Reductive Bergman-type cyclizations of cross-conjugated enediynes to fulvene and fulvalene anions: The role of the substituent

Article abstract of DOI:10.1021/ja0566477

Various cross-conjugated enediynes undergo "Bergman-type" cycloaromatizations upon reduction with potassium metal, generating anions of fulvenes and fulvalene derivatives. This new anionic cyclization is considerably more facile than the classic Bergman cyclization with linear enediynes, creating highly reactive diradicals at -78 °C. Not all cross-conjugated enediynes yield cyclized dianions upon reduction; some give uncyclized, Y-shaped, cross-conjugated dianions, while others apparently yield radical-anions that either dimerize or persist as monomers. One system yields both a cyclized and an uncyclized dianion. The substituents are thus shown to be a critical factor in determining the outcome of the reduction. Cyclization occurs within a specific "window of opportunity" that is governed by the substituents.

Full text of DOI:10.1021/ja0566477

Published on Web 03/17/2006
Reductive Bergman-Type Cyclizations of Cross-Conjugated
Enediynes to Fulvene and Fulvalene Anions: The Role of the
Substituent
Noach Treitel,† Lior Eshdat,†,‡ Tuvia Sheradsky,† Patrick M. Donovan,§
Rik R. Tykwinski,| Lawrence T. Scott,§ Henning Hopf, and Mordecai Rabinovitz*,†
Contribution from the Department of Organic Chemistry and The Lise Meitner MinerVa Center
for Computational Chemistry, Safra Campus, The Hebrew UniVersity of Jerusalem, GiVat Ram,
Jerusalem 91904, Israel, Department of Chemistry, UniVersity of Alberta, Edmonton, AB
T6G2G2, Canada, Merkert Chemistry Center, Department of Chemistry, Boston College,
Chestnut Hill, Massachusetts 02467-3860, and Organic Chemistry, Technical UniVersity of
Braunschweig, Hagenring 30 D-38106 Braunschweig, Germany
Received October 12, 2005; E-mail: mordecai@vms.huji.ac.il
Abstract: Various cross-conjugated enediynes undergo “Bergman-type” cycloaromatizations upon reduction
with potassium metal, generating anions of fulvenes and fulvalene derivatives. This new anionic cyclization
is considerably more facile than the classic Bergman cyclization with linear enediynes, creating highly reactive
diradicals at -78 °C. Not all cross-conjugated enediynes yield cyclized dianions upon reduction; some
give uncyclized, Y-shaped, cross-conjugated dianions, while others apparently yield radical-anions that
either dimerize or persist as monomers. One system yields both a cyclized and an uncyclized dianion. The
substituents are thus shown to be a critical factor in determining the outcome of the reduction. Cyclization
occurs within a specific “window of opportunity” that is governed by the substituents.
and molecular wires,11 conjugated polymers,11,12 carbon allot-
Introduction
ropes,12 and radialenes.13 Linear enediynes (1), containing a 1,2-
Recent years have witnessed a considerable surge in the study
of enediyne cyclizations. Many reactions, such as the Bergman,1
Myers-Saito,2 Schmittel3 and Schreiner4 cyclizations bring
about aromatic biradicals, with applications in pharmacology,
as these biradicals or their byproducts5 cause DNA cleavage,
ultimately destroying the DNA of viruses and bacteria. The
antitumor antibiotic drugs calicheamicin γ1,6 dynemicin,7 and
esperamicin A1
intermediates due to Bergman cyclizations, while a Myers-
Saito cyclization is the key step in the mechanism of action of
the antitumor agent neocarzinostatin.9
Additionally, enediynes serve as precursors for bowl-shaped
fullerene fragments10 and as building blocks of dendritic rods
diethynylethylene moiety with six π-electrons, undergo standard
Bergman cycloaromatizations (Scheme 1a). Indeed, this is the
(6) See, for instance: (a) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C.
C.; Morton, G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464. (b)
Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.;
Morton, G. O.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc. 1987,
109, 3466. (c) Magnus, P.; Lewis, R. T.; Huffman, J. C. J. Am. Chem.
Soc. 1988, 110, 6921. (d) Haseltine, J. N.; Danishefsky, S. J. J. Am. Chem.
Soc. 1989, 111, 7638. (e) Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P.
J. Am. Chem. Soc. 1990, 112, 4986. (f) Nicolaou, K. C. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1377. (g) Hitchcock, S. A.; Chu-Moyer, M. Y.;
Boyer, S. H.; Olson, S. H.; Danishefsky, S. J. J. Am. Chem. Soc. 1995,
117, 5750. (h) Thornson, J. S.; Sievers, E. L.; Ahlert, J.; Shepard, E.;
Whitwam, R. E.; Onwueme, K. C.; Ruppen, M. Curr. Pharm. Design 2000,
6, 1841.
(7) For example: (a) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne,
G. D.; Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715. (b) Nicolaou, K. C.;
Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387. (c) Maier, M.
E.; Bosse, F.; Niestroj, A. J. Eur. J. Org. Chem. 1999, 1.
(8) For instance: (a) Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.;
Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.-i.;
Doyle, T. W. J. Am. Chem. Soc. 1987, 109, 3461. (b) Golik, J.; Dubay, G.;
Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.;
Saitoh, K.-i.; Doyle, T. W. J. Am. Chem. Soc. 1987, 109, 3462.
(9) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114,
9369.
(10) Zimmermann, G.; Nu¨chter, U.; Hagen, S.; Nu¨chter, M. Tetrahedron Lett.
1994, 35, 4747.
(11) Schenning, A. P. H. J.; Arndt, J.-D.; Ito, M.; Stoddart, A.; Schreiber, M.;
Siemsen, P.; Martin, R. E.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M.;
Gramlich, V.; Diederich, F. HelV. Chim. Acta 2001, 84, 296 and references
therein.
(12) See, for instance: (a) Diederich, F.; Rubin, Y. Angew. Chem., Int. Ed. Engl.
1992, 31, 1101. (b) Zhao, Y.; Tykwinski, R. R. J. Am. Chem. Soc. 1999,
121, 458. (c) Diederich, F. Pure Appl. Chem. 1999, 71, 265.
(13) For example: (a) Lange, T.; Gramlich, V.; Amrein, W.; Diederich, F.; Gross,
M.; Boudon, C.; Gisselbrecht, J.-P. Angew. Chem., Int. Ed. Engl. 1995,
34, 805. (b) Eisler, S.; Tykwinski, R. R. Angew. Chem. Int. Ed. 1999, 38,
1940.
6c-e,8
all become active p-benzyne biradical
† The Hebrew University of Jerusalem.
‡ Present address: Liquid Crystal Materials Research Center, Department
of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder,
CO 80309-0215.
§ Boston College.
| University of Alberta.
Technical University of Braunschweig.
(1) (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. (b)
Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (c) Lockhardt, T. P.; Commita,
P. B.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 4082.
(2) (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111,
8057. (b) Saito, K.; Watanabe, T.; Takahashi, K. Chem. Lett. 1989, 2099.
(3) Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975.
(4) (a) Prall, M.; Wittkopp, A.; Schreiner, P. R. J. Phys. Chem. A 2001, 105,
9265. (b) Prall, M.; Wittkopp, A.; Fokin, A. A.; Schreiner, P. R. J. Comput.
Chem. 2001, 22, 1605.
(5) Under physiological conditions, a likely alternative mechanism of the
biradical transforming into a quinone exists: Jones, L. H.; Harwig, C. W.;
Wentworth, P., Jr.; Simeonov, A.; Wentworth, A. D.; Py, S.; Ashley, J.
A.; Lerner, R. A.; Janda, K. D. J. Am. Chem. Soc. 2001, 123, 3607.
9
10.1021/ja0566477 CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 4703-4709
4703

A R T I C L E S
Treitel et al.
Scheme 3. Systems Under Investigation in This Research
Scheme 1. (a) Standard Bergman Cyclization Observed for a Six
π-Electron Linear Enediyne and (b) Not Observed for a Six
π-Electron Cross-Conjugated Enediyne
Scheme 2. Cyclizations of 3 under (route a) Thermal Conditions,
Resulting in 4, and (route b) Reductive Conditions, Resulting in
52-
While other cyclizations yielding five-membered rings have
been previously investigated,21-23 until now, the closure of 3
to 5 has been the only such anionic “Bergman-type” cyclization
observed. The scope and limitations of this transformation,
therefore, are not known. We have now found new systems that
undergo such a cycloaromatization, thereby demonstrating that
the example in route b of Scheme 2 is not a unique occurrence
but rather a novel reaction of acetylenes leading to anions of
fulvenes, fulvalenes, and even heterocycles.
critical step in forming the benzene biradical that triggers DNA
cleavage. The related cycloisomerizations of linear 1,3-dien-5-
ynes, forming aromatic six-membered rings, were first reported
by Hopf and Musso.14 The utilization of this reaction for
synthesis took a massive leap in the 1990s, and today, these
cycloaromatizations are frequently exploited in syntheses of new
bowl-shaped PAHs and buckybowls mapping onto fullerene
surfaces.15,16 Cross-conjugated enediynes17 (Y-enediynes, 2),
however, contain only five π electrons in the longest line of
p-orbitals, insufficient for aromatization, and therefore cannot
follow this route (Scheme 1b). Under irradiation, however,
cyclization has been observed for a triaryl Y-enediyne.17
Under thermal conditions, 3 undergoes a “Hopf cyclization”16
to yield 4 (Scheme 2, route a).18 However, an anionic cyclization
of 3 was recently achieved for the first time, and the resulting
product was shown to be entirely different.19 Reduction by alkali
metals results in a new five-membered ring containing six
π-electrons via a “Bergman-type” cyclization, yielding the
dianion 52-. Oxidation with iodine generates the unstable20
fulvalene 5 (Scheme 2, route b).
Methodology.
To determine whether the anionic “Bergman-type” cyclization
is a reaction unique to 3, we reduced 11 more cross-conjugated
enediynes, namely, 6-16 (Scheme 3). The objective was to
examine the reduction of cross-conjugated enediynes differing
in size, geometry, π-electron structure, and aromaticity, as well
as to probe the ability of heteroatoms and substituents to alter
inductive effects. The ultimate goal was to outline which
structural features, if any, have a significant effect on this
cyclization.
Experimental Section
NMR experiments were carried out using a Bruker DRX-400
spectrometer equipped with a BGUII z-gradient, operating at 400.13
and 100.62 MHz for 1H and 13C, respectively. All samples were
dissolved in THF-d8, and the reported chemical shifts were calibrated
to the downfield THF signal (δH 3.575, δC 67.393). Full NMR
assignment, obtained by applying standard 1D- and 2D-NMR techniques
(14) Hopf, H.; Musso, H. Angew. Chem., Int. Ed. Engl. 1969, 8, 680.
(15) (a) Scott, L. T.; Hashemi, M. M.; Meyer, D. T.; Warren, H. B.; J. Am.
Chem. Soc. 1991, 113, 7082. (b) Rabideau, P. W.; Abdourazak, A. H.;
Folsom, H. E.; Marcinow, Z.; Sygula, A.; Sygula, R. J. Am. Chem. Soc.
1994, 116, 7891. (c) Scott, L. T. Pure Appl. Chem. 1996, 68, 291. (d)
Matsuda, M.; Matsubara, H.; Sato, M.; Okamoto, S.; Yamamoto, K. Chem.
Lett. 1996, 157.
(16) Zimmermann, G. Eur. J. Org. Chem. 2001, 457 and references therein.
(17) Kaafarani, B. R.; Neckers, D. C. Tetrahedron Lett. 2001, 42, 4099.
(18) Hopf, H.; Berger, H.; Zimmermann, G.; Nu¨chter, U.; Jones, P. G.; Dix, I.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1187.
(21) Reductive anionic cyclizations of o-bis(phenylethynyl)benzene linear-
conjugated enediynes yield five-membered rings as fulvene derivatives [(a)
Whitlock, H. W., Jr.; Sandvick, P. E.; Overman, L. E.; Reichardt, P. B. J.
Org. Chem. 1969, 34, 879.] and as fulvalene dianion derivatives [(b)
Youngs, W. J.; Djebli, A.; Tessier, C. Organometallics 1991, 10, 2089].
(22) Regiocontrolled reductive cyclization of diethynylsilanes in the endo-endo
mode has been investigated by Tamao and Yamaguchi: (a) Tamao, K.;
Yamaguchi, S.; Shiro, M. J. Am. Chem. Soc. 1994, 116, 11715. (b)
Yamaguchi, S.; Tamao, K. Tetrahedron Lett. 1996, 37, 2983. (c) Tamao,
K.; Yamaguchi, S. Pure Appl. Chem. 1996, 68, 139.
(19) Eshdat, L.; Berger, H.; Hopf, H.; Rabinovitz, M. J. Am. Chem. Soc. 2002,
124, 3822.
(20) The C1′-C9 double bond is highly susceptible to oxidation.
(23) Additionally, the feasibility of forming fulvenes from linear enediynes in
a nonreductive fashion has been investigated: see ref 4a.
9
4704 J. AM. CHEM. SOC. VOL. 128, NO. 14, 2006

Reductive Bergman-Type Cyclizations
A R T I C L E S
such as COSY, NOESY, HSQCSI, and HMBC, confirmed or refuted
the cyclization of the various compounds.
High-resolution mass spectra (DCI in methane) were recorded at
60-70 eV on a VG-Fisons Autospec mass spectrometer.
Monitored Reduction of Samples.
Hz, 2H), 1.24 (H-Me, s, 18H) ppm; δC (THF-d8, 220 K) 131.8 (C-8a/
9a), 121.4 (C-4a/4b), 118.0 (C-4/5), 117.7 (C-1/8), 115.1 (C-2/7), 106.6
(C-9), 106.5 (C-3/6), 96.2 (C-3′/4′), 95.5 (C-2′/5′), 94.5 (C-1′), 33.1
(C-Me), 30.5 (C-t-Bu) ppm.
152-: dark brown-red solution; δH (THF-d8, 220 K) 8.36 (H-8, d,
3
3
3J ) 8.1 Hz, 1H), 8.14 (H-1, d, J ) 8.1 Hz, 1H), 8.12 (H-5, d, J )
Reduction of 6-16 with potassium metal mirrors was carried out
under inert conditions at 195 K in NMR tubes with appropriate
extensions.24 After some contact with the alkali metal, the spectra of
the neutral species broaden, due to radical-anion formation. Additional
contact with the metal yields complex NMR spectra. Further reduction
eventually25 yields a straightforward NMR spectrum of a single
species.26 Full assignments of these species were attained using 1D-
and 2D-NMR as mentioned above.
3
3
8.1 Hz, 1H), 7.99 (H-4, d, J ) 7.6 Hz, 1H), 7.16 (H-7, dd, J1 ) 8.1
Hz, 3J2 ) 7.6 Hz, 1H), 7.02 (H-2, dd, 3J1 ) 8.1 Hz, 3J2 ) 7.6 Hz, 1H),
6.52-6.58 (H-3, m, 1H), 6.50-6.56 (H-6, m, 1H), 6.21 (H-o, d, 3J )
3
3
8.1 Hz, 1H), 5.95 (H-m′, dd, J1 ) 8.1 Hz, J2 ) 7.1 Hz, 1H), 5.85
(H-m, dd, 3J1 ) 8.1 Hz, 3J2 ) 7.1 Hz, 1H), 1H), 5.27 (H-o′, d, 3J ) 8.1
3
3
Hz, 1H), 4.65 (H-p, t, J1 ) J2 ) 7.1 Hz, 1H), 1.31 (H-Me, s, 9H)
ppm; δC (THF-d8, 220 K) 138.5 (C-i), 135.4 (C-9a), 132.3 (C-9), 131.2
(C-8a), 129.4 (C-m), 129.2 (C-m′), 120.3 (C-4b), 119.9 (C-4a), 119.1
(C-7), 118.8 (C-5), 118.6 (C-2), 118.2 (C-1), 118.1 (C-4), 117.4 (C-
3′), 114.3 (C-8), 113.0 (C-o′), 109.0 (C-3), 108.4 (C-o), 107.3 (C-4′),
107.1 (C-6), 103.6 (C-2′), 101.5 (C-5′), 97.5 (C-p), 95.5 (C-1′), 34.7
(C-t-Bu), 33.9 (C-Me) ppm.
NMR Spectroscopy Data For the Dianions. 62-: dark olive green
3
solution; δH (THF-d8, 220 K) 7.89 (H-4/5, d, J ) 7.7 Hz, 2H), 7.71
3
3
3
(H-1/8, d, J ) 8.2 Hz, 2H), 6.83 (H-2/7, dd, J1 ) 7.4 Hz, J2 ) 7.1
3
3
Hz, 2H), 6.83 (H-3/6, dd, J1 ) J2 ) 7.0 Hz, 2H), 0.10 (H-TMS, s,
18H) ppm; δC (THF-d8, 220 K) 132.7 (C-8a/9a), 130.2 (C-2′/5′), 123.0
(C-4a/4b), 119.2 (C-2/7), 119.1 (C-4/5), 115.9 (C-1/8), 108.2 (C-3/6),
91.4 (C-3′/4′), 88.9 (C-9), 36.0 (C-1′), 2.5 (C-TMS) ppm.
Cyclized dianion of 15: dark brown-red solution; δH (THF-d8, 220
K) 7.98 (H-1/8, d, 3J ) 7.6 Hz, 2H), 7.94 (H-4/5, d, 3J ) 7.6 Hz, 2H),
7.52 (H-o, d, 3J ) 7.6 Hz, 2H), 7.11 (H-m, t, 3J1 ) 3J2 ) 7.6 Hz, 2H),
7
2-: deep red-purple solution; δH (THF-d8, 180 K) 7.68 (H-5/6, d,
3
3J ) 9.1 Hz, 2H), 6.63 (H-2/9, dd, J1 ) J2 ) 7.6 Hz, 2H), 6.34 (H-
3
3
6.83-6.88 (H-2/7, m, 2H), 6.82 (H-p, t, J ) 7.6 Hz, 1H), 6.39 (H-
3
3
3
3
3
3/6, t, J1 ) J2 ) 7.6 Hz, 2H), 6.32 (H-5′, s, 1H), 6.17 (H-2′, s, 1H),
1.48 (H-Me, s, 3H) ppm; δC (THF-d8, 220 K) 147.0 (C-i), 129.1 (C-
8a/9a), 129.0 (C-o), 126.3 (C-m), 125.7 (C-3′), 121.9 (C-1′), 120.2 (C-
p), 120.2 (C-4′), 119.4 (C-4a/4b), 118.5 (C-2/7), 118.1 (C-4/5), 114.4
(C-1/8), 106.9 (C-3/6), 105.3 (C-2′), 102.4 (C-5′), 96.5 (C-9), 33.6 (C-
Me), 32.9 (C-t-Bu) ppm.
4/7, dd, J1 ) J2 ) 7.1 Hz, 2H), 6.31 (H-1/10, d, J ) 9.1 Hz, 2H),
3
3
5.57 (H-3/8, dd, J1 ) J2 ) 6.5 Hz, 2H), -0.01 (H-TMS, s, 18H)
ppm; δC (THF-d8, 180 K) 140.7 (C-5a/5c), 131.1 (C-2′/5′), 128.0 (C-
2/9), 126.6 (C-4/7), 119.9 (C-1/10), 116.4 (C-5/6), 106.8 (C-3/8), 93.1
(C-3′/4′), 78.1 (C-5b), 38.9 (C-1′), 1.6 (C-TMS) ppm.
Cyclized dianion of 8: golden-brown solution with lithium, blue-
gray solution with sodium, and purple-red solution with potassium; δH
Results and Discussion
3
3
(THF-d8, 220 K) 7.86 (H-4, d, J ) 7.8 Hz, 1H), 7.39 (H-o, d, J )
7.3 Hz, 4H), 7.21 (H-1, d, 3J ) 7.8 Hz, 1H), 7.00 (H-m, dd, 3J1 ) 3J2
) 7.3 Hz, 4H), 6.74 (H-6, d, J ) 2.9 Hz, 1H), 6.72 (H-p, t, J ) 7.3
Hz, 2H), 6.39 (H-3, dd, 3J1 ) 7.8 Hz, 3J2 ) 6.9 Hz, 1H), 6.34 (H-2′/5′,
s, 2H), 6.30 (H-2, dd, J1 ) 7.8 Hz, J2 ) 6.9 Hz, 1H), 5.83 (H-5, d,
3J ) 2.9 Hz, 1H) ppm; δC (THF-d8, 220 K) 143.1 (C-i), 130.1 (C-6b),
126.9 (C-o), 126.8 (C-m), 124.7 (C-4a), 120.2 (C-p), 118.6 (C-4), 118.4
(C-1), 116.3 (C-3′/4′), 111.8 (C-6), 111.7 (C-3), 111.5 (C-2), 106.8
(C-6a), 104.3 (C-2′/5′), 103.8 (C-1′), 89.9 (C-5) ppm.
Reductions with potassium of the unsymmetrical indenyl
derivative 8, the heterocyclic 9,27 the di-tert-butyl derivative
11, and the unsymmetrical 15 all gave rise to NMR patterns
indicative of cyclizations similar to that of 52-. Figure 1 shows
the unmistakable difference in the NMR patterns for the dianions
formed from 9 and 11, which undergo the cyclization, compared
to that of 6, which does not.
3
3
3
3
Key features common to the spectra of dianions formed from
9, 11, and all other compounds that underwent cyclization
include (a) elimination of the relatively large difference in NMR
shifts for protons analogous to H-1 and H-4 in 3 (due to loss of
anisotropic effect of the acetylene groups), (b) formation of a
relatively upfield28 singlet in the 1H NMR spectra, and (c) loss
of sp-hybridized carbon signals in the 13C NMR spectra.
Conversely, the reduced species 62-, 72-, and 142- still show
sp-hybridized carbon signals (slightly shifted upfield) in their
Cyclized dianion of 9: brown solution; δH (THF-d8, 260 K) 7.26
3
3
3
(H-o, d, J ) 7.6 Hz, 4H), 6.92 (H-m, dd, J1 ) J2 ) 7.6 Hz, 4H),
6.63 (H-p, t, 3J ) 7.6 Hz, 2H), 6.34 (H-1/8, d, 3J ) 7.1 Hz, 2H), 5.93
(H-2′/5′, s, 2H), 5.79 (H-2/7, dd, 3J1 ) 3J2 ) 7.1 Hz, 2H), 5.22 (H-4/5,
d, 3J ) 7.1 Hz, 2H), 5.16 (H-3/6, dd, 3J1 ) 3J2 ) 7.1 Hz, 2H) ppm; δC
(THF-d8, 260 K) 151.9 (C-4a/4b), 143.5 (C-i), 137.3 (C-8a/9a), 126.8
(C-m), 126.6 (C-o), 124.0 (C-2/7), 121.6 (C-1′), 119.6 (C-9), 119.5
(C-p), 116.9 (C-3′/4′), 109.8 (C-2′/5′), 109.5 (C-4/5), 108.5 (C-3/6),
106.9 (C-1/8) ppm.
Cyclized dianion of 11: dark reddish-brown solution; δH (THF-d8,
1
13C NMR spectra, show no singlet in their H NMR spectra,
3
3
250 K) 7.39 (H-1/4/5/8, d, J ) 9.0 Hz, 4H), 7.20 (H-o, d, J ) 7.5
and retain the difference for protons analogous to H-1 and H-4
in 3.29 Quenching of 62-, 72-, and 142- with oxygen gives the
corresponding neutral starting material in practically quantitative
yield.30 The symmetrical anthracene derivative 12, the bis[bis-
(trifluoromethyl)] derivative 13, and the “simple” dimethyl
derivative 16, differing from 3 by the two phenyl units, all
appear to form stable radical-anions.31
3
3
Hz, 4H), 6.85 (H-m, dd, J1 ) 7.6 Hz, J2) 7.5 Hz, 4H), 6.54 (H-2/
3
3
3/6/7, d, J ) 9.0 Hz, 4H), 6.54 (H-p, t, J ) 7.6 Hz, 2H), 6.04 (H-
2′/5′, s, 2H), 1.15 (H-Me, s, 18H) ppm; δC (THF-d8, 250 K) 144.0
(C-i), 143.9 (C-4a/4c), 129.4 (C-2a/6a), 126.6 (C-m), 126.2 (C-o), 124.3
(C-2/3/6/7), 124.2 (C-1′), 118.6 (C-p), 118.4 (C-1/4/5/8), 117.5 (C-3′/
4′), 108.0 (C-2′/5′), 32.9 (C-t-Bu), 32.1 (C-4b), 31.2 (C-Me) ppm.
142-: dark green-light brown solution; δH (THF-d8, 220 K) 7.88
3
3
(H-4/5, d, J ) 7.6 Hz, 2H), 7.77 (H-1/8, d, J ) 8.1 Hz, 2H), 6.80
(H-2/7, t, J1 ) J2 ) 7.4 Hz, 2H), 6.34 (H-3/6, dd, J1 ) J2) 7.1
Quenching of the cyclization products of 8, 9, 11, and 15
with iodine32 gave brown oils in very low yield, as demonstrated
3
3
3
3
(24) Samples of 6-16 contained 3-15 mg in ca. 0.7 mL of THF-d8 to yield
1.09-12.94 mM solutions. An account of the monitored reduction technique
can be found: Treitel, N.; Deichmann, M.; Sternfeld, T.; Sheradsky, T.;
Herges, R.; Rabinovitz, M. Angew. Chem., Int. Ed. 2003, 42, 1172.
Potassium metal mirrors vacuum distilled into the tube were used instead
of lithium wires.
(25) For several compounds, the reduction to a new diamagnetic species took
only 2-3 days. For others, it took as long as several weeks.
(26) While this is the general case, diyne 15 yields a mixture of two species.
See the text.
(27) The heterocycle 10 appears to undergo this cyclization as well. However,
the dianionic cyclized state is much more elusive than that of 9, making
this conclusion somewhat equivocal.
(28) Compared to the resonances for the protons of the aromatic unit receiving
the other electron upon reduction. See the text.
(29) Some compounds of this type undergo dimerization via position 1′. This
is also in good agreement with their chemical shifts and patterns. See the
text and (a) Schlenk, W.; Bergmann, E. Liebigs Ann. Chem. 1928, 463, 1.
(b) Schlenk, W.; Bergmann, E. Liebigs Ann. Chem. 1930, 479, 40.
(30) In the case of 142-, the yield was lower.
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Treitel et al.
Figure 1. 1H NMR and 13C NMR (THF-d8) spectra of the cyclic dianionic products, created from (a) 11 and (b) 9, compared with (c) those of the dianion
of 6, which does not undergo cyclization.
for 52-. These products could be identified as highly unstable
fulvenes, fulvalenes, and heterocycles, which are readily
oxidized. Therefore, characterization of these species via NMR
spectroscopy has not been feasible. However, high-resolution
mass spectroscopy of the quench products is in accord with the
addition of two protons, just as for 52-. While 8 has a calculated
mass of 328.1252 amu, DCI-HRMS analysis33 of the quench
product of the cyclized dianion detected no species with a mass
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A R T I C L E S
benzene biradical.35 High level calculations should provide
insight into the parameters that govern these cyclizations.
Given that compound 3 undergoes cyclization and 14 does
not, we thought it might be informative to examine the behavior
of compound 15 more closely. In fact, 15 does undergo
cyclization, but with a stipulation: unlike the other systems that
cyclize, where the result is a clean (or practically clean) cyclized
dianion, with 15 one obtains a mixture of both the “open”,
“plain” 152- and the cyclized dianionic product (Figure 2), with
the uncyclized product being favored, approximately 3:1. This
could be the result of 15 possessing partial character of 3 and
partial character of 14.
Scheme 4. Proposed Mechanism for a Reductive
“Bergman-Type” Cycloaromatization of a General
Cross-Conjugated Enediyne
The uncyclized 152- shows significant upfield shifts for the
phenyl substituent, as far upfield as 4.65 ppm and no farther
downfield than 6.21 ppm. This is due to partial conjugation
between the phenyl and the enediyne unit, which possesses
significant charge density. In turn, this causes the phenyl and
fluorenyl units to lose their symmetry, giving rise to a relatively
complex spectrum.
The fact that 15 gives both the “open” dianion (15a in Figure
2) and a cyclized dianion (15b in Figure 2) as two distinct,
stable species constitutes strong evidence that the reductive
Bergman-type cyclizations described herein are occurring after
the first single-electron reduction, at the anion-radical stage
(Scheme 4), not at the dianion stage. The “open” dianion 15a
is observed to be stable and does not cyclize to give 15b. The
two dianions are not in equilibrium; they are not even isomers.
15b has already abstracted the two additional hydrogens and
would certainly not give them up to go back to 15a. The most
reasonable conclusion is that 15a and 15b are both formed
irreVersibly from a common intermediate that represents a
branch point along the reaction pathway. That common inter-
mediate is the monoanion radical. In this particular case,
fortuitously, the competition between further reduction of the
monoanion radical (to make 15a) and cyclization (to make 15b)
must be nearly equally balanced.
within 1 amu of this value. On the other hand, addition of two
protons yields a calculated mass of 330.1409 amu for the
fulvalene product, and a peak was detected experimentally at
330.1404 amu.
The detailed mechanism for this cyclization reaction is not
known; however, the overall transformation of a diethynyl-
fulvene to a fulvalene dianion presumably proceeds through an
intermediate cyclopentadienide diradical, analogous to the
intermediate p-benzyne diradicals formed in Bergman cycliza-
tions (see Scheme 1). One plausible sequence of steps for the
formation of a cyclopentadienyl ring from a cross-conjugated
enediyne (Scheme 4) involves single-electron reduction to a
radical-anionic state, followed by formation of a new σ-bond
from the bent vinyl radical anion and further reduction, and
concluding with hydrogen or proton abstraction.
The exact order of steps in the mechanism notwithstanding,
creation of a cyclopentadienylic ring is possible only if the
following steps all occur: reduction, cyclization, and proton or
hydrogen abstraction. Cyclization in the radical anionic state is
presently only a postulate, although we will return to this point
later; the particular order in which these steps occur is currently
under investigation.
HRMS results for the oxidized dianions after the cyclization
indicates that the dianions or diradicals are not quenched by
deuterium atoms from the THF-d8 solvent. Additionally, no
deuterium signals in 2D-NMR experiments were observed,
excluding those of the solvent, undamaged during the reduction
and quench reactions. It is noteworthy that significant precipitate
was seen in the tube, after reduction to a new diamagnetic state
was completed. Therefore, we postulate that the hydrogen atoms
or protons were abstracted from intermediates on pathways to
other reduction products, rather than from the solvent.
Why do systems with a common Y-enediyne unit behave so
differently during the course of reduction? Two chief factors
may govern the outcome of the reaction: charge density on the
carbon skeleton and the relative distances between the two sites
that may bring about cyclization or form a charged acyclic
system. Carbon-carbon intramolecular distances play a key role
in the normal Bergman cyclization:6f,7b,34 in vivo, the cyclization
itself takes place after activation brings the carbons at the borders
of the enediyne close enough to each other, generating the active
Not all of the enediynes that fail to cyclize, however, are
transformed into “open” dianions analogous to 15a. Close
inspection of the 13C NMR spectra given by the new diamagnetic
species formed upon reduction of enediynes 6 and 7, for
example, reveals that the monoanion radicals from these cross
conjugated enediynes (CCEs) dimerize at position 1′, yielding
dianion dimers (Scheme 5).29 The dimerization is most clearly
indicated by the chemical shift of C-1′, which falls in the
aliphatic region for the reduction products of 6 and 7 (36.0 and
38.9 ppm, respectively), whereas the chemical shift of C-1′ in
the “open,” monomeric dianion 15a comes at 95.5 ppm.
The reductive dimerization of 6 and 7 actually explains why
these compounds fail to cyclize. Apparently, dimerization is the
kinetically favored pathway in these cases (Scheme 5 route a)
and is simply faster than either reduction to the open dianion
(route b) or cyclization (route c).
(34) For example: (a) Nicolaou, K. C.; Smith, A. L.; Wendeborn, S. V.; Hwang,
C. K. J. Am. Chem. Soc. 1991, 113, 3106. (b) Nicolaou, K. C.; Dai, W.
M.; Tsay, S. C.; Estevez, V. A.; Wrasidlo, W. Science 1992, 256, 1172.
(c) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 5881. (d) Turro, N. J.; Evenzahav, A.; Nicolaou, K. C.
Tetrahedron Lett. 1994, 35, 8089. (e) Schreiner, P. R. J. Am. Chem. Soc.
1998, 120, 4184. (f) Gaffney, S. M.; Capitani, J. F.; Castaldo, L.; Mitra,
A. Int. J. Quantum Chem. 2003, 95, 706.
(31) These compounds were all reduced numerous times, under several
conditions: at slow and fast rates and at low temperature, room temperature,
and under heating. In no case, for any of the enediynes studied, even after
months of charging, was a new diamagnetic species observed. Triplet
dianions are hypothetically possible, but have been ruled out on account
of energy calculations.
(35) See, for instance: (a) Snyder, J. P. J. Am. Chem. Soc. 1989, 111, 7630. (b)
Magnus, P.; Carter, P.; Elliot, J.; Lewis, R.; Harling, J.; Pitterna, T.; Bauta,
W. E.; Fortt, S. J. Am. Chem. Soc. 1992, 114, 2544. (c) Also see ref 5.
(32) In the same manner as for 52-; see ref 19.
(33) Methane gas was used in DCI-HRMS; see the Experimental Section.
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A R T I C L E S
Treitel et al.
Figure 2. 1H NMR (THF-d8) of the “open” 152- 29 (a) and of the cyclization product of the dianion of 15 (b).
Scheme 5. Three Possible Pathways for the Fate of the Monoanion Radical: (route a) Dimerization, Yielding a Dianionic Dimer, (route b)
Reduction, Yielding the “Open” Dianion, or (route c) Cyclization and Reduction, Yielding the Cyclopentadienylic Product
Unlike 6 and 7, however, 14 yields an “open” dianion,
analogous to 15a. The reasoning behind this, presumably, is
steric interference; the t-Bu groups collide in the dimer dianion
of 14, whereas the longer Si-C bonds in 6 and 7 allow their
monoanion radicals to dimerize without steric hindrance.36 Thus,
compounds of this type seem to prefer dimerization (route a),29
but when steric hindrance becomes a major factor, as in 14, a
different pathway is taken. Depending on the substituents, the
end result is either reduction to an “open” dianion (route b) or
cyclization followed by reduction, yielding a new five-
membered ring (route c).
Once a system follows either pathway b or c, it is impossible
for it to “retrace” its steps to get to a different one. Those paths
are one-way only, and no equilibrium exists between the
(36) Molecular geometries were calculated with PM3 in Spartan 02 (Linux
version), Wavefunction, Inc., Irvine, CA.
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A R T I C L E S
products of those routes. Pathway a, on the other hand, might
be reversible in some cases. In this regard, it is noteworthy that,
aside from 15, all the anionic Bergman cyclizations observed
to date [i.e., 3, 8, 9, (10) and 11] have phenyl groups on both
acetylenes. This is apparently a crucial factor in determining
the outcome of the reduction. Perhaps phenyl groups render a
pathway reversible, and that may be a prerequisite for success.
The bis-TMS and the bis-alkyl compounds all fail for one reason
or another. While 12 and 13 also fail, it is difficult to assess
their special electronic properties. 15 clearly behaves as a
borderline case, with partial bis-phenyl character and partial bis-
alkyl character.
As in standard Bergman cyclizations, substituent-inductive
effects play a significant role in dictating the result of the
reduction.37 In the Bergman cyclization, formation of an
aromatic benzene ring plays a key role; in this anionic
“Bergman-type” cyclization, formation of an aromatic cyclo-
pentadienide ring plays an equally important role. By some
criteria, the cyclopentadiene anion is actually more aromatic
than benzene,38 and this could, in part, account for why these
cyclizations occur at such low temperatures (195 K), whereas
neutral systems require 400-500 K for the classic Bergman
cyclization. This corresponds to an enormous difference in
kinetics.
are obtainable even when the reaction forms a new ring with
antiaromatic character.
Conclusions and Outlook
Various cross-conjugated enediynes undergo anionic cy-
cloaromatizations under reductive conditions, yielding novel
anions of fulvenes, fulvalenes, and even heterocycles. In
agreement with the view that the aromaticity of the cyclopen-
tadienyl anion exceeds that of benzene,38 this “Bergman-type”
cyclization is more favorable than the classic Bergman cycliza-
tion with a linear enediyne, resulting in lower activation energy.
The ability to generate a highly reactive diradical under
relatively mild conditions may prove useful for various func-
tions, such as the initiation of polymerizations. This new anionic
cyclization is a different type of cyclization from the classic
Bergman and related cyclizations and from other dianionic
cyclizations.40
Acknowledgment. Financial support from the Israel Science
Foundation (ISF), the Lise Meitner-Minerva Center for Com-
putational Quantum Chemistry, and the U.S. Department of
Energy is gratefully acknowledged. We also thank Schering-
Plough for generous support of the Boston College X-ray
facility. N.T. and M.R. are indebted to Prof. Silvio Biali, Prof.
Sason Shaik, and Dr. David Danovich, for very fruitful
discussions, to Dr. Rachel Perski, for assistance with the HRMS
experiments, and to Dr. Robert McDonald and Jarrod Blank,
for the crystallographic analyses of compounds 12 and 13.
These findings reinforce those of Kawatkar and Schreiner,
who theoretically studied the feasibility of cycloaromatizations
of 1,4-pentadiynes.39 In their theoretical study of “Bergman-
like cyclizations”, they proposed that σ-accepting capabilities
of the specific substituents on the acetylenes drastically affect
the energy barriers to cyclization. With appropriate substituents,
they postulated that relatively low energy barriers for cyclization
Supporting Information Available: Syntheses and experi-
mental spectroscopic data for all neutral compounds 6-16, CIF
files of 12 and 13, general crystallographic experimental
information for 12, ORTEP drawings of 12, and drawings of
13. This material is available free of charge via the Internet at
http://pubs.acs.org.
(37) For example: (a) Prall, M.; Wittkopp, A.; Fokin, A. A.; Schreiner, P. R.
J. Comput. Chem. 2001, 22, 1605. (b) Alabugin, I. V.; Manoharan, M.;
Kovalenko, S. V. Org. Lett. 2002, 4, 1119. (c) Alabugin, I. V.; Manoharan,
M. J. Am. Chem. Soc. 2003, 125, 4495.
(38) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jaio, H.; Hommes, N. J. R.
v. E. J. Am. Chem. Soc. 1996, 118, 6317.
(39) Kawatkar, S. P.; Schreiner, P. R. Org. Lett. 2002, 4, 3643.
JA0566477
(40) Langer, P.; Freiberg, W. Chem. ReV. 2004, 104, 4125.
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