Stereoselective formation of triphenylene ketals

Article abstract of DOI:10.1002/chem.200903249

The oxidative trimerization of catechol ketals by MoCl₅ or MoCl₅/ TiCl₄ mixtures leads preferentially to the all-syn stereoisomer of the corresponding triphenylene ketal. The concomitant metal salts of the oxidative coupling most probably form a multinuclear template that directs the diastereoselectivity in a subsequent iso-merization step under electrophilic conditions. Several functionalities can serve as coordination sites for the multinuclear metal chloro clusters. Suitable functional groups have to be stable towards the strong electrophilic and oxidizing conditions. Therefore, esters, nitriles, nitro derivatives, triazoles, and pyridines are successfully employed. Based on the flexibility and size of the substrate, different reagent mixtures lead to the stereoselective formation of the all-syn derivatives.

Full text of DOI:10.1002/chem.200903249

FULL PAPER
DOI: 10.1002/chem.200903249
Stereoselective Formation of Triphenylene Ketals
Nader M. Boshta,[a] Martin Bomkamp,[a] Gregor Schnakenburg,[b] and
Siegfried R. Waldvogel*[a]
Dedicated to Professor Julius Rebek, Jr. on the occasion of his 65th birthday
Abstract: The oxidative trimerization
merization step under electrophilic
conditions. Several functionalities can
serve as coordination sites for the mul-
tinuclear metal chloro clusters. Suitable
functional groups have to be stable to-
of catechol ketals by MoCl5 or MoCl5/
TiCl4 mixtures leads preferentially to
the all-syn stereoisomer of the corre-
sponding triphenylene ketal. The con-
comitant metal salts of the oxidative
coupling most probably form a multi-
nuclear template that directs the dia-
stereoselectivity in a subsequent iso-
wards the strong electrophilic and oxi-
dizing conditions. Therefore, esters, ni-
triles, nitro derivatives, triazoles, and
pyridines are successfully employed.
Based on the flexibility and size of the
substrate, different reagent mixtures
lead to the stereoselective formation of
the all-syn derivatives.
À
Keywords: C C coupling · diaste-
reoselectivity
·
molybdenum
·
oxidation · triphenylene ketal
Introduction
with the less symmetric anti,anti,syn derivative (B)
(Figure 1). The statistical formation strongly favors the gen-
eration of B, the less symmetric product, leading to a ratio
C3 symmetric scaffolds play an important role in nature and
supramolecular chemistry.[1] To achieve functional concave
structures, it is necessary to place all binding sites on one
side of the scaffold with a convergent orientation.[2] The all-
syn stereoisomer can be generated by two different conver-
gent synthetic strategies. First, optically pure starting materi-
als are used and by specific fusion the desired all-syn deriva-
tive is formed. This strategy was realized, for example, in
the synthesis of cyclic hexapeptides.[3] The major drawback
of this approach is the required enantiopure starting materi-
als or intermediates, which afford a multistep synthesis.[4]
This leads to an intrinsically chiral C3-symmetric platform in
which the efficient induction of stereoinformation is only re-
alized in a few examples.[5] As a second strategy, the all-syn
stereoisomer (A) can be obtained in a statistical mixture
Figure 1. Stereochemistry of concave and C3 symmetric scaffold forma-
tion.
of 3:1 for B/A. This challenge was solved in an elegant
manner for the hexasubstituted benzenes; conformational
control is achieved with an alternating orientation of the
substituents.[6] This concept can be exploited for truxenes
after statistical formation of an A/B mixture, which is then
deprotonated and subsequently alkylated.[7] Extending the
methodology to more expanded central moieties than ben-
zene failed, therefore, separation of the statistical A/B mix-
ture has to be performed and is eventually followed up by a
recycling or an isomerization step of the cleft with nanoscale
dimension.
Triphenylene ketals are unique concave clefts that exhibit
an electron-rich central core. This platform led to the first
artificial caffeine receptor[8] and supramolecular systems for
the enantiofacial differentiation of heterocyclic substrates,[9]
and it also exhibits a strong affinity towards oxopurines in
[a] N. M. Boshta, M. Bomkamp, Prof. Dr. S. R. Waldvogel
Kekulꢀ Institute for Organic Chemistry and Biochemistry
Bonn University
Gerhard-Domagk-Str. 1, 53121 Bonn (Germany)
Fax : (+49)228-739608
E-mail: waldvogel@uni-bonn.de
[b] Dr. G. Schnakenburg
X-ray Analysis Department, Institute for Inorganic Chemistry
Bonn University
Gerhard-Domagk-Str. 1, 53121 Bonn (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903249.
Chem. Eur. J. 2010, 16, 3459 – 3466
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the presence of aqueous media.[10] Triphenylene ketals rep-
resent triketals of 2,3,6,7,10,11-hexahydroxytriphenylene
When using silicon tetrachloride as an additive no improve-
ment was observed, whereas addition of tin(IV) chloride in-
creased the total yield of 2 to 62%, but still as a statistical
mixture of stereoisomers (Table 1, entries 2 and 3). Switch-
ing to TiCl4 as scavenger for HCl leads to a significant amel-
ioration; the triphenylene ketals are isolated in a total yield
of 72%. Most surprisingly, a reversal of the isomeric distri-
bution in contrast with the statistical expectation was found
(Table 1, entry 4). Variation of the MoCl5/TiCl4 ratio re-
vealed that an equimolar mixture of these metal chlorides is
beneficial for the formation of 2a (Table 1, entries 5–7). Op-
timal results are obtained when 3 equivalents of both com-
ponents are applied for a longer time, providing 68% yield
of 2a and only 4% of the less symmetric isomer 2b
(Table 1, entry 8). The conversion of 1 with three equiva-
lents of MoCl5 and TiCl4 was carried out with a systematic
variation of reaction time (Figure 2). The total yield of 2 for
and can be synthesized by oxidative trimerization of the cor-
[11]
responding catechol ketals, employing MoCl5
or anodic
protocols.[12,13] If functionalized benzo
ACTHNUGTRNE[NUG 1,3]dioxols are sub-
jected to these methods, the statistical mixture is produced,
yielding more than 75% of the undesired stereoisomer. A
repetitive sequence of isomer separation and isomerization
under strong acidic conditions allows the formation of larger
quantities of the all-syn functionalized triphenylene ketal.[13]
A more efficient approach to these compounds would facili-
tate access to these platforms and promote their application.
Herein, we report a stereoselective formation of tripheny-
lene ketals by the action of MoCl5 or MoCl5/TiCl4 mixtures.
Results and Discussion
MoCl5 is a very powerful reagent for the oxidative coupling
of arenes.[14] In contrast with other metal salts in higher oxi-
dation states, the molybdenum reagent prefers oxidative
coupling versus ketal cleavage. The use of additional Lewis
acids binds concomitant hydrogen chloride and keeps the re-
action mixture electrophilic, which is often accompanied by
higher reaction rates and improved yields.[15] Application of
this reagent mixture was tested to enhance the yield of oxi-
dative trimerization reactions (Scheme 1).
^
Figure 2. Change in isomeric ratio of triphenylene ketals 2a ( ) and 2b
&
( ) during the course of reaction.
each run is relatively constant (in the range of 72–79%), al-
though a tremendous reversal of the isomeric ratio is ob-
served. After a reaction time of 15 min, the ratio 2a/2b is
0.26 (as expected by the statistics). With time, a stereoselec-
tive isomerization is observed, resulting in a ratio 2a/2b of
about 17 after 480 min. Most likely, the metal salts—reagent
and reagent waste—form a template that promotes the ste-
reoselective isomerization. A multinuclear chlorocluster has
to be anticipated because the ester groups of the tripheny-
lene ketal 2a are more than 11 ꢂ apart. During the course
of the reaction MoCl4 is formed. A hexameric cyclic species
of MoCl4 is known and would be large enough for a tem-
plate.[17]
Scheme 1. Oxidative trimerization of catechol ketal 1.
2-Substituted-2-tert-butylbenzoACTHNUTRGNEUNG
[1,3]dioxoles[16] were used
as substrates because the isomeric triphenylene ketals are
easily separated. We used the methoxycarbonylmethyl deriv-
ative 1 because the all-syn product, 2a, is a key intermediate
of previous receptor studies.[8,10] If MoCl5 is used as the sole
reagent, products 2a and 2b are formed according to statis-
tics in 12 and 37% yield, respectively (Table 1, entry 1).
Table 1. Stereoselective oxidative trimerization of 1 by addition of Lewis
acids.
To gain insight into the isomerization of 2a and the re-
quired metal species, we subjected 2a to various Lewis acids
in dichloromethane at room temperature (Table 2). Addi-
tion of tin tetrachloride or titanium tetrachloride rendered
isomerization, but did not favor the all-syn derivative, 2a
(Table 2, entries 1 and 2). Applying mixtures of MoCl5 and
TiCl4 changed the scene dramatically and 2a was formed by
isomerization in up to 96% yield (Table 2, entries 3 and 4).
Variation of the amount of Lewis acidic components
clearly reveals that three equivalents of TiCl4 and at least
one equivalent of MoCl5 are essential for the triphenylene
Entry
Conditions[a]
Yield of
2a [%]
Yield of
2b [%]
1
2
3
4
5
6
7
8
MoCl5 (2 equiv), 2 h
12
11
14
50
15
48
52
68
37
38
48
22
42
23
25
4
MoCl5 (2 equiv), SiCl4 (2 equiv), 2 h
MoCl5 (2 equiv), SnCl4 (2 equiv), 2 h
MoCl5 (2 equiv), TiCl4 (2 equiv), 2 h
MoCl5 (2 equiv), TiCl4 (1 equiv), 2 h
MoCl5 (2 equiv), TiCl4 (4 equiv), 2 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 2 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 8 h
[a] Equivalents are in relation to 1 and reactions were carried out at 08C
in CH2Cl2.
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Triphenylene Ketals
FULL PAPER
Table 2. Isomerization reactions of anti,anti,syn-isomer 2b.
and was concomitant with triazole substitution at nitrogen
N1 to afford the regioisomer of 5h. Reduction of nitrile 5e
provides the amine 4, which was thermally arylated with 2-
bromopyridine to give 5i.[19] The homologue 5 f was synthe-
sized from 5e by standard transformations.
First, variation on the unfunctionalized side of the triphe-
nylene was studied (Table 3). A high degree of steric
demand is beneficial for the stability of benzoACTHNURTGNEU[GN 1,3]dioxoles
Entry
Conditions[a]
Yield of
Yield of
2b [%]
2a [%]
1
2
3
4
5
6
7
TiCl4 (9 equiv), 2 h
SnCl4 (9 equiv), 8 h
19
16
95
96
92
92
58
58
78
MoCl5 (6 equiv), TiCl4 (9 equiv), 2 h
MoCl5 (3 equiv), TiCl4 (9 equiv), 2 h
MoCl5 (1 equiv), TiCl4 (9 equiv), 2 h
MoCl5 (1 equiv), TiCl4 (3 equiv), 2 h
MoCl5 (1 equiv), TiCl4 (2 equiv), 4 h
trace
trace
trace
trace
26
under electrophilic conditions,[11a] therefore, we used sub-
strates with a tert-butyl group (Table 3, entries 4–9). Isopro-
pyl and cyclohexyl substituents can be employed as well,
leading to the syn-selective oxidative coupling reaction
(Table 3, entries 1 and 2). In the latter example, only the de-
sired stereoisomer of the triphenylene ketal was observed
(Table 3, entry 2a). The use of MoCl5 as the sole reagent
leads to a complete reversal of selectivity with moderate
yields for 6b and 7b (Table 3, entry 2b). Substrates with
aryl substituents in position 2 are not applicable to this
transformation because the ketal center is also benzylic and,
therefore, prone to electrophilic cleavage. During the course
of the reaction, compound 5c is consumed without detection
of 6c or 7c as products (Table 3, entry 3).
[a] All reactions were carried out in CH2Cl2 at room temperature.
ketal formation (Table 2, entries 6 and 7). Isolation and
characterization of 2a with bound molybdenum and/or tita-
nium fragments proved to be difficult.[18] MoCl5 might act as
an oxidant, generating a radical cation of 2, which allows
ring opening of the dioxole and subsequent isomerization of
ketal moieties.
To elucidate the scope of the syn-selective oxidative tri-
merization (Scheme 2), a variety of functionalized 2-tert-
Second, different coordinating groups for a multinuclear
metal cluster were envisioned for the reaction. The cyano
group was used instead of the ester moiety. With this sub-
strate, a slow, syn-selective oxidative trimerization is ob-
served when using the MoCl5/TiCl4 mixture. Faster and
better results were obtained by the application of MoCl5 as
the sole reagent (Table 3, entry 4). Subjecting the homo-
logue substrate 5e to the various conditions indicated that
the metal template might be similar to substrate 1 because
the MoCl5/TiCl4 mixture provided the best results (Table 3,
Scheme 2. Syn-selective oxidative trimerization.
butylbenzo
G
(5a–5i)
were
synthesized
(Scheme 3). Recently, the preparation of most substrates
was reported.[16] The heterocyclic derivatives, 5h and 5i, are
prepared from tosylate 3 and nitrile 5e, respectively. The
1,2,3-triazole was installed by nucleophilic substitution on 3,
entry 5). A propylene spacer between benzoACTHNUGRTENUNG[1,3]dioxole and
the coordinating moiety of the
template seems to allow inter-
action between different types
of clusters and the tripheny-
lene architecture. Therefore,
both
reaction
conditions
(MoCl5 and the MoCl5/TiCl4
mixture) give better results
than statistics, but are not truly
selective (Table 3, entry 6).
Nitro substituents are also suit-
able for this stereoselective tri-
merization reaction because
their oxygen atoms can inter-
act with an electrophilic chlor-
ocluster (Table 3, entry 7). Re-
duced flexibility in the spacer
renders higher yields and
better stereoselectivity. If the
Lewis basic center for coordi-
nation to the template is the
fourth atom away from posi-
Scheme 3. Synthesis of functionalized catechol ketals: a) 1,2,3-triazole, K2CO3, DMF, RT, 2 d, 36%; b) LiAlH4,
diethyl ether, 08C, 30 min, 91%; c) 2-bromopyridine, 2,2,6,6-tetramethylpiperidine, 2218C, 16 h, 53%;
d) NaOH, EtOH, H2O, 1008C, 17 h, 80%; e) LiAlH4, diethyl ether, 08C, 15 min, 93%; f) TsCl, pyridine, over-
night, RT, 87%; g) NaCN, DMSO, 808C, 3 h, 88%.
tion 2 of the benzo
ACHTUNGTREN[NUNG 1,3]dioxole
moiety, the MoCl5/TiCl4 combi-
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S. R. Waldvogel et al.
Table 3. Scope of the stereoselective oxidative trimerization of 5.
Substrate 5h, with a 1,2,3-tria-
zole-2-yl substituent, can be
stereoselectively trimerized by
using the MoCl5/TiCl4 mixture
(Table 3, entry 8). If the same
protocol is applied to the pyri-
dine derivative, 5i, the best
stereoselectivity can be ob-
tained by using MoCl5 as the
oxidant and templating precur-
sor (Table 3, entry 9). Assign-
ment of the all-syn or anti,an-
ti,syn configuration can be
done in most cases by
1H NMR spectroscopy. The sig-
nals for the triphenylene unit
are uniform, whereas the reso-
nances for the side arms of the
anti,anti,syn isomer are dis-
tinct, despite of their distance
of more than 11 ꢂ (see the
Supporting Information). Fur-
thermore, the molecular struc-
tures and stereochemistries of
7d and 6h were unequivocally
proven by the X-ray analysis
of suitable single crystals. In
the solid state, the tricyano de-
rivative, 7d, exhibits centered
polar groups on different sides
of the triphenylene plane,
which reveals the anti,anti,syn
Entry
Starting
material
Conditions[a]
Yield of
6 [%]
Yield of
7 [%]
1
MoCl5 (3 equiv), TiCl4 (3 equiv), 8 h
41 (6a)
6 (7a)
2a
b
MoCl5 (3 equiv), TiCl4 (3 equiv), 10 h
MoCl5 (3 equiv), 2 h
48 (6b)
7
–
24 (7b)
3
MoCl5 (3 equiv), TiCl4 (3 equiv), up to 10 h
–
–
4a
b
c
MoCl5 (3 equiv), TiCl4 (3 equiv), 15 min
MoCl5 (3 equiv), TiCl4 (3 equiv), 3 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 5 h
MoCl5 (3 equiv), CH2Cl2, 08C, 15 min
19 (6d)
36
48
54 (7d)
33
20
d
52
22
5a
b
c
MoCl5 (3 equiv), TiCl4 (3 equiv), 15 min
MoCl5 (3 equiv), TiCl4 (3 equiv), 3 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 5 h
MoCl5 (3 equiv), 15 min
21 (6e)
33
41
18
25
58 (7e)
36
21
51
47
d
e
MoCl5 (3 equiv), 3 h
6a
b
c
MoCl5 (3 equiv), TiCl4 (3 equiv), 15 min
MoCl5 (3 equiv), TiCl4 (3 equiv), 3 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 4 h
MoCl5 (3 equiv), 15 min
27 (6 f)
33
38
63 (7 f)
50
42
d
20
55
7a
b
c
MoCl5 (3 equiv), TiCl4 (3 equiv), 15 min
MoCl5 (3 equiv), TiCl4 (3 equiv), 3 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 5 h
MoCl5 (3 equiv), 15 min
23 (6g)
35
47
58 (7g)
40
28
nature
of
the
isomer
d
23
21
(Figure 3). The all-syn com-
pound 6h exposes the triazolo
moieties on the same side of
the molecule (Figure 4). Due
to the packing of the individual
triphenylene ketals, the arms
with the heterocycles are parti-
ally tilted. However, the con-
cave arrangement gives space
for the binding of a template
or other molecules in nano-
scale dimensions; the average
distance of Lewis basic nitro-
gen atoms is in the range of
12 ꢂ.[20] In both structures the
central triphenylene ketal ar-
chitecture is bent. The distan-
ces between the centroids of
8a
b
c
d
e
MoCl5 (3 equiv), TiCl4 (3 equiv), 1 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 2 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 4 h
MoCl5 (3 equiv), 1 h
25 (6h)
31
41
45
41
44 (7h)
33
22
35
32
MoCl5 (3 equiv), 2 h
9a
b
c
MoCl5 (3 equiv), TiCl4 (3 equiv), 1 h
MoCl5 (3 equiv), TiCl4 (3 equiv), 1 h
MoCl5 (3 equiv), 1 h
13 (6i)
14
31
28 (7i)
18
23
[a] All reactions were carried out in CH2Cl2 at 08C.
nation of reagents gives better results in terms of syn selec-
tivity and yield. This is the case for substrates 5e and 5g
(Table 3, entries 5 and 7). For smaller or larger spacings,
MoCl5 as the sole reagent is recommended. Five- and six-
membered heterocycles can also serve as ligands for the
multinuclear template in the oxidative trimerization process.
the outer six-membered rings of the triphenylene unit and
the least-squares plane defined by the atoms of the inner
ring are 8.0(2), 11.2(2), and À23.5(2) pm for 7d[21] and
0.9(1), 15.5(1), and 2.4(1) pm for 6h.
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Triphenylene Ketals
FULL PAPER
Figure 3. Molecular structure of 7d by X-ray analysis; top: side view,
bottom: top view.
Conclusion
The first syn-selective oxidative trimerization of catechol
ketals was found, paving the way to an attractive synthetic
access to these nanoscale-dimension clefts. The transforma-
tion consists of a nonselective oxidative coupling process,
which yields a statistical mixture in which the anti,anti,syn
isomer dominates. A subsequent in situ isomerization can
occur with partially reduced molybdenum chlorides, or with
TiCl4 as an additive, to form a multinuclear chlorocluster
that allows templating of polar groups that are more than
11 ꢂ apart. Esters, cyano, nitro, triazolo, and pyridine moiet-
ies can serve as polar groups for binding to the template. Se-
lectivity for the syn versus anti,anti,syn isomer in the conver-
sion of catechol ketals can be up to a ratio of 17:1, respec-
tively. Furthermore, isomerization of the less symmetric
isomer to the all-syn derivative can be achieved in up to
96% yield. Although the nature of the multinuclear chlor-
ocluster is not known, protocols using either the MoCl5/
TiCl4 mixture or MoCl5 as the sole reagent will affect the
stereoselective triphenylene ketal formation. These findings
clearly demonstrate that MoCl5, and reagent mixtures there-
of, are more than simple oxidants and might find application
in other stereoselective coupling reactions.
Figure 4. Molecular structure of 6h by X-ray analysis; top: side view,
bottom: top view.
Compound 5h: A mixture of 1,2,3-triazole (0.42 g, 6.0 mmol) and K2CO3
(3.00 g, 22 mmol) in DMF (30 mL) was stirred at RT for approximately
30 min before tosylate 3[16] (1.54 g, 4.00 mmol) was added. The reaction
mixture was stirred at RT for 2 d, poured onto ice water, and extracted
with ethyl acetate (100 mL). The organic portion was washed with H2O
(3ꢃ100 mL) and brine (100 mL), dried over anhydrous MgSO4, and fil-
tered. Evaporation of the solvent afforded a residue that was purified by
column chromatograpy (cyclohexane/ethyl acetate, 9.5:0.5) to give 5h
(0.4 g, 36%) and 5h’ (0.6 g, 54%), both as colorless powders. 5h: Rf =
0.55 (70% cyclohexane/ethyl acetate); m.p. 68–698C; 1H NMR
(400 MHz, CDCl3): d=1.06 (s, 9H), 2.65–2.69 (m, 2H), 4.52–4.56 (m,
2H), 6.71–6.78 (m, 4H), 7.55 (s, 2H); 13C NMR (100 MHz, CDCl3): d=
24.2, 34.2, 40.4, 49.4, 107.5, 121.1, 122.1, 134.0, 148.4; MS (ESI+): m/z:
296.1 [M+Na]+; HRMS: m/z calcd for C15H19N3NaO2: 296.1375
[M+Na+]; found: 296.1369. 5h’: Rf =0.21 (70% cyclohexane/ethylace-
tate); m.p. 95–968C; 1H NMR (400 MHz, CDCl3): d=1.04 (s, 9H), 2.65
(t, J=7.1 Hz, 2H), 4.46 (t, J=7.1 Hz, 2H), 6.72–6.81 (m, 4H), 7.44 (s,
1H), 7.66 (s, 1H); 13C NMR (100 MHz, CDCl3): d=24.3, 34.9, 40.5, 44.9,
107.6, 121.4, 122.1, 123.9, 133.4, 148.4; MS (ESI+): m/z: 296.1 [M+Na]+;
HRMS: m/z calcd for C15H19N3NaO2: 296.1375 [M+Na+]; found:
296.1369.
Compound 4: LiAlH4 (0.05 g, 1.3 mmol) was added to an ice-cold solu-
tion of nitrile 5e[16] (0.1 g, 0.43 mmol) in diethyl ether (10 mL), The reac-
tion mixture was stirred for 30 min at 08C and then carefully poured
onto ice water. tBuOMe (30 mL) was added and this mixture was filtered
through a pad of Celite. The organic phase was separated and washed
several times with H2O (5ꢃ30 mL) and brine (30 mL), dried over anhy-
drous MgSO4, filtered, and evaporated to give 4 (0.091 g, 91%) as a col-
Experimental Section
General: For details of all instumentation used, please see the Supporting
Information.
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3463

S. R. Waldvogel et al.
orless oil. Rf =0.12 (70% cyclohexane/ethyl acetate); 1H NMR
(400 MHz, CDCl3): d=1.02 (s, 9H), 1.45–1.53 (m, 4H), 1.92–1.98 (m,
2H), 2.64 (t, J=7.1 Hz, 2H), 6.64–6.71 (m, 4H); 13C NMR (100 MHz,
CDCl3): d=24.4, 25.9, 31.1, 40.3, 42.1, 106.8, 120.5, 123.6, 149.0; MS
(ESI+): m/z: 236.1 [M+H]+; HRMS: m/z calcd for C14H22NO2: 236.1651
[M+H+]; found: 236.1645.
6.70–6.76 (m, 4H); 13C NMR (100 MHz, CDCl3): d=17.2, 18.4, 24.4, 32.7,
40.4, 107.2, 119.3, 120.9, 123.0, 148.7; IR n˜ =2247 cmÀ1 (CN); MS (EI,
70 eV): m/z (%): 245.1 (12) [M]+; HRMS: m/z calcd for C15H19NO2:
245.1416 [M]+; found: 245.1415.
General procedure for the oxidative trimerization with MoCl5: Under an
inert atmosphere MoCl5 (1.64 g, 6.0 mmol) was dissolved in CH2Cl2
Compound 5i:
A sealed tube was charged with amine 4 (0.1 g,
(50 mL). The mixture was cooled to 08C and
a solution of ketal
0.425 mmol), 2-bromopyridine (0.67 g, 4.25 mmol), and 2,2,6,6-tetrame-
thylpiperidine (0.08 mL, 0.425 mmol). The mixture was kept at 2218C
(oil bath temperature) for 16 h. The mixture was cooled to RT, dissolved
in CH2Cl2 (20 mL), and transferred into a 50 mL flask. After evaporation
of the solvent, the crude product was purified by column chromatography
(cyclohexane/ethyl acetate, 8:2) to give 5i (0.069 g, 53%) as a colorless
powder. Rf =0.13 (80% cyclohexane/ethyl acetate); m.p. 65–668C;
1H NMR (400 MHz, CDCl3): d=1.03 (s, 9H), 1.65–1.72 (m, 2H), 2.04–
2.07 (m, 2H), 3.23–3.27 (m, 2H), 4.55 (brs, 1H), 6.28–6.30 (m, 1H), 6.51–
6.54 (m, 1H), 6.67–6.74 (m, 4H), 7.33–7.40 (m, 1H), 8.00–8.04 (m, 1H);
13C NMR (100 MHz, CDCl3): d=22.2, 24.5, 31.3, 40.4, 42.2, 106.5, 107.0,
112.6, 120.7, 123.6, 137.5, 147.8, 149.1, 158.6; MS (EI, 70 eV): m/z (%):
312.2 (24) [M]+; HRMS: m/z calcd for C19H24N2O2: 312.1838 [M]+;
found: 312.1834.
(2.0 mmol) in CH2Cl2 (5 mL) was added rapidly. The mixture was stirred
at 08C for the given time (see Table 3). After the conversion the mixture
was partitioned between ethyl acetate (100 mL) and a saturated aqueous
solution of NaHCO3 (100 mL). The aqueous layer was extracted with
ethyl acetate (2ꢃ50 mL) and the combined organic fractions were
washed with H2O (50 mL) and brine (50 mL), dried over anhydrous
MgSO4, and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica by using mixtures of cy-
clohexane and ethyl acetate. The corresponding yields with respect to re-
action time are given in Table 3.
General procedure for the oxidative trimerization with MoCl5/TiCl4 mix-
tures: Under an inert atmosphere MoCl5 (1.64 g, 6.0 mmol) was dissolved
in CH2Cl2 (50 mL), then TiCl4 (0.65 mL, 6.0 mmol) was added. The mix-
ture was cooled to 08C and a solution of ketal (2.0 mmol) in CH2Cl2
(5 mL) was added rapidly. The mixture was stirred at 08C for the given
time (see Table 3). After the conversion the mixture was partitioned be-
Compound I:
A solution of nitrile 5e (0.5 g, 2.2 mmol) in ethanol
(10 mL) was treated with a 10% aqueous solution of NaOH (5 mL). The
reaction mixture was heated at reflux for 17 h before the mixture was di-
luted with H2O (50 mL). The solution was cooled to RT and acidified
with 1m hydrochloric acid (10 mL). The formed solid was filtered off,
rinsed with pure water (3ꢃ50 mL), and subsequently dried under high
tween ethyl acetate (100 mL) and
a saturated aqueous solution of
NaHCO3 (100 mL). The aqueous layer was extracted with ethyl acetate
(2ꢃ50 mL) and the combined organic fractions were washed with H2O
(50 mL) and brine (50 mL), dried over anhydrous MgSO4, and subse-
quently concentrated under reduced pressure. The crude product was pu-
rified by column chromatography on silica by using mixtures of cyclohex-
ane and ethyl acetate. The corresponding yields with respect to time and
reagent mixture are given in Table 3.
vacuum (1ꢃ10À1 mbar) to give acid
I (0.43 g, 80%) as a colorless
powder. Rf =0.11 (80% cyclohexane/ethyl acetate); m.p. 155–1568C;
1H NMR (400 MHz, CDCl3): d=1.05 (s, 9H), 2.30–2.35 (m, 2H), 2.41–
2.46 (m, 2H), 6.66–6.76 (m, 4H); 13C NMR (100 MHz, CDCl3): d=24.4,
27.3, 29.2, 40.3, 107.2, 121.0, 122.8, 148.8, 179.4; MS (EI, 70 eV): m/z
(%): 250.1 (16) [M]+; HRMS: m/z calcd for C14H18O4: 250.1205 [M]+;
found: 250.1211.
Compound 2a (all-syn): Rf =0.10 (80% cyclohexane/ethyl acetate); m.p.
226–2278C; 1H NMR (400 MHz, CDCl3): d=1.11 (s, 27H), 3.09 (s, 6H),
3.44 (s, 9H), 7.70 (s, 6H); 13C NMR (100 MHz, CDCl3): d=24.1, 39.0,
41.0, 51.9, 100.0, 121.4, 124.5, 148.7, 168.9; MS (ESI+): m/z: 767.3
[M+Na]+; elemental analysis calcd (%) for C42H48O12 (744.8233): C
67.74, H 6.50; found: C 67.73, H 6.47.
Compound II: LiAlH4 (0.15 g, 3.6 mmol) was added to an ice-cooled so-
lution of acid I (0.3 g, 1.2 mmol) in diethyl ether (10 mL). The reaction
mixture was stirred for 15 min at 08C and then carefully poured onto ice
water. tBuOMe (30 mL) was added and the mixture was filtered through
a Celite pad. The organic phase was separated and washed several times
with H2O (5ꢃ50 mL) and brine (50 mL), dried over anhydrous MgSO4,
filtered, and evaporated to give II (0.26 g, 93%) as a colorless oil. Rf =
0.21 (80% cyclohexane/ethyl acetate); 1H NMR (400 MHz, CDCl3): d=
1.05 (s, 9H), 1.58–1.67 (m, 2H), 2.02–2.07 (m, 2H), 3.21 (s, 1H), 3.62 (t,
J=6.4 Hz, 2H), 6.64–6.74 (m, 4H); 13C NMR (100 MHz, CDCl3): d=
24.5, 25.5, 30.1, 40.4, 26.8, 107.0, 120.6, 123.7, 149.1; MS (EI, 70 eV): m/z
Compound 2b (anti,anti,syn): Rf =0.24 (80% cyclohexane/ethyl acetate);
m.p. 263–2648C; 1H NMR (400 MHz, CDCl3): d=1.12 (s, 27H), 3.09 (s,
6H), 3.39–3.42 (m, 9H), 7.70 (s, 6H); 13C NMR (100 MHz, CDCl3): d=
24.0, 38.9, 40.9, 51.8, 99.9, 121.4, 124.6, 148.7, 168.9; MS (ESI+): m/z:
767.3 [M+Na]+; HRMS: m/z calcd for C42H48NaO12: 767.3038 [M+Na+];
found: 767.3033.
Compound 6a (all-syn): Rf =0.11 (80% cyclohexane/ethyl acetate);
1H NMR (400 MHz, CDCl3): d=1.11 (d, J=6.8 Hz, 18H), 2.49 (sept, J=
6.8 Hz, 3H), 3.06 (s, 6H), 3.60 (s, 9H), 7.71 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=16.2, 36.0, 40.6, 52.0, 100.8, 119.9, 124.6, 147.9, 168.8; MS
+
+
C
C
(%): 236.1 (14) [M] ; HRMS: m/z calcd for C14H20O3: 236.1412 [M]
;
found 236.1415.
Compound III: A solution of II (0.236 g, 1.0 mmol) in pyridine (10 mL)
was treated with 4-toluenesulfonyl chloride (0.3 g, 1.5 mmol). The reac-
tion mixture was stirred for 8 h at RT, then poured onto ice water. The
formed solid was filtered off, washed with pure water (3ꢃ50 mL), and
desiccated under high vacuum (1ꢃ10À1 mbar) to give tosylate III (0.34 g,
87%) as a colorless powder. Rf =0.54 (80% cyclohexane/ethyl acetate);
m.p. 118–1198C; 1H NMR (400 MHz, CDCl3): d=0.99 (s, 9H), 1.67–1.73
(m, 2H), 1.92–1.96 (m, 2H), 2.44 (s, 3H), 4.01 (t, J=6.2 Hz, 2H), 6.62–
6.74 (m, 4H), 7.32–7.34 (m, 2H), 7.75–7.77 (m, 2H); 13C NMR
(100 MHz, CDCl3): d=21.6, 21.9, 24.4, 30.0, 40.3, 70.6, 107.0, 120.8, 123.1,
127.9, 129.8, 133.1, 144.7, 148.8; MS (EI, 70 eV): m/z (%): 390.1 (8) [M]+;
HRMS: m/z calcd for C21H26O5S: 390.1501 [M]+; found: 390.1502.
(ESI+): m/z: 725.3 [M+Na]+; HRMS: m/z calcd for C39H42NaO12
725.2568 [M+Na+]; found: 725.2564.
:
Compound 7a (anti,anti,syn): Rf =0.18 (80% cyclohexane/ethyl acetate);
1H NMR (400 MHz, CDCl3): d=1.05–1.13 (m, 18H), 2.46–2.54 (m, 3H),
3.01–3.07 (m, 6H), 3.59–3.62 (m, 9H), 7.71 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=16.2, 36.0, 40.6, 51.9, 100.7, 119.9, 124.6, 148.0, 168.7; MS
(ESI+): m/z: 725.3 [M+Na]+; HRMS: m/z calcd for C39H42NaO12
725.2568 [M+Na+]; found: 725.2564.
:
Compound 6b (all-syn): Rf =0.20 (80% cyclohexane/ethyl acetate); m.p.
120–1218C; 1H NMR (400 MHz, CDCl3): d=1.24–1.29 (m, 6H), 1.59–
1.70 (m, 12H), 1.79–1.94 (m, 12H), 2.08–2.15 (m, 3H), 3.05 (s, 6H), 3.60
(s, 9H), 7.69 (s, 6H); 13C NMR (100 MHz, CDCl3): d=25.8, 26.0, 26.9,
40.5, 45.6, 52.0, 100.7, 119.5, 124.6, 147.9, 168.8; MS (ESI+): m/z: 823.4
[M+H]+; HRMS: m/z calcd for C48H55O12: 823.3688 [M+H+]; found:
823.3664.
Compound 5 f: A mixture of tosylate III (0.2 g, 0.51 mmol) and sodium
cyanide (0.04 g, 0.77 mmol) in dimethylsulfoxide (10 mL) was stirred at
808C for 2 h, then poured onto ice water. The formed solid was filtered
off, rinsed with pure water (3ꢃ50 mL), and subsequently desiccated
under high vacuum (1ꢃ10À1 mbar) to give 5 f (0.11 g, 88%) as a colorless
powder. Attention! The filtrate has to be treated with [FeSO4·7H2O] in
acidic media to bind the highly toxic cyanide. Rf =0.37 (85% cyclohex-
ane/ethyl acetate); m.p. 63–648C; 1H NMR (400 MHz, CDCl3): d=1.05
(s, 9H), 1.72–1.79 (m, 2H), 2.09–2.13 (m, 2H), 2.34 (t, J=7.1 Hz, 2H),
Compound 7b (anti,anti,syn): Rf =0.32 (80% cyclohexane/ethyl acetate);
m.p. 126–1278C; 1H NMR (400 MHz, CDCl3): d=1.24–1.29 (m, 6H),
1.63–1.70 (m, 12H), 1.80–1.95 (m, 12H), 2.08–2.16 (m, 3H), 3.05 (s, 6H),
3.58–3.59 (m, 9H), 7.69 (s, 6H); 13C NMR (100 MHz, CDCl3): d=25.8,
25.9, 26.0, 40.5, 45.6, 52.0, 100.7, 119.5, 124.5, 147.9, 168.8; MS (ESI+):
3464
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3459 – 3466

Triphenylene Ketals
FULL PAPER
m/z: 823.4 [M+H]+; HRMS: m/z calcd for C48H54NaO12
845.3507; found: 845.3505.
:
[M+Na+]
0.071 mmÀ1; no absorption correction was applied; Z=16; tetragonal;
space group I41/a, l=0.71073 ꢂ; T=123(2) K; w and f scans; 49596 re-
flections collected; 9043 independent (Rint =0.1487); completeness to q=
25.258: 96.0%; 551 refined parameters, R1 =0.0786, wR2 =0.1960; largest
Compound 6d (all-syn): Rf =0.20 (80% cyclohexane/ethyl acetate); m.p.
209–2108C; 1H NMR (400 MHz, CDCl3): d=1.17 (s, 27H), 3.10 (s, 6H),
7.80 (s, 6H); 13C NMR (100 MHz, CDCl3): d=24.4, 29.1, 40.4, 101.2,
115.0, 119.6, 125.0, 147.8; MS (ESI+): m/z: 668.3 [M+Na]+; HRMS: m/z
calcd for C39H39N3NaO6: [M+Na+] 668.2737; found: 668.2731.
difference peak and hole: 0.293 and À0.395 eꢂÀ3
.
Compound 7h (anti,anti,syn): Rf =0.24 (85% cyclohexane/ethyl acetate);
1
m.p. 198–1998C; H NMR (400 MHz, CDCl3): d=1.12 (s, 27H), 2.76–2.80
(m, 6H), 4.57–4.63 (m, 6H), 7.55 (s, 6H), 7.71 (s, 6H); 13C NMR
(100 MHz, CDCl3): d=24.3, 34.2, 40.6, 49.3, 100.2, 123.1, 124.5, 134.0,
148.7; MS (ESI+): m/z: 836.4 [M+Na]+; HRMS: m/z calcd for
C45H51N9NaO6: 836.3860 [M+Na+]; found: 836.3855.
Compound 7d (anti,anti,syn): Rf =0.26 (80% cyclohexane/ethyl acetate);
m.p. 288–2898C; 1H NMR (400 MHz, CDCl3): d=1.15 (s, 27H), 3.10 (s,
6H), 7.81 (s, 6H); 13C NMR (100 MHz, CDCl3): d=24.3, 26.9, 40.4,
101.1, 115.1, 119.6, 125.0, 147.8; MS (ESI+): m/z: 668.3 [M+Na]+;
HRMS: m/z calcd for C39H39N3NaO6: 668.2737 [M+Na+]; found:
668.2731. X-ray crystal structure analysis for 7d: plate-like, colorless crys-
tals were obtained by evaporation of a solution of 7d in CH2Cl2 at ambi-
ent conditions; formula: C39H39N3O6; Mr =645.73; crystal size: 0.32ꢃ
0.24ꢃ0.04 mm; a=30.9263(9), b=14.2342(4), c=37.3935(14) ꢂ; a=g=
Compound 6i (all-syn): Rf =0.12 (30% cyclohexane/ethyl acetate); m.p.
157–1588C; 1H NMR (400 MHz, CDCl3): d=1.09 (s, 27H), 1.72–1.75 (m,
6H), 2.14–2.18 (m, 6H), 3.26–3.30 (m, 6H), 4.59 (s, 3H), 6.26–6.28 (m,
3H), 6.47–6.50 (m, 3H), 7.29–7.32 (m, 3H), 7.65 (s, 6H), 8.00–8.01 (m,
3H); 13C NMR (100 MHz, CDCl3): d=22.3, 24.6, 31.3, 40.5, 42.1, 99.5,
106.5, 112.6, 124.1, 124.6, 137.6, 147.7, 149.2, 158.6; MS (ESI+): m/z:
932.5 [M+H]+; HRMS: m/z calcd for C57H68N6O6: 932.5200 [M+H+];
found: 932.5164.
908, b=101.030(3)8; V=16156.9(9) ꢂ3; 1calcd =1.062 gcmÀ3
;
m=
0.072 mmÀ1, no absorption correction was applied; Z=16; monoclinic;
space group C2/c, l=0.71073 ꢂ; T=123(2) K, w, and f scans, 88731 re-
flections collected; 19508 independent (Rint =0.1283); completeness to
q=28.008: 99.9%; 872 refined parameters, R1 =0.0879, wR2 =0.2716;
Compound 7i (anti,anti,syn): Rf =0.21 (30% cyclohexane/ethyl acetate);
1
m.p. 130–1318C; H NMR (400 MHz, CDCl3): d=1.05 (s, 27H), 1.65–1.72
largest difference peak and hole: 0.528 and À0.418 eꢂÀ3
.
(m, 6H), 2.10–2.16 (m, 6H), 3.21–3.25 (m, 6H), 4.53 (s, 3H), 6.17–6.23
(m, 3H), 6.42–6.44 (m, 3H), 7.22–7.28 (m, 3H), 7.61 (s, 6H), 7.97–8.01
(m, 3H); 13C NMR (100 MHz, CDCl3): d=22.2, 24.6, 31.2, 40.6, 42.0,
99.7, 106.5, 112.7, 124.1, 124.7, 137.4, 147.8, 149.1, 158.5; MS (ESI+): m/
z: 931.5 [M+H]+; HRMS: m/z calcd for C57H67N6O6: 931.5122 [M+H+];
found: 931.5117.
Compound 6e (all-syn): Rf =0.13 (87% cyclohexane/ethyl acetate); m.p.
1
220–2218C; H NMR (400 MHz, CDCl3): d=1.10 (s, 27H), 2.47 (s, 12H),
7.71 (s, 6H); 13C NMR (100 MHz, CDCl3): d=10.9, 24.3, 30.3, 40.6, 100.3,
119.2, 122.8, 124.6, 148.7; MS (ESI+): m/z:710.3 [M+Na]+; HRMS: m/z
calcd for C42H45N3NaO6: 710.3206 [M+Na+]; found: 710.3201.
X-ray crystallography: CCDC-749439 (6h) and 749440 (7d) contain the
supplementary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Compound 7e (anti,anti,syn): Rf =0.21 (87% cyclohexane/ethyl acetate);
m.p. >3008C; 1H NMR (400 MHz, CDCl3): d=1.11 (s, 27H), 2.43–2.49
(m, 12H), 7.71 (s, 6H); 13C NMR (100 MHz, CDCl3): d=10.9, 24.3, 30.3,
40.6, 100.3, 119.2, 122.8, 124.6, 148.7; MS (ESI+): m/z: 710.3 [M+Na]+;
HRMS: m/z calcd for C42H45N3NaO6: 710.3206 [M+Na+]; found:
710.3201.
Compound 6 f (all-syn): Rf =0.27 (83% cyclohexane/ethyl acetate); m.p.
272–2738C; 1H NMR (400 MHz, CDCl3): d=1.10 (s, 27H), 1.78–1.85 (m,
6H), 2.19–2.25 (m, 6H), 2.36 (t, J=7.0 Hz, 6H), 7.67 (s, 6H); 13C NMR
(100 MHz, CDCl3): d=17.2, 18.4, 24.4, 32.7, 40.5, 99.9, 119.2, 124.0, 124.3,
149.0; MS (ESI+): m/z: 752.3 [M+Na]+; HRMS: m/z calcd for
C45H51N3NaO6: 752.3676 [M+Na+]; found: 752.3699.
Acknowledgements
Support by the DFG (SFB 624) is highly appreciated. A donation of
MoCl5 by H. C. Starck was very helpful. N.M.B. thanks the CHANNEL
program for a fellowship.
Compound 7 f (anti,anti,syn): Rf =0.36 (83% cyclohexane/ethyl acetate);
1
m.p. 274–2758C; H NMR (400 MHz, CDCl3): d=1.11 (s, 27H), 1.76–1.81
(m, 6H), 2.20–2.24 (m, 6H), 2.36 (t, J=7.0 Hz, 6H), 7.67 (s, 6H);
13C NMR (100 MHz, CDCl3): d=17.2, 18.4, 24.4, 32.7, 40.5, 99.9, 119.2,
124.1, 124.3, 149.0; MS (ESI+): m/z: 752.3 [M+Na]+; HRMS: m/z calcd
for C45H51N3NaO6: 752.3676 [M+Na+]; found: 752.3629.
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Compound 6g (all-syn): Rf =0.18 (92% cyclohexane/ethyl acetate); m.p.
>3008C; 1H NMR (400 MHz, CDCl3): d=1.12 (s, 27H), 2.87 (t, J=
7.2 Hz, 6H), 4.49 (t, J=7.1 Hz, 6H), 7.70 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=24.2, 31.9, 40.7, 70.0 100.5, 122.6, 124.7, 148.4; MS (ESI+):
m/z: 770.3 [M+Na]+; HRMS: m/z calcd for C39H45N3NaO12: 770.2901
[M+Na+]; found: 770.2895.
Compound 7g (anti,anti,syn): Rf =0.31 (92% cyclohexane/ethyl acetate);
m.p. 252–2538C; 1H NMR (400 MHz, CDCl3): d=1.13 (s, 27H), 2.87 (t,
J=7.1 Hz, 6H), 4.47 (t, J=7.1 Hz, 6H), 7.69 (s, 6H); 13C NMR
(100 MHz, CDCl3): d=24.2, 31.9, 40.7, 69.9, 100.5, 122.6, 124.7, 148.4;
MS (ESI+): m/z: 770.3 [M+Na]+; HRMS: m/z calcd for C39H45N3NaO12
770.2901 [M+Na+]; found: 770.2895.
:
Compound 6h (all-syn): Rf =0.15 (85% cyclohexane/ethyl acetate); m.p.
206–2078C; 1H NMR (400 MHz, CDCl3): d=1.12 (s, 27H), 2.76–2.79 (m,
6H), 4.60–4.65 (m, 6H), 7.55 (s, 6H), 7.71 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=24.3, 34.2, 40.7, 49.3, 100.2, 123.0, 124.5, 134.1, 148.8; MS
(ESI+): m/z: 836.4 [M+Na]+; HRMS: m/z calcd for C45H51N9NaO6:
836.3860 [M+Na+]; found: 836.3855. X-ray crystal structure analysis for
6h: plate-like, colorless crystals were obtained by evaporation of a solu-
tion of 6h in CH2Cl2 at ambient conditions; formula C45H51N9O6; Mr =
813.95; crystal size: 0.60ꢃ0.60ꢃ0.02 mm; a=b=17.5402(6), c=
67.560(3) ꢂ; a=b=g=908; V=20785.5(14) ꢂ3; 1calcd =1.040 gcmÀ3; m=
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Received: November 27, 2009
Published online: February 15, 2010
3466
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Chem. Eur. J. 2010, 16, 3459 – 3466