NbCl3-catalyzed [2+2+2] intermolecular cycloaddition of alkynes and alkenes to 1,3-cyclohexadiene derivatives

Article abstract of DOI:10.1039/b820352k

NbCl₃(DME)-catalyzed [2+2+2] intermolecular cycloaddition of alkynes and alkenes was successfully achieved to give 1,4,5-trisubstituted-1,3- cyclohexadiene derivatives in good yields. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b820352k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
NbCl3-catalyzed [2+2+2] intermolecular cycloaddition of alkynes and alkenes
to 1,3-cyclohexadiene derivatives†
Yasushi Obora,* Keisuke Takeshita and Yasutaka Ishii*
Received 13th November 2008, Accepted 26th November 2008
First published as an Advance Article on the web 8th December 2008
DOI: 10.1039/b820352k
NbCl3(DME)-catalyzed [2+2+2] intermolecular cycloaddi-
tion of alkynes and alkenes was successfully achieved to give
1,4,5-trisubstituted-1,3-cyclohexadiene derivatives in good
yields.
5-butyl-1,3-cyclohexadiene (4aa as 1,3,5-adduct) along with a
small amount of tri-tert-butylbenzenes (5a)10 in 72% total yield
(entry 1).‡ It is noteworthy that the 2:1 cross-cyclotrimerization
of 1a and 2a by the Nb complex was selectively catalyzed in
preference to the cyclotrimerization of 2a, which takes place very
easily, to give 1,3-cyclohexadienes (3aa + 4aa) in 83% selectivity.
The reaction also proceeded with high regioselectivity to afford the
1,4,5-adduct (3aa) as a major product (3aa : 4aa = 88 : 12). The
regiostructures of the cycloaddition products (3aa and 4aa) were
characterized by 1H and 13C NMR, the resonances being assigned
by means of 2D HMQC, HMBC, and NOESY spectroscopy
(see ESI†).
Improvement of the yield and the selectivity of the 3aa was
attained by controlling the reaction conditions. Thus, the best
yield and selectivity of 3aa was achieved when the reaction of 1a
and 2a was carried out with a 1:1 ratio (entry 1). However, when
1a and 2a were allowed to react in a stoichiometric ratio (namely
2 : 1), the yield and selectivity of the intermolecular cycloaddition
products (3aa and 4aa) were still high to moderate (entry 2).
The reaction was greatly affected by the solvent em-
ployed, and halogenated solvents such as 1,2-dichloroethane or
dichloromethane resulted in a high selectivity for 3aa (entries 1–
3). The use of other solvents such as THF, dioxane, toluene and
DME resulted in lower yields of 3aa (entries 4–7).
Transition metal-catalyzed cyclotrimerization of alkynes has been
extensively studied and provides a useful method for the syn-
thesis of aromatic compounds.1 In contrast, there have been
limited work on the intermolecular cycloaddition of alkynes and
alkenes because of the difficulty in controlling the chemo- and
regioselectivity.2,3
In 1993, Rothwell and coworkers reported the intermolec-
ular cycloaddition reaction of alkynes and alkenes to afford
1,3-cyclohexadienes by using a titanacyclopentadiene catalyst,3
although this approach is remains problematic with regard to
the yields and selectivity of the formation of 1,3-cyclohexadiene
adducts. In addition, this method typically includes an isomeriza-
tion step, which results in isomerized 1,3-cyclohexadiene adducts.3
As an alternative, low-valent niobium compounds are thermally
stable and have been utilized as reagents as well as catalysts
in several organic transformations.4–7 We have recently reported
several Nb(III)-mediated reactions with electrophiles.4 Low-valent
niobium and tantalum are also known to function as catalysts for
the cyclotrimerization of alkynes.8
As for the catalyst precursor of this reaction, the low-valent
Nb(III) complex, NbCl3(DME), is highly efficient. When the
Ta(III) analog, TaCl3(DME), was used as a catalyst, preferential
formations of the alkyne cyclotrimerization products (5a) (33%
yield) as well as the dimerization product, 1,4-di-tert-butyl-1-
buten-3-yne (9% yield), were observed, but the desired 1,3-cyclo-
hexadiene adduct was not produced at all (entry 8). Other Nb(IV),
Nb(V) and V(III) complexes such as NbCl5, Cp2NbCl2 and
VCl3(THF)3, were totally inactive as catalysts, and no cycloaddi-
tion products (3aa, 4aa, or 5aa) were formed at all (entries 9–11).
Under the optimized condition as shown in Table 1, entry 1,
reactions of various 1-alkynes (1a–d) with 1-alkenes (2b–2g) were
examined (Table 2). The selectivity of the adducts was greatly
influenced by the bulkiness of substituents both on the alkynes
and alkenes. The reaction of 1a with 2b or 1-decene (2c) led to
the corresponding intermolecular cycloaddition products, 1,4-di-
tert-butyl-5-hexyl-1,3-cyclohexadiene (3ab) or 1,4-di-tert-butyl-
5-octyl-1,3-cyclohexadiene (3ac), respectively, with high chemo-
(81–83%) and regioselectivities (91%) (entries 1–2). The best
result for the formation of 1,3-cyclohexadiene was obtained in
the reaction of 1a with ethylene (2d), which afforded 1,4-di-tert-
butyl-1,3-cyclohexadiene (3ad) in high yield (with 97% selectivity)
(entry 3). The proximal substituents on the double bond of alkenes
were found to decrease of the 1,3-cyclohexadienes (entries 4–7).
In this study, we found that a commercially available and
thermally stable low-valent Nb(III) compound, NbCl3(DME),5a
serves as an efficient catalyst for the [2+2+2] intermolecular
cycloaddition of terminal alkynes with alkenes, afford 1,4,5-
trisubstituted-1,3-cyclohexadiene derivatives as the major prod-
ucts in good yield and selectivity. This reaction involves the
unprecedented use of low-valent niobium(III) as the catalyst
in an organic transformation, as well as providing an efficient
and selective route to synthetically useful 1,3-cyclohexadiene
derivatives.9
tert-Butylacetylene (1a) and 1-hexene (2a) were chosen as
model substrates, and the reaction was carried out under various
conditions (Table 1). For instance, a mixture of 1a (2 mmol) and
2a (2 mmol) in dichloroethane (1 mL) was allowed to react under
the influence of a catalytic amount of NbCl3(DME) (10 mol%)
at 40 ◦C for 4 h, giving a mixture of 1,4-di-tert-butyl-5-butyl-
1,3-cyclohexadiene (3aa as 1,4,5-adduct) and 1,3-di-tert-butyl-
Department of Chemistry and Materials Engineering, Faculty of Chem-
istry, Materials and Bioengineering, Kansai University, Suita, Osaka,
564-8680, Japan. E-mail: obora@ipcku.kansai-u.ac.jp, ishii@ipcku.kansai-
u.ac.jp; Fax: +81-6-6339-4026; Tel: +81-6-6368-0876
† Electronic supplementary information (ESI) available: Characterization
data (1H and 13C NMR and MS) and other spectral data (1H–13C HMQC,
HMBC and NOESY) of the products. See DOI: 10.1039/b820352k
428 | Org. Biomol. Chem., 2009, 7, 428–431
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Table 1 NbCl3-catalyzed reaction of tert-butyl acetylene (1a) with 1-hexene (2a)a
Total yield
Selectivity for 1,3-cyclohexadienes
Entry
Catalyst
Solvent
(3aa–5aa)/%b
(3aa+4aa)/%c
1
2d
3
4
5
6
7
NbCl3(DME)
NbCl3(DME)
NbCl3(DME)
NbCl3(DME)
NbCl3(DME)
NbCl3(DME)
NbCl3(DME)
TaCl3(DME)
NbCl5
Cl(CH2)2Cl
Cl(CH2)2Cl
CH2Cl2
THF
Dioxane
Toluene
DME
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
72 [67]
83 (88)
70 (86)
79 (90)
22 (8)
36 (23)
47 (72)
—
0
—
—
—
66
71
45
64
3
0
33
0
8e
9f
10
11
Cp2NbCl2
VCl3(THF)3
0
0
a 1a (2 mmol) was allowed to react with 2a (2 mmol) in the presence of catalyst (0.2 mmol, 10 mol% based on 1a) in solvent (1 mL) at 40 ◦C for 4 h.
b Yields were determined based on 1a used. The number in brackets is an isolated yield. c Determined by GC. The numbers in the parentheses show the
selectivity (%) for 3aa. d 1a (2 mmol) and 2a (1 mmol) were used. e 1,4-Di-tert-butyl-1-buten-3-yne was obtained as a by-product (9%). f A intractable
mixture of unidentified oligomerization products was obtained.
Table 2 NbCl3-catalyzed reaction of terminal alkynes (1) with 1-alkenes (2)a
Total yield
Selectivity for 1,3-
Entry
R1 (alkyne)
R2 (alkene)
(3–5)/%b
cyclohexadienes 3+4/%c
1
2
3
4
5
6
7
8
9
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
Ph (1b)
n-C6H13 (2b)
n-C8H17 (2c)
H (2d)d
C2H5C(CH3)2CH2 (2e)
PhCH2 (2f)
Ph (2g)
70 [68]
75 [72]
78
45
54
67 [67]
63
73
72
74
83 (91)
81 (91)
97 (98)
49 (84)
67 (86)
55 (83)
60 (83)
8 (100)
18 (100)
5 (100)
45 (91)
36 (100)
4-CH3C6H4 (2h)
n-C4H9 (2a)
n-C4H9 (2a)
n-C4H9 (2a)
H (2d)c
c-Hex (1c)
Hex (1d)
Ph (1b)
10
11
12
56
58
Hex (1d)
H (2d)c
a 1 (2 mmol) was allowed to react with 2 (2 mmol) in the presence of NbCl3(DME) (0.2 mmol, 10 mol% based on 1) in dichloroethane (1 mL) at 40 ◦C
for 4 h. b Yields were determined based on 1 used. The numbers in brackets are the isolated yields. c Selectivity (%) of 1,3-cyclohexadienes (3+4) was
determined by GC. The numbers in the parentheses show the selectivity (%) of 3. d 2d (2 MPa) was used by using a 50 mL stainless steel autoclave.
The use of phenylacetylene (1b), cyclohexylacetylene (1c), and
hexylacetylene (1d) as alkynes resulted in a lower selectivity for 3
and 4. In these cases, formation of the alkyne cyclotrimerization
products (5) was unavoidable (entries 8–10). However, the selec-
tivity for the 1,3-cyclohexadienes (3 and 4) in the reaction of 1b
and 1d was improved when ethylene (2d) was used (entries 11–12).
It was reported by Rothwell and coworkers that the Ti-
catalyzed intermolecular cycloaddition of alkynes and alkenes
gave isomerized 1,3-cyclohexadienes as major products,3 which
are formed through the 1,5-hydrogen shift11 within the initially
produced titananorbornene intermediate. This is in sharp contrast
to our Nb(III)-catalyzed reaction, which did not involve such
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an isomerization pathway. For instance, the reactions of 1a with
2d gave 1,4-di-tert-butyl-1,3-cyclohexadiene12 (3ad) as the major
adduct in the present system (see entry 3, Table 2), but afforded 2,6-
di-tert-butyl-1,3-cyclohexadiene as a major adduct by Rothwell’s
method. Similarly, the reaction of 1a with 2g gave a mixture
of 1,4-di-tert-butyl-5-phenyl-1,3-cyclohexadiene (3ag) and 1,3-
di-tert-butyl-5-phenyl-1,3-cyclohexadiene (4ag) in our system,
but afforded 2,6-di-tert-butyl-4-phenyl-1,3-cyclohexadiene as the
major adduct by Rothwell’s method.
ably due to a relatively thermally stable niobanorbornene
intermediate.14
In conclusion, we have developed a new highly active cat-
alytic system for selective [2+2+2] cycloaddition of alkynes and
alkenes. Further investigation with regard to the detailed reaction
mechanism and the application of this reaction is currently in
progress.
This reaction can be successfully extended to the reaction of
1a and norbornylene 6 under the optimized reaction condition to
give the cycloaddition product (7) in the exo,exo form13 in 67%
yield, along with the formation of 5a (11%) (Scheme 1).
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan, “High-Tech Research Center” Project for
Private Universities: matching fund subsidy from the Ministry of
Education, Culture, Sports, Science and Technology, 2005–2009.
Notes and references
‡ A typical reaction procedure is as follows (Table 1, entry 1): A mixture
of 1a (2 mmol, 164 mg), 2a (2 mmol, 168 mg), NbCl3(DME) (0.2 mmol,
58 mg), and 1,2-dichloroethane (1 mL) was stirred for 4 h at 40 ◦C under
Ar. The yields of the products were estimated from the peak areas based on
the internal standard technique using GC (53% (3aa), 7% (4aa) and 12%
(5a)). The products were isolated as a mixture of 3aa, 4aa and 5a (by silica
gel column chromatography using n-hexane as eluent) due to the difficulty
in completely separating them.
Scheme 1
Although it is not possible to confirm a detailed reaction
mechanism at this stage, the cycloaddition of alkynes with alkenes
is thought to proceed in a similar way to the previously reported
Ta-7,1b and Ti- catalyzed cycloaddition3 with alkynes via the
formation of a metallacyclopentadiene as a key intermediate.
Thus, a plausible reaction pathway is shown in Scheme 2.
This reaction would be considered to proceed through a niobacy-
clopentadiene intermediate A formed by the oxidative cyclization
of two alkyne molecules on the low-valent niobium catalyst.
When bulky substituents such as tert-Bu are present on the
niobacyclopentadiene, the attack of (sterically less congested)
olefins upon A might take place preferentially to afford a
niobanorbornene intermediate B, resulting in 1,3-cyclohexadienes
(3 and 4) as the major products (path a). On the other hand,
less bulky alkynes lead to the formation of cyclotrimerization
products through competing attack of a third alkyne upon A to
form niobanorbornadiene C (path b).
1 (a) K. P. C. Vollhardt, Angew. Chem. Int. Ed., 1984, 23, 539; (b) N. E.
Schore, Chem. Rev., 1988, 88, 1081; (c) M. Lautens, W. Klute and W.
Tam, Chem. Rev., 1996, 96, 49; (d) E. Negishi, C. Coperet, S. Ma,
S.-Y. Liou and F. Liu, Chem. Rev., 1996, 96, 365; (e) I. Ojima, M.
Tzamarioudaki, Z. Li and R. J. Donovan, Chem. Rev., 1996, 96, 635;
(f) S. Saito and Y. Yamamoto, Chem. Rev., 2000, 100, 2901; (g) V.
Cadierno, S. E. Garcia-Garrido and J. Gimeno, J. Am. Chem. Soc.,
2006, 128, 15094. and references therein.
2 Examples of cycloaddition of diynes with alkenes, see: (a) Z. Zhou,
L. P. Battaglia, G. P. Chiusoli, M. Costa, M. Nardelli, C. Pelizzi and G.
Predieri, J. Chem. Soc. Chem. Commun., 1990, 1632; (b) Z. Zhou, M.
Costa and G. P. Chiusoli, J. Chem. Soc. Perkin Trans. 1, 1992, 1399; (c) Y.
Yamamoto, H. Kitahara, R. Ogawa and K. Itoh, J. Org. Chem., 1998,
63, 9610; (d) Y. Yamamoto, H. Kitahara, R. Ogawa, H. Kawaguchi, K.
Tatsumi and K. Itoh, J. Am. Chem. Soc., 2000, 122, 4310; (e) R. Grigg,
R. Scott and P. Stevenson, J. Chem. Soc. Perkin Trans. 1, 1988, 1365;
(f) T. Tsuda, H. Mizuno, A. Takeda and A. Tobisawa, Organometallics,
1997, 16, 932.
3 (a) G. J. Balaich and I. P. Rothwell, J. Am. Chem. Soc., 1993, 115, 1581;
(b) E. S. Johnson, G. J. Balaich and I. P. Rothwell, J. Am. Chem. Soc.,
1997, 119, 7685.
4 (a) Y. Obora, M. Kimura, M. Tokunaga and Y. Tsuji, Chem. Commun.,
2005, 901; (b) Y. Obora, M. Kimura, T. Ohtake, M. Tokunaga and Y.
Tsuji, Organometallics, 2006, 25, 2097.
5 (a) E. J. Roskamp and S. F. Pedersen, J. Am. Chem. Soc, 1987, 109,
6551; (b) J. B. Hartung and S. F. Pedersen, J. Am. Chem. Soc., 111, 5468;
(c) E. J. Roskamp, P. S. Dragovich, J. B. Hartung and S. F. Pedersen,
J. Org. Chem., 1989, 54, 4736; (d) J. B. Hartung and S. F. Pedersen,
Organometallics, 1990, 9, 1414.
6 (a) Y. Kataoka, J. Miyai, K. Oshima, K. Takai and K. Utimoto, J. Org.
Chem., 1992, 57, 1973; (b) Y. Kataoka, K. Takai, K. Oshima and K.
Utimoto, Tetrahedron Lett., 1990, 31, 365; (c) Y. Kataoka, J. Miyai, M.
Tezuka and T. Takai, Tetrahedron Lett., 1990, 31, 369; (d) A. Fu¨rstner,
A. Hupperts, A. Ptock and E. Janssen, J. Org. Chem., 1994, 59, 5215;
(e) J. Szymoniak, J. Besanc¸on and C. Mo¨ıse, Tetrahedron, 1992, 48,
3867.
7 (a) K. Fuchibe, K. Mitomi, R. Suzuki and T. Akiyama, Chem. Asian J.,
2008, 3, 261; (b) K. Fuchibe, Y. Oshima, K. Mitomi and T. Akiyama,
Org. Lett., 2007, 9, 1497; (c) K. Fuchibe, K. Mitomi and T. Akiyama,
Chem. Lett., 2007, 36, 24; (d) K. Fuchibe and T. Akiyama, J. Am. Chem.
Soc., 2006, 128, 1434.
Scheme 2 A plausible reaction pathway.
Unlike the Ti-catalyzed system,3 the present Nb-catalyzed
reaction did not involve an isomerization step, which is prob-
430 | Org. Biomol. Chem., 2009, 7, 428–431
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8 (a) T. Oshiki, H. Nomoto, K. Tanaka and K. Takai, Bull. Chem. Soc.
Jpn., 2004, 77, 1009; (b) J. A. K. Du Olessis, J. S. Viljoen and C. J. Du
Toit, J. Mol. Cat., 1991, 64, 269.
9 (a) W. H. Okamura and A. R. De Lera, In Comprehensive Organic
Synthesis, B. M. Trost and I. Fleming, Eds.; Pergamon Press, New
York, 1991; Vol 5, Chapter 6.2; (b) F. Fringuelli and A. Taticchi, Dienes
in the Diels–Alder Reaction, John Wiley, New York, 1990; (c) H. J. C.
Jacobs and E. Havinga, Adv. Photochem., 1979, 11, 305; (d) Organic
Reactions, L. A. Paquette, Ed.; John Wiley, New York, 1992; Vol. 42,
pp 1-334.
11 (a) W. Lamanna and M. Brookhart, J. Am. Chem. Soc., 1980, 102,
3490; (b) K. J. Karel, M. Brookhart and R. Aumann, J. Am. Chem.
Soc., 1981, 103, 2695; (c) M. B. Fischer, E. J. James, T. J. McNeese, S. C.
Nyburg, B. Posin, W. Wong-Ng and S. S. Wreford, J. Am. Chem. Soc.,
1980, 102, 4941.
12 J. F. Outlaw, J. R. Cozort, N. Garti and S. Siegel, J. Org. Chem., 1983,
48, 4186.
13 D. C. Craig, A. M. Oliver and M. N. Paddon-Row, J. Chem. Soc. Perkin
Trans 1, 1993, 197.
14 V. M. Visciglio, J. R. Clark, M. T. Nguyen, D. R. Mulford,
P. E. Fanwick and I. P. Rothwell, J. Am. Chem. Soc., 1997, 119,
3490.
10 5a was obtained as a mixture of 1,3,5- and 1,2,4-tri-tert-butylacetylene
in a 54:46 ratio.
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