Rhodium(III)-catalyzed intramolecular hydroarylation, amidoarylation, and heck-type reaction: Three distinct pathways determined by an amide directing group

Article abstract of DOI:10.1002/anie.201307631

The amide decides: Three different rhodium(III)-catalyzed reaction pathways of a wide variety of tethered alkenes can be accessed through changing the amide directing group. This provides an efficient route to a myriad of complex polycyclic products, many containing newly formed all-carbon quaternary centers. Amidoarylations can diastereoselectively deliver products with up to three contiguous stereocenters. Copyright

Full text of DOI:10.1002/anie.201307631

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Chemie
DOI: 10.1002/anie.201307631
Rhodium Catalysis
Rhodium(III)-Catalyzed Intramolecular Hydroarylation,
Amidoarylation, and Heck-type Reaction: Three Distinct Pathways
Determined by an Amide Directing Group**
Tyler A. Davis, Todd K. Hyster, and Tomislav Rovis*
RhIII catalysis has enabled a vast number of transformations
through C–H activation. Many examples exist of functional-
ization of arenes at the ortho position to a directing group,
thus eliminating the need for prior activation at that position.
through the meta position.[6] While this has the obvious
disadvantage of being a tethering strategy, we hoped to gain
insights into the reaction and use more complex stereochem-
ically defined internal alkenes to arrive at products IIIb and
IVb (Scheme 1). In particular, the ability to use 1,1-disub-
stituted and trisubstituted alkenes could lead to synthetically
challenging compounds containing all-carbon quaternary
stereocenters that have not been accessed through previous
methods.[7] We have previously demonstrated that {Cp*RhIII}
undergoes reversible C–H activation in the absence of
alkyne[8] and we thus felt that even if the more sterically
À
This is a powerful emerging strategy for forming Csp2 Csp3
[1]
À
bonds from aryl and alkenyl C H bonds.
The use of simple alkenes as partners in the C–H/N–H
activation of benzamides has been demonstrated previously,[2]
and in a few cases has been rendered enantioselective.[3]
Nevertheless, most cases are limited to functionalized
alkenes: styrenes and acrylates undergo regioselective inser-
tion (5:1 to 20:1) whereas terminal alkenes perform poorly
(ca. 1:1 to 2:1).[4] The situation is further exacerbated by the
use of unsymmetrical benzamide partners: 3-substituted
À
accessible C H bond was first to be activated (IIa, Scheme 1),
it should not undergo reaction because of the lack of an
appropriate coupling partner.
À
benzamides have two distinct C H bonds ortho to the
Subjection of a simple E-trisubstituted alkene tethered to
the 3-position of methylbenzamide to a cationic RhIII catalyst
(condition A, entry 1, Table 1) and stoichiometric pivalic acid
in DCE at 808C led to full conversion into the hydroarylation
product 4.[9] The subjection of the corresponding N-OMe
amide (entry 2, Table 1) to the same reaction conditions
directing group, thus leading to a pair of potential rhodacycles
(IIa and IIb, Scheme 1), and these benzamides give mixtures
of products sometimes dominated by steric effects and other
times by electronic effects.[5]
To understand these issues of regioselectivity, we sought
to use simple alkenes tethered to the benzamide system
Table 1: Initial optimization of hydroarylation conditions.[a]
Entry
X
Y
Condition
4/5/6
Conv. [%][b]
1
2
3
4
5
Me
Me
H
H
H
H
A, 17 h
A, 17 h
A, 17 h
B, 2 h
100:0:0
71:29:0
0:0:100
0:100:0
0:22:78
100
53
OMe
OPiv
OMe
OPiv
61[c]
100
100
Scheme 1. Regioselective C–H activation. Cp*=pentamethylcyclopen-
tadienyl.
B, 12 h
[a] Reactions conducted on 0.1 mmol scale. A: [RhCp*(MeCN)3](SbF6)2
(1 mol%), tBuCO2H (1 equiv), 1,2-dichloroethane (0.2m), 808C; B:
[RhCp*Cl2]2 (2.5 mol%), CsOAc (2 equiv), MeOH (0.2m), RT. [b] Con-
version determined by 1H NMR. [c] Hydrolysis of the starting material
was also observed. OPiv=pivalate.
[*] Dr. T. A. Davis, T. K. Hyster, Prof. T. Rovis
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA)
E-mail: rovis@lamar.colostate.edu
Homepage: http://sites.chem.colostate.edu/rovislab
provided a 71:29 mixture of the hydroarylation product 4 and
the dehydrogenative Heck-type (DH) product 5.[10] Reaction
of the N-OPiv amide resulted in the amidoarylation product 6
along with hydrolysis of the starting material (entry 3,
Table 1). Finally, conducting the reaction of amides 2 and 3
[**] We thank NIGMS (GM80442) for support and Johnson Matthey for
a generous gift of Rh salts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307631.
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under basic conditions resulted in products 5 and 6 selectively
at ambient temperature (entries 4,5, Table 1).
both ortho positions in the recovered starting material
[Eq. (1)].
Mechanistically, this reaction may proceed through a C–H
activation event and addition of the aryl rhodium species
across the alkene to provide the seven-membered metalla-
cycle VI (Scheme 2). Protonation could then lead to the
hydroarylation product 4. This common metallacycle could
also proceed to a reductive elimination pathway (6) or a b-
hydride elimination pathway (5) with reduction of the metal.
Validation of our hypothesis that the Rh catalyst samples both
ortho positions on the benzamide came from a deuterium
labeling experiment. Subjection of 1a to the hydroarylation
conditions in the presence of AcOD resulted in deuterium
incorporation at the ortho position in product 4a as well as at
We were intrigued by the ability to deliver three distinct
products simply by choice of amide substituent and sought to
delineate the scope of each transformation. Using the optimal
conditions for hydroarylation,[11,12] the amide portion of the
tethered alkene was varied to investigate its impact
(Scheme 3). An N,N-dimethylamide was used to provide
cyclized product 4d in 75% yield. A glycine amide led to
product 4e in excellent yield (92%). Changing the directing
group to an ester was detrimental since only a small amount
of conversion into product was observed by NMR spectro-
scopy under the standard conditions.
A wide variety of tethered alkenes were found to undergo
the desired cyclization. Modification of the alkene was
tolerated since several 1,1-di- and trisubstituted alkenes[13]
were converted into the cyclized products. In addition to five-
membered rings, six-membered rings (4g, 4n) could be
Scheme 2. Plausible mechanistic pathways.
Scheme 3. RhIII-catalyzed intramolecular hydroarylation. Reaction conditions: [RhCp*(MeCN)3](SbF6)2 (1 mol%), tBuCO2H (1 equiv), 1,2-dichloro-
ethane (0.2m), 808C, 16–23 h. [a] 5 mol% [RhCp*(MeCN)3](SbF6)2 used. [b] 2.5 mol% [RhCp*(MeCN)3](SbF6)2 used.
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formed. Electronic and steric modification of the aryl group
was also tolerated. Electron-deficient p-nitro and p-flouro
substrates each gave the corresponding bicyclic systems (4h
and 4i, respectively) in 91% yield. Ortho substitution of
a methyl group also led to good yield of product 4j (99%). An
electron-rich dioxanyl substrate was converted into product
4k in 83% yield. An alkene tethered to an indole cleanly
converted to product 4l (99%). An acrylate system reacted to
give the resulting ester 4m in 61% yield. A Weinreb amide
was also tolerated and delivered the hydroarylation product
4n in 91% yield.[14]
The b-H elimination/DH pathway produces another
useful product with an all-carbon quarternary stereocenter.
Direct intermolecular C–H allylations have been demon-
strated with a variety of metals but are limited by the
necessity to use electron-deficient arenes or harsh conditions.
More recently, allenes (Ir[15] and RhIII-catalyzed[16]) and allyl
carbonates (RhIII-catalyzed[17]) have been used in directed C–
H allylations. In contrast to the previous examples that use
a variety of leaving groups on the allyl fragment, this pathway
provides the allylated product from an allyl substrate by an
oxidative pathway.
Scheme 5. Amidoarylations of E and Z olefins. Reaction conditions:
[RhCp*Cl2]2 (2.5 mol%), CsOAc (2 equiv), MeOH (0.2m).
An extensive scope was demonstrated for this reaction as
shown in Scheme 6. This reaction tolerated mono-, 1,1-di-,
and trisubstituted olefins. An all-carbon-tethered alkene and
a phenyl-substituted alkene provided product in good yield
(6 f, 81% and 6g, 99%, respectively). Electron-poor (6h and
6j), electron-rich (6i), and ortho-substituted (6k) aryl prod-
ucts were prepared. E and Z tethered a,b-unsaturated esters
each successfully inserted to give a single diastereomer (E
giving 6l, 87%; Z giving 6m, 50%). An E-1,1-disubstituted
alkene cyclized to solely give the trans product 6n in good
yield.
We briefly explored the scope of this transformation
(Scheme 4). With the necessity to use an alkene with an
available b-hydride, we modified the aryl portion with tri-
substituted alkenes. Three additional substrates were shown
In an attempt to provide access to a broader range of
products, an ester-tethered substrate was subjected to the
optimal reaction conditions. Cyclization of N-methoxy amide
2 f (Scheme 7) proceeded smoothly to provide the cleavable
lactone product 5 f in 72% yield. By contrast, reaction of the
corresponding N-pivaloxy amide 3o resulted in the formation
of methanolysis product 7. This mild lactone cleavage is likely
an indication of considerable strain within this tricyclic system
and other similar systems shown in Scheme 6. Alternatively,
the use of a non-nucleophilic solvent (1,2-dichloroethane)
allowed the desired lactone 6o to be synthesized and isolated
in modest yield (45%).
To further demonstrate the utility of this reaction, we
explored the effect of a pre-existing stereocenter on these
transformations. It seemed likely that reactivity could be
directed to one face of the olefin based on the steric
constraints provided by a stereocenter. This would potentially
lead to a product with three contiguous stereocenters in
a highly controlled fashion. An alkyl substituent a to the
tethered alkene was well tolerated under the standard
conditions since the product 6p was obtained in 98% yield
(Scheme 8). Furthermore, this reaction was found to be highly
diastereoselective since the compound was isolated with
a d.r. > 20:1 as determined by 1H NMR and 72:1 by GC–MS.
A series of NOESY experiments[18] indicated a syn,syn
relationship between the three alkyl groups.
Scheme 4. RhIII-catalyzed intramolecular DH-type reactions. Reaction
conditions: [RhCp*Cl2]2 (2.5 mol%), CsOAc (2 equiv), MeOH (0.2m),
1–2 h. [a] 20 h reaction time.
to undergo the DH reaction in good yield (75–86%). An E-
1,1-disubstituted alkene also underwent the DH reaction to
form the dihydrobenzopyran product 5e in good yield and
moderate E/Z selectivity (86%, 4.5:1).
The third pathway identified in this work, the amidoaryl-
ation reaction, allowed us to examine the impact of olefin
geometry on the reaction. When the E olefin 3a was subjected
to the reaction conditions shown in Scheme 5, a single isomer
of desired insertion product was isolated in 65% yield with
a small amount of byproduct 5a (resulting from b-H
elimination) isolated in 18% yield. Subjection of the Z
alkene 3b to the same reaction conditions provided the
opposite diastereomer of the insertion product (6b) exclu-
sively (99% yield). Importantly, starting olefin geometry is
faithfully relayed into product stereochemistry.
In summary, we have found three distinct RhIII-catalyzed
reaction pathways of tethered olefin-containing benzamides.
Hydroarylation, amidoarylation, and dehydrogenative Heck-
type products can be accessed based on the type of amide
substrate used. A wide variety of tethered alkenes can cyclize
to make the five- or six-membered products in good to
excellent yields. Furthermore, high diastereoselectivity has
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Scheme 6. RhIII-catalyzed intramolecular amidoarylations. Reaction conditions: see Scheme 5, 0.3–6 h reaction time. [a] 18 h reaction time.
[b] 48 h reaction time.
Keywords: amidoarylation · C–H activation ·
.
Heck-type reaction · hydroarylation · rhodium
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Scheme 8. Diastereoselective cyclization. Reaction conditions: see
Scheme 5.
been observed in the amidoarylation reaction of a substrate
containing a pre-existing stereocenter. Efforts to further
expand the scope and impart enantioselectivity to this
reaction are underway.
Received: August 29, 2013
Published online: November 8, 2013
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(SbF6)2 or when substituting [RhCp*Cl2]2 for [RhCp*(MeCN)3]-
(SbF6)2.
[13] Under the same conditions, the reaction of the Z isomer of 1a
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tuted olefins were used exclusively.
[10] This same trend was observed by Glorius et al. with intermo-
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[18] See the Supporting Information.
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