Published on Web 02/10/2007
The Participation of Alkynylboronates in Inverse Electron
Demand [4 + 2] Cycloadditions: A Mechanistic Study
Enrique Gomez-Bengoa,*,† Matthew D. Helm, Andrew Plant, and
‡
§
Joseph P. A. Harrity*,‡
Departamento de Qu ´ı mica Org a´ nica I, Facultad de Qu ´ı mica, UniVersidad del Pa ´ı s Vasco,
San Sebastian, Spain, Department of Chemistry, UniVersity of Sheffield, Sheffield, S3 7HF,
United Kingdom, and Research Chemistry, Syngenta, Jealott’s Hill International Research
Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
Abstract: The participation of alkynylboronates in [4 + 2] cycloadditions has been investigated using both
kinetic and DFT studies. Kinetic studies of the cycloaddition of tetrazine 1 with alkynylboronate 2 strongly
suggest that a concerted cycloaddition mechanism is in operation. This mechanism has been confirmed
by DFT calculations; moreover, a highly synchronous transition state appears to operate in this process.
The experimentally observed poor reactivity of electron-rich dienes with alkynylboronates has also been
confirmed by theoretical studies by analyzing the transition states of the cycloadditions with bis-2,5-
trimethylsilyloxyfuran. The surprising conclusion has been made that alkynylboronates are relatively electron
rich and have a cycloaddition reactivity that resembles that of acetylene. In contrast, the related
dichloroalkynylborane cycloaddition reactivity resembles that of dimethylacetylene dicarboxylate.
aromatic boronic ester intermediates,6a,b we ultimately sought
to obviate the requirement for a stoichiometric organotransition
Introduction
Aromatic and heteroaromatic boronic acids and esters rep-
resent one of the most heavily utlilised classes of synthetic
intermediates in recent times. These compounds have tradition-
metal intermediate and attempted to design routes that were
metal-free”. Indeed, we have been able to realize this goal and,
“
1
to-date, have reported three complementary reaction processes
that fulfill the criteria of generating functionalized arylboronates
from simple alkynes in the absence of a transition metal
promoter. Specifically, as outlined in Figure 1, the use of
ally been prepared from appropriate aryl organolithium or
2
3
Grignard reagents; however, a milder Pd-catalyzed variant has
also received significant attention. In addition, the employment
of C-H activation processes toward this class of compounds
has shown promise as it avoids the preparation of a precursor
aromatic halide or triflate. An alternative strategy to these
intermediates that has gained widespread attention of late is the
7
a
8f
7c
cyclopentadienones, tetrazines, and 2-pyrones as diene
components provides direct access to highly functionalized
organoboron intermediates.
4
The reactions highlighted in Figure 1 show an interesting
trend: the alkynylboronates appear to perform as inverse
5
employment of cycloaddition processes of alkynylboronates.
Indeed, this approach has allowed a wide variety of benzenoid-
6,7
based boronic ester intermediates as well as heterocyclic
(
6) For metal mediated/catalyzed routes: (a) Davies, M. W.; Johnson, C. N.;
Harrity, J. P. A. Chem. Commun. 1999, 2107. (b) Davies, M. W.; Johnson,
C. N.; and Harrity, J. P. A. J. Org. Chem. 2001, 66, 3525. (c) Ester, C.;
Maderna, A.; Pritzkow, H.; Siebert, W. Eur. J. Inorg. Chem. 2000, 1177.
(d) Hilt, G.; Smolko, K. I. Angew. Chem., Int. Ed. 2003, 42, 2795. (e) Hilt,
G.; Luers, S.; Smolko, K. I. Org. Lett. 2005, 7, 251. (f) Hilt, G.; Hess, W.;
Schmidt, F. Eur. J. Org. Chem. 2005, 2526. (g) Yamamoto, Y.; Ishii, J.-i.;
Nishiyama, H.;Itoh, K. J. Am. Chem. Soc. 2004, 126, 3712. (h) Yamamoto,
Y.; Ishii, J.-i.; Nishiyama, H.; Itoh, K. Tetrahedron 2005, 61, 11501. (i)
Yamamoto, Y.; Hattori, K.; Ishii, J.-i.; Nishiyama, H. Tetrahedron 2006,
8
variants to become available from relatively simple starting
materials.
Although our preliminary studies focused on a Cr-mediated
benzannulation process for the synthesis of functionalized
†
Universidad del Pa ´ı s Vasco.
University of Sheffield.
Jealott’s Hill International Research Centre.
‡
62, 4294. (j) Gandon, V.; Leca, D.; Aechtner, T.; Vollhardt, K. P. C.;
§
Malacria, M.; Aubert, C. Org. Lett. 2004, 6, 3405. (k) Gandon, V.; Leboeuf,
D.; Amslinger, S.; Vollhardt, K. P. C.; Malacria, M.; Aubert, C. Angew.
Chem., Int. Ed. 2005, 44, 7114.
(
1) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005.
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H.; Santucci, L.; Swayampati, D. R.; Ranck, R. D. J. Am. Chem. Soc. 1957,
(
(7) For metal-free variants: (a) Moore, J. E.; York, M.; Harrity, J. P. A. Synlett
2005, 860. (b) Sato, S.; Isobe, H.; Tanaka, T.; Ushijima, T.; Nakamura, E.
Tetrahedron 2005, 61, 11449. (c) Delaney, P. M.; Moore, J. E.; Harrity, J.
P. A. Chem. Commun. 2006, 3323.
(8) (a) Bianchi, G.; Cogoli, A.; Gr u¨ nanger, P. J. Organomet. Chem. 1966, 6,
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7
9, 3077. (c) Wong, K. T.; Chien, Y. Y.; Liao, Y. L.; Lin, C. C.; Chou, M.
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(
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10.1021/ja068527k CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 2691-2699
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