Palladium-catalysed Heck reaction on 1,2-dien-1-ols: a stereoselective synthesis of α-arylated α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tet.2008.08.081

A new methodology for preparing α-arylated α,β-unsaturated aldehydes is reported. The starting materials are all commercially available alkyn-1-ols (1a-c) that have been easily isomerised to the corresponding allenes (2a-c). The key step is the Heck coupling of the 1,2-dien-1-ols with a series of iodo- and bromoarene. The products have been synthesised in good yields, and the reactions were carried out under very mild conditions.

Full text of DOI:10.1016/j.tet.2008.08.081

Tetrahedron 64 (2008) 10344–10349
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Palladium-catalysed Heck reaction on 1,2-dien-1-ols: a stereoselective
synthesis of
a-arylated a,b-unsaturated aldehydes
*
Annamaria Deagostino , Cristina Prandi, Antonio Toppino, Paolo Venturello
`
Dipartimento di Chimica Generale e Chimica Organica, Universita di Torino, Via Pietro Giuria 7, I-10125 Torino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2008
Received in revised form 8 August 2008
Accepted 27 August 2008
Available online 3 September 2008
A new methodology for preparing a-arylated a,b-unsaturated aldehydes is reported. The starting ma-
terials are all commercially available alkyn-1-ols (1a–c) that have been easily isomerised to the corre-
sponding allenes (2a–c). The key step is the Heck coupling of the 1,2-dien-1-ols with a series of iodo- and
bromoarene. The products have been synthesised in good yields, and the reactions were carried out
under very mild conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
and more prone to self-condensation through a Michael reaction.15
Furthermore, different methods have been developed to control the
a
-Arylated
a
,
b
-unsaturated aldehydes are widely diffused in
regioselectivity in the arylation or vinylation at the
-unsaturated ketones, in the -alkylation of lithium carboxylic
acids dienediolates with tosylates derived from both primary and
secondary alcohols and in the
-alkylation of copper dienolates.16
We decided to exploit the reactivity of allenes in Heck coupling;
these substrates easily undergo carbopalladation and are exten-
sively used for synthetic purposes.17,18 The pathway of this catalytic
process generally involves the attack of the aryl group at the central
g-position of
nature,1 and constitute interesting building blocks for the synthesis
of various natural products and their analogues.2,3 Previously they
have been prepared by the reaction of phenylacetaldehyde with
b,
g
a
g
acetaldehyde,3 from the corresponding
b,
g-unsaturated acetals
heated in the presence of formic acid,4 by the arylation of
a,b
-un-
saturated aldehydes with triaryl bismuth dichlorides(V),5 and by
the dehydration of secondary diols.6 Other methods exploit the
treatment of allylic nitro compounds with alkaline alcoxides,7 the
sp-carbon of the allene skeleton to give a
p-allylpalladium com-
8
hydroformylation of internal acetylenes by PdCl2(PCy3)2 and
plex intermediate. Then the attack of a nucleophile, mainly on
the less substituted terminus, yields the corresponding alkene. In
the thermolysis of the suitable adduct of piridinium salts with al-
lylic alcohol.9 To our knowledge, no general methods for the ster-
the absence of nucleophiles,
b-H elimination occurs, and gives
eoselective preparation of
a-arylated a,b-unsaturated aldehydes
2-substituted-1,3-dienes.19
have been proposed in the literature. In previous years we have
developed the synthesis of functionalised 1-ethoxybuta-1,3-dienes
2. Results and discussion
starting from a,b-unsaturated acetals in the presence of the mixed
lithium–potassium Schlosser’s superbase LIC-KOR,10,11 and more
recently we have exploited the reactivity of these derivatives
as valuable substrates for the Heck reaction,12 in order to prepare
In this paper, we wish to report the results obtained from
studies on the Heck cross-coupling arylation of protected 1,2-di-
enes-1-ols. The dienols were synthesised by the reaction of the
protected alkynes 1a–c with 3 equiv of BuLi, as shown in Scheme 1.
As expected, when the reaction is carried out on internal alkynes it
leads to an equilibrium mixture of propargyl and allenyl ethers.20
Moreover, in the case of THP-protected allenols, the obtained
g
-arylated
stereoselective manner.13 We are, at the present time, interested in
developing a new method for the synthesis of the -arylated
regioisomers exploiting the Heck reaction. It is known that the
arylation of -unsaturated aldehydes mainly produces the
-arylated isomer, in competition with the conjugate addition ad-
ducts.14 Moreover, the palladium-catalysed
-arylation of carbonyl
a,b-unsaturated carbonyl compounds in a regio- and
a
a,b
b
R
OR1
BuLi
a
THF, –78 °C, 2 h
R
OR1
compounds cannot be applied to conjugated unsaturated de-
rivatives, because dienolates are less nucleophilic than enolates,
1
2
1a: R = Me, R1 = THP
1b: R = n-Pr, R1 = THP
1c: R = Me, R1 = EtOCH2
2a: R = Me, R1 = THP (60%)
2b: R = n-Pr, R1 = THP (77%)
2c: R = Me, R1 = EtOCH2 (66%)
* Corresponding author. Tel.: þ390116707075; fax: þ390116707642.
E-mail address: annamaria.deagostino@unito.it (A. Deagostino).
Scheme 1. Isomerisation reaction of alkynes to allenes in presence of BuLi.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.081

A. Deagostino et al. / Tetrahedron 64 (2008) 10344–10349
10345
diastereoisomers were not separated and the mixture was used in
the subsequent Heck coupling (Scheme 2). This is because the
newly produced stereocenter does not affect the reaction outcome,
and is lost in the formation of the cross-coupled product.
(Bu4NþBrꢀ) as an ionic liquid suppressed the reaction. Among the
catalysts only Pd(OAc)2 was efficacious, we decided to utilise
a 2 mol % solution instead of a 5% one, also if in the latter case the
yield was slightly better, in an attempt to lower the catalyst loading.
On the other hand, the reaction also proceeded using 1% Pd(OAc)2,
but the outcome was less satisfactory. The identity of the protecting
group did not affect the coupling result (compare entries 8 and 12).
The experimental conditions that were selected for PhI were
modified in order to achieve satisfactory results using PhBr: only
the use of Pd(OAc)2 (5%) and PPh3 (10%), in DMSO, in the presence
of NaAcO as the base, ensured the formation of (E)-2-phenylbut-2-
enal (5a) in good yield (compare entries 14, 15 and 17).
PdX
Pd cat.
PhX
+
OR
solvent, base
OR1
Ph
3
X = Br, I
2a, 2c
β - elim.
OR
O
We applied the optimised reaction conditions to several aryl
halides and 1,2-allenols. The coupling reaction is shown in Scheme
3 and the results are listed in Table 2.
Ph
4
Ph
5
Scheme 2. Heck reaction of PhBr and PhI and allenols 2a and 2c to give (E)-2-phe-
nylbut-2-enal (5).
Pd(OAc)2,(PPh3),
R
NaOAc
R
O
ArX
+
T = 90 °C, DMSO
In order to optimise the experimental conditions for the Heck
cross-coupling, allenols 2a and 2c were reacted with iodo- or
bromobenzene using different solvents and bases, altering the
identity and the quantity of the catalyst, and finally exploiting
different protecting groups for the hydroxyl function. The results
are collected in Table 1.
OTHP
2a: R = H
Ar
5
X = Br, I
2c: R = Et
5a: R = H, Ar = Ph
5i: R = H, Ar = p-HOC6H4
5j: R = Et, Ar = 3-Py
5k: R = H, Ar = p-HCOC6H4
5l: R = Et, Ar = p-HCOC6H4
5b: R = Et, Ar = p-MeOC6H4
5c: R = Et, Ar = p-MeCO2C6H4
5d: R = H, Ar = m-MeC6H4
5e: R = H, Ar = o-MeC6H4
5f: R = H, Ar = p-MeOC6H4
5g: R = H, Ar = o-MeOC6H4
5h: R = H, Ar = 1-Np
A possible reaction mechanism is proposed in Scheme 2, where
the key step involves the addition of the phenyl group to the
5m: R = Et, Ar = p-MeCOC6H4
5n: R = Et, Ar = m-MeC6H4
5o: R = H, Ar = 2-Np
sp-carbon of the 1,2-diene 2 and affords the intermediate
palladium complex 3. Subsequently the -H elimination step leads
to the conjugate diene 4 (not isolated) that undergoes hydrolysis
affording the corresponding -arylated -unsaturated aldehyde 5.
p-allyl-
5p: R = Et, Ar = p-MeC6H4
b
Scheme 3. Heck couplings of aryl halides and allenols 2a and 2c to afford
-unsaturated aldehydes (5a–q).
a-arylated
a,b
a
a,b
The hydrolysis reaction takes place during the aqueous work-up
of the reaction mixture. As a matter of fact, the cross-coupling re-
action was carried out under anhydrous conditions, and moreover,
any attempt to isolate intermediate 4, or to obtain the corre-
sponding acetal derivative carrying out the reaction using anhy-
drous methanol as the solvent, was unsuccessful.
All the reactions were carried out in the presence of a 2:1 ratio of
1,2-allen-1-ol, with respect to the halobenzene, owing to its ther-
mal and chemical instability. Among the bases that we tested,
NaOAc gave the best results (entry 4), also anhydrous and aqueous
K2CO3 and TBAA (Bu4NþAcOꢀ) afforded comparable yields (entries
2 and 6). In the presence of Et3N (entry 3), the coupling reaction
was slower and the yield lower. DMSO gave better results in com-
parison to DMF (compare entry 4 with entry 6). The use of TBAB
The cross-coupling reactions have been accomplished using
various substituted iodo- and bromoarene that differ in the posi-
tion and the electronic features of the substituents. The reactions
proceed in a regio- and stereoselective way, and the (E) configu-
ration of the newly formed carbon–carbon double bond was de-
duced, when possible, by a NOESY experiment in which a negative
correlation spot between the aldehydic Hb and the vinylic proton
Ha, shown in Figure 1, is observed.
The outcome of the cross-coupling reactions turns out to be
strongly influenced by steric effects, as observed in the case of
o-halo derivatives that produce the corresponding
-unsaturated aldehydes (5f and 5g) in lower yields with respect
to the corresponding p- and m-derivatives. Moreover, the electronic
a-arylated
a,b
Table 1
Heck reaction of PhX and allenols 2a and 2c to give (E)-2-phenylbut-2-enal (5)a
Entry
PhX
Allen-1-ol
Base
Catalyst (%)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhBr
PhBr
PhI
PhBr
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2c
2a
2a
2a
2a
2a
K2CO3 (anhydrous)
K2CO3 (aqueous)
Et3N
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
TBAA
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
NaAcO (anhydrous)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Pd(OAc)2 (1)
Pd(PPh3) (1)
DMSO
DMSO
DMSO
DMSO
TBAB
0.5
0.5
3
0.5
16
6
0.5
0.75
0.75
1
0.75
1
70
72
55
80
Trace
65
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
68
74
9
65
10
11
12
13
14
15
16
17
0c
Pd(dba)2 (1)
0
75
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)/PPh3 (4)
Pd(OAc)2 (5)
Pd(OAc)2 (5)/PPh3 (10)
1
72d
Trace
Trace
30
16
16
16
16
68
a
Reaction conditions: PhX, 0.5 mmol, 2a or 2c 1.0 mmol, solvent 3 mL, base 0.5 mmol, T¼90 ꢁC.
Isolated products, purified by column chromatography.
Only PhI was recovered.
b
c
d
Reaction conditions: PhI, 0.5 mmol, diene 0.75 mmol, solvent 3 mL, base 0.5 mmol; unreacted PhI was recovered.

10346
A. Deagostino et al. / Tetrahedron 64 (2008) 10344–10349
Table 2
spectra at 50.2 MHz, in CDCl3. Data were reported as follows:
chemical shifts in parts per million from Me4Si as an internal
standard, integration, multiplicity, coupling constants (Hz) and
assignment. 13C NMR spectra were measured with complete proton
decoupling. Chemical shifts were reported in parts per million from
the residual pick solvent as an internal standard. GC–MS spectra
were obtained on a mass selective detector HP 5970 B instrument
operating at an ionising voltage of 70 eV connected to a HP 5890 GC with
Heck couplings of aryl halides and allenols 2a and 2b to afford
saturated aldehydes (5a–q)
a-arylated a,b-un-
Entry 1,2-Allen-1-ol Aryl halide
Product Time (h) E/Zc
Yieldd (%)
1
2
3
4
5
6
7
8
2a
2b
2b
2a
2a
2a
2a
2a
2b
2b
2a
2a
2b
2b
2b
2a
2a
PhI
PhI
5aa
5ba
5ca
5da
5ea
5fa
0.75
1
3
0.5
1
4
4.5
1.5
2
1
16
4
4
3
5
8
6
99:1 74
99:1 80
99:1 80
99:1 70
99:1 90
99:1 68
99:1 48
99:1 51
99:1 55
99:1 78
99:1 68
99:1 78
99:1 83
99:1 75
99:1 61
99:1 83
99:1 75
p-MeOC6H4I
p-MeO2CC6H4I
m-MeC6H4I
o-MeC6H4I
o-MeOC6H4I
1-NpI
p-HOC6H4I
3-IPy
PhBr
a cross-linked methyl silicone capillary column (25 mꢂ0.2 mmꢂ0.33
mm
5ga
5ha
5ia
film thickness). IR spectra were recorded on a Perkin Elmer BX
FT-IR.
9
10
11
12
13
14
15
16
17
5ja
4.2. Procedure for the tetrahydropyranylation of alkynols21
5ab
5lb
p-HCOC6H4Br
p-HCOC6H4Br
5mb
In a 100 mL three-necked round bottom flask, the alkynol
(10.0 mmol) was dissolved in anhydrous CH2Cl2 (25 mL) at rt, then
DHP (1.5 equiv, 15.0 mmol, 1.26 g) followed by PPTS (0.1 equiv,
1.0 mmol, 0.25 g) were added. The reaction mixture was stirred
overnight at rt under Ar, then the solvent was partly evaporated.
The mixture was diluted with Et2O, then washed with brine
(2ꢂ20 mL), dried over K2CO3, filtered and evaporated under re-
duced pressure, to give the crude reaction product that was used in
the subsequent step without further purification.
p-MeCOC6H4Br 5nb
m-MeOC6H4Br
2-NpBr
p-MeC6H4Br
5ob
5pb
5qb
a
Reaction conditions: PhI 0.5 mmol, 2a or 2b 1.0 mmol, DMSO 3 mL, NaOAc
0.5 mmol, T¼90 ꢁC, Pd(OAc)2 2 mol %.
b
Reaction conditions: PhBr 0.5 mmol, 2a or 2b 1.0 mmol, DMSO 3 mL, NaOAc
0.5 mmol, T¼90 ꢁC, Pd(OAc)2 5 mol %, PPh3 10 mol %.
c
Determined by 1H NMR.
Isolated products, purified by column chromatography.
d
4.2.1. 2-(But-2-ynyloxy)tetrahydro-2H-pyran (1a)
Pale yellow oil (1.43 g, 93%). Spectral data correspond to those
reported in the literature.22
effects of the substituents appear to be important when aryl bro-
mides are used as the arylating agent, and electron withdrawing
substituents increase the yield of the reaction (compare entries 11,
12 and 13).
4.2.2. 2-(Hex-2-ynyloxy)tetrahydro-2H-pyran (1b)
Pale yellow oil (1.80 g, 99%) that was at once used for the fol-
lowing reactions. Found C, 72.65; H, 9.92%. Calcd for C11H18O2:
C, 72.49; H, 9.95%. nmax (neat)/cmꢀ1 2943, 2250, 1728, 1054, 733. dH
(200 MHz; CDCl3, Me4Si) 0.94 (3H, t, J¼7.1 Hz, CH3), 1.25–1.80 (8H,
m, CH2), 2.12–2.21 (2H, m, CH2CC), 3.30–3.62 (1H, m, CHaO), 3.72–
3.95 (1H, m, CHbO), 4.05–4.54 (2H, m, CH2O), 4.74 (1H, br s, OCHO);
dC (50.2 MHz; CDCl3, Me4Si) 13.12 (1ꢂq), 18.80 (1ꢂt), 20.46 (1ꢂt),
21.74 (1ꢂt), 25.13 (1ꢂt), 29.98 (1ꢂt), 54.18 (1ꢂt), 61.50 (1ꢂt), 75.60
(1ꢂs), 86.01 (1ꢂs), 96.13 (1ꢂd). MS (EI, 70 eV): m/z (%)¼153 (2)
[MþꢀC2H5], 85 (100), 79 (94), 67 (54), 55 (59).
3. Conclusions
In summary, we have developed a new synthetic route that
allows the synthesis of a series of
a-arylated a,b-unsaturated
aldehydes starting from protected 1,2-diene-1-ols, exploiting
a Pd(0)-catalysed cross-coupling reaction. The reaction is regio-
and stereoselective, and moreover, experimental conditions turn
out to be very mild: in the case of aryl iodides, phosphines are not
required while with aryl bromides the cheap and easy available
triphenylphosphine is indispensable.
4.2.3. Synthesis of 1-(ethoxymethoxy)but-2-yne (1c)
4. Experimental
4.1. General
In a 100 mL three-necked round bottom flask, 2-butyn-1-ol
(10.0 mmol, 0.71 g) was dissolved in anhydrous CH2Cl2 (25 mL) and
cooled to 0 ꢁC, then Et(i-Pr)2N (2.0 equiv, 20.0 mmol, 3.48 mL) fol-
lowed by MeOCH2Cl (1.9 equiv, 19.0 mmol, 1.77 mL) were added.
The reaction mixture was stirred overnight at rt under Ar, then
a 20 mL of a solution of aqueous NaHCO3 (10%) was added. The
mixture was extracted with CH2Cl2 (2ꢂ20 mL), then washed with
aqueous HCl (5%, 1ꢂ20 mL) and H2O (1ꢂ20 mL), dried (K2CO3) and
evaporated under reduced pressure, affording 1.16 g (90%) of a pale
yellow oil. Found C, 65.78; H, 9.45%. Calcd for C7H12O2: C, 65.60; H,
9.44%. dH (200 MHz; CDCl3, Me4Si) 1.20 (3H, m, CH2CH3), 1.84 (3H,
m, CCCH3), 3.59 (2H, m, CCCH2O), 4.15 (2H, m, OCH2CH3), 4.73 (2H,
m, OCH2OCH2CH2); dC (50.2 MHz; CDCl3, Me4Si) 3.0 (1ꢂq), 14.7
(1ꢂq), 54.2 (1ꢂt), 63.0 (1ꢂt), 74.4 (1ꢂt), 81.5 (1ꢂs), 92.8 (1ꢂs). MS
(EI, 70 eV): m/z (%)¼83 (16) [MþꢀC2H5O], 69 (34), 59 (16), 54 (36),
53 (100).
Flasks and all equipments used for the generation and reaction
of moisture-sensitive compounds were dried by electric heat gun
under Ar. THF and CH2Cl2 were distilled from sodium benzophe-
none ketyl and CaH2, respectively. BuLi (1.6 M in hexanes) was
obtained from Aldrich. All commercially obtained reagents and
solvents were used as received. Products were purified by pre-
parative column chromatography on Macherey Nagel silica-gel for
flash chromatography, 0.04–0.063 mm/230–400 mesh.
Reactions were monitored by TLC using silica-gel on TLC-PET
foils Fluka, 2–25 mm, layer thickness 0.2 mm, medium pore di-
ameter 60 Å. 1H NMR spectra were recorded at 200 MHz, 13C NMR
4.3. General procedure for the isomerisation of alkynes
to allenes
Ha Hb
O
In a Schlenk vessel alkynol (10.0 mmol) was dissolved in anhy-
drous THF (20 mL) and cooled to ꢀ95 ꢁC, then n-BuLi (3.0 equiv,
30.0 mmol, 18.7 mL) was added. The reaction mixture was stirred
for 2 h at ꢀ95 ꢁC, then a solution of THF/H2O was added (20 mL).
The mixture was extracted with Et2O (2ꢂ20 mL), then washed with
R
Figure 1.

A. Deagostino et al. / Tetrahedron 64 (2008) 10344–10349
10347
brine (2ꢂ20 mL), dried (K2CO3), filtered and evaporated under re-
4.4.3. (E)-2-(4-Methoxyphenyl)hex-2-enal (5c)
duced pressure.
EP/EE 90:10, 1% Et3N. Pale yellow oil (90 mg, 88%). Found C,
76.20; H, 7.89%. Calcd for C13H16O2: C, 76.44; H, 7.90%. nmax (neat)/
cmꢀ1 3358, 3041, 1694, 1032, 805. dH (200 MHz; CDCl3, Me4Si) 0.94
(3H, t, J¼7.6, CH3), 1.56 (2H, sext, J¼7.4, CH3CH2), 2.39 (2H, q, J¼7.4,
CH2CH2), 3.83 (3H, s, OCH3), 6.69 (1H, t, J¼7.4, CH]C), 6.94 (2H, d,
J¼8.8, Ar), 7.12 (2H, d, J¼8.8, Ar), 9.64 (1H, s, CHO); dC (50.2 MHz;
CDCl3, Me4Si) 13.6 (1ꢂq), 22.0 (1ꢂt), 31.6 (1ꢂt), 55.0 (1ꢂq), 113.5
(1ꢂd), 124.5 (2ꢂd), 130.5 (2ꢂd), 143.3 (1ꢂs), 156.0 (1ꢂd), 159.0
(1ꢂs), 194.0 (1ꢂd). MS (EI, 70 eV): m/z (%)¼204 (100) [Mþ], 148
(75), 147 (70), 134 (51), 115 (62).
4.3.1. 2-(Buta-1,2-dienyloxy)tetrahydro-2H-pyran (2a)
EP/EE 98:2, 1% Et3N; diastereomeric mixture 60:40. Pale yellow
oil (0.92 g, 60%). Found C, 69.91; H, 9.14%. Calcd for C9H14O2: C, 70.10;
H, 9.15%. nmax (neat)/cmꢀ1 2945, 1961, 1730, 1119, 749. dH (200 MHz;
CDCl3, Me4Si) 1.20–195 (9H, m, (CH2)3CH3), 3.55 (1H, m, CHaO), 3.95
(1H, m, CHbO), 4.95 (1H, br s, OCHO), 5.65 (1H, m, CH3CHC]CCH),
6.55 (1H, m, CH3CHC]CCH); dC (50.2 MHz;CDCl3, Me4Si) 16.4 (1ꢂq),
16.5 (1ꢂq), 18.4 (2ꢂt), 24.9 (2ꢂt), 29.5 (2ꢂt), 61.5 (2ꢂt), 97.0 (2ꢂd),
99.7 (1ꢂd), 99.8 (1ꢂd), 116.4 (1ꢂd), 116.5 (1ꢂd), 194.4 (1ꢂs), 194.7
(1ꢂs). MS (EI, 70 eV): m/z (%)¼154 (2) [Mþ], 85 (100), 67(25), 57 (31),
55 (18); 154 (2) [Mþ], 85 (100), 67 (30), 57 (32), 55 (20).
4.4.4. (E)-Methyl 4-(1-oxobut-2-en-2-yl)benzoate (5d)
EP/EE 70:30, 1% Et3N. Pale yellow oil (71 mg, 70%). Found C,
70.80; H, 5.91%. Calcd for C12H12O3: C, 70.60; H, 5.92%. nmax (neat)/
cmꢀ1 3063, 2955, 1718, 1097. dH (200 MHz; CDCl3, Me4Si) 2.01 (3H,
d, J¼7.1, CH3), 3.92 (3H, s, OCH3), 6.91 (1H, q, J¼7.1, CH]C), 7.25 (2H,
d, J¼8.1, Ar), 8.08 (2H, d, J¼8.1, Ar), 9.61 (1H, s, CHO); dC (50.2 MHz;
CDCl3, Me4Si) 15.8 (1ꢂq), 52.0 (1ꢂq),129.3 (2ꢂd,1ꢂ s),129.4 (2ꢂd),
136.9 (1ꢂd), 144.1 (1ꢂs), 151.6 (1ꢂd), 166.6 (1ꢂs), 192.6 (1ꢂd). MS
(EI, 70 eV): m/z (%)¼204 (85) [Mþ], 145 (66), 117 (95), 116 (49), 115
(62).
4.3.2. 2-(Hexa-1,2-dienyloxy)tetrahydro-2H-pyran (2b)
EP/EE 99:1, 1% Et3N; diastereomeric mixture 55:45. Pale yellow
oil (1.40 g, 77%). Found C, 72.49; H, 9.95%. Calcd for C11H18O2: C,
72.27; H, 9.94%. nmax (neat)/cmꢀ1 2957, 2874, 1959, 1203. dH
(200 MHz; CDCl3, Me4Si) 0.93 (3H, t, J¼7.2, CH3), 1.42–2.12 (10H, m,
(CH2)3), 3.54 (1H, m, CHaO), 3.85 (1H, m, CHbO), 4.92 (1H, br s,
OCHO), 5.79 (1H, sext, J¼6.4, CH3CHC]CCH), 6.55 (1H, m,
CH3CHC]CCH); dC (50.2 MHz; CDCl3, Me4Si) 13.4 (2ꢂq), 18.5 (1ꢂt),
18.6 (1ꢂt), 21.4 (1ꢂt), 21.5 (1ꢂt), 25.0 (2ꢂt), 29.6 (2ꢂt), 32.7 (1ꢂt),
32.7 (1ꢂt), 61.5 (1ꢂt), 61.6 (1ꢂt), 96.9 (2ꢂd), 104.9 (1ꢂd), 105.0
(1ꢂd), 117.1 (1ꢂd), 117.2 (1ꢂd), 193.5 (1ꢂs), 193.8 (1ꢂs). MS (EI,
70 eV): m/z (%)¼182 (1) [Mþ], 85 (100), 67 (22), 57 (24), 55 (15); 182
(1) [Mþ], 85 (100), 67 (22), 57 (25), 55 (17).
4.4.5. (E)-2-m-Tolylbut-2-enal (5e)
EP/EE 95:5,1% Et3N. Pale yellow oil (72 mg, 90%). Found C, 82.44;
H, 7.54%. Calcd for C11H12O: C, 82.46; H, 7.55%. nmax (neat)/cmꢀ1
2923,1688, 1586, 791. dH (200 MHz; CDCl3, Me4Si) 2.01 (3H, d, J¼7.1,
CH3), 2.38 (3H, s, ArCH3), 6.80 (1H, q, J¼7.1, CH]C), 6.95–7.34 (4H,
m, Ar), 9.61 (1H, s, CHO); dC (50.2 MHz; CDCl3, Me4Si) 15.8 (1ꢂq),
21.3 (1ꢂq), 126.3(1ꢂd), 128.0 (1ꢂd), 128.5 (1ꢂd), 129.8 (1ꢂd), 132.0
(1ꢂs), 137.6 (1ꢂs), 145.0 (1ꢂs), 151.0 (1ꢂd), 193.4 (1ꢂd). MS (EI,
70 eV): m/z (%)¼160 (100) [Mþ], 117 (76), 116 (38), 115 (54), 91 (51).
4.3.3. 1-(Ethoxymethoxy)buta-1,2-diene (2c)
EP/EE 95:5, 1% Et3N. Pale yellow oil (0.84 g, 66%). Found C, 65.73;
H, 9.43%. Calcd for C7H12O2: C, 65.60; H, 9.44%. dH (200 MHz; CDCl3,
Me4Si) 1.20 (3H, m, CH2CH3), 1.76 (3H, m, CH3), 3.63 (2H, m, CH2O),
4.80 (2H, m, OCH2O), 5.74 (1H, m, CH3CHC]CCH), 6.53 (1H, m,
CH3CHC]CCH); dC (50.2 MHz; CDCl3, Me4Si) 14.8 (1ꢂq),16.6 (1ꢂq),
63.9 (1ꢂt), 93.3 (1ꢂt), 100.5 (1ꢂd), 117.0 (1ꢂd), 194.0 (1ꢂs). MS (EI,
70 eV): m/z (%)¼128 (6) [Mþ], 99 (34), 69 (38), 59 (100), 53 (38).
4.4.6. (E)-2-o-Tolylbut-2-enal (5f)
EP/EE 95:5, 1% Et3N. Pale yellow oil (54 mg, 68%). Found C,
82.45; H, 7.54%. Calcd for C11H12O: C, 82.46; H, 7.55%. nmax (neat)/
cmꢀ1 3061, 2816, 1689, 1635, 735. dH (200 MHz; CDCl3, Me4Si) 1.85
(3H, d, J¼7.0, CH3), 2.23 (3H, s, ArCH3), 6.95 (2H, m, CH]C, Ar),
7.22 (3H, m, Ar), 9.62 (1H, s, CHO); dC (50.2 MHz; CDCl3, Me4Si)
15.6 (1ꢂq), 19.4 (1ꢂq), 125.5 (1ꢂd), 128.0 (1ꢂd), 129.3 (1ꢂd), 129.9
(1ꢂd), 132.3 (1ꢂs), 136.2 (1ꢂs), 145.7 (1ꢂs), 151.3 (1ꢂd), 191.0
(1ꢂd). MS (EI, 70 eV): m/z (%)¼160 (62) [Mþ], 145 (70), 142 (55),
115 (90), 91 (100).
4.4. Typical procedure for the Heck couplings between
protected allenols and iodoarenes
Pd(OAc)2 (2 mol %, 0.010 mmol, 2.24 mg) was dissolved in an-
hydrous DMSO (3 mL) and the solution was degassed under Ar for
10 min at rt. Then NaAcO (0.5 mmol, 41 mg), iodoarene (0.5 mmol)
and allenol (1.0 mmol) were subsequently added. The reaction
mixture was stirred in a sealed tube at 90 ꢁC until the disappear-
ance of the allenol was observed by TLC and GC on a sample taken
and partitioned between Et2O and H2O. Then H2O was added and
the mixture was extracted with Et2O (2ꢂ20 mL), then washed with
brine (2ꢂ20 mL), dried (K2CO3), filtered and evaporated under re-
duced pressure.
4.4.7. (E)-2-(2-Methoxyphenyl)but-2-enal (5g)
EP/EE 90:10, 1% Et3N. Pale yellow oil (42 mg, 48%). Found C,
75.01; H, 6.85%. Calcd for C11H12O2: C, 74.98; H, 6.86%. nmax (neat)/
cmꢀ1 2940, 1687, 1492, 1246, 752. dH (200 MHz; CDCl3, Me4Si) 1.90
(3H, d, J¼7.0, CH3), 3.83 (3H, s, OCH3), 6.87–6.39 (3H, m, J¼7.1,
CH]C, Ar), 7.45–8.85 (2H, m, Ar), 9.80 (1H, s, CHO); dC (50.2 MHz;
CDCl3, Me4Si) 15.8 (1ꢂq), 55.3 (1ꢂq),110.9 (1ꢂd),120.3 (1ꢂd),121.5
(1ꢂs), 129.4 (1ꢂd), 130.8 (1ꢂd), 142.2 (1ꢂs), 150.9 (1ꢂs), 156.7
(1ꢂd), 192.9 (1ꢂd). MS (EI, 70 eV): m/z (%)¼176 (100) [Mþ], 131
(41), 119 (39), 115 (42), 91 (78).
4.4.1. (E)-2-Phenylbut-2-enal (5a)
EP/EE 90:10, 1% Et3N. Pale yellow oil (54 mg, 74%). The spectral
characterisation corresponded to those reported in the literature.23
4.4.8. (E)-2-(Naphthalen-1-yl)but-2-enal (5h)
4.4.2. (E)-2-Phenylhex-2-enal (5b)
EP/EE 80:20, 1% Et3N. White solid (49 mg, 51%). Found C,
85.89; H, 6.15%. Calcd for C14H12O: C, 85.68; H, 6.16%. Mp 89–
92 ꢁC. nmax (neat)/cmꢀ1 3044, 1675, 1638, 779. dH (200 MHz;
CDCl3, Me4Si) 1.83 (3H, d, J¼7.0, CH3), 7.19 (2H, m, CH]C, Ar),
7.53 (4H, m, Ar), 7.88 (2H, m, Ar), 9.60 (1H, s, CHO); dC
(50.2 MHz; CDCl3, Me4Si) 16.0 (1ꢂq), 124.8 (1ꢂd), 125.2 (1ꢂd),
125.7 (1ꢂd), 126.1 (1ꢂd), 127.2 (1ꢂd), 128.4 (2ꢂd), 130.4 (1ꢂs),
131.2 (1ꢂs), 133.5 (1ꢂs), 144.3 (1ꢂs), 152.5 (1ꢂd), 193.2 (1ꢂd).
MS (EI, 70 eV): m/z (%)¼196 (74) [Mþ], 167 (96), 165 (100), 153
(83), 152 (98).
EP/EE 90:10, 1% Et3N. Pale yellow oil (70 mg, 80%). Found C,
82.47; H, 8.11%. Calcd for C12H14O: C, 82.72; H, 8.10%. nmax (neat)/
cmꢀ1 3362, 3024, 1694, 728, 702. dH (200 MHz; CDCl3, Me4Si) 0.95
(3H, t, J¼7.3, CH3), 1.55 (2H, sext, J¼7.4, CH3CH2), 2.38 (2H, q, J¼7.5,
CH2CH2), 6.74 (1H, t, J¼7.5, CH]C), 7.18 (2H, m, Ar), 7.42 (3H, m, Ar),
9.63 (1H, s, CHO); dC (50.2 MHz; CDCl3, Me4Si) 13.6 (1ꢂq), 21.9
(1ꢂt), 31.5 (1ꢂt), 127.7 (1ꢂd), 128.0 (2ꢂd), 129.2 (2ꢂd), 132.5 (1ꢂs),
143.9 (1ꢂs), 156.3 (1ꢂd), 194.0 (1ꢂd). MS (EI, 70 eV): m/z (%)¼174
(100) [Mþ], 117 (62), 115 (65), 104 (61), 91 (60).

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A. Deagostino et al. / Tetrahedron 64 (2008) 10344–10349
4.4.9. (E)-2-(4-Hydroxyphenyl)hex-2-enal (5i)
4.5.4. (E)-2-(4-Acetylphenyl)hex-2-enal (5m)
EP/EE 50:50, 1% Et3N. Pale yellow oil (45 mg, 55%). Found C,
75.85; H, 7.41%. Calcd for C12H14O2: C, 75.76; H, 7.42%. nmax (neat)/
cmꢀ1 3369, 1672, 1611, 1516, 838. dH (200 MHz; CDCl3, Me4Si) 0.93
(3H, t, J¼7.3, CH3), 1.53 (2H, sext, J¼7.5, CH2CH3), 2.36 (2H, q, J¼7.5,
CH2), 5.93 (1H, br s, OH), 6.72 (1H, t, J¼7.5, CH]C), 6.81 (2H, d,
J¼8.6, Ar), 7.00 (2H, d, J¼8.6, Ar), 9.58 (1H, s, CHO); dC (50.2 MHz;
CDCl3, Me4Si) 13.6 (1ꢂq), 21.9 (1ꢂt), 31.7 (1ꢂq), 115.2 (2ꢂd), 123.9
(1ꢂs), 130.5 (2ꢂd), 143.5 (1ꢂs), 155.7 (1ꢂd), 157.2 (1ꢂs), 194.9
(1ꢂd). MS (EI, 70 eV): m/z (%)¼190 (100) [Mþ], 133 (44), 119 (44),
107 (32), 77 (34).
EP/EE 70:30, 1% Et3N. Pale yellow oil (81 mg, 75%). Found C,
77.71; H, 7.45%. Calcd for C14H16O2: C, 77.75; H, 7.46%. nmax (neat)/
cmꢀ1 2960, 1682, 1605, 1264, 958, 834. dH (200 MHz; CDCl3, Me4Si)
0.93 (3H, t, J¼7.4, CH3), 1.55 (2H, sext, J¼7.4, CH3CH2), 2.33 (2H, q,
J¼7.5, CH2CH2), 2.62 (3H, s, COCH3), 6.80 (1H, t, J¼7.6, CH]C), 7.26
(2H, d, J¼8.3, Ar), 8.00 (2H, d, J¼8.5, Ar), 9.62 (1H, s, CHO); dC
(50.2 MHz; CDCl3, Me4Si) 13.6 (1ꢂq), 21.8 (1ꢂt), 26.4 (1ꢂq), 31.6
(1ꢂt), 128.0 (2ꢂd), 129.6.1 (2ꢂd), 136.2 (1ꢂs), 137.5 (1ꢂs), 143.0
(1ꢂd), 157.1 (1ꢂs), 192.8 (1ꢂd), 197.6 (1ꢂs). MS (EI, 70 eV): m/z
(%)¼216 (100) [Mþ], 201 (57), 159 (86), 145 (32), 115 (54).
4.4.10. (E)-2-(Pyridin-3-yl)hex-2-enal (5j)
4.5.5. (E)-2-(3-Methoxyphenyl)hex-2-enal (5n)
EE, 1% Et3N. Pale yellow oil (68 mg, 78%). Found C, 75.62; H, 7.47;
N, 7.97%. Calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99%. nmax (neat)/
cmꢀ1 3031, 1686, 1024, 750, 717. dH (200 MHz; CDCl3, Me4Si) 0.93
(3H, t, J¼7.4, CH3), 1.55 (2H, sext, J¼7.4, CH3CH2), 2.35 (2H, q, J¼7.5,
CH2CH2), 6.83 (1H, m, J¼7.6, CH]C), 7.31 (1H, m, CHCHN), 7.52 (1H,
dt, J¼7.8, 1.9, CHCHCN), 8.40 (1H, dd, J¼2.1, 0.8, CCHN), 8.57 (1H, dd,
J¼4.9, 1.6, CHCHN), 9.62 (1H, s, CHO); dC (50.2 MHz; CDCl3, Me4Si)
13.6 (1ꢂq), 21.9 (1ꢂt), 31.6 (1ꢂt), 122.9 (1ꢂd), 128.3 (1ꢂs), 137.0
(1ꢂd), 140.6 (1ꢂd), 148.9 (1ꢂd), 149.8 (1ꢂs), 157.6 (1ꢂd), 192.8
(1ꢂd). MS (EI, 70 eV): m/z (%)¼175 (100) [Mþ], 118 (38), 117 (63),
105 (39), 104 (54).
EP/EE 70:30, 1% Et3N. Pale yellow oil (62 mg, 61%). Found C,
76.61; H, 7.89%. Calcd for C13H16O2: C, 76.44; H, 7.90%. nmax (neat)/
cmꢀ1 2959, 1688, 1578, 1038, 788, 721. dH (200 MHz; CDCl3, Me4Si)
0.94 (3H, t, J¼7.2, CH3), 1.55 (2H, sext, J¼7.4, CH3CH2), 2.33 (2H, q,
J¼7.4, CH2CH2), 3.81 (3H, s, OCH3), 6.72 (4H, m, CH]C, Ar), 6.89 (1H,
br d, J¼8.0, Ar), 7.32 (1H, br t, J¼8.0, Ar), 9.61 (1H, s, CHO); dC
(50.2 MHz; CDCl3, Me4Si) 13.6 (1ꢂq), 21.9 (1ꢂt), 31.5 (1ꢂt), 55.0
(1ꢂq), 113.2 (1ꢂd), 114.9 (1ꢂd), 121.6 (1ꢂd), 129.0 (1ꢂd), 133.9
(1ꢂs), 143.8 (1ꢂs), 156.1 (1ꢂd), 159.2 (1ꢂs), 193.4 (1ꢂd). MS (EI,
70 eV): m/z (%)¼204 (100) [Mþ], 148 (52), 147 (47), 115 (40), 91 (46).
4.5.6. (E)-2-(Naphthalen-2-yl)but-2-enal (5o)
4.5. Typical procedure for the Heck coupling between
protected allenols and bromoarenes
EP/EE 90:10, 1% Et3N. Yellow oil (81 mg, 83%). Found C, 85.93; H,
6.15%. Calcd for C14H12O: C, 85.68; H, 6.16%. nmax (neat)/cmꢀ1 3055,
2940,1683, 1628,1596, 749. dH (200 MHz; CDCl3, Me4Si) 2.06 (3H, d,
J¼7.1, CH3), 6.94 (1H, q, J¼7.2, CH]C), 7.28–7.92 (7H, m, Ar), 9.70
(1H, s, CHO); dC (50.2 MHz; CDCl3, Me4Si) 15.9 (1ꢂq), 125.9 (1ꢂd),
126.1 (1ꢂd), 127.0 (1ꢂd), 127.5 (1ꢂd), 127.6 (1ꢂd), 127.9 (1ꢂd),
128.6 (1ꢂd), 129.7 (1ꢂs), 132.7 (1ꢂs), 132.9 (1ꢂs), 144.8 (1ꢂs), 151.5
(1ꢂd), 193.4 (1ꢂd). MS (EI, 70 eV): m/z (%)¼196 (100) [Mþ], 168
(50), 167 (99), 165 (79), 152 (66).
Pd(OAc)2 (5%, 0.025 mmol, 5.6 mg) and PPh3 (10%, 0.05 mmol,
13 mg) were dissolved in anhydrous DMSO (3 mL) and degassed at
rt under Ar until the solution turned to purple. Then NaAcO
(0.5 mmol, 41 mg), the selected bromoarene (0.5 mmol) and the
allenol (1.0 mmol) were added. The reaction mixture was stirred in
a sealed tube at 90 ꢁC until the disappearance of the allenol spot
that was observed by TLC and GC on a sample taken and parti-
tioned between Et2O and H2O. H2O (5 mL) was added, and the
mixture was extracted with Et2O (2ꢂ20 mL), then washed with
brine (2ꢂ20 mL), dried (K2CO3), filtered and evaporated under
reduced pressure.
4.5.7. (E)-2-p-Tolylbut-2-enal24 (5p)
EP/EE 90:10, 1% Et3N. Pale yellow oil (60 mg, 75%). Found C,
82.16; H, 7.56%. Calcd for C11H12O: C, 82.46; H, 7.55%. nmax (neat)/
cmꢀ1 2921, 1685, 1632, 1514, 842, 818. dH (200 MHz; CDCl3, Me4Si)
2.06 (3H, dd, J¼7.1,1.4, CH3), 2.39 (3H, s, CH3), 6.83 (1H, qd, J¼7.0, 1.1,
CH]C), 7.08 (2H, d, J¼7.1, Ar), 7.23 (2H, d, J¼7.3, Ar), 9.62 (1H, br d,
J¼1.4, CHO); dC (50.2 MHz; CDCl3, Me4Si) 15.8 (1ꢂq), 21.1 (1ꢂq),
128.8 (2ꢂd), 129.0 (1ꢂs), 129.2 (2ꢂd), 137.5 (1ꢂs), 144.7 (1ꢂs),
150.8 (1ꢂd), 193.6 (1ꢂd). MS (EI, 70 eV): m/z (%)¼160 (100) [Mþ],
131 (61), 117 (69), 115 (77), 91 (74).
4.5.1. (E)-2-Phenylbut-2-enal (5a)
EP/EE 90:10, 1% Et3N. Pale yellow oil (50 mg, 68%). The spectral
characterisation corresponded to those reported in the literature.23
4.5.2. (E)-4-(1-Oxobut-2-en-2-yl)benzaldehyde (5k)
EP/EE 70:30, 1% Et3N. Pale yellow oil (68 mg, 78%). Found C,
75.65; H, 5.80%. Calcd for C11H10O2: C, 75.84; H, 5.79%. nmax (neat)/
cmꢀ1 3363, 2925, 1703, 1606, 842. dH (200 MHz; CDCl3, Me4Si) 2.03
(3H, d, J¼7.1, CH3), 6.95 (1H, m, J¼7.1, CH]C), 7.31 (1H, m, CHCHN),
7.37 (2H, d, J¼7.1, Ar), 7.93 (1H, d, J¼7.1, Ar), 9.63 (1H, s, CHO), 10.03
(1H, s, CHO); dC (50.2 MHz; CDCl3, Me4Si) 15.9 (1ꢂq), 129.4 (2ꢂd),
130.1 (2ꢂd), 135.5 (1ꢂs), 138.9 (1ꢂs), 143.0 (1ꢂs), 157.3 (1ꢂd), 191.7
(1ꢂd), 192.7 (1ꢂd). MS (EI, 70 eV): m/z (%)¼174 (44) [Mþ], 145 (27),
117 (63), 115 (100), 91 (43).
Acknowledgements
`
We thank the Ministero dell’Universita e della Ricerca (MIUR)
and the University of Turin for the financial support.
Supplementary data
1H and 13C spectra of products 5a–q. NOESY spectra of products
5f, 5j, 5o and 5q. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2008.08.081.
4.5.3. (E)-4-(1-Oxohex-2-en-2-yl)benzaldehyde (5l)
EP/EE 80:20, 1% Et3N. Pale yellow oil (84 mg, 83%). Found C,
76.97; H, 6.98%. Calcd for C13H14O2: C, 77.20; H, 6.98%. nmax (neat)/
cmꢀ1 2959, 1687, 1027, 840, 716. dH (200 MHz; CDCl3, Me4Si) 0.93
(3H, t, J¼7.3, CH3), 1.55 (2H, sext, J¼7.2, CH3CH2), 2.33 (2H, q, J¼7.5,
CH3), 6.82 (1H, m, J¼7.6, CH]C), 7.33 (2H, d, J¼7.2, Ar), 7.91 (2H, d,
J¼7.4, Ar), 9.62 (1H, s, CHO),10.03 (1H, s, CHO); dC (50.2 MHz; CDCl3,
Me4Si) 13.6 (1ꢂq), 21.8 (1ꢂt), 31.6 (1ꢂt), 129.3 (2ꢂd), 130.5 (2ꢂd),
135.5 (1ꢂs), 138.9 (1ꢂs), 143.0 (1ꢂs), 157.3 (1ꢂd), 191.7 (1ꢂd), 192.7
(1ꢂd). MS (EI, 70 eV): m/z (%)¼202 (100) [Mþ], 131 (40), 117 (48),
115 (71), 91 (52).
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