Gold-Catalyzed Rearrangement of Alkynyl Donor-Acceptor Cyclopropanes to Construct Highly Functionalized Alkylidenecyclopentenes

Article abstract of DOI:10.1021/acs.orglett.5b00671

A gold-catalyzed 1,7-addition-cyclization-elimination cascade sequence performed on a range of alkynyl-substituted donor-acceptor-type cyclopropanes provides facile entry to highly functionalized exo-alkylidenecyclopentenes under very mild conditions. Iso

Full text of DOI:10.1021/acs.orglett.5b00671

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Rearrangement of Alkynyl Donor−Acceptor
Cyclopropanes To Construct Highly Functionalized
Alkylidenecyclopentenes
Huiyu Chen, Jing Zhang, and David Zhigang Wang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A gold-catalyzed 1,7-addition−cyclization−
elimination cascade sequence performed on a range of
alkynyl-substituted donor−acceptor-type cyclopropanes pro-
vides facile entry to highly functionalized exo-alkylidenecyclo-
pentenes under very mild conditions. Isolation of the relevant allyl ether intermediate helped shed light on the reaction’s
mechanistic course.
onor−acceptor-substituted cyclopropanes1 (DACs) are
and carboxyl4g) are used as acceptors, and this strategy has been
successfully utilized in the total synthesis of several natural
products.4g,1c Werz conducted a systematic investigation on
reactivities of DACs by combining density functional theory
(DFT) studies6d and experimental preparations of spiroketals,6f
oligoacetals,6e,g bisthiophenes,6a oligopyrroles,6b,c and cyclic
nitronates4k using a ring-enlargement strategy.
To the best of our knowledge, compared with the known
studies on ring enlargements of DACs toward furan and pyrrole
derivatives, there are few examples to construct all-carbon rings
such as cyclopentane and cyclopentene derivatives which are
important building blocks for many natural products and
bioactive compounds.7,8 Leveraged on the well-established
gold activation mode of carbon−carbon triple bond,9 we are
motivated to uncovering a synthetic solution to such useful all-
carbon structures through catalytic rearrangements of alkynyl
DACs which have been successfully employed in [3 + 2]-
cycloaddition10 and 1,7-addition reactions (Scheme 1b).11
In the initial design summarized in Scheme 1c, the highly
alkynophilic cationic Au(I) would induce the 1,7-addition on
substrate 1 to give an allene intermediate 2, which would
undergo subsequent Au(I)-catalyzed cyclization to furnish
cyclopentene structure 3.
D
known to be competent substrates undergoing a variety of
transformations, such as ring-opening,2 cycloaddition,3 and
rearrangement reactions.4 Their robust reactivities are largely
attributed to high carbon−carbon bond polarization induced by
the push−pull effect of the relevant vicinal donor and acceptor.
Despite Wenkerst’s and Reissig’s pioneering works in the 1980s
in this field, ring enlargements of DACs have gained attention
only in recent years. In more recent studies,4 Lewis or Brønsted
acids are often used to coordinate to the acceptors and trigger the
subsequent rearrangements. Charette4f and other groups4a−e
reported the construction of pyrroles and dihydropyrroles using
a ring-opening/cyclization of DACs, which can be considered as
ring enlargement of DACs with imino substituents as the
acceptors (Scheme 1a). Feng5 reported an asymmetric version
toward the chiral dihydropyrroles through a kinetic resolution
process. Rearrangements of DACs would lead to dihydrofuran
and furan derivatives when carbonyl groups (ketone,4i ester,4h,j
Scheme 1. Ring-Opening/Cyclizations of DACs
Conceivably, to realize the designed transformation, the
activation of both the π-Lewis basic alkyne and the σ-Lewis basic
esters might be needed to facilitate the initial C−C bond cleavage
event. With cyclopropane 1a as the model substrate, we
employed the cationic Gagosz’s catalyst PPh3AuNTf2 and
Mg(ClO4)2 as the Lewis acids and MeOH as the nucleophile,
anticipating the formation of 1,7-addition/cyclization product
3a. The first trial gave alkylidenecyclopentene 4a as the major
product and enone 5a as the minor one without detectable
formation of 3a, which was suspected to be unstable under the
given reaction conditions and underwent further elimination to
Received: March 6, 2015
Published: April 22, 2015
© 2015 American Chemical Society
2098
DOI: 10.1021/acs.orglett.5b00671
Org. Lett. 2015, 17, 2098−2101

Organic Letters
Letter
Scheme 2. Reactivity Screenings on Substituent R1
form 4a. Solvent screenings (Table 1, entries 1−3) revealed that
DCE gave a better selectivity and yield. When EtOH was used
Table 1. Identification of the Optimal Reaction Conditions
a
[Au]
(0.05 equiv)
alcohol
(10 equiv)
4a yield (%) 5a yield
a
entry
solvent
(E/Z)
(%)
b
1
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
[Au]/AgOTf
[Au]/AgSbF6
[Au]/AgSbF6
[Au]/AgSbF6
[Au]/AgSbF6
PPh3AuNTf2
DCE
DCM
PhMe
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeOH
MeOH
MeOH
EtOH
57 (84:16)
43 (87:13)
19
32
b
2
b
3
b
4
21 (89:11)
60 (91:9)
trace
57
5
6
MeOH
16
trace
bc
,
7
8
9
EtOH
58 (84:16)
66 (93:7)
44 (91:9)
70 (88:12)
75 (93:7)
66 (87:13)
85 (90:10)
75 (90:10)
26 (76:24)
35 (62:38)
16
BnOH
10
11
12
13
cyclohexanol
tBuOH
trace
trace
trace
trace
trace
15
neopentanol
neopentanol
neopentanol
neopentanol
neopentanol
neopentanol
BnOH
d
d
14
e
15
16
17
18
19
f
30
g
h
22
a
Isolated yields are used, and E/Z ratios were determined by NMR
b
EtOH
analysis of crude reaction mixtures. Determined by 1H NMR analysis
using 1,3,5-trimethoxybenzene internal standard. Reaction was
a
Determined by 1H NMR analysis using 1,3,5-trimethoxybenzene
c
b
c
internal standard. Mg(ClO4)2 (1.0 equiv) was added. 6a was
obtained in 53% isolated yield. [Au] = PPh3AuCl. [Au] =
chloro[tris(p-trifluoromethylphenyl)phosphine]gold(I). [Au] =
(John-Phos)AuCl. [Au] = IPrAuCl. 100 wt % of 4 Å MS was
employed, no detectable reaction and substrate was recovered in 80%
yield. DCE = 1,2-dichloroethane, DCM = dichloromethane, IPr = 1,3-
bis(2,6-diisopropyl-phenyl)imidazol-2-ylidene, John-Phos = (2-
biphenyl)ditert-butylphosphine.
conducted at −10 to 0 °C with ice−salt bath.
d
e
f
g
h
instead of MeOH, enone 5a was obtained as the major product
(entry 4). Control experiments revealed that σ-Lewis acid
Mg(ClO4)2 is not necessary (entry 5). In the absence of MeOH,
only the ring-opening product 6a was isolated in 53% yield (entry
7). The absence of both alcohol and Mg(ClO4)2 can only lead to
trace amounts of 4a and 5a. Then we investigated the effect of
different alcohols (entries 8−12) and found that neopentanol
gave a respectable 75% yield and that a relatively slow
(4p, structure of (E)-4p was identified by X-ray crystallog-
raphy12) and furyl (4q) also acted as suitable residues to furnish
the desired products in acceptable yields. Alkyl-subsitituted DAC
also delivered the desired product in 49% yield with the enone
byproduct being formed in 32% yield as a mixture of E/Z isomers
(4s). Notably, in the cases of 4c and 4t, presumably due to the
conjugation-enhanced cation stabilization effects, the reactions
were found to be prone to formation of ring-opening byproducts,
which could be minimized to less than 5% by simply lowering the
reaction temperature. Unfortunately, for the thienyl-substituted
substrate (4r), lowering the temperature did not improve the
t
transformation was recorded when BuOH was utilized (entry
11). From further screenings of counterions and Au catalysts
(entries 12−17), the utilization of PPh3AuCl/AgSbF6 stood out
to be optimal (85%, entry 15). In most trials, an impurity was
observed, which was confirmed to be isomerized 7a by NMR
analysis.
With the optimal conditions identified, we next probed the
scope of this new reaction (Scheme 2). A range of phenyls
bearing various electron-donating and electron-withdrawing
groups were examined, and all were found to give products in
moderate to good yields and E/Z ratios (double-bond E/Z ratios
of 4b−o ranging from 7/1 to greater than 20/1). β-Naphthyl
1
reaction efficiency according to the H NMR analysis of the
crude reaction mixture (see the Supporting Information).
The effect of the alkyne residues was next examined, and their
corresponding results were compiled in Table 2. Primary alkyls
bearing phenyl and halogen delivered the desired product in
acceptable yields (entries 1 and 2). Secondary isopropyl also led
to the alkylidenecyclopentene as the major product, while
cyclohexyl resulted a cyclopentadiene in 76% yield without any
2099
DOI: 10.1021/acs.orglett.5b00671
Org. Lett. 2015, 17, 2098−2101

Organic Letters
Letter
Table 2. Reactivity Screenings on Substituent R2
Scheme 3. Substrates Bearing Internal Hydroxyl Groups
a
Determined by 1H NMR analysis using 1,3,5-trimethoxybenzene
internal standard.
To account for the observed reactivities, a plausible reaction
network is proposed and briefly depicted in Scheme 4.
Scheme 4. Plausible Reaction Pathway
a
Isolated yields are used, and E/Z ratios were determined by NMR
analysis of crude reaction mixtures.
formation of the corresponding alkylidenecyclopentene, which
apparently would be highly strained in this case (entry 3 and 4).
With phenyl attached on the alkyne residue, the substrate was
transformed into a multisubstituted cyclopentadiene in excellent
yield (entry 5). Treatment of TMS-substituted alkyne (entry 7)
only led to decomposition. The strained cyclopropyl was not
tolerated and was formally opened by the addition of alcohol
(entry 6, see the Supporting Information).
Substrates bearing internal hydroxyl groups were also
synthesized and subjected to the standard conditions without
addition of alcohols. As shown in Scheme 3, they displayed
interesting reactivities responding to their tether size. Treating
1u at room temperature provided a stable spiro bicyclic ether 3u
and only a trace amount of the subsequent elimination product.
The product yield was further improved when the reaction was
conducted at lower temperature (93% yield at 0 °C). For 1v,
running this reaction at room temperature led to alkylidenecy-
clopentene 4v in good yield, and the appearance and subsequent
consumption of spiro ether 3v (which was independnetly
prepared in 75% yield by lowering the reaction temperature to 0
°C) were clearly observed. For 1w with extended tether, the
expected alkylidenecyclopentene 4w was exclusively delivered in
76% yield.
Nucleophilic addition of alcohol13 to the alkyne was likely
triggered by alkynophilic Au(I) activation on 1, thus giving rise to
allene 913 and vinylgold species 10. In path A, starting from 10,
the enolate is captured by a proton and provides the observed
byproduct 5 following hydrolysis and protodeauration. This
process could be accelerated by a σ-Lewis acid Mg(ClO4)2
(Table 1, entry 4 vs entry 8). In path B, 10 undergoes cylclization
and protodeauration to provide ether 3, which is supported by
the isolation of 3u and 3v. In most of cases examined herein, 3
was reactive enough and readily underwent elimination to give
the products 4 and 7 through conceivably a π-allyl cationic
intermediate 12.14
Krapcho decarboxylation of 4a smoothly provided the
corresponding monoester, while 7a5 was transformed to
cyclopentadiene under the same conditions (see the Supporting
Information).
In summary, we have designed and realized the Au-catalyzed
1,7-addition/cyclization/elimination cascade reaction on alkynyl
donor−acceptor cyclopropanes under very mild conditions,
2100
DOI: 10.1021/acs.orglett.5b00671
Org. Lett. 2015, 17, 2098−2101

Organic Letters
Letter
(j) Sathishkannan, G.; Srinivasan, K. Org. Lett. 2011, 13, 6002.
(k) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J.
S. J. Am. Chem. Soc. 2008, 130, 8642. (l) Carson, C. A.; Kerr, M. A. J. Org.
Chem. 2005, 70, 8242. For selected examples of [3 + 3] cycloaddition
reactions, see: (m) Zhang, H.-H.; Luo, Y.-C.; Wang, H.-P.; Chen, W.;
Xu, P.-F. Org. Lett. 2014, 16, 4896. (n) Talukdar, R.; Tiwari, D. P.; Saha,
A.; Ghorai, M. A. Org. Lett. 2014, 16, 3954. (o) Young, I. S.; Kerr, M. A.
Angew. Chem., Int. Ed. 2003, 42, 3023. For selected examples of [4 + 3],
[8 + 3], and [2 + 2] reactions, see: (p) Ivanova, O. A.; Budynina, E. M.;
Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V. Angew. Chem., Int. Ed.
thereby uncovering a synthetically robust entry to a range of
highly functionalized alkylidenecyclopentenes. The direct
isolation and characterization of spiro-bicyclic ethers laid
experimental support on the proposed reaction pathways. The
achievements recorded here should find utilities in the
preparations of useful natural and unnatural substances bearing
those structural motifs.
ASSOCIATED CONTENT
* Supporting Information
■
́
́
2008, 47, 1107. (q) Rivero, A. R.; Fernandez, I.; Sierra, M. A. Org. Lett.
S
2013, 15, 4928. (r) Halskov, K. S.; Kniep, F.; Lauridsen, V. H.; Iversen,
E. H.; Donslund, B. S.; Jørgensen, K. A. J. Am. Chem. Soc. 2015, 137,
1685.
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(4) For selected examples of ring-opening/cyclization reactions to
construct pyrrole derivatives, see: (a) Zhang, Z.; Zhang, W.; Li, J.; Liu,
Q.; Liu, T.; Zhang, G. J. Org. Chem. 2014, 79, 11226. (b) Martin, M. C.;
Patil, D. V.; France, V. J. Org. Chem. 2014, 79, 3030. (c) Nambu, H.;
Fukumoto, M.; Hirota, W.; Yakura, T. Org. Lett. 2014, 16, 4012.
(d) Wang, P.; Song, S.; Miao, Z.; Yang, G.; Zhang, A. Org. Lett. 2013, 15,
3852. (e) Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz, D.
B. Angew. Chem., Int. Ed. 2012, 51, 11153. (f) Wurz, R. P.; Charette, A. B.
Org. Lett. 2005, 7, 2313. For selected examples of rearrangement
reactions to construct furan derivatives, see: (g) Grover, H. K.; Emmett,
M. R.; Kerr, M. A. Org. Lett. 2013, 15, 4838. (h) Gharpure, S. J.; Shukla,
M. K.; Vijayasree, U. Org. Lett. 2009, 11, 5466. (i) Bowman, R. K.;
Johnson, J. S. Org. Lett. 2006, 8, 573. (j) Weisser, R.; Yue, W.; Reiser, O.
Org. Lett. 2005, 7, 5353. For selected examples of rearrangement
reactions to construct nitronates, see: (k) Schmidt, C. D.; Kaschel, J.;
Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz, D. B. Org. Lett. 2013, 15,
6098. Formal Homo−Nazarov cyclization: (l) De Simone, F.; Andres,
J.; Torosantucci, R.; Waser, J. Org. Lett. 2009, 11, 1023.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dzw@pkusz.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation of China (Grant Nos.
20972008, 21272014, and 21290180), the National “973
Project” of the State Ministry of Science and Technology
(Grant Nos. 2013CB911500 and 2012CB722602), and the
Shenzhen Bureau of Science and Technology for financial
support.
(5) Xia, Y.; Liu, X.; Zheng, H.; Lin, L.; Feng, X. Angew. Chem., Int. Ed.
2015, 54, 227.
REFERENCES
■
(1) For recent reviews on donor−acceptor cyclopropanes, see:
(a) Grover, H. K.; Emmetta, M. R.; Kerr, M. A. Org. Biomol. Chem.
2015, 13, 655. (b) Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew.
Chem., Int. Ed. 2014, 53, 5504. (c) Cavitt, M. A.; Phun, L. H.; France, S.
Chem. Soc. Rev. 2014, 43, 804. (d) de Nanteuil, F.; De Simone, F.; Frei,
F.; Benfatti, F.; Serrano, E.; Waser, J. Chem. Commun. 2014, 50, 10912.
(e) Mel’nikov, M. Y.; Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V.
Mendeleev Commun. 2011, 21, 293. (f) De Simone, F.; Waser, J. Synthesis
2009, 3353. (g) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38,
3051. (h) Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061.
(i) Chagarovskiy, A. O.; Budynina, E. M.; Ivanova, O. A.; Grishin, Y. K.;
Trushkov, I. V.; Verteletskii, P. V. Tetrahedron 2009, 65, 5385.
(j) Agrawal, D.; Yadav, V. K. Chem. Commun. 2008, 6471. (k) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (l) Reissig, H.-U.; Zimmer,
R. Chem. Rev. 2003, 103, 1151.
(2) For selected examples of ring-opening reactions, see: (a) Lin, S.; Li,
L.; Liang, F.; Liu, Q. Chem. Commun. 2014, 50, 10491. (b) Garve, L. K.
B.; Barkawitz, P.; Jones, P. G.; Werz, D. B. Org. Lett. 2014, 16, 5804.
(c) Talukdar, R.; Tiwari, D. P.; Saha, A.; Ghorai, M. K. Org. Lett. 2014,
16, 3954. (d) Selvi, T.; Srinivasan, K. J. Org. Chem. 2014, 79, 3653.
(e) Venukumar, P.; Sudharani, C.; Sridhar, P. R. Chem. Commun. 2014,
50, 2218 And references in 1b..
(3) For selected examples of [3 + 2] cycloaddition reactions, see:
(a) Rakhmankulov, E. R.; Ivanov, K. L.; Budynina, E. M.; Ivanova, O. A.;
Chagarovskiy, A. O.; Skvortsov, D. A.; Latyshev, G. V.; Trushkov, I. V.;
Melnikov, M. Y. Org. Lett. 2015, 17, 770. (b) de Nanteuil, F.; Serrano, E.;
Perrotta, D.; Waser, J. J. Am. Chem. Soc. 2014, 136, 6239.
(c) Chakrabarty, S.; Chatterjee, I.; Wibbeling, B.; Daniliuc, C. D.;
Studer, A. Angew. Chem., Int. Ed. 2014, 53, 5964. (d) Mackay, W. D.;
Fistikci, M.; Carris, R. M.; Johnson, J. S. Org. Lett. 2014, 16, 1626.
(e) Zhu, M.; Liu, J.; Yu, J.; Chen, L.; Zhang, C.; Wang, L. Org. Lett. 2014,
16, 1856. (f) Xu, H.; Qu, J.-P.; Liao, S.; Xiong, H.; Tang, Y. Angew.
Chem., Int. Ed. 2013, 52, 4004. (g) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.;
Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851. (h) Goldberg, A. F. G.;
O’Connor, N. R.; Craig, R. A.; Stoltz, B. M. Org. Lett. 2012, 14, 5314.
(i) de Nanteuil, F.; Waser, J. Angew. Chem., Int. Ed. 2011, 50, 12075.
(6) (a) Kaschel, J.; Schmidt, C. D.; Mumby, M.; Kratzert, D.; Stalke, D.;
Werz, D. B. Chem. Commun. 2013, 49, 4403. (b) Kaschel, J.; Schneider,
T. F.; Kratzert, D.; Stalke, D.; Werz, D. B. Org. Biomol. Chem. 2013, 11,
3494. (c) Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz, D.
B. Angew. Chem., Int. Ed. 2012, 51, 11153. (d) Schneider, T. F.; Werz, D.
B. Org. Lett. 2011, 13, 1848. (e) Schneider, T. F.; Kaschel, J.; Awan, S. I.;
Dittrich, B.; Werz, D. B. Chem.Eur. J. 2010, 16, 11276. (f) Brand, C.;
Rauch, G.; Zanoni, M.; Dittrich, B.; Werz, D. B. J. Org. Chem. 2009, 74,
8779. (g) Schneider, T. F.; Kaschel, J.; Dittrich, B.; Werz, D. B. Org. Lett.
2009, 11, 2317.
(7) Silva, L. F., Jr. Tetrahedron 2002, 58, 9137.
(8) For selected examples of Conia−ene reacton to construct
cyclopentane derivatives, see: (a) Matsuzawa, A.; Mashiko, T.;
Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 7616.
(b) Yang, T.; Ferrali, A.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140.
(c) Review: Clarke, M. L.; France, M. B. Tetrahedron 2008, 64, 9003.
(d) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 4526. (e) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D.
Angew. Chem. Int. Ed. 2004, 43, 5350.
(9) For recent reviews on Au catalysis, see: (a) Rudolph, M.; Hashmi,
A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (b) Liu, L.-P.; Hammond, G. B.
Chem. Soc. Rev. 2012, 41, 3129. (c) Corma, A.; Leyva-Perez, A.; Sabater,
M. J. Chem. Rev. 2011, 111, 1657. (d) Krause, N.; Winter, C. Chem. Rev.
2011, 111, 1994. (e) Bandini, M. Chem. Soc. Rev. 2011, 40, 1358.
(f) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (g) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395.
(10) Haubenreisser, S.; Hensenne, P.; Schroder, S.; Niggemann, M.
̈
Org. Lett. 2013, 15, 2262.
́
(11) Cerat, P.; Gritsch, P. J.; Goudreau, S. R.; Charette, A. B. Org. Lett.
2010, 12, 564.
(12) The crystal structure of (E)-4p was deposited at the Cambridge
Crystallographic Data Centre (tracking no. 1051592).
(13) Aponick, A.; Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121.
(14) Herkert, L.; Green, S. L. J.; Barker, G.; Johnson, D. G.; Young, P.
C.; Macgregor, S. A.; Lee, A.-L. Chem.Eur. J. 2014, 20, 11540.
2101
DOI: 10.1021/acs.orglett.5b00671
Org. Lett. 2015, 17, 2098−2101