[2 + 2 + 1] cycloaddition between alkynes, acrylates, and titanocene(II): Regioselective formation of 5-alkoxycarbonyltitanacyclopent-2-enes and their addition to carbonyls

Article abstract of DOI:10.1246/cl.2010.723

5-Alkoxycarbonyltitanacyclopent-2-enes were produced regioselectively by the [2 + 2 + 1 ] cycloaddition between alkynes, acrylates, and titanocene(II) reagent Cp2Ti[P(OEt)₃]₂. Although the titanacycles were inactive toward carbonyl compounds, their addition proceeded in the presence of titanocene(II).

Full text of DOI:10.1246/cl.2010.723

doi:10.1246/cl.2010.723
Published on the web June 5, 2010
723
[2 + 2 + 1] Cycloaddition between Alkynes, Acrylates, and Titanocene(II):
Regioselective Formation of 5-Alkoxycarbonyltitanacyclopent-2-enes
and Their Addition to Carbonyls
Shigeki Oishi, Kaoru Ohomika, Akira Tsubouchi, and Takeshi Takeda*
Department of Applied Chemistry, Graduate School of Engineering,
Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588
(Received April 16, 2010; CL-100373; E-mail: takeda-t@cc.tuat.ac.jp)
5-Alkoxycarbonyltitanacyclopent-2-enes were produced
regioselectively by the [2 + 2 + 1] cycloaddition between
alkynes, acrylates, and titanocene(II) reagent Cp2Ti[P(OEt)3]2.
Although the titanacycles were inactive toward carbonyl
compounds, their addition proceeded in the presence of
titanocene(II).
Five-membered metallacycles of group 4 metals play
important roles in organic synthesis. For instance, metalla-
cyclopentadienes are utilized for the synthesis of biologically
active compounds1a-1c and organic functional materials such as
acenes1d-1f and ³-conjugated polymers.1g Therefore, the eluci-
dation of their structures and reactivities is significant in early-
transition-metal chemistry, and much effort has focused on the
preparation and isolation of five-membered group 4 metallocene
complexes such as metallacyclopentanes,2 -pent-3-enes,3 -pen-
tadienes,4 -pentynes,5 and -pentatrienes.6 As for the construction
of titanacyclopent-2-enes, a variety of protocols have been
disclosed.7 They include the ring enlargement of a titana[3]-
radialene,7a dimerization of a titanacyclocumulene,7b and the
[2 + 2 + 1] cycloaddition of alkynes, alkenes, and divalent
titanium species.7c-7f Although the third approach is apparently
most versatile and straightforward, only ethylene7c,7d and some
symmetric strained olefins have been employed.7e,7f
Scheme 1.
Our group is studying the formation of titanacycles by
[2 + 2]8 and [2 + 2 + 1]9 cycloadditions and their application
to organic synthesis. The [2 + 2 + 1] process between alkynes,
alkenes bearing a leaving group such as vinyl pivalate and
alkenyl sulfones, and titanocene(II)-triethyl phosphite complex
affords titanacyclopentenes bearing a leaving group ¢ to
titanium as transient intermediates. Simultaneous ¢-elimination
produces dienyltitaniums. This finding prompted us to pursue an
alternative regioselective mode of formation of functionalized
titanacyclopentenes. We describe here the regioselective for-
mation of 5-alkoxycarbonyltitanacyclopent-2-enes 1 by the
[2 + 2 + 1] cycloaddition between alkynes 2, acrylates 3, and
titanocene(II) reagent Cp2Ti[P(OEt)3]2 4 and their reactivity as
enolate equivalents (Scheme 1).
The treatment of diphenylacetylene (2a) with tert-butyl
acrylate (3a) in THF at 25 °C for 3 h in the presence of
titanocene(II) reagent 4 produced the titanacyclopent-2-ene 1a
with perfect regioselectivity. Although 1a was found to be
susceptible to both air and moisture, it could be isolated as a
dark red powder in 61% yield by alumina column chromatog-
raphy under N2. The molecular structure of 1a was unambig-
uously determined by X-ray diffraction analysis (Figure 1).10
The bond lengths of Ti-C1 and Ti-C4 are in the typical region,7b
Figure 1. The ORTEP view of molecular structure of 1a.
Selected bond distances (¡) and angles (°): Ti1-C1 2.178(3),
Ti1-C4 2.238(3), C1-C2 1.348(5), C2-C3 1.517(4), C3-C4
1.530(5); C1-Ti1-C4 79.23(12), Ti1-C1-C2 113.1(2), C1-C2-
C3 119.4(3), C2-C3-C4 110.8(3), C3-C4-Ti1 105.4(2).
and the structure further shows the expected C-C bond lengths
of a five-membered ring.
The metallacycle 1a showed interesting reactivity toward
carbonyl compounds.11 The titanium enolate equivalent 1a was
completely inactive toward ketones and aldehydes 5 even
at elevated temperature (Table 1, Entry 1). By contrast, the
reaction of 1a with carbonyl compounds carried out in the
presence of an equimolar amount of the low-valent titanium
reagent 4 at 25 °C for 2 h gave 2-(hydroxymethyl)alk-4-enoates
6. Thus the successive treatment of 1a with titanocene(II)
reagent 4 (1 equiv) and ketones 5a-5d (2 equiv) produced (Z)-2-
(1-hydroxymethyl)-4,5-diphenylpent-4-enoates 6a-6d in 45-
88% yields (Table 1). Decreasing the loading of 4 to 0.5 equiv
Chem. Lett. 2010, 39, 723-725
© 2010 The Chemical Society of Japan
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724
Table 1. The reaction of titanacyclopentene 1a with carbonyl
compounds 5
Entry
5
R4
R5
6
Yield/%a
1b
2c
3
4
5
5a
5a
5a
5b
5c
5d
5e
-(CH2)2CHPh(CH2)2-
-(CH2)2CHPh(CH2)2-
-(CH2)2CHPh(CH2)2-
6a
6a
6a
6b
6c
6d
6e
0
Scheme 2.
63d
88d
73
gave the 5-(2-thienyl)pent-4-enoate 7e preferentially (Entry 5).
These results might indicate that the regioselectivity of the
formation of titanacyclopenetene 1 is controlled by the coordi-
nation of a heteroatom to titanium.
Based on the above results, the one-pot, three-component
coupling of alkynes 2, acrylates 3, and carbonyl compounds 5
was examined (Scheme 2). After the preparation of 1a by the
reaction of 2a with 3a, the resulting titanacycle 1a was further
treated with pentan-3-one (5b) and the titanocene(II) species 4 to
produce 6b in good yield. A comparable result was also obtained
using 2b as a coupling component.
Et
Et
Ph(CH2)2 Ph(CH2)2
68
45e
72f
6
7
i-Pr
Ph(CH2)2
Me
H
aIsolated yield based on the titanacyclopentene 1a used.
bCarried out without 4 in the presence and absence of MgCl2.
cCarried out with 0.5 equiv of 4. Single isomer. The ratio
of diastereoisomers = 63:37. The ratio of diastereoisomers =
65:35.
d
e
f
In conclusion, we found that the [2 + 2 + 1] cycloaddition
between alkynes, acrylates, and titanocene(II) reagent produced
5-alkoxycarbonyltitanacyclopent-2-enes regioselectively.12 We
have succeeded in the isolation of a monocyclic titanacyclopent-
2-ene and elucidated its molecular structure and unique
reactivity toward carbonyl compounds. Further study on the
regioselective preparation of a variety of functionalized titana-
cyclopentenes and their synthetic application is currently under-
way.
Table 2. The cross-coupling between alkynes 2 and acrylates 3
Entry
2
R1
Ph
R2
Ph
3
R3
3a t-Bu 7a
7
Yield/%a
1
2b
3
4
5
2a
74
64
62c
64c
59c
54
2b Ph(CH2)3 Ph(CH2)3 3a t-Bu 7b
2c
2d
2e 2-Thienyl
2f Ph
Me
Bu
Pent
Ph
Hex
Ph
3a t-Bu 7c
3a t-Bu 7d
3a t-Bu 7e
3b Me 7f
This work was supported by Grant-in-Aid for Scientific
Research (No. 21350026) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
6
aIsolated yield based on alkyne 2 used. bQuenching the
reaction with excess D2O produced the dideuterated ester (C2;
c
93%D, C5; 91%D). The ratios of regioisomers = 62:38 (7c),
References and Notes
80:20 (7d), 82:18 (7e). The structures of major isomers are
given.
1
2
3
a) R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.
Sato, H. Urabe, J. Am. Chem. Soc. 2005, 127, 7774. b) H. A.
Reichard, J. C. Rieger, G. C. Micalizio, Angew. Chem., Int.
Ed. 2008, 47, 7837. c) L. J. Perez, H. L. Shimp, G. C.
Micalizio, J. Org. Chem. 2009, 74, 7211. d) L. Zhou, K.
Nakajima, K. Kanno, T. Takahashi, Tetrahedron Lett. 2009,
50, 2722. e) S. Li, H. Qu, L. Zhou, K. Kanno, Q. Guo, B.
Shen, T. Takahashi, Org. Lett. 2009, 11, 3318. f) Y. Ni, K.
Nakajima, K. Kanno, T. Takahashi, Org. Lett. 2009, 11,
3702. g) K. Atami, T. Kino, W.-M. Zhou, H. Nishiyama, I.
Tomita, Synth. Met. 2009, 159, 949.
a) Z. Xi, R. Hara, T. Takahashi, J. Org. Chem. 1995, 60,
4444. b) T. Takahashi, R. Fischer, Z. Xi, K. Nakajima,
Chem. Lett. 1996, 357. c) S. Mansel, D. Thomas, C. Lefeber,
D. Heller, R. Kempe, W. Baumann, U. Rosenthal, Organo-
metallics 1997, 16, 2886. d) H. Sun, V. V. Burlakov, A.
Spannenberg, W. Baumann, P. Arndt, U. Rosenthal, Organo-
metallics 2001, 20, 5472. e) H. Sun, V. V. Burlakov, A.
Spannenberg, W. Baumann, P. Arndt, U. Rosenthal, Organo-
metallics 2002, 21, 3360. f) T. Beweries, C. Fischer, S. Peitz,
V. V. Burlakov, P. Arndt, W. Baumann, A. Spannenberg, D.
Heller, U. Rosenthal, J. Am. Chem. Soc. 2009, 131, 4463.
a) C. Krüger, G. Müller, in Advances in Organometallic
Chemistry, ed. by F. G. A. Stone, R. West, Academic Press,
resulted in the formation of 6a in 63% yield (Entry 2). Although
we have no experimental evidence for the role of additional
titanocene(II) reagent 4, we tentatively assume that certain
organotitanium species would be formed by the treatment of 1
with 4. The aldehyde 5e also reacted with 1a to produce 6e in
good yield (Entry 7). When unsymmetrical carbonyl compounds
were employed, mixtures of diastereomers were produced
(Entries 6 and 7). The double bond formation in these reactions
was found to be completely stereoselective: the NOE experiment
of all the adducts indicated that two phenyl groups originating
from 2a were completely cis to each other.
The formation of titanacyclopent-2-enes 1 also proceeded
by using various alkynes 2. The titanacycles 1 other than 1a
were too unstable to be isolated and hence transformed into the
unsaturated esters 7 by hydrolysis (Table 2). This suggests that
the unusual stability of 1a is due to the kinetic stabilization
provided by the bulky two Cp rings and C1-phenyl group. When
unsymmetrical alkynes were employed, the interesting regiose-
lectivity was observed. The reaction of 1-phenyl-1-hexyne (2d)
produced the 4-phenylnon-4-enoate 7d as a major product
(Entry 4) whereas the reaction of 1-(2-thienyl)-1-octyne (2e)
Chem. Lett. 2010, 39, 723-725
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

725
London, 1985, Vol. 24, p. 1. b) H. Yasuda, Y. Kajihara, K.
Mashima, K. Lee, A. Nakamura, Chem. Lett. 1981, 519. c)
H. Yasuda, A. Nakamura, Angew. Chem., Int. Ed. Engl.
1987, 26, 723. d) R. Beckhaus, Angew. Chem., Int. Ed. Engl.
1997, 36, 686.
a) J. L. Atwood, W. E. Hunter, H. Alt, M. D. Rausch, J. Am.
Chem. Soc. 1976, 98, 2454. b) W. E. Hunter, J. L. Atwood,
G. Fachinetti, C. Floriani, J. Organomet. Chem. 1981, 204,
67. c) A. Ohff, S. Pulst, C. Lefeber, N. Peulecke, P. Arndt,
V. V. Burlakov, U. Rosenthal, Synlett 1996, 111. d) U.
Rosenthal, V. V. Burlakov, P. Arndt, W. Baumann, A.
Spannenberg, Organometallics 2003, 22, 884.
Shono, T. Nagasawa, T. Inoue, A. Tsubouchi, T. Takeda,
Tetrahedron Lett. 2008, 49, 6426. d) T. Shono, T. Nagasawa,
A. Tsubouchi, K. Noguchi, T. Takeda, Chem. Commun.
2008, 3537.
a) A. Ogata, M. Nemoto, K. Arai, K. Kobayashi, A.
Tsubouch, T. Takeda, Eur. J. Org. Chem. 2006, 878. b) A.
Ogata, M. Nemoto, K. Kobayashi, A. Tsubouchi, T. Takeda,
J. Org. Chem. 2007, 72, 3816. c) A. Ogata, M. Nemoto, K.
Kobayashi, A. Tsubouchi, T. Takeda, Chem.®Eur. J. 2007,
13, 1320. d) A. Ogata, M. Nemoto, Y. Takano, A. Tsubouchi,
T. Takeda, Tetrahedron Lett. 2008, 49, 3071.
9
4
10 Crystal data for titanacyclopent-2-ene 1a: C31H32O2Ti,
Mr = 484.47, 0.50 © 0.01 © 0.01 mm3, monoclinic, P21/c,
a = 7.55713(14), b = 24.3338(4), c = 14.7771(3) ¡, ¢ =
110.7360(10)°, V = 2541.40(8) ¡3, Z = 4, T = 193 K,
D = 1.266 g cm¹3, ®(Cu K¡) = 3.040 mm¹1, Rint = 0.0462,
number of measured/independent reflections = 47169/
4606, R = 0.0469 and wR = 0.1319 (all data). Crystallo-
graphic data reported in this manuscript have been deposited
with Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-760628. Copies of the data
can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge, CB2 1EZ,
U.K.; fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
11 Similar reactivity of titanacyclopentenes, generated by the
intramolecular cyclization of alk-2-en-7-ynoates and alk-2-
en-8-ynoates with (©2-propene)Ti(Oi-Pr)2, reacted with
carbonyl compounds at ¡ to the ester group was reported:
H. Urabe, K. Suzuki, F. Sato, J. Am. Chem. Soc. 1997, 119,
10014.
5
6
N. Suzuki, M. Nishiura, Y. Wakatsuki, Science 2002, 295,
660.
a) S. Pulst, P. Arndt, B. Heller, W. Baumann, R. Kempe, U.
Rosenthal, Angew. Chem., Int. Ed. Engl. 1996, 35, 1112. b)
P.-M. Pellny, F. G. Kirchbauer, V. V. Burlakov, W. Baumann,
A. Spannenberg, U. Rosenthal, J. Am. Chem. Soc. 1999, 121,
8313. c) P.-M. Pellny, V. V. Burlakov, P. Arndt, W.
Baumann, A. Spannenberg, U. Rosenthal, J. Am. Chem.
Soc. 2000, 122, 6317.
a) A. Maercker, A. Groos, Angew. Chem., Int. Ed. Engl.
1996, 35, 210. b) V. V. Burlakov, N. Peulecke, W. Baumann,
A. Spannenberg, R. Kempe, U. Rosenthal, J. Organomet.
Chem. 1997, 536-537, 293. c) K. Sato, Y. Nishihara, S. Huo,
Z. Xi, T. Takahashi, J. Organomet. Chem. 2001, 633, 18. d)
Q. Hu, D. Li, H. Zhang, Z. Xi, Tetrahedron Lett. 2007, 48,
6167. e) V. V. Bhide, M. F. Farona, A. Djebli, W. J. Young,
Organometallics 1990, 9, 1766. f) P. Binger, P. Müller, F.
Langhauser, F. Sandmeyer, P. Philipps, B. Gabor, R. Mynott,
Chem. Ber. 1993, 126, 1541.
7
8
a) T. Takeda, H. Shimokawa, Y. Miyachi, T. Fujiwara, Chem.
Commun. 1997, 1055. b) T. Shono, Y. Hayata, A. Tsubouchi,
T. Takeda, Tetrahedron Lett. 2006, 47, 1257. c) S. Oishi, T.
12 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2010, 39, 723-725
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/