Scope of the thermal cyclization of nonconjugated ene-yne-nitrile system: A facile synthesis of cyanofluorenol derivatives

Article abstract of DOI:10.1246/cl.2008.662

Thermal cyclizations of nonconjugated ene-diyne-nitrile 1 and ene-triyne-nitrile 2 systems were examined and proved to yield not azafluorenol. but cyanofluorenol derivatives (9 and 11, respectively), indicating that the cyano groups do not participate in the radical cycloaromatization but do play important roles to determine the mode of cyclization. Copyright

Full text of DOI:10.1246/cl.2008.662

662
Chemistry Letters Vol.37, No.6 (2008)
Scope of the Thermal Cyclization of Nonconjugated Ene–Yne–Nitrile System:
A Facile Synthesis of Cyanofluorenol Derivatives
Hidenori Kimura,ꢀ;y Kohei Torikai, Kazuhiro Miyawaki, and Ikuo Ueda
The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047
(Received March 18, 2008; CL-080297; E-mail: hidenori-kimura@ds-pharma.co.jp)
Thermal cyclizations of nonconjugated ene–diyne–nitrile 1
HO
CHO
R
and ene–triyne–nitrile 2 systems were examined and proved to
yield not azafluorenol, but cyanofluorenol derivatives (9 and
11, respectively), indicating that the cyano groups do not partic-
ipate in the radical cycloaromatization but do play important
roles to determine the mode of cyclization.
b,c
a
TMS
R
+
TMS
5a: R = Ph
5b: R =
3
4a: R = Ph
4b: R =
MeO
MeO
THPO
THPO
R1
R2
R1
Cycloaromatization
e
CN
Conjugated ene–yne compounds have attracted much atten-
tion in the broad field of organic chemistry, since their cycliza-
tion reactions were discovered to give aromatized products by
way of radical intermediates capable of DNA cleavage.1 Al-
though many compounds, including both natural1a,1c,1f and arti-
ficial products,1b,1f,1g have been synthesized to investigate their
reactivity and to develop more potent and selective antitumor
agents, modification of the conjugated ene–yne core structures
has not been well studied. We reported that non-conjugated
ene–ynes undergo thermal cycloaromatization (CA) reaction2
with cleaving DNA.3 As a new entry to the nonconjugated
ene–yne compounds, we focused on ene–yne–nitrile systems
(Scheme 1). The C–N triple bond (cyano group) is considered
as an alternative to the C–C triple bond (alkyne), therefore, if
the cyano group participates in the radical CA reaction, intrigu-
ing heterocyclic compounds, azafluorenol derivatives, whose
congeners are known to be biologically active (e.g. as thrombin
inhibitors,4 and the corresponding ketones, azafluorenone deriv-
atives act as phosphodiesterase inhibitors,5 calcium antagonistic
agents,6 and herbicides7), could be formed (path a). On the other
hand, if the cyano group is independent of CA (path b), the
expected fluorenol products8 whose photochemical properties9
have attracted a broad spectrum of interest are also worthwhile.
Herein, we report the synthesis and the CA reaction of ene–yne–
nitriles 1 and 2.
6a: R1 = Ph, R2 = H
1: R1 = Ph
2: R1
6b: R1
=
,R2 = H
=
d
MeO
MeO
7a: R1 = Ph, R2 = I
7b: R1 = Ph, R2 = I
OR
OR
O
NC
NC
8: R = THP
10: R = THP
11: R = H
f
f
9: R = H
Scheme 2. Reagents and conditions: (a) 4a, n-BuLi, THF,
ꢁ78 ꢂC, 1 h, then 3, ꢁ78 ꢂC to rt, 0.5 h, 79% (for 5a); 4b,
MeLi–LiBr complex, THF, 0 ꢂC, 2 h, then 3, 0 ꢂC to rt, 0.5 h,
63% (for 5b); (b) DHP, PPTS, CH2Cl2, rt, 6 h; (c) K2CO3,
MeOH, rt, 1 h, 98% (over 2 steps, for 6a), 91% (over 2 steps,
for 6b); (d) NIS, AgNO3, acetone, rt, 1 h; (e) CuCN, LiI, THF,
reflux, 72 h; (f) PPTS, MeOH, rt, 12 h, 44% (over 3 steps, from
6a to 9), 11% (over 3 steps, from 6b to 11, with recovery of
ene–triyne–nitrile (29%)).
duction of a cyano group to the alkynyl terminus of 7a.
Intriguingly, treatment of iodide 7a with CuCN in the pres-
ence of LiI11 in refluxing THF spontaneously furnished the
cycloaromatized product 8 by way of nitrile 1. Finally, removal
of the THP group from 8 with pyridinium p-toluenesulfonate
(PPTS) afforded 9,12 whose structure was determined as a cyano-
fluorenol derivative, in 44% yield over three steps.
Synthesis of 1 commenced with a commercially available
aldehyde 3 (Scheme 2). Addition of phenylethynyllithium to 3
gave alcohol 5a (79%). Protection of 5a as THP ether followed
by the removal of the TMS group with K2CO3 in MeOH afford-
ed terminal alkyne 6a (98% for two steps), which was converted
to the corresponding iodoalkyne 7a by treatment with N-iodo-
succinimide (NIS) and AgNO3.10 The final task was the intro-
We then turned our attention to the expansion of the alkynyl
moiety to set ene–triyne–nitrile system 2 as a substrate for
the thermal CA reaction. Synthesis of ene–triyne–nitrile 2 was
initiated with aldehyde 3 and diyne 4b2f instead of 4a, and the
alkynyl iodide 7b was prepared in the sequence analogous to
7a. As we expected, subjection of 7b to the cyanation conditions
resulted again in the formation of the cycloaromatized product
10 spontaneously. After the removal of the THP group, the struc-
ture of the resulting product was unambiguously determined by
1H–1H COSY and NOE experiments as fluorenol derivative
11.12 Contrary to the ene–yne–nitriles, the thermal cyclization
of the corresponding ene–triyne 12 (carbon congener) was found
to proceed through both a and b pathways (Scheme 3)13 to
give both 13 and 14, suggesting that the cyano group is useful
to determine the mode of cyclization, although it was not directly
OTHP
Ph
MeO
THPO
THPO
N
a
a
b
a
b
OTHP
C
N
C
N
2
1
b
NC
Scheme 1. Hypothetical cyclization mode of ene–diyne–nitrile
1 and ene–triyne–nitrile 2.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.6 (2008)
663
S. C. Tsay, V. A. Estevez, W. Wrasidlo, Science 1992, 256,
1172. c) J. W. Grissom, G. U. Gunawardena, D. Klingberg, D.
Huang, Tetrahedron 1996, 52, 6453. d) K. K. Wang, Chem. Rev.
1996, 96, 207. e) H. H. Wenk, M. Winkler, W. Sander, Angew.
HO
a
b
12
ˇ
´
Chem., Int. Ed. 2003, 42, 502. f) M. Gredicak, I. Jeric, Acta Pharm.
2007, 57, 133. g) M. Kar, A. Basak, Chem. Rev. 2007, 107, 2861.
a) K. Miyawaki, R. Suzuki, T. Kawano, I. Ueda, Tetrahedron Lett.
1997, 38, 3943. b) C. Ikemoto, T. Kawano, I. Ueda, Tetrahedron
Lett. 1998, 39, 5053. c) K. Miyawaki, T. Kawano, I. Ueda, Tetra-
hedron Lett. 1998, 39, 6923. d) K. Miyawaki, T. Kawano, I. Ueda,
Tetrahedron Lett. 2000, 41, 1447. e) T. Kawano, H. Inai, K.
Miyawaki, I. Ueda, Tetrahedron Lett. 2005, 46, 1233. f) T.
Kawano, H. Inai, K. Miyawaki, I. Ueda, Bull. Chem. Soc. Jpn.
2006, 79, 944.
benzene, reflux,
20 h
2
OH
OH
Ph
Ph
+
Ph
14 (product of path b, 35%)
13 (product of path a, 43%)
3
4
a) I. Ueda, Y. Sakurai, T. Kawano, Y. Wada, M. Futai, Tetra-
hedron Lett. 1999, 40, 319. b) I. Ueda, K. Miyawaki, T. Sugane,
Y. Sakurai, Y. Wada, M. Futai, Pharmazie 2000, 55, 192. c)
K. Torikai, Y. Otsuka, M. Nishimura, M. Sumida, T. Kawai, K.
Sekiguchi, I. Ueda, Bioorg. Med. Chem., in press.
K. J. Stauffer, P. D. Williams, H. G. Selnick, P. G. Nantermet,
C. L. Newton, C. F. Homnick, M. M. Zrada, S. D. Lewis, B. J.
Lucas, J. A. Krueger, B. L. Pietrak, E. A. Lyle, R. Singh, C.
Miller-Stein, R. B. White, B. Wong, A. A. Wallace, G. R. Sitko,
J. J. Cook, M. A. Holahan, M. Stranieri-Michener, Y. M. Leonard,
J. J. Lynch, D. R. McMasters, Y. Yan, J. Med. Chem. 2005, 48,
2282.
Scheme 3. Thermal cyclization of ene–triyne 12.
MeO
THPO
THPO
Me
O
C
N
O
NC
2
THPO
THPO
δ-
Me
O
δ+
I- or CN-
NC
5
a) G. R. Heintzelman, K. M. Averill, J. H. Dodd, K. T. Demarest,
Y. Tang, P. F. Jackson, PCT Int. Appl. WO 2003088963, 2003.
b) G. R. Heintzelman, K. M. Averill, J. H. Dodd, K. T. Demarest,
Y. Tang, P. F. Jackson, U.S. Patent Appl. Publ. US 2004082578,
2004.
NC
10
Scheme 4. Plausible mechanism of thermal cycloaromatization
of 2.
6
7
8
C. Safak, R. Simsek, Y. Altas, S. Boygas, K. Erol, Boll. Chim.
Farm. 1997, 136, 665.
involved in the radical CA reactions,14 probably owing to the
difficulty in the homolysis of a highly polar C–N triple bond.
Although the detailed mechanism of the thermal cyclization
of nonconjugated ene–yne systems is still controversial,9a,9c the
mechanism2f to furnish fluorenol 10 from ene–triyne–nitrile 2
is envisaged as follows (Scheme 4): the thermal cyclization
between yne and diyne moieties of 2 gives 1,2-diradical, which
is a mesomeric equivalent of benzyne. Since the present benzyne
is believed to be polarized by the aid of ethereal oxygen forming
6-membered cyclic transition state or intermediate, a good
nucleophile (iodide or cyanide) attacks the methyl group to gen-
erate the ether-ring-fused compound 10.
C. Rentzea, N. Meyer, J. Kast, P. Plath, H. Koenig, A. Harreus, U.
Kardorff, M. Gerber, H. Walter, Ger. Offen. DE 4301426, 1994.
For the synthesis of benzofluorene cores via the thermal cycliza-
tion of non-conjugated ene–ynes, see: a) M. Schmittel, M.
Strittmatter, W. A. Schenk, M. Hagel, Z. Naturforsch. 1998,
´
53b, 1015. b) D. Rodrıguez, L. Castedo, D. Domınguez, C. Saa,
Tetrahedron Lett. 1999, 40, 7701. c) D. Rodrıguez, A. Navarro,
´
´
´
´
´
L. Castedo, D. Domınguez, C. Saa, Org. Lett. 2000, 2, 1497.
For example, see: a) P. Wan, E. Krogh, J. Chem. Soc., Chem.
Commun. 1985, 1207. b) P. Wan, E. Krogh, J. Am. Chem. Soc.
1989, 111, 4887. c) S. L. Mecklenburg, E. F. Hilinski, J. Am.
Chem. Soc. 1989, 111, 5471. d) G. G. Gurzadyan, S. Steenken,
Chem.—Eur. J. 2001, 7, 1808.
9
In conclusion, we have demonstrated that the thermal cycli-
zation of nonconjugated ene–yne–nitrile systems furnishes
not azafluorenol but cyanofluorenol derivatives. These findings
indicate that the cyano group does not participate in the thermal
radical cycloaromatization reactions directly, but is useful to
determine the reaction fate to form cyanofluorenol derivatives.
Furthermore, since a cyano group is facilely manipulated to a
variety of functional groups, the cyanofluorenol derivatives
obtained in this work can potentially be pivotal intermediates
in photochemical and medicinal chemical researches. Further
investigations on thermal cyclization of nonconjugated ene–ynes
are in progress.
10 H. Hofmeister, K. Annen, H. Laurent, R. Wiechert, Angew. Chem.
1984, 96, 720.
11 F.-T. Luo, R.-T. Wang, Tetrahedron Lett. 1993, 34, 5911.
12 Spectral data of 9: 1H NMR (400 MHz, CDCl3) ꢀ 8.42 (1H, d,
J ¼ 6:6 Hz), 8.23 (1H, s), 8.19 (1H, d, J ¼ 8:3 Hz), 7.89 (1H, d,
J ¼ 8:3 Hz), 7.73 (1H, dd, J ¼ 5:2, 5.2 Hz), 7.65 (1H, ddd, J ¼
7:1, 7.1, 0.7 Hz), 7.57 (1H, dd, J ¼ 7:1, 7.1 Hz), 7.50–7.46 (2H,
m), 5.72 (1H, s), 2.39 (1H, s); IR (CHCl3) 3416, 2217 cmꢁ1
;
FAB-MS (NBA) m=z 258 [(M + H)þ]. Spectral data of 11:
1H NMR (400 MHz, CDCl3) ꢀ 8.48 (1H, d, J ¼ 7:8 Hz), 8.44
(1H, d, J ¼ 7:6 Hz), 7.67 (1H, d, J ¼ 7:6 Hz), 7.53–7.40 (4H,
m), 7.52 (1H, s), 7.25 (1H, d, J ¼ 7:6 Hz), 5.55 (1H, s), 5.06
(2H, s), 2.10 (1H, s); IR (CHCl3) 3424, 2217 cmꢁ1; FAB-MS
(NBA) m=z 311 [(M + H)þ].
13 Synthesis of 12 was accomplished according to the previously
reported methodology: See Ref. 2a.
14 The thermal cyclization reactions of the following nonconjugated
ene–yne–nitriles 15–20 failed even at 180 ꢂC in refluxing 1,2-
dichlorobenzene to yield only decomposed products.
We are grateful to Dr. Tomikazu Kawano in our laboratory
for discussions.
References and Notes
X
Y
y
Present address: Chemistry Research Laboratories, Dainippon
Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade Naka, Konohana-
ku, Osaka 554-0022.
X Y
X
Y
Ph
CN
CN
Ph
CN
MeO
1
For instance, see: a) K. C. Nicolaou, W.-M. Dai, Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1387. b) K. C. Nicolaou, W.-M. Dai,
15: X=OH, Y=H
16: X=O, Y=O
17: X=H, Y=H
18: X=Me, Y=Me
19: X=OH, Y=H
20: X=O, Y=O
Published on the web (Advance View) May 24, 2008; doi:10.1246/cl.2008.662