Recent advances in formal ruthenium-catalyzed [2+2+2] cycloaddition reactions of diynes to alkenes

Article abstract of DOI:10.1002/chem.200801088

Formal and standard Ru^II-catalyzed [2+2+2] cycloaddition of 1,6-diynes to alkenes gave bicyclic 1,3-cyclohexadienes in relatively good yields. When terminal 1,6-diynes 1 were used, two isomeric bicyclic 1,3-cyclohexadienes 4 or 6 were obtained, depending on the acyclic or cyclic nature of the alkene partner. When unsymmetrical substituted 1,6-diynes 7 were used, the reaction with acyclic alkenes took place regio- and stereoselectively to afford bicyclic 1,3-cyclohexadienes 8. A cascade process that behaves as a formal Ru^II-catalyzed [2+2+2] cycloaddition explained these results. Initially, a Ru-catalyzed linear coupling of 1,6-diynes 1 and 7 with acyclic alkenes occurs to give open 1,3,5-trienes of type 3, which after a thermal disrotatory 6e^- π- electrocyclization led to the final 1,3-cyclohexadienes 4 and 8. When disubstituted 1,6-diyne 10 was used with electron-deficient alkenes, new exo-methylene cyclohexadienes 12 arose from a competitive reaction pathway.

Full text of DOI:10.1002/chem.200801088

DOI: 10.1002/chem.200801088
Recent Advances in “Formal” Ruthenium-Catalyzed [2+2+2] Cycloaddition
Reactions of Diynes to Alkenes
Silvia García-Rubín, JesfflsA. Varela, Luis Castedo, and Carlos Saµ*[a]
Abstract: “Formal” and standard RuII-
catalyzed [2+2+2] cycloaddition of 1,6-
diynes to alkenes gave bicyclic 1,3-cy-
clohexadienes in relatively good yields.
When terminal 1,6-diynes 1 were used,
two isomeric bicyclic 1,3-cyclohexa-
dienes 4 or 6 were obtained, depending
on the acyclic or cyclic nature of the
alkene partner. When unsymmetrical
substituted 1,6-diynes 7 were used, the
reaction with acyclic alkenes took
place regio- and stereoselectively to
afford bicyclic 1,3-cyclohexadienes 8. A
1,6-diynes 1 and 7 with acyclic alkenes
occurs to give open 1,3,5-trienes of
type 3, which after a thermal disrotato-
ry 6eÀ p-electrocyclization led to the
cascade process that behaves as
a
“formal” RuII-catalyzed [2+2+2] cyclo-
addition explained these results. Initial-
ly, a Ru-catalyzed linear coupling of
final 1,3-cyclohexadienes
4 and 8.
When disubstituted 1,6-diyne 10 was
used with electron-deficient alkenes,
new exo-methylene cyclohexadienes 12
arose from a competitive reaction path-
way.
Keywords: alkenes
·
catalysis
·
cycloaddition reactions · cyclohexa-
dienes · diynes · ruthenium
Introduction
The development of new reactions that allow an increase in
molecular complexity from readily available starting materi-
als, but in an environmentally friendly way and with atom
economy, is one of the major goals in modern synthetic or-
ganic chemistry.[1] Among the reactions available for this
purpose, transition-metal-catalyzed cycloadditions represent
a powerful tool for the construction of polycyclic molecules
under very mild conditions.[2] Metal catalysts can complex to
an olefin, diene, or acetylene and significantly modify the
reactivity of this moiety to provide new opportunities for
highly selective cycloaddition reactions. For carbocyclic sys-
tems containing six-membered rings, the inter- and intramo-
lecular metal-catalyzed [2+2+2] cycloaddition reactions of
alkynes are very well established for the preparation of nu-
merous benzene and polycyclic benzene derivatives (reac-
tion type 1, Scheme 1).[3] Heteroarenes and unsaturated het-
erocycles have also been obtained by using alkynes and
carbon–heteroatom multiple bonds, such as nitriles (reaction
Scheme 1. Metal-catalyzed [2+2+2] cycloaddition reactions.
type 2), heterocumulenes (reaction type 3), or carbonyls (re-
action type 4).[4]
However, the corresponding metal-catalyzed [2+2+2] cy-
cloadditions between alkynes and alkenes to give 1,3-cyclo-
hexadienes are much less developed owing to either the ne-
cessity of equimolar amounts of metal promoters[5] or to the
lack of generality (reaction types 5 and 6, Scheme 1).[6]
As a further contribution to the above methodology, we
recently described a new “formal” [2+2+2] cycloaddition of
[a] S. García-Rubín, Dr. J.A. Varela, Prof. L. Castedo, Prof. C. Saµ
Departamento de Química Orgµnica
Facultad de Química, Universidad de Santiago de Compostela
15782 Santiago de Compostela (Spain)
Fax : (+34)981-595-012
E-mail: carlos.saa@usc.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801088.
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FULL PAPER
terminal 1,6-diynes 1 with acyclic alkenes 2 in the presence
of 10% of an equimolar amount of [Ru(CH3CN)3Cp*]PF6
Et4NCl, the cationic catalyst [RuACHRTE(UNG CH3CN)3Cp*]PF6 probably
G
generates the neutral complex [RuL2ClCp*] (I, L=
CH3CN), as suggested by changes in the 1H NMR spec-
trum.[9] Coordination to diyne 1 followed by oxidative cou-
pling would form the bis-carbene species III, which after co-
ordination to the alkene would give rise to ruthenacyclic
species of type IV for acyclic alkenes (endo approach) or
VIII for cyclic alkenes (exo approach). Formation of Ru-bi-
cyclic complexes V and IX followed by electrocyclic opening
would afford ruthenacycloheptadienes VI and X, from
which two alternatives can be envisioned depending on the
nature of the alkene: 1) the well-established reductive elimi-
nation to cyclohexadienes 6 in the case of cyclic alkenes[6g]
and 2) a new b-elimination leading to the ruthenium hydride
VII, followed by a reductive elimination to give the open
hexatrienes 3 in the case of acyclic alkenes. The hexatrienes
3 undergo a pure thermal disrotatory 6eÀ p-electrocycliza-
tion to give the observed cyclohexadienes 4.
(Cp*=pentamethylcyclopentadienyl) and Et4NCl to give
1,3-cyclohexadienes 4 (Scheme 2).[7]
Scheme 2. “Formal” Ru-catalyzed [2+2+2] cycloaddition of terminal 1,6-
diynes 1 with acyclic alkenes 2.
We also found that cyclic alkenes 5 reacted with diynes 1
to afford tricyclic cyclohexadienes 6 (Scheme 3).[7] Unlike
their acyclic alkene analogues 2, the double bonds in cyclo-
hexadienes 6 are in the position expected for a [2+2+2] cy-
cloadduct (as observed by Itoh).[6f,g]
Our mechanistic hypothesis for the Ru-catalyzed reaction
of diynes and alkenes involves two possible pathways, de-
pending on the alkene used (Scheme 4).[8] When mixed with
Herein, we present our recent advances in the regioselec-
tivity of the “formal” Ru-catalyzed [2+2+2] cycloaddition
when using unsymmetrical diynes and also interesting new
reaction avenues when using disubstituted diynes as part-
ners.[10]
Results and Discussion
Regioselectivity: For a better understanding of the rutheni-
um-catalyzed cycloaddition of diynes to alkenes, we now de-
cided to explore the regioselectivity of the reaction by using
unsymmetrical 1,6-diynes. For this purpose, reactions be-
tween selected alkenes and un-
Scheme 3. Standard RuII-catalyzed [2+2+2] cycloaddition of 1,6-diynes 1
with cyclic alkenes 5.
symmetrical 1,6-diynes 7 were
performed. Slow addition of a
solution of 7a in DMF to a
heated DMF solution of
methyl acrylate (2a) and the
usual catalytic mixture afford-
ed exclusively the cyclohexa-
diene 8aa in excellent yield
(moderate-to-good yields were
obtained with heterosubstitut-
ed diynes 7’a and 7’’a, Table 1,
entry 1).[11] When the substitut-
ed alkene 2b, with a metal-co-
ordinating heteroatom, and the
nonactivated alkene 2c were
used, disubstituted cyclohexa-
dienes 8ab and 8ac were ob-
tained in quite good yields (en-
tries 2 and 3). As expected, all
the observed products derive
from the corresponding Ru
complexes V (proposed inter-
mediate), in which the inser-
tion of the alkene occurs at the
Scheme 4. Proposed mechanisms for the “formal” and standard Ru-catalyzed [2+2+2] cycloadditions of termi-
À
nal 1,6-diynes with acyclic and cyclic alkenes.
less-substituted Ru C bond of
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C. Saµ et al.
Table 1. “Formal” RuII-catalyzed [2+2+2] cycloaddition of unsymmetri-
cal diynes 7 with acyclic alkenes 2.
maleate (2d) only gave the trans-substituted cyclohexadiene
8ad (Table 1, entry 4). Diynes 7b and 7c failed to react with
dimethyl maleate 2d, probably due to severe steric hin-
drance (entries 8 and 12).
Unexpectedly, when 2,5-dihydrofuran (5a) was used, the
bis-cyclopropanated product 9 was obtained in a reasonably
good yield (Scheme 5). The structure of 9 was elucidated by
Entry R3
Diyne R1
R2
H
Alkene
8
Yield [%][a]
1
Me
7a
7’a
7’’a
7a
7a
7a
CO2Me
2a
8aa 90 (82)
8’aa 60
8’’aa 50
2[b]
3
4
Me
Me
Me
CH2OEt
C5H11
CO2Me CO2Me 2d
H
H
2b
2c
8ab 70 (73)
8ac 69 (66)
8ad 70 (60)
8ba 68
5
6
7
8
CO2Me 7b
CO2Me 7b
CO2Me 7b
CO2Me 7b
CO2Me
CH2OEt
C5H11
H
H
H
2a
2b
2c
8bb 70[b]
8bc 63
–
[c]
CO2Me CO2Me 2d
–
9
Ph
Ph
Ph
Ph
7c
7c
7c
7c
CO2Me
CH2OEt
C5H11
H
H
H
2a
2b
2c
8ca 40
10
11
12
8cb 78[b]
8cc 47
[c]
Scheme 5. RuII-catalyzed reactions of diynes 7a and 1a with dihydrofuran
5a.
CO2Me CO2Me 2d
–
–
[a] Isolated yields from reactions performed at 808C by slow addition,
over 4 h, of 0.5 mmol of 7 in DMF to a mixture of 3 equiv of 2, 10%
Et4NCl, and 10% [Ru
ACHTREUNG
brackets, yields when neutral [RuClAHCTREUNG
X-ray analysis (Figure 1, see the Supporting Information for
details).[12] Interestingly, this result clearly contrasts with
that obtained between 5a and 1a (X=CACHTRE(UNG CO2Me)2) in which
the same reaction conditions. [b] Reaction performed by using 10 equiv
of 2 without slow addition of 7 (conditions B). [c] Unreacted alkene 2
and diyne 7 were recovered.
ruthenacyclopentadienes IV and the less-bulky substituent
(R2 =H) is located a to the ruthenium (steric control).
To gain further insight into the cata-
lytic species operative in the reaction,
we carried out the above experiments
by using a preformed neutral rutheni-
um complex, [RuClACTHRE(UNG cod)Cp*] (cod=
1,5-cyclooctadiene) instead of the
equimolar mixture of the cationic
complex [RuACHTREUNG(CH3CN)3Cp*]PF6 with Et4NCl (Table 1, en-
tries 1–4, yields in brackets). In all cases, comparable yields
were obtained, which showed that most probably the neutral
species “RuClCp*”, generated in situ when the cationic
complex is used, is the operative catalytic species. Thus, for
convenient reasons we used the mixture of [Ru-
Figure 1. ORTEP diagram of the structure of bis-cyclopropane 9.
ACHTREUNG
the diyne partner by reaction of selected alkenes with un-
symmetrical 1,6-diyne 7b containing a conjugated methoxy-
carbonyl group and 7c containing a phenyl group (Table 1,
entries 5–8 and 9–12, respectively). Both electron-poor and
conjugated diynes showed similar or slightly lower reactivity
than the electron-rich diyne 7a when reacted with monosub-
stituted alkenes. As above, the reaction took place regiose-
lectively producing the expected products (steric control)
for a “formal” RuII-catalyzed [2+2+2] cycloaddition with
acyclic alkenes.
an excellent 92% yield of cyclohexadiene 6a was ob-
tained.[7] The formation of the bis-cyclopropane 9 is proba-
bly due to the presence of the methyl group in 7a, which in-
hibits the standard [2+2+2] cycloaddition mechanism from
the corresponding ruthenabicyclocarbene IX favoring the
reductive elimination to a cyclopropane ring; then, a second
cyclopropanation of the resulting Ru–carbene species gives
the observed bis-cyclopropane product 9.[13]
Cycloadditions of disubstituted 1,6-diyne 10 with acyclic al-
kenes: We next turned our attention to the Ru-catalyzed re-
action of 2,7-nonadiyne 10, which possesses two internal
Interestingly, the reaction also took place stereoselectively
illustrated by the fact that the reaction of 7a with dimethyl
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Ruthenium-Catalyzed [2+2+2] Cycloaddition Reactions
FULL PAPER
alkyne termini,[14] with selected acyclic alkenes (Table 2). To
our surprise, when a solution of diyne 10 in DMF was
slowly added over 4 h to a heated solution of alkene 2a and
the usual catalytic mixture, an almost 1:1 ratio of the unex-
pected cyclohexadiene regioisomer 11a and the new methyl-
ene derivative 12a[15] was obtained in a 55% combined yield
(Table 2, entry 1). This is the first time that the observed
product, cyclohexadiene 11a, does not present the substitu-
ent (CO2Me) in the diene moiety. Furthermore, methylene
derivative 12d, with the two esters in relative trans positions,
was exclusively obtained in a moderate 42% yield when the
alkene partner was maleate 2d (entry 2).[16] Conversely,
when allylic ether 2b was used, the major product was the
expected cyclohexadiene 11b (65%) with the open hexa-
triene 13 (12%) formed as an unexpected minor product
(entry 3). Nonactivated 1-heptene (2c) gave the expected
“formal” [2+2+2] cycloadduct 11c in low yield (31%)
(entry 4), thus demonstrating the lower reactivity of the
starting disubstituted diyne 10 in these reactions (see
Table 1 for comparison).
Scheme 6. “Formal” Ru-catalyzed [2+2+2] cycloaddition of disubstituted
diyne 10 and methyl acrylate (2a).
yield through a 6eÀ p-electrocyclization. Further heating of
11a at 808C for several hours did not lead to any change,
which indicated that neither 14 nor 11a are intermediates in
the formation of 12a (Scheme 6).
The formation of the open triene 14 can be explained on
the basis of the formation of the less-
crowded ruthenabicycle Va’ (pro-
posed intermediate), which results
from the coordination and addition
of alkene 2a to the ruthenium bis-
For a better understanding of the above reactions, we per-
formed experiments at room temperature by using alkenes
2a and 2b under conditions B. Addition of diyne 10 at room
temperature to a DMF solution of 10 equiv of methyl acry-
late (2a) containing the catalytic mixture afforded exclusive-
ly the open triene 14[17] in a 35% yield (Scheme 6). It was
necessary to heat a solution of the open triene in CDCl3 at
508C for 36 h to obtain cyclohexadiene 11a in quantitative
carbene, thus locating the alkene
substituent a to the ruthenium, in which coordination of the
carbonyl group to the ruthenium cannot be ruled out.
Reaction of alkene 2b with diyne 10 at room temperature
in the presence of the Ru catalyst gave the two isomeric tri-
enes 15 and 13 in 49 and 15% yields, respectively. Heating
triene 15 at 508C for 22 h smoothly afforded cyclohexadiene
11b in quantitative yield (Scheme 7).
Formation of isomeric tri-
enes 15 and 13 can be ex-
plained by considering the two
regioisomeric ruthenacycles
Table 2. “Formal” RuII-catalyzed [2+2+2] cycloaddition of disubstituted diyne 10 with acyclic alkenes 2.
VIb and VIb’ (Scheme 8). b-
Hydride elimination from VIb
followed by reductive elimina-
tion would afford triene 15,
whereas b-hydride elimination
of the exocyclic hydrogen[18]
from VIb’ followed by reduc-
tive elimination and a subse-
quent [1,5]-hydrogen shift of
the resulting triene 16 would
afford 13 (Scheme 8).
Entry
1
Alkene
Products
Yield [%][a]
R1 =CO2Me R2 =H 2a
55[b]
Finally, dimethyl maleate
(2d) did not participate in the
reaction with diyne 10 at room
temperature, with only a small
amount of the dimer of the
diyne isolated from the reac-
tion.[19] Surprisingly, the slow
addition (4 h) of a solution of
diyne 10 in DMF to a heated
solution of dimethyl fumarate
(2d’)[20] containing the catalytic
mixture gave the same yield of
the same methylenecyclohex-
ene derivative 12d as when 2d
2
R1 =CO2Me R2 =CO2Me 2d
R1 =CH2OEt R2 =H 2b
R1 =C5H11 R2 =H 2c
42
3[c]
65, 12
4
31
[a] Isolated yields following conditions A as in Table 1. [b] Isolated yield of a 1.25:1 mixture of 11a and 12a.
[c] Conditions B, as in Table 1 were used.
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C. Saµ et al.
Scheme 7. “Formal” Ru-catalyzed [2+2+2] cycloaddition of disubstituted
diyne 10 and ethyl allyl ether (2b).
Scheme 9. New RuII-catalyzed cycloisomerization of diyne 10 and conju-
gated alkenes 2.
Conclusion
The course of the RuII-catalyzed [2+2+2] cycloaddition be-
tween 1,6-diynes and alkenes to give 1,3-cyclohexadienes
changes with the nature of the starting alkene: 1) if cyclic al-
kenes are present, standard tricyclic 1,3-cyclohexadienes are
obtained from the reductive elimination of intermediate X;
2) if acyclic alkenes are used, linear coupling of diynes and
alkenes to give 1,3,5-hexatrienes occurs through b-elimina-
tion of intermediate VI followed by reductive elimination.
Then, a pure thermal 6eÀ p-electrocyclization gives the bicy-
clic 1,3-cyclohexadienes. The whole cascade process can be
considered as a “formal” [2+2+2] cycloaddition of alkynes
and alkenes. Experimental observations and DFT calcula-
tions support this mechanism. When a nonterminal 1,6-
diyne 10 and conjugated alkenes were used, new methylene-
cyclohexene derivatives 12 were obtained from the initially
formed substituted Ru–bis-carbene of type XI.
Scheme 8. Formation of trienes 15 and 13 from ruthenacycloheptadiene
intermediates VIb and VIb’.
was used (Table 2, entry 2). The formation of compounds
12a and 12d and the reactivity shown by trans alkenes sug-
gests the possibility of a new competitive pathway to the
“formal” RuII-catalyzed [2+2+2] cycloaddition of diynes to
alkenes, which is operative only when internal alkynes such
as 10 are used (Scheme 9).
The proposed mechanism would start with the formation
of Ru–bis-carbene XI by coordination of diyne 10 to I fol-
lowed by oxidative coupling. If the reaction is performed at
À
808C or above, activation of a C H bond of an a-substitu-
ent by an electrophilic carbene would occur to afford the
ruthenium carbene XII,[21] which rearranges to the allyl–
ruthenium species XIII. These types of complexes (XII and
XIII) have been observed and characterized by X-ray dif-
fraction in the group of Kirchner when monosubstituted al-
kynes were reacted with an equimolecular amount of the
Experimental Section
General procedures for the Ru-catalyzed reactions between alkenes and
1,6-diynes
(CH3CN)2(Cp)SbPh3]PF6.[22] If a
cationic Ru complex [RuACHTREUNG
Conditions A: synthesis of trimethyl 7-methyl-1,3,6,7-tetrahydro-2H-
indene-2,2,5-tricarboxylate (8aa). Alkene 2a (129 mg, 0.14 mL, 1.5 mmol,
conjugated alkene is present, it is able to insert into the Ru
h3-allyl bond to give rise to the ruthenacycloheptene XIV
that, after reductive elimination, would afford the methyle-
necyclohexene derivative 12 and, therefore, make the whole
process catalytic. The observed relative trans geometry in
12, regardless of whether maleate 2d or fumarate 2d’ is
used, can be explained only if the trans-alkene 2d’ is in-
volved in the reaction.[23]
3 equiv) was added to a stirred solution of [RuACHTER(UNG CH3CN)3Cp*]PF6 (25 mg,
10% mol) and Et4NCl (8 mg, 10% mol) in DMF (1.5 mL) at room tem-
perature. After stirring for 10 min, a solution of diyne 7a (111 mg,
0.5 mmol, 1 equiv) in DMF (2 mL) was added over 4 h by syringe pump
and the solution was heated at 808C. Stirring was continued for 1 h after
completion of the slow addition. The reaction was quenched with saturat-
ed aqueous NH4Cl (10 mL) and extracted with diethyl ether (3”10 mL).
The organic layers were combined, dried over anhydrous Na2SO4, and
evaporated under vacuum. The resulting residue was chromatographied
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Ruthenium-Catalyzed [2+2+2] Cycloaddition Reactions
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on silica gel by using ethyl acetate/hexane 2:8 as the eluent to afford 1,3-
cyclohexadiene 8aa in 90% yield.
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Cp*]PF6 (25 mg, 10% mol) and Et4NCl (8 mg, 10% mol) in DMF
(1.5 mL) was prepared in a 10 mL round-bottomed flask under argon.
After stirring for 10 min at room temperature, alkene 2b (430 mg,
0.57 mL, 5 mmol, 10eq) was added. After stirring for another 10 min,
diyne 7a (111 mg, 0.5 mmol, 1 equiv) was added and the resulting solu-
tion was heated at 808C for 2 h. The reaction was quenched with saturat-
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cyclohexadiene 8ab in 70% yield.
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Acknowledgements
This work was supported by the M.E.C. (Spain) and FEDER (CTQ2005–
08613), Consolider Ingenio 2010 (CSD2007–00006), and by the Xunta de
Galicia (2007/XA084 and PGIDIT06PXIC209041PN). S.G-R. and J.A.V.
thank the M.E.C. for a FPU fellowship and a Ramón y Cajal research
contract, respectively.
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[11] Slow addition of 1,6-diynes 7 avoids self-dimerization or trimeriza-
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Chem. Eur. J. 2008, 14, 9772 – 9778
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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C. Saµ et al.
[12] This type of compounds has also been observed in Ru-catalyzed re-
actions of 1,6-diynes with electron-deficient cycloalkenes, see refer-
ence [6f]. CCDC-690287 contains the supplementary crystallograph-
ic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif.
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with alkynes; see reference [14].
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[15] Relative stereochemistry (Me and CO2Me) not determined.
[16] The relative stereochemistry of the methylenecyclohexene deriva-
tive 12d was determined by measurement of the two coupling con-
stants for the proton Hb (dd, J=11.5, 9.8 Hz) and by NOE experi-
ments (NOE of Ha with Hc and NOE of Ha and Hb with the
methyl).
[21] This process can be seen as a b-hydride elimination followed by re-
À
ductive elimination of the resulting Ru H bond.
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[23] Isomerization of dimethyl maleate 2d to dimethyl fumarate 2d’ has
been observed when the reaction mixture is heated under the reac-
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[17] The geometry of the disubstituted double bond in 14 was elucidated
from the value of the coupling constant between Ha and Hb (J=
12.1 Hz), typical of a cis relationship.
Received: June 4, 2008
Published online: September 2, 2008
9778
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9772 – 9778