Synthesis and chiroptical properties of arylimines of cholest-4-ene-3,6- dione

Article abstract of DOI:10.1021/jo301591g

In the hope of generating a new class of materials with large optical rotations, various arylamines were condensed with cholest-4-ene-3,6-dione (2) to give 3-arylimino steroids. These compounds possess moderately high specific rotations ([α]_D ～300a-800) and strong circular dichroism. One such derivative, 3-(4-methoxyphenylimino)cholest-4-en-6-one (3), crystallizes as the (E)-imine and upon dissolution undergoes mutarotation to an equilibrium mixture of (E)-and (Z)-isomers with a half-life of approximately 1 h at room temperature, as judged by both NMR spectroscopy and polarimetry.

Full text of DOI:10.1021/jo301591g

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Note
Synthesis and Chiroptical Properties of Arylimines of Cholest-4-ene-3,6-dione
Xin Geng, Joel T. Mague, and Robert Anthony Pascal
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 02 Nov 2012
Downloaded from http://pubs.acs.org on November 7, 2012
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Synthesis and Chiroptical Properties of Arylimines of Cholest-4-ene-3,6-dione
Xin Geng, Joel T. Mague, and Robert A. Pascal, Jr.*
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Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
E-mail: rpascal@tulane.edu
TOC/Abstract Graphic:
MeO
N
O
Abstract: In the hope of generating a new class of materials with large optical rotations, various
arylamines were condensed with cholest-4-ene-3,6-dione (2) to give 3-arylimino steroids. These
compounds possess moderately high specific rotations ([α]D ~ 300-800) and strong circular
dichroism. One such derivative, 3-(4-methoxyphenylimino)cholest-4-en-6-one (3), crystallizes
as the (E)-imine, and upon dissolution undergoes mutarotation to an equilibrium mixture of (E)-
and (Z)-isomers with a half-life of approximately one hour at room temperature, as judged by
both NMR spectroscopy and polarimetry.
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Our long-standing interest in twisted polycyclic aromatic compounds1 eventually led to the
preparation of resolvable twisted acenes (9,10,11,20,21,22-hexaphenyltetrabenzo[a,c,l,n]-
pentacene and a dimethyl derivative), which exhibited exceptionally high specific rotations ([α]D
~ 5000-7500).2 Unfortunately, these compounds are not configurationally stable at room
temperature. We subsequently prepared a number of configurationally stable twisted acenes, but
these proved to have relatively modest specific rotations.3 In any event, the synthetic yields of
such sterically crowded, polycyclic aromatics are at best fair, so that if one wished to employ
compounds of high specific rotation in materials science applications, one would have to look
elsewhere. For such a purpose, the various helicene quinones of Katz and coworkers are one
class of high-rotation compounds that may be prepared in multigram quantities,4 but even these
syntheses are not “simple”. Indeed, the most easily accessible high-rotation compounds remain
the aryliminocamphors of Forster and Thornley (e.g., compound 1, [α]D –1223), prepared by
condensation of aniline derivatives with readily available camphorquinone.5
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Me
Me
Me
O
MeO
N
1
We wondered if there might be other diketones, trivially derived from common natural
products, that would provide the basis for a new series of high-rotation materials. Steroid
diketones are an obvious possibility, and a few minutes spent browsing Fieser’s Steroids6
revealed several candidates. Cholest-4-ene-3,6-dione (2, Scheme 1), prepared in high yield by
dichromate oxidation of cholesterol without the need for chromatography,7 was judged to be the
best compound for an initial investigation after DFT calculations of an arylimino derivative
indicated that it might possess [α]D > 1000. We report herein the synthesis and chiroptical
properties of several arylimino derivatives of compound 2, and we compare these data to the
results of DFT calculations.
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The condensation of aryl amines with diketone 2 was straightforward, but chromatographic
purification of the product was required in all cases. The general method was to mix the steroid,
amine or diamine, and anhydrous Na2SO4 in ethanol in a screw-capped tube, and then to place
the tube in a boiling water bath (100 °C) or an oil bath (120 °C) for 1-48 h. Concentration and
chromatography gave the desired imines 3, 6, and 7 in modest yields (Scheme 1). An attempt to
methylate compound 2 at C-2, in order to limit the available conformations of the derived imines
(see below), gave mainly the 6-O-methylated product 4. Compound 4 was condensed with p-
anisidine, to give imine 5.
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Scheme 1
n-BuLi / MeI
THF / HMPA
66%
2
4
O
O
OMe
NH2
O
NH2
38%
21%
MeO
MeO
Na2SO4 / EtOH
Na2SO4 / EtOH
MeO
MeO
N
N
3
5
O
OMe
N
O
6 (24% from 2)
O
N
N
O
7 (11% from 2)
In principle, either the C-3 or the C-6 carbonyl group of compound 2 might react to form
imines, and although the C-3 carbonyl is presumed to be more reactive, the NMR spectra of the
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products do not unambiguously establish the regioselectivity of the condensation. Fortunately,
compound 3 is highly crystalline (the other imines are not), and ultimately its X-ray structure
was determined. The structure contains two crystallographically independent molecules of 3,
and both crystallize as the (E)-imine of the C-3 carbonyl group. The molecular structure of one
of these molecules is illustrated in Figure 1.
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Figure 1. Molecular structure of compound 3; thermal
ellipsoids are drawn at the 50% probability level.
The imines synthesized in this study proved to consist of a mixture of (E)- and (Z)-isomers
at the imine bond, and these isomers only slowly interconvert at room temperature. As a result,
these compounds tend to be poorly crystalline, if at all. An exception is compound 3, which
readily forms golden needles from ethanol, and which was shown to contain only the (E)-isomer
by X-ray analysis. Long before the crystal structure was determined, we noticed that when
proton NMR spectra of compound 3 were recorded shortly after dissolution in CDCl3, the
spectrum showed only a single olefinic resonance (δ 6.70) and a single methoxy resonance (δ
3.80). However, if a sample was left overnight before recording the spectrum, then two olefin
and two methoxy resonances were visible in an approximately 3:2 ratio, with the originally
observed resonances still predominant. Because the exclusive isomer in the NMR spectrum of
freshly dissolved 3 remains the major isomer after equilibration, the (E)-isomer is demonstrated
to be the lowest energy stereoisomer. In a kinetic study, the isomerization of compound 3 was
monitored by integration of the NMR spectra over several hours. The isomerization proved to be
a simple first-order process (see the Supporting Information) with a half-life of 53.5 min at 19
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°C, yielding ΔG‡ = 22.0 kcal/mol. This value is in good agreement with reported barriers for
imine rotation, although these can vary significantly, depending on the substituents present.8
With a variety of imines in hand, the specific rotations ([α]D) of all compounds were
recorded in chloroform solution at ambient temperature. These data are found in Table 1.
Circular dichroism (CD) spectra were also recorded in chloroform solution, and the spectra are
illustrated in the Supporting Information. The specific rotations these of imines are high, but not
exceptionally so, with no measured [α]D greater than 800. As seen from the computational
studies described below, the relatively modest rotations are due to the presence of accessible
conformations with both high positive and high negative rotatory power.
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Table 1. Experimental and Calculated Specific Rotations for Compounds 3, 5, 6, and 7.
_____________________________________________________________________________
cmpd
3
___________________________________________________________
5
6
7
[α]D (exptl)
+763 (3 min)
+581 (3 h)
+412
+552
+271
[α]D (calcd) [ΔE]a
conf Ab
+1404 [+0.8]
+1131 [+0.7]
–1207 [+0.9]
–1020 [+1.0]
–1096 [+1.0]
–727 [+0.7]
+1112 [0.0]
+869 [+0.2]
+1216 [+0.4]
+928 [+0.3]
–944 [+0.7]
–715 [+0.6]
–736 [+0.4]
–369 [+0.5]
+802 [0.0]
+525 [+0.1]
+2322 [+0.4]
–1780 [+0.5]
–2025 [+0.4]
+1985 [0.0]
+2291 [+0.7]c
–1437 [+1.5]c
–1377 [+1.2]c
+1127 [0.0]c
conf Acb
conf B
conf Bc
conf C
conf Cc
conf D
conf Dc
Boltzmann-
weighted sum
+609
+294
+558
n.d.c
_____________________________________________________________________________
a Relative energy of the various conformations calculated at the B3LYP/6-31G(d) level; zero
point energy corrections have been included. For compounds 3 and 5, conformations A, B, C,
b
and D, the methoxy methyl is trans to the imine bond; for conformations Ac, Bc, Cc, and Dc, the
methoxy methyl is cis. Only the four C2-symmetric conformations having the same orientation
c
of the imine and aryl ring for both steroids were calculated; the Boltzmann-weighted sum of the
calculated rotations was not determined, because there exist not fewer than 12 C1-symmetric
conformations of intermediate energy that were not calculated.
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One finding was expected: having observed the isomerization of compound 3 by NMR, we
were not surprised to see mutarotation as well. The specific rotation of 3 was observed to decay
from [α]D +763, 3 min after dissolution in CHCl3, to [α]D +581 at 3 hours, with little change
thereafter. The observed half-life for this first-order process (see the Supporting Information)
was 52.8 min at a nominal 23 °C, corresponding to ΔG‡ = 22.3 kcal/mol, in good agreement with
the NMR result.
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The steroids imines described herein are conformationally complex, and it would be
impractical to calculate the energies and specific rotations of all possible conformers at a
reasonable level of theory. In order to simplify the problem, only the most highly preferred
conformation of the steroid side chain, which is well known from analysis of hundreds of crystal
structures,9 was used as a starting point for the geometry optimizations. This conformation,
which contains the maximum number of anti torsion angles, is also the low-energy conformation
in gas phase calculations, and the conformation adopted by the molecule in Figure 1.
Conformations resulting from rotations about the single and double C-N bonds in all compounds,
as well as rotation about the aryl C-OMe bonds in compounds 3 and 5, were evaluated by a
systematic search of all possible rotamers. The results of these calculations are summarized in
Table 1. All calculations, including calculations of optical rotation, were performed at the
B3LYP/6-31G(d) level of theory using Gaussian03.10 Analytical frequency calculations were
performed for all conformations, and the relative energies shown in Table 1 contain zero point
energy corrections. The specific rotations of the conformations were calculated by using the
static polarizabilities. Frequency dependent polarizabilities are usually recommended for such
work,11 but an extensive evaluation of methods and basis sets for the calculation of the specific
rotation of compound 1 indicated that the use of frequency dependent polarizabilities led to a
gross overestimation of the specific rotation in this class of compounds (see the Supporting
Information).
It is evident from the calculations (Table 1) that most conformations of compounds 3, 5, 6,
and 7 have large calculated specific rotations—up to 2300 for compound 6. Unfortunately,
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different conformations of the same molecule have calculated rotations of opposite sign, so the
relative energy of the conformations determines the sign and magnitude of the observed specific
rotations. The Boltzmann weighted sum of the calculated rotations has been provided in Table 1
for compounds 3, 5, and 6. Only C2-symmetric conformations of compound 7 were calculated
(there are many C1 conformations); thus, no weighted average was calculated.
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At the B3LYP/6-31G(d) level, the most stable conformation for all of the compounds is
“conformation D”. For compound 3, the two lowest energy conformations are the (E)-isomers D
and Dc in Table 1, which differ only in the orientation of the p-methoxy group, and it is isomer
Dc that is observed in both independent molecules of the crystal structure (see Figure 1). There
are in total four (E)-isomers and four (Z)-isomers: in addition to the isomers D and Dc, the
conformations A and Ac are the (Z)-isomers in which the aryl ring is tilted above ring A;
conformations B and Bc are the (E)-isomers in which the aryl ring is tilted below ring A; and
conformations C and Cc are the (Z)-isomers in which the aryl ring is tilted below ring A.
However, all of these conformations lie within 1 kcal/mol of the ground state for compound 3, so
that each contributes significantly to the overall specific rotation at equilibrium. An analogous
situation exists for compounds 5 and 6. In this respect the steroid imines differ dramatically
from the imines of camphorquinone (e.g. 1), which generally possess only a single low energy
conformation. It should be noted that the NMR spectrum of 3 shows only two subspectra
because all four (E)-isomers interconvert rapidly at room temperature, as do all four (Z)-isomers;
it is only the E/Z isomerization that is slow.
In order to limit the number of available conformations, we attempted to introduce a methyl
group at C-2 of the steroid. The presence of the methyl would likely raise the energy of the (E)-
isomers to a degree that they would no longer contribute significantly to the overall rotation.
However, our alkylation reactions produced chiefly the 6-O-methylated compound 4, rather than
any C-methylated steroids. One imine of compound 4 was prepared (compound 5), but it proved
to have a somewhat lower specific rotation than the corresponding imine of 2 (compound 3),
although its ellipticity was rather greater. However, when detailed computational studies (which
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were concomitant with the experimental work) were completed, it became clear that elimination
of the (E)-isomers would still leave us with (Z)-isomer conformations of comparable energy but
opposite rotation (essentially conformations A and C). For this reason, further attempts to
alkylate at C-2 were abandoned.
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The computational studies indicated that larger aromatic π-systems and the use of aromatic
diamines for the synthesis of the arylimino steroids would at least give individual conformations
with higher specific rotations than were possible with simple aniline derivatives (see Table 1).
Furthermore, the camphorquinone derivative with the highest reported specific rotation ([α]D
2875°) is the bisimine derived from bis(4-aminophenyl)amine.12 It was for these reasons that we
prepared the aminopyrene- and diaminonaphthalene-derived compounds 6 and 7, but their
observed rotations were no higher than for the simpler compounds. An additional complication
for molecules with such large π-systems is that they have significant absorption at the sodium D
line (589 nm). For 6 and 7, the absorbance was tolerable, but the absorbance of moderately
concentrated solutions of steroid diimines prepared from bis(4-aminophenyl)amine and bis(4-
aminophenyl) ether was too great to permit the accurate measurement of their specific rotations
(data not shown).
A pleasing aspect of the present work is the very good agreement of the experimental and
calculated optical rotations, even though the calculations were performed at a relatively modest
level of theory, B3LYP/6-31G(d). It was clear from calculations of the specific rotation of
compound 1 (see the Supporting Information), that the results of the calculations show only
modest basis set dependence, but a high variability with respect to the choice of method.
B3LYP/6-31G(d) and B3PW91/6-31G(d) calculations employing static polarizabilities gave the
best results for compound 1, and so the former, very common method was chosen for the
calculations of the steroid imines, which are chemically similar. In the case of the steroid
imines, however, it is necessary to calculate accurately both the relative energies of the various
conformations and their specific rotations, yet the experimental and calculated data for
compounds 3 and 6 are in excellent agreement, and those for compound 5 are at least good.
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Unfortunately, a complete evaluation of the conformations of compound 7 was beyond the reach
of our present computational resources.
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In conclusion, imines of cholest-4-ene-3,6-dione (2) are easily prepared (two steps from
cholesterol) optically pure materials that exhibit specific rotations of several hundred degrees,
but these values are not so high as the specific rotations of analogous imines prepared from the
equally available camphorquinone. Individual conformations of the steroid imines are calculated
to have very high specific rotations, but accessible conformations with both high positive and
high negative rotations are present, so that the observed specific rotations are more modest. The
agreement of the experimental and calculated specific rotations is very good, so that it may be
possible to employ computational methods to design derivatives of related compounds with a
more limited set of conformations and higher observed specific rotations.
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Experimental
Cholest-4-ene-3,6-dione (2) was prepared by the method of Fieser.7 Mp 121.5-123.5 °C
(lit.7 122-123 °C); 1H NMR (CDCl3) δ 0.72 (s, 3 H), 0.861 (d, J = 7 Hz, 3 H), 0.866 (d, J = 7 Hz,
3 H), 0.92 (d, J = 7 Hz, 3 H), 1.16 (s, 3 H), 1.0-2.2 (methylene envelope, 22 H), 2.49 (m, 3 H),
2.68 (dd, J = 16 Hz, 4 Hz, 1 H), 6.17 (s, 1 H); 13C NMR (CDCl3) δ 11.9, 17.5, 18.6, 20.9, 22.6,
22.9, 23.8, 24.0, 28.00, 28.01, 34.0, 34.2, 35.5, 35.7, 36.0, 39.1, 39.4, 39.8, 42.5, 46.8, 50.9, 55.9,
56.5, 125.4, 161.1, 199.5, 202.3 (27 of 27 expected resonances).
3-(4-Methoxyphenylimino)cholest-4-en-6-one (3). Diketone 2 (199 mg, 0.500 mmol),
anisidine (62 mg, 0.504 mmol), Na2SO4 (0.5 g), and EtOH (1 mL) were heated in a screw-capped
tube on a boiling water bath for 1 h. The mixture was diluted with CHCl3, the salt was filtered
away, and the solution was concentrated to dryness. This material was fractionated by
preparative TLC (solvent, 20:1 benzene-EtOAc). A bright yellow band with Rf = 0.43 was
extracted from the silica with CHCl3, and upon concentration gave compound 3 as an orange oil
that crystallized upon standing (77.1 mg, 0.190 mmol, 38%). A portion of this material was
recrystallized from EtOH to give bright yellow needles, mp 147.5-148.5 °C. At equilibrium in
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solution, 1H NMR analysis indicated that the imine 3 consisted of a roughly 3:2 mixture of
1
isomers. H NMR (CDCl3) δ 0.71 (s, 3 H), 0.860 (d, J = 7 Hz, 3 H), 0.864 (d, J = 7 Hz, 3 H),
7
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0.91 (d, J = 6 Hz, ~1.8 H), 0.93 (d, J = 6 Hz, ~1.2 H), 1.11 (s, 3 H), 1.0-2.1 (methylene envelope,
22 H), 2.33 (m, 1 H), 2.64 (m, 3 H), 3.79 (s, ~1.2 H), 3.80 (s, ~1.8 H), 6.46 (s, ~0.4 H), 6.70 (s,
~0.6 H), 6.73 (m, 2 H), 6.86 (m, 2 H); 13C NMR (CDCl3) δ 11.8, 18.2, 18.3, 18.6, 20.9, 21.0,
22.5, 22.8, 23.7, 23.9, 24.5, 28.0, 30.7, 33.7, 33.9, 35.2, 35.5, 35.6, 36.0, 39.0, 39.2, 39.4, 39.7,
42.4, 42.5, 46.4, 46.6, 50.5, 50.8, 55.4, 55.9, 56.5, 114.0, 114.1, 118.7, 121.3, 121.6, 130.5,
142.9, 143.4, 153.4, 154.5, 156.4, 156.5, 164.2, 166.0, 202.1, 203.2 (48 of 64 possible
resonances for the cis and trans imine isomers); HRMS (ESI-TOF) m/z 504.3838 (M + H), calcd
for C34H50NO2 504.3836; UV (CHCl3) λmax (log ε) 264 (4.0), 378 (3.4); [α]D23 (t = 3 min) +763,
[α]D23 (t = 3 h) +581 (c 0.77, CHCl3); CD (CHCl3) λmax ([θ]) 279 (–36,000), 385 (23,000).
6-Methoxycholesta-4,6-dien-3-one (4). Diisopropylamine (0.47 g, 4.6 mmol) was
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dissolved THF (10 mL) and cooled to 0 °C under argon. A solution of n-butyllithium (1.8 ml,
2.5 M in hexanes, 4.5 mmol) was added, and the resulting solution was stirred for 20 min, and
then cooled to -78 °C. A solution of diketone 2 (1.20 g, 3.00 mmol) in THF (10 mL) was added,
and after 30 min, iodomethane (0.37 mL, 6.0 mmol). The resulting yellow solution was stirred
for 30 min, and then HMPA (1.8 mL) was added dropwise. After 2 h at -78 °C, the solution was
left to warm to room temperature overnight. Ether and water were added, the separated organic
layer was washed with saturated NH4Cl (5 × 5 mL) and brine (5 × 10 mL), and it was dried over
Na2SO4. This material was concentrated and fractionated by silica gel column chromatography
(solvent, 8:1 hexanes-EtOAc) to yield compound 4 as pale yellow oil (0.81 g, 2.0 mmol, 66%).
The site of methylation is evident from the fact that the two olefinic resonances in compound 4
are sharp singlets. This is to be expected for an isolated proton at C-4 (δ 6.23), and an olefinic
proton at C-7 (δ 5.15) cannot couple strongly to the C-8 proton because of the unfavorable
dihedral angle (~ 90°) formed by their respective C-H bonds. Had the product contained a 3-O-
methyl group, the C-2 olefinic proton resonance of the resulting enol ether would have been
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coupled to the C-1 protons. H NMR (CDCl3) δ 0.75 (s, 3 H), 0.856 (d, J = 7 Hz, 3 H), 0.859 (d,
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J = 7 Hz, 3 H), 0.91 (d, J = 6 Hz, 3 H), 1.10 (s, 3 H), 1.0-1.9 (methylene envelope, 20 H), 1.98
(ddd, J = 13, 5, 2 Hz, 1 H), 2.05 (dt, J = 16, 6 Hz, 1 H), 2.41 (dd, J = 18, 5 Hz, 1 H), 2.54 (ddd, J
= 18, 14, 5 Hz, 1 H), 3.58 (s, 3 H), 5.15 (s, 1 H), 6.23 (s, 1 H); 13C NMR (CDCl3) δ 12.0, 16.4,
18.6, 20.6, 22.5, 22.8, 23.8, 23.9, 28.0, 28.1, 33.7, 34.2, 35.4, 35.7, 36.1, 36.4, 39.4, 39.5, 43.3,
51.0, 54.3, 54.7, 56.0, 109.1, 119.3, 149.9, 159.4, 199.9 (28 of 28 expected resonances); HRMS
(ESI-TOF) m/z 413.3416 (M + H), calcd for C28H45O2 413.3414; UV (CHCl3) λmax (log ε) 304
(4.0); [α]D24 +4 (c 2.85, CHCl3).
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3-(4-Methoxyphenylimino)-6-methoxycholesta-4,6-diene (5). Ketone 4 (201 mg, 0.490
mmol), anisidine (67 mg, 0.54 mmol), Na2SO4 (0.5 g), acetic acid (5 drops) and EtOH (5 mL)
were mixed in a screw-capped tube and heated at 100 °C for 26 h. After cooling, the salt was
filtered away, and the filtrate was concentrated to dryness. This material was fractionated by
preparative TLC (solvent, 100:10:1 hexanes-EtOAc-Et3N. A bright yellow band with Rf = 0.48
was extracted from the silica with CHCl3, and concentration of this material gave imine 5 as
yellow oil (52.1 mg, 0.101 mmol, 21%). This material resisted crystallization, but 1H NMR
analysis indicated that it was an 87:13 mixture of the imine 5 and the starting ketone 4; the imine
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itself consisted of two isomers by NMR, present in a roughly 2:1 ratio. H NMR (CDCl3) δ 0.75
(s, 3 H), 0.858 (d, J = 7 Hz, 3 H), 0.862 (d, J = 7 Hz, 3 H), 0.90 (d, J = 6 Hz, ~2 H), 0.92 (d, J = 6
Hz, ~1 H), 1.05 (s, ~2 H), 1.08 (s, ~1 H), 1.0-2.8 (methylene envelope, 25 H), 3.45 (s, ~1 H, enol
ether Me), 3.58 (s, ~ 2 H, enol ether Me), 3.74 (s, ~1 H, arom. OMe), 3.79 (s, ~2 H, arom. OMe),
4.96 (d, J = 1.5 Hz, ~0.3 H), 4.98 (d, J = 1.5 Hz, ~0.7 H), 6.74 (m, 2 H), 6.85 (m, 2 H); 13C NMR
(CDCl3) δ 12.0, 16.6, 16.8, 18.6, 20.7, 20.8, 22.5, 22.8, 23.8, 23.9, 24.0, 24.6, 28.0, 28.1, 30.8,
34.1, 34.4, 35.2, 35.4, 35.7, 36.1, 36.5, 39.4, 39.6, 43.20, 43.23, 51.2, 51.3, 54.4, 54.56, 54.61,
54.65, 55.4, 55.7, 56.1, 105.2, 106.3, 111.4, 113.9, 114.7, 116.4, 121.4, 121.77, 121.81, 139.8,
144.3, 150.5, 150.6, 155.8, 165.4, 167.2 (51 of 66 possible resonances for the cis and trans imine
isomers); HRMS (ESI-TOF) m/z 518.3993 (M + H), calcd for C35H52NO2 518.3993; UV (CHCl3)
λmax (log ε) 302 (4.3), 352 (3.7); [α]D24 +368 (c 0.19, CHCl3) (this yields [α]D24 +412 when
corrected for the presence of 13% compound 4); CD (CHCl3) λmax ([θ]) 344 (47,000).
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3-(1-Pyrenylimino)cholest-4-en-6-one (6). Diketone 2 (202 mg, 0.51 mmol), 1-
aminopyrene (113 mg, 0.52 mmol ), Na2SO4 (0.5 g), and EtOH (2 mL) were mixed in a screw-
capped tube and heated to 120 °C for 20 h. After cooling the mixture to room temperature, it
was diluted with CHCl3, the salt was filtered away, and the solution was concentrated to dryness.
The resulting material was fractionated by preparative TLC (solvent, 7:1 hexanes-EtOAc). The
red band with Rf = 0.41 was extracted from the silica with CHCl3, and concentration gave crude
imine 6 as a red-orange oil (74 mg, 0.12 mmol, 24%). A portion of this material was crystallized
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from ethanol to give orange imine 6; mp 109-112 °C. H NMR analysis indicated that this
material was a 93:7 mixture of the imine 6 and the starting ketone 2; the imine itself consisted of
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two isomers by NMR, present in a roughly 7:3 ratio. H NMR (CDCl3) δ 0.70 (s, 3 H), 0.867 (d,
J = 7 Hz, 3 H), 0.872 (d, J = 7 Hz, 3 H), 0.90 (d, J = 6 Hz, ~2.1 H), 0.93 (d, J = 6 Hz, ~0.9 H),
1.13 (s, ~2.1 H), 1.17 (s, ~0.9 H), 1.0-3.0 (methylene envelope, 26 H), 6.24 (s, ~0.3 H), 6.98 (s,
~0.7 H), 7.33 (d, J = 8 Hz, ~0.3 H), 7.35 (d, J = 8 Hz, ~0.7 H), 7.99 (m, 5 H), 8.13 (m, 3 H); 13C
NMR (CDCl3) δ 11.9, 18.2, 18.3, 18.6, 20.9, 21.0, 22.5, 22.8, 23.8, 24.0, 25.2, 28.0, 30.9, 33.8,
34.0, 35.2, 35.6, 36.0, 39.2, 39.3, 39.4, 39.8, 42.4, 42.5, 46.6, 50.6, 50.9, 55.9, 56.5, 56.6, 116.4,
117.6, 118.9, 120.7, 122.6, 122.8, 124.6, 124.7, 124.8, 124.9, 125.0, 125.1, 125.3, 125.9, 126.0,
126.1, 126.8, 127.0, 127.3, 127.9, 128.2, 129.9, 131.3, 131.6, 144.2, 145.2, 154.5, 155.5, 165.8,
167.8, 202.4, 202.8 (62 of 86 possible resonances for the cis and trans imine isomers); HRMS
(ESI-TOF) m/z 598.4042 (M + H), calcd for C43H52NO 598.4049; UV (CHCl3) λmax (log ε) 274
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(4.4), 284 (4.4), 350 (4.2), 386 (3.7), 422 (3.6); [α]D24 +513 (c 0.19, CHCl3) (this yields [α]D
+552 when corrected for the presence of 7% compound 2); CD (CHCl3) λmax ([θ]) 292 (–10,000),
338 (–11,000), 422 (13,000).
1,6-Bis[(6-ketocholest-4-en-3-ylidene)amino]naphthalene (7). Diketone 2 (404 mg, 1.02
mmol ), 1,6-diaminonaphthalene (42 mg , 0.27 mmol ), Na2SO4 (0.5 g), and EtOH (2 mL) were
combined in a screw-capped tube and heated at 120 °C for 48 h. After cooling to room
temperature, the mixture was diluted with CHCl3, the salt was filtered away, and the solution was
concentrated to dryness. This material was fractionated by preparative TLC (solvent, 5:2
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hexanes-EtOAc). A yellow band with Rf = 0.26 was extracted from the silica with CHCl3, and
after concentration it was crystallized from EtOH to give yellow diimine 7 (27 mg, 0.029 mmol,
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11%), mp 162-168 °C. H NMR analysis showed two principal isomers, present in a roughly 7:3
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ratio, and less than 3% of the starting diketone 2. H NMR (CDCl3) δ 0.70 (s, 6 H), 0.857 (d, J =
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7 Hz, 6 H), 0.861 (d, J = 7 Hz, 6 H), 0.90 (d, J = 6 Hz, ~4.2 H), 0.92 (d, J = 6 Hz, ~1.8 H), 1.11
(s, ~4.2 H), 1.14 (s, ~1.8 H), 1.0-2.9 (methylene envelope, 52 H), 6.31 (s, ~0.6 H), 6.70 (m, 2 H),
6.88 (s, ~1.4 H), 7.34 (m, 2 H), 7.44 (d, J = 8 Hz, ~1.4 H), 7.49 (d, J = 8 Hz, ~0.6 H); 13C NMR
(CDCl3) δ 11.9, 18.2, 18.3, 18.6, 21.0, 22.5, 22.8, 23.7, 24.0, 24.8, 28.0, 30.7, 33.8, 34.0, 35.2,
35.6, 36.0, 39.2, 39.3, 39.4, 39.8, 42.5, 46.6, 50.6, 50.9, 55.9, 56.5, 56.6, 113.6, 114.9, 119.2,
119.6, 125.2, 125.3, 126.2, 127.2, 129.9, 146.2, 147.3, 154.3, 155.0, 165.1, 167.4, 202.4, 203.2
(45 resonances observed; a total of 130 resonances is possible for the three cis/trans isomers);
MS (MALDI-TOF) m/z 918 (M+, 100); HRMS (ESI-TOF) m/z 919.7076 (M + H), calcd for
C64H91N2O2 919.7081; UV (CHCl3) λmax (log ε) 266 (4.3), 308 (sh, 4.0), 404 (3.3); [α]D24 +271 (c
0.23, CHCl3); CD (CHCl3) λmax ([θ]) 281 (–4000), 314 (–15,000), 395 (15,000).
Acknowledgment. This work was supported in part by National Science Foundation Grant
CHE-0936862, which is gratefully acknowledged.
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Supporting Information: H and 13C NMR spectra of compounds 2-7, kinetic data for the
isomerization of 3, circular dichroism spectra of compounds 3, 5, 6, and 7, calculated specific
rotations of 1 and hexahelicene at various levels of theory, full reference 10, a crystallographic
information file (CIF) for 3, and an ASCII text file containing the atomic coordinates and
energies of the calculated conformations of compounds 3, 5, 6, and 7. This information is
available free of charge via the Internet at http://pubs.acs.org/.
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References
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