Pauson-khand reactions in water

Article abstract of DOI:10.1139/v05-112

We have investigated the cobalt mediated Pauson-Khand (PK) reaction in water. In the presence of detergents and surfactants, Co₂(CO) ₈ and Co₄(CO)₁₂ are effective under aqueous-phase, thermal PK reactions. In a

Full text of DOI:10.1139/v05-112

1006
Pauson–Khand reactions in water1
Marie E. Krafft, James A. Wright, and Llorente V.R. Boñaga
Abstract: We have investigated the cobalt mediated Pauson–Khand (PK) reaction in water. In the presence of deter-
gents and surfactants, Co2(CO)8 and Co4(CO)12 are effective under aqueous-phase, thermal PK reactions. In a water–
Triton®X-100 medium, Co4(CO)12 is catalytically active. Further, dicobalthexacarbonyl complexes of alkynes and
enynes undergo effective cyclization under thermal (70 °C) and NMO-promoted conditions. The oxidative nature of the
latter conditions inhibits the reductive PK reaction. In all protocols, moderate to excellent yields of the cycloadducts
are obtained. Substrates that are prone to hydrolysis, such as acetals, highly activated carboxylic acid derivatives, and
those bearing propargylic heteroatom groups are tolerated under appropriate conditions. Finally, the more challenging
intermolecular cycloadditions can also be easily achieved under aqueous conditions.
Key words: alkyne, cycloaddition, green chemistry, Pauson–Khand reaction, water.
Résumé : On a étudié la réaction de Pauson–Khand (PK) catalysée par le cobalt et effectuée dans l’eau. En présence
de détergents et d’agents de surface, le Co2(CO)8 et le Co4(CO)12 sont efficaces pour les réactions de PK thermiques,
effectuées en phase aqueuse. Dans un milieu d’eau et de Triton®X-100, le Co4(CO)12 est catalytiquement actif. De
plus, les complexes du dicobalthexacarbonyle des alcynes et des énynes subissent une cyclisation effective dans des
conditions thermiques (70 °C) catalysées par NMO. Dans tous les protocoles et dans des conditions appropriées, des
rendements allant de modérés à excellents ont été obtenus. Les substrats sujets à une hydrolyse, tels les acétals, les dé-
rivés hautement activés d’acides carboxyliques et ceux portant des groupes propargyliques avec hétéroatomes sont tolé-
rés. Enfin, dans des conditions aqueuses, il est possible de réaliser les cycloadditions intermoléculaires présentant les
plus grands défis.
Mots clés : alcyne, cycloaddition, chimie verte, réaction de Pauson–Khand, eau.
[Traduit par la Rédaction] Krafft et al. 1016
Introduction
reactants, such as organic compounds and metal complexes,
in water results in problems associated with phase separation
and inefficient mixing of reactants (1c). Instability and re-
duced reactivity of reactants also pose a problem. The solu-
bility issue has been addressed by taking advantage of the
solubilizing properties of organic co-solvents and surfac-
tants, and (or) employing hydrophilic ligand auxiliaries and
heterogenous or homogeneous catalysts (1).
Organometallic reactions conducted in nonorganic sol-
vents, such as water (1), ionic liquids (2), and supercritical
fluids (3) have become increasingly more relevant (4); the
Pauson–Khand (PK) and the PK-type reactions are no ex-
ception to this (5). These reactions are the widely studied
approaches to cyclopentenones, which incorporate two un-
saturated components with a carbonyl unit in a transition-
Relatively few studies have focused on aqueous-phase PK
reactions. Quite understandably, this is owing to the pre-
sumed sensitivity of the cobalt carbonyl complexes toward
water, such that early work concentrated only on supercriti-
cal fluids (3) and ionic liquids (8). Interestingly, water was
used as additive in a Co2(CO)8-catalyzed thermal protocol in
toluene (9), and was also found to accelerate the thermally
promoted cyclizations of cobalt carbonyl complexes of
enynes (10). In the context of green chemistry (4), Chung
and co-workers first described the use of water as solvent in
PK reactions promoted by colloidal cobalt nanoparticles, in
the presence of sodium dodecyl sulfate (11). More recently,
Kakiuchi and co-workers developed an effective
[RhCl(cod)]2-catalyzed PK-type reaction in water employing
a water-soluble phosphine salt, triphenylphosphane-3,3′,3′′ -
trisulfonic acid trisodium salt, in addition to 1,3-
bis(diphenylphosphanyl)propane (12). Chung and co-workers
also developed an asymmetric version of the [RhCl(cod)]2-
catalyzed PK-type reaction in aqueous media (13).
metal-mediated [2
+ 2 + 1] cycloaddition process
(Scheme 1, eq. [1]). To date, this transformation can be de-
rived from a reaction of alkynes with alkenes (5), allenes (6),
or dienes (7), and can also be promoted by complexes of ti-
tanium, zirconium, molybdenum, tungsten, iron, ruthenium,
rhodium, nickel, iridium and cobalt (5).
The use of water as an alternative solvent is most attrac-
tive for practical reasons. However, the poor solubility of the
Received 16 November 2004. Published on the NRC
Research Press Web site at http://canjchem.nrc.ca on
26 August 2005.
Dedicated to Professor Howard Alper for his exemplary work
in organometallic chemistry.
M.E. Krafft,2 J.A. Wright, and L.V.R. Boñaga. Department
of Chemistry and Biochemistry, The Florida State University,
Tallahassee, FL 32306-4390, USA.
1This article is part of a Special Issue dedicated to professor
Howard Alper.
We describe in this report the first comprehensive studies
on the cobalt-promoted PK reaction in water. The reactivity
2Corresponding author (e-mail: mek@chem.fsu.edu).
Can. J. Chem. 83: 1006–1016 (2005)
doi: 10.1139/V05-112
© 2005 NRC Canada

Krafft et al.
1007
R
Scheme 1. The Pauson–Khand and the Pauson–Khand-type reac-
–
tions.
reaction
[1]
O
O
R
R
R
R2
R
R
R1
1R3
X
R1
"MCO"
X
O
cobalt carbonyls
R2
R
R2
R3
R
1R2
R3
R3
[2]
X = C, N, O, S, Si
R = H, alkyl, aryl, SiR3
R1 = H, alkyl
reductive Pauson–
Khand reaction
R2
1R3
R2 = R3 = H, alkyl (alkene); =CHR (allene); CH2C=CHR (diene)
"MCO" = carbonyl complexes of Ti, Zr, Mo, W, Fe, Ru, Rh, Ni, Ir, Co
subsequently lead to the development of a mild and simple
aqueous-phase Co4(CO)12 catalyzed PK reaction protocol (14).
Stoichiometric amounts of Co4(CO)12 were used in our
initial studies (eq. [1], Table 1, reaction condition I). Based
on literature precedents we focused on surfactants and deter-
gents as additives in our aqueous-phase PK reactions.3 We
found that the cationic micelle-forming surfactant cetyltri-
methylammonium bromide (CTAB)4 worked as a general
surfactant for our aqueous reactions (vide infra). We were
gratified to find that Co4(CO)12 is active in a water–CTAB
media allowing enynes that typically undergo PK reactions
conducted in organic solvents to smoothly undergo cycliz-
ation (Table 1, condition I). 1,6-Enynes bearing an internal
alkyne and either a terminal alkene (Table 1, entries 1–3, 8
and 9) or a disubstituted alkene (Table 1, entries 13 and 14)
easily underwent cyclization. A 1,7-enyne also uneventfully
underwent the PK reaction (Table 1, entry 16). A particular
exception, however, is evident in the unsuccessful cycliz-
ation of substrates bearing the hydrolyzable ester and amide
groups (Table 1, entries 11 and 12). In contrast, substrates
possessing heteroatoms in the tether proved to be stable to
hydrogenolysis under these conditions (Table 1, entries 8
and 9 vs. 11 and 12).
We next examined the corresponding reactions of enynes
using catalytic amounts of Co4(CO)12, initially screening its
catalytic activity in water or a water–alcohol mixture, with
and without additives (Table 2). Cyclization of enyne 2 in
water alone, using only 10% of Co4(CO)12, under a blanket
of carbon monoxide is inefficient, providing only a modest
yield of the cycloadduct 18 and unreacted 2 (Table 2, entry 1).
Similar low efficiencies were observed in cyclizations con-
ducted in water–alcohol and water–THF mixtures (Table 2,
entries 2–4). Addition of triphenylphosphane-3,3,3-tri-
sulfonic acid trisodium salt (TPPTS)5 or cyclohexylamine
(10, 25) to PK reactions in a water–methanol solvent system
only resulted in the isolation of unreacted enyne as the major
product after the reactions (Table 2, entries 5 and 6). Incom-
plete conversions were noted in aqueous reactions carried
out with additives, such as TPPTS, tetrabutylammonium
of dicobalthexacarbonyl complexes of alkynes and enynes,
as well as uncomplexed enynes, with Co2(CO)8 and
Co4(CO)12 in water, and the effectiveness of surfactants and
detergents were examined. The scope and limitations of
these methods, in terms of substrate compatibility and reac-
tivity, and reaction conditions (thermal and oxidative promo-
tions) were also explored.
Results and discussion
Reactivity of dodecacarbonyltetracobalt in water (14)
There has been a limited amount of exploration on the use
of Co4(CO)12 in organometallic reactions despite its greater
stability towards air oxidation than the congeneric Co2(CO)8
(15, 16). The dinuclear complex has been widely used in the
Pauson–Khand (5) and Nicholas reactions (17), conversions
of aziridine to β-lactams (18), 1-(1-alkynyl)cyclopropanols
to cyclopentenones (19), enones to ketones (20), and in a
tandem cycloaddition reaction (21). We discovered the reac-
tivity of Co4(CO)12 in the PK reaction under mild reaction
conditions and reported its mechanistic implications in the
related reactivity of Co2(CO)8 (22, 23). Early studies demon-
strated that Co4(CO)12 catalyzed the PK reaction under ele-
vated temperatures and CO pressures to presumably favor
the formation of Co2(CO)8, the accepted precatalyst of the
reaction (23). We became interested in pursuing the syn-
thetic potential of this cobalt cluster, and found that it can
also induce a reductive PK reaction (eq. [2]) and reductive
cyclization of specific types of enynes (24). These results
further led us to examine its reactivity towards alkynes under
aqueous conditions since the reactivity of Co4(CO)12 with al-
kynes in water was unknown. Additionally, Co4(CO)12 cata-
lyzed PK reactions in aqueous media are significant from the
practical standpoint. We reported the unprecedented reactiv-
ity of Co4(CO)12 with alkynes (22), and more importantly,
its catalytic activity in water in the presence of additives that
3 Surfactants and detergents are amphiphiles (molecules carrying a hydrophilic headgroup and a hydrophobic tail) and are surface-active
agents, which assemble in aqueous or nonpolar media. They aggregate to form supramolecular assemblies in a colloidal dimension, such as
micelles, vesicles, and related species. Surfactants are adsorbed at the interfaces of aqueous and organic two-phase systems resulting in re-
duced interfacial tension. The very high polarity gradient between surface and core causes micelles to enclose organic species out of the sur-
rounding aqueous phase. The encapsulation of reactants in micelles often enhances or inhibits the reaction rates (1a). “Detergent” is often
used interchangeably with “surfactant”; detergent is a substance capable of cleaning, and contains, inter alia, surfactants (1a).
4 CTAB: [CH3(CH2)15N(CH3)3][Br].
5 TPPTS, with all three aromatic rings of triphenylphosphine sulfonated, is water-soluble. Metal compounds with this ligand are also water-
soluble.
© 2005 NRC Canada

1008
Can. J. Chem. Vol. 83, 2005
Table 1. Intramolecular Pauson–Khand reactions in water (cf. eq. [1]).
Yield (%)a
Entry
Enyne substrates
Cycloadduct
Reaction conditions
I
II
III
IV
R
1
2
3
R = Me
R = nPr
R = Ph
82
81
78
79
80
85
83
85
88
83
83
73
E
1
2
3
17
18
19
E
HO
OH
4
4
20
_
_
65
_
O
R1
R1 = Me
R1 = nC5H11
5
6
5
6
21
22
_
_
82
_
40
58
81
_
R1
O
E
7
7
23
_
78
78
80
R2
X = O, R2 = Ph
X = NTs, R2 = nPr
8
9
8
9
24
25
36
57
70
84
74
_
74
88
X
(CH2)2SEt
10
10
26
_
68
_
_
O
Ph
Z = NH, n = 1
Z = O, n = 2
11
12
11
12
27
28
0
0
73
80
_
_
0
0
Z
( )n
E
13
14
15
16
13
14
29b
30
31
32
34
60
_
_
_
_
86
91
_
E
E'
Et
E'
86
70
76
CH2CH(OEt)2
15
_
E
E
16
73
65
76
Note: I: 1 mol equiv. Co4(CO)12, 0.6 mol equiv. CTAB, water, 70 °C, ca. 18 h. II: 20 mol% Co4(CO)12, 0.5 mol equiv. Triton®X–100,
water 70 °C, CO atm in a resealable tube, ca. 18 h. III: 1 mol equiv. Co2(CO)8, 0.6 mol equiv. CTAB, water, 70 °C, ca. 18 h. IV: 1 mol
equiv. Co2(CO)8, 0.5 mol equiv. Triton®X-100, water, 6 mol equiv. NMO·H2O, rt, 6 h. For conditions III and IV, the cobalt complexes
were prepared from the enyne and Co2(CO)8 prior to cycloaddition. E = CO2Et; E′ = CO2Me.
aIsolated yields from reaction conditions III and IV are for two steps (preparation of the alkyne dicobalthexacarbonyl complex and the PK
reaction).
bExo cycloadduct.
© 2005 NRC Canada

Krafft et al.
1009
Table 2. Optimization of the thermally promoted, Co4(CO)12 catalyzed PK reaction in water.a
R
R
Cat. Co4(CO)12
H2O, 70 oC
EtO2C
EtO2C
EtO2C
EtO2C
O
R = nPr, 18
R = Ph, 19
R = nPr, 2
R = Ph, 3
Yield (%)
Solventb
Additive
(mol equiv.)
Co4(CO)12
(mol%)
Entry
Enyne
2
18
3
19
1
2
2
2
2
2
2
2
2
2
2
3
3
3
H2O
10
10
10
10
10
10
10
10
10
20
10
20
20
5
35
45
41
10
0
_
_
_
_
2
H2O–MeOH
_
3
H2O–iPrOH
35
44
62
38
19
32
15
_
–
H2O THF
4
–
H2O MeOH
5
TPPTS (0.3)
6
H2O-MeOH
H2O
13
22
28
64
64
CyNH2 (0.5)
7
TPPTS (0.3)
8
H2O
nBu4NBr (0.2)
Fisher detergentc
CTAB (0.5)
9
H2O
10
11
12
13
H2O
_
_
_
H2O
54
59
67
Tween 40 (0.5)
Tween 40 (0.5)
Triton X®-100 (0.5)
H2O
H2O
aReactions were conducted at concentrations of 0.05 mol/L (relative to enyne 2 or 3) in the appropriate solvent at 70 °C
under a CO atmosphere, and were complete in 12–15 h. Entry 10: 0.10 mol/L; entries 11–13: 1 mol/L.
bEntries 2–6: 1:1 (v/v) solvent mixture.
cSolution (20% (w/v)) in water.
bromide, and Fisher detergent3 (Table 2, entries 7–9). Ulti-
mately, CTAB, Tween 40, and polyoxyethylene(10)
isooctylcyclohexyl ether, Triton® X-100, all led to relatively
efficient catalytic activity of Co4(CO)12 in PK reactions in
water (Table 2, entries 10–13).
served as a side reaction in PK reactions conducted even in
organic solvents (26a, 26e). These types of substrates (8 and
9) underwent substantial hydrogenolysis (~50%) under
Co4(CO)12 mediated cycloadditions in DME, even in the
presence of only 20 equiv. of water (26b). Enyne 10, which
is devoid of substitution on the tether and thus lacking
Thorpe–Ingold assistance in the cyclization, cleanly under-
went PK reaction. Successful reaction of enynes 11 and 12
is particularly impressive since activated carboxylic acid de-
rivatives can easily be hydrolyzed, and the chemical reactiv-
ity of electron-deficient alkynes is unpredictable in the PK
reaction (27). It is worth nothing that the corresponding re-
actions of 11 and 12 using stoichiometric Co4(CO)12 in the
water–CTAB medium failed (Table 1, condition I). We
showed in our earlier work that cyclizations of substrates
bearing alkynes substituted with electron-withdrawing groups,
such as 11 and 12, occur in low to modest yields in organic
solvents (27). While the thermally promoted PK reaction of
11 (toluene, 70 °C, 3 days) gave a 15% yield of cycloadduct
27, the NMO-promoted variant (CH2Cl2, rt) gave a 59%
yield of 27 (cf. Table 1, entry 11) (27). Enynes 12 and 16
To explore the generality of the catalytic activity of
Co4(CO)12, we surveyed the cyclizations of various enynes
in water with the aid of Triton® X-100 (eq. [1], Table 1, con-
dition II). Efficient cyclization was achieved with enynes
that typically undergo PK reactions in organic solvents. Our
studies focused on the behavior of substrates that are poten-
tially unsuitable for aqueous conditions due to their procliv-
ity to hydrolyze, and revealed noteworthy results. The acetal
moieties in enynes 5 and 15 were stable in this aqueous me-
dium. Reaction of the dicobalthexacarbonyl complex of 5 in
water using Brij 35 or the anionic surfactant cetyltrimethyl-
ammonium hydrogen sulfate (CTAHS)3 as additives led to
cycloadducts with hydrolyzed acetal groups (vide infra).
Successful cyclizations of 8 and 9 are also striking since
hydrogenolysis of the heteroatom group in the propargylic
position could potentially occur. In fact, this has been ob-
© 2005 NRC Canada

1010
Can. J. Chem. Vol. 83, 2005
also provide examples of successful PK reactions of 1,7-
enynes providing the bicyclononenones. Substrates 14 and
15 bearing an internal alkyne and a disubstituted alkene
smoothly cyclized, furnishing highly substituted bicyclo-
octenone adducts. These results illustrate the catalytic effi-
ciency of Co4(CO)12 in promoting the PK reaction of various
types of enynes in water, by taking advantage of the micellar
properties of Triton®X-100 (Table 1, condition II).
We also addressed the issue of realizing a carbon-
monoxide-free, Co4(CO)12 catalyzed PK reaction (12). How-
ever, a slight decrease in the yield of cycloadducts from re-
actions conducted under an argon atmosphere was noted. PK
cyclization of enynes 2 and 3 in the water–Triton®X-100
medium using 20 mol% of Co4(CO)12 gave rise to 70% and
59% yields of bicyclooctenones 18 and 19, respectively (cf.
Table 1, condition II). Nevertheless, these results show the
potential of the aqueous protocol in the absence of carbon
monoxide and warrant further studies.
1,6-Enynes with a terminal alkene, and an alkyne compo-
nent bearing alkyl (Table 1, entries 1, 2, 5, and 7) and aryl
groups (Table 1, entries 3 and 8), underwent efficient cyli-
zation. Substitution on both alkene and alkyne moieties is
well tolerated, e.g., Table 1, entry 1 vs. 13 (cf. entry 14).
Groups prone to undergo hydrolysis, such as an acetal (Ta-
ble 1, entry 5) and propargylic heteroatom groups (Table 1,
entries 8 and 9), are stable under these aqueous conditions.
However, the amide and ester moieties were hydrolyzed un-
der these reaction conditions (Table 1, condition IV, entries
11 and 12, cf. conditions I and II). Cyclization of a 1,7
enyne occurred smoothly as well (Table 1, entry 16).
We further noted several interesting observations in the
cyclizations of enyne 2 while probing the manner of prepa-
ration of the alkyne cobalt complex and the amount and
source of NMO. The cobalt complex of enyne 2 can alterna-
tively be prepared directly in the reaction media, i.e., by
treatment of the enyne with Co2(CO)8 in the water-
Triton®X-100 mixture. Synthesis of the cobalt enyne com-
plex in this manner (1.5 h) and subsequent addition of cry-
stalline NMO·H2O (6 mol equiv.) gave 80% of adduct 18
after 6 h (cf. Table 1, entry 2, condition IV). Commercially
available NMO (6 mol equiv., 50% in water) or only 3 mol
equiv. of crystalline NMO·H2O can also be used in the reac-
tion, providing 68% and 76% of enone 18, respectively (cf.
Table 1, entry 2, condition IV).
Previously developed stoichiometric and catalytic thermal
PK reaction procedures proceed efficiently under aqueous
conditions, but are limited to enyne substrates bearing inter-
nal alkynes (vide supra). Enynes containing terminal alkynes
gave rise to bicyclooctanones (eq. [2]), either as a side prod-
uct (11) or the exclusive product (14, 28). These thermal
conditions, either stoichiometric or catalytic in the cobalt
carbonyl complex, are conducive to reductive PK reaction to
give ketones (eq. [2]) (24). We proposed earlier that residual
cobalt carbonyl complexes from PK reactions utilizing
Co2(CO)8, Co4(CO)12, and enyne–Co2(CO)6 complexes may
react with a proton source, such as aqueous and alcoholic
solvents, to form HCo(CO)4 (24a). A metal hydride transfer
from the hydridocobalt complex can effect a 1,4-reduction of
the enone generated in the PK reaction. We also found that
unsubstituted bicyclooctenones, derived from 1,6-enynes
with terminal alkynes (via eq. [1]), are prone to this second-
ary process. We became interested in the behavior of enynes
bearing terminal alkynes towards PK reaction (eq. [1]) or
reductive PK reaction (eq. [2]) in water, most importantly in
the inhibition of the reductive PK reaction as a side reaction.
Results revealed that the reductive PK reaction was pre-
ferred in aqueous reactions using stoichiometric amounts of
Co4(CO)12 leading to the favored formation of bicyclooctan-
ones instead (eq. [2], Table 4). In our control experiments,
we learned that thermal cyclization of an enyne bearing a
terminal alkyne such as 33 primarily furnished bicyclooctan-
one 37, along with the bicyclooctenone 35, in water as the
solvent (Table 4, entry 1). The nature of the additive, i.e.,
Triton®X-100 and CTAB (Table 4, entry 4 vs. 6) and quan-
tity (Table 4, entries 2–5) did not prevent the occurrence of
reductive PK reaction, i.e., the reaction depicted in eq. [1] is
Reactivity of dicobalthexacarbonyl–alkyne complexes in
water (28)
The ease with which dicobalthexacarbonyl complexed
enynes undergo PK reactions in water was also studied. We
prepared the dicobalthexacarbonyl complexes of several
enynes and surveyed their thermal reactions in water with
different additives (Table 3). Use of CTAB (Table 3, entries
4, 8, and 11) and Tween 40 (Table 3, entries 2 and 5) as ad-
ditives with preformed enyne–Co2(CO)6 complexes resulted
in consistently efficient aqueous PK reactions. PK cycliza-
tion of the cobalt carbonyl complex of 2 using tris[2-(2-
methoxyethoxy)ethyl]amine (TDA-1)6 and castor oil were a
little inferior when compared to the use of CTAB as an addi-
tive (Table 3, entry 8 vs. 6 and 7). Use of the surfactants Brij
35 (Table 3, entry 9) and CTAHS (Table 3, entry 10) led to
the hydrolysis of the acetal group. Under both conditions,
reactions of the dicobalthexacarbonyl complex of acetal 5
provided the bishydroxyl bearing cycloadduct 20, which is
also derived from the reaction of diol 4. We then examined
the cyclization efficiencies of a series of dicobalthexacar-
bonyl complexed enynes in water using CTAB as the addi-
tive (eq. [1], Table 1, condition III). As expected, results
showed a similar general trend as the reactions conducted
according to conditions I and II (Table 1).
Reactivity of dicobalthexacarbonyl–alkyne complexes
with NMO in water (29)
Using NMO as a reaction promoter, we also explored the
cyclization efficiencies of enynes with internal alkynes and
with various substitution patterns in the alkene component
(eq. [1], Table 1, condition IV). As anticipated, these sub-
strates underwent PK cyclizations efficiently resulting in
good to excellent yields of PK reaction cycloadducts. Ta-
ble 1 further shows that the yields in the NMO-promoted
cyclizations are comparable to or better than the yields de-
rived from the thermally promoted variant (70 °C, Table 1,
condition III). In both cases, enynes that undergo PK reac-
tions conducted in organic solvents also cyclized smoothly.
6 TDA-1 (N(CH2CH2OCH2CH2OCH3)3) is a very hydrophilic phase-transfer catalyst, which is most useful for solubilizing solid salts. It also
forms complexes with some metal carbonyls (1a).
© 2005 NRC Canada

Krafft et al.
1011
Table 3. Optimization of the thermally promoted PK reaction of enyne–Co2(CO)6 complexes in water.a,b
R
R
H2O, additive
70 oC
EtO2C
EtO2C
EtO2C
EtO2C
O
R = Me, 1
R = nPr, 2
R = Me, 17
R = nPr, 18
Yield (%)
Entry
Enyne
Additive
(mol equiv.)
17
18
21
Brij 35 (0.6)
74
74
82
83
1
1
1
1
1
2
2
2
2
5
5
5
Tween 40 (0.6)
CTAHS (0.6)
CTAB (0.6)
2
3
4
Tween 40 (0.5)
Castor Oil (1 mL)
TDA-1 (0.5 mL)
CTAB (0.6)
5
76
71
65
85
6
7
8
4 (56)c
0 (64)c
65
Brij 35 (0.6)
9
CTAHS (0.6)
CTAB (0.6)
10
11
aReactions were conducted at concentrations of 0.05 mol/L in water at 70 °C under a nitrogen atmosphere and were
complete in 18 h. Enynes were first converted to the corresponding dicobalthexacarbonyl complexes.
bEntries 5 and 6: 3.0 mol/L reaction concentrations; entry 7: 0.8 mol/L reaction concentration.
O
O
HO
HO
Me
Me
O
O
20
21
less favored than in eq. [2]. Understandably, the amount of
the cobalt cluster affected the efficiency of cycloaddition
and the extent of the reductive PK reaction (Table 4, entry 2
vs. 4 and 3 vs. 5) (24a).
Preformed dicobalthexacarbonyl complexes of substrates
bearing a terminal alkyne behaved as expected under thermal
conditions, undergoing inefficient PK reactions in water
(28). Use of additives such as cyclodextrins β-CD and γ-CD
(30), Triton®X-100, and Triton®X-100 (reduced form) did
not significantly improve the reaction efficiency in water and
in a water–methanol system. In these reactions, up to 10% of
saturated bicyclooctanones was observed as a side product.7
larly striking since the corresponding bicyclooctanone was
not observed. In contrast, Me3NO promoted cyclization of
complex 39 in dichloromethane under an argon atmosphere
(–78 °C to rt) furnished an 82% yield of a 4:1 mixture of
bicyclooctenone 40 and the corresponding bicyclooctanone
(31b). The oxidative nature and (or) the ambient temperature
of these present reaction conditions have apparently pre-
vented the occurrence of the reductive PK reaction. Further,
NMO is water-soluble, thus is advantageous in promoting
the PK reaction in water.
The behavior of various terminal alkynes in the NMO pro-
moted PK reaction was examined to gain a sense of the
scope and limitations of this important observation. Results
indeed show that enynes with terminal alkynes generally un-
derwent the PK reaction smoothly, providing good yields of
enones (eq. [1], Table 5). Substitution on the alkene moiety
We were however delighted to discover that when NMO
was used as promoter, room-temperature cyclization of the
dicobalthexacarbonyl enyne complex of 39 furnished 74% of
the bicyclooctenone 40 (eq. [3]) (31). This result is particu-
7 We inadvertently overlooked the formation of by-products from reductive PK reaction in our preliminary communication (28).
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
Table 4. Thermally promoted, Co4(CO)12 mediated PK reaction of enynes bearing terminal alkynes in water.a
Co4(CO)12
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
+
O
O
R
H2O, ∆
R
R
R = H, 33
R = Me, 34
R = H, 35
R = Me, 36
R = H, 37
R = Me, 38
Yield (%)
Co4(CO)12
(mol equiv.)
Entry
Enyne
Additive (mol equiv.)
35
37
38
_
1
2
3
4
5
6
7
33
33
33
33
33
33
34
1
1
1
2
2
2
2
5
21
46
28
59
61
66
Triton X®-100 (1)
Triton X®-100 (2)
Triton X®-100 (1)
Triton X®-100 (2)
CTAB (1)
0
16
0
0
0
Triton X®-100 (2)
46
aReactions were conducted at concentrations of 0.05 mol/L (relative to enyne) in water at 70 °C under a nitrogen atmo-
sphere and were complete in 18 h.
Intermolecular PK reactions in water
We were also interested in the application of several aque-
Co2(CO)6
water-Triton® X-100
ous protocols to the intermolecular PK reaction (6) (Table
6). We felt that the challenging intermolecular nature of such
reactions under aqueous conditions deserved study. Results
showed that both strained and unstrained alkenes reacted
with alkynes to provide good yields of PK reaction cyclo-
adducts. The good results observed in the intermolecular PK
cyclization of a less reactive alkene, such as 1-nonene, under
three different sets of aqueous conditions is particularly worth
emphasizing. As expected, the regiochemical outcomes par-
allel that observed in adducts generated from intermolecular
reactions conducted in organic solvents (26a).
[3]
Ts
O
Ts
N
N
NMO, rt, 6 h
39
40, 74%
(Table 5, entry 1 vs. 6) and a longer tether length (Table 5,
entries 6 and 7) are tolerated. As a comparison, the thermal
version was also conducted and showed the significant for-
mation (up to 46%) of the reductive PK reaction adduct (Ta-
ble 5, entries 2, 3 and 5).
Cyclization of the dicobalthexacarbonyl complex of enyne
33 under various thermal conditions deserves comment. In a
water – sodium dodecyl sulfate medium and using colloidal
cobalt nanoparticles as the catalyst (20 atm CO (1 atm =
101.325 kPa), 130 °C), a significant amount of the bicyclo-
octanone (24%), in addition to enone 35 (71%), was
observed (11). In the presence of either catalytic or stoichio-
metric amounts of Co4(CO)12, thermally promoted reaction
of the complex of 33 in water with additives, such as Tri-
ton®X-100 and CTAB exclusively provided the correspond-
ing bicyclooctanone (Table 4). It also gave 80% of bicyclo-
octanone 34, when it was treated with an equivalent of
Co2(CO)8 and 20 mol equiv. of water in refluxing DME
(26b).
The room temperature, NMO promoted PK reaction pro-
ceeds efficiently in the water–Triton®X-100 medium (Ta-
ble 1, condition IV), and is as efficient as the thermal
reaction in the water–CTAB medium (Table 1, condition III).
This procedure is particularly useful for the PK reactions of
enynes bearing terminal alkynes because of the inhibition of
further 1,4-reduction of the enone (cf. eq. [2]). Substrates
that possess acetals prone to undergo hydrolysis are stable
under these aqueous conditions.
Summary and conclusions
We have studied the PK reaction under aqueous condi-
tions, where we have focused on the (a) reactivity of
Co2(CO)8 and Co4(CO)12 towards alkynes, (b) determination
of optimal aqueous conditions, (c) compatibility of the PK
reaction with various detergents and surfactants, and (d) sta-
bility of the substrates. In the presence of detergents and sur-
factants, such as Triton®X-100 and CTAB, PK reactions of
enynes in water were efficiently promoted by Co2(CO)8 and
Co4(CO)12 at 70 °C. A desirable catalytic protocol was de-
veloped using Co4(CO)12, which further delineated the un-
precedented reactivity of the cobalt cluster under aqueous
conditions. We have noted however that these thermal aque-
ous procedures were only suitable for enynes with internal
alkynes. Enynes with terminal alkynes underwent the
reductive PK reaction providing bicyclooctanones. Gratify-
ingly, this problem was avoided by promoting the aqueous
PK reaction with NMO. Lastly, our studies have defined the
type of enyne substrates that are compatible with water, and
© 2005 NRC Canada

Krafft et al.
1013
Table 5. NMO and thermally promoted PK reaction of substrates bearing terminal alkynes in water.
Co2(CO)6
H
H2O, Triton X®-100
H
O
Substrate(s)a
PK reaction
adduct
Entry
1
Yield (%)b
d
NMOc
∆
_
33
35
72 (5)
R
R
30 (46)
40 (26)
R = CH2OC6H13
R = CH2OBn
2
3
41
43
73
70
42
44
TsN
_
39
45
40
49
74
4
5
61 (13)
52 (23)
TBSO
E
_
71e
63
6
7
46
47
50
51
E
Ph
_
_
E
E
TBSO
8
48
52
75f
aAs alkyne dicobalthexacarbonyl complexes.
bReported yields are for two steps (preparation of the alkyne dicobalthexacarbonyl complex and the PK reac-
tion). Numbers in parenthesis are isolated yields of the corresponding bicyclooctanones.
cWater, 0.5 mol equiv. Triton®X-100, 5 mol equiv. NMO, rt, 6 h.
dWater, 0.5 mol equiv. Triton®X-100, 70 °C, 6 h.
eExo cycloadduct.
f Diastereomeric ratio (1:1); E = CO2Et.
illustrated various examples of successful intermolecular re-
actions.
deionized water was used for these reactions. Base-washed
glassware was also used.
Reaction condition I
Experimental section
To a round-bottomed flask containing enyne 1 (83 mg,
0.329 mmol) and Co4(CO)12 (188 mg, 0.329 mmol) was
added CTAB (72 mg, 0.197 mmol) followed by water
(4 mL). The reaction mixture was then placed under an at-
mosphere of nitrogen and heated at 70 °C for 18 h. Upon
completion of the reaction, the mixture was filtered through
paper on a Büchner funnel, extracted with ethyl acetate,
dried over MgSO4, and filtered through a short pad of Celite.
General procedure
Co4(CO)12 and Co2(CO)8 were purchased from Strem
Chemicals Co. and used without further purification. Brij 35,
n-Bu4NBr, castor oil, β- and γ-CD, CTAB, CTAHS, CyNH2,
Fisher detergent, TDA-1, TPPTS, Triton®X-100, Triton® X-
100 (reduced form), and Tween 40 were purchased from
commercial suppliers and used as received. Distilled
© 2005 NRC Canada

1014
Can. J. Chem. Vol. 83, 2005
Table 6. Representative intermolecular PK reactions in water.
Reaction
Alkynea
Yield (%)d
Alkeneb
Entry
PK reaction
adduct
conditionc
64
70
62
63
1
2
3
4
I
II
53
Ph
Ph
III
IV
13 (1:1)
54 (1:1)
67 (1:1)
72 (1:1)
I
5
6
II
54/55
III
IV
7
8
nC7H15
aAs alkyne dicobalthexacarbonyl complexes (conditions III and IV, see Table 1).
bFive mol equiv.
cSee Table 1 for conditions.
dReported yields for conditions III and IV are for two steps (preparation of the alkyne dicobalthexacarbonyl
complex and the PK reaction).
O
O
O
Ph
nC7H15
Ph
Ph
nC7H15
54
53
55
Subsequent concentration and purification by flash column
chromatography (SiO2, 25% EtOAc in hexanes) provided
75 mg of enone 17 (82% yield).
mixture. These complexes were then subjected immediately
to reaction conditions III and IV.
Reaction condition III
To
a round-bottomed flask containing the enyne–
Reaction condition II
Co2(CO)6 complex of 2 (0.31 mmol) was added water
(3 mL), followed by CTAB (67 mg, 0.18 mmol) and a small
amount of Celite. The reaction mixture was then placed un-
der an atmosphere of nitrogen and heated at 70 °C. Upon
completion of the reaction (6–18 h), the mixture was filtered
through a filter paper on a Büchner funnel, extracted with di-
ethyl ether, and dried over MgSO4. Subsequent concentra-
tion and purification by flash column chromatography (SiO2,
25% EtOAc in hexanes) afforded 80 mg of enone 18 (85%
yield). In some cases, a small amount of Celite was added
into these reaction mixtures to facilitate stirring and to ad-
sorb cobalt residues after the reaction. Insignificant differ-
ences in the yields were observed when Celite was not
added to the reaction mixture.
To a resealable tube containing enyne 3 (90 mg,
0.28 mmol), Co4(CO)12 (32 mg, 0.57 mmol, 20 mol%), and
Triton®X-100 (91 mg, 0.14 mmol, 0.5 mol equiv.) was
added water (1 mL). Carbon monoxide was then bubbled
through the mixture (1 to 2 min), the tube was then sealed,
and the reaction mixture was heated at 70 °C. Upon comple-
tion of the reaction (6–18 h), the mixture was filtered
through a filter paper on a Büchner funnel, extracted with
EtOAc, dried over MgSO4, and filtered through a short pad
of Celite. Subsequent concentration, followed by purification
by flash column chromatography (SiO2, 20% EtOAc in hex-
anes) provided 83 mg of enone 19 (85% yield).
Synthesis of dicobalthexacarbonyl complexes of alkynes
and enynes
Reaction condition IV
To a solution of enyne 3 (85 mg, 0.30 mmol) in CH2Cl2
(1 mL) was added Co2(CO)8 (114 mg, 0.332 mmol). The re-
action mixture was then stirred at room temperature under
N2 for 1 h or until complex formation was complete. Con-
centration under reduced pressure provided the correspond-
ing enyne–Co2(CO)6 complex in quantitative yield. These
organocobalt complexes can alternatively be prepared by
treating the enyne with Co2(CO)8 in a water–Triton®X-100
To a round-bottomed flask containing the enyne–
Co2(CO)6 complex of 13 (0.285 mmol) was added Triton®X-
100 (91 mg, 0.14 mmol), water (1 mL), and NMO·H2O
(235 mg, 1.7 mmol). The reaction mixture was then placed
under an atmosphere of nitrogen and stirred at rt for 6 h.
Upon completion of the reaction, the mixture was filtered
through paper on a Büchner funnel, extracted with EtOAc,
and dried over MgSO4. Subsequent concentration and purifi-
© 2005 NRC Canada

Krafft et al.
1015
2. (a) C.E. Song. Chem. Commun. 1033 (2004); (b) J.H. Davis,
Jr. and P.A Fox. Chem. Commun. 1209 (2003); (c) H. Zhao
and S.V. Malhotra. Aldrichimica Acta, 35, 75 (2002); (d) R.
Sheldon. Chem. Commun. 2399 (2001).
cation by flash column chromatography (SiO2, 25% EtOAc
in hexanes) afforded 72 mg of enone 29 (86% yield).
The following compounds were previously reported and
characterized: 3, 13, 19, 29, 42, 44, and 51, (ref. 24); 2, 9,
10, 18, 25, 26, 33, 35, 47–49, 52, 53, 56, and 57 (ref. 25); 4–
7, 16, 20–23, 30, and 32 (ref. 28); 11, 12, 27, and 28
(ref. 27); 1 and 17 (ref. 32); 54 and 55 (ref. 33).
3. (a) 2.5 mol% Co2(CO)8, PCO = 112 atm (37 °C), PCO = 30 atm,
90 °C, 24 h: N. Jeong, S.H. 2Hwang, Y.W. Lee, and J.S. Lim. J.
Am. Chem. Soc. 119, 10 549 (1997); (b) Co4(CO)11P(OPh)3,
5 atm CO, 110 atm ethylene, 34–85 °C, 24 h: N. Jeong and
S.H. Hwang. Angew. Chem. Int. Ed. 39, 636 (2000).
4. Development of cost-effective, safe, and environmentally be-
nign organic processes has been an increasing research focus.
(a) P. Tundo and P.T. Anastas. Green chemistry: Challenging
perpectives. Oxford University Press, Oxford. 2000; (b) P.T.
Anastas and J.C. Warner. Green chemistry: Theory and prac-
tice. Oxford University Press, Oxford. 1998.
5. For recent reviews, see: (a) J. Blanco-Urgoiti, L. Añorbe, L.
Perez-Serrano, G. Dominguez, and J. Perez-Castells. Chem.
Soc. Rev. 33, 32 (2004); (b) S.E. Gibson and A. Stevenazzi.
Angew. Chem. Int. Ed. 42, 1800 (2003); (c) K.M. Brummond
and J.L. Kent. Tetrahedron, 56, 3263 (2000).
Enyne 41
1H NMR (CDCl3, 500 MHz) δ: 5.81 (ddt, J = 16.8, 10.1,
7.4 Hz, 1H, CH2CH=CH2), 5.08 (dm, J = 16.8 Hz, 1H,
CH2CH=CHH), 5.05 (dm, J = 10.1 Hz, 1H, CH2CH=CHH),
3.38 (t, J = 6.7 Hz, 4H, 2 × (CH3(CH2)4CH2OCH2)), 3.28
(AB, JAB = 9.4 Hz, 2H, CH3(CH2)4CH2OCH2), 3.24 (AB,
JAB = 9.4 Hz, 2H, CH3(CH2)4CH2OCH2), 2.21 (d, J =
2.7 Hz, 2H, CH2CCH), 2.17 (d, J = 7.4 Hz, 2H,
CH2CH=CH2), 1.94 (t, J = 2.7 Hz, 1H, CH2CCH), 1.46–1.60
(m, 4H, 2 × (CH3(CH2)3CH2CH2OCH2)), 1.22–1.40 (m,
12H, 2 × (CH3(CH2)3(CH2)2OCH2)), 0.88 (t, J = 7.4 Hz, 6H,
2 × (CH3(CH2)5OCH2)). 13C NMR (CDCl3, 75 MHz) δ:
134.14, 117.67, 81.50, 71.88, 71.27, 69.68, 41.60, 36.07,
31.45, 29.36, 25.62, 22.40, 21.84, 13.78. IR (cm–1): 3312,
3076, 2956, 2930, 2860, 2796, 1638, 1482, 1466, 1458,
1438, 1376, 1112, 1002, 916. Anal. calcd. for C21H38O2: C
78.20, H 11.87; found: C 78.44, H 11.99.
6. (a) B. Alcaide and P. Almendros. Eur. J. Org. Chem. 3377
(2004); (b) K.M. Brummond, H. Chen, K.D. Fisher, A.D.
Kerekes, B. Rickards, P.C. Sill, and S.J. Geib. Org. Lett. 4,
1931 (2002); (c) K.M. Brummond. In Advances in cyclo-
addition chemistry. Vol 6. Edited by M. Harmata. JAI Press
Inc., Greenwich, Connecticut. 1999. p. 211.
7. P.A. Wender, N.M. Deschamps, and G.G. Gamber. Angew.
Chem. Int. Ed. 42, 1853 (2004).
Enone 43
1H NMR (CDCl3, 500 MHz) δ: 5.84 (br s, 1H,
CH2C=CHC=O), 3.44 (obscured t, J = 6.6 Hz, 2H,
CH3(CH2)4CH2OCH2C), 3.42 (obscured AB, JAB = 8.7 Hz,
1H, CH3(CH2)5OCHHC), 3.39 (obscured AB, JAB = 8.7 Hz,
1H, CH3(CH2)5OCHHC), 3.37 (obscured t, J = 6.6 Hz, 2H,
CH3(CH2)4CH2OCH2C), 3.25 (AB, JAB = 8.7 Hz, 1H,
8. A. Becheanu and S. Laschat. Synlett, 1865 (2002).
9. 4 mol% of water, 10 mol% Co2(CO)8, toluene, 7 atm CO,
120 °C, 10 h: T. Sugihara and M. Yamaguchi. Synlett, 1384
(1998).
10. 1,4-dioxane and 2 mol/L aq. NH4OH (1:3, v/v): T. Sugihara,
M. Yamada, H. Ban, M. Yamaguchi, and C. Kaneko. Angew.
Chem. Int. Ed. Engl. 36, 2801 (1997).
11. Stabilized cobalt nanoparticles, water, sodium dodecyl sulfate,
20 atm CO, 130 °C, 12 h: S.U. Son, S.I. Lee, Y.K. Chung,
S.W. Kim, and T. Hyeon. Org. Lett. 4, 277 (2002).
12. 5 mol% [RhCl(cod)]2, 10 mol% dppp, 10 mol% TPPTS,
2 mol equiv. SDS, water, 100 °C, nitrogen, 2–12 h: F. Koji, T.
Morimoto, K. Tsutsumi, and K. Kakiuchi. Angew. Chem. Int.
Ed. 42, 2409 (2003).
13. 3 mol% [Rh(cod)Cl]2, 6 mol% BINAP, water–dioxane (1:1),
90 °C, 1.5 h: W.H. Suh, M. Choi, S.I. Lee, and Y.K. Chung.
Synthesis, 2169 (2003).
14. For a preliminary report, see: L.V.R. Boñaga, J.A. Wright, and
M.E. Krafft. Chem. Commun. 1746 (2004).
15. General review on tetranuclear clusters contains many refer-
ences to Co4(CO)12: (a) P. Chini and B.T. Heaton. Top. Curr.
Chem. 71, 3 (1977). See also: (b) R.D.W. Kemmitt and D.R.
Russell. In Comprehensive organometallic chemistry. Vol 5.
Edited by E.W. Abel, F.A. Stone, and G. Wilkinson. Pergamon
Press, Oxford. 1982. p. 7.
CH3(CH2)5OCHHC), 3.20 (AB, JAB
= 8.7 Hz, 1H,
CH3(CH2)5OCHHC), 3.12 (m, 1H, CH2CHCH2C=O), 2.59
(dd, J = 18.1, 6.6 Hz, 1H, CH2CHCHHC=O), 2.53 (br s, 2H,
CH2C=CHC=O), 2.11 (dd, J = 12.6, 8.7 Hz, 1H, CHHCH-
CH2C=O), 2.03 (dd, J = 18.1, 2.9 Hz, 1H, CH2CHCHHC=O),
1.45–1.62 (m, 4H, 2 × (CH3(CH2)3CH2CH2OCH2C)), 1.18–
1.40 (m, 12H, 2 × (CH3(CH2)3CH2CH2OCH2C)), 1.07 (dd,
J = 12.8, 12.8 Hz, 1H, CHHCHCH2C=O), 0.88 (t, J =
7.0 Hz, 6H, 2 × (CH3(CH2)5OCH2C)). 13C NMR (CDCl3,
75 MHz) δ: 211.04, 190.34, 124.43, 75.05, 74.75, 71.28,
71.19, 49.55, 44.25, 42.48, 37.34, 33.95, 31.29, 31.27,
29.20, 29.08, 25.52, 25.44, 22.24, 13.64. IR (cm–1): 2931,
2857, 2793, 1713, 1634, 1483, 1466, 1412, 1377, 1294,
1259, 1220, 1201, 1170, 1111, 900, 831. Anal. calcd. for
C22H38O3: C 75.38, H 10.93; found: C 75.39, H 11.00.
Acknowledgments
16. The use of Co3(CO)9(µ3-CH) in organic transformations, pre-
pared by treating Co2(CO)8 with CHBr3, has been exploited by
the Sugihara laboratory. For Pauson–Khand reactions: (a) T.
Sugihara and M. Yamaguchi. J. Am. Chem. Soc. 120, 10 782
(1998); (b) T. Sugihara, M. Yamaguchi, and M. Nishizawa.
Chem. Eur. J. 7, 1589 (2001); Co4(CO)12 is inferior to
Co3(CO)9(µ3-CH) in alkyne cyclotrimerizations: (c) T. Sugihara,
A. Wakabayashi, Y. Nagai, H. Takao, H. Imagawa, and M.
Nishizawa. Chem. Commun. 576 (2002). For cyclopentadi-
enone synthesis: (d) T. Sugihara, A. Wakabayashi, H. Takao,
H. Imagawa, and M. Nishizawa. Chem. Commun. 2456 (2001).
We thank the National Science Foundation and the MDS
Research Foundation for the generous financial support of
this work.
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© 2005 NRC Canada