Efficient synthesis of trifluoromethylated cyclopentadienes/fulvenes/ norbornenes from divinyl ketones

Article abstract of DOI:10.1039/c3ob41400k

The synthetic methods of trifluoromethylated cyclopentadienes/fulvenes/ norbornenes have been developed using 3-CF₃-1,4-dien-3-ols as the synthons, which can be easily prepared by the regiospecific 1,2-addition of the Ruppert-Prakash reagent (TMSCF₃) to divinyl ketones. All the reactions are carried out under mild, metal-free conditions to afford the corresponding products in high to excellent yields.

Full text of DOI:10.1039/c3ob41400k

Organic &
Biomolecular Chemistry
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Efficient synthesis of trifluoromethylated
cyclopentadienes/fulvenes/norbornenes from
Cite this: Org. Biomol. Chem., 2013, 11,
6703
divinyl ketones†
Received 8th July 2013,
Accepted 16th August 2013
Xiao Liu, Xianxiu Xu, Ling Pan,* Qian Zhang and Qun Liu*
DOI: 10.1039/c3ob41400k
www.rsc.org/obc
The synthetic methods of trifluoromethylated cyclopentadienes/ method for the synthesis of suitable substrates, such as CF3-
fulvenes/norbornenes have been developed using 3-CF3-1,4-dien- 1,4-dien-3-ols.7–13 In Gassman’s method, the only CF3-1,4-
3-ols as the synthons, which can be easily prepared by the regio- dien-3-ol intermediate ((2E,5E)-3,5-dimethyl-4-(trifluoromethyl)-
specific 1,2-addition of the Ruppert–Prakash reagent (TMSCF3) to hepta-2,5-dien-4-ol) was prepared in a two-step process from
divinyl ketones. All the reactions are carried out under mild, trans-2-butene and ethyl trifluoroacetate and involved the use of
metal-free conditions to afford the corresponding products in 2 equivalents of lithium metal (Scheme 1b).7
high to excellent yields.
The introduction of a CF3 group into a molecule could pro-
foundly modify its properties through alteration of its steric,
electronic and lipophilic characteristics.8 Thus, CF3-containing
compounds have attracted considerable attention in organic
synthesis.9 The introduction of the CF3 group into Cps, which
are useful ligands in organometallic chemistry,10 is an
effective strategy for modulating the physical properties and
chemical reactivities for the substituent effects.11 In 1963 Wilk-
inson and Dickson reported the synthesis of tetrakis(trifluoro-
methyl)cyclopentadienone, prepared by the coupling of
hexafluoro-2-butyne and CO mediated by [Rh(CO)2Cl]2.12 Since
then, several methods for synthesizing CF3-Cps have been
reported13 and the Gassman ligand has been obtained as a
mixture of double-bond isomers.7
Divinyl ketones (DVKs) are important intermediates in [5 + 1]
annulations1,2 and Nazarov cyclizations.3,4 Recently, we have
developed the synthesis of substituted halocyclopentadienes
(halo-Cps) via tandem Nazarov cyclization–halovinylation
sequence of DVKs under Vilsmeier conditions (Scheme 1a).5a
It has been reported that Nazarov cyclization can also be
achieved using 1,4-dien-3-ols to afford Cp derivatives,6 includ-
ing the Gassman ligand (1,2,3,4-tetramethyl-5-(trifluoro-
methyl)cyclopentadiene) synthesized by acid mediated
cyclization of (2E,5E)-3,5-dimethyl-4-(trifluoromethyl)hepta-
2,5-dien-4-ol. Up to now, however, there has been no efficient
As part of our continuing interest in developing useful
synthetic methods using DVKs,1,2,5 combining the utilization
of (trifluoromethyl)trimethylsilane (TMSCF3, the Ruppert–
Prakash reagent),14,15 we herein wish to report the efficient
and direct synthesis of CF3-Cps 4 and CF3-fulvenes 5 starting
from 3-CF3-1,4-dien-3-ols 3, which are easily prepared from
DVKs 1 and Ruppert–Prakash reagent.5 In addition, the syn-
thesis of trifluoromethyl norbornenes 6 through the Diels–
Alder reaction of CF3-Cps 4 with maleimide is also described.
It is known that the reactions of TMSCF3 with enones tend
to give the 1,2-adducts.14,15 Therefore, we began our recent
research by examining the efficiency and regioselectivity of
nucleophilic addition of TMSCF3 to DVKs 1. We were pleased
to find that the 1,2-adducts 2a–2n could be obtained in
high to excellent yields under optimal conditions (Table 1).
For example, ((1E,4E)-1,5-ditolyl-3-(trifluoromethyl)penta-1,4-
dien-3-yloxy)trimethylsilane 2a was obtained in 95% yield
(Table 1, entry 1) upon treatment of a mixture of 1a (2.0 mmol)
and anhydrous NaOAc (2.0 eq.) in anhydrous DMF (2.0 mL) at
Scheme 1 Nazarov cyclizations of divinyl ketones and alcohols.
Department of Chemistry, Northeast Normal University, 5268 Renmin Street,
Changchun, 130024, China. E-mail: panl948@nenu.edu.cn, liuqun@nenu.edu.cn;
Fax: +86-431-85099759; Tel: +86-431-85099759
†Electronic supplementary information (ESI) available: Detailed experimental
procedures, analytical and spectral data for all the new compounds. CCDC
851500 (5b). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3ob41400k
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Table 1 Preparation of 2 and 3
Table 2 Preparation of CF3-Cps 4 and CF3-fulvenes 5
Yield of Yield of
Entry Ar
R
R′
2a (%)
3a (%)
1
2
3
4
5
6
7
8
4-MeC6H4
Ph
3-MeC6H4
4-OMeC6H4 4-OMeC6H4
4-ClC6H4
4-FC6H4
2-FC6H4
4-BrC6H4
4-MeC6H4
Ph
3-MeC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
2a 95
2b 93
2c 94
2d 95
2e 90
2f 89
2g 88
2h 91
2i 85
2j 90
2k 92
2l 89
2m 95
3a 92
3b 93
3c 91
3d 96
3e 95
3f 90
3g 88
3h 89
3i 87
3j 90
3k 88
3l 85
3m 94
3n 88
4-ClC6H4
4-FC6H4
2-FC6H4
4-BrC6H4
9
2,4-Cl2C6H3 2,4-Cl2C6H3
10
11
12
13
14
4-ClC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
Ph
4-BrC6H4
4-MeC6H4
Ph
Me
Ph
Yield of
Yield of
Entry
t (min)
4a (%)
3
Entry
t (min)
5a (%)
4-OMeC6H4 2n 86
a Isolated yields of 2 or 3.
1
2
3
4
5
6
7
8
20
20
30
20
30
35
50
30
80
40
25
25
180
240
4a 83
4b 85
4c 82
4d 79
4e 95
4f 97
4g 95
4h 90
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
1′
2′
3′
4′
5′
6′
7′
8′
50
55
60
50
60
65
85
55
110
70
55
55
30
5a 78
5b 83
5c 80
5d 76
5e 94
5f 84
5g 92
5h 85
room temperature for 5 min with subsequent addition of
TMSCF3 (1.5 eq.) in one portion and stirring for another
15 min. Furthermore, the corresponding CF3-1,4-dien-3-ols
3a–3n were prepared in high to excellent yields by hydrolysis of
2a–2n with aqueous HCl in THF at room temperature for
20–24 h (Table 1). It was noticed that, in the preparation of 2,
no 1,4-adducts could be detected.
9
4i 89
9′
5i 84
10b
11b
12b
13b,c
14c
4j+4j′ 96
4k+4k′ 87
4l+4l′ 92
4m+4m′ 86
4n 83
10′b
11′b
12′b
13′d
5j+5j′ 92
5k+5k′ 81
5l+5l′ 86
5m 84
With the trifluoromethylated 1,4-dien-3-ols 3 at hand, the
transformation of 3 to CF3-Cps 4 was first studied. Treatment
of 3b with p-toluenesulfonic acid (TsOH, 5.0 eq.) in THF at
reflux temperature for 5 h resulted in a symmetry-allowed cycli-
zation to give CF3-Cp 4b in 90% yield. Under identical con-
ditions but at room temperature, the above transformation
required 3 days. Fortunately, it was found that CF3-Cps 4 could
be prepared by the reaction of 3 in the presence of BF3·Et2O
(2.0 eq.) in 1,2-dichloroethane (DCE) at 35 °C (Table 2). As a
result, Cps 4a–4n were obtained in high to excellent yields
(Table 2, entries 1–14). Among them, double-bond isomers of
4j–m/4j′–m′, without further assignment, were obtained from
unsymmetrical 1,4-dien-3-ols 3j–m due to the facile migration
of the endocyclic double bonds.5a,7,16
Encouraged by the above results, we then turned to the one-
pot synthesis of CF3-fulvenes 5 starting from the corres-
ponding 1,4-dien-3-ols 3. Fulvenes are an important class of
cyclic cross-conjugated molecules and have attracted much
attention due to their unique properties in the fields of
organometallic and medicinal chemistry, as well as in organic
synthesis.17,18 Fulvenes are traditionally prepared by base
mediated condensation of Cps with carbonyl compounds, a
method which is typically limited by the availability of suitable
Cps and the regioselectivity of the reaction.19 In addition, to
our knowledge, there has been no report on the synthesis of
CF3-fulvenes.17–22
a Isolated yields of 4 or 5. b Mixture of double bond isomers with the
ratios of 4j–l : 4j′–l′ = 1 : 1; 4m : 4m′ = 3 : 1; 5j : 5j′ = 1 : 1; 5k : 5k′ = 1.5 : 1;
5l : 5l′ = 1.1 : 1. c The reaction was carried out in THF in the presence of
TsOH (5.0 eq.) at reflux temperature. d Synthesized from 4m.
To our delight, it was found that highly functionalized CF3-
fulvenes 5 could be synthesized from 1,4-dien-3-ols 3 directly
by combining the BF3·Et2O-promoted Nazarov cyclization of 3
with subsequent functionalization under Vilsmeier condi-
tions.5a For example, TFM-substituted fulvene 5b was prepared
in 83% yield upon treatment of 3b with BF3·Et2O followed by
addition of DMF and POCl3 (Table 2, entry 2′). Under similar
conditions, the desired CF3-fulvenes 5a and 5c–m were pre-
pared in high to excellent yields (Table 2, entries 1′ and 3′–13′).
1
According to the H NMR and 13C NMR spectra of fulvenes
5, the reactions of 3a–h gave 5a–h as a single isomer (Table 2,
entries 1′–8′).23 Similar to the corresponding CF3-Cps 4, CF3-
fulvenes 5j–l/5j′–l′ were obtained as a mixture of endocyclic
double-bond isomers (Table 2, entries 10′–12′). However, the
single isomer 5m was produced from unsymmetrical 1,4-dien-
3-ol 3m bearing a β-alkyl and a β-aryl substituent, respectively
(Table 2, entry 13′, the configuration of 5m was confirmed by
the 2D 1H–1H NOESY spectrum). In addition, inspection of the
1H NMR spectrum of 5i indicated the formation of two pairs of
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reaction of 3 with maleimide. All the reactions were carried
out under mild, metal-free conditions with high to excellent
yields. Further studies are in progress.
Financial support of this research by the National Natural
Sciences Foundation of China (21072027, 21272034 and
21202015), the Project sponsored by SRF for ROCS, SEM are
greatly acknowledged.
Notes and references
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Scheme 2 Proposed mechanism for formation of 4 and 5.
2 For selected recent reports, see: (a) J. Tan, X. Xu, L. Zhang,
Y. Li and Q. Liu, Angew. Chem., Int. Ed., 2009, 48, 2868;
(b) Y. Li, X. Xu, J. Tan, C. Xia, D. Zhang and Q. Liu, J. Am.
Chem. Soc., 2011, 133, 1775; (c) X. Bi, D. Dong, Q. Liu,
W. Pan, L. Zhao and B. Li, J. Am. Chem. Soc., 2005, 127,
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3 For reviews on Nazarov cyclizations, see: (a) H. Pellissier,
Tetrahedron, 2005, 61, 6479; (b) A. J. Frontier and
C. Collison, Tetrahedron, 2005, 61, 7577; (c) M. A. Tius,
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and A. J. Frontier, ChemCatChem, 2011, 3, 1531.
4 For a recent review on interrupted Nazarov cyclizations,
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atropisomers in the ratio of 1.2 : 1.0 due to the hindered
rotation of the 2-chlorophenyl rings.
On the basis of the above results and related reports,1–5
a possible mechanism for the formation of CF3-Cps 4 and
CF3-fulvenes 5 is proposed in Scheme 2 (with 4b/5b as
an example). The reaction begins with the generation of penta-
dienyl cation I from 1,4-dien-3-ol 3 induced by Lewis acid such
as BF3·Et2O (or BF3·H2O generated in situ).24 Then, cyclization
of I (to give cyclopentenyl cation II) followed by the elimination
of a proton from II leads to CF3-Cps 4.7 Furthermore, the N,N-
dimethylmethanamine intermediate V could be formed from
the reaction of a tautomer of 4 with the Vilsmeier regent
(4→III→IV→V). Finally, further reaction of V under Vilsmeier
conditions and subsequent hydrolysis result in the formation
of fulvenes 5.
The formation of CF3-fulvenes 5 from CF3-Cps 4 was further
supported by the reaction of CF3-Cp 4b under Vilsmeier con-
ditions to give 5b in 95% yield. As another application of CF3-
Cps 4, the reactions of 4a and 4e with maleimide were also
examined. As a result, the Diels–Alder adducts, 1,2-diaryl-4-(tri-
fluoromethyl)norbornene derivatives 6a and 6e were obtained
in excellent yields, respectively (Scheme 3).
In conclusion, a series of trifluoromethylated 1,4-dien-3-ols
3 were successfully synthesized in excellent yields from DVKs 1
and Ruppert–Prakash reagent. The reactions of 3 could lead to
the formation of either CF3-Cps 4 via the BF3·Et2O mediated
Nazarov cyclization or CF3-fulvenes 5 via the cyclofunctionali-
zation, a combination of Nazarov cyclization, followed by
in situ derivatization under Vilsmeier conditions. Additionally,
CF3-norbornenes 6 were also obtained by the Diels–Alder
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Scheme 3 Synthesis of trifluoromethyl norbornenes 6.
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