Iron-catalyzed three-component reaction: Multiple C-C bond cleavages and reorganizations

Article abstract of DOI:10.1021/ol4014552

An unexpected three-component iron-catalyzed reaction, comprising C-C bond cleavages in two components together with three times the cyclopropane formation and ring opening, is developed. The current reaction provides an unprecedented and efficient approa

Full text of DOI:10.1021/ol4014552

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3606–3609
Iron-Catalyzed Three-Component
Reaction: Multiple CÀC Bond
Cleavages and Reorganizations
Peng Wang, Saihu Liao, Jian-Bo Zhu, and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
tangy@sioc.ac.cn
Received May 23, 2013
ABSTRACT
An unexpected three-component iron-catalyzed reaction, comprising CÀC bond cleavages in two components together with three times the
cyclopropane formation and ring opening, is developed. The current reaction provides an unprecedented and efficient approach for the synthesis of
cyclopentadienes in high yields.
Reactions involving CÀC bond cleavages and reorgani-
zations frequently provide us with unusual but efficient
access to molecules that are difficult to reach by routine
methods or require multiple steps to synthesize, through
confronting the inherent inactivity of CÀC bonds.1,2 An
eminent example could be the double CÀC bond cleavage
of a cyclopentadienyl ligand, in which the resulting
two pieces, a two-carbon unit and a three-carbon unit,
were later transformed into a benzene derivative and
a pyridine derivative, respectively.3 To date, CÀC bond
cleavages and recombinations are frequently encountered
in strained-ring-opening-4 and retro-addition-initiated
tandem reactions,5 metathesis of alkenes and alkynes,6
enyne isomerization reactions,7 etc. However, in most
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Curr. Org. Chem. 2006, 10, 185. (d) Monfette, S.; Fogg, D. E. Chem. Rev.
2009, 109, 3783. (e) Nolan, S. P.; Clavier, H. Chem. Soc. Rev. 2010, 39,
3305. (f) Furstner, A. Angew. Chem., Int. Ed. 2013, 52, 2794.
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813. (b) Echavarren, A. M.; Nevado, C. Chem. Soc. Rev. 2004, 33, 453.
(c) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317. (d) Anorbe,
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M. T.; Reddy, V. J.; Hyster, T. K.; Douglas, C. J. Angew. Chem., Int. Ed.
2009, 48, 6121. (b) Rathbun, C. M.; Johnson, J. B. J. Am. Chem. Soc.
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r
10.1021/ol4014552
Published on Web 07/05/2013
2013 American Chemical Society

cases, the CÀC bond cleavages only occurred in one reac-
tion component. As in a multicomponent reaction, the
CÀC cleavages of n components will generate 2n reactive
intermediates, and then there would be multiple types of
recombination possibility. Thus a very high convergence
will be required to ensure the reaction proceeds in one
direction to deliver the desired product in a high yield. The
examples involving CÀC splitting of at least two reaction
components are rare. The best known reactions of this type
involving CÀC bond breakage in more than one reac-
tion component could be the alkene cross metathesis, but
another molecule of alkene such as ethylene is usually
generated besides the desired alkene.6a,8
structures of products 4e and 4f (phenyl with para nitro
and trifluoromethyl substitution, respectively). The forma-
tion of the cyclopentadiene product is completely unex-
pected, as the adjacency of the aryl group to the quaternary
carbon of the cyclopentadiene suggests an unusual but
programmed cleavage and reorganization of the CÀC
bonds in both bromoacetophenone 3a and the crotonate-
derivative 1.
Scheme 2. Three-Component to Cyclopentadienes
Recently, we discovered an iron-catalyzed9,10 three-
component reaction of crotonate derivatives, diazo acetates,
and bromoketones for the synthesis of cyclopentadienes,
in which the CÀC bonds of the two components were cut
and recombined under mild conditions, including cleavages
of the CÀC double bond in crotonate and the CÀC single
bond in bromoketones (Scheme 1). Remarkably, mecha-
nistic studies revealed a domino process that involves three
times the cyclopropane formation and ring opening, which
also represents an unprecedented route to cyclopentadienes.
Here, we wish to report this reaction in detail.
A possible reaction pathway was proposed as shown
in Scheme 3. The cyclopropanation/ring-opening/proton
transfer process11b (from 1 to 8) is very likely also involved
in the current reaction, and the subsequent proton transfer
affords ylide 8 for the following transformation steps.
γ-Alkylation of 8 with 2-bromoacetophenone furnishes
vinyl phosphonium salt 9 which is subsequently deproto-
nated to produce enolate 10 under the basic conditions.12
Intramolecular addition of the enolate to vinyl phospho-
nium provides the second ylidic cyclopropane intermediate
11 which resembles the structure of 6 and should also be
prone to undergoing another ylidic carbanion-triggered
ring-opening reaction. The subsequent attack to the car-
bonyl group that arises from 2-bromo-acetophenone
affords the third cyclopropane intermediate 13. Then, a
negative oxygen anion facilitates the ring-opening reaction
of cyclopropane intermediate 13 from the vinyl phospho-
nium salt side and generates the allylic phosphorus ylide
14. Finally, the cyclopentadiene 4a was formed through
an intramolecular Wittig reaction. Consequently, in the
wholeprocess, three times the cyclopropane formation and
ring opening are involved. Cleavage of the CÀC double
bond of 1 proceeds via the cyclopropane ring opening of
intermediate 6 or 11 which behaves similarly to a DÀA
cyclopropane with the ylidic carboanion as the donor and
one ester group as the acceptor.4a In a similar fashion, the
cleavage of the C(CO)ÀCR single bond of acetophenone
occurs in the ring-opening step of cyclopropane 13, which
is facilitated by the oxygen anion.
Scheme 1. Unexpected CÀC Cleavage and Reorganization
During our studies11 on the iron-catalyzed reaction of
diazoacetate with ylide 1, we tried to capture the reac-
tion intermediate with 2-bromo-1-phenylethanone. To
our great surprise, unanticipated cyclopentadiene 4a was
obtained in 29% yield (Scheme 2). The cyclopentadiene
structure of 4a was deduced through extensive NMR
analyses and further confirmed by the X-ray crystal
(8) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900.
(9) For reviews of iron catalysis: (a) Plietker, B., Eds. Iron catalysis in
organic chemistry: reactions and applications; Wiley-VCH: Weinheim,
2008. (b) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem. Rev. 2004, 104,
~
6217. (c) Correa, A.; Mancheno, O. G.; Bolm, C. Chem. Soc. Rev. 2008,
37, 1108. (d) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282. (e) Plietker,
B. Top. Organomet. Chem. 2011, 33, 1. (f) Jana, R.; Pathak, T. P.;
Sigman, M. S. Chem. Rev. 2011, 111, 1417. (g) Sun, C.-L.; Li, B.-J.; Shi,
Z.-J. Chem. Rev. 2011, 111, 1293. (h) Chin. Sci. Bull. 2012, 57, 2335. (i)
Gopalaiah, K. Chem. Rev. 2013, 113, 3248.
Fortunately, we successfully trapped and characterized
several key reaction intermediates. When Na2CO3 was
employed as a base, vinyl phosphonium salt 9a can be
isolated in 82% yield and identified by an X-ray crystal
structural analysis (Scheme 4).13 This intermediate can be
alsoobtained in a quantitative yield when no base was used
in the reaction. Furthermore, the vinyl phosphonium salt
(10) For selected iron catalyzed carbene transfer reactions: (a) Wolf,
J. R.; Hamaker, C. J.; Djukic, J.-P.; Kodadek, T.; Woo, L. K. J. Am.
Chem. Soc. 1995, 117, 9194. (b) Hamaker, C. G.; Mirafzal, G. A.; Woo,
L. K. Organometallics 2001, 20, 5171. (c) Li, Y.; Huang, J.-S.; Zhou,
Z.-Y.; Che, C.-M.; You, X.-Z. J. Am. Chem. Soc. 2002, 124, 13185. (d)
Chen, Y.; Zhang, X. P. J. Org. Chem. 2007, 72, 5931. (e) Morandi, B.;
Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 938. (f) Morandi, B.;
Cheang, J.; Carreira, E. M. Org. Lett. 2011, 13, 3080. (g) Cai, Y.; Zhu,
S.-F.; Wang, G.-P.; Zhou, Q.-L. Adv. Synth. Catal. 2011, 353, 2939. (h)
Morandi, B.; Carreira, E. M. Science 2012, 335, 1471. (i) Holzwarth,
M. S.; Alt, I.; Plietker, B. Angew. Chem., Int. Ed. 2012, 51, 5351.
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Soc. 2009, 131, 4192. (b) Wang, P.; Ling, L.; Zhu, J.-B.; Liao, S.-H.;
Wang, S. R.; Li, Y.-X.; Tang, Y. Chem.;Eur. J. 2013, 19, 6766.
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Trans. 1 1993, 2269. (b) Hatanaka, M.; Himeda, Y.; Imashiro, R.;
Tanaka, Y.; Ueda, I. J. Org. Chem. 1994, 59, 111.
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effects, see: Ouyang, K.; Xi, Z. Acta Chim. Sinica 2013, 71, 13.
Org. Lett., Vol. 15, No. 14, 2013
3607

Scheme 3. Proposed Reaction Pathway
Scheme 5. Trapping of 11a with Aldehyde and 13C-Labeled
Experiments
R-13C-labeled 2-bromoacetophenone gave the final cyclo-
pentadiene product bearing the 13C-labeled carbon at the
position away from the phenyl group (δ 139.2 ppm). These
13C-labeled experiments confirmed that the cleavage of
the C(CO)ÀCR bond instead of the C(CO)ÀC(Ph) bond
occurred in this domino process, just as proposed. There-
fore, the wholereactionpathwayproposed in Scheme 3 has
been established. Impressively, there are three times carbonÀ
carbon bond cleavages in the reaction. The high convergence
method to the final cyclopentadiene product over a sequential
domino process is rare and remarkable.
Scheme 4. Isolation of Intermediates and Their Transformation
to Cyclopentadienes
The current reaction represents a novel and facile syn-
thetic route to useful cyclopentadienes12,14 with a quatern-
ary carbon atom. We then moved to the optimization of
reaction parameters, such as solvents, bases, and reagent
loadings.13 Finally, using Cs2CO3 as the base and CH2Cl2
as the solvent with 2.0 equiv of methyl 2-diazoacetate
(MDA), the desired cyclopentadiene product 4a can be
obtained in a good yield (entry 1, Table 1). The generality
of this domino reaction was thus evaluated next. As shown
in Table 1, various acetophenone bromides are suitable
substrates, leading to the desired products in moderate to
excellent yields. The electronic nature of the substituents
on the benzene ring greatly influenced the yield (entries
1À10). In general, the substrates with electron-withdrawing
groups at the para position provided better yields than
those with electron-donating groups. The ortho and meta
bromo-substituted bromides gave similar results to the
para bromo-substituted acetophenone (entry 4 vs entries
11 and 12). A 74% yield was obtained in the reaction of
2-bromoacetonaphthalenone (entry 13). Notably, the bro-
mides bearing a heteroaromatic ring, such as 2-benzofur-
anyland 4-pyridyl, are alsosuitablefor thisreaction, giving
9a can be converted to the corresponding cyclopentadiene
4a in 86% yield under the standard reaction conditions
(Scheme 4). Similarly, intermediate 9f bearing a para-
trifluoromethyl phenyl group gave cyclopentadiene 4f
in 95% yield. Moreover, in the reaction starting with 9a,
the second cyclopropane intermediate ylide 11a can also
be trapped by p-nitrobenzaldehyde via an intermolecular
Wittig reaction to give vinyl cyclopropane 15 (eq I, Scheme 5).
The successful identification of the two key intermediates 9
and 11 strongly supports the proposed mechanism in the
whole reaction (Scheme 3).
As proposed in Scheme 3, the CÀC bond break of
acetophenone happens in the transformation of intermedi-
ate 12 into intermediate 14. To verify this proposal, we
performed 13C-labeled experiments with the 13C label
located at the carbonyl- and R-carbon of 2-bromoaceto-
phenone, respectively, to track the phenyl migration. As
shown in Scheme 5, the 13C-labeled carbonyl carbon was
found still linked to the phenyl group (δ 148.8 ppm), while
(14) Synthesis and application of cyclopentadienes: Togni, A.,
Halterman, R. L., Eds. Metallocenes. Synthesis, Reactivity, Applications;
Wiley-VCH: Weinheim, 1998; Vols. 1 and 2. (b) Long, N. J. Metallocene.
An Introduction to Sandwich Complexes; Blackwell Science: Oxford, 1998.
(c) Wilson, P. J.; Wells, J. H. The chemistry and utilization of cyclopenta-
diene. Chem. Rev. 1944, 34, 1. (d) Okuda, J. Top. Curr. Chem. 1992, 160,
97 and references cited therein. (e) Winterfeldt, E. Chem. Rev. 1993, 93,
827. (f) Xi, Z. Top. Catal. 2005, 35, 63 and references cited therein.
3608
Org. Lett., Vol. 15, No. 14, 2013

the corresponding cyclopentadienes in 72% and 85% yield
respectively (entries 14 and 15). It is worth noting that
lower yields in the cases of electron-rich substrates is
consistent with the mechanism, because in the formation
of the third cyclopropane intermediate 13, an electron-rich
substituent will decrease the electrophilicity of the car-
bonyl group.
recovered starting material). Acid 18 was obtained in 83%
yield aftersaponification withNaOH, which can be further
transformed to the bicyclo[3.3.0] lactone 19 in 80% yield in
the presence of a catalytic amount of Cu(OTf)2.
In conclusion, an iron-catalyzed novel carbonÀcarbon
bond programmed cleavage and reorganization reaction
leading to cyclopentadienes under mild conditions was
discovered and further developed. The reaction proceeds
by rolling over three times the cyclopropane forming and
ring-opening process, and involves three carbonÀcarbon
bond cleavages and six carbonÀcarbon bond formations.
It is potentially useful for the development of a new CÀC
bond cleavage reaction. 13C-labeled experiments, along with
the isolation and capture of different reaction intermediates,
were carried out to establish the reaction pathway. The
current domino reaction also provides an unprecedented
and efficient approach for the synthesis of cyclopentadienes.
Table 1. Reaction Scope
t
yield
(%)c
entrya
R
(h)b
1
Ph-
4a
4b
4c
4d
4e
4f
24
24
24
24
24
24
24
26
41
24
24
24
24
24
37
71
53
71
77
86
88
93
90
53
40
76
75
74
72
85
2
p-FC6H4-
3
p-ClC6H4-
Scheme 6. Chemical Transformations of the Cyclopentadiene
Product
4
p-BrC6H4-
5
p-NO2C6H4-
p-CF3C6H4-
p-CNC6H4-
3,4-Cl2C6H3-
p-C6H5-C6H4-
p-CH3C6H4-
o-BrC6H4-
6
7
4g
4h
4i
8
9
10
11
12
13
14
15
4j
4k
4l
m-BrC6H4-
2-naphanyl-
2-benzofuranyl-
4-pyridyl-
4m
4n
4o
a Ylide 1 (259.2 mg, 0.72 mmol), Fe(TCP)Cl (1.7 mg, 0.002 mmol),
MDA (67 μL, 0.8 mmol), RCOCH2Br (0.4 mmol), Cs2CO3 (156 mg,
0.48 mmol), CH2Cl2 (4.0 mL), rt. b The reaction time was not optimized.
c Isolated yield
Acknowledgment. We are grateful for the financial
support from the Natural Sciences Foundation of China
(Nos. 21121062, 20932008, and 21272248), the Major
State Basic Research Development Program (Grant No.
2009CB825300), and the Chinese Academy of Sciences.
Cyclopentadiene is a useful type of feedstock and has
been widely employed in a variety of transformations.14
Our current reaction also provides a new approach for the
synthesis of cyclopentadiene derivatives, and the products
can be readily converted into other useful compounds14
as shown in Scheme 6. Hydrogenation of the products
gave the substituted cyclopentane 16 in 94% yield. Selec-
tive reduction of the ester group with DIBAL-H led
to 2-oxaspiro-[4.4]-lactone 17 in 95% yield (based on the
Supporting Information Available. Experimental pro-
cedures, spectral data, and X-ray crystallographic data of
4e, 4f, and 9a are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3609