Chiral tetrakis(2-thienyl)methane derivative: A possible precursor for cryptochiral tetraalkylmethanes

Article abstract of DOI:10.1246/cl.2008.1236

(5-Acetyl-2-thienyl)(5-benzoyl-2-thienyl)(5-bromo-2-thienyl) -(5-cyano-2-thienyl)methane has been synthesized as the first chiral tetrakis(2-thienyl)methane derivative. This compound can be resolved by chiral HPLC. Since Raney nickel reduction of tetrakis(2-thienyl)methane derivatives gave tetraalkylmethane derivatives, chiral tetrakis(2-thienyl)methane derivatives will be good precursors for a number of cryptochiral tetraalkylmethanes and their derivatives. Copyright

Full text of DOI:10.1246/cl.2008.1236

1236
Chemistry Letters Vol.37, No.12 (2008)
Chiral Tetrakis(2-thienyl)methane Derivative: A Possible Precursor
for Cryptochiral Tetraalkylmethanes
Kouzou Matsumoto,ꢀ1 Kaori Miki,1 Hiroyuki Kurata,1 Nobuo Rikitake,1 Tatsuo Nehira,2 Takuya Inagaki,1
Gennaro Pescitelli,3 Yasukazu Hirao,1 Takeshi Kawase,1 Masaji Oda,1 and Takashi Kubo1
1Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043
2Graduate School of Integrated Arts and Sciences, Hiroshima University, 1-7-1 Kagamiyama, Higashi-hiroshima 739-8521
3Department of Chemistry, University of Pisa, 56126 Pisa, Italy
(Received September 16, 2008; CL-080889; E-mail: kmatsu@chem.sci.osaka-u.ac.jp)
(5-Acetyl-2-thienyl)(5-benzoyl-2-thienyl)(5-bromo-2-thienyl)-
S
S
(5-cyano-2-thienyl)methane has been synthesized as the first chi-
ral tetrakis(2-thienyl)methane derivative. This compound can be
resolved by chiral HPLC. Since Raney nickel reduction of tetra-
kis(2-thienyl)methane derivatives gave tetraalkylmethane deriv-
atives, chiral tetrakis(2-thienyl)methane derivatives will be good
precursors for a number of cryptochiral tetraalkylmethanes and
their derivatives.
(b)
S
(a)
S
S
S
S
S
Me
O
NC
NC
2
Br
Br
S
S
(c)
S
S
+
+
Br
2
1
Cryptochirality means the ‘‘hidden’’ chirality of such com-
pounds that are virtually optically inactive in spite of inherently
chiral molecular structure.1 Chiral tetraalkylmethanes do not
contain any functional groups, and they can be classified as cryp-
tochiral compounds. These cryptochiral tetraalkylmethanes have
been studied for several decades in relation to their optical activ-
ity,2 chiral discrimination,3 and absolute configuration determi-
nation.4 Recently, we reported the synthesis and chiroptical
properties of phenyl(2-pyridyl)(3-pyridyl)(4-pyridyl)methane
as the first chiral molecule based on a tetraarylmethane frame-
work (Chart 1).5 Now we have devised another type of chiral
molecule based on a tetraarylmethane framework; chirality is in-
troduced by the four different substituents on a symmetrical tet-
raarylmethane core. We chose tetrakis(2-thienyl)methane6
(Th4C) as the core unit. It is expected that a number of crypto-
chiral tetraalkylmethanes and their derivatives could be system-
atically synthesized by Raney nickel reduction of the corre-
sponding chiral Th4C derivatives. In addition, optical resolution
and absolute configuration determination of Th4C derivatives
would be more practical than those of tetraalkylmethane itself.
Therefore, chiral Th4C derivatives are interesting not only in
their own chiroptical properties, which would be dependent upon
their substituents, but also as promising precursors of enantio-
merically pure cryptochiral tetraalkylmethane derivatives. We
now report the synthesis and chiroptical properties of 1 as the
first example of a chiral Th4C derivative. Raney nickel reduction
of Th4C is also presented.
S
S
S
S
Me
Me
O
O
NC
NC
3
4
Scheme 1. Synthesis of 1. Reagents and conditions: (a)
CH3COCl (1.0 equiv), SnCl4 (1.0 equiv), CS2, rt, 2 h, 56%;
(b) NBS (1.0 equiv), DMF, in the dark, rt, 24 h; (c) PhCOCl
(20 equiv), AlCl3 (20 equiv), rt, 20 h, 35% (2 steps).
The synthesis of 1 is illustrated in Scheme 1. Friedel–Crafts
acylation of (5-cyano-2-thienyl)tris(2-thienyl)methane6b afford-
ed 2 in 56% yield. Bromination of 2 with NBS in DMF afforded
a mixture of the starting material 2, mono-brominated compound
3, and di-brominated compound 4. Since the purification of 3
was difficult, the crude product was used without further purifi-
cation. Thus, the mixture containing 3 was treated with excess
benzoyl chloride and AlCl3 to afford a mixture of 4, monoben-
zoylated product 1, and dibenzoylated product. The target chiral
molecule 1 in turn, was purified by column chromatography on
silica gel. Identification of 1 was achieved by EI-MS, NMR, and
elemental analysis.7,8
The enantiomeric pair of 1 was successfully resolved by chi-
ral HPLC with a CHIRALPAK AS-H column (Figure 1). As ex-
pected, the electronic CD spectra of the two fractions in acetoni-
trile (Figure 2) are mirror images of each other. In order to assign
the absolute configuration of 1, we attempted to calculate the
electronic CD curve for comparison with the experimental CD
spectra.5,9 However, a standard molecular-mechanics conforma-
tional analysis with MMFF94S10 gave as many as 663 stable
conformations within 20.25 kJ molꢁ1, which correspond to the
various rotamers not only around the four C–aryl bonds but also
around the single bonds in acetyl and benzoyl groups. The pop-
ulation of the most stable conformer was estimated to be only
1.7% at room temperature. Accordingly, it was practically im-
possible to achieve the absolute configuration determination of
1 by calculation of the CD curve.
Br
S
N
S
O
S
S
N
Ph
S
S
S
S
Me
N
O
NC
Th4C
Chart 1.
1
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.12 (2008)
1237
ing trialkylmethane derivative 7, produced by the hydrogenoly-
sis of one C–C bond of the central carbon atom in 5.12
4.0
+1.0
In summary, we have synthesized the first chiral Th4C deriv-
ative 1 and enclosed chiroptical properties of 1. We have also
shown that Raney nickel reduction of 5 gives tetraalkylmethane
derivative 6 in moderate yield. These results would open the way
to a number of optically pure samples of cryptochiral tetraalkyl-
methanes and their derivatives. Synthesis of other chiral Th4C
derivatives, absolute configuration determination and Raney
nickel reduction of 1 are now under investigation.
0
2.0
–1.0
0
0
20
40
60
0
20
40
60
retention time / min
retention time / min
Figure 1. Chromatogram for the enantiomeric separation of 1.
Left: UV detection (ꢁ ¼ 275 nm). Right: CD detection (ꢁ ¼
275 nm). Conditions: column; CHIRALPAK AS-H, eluent;
hexane/ethanol = 90:10 (v/v), flow rate; 1.0 mL minꢁ1, tem-
perature; 35 ꢂC, t1 ¼ 49:5 min, t2 ¼ 51:5 min.
The authors would like to thank Iketani Foundation for par-
tially supporting this research.
References and Notes
1
a) K. Mislow, P. Bickart, Isr. J. Chem. 1977, 15, 1. b) K. Mislow,
Collect. Czech. Chem. Commun. 2003, 68, 849.
4.0
2
a) H. Wynberg, G. L. Hekkert, J. P. M. Houbier, H. W. Bosch, J.
Am. Chem. Soc. 1965, 87, 2635. b) W. T. Hoeve, H. Wynberg, J.
Org. Chem. 1980, 45, 2754.
+1.0
3.0
3
4
T. Kawasaki, H. Tanaka, T. Tsutsumi, T. Kasahara, I. Sato, K.
Soai, J. Am. Chem. Soc. 2006, 128, 6032.
a) J. Haesler, I. Schindelholz, E. Riguet, C. G. Bochet, W. Hug,
Nature 2007, 446, 526. b) T. Fujita, K. Obata, S. Kuwahara, N.
Miura, A. Nakahashi, K. Monde, J. Decatur, N. Harada, Tetrahe-
dron Lett. 2007, 48, 4219.
K. Matsumoto, T. Inagaki, T. Nehira, M. Kannami, D. Inokuchi,
H. Kurata, T. Kawase, G. Pescitelli, M. Oda, Chem. Asian J.
2007, 2, 1031.
a) K. Matsumoto, H. Nakaminami, M. Sogabe, H. Kurata, M. Oda,
Tetrahedron Lett. 2002, 43, 3049. b) K. Matsumoto, T. Tanaka,
M. Oda, Synth. Commun. 2004, 34, 4037. c) K. Matsumoto, T.
Tanaka, S. Kugo, T. Inagaki, Y. Hirao, H. Kurata, T. Kawase, T.
Kubo, Chem. Asian J. 2008, 3, in press.
2.0
1.0
0
0.0
ε
ε
–1.0
5
6
250
300
350
400
250
300
350
400
Wavelength / nm
Wavelength / nm
Figure 2. Left: UV–vis spectrum of 1 in acetonitrile. Right: CD
spectra of the enantiomeric pair of 1 in acetonitrile. The first and
second eluted fractions are plotted as solid and dashed lines,
respectively.
7
Spectroscopic data for 1: pale yellow solid; mp 61.5–62.5 ꢂC;
EIMS m=z (rel intensity) 595 (Mþ, 81Br, 100), 593 (Mþ, 79Br,
81), 552 (½M ꢁ CH3COꢃþ, 81Br, 61), 550 (½M ꢁ CH3COꢃþ,
79Br, 45), 514 (½M ꢁ Brꢃþ, 85), 490 (½M ꢁ PhCOꢃþ, 81Br, 33),
488 (½M ꢁ PhCOꢃþ, 79Br, 31); 1H NMR (500 MHz, CDCl3): ꢀ
2.55 (s, 3H), 6.84 (d, J ¼ 4:0 Hz, 1H), 7.02 (d, J ¼ 4:0 Hz, 1H),
7.13 (d, J ¼ 4:0 Hz, 1H), 7.14 (d, J ¼ 4:0 Hz, 1H), 7.15 (d,
J ¼ 4:0 Hz, 1H), 7.49–7.52 (m, 2H), 7.55 (d, J ¼ 4:0 Hz, 1H),
7.56 (d, J ¼ 4:0 Hz, 1H), 7.61 (d, J ¼ 4:0 Hz, 1H), 7.59–7.63
(m, 1H), 7.84–7.86 (m, 2H); 13C NMR (125 MHz, CDCl3): ꢀ
26.57, 54.26, 110.58, 113.43, 114.10, 128.60, 128.64, 128.96,
128.99, 129.20, 129.23, 130.03, 131.87, 132.68, 134.17, 137.28,
137.41, 143.81, 144.59, 149.70, 157.25, 157.26, 157.47, 187.96,
190.57; Anal. Calcd for C27H16BrNO2S4: C, 54.54; H, 2.71; N,
2.36%. Found: C, 54.22; H, 2.98; N, 2.34%.
Ar
Ar
S
(a)
S
R
Ar
Ar
S
S
Ar
Ar
Ar
5
6: R = (CH2)6Ar
7: R = H
a: Ar = 4-(MeO)-C6H4
b: Ar = 2,5-(MeO)2-C6H3
Scheme 2. Raney nickel reduction of Th4C derivative 5. Re-
agents and conditions: (a) Raney nickel W7 (50 equiv),
0.3 MPa H2, ethanol–benzene, 85 ꢂC, 5 h, 6a (40%), 7a (27%),
6b (53%), and 7b (24%).
1
8
9
Full assignment of the H and 13C NMR spectra was achieved by
the acquisition of heteronuclear multiple-quantum correlation
(HMQC) and heteronuclear multiple-bond correlation (HMBC)
spectra.13
a) C. Diedrich, S. Grimme, J. Phys. Chem. A 2003, 107, 2524.
b) T. D. Crawford, Theor. Chem. Acc. 2006, 115, 227. c) N.
Berova, L. D. Bari, G. Pescitelli, Chem. Soc. Rev. 2007, 36, 914.
Providing for the reduction of chiral Th4C derivative 1,
Raney nickel reduction of 5 was examined as a model experi-
ment for the synthesis of tetraalkylmethane from the correspond-
ing Th4C derivative (Scheme 2). Since we studied the Raney
nickel reduction of tris(2-thienyl)methane derivatives,11 we ap-
plied similar conditions to the reduction of 5. For convenient
UV-detection by TLC analysis and the assignment of NMR
chemical shifts of the products, methoxyphenyl groups were at-
tached at the terminals of the Th4C framework. When an isomer-
ic mixture of 5 was treated with excess Raney nickel under me-
dium pressure of hydrogen, the tetraalkylmethane derivative 6
was obtained in moderate yield accompanied by the correspond-
10 a) T. A. Halgren, J. Am. Chem. Soc. 1992, 114, 7827. b) T. A.
Halgren, J. Comput. Chem. 1996, 17, 490. c) T. A. Halgren, R. B.
Nachbar, J. Comput. Chem. 1996, 17, 587. d) T. A. Halgren, J.
Comput. Chem. 1999, 20, 720.
11 H. Kurata, N. Rikitake, A. Okumura, M. Oda, Chem. Lett. 2004,
33, 1018.
12 Experimental details of the Raney nickel reduction of 5 and spec-
troscopic data of the products are described in the Supporting
Information.
13 Supporting Information is also available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Published on the web (Advance View) November 8, 2008; doi:10.1246/cl.2008.1236