Rhodium-Catalyzed Synthesis of α,β-Unsaturated Ketones through Sequential C-C Coupling and Redox Isomerization

Article abstract of DOI:10.1021/acs.orglett.8b02190

A novel Rh(I)-catalyzed sequential C-C coupling and redox isomerization between allylic alcohols and 1,3-dienes has been accomplished. This versatile protocol provides expeditious access to a broad range of polysubstituted α,β-unsaturated ketones with excellent atom economy and regioselectivity.

Full text of DOI:10.1021/acs.orglett.8b02190

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Synthesis of α,β-Unsaturated Ketones through
Sequential C−C Coupling and Redox Isomerization
Hong-Shuang Li,*,† Guili Guo,‡ Rui-Ze Zhang,† and Fei Li†
†Institute of Pharmacology, School of Pharmaceutical Sciences, Taishan Medical University, 619 Changcheng Road, Taian 271016,
P. R. China
‡School of Basic Medical Sciences, Taishan Medical University, 619 Changcheng Road, Taian 271016, P. R. China
S
* Supporting Information
ABSTRACT: A novel Rh(I)-catalyzed sequential C−C
coupling and redox isomerization between allylic alcohols
and 1,3-dienes has been accomplished. This versatile protocol
provides expeditious access to a broad range of polysub-
stituted α,β-unsaturated ketones with excellent atom economy
and regioselectivity.
ince extensive efforts were dedicated to the 1,3-diene-
tandem C−C coupling and transfer hydrogenation, with the
Sparticipated C−C coupling reaction, it has been illustrated explanation that the rhodium hydride formed in situ could
serve as a crucial mediator in both processes. Herein, the
successful establishment of the hypothesis is described. In
contrast with other approaches for synthesizing polysubstituted
enones (e.g., oxidation of cyclopropenylcarbinols,16a Pd-
catalyzed formal hydroacylation of allenes,16b Pd-catalyzed
oxidative coupling of allylic alcohols with nucleophiles,16c Ti-
promoted coupling of alkynes with Weinreb amides,16d base-
mediated conversion of propargylic tosylates,16e Pd-catalyzed
cross-coupling of propargyl alcohols and allyl carbonates,16f
Au-catalyzed acyl migration of propargylic esters,16g etc.), our
protocol features ready availability of starting materials, good
functional group compatibility, and excellent atom economy
and reactant site selectivity.
To commence the study, we selected cinnamic alcohol 1a
and isoprene 2a as the initial substrates for optimizing the
reaction conditions (Table 1). When the reaction was
performed in the presence of the [Rh(COD)OH]2/PPh3
catalytic couple under toluene refluxing conditions for 24 h,
the C−C coupling/isomerization product 3a was isolated in
9% yield (entry 1). Further screening of other rhodium
catalysts revealed that [Rh(COD)Cl]2 was the optimal choice
(entries 2−6). To our delight, the product yield was increased
to 41% when KF was used as an additive (entry 7). Switching
PPh3 to other ligands such as PCy3, (p-Me-C6H4)3P, and (p-
MeO-C6H4)3P was found to be ineffective to improve the
reaction conversion (entries 8−10). Among the bases
evaluated, K2CO3 delivered a higher yield than other species
(entries 11 and 12). It was observed that increasing the loading
of isoprene 2a or elevating the reaction temperature to 140 °C
led to an enhanced yield of 3a (entries 13 and 14). By simply
changing the solvent to p-xylene, the enone could be provided
as a robust and straightforward method to access a series of
value-added compounds.1 In connection with the field, the
effects of various transition metal catalysts on the reductive
coupling reactions of 1,3-dienes to alcohols or carbonyl
compounds1a have been well-documented, including the
limited examples depending on the rhodium catalysis system.2
A superstoichiometric amount of external reductant, such as
H2,2a HCOOH,3 i-PrOH,3b,4 1,4-butanediol,5 Et2Zn,6
Et3B,2b,6a,7 or Et3SiH,8 was often required in the trans-
formations to deliver the coupling products. In contrast, the
hydrogen autotransfer process utilizing primary alcohols not
only as the reactants but also as the hydrogen donors
represented an excellent atom-economical method for the
intermolecular reductive couplings.4d,5a,9 Typically, the metal
hydride species generated in situ is transferred to the diene
pronucleophile to form the π-allylmetal precursor, which
engages in a subsequent C−C coupling reaction with
distinguished regioselectivity. In view of the inherent
advantages highlighted, establishing a synthetic methodology
with readily available simple primary alcohols as the substrates
for versatile synthesis of functionalized ketones would be more
broadly meaningful and constructive.
On the other hand, the redox isomerization of allylic
alcohols relying on various transition-metal complexes,10
including Pd,11 Ir,12 Ru,13 and Rh,14 has been viewed as an
appealing approach to afford carbonyl-containing molecules
because no external reagent is required in the redox-neutral
process. Furthermore, significant advances in the stereospecific
isomerization of allylic alcohols to α- or β-substituted ketones
have been achieved.15
Enthused by the impressive allylic alcohol isomerization, we
assumed that the coupling reactions of allylic alcohols with 1,3-
dienes under Rh(I) catalysis might enable highly efficient
synthesis of polyalkyl-substituted unsaturated ketones through
Received: July 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
Rh (5 mol %)
ligand (10 mol %)
base (10 mol %)
additive (100 mol %)
solvent
yield (%)
1
2
3
4
5
6
7
8
[Rh(COD)OH]2
[Rh(COD)Cl]2
Rh2Cl2(CO)4
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
(p-Me-C6H4)3P
(p-MeO-C6H4)3P
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Ag2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
\
\
\
\
\
\
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
p-xylene
p-xylene
p-xylene
9
22
8
trace
trace
trace
41
38
21
16
33
21
48
56
73
60
78
RhH(CO)(PPh3)3
Rh(COD)2SbF6
Rh(COD)2BF4
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
9
10
11
12
13
14
15
16
17
c
cd
,
cd
,
cde
,
,
cdf
,
,
a
Unless otherwise noted, all reactions were carried out in N2 atmosphere, using 1a (0.3 mmol, 1 equiv) and 2a (3.0 equiv) in 1.5 mL of solvent at
b
c
d
e
f
110 °C for 24 h. Isolated yield. 2a (5.0 equiv). 140 °C. PPh3 (20 mol %). K2CO3 (20 mol %).
in 73% isolated yield (entry 15). Variation of ligand loading
suffered from an inferior yield (entry 16), whereas the
employment of 20 mol % of the base allowed highly efficient
formation of polysubstituted α,β-unsaturated ketone (entry
17), thus identifying the feasibility of this coupling reaction.
A variety of allylic alcohols were then examined for the C−C
coupling/isomerization with isoprene (2a) under the opti-
mized reaction conditions, and the results are presented in
Scheme 1. Good compatibility with a wide range of functional
groups for the construction of enones was observed, with
methyl (3b), methoxy (3c), dimethylamino (3d), fluoro (3e,
3f), and chloro (3g, 3h) groups all being well-tolerated.
However, the more electron-deficient cinnamic alcohols
participated in the coupling reactions sluggishly (3i, 3j).
Interestingly, coniferyl alcohol bearing a free phenolic hydroxyl
group expressed moderate reactivity to afford the anticipated
compound 3k. When our attention was turned to the
transformation of the heterocycle-substituted allylic alcohol
component, the corresponding trimethyl-substituted enone 3l
was produced in 64% yield. The good chemical yields achieved
with the substrates bearing an alkyl group (3m) or aromatic
rings (3n) at the α- or β-position of the hydroxyl group
highlighted the generality of our catalytic system. It was found
that the coupling reaction succeeded to proceed with 2-phenyl-
substituted allylic alcohol to provide the desired product 3o,
albeit in low yield. In addition, cyclohex-1-en-1-yl methanol
was a suitable substrate for the C−C coupling/isomerization
(3p), and such a circumstance was the same as that of perillyl
alcohol, regardless of the presence of a distal vinyl group (3q).
It is worth mentioning that the linear substrates such as (E)-
hept-2-en-1-ol and (E)-non-2-en-1-ol underwent the coupling
reactions smoothly to obtain the high-boiling-point products
(3r, 3s) in yields of 56% and 65%, respectively. Unfortunately,
3-phenyl-2-propyn-1-ol was not allowed for this conversion,
and only a trace amount of 3a was detected.
Besides isoprene, other conjugated dienes were also
inspected for the coupling reactions with the representative
allylic alcohols to access polysubstituted α,β-unsaturated
ketones (Scheme 2). For example, myrcene was successfully
coupled with cinnamic alcohols together with 3-(furan-2-
yl)prop-2-en-1-ol, generating the corresponding ketones in
43% to 69% yield (3t−3v). Alkyl-substituted linear allylic
alcohols delivered higher isolated yields of C−C coupling/
isomerization products (3w, 3x) than the branched ones (3y,
3z). Furthermore, the incorporation of 1,3-butadiene to
cinnamic alcohol 1a under [Rh(COD)OH]2 catalysis led to
a pair of dimethyl-substituted enones with a ratio of 1.6:1 in
65% combined yield (3aa, 3aa′). However, only trace
quantities of product were detected while performing the
reactions of 1,3-pentadiene, 1-phenyl-1,3-butadiene, and 2-
phenyl-1,3-butadiene with cinnamic alcohol.
Control experiments were carried out to probe the
mechanism of the Rh-catalyzed synthesis of enones (Scheme
3). The C−C coupling reaction of 3-phenylpropan-1-ol 4 with
isoprene 2a under the standard conditions delivered a
saturated ketone 5 in 51% yield (Scheme 3a). While
conducting only cinnamic alcohol 1a in another control
experiment, 3-phenylpropanal 6 and an aldol condensation
product 7 were isolated (Scheme 3b), which demonstrated
that the transfer hydrogenation in the present catalytic system
occurred in an intramolecular fashion.15 Additionally, cinnamic
aldehyde 8 was subjected to the standard conditions with
isoprene 2a by virtue of i-PrOH as an external reductant,3b,4
furnishing the product 3a in 62% yield (Scheme 3c). The
results unambiguously suggest that 8 was involved in the
coupling reaction as a key intermediate and that the Rh−H
species formed in situ played a pivotal role in the C−C
coupling/isomerization. Finally, an isotopic labeling experi-
ment using deuterated cinnamic alcohol 1a-D2 as the substrate
was carried out (Scheme 3d). 1H and 2H NMR analysis of the
product revealed that about 97% deuterium was incorporated
B
DOI: 10.1021/acs.orglett.8b02190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of the Allylic Alcohols for the C−C
Scheme 2. Scope of 1,3-Dienes for the C−C Coupling/
a b
,
a,
b
Coupling/Isomerization
Isomerization
a
Unless otherwise noted, all reactions were carried out with allylic
alcohol 1 (0.3 mmol) and 1,3-diene 2 (1.5 mmol) in p-xylene (1.5
b
c
mL) at 140 °C under N2 for 24 h. Isolated yield. Reaction was
performed using [Rh(COD)OH]2 (5 mol %) as the catalyst in
toluene (1.5 mL) at 110 °C under N2 for 24 h.
Scheme 3. Control Experiments
a
Unless otherwise noted, all reactions were carried out with allylic
alcohol 1 (0.3 mmol) and isoprene 2a (1.5 mmol) in p-xylene (1.5
b
c
mL) at 140 °C under N2 for 24 h. Isolated yield. Reaction was
performed at a 1 mmol scale.
into the methylene carbon at the β-position of the carbonyl
group, and about 71% of deuterium incorporation was at the
methyl group β to the resulting ketone.
On the basis of the aforementioned experimentations as well
as the previous documents on the functionalization of 1,3-
dienes,9a,17 a plausible mechanism is postulated (Scheme 4).
The reaction of the rhodium catalyst with cinnamic alcohol 1a
in the presence of the base generates alkyloxyrhodium
intermediate I,18 which undergoes β-H elimination to give
rise to the Rh−H active species and cinnamic aldehyde 8. After
the addition of the Rh−H species to isoprene 2a, the resulting
π-allylrhodium intermediate II nucleophilicly attacks the
aldehyde 8 through the indicated six-centered transition state
III to access homoallyloxyrhodium intermediate IV, which
upon a second β-H elimination yields the complex V (C−C
coupling process). Double bond isomerization exerted by the
rhodium hydride through successive hydrorhodation/β-H
elimination17c,18 affords the more stable penta-1,4-dien-3-one
VI. Note that reduction of the less sterically hindered double
bond of the enone by the rhodium hydride is favorable to form
the intermediate VII. Subsequent tautomerization and
protonation delivers the target product 3a with concomitant
reproduction of the rhodium catalyst, thus achieving the redox
isomerization process.14b,15
In summary, a rhodium-catalyzed strategy enabling efficient
construction of tetraalkyl-substituted α,β-unsaturated ketones
has been developed from a host of allylic alcohols and 1,3-
dienes, including isoprene, myrcene, and 1,3-butadiene.
Mechanistic investigations show that this atom-economical,
diene C3-regioselective3b,4b methodology proceeds through
tandem C−C coupling and intramolecular redox isomerization.
We optimistically think that the coupling reaction will find
applications in the preparation of polyalkyl-substituted enones
with pharmaceutical value.
C
DOI: 10.1021/acs.orglett.8b02190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02190.
■
S
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Experimental details, characterization data, and spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lihongshuang8625@163.com.
ORCID
Hong-Shuang Li: 0000-0002-1740-8876
Notes
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Lundberg, H.; Eden, M.; Ahlsten, N.; Wan, W.; Zou, X.; Martín-
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3643 and references cited therein..
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Key
Research and Development Program of Shandong Province,
China (2018GGX109010, 2017GSF19106).
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DOI: 10.1021/acs.orglett.8b02190
Org. Lett. XXXX, XXX, XXX−XXX