Expeditious synthesis of tetrasubstituted helical alkenes by a cascade of palladium-catalyzed C-H activations

Article abstract of DOI:10.1002/anie.201204226

Twisted molecules: A modular approach for the synthesis of tetrasubstituted helical alkenes by a palladium-catalyzed norbornene-mediated domino reaction is presented. This intermolecular domino process allows the formation of three C-C bonds in one operation through a C-H activation/carbopalladation/C-H activation sequence. Copyright

Full text of DOI:10.1002/anie.201204226

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Chemie
DOI: 10.1002/anie.201204226
Domino Reactions
Expeditious Synthesis of Tetrasubstituted Helical Alkenes by a Cascade
À
of Palladium-Catalyzed C H Activations**
Hongqiang Liu, Mohamed El-Salfiti, and Mark Lautens*
particular, domino reactions[11] involving sequential C H
activations have become more attractive, as they significantly
shorten the number of synthetic steps, thus avoiding the
necessity to prefunctionalize one or both of the coupling
partners.[12]
À
The design and construction of molecular analogues of
mechanical machines has attracted increasing attention over
the past decade.[1–4] In particular, artificial molecular devices
based on chiral tetrasubstituted helical alkenes, which were
developed by Feringa and co-workers,[5] have received grow-
ing interest. Synthetic rotary molecular motors such as 1 are
capable of performing perpetual unidirectional 3608 rotation
around the center of the olefin upon light irradiation
(Figure 1).[6] The direction of rotary motion is governed by
We have previously demonstrated the feasibility of
forming tetrasubstituted alkene 5 by a Pd-catalyzed norbor-
À
nene mediated domino reaction involving multiple C H
functionalizations [Scheme 1, Eq. (1)].[10a] In this reaction,
norbornene not only acts as a promoter,[13] but is incorporated
into the product. To increase the molecular diversity of these
products and to allow for the fine-tuning of their photo-
chemical properties, we disclose herein a novel domino
reaction to access sterically crowded helical alkenes 7 without
norbornene incorporation, whilst using norbornene to facil-
À
itate the C H activations.
Figure 1. Representative examples of a light-driven molecular motor
(1), a switch (2,3) and a motor-based asymmetric catalyst (4).
the chirality of the stereogenic center(s) in the helical
molecule. Furthermore, molecules with different applications
have been designed and studied in recent years, such as
molecular switches[7] (for example, 2 and 3) with the potential
for optical data storage. Moreover, asymmetric organocata-
lyst 4[8] can be modulated by light in situ to generate either
enantiomer of the product. Subtle and distinct structural
modifications are generally required for fine-tuning of the
rotary motion of such artificial molecular devices.[9] To attain
this goal, methods for the rapid and modular synthesis of
tetrasubstituted helical alkenes are highly desirable.[7,10] In
Scheme 1. Work preceding this report and a proposed retrosynthetic
disconnection of 7.
[*] Dr. H. Liu, M. El-Salfiti, Prof. Dr. M. Lautens
Department of Chemistry, University of Toronto
80 St. George St., Toronto, Ontario, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/ML
Our design was inspired by our previous synthesis of fused
tetracyclic pyrroles 6 using a Pd-catalyzed domino reaction[14]
[Scheme 1, Eq. (2)], wherein a norbornene mediated ortho-
alkylation of an aryl iodide followed by carbopalladation of
a tethered alkyne resulted in a vinylpalladium species. This
[**] We gratefully acknowledge the Merck Frosst Center for Therapeutic
Research, the Natural Science and Engineering Research Council
(NSERC), and the University of Toronto for financial support. H.L.
thanks the Ontario Postdoctoral Fellowship for financial support.
M.E. thanks NSERC for financial support (CGS-M). We also thank
Dr. Alan Lough for X-ray analysis.
À
intermediate subsequently underwent an intramolecular C H
functionalization on the pendant pyrrole to afford the desired
product. We envisioned that, if the bromoalkyl aryl alkyne
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204226.
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precursor was appended with a 2-substituted aryl/heterocyclic
group on the aromatic ring [Scheme 1, Eq. (3)], then carbon–
carbon bond formation should occur between the vinylpalla-
tively) in good yields. Aryl iodides containing both an ortho-
methyl group and either a para-nitro (9d), meta-chloro (9e),
or meta-fluoro (9 f) substituent gave the corresponding
products (7d–f) in good yields. More importantly, the
tolerance of nitro or chloro substitutents in the final product
allows for further manipulation and is suitable for incorpo-
ration into a larger system.[18,19] Notably, the helical alkene 7g,
which bears a naphthalene substitutent, can be prepared in
good yield from 1-iodonaphthalene (9g). The X-ray crystal
structures of 7d and 7g confirm the connectivity and relative
configuration of the tetrasubstituted alkenes (Figure 2). The
À
dium species and the pendant aryl/heterocyclic group by C H
functionalization, thereby providing tetrasubstituted alkenes
lacking the norbornene moiety.
To test this approach, we chose a pyrrole moiety as the
pendant heterocycle in the bromoalkyl aryl alkyne precursor.
The 2-pyrrolyl substituted bromoalkyl aryl alkyne 8 can be
easily obtained from o-iodoanilines in a three step syn-
thesis.[15] With substrate 8 in hand, we examined this domino
process using the standard reaction conditions previously
used in our earlier work. To our delight, the desired
tetrasubstituted alkene 7a was obtained in 31% yield
(Scheme 2). Interestingly, the product was isolated as a mix-
Figure 2. X-ray crystal structures of 7d and 7g.
helical structure of 7g was also unambiguously confirmed by
proton NMR spectroscopy. The chemical shift of one of the
protons in the pyrrole ring is shifted significantly upfield
compared to the corresponding proton in 7d (4.23 ppm vs.
5.38 ppm). Presumably, this is due to a shielding effect by the
ring current of the aromatic naphthalene moiety, as suggested
by the crystal structure of 7g. The reaction can also be
performed on a preparatively useful scale (1 mmol), resulting
in a similar yield and affording more than 200 mg of material.
The reaction scope was further investigated using bro-
moalkyl aryl alkynes 10a–i[15] (Scheme 3), which were easily
accessible in a similar manner to 7. A variety of substituents
(F, Cl, NO2) at different positions on the aryl ring of the
alkyne system were tolerated, producing the corresponding
products 11a–c in moderate to good yields. 11c was isolated
as a mixture of E/Z isomers (1:1) despite all efforts to prevent
the acid catalyzed isomerization. Presumably, this compound
undergoes fast isomerization upon exposure to visible light.
Substrate 10d, which bears a differently substituted 2-pyrrolyl
moiety, afforded product 11d in good yield. This reaction also
Scheme 2. Scope of the reaction with ortho-substituted aryl iodides.
Reagents and reaction conditions: 2-pyrrolyl substituted aryl alkyne 8
(ca. 0.2 mmol; 1 equiv), aryl iodide 9a–g (2.0 equiv), norbornene
(2.0 equiv), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (3.0 equiv),
acetonitrile (2.0 mL), 908C, 24 h, sealed tube. Yields given are of
isolated products. [a] Reaction conducted under earlier conditions: as
described, but using TFP in place of PPh3 and with norbornene
(3 equiv). [b] Reaction conducted on 1.0 mmol of 8.
À
tolerated pendant heterocycles other than pyrrole; C H
activation was successful on indole, furan, and thiophene
systems to form products 11e–g, respectively, in moderate to
good yields. Interestingly, single isomers were observed for
furyl and thienyl substituted compounds (11 f and 11g,
respectively); unlike their pyrrole based counterparts, these
compounds were not sensitive to acid. We also observed that
nonheterocyclic nucleophile 10h can be used to give 11h in
moderate yield. The reaction scope can be further extended to
form crowded helical alkene 11i with four aromatic substi-
tutents, which was found to be very sensitive to light when in
solution.[20]
ture of E/Z isomers.[16] Presumably, the isomerization could
be acid-catalyzed and/or light-driven.[17] Indeed, under acid-
free conditions and with protection from light, the desired
product was obtained as a single isomer. In the optimization
study we found that upon switching the ligand from tri(2-
furyl)phosphine (TFP) to triphenylphosphine (PPh3), 7a can
be isolated in 68% yield.
We then investigated the scope of the reaction using
various ortho-substituted aryl iodides (Scheme 2). Both aryl
iodides bearing electron-donating (OMe, 9b) and electron-
withdrawing (CF3, 9c) substitution in the ortho-position
afforded the corresponding products (7b and 7c, respec-
This method also provides quick access to chiral and
enantiomerically enriched tetrasubstituted helical alkenes,
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Scheme 4. Stereoselective synthesis of tetrasubsituted alkenes 13a–f.
Reagents and reaction conditions: bromoalkyl aryl alkynes 12a–f (ca.
0.2 mmol, 1 equiv), aryl iodide (2.0 equiv), norbornene (2.0 equiv),
Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (3.0 equiv), acetonitrile
(2.0 mL), 908C, 24 h, sealed tube. Yields given are of isolated
products. [a] d.r. determined by 1H NMR analysis of the crude product.
[b] ee determined by HPLC analysis on a chiral stationary phase.
[c] Reaction conducted at 1208C with TFP as the ligand.
reactions involving oxidative addition of the aryl iodide,
carbopalladation of norbornene, and electronic metalation
followed by deprotonation gives palladacycle B. Oxidative
addition of a bromoalkyl aryl alkyne leads to C, and rapid
reductive elimination delivers ortho-alkylated intermediate
D. Because of increased steric demand, a retrocarbopallada-
tion of norbornene then occurs, leading to arylpalladium
species E. Next, intramolecular carbopalladation on the
tethered alkyne generates the vinylpalladium species F. At
Scheme 3. Scope of the reaction with bromoalkyl aryl alkynes.
Reagents and reaction conditions: bromoalkyl aryl alkynes 10a–i (ca.
0.2 mmol, 1 equiv), aryl iodide 9a, 9b, or 9d (2.0 equiv), norbornene
(2.0 equiv), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (3.0 equiv),
acetonitrile (2.0 mL), 908C, 24 h, sealed tube. Yields given are of
isolated products. [a] Product was isolated as an E/Z mixture (1:1).
[b] Reaction conducted with TFP as the ligand. [c] Reaction conducted
at 1208C with TFP as the ligand.
À
this point the intermediate can directly induce C H function-
alization on the adjacent pyrrole ring to form G, and
subsequent reductive elimination generates the desired
product H. Because of the high reactivity associated with
norbornene (strain energy = 21.6 kcalmolÀ1)[23] and its pres-
ence in large excess, the vinyl palladium species F could
undergo intermolecular carbopalladation of norbornene, thus
(13a–f) which possess a stereogenic center next to the olefin
(Scheme 4). It is noteworthy that, as shown by Feringa, the
absolute stereochemistry in these alkenes can dictate the
direction of molecular rotation upon irradiation.[7a] Utilizing
the optically pure bromoalkyl aryl akynes 12a–f,[15] the
domino reaction with 2-iodotoluene afforded the correspond-
ing chiral helical alkenes in excellent yield and good
stereoselectivity. Both enantiomers can be accessed from
the corresponding enantiomerically pure precursors, which
allows for the study of their distinct rotational behavior upon
irradiation. These reactions proceed with retention of stereo-
chemistry of the bromide precursors in excellent enantiose-
lectivity (up to 99% ee). The induction of helical chirality in
this multiple bond forming process was observed, as was
suggested by the moderate diastereoselectivity of the reac-
tion. We reported a stereoselective synthesis of tetrasubsti-
tuted alkenes bearing norbornene, which also bear the
observed helical chirality, in accordance with these findings.[22]
The proposed mechanism of the domino reaction is
outlined in Scheme 5. Similar to the other norbornene
À
leading to complex I, to which another C H functionalization
on the adjacent aromatic ring could occur to liberate
tetrasubstituted alkene J. However, this reaction pathway is
not followed, as revealed by the formation of product H.
À
Presumably, the C H functionalization of F to provide G is
much faster than the carbopalladation of norbornene, thereby
preventing the formation of I. Another potential explanation
could be the increased steric congestion in complex I, which
would result from the bulky 2-substituted aryl/heterocyclic
group. If formed, this species, particularly for 12a–f contain-
ing a pendant stereogenic center, would favor the retrocar-
bopalladation of norbornene to produce F, despite the use of
a large excess of norbornene.[24]
In conclusion, we have developed an effective and highly
modular synthesis of sterically crowded tetrasubstituted
helical alkenes possessing high structural diversity through
À
a palladium-catalyzed norbornene mediated cascade of C H
[13]
À
mediated C H functionalization processes,
a series of
activations. The molecules synthesized can act as lead
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À
[12] For selected reviews on palladium-catalyzed C H functionali-
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Dyker), Wiley-VCH, Weinheim, 2005; b) D. Alberico, M. E.
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Scheme 5. Proposed reaction mechanism for the domino process.
Ligand and solvent molecules omitted for clarity.
À
[13] For reviews on the use of norbornene as a promoter for C H
activations, see: a) M. Catellani, Top. Organomet. Chem. 2005,
14, 21; b) A. Martins, B. Mariampillai, M. Lautens, Top. Curr.
Chem. 2010, 292, 1.
structures for the design of light-driven molecular devices.
Investigations into their photochemical behavior upon light
irradiation are currently underway.
[14] K. M. Gericke, D. I. Chai, M. Lautens, Tetrahedron 2008, 64,
6002 – 6014.
[15] See the Supporting Information for substrate synthesis.
[16] 1H NMR analysis showed that the ratio of the two isomers varied
over time in a CDCl3 solution when not protected from light.
[17] a) For the acid – base reactivity of pyrrole, see: M. Balꢀn, M. C.
Received: May 30, 2012
Published online: && &&, &&&&
À
Keywords: C H activation · domino reactions · palladium ·
strained molecules · tetrasubstituted alkenes
.
ˇ
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C. W. M. Bastiaansen, D. J. Broer, B. L. Feringa, Nature 2006,
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[20] 11i was isolated as a mixture of E/Z isomers because of a rapid
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11i changed color and decomposed at room temperature after
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4
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one day under visible light, as confirmed by 1H NMR analysis of
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[21] Diastereoselectivity in helical alkene formation induced by
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[24] It was found that even with a large excess of norbornene
(8.0 equiv), 7a was still formed in 55% yield, based on NMR
analysis. This suggests that the norbornene incorporation path-
À
way is less favorable than the directed C H functionalization.
Perhaps this is due to the presence of the pyrrole, which disfavors
species I.
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Communications
Domino Reactions
H. Liu, M. El-Salfiti,
M. Lautens*
&&&& — &&&&
Expeditious Synthesis of Tetrasubstituted
Helical Alkenes by a Cascade of
À
Palladium-Catalyzed C H Activations
À
Twisted molecules: A modular approach
for the synthesis of tetrasubstituted hel-
ical alkenes by a palladium-catalyzed
norbornene mediated domino reaction is
presented. This intermolecular domino
process allows the formation of three C
À
C bonds in one operation through a C H
À
activation/carbopalladation/C H activa-
tion sequence.
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!