Palladium-Catalyzed Remote ortho-C-H Alkenylation of Alkyl Aryl Sulfones: Access to Densely Functionalized Indane Derivatives

Article abstract of DOI:10.1002/adsc.201501129

A practical method for the palladium-catalyzed ortho-olefination of benzyl and phenethyl 2-pyridyl sulfones with electron-deficient alkenes using N-fluoro-2,4,6-trimethylpyridinium triflate ([F⁺]) as the terminal oxidant is described. The chela

Full text of DOI:10.1002/adsc.201501129

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DOI: 10.1002/adsc.201501129
À
Palladium-Catalyzed Remote ortho-C H Alkenylation of Alkyl
Aryl Sulfones: Access to Densely Functionalized Indane
Derivatives
Pablo D. Legarda,a Alfonso García-Rubia,a Ramón Gómez Arrayµs,a,*
and Juan C. Carreteroa,*
a
Departamento de Química Orgµnica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049
Madrid, Spain
E-mail: ramon.gomez@uam.es or juancarlos.carretero@uam.es
Received: December 10, 2015; Revised: January 20, 2016; Published online: March 17, 2016
Dedicated to Prof. JosØ L. García Ruano on the occasion of his retirement.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501129.
Abstract: A practical method for the palladium-cat-
alyzed ortho-olefination of benzyl and phenethyl 2-
pyridyl sulfones with electron-deficient alkenes
using N-fluoro-2,4,6-trimethylpyridinium triflate
([F+]) as the terminal oxidant is described. The che-
lating auxiliary (2-pyridyl)sulfonyl unit was demon-
strated to be the key to the success of this reaction,
which occurs efficiently with excellent regioselectiv-
ity and monosubstitution selectivity. A variety of
steric and electronic changes to both coupling part-
ners is tolerated, including substitution at the ben-
zylic position of the sulfone compound. Further-
more, no appreciable loss of enantiopurity is ob-
served when using non-racemic substrates. This
method provides access to indane derivatives hold-
ing three contiguous stereogenic centers with high
diastereocontrol. The indane framework was con-
structed by intramolecular Michael addition of the
a-sulfonyl carbanion to the electrophilic alkene.
alkenyl group into the product.[2] Furthermore, the
use of chemically flexible directing groups provides
an additional handle for the diversification of the
product into architectures commonly found in natural
products or medicines.[3]
For example, indane-derived compounds are valua-
ble structural motifs present in many natural products,
and biologically active molecules.[4] This versatile scaf-
fold has also been employed in the fields of functional
materials,[5] chiral auxiliaries,[6] ligands for transition
metal-catalyzed reactions,[7] and organocatalysts for
asymmetric transformations.[8] In connection with
a project aimed at exploiting the efficiency and versa-
tility of the (2-pyridyl)sulfonyl (SO2Py) moiety as a di-
[9]
À
recting group in C H functionalization processes,
we envisioned that the densely functionalized indane
skeleton I might be readily accessed from simple phe-
nethyl sulfone derivatives III via a Pd(II)-catalyzed,
SO2Py-directed ortho-olefination followed by an in-
tramolecular Michael-type addition of the a-sulfonyl
carbanion to the newly introduced electrophilic
alkene in the olefinated product II (Scheme 1).[10] In
turn, chiral benzyl-substituted phenethyl sulfones III
À
Keywords: C H alkenylation; indanes; Michael-
type addition; palladium; 2-pyridyl sulfones
À
The selective functionalization of C H bonds is one
of the most prevalent technologies for the atom- and
step-economical synthesis of complex targets due to
its potential to minimize the number of synthetic ma-
nipulations and reduce chemical wastes.[1] In particu-
lar, the directing group-promoted, transition metal-
catalyzed oxidative coupling between arenes and ole-
fins (Fujiwara–Moritani reaction) is a valuable tool as
it enables the incorporation of a synthetically versatile Scheme 1. Proposed access to indane derivatives.
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Table 1. Evaluation of the directing ability of the 2-pyridyl
could be easily prepared, even in an enantioselective
fashion, by catalytic conjugate addition of nucleophil-
ic reagents to a,b-unsaturated sulfones.[11]
sulfone moiety[a]
Despite the simplicity of this approach, we antici-
pated several key challenges. First, although sulfur-
containing functions such as sulfonamide,[9,12] sulfo-
nate,[13] sulfoximine,[14] sulfonic acid,[15] sulfoxide[16]
and sulfide[17] have recently been incorporated as di-
À
recting groups in C H functionalizations, sulfones
have been scarcely explored.[18] Second, the chelation
assistance is typically limited by the size of the cyclo-
metalated intermediate, generally proceeding through
a five- or six-membered ring intermediate. Instead,
Entry Substrate
n
R
Product mono/di[b] Yield [%][c]
À
the C H olefination of phenethyl sulfone III would
1
2
3
4
5
1a
2
3
4
5
0
1
2
0
1
H
H
H
Et
6a
7
8
95:5
67
represent an intriguing remote functionalization[19] of
81:19
41
À
[d]
–
<5[d]
a C H bond at the d-position with regard to the sul-
fonyl group involving a seven-membered palladacycle
intermediate[20] (assuming coordination to the sulfonyl
oxygen) or eight-membered palladacycle species (if
coordination to the pyridyl function dominates). In
this regard, Zhang and co-workers have recently de-
9
>97:<3 87
>97:<3 74
Me 10
[a]
Conditions: substrate (0.15 mmol), phenyl vinyl sulfone
(0.165 mmol), Pd(OAc)2 (0.015 mmol), [F+] (0.30 mmol),
DCE, 1108C, 14 h.
À
Determined by 1H NMR.
vised a method for the remote ortho-C H alkenyla-
[b]
[c]
tion at the d- or e-position of benzyl, phenethyl and
phenylpropyl p-tolyl sulfoxides in which the sulfur
atom acts as the anchoring atom in the palladacy-
cles.[16h] Third, achieving compatibility with benzylic
substitution (including preservation of its stereochem-
ical integrity) and control of the relative stereochem-
Isolated yield of the monoolefination product after pu-
rification.
[d]
The starting material was recovered unaltered. [F+]=N-
fluoro-2,4,6-trimethylpyridinium triflate.
À
istry of the three contiguous stereogenic centers in I contrast to the majority of reported C H alkenylation
(four diastereomers can be formed in the cyclization reactions for which the diolefination of substrates
step) present key challenges for the synthetic utility bearing two equivalent ortho-C H bonds is a persis-
of this method.
À
tent problem,[23] this approach allowed for facile and
For testing our proposal, we first examined the di- high yielding formation of the monoalkenylated prod-
recting ability of the (2-pyridyl)sulfonyl group and ucts of benzyl and phenethyl 2-pyridyl sulfones with
À
how it is affected by the proximity to the target C H excellent ortho-regiocontrol and mono-/disubstitution
bond and the presence of a benzylic substitution. For selectivity using 1.1 equiv, of the alkene.[24]
this purpose, the 2-pyridyl sulfones 1–5 were prepared
The key directing role of the (2-pyridyl)sulfonyl
and subjected to the reaction with phenyl vinyl sul- unit was established through a control experiment
fone under typical conditions previously optimized showing the complete lack of reactivity of the related
for N-sulfonylaniline derivatives[9c] {Pd(OAc)2, benzyl phenyl sulfone (1b) when submitted to the re-
(10 mol%) and N-fluoro-2,4,6-trimethylpyridinium tri- action with phenyl vinyl sulfone under otherwise
flate[21] as stoichiometric oxidant ([F+], 2.0 equiv.) in identical reaction conditions to those in Table 1, the
DCE at 1108C for 14 h; Table 1}. To our satisfaction, reaction leading to exclusive recovery of starting ma-
the parent benzyl and phenethyl derivatives 1a and 2 terial even after a prolonged time (Scheme 2).
did participate in the alkenylation reaction in accepta-
An evaluation of the scope of the olefination of
ble yields, although in the case of the latter lower a variety of benzylic 2-pyridyl sulfones and electro-
monoolefination selectivity was observed (products 6a
and 7, entries 1 and 2). However, the reaction falls off
with the phenylpropyl sulfone 3, holding the targeted
À
C H bond one position further away from the chelat-
ing atom (n=2, entry 3). Interestingly, consistent with
the known influence of steric effects in the site selec-
tivity of many C H functionalizations,[22] the introduc-
À
tion of a substituent at the benzylic position in both
substrates allowed a very high monoalkenylation re-
action while improving the yield (9 and 10, 87% and
74%, respectively, entries 4 and 5). Remarkably, in Scheme 2. Control experiment with phenyl sulfone 1b.
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Pd-Catalyzed Remote ortho-C H Alkenylation of Alkyl Aryl Sulfones
1
philic alkenes is summarized in Scheme 3. Synthetical- of 80:14:6 (judged by H NMR analysis of the crude
ly useful yields of monoolefinated products were at- reaction mixture), of which the two main components
tained for nearly all substrates examined, regardless were isolated and characterized. The major product,
of the steric and the electronic properties of the arene identified as 20 (77%), was accompanied by the alke-
partner (typically >60% yield). In most cases, howev- nylation product at the most hindered ortho’ position
er, a small amount of other isomers (mainly diolefi- (20’, 10%, not shown), along with traces of the di-
nated product in substrates lacking substitution at the ortho-olefination product that could not be character-
benzylic position) was detected in the crude mixtures. ized because of its limited quantity. Nevertheless, the
When a meta-substituted starting material is em- survival of the Cl substituent is remarkable, providing
ployed, the regioisomer with the alkene moiety being products suitable for further elaboration. The reaction
installed at the less hindered ortho-position is pro- of the meta-methoxy derivative 14, led to an 88:12
duced as the major product. For example, the meta- mixture of mono-/diolefination products, where the
chloro sulfone 13 produced three products in a ratio major isomer 21 was isolated in 58% yield. On the
other hand, the presence of a strongly deactivating
substituent at the meta-position such as an ester
group (substrate 15) provided 22 in reduced yields
(45%) due to incomplete conversion (59%). Mean-
À
while ortho-C H functionalization is typically very
sensitive to the steric hindrance imposed by aryl
ortho’-substituents, leading to non-productive sub-
strates or much lessened reactivity. In this alkenyla-
tion method, however, ortho-substitution does not
seem to affect the outcome of the reaction, yet it re-
sulted in reduced reactivity, requiring 2–3 equivalents
of the alkene reactant (23 and 24, 61–62%). The reac-
tions with substrates branched at the benzylic position
gave generally higher monosubstitution selectivity (ꢀ
95%). The compatibility with heteroarenes, illustrated
with thienyl derivatives 30 and 31, is also noteworthy.
With respect to the alkene reaction partner, not only
the typical conjugated electron-deficient alkenes but
also 1,2-disubstituted alkenes such as diethyl fumarate
(28, 73%) and E-methyl cinnamate (29, 62%) proved
to be efficient substrates for this transformation.
Encouraged by the good tolerance of our catalyst
system towards different substitution patterns and
functional groups, the scope of phenethyl sulfone de-
rivatives as coupling partners was next evaluated
(Scheme 4). The results nicely parallel those previous-
ly found with benzyl sulfone derivatives in terms of
tolerance to a broad range of para-, meta-and ortho-
substituted aryl rings with diverse steric and electron-
ic properties, and versatility with regard to the substi-
tution at the alkene coupling partner, yet a fine ad-
justment of the amount of alkene (1–3 equiv.) was
needed for obtaining the optimum balance between
conversion and mono-/diolefination selectivity. It is
interesting to note that even a bulky ortho-bromo
substituent was relatively well tolerated (52, 57%).
The presence of a strongly deactivating substituent
(e.g., CF3) typically reduces the reactivity providing
lower yields (products 49 and 51), an effect that
seems to be much more pronounced when the elec-
tron-withdrawing group is attached to the meta-posi-
tion as previously observed in the benzyl sulfone
series (22 and 51). Also worthy of mention is that the
Scheme 3. Olefination of benzyl sulfone derivatives.
R1 substituent at the benzylic position can range in
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purity, affording the corresponding olefination prod-
uct (+)-44 in 81% yield with 91% ee (Scheme 4).
The tolerance to aryl substituents at the benzylic
position led us to question whether this catalyst
system might enable the chemoselective alkenylation
of a substrate having two electronically distinct aryl
groups. To test the electronic bias for the olefination
reaction, b,b-diaryl-substituted sulfone 60 holding an
electron-deficient and an electron-releasing aromatic
rings was prepared and subjected to the reaction with
methyl acrylate (1.2 equiv.) under the standard reac-
tion conditions (Scheme 5). This experiment revealed
a strong preference for the electron-rich p-methoxy-
phenyl group (61/62=88:12).
Scheme 5. Evaluation of the electronic bias for the olefina-
tion reaction.
In accordance with our desired goal of developing
a method to access indane derivatives, we secured
conditions for the efficient cyclization of the alkenyla-
tion products. Simple treatment of a solution of the
products shown in Scheme 3 in THF at 08C with
KHMDS (1.1 equiv.) enabled the rapid access to func-
tionally dense indane derivatives with excellent con-
trol of the stereorelationship between the three con-
tiguous stereocenters (Scheme 6). In all cases studied,
Scheme 4. Olefination of phenethylamine derivatives.
a single stereoisomer of the indane derivative was de-
1
steric demand from methyl to hexyl (53, 55%) and tected by H NMR. The all-trans relative stereochem-
isobutyl (54, 43%), and it can also be aromatic (55– istry pattern was confirmed by means of NMR spec-
59, 57–86%).
troscopy (mainly by NOE experiments) and, in the
We were eager to test whether this alkenylation case of products 66, 70, 76, and 77 by single-crystal X-
protocol preserves the stereochemical integrity of the ray crystallography.[25]
stereogenic center at the benzylic position when using
We confirmed that this base-promoted cyclization
enantiomerically enriched substrates. For that pur- reaction takes place with no appreciable racemiza-
pose, substrate (+)-5 was prepared with 91% ee, fol- tion, as demonstrated in the reaction with maleate
lowing our previously reported Cu-catalyzed asym- (+)-44 (91% ee), which occurred with full preserva-
metric conjugate reduction of b,b-disubstituted a,b- tion of its stereochemical integrity [product (+)-66,
unsaturated sulfones[11h] (see the Supporting Informa- 85% yield, 91% ee].
tion). Pleasingly, the reaction of (+)-5 (91% ee) with
Finally, our attention was shifted to the removal of
diethyl fumarate took place without loss of enantio- the directing group in the final products. Typical liter-
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Pd-Catalyzed Remote ortho-C H Alkenylation of Alkyl Aryl Sulfones
Scheme 7. Desulfonylation attempts with sodium amalgam.
cedure. For example, treatment of derivatives 72, 74
and 77 with KO-t-Bu (1 equiv.) in THF at 08C afford-
ed in all cases a 1:1 mixture of the two regioisomeric
alkenes resulting from b-elimination, for which stan-
dard catalytic hydrogenation conditions provided the
corresponding cis-1,3-disubstituted indane derivatives
82–84 in moderate yields (55–63%) with excellent ste-
reoselectivity (Scheme 8).
Scheme 8. Base-promoted desulfonylation/hydrogenation to
afford cis-1,3-disubstituted indane derivatives.
In summary, we have developed a Pd-catalyzed
À
method to alkenylate remote ortho C H bonds of
benzyl and phenethyl sulfone derivatives with elec-
tron-deficient olefins. The reaction is tolerant of sub-
stitution at the benzylic position, with no appreciable
loss of enantiomeric purity when starting from chiral
Scheme 6. Stereocontrolled access to indane derivatives with
three contiguous stereocenters.
ature conditions for reductive cleavage of the sulfone non-racemic phenethylamine derivatives. The process
group with sodium amalgam or samarium diiodide[26] is enabled by the use of a (2-pyridyl)sulfonyl directing
failed to produce the desired desulfonylated indane group that also allows for a quick and efficient assem-
derivatives. For example, the reaction of 63 and 72 bly of indane derivatives having a variety of substitu-
with Na(Hg) established, unexpectedly, that cleavage tion patterns and up to three contiguous stereogenic
À
À
of the 2-Py S bond took place instead of the alkyl S centers with high degree of stereocontrol.
bond, leading to the corresponding indane-2-sulfi-
nates 78 and 79, respectively (Scheme 7). Although
these sulfinates were sufficiently stable for isolation
and characterization by H NMR spectroscopy, they
Experimental Section
1
turned brown upon standing for several hours at
À
Typical Procedure for the ortho C H Alkenylation
Reaction: Synthesis of 10
room temperature and decomposed. Nevertheless,
both sulfinates could be converted in situ into the cor-
responding methyl sulfone derivatives 80 and 81 in
synthetically useful yields by methylation with iodo-
methane.
We were pleased to find, however, that a base-pro-
moted desulfonylation proceeded smoothly in those
indanes having an aromatic substituent at C-3, there-
A screw-capped test tube was charged with sulfone 5
(39.2 mg, 0.15 mmol), Pd(OAc)2 (3.32 mg, 0.015 mmol,
10 mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate
(87 mg, 0.3 mmol, 2.0 equiv.) and phenyl vinyl sulfone
(28 mg, 0.165 mmol, 1.1 equiv.). The mixture was placed
under a nitrogen atmosphere (evacuated and flushed with
nitrogen three times) before DCE (1.5 mL) was added. The
by further qualifying the synthetic utility of this pro- mixture was heated to 1108C for 16 h before it was allowed
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to cool to room temperature, diluted with CH2Cl2 (10 mL)
and filtered through a pad of Celite. The filtrate was concen-
trated under reduced pressure and the residue was purified
by flash chromatography (cyclohexane-EtOAc, 5:1) to
afford 10 as a pale yellow solid; yield: 47 mg (74%); mp
106–1088C.
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Compound characterization data are available in the Sup-
porting Information.
Typical Procedure for the Cyclization Reaction:
Synthesis of Indane 64
À
[3] For reviews on directing group strategy in C H activa-
To a solution of 42 (52 mg, 0.15 mmol) in dry THF (1.5 mL),
cooled to 08C and under a nitrogen atmosphere, was added
a solution of potassium bis(trimethylsilyl)amide (0.5M in
toluene, 300 mL, 0.15 mmol). The resulting mixture was
stirred at 08C for 15 min (TLC monitoring) before a saturat-
ed aqueous solution of NH4Cl (5 mL) was added. The aque-
ous phase was extracted with EtOAc (3”5 mL) and the
combined organic phase was washed sequentially with water
(5 mL) and brine (5 mL) before it was dried (MgSO4) and
concentrated to dryness. The residue was purified by flash
chromatography (cyclohexane-EtOAc, 1:1) to give 64 as
a white solid; yield: 44 mg (85%); mp 1308C (decomp.).
Compound characterization data are available in the Sup-
porting Information.
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Acknowledgements
We thank the Spanish Government (MINECO, CTQ2012-
35790) for financial support. P.D. L. thanks the Spanish Gov-
ernment (MINECO) for an FPU predoctoral fellowship.
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[24] Interestingly, just by increasing the amount of the
alkene to 2–2.5 equivalents in the reaction with 1a
under otherwise identical conditions to those shown in
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Pablo D. Legarda et al.
[25] See the Supporting Information. CCDC 1436280,
CCDC 1436281, CCDC 1436282 and CCDC 1436283
contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
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Table 1 resulted in a clean diolefination reaction (prod-
ucts 85 and 86 in the formula above).
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Adv. Synth. Catal. 2016, 358, 1065 – 1072