Ru3(CO)12-Catalyzed intermolecular cyclocoupling of ketones, alkenes or alkynes, and carbon monoxide. [2 + 2 + 1] Cycloaddition strategy for the synthesis of functionalized γ-butyrolactones

Article abstract of DOI:10.1021/ja003018i

The ruthenium-catalyzed intermolecular cyclocoupling of ketones (or aldehydes), alkenes (or alkynes), and CO, which leads to γ-butyrolactones, is described. The reaction represents the first example of the catalytic synthesis of heterocycles via an interm

Full text of DOI:10.1021/ja003018i

J. Am. Chem. Soc. 2000, 122, 12663-12674
12663
Ru3(CO)12-Catalyzed Intermolecular Cyclocoupling of Ketones,
Alkenes or Alkynes, and Carbon Monoxide. [2 + 2 + 1]
Cycloaddition Strategy for the Synthesis of Functionalized
γ-Butyrolactones
Mamoru Tobisu, Naoto Chatani,* Taku Asaumi, Katsuya Amako, Yutaka Ie,
Yoshiya Fukumoto, and Shinji Murai*
Contribution from the Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity,
Suita, Osaka 565-0871, Japan
ReceiVed August 14, 2000
Abstract: The ruthenium-catalyzed intermolecular cyclocoupling of ketones (or aldehydes), alkenes (or alkynes),
and CO, which leads to γ-butyrolactones, is described. The reaction represents the first example of the catalytic
synthesis of heterocycles via an intermolecular carbonylative [2 + 2 + 1] cycloaddition. A wide variety of
ketones, such as R-dicarbonyl compounds and N-heterocyclic ketones, can be used in this cycloaddition. The
addition of phosphines is quite effective in reactions of R-dicarbonyl compounds. Of the phosphines examined,
P(4-CF3C6H4)3 represents the additive of choice. Cyclic olefins, unpolarized terminal olefins, and internal
alkynes can be successfully used in the synthesis of highly functionalized lactones. The introduction of a CF3
group to the aromatic portion of an aromatic keto ester accelerates the reaction of the keto ester with ethylene,
while the introduction of a MeO group enhances the rate of the reaction of N-heterocyclic ketones with ethylene.
The rate of the reaction increases with increasing pressure of ethylene or a lower pressure of CO relative to
the reaction of a keto ester. However, these pressure-rate relations are reversed for the reaction of an
N-heterocyclic ketone with ethylene. Such differences can be rationalized by assuming that the rate-limiting
step in the catalytic cycle is different for these reactions.
Introduction
Scheme 1. Synthesis of Five-Membered Carbonyl
Compounds via [2 + 2 + 1] Cyclocoupling
Transition-metal-catalyzed cycloaddition reactions have clearly
been demonstrated to be a powerful tool in organic synthesis.1
Metal catalysts enable one to employ molecules that are
thermally unreactive toward cycloadditions by taking advantage
of their ability to be activated through complexation. An
important example of this is the utilization of carbon monoxide
as a one-carbon unit in cycloaddition chemistry. This approach
leads to the direct formation of carbocyclic and heterocyclic
carbonyl compounds from simple acyclic building blocks.2,3
Among such carbonylative cycloaddition processes, the Pau-
son-Khand reaction, in which an alkyne, an alkene, and carbon
monoxide are condensed in a formal [2 + 2 + 1] cycloaddition
to form cyclopentenones (Scheme 1a), has attracted considerable
attention. Significant progress, including the development of a
catalytic variant for use in this process, has been reported
recently.3
cycloadditions, it would open new pathways for the construction
of γ-lactones or γ-lactams, respectively (Scheme 1b,c). How-
ever, as of 1996, such an approach had not been reported. Crowe
and Vu reported a titanium-mediated synthesis of γ-lactones
which proceeds via the reaction sequence involving reductive
coupling of an olefinic aldehyde/insertion of CO/reductive
elimination.4 This process requires the use of a stoichiometric
amount of a titanium complex. Buchwald et al. independently
reported a similar transformation and found that the reaction
can be conducted catalytically when olefinic ketones which
contain an aryl ketone moiety were used as substrates.5
If the π-bond of a carbonyl or an imino moiety can be utilized
in place of the alkene or alkyne π-bond in [2 + 2 + 1]
(1) For general reviews on transition-metal-promoted cycloadditions,
see: Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. Ojima, I.;
Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635.
Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523.
(2) For recent papers on the carbonylative cycloadditions, see the
following. (a) [4 + 1]: Morimoto, T.; Chatani, N.; Murai, S. J. Am. Chem.
Soc. 1999, 121, 1758. Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc.
1999, 121, 4130. (b) [4 + 4 + 1]: Murakami, M.; Itami, K.; Ito, Y. Angew.
Chem., Int. Ed. 1998, 37, 3418.
(4) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557.
(5) Kablaouni, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 5818. Kablaouni, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 4424.
(3) For recent reviews on the Pauson-Khand reaction, see: Chung, Y.
K. Coord. Chem. ReV. 1999, 188, 297. Brummond, K.; Kent, J. L.
Tetrahedron 2000, 56, 3263.
10.1021/ja003018i CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/27/2000

12664 J. Am. Chem. Soc., Vol. 122, No. 51, 2000
Tobisu et al.
Table 1. Effect of the Additives on Ru3(CO)12-Catalyzed
Subsequently, we reported on the Ru3(CO)12-catalyzed cyclo-
carbonyltions of yne-aldehydes6 and yne-imines,7 which pro-
duced bicyclic R,â-unsaturated γ-lactones and γ-lactams, re-
spectively. With respect to the catalytic method, Buchwald’s
methodology and ours were the only successful systems that
exemplified the strategies shown in reactions b and c of Scheme
1. These two systems fall in the class of an intramolecular
cycloaddition, and there was no precedent for intermolecular
variants of the process. Quite recently, we discovered that Ru3-
(CO)12 catalyzes the [2 + 2 + 1] cyclocoupling of ketones which
contain a carbonyl group or N-heterocycles, ethylene, and CO.8,9
The reaction represents the first example of the catalytic
synthesis of heterocycles via intermolecular carbonylative [2
+ 2 + 1] cycloaddition. In addition, it is interesting to note
that the original meaning of the word “synthesis” is “to put
together” in Greek. In this context, the intermolecular cyclo-
coupling described here is really a “synthesis” of cyclic carbonyl
compounds. The full details of our investigation, including the
scope and mechanistic aspects of this new cycloaddition, are
reported herein.
Cyclocouplinga
additive
pKab
yieldc
none
PCy3
PBu3
PPh2Me
P(4-MeOC6H4)3
P(4-MeC6H4)3
P(2-MeC6H4)3
PPh3
23%
60%
25%
50%
59%
54%
32%
61%
64%
72%
94%
9%
9.70
8.43
4.59
4.57
3.84
3.08
2.73
1.97
1.03
P(4-FC6H4)3
P(4-ClC6H4)3
P(4-CF3C6H4)3
P(OPh)3
dppmd
-1.55
-1.20
Results and Discussion
3%
dpped
14%
25%
56%
In our attempts to carry out the cyclocoupling reaction shown
in reaction b of Scheme 1, we began by employing a wide
variety of aldehydes and ketones as substrates. However, the
desired cyclocoupling did not occur. We then extended our
efforts to more reactive carbonyl compounds including R-di-
carbonyl compounds, and, as a result, we found that reaction b
of Scheme 1 can be realized by the use of R-keto esters as the
substrate in conjunction with Ru3(CO)12 as the catalyst. The
reaction of methyl benzoylformate (1b) (2 mmol) with ethylene
(initial pressure 3 atm at 25 °C in a 50-mL stainless steel
autoclave) at 5 atm of CO (initial pressure at 25 °C) at 160 °C
in toluene (6 mL) in the presence of Ru3(CO)12 (0.05 mmol)
for 20 h gave tetrahydro-5-oxo-2-phenyl-2-furancarboxylic acid
methyl ester (2b) in 23% isolated yield, with 75% of 1b being
recovered (eq 1). A prolonged reaction time (40 h) did not
dpppd
dppbd
a Reaction conditions: ketone (2 mmol), ethylene (initial pressure
3 atm at 25 °C), CO (initial pressure 5 atm at 25 °C), Ru3(CO)12 (0.05
mmol), and additive (0.15 mmol) in toluene (6 mL) at 160 °C for 20
h in a 50-mL stainless autoclave, unless otherwise noted. b pKa values
of the corresponding conjugate acids.10 c Isolated yields based on the
starting ketones. d 0.075 mmol of the phosphine was added.
found that the yields are relatively parallel to the basicity of
phosphines, except for the case of PCy3. Thus, the lower the
pKa, the higher the yield. It was found that, of the phosphines
investigated, P(4-CF3C6H4)3 gave the highest yield of 2b.
Decreasing the amount of P(4-CF3C6H4)3 to 0.05 mmol (i.e., 1
equiv to Ru3(CO)12 molecule) resulted in a lower yield of 2b
(56%), with 36% of 1b being recovered. This indicates that one
molecule of the phosphine per Ru atom is necessary in order to
generate an active catalyst. We had postulated that the phosphine
complex Ru3(CO)9(PPh3)3 might show a comparable activity.
As expected, the use of Ru3(CO)9(PPh3)3 as a catalyst under
otherwise identical conditions afforded 62% of 2b, comparable
to the yield obtained when 0.15 mmol of PPh3 was added to
0.05 mmol of Ru3(CO)12. Similarly, the use of a mononuclear
phosphine complex Ru(CO)2(PPh3)3 (0.15 mmol) resulted in
51% of 2b. Bidentate phosphines were also examined as
additives. Of interest here is the fact that the yield of 2b is
dependent on the length of the carbon tether between the two
phosphorus atoms. Of the bidentate phosphines examined, 1,4-
bis(diphenylphosphino)butane (dppb) gave the highest yield of
2b (56%), comparable to the yield obtained when PPh2Me was
used (50%). This observation suggests that only one phosphorus
atom in dppb coordinates to the ruthenium to generate an active
catalyst. In addition, non-phosphine additives, such as triethy-
lamine (32%), 2,6-lutidine (23%), tert-butyl isocyanide (31%),
2,6-xylyl isocyanide (18%), and triphenylarsine (20%), were
found to be less effective for this coupling.
significantly increase the product yield (40%). A variety of other
transition metal complexes were examined for their ability to
catalyze the coupling reaction, and none of these catalysts, which
included Fe3(CO)12, Co2(CO)8, Rh4(CO)12, Ir4(CO)12, Os3(CO)12,
[RuCl2(CO)3]2, RuCl2(PPh3)3, and CpRuCl(PPh3)2, were found
to be active.
Effect of Additives. To improve catalytic efficiency, we next
examined the effect of additives. The use of PPh3 (0.15 mmol,
i.e., 1 equiv to each Ru atom) in the Ru3(CO)12-catalyzed
reaction of 1b increased the yield of 2b from 23% to 61%. This
dramatic effect prompted us to survey an array of phosphines
as additives. Some selected results are shown in Table 1. It was
(6) Chatani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am. Chem.
Soc. 1998, 120, 5335.
r-Dicarbonyl Compounds as a Ketone Component. Hav-
ing optimized the reaction conditions and the additive of choice,
we then performed cyclocoupling reactions with a range of
R-dicarbonyl compounds as the ketone component. The results
are shown in Table 2. In all cases, the reactions were clean,
and no byproducts could be detected by GC or TLC, even in
the crude reaction mixture. We first examined a set of R-keto
(7) Chatani, N.; Morimoto, T.; Kamitani, A.; Fukumoto, Y.; Murai, S.
J. Organomet. Chem. 1999, 579, 177.
(8) A preliminary result has been communicated: Chatani, N.; Tobisu,
M.; Asaumi, T.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 1999, 121,
7160.
(9) For a related [2 + 2 + 1] cycloaddition leading to γ-lactams, see:
Chatani, N.; Tobisu, M.; Asaumi, T.; Murai, S. Synthesis 2000, 925.

Synthesis of Functionalized γ-Butyrolactones
J. Am. Chem. Soc., Vol. 122, No. 51, 2000 12665
Table 2. Ru3(CO)12-Catalyzed [2 + 2 + 1] Cyclocoupling of
R-Dicarbonyl Compounds, Ethylene, and COa
esters. The substituents on the ketone moiety have a significant
effect on the efficiency of the reaction. The introduction of an
electron-withdrawing group on the phenyl ring, as in 1a,
increased the yield of the lactone, while an electron-donating
group, as in 1c, retarded the reaction. A keto ester 1d which
contains an aliphatic keto moiety was less reactive in this
coupling. As was the case with the aromatic keto esters, the
introduction of electron-withdrawing groups, as in 1e, enhanced
the reactivity to afford the corresponding lactone 2e (detailed
discussion on the substituent effect, vide infra). Oxomalonic
acid diethyl ester (3) also serves as a good substrate.
We next examined R-keto amides as possible substrates. The
results obtained with acyclic keto amides such as N,N-dimethyl
benzoylformamide (no reaction) and N-methyl-N-phenyl ben-
zoylformamide (14%) were disappointing. However, a cyclic
keto amide 5 afforded the corresponding spirolactone 6 in
excellent yield. Interestingly, the addition of phosphine was not
necessary for this substrate. The enhanced reactivity of 5
presumably stems from the rigid s-cis orientation of the
dicarbonyl moiety in 5, which permits the facile formation of a
chelation complex with ruthenium, which we currently believe
to be a key intermediate in this catalysis, as in 13 (vide infra).
Finally, R-diketones were investigated as a family of R-di-
carbonyl compounds. In contrast to R-keto esters, both aromatic
and aliphatic ketones gave the coupling products in good yields.
Electron-poor as well as electron-rich diketones, such as 7b and
7c, efficiently afforded the corresponding lactones 8b and 8c,
respectively. Furthermore, heteroaromatic groups, including a
furan 7e and a thiophene 7f, can be tolerated. Indane-1,2,3-
trione (9) was also a good substrate for this cyclocoupling
reaction. The reaction took place specifically at the central
carbonyl group, which would be expected to be more reactive
than the terminal carbonyl groups in 9,11 to give a spirolactone
10. When unsymmetrical R-diketone 11 was reacted with
ethylene and CO under the same conditions as mentioned above,
isomeric lactones 12a and 12b were formed in favor of 12a
(eq 2). The preferential incorporation of a benzoyl group over
an acetyl group into the lactone ring is consistent with the fact
that 7a showed a higher reactivity than 7d in this cyclocoupling
reaction.
N-Heterocyclic Ketones as a Ketone Component. All the
applicable substrates discussed thus far have a carbonyl group
adjacent to the reacting ketone moiety. To better understand
the role of the adjacent carbonyl group, we examined some
ketones bearing other electron-withdrawing groups. Reactions
of benzoyl cyanide and pentafluoroacetophenone, as electroni-
cally activated ketones, were first investigated. However, no
reactions occurred with these substrates. On the basis of these
observations, we speculate that the adjacent carbonyl group was
not able to serve as an electron-withdrawing group but, rather,
functioned as a coordinating group and that the chelation
a Reaction conditions: ketone (2 mmol), ethylene (initial pressure
3 atm at 25 °C), CO (initial pressure 5 atm at 25 °C), and Ru3(CO)12
(0.05 mmol) in toluene (6 mL) at 160 °C for 20 h in a 50-mL stainless
autoclave, unless otherwise noted. b +, P(4-CF3C6H4)3 (0.15 mmol) was
added; -, no phosphine was added. c Isolated yields based on the
starting ketones. d For a reaction run at 180 °C.
(10) Golovin, M. N.; Rhaman, Md. M.; Belmonte, J. E.; Giering, W. P.
Organometallics 1985, 4, 1981. Neubrand, A.; Poe¨, A. J.; van Eldik, R.
Organometallics 1995, 14, 3249.
(11) Gill, R. B.; Idris, M. S. Hj.; Kirollos, K. S. J. Chem. Soc., Perkin
Trans. 1 1992, 2355.

12666 J. Am. Chem. Soc., Vol. 122, No. 51, 2000
Tobisu et al.
Table 3. Ru3(CO)12-Catalyzed [2 + 2 + 1] Cyclocoupling of
Chart 1
N-Heterocyclic Ketones, Ethylene, and COa
complex 13 (Chart 1) would be a key intermediate in this
cyclocoupling reaction. This speculation led us to employ the
2-pyridyl group as an adjacent group, since it could participate
in forming a chelation ring, as in 14 (Chart 1). Indeed, the
reactions proceeded well. In contrast to the reactions of
R-dicarbonyl compounds, the addition of phosphines was,
curiously, not required to obtain lactones in good yields (eq 3).
The reactions of a range of N-heterocyclic ketones and
aldehydes were carried out (Table 3). Both aromatic and
aliphatic ketones, even the sterically congested ketone 15g, can
be incorporated into the lactone ring efficiently in the absence
of phosphines. In the case of aldehyde 15h, the addition of PPh3
was effective in giving a high yield of the lactone 16h. It should
be noted that a variety of functional groups, such as trifluo-
romethyl, methoxy, and dimethylamino groups, can be tolerated
(see 15a, 15c, and 17, respectively). The spirolactone 20 is also
accessible from the reaction of the cyclic ketone 19. Heteroaro-
matic ketones containing pyrazine, 21, thiazole, 23, and oxazole,
25, rings gave the corresponding lactones in nearly quantitative
yields. Furthermore, the reaction is not limited to heteroaromatic
ketones. An oxazoline system, 27, also served as a good
substrate.
It is important to note that heteroaromatic ketones which do
not contain an sp2 nitrogen, such as 2-acetylpyrrole (29),
2-acetylfuran (30), and 2-acetylthiophene (31) (Chart 2), did
not give the corresponding lactones. In addition, the cyclocou-
pling reaction of 3-acetylpyridine (32) and 2-pyridylacetone (33)
did not take place. These results indicate that the five-membered
chelation complex, formed through the coordination of sp2-
hybridized heteroatom (N or O) to the ruthenium, as in 13 and
14 (Chart 1), appears to be a key intermediate as speculated
above. Interestingly, 4-acetylthiazole (34), which is able to form
a five-membered chelation complex similar to 14, did not afford
a cyclocoupling product, while the isomeric ketone 23 proved
to be a good substrate. This observation has an important
implication, in that conjugation between the adjacent CdX
moiety (X ) O, N) and the reacting carbonyl group is a
significant factor for this coupling reaction to proceed.
Substituted Alkenes as an Olefin Component. We next
examined the scope of the reaction in the context of the olefin
component. The reactions of unsymmetrical ketones with
unsymmetrical olefins could, in theory, result in the formation
of four isomeric lactones. To avoid complexities that might arise
in these reactions, we initially investigated the reactions of
symmetrical ketones with an array of symmetrical olefins (Table
4). The reaction of di-2-pyridyl ketone (15d) with cis-5-decene
in the presence of Ru3(CO)12 and P(4-CF3C6H4)3 afforded the
cis-substituted lactone 35 as the sole product in modest yield.
a Reaction conditions: ketone (2 mmol), ethylene (initial pressure
3 atm at 25 °C), CO (initial pressure 5 atm at 25 °C), and Ru3(CO)12
(0.05 mmol) in toluene (6 mL) at 140 °C for 20 h in a 50-mL stain-
less autoclave, unless otherwise noted. b Isolated yields based on the
starting ketones. c For a reaction run at 160 °C. d PPh3 (0.15 mmol)
was added.

Synthesis of Functionalized γ-Butyrolactones
J. Am. Chem. Soc., Vol. 122, No. 51, 2000 12667
Table 4. Ru3(CO)12-Catalyzed [2 + 2 + 1] Cyclocoupling of
Di-2-pyridyl Ketone (15d), Symmetrical Olefins, and COa
Chart 2
Prolongation of the reaction time (60 h) increased the yield to
85% with no loss of stereoselectivity. Likewise, the use of trans-
5-decene as an olefin produced the trans-substituted lactone 36
stereospecifically, while the reaction rate was considerably slow
relative to that of cis-isomer. Based on the observation that the
cis-isomer showed a higher reactivity than the trans-isomer,
cyclic olefins were assumed to serve as a good coupling partner.
As expected, the reaction of 15d with cyclopentene furnished
the bicyclic lactone 37 in excellent yield, even in the absence
of the phosphine ligand. The remarkable acceleration effect of
P(4-CF3C6H4)3 was again observed in the reactions with larger
membered cycloalkenes, such as cyclohexene, cycloheptene, and
cyclooctene, which afforded cis-fused bicyclic lactones 38-40
quite efficiently. Furthermore, the reaction of stereoisomeric
mixture of cyclododecene (cis/trans ) ca. 2/1) afforded the
corresponding lactone 41 as a mixture of stereoisomers. As
would be expected from the higher reactivity of cis-olefins, the
stereochemistry of the major isomer of 41 was determined to
be cis by an NOE experiment (see Supporting Information for
details). 1,4-Cyclohexadiene also serves as an olefin component
to give bicyclic lactone 42, which contains an olefin moiety,
which can be amenable to further elaboration. The tetrahydro-
furan-fused lactone 43 was also synthesized through this
catalysis, although the reaction rate was relatively slow com-
pared to that of cyclopentene. These results obtained for the
reactions with cycloalkenes demonstrate that the present inter-
molecular [2 + 2 + 1] cycloaddition would provide a new
convergent method for the construction of a wide range of
bicyclic skeletons, which are not otherwise easily accessible.
We then turned our attention to the use of terminal olefins
as the alkene component and discovered that some unpolarized
olefins were applicable to this cyclocoupling, as shown in Table
5. In all cases, regioisomeric products were obtained. Both
regioisomers a and b can be isolated in pure form by flash
chromatography. The constitutions of the products have been
determined by either deuterium exchange experiments, X-ray
crystallography, or long-range C-H COSY spectra (see Sup-
porting Information for details). Propylene can be coupled with
15d and CO in the absence of phosphines to give the
â-substituted lactone 44a regioselectively (entry 1). A similar
trend was observed in the cyclocoupling reactions using other
terminal olefins such as 1-hexene and allyltrimethylsilane, which
afforded â-substituted isomers preferentially (entries 3 and 5).
The decrease in regioselectivities compared to the case of
propylene indicates that the increased steric bulk of the olefin
favors the formation of the R-substituted isomers. The cyclo-
coupling reactions of 1,1-disubstituted, conjugated, and electron-
deficient olefins, as shown in Chart 3, did not proceed at an
appreciable rate.
a Reaction conditions: ketone (1 mmol), olefin (10 mmol), CO
(initial pressure 5 atm at 25 °C), and Ru3(CO)12 (0.025 mmol) in toluene
(3 mL) at 160 °C for 20 h in a 50-mL stainless autoclave, unless
otherwise noted. b +, P(4-CF3C6H4)3 (0.075 mmol) was added; -, no
phosphine was added. c Isolated yields based on the starting ketones.
d For a reaction run for 60 h. e Ca. 2:1 cis/trans mixture. f The numbers
1
in the parentheses are the ratios of isomers determined by H NMR.
g For a reaction run for 64 h. h For a reaction run for 80 h.
additives to clarify the factors which control the regioselectivity
of the reaction. As a result, it was found that neither an increase
in the amount of the phosphine nor the change in the electronic
nature of the phosphine affected the regioselectivity significantly
(see table in Supporting Information for details).
We next investigated the reactions of unsymmetrical ketones
with symmetrical cyclic olefins, in which the formation of two
stereoisomeric lactones is possible (Table 6). It was found that
2-benzoylthiazole (47) reacted with cyclopentene smoothly to
furnish the bicyclic lactone 48 as the sole product (entry 1),
the stereochemistry of which was determined by X-ray crystal-
It is noteworthy that the addition of PPh3 led to the converse
in regioselectivity, namely, R-substituted lactones b predomi-
nated over â-substituted isomers a (entries 2, 4, and 6). This
finding led us to examine a series of phosphines, as potential

12668 J. Am. Chem. Soc., Vol. 122, No. 51, 2000
Tobisu et al.
Table 5. Ru3(CO)12-Catalyzed [2 + 2 + 1] Cyclocoupling of
Di-2-pyridyl Ketone (15d), Terminal Olefins, and COa
Table 6. Ru3(CO)12-Catalyzed [2 + 2 + 1] Cyclocoupling of
Unsymmetrical Ketones, Cyclopentene, and COa
entry
olefin
R ) Med
additiveb
yield (a/b)c
1
2
3
4
5
6
-
+
-
+
-
+
44, 91% (94/5)
44, 90% (40/60)
45, 91% (78/22)
45, 90% (13/87)
46, 85% (81/19)
46, 88% (14/86)
R ) Bu
R ) CH2SiMe3
a Reaction conditions: ketone (2 mmol), olefin (20 mmol), CO
(initial pressure 5 atm at 25 °C), and Ru3(CO)12 (0.05 mmol) in toluene
(6 mL) at 160 °C for 20 h in a 50-mL stainless autoclave, unless
otherwise noted. b +, PPh3 (0.15 mmol) was added; -, no phosphine
was added. c Isolated yields based on the starting ketones. The numbers
in the parentheses are the ratios of isomers determined by GC analysis.
d Initial pressure 3 atm at 25 °C of propylene was used.
Chart 3
a Reaction conditions: ketone (2 mmol), olefin (20 mmol), CO
(initial pressure 5 atm at 25 °C), and Ru3(CO)12 (0.05 mmol) in toluene
(6 mL) at 160 °C for 20 h in a 50-mL stainless autoclave, unless
otherwise noted. b +, P(4-CF3C6H4)3 (0.15 mmol) was added; -, no
phosphine was added. c Isolated yields based on the starting ketones.
The numbers in the parentheses are the ratios of isomers determined
lography. Similarly, the reaction of 2-benzoylpyridine (15b) also
proceeded in a stereoselective manner to give the corresponding
lactone 49 (entry 3). The stereochemistry of 49 was determined
by analogy to 48. On the other hand, a very low selectivity as
well as a low reactivity was observed for 2-acetylpyridine (15e)
(entry 5). When P(4-CF3C6H4)3 was used as an additive, 50
was formed with a high degree of stereoselectivity (entry 6),
while no significant change in stereoselectivity was observed
for the reactions of phenyl ketones (entries 2 and 4). The
stereochemistry of the major isomer of 50 was determined by
comparison with related compounds (see Supporting Information
for details).
Finally, the reaction of unsymmetrical ketone 15e with
propylene, in which four stereoisomeric lactones could be
formed, was performed. The reaction proceeded in a normal
manner with a high degree of regioselectivity, affording
â-substituted lactones 51a and 51b in a ratio of 57:43 (eq 4).
1
by H NMR and GC analysis. d The stereochemistry was determined
by X-ray crystallography. e The stereochemistry was determined by
analogy to 48. f The stereochemistry was determined by comparison
with related compounds. g For a reaction run for 72 h.
of alkynes as a two-carbon π-system. A representative selection
of internal alkynes was tested in the catalyzed cycloaddition of
di-2-pyridyl ketone (15d). The results are summarized in Table
7. The reaction of 15d with diphenylacetylene and CO in the
presence of Ru3(CO)12 and PPh3 led to the formation of the
unsaturated lactone 52 in excellent yield (entry 1). Dialkyl
acetylene can also be incorporated to give the corresponding
lactone 53 in modest yield. (entry 2). In addition, it was found
that phenyl and methyl groups on the alkyne moiety were well-
differentiated in the present cyclocoupling. The use of 1-phenyl-
1-propyne resulted in the formation of 54 in a regioselective
manner (entry 3). Furthermore, silyl alkynes were found to be
good coupling partners. The silyl group serves not only as an
activating agent for the alkyne moiety toward cycloaddition but
also to regulate the regiochemical course of the cycloaddition.
As a result, the R-silylated lactone 55a was produced highly
regioselectively in an excellent yield (entry 4). The silylated
phenyl acetylene gave 56 in a similar manner (entry 5). Since
the silyl groups in 55 and 56 can be removed by treatment with
tetrabutylammonium fluoride in methanol, the silyl alkynes can
therefore function as the equivalent of terminal alkynes. Bis-
(trimethylsilyl)acetylene and dimethyl acetylenedicarboxylate
did not give the corresponding lactones.
The reactions presented in Table 7 can be regarded as the
hetero Pauson-Khand type reaction, in which a carbonyl group
in place of an olefin is incorporated into the five-membered
Cyclocoupling Using Alkynes. To further extend the scope
of this new cycloaddition, we next investigated the reactivity

Synthesis of Functionalized γ-Butyrolactones
J. Am. Chem. Soc., Vol. 122, No. 51, 2000 12669
Table 7. Ru3(CO)12-Catalyzed [2 + 2 + 1] Cyclocoupling of
Di-2-pyridyl Ketone (15d), Alkynes, and COa
(eq 6). The cyclopentane-fused lactone 60b is presumably
formed via the cyclization of the isomerized starting material.13
Substituent Effects. In the course of our investigation on
functional group compatibility of the reaction, it was observed
that the electronic nature of the reacting ketone moiety has a
significant effect on the reaction rate. Because of this, the
substituent effects of a representative set of the reactions were
examined.
First, the cyclocoupling of a set of aromatic keto esters 1
was tested. As shown in Table 2, both 1a and 1b gave the
corresponding lactones in excellent yields when the reactions
were carried out in the presence of P(4-CF3C6H4)3, whereas the
use of 1c, which contains an electron-donating group, led to a
lowered yield. To evaluate the reactivity of each substrate, the
reaction was conducted in the absence of the phosphine (eq 7).
As a result, it was found that the order of the reactivity is as
follows: OCH3 < H < CF3.
a Reaction conditions: 15d (1 mmol), alkyne (10 mmol), CO (initial
pressure 5 atm at 25 °C), Ru3(CO)12 (0.025 mmol), and P(4-CF3C6H4)3
(0.075 mmol) in toluene (3 mL) at 160 °C for 20 h in a 50-mL stainless
autoclave, unless otherwise noted. b Isolated yields based on 15d. c 1.1
mmol of diphenyl acetylene and PPh3 in place of P(4-CF3C6H4)3 were
used. d 6% of unidentified isomers and 22% of 15d were also obtained.
e For a reaction run for 70 h. f The ratio of the isomers was determined
by 1H NMR. g The ratio of the isomers was determined by GC analysis.
h 2 mmol of trimethyl(phenylethynyl)silane was used.
ring. To our knowledge, there is no precedent for catalytic
intermolecular variants of this process.12
Intramolecular Cyclocoupling. Although an intramolecular
[2 + 2 + 1] cycloaddition of ketones, olefins, and CO has been
achieved by use of titanium complexes as mentioned above,4,5
it remains a rare phenomenon. Our successful application of
intermolecular [2 + 2 + 1] cycloaddition to the synthesis of
γ-butylolactone encouraged us to examine the intramolecular
cyclocoupling, which leads to relatively complex bicyclic
lactones in a single step. As a result, we were pleased to find
that N-heterocyclic ketones, which contain a suitably positioned
olefin, underwent the expected carbonylative cycloaddition.
Olefinic ketone 57 reacted with CO in the presence of the Ru3-
(CO)12 catalyst, affording the bicyclic lactone 58 in good yield
(eq 5). Lengthening the tethered chain resulted in the formation
of cyclohexane-fused γ-lactone 60a, along with cyclopentane-
fused γ-lactone 60b, while the reaction rate was relatively slow
The reactions of a set of pyridyl aryl ketones 15 in the absence
of the phosphine were next investigated. In sharp contrast to
the results obtained for the keto esters shown in eq 7, the
introduction of an electron-donating group enhanced the reactiv-
ity, and a dramatic decrease in rate was observed for the case
of the CF3 containing ketone 15a (eq 8).
Last, we examined the substituent effects on the reactions of
pyridyl ketones 15 with cyclohexene, in which the remarkable
acceleration effect of P(4-CF3C6H4)3 was observed, as shown
in Table 4. Interestingly and importantly, an inverse order
(12) For a catalytic intramolecular hetero Pauson-Khand type reaction,
in which an alkyne, a CdX moiety (X ) O, N), and CO are incorporated,
see refs 6 and 7.
(13) Olefin isomerization occurred to some extent after 20 h of reaction.

12670 J. Am. Chem. Soc., Vol. 122, No. 51, 2000
Tobisu et al.
Table 8. Effects of Ethylene and CO Pressures on the
Cycloaddition of 1b, Ethylene, and COa
entry
ethylene (atm)
CO (atm)
yieldb (%)
1
2
3
4
5
6
7
5
10
15
20
5
5
5
5
5
5
59
64
71
79
27
15
11
compared to the reaction with ethylene was observed, namely,
the reactivity order was as follows: OCH3 < H < CF3 (eq 9).
5
10
15
20
a Reaction conditions: 1b (0.5 mmol), ethylene, CO, Ru3(CO)12 (0.04
mmol), and P(4-CF3C6H4)3 (0.12 mmol) in toluene (6 mL) at 160 °C
for 8 h in a 50-mL stainless autoclave. b GC yields based on 1b.
Table 9. Effects of Ethylene and CO Pressures on the
Cycloaddition of 15b, Ethylene, and COa
entry
ethylene (atm)
CO (atm)
yieldb (%)
1
2
3
4
5
6
7
5
10
15
20
5
5
5
5
5
5
54
49
45
30
74
78
100
As shown in eqs 7-9, the reactions are quite sensitive to the
electronic nature of the reacting keto moiety. The trends in
substituent effect are closely related to the additive effect of
phosphine derivatives. In the case of reactions in which the
addition of phosphines accelerates the reaction rate, electron-
deficient ketones are more reactive (eqs 7 and 9). On the other
hand, electron-rich ketones show a higher reactivity in the
reactions in which it is not necessary to use a phosphine ligand
to obtain a high product yield (eq 8).
5
10
15
20
a Reaction conditions: 15b (1 mmol), ethylene, CO, and Ru3(CO)12
(0.01 mmol) in toluene (6 mL) at 140 °C for 9 h in a 50-mL stainless
autoclave. b GC yields based on 15b.
Scheme 2. A Related Stoichimetric Reaction (1)14
Effects of CO and Ethylene Pressures. In view of the
marked difference in the substituent effect between the reactions
of keto esters and those of pyridyl ketones, a comparison
between these reactions with regard to other reaction parameters,
such as CO and ethylene pressure, has been made. Initially, the
cyclocoupling of the keto ester 1b was conducted under various
pressures of ethylene and CO, as shown in Table 8. As the
pressure of ethylene increased, higher yields of 2b were
observed (entries 1-4). In contrast, the reaction rates were
lowered when higher pressures of CO were used (entries 1, 5,
6, and 7).
Next, the effects of ethylene and CO pressures on the
cycloaddition of 15b were investigated (Table 9). Again, 15b
behaved in a manner distinctly different from 1b. The higher
yields of 16b were obtained either at a lower pressure of
ethylene or at a higher pressure of CO. These observations
provide valuable insight into the rate-limiting step of the catalytic
cycle (vide infra).
maleate and CO to afford the metallacycle 64 (Scheme 2).14
The formation of 64 was rationalized by assuming the formation
of complex 63, which could be formed via the cycloaddition of
dimethyl maleate onto the complex 62.15
Another example is the reaction of the iron complex of 1-aza-
4-oxo-1,3-butadiene 65 with dimethyl acetylenedicarboxylate
Mechanistic Aspects. A literature survey led us to discover
a stoichiometric transformation which is relevant to the present
results, reported by Fru¨hauf and co-workers. They reported a
series of reactions of complexes M(CO)3(RsNdCsCdNsR)
and M(CO)3(RsNdCsCdO) (M ) Fe, Ru) with electron-
deficient alkenes and alkynes. For example, the ruthenium
complex of 1,4-diaza-1,3-butadiene 62 reacted with dimethyl
(14) van Wijnkoop, M.; de Lange, P. P. M.; Fru¨hauf, H.-W.; Vrieze,
K.; Smeets, W. J. J.; Spek, A. L. Organometallics 1995, 14, 4781.
(15) A related complex was characterized by X-ray crystallography: van
Wijnkoop, M.; de Lange, P. P. M.; Fru¨hauf, H.-W.; Vrieze, K.; Wang, Y.;
Goubitz, K.; Stam, C. H. Organometallics 1992, 11, 3607.

Synthesis of Functionalized γ-Butyrolactones
J. Am. Chem. Soc., Vol. 122, No. 51, 2000 12671
Scheme 3. A Related Stoichiometric Reaction (2)16a
ligands enhanced the reactivity of the related iron complex
toward cycloaddition with electron-deficient alkenes and alkynes.21
It therefore seems likely in our system that the phosphine
derivative serves as a σ-donor ligand and thus facilitates the
cycloaddition step. Although a σ-donor ligand has a positive
effect on the rate of the cycloaddition step, the use of more
basic phosphines could inhibit both the initial formation of
coordinatively unsaturated ruthenium species and the coordina-
tion of the substrate to the ruthenium center. Accordingly, the
success of the utilization of P(4-CF3C6H4)3 presumably stems
from its less basic character that facilitates the oxametallacycle
C-forming process without interrupting the formation of the
catalytically active species.
The issue of whether the addition of phosphine ligands
increases the yield largely depends on the structures of the
ketones and olefins. In the reactions of R-dicarbonyl compounds
with ethylene and those of N-heterocyclic ketones with internal
alkenes, the yields are dramatically increased by using P(4-
CF3C6H4)3. Following the rationale of the role of the phosphine
ligands, it is most likely that the rate-limiting step in these
reactions is the cycloaddition step of an alkene to complex B.
Substituent effects of these reactions also support this view. The
oxametallacycle C-forming step can be regarded as a formal
oxidative cyclization, in which the valence of the ruthenium
increases by 2. During this event, the ligand which participates
in the oxidative cyclization (i.e., A) is reduced, so that an
electron-deficient ketone would be expected to form oxamet-
allacycle C more rapidly. Consistent with this consideration,
the introduction of an electron-withdrawing group on the ketone
moiety indeed led to an increased yield of the products in the
phosphine-accelerated reactions, as shown in eqs 7 and 9.
Furthermore, the effects of pressures of ethylene and CO, as
shown in Table 8, can also be explained by the assumption that
the cycloaddition of an olefin onto B is rate-limiting. A higher
pressure of ethylene clearly would enhance the rate of the
catalysis, since ethylene is involved in the rate-limiting step. In
contrast, a higher pressure of CO should render it difficult both
for the coordinatively unsaturated ruthenium species to be
generated and for the substrate to coordinate to ruthenium, thus
retarding the overall reaction.
Scheme 4. A Possible Mechanism
and CO, which leads to the formation of butenolide complex
68, presumably via the reductive elimination of the iron moiety
from the metallacycle 67 (Scheme 3).16a
In light of the results of these stoichiometric reactions, we
propose a reaction mechanism as shown in Scheme 4. The
coordination of the substrate A (X ) O or N) to a coordinatively
unsaturated ruthenium species,17 such as Ru(CO)3 or Ru(CO)2-
(PAr3),18 forms a σ,σ-chelate ruthenium complex B.19 The
complex B reacts with an alkene (or an alkyne) to give the
oxametallacycle C, with the coordination of X to ruthenium
remaining intact. The subsequent CO insertion into a Ru-O
bond20 in C affords the metallacycle D, as for the cases of 64
and 67 in Schemes 2 and 3, respectively. The reductive
elimination of D leads to the formation of the final product E.
The rate of the cycloaddition of B with an alkene would be
expected to be accelerated by increasing the electron density in
the vicinity of the ruthenium, since the ruthenium is oxidized
from 0 to 2+ when C is formed. Indeed, Fru¨hauf et al. reported
that replacing the CO ligands with more σ-donating isonitrile
On the other hand, the cyclocoupling occurs smoothly, even
in the absence of phosphine derivatives in the reactions of
N-heterocyclic ketones with relatively reactive alkenes, such as
ethylene, cyclopentene, and terminal olefins. The observation
indicates that the rate-limiting step in these reactions is not the
oxidative cyclization process but a later step, most likely CO
insertion or reductive elimination. The observation that the
cyclocoupling of the pyridyl ketone is retarded at higher pressure
of ethylene (see Table 9) is also indicative of its irrelevance to
the rate-limiting step. Considering the observation on the effect
of CO pressures (see Table 9), the CO insertion step (i.e., C f
D) is likely to be rate-limiting. This rationale is corroborated
by the finding that the opposite substituent effect relative to
the phosphine-accelerated reactions was observed, as shown in
eq 8. The fact that the CO insertion process is accelerated by
the introduction of an electron-donating group on the migrating
group22 could account for the observed substituent effect.
(16) (a) van Wijnkoop, M.; Siebenlist, R.; de Lange, P. P. M.; Fru¨hauf,
H.-W.; Vrieze, K.; Smeets, W. J. J.; Spek, A. L. Organometallics 1993,
12, 4172. For a related stiochiometric reaction using methyl propynoate,
see: (b) van Wijnkoop, M.; Siebenlist, R.; Ernsting, J. M.; de Lange, P. P.
M.; Fru¨hauf, H.-W.; Horn, E.; Spek, A. L. J. Organomet. Chem. 1994,
482, 99.
(17) The precise structure of the catalytically active species is not clear.
A mononuclear species is postulated here on the basis of the related
stoichiometric reactions, as shown in Schemes 2 and 3.
(18) In the phosphine-accelerated reactions, it is likely that the mono-
phosphine complex is responsible for the catalysis. Both the catalyst/ligand
ratio and the observed low activity on using bidentate phosphines support
this view.
(21) de Lange, P. P. M.; Fru¨hauf, H.-W.; van Wijnkoop, M.; Vrieze,
K.; Wang, Y.; Heijdenrijk, D.; Stam, C. H. Organometallics 1990, 9, 1691.
de Lange, P. P. M.; Fru¨hauf, H.-W.; Kraakman, M. J. A.; van Wijnkoop,
M.; Kranenburg, M.; Groot, A. H. J. P.; Vrieze, K.; Fraanje, J.; Wang, Y.;
Neuman, M. Organometallics 1993, 12, 417. de Lange, P. P. M.; de Boer,
R. P.; van Wijnkoop, M.; Ernsting, J. M.; Fru¨hauf, H.-W.; Vrieze, K.;
Smeets, W. J. J.; Spek, A. L.; Goubitz, K. Organometallics 1993, 12, 440.
(19) Beers, O. C. P.; Bouman, M. M.; Elsevier, C. J.; Smeets, W. J. J.;
Spek, A. L. Inorg. Chem. 1993, 32, 3015.
(20) The possibility that CO is inserted into a Ru-C bond in C cannot
be excluded.

12672 J. Am. Chem. Soc., Vol. 122, No. 51, 2000
Scheme 5. An Alternative Mechanism
Tobisu et al.
CF3C6H4)3 led to a dramatically enhanced reaction rate. A
variety of cyclic olefins, unpolarized terminal olefins, and
internal alkynes have been successfully used in the synthesis
of highly functionalized γ-lactones. Remarkable differences in
additive effects, substituent effects, and a dependence on reaction
parameters, such as the pressure of ethylene and CO, were
observed between the reactions of R-dicarbonyl compounds and
those of N-heterocyclic ketones with ethylene. Such differences
can be rationalized by assuming that the rate-limiting step in
the catalytic cycle is different for these two types of reactions.
The present catalytic reactions demonstrate the potential utility
of the intermolecular [2 + 2 + 1] cycloaddition protocol for
the synthesis of functionalized lactones. Further studies on this
and related carbonylative cycloadditions are currently underway.
Experimental Section
The distinct difference in reactivities between R-dicarbonyl
compounds and N-heterocyclic ketones can be attributed to
differences in the coordination ability between oxygen and
nitrogen atoms. Because of the strong basicity of the nitrogen
atom, N-heterocyclic ketones themselves can serve as a good
σ-donor ligand that renders the ruthenium center sufficiently
electron-rich to undergo the cycloaddition with relatively
reactive alkenes, such as ethylene, cyclopentene, and terminal
olefins, in the absence of external σ-donor ligands. While the
exact mechanism for the key oxidative cyclization step (i.e., B
f C) remains unknown,23 the conjugation between the CdX
moiety (X ) N, O) and CdO in A appears to be one of the
important factors for the cycloaddtion step to proceed. It should
be noted that an alternative mechanism, which consists of the
initial CO insertion to F and the subsequent addition of an alkene
(or an alkyne) onto the resulting metallacycle G, cannot be
excluded (Scheme 5).
Although the regio- and stereoselectivities observed in the
reactions of unsymmetrical substrates (Tables 5 and 6) represent
quite interesting phenomena, the issue of what determines the
regio- or stereochemical course of the reactions is not presently
clear. With respect to the regioselectivity in reactions which
involve the use of terminal alkenes, not only steric and electronic
properties of the olefin employed but also steric and electronic
environments provided by the ligand significantly affect the
regioselectivity of the reaction. The unraveling of these en-
tangled factors will be the subject of future studies.
Materials. Commercial grade reagents were used as received except
as indicated below. Toluene was distilled over CaH2. PBu3 and 15h
were purified by distillation prior to use. Ru3(CO)12 was prepared
according to the literature procedure24 and used after recrystallization
from hexane. Ketones 1b, 1d, 1e, 3, 5, 7a-7f, 9, 11, 15b, 15d, 15h,
21, 23, 29, 30, 31, and 32 are commercially available and were used
as received. 1c,25 1f,26 9,11 15g,27 19,28 25,29 27,30 33,31 34,32 and
trimethyl(phenylethynyl)silane33 were prepared according to the litera-
ture procedures. 1a was prepared by the Ti(OiPr)4-catalyzed transes-
terification34 of the corresponding ethyl ester.35 15a and 15c were
prepared by the reactions of the corresponding arylmagnesium bromides,
with 15h, followed by PCC oxidation. 15f was prepared from butyl-
magnesium bromide and 2-cyanopyridine. 47 was prepared by the
reaction of 2-lithiothiazole and benzonitrile. See Supporting Information
for the preparation of 17, 57, and 59.
Typical Procedure for Cyclocoupling of Ketones, Ethylene, and
CO. A 50-mL stainless autoclave was charged with methyl benzoyl-
formate (1b) (2 mmol, 328 mg), P(4-CF3C6H4)3 (0.15 mmol, 70 mg),
toluene (6 mL), and Ru3(CO)12 (0.05 mmol, 32 mg) under N2. After
the system was flushed with 10 atm of ethylene three times, it was
pressurized with ethylene to 3 atm and then with carbon monoxide to
an additional 5 atm. The autoclave was then immersed in an oil bath
at 160 °C. After 20 h had elapsed, it was removed from the oil bath
and allowed to cool for ca. 1 h, and the gases were then released. The
contents were transferred to a round-bottomed flask with toluene, and
the volatiles were removed by flash evaporation. The residue was
subjected to column chromatography on silica gel (eluent, hexane/
EtOAc ) 5/1) to give tetrahydro-5-oxo-2-phenyl-2-furancarboxylic acid
methyl ester (2b) (413 mg, 94% yield) as a colorless solid. Purification
by bulb-to-bulb distillation afforded an analytically pure product.
Tetrahydro-5-oxo-2-phenyl-2-furancarboxylic acid methyl ester
(2b): colorless solid; mp 54-56 °C (hexane); Rf 0.34 (hexane/EtOAc
Conclusion
We have demonstrated herein that Ru3(CO)12 catalyzes the
intermolecular cyclocoupling of ketones (or aldehydes), alkenes
(or alkynes), and CO. The reaction represents the first example
of the catalytic synthesis of heterocycles via an intermolecular
carbonylative [2 + 2 + 1] cycloaddition. A variety of ketones,
such as R-dicarbonyl compounds and N-heterocyclic ketones,
are applicable to the present reaction. In the case of the
cycloaddition of R-dicarbonyl compounds, the addition of P(4-
1
) 5/1); H NMR (CDCl3) δ 2.52-2.71 (c, 3H), 3.06-3.12 (m, 1H),
3.75 (s, 3H), 7.38-7.43 (c, 3H), 7.49-7.53 (c, 2H); 13C NMR (CDCl3)
δ 28.00, 33.37, 53.30, 86.79, 124.92 (2C), 128.63 (2C), 128.77, 137.92,
(24) Bruce, M. I.; Jensen, C. M.; Jones, N. L. Inorg. Synth. 1989, 26,
259.
(25) Rossi, R.; Carpita, A.; Pazzi, P.; Mannina, L.; Valensin, D.
Tetrahedron 1999, 55, 11343.
(26) Sugimura, H.; Yoshida, K. Bull. Chem. Soc. Jpn. 1992, 65, 3209.
(27) Nordstro¨m, K.; Macedo, E.; Moberg, C. J. Org. Chem. 1997, 67,
11604.
(28) Epsztajn, J.; Bieniek, A. J. Chem. Soc., Perkin Trans. 1 1985, 213.
(29) Harn, N. K.; Gramer, C. J.; Anderson, B. A. Tetrahedron Lett. 1995,
36, 9453.
(30) Meyers, A. I.; Slade, J. J. Org. Chem. 1980, 45, 2785.
(31) Cassity, R. P.; Taylor, L. T.; Wolf, J. F. J. Org. Chem. 1978, 43,
2286.
(32) De Maria, P.; Fontana, A.; Arlotta, M.; Chimichi, S.; Spinelli, D.
J. Chem. Soc., Perkin Trans. 2 1994, 415.
(33) Kurita, J.; Ishii, M.; Yasuike, S.; Tsuchiya, T. J. Chem. Soc., Chem.
Commun. 1993, 17, 1309.
(34) Imwinkelried, K.; Shiess, M.; Seebach, D. Org. Synth. 1987, 65,
230.
(22) (a) The rates of migration of M-C onto CO are accelerated by the
presence of an electron-donating group: Collman, J. P.; Hegedus, L. S.;
Norton, J. R.; Finke, R. G. Principles and Applications of Organotransition
Metal Chemistry; University Science Books: Mill Valley, CA, 1987;
Chapter 6 and references therein. (b) The rates of migratory insertion of
CO into M-O bonds are thought to be accelerated by the presence of an
electron-donating group, since the nucleophilicity of alkoxo ligands is an
impotant factor for the process: Rees, W. M.; Churchill, M. R.; Fettinger,
J. C.; Atwood, J. D. Organometallics 1985, 4, 2179.
(23) Fru¨hauf mentioned in his reports that the addition of an activated
alkene (or alkyne) toward σ-N, σ-X chelate iron and ruthenium complexes,
such as 62 and 65, can be regarded as a 1,3-dipolar cycloaddition, in view
of the isolobal relationship. However, some of the results obtained in our
system, such as the low reactivity of electron-deficient olefins, are difficult
to explain by the 1,3-dipolar cycloaddition mechanism.
(35) Creary, X. J. Org. Chem. 1987, 52, 5026.

Synthesis of Functionalized γ-Butyrolactones
J. Am. Chem. Soc., Vol. 122, No. 51, 2000 12673
170.78, 174.88; IR (KBr) 1796 s, 1746 s, 1603 w; MS, m/z (relative
intensity) 220 (M+, 1), 161 (100). Anal. Calcd for C12H12O4: C, 65.44;
H, 5.49. Found: C, 65.34; H, 5.49.
Hz, 1H), 7.21 (ddd, J ) 7.6 Hz, J ) 5.0 Hz, J ) 1.0 Hz, 1H), 7.51
(dd, J ) 7.9 Hz, J ) 1.0 Hz, 1H), 7.70 (ddd, J ) 7.9 Hz, J ) 7.6 Hz,
J ) 1.7 Hz, 1H), 8.59 (ddd, J ) 5.0 Hz, J ) 1.7 Hz, J ) 1.0 Hz, 1H);
13C NMR (CDCl3) δ 23.65, 26.29, 28.42, 28.82, 45.46, 49.73, 87.32,
118.34, 122.23, 136.79, 148.91, 163.78, 180.36; IR (neat) 1786 s; MS,
m/z (relative intensity) 217 (M+, 9), 122 (100). Anal. Calcd for C13H15-
NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.79; H, 7.18; N, 6.44.
Minor isomer: colorless oil; Rf 0.26 (hexane/EtOAc ) 1/1); 1H
NMR (CDCl3) δ 0.77-0.88 (m, 1H), 1.42-1.55 (s, 3H), 2.03 (q, J )
5.6 Hz, 2H), 3.06 (q, J ) 7.9 Hz, 1H), 3.33 (td, J ) 7.9 Hz, J ) 5.6
Hz, 1H), 7.18 (ddd, J ) 7.6 Hz, J ) 4.6 Hz, J ) 1.0 Hz, 1H), 7.55 (d,
J ) 7.9 Hz, 1H), 7.69 (ddd, J ) 7.9 Hz, J ) 7.6 Hz, J ) 1.6 Hz, 1H),
8.59 (ddd, J ) 4.6 Hz, J ) 1.6 Hz, J ) 1.0 Hz, 1H); 13C NMR (CDCl3)
δ 26.09, 29.13, 29.21, 29.86, 46.13, 51.31, 88.17, 119.01, 122.12,
136.54, 148.94, 161.32, 179.85; IR (neat) 1776 s; MS, m/z (relative
intensity) 217 (M+, 3), 146 (100); HRMS calcd for C13H15NO2
217.1103, found 217.1107. The stereochemistry of the minor isomer
was determined by comparison with 51a. The upfield shift of 4-H
(0.77-0.88 ppm) in the minor isomer relative to 4-H in the major
isomer (1.53-2.17 ppm) indicates the cis relationship between the
pyridine ring and the fused ring.36
cis-Dihydro-4,5-dimethyl-5-(2-pyridinyl)-2(3H)-furanone (51a):
colorless oil; bp 130 °C (2 mmHg); Rf 0.09 (hexane/EtOAc ) 3/1); 1H
NMR (CDCl3) δ 0.67 (d, J ) 6.9 Hz, 3H), 1.82 (s, 3H), 2.35 (dd, J )
17.2 Hz, J ) 5.9 Hz, 1H), 2.72 (ddd, J ) 8.3 Hz, J ) 6.9 Hz, J ) 5.9
Hz, 1H), 2.87 (dd, J ) 17.2 Hz, J ) 8.3 Hz, 1H), 7.20 (ddd, J ) 7.6
Hz, J ) 4.0 Hz, J ) 1.7 Hz, 1H), 7.43 (d, J ) 7.9 Hz, 1H), 7.69 (ddd,
J ) 7.9 Hz, J ) 7.6 Hz, J ) 1.7 Hz, 1H), 8.60 (d, J ) 4.0 Hz, 1H);
13C NMR (CDCl3) δ 16.18, 26.00, 36.98, 40.56, 89.52, 119.64, 122.39,
136.50, 149.00, 159.84, 176.42; IR (neat) 1781 s; MS, m/z (relative
intensity) 191 (M+, 2), 122 (100). Anal. Calcd for C11H13NO2: C, 69.09;
H, 6.85; N, 7.32. Found: C, 69.12; H, 6.90; N, 7.43. The regiochemistry
of 51a was determined by long-range 13C-1H COSY measurements
(see Supporting Information for details). The stereochemistry of 51a
was determined by comparison with 4,5-dimethyl-5-phenyl-2(3H)-
furanone.36
trans-Dihydro-4,5-dimethyl-5-(2-pyridinyl)-2(3H)-furanone (51b):
colorless oil; bp 130 °C (2 mmHg); Rf 0.14 (hexane/EtOAc ) 3/1); 1H
NMR (CDCl3) δ 1.28 (d, J ) 6.9 Hz, 3H), 1.64 (s, 1H), 2.29 (dd, J )
17.5 Hz, J ) 7.3 Hz, 1H), 2.61 (dd, J ) 17.5 Hz, J ) 7.9 Hz, 1H),
2.92 (qdd, J ) 7.9 Hz, J ) 7.3 Hz, J ) 6.9 Hz, 1H), 7.22 (ddd, J )
7.6 Hz, J ) 4.0 Hz, J ) 1.0 Hz, 1H), 7.54 (dd, J ) 7.9 Hz, J ) 1.0
Hz, 1H), 7.71 (ddd, J ) 7.9 Hz, J ) 7.6 Hz, J ) 1.7 Hz, 1H), 8.57 (d,
J ) 4.0 Hz, 1H); 13C NMR (CDCl3) δ 15.19, 21.66, 36.73, 38.94, 89.56,
118.67, 122.48, 136.87, 148.84, 162.93, 175.99; IR (neat) 1781 s, 1692
s; MS, m/z (relative intensity) 191 (M+, 9), 122 (100). Anal. Calcd for
C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.15; H, 6.86; N,
7.47. The regiochemistry of 51b was determined by long-range 13C-
1H COSY measurements (see Supporting Information for details).
cis-3,4-Dibutyldihydro-5,5-di(2-pyridinyl)-2(3H)-furanone (35):
colorless oil; Rf 0.34 (hexane/EtOAc ) 1/1); 1H NMR (CDCl3) δ 0.62
(t, J ) 6.9 Hz, 3H), 0.89 (t, J ) 6.9 Hz, 3H), 0.95-1.08 (c, 4H), 1.22-
1.58 (c, 7H), 1.72-1.87 (m, 1H), 2.17-2.57 (m, 1H), 4.11-4.17 (m,
1H), 7.12-7.20 (c, 2H), 7.48 (dd, J ) 7.9 Hz, J ) 1.0 Hz, 1H), 7.61
(td, J ) 7.9 Hz, J ) 1.0 Hz, 1H), 7.69 (td, J ) 7.9 Hz, J ) 1.0 Hz,
1H), 7.78 (td, J ) 7.9 Hz, J ) 1.0 Hz, 1H), 8.58 (ddd, J ) 4.6 Hz, J
) 1.0 Hz, J ) 0.7 Hz, 1H), 8.66 (ddd, J ) 5.0 Hz, J ) 1.0 Hz, J )
0.7 Hz, 1H); 13C NMR (CDCl3) δ 13.53, 13.91, 22.61, 23.03, 24.95,
25.09, 28.24, 30.05, 44.44, 44.82, 90.96, 120.01, 121.56, 122.07, 122.54,
136.39, 136.63, 148.54, 149.01, 158.82, 160.12, 178.17; IR (neat) 1784
s; MS, m/z (relative intensity) 352 (M+, 4), 185 (100); HRMS calcd
for C22H28N2O2 352.2151, found 352.2158. The stereochemistry of 35
was assigned to be cis on the basis of the NOE enhancement exhibited
between the ring junction protons (12%).
trans-3,4-Dibutyldihydro-5,5-di(2-pyridinyl)-2(3H)-furanone (36):
white solid; mp 65-67 °C (hexane/EtOAc); Rf 0.40 (hexane/EtOAc )
1/1); 1H NMR (CDCl3) δ 0.77-0.86 (c, 6H), 0.92-0.97 (m, 1H), 1.13-
1.80 (c, 11H), 2.70-2.75 (m, 1H), 3.53-3.61 (m,1H), 7.13-7.18 (m,
1H), 7.22-7.29 (c, 2H), 7.51 (dd, J ) 7.9 Hz, J ) 0.7 Hz, 1H), 7.58-
7.70 (c, 2H), 8.59 (ddd, J ) 4.6 Hz, J ) 1.0 Hz, J ) 0.7 Hz, 1H), 8.68
(ddd, J ) 4.6 Hz, J ) 1.0 Hz, J ) 0.7 Hz, 1H); 13C NMR (CDCl3) δ
13.87, 13.98, 22.61, 22.86, 28.91, 29.63, 29.98, 31.18, 46.48, 46.87,
90.70, 120.71, 121.84, 122.24, 122.77, 136.09, 136.63, 148.20, 148.98,
159.11, 160.81, 179.06; IR (neat) 1780 s; MS, m/z (relative intensity)
352 (M+, 5), 185 (100). Anal. Calcd for C22H28N2O2: C, 74.97; H,
8.01; N, 7.95. Found: C, 75.04; H, 8.10; N, 7.97.
Dihydro-4-methyl-5,5-di(2-pyridinyl)-2(3H)-furanone (44a): col-
1
orless oil; bp 200 °C (5 mmHg); Rf 0.26 (hexane/EtOAc ) 1/1); H
NMR (CDCl3) δ 0.92 (d, J ) 6.9 Hz, 3H), 2.45 (dd, J ) 16.5 Hz, J )
3.6 Hz, 1H), 2.80 (dd, J ) 16.5 Hz, J ) 7.9 Hz, 1H), 3.94-4.01 (m,
1H), 7.16-7.26 (c, 2H), 7.46 (d, J ) 8.3 Hz, 1H), 7.49 (d, J ) 7.9 Hz,
1H), 7.63-7.71 (c, 2H), 8.61 (d, J ) 4.6 Hz, 1H), 8.67 (d, J ) 5.0 Hz,
1H); 13C NMR (CDCl3) δ 16.52, 37.40, 37.63, 92.22, 120.42, 122.17,
122.37, 122.93, 136.41, 136.71, 148.45, 149.25, 158.69, 159.93, 176.28;
IR (neat) 1789 s; MS, m/z (relative intensity) 254 (M+, 20), 185 (100).
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.59; H, 5.46; N, 11.02. The regiochemistry was determined by long-
1
range H-13C COSY measurements (see Supporting Information for
details).
Dihydro-3-methyl-5,5-di(2-pyridinyl)-2(3H)-furanone (44b): col-
1
orless oil; bp 200 °C (5 mmHg); Rf 0.20 (hexane/EtOAc ) 1/1); H
NMR (CDCl3) δ 1.29 (d, J ) 7.3 Hz, 3H), 2.62 (t, J ) 12.0 Hz, 1H),
2.75-2.84 (m, 1H), 3.79 (dd, J ) 12.6 Hz, J ) 8.2 Hz, 1H), 7.18-
7.23 (c, 2H), 7.48 (d, J ) 7.0 Hz, 1H), 7.57 (d, J ) 6.8 Hz, 1H),
7.64-7.72 (c, 2H), 8.62 (d, J ) 4.9 Hz, 2H); 13C NMR (CDCl3) δ
14.86, 34.90, 40.72, 87.96, 120.11, 120.86, 122.71, 122.82, 136.77 (2C),
149.06, 149.18, 159.87, 160.61, 179.01; IR (neat) 1786 s; MS, m/z
(relative intensity) 254 (M+, 11), 210 (100). Anal. Calcd for
C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C, 70.87; H, 5.59;
3-Methyl-4-phenyl-5,5-di(2-pyridinyl)-2(5H)-furanone (54a): white
solid; mp 158-159 °C (hexane/EtOAc); Rf 0.34 (hexane/EtOAc ) 1/1);
1H NMR (CDCl3) δ 2.01 (s, 3H), 7.00 (ddd, J ) 7.1 Hz, J ) 4.6 Hz,
J ) 1.0 Hz, 2H), 7.19-7.28 (c, 5H), 7.42 (dt, J ) 7.9 Hz, J ) 1.0 Hz,
2H), 7.69 (ddd, J ) 7.9 Hz, J ) 7.1 Hz, J ) 1.0 Hz, 2H), 8.50 (ddd,
J ) 4.6 Hz, J ) 1.6 Hz, J ) 1.0 Hz, 2H); 13C NMR (CDCl3) δ 10.49,
93.23, 122.78 (2C), 123.22 (2C), 125.46, 127.69 (2C), 128.55, 129.07
(2C), 132.35, 136.63 (2C), 148.62 (2C), 157.34, 162.95, 173.64; IR
(KBr) 1758 s, 1652 m; MS, m/z (relative intensity) 328 (M+, 4), 283
(100). Anal. Calcd for C21H16N2O2: C, 76.81; H, 4.91; N, 8.53.
Found: C, 76.55; H, 4.95; N, 8.41. The regiochemistry of 54a was
1
N, 10.95. The regiochemistry was determined by long-range H-13C
COSY measurements (see Supporting Information for details).
Hexahydro-3-phenyl-3-(2-thiazolyl)-1H-cyclopenta[c]furan-1-
one (48): colorless crystals; mp 119-120 °C (hexane); Rf 0.03 (hexane/
EtOAc ) 5/1); 1H NMR (CDCl3) δ 1.10-1.18 (m, 1H), 1.50-1.67 (c,
3H), 2.04-2.13 (m, 2H), 3.28 (td, J ) 12.4 Hz, J ) 4.1 Hz, 1H),
3.98-4.07 (m, 1H), 7.25-7.40 (c, 4H), 7.56 (dd, J ) 8.0 Hz, J ) 1.2
Hz, 2H), 7.76 (d, J ) 3.0 Hz, 1H); 13C NMR (CDCl3) δ 25.64, 29.02,
29.51, 46.40, 50.93, 88.72, 120.88, 125.01 (2C), 128.01, 128.30 (2C),
139.30, 142.37, 174.03, 179.44; IR (KBr) 1780 s; MS, m/z (relative
intensity) 285 (M+, 13), 105 (100). Anal. Calcd for C16H15NOS: C,
67.35; H, 5.30; N, 4.91; S, 11.24. Found: C, 67.20; H, 5.33; N, 4.83;
S, 11.22. The stereochemistry of 48 was determined by X-ray
crystallography.
1
determined by comparison with 55. A lower H chemical shift of Me
group in 54a (2.01 ppm) relative to that in 54b (2.46 ppm) indicates
that the Me group in 54a is at the 3-position.
4-Methyl-3-phenyl-5,5-di(2-pyridinyl)-2(5H)-furanone (54b). An
analytical sample was obtained as a 35/64 regioisomeric mixture of
54b/54a: Rf 0.31 (hexane/EtOAc ) 1/1); 1H NMR (CDCl3) ïf the
sample showed only two well-resolved peaks, δ 8.61 (ddd, J ) 4.6
Hz, J ) 1.6 Hz, J ) 1.0 Hz, 2H), 2.46 (s, 3H); MS, m/z (relative
Hexahydro-3-methyl-3-(2-pyridinyl)-1H-cyclopenta[c]furan-1-
one (50). Major isomer: colorless oil; bp 180 °C (1 mmHg); Rf 0.31
(hexane/EtOAc ) 1/1); 1H NMR (CDCl3) δ 1.53-1.82 (c, 6H), 1.89-
2.17 (c, 3H), 2.88 (td, J ) 8.9 Hz, J ) 3.6 Hz, 1H), 3.34 (q, J ) 7.9
(36) Hoppe, D.; Bro¨nneke, A. Tetrahedron Lett. 1983, 24, 1687. Fang,
J.-M.; Hong, B.-C.; Liao, L.-F. J. Org. Chem. 1987, 52, 855.

12674 J. Am. Chem. Soc., Vol. 122, No. 51, 2000
Tobisu et al.
intensity) 328 (M+, 27), 78 (100); HRMS calcd for C21H16N2O2
328.1211, found 328.1218.
regiochemistry was confirmed on the basis of 1H NMR analysis of the
desilylated lactone (see Supporting Information for details).
4-Methyl-5,5-di(2-pyridinyl)-3-(trimethylsilyl)-2(5H)-furanone
(55a): white solid; mp 100-102 °C (hexane/EtOAc); Rf 0.23 (hexane/
EtOAc ) 1/1); H NMR (CDCl3) δ 0.35 (s, 9H), 2.42 (s, 3H), 7.25-
Acknowledgment. This work was supported, in part, by
grants from Monbusho. M.T. acknowledges the Foundation
“Hattori-Hokokai”. We acknowledge the Instrumental Analysis
Center, Faculty of Engineering, Osaka University, for assistance
in obtaining MS, HRMS, and elemental analyses.
1
7.30 (m, 2H), 7.45 (d, J ) 7.9 Hz, 2H), 7.73 (dd, J ) 7.9 Hz, J ) 7.6
Hz, 2H), 8.60 (d, J ) 4.6 Hz, 2H); 13C NMR (CDCl3) δ -0.95 (3C),
16.28, 94.02, 122.07 (2C), 123.09 (2C), 125.46, 136.87 (2C), 148.77
(2C), 158.47 (2C), 175.78, 179.01; IR (KBr) 1739 s, 1613 m; MS, m/z
(relative intensity) 324 (M+, 8), 185 (100). Anal. Calcd for
C18H20N2O2: C, 66.63; H, 6.21; N, 8.63. Found: C, 66.86; H, 6.06; N,
8.58. The regiochemistry of 55a was determined by its conversion to
44a (see Supporting Information for details).
Note Added in Proof: Following the submission of this
manuscript, the thermal [2 + 2 + 1] cycloaddition reaction of
quinones, dimethyl acetylenedicarboxylate, and isocyanide has
been reported: Nair, V.; Vinod, A. U.; Nair, J. S.; Sreekanth,
A. R.; Rath, N. P. Tetrahedron. Lett. 2000, 41, 6675.
3-Methyl-5,5-di(2-pyridinyl)-4-(trimethylsilyl)-2(5H)-furanone
(55b): colorless oil; Rf 0.51 (hexane/EtOAc ) 1/1); 1H NMR (CDCl3)
δ 0.11 (s, 9H), 2.11 (s, 3H), 7.24-7.28 (m, 2H), 7.39 (d, J ) 7.9 Hz,
2H), 7.71 (t, J ) 7.9 Hz, 2H), 8.54 (d, J ) 4.6 Hz, 2H); 13C NMR
(CDCl3) δ -0.27 (3C), 11.79, 95.76, 122.77 (2C), 123.16 (2C), 135.38,
136.53 (2C), 148.27 (2C), 158.69 (2C), 169.00, 174.34; IR (neat) 1760
s; MS, m/z (relative intensity) 324 (M+, 0), 309 (M+ - 15, 79), 78
(100); HRMS calcd for C18H20N2O2Si 324.1293, found 324.1292. The
Supporting Information Available: Full characterization
data for all new compounds and a table concerning the effect
of additives on the regioselectivity in the cycloaddition of 15d,
1-hexene, and CO (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA003018I