Rh(I)-catalyzed Pauson-Khand-type cycloaddition reaction of ene-vinylidenecyclopropanes with carbon monoxide (CO)

Article abstract of DOI:10.1021/ol302705z

An intramolecular Pauson-Khand type cycloaddition reaction of ene-vinylidenecyclopropanes with carbon monoxide has been established by using [Rh(COD)Cl]₂ as the catalyst. The reaction was found to be highly efficient in solvents of 1,2-dichloroethane and 1,1,2,2-tetrachloroethane to give excellent yields of 90-99%. The reaction provides easy access to a series of fused 6,5-ring structures containing spiro-cyclopropane units that are useful for drug design and development. A mechanism of this cycloaddition process has been proposed accounting for structures of resulting products that were unambiguously assigned by X-ray diffractional analysis.

Full text of DOI:10.1021/ol302705z

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5582–5585
Rh(I)-catalyzed Pauson-Khand-type
Cycloaddition Reaction of
Ene-vinylidenecyclopropanes with
Carbon Monoxide (CO)
Wei Yuan,† Xiang Dong,† Min Shi,*,† Patrick McDowell,‡ and Guigen Li*,‡,§
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China,
Institute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093,
P. R. China, and Department of Chemistry and Biochemistry, Texas Tech University,
Lubbock, Texas 79409-1061, United States
mshi@mail.sioc.ac.cn; guigen.li@ttu.edu
Received September 30, 2012
ABSTRACT
An intramolecular Pauson-Khand type cycloaddition reaction of ene-vinylidenecyclopropanes with carbon monoxide has been established by
using [Rh(COD)Cl]2 as the catalyst. The reaction was found to be highly efficient in solvents of 1,2-dichloroethane and 1,1,2,2-tetrachloroethane to
give excellent yields of 90ꢀ99%. The reaction provides easy access to a series of fused 6,5-ring structures containing spiro-cyclopropane units
that are useful for drug design and development. A mechanism of this cycloaddition process has been proposed accounting for structures of
resulting products that were unambiguously assigned by X-ray diffractional analysis.
The Pauson-Khand reaction has been actively investi-
gated for several decades because it can provide easy access
to cyclopentanone derivatives to serve as important struc-
tural motifs that exist in a huge number of pharmaceutical
substances and biologically active natural products.1ꢀ3
This reaction occurs through a [2 þ 2 þ 1] cycloaddition
mechanism involving alkyne, alkene and CO as reactants.
Besides the use of alkyne and alkene as starting materials,
allene derivatives including allenynes have also been em-
ployed for the Pauson-Khand reaction.2 In 1994, Narasaka
and co-workers reported the first intramolecular version
of the Pauson-Khand reaction by using allenynes as
substrates in the presence of an iron complex.3 Later,
Brummond’s group extensively studied the allene-based
Pauson-Khand reaction by using transition metals, mo-
lybdenum or rhodium, as the catalysts for highly efficient
control of regioselectivity of this cycloaddition reaction.4
During our ongoing project on vinylidenecyclopropanes’
(VDCPs) chemistry,5 we have developed a Rh(I)-catalyzed
(4) (a) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245. (b)
Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995, 36,
2407. (c) Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.;
Rickards, B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931. (d)
Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63,
6535. (e) Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491. (f)
Brummond, K. M.; Curran, D.-P.; Mitasev, B.; Fisher, S. J. Org. Chem.
2005, 70, 1745. (g) Bayden, A. S.; Brummond, K. M.; Jordan, K. D.
Organometallics 2006, 25, 5204. For selected recent reports on the
Pauson-Khand-type reaction of allenes, see: (h) Grillet, F.; Huang, C.;
Brummond, K. M. Org. Lett. 2011, 13, 6304. (i) Inagaki, F.; Itoh, N.;
Hayashi, Y.; Matsui, Y.; Mukai, C. Beilstein J. Org. Chem. 2011, 7, 404.
(j) Antras, F.; Laurent, S.; Ahmar, M.; Chermette, H.; Cazes, B. Eur. J.
Org. Chem. 2010, 3312. (k) Kawamura, T.; Inagaki, F.; Narita, S.;
Takahashi, Y.; Hirata, S.; Kitagaki, S.; Mukai, C. Chem.;Eur. J. 2010,
16, 5173. (l) Inagaki, F.; Mukai, C. Org. Lett. 2006, 8, 1217. (m) Alcaide,
B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377. (n) Mukai, C.;
Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett. 2002, 4, 1755. (o)
Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.; Rickards,
B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931.
† Chinese Academy of Sciences.
‡ Texas Tech University.
§ Nanjing University.
(1) Narasaka, K.; Shibata, T. Chem. Lett. 1994, 315.
(2) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377.
(3) Narasaka, K.; Shibata, T. Chem. Lett. 1994, 315.
r
10.1021/ol302705z
Published on Web 10/25/2012
2012 American Chemical Society

Table 1. Optimization of Rh(I)-catalyzed Pauson-Khand-type
Cycloaddition Reaction of Ene-vinylidenecyclopropane 1a with
CO
Scheme 1. Rh(I)-catalyzed Pauson-Khand Reaction of Ene-VDCPs
entrya
catalyst
xb
solvent
yield (%)c 2a
1
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
Rh(CO)Cl(PPh3)2
[Rh(COD)Cl]2
[Rh(CO)2Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
Pd(PPh3)2Cl2
5
20
10
10
10
10
10
10
5
toluene
toluene
toluene
toluene
toluene
DCE
9d
30d
54
2
3
4
5
66
73
91
99
99
99
94
6
7
DCE
8
TCE
9
TCE
TCE
10
11
12
2
Pauson-Khand-type [3 þ 2 þ 1] cycloaddition reaction of
ene-vinylidenecyclopropanes (ene-VDCPs) with carbon
monoxide to generate a series of aza- or oxa-bicyclic
products in moderate to good yields with a highly regio-
and diastereoselective fashions (Scheme 1).6 In this com-
munication, we would like to report a highly efficient
Rh(I)-catalyzed intramolecular Pauson-Khand type cy-
cloaddition reaction of ene-vinylidenecyclopropanes with
carbon monoxide for the synthesis of a series of fused 6,5-
ring structures containing spiro-cyclopropane motifs,
which afforded up to 99% chemical yields (Scheme 1).
1
TCE
4
TCE
a Ene-VDCP 1a (0.2 mmol), catalyst (x mol %) and the solvent
(2.0 mL) were added into a reaction tube under argon. Then, the reaction
was carried out under CO atmosphere at 80 °C within 1 h. b Loading of
the catalyst. c Isolated yields. d Reaction was carried out under argon.
Our initial study on this catalytic reaction started with
ene-vinylidenecyclopropane 1a as the substrate. In this
substrate alkene and vinylidenecyclopropane moieties are
connected by an anchor of “TsN” (Ts = 4-toluenesulfonyl).
As shown in Table 1, we found that when the reaction was
carried out at 80 °C in toluene under argon atmosphere
protection (without the use of CO) in the presence of 5 or
20 mol % of [Rh(CO)2Cl]2, the corresponding cycloaddition
adduct 2a was obtained in 9 and 30% yields, respectively
(Table 1, entries 1 and 2). The reaction was then conducted
under CO atmosphere and in the presence of 10 mol %
[Rh(CO)2Cl]2 as the catalyst, adduct 2a was produced in a
chemical yield of 54% (Table 1, entry 3). However, a similar
catalyst, Rh(CO)Cl(PPh3)2, was found to be catalytically
inactive under this condition. Pleasingly, [Rh(COD)Cl]2
was confirmed as more efficient catalyst for this reaction
to afford 2a in 66% yield (Table 1, entries 4 and 5). Our
examination of solvent effects revealed that DCE (1,2-
dichloroethane) and TCE (1,1,2,2-tetrachloroethane) are
suitable solvents together with 10 mol % of [Rh(CO)2Cl]2
as the catalyst, giving 2a in 91 and 99% yields, respectively
(Table 1, entries 7 and 8). Decreasing the loading of
[Rh(COD)Cl]2 from 10 mol % to less than 5 mol % can
also give product 2a in 94ꢀ99% yields under the above
conditions (Table 1, entries 9ꢀ11). Using Pd(PPh3)2Cl2
(4 mol %) as the catalyst, no reaction occurred (Table 1,
entry 12).
(5) For vinylidenecyclopropane chemistry, see: (a) Poutsma, M. L.;
Ibarbia, P. A. J. Am. Chem. Soc. 1971, 93, 440. (b) Smadja, W. Chem.
Rev. 1983, 83, 263. (c) Sugita, H.; Mizuno, K.; Saito, T.; Isagawa, K.;
Otsuji, Y. Tetrahedron Lett. 1992, 33, 2539. (d) Mizuno, K.; Sugita, H.;
Kamada, T.; Otsuji, Y. Chem. Lett. 1994, 449 and references therein. (e)
Sydnes, L. K. Chem. Rev. 2003, 103, 1133. (f) Mizuno, K.; Maeda, H.;
Sugita, H.; Nishioka, S.; Hirai, T.; Sugimoto, A. Org. Lett. 2001, 3, 581.
(g) Shi, M.; Shao, L.-X.; Lu, J.-M.; Wei, Y.; Mizuno, K.; Maeda, H.
Chem. Rev. 2010, 110, 5883. (h) Xu, G.-C.; Liu, L.-P.; Lu, J.-M.; Shi, M.
J. Am. Chem. Soc. 2005, 127, 14552. (i) Li, W.; Yuan, W.; Pindi, S.; Shi,
M.; Li, G.-G. Org. Lett. 2010, 12, 64. (j) Lu, B.-L.; Wei, Y.; Shi, M.
Chem.;Eur. J. 2010, 16, 10975. (k) Lu, B.-L.; Shi, M. Eur. J. Org. Chem.
2011, 243. (l) Lu, B.-L.; Shi, M. Angew. Chem., Int. Ed. 2011, 50, 12027.
(6) (a) Lu, B.-L.; Wei, Y.; Shi, M. Organometallics 2012, 31, 4601. For
selected reviews on the rhodium-catalyzed Pauson-Khand reaction, see:
(b) Jeong, N.; Sung, B. K.; Kim, J. S.; Park, S. B.; Seo, S. D.; Shin, J. Y.;
In, K. Y.; Choi, Y. K. Pure Appl. Chem. 2002, 74, 85. (c) Baik, M.-H.;
Mazumder, S.; Ricci, P.; Sawyer, J. R.; Song, Y.-G.; Wang, H.; Evans,
P. A. J. Am. Chem. Soc. 2011, 133, 7621. (d) Kim, D.-E.; Park, S.-H.;
Choi, Y.-H.; Lee, S.-G.; Moon, D.-H.; Seo, J.-J.; Jeong, N.-C. Chem.
Asian J. 2011, 6, 2009. (e) Turlington, M.; Pu, L. Org. Lett. 2011, 13,
4332. (f) Kim, D. E.; Ratovelomanana-Vidal, V.; Jeong, N. Adv. Synth.
Catal. 2010, 352, 2032. For selected recent reports on the Pauson-
Khand-type reaction of heteroalkenes, see: (g) Saito, T.; Furukawa,
N.; Otani, T. Org. Biomol. Chem. 2010, 8, 1126. (h) Mukai, C.; Yoshida,
T.; Sorimachi, M.; Odani, A. Org. Lett. 2006, 8, 83. For selected recent
reports on the Pauson-Khand-type reaction of cyclopropanes, please
see: (I) Jiao, L.; Lin, M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12,
2528. (j) Fan, X.; Tang, M.-X.; Zhuo, L.-G.; Tu, Y. Q.; Yu, Z.-X.
Tetrahedron Lett. 2009, 50, 155. (k) Fan, X.; Zhuo, L.-G.; Tu, Y.-Q.; Yu,
Z.-X. Tetrahedron 2009, 65, 4709. (l) Jiao, L.; Yuan, C.; Yu, Z.-X. J. Am.
Chem. Soc. 2008, 130, 4421. (m) Kim, S. Y.; Lee, S. I.; Choi, S. Y.;
Chung, Y. K. Angew. Chem., Int. Ed. 2008, 47, 4914. (n) Wang, Y.;
Wang, J.; Su, J.; Huang, F.; Jiao, L.; Liang, Y.; Yang, D.; Zhang, S.;
Wender, P. A.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 1006. (o) Wender,
P. A.; Gamber, G. G.; Hubbard, R. D.; Pham, S. M.; Zhang, L. J. Am.
Chem. Soc. 2005, 127, 2836. (p) Wegner, H. A.; de Meijere, A.; Wender,
P. A. J. Am. Chem. Soc. 2005, 127, 6530.
Having identified the optimal conditions, we next exam-
ined the scope and limitations of this Rh(I)-catalyzed cyclo-
addition reaction; the results are summarized in Table 2.
Using ene-VDCPs 1bꢀ1k as the substrates in which R can
Org. Lett., Vol. 14, No. 21, 2012
5583

Scheme 2. Rh(I)-catalyzed Pauson-Khand-type Cycloaddition
Reaction of Ene-vinylidenecyclopropane 1a (2 mmol) and CO
Figure 1. X-ray Crystal Structure of Product 2a.
Scheme 3. Plausible Reaction Mechanism
Table 2. Substrate Scope of Rh(I)-catalyzed Pauson-Khand-
type Cycloaddition Reaction of Ene-vinylidenecyclopropanes
and CO
reaction was observed under the above conditions (Table 2,
entry 14). The substrates with other different R groups are
difficult to be prepared.
To our delight, on enlarging the reaction scale to 2.0 mmol
by employing 1a as the substrate, similar results could be
obtained, affording 2a in 82% yield (Scheme 2).
The resulting products have been determined by NMR
spectroscopic and HRMS analysis (see Supporting
Information); and the product of 2a has been unambigu-
ously assigned by X-ray diffractional analysis. The CIF
data of this X-ray analysis are summarized in Supporting
Information and corresponding ORTEP drawing is pres-
ented in Figure 1.7
A plausible reaction mechanism has been shown in
Scheme 3 using 1a for the model reaction. At first, the
coordination of Rh(I) with alkene and allene moieties in
VDCP leads to formation of intermediate A; this inter-
mediate then undergoes oxidative cyclization to give the
rhodacycle intermediate B. Insertion of CO into B gener-
ates two regioisomers C and D which is subjected to
reductive elimination followed by the formation of cyclo-
adduct 2a. At this last step, the species Rh(I) is regenerated
for catalytic cycles.
a 1 (0.2 mmol), [Rh(COD)Cl]2 (2 mol %), and TCE (2.0 mL) were
added into a schlaker reaction tube under CO (1 atm). The reactions
were carried out at 80 °C within 1 h. b Isolated yields.
be various primary or secondary alkyl groups with X as
TsN or BsN anchor (Bs = 4-bromobenzenesulfonyl), the
desired products 2bꢀ2k were obtained in excellent yields
ranging from 92% to 97% (Table 2, entries 2ꢀ11). Moreover,
as for substrates 1l and 1m, in which alkene and vinylidene-
cyclopropane moieties are connected by oxygen and carbon
anchors, the reactions was performed smoothly to give the
corresponding products 2l and 2m in 91% and 90% yields,
respectively (Table 2, entries 12 and 13). Interestingly,
when ene-vinylidenecyclopropane 1n which contains an
additional CH2 extension was used as the substrate, no
In conclusion, we have developed a highly efficient
Rh(I)-catalyzed intramolecular Pauson-Khand type cyclo-
addition reaction of ene-vinylidenecyclopropanes with
CO, which can efficiently result in fused 6,5-ring structures
(7) The crystal data of 2a have been deposited in CCDC with number
830675.
5584
Org. Lett., Vol. 14, No. 21, 2012

containing spiro-cyclopropane units with excellent yields
(>90% for all cases). Further work will be devoted toward
applications of this new methodology to the synthesis of
biologically important targets.
(D-1361) and NIH (R21DA031860-01) for their generous
support.
Supporting Information Available. The reaction proce-
dure for preparation of ene-vinylidenecyclopropanes and
spectroscopic data of the compounds shown in Tables 1ꢀ2
along with the detailed descriptions of experimental pro-
cedures as well as the crystal structures of 2a. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (11JC1402600),
National Basic Research Program of China (973)-
2009CB825300, and the National Natural Science Founda-
tion of China (21072206, 20472096, 20872162, 20672127,
21121062, 20732008), and Robert A. Welch Foundation
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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