Ethylene Glycol Assisted Intermolecular Pauson-Khand Reaction

Article abstract of DOI:10.1055/s-0036-1588813

The use of ethylene glycol as additive in the N -oxide-promoted intermolecular Pauson-Khand reaction (PKR) has been studied. The addition of 15% ethylene glycol to the reaction mixture consistently increased (from 20% up to 2-4-fold) the reaction yields.

Full text of DOI:10.1055/s-0036-1588813

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
special topic
A
en
A. Cabré et al.
Special Topic
Synthesis
Ethylene Glycol Assisted Intermolecular Pauson–Khand Reaction
Albert Cabréa
Xavier Verdaguer*a,b
Antoni Riera*a,b
O
X
0
0
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0-
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9-
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9-
6
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X
OH
R1
R1
HO
Co2(CO)8
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0
0
0
0-
0
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1
7-
1
4
2
7-
6
7
5
R2
R2
a Institute for Research in Biomedicine (IRB Barcelona), The Barcelona
Institute of Science and Technology, Baldiri Reixac 10, Barcelona
08028, Spain
NMO, 4Å MS
RT, CH2Cl2
- 17 examples
up to 95% yield
- broad range of alkenes
- high FG tolerance
O
antoni.riera@irbbarcelona.org
xavier.verdaguer@irbbarcelona.org
b Departament de Química Inorgànica i Orgànica, Secció Orgànica,
Universitat de Barcelona, Martí i Franquès 1, Barcelona 08028, Spain
2–4 fold increased yields of PKR with unstrained alkenes
Published as part of the Special Topic Cobalt in Organic Synthesis
Received: 15.03.2017
Accepted after revision: 10.04.2017
Published online: 27.04.2017
termolecular PKR using 1,4-bis[(trimethylsilyl)oxy]but-2-
ene (Scheme 1). The success of the PKR with this unstrained
olefin was possible only when using NMO as promoter and
adding monoethylene glycol (MEG)11 and 4 Å molecular
sieves (MS) to the reaction. Under these conditions, a re-
markable 46–58% yield was obtained (without MEG, yields
dropped to 15–25%). Although Baran and co-workers stated
that ethylene glycol was an essential additive, to the best of
our knowledge, these conditions have not been used in any
other PKR reported to date. We envisioned that, using this
novel methodology, other olefins might give better yields
and therefore a wider range of alkenes could be used.
DOI: 10.1055/s-0036-1588813; Art ID: ss-2017-c0165-st
Abstract The use of ethylene glycol as additive in the N-oxide-promot-
ed intermolecular Pauson–Khand reaction (PKR) has been studied. The
addition of 15% ethylene glycol to the reaction mixture consistently in-
creased (from 20% up to 2–4-fold) the reaction yields.
Key words Pauson–Khand reaction, cobalt, ethylene glycol, cyclopen-
tenones, cycloaddition
The Pauson–Khand reaction (PKR)1 is one of the few di-
rect methods to synthesize five-membered ring carbocycles
from acyclic precursors. When executed in an intramolecu-
lar fashion, this cobalt-mediated [2+2+1] cyclization is an
extremely efficient way to build up complex cyclopentane
polycycles.1,2 The intermolecular PKR has found more limit-
ed use due to the narrow scope of the alkene. In fact, only
strained olefins, such as norbornadiene or cyclopropene3 or
highly unhindered alkenes such as ethylene4 gave high
yields. However, the intermolecular version has a great po-
tential since it allows cyclopentenones to be built up from
very simple starting materials, namely an alkene, an alkyne,
and carbon monoxide.5
During recent decades, much effort has been devoted to
enhance the yields of this reaction using a variety of pro-
moters or additives.6 In 1990, Schreiber and co-workers dis-
covered that the PKR, which was typically performed at
high temperatures (60–110 °C), could also be promoted us-
ing N-oxides7 such as N-methylmorpholine-N-oxide (NMO)
in dichloromethane.8 These conditions allowed the reaction
to take place at room temperature and often gave better
yields.9
OTMS
O
TMSO
Co2(CO)8, NMO
+
TMSO
TMSO
NHBoc
MEG, 4Å MS
CH2Cl2
NHBoc
46–58%
Scheme 1 Ethylene glycol assisted intermolecular PKR used in Baran’s
synthesis of axinellamines
Here, we studied the role that ethylene glycol displays in
the stoichiometric N-oxide-promoted intermolecular PKR.
The effect of Baran’s conditions was tested when perform-
ing the reaction with strained alkenes such as norborna-
diene, poorly reactive cyclopentenes,12 and several ethylene
synthetic equivalents.13
The new protocol was tested first with norbornadiene
(NBD), which is the most relevant alkene substrate in inter-
molecular PKR. We observed that in all cases, the yields us-
ing ethylene glycol and molecular sieves as additives were
substantially higher (Table 1, entries 2, 4, 6, and 8). The re-
action is usually stereoselective affording the exo-adduct as
the major stereoisomer. In the case of the reactions with
ethylene glycol, the stereoselectivity towards the exo fur-
ther increased slightly. The presence of ethylene glycol low-
In 2011, Baran and co-workers reported the total syn-
theses of (±)-axinellamines A and B.10 The starting material
of these synthesis was a cyclopentenone prepared by an in-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
A. Cabré et al.
Special Topic
Synthesis
Table 1 Intermolecular Pauson–Khand Reactions of Internal Alkynehexacarbonyldicobalt Complexes with Norbornadienea
O
O
NMO·H2O
additives
H
H
R1
R2
R1
R2
R1
R2
+
CH2Cl2, RT
Co2(CO)6
H
H
1a–d
exo-2a–d
endo-2a–d
Entry
R1
CH2SPh
R2
Alkyne
Additives
–
Time (h)
Product
Yield (%)
exo/endo
1
2
3
4
5
6
7
8
H
1a
1a
1b
1b
1c
1c
1d
1d
4
2a
2a
2b
2b
2c
2c
2d
2d
8
51
65
85
72
89
79
95
>99
CH2SPh
CH2NHBoc
CH2NHBoc
TMS
H
H
H
H
H
MEG, 4 Å MS
17
>99
–
17
91:9
93:7
96:4
98:2
99:1
99:1
MEG, 4 Å MS
24
–
2
TMS
MEG, 4 Å MS
–
48–72
24
n-Pr
CH2OTBS
CH2OTBS
n-Pr
MEG, 4 Å MS
48–72
a The reactions were performed in CH2Cl2. NMO (6–10 equiv) was added in one portion.
ered the reaction rate and sometimes more than 6 equiva-
lents of NMO were needed to complete the reaction. The re-
action crudes using Baran’s conditions were easier to
workup because the ethylene glycol trapped the cobalt by-
products, thus affording a cleaner crude.
Another type of strained alkenes that showed satisfac-
tory reactivity in the intermolecular PKR were medium-
sized trans-cycloalkenes.14 The PKR of these alkenes offered
a modular, regioselective, and straightforward entry to
trans-fused [n.3.0] bicyclic scaffolds.15 In general, good to
excellent yields were achieved using few equivalents of
alkene and NMO as promoter. However, when using pro-
tected propargylic alcohols such as 1e, the yield of the cor-
responding cyclopentenone dropped. We have found that
under Baran’s protocol the yield of 3e increased from 38 to
60% as shown in Table 2.
low solubility. The latter issue can be improved by adding
molecular sieves18 and/or by slowly adding NMO. Thermal
activation or other promoters usually worsened the reac-
tion yields. Several alternatives to the use of ethylene gas
have been described. For example, the use of supercritical
ethylene was applied in the two-fold PKR of cyclic diynes19
or in a catalytic version of the intermolecular PKR.20 In
1999, Kerr and Pauson13 reported the use of vinyl esters
such as vinyl benzoate (5) as ethylene surrogates in the PKR.
Therefore, we tested Baran’s protocol on several ethylene
equivalents as alkenes (Table 3).
Terminal alkynes 1b,c were reacted with ethylene under
the standard N-oxide-promoted PKR conditions (Table 3).
For the sake of comparison, the standard protocol with vi-
nyl benzoate by adding NMO in a single portion was used.
Under these conditions the corresponding cyclopentenones
7b,c were obtained in significantly lower yields than with
ethylene. However, when using vinyl benzoate in the pres-
ence of ethylene glycol and 4 Å MS as additives, and also
adding NMO in a single portion, the yields recovered or
were higher than those achieved with ethylene. We also at-
tempted, for the first time, the use of vinyltrimethylsilane
(6) as ethylene surrogate (Table 3, entries 4 and 12). Olefin
6 showed good reactivity under these conditions, and the
yields were comparable to those obtained with vinyl benzo-
ate. However, a treatment with fluoride to cleave the silylat-
ed cyclopentenones was required.
Ethylene (4) is a useful alkene in intermolecular PKR. It
has been used in the synthesis of taylorione13 and phyto-
prostanes B1,16 among others.17 Its main drawbacks are the
need of the equipment to manipulate a gas and its relatively
Table 2 Comparative Study of the Intermolecular Pauson–Khand Re-
action Using Terminal Alkyne 1e with trans-Cyclooctene
O
H
conditions
OTBS
OTBS
CH2Cl2, RT
Co2(CO)6
H
Again, using Baran’s conditions the workup was much
cleaner and all cobalt residues were easily removed by a
simple decantation. In terms of reactivity, vinyl benzoate
proved to be the most useful ethylene equivalent. The yields
were comparable to those achieved with ethylene, and in
1e
3e
Entry Alkyne Conditions
Product Yield (%)
1
2
1e
1e
NMO (6 equiv), 0 °C to r.t., 2 h
3e
3e
3814
60
NMO (10 equiv), MEG, 4 Å MS, 48 h
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
A. Cabré et al.
Special Topic
Synthesis
Table 3 Intermolecular Pauson–Khand Reactions of Terminal Alkynehexacarbonyldicobalt Complexes with Ethylene and Ethylene Equivalentsa
NMO·H2O
additives
7b; R = CH2NHBoc
7c; R = TMS
7e; R = CH2OTBS
7f; R = CH2NHTs
O
X
R
+
R
Co2(CO)6
CH2Cl2, RT
4, X = H
1b,c,e,f
5, X = OBz
6, X= TMS
Entry
R
Alkyne
X
Alkene
Additives
Time (h)
Product
Yield (%)
1
2
CH2NHBoc
CH2NHBoc
CH2NHBoc
CH2NHBoc
TMS
1b
1b
1b
1b
1c
1c
1c
1e
1e
1f
H
4
5
5
6
4
5
5
4
5
4
5
6
–
4
5
7b
7b
7b
7b
7c
7c
7c
7e
7e
7f
63
36
67
57
67
15
43
20
40
54
72
64
OBz
OBz
–
3
MEG, 4 Å MS
17
17
4
4b
5
TMS
H
MEG, 4 Å MS
–
6
TMS
OBz
OBz
H
–
5
7
TMS
MEG, 4 Å MS
–
24
3
8
CH2OTBS
CH2OTBS
CH2NHTs
CH2NHTs
CH2NHTs
9
OBz
H
MEG, 4 Å MS
–
17
5
10
11
12b
1f
OBz
TMS
MEG, 4 Å MS
MEG, 4 Å MS
17
17
7f
1f
7f
a The reactions were performed in CH2Cl2 with 6 equiv of NMO.
b Once complete, the reaction was quenched with a catalytic amount of HF·Pyr.
some cases even improved (Table 3, entries 3, 9 and 11). The
presence of additives did not affect the C–O cleavage to take
place, which still occurred spontaneously.
Ethylene glycol can help to extend the scope of alkynes
available for this transformation. In this regard, when inter-
nal alkynes are used in the intermolecular PKR, the reactiv-
Table 4 Intermolecular Pauson–Khand Reaction of Internal Alkynehexacarbonyldicobalt Complexes with Ethylene and Ethylene Equivalentsa
O
NMO·H2O
X
8d; R1 = n-Pr, R2 = CH2OTBS
8g; R1 = CH2CO2Et, R2 = CH2NHBoc
8h; R1 = Bn, R2 = CO2Me
R1
R2
R1
R2
additives
+
Co2(CO)6
CH2Cl2, RT
8i; R1 = CH2CO2Et, R2 = CH2OTBS
4, X = H
5, X = OBz
6, X = TMS
1d,g–i
8
Entry
R1
n-Pr
R2
Alkyne
X
Alkene
Additives
Time (h)
Product
Yield (%)
1
2
CH2OTBS
CH2OTBS
CH2NHBoc
CH2NHBoc
CH2NHBoc
CH2NHBoc
CO2Me
1d
1d
1g
1g
1g
1g
1h
1h
1h
1i
H
4
5
4
5
5
6
4
5
5
4
5
6
–
5
36
4
8d
8d
8g
8g
8g
8g
8h
8h
8h
8i
65
12
75
20
64
56
57
11
46
53
49
43
n-Pr
OBz
H
MEG, 4 Å MS
3
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2Ph
–
4
OBz
OBz
TMS
H
–
5
5
MEG, 4 Å MS
17
17
4
6b
7
MEG, 4 Å MS
–
8
CH2Ph
CO2Me
OBz
OBz
H
–
5
9
CH2Ph
CO2Me
MEG, 4 Å MS
–
24
4
10
11
12b
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2OTBS
CH2OTBS
CH2OTBS
1i
OBz
TMS
MEG, 4 Å MS
MEG, 4 Å MS
17
17
8i
1i
8i
a The reactions were performed in CH2Cl2. NMO (6–10 equiv) was added.
b Once completed, the reaction was quenched with catalytic amount of HF·Pyr.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
A. Cabré et al.
Special Topic
Synthesis
ity decreases. To the best of our knowledge, there is no
precedent in which internal alkynes have been used to syn-
thesize α,β-substituted cyclopentenones via regioselec-
tive21 PKR with ethylene surrogates. We observed (Table 4)
that when using ethylene equivalents with Baran’s protocol,
reaction yields were comparable to those obtained with
ethylene in most cases (Table 4, entries 5, 9, and 11). Only
for the one bearing an alkyl chain, the reactivity decreased
considerably (entry 2).
Table 6 Comparative Study of the Intermolecular Pauson–Khand Re-
action Using Terminal Alkynes and 2,3-Dihydrofurana
O
NMO·H2O
additives
O
R
R
+
Co2(CO)6
O
CH2Cl2, RT
1b, R = CH2NHBoc
1c, R = TMS
10
12b R = CH2NHBoc
12c R = TMS
Entry
Alkyne
Additives
Time (h)
Product
Yield (%)
Finally, we sought to explore the effect of Baran’s condi-
tions when using other alkenes such as cyclopentene (9) or
2,3-dihydrofuran (10), which are poorly reactive and less
common in PKR. N-Boc propargylamine and trimethylsily-
lacetylene complexes 1b and 1c were selected due to their
synthetic importance.22 Using ethylene glycol as additive,
the yields of N-oxide-promoted cyclizations of cyclopen-
tene, doubled those achieved when using the standard pro-
tocol or when 4 Å MS was the only additive (Table 5). The
reaction using of 2,3-dihydrofuran afforded the products
with the biggest yield increase and with complete regiose-
lectivity (Table 6).
1
2
3
4
1b
1b
1c
1c
–
17
36
4
12b
12b
12c
12c
40
57
21
82
MEG, 4 Å MS
–
MEG, 4 Å MS
24
a The reactions were performed in CH2Cl2. NMO (6 equiv) was added in one
portion.
the reactions because the ethylene glycol absorbs the cobalt
by-products. Moreover, since the reaction rate decreases,
the addition of the N-oxide promoter can be done in a sin-
gle portion. We believe that the main effect of ethylene gly-
col is to stabilize the unsaturated cobalt complexes that are
the key intermediates of the PKR. This new protocol may
help to address one of the most important drawbacks of the
intermolecular PKR, namely the limited range of reactive
alkenes.
Table 5 Comparative Study of the Intermolecular Pauson–Khand Re-
action Using Terminal Alkynes and Cyclopentenea
O
NMO·H2O
additives
R
+
R
Co2(CO)6
CH2Cl2, RT
1b, R = CH2NHBoc
1c, R = TMS
9
11b R = CH2NHBoc
11c R = TMS
Reactions were carried out under N2 in previously oven-dried vials or
round-bottomed flasks. CH2Cl2 was degassed and dried with a solvent
purification system (SPS PS-MD-3). Reactions were monitored by TLC
analysis using Merck silica gel 60 F-254 thin layer plates. Solvents
were removed under reduced pressure with a rotary evaporator. Silica
gel chromatography was performed using an automated chromatog-
raphy system (PuriFlash® 430, Interchim). NMR spectra were record-
Entry
Alkyne
Additives
Time (h)
Product
Yield (%)
1
2
3
4
5
6
1b
1b
1b
1c
1c
1c
–
3
11b
11b
11b
11c
11c
11c
35
37
60
16
14
31
4 Å MS
3
MEG, 4 Å MS
–
5
1
ed at 400 MHz for H and at 101 MHz for 13C. Chemical shifts (δ) are
4
given in ppm and referenced to internal solvent resonances and re-
ported relative to TMS. The coupling constants (J) are reported in
hertz (Hz). High-resolution mass spectra (ESI) were recorded on a
LC/MSD-TOF G1969A spectrometer (Agilent Technologies).
4 Å MS
4
MEG, 4 Å MS
48–72
a The reactions were performed in CH2Cl2. NMO (6 equiv) was added in one
portion.
The synthesis of alkynes and their hexacarbonyldicobalt complexes
are described in detail in the Supporting Information.
In conclusion, we have shown that the use of ethylene
glycol as additive consistently improves the N-oxide-pro-
moted intermolecular PKR in terms of yield, stereoselectivi-
ty, and practicality. When using norbornadiene as alkene,
which is the most reactive alkene in the intermolecular
PKR, a slight increase in both yield and stereoselectivity was
observed. Using ethylene surrogates such as vinyl benzoate
and vinyltrimethylsilane, the yields of the corresponding
cyclopentenones were similar to those achieved with eth-
ylene gas. The greatest advantage was found when using
less activated alkenes such as cyclopentene or 2,3-dihydro-
furan. This methodology greatly facilitates the workup of
Intermolecular Pauson–Khand Reaction Using the Standard Pro-
tocol; General Procedure
Method A: The corresponding hexacarbonyldicobalt complex (1.0
equiv) was dissolved in anhyd CH2Cl2 (11 mL/mmol complex) and
charged to a vial, which was previously purged with N2. The respec-
tive alkene (5.0 equiv, unless otherwise indicated) was then added.
The reaction mixture was stirred for 10 min. A solution of NMO (6
equiv, unless otherwise indicated) in anhyd CH2Cl2 was added in a
single portion. The reaction was monitored by TLC until no cobalt
complex was observed. Then, the crude was filtered through a plug of
SiO2 and washed with CH2Cl2 (3 ×). The solvent was concentrated un-
der vacuum and the crude was purified by column chromatography
on SiO2 using mixtures of hexanes/EtOAc of increasing polarities.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
A. Cabré et al.
Special Topic
Synthesis
Ethylene Glycol-Assisted Intermolecular Pauson–Khand Reaction;
General Procedures
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 2.5 Hz, 1 H), 6.27 (dd, J = 5.7,
3.1 Hz, 1 H), 6.20 (dd, J = 5.6, 3.0 Hz, 1 H), 2.91 (d, J = 2.8 Hz, 1 H), 2.83
(s, 1 H), 2.69 (s, 1 H), 2.28 (d, J = 5.2 Hz, 1 H), 1.37 (d, J = 9.3 Hz, 1 H),
1.19 (d, J = 9.3 Hz, 1 H), 0.17 (s, 9 H).
Method B: The corresponding hexacarbonyldicobalt complex (1.0
equiv) was dissolved in anhyd CH2Cl2 (11 mL/mmol complex) and
charged to a vial containing 4 Å MS (317 mg/mmol complex), which
was previously purged with N2. The respective alkene (5.0 equiv, un-
less otherwise indicated) and ethylene glycol (1.7 mL/mmol complex)
were then added. The reaction mixture was stirred for 10 min. A solu-
tion of NMO (6 equiv, unless otherwise indicated) in anhyd CH2Cl2
was added in a single portion. The reaction was monitored by TLC un-
til no cobalt complex was observed. Then, the crude was filtered
through a plug of neutral Al2O3 and washed with CH2Cl2 (3 ×). The sol-
vent was concentrated under vacuum and the crude was purified by
column chromatography on SiO2 using mixtures of hexanes/EtOAc of
increasing polarities.
The analytical and spectral data for this compound were in excellent
agreement with the reported data.23
(3aS,4S,7R,7aR)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-pro-
pyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoinden-1-one (2d)
Starting from 0.27 mmol of Co complex 1d; isolated yield; Method A:
69 mg (79%); Method B: 84 mg (95%); colorless oil. 10 equiv of NMO
were used in both cases.
1H NMR (400 MHz, CDCl3): δ = 6.19 (dd, J = 5.6, 3.1 Hz, 1 H), 6.12 (dd,
J = 5.6, 2.9 Hz, 1 H), 4.51 (d, J = 15.1 Hz, 1 H), 4.41 (dd, J = 15.1, 1.0 Hz,
1 H), 2.83 (dd, J = 3.0, 1.6 Hz, 1 H), 2.81–2.75 (m, 2 H), 2.19 (dd, J = 5.2,
1.5 Hz, 1 H), 2.13–2.08 (m, 1 H), 2.02 (dt, J = 7.5, 6.2 Hz, 1 H), 1.37–
1.26 (m, 3 H), 1.10 (dtd, J = 9.2, 1.4, 0.7 Hz, 1 H), 0.87 (s, 9 H), 0.80 (d,
J = 7.3 Hz, 3 H), 0.04 (s, 6 H).
Method C: The corresponding hexacarbonyldicobalt complex (1.0
equiv) was dissolved in anhyd CH2Cl2 (11 mL/mmol complex) and
charged to a vial containing 4 Å MS (317 mg/mmol complex), which
was previously purged with N2. Vinyltrimethylsilane (5.0 equiv) and
ethylene glycol (1.7 mL/mmol complex) were then added. The reac-
tion mixture was stirred for 10 min. A solution of NMO (6 equiv, un-
less otherwise indicated) in anhyd CH2Cl2 was added in a single por-
tion. The reaction was monitored by TLC until no cobalt complex was
observed. Once completed, the reaction was quenched with a catalyt-
ic amount of HF·Pyr and stirred for 10 min. Afterwards, the mixture
was quickly filtered through a short plug of neutral Al2O3. The solvent
was concentrated under vacuum and the crude was purified by col-
umn chromatography on SiO2 using mixtures of hexanes/EtOAc of in-
creasing polarities.
The analytical and spectral data for this compound were in excellent
agreement with the reported.21
(3aS,9aR)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-
3a,4,5,6,7,8,9,9a-octahydro-1H-cyclopenta[8]annulen-1-one (3e)
Starting from 0.22 mmol of Co complex 1e; isolated yield; Method A:
19 mg (38%);14 Method B (using 10 equiv of NMO): 31 mg (60%); col-
orless oil. In both cases, 3 equiv of alkene were used.
1H NMR (400 MHz, CDCl3): δ = 7.28 (q, J = 2.0 Hz, 1 H), 4.34 (dd, J = 2.9,
1.9 Hz, 2 H), 2.68 (dq, J = 12.3, 3.0 Hz, 1 H), 2.20–1.20 (m, 13 H), 0.91
(s, 9 H), 0.07 (s, 6 H).
(3aR,4S,7R,7aR)-2-[(Phenylthio)methyl]-3a,4,7,7a-tetrahydro-1H-
4,7-methanoinden-1-one (2a)
The analytical and spectral data for this compound were in excellent
agreement with the reported data.14
Starting from 0.33 mmol of Co complex 1a; isolated yield; Method A:
7 mg (8%); Method B: 46 mg (51%); colorless oil.
tert-Butyl [(5-Oxocyclopent-1-en-1-yl)methyl]carbamate (7b)
1H NMR (400 MHz, CDCl3): δ = 7.33–7.21 (m, 5 H), 7.20–7.14 (m, 1 H),
6.24 (dd, J = 5.6, 3.1 Hz, 1 H), 6.18 (dd, J = 5.6, 3.0 Hz, 1 H), 3.74–3.58
(m, 2 H), 2.91 (p, J = 1.4 Hz, 1 H), 2.68 (dhept, J = 5.4, 1.3 Hz, 1 H), 2.57
(dt, J = 2.9, 1.5 Hz, 1 H), 2.31 (dt, J = 5.0, 1.4 Hz, 1 H), 1.30 (dp, J = 9.4,
1.6 Hz, 1 H), 1.07 (dd, J = 9.4, 1.6 Hz, 1 H).
Starting from 0.23 mmol of Co complex 1b; isolated yield; Method A:
17 mg (36%); Method B: 32 mg (67%); Method C: 28 mg (57%); pale
orange oil.
IR (ATR-FTIR): 3368, 2981, 2928, 1735, 1698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.49 (s, 1 H), 5.02 (br s, 1 H), 3.91 (d, J =
6.7 Hz, 2 H), 2.69–2.55 (m, 2 H), 2.47–2.38 (m, 2 H), 1.44 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 209.22, 159.29, 155.81, 143.05, 79.43,
The analytical and spectral data for this compound were in excellent
agreement with the reported data.22a
36.09, 34.81, 28.33, 26.61.
tert-Butyl {[(3aR,4S,7R,7aR)-1-Oxo-3a,4,7,7a-tetrahydro-1H-4,7-
HRMS (ESI): m/z [M + Na]+ calcd for C11H17NO3Na: 234.1101; found:
methanoinden-2-yl]methyl}carbamate (2b)
Starting from 0.30 mmol of Co complex 1b; isolated yield; Method A:
234.1099.
54 mg (65%); Method B: 70 mg (85%); off-white solid; mp 161–163 °C.
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 2.6 Hz, 1 H), 6.27 (dd, J = 5.6,
3.1 Hz, 1 H), 6.18 (dd, J = 5.6, 3.0 Hz, 1 H), 5.04 (br s, 1 H), 3.85 (t, J =
6.5 Hz, 2 H), 2.89 (t, J = 1.8 Hz, 1 H), 2.74 (ddp, J = 5.3, 2.6, 1.3 Hz, 1 H),
2.70–2.65 (m, 1 H), 2.29 (dt, J = 5.1, 1.4 Hz, 1 H), 1.41 (s, 9 H), 1.38–
1.33 (m, 1 H), 1.21–1.16 (m, 1 H).
2-(Trimethylsilyl)cyclopent-2-en-1-one (7c)
Starting from 0.22 mmol of Co complex 1c; isolated yield; Method A:
6 mg (15%); Method B: 16 mg (43%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.79 (t, J = 2.6 Hz, 1 H), 2.66 (dt, J = 7.5,
2.5 Hz, 2 H), 2.37–2.30 (m, 2 H), 0.18 (s, 9 H).
The analytical and spectral data for this compound were in excellent
agreement with the reported data.22a
The analytical and spectral data for this compound were in excellent
agreement with the reported data.22c
(3aS,4S,7R,7aR)-2-(Trimethylsilyl)-3a,4,7,7a-tetrahydro-1H-4,7-
methanoinden-1-one (2c)
2-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclopent-2-en-1-one
(7e)
Starting from 0.36 mmol of Co complex 1c; isolated yield; Method A:
69 mg (72%); Method B: 53 mg (89%); white solid; mp 94–95 °C.
Starting from 0.41 mmol of Co complex 1e; isolated yield; Method B:
36 mg (40%); colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
A. Cabré et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.53 (ddd, J = 4.6, 2.7, 1.9 Hz, 1 H), 4.37
(td, J = 2.8, 1.8 Hz, 2 H), 2.66–2.57 (m, 2 H), 2.54–2.42 (m, 2 H), 0.92 (s,
9 H), 0.08 (s, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H15O3: 231.1016; found:
231.1022.
Ethyl 2-(2-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-oxocyclo-
pent-1-en-1-yl)acetate (8i)
The analytical and spectral data for this compound were in excellent
agreement with the reported data.24
Starting from 0.22 mmol scale of Co complex 1i; isolated yield; Meth-
od B: 34 mg (49%); Method C: 29 mg (43%); colorless oil.
4-Methyl-N-[(5-oxocyclopent-1-en-1-yl)methyl]benzenesulfon-
IR (ATR-FTIR): 2958, 2923, 2856, 1734, 1702 cm–1
.
amide (7f)
Starting from 0.22 mmol of Co complex 1f; isolated yield; Method B:
43 mg (72%); Method C: 38 mg (64%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.58 (s, 2 H), 4.12 (q, J = 7.1 Hz, 2 H),
3.32 (s, 2 H), 2.64 (dtd, J = 7.1, 2.3, 1.2 Hz, 2 H), 2.44–2.39 (m, 2 H),
1.25 (t, J = 7.1 Hz, 3 H), 0.92 (s, 9 H), 0.10 (s, 6 H).
IR (ATR-FTIR): 3270, 3017, 1689 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.73–7.68 (m, 2 H), 7.41 (tt, J = 2.7, 1.3
Hz, 1 H), 7.32–7.27 (m, 2 H), 5.14 (t, J = 6.4 Hz, 1 H), 3.80 (dtd, J = 6.6,
1.8, 1.2 Hz, 2 H), 2.51–2.45 (m, 2 H), 2.42 (s, 3 H), 2.28–2.24 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 208.41, 174.71, 170.44, 132.66, 62.44,
61.04, 33.80, 28.67, 27.55, 25.95, 18.46, 14.30, –5.40.
HRMS (ESI): m/z [M + H]+ calcd for C16H29O4Si: 313.1830; found:
313.1834.
13C NMR (101 MHz, CDCl3): δ = 208.98, 160.31, 143.48, 140.71,
136.93, 129.60, 127.24, 39.18, 34.53, 26.87, 21.49.
HRMS (ESI): m/z [M + H]+ calcd for C13H16NO3S: 266.0845; found
tert-Butyl [(1-Oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)meth-
yl]carbamate (11b)
266.0844.
Starting from 0.23 mmol of Co complex 1b; isolated yield; Method A:
20 mg (35%); Method B: 35 mg (60%); colorless oil.
3-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-propylcyclopent-2-
IR (ATR-FTIR): 2937, 2869, 1724, 1525, 758 cm–1
.
en-1-one (8d)
Starting from 0.18 mmol of Co complex 1d; isolated yield; Method B
(using 10 equiv of NMO): 6 mg (12%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.26 (m, 1 H), 5.02 (br s, 1 H),
3.86 (d, J = 6.2 Hz, 2 H), 3.33–3.18 (m, 1 H), 2.74 (ddd, J = 10.1, 5.6, 1.8
Hz, 1 H), 1.91–1.83 (m, 1 H), 1.75–1.65 (m, 2 H), 1.63–1.54 (m, 2 H),
1.42 (s, 9 H), 1.19 (qt, J = 12.4, 6.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 212.36, 162.22, 155.79, 143.11, 79.44,
50.51, 44.25, 36.04, 30.07, 29.35, 28.33, 23.55.
IR (ATR-FTIR): 2950, 1770, 1464, 840 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.54 (s, 2 H), 2.59 (dtd, J = 7.1, 2.3, 1.2
Hz, 2 H), 2.41–2.33 (m, 2 H), 2.21–2.10 (m, 2 H), 1.39 (dq, J = 14.8, 7.4
Hz, 2 H), 0.92 (s, 9 H), 0.87 (t, J = 7.4 Hz, 3 H), 0.10 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 210.07, 171.72, 139.49, 61.36, 34.19,
HRMS (ESI): m/z [M + H]+ calcd for C14H22NO3: 252.1594; found:
27.09, 25.96, 25.20, 21.91, 18.47, 14.20, –5.29.
252.1591.
HRMS (ESI): m/z [M + H]+ calcd for C15H29O2Si: 269.1931; found:
269.193.
2-(Trimethylsilyl)-4,5,6,6a-tetrahydropentalen-1(3aH)-one (11c)
Starting from 0.23 mmol of Co complex 1c; isolated yield; Method A:
7 mg (16%); Method B: 14 mg (31%); colorless oil.
Ethyl 2-(2-{[(tert-Butoxycarbonyl)amino]methyl}-5-oxocyclo-
IR (ATR-FTIR): 2918, 2850, 1734, 1215, 758 cm–1
.
pent-1-en-1-yl)acetate (8g)
Starting from 0.23 mmol of Co complex 1g; isolated yield; Method A:
14 mg (20%); Method B: 43 mg (64%); Method C: 37 mg (56%); color-
less oil.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 2.6 Hz, 1 H), 3.30 (ddt, J =
8.5, 5.4, 2.5 Hz, 1 H), 2.71–2.62 (m, 1 H), 1.89 (dd, J = 12.7, 6.3 Hz, 1 H),
1.75–1.61 (m, 2 H), 1.56 (dt, J = 12.5, 6.0 Hz, 2 H), 1.13 (ddq, J = 18.8,
12.5, 6.4 Hz, 1 H), 0.16 (s, 9 H).
IR (ATR-FTIR): 3359, 2972, 1701, 1693, 1650 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.05 (br s, 1 H), 4.17–4.10 (m, 2 H),
4.12 (s, 2 H), 3.30 (s, 2 H), 2.69–2.58 (m, 2 H), 2.48–2.40 (m, 2 H), 1.46
(s, 9 H), 1.25–1.28 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 216.84, 174.91, 147.66, 50.81, 47.85,
30.60, 29.75, 23.50, –1.64.
HRMS (ESI): m/z [M + H]+ calcd for C11H19OSi: 195.1200; found:
195.1197.
13C NMR (101 MHz, CDCl3): δ = 208.04, 172.77, 171.21, 170.73,
156.13, 134.01, 80.01, 61.29, 60.46, 40.85, 33.90, 28.42, 21.11, 14.27.
HRMS (ESI): m/z [M + H]+ calcd for C15H24NO5: 298.1649; found:
tert-Butyl [(6-Oxo-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-5-
yl)methyl]carbamate (12b)
298.1650.
Starting from 0.23 mmol of Co complex 1b; isolated yield; Method A:
23 mg (40%); Method B: 33 mg (57%); colorless oil.
Methyl 2-Benzyl-3-oxocyclopent-1-ene-1-carboxylate (8h)
Starting from 0.36 mmol of Co complex 1h; isolated yield; Method A:
IR (ATR-FTIR): 2955, 2917, 2850, 1715, 1168, 758 cm–1
.
9 mg (11%); Method B: 36 mg (46%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 2.7 Hz, 1 H), 5.02 (br s, 1 H),
4.33 (d, J = 5.6 Hz, 1 H), 3.96 (ddd, J = 9.3, 7.4, 2.0 Hz, 1 H), 3.88 (d, J =
6.9 Hz, 2 H), 3.56–3.48 (m, 1 H), 3.46–3.38 (m, 1 H), 2.07 (dddd, J =
10.9, 7.5, 3.4, 2.2 Hz, 1 H), 1.79 (ddt, J = 12.6, 5.4, 2.1 Hz, 1 H), 1.41 (s,
9 H).
13C NMR (101 MHz, CDCl3): δ = 206.00, 159.05, 155.76, 143.56, 80.48,
67.48, 42.88, 35.96, 30.06, 28.31.
IR (ATR-FTIR): 2976, 2954, 1715, 1709 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30 (ddt, J = 7.6, 1.5, 0.7 Hz, 2 H),
7.27–7.21 (m, 2 H), 7.20–7.14 (m, 1 H), 3.91 (s, 2 H), 3.87 (s, 3 H),
2.81–2.75 (m, 2 H), 2.50–2.44 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 209.03, 165.57, 154.54, 149.60,
138.28, 129.00, 128.36, 126.32, 52.14, 33.97, 29.65, 26.65.
HRMS (ESI): m/z [M + H]+ calcd for C13H20NO4: 254.1387; found:
254.1382.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
A. Cabré et al.
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Synthesis
5-(Trimethylsilyl)-2,3,3a,6a-tetrahydro-6H-cyclopenta[b]furan-6-
one (12c)
(5) (a) The Pauson-Khand Reaction: Scope, Variations and Applica-
tions; Ríos Torres, R., Ed.; Wiley: Chichester, 2012. (b) Lee, H.-
W.; Kwong, F.-Y. Eur. J. Org. Chem. 2010, 789. (c) Blanco-Urgoiti,
J.; Anorbe, L.; Perez-Serrano, L.; Dominguez, G.; Perez-Castells, J.
Chem. Soc. Rev. 2004, 33, 32.
(6) For other additives tried in the intermolecular PKR, see:
(a) Wang, Y.; Xu, L.; Yu, R.; Chen, J.; Yang, Z. Chem. Commun.
2012, 48, 8183. (b) Gibson, S. E.; Johnstone, C.; Stevenazzi, A.
Tetrahedron 2002, 58, 4937. (c) Hayashi, M.; Hashimoto, Y.;
Yamamoto, Y.; Usuki, J.; Saigo, K. Angew. Chem. Int. Ed. 2000, 39,
631. (d) Sugihara, T.; Yamaguchi, M. Synlett 1998, 1384.
(e) Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. Am. Chem. Soc.
1994, 116, 3159.
Starting from 0.23 mmol of Co complex 1c; isolated yield; Method A:
9 mg (21%); Method B: 35 mg (82%); colorless oil.
IR (ATR-FTIR): 2955, 2859, 1706, 1248, 841 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 2.7 Hz, 1 H), 4.28 (d, J = 5.7
Hz, 1 H), 3.95 (ddd, J = 9.3, 7.4, 2.0 Hz, 1 H), 3.52–3.41 (m, 2 H), 2.08
(dddd, J = 12.5, 10.9, 9.8, 7.4 Hz, 1 H), 1.79 (ddt, J = 12.5, 5.5, 2.0 Hz, 1
H), 0.18 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 210.18, 171.32, 148.39, 80.92, 67.25,
46.04, 30.41, –1.80.
HRMS (ESI): m/z [M + H]+ calcd for C10H17O2Si: 197.0992; found:
197.0996.
(7) (a) Kerr, W. J.; McLaughlin, M. J.; Pauson, P. L.; Robertson, S. M.
J. Organomet. Chem. 2001, 630, 104. (b) Jeong, N.; Chung, Y. K.;
Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204.
(8) Shambayani, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289.
Funding Information
(9) Hay, A. M.; Kerr, W. J.; Kirk, G. G.; Middlemiss, D. Organometal-
lics 1995, 14, 4986.
(10) Su, S.; Rodriguez, R. A.; Baran, P. S. J. Am. Chem. Soc. 2011, 133,
13922.
(11) For other examples of MEG as cobalt NPs stabilizer, see: Muller,
J.-L.; Klankermayer, J.; Leitner, W. Chem. Commun. 2007, 1939.
(12) (a) Ford, J. G.; Kerr, W. J.; Kirk, G. G.; Lindsay, D. M.; Middlemiss,
D. Synlett 2000, 1415. (b) Kerr, W. J.; Lindsay, D. M.; Watson, S.
P. Chem. Commun. 1999, 2551.
We thank the Spanish Ministerio de Economia y Competividad
(CTQ2014-56361-P) and IRB Barcelona for financial support. IRB Bar-
celona is the recipient of a Severo Ochoa Award of Excellence from
MINECO (Government of Spain). CTQ2014-56361-P
Acknowledgment
A.C. thanks IRB Barcelona for a pre-doctoral fellowship.
(13) (a) Kerr, W. J.; McLaughlin, M.; Pauson, P. L.; Robertson, S. M.
J. Organomet. Chem. 2001, 630, 104. (b) Kerr, W. J.; McLaughlin,
M.; Pauson, P. L.; Robertson, S. M. Chem. Commun. 1999, 2171.
(14) Lledo, A.; Fuster, A.; Reves, M.; Verdaguer, X.; Riera, A. Chem.
Commun. 2013, 49, 3055.
(15) This system is typically accessed by indirect routes involving
ring expansion reactions: (a) Fan, X.; Zhuo, L.-G.; Tu, Y. Q.; Yu,
Z.-X. Tetrahedron 2009, 65, 4709. (b) Shinohara, I.; Nagaoka, H.
Tetrahedron Lett. 2004, 45, 1495. (c) Roxburgh, C. J. Tetrahedron
1993, 49, 10749.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588813. Included are experimental
procedures for the preparation of alkynes and alkynehexacarbonyldi-
cobalt complexes, as well as 1H and 13C spectra of the new PK adducts
synthesized in this work.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(16) (a) Vázquez-Romero, A.; Verdaguer, X.; Riera, A. Eur. J. Org.
Chem. 2013, 1716. (b) Vázquez-Romero, A.; Cárdenas, L.; Blasi,
E.; Verdaguer, X.; Riera, A. Org. Lett. 2009, 11, 3104.
(17) (a) Jahn, U.; Galano, J.-M.; Durand, T. Angew. Chem. Int. Ed. 2008,
47, 5894. (b) Das, U. N. Biotechnol. J. 2006, 1, 420. (c) Marks, F.;
Fürstenberger, G. Prostaglandins, Leukotrienes and other Eicosa-
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S. P.; Hwang, S.-W.; Adiyaman, M.; Lawson, J. A.; FitzGerald, G.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G