Iron(III)-Catalyzed Cycloisomerizations of Acetal-Vinylidenecyclopropanes: An Efficient Synthetic Route to 1,2-Disubstituted Cyclobutenes

Article abstract of DOI:10.1002/chem.201502634

A novel iron(III)-catalyzed intramolecular cycloisomerization of acetal-vinylidenecyclopropanes to afford a series of halogenated 1,2-disubstituted cyclobutenes tethered with a tetrahydropyrrole has been developed. The reaction is thought to proceed through a formal iron-catalyzed Prins cyclization followed by a ring-enlarging rearrangement of the methylenecyclopropane carbocation. The present protocol provides an alternative route to functionalized disubstituted cyclobutenes and the corresponding products could be successfully transformed into eight-membered oxacyclic products.

Full text of DOI:10.1002/chem.201502634

DOI: 10.1002/chem.201502634
Communication
&
Iron Catalysis
Iron(III)-Catalyzed Cycloisomerizations of Acetal–
Vinylidenecyclopropanes: An Efficient Synthetic Route to
1,2-Disubstituted Cyclobutenes
Song Yang,[a] Wei Yuan,[b] Qin Xu,[a] and Min Shi*[a, b]
Abstract: A novel iron(III)-catalyzed intramolecular cyclo-
isomerization of acetal–vinylidenecyclopropanes to afford
a series of halogenated 1,2-disubstituted cyclobutenes
tethered with a tetrahydropyrrole has been developed.
The reaction is thought to proceed through a formal iron-
catalyzed Prins cyclization followed by a ring-enlarging re-
arrangement of the methylenecyclopropane carbocation.
The present protocol provides an alternative route to
functionalized disubstituted cyclobutenes and the corre-
sponding products could be successfully transformed into
eight-membered oxacyclic products.
Vinylidenecyclopropanes (VDCPs), bearing an allene moiety
connected to a highly strained cyclopropane ring, serve as fas-
cinating building blocks in organic synthesis and have attract-
ed great attention from organic chemists. In the past few
years, numerous useful and unique transformations of VDCPs
have been discovered by our group and other research
groups.[1] As one of the most important structural motifs, cyclo-
butene moieties are present in a great number of natural prod-
ucts and pharmacological compounds with diverse biological
properties (Figure 1).[2] Despite the many applications of cyclo-
butenes, methods for their synthesis are limited. Among the
approaches to access cyclobutenes, cycloaddition of alkynes
and alkenes[3] and ring-expansions of cyclopropane deriva-
tives,[4] including alkylidenecyclopropanes,[5] allenylcyclopro-
panes[6] and a-diazo cyclopropanes,[7] are the most effective
synthetic strategies. In 2006, PtII- and PdII-catalyzed ring expan-
sions of alkylidenecyclopropanes (ACP) into monosubstituted
cyclobutene derivatives have been disclosed by Fürstner and
A¨ıssa[5f] and our group,[5g] respectively (Scheme 1A). More re-
cently, we also developed a RhI-catalyzed intramolecular [2+2]
Figure 1. Representative biologically active natural products containing a cy-
clobutene core.
[a] S. Yang, Dr. Q. Xu, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine Chemicals
East China University of Science and Technology
Meilong Road No. 130, Shanghai, 200237 (P. R. China)
[b] W. Yuan, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China).
E-mail: mshi@mail.sioc.ac.cn
Scheme 1. Syntheses of cyclobutene: A) ring-expansion of MCP; B) FeX3-pro-
moted cyclization of alkynyl acetals; C) current work.
cycloaddition of the yne–VDCPs to build tetrasubstituted cy-
clobutenes.[1k]
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502634.
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During the last few decades, iron catalysis has emerged as
a promising and environmentally benign alternative to tradi-
tional transition metal catalysis for a wide range of organic
transformations, due to its many advantages, such as low cost,
nontoxicity, good stability, and easy handling.[8] Compared with
traditional transition metal catalysis, iron takes part in various
biological systems as a key essential element, for example, in
metalloproteins for the transport or metabolism of small mole-
cules (e.g., oxygen, nitrogen, methane) and electron-transfer
reactions.[9] The principal use of iron in organic catalysis is re-
lated to oxo and hydride transfer reactions, as well as related
transformations of carbenes, nitrenes, and carbanions.[10] An-
other important use of iron as a catalyst profits from its Lewis
acidic character, which allows its participation in a broad range
of synthetic transformations, such as Diels–Alder reactions,[11]
1,3-dipolar cyclizations,[12] Friedel–Crafts reactions,[13] or Man-
nich reactions.[14] In addition, FeX3 and other Lewis acid-pro-
moted carbon–carbon bond-forming cyclizations of alkenyl
and allenyl acetals have been frequently reported.[15] In 2009,
Yu and co-workers[15d,e] discovered that intramolecular alkynyl
acetal derivatives could be transformed into various cyclopen-
tanes, tetrahydropyrans, and tetrahydropyrroles in the pres-
ence of FeX3 (Scheme 1B). Intrigued by the versatile interac-
tions of Lewis acids with acetals, we envisaged that a highly
strained methylenecyclopropane (MCP) carbocation might be
generated from a Prins cyclization of acetal–VDCPs catalyzed
by FeIII. The MCP carbocation would then undergo an intramo-
lecular rearrangement with the ring-opening of the cyclopro-
pane to give the corresponding cyclobutene derivatives.
Herein we report the iron-catalyzed intramolecular cyclo-
isomerization of acetal–vinylidenecyclopropanes to afford
a series of disubstituted cyclobutenes tethered with a tetrahy-
dropyrrole (Scheme 1C; X=Cl or Br).
Table 1. Screening conditions for cycloisomerization of 1a.
Entry[a]
x
Solvent
R
y
Yield [%][b,c]
1
2
3[d]
4[e]
5
6
7
8
9
10
11
12[f]
13
100
5
5
5
5
5
5
5
5
5
–
5
5
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
THF
toluene
CH2Cl2
DCE
–
Ac
–
–
69
75
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
<5
<5
70
–
TMS
Bz
Ac
Ac
Ac
Ac
Ac
Ac
Ac
72
<5
<5
51
61
<5
67
DCE
DCE
85
[a] Substrate 1a (0.2 mmol), FeCl3 (x mol%), RCl (y equiv) and the corre-
sponding solvent (2 mL); [b] yield of isolated product; [c] product 2a con-
sists of a pair of diastereoisomers and the ratio is 1:1; [d] nBu4N+ClÀ was
employed; [e] N-chlorosuccinimide (NCS) was employed; [f] 4 Š molecular
sieves were added.
no identifiable product was formed in THF or CH3CN (Table 1,
entries 7–10). Without FeCl3, the reaction gave 2a in less than
5% yield and the addition of 4 Š molecular sieves did not im-
prove the yield of 2a (Table 1, entries 11 and 12). Gratifyingly,
an improvement was achieved by increasing the employed
amount of acetyl chloride to 1.5 equivalents, giving 2a in 85%
yield (Table 1, entry 13). We finally identified that carrying out
the reaction in DCE at room temperature for 2 h using 5 mol%
FeCl3 as the catalyst with MeCOCl as a halogen source as the
best reaction conditions.
To test the feasibility of our hypothesis, acetal–vinylidenecy-
clopropane 1a was selected as the substrate, in which the
acetal and vinylidenecyclopropane moieties are connected by
a “BsN” anchor (Bs=4-bromobenzenesulfonyl). To our delight,
the desired reaction proceeded smoothly in the presence of
FeCl3 in 1,2-dichloroethane (DCE) at room temperature, afford-
ing the chlorinated cyclobutene tethered by a tetrahydropyr-
role, product 2a, in 69% yield (Table 1, entry 1). The structure
of syn-2a was unambiguously assigned by X-ray diffraction
(see the Supporting Information).[16] Notably, product 2a was
formed as a pair of diastereoisomers with a 1:1 ratio. Encour-
aged by this preliminary result, we attempted to improve the
reaction performance by screening various conditions. First of
all, acetyl chloride (1.0 equiv) was found to be a better chloride
source, so that only a catalytic amount of FeCl3 (e.g., 5 mol%)
was required to afford the desired product 2a in 75% yield
(Table 1, entry 2). When N-chlorosuccinimide (NCS) and tetra-
butylammonium chloride (TBACl) were utilized as chloride
sources, only traces of 2a could be detected by thin-layer
chromatography (TLC) monitoring (Table 1, entries 3 and 4). Tri-
methylsilyl chloride (TMSCl) and benzoyl chloride showed simi-
lar reactivities to that of acetyl chloride to give 2a in 70% and
72% yield, respectively (Table 1, entries 5 and 6). The reaction
was less efficient when carried out in toluene or CH2Cl2, and
Having optimzed the reaction conditions, we next examined
the scope and limitations of this FeCl3-catalyzed cycloisomer-
ization (Table 2). With acetal–VDCPs 1b–i as the substrates (R=
primary or secondary alkyl groups; X=TsN or BsN anchor), the
desired products 2b–i were obtained in moderate to good
yields (46–81%; Table 2, entries 2–9). When acetal–VDCP 1j
was employed as substrate, in which R was benzyl (Bn) group,
the corresponding product 2j could also be afforded in 71%
yield (Table 2, entry 10). However, when acetal–VDCP 1k (X=
O, R=Me) or 1l (X=CH2, R=Me), with O or CH2 as anchors,
was used as substrate, the reaction gave the desired product
2k in 25% yield or a complex product mixture, respectively
(Table 2, entries 11 and 12).
To further investigate the scope of this reaction, other halo-
gen sources were surveyed as well. When acetyl bromide was
used as halogen source and FeBr3 (5 mol%) was used as the
catalyst, the corresponding brominated product 3a was ob-
tained in 71% yield (Table 2, entry 13). However, when benzoyl
fluoride and other halogen sources, such as KF and NaI, were
used, none of the corresponding halogenated products could
be detected. Thus, the reactions of acetyl bromide and FeBr3
with other acetal–VDCPs 1 were then carried out to define the
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Table 2. FeIII-catalyzed cycloisomerization of 1.
Table 3. Further exploration of FeIII-catalyzed cycloisomerizations of 1.
Entry[a]
Substrate
R2 m/
Yield [%][b]
2 or 3
d.r.[c]
Entry[a]
Substrate
R
Yield [%][b]
2 or 3
d.r.[c]
1.1:1
1:1.3
1:1.1
1.2:1
1:1.5
1:1.2
1:1.1
X/Y R1
X/Y
BsN/Cl
n
1
2
3
4
5
6
7
8
Me
Me
Et
Et
iPr
1a
1b
1c
1d
1e
1 f
1g
1h
1i
2a, 85
2b, 80
2c, 72
2d, 71
2e, 74
2 f, 73
2g,81
2h, 60
2i, 46
2j, 71
2k, 25
1
2
3
4
5
6
7
8
9
BsN/
Cl
BsN/
Br
BsN/
Cl
TsN/
Cl
Me
Me
Me
Et
Me 2/ 1m
2m, 64
1:1.4
1:1.8
TsN/Cl
BsN/Cl
TsN/Cl
BsN/Cl
BsN/Cl
TsN/Cl
BsN/Cl
TsN/Cl
BsN/Cl
O/Cl
CH2/Cl
BsN/Br
TsN/Br
BsN/Br
TsN/Br
BsN/Br
BsN/Br
TsN/Br
BsN/Br
TsN/Br
BsN/Br
1
Me 2/ 1m
3m, 56
1
Me 3/ 1n
complex mixture
2o, 61 >10:1
nBu
nBu
3-butenyl
3-butenyl
Bn
Me
Me
Me
Me
Et
Et
iPr
nBu
1
Me 1/ 1o
1.2:1
2
9
1:1.0
1:1.0
1:1.0
TsN/
Br
Et
Me 1/ 1o
3o, 63
>10:1
10
11
12
13
14
15
16
17
18
19
20
21
22
1j
1k
1l
2
TsN/ OCH2CH2O Me 1/ 1p
Cl
TsN/ 2-propen- Me 1/ 1q
Cl yl
TsN/ 2-propen- Me 1/ 1q
Br yl
BsN/ 2-propen- Me 1/ 1r
Br yl
complex mixture
2q, 86
complex mixture
1
1a
1b
1c
1d
1e
1 f
1g
1h
1i
3a, 71
3b, 66
3c, 65
3d, 65
3e, 65
3 f, 66
3g, 68
3g, 50
3i, 57
3j, 63
1:1.1
1:1.1
1:1.4
1:1.1
1:1.5
1:1.2
1:1.3
1.2:1
1:1.0
1:1.2
1.2:1
1
3q, 67
1:1.1
1
3r, 68
1:1.1
1:1.0
1
nBu
3-butenyl
3-butenyl
Bn
1j
10
11
12
1s
1t
[a] 1 (0.2 mmol), FeY3 (5 mol%), MeCOY (1.5 equiv), (Y=Cl or Br), and DCE
(2.0 mL). [b] yield of isolated product; [c] diastereoisomeric ratio, syn/anti.
1.1:1
generality of this protocol. Similarly, when using acetal–VDCPs
1b–j as the substrates, the desired brominated products 3b–j
were obtained in moderate to good yields (50–68%; Table 2,
entries 14–22).
1u
1:1.2
Next, the carbon chain length of acetal–VDCPs was extend-
ed and different acetals were synthesized to expand the sub-
strate scope and conduct further transformation of the prod-
ucts (Table 3). Interestingly, when acetal–VDCP 1m, which con-
tains a (CH2)2 carbon chain to connect the anchor with the
VDCP moiety, was used as substrate, the desired cycloisomer-
ization products 2m and 3m could also be produced in mod-
erate yields under the optimal conditions (Table 3, entries 1
and 2). However, when acetal–VDCP 1n, bearing a (CH2)3
carbon chain to the VDCP moiety, was used as substrate, the
reaction afforded a complex product mixture (Table 3, entry 3).
Extending the carbon chain to the acetal moiety with a (CH2)2
tether, the desired products 2o and 3o were obtained in 61
and 63% yields, respectively (Table 3, entries 4 and 5). It should
be noted that products 2o and 3o were formed with better
diastereoselectivities than 2m and 3m, presumably due to the
increased steric flexibility. Next, ethylene glycol acetal–VDCP
1p and diallyl acetal–VDCPs 1q–u were synthesized, because
their corresponding products are suitable for further transfor-
mations. Upon examination, we found that 1p decomposed
when FeCl3 was employed as the catalyst (Table 3, entry 6).
[a] 1 (0.2 mmol), FeY3 (5 mol%), MeCOY (1.5 equiv), (Y=Cl or Br), and DCE
(2.0 mL). [b] yield of isolated product; [c] diastereoisomeric ratio, syn/anti.
However, when 1q–u were used as substrates, the correspond-
ing reactions took place smoothly, affording the desired prod-
ucts in moderate to good yields under the optimal conditions
(44–86%; Table 3, entries 7–12).
Ruthenium-catalyzed intramolecular ring-closing olefin meta-
thesis has become a powerful strategy to construct five-, six-,
and seven-membered cyclic compounds and has been used as
a crucial step in total synthesis of many natural products.[17]
The construction of eight-membered rings, especially those
containing one heteroatom, by ring-closing olefin metathesis
is thought to be relatively difficult, due to unfavorable entropy
loss. Therefore, the synthesis of eight-membered oxacyclic
compounds remains a challenge.[18] We further explored the
transformations of products 2 and 3 in order to illustrate their
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Scheme 2. Transformation of products syn-2s and syn-2u into syn-4s and
syn-4u.
synthetic utility. Products syn-2s and syn-2u could be easily
transformed to compounds syn-4s and syn-4u in moderate
yields by intramolecular ring-closing olefin metathesis using
Grubbs I catalyst (Scheme 2). The structures of syn-2u and syn-
4u were determined by NMR spectroscopic investigations, in-
cluding COSY, HSQC, HMBC, and NOESY (see the Supporting
Information). Compounds syn-4s and syn-4u both contain an
eight-membered oxacyclic core, which is frequently found in
natural products, a fused pyrrolidine ring, and a cyclobutene
side chain.[19]
Scheme 4. Proposed mechanism for the formation of 2a.
In our previous work, we reported that the reaction of
VDCPs with 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers
selectively produced 4-dihydro-1H-cyclopenta[b]naphthalene
derivatives or 1,2,3,8-tetrahydrocyclopenta[a]indene derivatives
in the presence of Lewis acid, depending on the substituents
at the cyclopropane.[22] However, the intramolecular reaction of
VDCPs with propargyl alcohol has not been explored to date.
On the basis of the above investigation, we synthesized a new
propynol–VDCP 6 to investigate its reactivity in the presence
of various Lewis acids, and the results are summarized in Sup-
porting Information (Table S1). The reaction proceeded
smoothly in DCE to afford product 7 in 51% yield within 1 h at
608C in the presence of BF3·OEt2 (10 mol%) and 4 Š molecular
sieves (50 mg; Scheme 5). The structure of 7 was unambigu-
Intramolecular palladium-catalyzed oxidative cyclization is
another powerful method for the construction of heterocy-
cles.[20] Products anti-3q and anti-3t could be successfully con-
verted into the tricyclic compounds anti-5q and anti-5t bear-
ing an eight-membered oxacyclic diene core in good to excel-
lent yields in the presence of 10 mol% of Pd(OAc)2 (Scheme 3).
Scheme 3. Transformation of products anti-3q and anti-3t into anti-5q and
anti-5t. Reagents and conditions: a) Cs2CO3 (1.0 equiv), Pd(OAc)2 (10 mol%),
PPh3 (0.25 equiv), DMF, 80–858C, 10 h.
Scheme 5. Cycloisomerization of propynol–VDCP 6 in the presence of
BF3·OEt2.
The structure of anti-5t was also confirmed by NMR spectros-
copy (COSY, HSQC, HMBC, and NOESY; see the Supporting In-
formation).
A reaction mechanism is proposed in Scheme 4, using 1a as
a model substrate for the cycloisomerization on the basis of
previous reports.[21] Initially, FeCl3 abstracts a methoxy group
from 1a to form a [FeCl3(OMe)]À anionic species and an oxo-
carbenium intermediate A. Then, a Prins-type cyclization takes
place to give the cationic MCP intermediate B in a 5-exo-trig
manner. The ring-enlarging rearrangement of MCP in inter-
mediate B occurs to afford intermediate C, followed by nucleo-
philic attack of the chloride anion from MeCOCl to yield the
desired product 2a along with the regeneration of FeCl3 for
the catalytic cycle.
ously assigned by X-ray diffraction (see the Supporting Infor-
mation).[16] This product is slightly labile during purification
with silica gel column chromatography.
A plausible mechanism for BF3·OEt2 promoted cycloisomer-
ization of 6 is proposed in Scheme 6, which is quite similar to
the cycloisomerization of 1a indicated in Scheme 4. At first,
BF3·OEt2 activates the hydroxyl group in 6 to give a propargyl
carbocation species D, which cyclizes with the C-1 carbon in
the tethered VDCP to give the corresponding cationic MCP in-
termediate E in a 5-exo-dig manner. Then, the intermediate E
gives intermediate F via a ring-enlarging rearrangement, fol-
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lowed by nucleophilic attack of hydroxyl anion to give the de-
sired product 7 along with the regeneration of BF3·OEt2. Nota-
bly, the key step, which is the ring-enlargement of the cationic
MCP intermediate, is identical in these two kinds of reactions.
In conclusion, we have developed a novel FeIII-catalyzed in-
tramolecular cycloisomerization of acetal–VDCPs, which can be
used to efficiently synthesize halogenated 1,2-disubstituted cy-
clobutenes tethered with a tetrahydropyrrole in moderate to
good yields under mild conditions. The further transformation
of these products into functionalized eight-membered hetero-
cycles can be easily realized by Ru-catalyzed ring-closing olefin
metathesis or palladium-catalyzed oxidative cyclization. More-
over, propynol–VDCP can be converted into a novel cyclobut-
1-enol tethered with an allenic tetrahydropyrrole in moderate
yield in the presence of BF3·OEt2. Further work will be devoted
to applying this new methodology to synthesize biologically
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Acknowledgements
We are grateful for financial support from the National Basic
Research Program of China [(973)-2015CB856603] and the Na-
tional Natural Science Foundation of China (20472096,
21372241, 21361140350, 20672127, 21421091, 21372250,
21121062, 21302203, 20732008, and 21572052) for financial
support.
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Keywords: cycloisomerization · homogeneous catalysis · iron ·
ring expansion · small ring systems
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Received: July 6, 2015
Published online on September 18, 2015
Chem. Eur. J. 2015, 21, 15964 – 15969
www.chemeurj.org
15969
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim