Synthesis and structure of optically active 1,12-diethyl-and 1,12-diisopropylbenzo[c]phenanthrenes: An isopropyl group can be smaller than a methyl group

Article abstract of DOI:10.1246/cl.2007.72

1,12-Diethyl- and 1,12-diisopropylbenzo[c]phenanthrene-5,8-dicarboxylic acids were synthesized, and resolved. The dihedral angles formed by the A and D rings increased in the order of diisopropyl < diethyl < dimethyl as indicated by X-ray analysis, which showed that the strain decreased with the increase of the bulkiness at the 1,12-groups. Copyright

Full text of DOI:10.1246/cl.2007.72

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Chemistry Letters Vol.36, No.1 (2007)
Synthesis and Structure of Optically Active 1,12-Diethyl-
and 1,12-Diisopropylbenzo[c]phenanthrenes:
An Isopropyl Group Can Be Smaller than a Methyl Group
Hiroki Sugiura, Daisuke Sakai, Harunori Otani, Kazuhiro Teranishi, Yusuke Takahira,
Ryo Amemiya, and Masahiko Yamaguchiꢀ
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aoba, Sendai 980-8578
(Received October 3, 2006; CL-061160; E-mail: yama@mail.pharm.tohoku.ac.jp)
1,12-Diethyl- and 1,12-diisopropylbenzo[c]phenanthrene-
R R
R R
H
H
1112α C C 1α
2
5,8-dicarboxylic acids were synthesized, and resolved. The dihe-
dral angles formed by the A and D rings increased in the order of
diisopropyl < diethyl < dimethyl as indicated by X-ray analy-
sis, which showed that the strain decreased with the increase
of the bulkiness at the 1,12-groups.
1
12
12a 4b
D
A
9
4
HO2C
CO2H
HOCH2
CH2OH
12b
4a
5
(P)-4 (R = Me)
(P)-1 (R = Me)
8
6a
(P)-5 (R = Et)
(P)-2 (R = Et)
6
(P)-6 (R = i-Pr)
(P)-3 (R = i-Pr)
RR
RR
O2
S
Helicenes are a group of chiral compounds possessing a
nonplanar o-condensed polycyclic aromatic ring system.1 If a
series of helicenes with different pitches could be provided by
the modification of their molecular structures, the properties of
helical compounds can be better understood and fine-tuned.
The effect of substituents on strain was compared in a series
of 4,5-disubstituted phenanthrenes by experiments and calcula-
tions.2,3 The following orders of the 4,5-substituent were ob-
tained regarding the dihedral angle between the A and C rings,
dihydro < difluoro < dimethyl < dichloro;2 dihydro < dimethyl
< diisopropyl < di(t-butyl).3 The orders of the strain are in
accordance with the bulkiness of the substituents. These com-
pounds, however, generally racemize in solution at room tem-
perature, and may not be suitable to study the effect of pitch.
Thiaheterohelicenes with different substituents at the terminal
benzene rings were compared.4–7 It was shown that, in the solid
state, the dihedral angles of the terminal benzenes changed de-
pending on the structure of the bridged moiety, which connected
the terminal benzenes.5 Since the angle considerably changed by
inclusion complexation, thiaheterohelicenes appear to possess
a flexile structure.6 A systematic study is needed to provide a
series of optically active helicenes with different pitches.
1,12-Dimethylbenzo[c]phenanthrene is one of the configu-
rationally stable helicenes, and their chirality is generated by
the repulsion between the 1,12-dimethyl groups. Unlike 4,5-
dimethylphenanthrenes, 1,12-dimethylbenzo[c]phenanthrenes
do not racemize even at higher temperatures. In addition, this
all-carbon helicene possesses a rigid structure as inferred by
the invariable dihedral angles formed by the average plane of
the A and D rings: (P)-1,12-Dimethylbenzo[c]phenanthrene-
5,8-dicarboxylic acid bis(l-camphorsultam) amide (P)-7,8
47.9ꢁ; (M)-1,12-dimethylbenzo[c]phenanthrene-5,8-di(methyl-
amine) dihydrochloride,9 46.99ꢁ; (ꢂ)-1,12-dimethylbenzo[c]-
phenanthrene-5,8-di(methylamine) dihydrochloride,9 47.03ꢁ. It
was therefore considered interesting to modify the helical struc-
ture by substituting the 1,12-dimethyl group with other groups.
Synthesized in this study are 1,12-diethylbenzo[c]phenanthrene
and 1,12-diisopropylbenzo[c]phenanthrenes: Racemic 5,8-dini-
triles (ꢂ)-17 and (ꢂ)-18; 5,8-dicarboxylic acids (ꢂ)-2 and
(ꢂ)-3; optically pure 5,8-dimethanols (P)-5, (M)-5, (P)-6, and
X =
COX
XOC
COX
XOC
N
(P)-7 (R = Me)
(P)-8 (R = Et)
(P)-9 (R = i-Pr)
(M)-10 (R = i-Pr)
Chart 1.
(M)-6; biscamphorsultams (P)-8, (P)-9, and (M)-10 (Chart 1).
The structures were compared with the 1,12-dimethyl deriva-
tives: dinitrile (ꢂ)-19, dicarboxylic acid (ꢂ)-1, dimethanol
(P)-4, and biscamphorsultam (P)-7.8 Contrary to the expectation
that replacing the 1,12-dimethyl group with diethyl and diiso-
propyl groups would increase the strain of the helicene ring sys-
tem, the diisopropyl derivative was less strained than the
dimethyl derivative.
The dicarboxylic acids (ꢂ)-2 and (ꢂ)-3 were synthesized
employing the same method8 with (ꢂ)-1 starting from o-ethyl-
aniline 11 and o-isopropylaniline 12, respectively (Scheme 1).
A diacid 13, which was obtained from 11 in 5 steps, was treated
with polyphosphoric acid giving a diketone (ꢂ)-15 in 70% yield.
The same reaction of another diacid 14, synthesized from 12,
gave (ꢂ)-16 (43%), which was accompanied by substantial
deisopropylation (40%). The side reaction may be ascribed to
the increased steric repulsions and/or cation stabilization of iso-
propyl group. Cyanation and aromatization of (ꢂ)-15 and (ꢂ)-16
gave 5,8-dinitriles (ꢂ)-17 and (ꢂ)-18, respectively, which were
hydrolyzed to provide (ꢂ)-2 and (ꢂ)-3. Diethyl derivative (ꢂ)-2
was resolved as brucine salt. Optically pure (P)-2 was converted
to biscamphorsultam (P)-8 to determine the absolute configura-
tion by X-ray analysis,10,11 and was transformed to 5,8-dimetha-
RR
H
R R
R
CHO
O
O
HO2C
CO2H
13 (R = Et)
14 (R = i-Pr)
H
11 (R = Et)
12 (R = i-Pr)
( )-15 (R = Et)
( )-16 (R = i-Pr)
RR
( )-2 (R = Et)
( )-3 (R = i-Pr)
( )-17 (R = Et)
( )-18 (R = i-Pr)
( )-19 (R = Me)
NC
CN
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
73
organic chemistry, and it is well established that an isopropyl
group is larger than a methyl group. The concept has been
qualitatively discussed using, for example, the A values,13 Es
values,14 or IX{H values.15 It was noticed in several occasions
that isopropyl group can behave as a slightly larger substituent
compared to a methyl group, which was explained by the
rotation directing the proton to the hindered site.3,12 However,
described in the present study is a reverse to this rule.
The rotation of the Cð1ꢂÞ–Cð1Þ bond in (P)-9 is restricted,
whereas the methyl group in (P)-7 can freely rotate. The anti-
periplanar arrangements of the Cð1ꢂÞ–H bond and Cð12ꢂÞ–H
bond in (P)-9 appear to have contributed to decrease repulsions
of the isopropyl group, torsion angle H–Cð12ꢂÞꢃꢃꢃCð1ꢂÞ–H:
158.8(5)ꢁ for (P)-9. The reduced mobility of the isopropyl group
minimized the steric repulsion, and have decreased the formal
size of the isopropyl group compared to the methyl group. Since
the discussions of A values or Es values treat the free rotating
groups, the inhibition of the rotation would provide different
conclusions.
(a)
(b)
(c)
Figure 1. X-ray structures of biscamphorsultams (P)-7 (a), (P)-
8 (b), and (P)-9 (c): shown in orange are the A and D ring, in
which the arrows indicate the increased volume of the helicene
moiety.
nol (P)-5 by lithium aluminum hydride reduction. Diisopropyl
derivative (ꢂ)-3 was converted to biscamphorsultams (P)-9
and (M)-10, which were chromatographically separated. The
compound (P)-9 was subjected to X-ray analysis to determine
the absolute configuration.10,11 The chiral auxiliaries of (P)-9
and (M)-10 were removed by reduction giving enantiomeric
(P)-6 and (M)-6, respectively.
The X-ray structures (P)-8 and (P)-9 were compared with
(P)-7.11 Two distinct methyl groups are present in (P)-9,
out-of-plane and in-plane methyls, and the rotation of isopropyl
group is restricted. Notable are the bottom views (Figures 1a–
1c). The A and D rings of the benzo[c]phenanthrene moiety col-
ored orange were larger in (P)-7 compared to (P)-9 as indicated
by the arrows. In order to confirm this qualitatively, the dihedral
angles obtained by the average plane of the A and D rings at the
benzo[c]phenanthrene ring were compared: (P)-7, 47.9(1)ꢁ;8
(P)-8, 45.2(1)ꢁ; (P)-9, 41.8(2)ꢁ. The dihedral angles of the relat-
ed compounds were reported: benzo[c]phenanthrene, 26.68ꢁ and
1,4-dimethylbenzo[c]phenanthrene, 36.65ꢁ.12 It is reasonable
that the angle increases as the number of 1,12-methyl groups
increases. However, as shown in this study, the decrease of the
angle in the 1,12-diethyl and 1,12-diisopropyl derivatives is
unusual, and is reverse to the well-accepted bulkiness of the
substituent. The dimethyl group exerts more hindrance than
the diisopropyl group on the strain of 1,12-disubstituted
benzo[c]phenanthrene.
The UV spectra of dinitriles (ꢂ)-17, (ꢂ)-18, and (ꢂ)-19
were compared (Figure 2a). The ꢀmax at ca. 300 nm attributable
to ꢁ–ꢁꢀ transition shifted to longer wavelengths as the 1,12-sub-
stituent changes from dimethyl to diisopropyl: (ꢂ)-19, 308 nm,
(ꢂ)-17, 312 nm, and (ꢂ)-18, 317 nm. Such trend in the UV spec-
tra was also observed with the racemic 5,8-dicarboxylic acids
(ꢂ)-1, (ꢂ)-2, and (ꢂ)-311 and optically active 5,8-dimethanols
(P)-4, (P)-5, and (P)-6 (Figure 2b).11 A stronger Cotton effect
at ca. 300 nm was observed for (P)-6 than for (P)-4 (Figure 2c).
The steric effect of substituent is an important concept in
This work was supported by grants from JSPS. A fellowship
to H.S. from JSPS for young Japanese scientists is also gratefully
acknowledged.
References and Notes
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Figure 2. (a) UV spectra of (ꢂ)-17, (ꢂ)-18, and (ꢂ)-19 (2:0 ꢄ
10ꢅ5 mol/L, 25 ꢁC) in chloroform. (b) UV (2:0 ꢄ 10ꢅ5 mol/L,
25 ꢁC), and (c) CD (5:0 ꢄ 10ꢅ5 mol/L, 25 ꢁC) spectra of (P)-4,
(P)-5, and (P)-6 in methanol.
Published on the web (Advance View) November 29, 2006; doi:10.1246/cl.2007.72