Studies of iron-mediated Pauson-Khand reactions of 1,1-disubstituted- allenylsilanes: Mechanistic implications for a reactive three-membered iron metallacycle

Article abstract of DOI:10.1039/c2sc21404k

Pauson-Khand reactions of 1,1-disubstituted allenylsilanes have been explored using diiron nonacarbonyl. These studies describe the characterization of three-membered iron metallacycles as reaction-competent intermediates leading to stereoselective formation of highly functionalized 4-alkylidene-2- cyclopenten-1-ones. Studies of the reaction profile provide insights leading to the proposal of a stereoselective mechanistic pathway, which has not been previously explored. Furthermore, these reactions have been examined using computational chemistry, and these efforts have detailed the unique behavior of Fe(CO)₄ and its role in Pauson-Khand processes.

Full text of DOI:10.1039/c2sc21404k

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Studies of iron-mediated Pauson–Khand reactions of
1,1-disubstituted-allenylsilanes: mechanistic
implications for a reactive three-membered iron
metallacycle†
Cite this: Chem. Sci., 2013, 4, 238
*
*
David R. Williams, Akshay A. Shah, Shivnath Mazumder and Mu-Hyun Baik
Pauson–Khand reactions of 1,1-disubstituted allenylsilanes have been explored using diiron nonacarbonyl.
These studies describe the characterization of three-membered iron metallacycles as reaction-competent
intermediates leading to stereoselective formation of highly functionalized 4-alkylidene-2-cyclopenten-
1-ones. Studies of the reaction profile provide insights leading to the proposal of a stereoselective
mechanistic pathway, which has not been previously explored. Furthermore, these reactions have been
examined using computational chemistry, and these efforts have detailed the unique behavior of
Fe(CO)4 and its role in Pauson–Khand processes.
Received 1st September 2012
Accepted 12th October 2012
DOI: 10.1039/c2sc21404k
www.rsc.org/chemicalscience
including the use of other transition-metal catalysts. Synthetic
utility has been substantially enhanced by the use of more
Introduction
Our recent studies have explored the development of bifunc-
tional reagents which permit the sequential execution of cross-
coupling processes in tandem with other high value reactions.1
A goal of these efforts is the design of versatile methodology
which provides for the rapid assembly of molecular complexity.
In this regard, the Pauson–Khand reaction (PKR), a formal [2 +
2 + 1] cycloaddition, has emerged as an important development
for the synthesis of cyclopentenones via a carbonyldicobalt-
mediated carbocyclization of an alkene, an alkyne, and carbon
monoxide.2 Intramolecular variants of the PKR are especially
effective for the synthesis of polycyclic cyclopentenones and
natural products.3
reactive allenes in place of alkenes, although issues of regiose-
lectivity can arise based on steric effects imposed by the allenyl
substitution pattern.8
In this article, we describe a PKR process which proceeds at
ambient temperature using 1,1-disubstituted allenylsilanes and
diiron nonacarbonyl. Reactions with a variety of terminal
alkynes lead to stereoselective formation of highly functional-
ized (E)-4-alkylidene-2-cyclopentenones. We have investigated
the potential for catalytic turnover of the iron-promoted PKR
under elevated CO concentrations. We have undertaken kinetic
studies to provide supporting evidence that this variant of the
PKR occurs via an alternative mechanistic pathway which does
not involve initial complexation of the alkyne component. Our
study details the rst report of a reaction-competent, three-
membered iron metallacycle intermediate which has important
implications for understanding of these [2 + 2 + 1] cyclizations,
and the stereoselectivity of these iron-mediated processes.
Although the initial studies of intermolecular PKR processes
using aliphatic and alicyclic olens generally provided poor
results, signicant contributions by Cazes,4 Brummond,5 Nar-
asaka,6 and others7 have improved the scope of the reaction
Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington,
IN, 47405, USA. E-mail: williamd@indiana.edu; mbaik@indiana.edu
Results and discussion
† Electronic supplementary information (ESI) available: General reaction
procedures and characterizations of the 1,1-disubstituted allenes and the iron
metallacycles from 9, 10, 11, and 23. Experimental procedures and
characterization data for products 7, 8, 12–22, and 25. 1H NMR, 13C NMR and
2D NOESY spectra for all products, and X-ray crystal structure data for 18 and
24. A kinetic study of the reaction prole and a rate study which determines the
Our initial discovery of regioselective sp2–sp2 Stille cross-
coupling reactions of 3-tri-n-butylstannyl-1-trimethylsilyl-1-pro-
pyne demonstrate isomerization following the transmetalation
of the propargylic stannane 2 (Scheme 1), which results in an
order of the reaction with respect to alkyne concentration. Computational allenylpalladium species for reductive coupling to yield 1,1-
disubstituted allenylsilanes 3.9 This novel cross-coupling has
supplied direct access to a series of conjugated allenes, and we
have sought to explore these results in tandem with a mild [2 +
information regarding structure of the iron metallacycle, regiochemistry of
Fe(CO)4 complexation, energies of possible intermediates in the mechanistic
pathway, HOMO and LUMO calculations and exploration of the triplet potential
energy surface. Also included are calculations of alternative structures of
2 + 1] carbocyclization as an efficient route to complex cyclo-
pentenones. Inspired by efforts for target-oriented total
comparisons (S1–S145). CCDC 904093 and 824471. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2sc21404k
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Table 1 Formation of 4-alkylidene-2-cyclopenten-1-ones
Entry Allene Alkyne
Major producta
Yieldb [isomer/ratio]c
73% [>97 : 3]
Scheme 1 Sequential Stille and Pauson–Khand reactions.
1
2
9
9
synthesis, our initial studies serve to illustrate the two-stage
process. Thus, butyrolactone 6 (Fig. 1) is reacted with 2 in the
presence of 20 mol% Pd2(dba)3 in dimethylformamide at 22 ꢀC
with triphenylarsine (0.8 mmol) and copper(I) iodide (0.8 mmol)
additives. Small quantities of lithium chloride (20 mol%) are
added to bring the reaction to completion providing a 60% yield
of conjugated allene. Subsequent cycloaddition with trime-
thylsilylacetylene using Fe2(CO)9 at 22 ꢀC in anhydrous THF
containing N-methylmorpholine-N-oxide (3.0 equiv.) results in
the stereoselective formation of the cyclopentenone 7 (62%).
Similarly, the sequence has been employed for direct access to
cyclopentenone 8 via a sterically demanding [2 + 2 + 1] carbo-
cyclization at room temperature (50% yield; 75% brsm). Based
on these early results, we initiated a survey of the scope and
generality of the [2 + 2 + 1] cycloaddition using three examples
of our 1,1-disubstituted allenylsilanes, 9, 10 and 11, (Fig. 2) with
a variety of terminal alkynes. Our results are compiled in Table
1, providing yields of cyclopentenones 12–22 ranging from 50–
80% based on starting allene. We note that Narasaka rst
described the intermolecular Pauson–Khand reactions of
69% [92 : 8]
77% [93 : 7]
3
4
9
10
81% [94 : 6]
51% [100 : 0]
52% [80 : 20]
61% [>97 : 3]
5
6
7
10
10
10
8
11
11
11
74% [83 : 17]
64% [100 : 0]
72% [>97 : 3]
9
10
11
11
61% [97 : 3]
a
Conditions: to a 0.2 M solution of dry THF containing NMO (3.0 equiv.)
was added Fe2(CO)9 (1.5 equiv.) and allene (1.0 equiv.) at ꢁ50 ꢀC under
N2. Alkyne (1.5–3.0 equiv.) was immediately added with stirring for 5
min, and the mixture was then warmed to rt with stirring for an
additional 1–3 h. Dilution with hexanes and ltration through a plug
of Florisilꢀ was followed by concentration under reduced pressure to
Fig. 1 Initial examples of sequential Stille and Pauson–Khand reactions.
b
give the crude product. Yields are quoted for major products aer
c
purication by ash silica gel chromatography. Isomer ratios are
based on GC-MS analyses of crude products except for entries 6 and 8,
where integrations of selected 1H NMR signals were used.
Fig. 2 Allenylsilanes 9–11.
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allenylsilanes using Fe(CO)4(NMe3) under conditions of photo- formation of a product which was rst observed at ꢁ20 ꢀC and
irradiation.6 Excitation of the metal facilitates the loss of a persisted throughout the course of the reaction. In most cases,
ligand to open a site for p-coordination of the alkyne or alle- this substance remained as a minor component of the crude
nylsilane substrate. However, these reactions yielded a mixture product mixture aer consumption of starting allene. Isolation
of four isomeric 4-alkylidene-2-cyclopenten-1-ones suggesting by ash silica gel chromatography and characterization using
the characteristic involvement of radical mechanisms in E/Z- HRMS and 1H NMR data proved that these isomerically pure
alkene equilibrations. Eaton and coworkers have also demon- substances were adducts of Fe(CO)4 and our starting allenes.
strated the Fe2(CO)9 mediated [4 + 1] cycloadditions of allenyl This intriguing aspect was investigated by combining 1-(1-
imines, allenyl ketones, and diallenes to produce the corre- napthyl)-1-trimethylsiꢀlylallene (23) with diiron nonacarbonyl (1
sponding ve-membered carbonyl derivatives.10 It is proposed equiv.) in THF at 22 C, and led to the isolation of the three-
that these cycloaddition events are initiated by precoordination membered iron metallacycle 24 in 41% yield with recovery of
of allene as an h2-complex via formation of Fe(CO)4. While other starting 23 (55%) (Fig. 3). No other products were obtained. An
metal carbonyl species, including Co2(CO)8, Mo(CO)6 and X-ray diffraction study has afforded an unambiguous structure
W(CO)6 have been reported for [2 + 2 + 1] cycloadditions of determination of the complex 24 as illustrated in the ORTEP
allenes, we have observed no reactions at room temperature for (Fig. 3).14 In similar fashion, the analogous metallacycle has also
9, 10, and 11 with the usual cobalt and molybdenum reagents, been prepared in 67% yield from allene 9.
and the use of tungsten hexacarbonyl led to poor conversions
Structures from the X-ray determination and density func-
(5–10%). The use of solid diiron nonacarbonyl is operationally tional theory (DFT) calculations of the three-membered metal-
preferred, however, similar results are achieved with Fe(CO)5 lacycle have been compared in Table 2. Geometric parameters
(liquid at 22 ꢀC). Cycloadditions are conducted in anhydrous of the calculations are in good agreement and validate our
THF under nitrogen atmosphere and may lead to a reactive computational methodology. The results of the X-ray study
Fe(CO)4$THF complex via a disproportionation and/or CO (ORTEP; Fig. 3) illustrate an expected conformational feature of
dissociation pathway.11 The use of a CO atmosphere greatly the complex which places the aryl moiety of the alkenylsilane
impeded the rate of our reactions, and in some cases, led to no nearly perpendicular to the plane of the metallacycle. To gain
product formation. Rate enhancements are observed by the insights with regard to the hybridization at C1 and C2, and to
addition of N-methylmorpholine-N-oxide (NMO) or trimethyl- assess the nature of bound iron in the complex, we initially
amine-N-oxide (TMANO).12 It is anticipated that amine oxides compared the C1–C2 bond length (1.401 A) of 24 with X-ray
˚
promote a rate acceleration by initial reaction with Fe(CO)5 crystallographic data for the length of the terminal C]C of 1,1-
15
˚
leading to a vacant coordination site with release of carbon disubstituted allenes (1.29 A), and for the corresponding C1–
16
˚
dioxide and amine. Product formation is not observed in dry C2 bond of methylenecyclopropanes (1.467 A). This compar-
DMSO, a highly coordinating solvent, whereas our reactions ison shows that the C1–C2 bond of 24 is similar to the bonding
proceed in toluene, albeit at a slower rate.
length which characterizes the analogous carbocycle. In addi-
In all cases, the products of Table 1 are characterized by the tion, the C1–C2–C3 bond angle (149.21ꢀ) of 24 shows consider-
exclusive formation of the exocyclic-(E)-alkenylsilane geometry. able deviation from linearity. Thus, an analysis of the X-ray data
The E-stereochemistry of the alkenylsilane has been determined is in close agreement with our DFT calculations which describe
by two-dimensional NOE experiments which established the cis- a three-membered metallacycle structure.
relationship of TMS and the cyclopentenyl methylene of our
products. Furthermore, cyclopentenone 18 (entry 7 of Table 1)
afforded suitable crystals leading to an unambiguous structure
determinationviaanX-raydiffractionstudy.13 Stericeffectsplayan
important role in determining the regiochemistry for incorpora-
tion of terminal alkynes. As a result, the use of trialkylsilyl and
tri-n-butylstannyl acetylenes give rise to the anticipated a-
substituted-2-cyclopentenones12, 15, 16, 18and 20 (entries1, 4, 5,
7, 9). On the other hand, reactions with phenylacetylene and alkyl-
substituted terminal alkynes (entries 2, 6, 8 and 11; Table 1)
generally produced small amounts of the corresponding b-
Fig. 3 Formation of three-membered metallacycle 24.
substituted-2-cyclopentenones. These ratios of positional isomers Table 2 A comparison of X-ray data and DFT calculations for the characteriza-
tion of iron metallacycle
were determined by GC-MS prior to chromatographic purication
of the major product. The compatibility of the reaction conditions
Bond
X-ray
data
DFT
calcd
Bond
X-ray
data
DFT
calcd
with numerous functionalities is a particularly valuable feature.
The direct incorporation of sensitive vinylsilanes and stannanes,
allylic silanes, and halides allows for further site-specic elabo-
rations of the cyclopentenone framework.
Signicantly, our studies have provided new insights
regarding the reaction mechanism for these Pauson–Khand
cycloadditions. Each of the starting allenes 9–11 led to the
lengthsa
anglesb
Fe–C2
Fe–C1
C2–C3
C1–C2
2.025
2.094
1.317
1.401
2.051
2.115
1.331
1.401
:Fe–C2–C1
:Fe–C1–C2
:C2–Fe–C1
:C1–C2–C3
72.79
67.49
39.72
72.84
67.90
39.26
149.21
148.01
a
b
˚
Bond lengths are in A. Bond angles are in degrees.
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For each allene 9–11, these iron metallacyclopropanes were without the addition of carbon monoxide. Percentages of allene
shown to be reaction competent. Reconstitution of our Pauson– 9 and product 25 were measured by 1H NMR integration relative
Khand reactions with the iron complexes in anhydrous THF to an internal standard aer removal of paramagnetic iron
with alkyne and NMO (1.0 equiv.) at room temperature led to byproducts by ltration through Florisilꢀ. The data in Table 3
the rapid production of the expected cyclopentenones without show a stoichiometric dependence on Fe2(CO)9, and in fact,
additional requirements of a carbon monoxide atmosphere or demonstrate that the presence of additional CO effectively halts
elevated temperatures. Reactions, monitored over 30 h in the the progress of the reaction (compare A to C).
absence of NMO, showed very slow production of cyclo-
Moreover, our kinetic studies have examined the reaction
pentenone in the presence of the starting iron metallacycles and coordinate for consumption of allene, and production of met-
alkyne. We attribute this background reaction to a photo- allacycle and PKR product as a function of time. The PKR
induced activation of the iron complex which allows for loss of reaction prole is shown in Fig. 4. The reactants were dissolved
one CO ligand. In both instances, small amounts of starting in dry THF at ꢁ50 ꢀC under N2 atmosphere, and a small amount
allene were detected in solution.17 The catalytic behavior of of 1,3,5-trimethoxybenzene was added as an internal standard.
these reactions was examined by evaluating three reactions of Aliquots were removed periodically and were immediately
allene 9 in the presence of 20 mol% Fe2(CO)9 (Table 3). In each passed through a pipette plug of Florisilꢀ using diethyl ether to
case, reagents were combined in THF solution at ꢁ60 ꢀC under sequester paramagnetic iron species. Each sample was then
nitrogen, and were allowed to warm to 22 C. One reaction (A) analyzed by 1H NMR spectroscopy to measure amounts of allene
ꢀ
was transferred to an autoclave and placed under CO atmo- 9, PKR product 25 and the iron metallacycle 26. Data from three
sphere (50 psi) for 24 hours. A second reaction (B) was initiated experimental iterations were averaged and graphed. The results
at the same time and under identical conditions as reaction A. display a facile conversion of allene 9 into the cyclopentenone
However, reaction B was quenched when A was fully pressurized 25 within 50 minutes. However, a small amount of iron metal-
with CO in order to measure the background conversion to lacycle 26 is rapidly produced and is not consumed as the
product 25 which would occur without the presence of a CO reaction proceeds to completion. We then examined the
atmosphere. Reaction C was maintained under N2 for 24 hours production of PKR product 25 and metallacycle 26 as a function
of alkyne concentration over linear regions of the initial reac-
tion prole (Fig. 5). In this study, seven reaction vials were
charged with Fe2(CO)9, (20 mol%) allene 9 (0.037 mmol), and
Table 3 Studies of stoichiometric behavior of Fe2(CO)9
NMO (3 equiv.) in dry THF at ꢁ50 ꢀC under N2 atmosphere. An
internal standard of 1,3,5-trimethoxybenzene was added, and
various amounts of trimethylsilylacetylene (0.011–0.077 mmols)
were introduced at ꢁ50 ꢀC followed by warming to 22 ꢀC. Aer
stirring for 60 min, each reaction was diluted with a small
amount of hexanes and ltered through a pipette plug of Flo-
risilꢀ. The analysis of these samples by 1H NMR spectroscopy is
Experiment
Conditions
Results
shown in Fig. 5, and illustrates a linear relationship for the
conversion of allene 9 into the cyclopentenone 25 with a steady
state amount of metallacycle 26 throughout the range of
increasing alkyne concentrations.
A
B
C
50 psi CO atm; 24 h
N2 atm; 10 min
N2 atm; 24 h
25 (10%); 9 (90%)
25 (10%); 9 (90%)
25 (18%); 9 (82%)
Fig. 4 Reaction profile for the iron-mediated allenic Pauson–Khand reaction (an
Fig. 5 Conversion of allene into PKR product 25 and metallacycle 26 as a
average of three experimental iterations).
function of alkyne concentration (an average of three experimental iterations).
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A kinetic study was undertaken for regions of the reaction
prole which display linear behavior. Four reaction vessels
containing dry THF under N2 atmosphere were charged with
NMO (3 equiv.) Fe2(CO)9 (20 mol%), and allene 9 (0.023 mmol)
at ꢁ50 ꢀC. A quantity of trimꢀethylsilylacetylene (0.014–0.034
mmol) was introduced at ꢁ50 C along with 1,3,5-trimethoxy-
benzene in THF solution which established a reaction of 0.023
M concentration with respect to allene 9. This concentration
ensured reactions were sufficiently slow for periodic removal of
aliquots over a timeframe of 10 to 120 minutes. Samples were
analyzed by gas chromatography to measure the amount of PKR
product 25 leading to the data of Fig. 6.
The rates of each reaction at different alkyne concentrations
were determined from the slopes of each plot of Fig. 6. These
data are tabulated (Table 4) and display the linear behavior of
the graph in Fig. 7. The corresponding log/log plot of data from
Table 4 shows that the order of the reaction is 1.6 with respect to
alkyne concentration (see ESI†). This behavior is indicative of a
complex reaction involving a sequence of steps. In contrast, the
kinetic analysis of the classic intermolecular PKR, mediated by
CO2(CO)8, demonstrates rate dependence behavior which is
zero-order [alkyne].18 Based on these studies, we have concluded
that our reactions are stoichiometric with respect to Fe2(CO)9,
and suggest that the rate-limiting step is subsequent to the
formation of the iron metallacycle. Our reaction prole is not
characteristic of the classical PKR and supports evidence of an
alternative mechanistic pathway.
Fig. 7 Initial reaction rate as a function of alkyne concentration.
Our ndings describe the formation of stable tetracarbonyl-
iron–alkene complexes. There has been long-standing interest
in the interactions of allenes with transition-metal reagents,
and particularly the ability to distinguish between p-bonding
and metallacycle formation.19 It appears that Pettit may have
isolated a stable three-membered iron metallacycle from reac-
tions of tetramethylallene and diiron nonacarbonyl as early as
1967. Although this product was not characterized, it was
described as a stable p-complex.20 Subsequently, Foxman
described the tetramethylallene derivative [Cp(CO)2Fe(h2-
Me2C]C]CMe2)].21 Proton NMR studies showed that the four
methyl groups become equivalent with increasing temperature.
This behavior suggests rotation about the Fe-allene axis and
migration of Cp(CO)2Fe between both orthogonal alkene units.
Wojcicki and Lichtenberg reported that h2-allenes derived from
coordination of Cp(CO)2Fe undergo nucleophilic attack at the
terminal carbon to yield vinylic iron complexes.22 In related
studies, Lindner, et al. found that the complexes L(CO)3Fe(h2–
C2H4) are obtained by nucleophilic reactions of the bis-triate
of ethylene glycol with the anions [Fe(CO)3L]ꢁ2 (where L ¼ PPh3
or POMe3).23 More recently, Sappa and coworkers have
described the stable diiron complex Fe2(CO)6(PPh3)[m-h3-
(H2CCCH2)] which has been characterized by X-ray analysis.24
Kukolich and coworkers have reported extensive DFT calcula-
tions and low temperature microwave spectroscopy to charac-
terize tetracarbonyl-ethyleneiron,25 and their ndings have been
compared to structural details stemming from X-ray diffraction
data of stable tetracarbonylethyleneosmium, which exhibits
evidence of greater back-bonding donation from osmium.26
To gain insights into the fundamental reactivity of our iron
metallacycles, we designed a crossover experiment in which the
puried complex 26 (1 equiv.) was allowed to react with trime-
Fig. 6 Reaction profile dependence on alkyne concentration in regions which
display linear behavior (an average of three experimental iterations).
Table 4 Reaction rates determined for alkyne concentrations
Initial rate
(mmol minꢁ1 mLꢁ1
)
Log[alkyne]
Log(rate)
ꢀ
Entry
Alkyne (M)
thylsilylacetylene (1.5 equiv.) in anhydrous THF at 22 C with
the addition of NMO (3 equiv.) in the presence of the alternative
allenylsilane 11 (1 equiv.). Upon completion, this experiment
produced approximately equal amounts of two PKR products,
the previously characterized 25 and 27 (ratio 1 : 1). Analyses by
1
2
3
4
0.0137
0.0206
0.0275
0.0344
2.132 ꢂ 10ꢁ5
4.517 ꢂ 10ꢁ5
6.329 ꢂ 10ꢁ5
9.479 ꢂ 10ꢁ5
ꢁ1.86
ꢁ1.69
ꢁ1.56
ꢁ1.46
ꢁ4.67
ꢁ4.35
ꢁ4.19
ꢁ4.02
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1H NMR spectroscopy and GCMS also showed equal amounts of 16 kcal molꢁ1, and leads to two fragments, Fe(CO)4 and Fe(CO)5.
the starting allenylsilanes 9 and 11 remaining in solution. Our The coordinatively unsaturated iron tetracarbonyl species binds
crossover experiment indicates a facile and highly reversible the allene, and our calculations suggest that this process is
coordination of Fe(CO)4 with the p-system of the allene. This energy neutral. Thus, it is anticipated that Fe(CO)4 complexa-
equilibration leads to statistically equal amounts of iron tetra- tion with allene substrate is likely to be reversible, and this
carbonyl complexes derived from 9 and 11 which yield the conclusion is supported by our crossover experiments. The
corresponding cyclopentenones products.
formation of a stable, nearly octahedral, six-coordinate tetra-
carbonyliron–allene complex poses questions about the nature
of the interaction of electrophilic iron species with alkenes.
Specically, these questions address the ability to distinguish
between p-complex and ferracyclopropane formation. Our
calculations have provided insights which describe the bonding
of allene and Fe(CO)4 components. As summarized in Fig. 8, the
1a1 and 2a1 orbitals of Fe(CO)4 have the correct symmetry to
overlap with the occupied p-orbital of allene 9. These interac-
tions are viewed as forward donation where electron density is
shied from the C]C region toward the metal. Back donation is
represented by the overlap of the lled b2 orbital of Fe(CO)4 and
A mechanistic rationale for the PKR was rst proposed by
Magnus and coworkers in 1985 based upon the precomplex-
ation of Co2(CO)8 with alkyne reagents,27 and this aspect has
been broadly applied with additional insights as a general
pathway for [2 + 2 + 1] cycloadditions.4a,28 However, our experi-
ments suggest an alternative mechanism resulting from high
facial selectivity for the initial complexation leading to the E-
alkene geometry of the three-membered metallacycle 28
(Scheme 2). By considering the iron complex 28 as a reactive
species for the PKR, we have illustrated two possible pathways
leading to cyclopentenone formation. One hypothesis features a
stereospecic insertion of carbon monoxide involving bond (b)
of 28 which would provide a four-membered intermediate with
an open coordination site for alkyne complexation in 29.
Subsequent insertion involving bond (a) leads to the acyl metal
species 30 for reductive elimination to cyclopentenone product.
Alternatively, the loss of carbon monoxide from metallacycle 28
would provide a vacant coordination site for alkyne complexa-
tion in 31 followed by selective insertion involving the vinylic
bond (a) to produce 32 for conversion to the acyl intermediate
30. In either case, the differential and selective reactions of the
allylmetal bond (b) versus the alkenylmetal linkage (a) in 28, in
combination with the observed face selectivity for complexation
of Fe(CO)4 with the starting allenylsilanes, would suggest new
opportunities to explore the chemical behavior of these three-
membered metallacycles.
Fig. 8 Schematic orbital interaction diagram between Fe(CO)4 and allenylsilane.
To examine these questions and probe the mechanism of the
iron-mediated Pauson–Khand reaction, we have employed
computational methods based on DFT.29 The dissociation of
Fe2(CO)9 is thermodynamically advantageous by approximately
Fig. 9 DFT calculated molecular orbitals of the metallacycle 26. Energy states are
Scheme 2 Possible mechanistic pathways involving 28.
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the empty p* orbital of the allene. Both forward and back
donations play a role in activating the allene for further
chemistry.
DFT calculations reveal ve d-type Fe-based molecular
orbitals (MO) in the complex 26 (Fig. 9). Molecular orbitals 88
and 89 are regarded as dxz and dyz orbitals, respectively. The
mixing of dxy and dx2ꢁy2 gives rise to the MOs 91 and 94. These
four MOs are occupied in both a and b subspaces while the
higher energy MO 100, which is essentially the dz2 orbital of Fe,
is unoccupied. Thus, it is reasonable to classify compound 26 as
a d8 Feꢀ complex. We conclude that bonding of the allenic p-
system is so signicantly distorted that this arrangement
cannot be described as a p-complex. However, it is also not
reasonable to describe 26 as a ferracyclopropane which is ach-
ieved by the inclusion of a suitably complexed Fe2+ species. The
reality lies between these opposing models.
Our experimental studies have shown that Fe(CO)4 complex-
ation occurs in a regioselective, as well as a stereoselective
fashion. DFT calculations have examined the reasons for this
behavior. For example, the reaction of Fe2(CO)9 with allene 10
leads to exclusive formation of the complex 33 (Fig. 10). Our
calculations show that the more substituted isomer 34 is ther-
modynamically less stable by 6.5 kcal molꢁ1. This energy
difference may be attributed to two factors. Firstly, the conju-
gation of the C2–C3 double bond of the starting allene with the
aryl substituent may reduce the reactivity of this p-bond for
coordination. Secondly, steric repulsions in the ferracyclopro-
pane complex are minimized in 33 as compared to 34.
Fig. 11 Model study of face selectivity for the initial complexation event.
Structures 36 and 37 are also shown with ball and stick illustrations; hydrogen
atoms on the aryl ring are omitted for clarity.
Fig. 12 Relative energies leading to ferracyclobutanone 39.
spherical topology which occupies greater spatial volume than
aryl. In fact, the replacement of TMS with a methyl group
reverses the trend. As shown in Fig. 11, the latter calculations
favor isomer 37 in which the optimized geometry permits p-
conjugation of the aromatic ring as compared to 36.
Our calculations have provided valuable insights regarding the
mechanistic pathways outlined in Scheme 2. Computations show
that the insertion of carbon monoxide from 33 (Fig. 12) which
leads to a ring expansion to 38, is highly endothermic by 32.7 kcal
molꢁ1. This can be attributed to stable properties of the relatively
strain-free and coordinately saturated complex 33. However, the
coordination of one THF molecule in 39 is not energetically
helpful, andunderscores anincreaseinringstrainassociated with
this four-membered system compared to the starting 33.
To assess these factors, we have computationally explored
the replacement of aryl and trimethylsilyl substituents of 33 and
34 with sterically less demanding vinyl and methyl substitution,
respectively (see ESI†). Furthermore, we have calculated the
thermodynamic preference for complexation of Fe(CO)4 with
1,1-dimethylallene. In both instances, regioselective coordina-
tion is predicted to occur at the terminal olen.30 We have also
examined the face selective outcome which leads to the E-alkene
C2–C3 geometry in 33 versus the Z-geometry of 35. DFT calcu-
lated geometries conrm that the aryl moiety is nearly perpen-
dicular to the plane of the ferracyclopropane in 33, and this
conformation avoids steric interactions with neighboring CO
ligands. On the other hand, the TMS functionality has a
A direct dissociation of CO from 33 provides an open coor-
dination site and results in a sixteen-electron, square pyramidal
intermediate. The process is energetically uphill by +20.7 kcal
molꢁ1, and this tight ligand binding explains the absence of
catalytic turnover when a CO atmosphere is applied. On the
other hand, the introduction of NMO provides for nucleophilic
attack on the complex 33 which leads to a fragmentation
producing carbon dioxide, N-methylmorpholine and the coor-
dinately unsaturated species 40. This conversion is signicantly
exothermic by 50.6 kcal molꢁ1. When we consider lling the
coordination sphere to give 41, the overall process is favorable
by 51.9 kcal molꢁ1
.
Fig. 13 summarizes our calculated reaction energy proles
for the insertion of alkynes using trimethylsilylacetylene.
Although the coordination of THF in 41 (Fig. 14) is downhill by
Fig. 10 Regio- and stereoselectivity for complexation of allene 10 with Fe(CO)4.
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Fig. 15 Optimized geometries 48 and 49 of alkyne insertion transition states
47-TS1 and 47-TS2. Hydrogen atoms are omitted for clarity.
insertions into the alkenyl–Fe bond to yield 43 and 45 occur
with activation barriers of 12.3 and 23.7 kcal molꢁ1, respec-
tively. The lowest energy pathway involves arrangement 47-TS1
(12.3 kcal molꢁ1) to produce intermediate 43. Gratifyingly, this
regio- and stereoselective insertion gives rise to the experi-
mentally observed cyclopentenones of Table 1. Other insertion
pathways are much higher in energy, and thus, imply the greatly
preferred formation of a-substituted-2-cyclopentenones.
To investigate fundamental aspects of this reactivity pattern,
we have optimized transition states for the arrangements of 47-
TS1 and 47-TS2. As shown in Fig. 15, the transition state
stemming from 47-TS2 displays a ve-coordinate Fe center as a
trigonal bipyramidal structure 49 while 47-TS1 has a classic,
three-legged piano stool geometry31 in transition state 48. Bond
formation occurs between C2 and C4 in 48, and the calculated
Fig. 13 Reaction energy profiles for stereoselective insertion of trimethylsilyla-
cetylene via 42 for production of metallacycles 43–46.
˚
˚
Fe–C2 and Fe–C4 bond distances are 2.057 A and 2.134 A,
respectively. New bond formation must proceed between C3 and
C4 atoms in 49 although Fe–C3 and Fe–C4 bond distances are
˚
˚
signicantly longer at 2.213 A and 2.237 A, respectively.
In transition state 48, a carbonyl moiety is positioned trans to
the bound alkyne, and this feature has important electronic
consequences. As a result, the empty dz2 orbital of Fe is positioned
Fig. 14 Decarboxylation of 36 with NMO.
1.3 kcal molꢁ1, alkyne binding is slightly endothermic by 1.7
kcal molꢁ1 to produce p-complexes, such as 42. We have
considered four orientations for this complexation leading to
the isomeric ferracyclopentenes 43, 44, 45, and 46. The alkyne
insertion event is exothermic by 4.6 to 10.3 kcal molꢁ1, and
favored intermediates 43 and 45 present a six-coordinate, 18-
electron Fe(II) species with a four electron allenic donor (frag-
ment C1–C2–C3) displaying h3 coordination. In structure 43, the
Fig. 16 Electronic considerations in 50 compared to 51.
˚
C1–C2 bond distance (1.422 A) is essentially equal to the C2–C3
˚
distance (1.423 A). We have examined the transition state
arrangements of 47-TS1 and 47-TS3 for insertion of trime-
thylsilylacetylene into the alkenyl–Fe linkage as well as 47-TS2
and 47-TS4 arrangements for insertion into the allyl–Fe bond as
pertains to the orientation and reactivity of the p-complexation
shown as 42. Our calculations nd that the processes stemming
from insertion of the allylmetal linkage via 47-TS2 and 47-TS4
require activation energies of 19.5 and 23.7 kcal molꢁ1 while
Fig. 17 Mechanistic pathway of the iron-mediated PKR.
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to overlap with the lled p orbital of the alkyne as illustrated in 50
(Fig. 16). This attractive interaction effectively lowers the activa-
tion energy (12.3 kcal molꢁ1) of the insertion such that the
impending cyclization to metallacycle 43 occurs under very mild
conditions. In contrast, structure 49 positions the empty dz2
orbital paralleltothe lled p systemas shown in51, and thiseffect
is destabilizing. Further calculations involving the arrangements
shown in 47-TS3 and 47-TS4 (Fig. 13) have highlighted destabi-
lizing steric interactions associated with the relative position of
the large TMS substituent at the site of C–C bond formation as
compared to 47-TS1 and 47-TS2, respectively. Overall, our
computational studies have identied a low energy pathway for
the iron-mediated PKR process which proceeds via the three-
membered d8 Feꢀ complex 28. As illustrated in Fig. 17, reaction of
28 with NMO provides for decarboxylation and an open coordi-
nation site in the reactive complex 40. Addition of alkyne gives 42
which undergoes insertion to 43. Final transformation involves
insertion of CO (highlighted in red) to yield complex 52 leading to
reductive elimination and formation of the a-substituted-2-
cyclopenten-1-one product.
Notes and references
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In summary, a broad-based investigation of iron-mediated [2 +
2 + 1] carbocyclization reactions has been described. An effi-
cient PKR process occurs at ambient temperature using diiron
nonacarbonyl, an inexpensive and readily available reagent. In
this manner, highly functionalized 4-alkylidene-2-cyclopenten-
1-ones are directly available. The process is initiated by a novel
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is crucial for C–C bond formation. These ndings have signi-
cant ramications for the design of iron catalysts for cross-
coupling processes. Overall, we have documented an alternative
pathway demonstrating the role of Fe(CO)4 in novel PKR
processes which occur under extraordinarily mild conditions.
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Acknowledgements
The authors acknowledge the support of the National Science
Foundation (CHE-1055441, D.R.W), (CHE-0645381, M.-H.B.)
and (CHE-1001589, M.-H.B.).
246 | Chem. Sci., 2013, 4, 238–247
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˚
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˚
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ꢂ
0.124
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ꢀ
˚
˚
˚
A, b ¼ 29.386(3) A, c ¼ 9.6851(10) A, b ¼ 100.773(2) , V ¼
1999.4(4) A , rcalc ¼ 1.350 Mg mꢁ3, m ¼ 0.835 mmꢁ1, 150
3
˚
K, Mo Ka, 2qmax ¼ 60ꢀ. A total of 21 632 reections were
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´
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a
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´
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´
´
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