Development of a Palladium-Catalyzed Carbonylative Coupling Strategy to 1,4-Diketones

Article abstract of DOI:10.1021/acscatal.6b00733

We report on a three-component palladium-catalyzed coupling strategy for accessing a wide range of 1,4-diketones, which represent important precursors to heterocycles. Our method relies on a carbonylative Heck reaction employing substituted allylic alcohols, aryl iodides, and carbon monoxide. The reaction conditions are mild and do not require high CO pressure, and a wide functional group tolerance is revealed, providing the desired 1,4-diketones in moderate to good yields. Furthermore, the methodology is adaptable to the selective installment of ¹³C-carbon isotopes at either one or both of the carbonyl positions.

Full text of DOI:10.1021/acscatal.6b00733

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Letter
Development of a Palladium-Catalyzed
Carbonylative Coupling Strategy to 1,4-Diketones
Hongfei Yin, Dennis U. Nielsen, Mette K. Johansen, Anders T. Lindhardt, and Troels Skrydstrup
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00733 • Publication Date (Web): 06 Apr 2016
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Page 1 of 5
ACS Catalysis
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Development of a Palladium-Catalyzed Carbonylative Cou-
pling Strategy to 1,4-Diketones
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Hongfei Yin,† Dennis U. Nielsen,† Mette K. Johansen,† Anders T. Lindhardt‡ and Troels Skrydstrup*†
†
Carbon Dioxide Activation Center (CADIAC), Interdisciplinary Nanoscience Center (iNANO) and Department of Chemis-
try, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
‡
Carbon Dioxide Activation Center (CADIAC), Interdisciplinary Nanoscience Center (iNANO) and Department of Engi-
neering, Aarhus University, Finlandsgade 22, 8200 Aarhus N, Denmark
Supporting Information Placeholder
ABSTRACT: We report on a three-component palladium-catalyzed coupling strategy for accessing a wide range of 1,4-diketones,
which represent important precursors to heterocycles. Our method relies on a carbonylative Heck reaction employing substituted
allylic alcohols, aryl iodides and carbon monoxide. The
reaction conditions are mild and do not require high CO
pressure, and a wide functional group tolerance is revealed,
providing the desired 1,4-diketones in moderate to good
yields. Furthermore, the methodology is adaptable to the
selective installment of 13C-carbon isotopes at either one or
both of the carbonyl positions.
KEYWORDS: palladium catalysis, 1,4-diketones, carbonylative Heck, migration, Carbon-13 isotope-labeling
O
1,4-Diketones have drawn considerable attention resulting
SO2Ph
from their abundant occurrence in natural products and bioac-
O
R'
tive compounds.1 This class of dicarbonyl structures also
represents important synthetic precursors to 1,4-diols, as well
as 5-membered ring heterocycles, such as furans, pyrroles,
thiophenes and selenophenes, which are of interest because of
their biological or electronic properties (Figure 1, compounds
1–4).2,3
Ru(bpy)3Cl2—6H2O
f
R'
CN– or
thiazolium salt
+
hv
R''
OLi
CuCl2
O
+
a
e
R'
O
R''
C
OH
R''
R'
C
O
PdCl2(PPh3)2
In/LnCl3
Et2Zn
Pd(PPh3)4
O
+
R'
Cl
O
O
OMe
b
d
amidine
c
Pd2(dba)3—CHCl3
OH
OMe
OH
R'
Cl
OH
R''
O
MeO
OMe
R'
C
H
C R''
H
amidine
OH
2
1
MeO
O
C
(Trypanocidal
activity)
(DNA and RNA selective
targeting reagent)
Scheme 1. Synthetic Routes to 1,4-Diketones
OMe
Ar''
Ar'
C
O
The traditional route relies on a Stetter reaction catalyzed
either by cyanide or thiazolium salts (route a), but which can
also lead to an undesired benzoin reaction.5 Palladium-
mediated strategies have been reported, including the reduc-
tive coupling of acid chlorides with unsaturated ketones (route
b) or with cyclopropanols (route d),6 as well as the isomeriza-
tion of alkynediols (route c).7 However, in these cases draw-
backs include the use of labile starting materials, reactive
intermediates and reagents, thereby limiting the substrate
scope. Other approaches comprise of the oxidative homocou-
R
Ph
N
N
H
NH2
NH
Se
R'
O
EtO
3 (BACEꢀ1 inhibitor)
4 (Electronic properties)
Figure 1. Examples of Applications of 1,4-Diketone Motifs
Numerous competent synthetic protocols have previously
been developed for accessing 1,4-diketones, as illustrated in
Scheme 1, although each has its specific limitations.4
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ACS Catalysis
pling of ketone enolates (route e, R’ = R’’),8 or a recent pho-
Page 2 of 5
Table 1. Optimization of the Carbonylative Redox-Relay
Heck Reactiona
1
tocatalytic carbon–sulfur bond cleavage of sulfonylketones
followed by dimerization (route f, R’ = R’’).9 In such work,
only the symmetrical 1,4-diketones could be prepared. Re-
cently, Sigman and coworkers reported on a series of Pd-
catalyzed redox-relay reactions between alkenyl alcohols with
different aryl coupling partners (ArB(OH)2, ArN2X, or
ArOTf). They could successfully direct the double bond mi-
gration along the carbon chain towards the hydroxyl group,
resulting in the preparation of a variety of ketones and alde-
hydes possessing remote stereocenters with high enantiomeric
excess.10 In this context, many other groups have reported the
conversion of substituted allylic alcohols to aldehydes or
ketones via Pd-catalyzed coupling reactions, including more
recent examples from the groups of Lei,11 Huang,12 Jiang,13
Kommu14 and Nájera.15 With our own interest in the devel-
opment of new multi-component coupling approaches for the
preparation of dicarbonyl compounds with carbon monoxide,
including 1,3-diketones,16a–c ketoesters16d and amides,16e ke-
toesters,16f and acyl carbamates16g, we set out to develop a
carbonylative procedure for the assembly of 1,4-diketones. In
particular, the above-described redox relay reactions caught
our attention as a three component carbonylation coupling
involving an aryl halide and an allylic alcohol would lead to a
valuable and mild synthetic route to the target 1,4-dicarbonyl
compounds. In this report, we demonstrate the viability of
such a synthetic option, which not only allows access to a
wide scope of 1,4-diketones, but can also be adapted to 13C-
carbon isotope-labeling. In particular, we demonstrate that our
new protocol can install the isotope-label at either or both
carbonyl positions thereby providing a valuable technique for
site-selective isotope-labeling of heterocycles.
2
3
4
5
6
7
8
9
O
O
C
Ph
Ph
I
O
MeO
MeO
MeO
CO (2.2 equiv)
Pd (x mol%)
Ligand (y mol%)
Base (3.0 equiv)
7
8
MeO
Desired product
5
O
C
O
Ph
OH
Ph
C
Dioxane
O
100 οC, 18 h
Ph
OH
MeO
9
10
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield
7/8
[Pd]ꢀsource
(mol%)
Entry
Ligand (mol%)
Base
(%)[b]
(tBu)3P•HBF4
(12.5)
1
2
3
Pd(COD)Cl2 (5)
Pd(COD)Cl2 (5)
Pd(COD)Cl2 (5)
Cy2NMe
Cy2NMe
Cy2NMe
11/2
58/16
59/16
tBuBrettphos
(12.5)
tBuBrettphos
(2.5)
4
5
Pd(COD)Cl2 (5)
Pd(COD)Cl2 (5)
Pd(COD)Cl2 (5)
Pd(COD)Cl2 (5)
Pd(OAc)2 (5)
XPhos (2.5)
XantPhos (2.5)
dppb (2.5)
dppb (2.5)
dppb (2.5)
dppb (2.5)
dppb (2.5)
Cy2NMe
Cy2NMe
Cy2NMe
DIPEA
64/18
52/22
62/22
71/19
62/29
51/36
71/14
81/18
(65)
6
7
8
DIPEA
9
Pd(dba)2 (5)
DIPEA
10
(PdC3H5Cl)2 (2.5)
DIPEA
11
12
(PdC3H5Cl)2 (2.5)
(PdC3H5Cl)2 (2.5)
Xphos (2.5)
ꢀ
DIPEA[c]
DIPEA[c]
22/16
aReactions were carried out in a two-chamber system. Cham-
ber A: 5 (0.2 mmol), 6 (1.2 mmol), Pd (x mol%), ligand (y
mol%), base (0.6 mmol) and dioxane (1 mL). Chamber B: COgen
(0.44 mmol), Pd(COD)Cl2 (0.0044 mmol), HBF4tBu3P (0.0044
mmol), Cy2NMe (0.88 mmol, 0.19 mL) and solvent (1 mL). bGC-
yield with 1,3,5-trimethoxybenzene as internal standard. Isolated
yield of compound 7 in brackets. cDIPEA (0.3 mmol).
As seen from the diagram in Table 1, our synthetic ap-
proach to 1,4-diketones such as compound 7 is not without
problems as a variety of alternative reactions pathways could
potentially take place. This includes the redox-relay Heck
coupling without CO insertion (compound 8), direct carbonyl-
ative Heck coupling to the α,β−unsaturated ketone 9,17 and
alkoxycarbonylation with the allylic alcohol to provide 10,
which would presumably be followed by oxidative addition
with Pd(0) generating a cationic allylpalladium complex. The
palladium source, the ligand and base composition, as well as
the carbon monoxide pressure will most likely influence the
direction of the reaction pathway.
The yield of 7 increased significantly when tBuBrettphos
was used (entry 2). From our previous studies on the car-
bonylative Heck reactions, employing a 2:1 ratio between
palladium and ligand proved beneficial for the coupling
yield.17d The ligand loading could be reduced five fold to 2.5
mol% without degradation of the yield (entry 3). XPhos
proved to be slightly more efficient for this transformation
than tBuBrettPhos (entry 4). Applying the more standard
phosphine ligands for Pd-catalyzed carbonylations, such as
XantPhos or dppb, proved in this case to be slightly inferior to
XPhos (entries 5 and 6). Nevertheless, further optimizations
were carried out with dppb. Substituting dioxane for solvents
such as toluene, DMF, DMSO or anisole did not improve the
efficiency of the reactions (results not shown). A base screen-
ing revealed DIPEA to be the base of choice (entry 7), while
screening the Pd-precursors, the allyl palladium(II) chloride
dimer provided the best result (entries 8–10). Combining the
allyl palladium(II) chloride dimer with XPhos and lowering
the amount of DIPEA to 1.5 equiv, finally allowed the for-
mation of 7 in a good 65% isolated yield (entry 11). Lowering
the temperature, the CO pressure or the equivalents of the
alcohol all led to a decrease in the formation of 7 (results not
A screening of a variety of reaction conditions was there-
fore initiated with 4-iodoanisole (5), 1-phenylprop-2-en-1-ol
(6) and Cy2NMe as base with different Pd-ligand systems in
dioxane under a CO atmosphere, a selection of which is de-
picted in Table 1.18 This amine base was previously used in
successful carbonylative Heck reactions.17d,e
Our two-chamber technology including COware and the
carbon monoxide precursor COgen was employed for all
reactions. Pleasingly, from our first experiment performed
with Pd(COD)Cl2 and HBF4P(tBu3), an 11% GC yield of the
desired 1,4-diketone product 7 together with 2% of ketone 8
(entry 1) and traces of 4-methoxybenzoic acid were obtained.
In order to simplify the optimization process, only the GC
yields of compounds 7 and 8 were subsequently determined.
2
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Page 3 of 5
ACS Catalysis
shown). Finally, removing XPhos from the catalytic system to the corresponding aldehyde. With 3-propen-2-ol, a variety
1
lowered the yield to 22% (entry 12).
of different substituted aryl iodides could be transformed to
2
3
4
5
6
7
8
9
CO (2.2 equiv)
(PdC3H5Cl)2 (2.5 mol%)
XPhos (2.5 mol%)
DIPEA (1.5 equiv)
With these conditions in hand, we next investigated the
scope and limitations of the reaction (Scheme 2). In general,
moderate to good yields of the desired 1,4-diketones were
obtained. In accordance with previous reports, aryl halides
carrying electron-donating groups are more efficient at insert-
ing CO between the coupling partners, affording carbonyla-
tive products in better yields compared to aryl iodides with
electron-withdrawing groups.17d Employing aryl iodides with
alkyl substituents resulted in isolation of the corresponding
1,4-diketones in acceptable yields (Scheme 2, 11 and 12).
Sulfur- and aniline-containing 1,4-diketones could be formed
in good yields (13–15). Aryl iodides displaying protected
phenol groups proved to be the most efficient electrophile for
this reaction
O
I
C
R'
OH
R'
R
R
+
O
Dioxane,100 oC, 18 h
0.2 mmol
6.0 equiv
23–45
O
C
O
C
O
C
O
C
O
R
O
S
O
MeO
O
O
OMe
a
]
30, 71%[
31, 70%
a
29, 55%[
]
a
R = 4ꢀMeO, 23, 85%[
]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
4ꢀBnO, 24, 74%[
4ꢀPhenyl, 25, 57%[
4ꢀTBDMSO, 26, 70%[
]
O
C
O
C
a
]
BnO
BnO
a
]
a
3ꢀMeO, 27, 80%[
]
O
O
O
a
]
H, 28, 60%[
32, 74%
33, 63%
O
C
O
C
O
Ph
C
NHCbz
Me
NHBoc
MeO
O
O
O
O
MeO
MeO
MeO
34, 64%
36, 60%
35, 63%
OMe
O
O
O
C
O
C
O
C
CO (2.2 equiv)
(PdC3H5Cl)2 (2.5 mol%)
XPhos (2.5 mol%)
O
C
OH
I
O
O
MeO
MeO
R
+
DIPEA (1.5 equiv)
b
]
38, 72%
39a, 70% (70%)[
R
37, 56%
O
6
Dioxane,100 oC, 18 h
CF3
Me
0.2 mmol
6.0 equiv
11–22
O
O
C
O
C
C
N
O
C
O
O
C
Me
O
C
O
O
MeO
MeO
MeO
MeO
O
40, 59%
41, 74%
42, 60%
O
O
O
O
tBu
MeS
O
C
O
C
O
C
S
13, 60%
12, 53%
11, 51%
Me
H
O
C
O
C
O
C
O
O
O
MeO
MeO
43, 40%
45, 44%
44, 66%
O
O
BocHN
Bn2N
TBDMSO
16, 71%
15, 62%
14, 50%
General conditions: Chamber A: Chamber 1: Aryl iodide (0.20
mmol), allylic alcohol (1.2 mmol), (PdC3H5Cl)2 (2.5 mol%),
XPhos (2.5 mol%), DIPEA (1.5 equiv) and dioxane (1 mL).
Chamber B: COgen (0.44 mmol), Pd(COD)Cl2 (0.0044 mmol),
HBF4tBu3P (0.0044 mmol), Cy2NMe (0.88 mmol, 0.19 mL) and
dioxane (1 mL). aAlcohol (2.0 mmol). b2.0 mmol scale.
O
O
C
O
MeO
MeO
C
MeO
C
O
O
O
BnO
MeO
MeO
OMe
17, 75%
19, 55%
18, 65%
O
O
O
C
C
C
O
O
O
O
Scheme 3. Carbonylative Redox-Relay Reactions with
Various Allylic Alcohols
MeO
COOMe
Cl
21, 58%
22, 61%
20, 60%
the corresponding 1,4-diketones in high yields (23–28). Het-
eroaromatic iodides could also be incorporated in moderate to
good yields (29 and 30). Employing other aliphatic allylic
alcohols enabled the formation of 1,4-diketones carrying ethyl,
cyclopentyl, cyclohexyl or phenylethyl groups (31–34). Inter-
estingly, protected amines proved compatible using this strat-
egy (35 and 36). 1,4-Diarylketones could also be synthesized
using different aromatic allyl alcohols. Both nucleophiles with
electron-rich and electron-poor aryl rings could be converted
to the desired 1,4-diketones in good yields (37–41). Further-
more, the reaction could be conducted on a 2.0 mmol scale,
resulting in an identical isolated yield of 39a. Heteroaromatic
allylic alcohols were feasible coupling partners, which al-
lowed for the synthesis of 1,4-diketones with a pyridine, thio-
phene and a furan moiety (42–44). Finally, employing 2-
propenol enabled the formation of the corresponding 1,4-
ketoaldehyde 45. Unfortunately, di-substituted allylic alcohols
did not provide any product and using homo-allylic alcohols
only allowed for the formation of 1,5-diketones in a very low
yield (results not shown).
Chamber A: Aryl iodide (0.20 mmol), 6 (1.2 mmol),
(PdC3H5Cl)2 (2.5 mol%), XPhos (2.5 mol%), DIPEA (1.5 equiv)
and dioxane (1 mL). Chamber B: COgen (0.44 mmol),
Pd(COD)Cl2 (0.0044 mmol), HBF4tBu3P (0.0044 mmol),
Cy2NMe (0.88 mmol, 0.19 mL) and dioxane (1 mL).
Scheme 2. Carbonylative Redox-Relay Reactions between
1-Phenylprop-2-enol and Various Aryl Iodides
resulting in isolated yields of 71% and 75%, respectively (16
and 17). Utilizing the dimethoxy- or trimethoxy-derivatives
resulted in a diminished yield, probably due to the increased
electron withdrawing effect (18 and 19). Functional groups,
such as chloro or methyl ester could be well-tolerated under
these conditions (20 and 21). Finally, a dihydrobenzofuran
1,4-diketone 22 could also be accessed.
Having investigated the scope of the aryl iodide, attention
was then turned to testing a range of allylic alcohols, as illus-
trated in Scheme 3. These coupling partners were either com-
mercially available or prepared via a simple Grignard addition
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Having demonstrated the potential of this methodology,
Page 4 of 5
O
C
Ph
1
2
3
4
we decided to use the 1,4-diketones for formation of hetero-
cycles. 13C-labeling of bioactive molecules has become an
important tool for imaging and following the pharmacokinet-
ics of low molecular weight compounds.19 By employing 13C-
I
O
7
MeO
MeO
Pd0
A
Base
5
6
7
8
9
13CO (1.5 equiv)
HCO2K (2.0 equiv)
Pd(dba)2 (5 mol%)
O
C
PdI
PdI
Ph
Hb
OH
H
HO
O
C
MeO
HBF4PCy3 (5 mol%)
TBAI (30 mol%)
Ha OH
I
Ph
C
MeO
B
(Vinyl)MgBr
THF
H
D
MeCN, 80 oC, 18 h
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ref 20
CO
MeO
13CO (2.2 equiv)
Ph
O
C
OH
8
(PdC3H5Cl)2 (2.5 mol%)
XPhos (2.5 mol%)
O
C
PdI
Ph
C
DIPEA (1.5 equiv)
C
MeO
Dioxane,100 oC, 18h
OH
O
MeO
39a, C = 12C, C = 12C, 70%
39b, C = 12C, C = 13C, 60%
39c, C = 13C, C = 12C, 69%
39d, C = 13C, C = 13C, 67%
Ph
from 39a
Ref 21a
from 39a
O
C
Ph
Ref 21c
O
MeO
from 39a–d
MeO
10
C
C
O
Ref 21b
C
N
C
Figure 2. Possible Mechanistic Cycle for the Formation of 1,4-
Diketones (Ligand omitted for clarity)
C
C
S
MeO
46, C = 12C, C = 12C, 75%
MeO
MeO
47a, C = 12C, C = 12C, 82% 48, C = 12C, C = 12C, 62%
47b, C = 12C, C = 13C, 71%
A plausible mechanistic cycle for the reported transfor-
mation is illustrated in Figure 2. After generation of the active
Pd(0)-species A, an oxidative addition takes place with the
aryl iodide to create the Pd(II)-complex B. This can then
undergo a carbopalladation, which will eventually give rise to
direct Heck product 8. On the other hand, CO insertion with B
will form the acyl-palladium(II) complex C. Subsequent reac-
tion with the allylic alcohol will then provide the 1,4-diketone
7 if hydride elimination occurs with hydrogen Hb, regenerat-
ing Pd(0) from a base-assisted reductive elimination. Alterna-
tively, an alkoxycarbonylation may take place with complex C
providing the benzoylated allylic alcohol 10. This product
might be an intermediate for forming 7, however, replacing
the aryl iodide and allylic alcohol with 10 under the optimized
conditions, did not provide any formation of 7. Futhermore,
the presence of 10 was not observed under the optimized
conditions.
47c, C = 13C, C = 12C, 71%
47d, C = 13C, C = 13C, 71%
Scheme 4. Formation and 13C-Labeling of Heterocycles
labeled COgen, 13CO can be liberated and incorporated into
the potential molecule as shown earlier.16 Furthermore, the
ketone group formed from the allylic alcohol can also be 13C-
labeled by forming the corresponding labeled aldehyde and its
reaction with a vinyl Grignard reagent (Scheme 4).20 Furan 46,
thiophene 47a and the pyrrole 48 could be formed from 39a in
good isolated yields applying standard procedures.21 By em-
ploying either 13C-labeled allylic alcohol, 13C-labeled CO or
both enabled full control of the position of the 13C-labeling
carbon atom in the 1,4-diketones 39b–d and subsequently in
the thiophenes 47b–47d.
In conclusion, a synthetic route to 1,4-diketones has been
shown via a Pd-catalyzed carbonylative coupling between aryl
iodides and substituted allyl alcohols. Various aryl iodides and
alcohols were compatible with this method. Substituted heter-
ocycles could be obtained from the products of this methodol-
ogy. Moreover, 13C-labeled diketones and heterocycles could
be synthesized by employing this method. This methodology
could become a complementary route to the synthesis of di-
verse 1,4-diketones.
ASSOCIATED CONTENT
Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ts@chem.au.dk.
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Notes
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The authors declare the following competing financial interest(s):
Anders T. Lindhardt and Troels Skrydstrup are co-owners of
SyTracks a/s, which commercializes the two-chamber technolo-
gy.
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W.; Burckle, A. J.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135,
6830–6833. b) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J.
Am. Chem. Soc. 2015, 137, 7290–7293. c) Patel, H. H.; Sigman, M. S.
J. Am. Chem. Soc. 2015, 137, 3462–3465. d) Mei, T.-S.; Patel, H. H.;
Sigman, M. S. Nature. 2014, 508, 340–344. e) Hilton, M. J.; Cheng,
B.; Buckley, B. R.; Xu, L.; Wiest, O.; Sigman, M. S. Tetrahedron.
2015, 71, 6513–6518. f) Hilton, M. J.; Xu, L.; Norrby, P.; Wu, Y.;
Wiest, O.; Sigman, M. S. J. Org. Chem. 2014, 79, 11841–11850. g)
Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science.
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(11) Chen, M.; Wang, J.; Chai, Z.-Y.; You, C.; Lei, A.-W. Adv.
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(12) Zhu, Z.-Q.; He, J.-S.; Wang, H.-J.; Huang, Z.-Z. J. Org. Chem.
2015, 80, 9354–9359.
(13) Liao, J.-H; Zhang, Z.-M; Tang, X.-D.; Wu, W.-Q.; Guo, W.;
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ACKNOWLEDGMENT
We are deeply appreciative of the generous financial support
from the Danish National Research Foundation (Grant No.
DNRF118), the Danish Innovation Foundation through the iDEA
project, the Villum Foundation, the Danish Council for Independ-
ent Research: Technology and Production Sciences, and Aarhus
University for generous financial support. Furthermore, we thank
the China Scholarship Council for a grant to H. Y.
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