Preparation of phenyl-butyraldehydes using a base-catalyzed aromatization of dienones

Article abstract of DOI:10.1016/j.tetlet.2008.03.038

Seven aldehydes were prepared using a five-step sequence synthesis. The synthetic strategy involved the use of a novel aromatization reaction of dienones. These key intermediates were prepared following a sequence involving BAR of substituted tetralones,

Full text of DOI:10.1016/j.tetlet.2008.03.038

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2872–2874
Preparation of phenyl-butyraldehydes using
a base-catalyzed aromatization of dienones
*
´
Marıa Fernanda Plano, Guillermo R. Labadie, Raquel M. Cravero
Instituto de Quı´mica Rosario (IQUIR-CONICET), Facultad de Ciencias Bioquı´micas y Farmace´uticas,
Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina
Received 12 February 2008; revised 4 March 2008; accepted 6 March 2008
Available online 18 March 2008
Abstract
Seven aldehydes were prepared using a five-step sequence synthesis. The synthetic strategy involved the use of a novel aromatization
reaction of dienones. These key intermediates were prepared following a sequence involving BAR of substituted tetralones, ketones
reduction, protection of alcohol, and bis-allylic oxidation. The key step of the route is an aromatization promoted by basic reaction
conditions of dienones leading to substituted 4-phenyl butanals.
Ó 2008 Elsevier Ltd. All rights reserved.
Arene transformation is still an important research area
in organic chemistry and is continuously used as a key step
in industrial synthesis. The controlled introduction of sub-
stituents and the carbon–carbon bond formation to arenes
are of special interest and have many applications in the
synthesis of complex molecules.1 The Friedel–Crafts alkyl-
ation even now is the most important reaction to introduce
substituents over the aromatic rings, but in general only
exhibits moderate regioselectivity. Aryl butanals have been
employed along the years for different synthetic applica-
tions. They were synthesized by hydroformilation of substi-
tuted allyl and propenyl benzene.2,3 The possibility to form
an aromatic ring during the course of a reaction guarantees
its exothermicity. This property has been exploited in the
oxidation of alicyclic rings producing aromatic or hetero-
aromatic rings. Recently different research groups have
been studying aromatization reactions as a new tool in
organic synthesis. Taking advantage of substrates that
are susceptible to be aromatized, Walton’s and Studer’s
groups have been using 1-functionalized 2,5-cyclohexadi-
enes as radical precursors that undergo b-scission restoring
the aromaticity of the ring.4 Employing a similar approach,
Linker has produced a two-step ipso-substitution over aro-
matic carboxylic acids by means of an acid-catalyzed aro-
matization.5 It is also known that monocyclic enones
derived from benzoic acid can be transformed into related
4-alkyl and carbalcoxiphenols by acid or basic catalysis.6
To the best of our knowledge, there is no other application
of basic aromatization reaction as a synthetic tool along
with those examples.
During the course of our investigations on the applica-
tions of the Birch alkylation reaction (BAR) of a-tetralones
we had previously found that the hydrolysis of benzoate 1a
produced as the only isolated product aldehyde 3a instead
of the expected alcohol 2a (Scheme 1). With the purpose of
OH
OR
a
O
O
β
β
1a R=Bz -ol
2a -ol
1b
β
2b α
R=Ac -ol
-ol
α
1c R=Bz -ol
CHO
HO
3a
*
Scheme 1. Hydrolysis of the dienone ester. Reagents and condition: (a)
K2CO3, MeOH, rt.
Corresponding author. Tel./fax: +54 341 4370477.
E-mail address: cravero@iquios.gov.ar (R. M. Cravero).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.038

M. F. Plano et al. / Tetrahedron Letters 49 (2008) 2872–2874
2873
ride, and allyl bromide that will allow introducing chains
with different degrees of oxidation susceptible to be trans-
formed into alcohol, aldehyde, or acids. The BAR pro-
vided the expected diene with good yields (70–98%). The
ketones were reduced with sodium borohydride to produce
b-alcohols exclusively (60–95%), and then were protected
as benzoate, using standard protocol to provide benzoates
5a–g (80–98%). Following the reported procedure,8 bis-
H
O
R1
OR
5´
R1 CHO
R
R
R
6´
1´
4´
3´
HO
O
2´ 3
1
4
Scheme 2. Synthetic strategy.
studying the scope and limitations of this reaction we
decided to test the product formation of acetate 1b and also
the a-benzoate 1c to find out if the course of the reaction
would be affected by the stereochemistry of the alcohol
or the acyl group bonded to it. When enones 1b and 1c
were submitted to hydrolysis under the same reaction con-
ditions the only isolated product was aldehyde 3, without
any traces of alcohols 2a–b, respectively (Scheme 1).
These results demonstrate unequivocally that the reac-
tion product was independent of the nature of the acyl
group and of the stereochemistry of the alcohol, as we
initially assumed.
t
allylic oxidation was achieved using PDC, BuOOH giving
dienones 1a–g (60–85%). The full details on the preparation
and characterization of compounds 1a,c–3a (Scheme 1)
had been previously described.7a In all cases, the reaction
sequences proceeded efficiently with moderate to high
yield, except for the 7-methoxy tetralone which in all
attempts of Birch alkylation with MOMCl gave methoxy
methyl 4-phenyl butanoate9 as the sole isolated product
in 40% yield from the recovered starting material. It should
be pointed out that the presence of allyl or methoxy methyl
groups on ring junction makes the chromatographic purifi-
cation of the dienones difficult in extreme.
With these results in hand, we decided to extend our
work on tetralones as synthetic precursors in organic syn-
thesis,7 using this aromatization reaction to prepare substi-
tuted 4-phenyl-butyraldehydes. The aromatization reaction
would be used on dienones prepared from tetralones with
different patterns of substitution over the aromatic ring.
The retrosynthetic analysis of our strategy is shown in
Scheme 2. This approach allowed the specific introduction
of an alkyl chain and hydroxyl group on the positions 60
and 30 of the phenyl butanal, respectively.
To prepare dienones, we focused on the application of
BAR on tetralones where the alkyl chain would be intro-
duced followed by carbonyl reduction and protection as
benzoate; finalizing by bis-allylic oxidation.
Having demonstrated that the stereochemistry of the
alcohol does not affect the course of the aromatization,
we selected the beta stereochemistry because sodium boro-
hydride reduction provided better yields.7a Initially, sub-
stituents on the aromatic ring were introduced in the first
reaction over tetralones 4a–g, Scheme 3. The chosen alkyl-
ating reagents were methyl iodide, methoxy methyl chlo-
The key step of the path was performed according to the
previously optimized conditions10 using K2CO3 as base in
MeOH at room temperature. The reaction produced the
expected products 3a–g with moderate to good yields
(Scheme 4).11
R1
R1
OBz
R
a
3´
4
HO
O
R
CHO
3a R = H R1 = H, 94%
1a-g
3b R = 2,4,6-trimethyl R1= H, 80%
3c R = 2-MeO, R1= H, 63%
3d R = H R1= allyl, 87%
3e R = H R1= allyl, 94%
3f R = 2,6-dimethyl R1= H, 80%
3g R = H R1= H 4-Me, 50%
Scheme 4. Dienones aromatization. Reagents and condition: (a) K2CO3,
MeOH, rt.
O
O
R1
O
Ph
R1
O
Ph
O
a, b, c
d
R
O
R
R
5a R = H, R1 = H, 91%e
4a R = H
1a R = H, R1 = H, 85%
1b R = 5,7-diCH3, R1 = H, 60%
1c R = 5-OCH3, R1 = H, 59%
1d R = H, R1 = OCH3, 73%
1e R = H, R1 = allyl, 75%
5b R = 5,7-diCH3, R1 = H, 43%
5c R = 5-OCH3, R1 = H, 34%
5d R = H, R1 = OCH3, 75%
5e R = H, R1 = allyl, 45%
4b R = 5,7-diCH3
4c R = 5-OCH3
4g R = 4-CH3
1f R = 5,7-diCH3, R1 = allyl, 85%
1g R = 4-CH3, R1 = H, 60%
5f R = 5,7-diCH3, R1 = allyl, 64%
5g R = 4-CH3, R1 = H, 54%
t
Scheme 3. Reagents and conditions: (a) (1) NH3, K, Et2O, BuOH, ꢀ78 °C; (2) LiBr; (3) R–X, ꢀ78 °C to rt; (b) NaBH4, MeOH, ꢀ78 °C, 30 min; (c)
t
PhCOCl, Py, DMAP, 0 °C, 2 h; (d) PDC, BuOOH, DCM. e Yields of 5a–g are based on 4 (a, b, c steps).

2874
M. F. Plano et al. / Tetrahedron Letters 49 (2008) 2872–2874
R1
References and notes
R1
OBz
H O
R
1. (a) Olah, G. A. Friedel–Crafts and Related Reactions; Interscience:
New York, 1963–1964; (b) Roberts, R. M.; Khalaf, A. A. Friedel–
Crafts alkylation Chemistry: A Century of Discovery; Marcel Dekker:
New York, 1984.
O
O
HO
R
2-
CO3
´
ˆ
2. Kollar, L.; Farkas, E.; Batiu, J. J. Mol. Catal. A: Chem. 1997, 115,
283–288.
R1
R1
3. Paganelli, S.; Ciappa, A.; Marchetti, M.; Scrivanti, A.; Matteoli, U. J.
Mol. Catal. A: Chem. 2006, 247, 138–144.
4. Walton, J. C.; Studer, A. Acc. Chem. Res. 2005, 38, 794–802 and
reference cited therein.
5. Vorndran, K.; Linker, T. Angew. Chem., Int. Ed. 2003, 42, 2489–2491.
6. Schultz, A. G.; Harrington, H. M.; Metha, P. G.; Taveras, A. G. J.
Org. Chem. 1987, 52, 5482–5489.
H
O
H O
R
R
O
Scheme 5. Proposed mechanism for aromatization under basic conditions.
´
7. (a) Labadie, G. R.; Cravero, R. M.; Gonzalez-Sierra, M. Synth.
Commun. 2000, 30, 4065–4079; (b) Plano, M. F.; Labadie, G. R.;
For some substrates the reaction time was longer than
others and that can be explained based on difficulties to
produce ester hydrolysis. From the inspection of the struc-
tural differences for the transformation of compounds 1
into the final products 3, there is neither required stereo-
chemistry nor the nature of R substituent for any ester
group which would significantly affect the course of the
reaction.
´
Gonzalez-Sierra, M.; Cravero, R. M. Tetrahedron Lett. 2006, 47,
7447–7449.
8. (a) Chimdanbaran, N.; Chandrasekaran, S. J. Org. Chem. 1987, 52,
5049; (b) Guo, Z.; Schultz, A. G. Org. Lett. 2001, 3, 1177–1180.
9.
MeO
O
O
O
O
O
From the mechanistic point of view the conversion of
dienones 1 to aldehyes 3 under basic conditions suggests
the participation of the benzoyloxy group to generate the
corresponding alcoxide which promotes the cleavage of
the bicyclic dienone to the corresponding phenolate and
this takes a proton from the solvent to form the final prod-
uct 3. The fragmentation process allows the formation of
an aromatic ring that results in gain on resonance stabiliza-
tion energy, that is, ultimately the driving force of the reac-
tion (Scheme 5). Likewise, it could be also interpreted as
the reversal reaction to the ipso-alkylation with KOtBu
described by Mander12 to afford oxodienones from
aromatic compounds.
10. General procedure to aldehydes preparation. To a solution of dienone 1
(1 mmol) in MeOH (35 mL), K2CO3 (3 mmol) was added and the
reaction mixture was maintained with magnetic stirring at room
temperature until complete. The reaction was quenched with brine
and methanol was concentrated in vacuo. The aqueous layer was
extracted with Et2O (3 ꢁ 25 mL) and EtOAc (25 mL), combined
organic extracts were dried (anhyd Na2SO4) and evaporated in vacuo
to give a residue that was purified by column chromatography.
11. All new compounds were characterized on the basis of IR, 1H, 13C
NMR and HRMS data. Spectral data for selected compounds:
4-(3-Hydroxy-2,4,6-trimethyl phenyl)-butanal (3b). Colorless oil
(80%), Rf = 0.51 (hexane/EtOAc 70:30). IR (film) m 3474, 3007,
2949, 2882, 1716, 1480, 1456, 1410, 1386, 1246, 1212, 1094, 1012,
869 cmꢀ1 1HNMR d (ppm) 9.81 (t, 1H, J = 1.0, CHO), 6.80 (s, 1H,
.
Ar-H-5), 4.71 (s, 1H, OH), 2.64 (t, 2H, J = 5.4 Hz, H-4), 2.54 (dt, 2H,
J = 4.7, 1.0 Hz, H-2), 2.24 (s, 3H, CH3-6), 2.23 (s, 3H, CH3-2), 2.21 (s,
3H, CH3-4), 1.79 (q, 2H, J = 4.8 Hz, H-3). 13CNMR d (ppm, CDCl3)
202.4 (CHO), 150.4 (Ar-C-3), 137.0 (Ar-C-1), 129.8 (Ar-C-5), 127.5
(Ar-C-6), 121.8 (Ar-C-2), 120.4 (Ar-C-4), 43.8 (C-2), 29.2 (C-4), 21.9
(C-3), 19.3 (CH3-6), 15.7 (CH3-4), 11.8 (CH3-2). ESI-HRMS Calcd
for (M+H+) C13H19O2, 207.1380; found, 207.1377.
4-(6-Allyl-3-hydroxy-2,4-dimethylphenyl)butanal (3f). White solid
(80%), Rf = 0.30 (hexane/EtOAc 80:20). IR (film) m 3476, 3077,
2932, 2870, 1717, 1637, 1579, 1480, 1412, 1389, 1212, 1095, 912, 874,
684 cmꢀ1 1HNMR d (ppm) 9.81 (t, 1H, J = 0.8 Hz, CHO), 6.80 (s,
.
1H, ArH-5), 5.95 (m, 1H, –CH2CH@CH2), 5.04 (dd, 1H, J = 6.3,
1.0 Hz, –CH2CH@CH2), 4.96 (dd, 1H, J = 2.0, 1.0 Hz,
–CH2CH@CH2), 4.69 (d, 1H, J = 1.6 Hz, –OH), 3.33 (d, 2H,
J = 4.1 Hz, –CH2CH@CH2), 2.64 (t, 1H, J = 5.5 Hz, H-4), 2.62 (d,
1H, J = 4.1 Hz, H-4), 2.54 (dt, 2H, J = 4.7, 0.8 Hz, H-2), 2.24 (s, 3H,
CH3-Ar-4), 2.22 (s, 3H, CH3-Ar-2), 1.79 (m, 2H, H-3). 13CNMR d
(ppm) 202.3 (C@O), 150.8 (Ar-C-3), 138.2 (–CH2CH@CH2), 137.0
(Ar-C-1), 129.4 (Ar-C-6), 129.3 (Ar-C-5), 121.9 (Ar-C-2), 120.6
(Ar-C-4), 115.6 (–CH2CH@CH2), 43.9 (C-2), 37.3 (–CH2CH@CH2),
28.8 (C-4), 22.6 (C-3), 15.8 (CH3-4), 11.9 (CH3-4). ESI-HRMS Calcd
for (M+H+) C15H20O2: 233.1537; found, 233.1542.
These 4-aryl-butanals are important building blocks to
construct bioactive natural products or their analogs. As
an example of that, the methyl ether of compound 3a
had been previously prepared by Taber’s group as an inter-
mediate in (ꢀ)-astrogorgiadiol synthesis.13
Conclusions: We have developed an efficient synthetic
procedure (five steps, 42% average overall yield) to prepare
new substituted phenolic aldehydes by means of a protocol
of dearomatization by BAR methodology, and aromatiza-
tion in a further stage under basic conditions.
Acknowledgments
The authors wish to express their gratitude to UNR
´
(Universidad Nacional de Rosario) and Fundacion Prats.
This work was supported by CONICET (Consejo Nacional
´
´
de Investigaciones Cientıficas y Tecnicas) and ANPCYT
´
´
´
(Agencia Nacional de Promocion Cientıfica y Tecnica).
M.F.P. thanks CONICET and UNL (Universidad
Nacional del Litoral) for a fellowship.
12. Mander, L. N. Synlett 1991, 134–144.
13. Taber, D. F.; Malcolm, S. C. J. Org. Chem. 2001, 66, 944–
953.