Synthesis of hexahydrocyclopenta[c]furans by an intramolecular iron-catalyzed ring expansion reaction

Article abstract of DOI:10.1002/adsc.200700035

The intramolecular iron-catalyzed ring expansion reaction of epoxyalkenes was investigated with a preformed iron(salen) [Fe(Salen)] complex. The formal insertion of the alkene into the epoxide generated hexahydrocyclopenta[c]furan derivatives in moderate to good yields and diastereoselectivities depending on other functional groups present in the starting materials. In addition, oxygen-tethered epoxyalkenes were used for the synthesis of lignan isomers. The scope and limitations of the Fe (Salen)-catalyzed process of the reaction are discussed.

Full text of DOI:10.1002/adsc.200700035

FULL PAPERS
DOI: 10.1002/adsc.200700035
Synthesis of Hexahydrocyclopenta[c]furans by an Intramolecular
Iron-Catalyzed Ring Expansion Reaction
Gerhard Hilt,a,* Patrick Bolze,a Maja Heitbaum,a Katrin Hasse,a Klaus Harms,a
and Werner Massaa
a
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Str., 35043 Marburg, Germany
Fax : (+49)-6421-2825677; e-mail: hilt@chemie.uni-marburg.de
Received: January 22, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The intramolecular iron-catalyzed ring ex- starting materials. In addition, oxygen-tethered epox-
pansion reaction of epoxyalkenes was investigated yalkenes were used for the synthesis of lignan iso-
with a preformed iron
A
G
N
The formal insertion of the alkene into the epoxide alyzed process of the reaction are discussed.
generated hexahydrocyclopenta[c]furan derivatives
in moderate to good yields and diastereoselectivities Keywords: catalysis; epoxides; iron; ring expansion;
depending on other functional groups present in the salen ligands
Introduction
plex, NEt3 and zinc powder in acetonitrile as the sol-
vent of choice at elevated temperatures.[4] Under
The synthetic usefulness of iron-catalyzed reactions, these conditions the amount of polymerized side
particularly in carbon-carbon bond formation process- products could be minimized. This improved catalyst
es, is mostly driven by the environmental and eco- system was able to increase the yield of the intermo-
nomic advantages associated with the use of iron cata- lecular ring expansion reaction by 20–45% compared
lysts in organic chemistry. In the last couple of years to Fe
an increasing number of innovative applications of the very prominent class of NHC ligands reported
iron catalysts indicates that some advantageous and earlier.[5] Also, with the preformed Fe
(Salen) catalyst
(dppe)Cl2 or other catalyst systems containing
AHCTREUNG
intriguing characteristics of iron as a transition metal the initial scope of substrates could be considerably
in organic synthesis compared to the higher homo- enlarged and an increasing number of epoxides (radi-
logues and other prominent transition metals justifie cal donor) could be used in combination with a large
a closer look at the organic chemistry of iron.[1] The number of functionalized alkenes (radical acceptor).
iron catalysts used either are addressing an alternative An impressive variety of structural modifications and
substrate spectrum or different chemo- or regioselec- polyfunctionalized products suitable as building
tivities can be obtained spanning wide fields of useful blocks for further transformations could be generated.
synthetic organic reactions.[2] Among such transforma- These results prompted us to explore the scope and
tions we identified some iron catalyst systems that limitations of the iron-catalyzed ring expansion in in-
were able to convert epoxides into tetrahydrofurans tramolecular reactions applying internal epoxyalkene
under formal insertion of an alkene on applying re- derivatives 1. Thereby, the synthesis of bicyclic prod-
ductive conditions.[3] At the beginning of the investi- ucts, mainly hexahydrocyclopenta[c]furans 2 (X=CH2)
gations the intermolecular reaction was mostly ham- and derivatives was envisaged (Figure 1). The incor-
pered by polymerization side products deriving from poration of heteroatoms in the linker interconnecting
the radical mechanism proposed. The electron trans- the epoxide and the alkene functionality should allow
fer from the in situ generated reduced iron catalyst bicyclic systems with a heteroatom in each of the five-
species to the epoxide initiated the ring opening se- membered rings to be addressable, such as the class
quence of the reaction mechanism which could also of tetrahydrofuro[3,4-c]furans 2 (X=O) and their de-
U
have led to a radical-based polymerization. An inten- rivatives. This type of substructure can be found in
sive catalyst optimization led to a rather simple cata- the vast variety of lignan derivatives and several cy-
lyst system consisting of a preformed Fe
(Salen) com- clopentanoids (Figure 1).[6]
G
2018
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Synthesis of Hexahydrocyclopenta[c]furans
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substituent (Ar). This is based on the assumption
that, in the proposed radical mechanism for the ring
expansion reaction, the intermediately formed benzyl-
ic radical is stabilized by this aromatic substituent and
favours the ring opening process initiated by an elec-
tron transfer from a reduced iron catalyst species to
the epoxide subunit.
The synthesis of the desired epoxyalkenes of type 1
was accomplished by a reaction sequence outlined in
Scheme 2. Starting from aromatic bromides 5 a
Grignard reaction with cyclopentanone 6 and direct
dehydration under forcing acidic conditions led to the
cyclopentene derivative 4.[7] An ozonolysis with re-
ductive work-up utilizing triphenylphosphine generat-
ed the dicarbonyl compounds of type 3 by applying
standard protocols.[7] The chemoselective functionali-
zation of the oxo-aldehyde 3 was accomplished by a
Wittig reaction which gave exclusively the oxo-alkene
7 as a mixture of the corresponding E- and Z-isomers.
As could be shown recently,[5] the E/Z-stereochemis-
try of the alkene is irrelevant for the diastereoselec-
Figure 1. Retrosynthetic approach towards the lignan and
cyclopentanoid scaffolds.
Results and Discussion
Synthesis of Epoxyalkenes
For the investigation of the key step of the intramo- tivity in an iron-catalyzed intermolecular ring expan-
lecular iron-catalyzed ring expansion reaction of an sion reaction. This indicates that a fast racemization
epoxyalkene derivative 1 leading to bicyclic products takes place on the step of a radical intermediate.
2, we choose a retrosynthetic approach outlined in Therefore, very little attention was applied to control
Scheme 1. The epoxyalkene 1 should be generated the stereochemistry in the olefination reaction. The
from a 1,5-dicarbonyl compound 3 which is accessible formation of the epoxide subunit could then be realiz-
from a 1-substituted cyclopentene 4. Based on our ed by the addition of a simple sulfur ylide[8] affording
preliminary results,[3,4] the substituent on the cyclo- the desired epoxyalkene 1 in a relatively short reac-
pentene derivative 4 was chosen to be an aromatic tion sequence and leaving considerable flexibility for
Scheme 1. Retrosynthesis of the cyclopenta[c]furans.
Scheme 2. Synthesis of the ring expansion precursors 1.
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Table 1. Compiled results for the synthesis of the precursors 1.
No.
Ar
Yield (4)
Yield (3)
R1, R2
Yield (7)
Yield (1)
Product (1)
1
Ph
52%
82%
Ph, H
61%
94%
2
3
4-MeOC6H4
2-MeOC6H4
68%
64%
38%
41%
Ph, H
Ph, H
61%
43%
76%
92%
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
-
-
-
-
-
-
-
-
-
-
4-ClC6H4, H
4-FC6H4, H
Ph, CH3
58%
56%
38%
52%
97%
97%
89%
90%
CH2, H
CH3, CH3
9
Ph
Ph
-
-
-
-
H2C=CH, H
10
CHBr, H
75%
-
-
the access of differently substituted starting materials. no efforts were undertaken to optimize the yields.
With the terminal alkene functionality (R=H, 1g) a Nevertheless, the desired precursors 1a–1i for the in-
ruthenium-catalyzed cross-metathesis reaction led to tramolecular iron-catalyzed ring expansion reaction
products (1k, 1l) not chemoselectively accessible by could be obtained in reasonable amounts to investi-
the regular Wittig olefination route.
gate the key step reaction in detail.
The results for the reaction sequence illustrate the
The bromoalkene intermediate of type 7 (Table 1,
flexible access towards the desired epoxyalkenes 1 by entry 10) was generated to modify this intermediate
the reaction sequence. Based on the adopted proce- in a Sonogashira-type transformation into the enyne
dures without an extensive optimization the desired 1j (Scheme 3). On the other hand, the compound 1g
products could be obtained in a 5–10-mmol scale (entry 7) was used to prepare some acceptor-substitut-
within a short period of time. However, some only ed epoxy alkenes such as 1k and 1l by means of a
moderate yields were encountered when electron-rich ruthenium-catalyzed cross-metathesis reaction with
aromatic substituents were applied in the ozonolysis acceptor-substituted alkenes such as methyl vinyl
which is attributed to an oxidative degradation of the ketone and ethyl acrylate.
aromatic nucleus and the formation of side products.
The replacement of cyclopentanone with cyclohexa-
Also, the Wittig olefination to afford 7 gave only none (Scheme 4) in the reaction sequence led
moderate yields despite the observation that the che- straightforwardly to the chain-elongated higher homo-
moselectivity of this transformation was excellent for logue 8 which could then be tested in a ring expansion
all cases resulting in the olefination of the aldehyde reaction leading to the bicyclic 6–5 fused ring system
moiety rather than the ketone functionality. However, of the octahydroisobenzofuran derivative.
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Synthesis of Hexahydrocyclopenta[c]furans
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Scheme 3. Sonogashira and Grubbs cross-metathesis reactions for the synthesis of ring expansion precursors 1.
investigations. On the other hand, compound 1n
could be obtained in good yields after esterification
and chemoselective epoxidation with mCPBA.
Quite in contrast to the synthesis of 1m, compound
1o could be obtained in excellent yields in the etheri-
fication of the phenylglycidol with cinnamyl bromide
without the formation of side products.
Scheme 4. Reaction sequence for the synthesis of ring ex-
pansion precursors 8.
Iron-Catalyzed Ring Expansion Reaction
Synthesis of Oxygen-Tethered Epoxyalkenes
The epoxyalkenes of type 1 and the compound 8 were
then applied in iron-catalyzed intramolecular ring ex-
In a further attempt to broaden the scope of the iron- pansion reactions utilizing the standard conditions
catalyzed ring expansion reaction, we envisaged the that had proved feasible in such reactions. Therefore,
use of derivatives of the epoxyalkene 1 where an the preformed Fe(Salen) complex (20 mol%), trie-
G
oxygen-tether interconnects the epoxy and the alkene thylamine (30 mol%), zinc powder (140 mol%) and
subunit either as an ether or as an ester functionality, the starting material (0.5–1.0 mmol) were heated in
such as in the epoxyalkenes 1m–1o (Scheme 5). For acetonitrile (0.5 mL) under a nitrogen atmosphere at
the synthesis of 1m the etherification was undertaken 608C overnight (Scheme 6).
first before the epoxidation was performed in moder-
ate yield. The alternative access was not successful be- ring expansion reaction are summarized in Table 2.
cause the etherification of the corresponding epoxide The intramolecular iron-catalyzed ring expansion
of 2-phenyl-3-propen-1-ol (phenylglycidol) could not reaction was performed with a preformed Fe(Salen)
The results for the intramolecular iron-catalyzed
ACHTREUNG
be realized to give a clean enough product for further complex under identical conditions for all substrates
Scheme 5. Synthesis of heteroatom-tethered ring expansion precursors of type 1.
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Scheme 6. Iron-catalyzed ring expansion reaction.
Table 2. Results for the iron-catalyzed ring expansion reaction.
No
Epoxyalkene
Products (9 + 10)
Yield (ratio 9:10)
1
77% (80:20)
2
26%[a] (98:2)
3
4
75% (93:7)
88% (78:22)
5
83% (77:23)
6
7
79% (96:4)
12% -
8
63% (66:34)
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Synthesis of Hexahydrocyclopenta[c]furans
Table 2. (Continued)
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Yield (ratio 9:10)
57% (50:50)
No
Epoxyalkene
Products (9 + 10)
9
10
11
12
13
29% (99:1)
39% (99:1)
67% (93:7)
30% (99:1)
14
15
26% (95:5[b])
traces
[a]
[b]
Rearrangement to a corresponding aldehyde side-product was also observed.
Combined ratio of two additional diastereomers.
listed in Table 2.[9] The ring expansion of 1a proceed- tionalized by the stronger electron donating character
ed in good yield to afford the two diastereomers 9a of the 4-methoxyphenyl functionalized over the 2-me-
and 10a in a 80:20 ratio. The cyclization products of thoxyphenyl functionalized starting material due to
type 9 and 10 were all formed as the cis-fused cyclo- increasing electron density in the epoxide. Therefore
penta[c]furan derivatives and no traces of the corre- the driving force for an electron transfer from the re-
sponding trans-fused products were detected or isolat- duced iron catalyst species to the epoxide is reduced
ed. The introduction of a methoxy group in the ben- to initiate the ring expansion. This decreased reactivi-
zene ring attached to the epoxide in 1b and 1c led to ty is associated with a higher selectivity in the bond
interesting results. While the ring expansion reaction formation processes to follow. Nevertheless, the elec-
proceeded in good yield with the sterically more de- tron-donating groups such as in 1b promoted the
manding 2-methoxy derivative 1c, the less sterically Lewis acid-initiated ring opening of the epoxide and
demanding 4-methoxy derivative 1b gave only moder- the formation of a rearranged aldehyde as a side
ate yields. In addition the diastereoselectivities for product.[10] Unfortunately, this side product had an
these two ring expansion reactions are considerably almost identical chromatographical behaviour as the
better (up to 98:2) than for the reactions with the un- desired products of type 9 and 10 so that extended
substituted phenyl substituent attached to the radical column chromatography had to be employed to
donor epoxide functionality. This behaviour can be ra- obtain analytically pure samples of the bicyclic prod-
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Gerhard Hilt et al.
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ucts. This also reduced the yield for the ring expan- induce a cisoid conformation did not result in a con-
sion of the 4-methoxy-functionalized epoxyalkene 1b. siderably increased yield.[11] The application of the in-
On the other hand, if the radical acceptor functionali- ternal epoxide functionality in 1o was investigated
ty was modified with electron-abstracting 4-chloro- (entry 14) to determine if the iron-induced ring ex-
benzene and 4-fluorobenzene substituents (1d and 1e) pansion can be used for the formation of bridged bi-
the ring expansion reaction led to very good results in cyclic ring systems. Unexpectedly, the 3,6-
terms of the chemical yields while the diastereoselec- dioxabicyclo[3.2.1]octane derivative 11 could be ob-
A
tivities are comparable to those with the unsubstitut- tained in moderate yield but in good diastereoselec-
ed phenyl derivative 1a. The additional methyl group tivity. This reaction not only represents the first intra-
in 1f led to a more stabilized radical intermediate and molecular example of an internal epoxide functionali-
therefore probably increased the yield for the ring ex- ty suitable for the iron-catalyzed ring expansion reac-
pansion reaction to give 9f and 10f. The considerably tion, but also, an unusual strained bicyclic ring system
increased chemical yields for the substrates 1i and 1j could be obtained from simple starting materials in a
compared to 1h illustrate that acceptable to good short reaction sequence. Beside 11 also two additional
yields are only obtained when the radical acceptor diastereomers were detected by GC-MS, however, the
functionality, the alkene, is in conjugation to addition- low amount of these side product did not allow us to
al double or triple bond functionalities. The inter- determine their structure or stereochemistry. The
mediately formed benzyl, allyl or propargyl radical in- main product 11 could be isolated and the connectivi-
termediates seem to be essential for the ring closure ty and relative stereochemistry could be verified by
reaction to occur effectively. While the formation of X-ray analysis. Also, the regioisomeric lignan deriva-
an allylic radical, starting from 1i gives the desired tive 9m as well as the cyclopenta[c]furan derivative
products 9i and 10i in moderate yield, the ring expan- 9d could be obtained in crystalline form suitable for
sion of 1h leading to a tertiary radical is less favoura- X-ray analysis and their structures are shown in
ble. Consequently, the observation that the unsubsti- Figure 2.
tuted epoxyalkene 1g (Table 1, entry 8) did not under-
The rather optimistic approach to verify if, in the
go the ring expansion reaction can be rationalized. iron-catalyzed ring expansion reaction, the main re-
The formation of a propargylic radical for the trans- strictions embedded in the Baldwin rules disfavouring
formation of 1j to give 9j and 10j in acceptable yields 6-exo-trig cyclization for radical reaction pathways
takes place as a 1:1 mixture of diastereomers based can be overcome was investigated in the use of the
on the rod-like substructure of the phenylacetylenic chain-elongated epoxyalkene 8. As expected, the de-
substituent minimizing steric interactions. For the ac- sired synthesis of the cyclohexa[c]furan derivative 12
ceptor substituted epoxyalkenes 1k and 1l in en- (entry 15) could not be realized in more than trace
tries 10 and 11 of Table 2, only moderate yields were amounts. The iron-catalyzed ring expansion reaction
obtained, however, the products 9k and 9l were isolat- of this substrate is hampered by the disfavoured 6-
ed essentially as single diastereomeres. The electron- exo-trig cyclizations for the formation of the new
abstracting carbonyl-type substituents in 1k and 1l led carbon-carbon bond. Instead, the epoxide ring
to a decreased reactivity and a higher selectivity opened intermediates led to a number of unidentified
based on the stronger stabilized radical intermediates. side products. Nevertheless, it is noteworthy to point
The electronic character of the substituents on the out that the iron-catalyzed ring expansion reaction
radical donor functionality as well as on the radical does not rely on the Thorpe–Ingold (gem-dimethyl)
acceptor functionality seems to be critical for the ring effect which is often needed in other reactions to en-
expansion reaction to proceed with good yields and/ hance the rate of formation of mono- and bicyclic
or good diastereoselectivities.
ring systems. The shown examples represent a range
Of particular interest were starting materials where of substrates mostly suitable for the intramolecular
additional heteroatoms or functionalities were in- iron-catalyzed ring expansion reaction. In combina-
volved leading to regioisomeric lignan and lactone de- tion with the still ongoing investigations concerning
rivatives. In this respect the application of the ether other challenging intermolecular iron-catalyzed ring
derivatives 1m and 1o as well as the ester derivative expansion reactions, further improvements in terms of
1n in the iron-catalyzed ring expansion reaction was functional group tolerance, scope of substrates and
investigated. The ring expansion reaction for 1m stereochemical aspects can be expected.
could be optimized to give the desired products 9m
and 10m in acceptable yields and in a good diastereo-
selectivity of 93:7. The ester substrate 1n could be Conclusions
transformed into the diastereomerically pure lactone
9n only in moderate yield. This is most likely based In the iron-catalyzed intramolecular ring expansion
on the conformation of the ester functionality which reaction of epoxyalkenes not only considerable im-
adopts a transoid conformation and all attempts to provements were reported concerning the scope and
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Synthesis of Hexahydrocyclopenta[c]furans
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can most efficiently be realized when hyperconjuga-
tion effects are combined with mesomeric stabiliza-
tion of these radicals in allylic, benzylic or propargylic
positions. Also, excellent diastereoselectivities were
observed with ketone- or ester-functionalized double
bonds as radical acceptors. The application of an in-
ternal epoxide was realized in combination with the
formation of a rather unusual dioxobicyclic ring
system (11). These results illustrate that the applica-
tion of iron catalysts in organic chemistry can gener-
ate rather complex bicyclic systems in mostly good
diastereoselectivities and moderate to good yields in a
short reaction sequence. Further investigations based
on these results will lead to new and innovative ap-
proaches towards cyclopenta[c]furans and other deriv-
atives.
Experimental Section
General Remarks
NMR-spectra were recorded on a Bruker Avance 300 or
DRX 500 (1H: 300 MHz or 500 MHz, 13C: 75 MHz or
125 MHz) spectrometer using TMS as internal standard (d=
0) unless otherwise noted. MS and GC/MS were measured
on a Hewlett Packard 6890 GC-System including a Hewlett
Packard 5973 Mass Selective Detector. For (high resolution)
mass spectra a Finnigan MAT 95S and a Finnigan LTQ
(ESI, HRMS) spectrometer were used. Analytical thin layer
chromatography was performed on Merck silica gel 60 F254.
For column chromatography Merck silica gel 60 (230–400
mesh ASTM) was used. All reactions were carried out
under an inert atmosphere (nitrogen or argon) using stan-
dard Schlenk techniques. Dichloromethane and acetonitrile
were dried over phosphorus pentoxide, tetrahydrofuran and
diethyl ether over sodium.
The Grignard Reaction and the following dehydration for
the synthesis of the cyclopentene derivatives 4, the ozonoly-
sis under reductive work-up for the generation of the keto
aldehydes 3 and the Wittig olefination reaction to obtain the
keto alkenes 7 were performed following known or adopting
similar literature procedures.
Epoxidation
Sodium hydride (60% in mineral oil, 4.0 equivs.) was sus-
pended in dimethyl sulfoxide. The suspension was carefully
heated until a gas evolution started. Then the solution was
stirred for 20 min, the four-fold amount of tetrahydrofuran
(DMSO:THF=1:4) was added and cooled to 08C. After the
addition of trimethylsulfonium iodide (4.0 equivs.) the solu-
tion was stirred for 1 h at 08C and then the ketone was
added. After stirring for 24 h at room temperature the solu-
tion was diluted with water and methyl tert.-butyl ether was
added. The phases were separated and the water phase was
extracted with methyl tert.-butyl ether three times. The com-
bined organic phases were washed with water, brine, dried
over sodium sulphate and concentrated under reduced pres-
Figure 2. X-Ray structures of 9d (top), 9m (middle) and 11
(bottom).
limitations of the reaction but most importantly an in-
sight into the electronic demands responsible for high
yield or good to excellent diastereoselectivities were
obtained. Generally, the radical donor epoxide func-
tionality will lead to good results in terms of reactivity
and selectivity when moderately electron-enriched
arene substituents are attached to the epoxide. On
the other hand, the stabilization of an intermediately
formed radical in the radical acceptor functionality sure. The residue was purified by column chromatography
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Gerhard Hilt et al.
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and 3% triethylamine was added to the eluent to avoid the
rearrangement of the epoxide.
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The Grubbs II catalyst (5 mol%) was suspended in di-
chloromethane and then the alkene (2.0 equivs.) and the ep-
oxyalkene (1.0 equiv.) were added. The solution was stirred
at 408C overnight, filtered over a small pad of silica (eluent:
Et2O) and concentrated. The residue was purified by
column chromatography and 3% triethylamine was added
to the eluent to avoid the rearrangement of the epoxide.
Sonogashira Cross-Coupling Reaction
To a solution of phenylacetylene (2.1 equivs.) in triethyla-
mine the bromoalkene (1.0 equiv.) copper(I) iodide (5
mol%) and bis(triphenylphosphino)palladium(II) chloride
(5 mol%) were added. After the solution had been stirred
at 608C overnight the mixture was concentrated under re-
duced pressure and filtered over a small pad of silica
(eluent: Et2O). The solution was concentrated and the resi-
due was purified by column chromatography.
[6] I. J. S. Fairlamb, S. Grant, G. Grogan, D. A. Maddrell,
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[9] Neither the use of polar solvents such as NMP nor di-
luted reaction conditions led to enhanced yields.
[10] C. Lemini, M. Ordonez, J. Perez-Flores, R. Cruz-Al-
manza, Synth. Commun. 1995, 25, 2695.
Intramolecular Fe(II)Salen-Catalyzed Ring
Expansion Reaction
Fe(II)Salen (20 mol%) and zinc (140 mol%) were suspend-
ed in 0.5 mL of acetonitrile and triethylamine (30 mol%)
was added. Then the solution was heated until boiling. Af-
terwards, the epoxyalkene (0.5–1.0 mmol) was added by sy-
ringe and the solution was stirred at 608C for 15–20 h. Then
the mixture was filtered over a pad of silica (eluent: diethyl
ether) and concentrated under reduced pressure. The resi-
due was purified by column chromatography.
[11] Neither the addition of Lewis acids leading to a cisoid
conformation of the ester functionality in 1n nor the
addition of orthoesters leading to the formation of or-
thoesters of 1n did result in enhanced yields.
References
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