Unexpected dehydrogenation products in the furan series arising from ruthenium-catalyzed 4-oxo-1,6-enyne metathesis

Article abstract of DOI:10.1081/SCC-200058011

Metathesis of 4-oxo-1,6-enynes afforded the usual dihydrofuran products accompanied for the first time by unexpected side products identified as the corresponding furans. It probably arose from ruthenium-catalyzed dehydrogenation of dihydrofurans in the m

Full text of DOI:10.1081/SCC-200058011

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Unexpected Dehydrogenation
Products in the Furan
Series Arising from
Ruthenium‐Catalyzed
4
‐Oxo‐1,6‐enyne Metathesis
a a a
Laurent Evanno , Bastien Nay & Bernard Bodo
a
Laboratoire de Chimie et Biochimie des Substances
Naturelles , UMR 5154 CNRS, Muséum National
d'Histoire Naturelle , Paris, France
Published online: 17 Dec 2010.
To cite this article: Laurent Evanno , Bastien Nay & Bernard Bodo (2005) Unexpected
Dehydrogenation Products in the Furan Series Arising from Ruthenium‐Catalyzed
4
‐Oxo‐1,6‐enyne Metathesis, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:11, 1559-1565, DOI:
0.1081/SCC-200058011
1
To link to this article: http://dx.doi.org/10.1081/SCC-200058011
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Synthetic Communications , 35: 1559–1565, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200058011
Unexpected Dehydrogenation Products
in the Furan Series Arising from
Ruthenium-Catalyzed 4-Oxo-1,6-enyne
Metathesis
Laurent Evanno, Bastien Nay, and Bernard Bodo
Laboratoire de Chimie et Biochimie des Substances Naturelles,
UMR 5154 CNRS, Mus e´ um National d’Histoire Naturelle, Paris, France
Abstract: Metathesis of 4-oxo-1,6-enynes afforded the usual dihydrofuran products
accompanied for the first time by unexpected side products identified as the corre-
sponding furans. It probably arose from ruthenium-catalyzed dehydrogenation of
dihydrofurans in the metathesis reaction mixture.
Keywords: Aromatization, dehydrogenation, enyne metathesis, furan
INTRODUCTION
Ring-closing enyne metathesis (RCEYM) is an intramolecular bond reorgan-
ization of an alkene and an alkyne (I) to produce a cyclic 1,3-diene II
[
1]
(
Scheme 1). This reaction catalyzed by Grubbs’ ruthenium complexes 1
and 2 has been applied to the short synthesis of unsaturated heterocycles,
[
especially azacyclic and oxacyclic dienes, which are useful synthons
2]
[3]
[
1,4]
in the synthesis of more complex heterocycles. Herein, we report an un-
expected dehydrogenation product arising from our attempts to prepare
oxacyclic dienes of type II (X ¼ O).
Received in the UK December 13, 2004
Address correspondence to Bastien Nay, Laboratoire de Chimie et Biochimie des
Substances Naturelles, UMR 5154 CNRS, Mus e´ um National d’Histoire Naturelle, 63
rue Buffon, 75005 Paris, France. Tel.: þ33 (0)1 40 79 56 09; Fax: þ33 (0)1 40 79
3
1 35; E-mail: bnay@mnhn.fr
1
559

1560
L. Evanno, B. Nay, and B. Bodo
Scheme 1. The general ring-closing enyne metathesis reaction and the metathesis
catalysts 1 and 2 (framed).
RESULTS AND DISCUSSION
In the course of our work toward the synthesis of natural products, we
envisaged to use RCEYM to form dihydrofuran building blocks from
4
-oxo-1,6-enynes in the presence of the first generation Grubbs’ catalyst
1). Enyne 4a (Scheme 2) was synthesized in five sequential steps and 45%
(
overall yield from butan-1,4-diol (3),
[
5,6]
and was also brominated into 4b
(
PPh /CBr ) in 78% yield after deprotection of the hydroxyl.
3 4
The metathesis step proceeded in the presence of catalyst 1 in refluxing
dichloromethane and under an atmosphere of ethylene, affording the dihydro-
furans 5a, b and side products 6a, b and 7a, b (63% and 87% global yields in
the O-silylated and brominated series, respectively). Neither the O-silylated
nor the brominated products 5a, b; 6a, b; and 7a, b were separable by chroma-
tography at this stage. It is worthy of note that the formation of the side
products, especially 7, proved to be uncertain and appeared to us unpredic-
table, so we tried to investigate it.
RCEYM of compound 4a was also attempted in the presence of the second
generation Grubbs’ catalyst 2 (Scheme 3). As expected and according to the
[
4b]
results obtained by Mori et al., two major products were isolated: the dihy-
drofuran 5a (56% yield) and the isomeric exo-methylene dihydropyran 8
Scheme 2. Synthesis of dihydrofuran derivatives 5a, b from enynes 4a, b and side
products (6a, b; 7a, b) observed during metathesis.

Dehydrogenation Products from Enyne Metathesis
1561
Scheme 3. RCEYM of enyne 4a with catalyst 2.
(33%). Moreover, traces of the cyclopropane derivative 6a were also observed
by mass spectrometry, but no dehydrogenated product 7a in this case.
In all these metathesis reactions, cyclopropane side products 6a, b were
only present in about 10% of the mixture (quantity limited by the amount of
catalyst) and were mainly observed by mass spectrometry, showing an extra
methylene group, and by NMR spectroscopy, showing residual peaks charac-
teristic of the cyclopropane moiety in the high fields. Such products have
[
2]
already been described by Mori et al. in the pyrrolidine series and could
be formed by reductive elimination of the ruthenium complex RuCl (PCy3)2
2
from the ruthenacyclobutane intermediate 9 occurring in the catalytic cycle.
They were always observed in our experiments and the cyclopropane deriva-
tive 12 could be fully characterized after deprotection of 6a (Scheme 4).
In the case of the reactions with the first generation Grubbs’ catalyst (1),
the other side products (7a, b) were surprisingly identified as furan derivatives
1
13
by H NMR, C NMR, and mass spectrometry. As for compound 6a, furan 7a
was characterized after deprotection of the silylated hydroxyl group of the
product mixture from metathesis of enyne 4a (Scheme 4). Indeed, subsequent
separation by silica-gel chromatography gave the labile compound 10 (53%,
overall yields from enyne 4a) and the pure furan derivative 11 (4%), along
with cyclopropane 12 (6%). It is important to mention that some furan-free
samples of dihydrofuran 5a yielded up to 34% of furan 11 after desilylation
that was later attributed to residual contamination by dehydrogenating
catalyst derivatives.
Scheme 4. Deprotection of the unseparable metathesis mixture from 4a to obtain
separable products 10, 11, and 12.

1562
L. Evanno, B. Nay, and B. Bodo
Interestingly, when the reaction time of enyne 4a metathesis was increased
6 days without more catalyst loading), the quantity of furan 7a was magnified,
(
leading to a ca. 2 : 1 mixture of 5a and 7a, respectively, and giving 43% of
compound 10 and 25% of 11 after deprotection and purification of the
1
mixture (yields from enyne). The H NMR spectrum of derivative 11 clearly
showed the characteristic signals of the furan ring at 6.17 and 7.31 ppm.
The formation of furan compounds (7) when using the first generation
catalyst 1 was all the more surprising because, to our knowledge, side
reactions involving dehydrogenation had yet never been described during
metathesis reactions of oxo-derivatives. Some examples were reported in
the pyrroline series and the pyrrole side products could not be formed in
more than 30% yield, unless a dehydrogenation catalyst (RuCl ꢀ H O)
3
2
[7a]
[7b,c]
was added.
This report and others
in the aza series mentioned that
excessive heating might be responsible for the formation of the dehydro-
genated products and that the presence of a basic amino group could favor
this reaction. Indeed, we made observations in the same way, as overheating
seemed to favor the formation of the furan.
Neither spontaneous oxidation of the dihydrofuran 5a in refluxing
dichloromethane (air atmosphere) nor its dehydrogenation in the presence
of fresh Grubbs’ catalyst 1 and under ethylene atmosphere was possible.
Thus, dehydrogenation must happen in the reaction mixture during enyne
metathesis and could be catalyzed by a product of decomposition of
the catalyst or of a catalytic intermediate resulting from excessive heating.
The separation of the products from the ruthenium species usually proved
to be difficult. As mentioned, we observed that in the case of purified but
still catalyst-contaminated dihydrofuran 5a, the furan 7a was readily formed
during the desilylation step; that could be consistent with the fact that
[
7a]
basicity favors this reaction.
As usual, elimination of all ruthenium
contaminants after the metathesis steps is therefore very important.
The observation of cyclopropane side products led us to envisage a
mechanism of dehydrogenation involving the ruthenium(II) complex
RuCl (PCy ) which may result from reductive elimination from intermediate
2
3 2
[2a]
9
.
Some authors recently showed that this complex could also be formed by
[
8]
decomposition of the catalyst. We then tried to transform the dihydrofuran
a in the presence of the related catalyst RuCl (PPh ) , but no reaction could
5
2
3 3
be observed. Even so, this experiment does not rule out the involvement of
RuCl (PCy ) .
Metathesis catalysts or derivatives are well known to give rise occasion-
2
3 2
[
9]
ally to olefin isomerization that has been useful in the development of new
[
10]
tandem reactions to synthesize cyclic enol ethers.
or decomposition has been suspected by several authors in this process.
Particularly, hydridoruthenium species would be involved in these trans-
Catalyst transformation
[11]
[10,12]
formations. For instance, the formation, isolation, and catalytic
activity of ruthenium dihydride complex RuCl (PCy ) (H) has been
2
3 2
2
[
13]
discussed by F u¨ rstner et al.
Other authors showed that upon treatment

Dehydrogenation Products from Enyne Metathesis
1563
with alcohols, catalysts 1 and 2 decompose into hydridocarbonyl–chloride
complex RuCl(L) (CO)(H) [L ¼ ligands] with high catalytic activ-
2
[10a,11b,11c,12]
ities.
isomerization. Grubbs recently isolated a diruthenium complex originated
A number of these complexes are able to catalyze olefin
[11d]
from thermal decomposition of the second-generation complex 2.
already mentioned, RuCl (L) complexes can be formed either from
As
2
2
ruthenacyclobutane
followed by dealkylidenation in a substrate-induced catalyst decompo-
9 or from ligand exchange (PCy /CH 55 CH )
3 2 2
[8]
sition. On the other hand, several transition-metal complexes [in particular
RuCl (PPh ) ] have been reported to be effective catalysts for the hydrogen-
2
3 3
ation of dihydrofurans under an atmosphere of hydrogen, but also as isomer-
ization catalysts or more remarkably as disproportionation catalysts under an
inert atmosphere, giving rise to equimolar amounts of furan and tetrahydro-
[
14]
furan derivatives.
ation from alcohols to ketones.
Complex 1 itself is able to catalyze transfer hydrogen-
[
15]
In our case, neither a tetrahydrofuran
derivative possibly arising from disproportionation nor olefin isomerization
could be observed.
In Scheme 5, we propose a mechanism for the dehydrogenation that could
be promoted by a ruthenium(II) species, maybe RuCl (PCy ) . After ligand
2
3 2
exchange, the dihydrofuran compound would be engaged in the ruthenium(II)
complex (A). Allylic insertion of ruthenium would lead to a transient p-allyl-
hydridoruthenium(IV) intermediate (B) in equilibrium with (C). Reductive
elimination of ruthenium from intermediate (C) would then lead to the
dehydrogenated product. Hydrogen transfert on an alkene substrate during
metathesis is unlikely as no hydrogenated product (tetrahydrofuran) could be
detected and as dehydrogenation also happens in the absence of ethylene.
We then suggest that molecular hydrogen is released during this
transformation.
Scheme 5. Proposed mechanism for the dehydrogenation of dihydrofurans.

1564
L. Evanno, B. Nay, and B. Bodo
In conclusion, during our effort to synthesize 3-isopropenyldihydrofurans
5a, b) through enyne metathesis, we observed the formation of the corre-
(
sponding isopropenylfurans (7a, b). These compounds certainly arose from
in situ dehydrogenation of products 5a, b. The involved catalytic species
may result from heat-promoted decomposition of Grubbs’ catalyst 1 in the
reaction mixture. This is the first example of ring-closing enyne metathesis
that gives rise to dehydrogenated products in the furan series.
EXPERIMENTAL SUPPORT
Typical procedure for the metathesis step: to a 0.1-M solution of the enyne in
distilled (CaH ) dichloromethane, catalyst 1 (0.1 eq) was added. Bubbling of
2
ethylene was passed through the solution for 5 min and the mixture was
refluxed for 16 h, keeping an atmosphere of ethylene under balloon
pressure. After evaporation of the solvent, the crude mixture was purified
by silica-gel chromatography (dichloromethane–heptane 1:1).
1
Enyne 4a (colorless oil): H NMR (CDCl , 300 MHz): d 0.06 [s, 6H,
3
(
(
CH ) Si], 0.86 [s, 9H, (CH ) CSi], 1.61 [m, 4H, (CH ) 22 CH OTBS], 1.85
3 2 3 3 2 2 2
t, 3H, J ¼ 2.2 Hz, CH 22 C ;; C), 3.62 (m, 2H, CH OTBS), 3.82 (m, 1H,
3
2
CH 55 CH 22 CH), 3.97 (dq, 1H, J ¼ 2.2 Hz, J ¼ 15.0 Hz), 4.15 (dq, 1H, J ¼
2
2
.2 Hz, J ¼ 15.0 Hz) (C ;; C 22 CH 22 O), 5.20 (m, 1H, trans CH 55 CH 22 CH),
2 2
2
2
1
.24 (m, 1H, cis CH 55 CH 22 CH), 5.65 (m, 1H, CH 55 CH 22 CH). C NMR
3
5
(CDCl , 75 MHz): d 138.2, 117.6, 81.6, 79.8, 75.6, 62.9, 55.8, 31.5, 28.6,
3
2
6.0, 20.3, 3.6, 25.3. IR (CH Cl solution): 2955–2857 (nC 22 H), 2242–
2 2
2
220 (nC ;; C), 1472, 1465, 1390, 1361, 1250 (n
), 1099 (nSi-O). HRMS
Si-Me
þ
(CIþ, CH ): m/z calculated for C H O Si (MH ): 283.2093; observed:
4
16 31 2
2
83.2097. R (heptane/AcOEt 7:3, Merck TLC plates 1.05554.0001):0.7.
f
1
Dihydrofuran 5a (colorless oil): H NMR (CDCl , 400 MHz): d 0.02
3
[s, 6H, (CH ) Si], 0.87 [s, 9H, (CH ) CSi], 1.59 [m, 4H, (CH ) 22 CH OTBS],
3 2 3 3 2 2 2
1
.91 (s, 3H, CH 22 C 55 CH ), 3.61 (m, 2H, CH OTBS), 4.68 (large s, 1H,
3 2 2
trans C 55 CH ), 4.69 (ddd, 1H, J ¼ 2.0 Hz, J ¼ 3.6 Hz, J ¼ 11.4 Hz), 4.77
2
(
ddd, 1H, J ¼ 2.0 Hz, J ¼ 5.2 Hz, J ¼ 11.4 Hz) (CH 22 O 22 CH), 4.91
2
(m, 1H, CH 22 O 22 CH), 4.95 (large s, 1H, cis C 55 CH ), 5.71 (m, 1H,
C 55 CH 22 ). C NMR (CDCl , 100 MHz): d 140.5, 136.4, 125.8, 113.9,
2
2
1
3
3
8
6.9, 74.5, 63.1, 32.3, 28.5, 26.0, 20.5, 18.3, 25.3. IR (CH Cl solution):
2 2
2
930–2853 (nC-H), 1606 (n
), 1475, 1389, 1260 (nSi-Me), 1095 (nSi-O).
C 55 C
þ
MS (ESIþ): m/z 283.19 (MH ). R (CH Cl /heptane 7:3): 0.3.
f
2
2
1
Furan 11 (colorless oil): H NMR (CDCl , 300 MHz): d 1.59 (large s, 1H,
3
OH), 1.88 (quint., 2H, J ¼ 7 Hz, CH 22 CH OH), 1.97 (s, 3H, CH 22 C 55 CH ),
2
2
3
2
2
.69 (t, 2H, J ¼ 7.4 Hz, furan–CH ), 3.67 (t, 2H, J ¼ 6.3 Hz, CH OH), 4.86
3 2
2
2
(
s, 1H), 5.13 (s, 1H) (CH 22 C 55 CH ), 6.17 (s, 1H, HC 55 C 22 CH 55 C), 7.31
1
s, 1H, HC 55 C 22 CH 55 C). C NMR (CDCl , 75 MHz): d 156.4, 137.5,
3
(
3
1
35.2, 128.2, 110.3, 103.4, 61.9, 30.8, 24.3, 20.8. IR (CH Cl solution):
2 2

Dehydrogenation Products from Enyne Metathesis
1565
þ
3
598, 3212, 3064, 2978, 1765, 1601, 1454. MS (ESI þ ): m/z 167.10 (MH ).
R (DCM/heptane 7:3): 0.2.
f
1
Cyclopropane 12 (colorless oil): H NMR (CDCl , 300 MHz):
0.73–0.96 (m, 3H, cyclopropane CH), 1.47–1.70 [m, 4H,
3
d
(
CH ) 22 CH OH], 1.71 (m, 3H, CH 22 C 55 CH ), 3.68 (m, 2H, CH OH),
2 2 2 3 2 2
3
4
1
.78 (d, J ¼ 8.3 Hz, 1H) and 3.91 (m, 2H) (CH 22 O 22 CH), 4.75 and
2
1
3
.85 (2 m, 2H CH 22 C 55 CH ). C NMR (CDCl , 75 MHz): d 143.1,
3
2
3
10.8, 80.9, 69.2, 63.0, 31.9, 31.5, 29.7, 28.4, 20.8, 14.4. IR (CH Cl
2
2
solution): 3687, 3023, 3003, 2991, 2928, 2862, 1634, 1609, 1450, 1380,
1
250, 1120, 1040, 1019. HRMS (CIþ, CH ): m/z calculated for
4
þ
C H O (MH ): 183.1385; observed: 183.1383. R (CH Cl /heptane
1
1
19
2
f
2
2
7
:3): 0.1.
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