Low-valent niobium-mediated double activation of C-F/C-H bonds: Fluorene synthesis from o-arylated α,α,α-trifluorotoluene derivatives

Article abstract of DOI:10.1021/ja0565323

By the treatment of 0.3 molar amount of NbCl₅ and LiAlH₄, o-arylated α,α,α-trifluorotoluenes afforded fluorene derivatives in good yields. C-F bonds of the CF₃ group and the neighboring ortho C-H bond were doubly activated to give the coupling products. Copyright

Full text of DOI:10.1021/ja0565323

Published on Web 01/11/2006
Low-Valent Niobium-Mediated Double Activation of C-F/C-H Bonds:
Fluorene Synthesis from o-Arylated r,r,r-Trifluorotoluene Derivatives
Kohei Fuchibe and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin UniVersity, 1-5-1 Mejiro, Toshima-ku,
Tokyo 171-8588, Japan
Received September 23, 2005; E-mail: takahiko.akiyama@gakushuin.ac.jp
Table 1. Formation of Fluorenea
The C-F bond is the strongest single bond connected to carbon.1
Although several aromatic and aliphatic C-F bond activations have
been reported in recent years,2,3 the development of a novel method
for C-F bond activation remains elusive. In particular, the CF3
group attached to an aromatic ring is surprisingly stable, and the
activation of these benzylic C-F bonds is quite limited.4 The
transformation of the CF3 groups is thus a challenging task from
the viewpoint of both synthetic organic chemistry and organofluo-
rine chemistry.
We previously reported the reductive cleavage of aromatic C-F
bonds by means of low-valent niobium generated in situ.5 Under
similar conditions, we recently found that the CF3 group of
o-phenyl-R,R,R-trifluorotoluene 1a could also be activated, generat-
ing fluorene 2a (Table 1, entry 1). To a DME solution of 1a and
an equimolar amount of NbCl5 was added solid LiAlH4 (10 mol
amt) in one portion. After refluxing for 6 h, we isolated fluorene
2a in 61% yield, together with conventional reduction product 3a
in 18% yield. Although coupling reactions via C-F bond activation
remain underdeveloped,3 we were able to accomplish the C-C
coupling reaction via the double activation of C-F and C-H
bonds.6 Other metal salts, such as TaCl5 or VCl3, gave inferior
results (entries 2-5). When the reaction was carried out in the
absence of metal salts, partial reduction product 4 was obtained as
the major product (entry 6).
entry
MXn
2a/%
3a/%
4/%
1a/%
1
2
3
4
5
6
NbCl5
TaCl5
VCl3
ZrCl4
PdCl2
none
61
57
36
40
41
-
18
27
29
29
44
11
-
-
-
-
4
-
-
-
-
-
33
52
a DME ) 1,2-dimethoxyethane.
Scheme 1. Slow Addition of LiAlH4
The ratio of 2a to 3a was dramatically improved when a DME
suspension of LiAlH4 was added to the medium and the reaction
was allowed to proceed for 1 h (65% of 2a and 3% of 3a, Scheme
1). Use of 1,4-dioxane as solvent further increased the yield of 2a
up to 82%.
Scheme 2. Formation of 9,9-Ditolylfluorene in Toluenea,b
Unexpectedly, intermolecular C-C coupling reaction took place
when the reaction was carried out in toluene (Scheme 2). 9,9-
Ditolylfluorene 5 and 9-tolylfluorene 6 were obtained in 71% and
14% yields, respectively. 9,9-Difluorofluorene 7, prepared from
9-fluorenone, gave essentially the same products under the identical
conditions.
The reaction is outlined as follows in Scheme 3. o-Phenyl trifluo-
rotoluene 1a undergoes low-valent niobium-mediated formal de-
hydrofluorination from benzylic C-F bond and aromatic ortho
C-H bond to give 9,9-difluorofluorene 7.7 7 is readily reduced
under the conditions to produce parent fluorene 2a.8 On the other
hand, 1a is competitively reduced with excess LiAlH4 present in
the reaction medium to give 3a via partial reduction product 4.8
The slow addition of LiAlH4 suppresses the latter process to give
a high 2a/3a ratio. When the reaction is carried out in toluene, 7
undergoes intermolecular formal dehydrofluorination to give 5 and
6.
a Toluene suspension of LiAlH4 was added over 1 h. bRegioisomer ratios
c
of the tolyl groups were determined by GC analysis. m-m:m-p:p-p ) 13:
d
e
51:36. m:p ) 41:59. m-p:p-p ) 22:78.
might undergo intramolecular coupling with ortho C-H bond to
give 7.10
This reaction could be carried out with 0.3 molar amount of
NbCl5 and 6 molar amounts of LiAlH4 (Table 2). Various o-arylated
trifluorotoluene derivatives gave the corresponding fluorenes in
good yields. In particular, it is of great interest that the CF3 group
was activated prior to C-O, C-S, C-N, and aromatic C-F bonds
to give the heteroatom-substituted fluorenes in good yields (entries
4-7). The loading of NbCl5 could be reduced to 0.1 molar amount
with a slight decrease of the yield (entry 8).
One possible mechanism for the formation of difluorofluorene
7 is that difluorobenzylic niobium species is generated from 1a
and the low-valent niobium.9 The difluorobenzylic niobium species
9
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J. AM. CHEM. SOC. 2006, 128, 1434-1435
10.1021/ja0565323 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Outline of the Double Activation Reactiona
preparation of 1. We are grateful to Dr. Keiichi Ajito (Meiji Seika
Kaisha Ltd., (Tokyo, Japan)) for his kind communication. We also
appreciate the suggestions from the reviewers.
Supporting Information Available: Supplementary data, prepara-
tion of the starting materials, typical procedures, and characterization
data of the compounds 1a-m, 2a-m, 4, 5, 6, and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
(2) (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem. ReV. 1994,
94, 373. (b) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Chem. Ber. 1997,
130, 145. (c) Richmond, T. G. In ActiVation of UnreactiVe Bonds and
Organic Synthesis; ; Murai, S., Eds.; Topics in Organometallic Chemistry,
Vol. 3; Springer: Berlin, 1999; p 243.
a [Nb] ) low valent niobium.
Table 2. Synthesis of Fluorenes
(3) (a) Terao, J.; Watabe, H.; Kambe, N. J. Am. Chem. Soc. 2005, 127, 3656.
(b) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc.
2003, 125, 5646. (c) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125,
1696. (d) Steffen, A.; Sladek, M. I.; Braun, T.; Neumann, B.; Stammler,
H.-G. Organometallics 2005, 24, 4057. (e) Saeki, T.; Takashima, Y.;
Tamao, K. Synlett 2005, 1771.
(4) (a) Scott, V. J.; Celenligil-Cetin, R.; Ozerov, O. V. J. Am. Chem. Soc.
2005, 127, 2852. (b) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. J.
Org. Chem. 2001, 66, 7216. (c) Saboureau, C.; Troupel, M.; Sibille, S.;
Pe´richon, J. J. Chem. Soc., Chem. Commun. 1989, 1138. (d) Clavel, P.;
Le´ger-Lambert, M.-P.; Biran, C.; Serein-Spirau, F.; Bordeau, M.; Roques,
N.; Marzouk, H. Synthesis 1999, 829.
(5) (a) Fuchibe, K.; Akiyama, T. Synlett 2004, 1282. See also; (b) Sato, M.;
Oshima, K. Chem. Lett. 1982, 157.
(6) J. H. Teuben and co-workers reported 2-fluorobiphenyl was formed from
fluorobenzene and (Cp*2YH)2: Booij, M.; Deelman, B.-J.; Duchateau,
R.; Postma, D. S.; Meetsma, A.; Teuben, J. H. Organometallics 1993,
12, 3531.
(7) We observed the formation of the niobium mirror inside of the reaction
vessel when stoichiometric amount of NbCl5 was employed (e.g. in entry
1, Table 1). Kost, M. E.; Golovanova, A. I. Zh. Neorg. Khim. 1977, 22,
977.
(8) (a) Paleta, O. In Organo-Fluorine Compounds; Baasner, B., Hagemann,
H., Tatlow, J. C., Eds.; Methods of Organic Chemistry, Vol. E 10b/Part
2; Houben-Weyl: Stuttgart, 2000; p 306. (b) Alonso, F.; Beletskaya, I.
P.; Yus, M. Chem. ReV. 2002, 102, 4009. (c) Jones, W. D. J. Chem. Soc.,
Dalton Trans. 2003, 3991. (d) Kraft, B. M.; Lachicotte, R. J.; Jones, W.
D. J. Am. Chem. Soc. 2001, 123, 10973. (e) Vela, J.; Smith, J. M.; Yu,
Y.; Ketterer, N. A.; Flaschenriem, C. J.; Lachicotte, R. J.; Holland, P. L.
J. Am. Chem. Soc. 2005, 127, 7857. (f) Aizenberg, M.; Milstein, D. Science
1994, 265, 359; ref 4a. See ref 2, also.
(9) Difluorobenzylic radical species may not be involved because this reaction
was not inhibited by an equimolar amount of 9,10-dihydroanthracene
(NbCl5 (0.3), LiAlH4 (6) over 1 h, dioxane, reflux, 4 h, 60% of 2a and
3% of 3a). Electrophilic aromatic substitution might not be operative
because considerable amounts of m-tolylated 5 and 6 were obtained
(Scheme 2).
(10) (a) Catellani, M. Synlett 2003, 298. (b) Dyker, G. Chem. Ber. 1997, 130,
1567. Another mechanism such as σ-bond metathesis is also conceivable.
(11) (a) Sulsky, R.; Robl, J. A.; Biller, S. A.; Harrity, T. W.; Wetterau, J.;
Connolly, F.; Jolibois, K.; Kunselman, L. Bioorg. Med. Chem. Lett. 2004,
14, 5067. (b) Lyakhov, S. A.; Lyakhova, E. A.; Karpenko, A. S.; Mal’tsev,
G. V.; Vel’cheva, I. V.; Litvinova, L. A.; Lebedyuk, M. N.; Khorokhorina,
G. A.; Fedchuk, V. P. Pharm. Chem. J. 2004, 38, 128. (c) Morgan, L. R.;
Thangaraj, K.; LeBlanc, B.; Rodgers, A.; Wolford, L. T.; Hooper, C. L.;
Fan, D.; Jursic, B. S. J. Med. Chem. 2003, 46, 4552. (d) Pan, H.-L.;
Fletcher, T. L. J. Med. Chem. 1965, 8, 491. (e) Miller, E. C. Cancer Res.
1978, 38, 1479. (f) Robillard, B.; Lhomme, M. F.; Lhomme, J. Tetrahedron
Lett. 1985, 26, 2659. (g) Doisy, R.; Tang, M.-S. Biochemistry 1995, 34,
4358. (h) Fletcher, T. L.; Namkung, M. J.; Pan, H.-L. J. Med. Chem.
1967, 10, 936. (i) Scherf, U.; List, E. J. W. AdV. Mater. 2002, 14, 477. (j)
Ohmori, Y.; Uchida, M.; Muro, K.; Yoshino, K. Jpn. J. Appl. Phys. 1991,
30, L1941. 1. See also; (k) Rathore, R.; Chebny, V. J.; Abdelwahed, S.
H. J. Am. Chem. Soc. 2005, 127, 8012. (l) Wang, Z.; Xing, Y.; Shao, H.;
Lu, P.; Weber, W. P. Org. Lett. 2005, 7, 87. (m) Saikawa, Y.; Hashimoto,
K.; Nakata, M.; Yoshihara, M.; Nagai, K.; Ida, M.; Komiya, T. Nature
2004, 429, 363.
a NbCl5 0.1 mol. amt., LiAlH4 5 mol. amt. b NbCl5 1.0 mol. amt., LiAlH4
0.1 mol. amt.
Fluorene is the core structure of (naturally occurring) potent
molecules11 such as the MTP inhibitor,11a interferon inducers,11b
antitumor compounds,11c,d and on the contrary, carcinogens.11e-h
Fluorenes in polymer form have also attracted much attention as
molecular devices for blue-light-emitting materials.11i, j The niobium-
mediated cyclization described here might contribute to these areas
of research by supplying these fluorene-containing materials.12
In summary, we have developed a double C-F/C-H bond
activation protocol for o-arylated trifluorotoluenes. By means of
this low-valent niobium-mediated system, a variety of substituted
fluorenes were synthesized in good yields.
(12) Other reports on fluorene synthesis; (a) Ferraris, D.; Cox, C.; Anand, R.;
Lectka, T. J. Am. Chem. Soc. 1997, 119, 4319. (b) Olah, G. A.; Mathew,
T.; Farnia, M.; Prakash, G. K. S. Synlett 1999, 1067. (c) Ohwada, T.;
Suzuki, T.; Shudo, K. J. Am. Chem. Soc. 1998, 120, 4629. (d) Campo,
M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
Acknowledgment. We appreciate Asahi Glass Co., Ltd. (Tokyo,
Japan) for supplying us with 2-bromo-R,R,R-trifluorotoluene for
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