Annelation of Baylis-Hillman derivatives: Synthesis of highly functionalised tetrahydronaphthalenes

Article abstract of DOI:10.3184/030823409X12532103537360

PTSA-promoted Robinson annelation of a-(3-oxobutyl)cyclohex-2-en-1-one derivatives in refluxing toluene, affords efficiently in a one pot process a variety of hydroxytetrahydronaphthyl carbonyl compounds in good yields. Further highly regioselective elect

Full text of DOI:10.3184/030823409X12532103537360

642 RESEARCH PAPER
OCTOBER, 642–644
JOURNAL OF CHEMICAL RESEARCH 2009
Annelation of Baylis–Hillman derivatives: synthesis of highly
functionalised tetrahydronaphthalenes
Asma J'mour and Farhat Rezgui*
Laboratoire de Chimie Organique, Faculté des Sciences de Tunis, Campus Universitaire 2092 Tunis, Tunisia
PTSA-promoted Robinson annelation of a-(3-oxobutyl)cyclohex-2-en-1-one derivatives in refluxing toluene, affords
efficiently in a one pot process a variety of hydroxytetrahydronaphthyl carbonyl compounds in good yields. Further
highly regioselective electrophilic bromination of these intermediates gave the corresponding bromide derivatives
in 92–97% yield.
Keywords: Baylis–Hillman alcohols, tetrahydronaphthyl carbonyl compounds, Robinson annelation, electrophilic bromination,
regioselectivity
O
O
O
Hydroxyaryl carbonyl compounds are useful intermediates in
organic chemistry and for the preparation of biologically active
targets.1 These versatile derivatives are commonly prepared
from the Fries rearrangement of aryl esters in the presence of
Lewis acids such as aluminium(III) chloride,2,3 titanium(III)
chloride4-6 or zirconium(III) chloride.7 Unfortunately, in
many cases, this protocol furnished a mixture of regioisomers
together with side-products.8-10 Therefore, intense efforts have
been undertaken either to improve the regioselectivity of the
Fries rearrangement11 or to develop new approaches towards
this important class of compounds.12
i or ii
R
O
R = alkyl, aryl
1
2
i : Et3N /EtOH then K2CO3/EtOH
ii : Excess of K2CO3/EtOH
Scheme 1 Annelation of compounds 1 in basic conditions.
Furthermore, in our previous papers,13,14 starting from
a-(3-oxobutyl)cyclohex-2-en-1-one derivatives 1 in basic
conditions, we have described two synthetic routes (i) or (ii)
to a new series of bicyclic dienones 2 (Scheme 1).
O
O
OH
PTSA
R
toluene, reflux
R
O
In continuation of our study on the intramolecular aldol
condensation of multifunctional derivatives 1, we report
here their use as intermediates in a simple synthetic method
for hydroxy-5,6,7,8-tetrahydronaphthyl carbonyl compounds
(THN) 3. We also disclosed a general procedure for highly
regioselective electrophilic bromination of these aryl carbonyl
derivatives 3, yielding a new series of potential intermediates
4 for AMP deaminase inhibitors.15,16
O
3
1
R = Me, Ph, OMe, OEt
Scheme 2 PTSA-catalysed annelation of 1,5-diketones 1.
describes their acidic Robinson annelation into functionalised
THN 3, however, without further deacylation reactions.
In the literature,15,16 bromohydroxytetrahydronaphthyl
carbonyl compounds 3 are described as potential precursors,
via their corresponding homobenzylic bromide derivatives 5,
for potent inhibitors 6 of adenosine deaminase (Scheme 4).
Treatment of compound 3d with bromine in acetic acid,
we first prepared through a highly regioselective electrophilic
bromination, the single bromohydroxynaphthyl ester 4d in
excellent yield (Scheme 5, Table 2).
Results and discussion
During our investigation on Robinson annelation of 1,5-
dicarbonyl compounds 1 in acidic conditions, we first found
that intramolecular aldol reaction of compound 1a and a
catalytic amount (0.1 equiv.) of PTSA (p-toluene sulfonic
acid) proceeded rapidly in refluxing toluene, affording cleanly
in a straightforward process the single hydroxyaryl ketone 3a
in 90% yield (Scheme 2).
Concerningthemechanisticaspectofthisreaction,weassume
that the present protocol proceeded in a three-step reaction
sequence including (i) Robinson annelation-crotonisation
giving I1 that underwent further tautomerisation (ii) and (iii)
aromatisation, affording hydroxytetrahydronaphthyl ketone
3a in good yield (Scheme 3).
The crystalline structure of compound 4d,18,19 confirmed
the preferential attack at the ortho position to the hydroxyl
group of 3d. This interesting regioselectivity is in agreement
with the fact that the hydroxyl group is a strongly activating
o- (exclusively available here), p-directing substituent.
This simple, efficient procedure (e.g. Br2 in AcOH) has
been also applied to perform the electrophilic bromination
of hydroxytetrahydronahthyl carbonyl compounds 3a–c.
As seen in Table 2, we have successfully and cleanly prepared
the corresponding bromide derivatives 4a–c in 92–97% yield.
The spectroscopic data of 3a are in agreement with those of
literature.12,17
Using the optimal cyclisation conditions (0.1 equiv of PTSA
in refuxing toluene) previously etablished for the preparation
of 3a, we then examined the access to its analogous
derivatives 3b–d. During our study, we similarly observed
that a one pot three-step reaction proceeded smoothly to give
regioselectively and in good yields the corresponding THN
3b–d (Scheme 2, Table 1).
Note that in contrast to our previous communications on
K2CO3-promoted intramolecular cyclisation of compounds 1
into bicyclic dienones 213,14 (Scheme 1), the present procedure
Table 1 PTSA-catalysed annelation of 1,5-diketones 1
3
a
b
c
d
R
Me
90
Ph
91
OMe
75
OEt
82
Yield (%)
Table 2 Electrophilic bromination of compounds 3
4
a
b
c
d
R
CH3
97
Ph
92
OMe
92
OEt
96
Yield/%
* Correspondent. E-mail: rez_far@yahoo.fr

JOURNAL OF CHEMICAL RESEARCH 2009 643
OH
O
O
O
R
O
OH
R
i
ii, iii
R
O
3
1
I1
i: Robinson annelation-crotonisation, ii: tautomerisation, iii: aromatisation
Scheme 3 A plausible reaction mechanism of PTSA-catalysed annelation of compound 1.
Br
HO
N
Br
OMe
N
OH
OH
ref. 15,16
ref. 15,16
HN
N
COR
COR
COR
6
5
4
Scheme 4 Bromide derivatives 4 as useful precursors for inhibitors 6 of adenosine deaminase.
1H NMR (300 MHz, CDCl3): d 11.81 (s, 1H), 7.66–7.45 (m, 5H), 7.25
(s, 1H), 6.76 (s, 1H), 2.77–2.75 (m, 2H), 2.63–2.61 (m, 2H), 1.77–
1.73 (m, 4H). 13C NMR (75 MHz, CDCl3): d 201.1, 160.7, 147.4,
138.2, 133.6, 131.5, 129.0, 128.2, 127.7, 117.6, 117.3, 30.0, 28.5,
23.1, 22.6. HRMS Calcd for C17H16O2 252.1150. Found 252.1150.
Methyl-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate
(3c): Yellow oil; yield (75%). IR (CHCl3): 3219, 1675 cm-1.
1H NMR (300 MHz, CDCl3): d 10.41 (s, 1H), 7.51 (s, 1H), 6.67 (s,
1H), 3.91 (s, 3H), 2.74–2.68 (m, 4H), 1.77–1.76 (m, 4H). 13C NMR
(75 MHz, CDCl3): d 170.5, 158.9, 146.3, 129.8, 128.1, 116.9, 110.0,
52.0, 29.8, 28.4, 23.2, 22.7. HRMS Calcd for C12H14O3 206.0943.
Found 206.0942.
Ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate
(3d): Yellow oil; yield (82%). IR (CHCl3): 3674, 3532, 3211, 1671 cm-1.
1H NMR (300 MHz, CDCl3): d 10.52 (s, 1H), 7.51 (s, 1H), 6.65 (s,
1H), 4.36 (q, 2H, J = 6.73 Hz), 2.77–2.66 (m, 4H), 1.79–1.74 (m,
4H), 1.40 (t, 3H, J = 6.39 Hz). 13C NMR (75 MHz, CDCl3): d 170.1,
159.1, 146.0, 129.8, 128.0, 116.8, 110.3, 61.0, 30.0, 28.4, 23.2, 22.7,
14.2. MS (EI, 70 eV); m/z (%): 117 (17), 146 (11), 174 (100), 220
(M+, 31). HRMS Calcd for C13H16O3 220.1099. Found 220.1099.
Br
OH
OH
Br2
AcOH, t.a
R = Me, Ph, OMe, OEt
R
R
3
4
O
O
Scheme 5 Electrophilic bromination of compounds 3.
Conclusions
The present work describes PTSA-promoted Robinson
annelation of 2-(3-oxobutyl)cyclohex-2-en-1-one derivatives
1 in refluxing toluene to give, via an efficient tandem reactions
sequence, a variety of THN 3 which were further subjected to
electrophilic bromination conditions in acetic acid, to afford
in good yields and in high regioselectivity the corresponding
bromohydroxynaphthyl derivatives 4 as useful intermediates
for the synthesis of AMP deaminase inhibitors.
Typical procedure for the preparation of 4a–d
To a solution of tetrahydronaphthyl carbonyl compounds (2 mmol)
3 in 2 mL of acetic acid, was added dropwise a solution of bromine
(2 mmol) in 2 mL of acetic acid under stirring at room temperature.
After additional 2 h, the resulting mixture was diluted with water and
extracted with dichloromethane. The organic layer was washed with
water until neutrality. After usual work up, the residue was purified
by a column chromatography (petroleum ether).
1-(4-Bromo-3-hydroxy-5,6,7,8-tetrahydro-2-naphthyl)ethanone
(4a): M.p. 142°C, yield (97%). 1H NMR (300 MHz, CDCl3): d 12.78
(s, 1H), 7.38 (s, 1H), 2.78–2.70 (m, 4H), 2.67 (s, 3H), 1.83–1.72
(m, 4H). 13C NMR (75 MHz, CDCl3): d 203.8, 156.4, 146.2, 129.5,
129.3, 117.9, 114.3, 31.3, 29.4, 26.5, 22.7, 22.5. MS (EI, 70 eV);
m/z (%): 115 (26), 117 (12), 145 (16), 146 (27), 253 (100), 255
(97), 268 (M+, 66). HRMS Calcd for C12H13BrO2 268.0099. Found
268.0100.
1-(4-Bromo-3-hydroxy-5,6,7,8-tetrahydro-2-naphthyl)(phenyl)
methanone (4b): M.p. 121°C; yield (92%). 1H NMR (300 MHz,
CDCl3): d 12.49 (s, 1H), 7.58–7.38 (m, 5H), 7.18 (s, 1H), 2.75–2.71
(m, 2H), 2.59–2.55 (m, 2H), 1.77–1.59 (m, 4H). 13C NMR (75 MHz,
CDCl3): d 200.8, 157.2, 146.2, 137.6, 132.3, 132.0, 129.1, 128.4,
128.3, 117.4, 114.5, 31.3, 29.6, 22.7, 22.6. MS (EI, 70 eV); m/z (%):
77 (79), 105 (80), 253 (58), 255 (53), 329 (82), 330 (M+, 96), 331
(MH+, 100).
Methyl-4-bromo-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-
carboxylate (4c): M.p. 86°C; yield (92%). 1H NMR (300 MHz,
CDCl3): d 11.13 (s, 1H), 7.42 (s, 1H), 3.85 (s, 3H), 2.70–2.59 (m,
4H), 1.75–1.60 (m, 4H). 13C NMR (75 MHz, CDCl3): d 170.2, 155.6,
145.2, 129.6, 128.6, 113.6, 110.4, 52.5, 31.2, 29.3, 22.7, 22.5. MS
(EI, 70 eV); m/z (%): 115 (20), 117 (12), 173 (18), 252 (100), 254
(98), 284 (M+, 22). HRMS Calcd for C12H13BrO3 284.0048. Found
284.0049.
Experimental
General
1H NMR spectra were recorded in CDCl3 solutions at 300 MHz
with tetramethylsilane as internal reference. 13C NMR spectra were
recorded at 75 MHz with CDCl3 as internal reference. Chemical
shifts are given in ppm (d) and coupling constants J are reported in
Hz. IR spectra were obtained on a Perkin Elmer Paragon 1000 PC
IR spectrometer. Mass spectra were measured on a Hewlett-Packard
5890 spectrometer at 70 eV (EI). Column chromatography was
performed using silica gel 60 (70–230 mesh).
Typical procedure for the preparation of tetrahydronaphthyl carbonyl
compounds 3a–d
A mixture of 2-(3-oxobutyl)cyclohex-2-en-1-one 1 (2 mmol),13
a catalytic amount (0.1 equiv.) of PTSA and 5 mL of toluene, was
refluxed for 2 h. The reaction mixture was diluted with dichloro-
methane (20 mL) and washed successively with saturated aqueous
NaHCO3 and with brine. The organic layer was dried over Na2SO4.
After evaporation of the solvents, the product was purified by a
column chromatography (ether/petroleum ether: 5/95).
1-(3-Hydroxy-5,6,7,8-tetrahydro-2-naphthyl)ethanone (3a): A known
compound.17 M.p. 71°C (lit.17: m.p. 71–72°C); yield (90%).
IR (CHCl3): 3673, 1639 cm-1. 1H NMR (300 MHz, CDCl3): d 11.98
(s, 1H), 7.40 (s, 1H), 6.67 (s, 1H), 2.78–2.72 (m, 4H), 2.63 (s, 3H),
1.81–1.74 (m, 4H). 13C NMR (75 MHz, CDCl3): d 203.9, 159.8,
147.4, 130.8, 127.8, 117.9, 117.5, 29.9, 28.5, 26.5, 23.1, 22.6. MS
(EI, 70 eV); m/z (%): 147 (15), 175 (100), 190 (M+, 43). HRMS
Calcd for C12H14O2 190.0994. Found 190.0994.
1-(3-Hydroxy-5,6,7,8-tetrahydro-2-naphthyl)phenylmethanone
(3b): Yellow oil; yield (91%). IR (CHCl3): 3684, 1632 cm-1.

644 JOURNAL OF CHEMICAL RESEARCH 2009
7
8
D.C. Harroweven and R.F. Dainty, Tetrahedron Lett., 1996, 37, 7659.
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Ethyl-4-bromo-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-
carboxylate (4d): M.p. 104°C, yield (96%). 1H NMR (300 MHz,
CDCl3): d 11.32 (s, 1H), 7.51 (s, 1H), 4.39 (q, 2H, J = 7.35 Hz),
2.78–2.68 (m, 4H), 1.82–1.70 (m, 4H), 1.41 (t, 3H, J = 7.36 Hz).
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113.6, 110.7, 61.7, 31.2, 29.3, 28.4, 22.7, 14.2. MS (m/z); 115 (22),
117 (14), 173 (19), 252 (100), 254 (100), 298 (M+, 25). HRMS Calcd
for C13H15BrO3 298.0205. Found 298.0202.
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Received 12 June 2009; accepted 11 September 2009
Paper 09/0637 doi: 10.3184/030823409X12532103537360
Published online: 8 October 2009
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