Oxidative Cyclization Reaction of 2-Aryl-Substituted Cinnamates To Form Phenanthrene Carboxylates by Using MoCl5

Article abstract of DOI:10.1002/chem.201403442

The oxidative cyclization reaction of 2-aryl cinnamates and derivatives thereof can be easily performed with MoCl₅as the oxidant. This powerful reagent allows oxidative coupling reactions for which other reagents fail. The best results are obtained when the 2-phenyl substituent of the cinnamate is equipped with two methoxy groups. Even iodo moieties in the bay region of phenanthrene are tolerated under the reaction conditions. If naphthalene moieties are involved, a rearrangement of the skeleton occurs, providing an elegant route to highly functionalized angular arenes. The cyclization is demonstrated for 15 example substrates with isolated yields of up to 99 % for the phenanthrene derivative. The broad scope of the reaction underlines the usefulness of MoCl₅and MoCl₅/TiCl₄in the oxidative coupling reaction.

Full text of DOI:10.1002/chem.201403442

DOI: 10.1002/chem.201403442
Full Paper
&
Oxidative Coupling
Oxidative Cyclization Reaction of 2-Aryl-Substituted Cinnamates
To Form Phenanthrene Carboxylates by Using MoCl5
Kathrin Wehming,[a] Moritz Schubert,[a] Gregor Schnakenburg,[b] and
Siegfried R. Waldvogel*[a]
Abstract: The oxidative cyclization reaction of 2-aryl cinna-
mates and derivatives thereof can be easily performed with
MoCl5 as the oxidant. This powerful reagent allows oxidative
coupling reactions for which other reagents fail. The best re-
sults are obtained when the 2-phenyl substituent of the cin-
namate is equipped with two methoxy groups. Even iodo
moieties in the bay region of phenanthrene are tolerated
under the reaction conditions. If naphthalene moieties are
involved, a rearrangement of the skeleton occurs, providing
an elegant route to highly functionalized angular arenes.
The cyclization is demonstrated for 15 example substrates
with isolated yields of up to 99% for the phenanthrene de-
rivative. The broad scope of the reaction underlines the use-
fulness of MoCl5 and MoCl5/TiCl4 in the oxidative coupling
reaction.
Introduction
potent growth-inhibitory effects against a wide range of
human cancer cell lines.[4] This is caused by the irreversible in-
hibition of protein synthesis at the elongation stage of the
translation cycle.[4e,5]
Phenanthrene derivatives are common structural motifs in a va-
riety of natural products.[1] (À)-Tylophorine (1) or (À)-crypto-
pleurine (2) are just two prominent members of the phenan-
throquinolizidine and -indolizidine family of over 60 known
compounds (Figure 1).[2] These pentacyclic alkaloids, as well as
many synthetic derivatives of them (e.g., 3),[2b,c] show diverse
but very potent biological and pharmacological activities rang-
ing from antitumor properties to anti-inflammatory, antihisti-
matic, antifungal, or antibacterial activities.[3] Tylophorine (1)
and its analogues exhibit, amongst other characteristics,
Compound 1, for example, is able to arrest carcinoma cells
in the G1 phase by down regulation of cyclin A2 expression.[6]
This alkaloid was first isolated in 1935 from the perennial
climbing plant Tylophora indica,[7] which has been used in ar-
yuvedic medicine for the treatment of various ailments of the
respiratory tract. Another phenanthroindolizidine, antofine, in-
terferes in the G2/M phase of the cell cycle of carcinoma
cells.[8] Many compounds with such molecular architectures
show significant activity against multidrug-resistent cancer cell
lines.[4,9] Cryptopleurine (2), a member of the phenanthroqui-
nolizidine family, was isolated in 1948 from the bark of the
Australian laurel cryptocarya pleurosperma.[10] At low concen-
trations cryptopleurine (2) blocks the translocation of peptid-
yl–tRNA from the ribosome, whereas high concentrations of
cryptopleurine inhibit peptide bond formation on eukaryotic ri-
bosomes.[2c,3c,5d] Based on these biological properties, various
total syntheses of racemic, as well as enantiomerically en-
riched, alkaloids have been reported.[2b,c,3c,11–13]
Figure 1. Some important phenanthrene alkaloids.
The most prominent route to phenanthrene derivatives for
the construction of complex molecules is based on the intra-
molecular cyclization of stilbenes or a-aryl cinnamates. The in-
tramolecular bond formation can be achieved by the use of
leaving groups. The Pschorr arylation is a widely used and ver-
satile method for the synthesis of 9-phenanthrene carboxy-
lates.[14] More recently, transition-metal-catalyzed dehydrohalo-
genation and alkyne addition have been exploited for the con-
struction of the central ring of the targeted phenanthrene.[3c]
These methods allow the incorporation of less electron-rich
aryl moieties, and make it possible to adjust the reactivity ac-
cordingly. For practical reasons, the reaction is restricted to 2-
[a] Dr. K. Wehming, M. Schubert, Prof. Dr. S. R. Waldvogel
Mainz University, Institute for Organic Chemistry
Duesbergweg 10–14, 55128 Mainz (Germany)
Fax: (+49)6131 3926777
E-mail: waldvogel@uni-mainz.de
[b] Dr. G. Schnakenburg
Bonn University, X-ray Analysis Department
Institute for Inorganic Chemistry
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.201403442.
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nitrobenzaldehyde derivatives for the long linear synthesis.
Therefore, oxidative cyclization of a-arylcinnamates seems to
be an ideal synthetic pathway with respect to both atom econ-
omy and the number of linear steps.
Metal-based intramolecular oxidative coupling to phenan-
threnes has been demonstrated by employing vanadium oxy-
fluoride,[13a,14e,15] thallium(III) trifluoroacetate,[16] lead(IV) ace-
tate,[17] manganese(IV) oxide,[18] and ferric chloride in different
combinations. The iron(III) reagent can be used in excess or in
a catalytic fashion fueled by per acids.[12b,19] Despite the im-
pressive results under the latter reaction conditions, most suc-
cessfully converted substrates require a 2,3,6,7 donor-substitu-
tion pattern on the phenanthrene. In a few examples, 3,6,7- or
2,3,6-trialkoxy-substituted phenanthrenes can be furnished in
significantly lower yields.[19e] Hypervalent iodo reagents allow
the oxidative cyclization of heterocyclic analogues of a-aryl
cinnamates.[20] Photocyclization in the presence of iodine gives
access to less electron-rich phenanthrenes with an unusual
substitution pattern but in significantly lower yields.[12d]
For a modular approach to a broad range of phenanthrenes,
a general oxidation coupling process is highly desirable. Fur-
thermore, reagent waste contamination has to be bio-compati-
ble or environmentally benign, as is the case for iron or molyb-
denum reagents.
Scheme 1. Retrosynthetic approach to the formation of phenanthrene
moieties.
a strong preference for the Z product, as theoretical and exper-
imental studies have revealed.[32] Therefore, we developed
a stereoselective route to (E)-a-aryl cinnamates by starting
from the aryl-substituted phosphono acetates 6.[33] When using
1,8-diazabicycloundec-7-ene (DBU)–LiCl in acetonitrile as
a base, the reaction requires 4 to 18 days for completion, but
the transformation is very clean and provides the a-aryl cinna-
mates in an E/Z ratio of at least 80:20. The derivatives of 4 are
shown in Scheme 2.
The electronic nature of aldehyde component 7 seems to
have less influence on the olefination process. Cinnamates
from electron-rich aldehydes (4g), unsubstituted (4i), or 4-
fluoro derivatives (4j) are obtained in comparable yields. Steric
repulsion appears to have more impact on the olefination re-
action. A single substituent ortho to the aldehyde slows down
the olefination process significantly. The conversion to 4d took
about 14 days. An analogous transformation of a 2,4,6-trisub-
stituted benzaldehyde failed completely.
MoCl5 is a very powerful reagent for oxidative coupling/
Scholl-type transformations and is comparable with hyperva-
lent iodine reagents.[21,22] Its strong oxidative nature allows
a fast transformation and, consequently, several sensitive moi-
eties are tolerated that are not compatible with standard re-
agents like ferric chloride.[23] Our previous studies have indicat-
ed that MoCl5 acts as a one-electron oxidant.[24] Its oxidative
performance in the coupling process can be increased by the
addition of Lewis acids to intercept the concomitant hydrogen
chloride without decreasing the electrophilic properties of the
reagent.[25] This method was successfully applied to the oxida-
tive cyclization of five- to eight-membered ring systems.[21,26]
Recently, we found that the metal waste formed in the course
of the transformation can act as a stereo directing template in
the oxidative trimerization of catechol ketals.[27] The high oxi-
dative performance of MoCl5 allows multiple oxidations to
occur, which can be exploited in unique domino reaction se-
quences.[24b,28]
The oxidative cyclization reaction of 4a to form ethyl 2,3,6,7-
tetramethoxyphenanthrene carboxylate (5a) was achieved by
molybdenum pentachloride as the sole reagent in 80% yield
(Scheme 3). When applying a more elaborate reagent system
consisting of an equimolar mixture of MoCl5 and TiCl4, a signifi-
cant enhancement in the conversion was observed, and com-
pound 5a was almost quantitatively isolated. When the trans-
formation is carried out on a multigram scale the yield of ana-
lytically pure compound 5a is still 92% (SI). TiCl4 acts as a chlor-
ine scavenger in the reaction mixture leading to fewer chlori-
nated byproducts.[25] Similar results for the oxidative cyclization
reaction to form seven- or eight-membered ring systems, as
well as thianthrenes, were recently found.[23e,26]
This reagent mixture was, therefore, employed in the follow-
ing synthetic studies (Scheme 4). The cinnamate 4b, equipped
with a benzo[1,3]dioxole moiety instead of a veratryl fragment,
is quantitatively converted into 5b. The less electron-rich sub-
strate, which leads to the phenanthrene portion of crypto-
pleurine, is synthesized in excellent yield, providing 5c as
slightly yellow crystals. The presence of additional methyl
groups on the aromatic core of the cinnamate gives rise to
very good yields of the highly modified phenanthrene 5d. Fur-
ther reduction of the electron density in the substrate, for ex-
ample, in compound 4e, in which only an isopropyl group is
present, gives rise to oxidative coupling products. The desired
compound 5e is obtained in 78% yield with 11% of the 10-
chloro product 8e. Most remarkably, 4e is not oxidized at the
highly activated benzylic position.
Results and Discussion
Several strategies for the construction of the architectures of
the type displayed in Scheme 1 are based on the prior forma-
tion of phenanthrene-9-carboxylates 5.[29] These valuable inter-
mediates can be obtained through oxidative coupling of a-aryl
cinnamates 4.
Some cinnamates can be prepared by exploiting the Perkin
reaction, starting from arylacetic acids and the appropriate
benzaldehyde.[30,31] This conversion requires acidic conditions
at elevated temperatures. Consequently, the Perkin reaction
has found limited application when either the benzaldehyde is
too electron rich or acid-labile moieties are involved. Further-
more, this reaction leads to a mixture of stereoisomers with
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this angular arene system can be explained by the fact that
the skeletal arrangement is similar to that required for the spi-
rodienone–phenol rearrangement (Scheme 5).[21d,34,35] Upon ox-
idation of the veratryl system 4 f, a five-membered spiro inter-
mediate 9 is likely. The formation of this architecture can be at-
tributed to an entropy preference and to reaction at the most
electron-rich position on the methoxy naphthalene. The cat-
ionic species undergoes a 1,2-shift to form the thermodynami-
cally preferred structure 10. The stabilizing effects of the me-
thoxy group, as well as of the annulated benzo moiety, pro-
mote the formation of this structure. Extrusion of a proton
then results in the angular arene 5 f’. The subtle interplay be-
tween these particular effects provides an elegant route to
structures like 5 f’, which are usually difficult to prepare.[36]
Despite the steric demands of a bulky bromo substituent ad-
jacent to the freshly formed CÀC bond, the reaction provided
5g in 70% yield. In addition, an 11% yield of the 10-chloro de-
rivative 8g was obtained. When applying the same protocol to
the iodo substrate 4h, the transformation yielded the desired
phenanthrene 5h in 85% yield. Under the electrophilic reac-
tion conditions, protodeiodination caused the formation of 5a
in 10% yield. Although the iodo group represents a labile
moiety and the steric hindrance does not promote the conver-
sion, this example underlines the power of the MoV-mediated
oxidative coupling. The discussed substrates, 4a–4h, involve
activation of both aryl moieties that are involved in the cou-
pling process. The coupling of cinnamate 4i, which is not
equipped with an electron-releasing group, was accomplished
in a total yield of about 80% (5i and 8i). A 22% yield of the
product mixture shows the installation of an additional chloro
group in position 10 (8i) (Scheme 4).
Further deactivation by fluorine in the periphery allowed
even the oxidative coupling of 4j, which resulted in 5j being
obtained in 26% yield. However, fluorinated phenanthrene de-
rivatives can be synthesized in good to excellent yields when
the substrates are activated by an additional methoxy moiety
(5k: 86% and 5l: 92%). These fluorinated compounds might
be highly desirable because of their potential biological and
pharmacological activity in combination with their high biolog-
ical persistence.[37]
Scheme 2. Stereoselective synthesis of 2-aryl-substituted cinnamates.
Structural elucidation of the products required the whole
range of analytical methods. The molecular structures of two
oxidative coupling products (5 f and 5g) were obtained by X-
ray analysis of suitable single crystals (Figure 2). The chrysene
portion of 5 f is completely planar and has the anticipated
structure. A bulky bromo substituent in the bay region of the
phenanthrene causes an unusual distortion of the geometry.
The bromine atom in 5g is bent slightly towards the oxygen
atom of the neighboring methoxy group (Br1-C4-C3=
111.7(2)8, Br2-C17-C16=112.1(2)8) as a result of a week halogen
bond, as can be seen from the short BrÀO contacts of 285.5(2)
(Br1···O4), and 286.4(2) pm. These contacts are considerably
shorter (51 pm) than the sum of the van der Waals radii
(337 pm).
Scheme 3. Influence of a Lewis acidic additive on the coupling reaction.
The transformation can be extended to substrates contain-
ing naphtho moieties. Compound 4 f affords the desired chrys-
ene derivative 5 f in moderate yield upon treatment with the
MoCl5/TiCl4 mixture. Additionally, a 53% yield of 5 f’ with al-
tered connectivity was isolated. The preferential formation of
Unfortunately, the angular product 5 f’ did not produce suit-
able single crystals. Therefore, NOE experiments were used to
verify the anticipated architecture (see the Supporting Informa-
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Similar reaction pathways have
been described for niobium pen-
tachloride in demethylation reac-
tions.[38] To determine the poten-
tial of the MoCl5-mediated phen-
anthrene formation, we subject-
ed substrates with no or less ac-
tivation on the a-aryl substituent
to our optimized reaction condi-
tions. Installation of another me-
thoxy group on the cinnamate
(4m) led to a lower yield of the
corresponding compound, 5m,
since the electron-rich aromatic
core was chlorinated to form
8m. Substrates with two me-
thoxy groups in positions 3 and
5 should be appropriately acti-
vated for an oxidative coupling
process.[21c] Despite the distor-
tion in the product, the phenan-
threne derivative 5n was isolat-
ed in 60% yield. The absence of
coordination sites for MoCl5 is
reflected in the prolonged reac-
tion time of 20 h, whereas the
transformations of substrates
with a veratryl moiety (5a–l;
Scheme 4) usually requires 20–
60 min. The oxidative coupling
reaction of 4o provided a 40%
yield of 5o. Switching the posi-
tion of the methoxy groups on
to the cinnamate functionality
results in substantially inferior
yields compared to the forma-
tion of 5i.
The observed reactivity of
compounds 4 depends heavily
on the substitution pattern but
creates
a
consistent picture.
Most probably, precoordination
of MoCl5 to the 3,4-dimethoxy-
Scheme 4. Oxidative coupling of 2-phenylsubstituted ethyl cinnamates.
decorated aryl fragment occurs.
Since an a-aryl substituent on
tion). Irradiation of the isolated signal of the naphthyl moiety
allowed the unequivocal identification of the adjacent me-
thoxy group and the signal assigned as 12. This allowed the
differentiation between the signals of the 7 and 12 positions.
Irradiation of the frequencies attributed to the 6 and 7 posi-
tions shows strong through-space interactions, indicating an
angular geometry.
a cinnamate is usually tilted out of the plane,[31] it will experi-
ence no electron-withdrawing effect by the carbonyl group.
Consequently, the oxidative cyclization sequence should be in-
duced on this aryl system. Upon electron transfer to the mo-
lybdenum chloro fragment,
a radical cation is formed
(Figure 3). Such an intermediate can undergo the electrophilic
cyclization step. This view is strongly supported by recent ex-
perimental and theoretical studies of similar reactions with
MoCl5 and a newly developed MoV reagent.[24b] If methoxy
groups are present on the a-aryl moiety and not on the cinna-
mate, as is the case in 5i, the yield is significantly higher than
for the corresponding substrate 5o.
The oxidative coupling process was successfully carried out
with substrates containing a veratryl moiety in the position
a to the cinnamate. Previous studies have revealed that MoCl5-
mediated oxidations favor an ortho-dialkoxy substitution pat-
tern. Most probably, precoordination of the reagent occurs.[24]
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From the syntheses of the phen-
anthrene derivatives 5e, 5g, and
5i, the respective 10-chloro by-
products 8e, 8g, and 8i were iso-
lated. The additional installation of
a halogen as a leaving functionality
in that particular position has been
used in the total synthesis of natu-
ral products.[13d,e,39] Furthermore,
a halogen moiety at this position
may serve as a protecting group
Figure 3. Postulated inter-
mediate for conversion by
MoCl5.
for that part of the aromatic system. Removal of the unwanted
chloro group can be achieved in almost quantitative fashion
by reductive treatment (Scheme 6). Best results are obtained
by prior formation of low-valent nickel from sodium borohy-
dride and nickel(II) salts.[40] This treatment can also be applied
to the crude product mixture of phenanthrenes 5e/8e, 5i/8i,
or 5g/8g, which simplifies the purification process and enhan-
ces the yield.
Scheme 5. Migration of a naphthyl moiety during the oxidative-coupling
process.
Scheme 6. Dechlorination of phenanthrene species.
Conclusion
The oxidative cyclization reaction of a-aryl-substituted cinna-
mates to the corresponding phenanthrenes can be efficiently
performed by the MoCl5/TiCl4 reagent mixture. This oxidation
is easy to perform and much more powerful than other re-
agents. For several substrates that could not be converted suc-
cessfully by using other protocols, our method represents a reli-
able and superior process. By oxidative coupling, a wide varie-
ty of substitution patterns can be realized, including several
donor functionalities and fluoro derivatives. Most remarkably,
an iodo substituent in the bay region of the phenanthrene is
tolerated under these reaction conditions. The application of
these products (in the syntheses of indolicine and chinolicidine
alkaloids and their analogues) and their biological activities will
be reported in due course.
Experimental Section
Horner–Wadsworth–Emmons reaction (4)
General procedure: A flame-dried round-bottomed flask was
charged with lithium chloride (5.04 g, 120 mmol, 3.0 equiv), 1,8-
diazabicyclo[5.4.0]undec-7-ene
(DBU)
(16.8 mL,
112 mmol,
2.8 equiv), phosphonate 6 (40.0 mmol), and acetonitrile (100 mL)
under nitrogen. After 10 min of stirring at ambient temperature, al-
Figure 2. Molecular structure of chrysene derivative 5 f (a) and phenan-
threne 5g (b) based on X-ray analysis.
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dehyde 7 (60.0 mmol, 1.5 equiv) was added and the mixture was
kept for about one week. Next, the reaction was quenched by the
addition of aqueous citric acid (50 mL, 10%) and stirred for 10 min,
followed by extraction with EtOAc (3ꢁ50 mL). The organic layer
was washed with brine (30 mL) and dried over MgSO4. Volatile
compounds were removed under reduced pressure. The crude
product was purified by column chromatography on silica using
a mixture of EtOAc/cyclohexane to afford the desired products 4.
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General procedure: Under inert conditions, MoCl5 (5.54 g,
20.3 mmol, 2.2 equiv) was dissolved in anhydrous CH2Cl2 (70 mL),
chilled to 08C, and treated with TiCl4 (2.4 mL, 21.2 mmol,
2.3 equiv), before the corresponding 2-aryl-substituted cinnamic
acid ester 4 (9.2 mmol) was added. The mixture was stirred at 08C
until complete conversion of the cinnamic acid ester had occurred.
After quenching with saturated NaHCO3 solution (70 mL), the
aqueous layer was extracted with EtOAc (3ꢁ30 mL). Subsequent
treatment with brine (30 mL) and anhydrous MgSO4, followed by
concentration of the organic fraction, provided the crude product,
which was purified by column chromatography on silica with a cy-
clohexane/EtOAc mixture as the eluent. All phenanthrenes were
obtained as colorless or slightly yellow solids and were dried under
a high vacuum.
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Acknowledgements
The authors thank B. T. King (Reno/Nevada) for fruitful discus-
sions. A donation of MoCl5 by H. C. Stark (Goslar, Germany)
was very helpful.
Keywords: arene coupling · CÀC coupling · cyclization ·
molybdenum · oxidative coupling
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Received: May 7, 2014
Published online on July 17, 2014
Chem. Eur. J. 2014, 20, 12463 – 12469
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim