Nd(OTf)3-catalyzed cascade reactions of vinylidenecyclopropanes with enynol: a new method for the construction of the 5-7-6 tricyclic framework and its scope and limitations

Article abstract of DOI:10.1002/ejoc.200900660

We report in this paper a Lewis acid [Nd(OTf)₃]-catalyzed protocol to construct compounds containing a 5-7-6 tricyclic framework in good, yield from readily accessible starting materials vinylidenecyclopropanes (VDCP_s) 1 and. enynols

Full text of DOI:10.1002/ejoc.200900660

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900660
Nd(OTf)3-Catalyzed Cascade Reactions of Vinylidenecyclopropanes with
Enynol: A New Method for the Construction of the 5–7–6 Tricyclic Framework
and Its Scope and Limitations
Liang-Feng Yao[a] and Min Shi*[a,b]
Keywords: Lewis acids / Small ring systems / Fused-ring systems / Enynes
We report in this paper a Lewis acid [Nd(OTf)3]-catalyzed
protocol to construct compounds containing a 5–7–6 tricyclic
framework in good yield from readily accessible starting ma-
terials vinylidenecyclopropanes (VDCPs) 1 and enynols 2a–c
under mild conditions. Upon examination of the scope and
limitations of this reaction, it was found that the correspond-
ing highly functionalized cyclopentane derivatives could be
formed in good yields from the reaction VDCPs 1 and enol
2e or dienol 2c under identical conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Polycyclic natural products that contain an embedded
polyhydroazulene subunit, for example, dilatriol (A),[1a] ra-
meswaralide (B),[1b] grayanotoxin (C),[1c] and guanacastep-
ene A (D),[2] possess diverse biological activities. Further-
more, these natural products contain a common 5–7–6 tri-
cyclic framework. By far, the most commonly used strategy
in the synthesis of the 5–7–6 framework involves a Ru-cata-
lyzed intramolecular [5+2] cycloaddition reaction involving
cyclopropyl enynes.[3] Although this method effectively
forms the 5–7–6 ring system, it requires the reaction of
complex starting materials with expensive transition-metal
catalysts. Considering this result, a much more appealing
strategy that accesses the assembly of the 5–7–6 tricyclic
framework from readily available starting materials and cat-
alysts is still highly desired.
Vinylidenecyclopropanes (VDCPs) 1[4] are one of the
most remarkable organic compounds known in the area of
highly strained small ring systems. They have an allene moi-
ety connected to a cyclopropane ring, and yet, they are
thermally stable and reactive substances in organic synthe-
sis. Thermal and photochemical skeletal conversions of
VDCPs 1 have attracted much attention from mechanistic,
theoretical, spectroscopic, and synthetic viewpoints.[5] Re-
cently, we and others reported the Lewis acid catalyzed re-
action of arylvinylidenecyclopropanes with a number of
electrophiles such as acetals and imines as well as 3-meth-
oxy-1,3,3-triarylprop-1-yne or 1,1,3-triarylprop-2-yn-1-ol
under mild conditions, affording the corresponding prod-
ucts with complex molecular frameworks in good yields.[6]
These interesting results have stimulated us to further ex-
plore such cascade electrophilic attack, followed by Friedel–
Crafts reaction processes with VDCPs as the substrates
with a number of interesting electrophiles in the presence
of Lewis acids or Brønsted acids. Herein, we wish to present
an interesting cascade reaction to construct compounds
containing the 5–7–6 tricyclic framework by the Lewis acid
catalyzed intermolecular reaction of VDCPs with enynols
as well as the results of VDCPs with enol and dienol to
show its scope and limitations.
[a] School of Chemistry & Molecular Engineering, East China
University of Science and Technology,
130 Mei Long Road, Shanghai 200237, China
Fax: +86-21-64166128
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900660.
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Eur. J. Org. Chem. 2009, 4036–4040

A New Method for the Construction of 5–7–6 Tricyclic Frameworks
Results and Discussion
In an initial examination, the reaction of arylvinylidene-
cyclopropane 1a (0.24 mmol) and enynol 2a (0.2 mmol)[7]
was performed in dichloromethane (DCM) in the presence
of BF3·OEt2 (10 mol-%) at room temperature (20 °C) and
it was found that product 3a was obtained in 68% yield
after 24 h (Table 1, Entry 1). The structure of 3a was unam-
biguously determined by X-ray diffraction (Figure 1).[8]
Next, we screened several other Lewis acids and solvents to
determine the optimal reaction conditions, and the results
of these experiments are summarized in Table 1. The exami-
nation of Lewis acid revealed that Nd(OTf)3 was the opti-
mal catalyst for this transformation among others such as
Sc(OTf)3, Zr(OTf)4, Zn(NTf2)2, Sm(OTf)3, and TMSOTf,
as well as the Brønsted acid trifluoromethanesulfonic acid
(CF3SO3H, TfOH) (Table 1, Entries 2–8). Meanwhile, we
also found that DCM was the most suitable solvent in this
reaction (Table 1, Entries 9–12). Moreover, adjustment of
the ratio of 1a/2a from 1.2:1 to 1:1.2 improved the yield of
3a slightly, affording 3a in 93% yield under identical condi-
tions (Table 1, Entry 13). Therefore, the optimized reaction
conditions involve carrying out the reaction in DCM at
room temperature by using 1a (1.0 equiv.) and 2a
(1.2 equiv.) as the substrates in the presence of Nd(OTf)3
(10 mol-%).
Figure 1. ORTEP drawing of 3a.
1b, 1c, 1d, and 1e, the corresponding products 3b, 3c, 3d,
and 3e were obtained in excellent yields, and the electronic
nature of the substituents on the aromatic rings of 1 did not
significantly affect the outcomes of the reactions (Table 2,
Entries 1–4). The reaction of unsymmetrical substrates 1f–
h with 2a afforded annelated derivatives 3f–h in moderate
to excellent yields as E- and Z-isomeric mixtures in a ratio
of 1:1 to 4:1 (Table 2, Entries 3–7) and the reaction of 1i,
having a monoaliphatic group (R1 = Et and R2 = C6H5),
furnished the corresponding product 3i in 62% yield as a
single stereoisomer with Z-configuration on the basis of
NOE investigation (see Supporting Information; Table 2,
Entry 8). Substrates 1j and 1k (R3 and R4 are aromatic
groups and R5 and R6 are hydrogen atoms) could also pro-
vide the corresponding products 3j and 3k in 63 and 45%
yield, respectively, under the standard conditions (Table 2,
Entries 9 and 10). Moreover, using aliphatic VDCP 1l as
the substrate, in which R1 and R2 are butyl groups and R3
and R4 are aromatic groups, the corresponding product 3l
was formed in 40% yield along with the recovery of 20%
of starting materials (Table 2, Entry 11). By using 2-en-4-
yn-1-osl 2b and 2c as the substrates, similar reaction out-
comes were obtained under identical conditions (Table 2,
Entries 12 and 13).
Table 1. Optimization of the reaction conditions of 1a and 2a.
Entry[a]
Lewis acid
Solvent
Time [h] Yield of 3a [%][b]
1
2
3
4
5
6
7
8
BF3·OEt2
Sc(OTf)3
Zr(OTf)4
Zn(NTf2)2
Sm(OTf)3
Nd(OTf)3
TMSOTf
TfOH
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
DCE
24
32
28
29
23
30
12
19
11
22
24
30
22
68
72
83
73
74
91
87
87
55
9
10
11
12
13
72
CH3CN
THF
DCM
complex
48[c]
93[d]
A plausible mechanism for the formation of tricyclic
products 3 is outlined in Scheme 1. Initially, the reaction of
2a with Nd(OTf)3 generates cationic intermediate A, which
can furnish its mesomeric cationic intermediate B. The reac-
tion of intermediate B with 1a gives the corresponding cy-
clopropyl ring-opened π-allylic cationic intermediate C. The
[a] All reactions were carried out with 1a (0.24 mmol) and 2a
(0.2 mmol) in various solvents (2.0 mL) in the presence of a variety
of Lewis acids (10 mol-%) at room temperature. [b] Isolated yield.
[c] The reaction was carried out at 50 °C. [d] The reaction was car-
ried out with 1a (0.2 mmol) and 2a (0.24 mmol).
Under these optimized reaction conditions, we then reaction of intermediate B with 1a can take place more eas-
turned our attention to examine the generality of this ily than that of intermediate A with 1a presumably because
Nd(OTf)3-catalyzed interesting reaction and the results are intermediate B is less sterically hindered than intermediate
summarized in Table 2. It was found that the corresponding A. Intermediate C, through intramolecular electrophilic at-
tricyclic products 3 were obtained in moderate to excellent tack, affords intermediate D, which undergoes intramolecu-
yields from a variety of VDCPs 1. In the case of substrates lar Friedel–Crafts reaction to give final product 3a.
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L.-F. Yao, M. Shi
SHORT COMMUNICATION
Table 2. Nd(OTf)3-Catalyzed reaction of vinylidenecyclopropanes 1 with enynols 2.
Entry
R1/R2/R3/R4/R5/R6
R7
Time [h]
Yield of 3 [%]
1
2
3
4
5
6
7
8
p-MeOC6H4/p-MeOC6H4/Me/Me/Me/Me, 1b
p-ClC6H4/p-ClC6H4/Me/Me/Me/Me, 1c
p-MeC6H4/p-MeC6H4/Me/Me/Me/Me, 1d
p-FC6H4/p-FC6H4/Me/Me/Me/Me, 1e
p-MeOC6H4/C6H5/Me/Me/Me/Me, 1f
p-ClC6H4/C6H5/Me/Me/Me/Me, 1g
o-MeC6H4/C6H5/Me/Me/Me/Me, 1h
Et/C6H5/Me/Me/Me/Me, 1i
C6H5/C6H5, 2a
30
24
23
29
15
24
36
18
6
3b, 80
2a
3c, 84
2a
3d, 84
3e, 94
2a
2a
3f, 75 (61:39)[a]
3g, 95 (50:50)[a]
3h, 54 (80:20)[a]
3i, 62[b]
2a
2a
2a
9
C6H5/C6H5/C6H5/C6H5/H/H, 1j
C6H5/C6H5/p-MeC6H4/p-MeC6H4/H/H, 1k
nBu/nBu/C6H5/C6H5/H/H, 1l
1a
2a
3j, 63
10
11
12
13
2a
8
3k, 45
2a
48
48
24
3l, 40[c]
p-MeC6H4, 2b
p-MeOC6H4, 2c
3m, 88
3n, 71
1a
1
[a] The ratio of E/Z or Z/E was determined on the basis of the H NMR spectroscopic data. [b] Isolated as a single stereoisomer on the
1
basis of the H NMR spectroscopic data. [c] Compound 1l was recovered in 20%.
Scheme 1. A plausible mechanism for the formation of 3a.
Interestingly, by using 2d as the substrate to react with 1a
under identical conditions, an unexpected product 3o was
formed in 68% yield rather than the desired tricyclic prod-
uct, perhaps due to the electronic properties of the TMS
group (Scheme 2). This result promoted us to examine the
reaction of 1a with several analogues of 2a. Because the
carbon–carbon triple bond of 2d did not participate in the
reaction, we envisaged that the reaction of enol 2e, in which
the alkyne moiety was replaced by phenyl group, with 1a
under identical conditions might produce similar com-
pound 3p in good yield. The experimental result disclosed
that 3p was indeed obtained in 75% yield as a single dia-
stereoisomer (Scheme 2). The structure of 3p was unambig-
uously confirmed by X-ray diffraction (Figure 2).[9]
Scheme 2. The reaction of 1a with 2d and 2e.
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A New Method for the Construction of 5–7–6 Tricyclic Frameworks
Scheme 3. The reaction of 1a with 2f.
Figure 2. ORTEP drawing of 3p.
In order to further understand the scope and limitations
of this reaction, we introduced another carbon–carbon
double bond into enol 2e, namely, by using 2,4-dien-1-ol 2f
as the substrate to examine the reaction outcome. It was
found that the reaction of 1a with 2f under identical condi-
tions afforded product 3q in 82% yield with high geometric
selectivity (E/Z = 95:5) (Scheme 3). The structure of major
product (E)-3q was confirmed by X-ray diffraction analysis
(Figure 3).[10]
A plausible mechanism for the formation of 3p and 3q
was depicted in Scheme 4. Initially, the treatment of 2e or
2f with Nd(OTf)3 gives cationic intermediate E. Intermedi- Figure 3. ORTEP drawing of 3q.
Scheme 4. A plausible mechanism for the formation of 3p and 3q.
Eur. J. Org. Chem. 2009, 4036–4040
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L.-F. Yao, M. Shi
SHORT COMMUNICATION
ate E produces its mesomeric intermediate F. The reaction
of intermediate F with 1a affords cyclopropyl ring-opened
π-allylic cationic intermediate G, which can either furnish
intermediate H (n = 1) or produce intermediate I (n = 2) by
intramolecular electrophilic attack. Nucleophilic attack by
the in situ generated H2O at intermediate H affords final
product 3p. In contrast, intermediate I undergoes deproton-
ation to afford final product 3q.
[1] a) G. R. Pettit, R. H. Ode, C. L. Herald, R. B. Von Dreele, C.
Michel, J. Am. Chem. Soc. 1976, 98, 4677–4678; b) P. Ramesh,
N. Srinivasa, Y. Venkateswarlu, M. V. R. Reddy, D. J. Faulkner,
Tetrahedron Lett. 1998, 39, 8217–8220; c) K. Nakanishi, T.
Goto, S. Ito, S. Natori, S. Nozoe, Natural Product Chemistry,
Academic Press, New York, 1974, vol. 1, p. 285, and references
cited therein.
[2] For isolation, see: a) S. F. Brady, M. P. Singh, J. E. Janso, J.
Clardy, J. Am. Chem. Soc. 2000, 122, 2116–2117; for the first
synthesis, see: b) S. Lin, G. S. Dudley, D. S. Tan, S. J. Danishef-
sky, Angew. Chem. 2002, 114, 2292–2295; Angew. Chem. Int.
Ed. 2002, 41, 2188–2191.
Conclusions
[3] B. M. Trost, H. C. Shen, Angew. Chem. 2001, 113, 2375–2378;
Angew. Chem. Int. Ed. 2001, 40, 2313–2316.
In summary, we have developed an effective Lewis acid
catalyzed protocol to construct compounds containing a 5–
7–6 tricyclic framework in good yields from readily access-
ible starting materials vinylidenecyclopropanes 1 and enyn-
ols 2a–c under mild conditions. This method provides an
alternative way to access natural products containing the 5–
7–6 tricyclic framework. Upon examination of the scope
and limitations of this reaction, it was found that the corre-
sponding highly functionalized cyclopentane derivatives
could be formed in good yields from the reaction of 1 and
enol 2e or dienol 2f under identical conditions. Plausible
mechanisms for all of these transformations have been dis-
cussed on the basis of the obtained results. Efforts are in
progress to elucidate further the mechanistic details and to
understand the scope and limitations of these reactions.
[4] For the synthesis of vinylidenecyclopropanes, see: a) K. Isa-
gawa, K. Mizuno, H. Sugita, Y. Otsuji, J. Chem. Soc. Perkin
Trans. 1 1991, 2283–2285 and references cited therein; b) J. R.
Al-Dulayymi, M. S. Baird, J. Chem. Soc. Perkin Trans. 1 1994,
1547–1548; for some other papers related to vinylidenecyclo-
propanes, see: c) H. Maeda, T. Hirai, A. Sugimoto, K. Mizuno,
J. Org. Chem. 2003, 68, 7700–7706; d) D. J. Pasto, J. E. Brophy,
J. Org. Chem. 1991, 56, 4554–4556.
[5] a) M. L. Poutsma, P. A. Ibarbia, J. Am. Chem. Soc. 1971, 93,
440–450; b) W. Smadja, Chem. Rev. 1983, 83, 263–320; c) M. E.
Hendrick, J. A. Hardie, M. Jones, J. Org. Chem. 1971, 36,
3061–3062; d) H. Sugita, K. Mizuno, T. Saito, K. Isagawa, Y.
Otsuji, Tetrahedron Lett. 1992, 33, 2539–2542; e) K. Mizuno,
H. Sugita, T. Kamada, Y. Otsuji, Chem. Lett. 1994, 449–452
and references cited therein; f) L. K. Sydnes, Chem. Rev. 2003,
103, 1133–1150.
[6] a) J.-M. Lu, M. Shi, Org. Lett. 2006, 8, 5317–5320; b) M. Shi,
L.-F. Yao, Chem. Eur. J. 2008, 14, 8725–8731; c) L.-F. Yao, M.
Shi, Chem. Eur. J. 2009, 15, 3875–3881; d) A. V. Stepakov,
A. G. Larina, A. P. Molchanov, L. V. Stepakova, G. L. Starova,
R. R. Kostikov, Russ. J. Org. Chem. 2007, 43, 41–49; e) J.-M.
Lu, Z.-B. Zhu, M. Shi, Chem. Eur. J. 2009, 15, 963–971; f) Z.-
B. Zhu, M. Shi, Chem. Eur. J. 2008, 14, 10219–10222.
[7] For the synthesis of enynol 2a, see: X.-W. Du, H.-Y. Chen, Y.-
H. Liu, Chem. Eur. J. 2008, 14, 9495–9498.
[8] Crystal data for 3a (CCDC-710597): Empirical formula:
C44H38; Fw 566.74; crystal size: 0.269ϫ0.245ϫ0.210; crystal
color, habit: colorless, prismatic; crystal system: triclinic; lattice
type: primitive; lattice parameters: a = 9.7927(8) Å, b =
Experimental Section
Typical Procedure for the Reaction of Vinylidenecyclopropanes 1
with (Z)-1,1,5-Triarylpent-2-en-4-yn-1-ols 2: To a solution of 1a
(55 mg, 0.2 mmol) and 2a (74 mg, 0.24 mmol) dissolved in DCM
(2.0 mL) was added then Nd(OTf)3 (10 mol-%). The mixture was
stirred for 22 h at room temperature (25 °C). The solvent was re-
moved in vacuo, and the residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc, 500:1) to
give 3a (105 mg, 93%) as a white solid.
10.7809(8) Å, c = 15.4960(12) Å, α = 87.2820(10)°, β =
3
¯
89.996(2)°, γ = 85.610(2)°, V = 1629.3(2) Å ; space group: P1;
Z = 2; Dcalcd. = 1.155 gcm–3; F(000) = 604; R1 = 0.0604, wR2
= 0.1428. Diffractometer: Rigaku AFC7R.
CCDC-710597 (for 3a), -721041 (for 3p), and -733543 (for 3q) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[9] Crystal data for 3p (CCDC-721041): Empirical formula:
C42H40O; Fw: 560.74; crystal size: 0.350ϫ0.313ϫ0.187; crys-
tal color, habit: colorless, prismatic; crystal system: monoclinic;
lattice type: primitive; lattice parameters: a = 10.4101(9) Å, b
= 26.298(2) Å, c = 11.7200(10) Å, α = 90°, β = 91.473(2)°, γ =
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for 2a–d and
3a–q.
90°, V = 3207.5(5) Å3; space group: P21/c; Z = 4; Dcalcd.
=
1.161 gcm–3; F(000) = 1200; R1 = 0.0528, wR2 = 0.0960. Dif-
fractometer: Rigaku AFC7R.
[10] Crystal data for 3q (CCDC-733543): Empirical formula:
C44H40; Fw: 568.76; crystal size: 0.408ϫ0357ϫ0.211; crystal
color, habit: colorless, prismatic; crystal system: triclinic; lattice
type: primitive; lattice parameters: a = 10.5111(10) Å, b =
Acknowledgments
We thank the Shanghai Municipal Committee of Science and Tech-
nology (06XD14005 and 08dj1400100–2), National Basic Research
Program of China ((973)-2009CB825300), and the National Natu-
ral Science Foundation of China for financial support (20872162,
20672127, 20872162, 20821002, and 20732008). Mr. Jie Sun is
thanked for performing the X-ray analysis.
11.6798(12) Å,
c = 14.4855(15) Å, α = 85.297(2)°, β =
3
¯
71.728(2)°, γ = 83.183(2)°, V = 1674.9(3) Å ; space group: P1;
Z = 2; Dcalcd. = 1.128 gcm–3; F(000) = 608; R1 = 0.0540, wR2
= 0.1282. Diffractometer: Rigaku AFC7R.
Received: June 16, 2009
Published Online: July 10, 2009
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Eur. J. Org. Chem. 2009, 4036–4040