Intramolecular Acetyl Transfer to Olefins by Catalytic C?C Bond Activation of Unstrained Ketones

Article abstract of DOI:10.1002/anie.201711394

A rhodium-catalyzed intramolecular acetyl-group transfer has been achieved through a “cut and sew” process. The challenge arises from the existence of different competitive pathways. Preliminary success has been achieved with unstrained enones that contain a biaryl linker. The use of an electron-rich N-heterocycilc carbene (NHC) ligand is effective to inhibit undesired β-hydrogen elimination. Various 9,10-dihydrophenanthrene derivatives can be prepared with excellent functional-group compatibility. The ¹³C-labelling study suggests that the reaction begins with cleavage of the unstrained C?C bond, followed by migratory insertion and reductive elimination.

Full text of DOI:10.1002/anie.201711394

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Title: Intramolecular Acetyl Transfer to Olefins via Catalytic C-C Bond
Activation of Unstrained Ketones
Authors: Zi-Qiang Rong, Hee Nam Lim, and Guangbin Dong
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10.1002/anie.201711394
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Intramolecular Acetyl Transfer to Olefins via Catalytic C−C Bond
Activation of Unstrained Ketones
Zi-Qiang Rong,[a] Hee Nam Lim[a,b] and Guangbin Dong*[a]
Dedicated to Professor Robert H. Grubbs on the occasion of his 75th birthday
Abstract: A rhodium-catalyzed intramolecular acetyl-group transfer
has been achieved through a “cut and sew” process. The challenge
arises from existence of different competitive pathways. Preliminary
success has been achieved with unstrained enones that contain a
biaryl linker. The use of electron-rich N-heterocycilc carbene (NHC)
ligand is effective to inhibit undesired β-H elimination. Various 9,10-
dihydrophenanthrene derivatives can be prepared with excellent
functional group compatibility. The 13C-labelling study suggests that
the reaction begins with cleavage of the unstrained C−C bond,
followed by migratory insertion and reductive elimination.
ketones through in situ forming an imine DG.[7] Unfortunately,
using such a strategy to couple olefins only led to an alkyl
exchange reaction. Indeed, during our exploration of the “cut
and sew” transformation between ketones and olefins, many
difficulties have been experienced. First, simple unstrained
acyclic ketone suffers from low reactivity, and the reaction is
sensitive to the sterics of the ketone substrate. Second, β-
hydrogen elimination is generally favored over either migratory
insertion or reductive elimination, leading to fragmentation of the
substrate.[8] Third, olefins easily underwent isomerization or
polymerization, which is particularly problematic when excess
olefins cannot be used, i.e. in an intramolecular setting. Finally,
Acetyl transfer reactions are heavily involved in many
important biological processes, e.g. histone modulation, and
catalyzed by various acyltransferases.[1] In organic chemistry,
acetyl transfer is often realized between an acetic acid derivative
and a nucleophile, and has been frequently utilized in complex
molecule synthesis. Despite the ease of transferring an acetyl
group from a “hot” acylating source, such as acetyl chloride or
anhydride, an interesting question is whether simple methyl
ketones can serve as an acetyl transfer agent through cleavage
of an unactivated C−C bond? [2] To avoid “wasting” the remaining
carbon fragment, perhaps, a more constructive process is to
break the acetyl−carbon bond and add both fragments across an
unsaturated unit, e.g. olefin, thereby enabling formation of two
new C−C bonds (Eq.1).[3]
a
Conia-Ene-type reaction often competes via
a
C−H
functionalization pathway.[9]
A. strained systems
O
O
O
A
A
B
B
O
B. permanent directing group (Douglas, 2009)
O
N
Me
cat. Rh(I)Cl
N
O
O
O
Me
C. this work
O
O
Me
N
N
cat. Rh/NHC
Me
Me
[Rh]
Ar
Ar
2-aminopyridine
Ar
Ar
Ar
Such a “cut and sew” transformation[4] between ketones and
unsaturated moieties has been previously realized using highly
strained ketones (Scheme 1A)[5] or aryl ketones with a covalently
bonded directing group (DG), e.g. 8-acylquinolins (Scheme
1B).[6] To the best of our knowledge, carboacylation of
unstrained regular ketones and 2π-units remained to be
demonstrated yet. Herein, we describe our initial development of
a Rh-catalyzed intramolecular “cut and sew” reaction between
methyl ketones and olefins, enabled by biaryl linkers (Scheme
1C). This acetyl transfer/C−C coupling reaction offers a unique
approach to construct various 9,10-dihydrophenanthrene
derivatives.
Ar
acetyl-transfer
Scheme 1. “Cut and sew” transformations via C−C activation of ketones.
After extensive search and studies, enone substrates with a
biaryl linkage, such as 1a, were found to be particularly suitable
for a carboacylation process. Careful optimization of the reaction
conditions eventually afforded the desired acetyl transfer product
2a in 60% yield (69% based on the unreacted 1a) using
[Rh(C2H4)2Cl]2 in the combination of IMes ligand and 2-
aminopyridine (D1) as the temporary cofactor (Table 1, entry 1).
The 9,10-dihydrophenanthrene product (2a) is proposed to form
through
a pathway involving C−C oxidative addition, then
migratory insertion and reductive elimination (path a, Scheme 2).
This proposal is supported by a 13C labelling study, which
indicates that the terminal carbon of the olefin is connected to
the carbonyl moiety during the reaction (Eq 2). In addition to
polymerization of 1a (path d), two major side products were
identified during our exploration of the reaction (Scheme 2). The
9-methylphenanthrene product (3a) is likely yielded through β-
hydrogen elimination of the intermediate after olefin migratory
insertion, followed by olefin isomerization (path b). Product 4a
should come from a Rh-catalyzed Conia-Ene pathway (path c).
In 1999, seminal work by Jun and coworkers reported an
elegant cofactor strategy for C−C cleavage of unstrained
[a] Department of Chemistry, University of Chicago, Chicago, Illinois,
60637, United States
[b] Korea Research Institute of Chemical Technology, 141, Gajeong-ro,
Yuseong-gu, Daejeon, 34114, South Korea
* Correspondence: gbdong@uchicago.edu (G. D.)
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201711394
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Table 1. Selected optimization studies of the intramolecular acetyl-group
transfer.[a]
1a
2a
3a
4a
Variation from standard
conditions
Entry[b]
(%) (%) (%) (%)
1
2
3
4
5
6
7
8
9
none
13
72
30
21
15
10
22
50
27
60
-
3
-
3
-
w/o [Rh]
w/o D1
-
3
5
4
3
6
-
7
3
1
2
3
1
1
D1 (50 mol%)
D2 instead of D1
D3 instead of D1
D4 instead of D1
D5 instead of D1
w/o MsOH
43
53
56
10
18
24
Scheme 2. Challenges for the intramolecular acetyl-group transfer reaction.
1
Rh(acac)(C2H4)2 instead of
[Rh(C2H4)2Cl]2
10
11
12
71
63
-
5
-
2
3
4
2
Under the optimized conditions, both side products 3a and 4a
are largely diminished. Hence, to gain a better understanding of
the role of each reaction component, control experiments were
performed (Table 1). Unsurprisingly, both the Rh and 2-
aminopyridine (D1) played pivotal roles in this reaction (entries 2
and 3). Interestingly, in the absence of D1, a small amount of
C−C cleavage product (3a) was still observed. Decreasing the
amount of D1 gave a lower yield (entry 4). When 3-methyl and
4-methyl 2-aminopyridines (D2 and D3) were employed, the
reaction still offered similar yields (entries 5 and 6). However,
the use of 6-methyl-2-aminopyridine (D4) or 4-pyrrolidinyl-2-
aminopyridine (D5) significantly inhibited the reaction (entries 7
and 8). In addition, the “cut and sew” product (2a) was only
obtained in a low yield in the absence of the acid co-catalyst,
likely due to the inefficiency to form the imine intermediate (entry
9). Replacing [Rh(C2H4)2Cl]2 with other Rh(I) precursors was
unfruitful (entries 10 and 11), suggesting both the ethylene and
Cl moieties are important to generate the active catalyst. The
use of NHC ligands is also important to promote formation of the
“cut and sew” product, likely through inhibiting β-hydrogen
elimination;[10] in contrast, Wilkinson’s catalyst afforded high
selectivity for the cyclization/de-acylation product (3a), and PCy3
ligand promotes Conia-Ene reaction (entries 12 and 13). Among
various NHC ligands, IMes proved to be most efficient (entries
14-16). A survey of the solvent effect revealed cholorobenzene
to be optimal (entries 17 and 18). A relatively high concentration
(1.0 M) was found to give the best yield likely through promoting
installation of the imine DG. Finally, variation of the reaction
temperatures resulted in diminished yields, as lower temptation
led to a lower conversion but higher temperature caused more
polymerization of the substrate (entries 19 and 20).
[Rh(cod)Cl]2 instead of
[Rh(C2H4)2Cl]2
RhCl(PPh3)3 instead of
[Rh]/IMes
<2
60
10
13
14
15
16
PCy3 instead of IMes
MeIMes instead of IMes
IPr instead of IMes
65
19
22
50
<1
39
45
22
0
3
1
1
8
1
2
2
ICy instead of IMes
1,4-dioxane instead of
chlorobenzene
17
33
48
3
3
18
19
20
THF instead of chlorobenzene
24
45
6
48
28
41
3
1
5
2
2
2
110 °C
130 °C
[a] Run on a 0.1 mmol scale (1.0 M) for 120 h in a 2 mL vial. [b] Determined by
1H NMR using 1,1,2,2-tetrachloroethane as the internal standard.
Table 2. Substrate Scope.[a]
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Table 2: (Continued)
[a] Run on a 0.2 mmol scale for 120 h in a 2 mL vial. [b] Isolated yield. [c] 4-
tert-butyl catechol (2 mol%) was added. [d] MeIMes (at 130 °C for 96 h) was
used instead. [e] 47% based on recovered starting material.
With the optimized conditions in hand, we next investigated
the scope and generality of this rhodium-catalyzed acetyl-group
transfer reaction. As shown in Table 2, both electron-rich and
deficient substituents are tolerated on either arenes, affording
the 9,10-dihydrophenanthrene products in synthetically useful
yields. Substrates with substitutions at various positions are
competent to deliver the desired “cut and sew” products. In
addition, this reaction exhibits excellent compatibility for a broad
range of functional groups, such as aryl chloride (2b, 2f, 2k and
2n), ether (2c and 2m), fluoride (2e, 2j and 2q), ester (2g),
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cyanide (2h), trifluoromethyl (2o) and methylenedioxy group (2p). efficient catalytic system are currently underway in our
Gratifyingly, the substrate (1i) containing an acid/oxidant-
sensitive furan moiety successfully engaged in this
transformation, which is attributed to the redox neutral reaction
conditions. As expected, sterically hindered substrates, such as
those with an ortho substituent on either arene (2j, 2p and 2q)
showed lower reactivity. Substrates with different types of
tethers or more substituted olefins have also been prepared;
unfortunately, attempts to enable “cut and sew” transformations
with these substrates remain unfruitful yet (for details, see
supporting information).
laboratory.
Acknowledgements
We acknowledge NIGMS (R01GM109054-01) and Eli Lilly for
funding. G.D. is a Sloan fellow. Dr. Ying Xia is acknowledged for
a generous donation of NHC ligands. We thank Mr. Ki-young
Yoon for X-ray structures and Dr. Antoni Jurkiewicz for NMR
advices.
To demonstrate the synthetic potential of this transformation,
a gram-scale reaction was carried out (Eq 3). The desired
intramolecular acetyl-group transfer product 2a was isolated in
57% yield. It is noteworthy that the 9,10-dihydrophenanthrene-
derived ketone product (2a) (or its closely related structure) has
not been synthesized previously.
Keywords: cyclization• C−C activation • rhodium catalysis • cut
and sew • unstrained ketones
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The tricyclic scaffold can undergo
a number of simple
transformations to access different structures (Scheme 3). The
linear ketone 2a was converted to terminal olefin 7 through
Wittig reaction. α,β-Unsaturated ketone 8 was conveniently
prepared by aldol condensation with benzaldehyde. In addition,
hydrazone formation[11] and carbonyl addition reactions occurred
smoothly to deliver the corresponding structures in excellent
yields.
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Scheme 3. Synthetic Applications
In summary, a unique acetyl transfer reaction was developed
through catalytic activation of unstrained C−C bonds. While the
scope and efficiency are moderate at this initial stage, this
reaction nevertheless demonstrates the first example of a “cut
and sew” transformation with regular unstrained ketones. The
use of a NHC ligand to inhibit undesired β-hydrogen elimination
side-products should have a broad implication beyond this work.
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Detailed mechanistic studies and development of
a more
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[10] a) Y. Xia, G. Lu, P. Liu, G. Dong, Nature 2016, 539, 546; b) Y. Xia, J.
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[11] CCDC 1583909 (9) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
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Entry for the Table of Contents
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Zi-Qiang Rong, Hee Nam Lim and
Guangbin Dong*
Page No. – Page No.
A rhodium-catalyzed intramolecular acetyl-group transfer has been achieved
through a “cut and sew” process. Using unstrained enones that contain a biaryl
linker, C−C activation occurs assisted by a temporary directing group. Various 9,10-
dihydrophenanthrene derivatives can be prepared with excellent functional group
compatibility.
Intramolecular Acetyl Transfer to
Olefins via Catalytic C−C Bond
Activation of Unstrained Ketones
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