Preparation of 1,4-dienes by the reaction of titanocene cycloalkenylidenes with 1-alkenes

Article abstract of DOI:10.1016/j.tetlet.2015.04.124

Titanocene cycloalkenylidenes, generated by the reductive titanation of 3-(arylthio)-1-chloro-1-cycloalkenes with titanocene(II)-triethyl phosphite complex, reacted with styrene derivatives to produce (E)-1,4-dienes. Their reaction with vinyl-borane and -

Full text of DOI:10.1016/j.tetlet.2015.04.124

Tetrahedron Letters 56 (2015) 3916–3918
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Tetrahedron Letters
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Preparation of 1,4-dienes by the reaction of titanocene
cycloalkenylidenes with 1-alkenes
⇑
Takeshi Takeda , Yuzo Teramoto, Yuta Inoue, Akira Tsubouchi
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Titanocene cycloalkenylidenes, generated by the reductive titanation of 3-(arylthio)-1-chloro-1-
cycloalkenes with titanocene(II)-triethyl phosphite complex, reacted with styrene derivatives to produce
(E)-1,4-dienes. Their reaction with vinyl-borane and -silane also produced 1-boryl- and silyl-1,4-dienes,
which were transformed into 1-substituted 1,4-dienes through the palladium(0)-catalyzed or copper(I)-
promoted reaction with organic halides.
Received 23 March 2015
Revised 23 April 2015
Accepted 28 April 2015
Available online 6 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dienes
Chloro sulfides
Titanocene(II)
Titanium carbene complexes
1-Alkenes
We have studied the preparation of alkenylcarbene complexes 1
by the reductive titanation of b,
-unsaturated thioacetals,1 1,3-
Cp2Ti
Cp2Ti
c
bis(phenylthio)-1-propene derivatives,2 or 1-chloro-3-(phe-
nylthio)-1-propene derivatives.3 The organometallic reagents 1
are useful for the preparation of di-2 and trienes,4 and alkenylcy-
clopropanes.2 The synthetic application of alkenylcarbene com-
plexes 1, however, is largely restricted by the fact that they exist
in equilibrium with their valence tautomers, titanacyclobutenes 2
(Scheme 1). The position of equilibrium depends on their substitu-
tion pattern,3 and the highly substituted titanium alkenylcarbene
complexes are difficult to utilize as synthetic intermediates.
Since titanocene cycloalkenylidenes exist only as alkenylcar-
bene complexes due to their fixed cisoid conformation, we have
studied their reactivity toward multiple bond compounds. Here
we describe the preparation of 1 by the reductive titanation of 3-
(arylthio)-1-chloro-1-cycloalkenes 3 with titanocene(II)-triethyl
phosphite complex 4 and application of these species for the regio-
and stereoselective preparation of 1,4-dienes 5 by their reaction
with terminal olefins 6 (Scheme 2).
1
2
Scheme 1. Equilibrium between alkenylcarbene complexes 1 and titanacyclobute-
nes 2.
which 8a predominates due to the favorable formation of stable
benzylic carbon–titanium bond (Scheme 3). The following b-hy-
dride elimination with the opening of four-membered metallacy-
cles and reductive elimination of the resulting allyltitanium
species 9 afford the unconjugated and conjugated dienes 5a and
7a, respectively. Unlike the reaction of 3a, the predominant forma-
tion of unconjugated dienes was observed in a similar reaction of
1,3-disubstituted 1-chloro-3-(phenylthio)-1-propenes, acyclic
counterparts of 3a, with styrene.3 The reason for such difference
in product selectivity is not clear at present.
Skipped dienes are important motifs in natural products and
much effort has been devoted to establish efficient routes to these
substructures.5 The major routes include the allylation of alkenyl-
metals5b,e,f,i,l,p,s,w–z and hydrovinylation of 1,3-dienes.5a,g,h,m,n,r
There are, however, limited accesses to such compounds
containing a cycloalkene moiety.6 Then we further investigated
the reaction of titanocene cycloalkenylidenes 1 with terminal ole-
fins 6 to establish a new route to 1,4-dienes. For the selective for-
mation of 5a, the influence of leaving group on the mode of
reaction was examined. The results of the reaction of 1-chlorocy-
The treatment of 1-chloro-3-(phenylthio)-1-cyclohexene (3a)
with the low-valent titanium species 4 (3 equiv) in the presence
of styrene (6a) (4 equiv) at 50 °C for 1 h produced a mixture of
the (E)-1,4-diene 5a and 1,3-diene 7a (5a:7a = 87:13) in 76% yield
(Table 1, entry 1). The formation of two dienes is well explained by
the intermediary regioisomeric titanacyclobutanes 8a and 8b, in
⇑
Corresponding author. Tel./fax: +81 42 388 7034.
E-mail address: takeda-t@cc.tuat.ac.jp (T. Takeda).
clohexenes having
a 4-substituted phenylthio group 3b–d
http://dx.doi.org/10.1016/j.tetlet.2015.04.124
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

T. Takeda et al. / Tetrahedron Letters 56 (2015) 3916–3918
3917
Table 1
Cp2Ti[P(OEt)3]2
n = 1-3
4
ArS
Cl
TiCp2
Reaction of 3-(arylthio)-1-chloro-1-cyclohexenes 3a–g with styrene (6a)a
n
n
3
1
6a
ArS
Cl
Ph
Ph
+
Ph
7a
6
R
R
Cp2Ti[P(OEt)3]2
4
3
5a
5
n
Entry
3
Yieldb (%)
5a:7ac
ArS
Cl
ArS
Cl
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
76
83
74
70
88
80
81
87:13
88:12
91:9
87:13
78:22
99:1
3a
3b
3h
: Ar = Ph
: Ar = 4-MeC6H4
: Ar = 2-pyridyl
3i: Ar = 2-MeC6H4
3c: Ar = 4-MeOC6H4
ArS
Cl
3d
: Ar = 4-ClC6H4
3e: Ar = 2-pyridyl
3f
3g
90:10
: Ar = 2-MeC6H4
3g
a
: Ar = 2,6-(Me)2C6H3
3j: Ar = 2-pyridyl
Carried out at 50 °C for 1 h in THF using chloro sulfide
3
(0.3 mmol),
Cp2Ti[P(OEt)3]2 4 (0.9 mmol), and 6a (1.2 mmol).
b
Isolated yield based on 3 used.
Determined by NMR spectroscopy.
c
6a
6b
2 and 3), a substantial amount of the 1,3-diene 7b was formed
when 4-methoxystyrene (6d) was employed (entry 4).
Furthermore, no selectivity was observed in the reaction of 3f with
1-octene (6e) (entry 5). Similarly to the six-membered congener,
the reaction of five-membered carbene complex generated from
3i with styrene (6a) selectively produced the (E)-1,4-diene 5f
(entry 6).
6c
Bpin
6f
SiBnMe2
OMe
Hex
6e
6g
6d
Scheme 2. Preparation of 1,4-dienes 5 by the reaction of titanocene cycloalkenyli-
denes 1 with 1-alkenes 6.
To overcome the limitation of the above reaction that the highly
selective formation of skipped dienes 5 is observed only in the
reaction of particular substrates, we next examined a diversity-ori-
ented access to 5 which consists of the reaction of carbene com-
plexes 1 with vinylboranes or vinylsilanes and the cross-coupling
between the resulting 1-boryl or silyl-1,4-dienes and organic
halides. As was expected from the results described above, the
reaction of titanocene cyclohexenylidene (1a), generated from 3f,
with sterically demanding vinylboronic acid pinacol ester
(vinylBpin) (6f) and benzyldimethylvinylsilane (6g) produced the
H
H
Ph
Ph
TiCp2
6a
+
TiCp2
TiCp2
8a
1a
8b
TiCp2
H
Ph
Cp2Ti
H
Ph
9a
9b
Table 2
Reaction of 1-chloro-3-(o-tolylthio)-1-cycloalkenes 3 with terminal olefins 6a
Cp
Ti SAr
Cp
- Cp2Ti
- Cp2Ti
Entry
1d
3
6
Products
Yieldb (%) (5:7c)
10
7a
5a
3f 6a
80 (99:1)
Scheme 3. Formation of 1,4- and 1,3-dienes 5a and 7a by the reaction of titanocene
cyclohexenylidene (1a) with styrene (6a).
5a
7a
2e
3e
3f 6b
3f 6c
80
87
5b
5c
indicated that both the electron-donating and electron-withdraw-
ing groups had little effect on the mode of the reaction (entries
2–4). Although the use of 2-pyridylthio group substituted chloro
sulfide 3e improved the yield of dienes, the selectivity for the
formation of unconjugated diene 5a slightly decreased (entry 5).
What is striking is that the reaction of 3f having an o-tolylthio
group selectively furnished the diene 5a (entry 6). In contrast,
the selectivity was not improved when the sulfide bearing a
2,6-dimethylphenylthio group 3g was employed (entry 7).
Although the reason for the arylthio group-dependence of
selectivity observed in the reaction of chloro sulfides 3 with 6a is
not clear at present, we assume that it would be attributable to
the formation of the arylthio group coordinated titanate 10.
Next the scope of the formation of unconjugated dienes 5 was
examined using the o-tolylthio group-containing chloro sulfide 3f
and its five-membered congener 3i, and various terminal olefins
6 (Table 2). Although the reaction of 3f with sterically demanding
2,4-dimethylstyrene (6b) and 1-vinylnaphthalene (6c) produced
the (E)-unconjugated dienes 5b and 5c as sole products (entries
OMe
4e
3f 6d
81 (92:8)
OMe
5d
Hex
7b
5d
6d
3f 6e
3i 6a
85 (50:50)f
69
Hex
5e
7c
5f
a
Carried out at 50 °C for 1 h in THF using chloro sulfide 3 (0.3 mmol) and
Cp2Ti[P(OEt)3]2 4 (0.9 mmol).
b
Isolated yield based on 3 used.
Determined by NMR spectroscopy.
Olefin 6 (1.2 mmol) were used.
c
d
e
Olefin 6 (0.36 mmol) were used.
1H NMR spectrum of the products contained unidentified signals.
f

3918
T. Takeda et al. / Tetrahedron Letters 56 (2015) 3916–3918
aryl halides through the Pd(0)-catalyzed process.8 These alkenylsi-
lanes are also potential substrates for the copper(I)-promoted
cross-coupling with alkyl and allyl halides.5x The advantage of
this approach is clearly shown in Scheme 4; 3-(4-
Table 3
Preparation of 1-boryl- and 1-silyl-1,4-dienesa
Entry
3
6
5
Yieldb (%)
Bpin
Bpin
1c
2c
3c
3f
6f
6f
6f
80
87
64
methoxystyryl)-1-cyclohexene (5d) was obtained as
a sole
5g
product by the two-step process. The stereoselective preparation
of 1,4,7-triene 5n was achieved by the cinnamylation of 5g. The
3e
3h
5g
copper(I)
iodide-promoted
cross-coupling
between
the
5h
5i
alkenylbenzyldimethylsilane 5j and methallyl chloride also
furnished the 1,4,7-triene 5o in good yield. All these results
clearly show the potential utility of 5g–l for diversity-oriented
approach to skipped dienes.
In summary, we have developed a new method for the prepara-
tion of skipped dienes bearing a cycloalkene moiety. It is expected
that the diversity-oriented approach via dienylboranes and dienyl-
silanes described here will become a useful tool for the construc-
tion of highly unsaturated systems.
Bpin
4c
3j
6f
69
SiBnMe2
5d
6d
7d
3f
6g
6g
6g
60e
75e
65
5j
3e
3h
5j
SiBnMe2
SiBnMe2
5k
5l
8d
3j
6g
74e
Supplementary data
a
Carried out at 35 °C for 1 h in THF using chloro sulfide 3 (0.3 mmol) and
Cp2Ti[P(OEt)3]2 4 (0.9 mmol).
b
Supplementary data (experimental procedures and full charac-
terization of chloro sulfides and all products) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2015.04.124.
Isolated yield based on 3 used.
Olefin 6 (1.2 mmol) were used.
Olefin 6 (0.36 mmol) were used.
c
d
e
1H NMR spectrum of the product contained unidentified signals.
References and notes
CN
1. Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J. Am. Chem. Soc. 1997, 119,
1127.
2. Horikawa, Y.; Nomura, T.; Watanabe, M.; Fujiwara, T.; Takeda, T. J. Org. Chem.
1997, 62, 3678.
5m; 81%
3. Shono, T.; Kurashige, R.; Mukaiyama, R.; Tsubouchi, A.; Takeda, T. Chem. Eur. J.
2007, 13, 4074.
5g, Method A
NC
I
4. Takeda, T.; Fukada, T.; Tsubouch, A. Tetrahedron Lett. 2014, 55, 1434.
5. For recent examples, see: (a) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006,
128, 54; (b) Kabalka, G. W.; Al-Masum, M. Org. Lett. 2006, 8, 11; (c) Hilt, G.;
Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500; (d) Kolundzic, F.; Micalizio, G.
C. J. Am. Chem. Soc. 2007, 129, 15112; (e) Lee, Y.; Akiyama, K.; Gillingham, D. G.;
Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 446; (f) Dey, R.;
Chattopadhyay, K.; Ranu, B. C. J. Org. Chem. 2008, 73, 9461; (g) Shimp, H. L.; Hare,
A.; McLaughlin, M.; Micalizio, G. C. Tetrahedron 2008, 64, 3437; (h) Moreau, B.;
Wu, J. Y.; Ritter, T. Org. Lett. 2009, 11, 337; (i) Alacid, E.; Nájera, C. J. Org. Chem.
2009, 74, 2321; (j) Hilt, G.; Treutwein, J. Chem. Commun. 2009, 1395; (k) He, H.;
Liu, W.-B.; Dai, L.-X.; You, S.-L. J. Am. Chem. Soc. 2009, 131, 8346; (l) Akiyama, K.;
Gao, F.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2010, 49, 419; (m) Sharma, R. K.;
RajanBabu, T. V. J. Am. Chem. Soc. 2010, 132, 3295; (n) Arndt, M.; Reinhold, A.;
Hilt, G. J. Org. Chem. 2010, 75, 5203; (o) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L.
Chem. Eur. J. 2010, 16, 7376; (p) Gao, F.; McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J.
Am. Chem. Soc. 2010, 132, 14315; (q) Macklin, T. K.; Micalizio, G. C. Nature Chem.
2010, 2, 638; (r) Arndt, M.; Dindarog˘lu, M.; Schmalz, H.-G.; Hilt, G. Org. Lett.
2011, 13, 6184; (s) Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490; (t)
Stokes, B. J.; Opra, S. M.; Sigman, M. S. J. Am. Chem. Soc. 2012, 134, 11408; (u)
Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2013, 135, 994; (v) Ma,
X.-T.; Wang, Y.; Dai, R.-H.; Liu, C.-R.; Tian, S.-K. J. Org. Chem. 2013, 78, 11071; (w)
Tsubouchi, A.; Muramatsu, D.; Takeda, T. Angew. Chem., Int. Ed. 2013, 52, 12719;
(x) Takeda, T.; Matsumura, R.; Wasa, H.; Tsubouchi, A. Asian J. Org. Chem. 2014, 3,
838; (y) Gao, F.; Carr, J. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2014, 136, 2149; (z)
Takeda, T.; Obata, R.; Muramatsu, D.; Takeda, Y.; Tsubouchi, A. Chem. Commun.
2014, 15156.
Br
OMe MeO
I
Ph
Ph
5g or 5j
5g, Method A
5g, Method A
5d; 84%
5n; 56%
5j, Method B
Cl
5o
; 57%
Method A: Pd(PPh)4, NaOH aq, dioxane, 50 °C, 24 h
Method B: CuI / P(OEt)3, TBAF (tBuOH)4, DMF, 25 °C, 24 h
Scheme 4. Cross-coupling of 1-boryl- and 1-silyl-1,4-dienes 5g and 5j with organic
halides.
(E)-1,4-dienes 5g and 5j with complete regio and stereoselectivity
(Table 3, entries 1 and 5). The yields of the products were increased
by using the 2-pyridylthio group-containing chloro sulfide 3e
(entries 2 and 6). In a similar fashion, five- and seven-membered
homologues were obtained in good yields with perfect selectivity
(entries 3, 4, 7, and 8).
The alkenylboranes 5g–i thus formed were good substrates for
the Suzuki–Miyaura cross-coupling reaction.7 Likewise 1,4-dienes
5j–l bearing a benzyldimethylsilyl group are expected to react with
6. (a) Larock, R. C.; Gong, W. H. J. Org. Chem. 1989, 54, 2047; (b) Luparia, M.; Vadalà,
A.; Zanoni, G.; Vidari, G. Org. Lett. 2006, 8, 2147; (c) Nakao, Y.; Ebata, S.; Chen, J.;
Imanaka, H.; Hiyama, T. Chem. Lett. 2007, 36, 606; (d) Lysenko, I. L.; Kim, K.; Lee,
H. G.; Cha, J. K. J. Am. Chem. Soc. 2008, 130, 15997; (e) Nishimoto, Y.; Kajioka, M.;
Saito, T.; Yasuda, M.; Baba, A. Chem. Commun. 2008, 6496; (f) Yue, H.; Wei, W.;
Li, M.; Yang, Y.; Ji, J. Adv. Synth. Catal. 2011, 353, 3139.
7. Miyaura, N.; Suzuki, M. Chem. Rev. 1995, 95, 2457.
8. Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895.