Grubbs catalyst-mediated cycloisomerization of allenenes

Article abstract of DOI:10.1016/j.tetlet.2006.04.017

The novel ruthenium benzylidene catalyst-mediated cycloisomerization of allenenes, having an alkyl appendage at the allenic terminus, resulting in the construction of cyclohexene, tetrahydropyran, and tetrahydropyridine skeletons was developed.

Full text of DOI:10.1016/j.tetlet.2006.04.017

Tetrahedron Letters 47 (2006) 3971–3974
Grubbs catalyst-mediated cycloisomerization of allenenes
Chisato Mukai* and Rumiko Itoh
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
Received 13 March 2006; revised 6 April 2006; accepted 7 April 2006
Available online 2 May 2006
Abstract—The novel ruthenium benzylidene catalyst-mediated cycloisomerization of allenenes, having an alkyl appendage at the
allenic terminus, resulting in the construction of cyclohexene, tetrahydropyran, and tetrahydropyridine skeletons was developed.
Ó 2006 Elsevier Ltd. All rights reserved.
The ring-closing metathesis between two alkene p-
bonds1 is well recognized as one of the most powerful
methodologies for the construction of a variety of cyclic
compounds. This ring-closing reaction can be applicable
to the enyne substrates (between the alkene p-bond and
the alkyne p-bond),2 leading to the formation of cyclic
products having a 1,3-diene moiety. In contrast to these
extensive studies, there are only two available exam-
ples3,4 that investigated the ring-closing metathesis of
allenene or allenyne derivatives.5 In 2001, Rutjes and
co-workers3 examined the ring-closing metathesis of
allenene 2 (R = H) in the presence of the ruthenium
benzylidene complex 4 or 5 hoping for the construction
of the tetrahydropyridine 3, but no reaction took place
and 2 was recovered intact. When allenene 2 (R = Me)
was exposed to similar conditions [second-generation
Grubbs catalyst (5)], the exclusive isomerization of
the allenyl moiety to the (E)-1,3-diene functionality
occurred to afford 1 in quantitative yield. On the other
hand, Murakami et al.4 reported the efficient ring-
closing metathesis of the allenynes 6 in the presence of
the Schrock catalyst resulting in the formation of the
1,2,4-triene compounds 7 (Scheme 1).
In line with our recent interest6 in the metal-catalyzed
cycloisomerization reactions of allenynes and allenenes,7
R
Grubbs catalyst
Grubbs catalyst
5
4 or 5
•
R=Me
R=H
N
N
N
Ts
Ts
Ts
PCy3
1
2
3
Cl
Ru
Cl
Ph
PCy3
R'
R'
R
first-generation Grubbs catalyst (4)
•
R
•
Schrock
catalyst
MesN
NMes
Z
Z
Cl
Cl
Ru
6
7
Ph
PCy3
Z=NTs, C(CO2Me)2, etc
R, R'=H, Me, Ph, etc
second-generation Grubbs catalyst (5)
Scheme 1.
Keywords: Grubbs catalyst; Cycloisomerization; Allenene; Ring-closing reaction.
*
Corresponding author. Tel.: +81 76 234 4411; fax: +81 76 234 4410; e-mail: cmukai@kenroku.kanazawa-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.017

3972
C. Mukai, R. Itoh / Tetrahedron Letters 47 (2006) 3971–3974
we became interested in the cycloisomerization of allenes
in the presence of the ruthenium benzylidene complex.
We envisaged that allene 8, having a terminal alkyl
appendage, would be susceptible to the ruthenium benz-
ylidene complex-mediated isomerization to the (Z)-1,3-
diene derivative 9 based on Rutjies’ results.3 The thus
formed 9 would then undergo the ring-closing metathe-
sis to produce the seven-membered 1,3-diene compound
10. The selective formation of the (Z)-1,3-diene deriva-
tive 9 might be expected because the (E)-congener 90
must be significantly destabilized due to the nonbonding
interaction between a phenylsulfonyl group and a vinyl
group. In addition, we anticipated that a phenylsulfonyl
functionality (electron-withdrawing group) would possi-
bly reduce the participation of the proximal double
bond of the allenyl moiety in the metal-catalyzed reac-
tion (Scheme 2). On the basis of these predictions, we
investigated the ruthenium benzylidene complex-medi-
ated reaction of allenenes.
cyclohexene derivatives 15b and 15c9 in higher yields
(92% and 98%, respectively) (entries 3 and 4). The
tetra-substituted allenes 14d and 14e were found to be
inactive toward the ring-closing reaction resulting in
the complete recovery of the starting materials (entries
5 and 6). No reaction occurred when 14c was exposed
to the first-generation Grubbs catalyst (4) (entry 7).
The Hoveyda catalyst (16) was more ineffective than
the second-generation Grubbs catalyst (5) during the
conversion of 14c into 15c to provide the latter in 21%
yield along with the starting material (59%) (entry 8).
The unexpected formation of the cyclohexene derivative
15 might be tentatively rationalized in terms of the inter-
mediacy of the ruthenacyclopentene intermediate A.10
The methyl (or methylene) hydrogen of the thus formed
metallacycle A would be abstracted via b-hydride elimi-
nation11 collapsing into the 1,3-diene derivative 15.
Alternatively, the formation of 15 might be interpreted
as a result of the direct thermal ene-type reaction of
14. To understand the latter process, compound 14b
was refluxed in CH2Cl2 without the ruthenium benzyl-
idene catalyst for a prolonged time, but no reaction took
place. In addition, when heated at a higher temperature
(refluxing in toluene or in xylene), the thermal
[2+2]cycloaddition between the terminal olefin and the
distal double bond of the allenyl moiety12 furnished
the cyclobutane derivative 17. On the basis of these
experiments, the possibility of the ene-type reaction for
the conversion of 14 into 15 could be ruled out.13
The required allenenes 14 were prepared by the conven-
tional procedures shown in Scheme 3. The acetylide, de-
rived from the known malonate 11,8 was quenched by
the carbonyl compounds 12 to afford adducts 13, which
were then converted into allenenes 14 by successive
exposure to PhSCl and mCPBA.
Our initial evaluation for the cycloisomerization of phen-
ylsulfonylallenenes was carried out using compound
14a (Table 1). A solution of 14a in CH2Cl2 was refluxed
for 10 h in the presence of 5 mol % of the ruthenium
benzylidene complex 5, but no cyclized product could
be detected and the starting material was completely
recovered (entry 1). Increasing the loading amounts of
5 from 5 to 20 mol % provided the cyclohexene deriva-
tive 15a in 41% yield along with 14a (54%) (entry 2).
Contrary to our prediction described in Scheme 2, nei-
ther the seven-membered compound 10 [X = C(CO2Me)2],
or the acyclic 1,3-diene derivative [e.g., 9, X =
C(CO2Me)2, R = H] could be obtained. The benzyl and
ethyl congeners 14b and 14c furnished the corresponding
We next investigated the scope of the ruthenium benzyl-
idene catalyst 5-mediated cycloisomerization using sev-
eral substrates 18.14 These results are summarized in
Table 2. The 3,4,9-decatriene derivative 18a, which does
not provide the Thorpe–Ingold type effects15 due to loss
of a bis(methoxycarbonyl) group, also produced the
cyclohexene derivative 19a9 in a good yield (entry 1).
Allenene 18b, having an oxygen atom on the alkyl
tether, produced the corresponding tetrahydropyran
compound 19b in a rather low yield compared to the
H
PhO2S
X
PhO2S
X
PhO2S
PhO2S
R
R
•
R
X
X
9'
8
9
10
Scheme 2.
R
R'
OH
PhO2S
R
•
a
b,c
Z
Z
Z
Z
R'
O
Z
Z
R
R'
12
11
13
14
Z=CO2Me
a: R=R'=H; b: R=Ph, R'=H; c: R=Me, R'=H; d: R=H, R'=Me; e: R+R'=-(CH2)4-
Scheme 3. Reagents and conditions: (a) LDA, THF, ꢀ78 °C, (40–76%); (b) PhSCl, Et3N, THF, ꢀ78 °C; (c) mCPBA, CH2Cl2, 0 °C, (59–86%).

C. Mukai, R. Itoh / Tetrahedron Letters 47 (2006) 3971–3974
Table 1. Ruthenium benzylidene catalyst-mediated cycloisomerization of 14
PhO2S
3973
SO2Ph
R
20 mol % ruthenium
benzylidene complex
•
R
R'
MeO2C
MeO2C
MeO2C
MeO2C
CH2Cl2, reflux
15
14
a: R=R'=H; b: R=Ph, R'=H; c: R=Me, R'=H; d: R=H, R'=Me; e: R+R'=-(CH2)4-
Entry
Allenene
Ru catalyst
R
R0
t (h)
Product (%)
1
2
3
4
5
6
7
8
14a
14a
14b
14c
14d
14e
14c
14c
5a
5
H
H
Ph
Me
H
H
H
H
H
10
3.5
0.5
0.5
2
5
4
1
14a (98)
15a (41) + 14a (54)
15b (92)
15c (98)
14d (74)
14e (84)
14c (99)b
15c (21) + 14c (59)
5
5
5
Me
5
–(CH2)4–
4
16
Me
Me
H
H
a Reaction was carried out in the presence of 5 mol % of 5.
b Reaction was carried out in toluene at 40–80 °C.
MesN
NMes
PhO2S
SO2Ph
R'
R
Cl
Cl
iPr
Ru
O
Ph
Ru
MeO2C
MeO2C
MeO2C
MeO2C
A
17
Hoveyda catalyst (16)
Table 2. Ruthenium benzylidene catalyst 5-mediated cycloisomerization of 18
SO2Ph
PhO2S
R
•
R
20 mol % 5
X
X
CH2Cl2, relfux
n
n
18
19
a: n=1,R=Me, X=CH2; b: n=1, R=Me, X=O; c: n=1, R=Me, X=NTs;
d: n=1, R=Ph, X=NTs; e: n=2, R=Me, X=C(CO2Me)2
Entry
Allenene
n
R
X
Ti(OPri)4
Product (%)
1
2
3
4
5
6
7
8
18a
18b
18c
18d
18b
18c
18d
18e
1
1
1
1
1
1
1
2
Me
Me
Me
Ph
Me
Me
Ph
CH2
O
NTs
NTs
O
NTs
NTs
C(CO2Me)2
ꢀ
ꢀ
ꢀ
ꢀ
+
+
+
ꢀ
19a (77)
19b (33) + 18b (50)
19c (50) + 18c (11)
19d (44) + 18d (39)
19b (46) + 18b (13)
19c (62) + 18c (23)
19d (62) + 18d (34)
18e (82)a
Me
a The desired 19e could not be detected even at a higher reaction temperature (in toluene at 80 °C).
carbon analogue 14c (entry 2). Similarly, the nitrogen
congeners 18c and 18d underwent cycloisomerization
to give the tetrahydropyridine derivatives 19c and 19d
in moderate yields (entries 3 and 4). Improvement of
the chemical yields for compounds 18b–d were realized
isomerization of allenenes cannot be used for the con-
struction of seven-membered compounds.
In summary, we have described the novel ruthenium
benzylidene catalyst-mediated cycloisomerization of
allenenes having an alkyl appendage at the allenic termi-
nus, leading to the formation of the cyclohexene deriva-
tives. This method was shown to be applicable for the
construction of heterocycles such as the tetrahydropyran
and tetrahydropyridine derivatives. The determination
of the scope and limitations of this method is now in
progress.
by the addition of 1 equiv of Ti(OPri)4 as shown in
16
entries 5–7, although the role of Ti(OPri)4 is uncertain
at this stage.17 No consumption of the one-carbon
homologated allenene 18e was observed when exposed
to the standard conditions for a prolonged time (entry
8). These results clarified that the newly developed
second-generation Grubbs catalyst (5)-mediated cyclo-

3974
C. Mukai, R. Itoh / Tetrahedron Letters 47 (2006) 3971–3974
9. The (E)-stereochemistry of the cyclized product was
Acknowledgements
1
determined by H NMR spectrum.
10. For selected nonmetathetic reactions using the Grubbs
catalyst, see: (a) Arisawa, M.; Terada, Y.; Nakagawa, M.;
Nishida, A. Angew. Chem., Int. Ed. 2002, 41, 4732–4734;
(b) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9,
1259–1262; (c) Schmidt, B. Eur. J. Org. Chem. 2004, 1865–
1880; (d) Terada, Y.; Arisawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2004, 43, 4063–4067; (e) Arisawa, M.;
Terada, Y.; Theeraladanon, C.; Takahashi, K.; Naka-
gawa, M.; Nishida, A. J. Organomet. Chem. 2005, 690,
5398–5406, and references cited therein.
This work was supported in part by a Grant-in Aid for
Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan, for which
we are thankful.
References and notes
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¨
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11. No reaction took place when 5,5-bis(methoxycarbonyl)-3-
phenylsulfonylocta-1,2,7-triene, which does not have the
terminal alkyl appendage, was exposed to the second-
generation Grubbs catalyst (5).
12. For extensive studies on the thermal [2+2]cycloaddition
of allenenes, see: (a) Padwa, A.; Filipkowski, M. A.;
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13. A mechanistic discussion is premature at this point, but we
examined the following experiments to understand the
reaction pathway. According to Arisawa and Nishda’s
procedure,10a,d,e trimethylsilyl vinyl ether was added to the
reaction of 14b with 5, but no improvement on the
chemical yield of 15b could be attained. Furthermore,
after consumption of the starting material in the reaction
between 14b and a catalytic amount of 5 (monitored by
TLC), diethyl bis(allyl)malonate was added to the reaction
mixture, which was then refluxed for one hour to give 4,4-
bis(ethoxycarbonyl)cyclopent-1-ene (ring-closed metathe-
sis product) together with 15b. These results indicate that
the actual active catalyst in the transformation of 14c to
15c might not be the newly generated species in situ, but 5
itself.
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17. In order to confirm the effect of Ti(OPri)4, the carbon
analogues 14a and 14b were independently treated with 5
in the presence of Ti(OPri)4 to afford 15a and 15b,
respectively, in yields similar to those obtained in the
absence of Ti(OPri)4 (Table 1, entries 2 and 3).