Microwave-assisted ethylene-alkyne cross-metathesis: Synthesis of chiral 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes

Article abstract of DOI:10.1016/j.tetasy.2005.08.002

Chiral 1-arylpropargyl amides, which are resistant to undergoing ethylene-alkyne cross-metathesis at atmospheric pressure, were reacted under microwave irradiation to afford enantiomerically enriched 2-(N-1-acetyl-1- arylmethyl)-1,3-butadienes within a fe

Full text of DOI:10.1016/j.tetasy.2005.08.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2893–2896
Microwave-assisted ethylene–alkyne cross-metathesis: synthesis
of chiral 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes
Daniele Castagnolo, Michela L. Renzulli, Elena Galletti,
Federico Corelli and Maurizio Botta*
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, via A. Moro, 53100 Siena, Italy
Received 13 July2005; accepted 1 August 2005
Available online 26 August 2005
Abstract—Chiral 1-arylpropargyl amides, which are resistant to undergoing ethylene–alkyne cross-metathesis at atmospheric pres-
sure, were reacted under microwave irradiation to afford enantiomericallyenriched 2-( N-1-acetyl-1-arylmethyl)-1,3-butadienes
within a few minutes. Enantiomerically enriched amides underwent ethylene–alkyne cross-metathesis with retention of configuration
at the propargylic/allylic position. A series of chiral 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes were synthesised with ee P95%;
these latter compounds could be used as building blocks for the synthesis of new antifungal and antiaromatase agents.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
fungal and antiaromatase agents6 and in view of our
previous studies related to the synthesis of chiral syn-
thons of high enantiomeric purityuseful for the prepara-
tion of bioactive compounds in a non-racemic form,7 we
turned our attention to the synthesis of enantiomerically
enriched 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes 7 as
building blocks for the stereoselective synthesis of com-
pounds related to bifonazole 3, letrazole 4 and more
Enyne metathesis (EYM) is a bond reorganisation of an
alkene and an alkyne to give a 1,3-diene. It has been
used in both intramolecular and intermolecular applica-
tions.1 Intramolecular examples of alkyne–alkene
metathesis (enyne RCM) are well documented in the lit-
erature.2–4 Intermolecular enyne metathesis has seen
fewer synthetic applications because it has additional
difficulties when compared to the unimolecular one. Re-
cently, Mori et al.5a–c and Diver et al.5d–f developed an
approach to 1,3-butadienes byethlyene–alkyne cross-
metathesis using the first and second-generation GrubbsÕ
catalyst (Fig. 1).
complex antifungal azole derivatives such as
5
(Fig. 2).6a,b
Diene 7 was transformed via a Diels–Alder reaction, fol-
lowed byan oxidation–cyclisation, into 6. Compound 7
was obtained in enantiomericallyenriched form from
chiral 1-arylpropargyl amides 8 via ethylene–alkyne
cross-metathesis reaction (Scheme 1).
2. Results and discussion
Onlya few cases of enyne cross-metathesis with NH-
amides have been reported in the literature,8 in particu-
lar it has been reported that secondaryacetamides and
pivaloylamides undergo cross-metathesis with low yield
also in the presence of high GrubbsÕ catalyst loading. In
some cases, the metathesis reactions are problematic,
since the catalyst may be inhibited by the complex for-
mation properties of amines and amides, in the specific
case of amides, the catalyst may become inhibited by
intramolecular interaction with the carbonyl group.1d
Recently, Smulik and Diver investigated the ethylene
metathesis for 1-substituted-propargyl alcohols, these
substrates reacted poorly in ethylene–alkyne cross-
metathesis. In order to circumvent this problem, a high
In the context of our synthetic and molecular modelling
studies on racemic and enantiomericallypure new anti-
Mes
N
N Mes
PCy3
Ru CHPh
PCy3
Cl
Cl
Cl
Ru CHPh
PCy3
Cl
1 (Ru gen-1)
2 (Ru gen-2)
Figure 1.
*
Corresponding author. Tel.: +39 0577234306; fax: +39
0577234333; e-mail: botta@unisi.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.002

2894
D. Castagnolo et al. / Tetrahedron: Asymmetry 16 (2005) 2893–2896
Cl
NC
CN
O
N
N
N
N
N
N
N
3
4
5
Figure 2.
R
R'
R
R
N
X
NHCOCH3
NHCOCH3
N
6
7
8
X = CH, N
Scheme 1.
pressure of ethylene (60 psi) was used.5d,e Metathesis
reactions were carried out at room temperature or at
slightlyelevated temperature, sometimes requiring sev-
eral hours to achieve full conversion. Due to our previ-
ous experience in the field of microwave-assisted organic
reactions,9 we decided to circumvent the problem of
long reaction time and high pressure of ethylene, by car-
rying out the ethylene–alkyne metathesis reaction under
microwave irradiation.10 While several examples of
microwave-assisted diene ring closing metathesis and
diyne ring closing metathesis have been reported, to
the best of our knowledge, no microwave-assisted inter-
molecular EYM has been described.11
gyl acetamides (R)-8a–e were prepared bystereo-
selective amidation using acyl transfer reactions cataly-
sed by Candida antarctica lipase (CAL) of racemic
1-arylpropargylamines 9a–e,7 obtained after acidic
hydrolysis of racemic 8a–e. Enantiomericallypure
amines (S)-9a–e were converted into the corresponding
enantiopure acetamides (S)-8a–e byacetlyation with
acetic anhydride in the presence of triethylamine with
a retention of configuration at the propargylic position
(Scheme 2 and Table 1).
We initiallyinvestigated the reaction of 1-phen-
ylpropargylamide (R)-8a with ethylene at 1 atm using
different solvents and different temperatures. First- and
second-generation GrubbsÕ catalysts were used in differ-
ent loadings but in not one case were traces of diene (R)-
7a detected. Hence, we decided to investigate the reactiv-
ityof ( R)-8a with ethylene under microwave irradia-
tion.11 Microwave irradiation produces efficient
internal heating; this leads to a dramatic rate enhance-
ment of the metathesis reaction and to an increased cat-
alyst lifetime by the elimination of wall effects.12 The
results of the ethylene–alkyne metathesis of (R)-8a un-
der microwave irradiation are summarised in Table 2.
Bycarrying out the reaction in a closed vessel saturated
with ethylene, in toluene at 80 ꢁC with 5 mol % of 2 for
Herein, we report the synthesis of enantiomerically
enriched
2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes,
important building blocks for synthesis of potential
biologicallyactive compounds, via microwave-assisted
EYM between chiral 1-arylpropargyl amides and
ethylene.
Racemic 1-arylpropargyl amides 8a–e were prepared
according to our previous work via a Ritter reaction
of the corresponding propargyl alcohols, obtained by
the addition of ethynylmagnesiumbromide to the appro-
priate aldehydes.7 Enantiomericallypure 1-arylpropar-
R
R
R
R
CAL
AcOEt
HCl
+
NHCOCH3
NH2
NHCOCH3
NH2
(R)-8a-e
(S)-9a-e
8a-e
9a-e
R
R
(AcO)2O
Et3N
NHCOCH3
(S)-8a-e
NH2
(S)-9a-e
Scheme 2.

D. Castagnolo et al. / Tetrahedron: Asymmetry 16 (2005) 2893–2896
2895
(S)-7a–e were determined to have P95% ee byHPLC. 16
The enantiomeric excesses are reported in Table 3 as
well as the yields, the specific rotation and the HPLC
retention times.
Table 1. Chiral 1-arylpropargyl amides
20
D
b
R
eea (%)
½aŠ
(R)-8a
(R)-8b
(R)-8c
(R)-8d
(R)-8e
4-H
4-F
4-Cl
3-F
98
98
98
98
98
+61
+51
+81
+59
+58
Table 3. Enantioenriched 2-substituted butadienes
3-Me
20
c
a
R
eea
Yieldb
(%)
½aŠD ðcÞ
HPLC tR
(min)
(S)-8a
(S)-8b
(S)-8c
(S)-8d
(S)-8e
4-H
4-F
4-Cl
3-F
98
98
97
98
97
À60
À52
À78
À59
À57
4-H
4-F
4-Cl
3-F
(R)-7a
(R)-7b
(R)-7c
(R)-7d
(R)-7e
96
97
95
96
95
45
64
70
55
48
+34 (0.8)
+36 (1.0)
+69 (1.0)
+20 (0.6)
+35 (0.7)
56.6
67.2
52.4
67.8
39.4
3-Me
a Determined bychiral HPLC–MS using an ( S,S)-Whelk-O1 column
(50% water–methanol, 0.8 ml/min, UV-254).
b Measured in CHCl3 solution (c 1.0).
3-Me
4-H
4-F
4-Cl
3-F
(S)-7a
(S)-7b
(S)-7c
(S)-7d
(S)-7e
95
96
95
95
96
44
62
68
54
49
À30 (0.8)
À32 (1.0)
À65 (0.4)
À18 (0.6)
À37 (0.7)
58.9
84.9
59.4
72.4
42.1
Table 2. Reaction of (R)-8a with ethylene under microwave irradiation
3-Me
EntrySolvent
2 (mol %) T (ꢁC) Time (min) Yielda (%)
a Determined bychiral HPLC–MS using an ( S,S)-Whelk-O1 column
(50% water–methanol, 0.8 ml/min, UV-254).
b Referred to isolated and purified materials.
c Measured in CHCl3 solution.
1
2
3
4
Toluene
5
Toluene 10
Toluene 10
80
80
80
80
2 · 10
2 · 5
2 · 10
2 · 10
NR
NC
45
DCE
10
42
NR = no reaction; NC = not completed.
a Referred to isolated and purified materials.
3. Conclusion
In conclusion, a new methodologyfor the synthesis of
enantioenriched 2-substituted butadienes has been
developed. It has been shown that chiral 1-arylpropargyl
amides do not undergo cross-metathesis with ethylene at
atmospheric pressure; microwave irradiation is essential
to afford chiral 2-substituted butadienes within a few
minutes. Enantiomericallyenriched alkynes underwent
ethylene cross-metathesis with retention of configura-
tion at the propargylic/allylic position, making this
method suitable for preparing enantiomericallyenriched
dienes. This method is currentlybeing used to prepare
new potential biologicallyactive derivatives of general
structure 6.
20 min (two runs of 10 min) (entry1), no traces of diene
(R)-7a were detected and (R)-8a was fullyrecovered.
With a higher catalyst loading (10 mol % of 2) after
10 min (two runs of 5 min), HPLC–MS analysis of the
crude mixture revealed the formation of (R)-7a and of
a small amount of (R)-8a (entry2). Longer reaction
times resulted in better yields; no traces of (R)-8a could
be detected (entry3). After work-up with dimethylsulf-
oxide (DMSO),13 to remove ruthenium by-products
generated during the metathesis and purification by
chromatographyof the crude mixture, ( R)-7a was recov-
ered in 45% yield.14,15 With the intention of improving
the yield, we studied the effects of higher catalyst loading
and higher temperatures, but all our efforts proved
unsuccessful. The reaction of (R)-8a with ethylene in
dichloroethane, a solvent non-transparent to micro-
waves, was investigated, but no improvement in the
yield was observed (entry 4). On the basis of these data,
the conditions reported in entry2 were chosen to synthe-
sise a series of substituted enantioenriched 2-(N-1-ace-
tyl-1-phenylmethyl)-1,3-butadienes (R)-7a–e and (S)-
7a–e (Scheme 3). The dienyl derivatives (R)-7a–e and
Acknowledgements
FIRB (RBAU01LR5P) ÔDevelopement of a Common
Pharmacophore Model for Microtubule-stabilising
Anticancer Agents to be used to Design and Synthesise
Novel Paclitaxel MimicsÕ is gratefullyacknowledged.
M.B. thanks the Merck Research Laboratories for the
2004 Academic Development Program (ADP) Chemis-
tryAward.
R
R
H2C CH2
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Scheme 3.

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14. Characterisation of compound 7a: oil. 1H NMR (CDCl3):
d 7.47–7.26 (5H, m, Ph), 6.39–6.24 (1H, dd, J = 17.7 Hz,
J = 11.5 Hz, CCHCH2), 5.89 (1H, d, J = 7.9 Hz, CHN),
5.81 (1H, br d, J = 7.9 Hz, NH), 5.31 (1H, s, CCH2), 5.19
(1H, d, J = 17.7 Hz, CCHCH2), 5.09 (1H, s, CCH2), 5.05
(1H, d, J = 11.5 Hz, CCHCH2), 2.00 (3H, s, CH3). IR
(KBr): 1674, 1492 cmÀ1. ElectrosprayMS m/z: 202 (M+),
224 (M+Na).
15. General procedure for the synthesis of (R)-7a. Into an
oven-dried pressure vessel equipped with a magnetic
stirrer under argon, a solution of (R)-N-1-acetyl-1-aryl-
propynylamine (R)-8a (0.6 mmol) in 4 ml of drytoluene
was added. GrubbsÕ catalyst second-generation (10 mol %)
was then added and the mixture submitted to an ethylene
atmosphere under stirring. The vessel was introduced
into the microwave oven and heated at 80 ꢁC twice for
10 min under microwave irradiation. Dimethylsulfoxide
(DMSO) (50 equiv) was added and the reaction mixture
left under stirring for 12 h. The solvent was then removed
in vacuo to afford a dark brown oil that was purified by
flash chromatography(Et O–petroleum ether, 2:1) to give
2
(R)-7a as a clear oil.
16. Enantiomeric excesses of chiral (R)-7a–e and (S)-7a–e
were determined byHPLC–MS using an ( S,S)-Whelk-O1
column (50% water–methanol, 0.8 ml/min, UV-254).