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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 Downloaded from http://pubs.acs.org on April 7, 2016
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ACS Catalysis
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*† †
Carbon Dioxide Activation Center (CADIAC), Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark ‡
Carbon Dioxide Activation Center (CADIAC), Interdisciplinary Nanoscience Center (iNANO) and Department of Engineering, 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
1,4-Diketones have drawn considerable attention resulting from their abundant occurrence in natural products and bioactive 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
MeO
amidine OMe
R'
+ R'' O
a PdCl 2(PPh 3) 2 In/LnCl 3
O
R
Ar'
f
CN – or thiazolium salt
Cl + O
R'
O C
C O
Ar''
N Se R' 4 (Electronic properties)
Ph H N
O EtO 3 (BACE-1 inhibitor)
NH 2 NH
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
e C O
OLi R'
R''
OH
Et 2Zn Pd(PPh 3) 4
R'' O
d c Pd 2(dba) 3CHCl 3 OH OH R'
amidine 2 (DNA and RNA selective targeting reagent)
O C
Ru(bpy) 3Cl26H 2O hv CuCl2
b
OMe OH 1 (Trypanocidal OMe activity)
SO 2Ph
R'
R''
O
MeO
O
R'
OMe OH
O
C H
R'
+ Cl
C R'' H
Scheme 1. Synthetic Routes to 1,4-Diketones 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 Palladiummediated strategies have been reported, including the reductive coupling of acid chlorides with unsaturated ketones (route b) or with cyclopropanols (route d),6 as well as the isomerization of alkynediols (route c).7 However, in these cases drawbacks include the use of labile starting materials, reactive intermediates and reagents, thereby limiting the substrate scope. Other approaches comprise of the oxidative homocou-
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pling of ketone enolates (route e, R’ = R’’),8 or a recent photocatalytic 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. Recently, Sigman and coworkers reported on a series of Pdcatalyzed redox-relay reactions between alkenyl alcohols with different aryl coupling partners (ArB(OH)2, ArN2X, or ArOTf). They could successfully direct the double bond migration along the carbon chain towards the hydroxyl group, resulting in the preparation of a variety of ketones and aldehydes 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 development 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 ketoesters,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 13Ccarbon 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. As seen from the diagram in Table 1, our synthetic approach 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 carbonylative 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. A screening of a variety of reaction conditions was therefore 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 depicted 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.
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Table 1. Optimization of the Carbonylative Redox-Relay Heck Reactiona O
O C
I
Ph O
MeO
CO (2.2 equiv) MeO 7 Desired product Pd (x mol%) Ligand (y mol%) O Base (3.0 equiv) C Ph OH Dioxane 100 οC, 18 h OH Ph MeO 9 6
Ph MeO
8
5
Entry
[Pd]-source (mol%)
Ligand (mol%) (tBu)3P•HBF4
O C MeO
Ph O
10
Base
Yield 7/8 [b] (%)
Cy2NMe
11/2
Cy2NMe
58/16
Cy2NMe
59/16
1
Pd(COD)Cl2 (5)
2
Pd(COD)Cl2 (5)
3
Pd(COD)Cl2 (5)
4
Pd(COD)Cl2 (5)
XPhos (2.5)
Cy2NMe
64/18
5
Pd(COD)Cl2 (5)
XantPhos (2.5)
Cy2NMe
52/22
6
Pd(COD)Cl2 (5)
dppb (2.5)
Cy2NMe
62/22
7
Pd(COD)Cl2 (5)
dppb (2.5)
DIPEA
71/19
8
Pd(OAc)2 (5)
dppb (2.5)
DIPEA
62/29
9
Pd(dba)2 (5)
dppb (2.5)
DIPEA
51/36
10
(PdC3H5Cl)2 (2.5)
dppb (2.5)
DIPEA
71/14
11
(PdC3H5Cl)2 (2.5)
Xphos (2.5)
DIPEA[c]
12
(PdC3H5Cl)2 (2.5)
-
DIPEA[c]
(12.5) tBuBrettphos (12.5) tBuBrettphos (2.5)
81/18 (65) 22/16
a Reactions were carried out in a two-chamber system. Chamber 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). bGCyield with 1,3,5-trimethoxybenzene as internal standard. Isolated yield of compound 7 in brackets. cDIPEA (0.3 mmol).
The yield of 7 increased significantly when tBuBrettphos was used (entry 2). From our previous studies on the carbonylative 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 screening 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 formation 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
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ACS Catalysis
shown). Finally, removing XPhos from the catalytic system lowered the yield to 22% (entry 12). 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 inserting CO between the coupling partners, affording carbonylative 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
to the corresponding aldehyde. With 3-propen-2-ol, a variety of different substituted aryl iodides could be transformed to I R
CO (2.2 equiv) (PdC 3H 5Cl)2 (2.5 mol%) XPhos (2.5 mol%) DIPEA (1.5 equiv)
OH +
0.2 mmol
R' 6.0 equiv
O C
O C
R
29, 55%[a] R = 4-MeO, 23, 85%[a] 4-BnO, 24, 74%[a] 4-Phenyl, 25, 57%[a] 4-TBDMSO, 26, 70%[a] 3-MeO, 27, 80%[a] O H, 28, 60%[a] O C
Ph O
CO (2.2 equiv) (PdC3H 5Cl) 2 (2.5 mol%) XPhos (2.5 mol%) DIPEA (1.5 equiv)
R
+ 6 6.0 equiv
0.2 mmol O C
Dioxane,100 oC, 18 h
Me
O
11, 51%
O
MeO O
COOMe 20, 60%
19, 55% O C
O
MeO
O OMe
18, 65%
O
O C
MeO
O C
O C
21, 58%
36, 60% OMe
O
O 39a, 70% (70%) [b] CF 3
O
MeO
40, 59%
O 43, 40%
N
MeO
42, 60% O
O C MeO
O C O
41, 74% S
Me
O C
MeO
O C
O
NHCbz O
MeO
O 44, 66%
O C
H O
MeO 45, 44%
16, 71% MeO
O
MeO
17, 75%
Cl
O C
O C
NHBoc
MeO
Me
MeO
O
TBDMSO
15, 62%
O C
MeO
O
BocHN
14, 50%
BnO
O C
33, 63%
38, 72%
O C
13, 60%
O C
O C Bn 2N
12, 53%
Me
MeO
O
MeS
O
BnO
32, 74% O C
O C
O O
O C
O C
O
tBu
O
31, 70% O C
BnO O
37, 56%
11 –22
O C
30, 71% [a] O C
35, 63%
MeO
R
O
O MeO
O
O
O C
O C
O C
O
MeO
34, 64%
OH
23–45
OMe
MeO
I
O
O C O
R'
R
Dioxane,100 oC, 18 h
S
O
O C
O
O 22, 61%
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 illustrated in Scheme 3. These coupling partners were either commercially available or prepared via a simple Grignard addition
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.
Scheme 3. Carbonylative Redox-Relay Reactions with Various Allylic Alcohols the corresponding 1,4-diketones in high yields (23–28). Heteroaromatic 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). Interestingly, protected amines proved compatible using this strategy (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). Furthermore, 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 allowed for the synthesis of 1,4-diketones with a pyridine, thiophene and a furan moiety (42–44). Finally, employing 2propenol enabled the formation of the corresponding 1,4ketoaldehyde 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).
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Having demonstrated the potential of this methodology, we decided to use the 1,4-diketones for formation of heterocycles. 13C-labeling of bioactive molecules has become an important tool for imaging and following the pharmacokinetics of low molecular weight compounds.19 By employing 13C-
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Ph
7
MeO
I
O MeO
Pd 0 A Base
13 CO (1.5 equiv) HCO 2K (2.0 equiv) Pd(dba) 2 (5 mol%) HBF 4PCy 3 (5 mol%) TBAI (30 mol%)
I
O C
H
HO H
O C
PdI
Ph Hb OH
Ha
MeO
C
(Vinyl)MgBr
MeCN, 80 oC, 18 h
PdI
OH MeO B
D
THF
O
Ref 20 13 CO
O C
39a, C = 12 C, C = 12 C, 39b, C = 12 C, C = 13 C, 39c, C = 13 C, C = 12 C, 39d, C = 13 C, C = 13 C,
Ref 21a
C C O
70% 60% 69% 67%
from 39a–d Ref 21b
C MeO
(2.2 equiv) (PdC 3H 5Cl) 2 (2.5 mol%) XPhos (2.5 mol%) DIPEA (1.5 equiv) Dioxane,100 oC, 18h
C O
MeO from 39a
Ph
S
Ph MeO
CO MeO
C OH
from 39a
O C
Ref 21c
MeO
MeO
C N C
MeO 82% 71% 71% 71%
Ph 8
PdI
Ph
C
MeO 46, C = 12 C, C = 12 C, 75% 47a, C = 12 C, C = 12 C, 47b, C = 12 C, C = 13 C, 47c, C = 13 C, C = 12 C, 47d, C = 13 C, C = 13 C,
O C
OH
48, C = 12 C, C = 12 C, 62%
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 13Clabeled 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 employing 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.
Ph O
10
Figure 2. Possible Mechanistic Cycle for the Formation of 1,4Diketones (Ligand omitted for clarity)
A plausible mechanistic cycle for the reported transformation 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 reaction with the allylic alcohol will then provide the 1,4-diketone 7 if hydride elimination occurs with hydrogen Hb, regenerating Pd(0) from a base-assisted reductive elimination. Alternatively, 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. 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 heterocycles could be obtained from the products of this methodology. Moreover, 13C-labeled diketones and heterocycles could be synthesized by employing this method. This methodology could become a complementary route to the synthesis of diverse 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:
[email protected].
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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 technology.
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 Independent 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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