish oil. RF (SiO2; pentane/dichloromethane;
1
3 : 2 ¼ 0.7; bp ¼ .2008C/5 torr; H NMR (400.1 MHz, CDCl3): d ¼ 0.98
3
3
(s, 9 H, tert-butyl), 1.24 (t, J ¼ 7.1 Hz, 3H, 11-H), 2.53 (t, J ¼ 5.6 Hz, 1H,
3
6-H), 2.71 (m, 4H, 1/3-H), 4.15–4.19 (q, J ¼ 7.1 Hz, 2H, 10-H), 4.45–
3
4.54 (m, 1H, 2-H), 5.19–5.24 (m, 2H, 5/7-H), 6.04-6.08 (2 ꢀ d, J ¼ 9.4,
9.3 Hz, 4/8-H), 7.08–7.28 (m, 6H, 14–16/14a-16a-H), 7.49–7.52 (m, 4H,
13, 17/13a, 17a-H); 13C NMR (100.6 MHz, CDCl3): d ¼ 14.20 (q, C-11),
19.08 (s, tert-butyl), 26.87 [q, (-CH3)3], 45.06 (d, C-6), 45.73 (t, C-1/3),
60.99 (t, C-10), 72.73 (d, C-2), 117.13 (d, C-5/7), 125.07 (d, C-15/15a),
127.57 (d, C-14, 16/14a, 16a), 129.57 (d, C-4/8), 134.29 (s, C-3a/8a),
135.67 (d, C-13, 17/13a, 17a), 139.52 (s, C-12/12a), 173.08 (s, C-9); IR
(film): n ¼ 2959 cm21, 2932 (w, CH-stretching), 1737 (s, C55O), 1428 (m),
˜
1199, 1161, 1111, 1086 (m), 702 (s); UV/Vis (CH3CN): lmax (lg
1) ¼ 196 nm (4.91), 266 (3.75), 202 (4.79), 296 (3.46), 312 (3.27); MS (EI,
70 eV): m/z (%) ¼ 458 [Mþ] (10), 429 [Mþ-C2H5] (1.6), 401 [Mþ-tert-
But.] (58), 385 [Mþ-C3H5O2] (98), 323 [401-C6H6] (30), 295 [323-C2H4]
(8), 199 [C13H11O2] (100); HRMS (C29H34O3Si): calcd. 458.22772; found
458.22788 + 4 ppm.
Ethyl 1,3-dibromo-6-azulen-carboxylate (6): RF (SiO2; pentane/dichloro-
methane; 8:2 ¼ 0.7; mp ¼ 115–1168C; 1H NMR (400.1 MHz, CDCl3):
3
3
d ¼ 1.37–1.40 (t, J ¼ 7.12 Hz, 3H, 11-H), 4.36–4.41 (q, J ¼ 7.12 Hz, 2H,
10-H), 7.83 (s, 1H, 2-H), 8.01–8.28 (AB q, 3J ¼ 10.30 Hz, 4H, 4, 8/5,
7-H); 13C NMR (100.6 MHz, CDCl3): d ¼ 14.25 (q, C-11), 76.68 (t, C-10),
103.86 (2 ꢀ s, C-1/3), 124.18 (d, C-5/7), 135.14 (d, C-4/8), 136.87 (2 ꢀ s,
C-3a/8a), 138.98 (s, C-6), 140.81 (d, C-2), 167.26 (s, C-9).
IR (KBr): v˜ ¼ 2991 cm21, 2974 (w, CH-stretching), 1721 (s, C55O),
1480, 1386 (m, C55C stretching), 1292, 1270 (s), 1211 (m); UV/Vis
(CH3CN): lmax (lg 1) ¼ 206 nm (4.27), 222 (4.32), 246 (4.28), 298 (4.81),
344 (3.74), 358 (3.84), 366 (3.32); MS (EI, 70 eV): m/z (%) ¼ 358 [Mþ]
(87), 330 [Mþ-C2H4] (100), 313 [Mþ-C2H5O] (4), 285 [Mþ-C3H5O2] (10),
206 [285-Br] (29); anal. calcd. for C13H10O2Br2 (358.02): C, 43.61%; H,
2.82%; found C, 43.86%; H, 2.53%.
Synthesis of 2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-carboxylic
Acid Ethyl Ester (13)
In a 1-L, three-necked flask, compound 5 (5.66 g, 12.35 mmol) was dissolved
in 650 mL of dry THF. The solution was cooled to 2788C with an acetone–
liquid nitrogen bath and tetrabutylammoniumfluoride (TBAF) (68 mL,
68.00 mmol) was added in one portion. Cooling was removed, and the
solution was stirred for 4 h at room temperature. When the reaction was
complete, 200 mL of saturated NH4Cl solution was added. The THF was evap-
orated, and the resulting mixture extracted thrice with ethyl acetate. The

568
Z. Hussain et al.
combined organic phase was washed three times with brine and dried with
MgSO4, and the solvent was evaporated to give the crude product. The new
material was purified by using silica-gel column chromatography with a
mixture of ether and pentane (1 : 3). When all the impurities had emerged
from the column, the column was washed with ether to yield the desired
product in 62.5% (1.72 g) yield. The product was isolated as a bluish
viscous liquid, which solidified in the refrigerator.
1
RF (ether/pentane, 3 : 2) ¼ 0.32; H NMR (200.1 MHz, CDCl3): d ¼ 6.23
(d, 3J ¼ 9.26 Hz, 2H, 4/8-H), 5.42 (m, 2H, 5/7-H), 4.54 (m, 1H, 2-H),
4.24 (q, 3J ¼ 7.15 Hz, 2H, 10-H), 3.06/2.72 (m, 4H, 1/3-H), 2.60
(t, 3J ¼ 5.4 Hz, 1H, 6-H), 1.30 (t, 3J ¼ 7.14 Hz, 3H, 11-H); 13C NMR
(50.3 MHz, CDCl3): d ¼ 173.0 (s, C-9), 139.3 (s, C-3a/8a), 125.00 (d, C-4/
8), 117.01 (d, C-5/7), 70.84 (d, C-2), 61.01 (t, C-10), 45.05 (d, C-6), 46.36
(t, C-1/3), 14.2 (q, C-11); IR (film): n ¼ 3427 cm21 (m), 2980, 2930, 2907
˜
(m, CH-stretching), 1736 (s, C55O), 1368 (m), 1297 (m), 1263 (m), 1194
(m), 1174 (m), 1040 (m); UV/Vis (CH3CN): lmax (lg 1) ¼ 194 nm (4.00),
206 (4.10), 274 (3.43), 294 (3.18), 310 (2.84), 330 (2.44); MS (EI, 70 eV):
m/z (%) ¼ 220 [Mþ] (12), 211 (3), 200 (3), 191 [Mþ-CH3CH2] (4), 173
[191-H2O] (9), 147 [Mþ-EtOOC] (100), 129 [147–H2O] (49), 115 (11);
HRMS (C13H16O3): calcd. 220.1099; found 220.10964 + 4 ppm.
Synthesis of 2-Chloro-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid
Ethyl Ester (14)
Alcohol 13 (100mg, 0.45mmol) dissolved in 10mL of CCl4 was placed in a
50-mL, three-necked flask. Then Ph3P (132mg, 1.1 eq) was added, and the
mixture was refluxed overnight. When the reaction was complete the mixture
was filtered to remove unreacted Ph3P. The product was purified by silica-gel
column chromatography using a mixture of CH2Cl2 and pentane (1: 3) as the
eluent. The first compound to elute was unreacted Ph3P; then the product
started eluting. The last fraction to emerge was unreacted starting material.
The product was isolated as a light bluish liquid in 60% yield (64.5 mg).
RF (CH2Cl2) ¼ 0.73; bp ¼ 120–1238C/5 torr; 1H NMR (200.1 MHz, CDCl3):
d ¼ 6.22 (m, 2H, 4/8-H), 5.47 (m, 2H, 5/7-H), 4.60 (m, 1H, 2-H), 4.25
(q, 3J ¼ 7.14 Hz, 2H, 10-H), 3.01–3.32 (m, 4H, 1/3-H), 2.68
(t, 3J ¼ 5.61 Hz, 1H, 6-H), 1.30 (t, 3J ¼ 7.14 Hz, 3H, 11-H); 13C NMR
(50.3 MHz, CDCl3): d ¼ 173.0 (s, C-9), 134.8 (s, C-3a/8a), 124.4 (d, C-4/
8), 117.5 (d, C-5/7), 61.2 (t, C-10), 47.1 (t, C-1/3), 45.1 (d, C-2), 44.2
(d, C-6), 14.2 (q, C-11). IR (film): n ¼ 3450 cm21 (w), 3026 (w), 2981 (m),
˜
2938 (m), 2906 (w), 2852 (w), 1737 (s), 1368 (m), 1303 (s), 1258 (s),
1196 (s), 1176 (s), 1166 (m), 1117 (w), 751 (w), 712 (m); UV/Vis
(CH3CN): lmax (lg 1): 206 nm (4.26), 272 (3.56); MS (EI, 70 eV): m/z

2-Hydroxy-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid Ethyl Ester
569
(%) ¼ 240 [Mþ(37Cl)] (3), 238 [Mþ(35Cl)] (7), 212 [Mþ-HCl] (1), 209 [35Mþ-
CH3CH2] (6), 200 (6), 173 [Mþ-CH3CH2–HCl] (8), 167 [37Mþ-EtOOC] (29),
165 [35Mþ-EtOOC] (100), 129 [167/165-HCl] (86); anal. calcd. for
C13H15O2Cl (238.71): C, 65.41%; H, 6.33%; found C, 65.52%; H, 6.27%.
Synthesis of 2-Bromo-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid
Ethyl Ester (15)
In a 250-mL, three-necked flask PPh3 (1.25 g, 4.77 mmol) was dissolved in
50 mL of CCl4 under nitrogen. The solution was cooled with an ice bath
and Br2 (762 mg, 4.77 mmol) in 20 mL of CCl4 was added dropwise to the
solution from a dropping funnel. When the addition was complete the ice
bath was removed, and the mixture was left to stir at room temperature.
After 15 min alcohol 13 (1.0 g, 4.54 mmol) in 20 mL of CCl4 was added
from a dropping funnel in one portion. When the addition was complete the
mixture was refluxed for 1 h. Water was added, and the organic layer was
extracted with diethyl ether. The organic layer was again washed with
water, separated, and dried with MgSO4. The solvent was evaporated and
the product purified by silica-gel column chromatography using a mixture
of CH2Cl2 and pentane as the eluent. The purification yielded 390 mg
(30%) of the product as a light blue liquid.
RF (CH2Cl2/pentane, 1 : 1) ¼ 0.6; bp. ¼ 134–1368C/5 Torr (distilled as a
colorless liquid but also visibly decomposed simultaneously; 1H NMR
(200.1 MHz, CDCl3): d ¼ 6.17 (m, 2H, 4/8-H), 5.40 (m, 2H, 5/7-H), 4.57
3
(m, 1H, 2-H), 4.19 (q, J ¼ 7.14Hz, 2H, 10-H), 3.36–3.02 (m, 4H, 1/3-H),
3
3
2.68 (t, J ¼ 5.63Hz, 1H, 6-H), 1.24 (t, J ¼ 7.13Hz, 3H, 11-H); 13C NMR
(50.3MHz, CDCl3): d ¼ 173.2 (s, C-9), 139.1 (s, C-3a/8a), 124.3 (d, C-4/8),
118.1 (d, C-5/7), 61.1 (t, C-10), 47.8 (t, C-1/3), 47.5 (d, C-6), 45.1 (d, C-2),
14.2 (q, C-11). IR (film): n ¼ 3452cm21 (w), 3025 (w), 2980, 2938 (m, CH-
˜
stretching), 2873, 2824 (w), 1736 (s, C55O), 1368 (m), 1302 (s), 1226 (s),
1196 (s), 1173 (s), 1040 (m); UV/Vis (CH3CN): lmax (lg 1): 206 nm (4.31),
270 (3.55), 312 (2.79), 320 (2.69), 340 (2.60); MS (EI, 70 eV): m/z
(%) ¼ 284 [(81Br)Mþ] (2), 282 [(79Br)Mþ] (2), 253 [79Mþ-CH3CH2] (1), 211
[81Mþ-EtOOC] (26), 209 [79Mþ-EtOOC] (26), 202 [Mþ-HBr] (12), 185(12),
172 [Mþ-HBr–CH3CH2] (14), 129 [Mþ-EtOOC–HBr] (100); anal. calcd. for
C13H15O2Br (283.16): C, 55.14%; H, 5.34%; found C, 55.46%; H, 5.44%.
Synthesis of 2-Iodo-1,2,3,6-tetrahydro-azulen-6-carboxylic Acid
Ethyl Ester (16)
To a mixture of alcohol 13 (200 mg, 0.91 mmol) in 10 mL of iodo-
benzene (461 mg, 1.82 mmol) were added PPh3 (476 mg, 1.82 mmol) and

570
Z. Hussain et al.
hexamethylphosphorous triamide (651 mg, 3.63 mmol) in one portion. The
dark mixture was stirred at room temperature for 5 h until TLC analysis
showed consumption of all starting material. The mixture was diluted with
ether (40 mL) and quenched with an ice-cold saturated solution of sodium
bicarbonate. The organic layer was separated and washed consecutively
with 1M H2SO4, water, and finally a saturated solution of NaHCO3. The
organic phase was dried with MgSO4. The product was purified by silica-
gel column chromatography using a mixture of CH2Cl2 and pentane (1 : 2)
as the eluent. The product was isolated as a colorless liquid (180 mg) in
60% yield. The product can be preserved for a few days in deep freeze but
the colorless liquid turns gradually dark brown, decomposing.
1
RF (CH2Cl2/pentane, 1 : 2) ¼ 0.42; bp ¼ decomposed on heating; H NMR
(200.1 MHz, CDCl3): d ¼ 6.22 (m, 2H, 4/8-H), 5.43 (m, 2H, 5/7-H), 4.76
3
(m, 1H, 2-H), 4.25 (q, J ¼ 7.16 Hz, 2H, 10-H), 3.38–3.12 (m, 4H, 1/3-H),
3
3
2.74 (t, J ¼ 5.58 Hz, 1H, 6-H), 1.30 (t, J ¼ 7.13 Hz, 3H, 11-H); 13C NMR
(50.3 MHz, CDCl3): d ¼ 173.0 (s, C-9), 134.8 (s, C-3a/8a), 124.3 (d, C-4/
8), 118.0 (d, C-5/7), 61.1 (t, C-10), 49.8 (t, C-1/3), 49.9 (d, C-6), 45.1
(d, C-2), 14.2 (q, C-11); UV/Vis (CH3CN): lmax (lg 1): 198 nm (4.32), 264
(3.60); MS (EI, 70 eV): m/z (%) ¼ 330 [Mþ] (0.5), 257 [Mþ-EtOOC] (4),
202 [Mþ-HI] (13), 173 [20222CH3CH2] (6), 129 [Mþ-HI–EtOOC] (100);
anal. calcd. for C13H15O2I (330.17): C, 47.29%; H, 4.58%; found C,
47.68%; H, 4.57%.
ACKNOWLEDGMENT
Support of the Freunde des Instituts fu¨r Organische Chemie and the Fonds der
Chemischen Industrie is gratefully acknowledged. Z.H. is grateful to
¨
W. Gartner, Max-Planck-Institut fur Bioanorganische Chemie, Mulheim,
Germany, for proofreading the manuscript.
¨
¨
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