Substrate-directed hydroacylation: Rhodium-catalyzed coupling of vinylphenols and nonchelating aldehydes

Article abstract of DOI:10.1002/anie.201309987

We report a protocol for the hydroacylation of vinylphenols with aryl, alkenyl, and alkyl aldehydes to form branched products with high selectivity. This cross-coupling yields α-aryl ketones that can be cyclized to benzofurans, and it enables access to eu

Full text of DOI:10.1002/anie.201309987

Angewandte
Chemie
DOI: 10.1002/anie.201309987
À
C H Activation
Substrate-Directed Hydroacylation: Rhodium-Catalyzed Coupling of
Vinylphenols and Nonchelating Aldehydes**
Stephen K. Murphy, Achim Bruch, and Vy M. Dong*
Abstract: We report a protocol for the hydroacylation of
vinylphenols with aryl, alkenyl, and alkyl aldehydes to form
branched products with high selectivity. This cross-coupling
yields a-aryl ketones that can be cyclized to benzofurans, and it
enables access to eupomatenoid natural products in four steps
or less from eugenol. Excellent reactivity and high levels of
regioselectivity for the formation of the branched products
Scheme 1. Proposed regioselective hydroacylation of alkenes bearing
an anionic directing group.
were observed. We propose that aldehyde decarbonylation is
avoided by the use of an anionic directing group on the alkene
and a diphosphine ligand with a small bite angle.
S
ubstrate-directed hydroacylation enables the regioselec-
tive construction of ketones with high atom economy.[1–3] By
using a directing group on the alkene component (for
example, 1,5-dienes,[4] homoallylic sulfides,[5] allylic alcohols,[6]
or homoallylic alcohols[7]), the linear selectivity of rhodium-
catalyzed hydroacylation can be overturned to yield branched
ketones.[8] However, most hydroacylation processes are
limited by the need for chelating aldehydes, such as salicy-
laldehydes,[9] 2-aminobenzaldehydes,[10] b-sulfur-substituted
could enable branched-selective hydroacylation with broad
scope in terms of the aldehyde substrate (Scheme 1).
The choice of an anionic directing group allows the use of
a neutral Rh catalyst, which is highly electron-rich as
compared to the commonly used cationic catalysts. Neutral
Rh complexes, such as the complex [(Me3P)3RhCl] described
by Milstein and the Brookhart catalyst [Cp*Rh(olefin)2]
(Cp* = pentamethylcyclopentadienyl), are reactive towards
aldehydes,[11] or (2-pyridyl)aldimines,[12] to facilitate C H
nondirected aldehyde C H bond activation.[15] On the basis of
À
À
bond activation and suppress competitive decarbonylation.
The development of new catalysts for the branched-selective
hydroacylation of olefins with nonchelating aldehydes
remains challenging. As alternatives to Rh catalysis, the
research groups of Krische and Ryu applied ruthenium
hydrides for the branched-selective addition of nonchelating
aldehydes to enones and 1,3-dienes.[13] Recently, Glorius and
co-workers reported an N-heterocyclic-carbene-catalyzed
method for the efficient linear-selective coupling of benzal-
dehydes and electron-deficient styrenes.[14] Additionally,
a few promising examples of branched-selective coupling
with electron-rich styrenes were reported, albeit with low-to-
moderate yields. In light of this challenging transformation,
we hypothesized that an anionic directing group on the alkene
our double-chelation-assisted hydroacylations with salicylal-
dehydes,[5–7] we reasoned that an anionic group should
promote binding of the alkene and guide the formation of
the branched ketone. We focused on the use of bidentate
phosphines to make the acyl rhodium(III) hydride coordina-
tively saturated and therefore stable toward decarbonyla-
tion.[16]
In principle, a wide range of acidic functional groups could
be used to generate the requisite anionic directing group in
the presence of a catalytic base. Owing to the prevalence of
phenols and their wide range of pKa values, we chose
vinylphenols as the alkene substrates for initial studies
(Scheme 2). Willis and co-workers recently reported
a method to access furans through alkyne hydroacylation.[17]
Their method relied on the coupling of b-sulfur-substituted
aldehydes with propargylic alcohols, and the sulfide directing
group was retained in all of the furan products. In our case, the
products of vinylphenol hydroacylation can be cyclized into
a wide variety of benzofurans, including biologically relevant
eupomatenoids.
[*] S. K. Murphy, Dr. A. Bruch, Dr. V. M. Dong
Department of Chemistry, University of California
Irvine, CA 92697-2025 (USA)
and
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada)
E-mail: dongv@uci.edu
To test our hypothesis, we examined the coupling of
hydrocinnamaldehyde with 4-chloro-2-vinylphenol in the
presence of a catalytic base, Rh, and various ligands
(Table 1). We maintained a 2:1 P/Rh ratio to generate the
proposed saturated acyl rhodium(III) hydride intermediate
(Scheme 1). Both P(OMe)3 and bis(diphenylphosphino)me-
thane (dppm) were effective ligands and provided the
branched product with > 20:1 branched/linear (b/l) selectivity
(Table 1, entries 1 and 2). Weller, Willis, and co-workers used
[**] S.K.M. is grateful for a Canada Graduate Scholarship (CGS), and
A.B. is grateful for a fellowship within the Postdoctoral Program of
the German Academic Exchange Service (DAAD). We thank the
NSERC, the National Institutes of Health (GM105938), and Eli Lilly
for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309987.
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Table 2: Scope of the hydroacylation with respect to the aldehyde.[a,b]
Entry
Aldehyde
Yield
[%]
b/l
1
2
3
4
5
R=Bn
R=Bu
R=iPr
R=Ph
96
99
91
98
68
>20:1
>20:1
>20:1
>20:1
>20:1
R=CH2OTBS
6[c]
99
>20:1
Scheme 2. Hydroacylation of vinylphenols with alkyl, alkenyl, and aryl
aldehydes.
7
94
>20:1
8
91
>20:1
Table 1: Optimization of the reaction conditions.[a]
9
10
11
12
13
14
15
R1 =Ph; R2,R3 =H
R1,R2 =Me; R3 =H
R1,R2 =H; R3 =Me
R=NMe2
R=OMe
R=H
95
62
31
77
79
78
94
>20:1
10:1
>20:1
>20:1
>20:1
16:1
Entry
Rh
Ligand
Additive T [8C] Yield [%]
1[b]
2[c]
3[c]
4[d]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)OMe}2]
P(OMe)3
dppm
dcpm
K3PO4
K3PO4
K3PO4
none
80
60
60
60
75
90
99
99
R=CO2Me
12:1
16
82
19:1
dcpm
[a] The b/l ratio was >20:1 in all cases, as determined by 1H NMR
spectroscopic analysis of the crude reaction mixture. [b] Rh dimer
(5 mol%), ligand (20 mol%), K3PO4 (10 mol%), 1,2-DCE solvent, 0.4m
in the vinylphenol. [c] Rh dimer (2.5 mol%), ligand (5 mol%), K3PO4
(10 mol%), 1,2-DCE solvent, 0.4m in the vinylphenol. [d] Rh dimer
(2 mol%), ligand (4 mol%), THF solvent, 1m in the vinylphenol.
cod=1,5-cyclooctadiene, 1,2-DCE=1,2-dichloroethane.
[a] The b/l ratios were determined by 1H NMR spectroscopic analysis of
the crude reaction mixture. [b] With alkyl aldehydes: [{Rh(cod)OMe}2]
(2 mol%), dcpm (4 mol%), THF, 608C; with alkenyl and aryl aldehydes:
[{Rh(cod)OMe}2] (4 mol%), dcpm (8 mol%), 1,4-dioxane, 1008C. All
reactions were carried out at a concentration of 1m with respect to the
vinylphenol. [c] The product had a diastereomeric ratio of 1:1.
secondary aliphatic aldehydes were routinely transformed
into ketones in yields above 90% (Table 2, entries 1–8), and
acidic a-hydrogen atoms (entry 4) and potentially labile b-
silyloxy groups (entry 5) were tolerated. Alkenyl aldehydes
are traditionally challenging substrates in hydroacylation
owing to issues of chemoselectivity and their tendency to
form p-complexes with Rh.[15c] Nonetheless, we report the
first rhodium-catalyzed hydroacylation reactions with alkenyl
aldehydes in the absence of an aldehyde directing group
(Table 2, entries 9–11). These substrates react at a slightly
higher temperature and catalyst loading (1008C, 4 mol%
[{Rh(cod)OMe}2], 8 mol% dcpm). With electron-rich ben-
zaldehydes (Table 2, entries 12 and 13), the > 20:1 b/l ratio
observed for most other substrates was maintained, whereas
the use of electron-neutral and electron-deficient variants led
to slightly lower but synthetically useful regioselectivities
(entries 14 and 15). Vanillin was effectively transformed in
82% yield into the corresponding a-aryl ketone product
(Table 2, entry 16). The scope of this protocol with respect to
the aldehyde is among the broadest reported for hydro-
acylation to date, thus highlighting the unique reactivity of
neutral [Rh(X)(dcpm)] fragments towards the activation of
similar small-bite-angle diphosphines to enable the hydro-
acylation of alkenes and alkynes with b-sulfur-substituted
aldehydes, and they suggested that the small bite angle
promotes reductive elimination.[11e]
A more sterically
demanding and basic ligand, bis(dicyclohexylphosphino)me-
thane (dcpm), provided a faster reaction rate and higher yield
(Table 1, entry 3; 99% yield). Diphosphines with larger bite
angles were completely ineffective, and the dearth of chiral
small-bite-angle diphosphines precluded an enantioselective
process. A change in the solvent from 1,2-DCE to THFand an
increase in the vinylphenol concentration to 1m further
increased the reaction rate. In line with the observation by
Bergman and co-workers that rhodium–alkoxide complexes
undergo rapid exchange with phenols,[18] [{Rh(cod)OMe}2]
was found to be an effective catalyst in the absence of an
added base (Table 1, entry 4; 99% yield). Conveniently, this
protocol requires commercially available catalyst compo-
nents, and unlike the cationic rhodium diphosphine catalysts
currently used for hydroacylation, does not require hydro-
genation to activate the catalyst.
Aldehydes with diverse steric and electronic properties
are excellent coupling partners (Table 2). Primary and
À
aldehyde C H bonds.
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Vinylphenols with highly varied pKa values coupled with
hydrocinnamaldehyde in 50–93% yield with > 20:1 b/l regio-
selectivity (Table 3, entries 1–4). Sterically demanding vinyl-
phenols were suitable substrates (Table 3, entries 5–7), but
Sterically demanding alkene substrates, including a bulky 4,6-
tBu2-substituted vinylphenol, were excellent coupling part-
ners for benzaldehyde (Table 3, entries 18–20).
This method provides an alternative approach to the
synthesis of ortho-substituted a-aryl ketones, which are
typically difficult to access by traditional ketone a-aryla-
tion.[19] The products of this directed olefin hydroacylation
can be further elaborated in a straightforward manner. For
example, the phenol component can be triflated and sub-
jected to Suzuki–Miyaura cross-coupling [Scheme 3,
Table 3: Scope of the hydroacylation with respect to the alkene.[a,b]
Entry
Product
R2
Yield [%]
b/l
1
2
3
4
5
6
7
6-OMe
5-OMe
4-OMe
4-F
6-Me
3-Me
80
50
55
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
93
11 (50[c])
93
67
4,6-tBu2
8
9
10
11
6-OMe
4-OMe
6-Me
93
74
91
95
11:1
10:1
>20:1
>20:1
3-Me
12
13
14
15
6-OMe
4-OMe
6-Me
92
52
62
96
>20:1
>20:1
>20:1
>20:1
Scheme 3. Derivatization of hydroacylation products. Ar=4-methoxy-
phenyl, Bn=benzyl, Tf=trifluoromethanesulfonyl.
3-Me
16
17
18
19
20
6-OMe
4-OMe
6-Me
3-Me
4,6-tBu2
88
53
81
77
84
19:1
9:1
>20:1
>20:1
>20:1
Eq. (1)].[20] Alternatively, treatment of the resulting ketones
with trifluoroacetic acid (TFA) induces cyclocondensation to
the corresponding benzofurans in quantitative yield
[Scheme 3, Eq. (2)].[21]
[a] The b/l ratios were determined by 1H NMR spectroscopic analysis of
the crude reaction mixture. [b] With alkyl aldehydes: [{Rh(cod)OMe}2]
(2 mol%), dcpm (4 mol%), THF, 608C; with alkenyl and aryl aldehydes:
[{Rh(cod)OMe}2] (4 mol%), dcpm (8 mol%), 1,4-dioxane, 1008C.
Reactions were carried out at a concentration of 1m with respect to the
vinylphenol unless otherwise noted. [c] Yield for a reaction carried out at
a concentration of 0.2m with respect to the vinylphenol. Cy=cyclohexyl.
This benzofuran synthesis prompted us to target the
eupomatenoid class of neolignans (Table 4), which exhibit
Table 4: Eupomatenoid natural product synthesis.
the 6-Me-substituted substrate was converted into the desired
product in only 11% yield owing to competitive aldol
condensation. We predicted a concentration-dependent che-
moselectivity for aldol condensation and hydroacylation as
a result of the strong binding of the vinylphenol to Rh. In line
with this hypothesis, we observed an increased yield of 50%
upon fivefold dilution of the reaction mixture. A disubstituted
vinylphenol (2-propenylphenol) and a further homologated
substrate (2-allylphenol) were unreactive with hydrocinna-
maldehyde. Secondary aldehydes were generally transformed
in higher yields than primary aldehydes, presumably because
they are resistant to aldol condensation (Table 3, entries 8–11;
74–95% yield). These bulkier substrates exhibited slightly
diminished regioselectivity with electron-rich vinylphenols.
The third substrate class, alkenyl aldehydes, gave almost
identical results to hydrocinnamaldehyde (Table 3,
entries 12–15). Transformations with benzaldehyde displayed
varied regioselectivities (from 9:1 to > 20:1) depending on the
electronic nature of the vinylphenol (Table 3, entries 16–20).
Entry
Name
R1
R2
T [8C]
Yield [%]
1
2
3
4
eupomatenoid 12
eupomatenoid 16
eupomatenoid 17
eupomatenoid 18
OMe
H
H
1-propenyl
1-propenyl
allyl
80
80
70
70
70
80
78
82
OMe
allyl
insecticidal, antimicrobial, antioxidant, and antitumor activ-
ity.[22] Most of the recent syntheses of these compounds
establish the benzofuran core first and rely on either Stille or
Kumada coupling to append propenyl or allyl units.[23] In
contrast, we derived a fully functionalized vinylphenol from
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Chem. Pharm. Bull. 2009, 57, 1158; e) D. H. T. Phan, K. G. M.
Kou, V. M. Dong, J. Am. Chem. Soc. 2010, 132, 16354.
eugenol and used hydroacylation and cyclocondensation to
forge the benzofuran core. These coupling partners are highly
reactive and allow hydroacylation to occur at moderate
temperatures of 70–808C. Our approach enabled three-step
syntheses of eupomatenoids 17 and 18, and four-step synthe-
ses of eupomatenoids 12 and 16. The alkene proximal to the
phenol reacted chemoselectively in the presence of distal allyl
and propenyl units (depicted as R2).
In summary, we have developed a catalyst system for the
branched-selective hydroacylation of alkenes bearing anionic
directing groups with a wide range of aryl, alkenyl, and alkyl
aldehydes. High branched selectivity and high reactivity were
generally observed. In combination with a cyclocondensation,
we applied this method to access several neolignan natural
products. On the basis of these studies, we expect that it will
be possible to use other acidic functional groups (e.g. anilines,
sulfonamides, hydroxy groups, and carboxylic acids) to
generate anionic directing groups in situ and thus further
expand the application of hydroacylation. Given the mild
reaction conditions, neutral [Rh(X)(dcpm)] fragments are
[10] 2-Aminobenzaldehydes have recently been demonstrated to
undergo efficient coupling with alkynes under Rh catalysis: M.
Castaing, S. L. Wason, B. Estepa, J. F. Hooper, M. C. Willis,
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À
highly reactive towards aldehyde C H bond activation and
hold promise for future hydroacylation reactions with non-
chelating aldehydes. A detailed mechanistic study is under
way to elucidate the factors leading to this high reactivity and
selectivity.
Received: November 18, 2013
Published online: January 29, 2014
À
that proceed by a mechanism other than aldehyde C H bond
activation, see: J. C. Leung, M. J. Krische, Chem. Sci. 2012, 3,
2202.
À
Keywords: benzofurans · C H activation · hydroacylation ·
regioselectivity · rhodium catalysis
.
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