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Copper(I)-USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S- and C-Arylation Reactions: Scope and Application to Total Synthesis Tony GARNIER, Mathieu DANEL, Valentin MAGNE, Anthony PUJOL, Valérie BENETEAU, Patrick Pale, and Stefan CHASSAING J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00620 • Publication Date (Web): 23 May 2018 Downloaded from http://pubs.acs.org on May 23, 2018
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The Journal of Organic Chemistry
Copper(I)-USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S- and C-Arylation Reactions: Scope and Application to Total Synthesis Tony Garnier,a Mathieu Danel,a Valentin Magné,a Anthony Pujol,a Valérie Bénéteau,b Patrick Pale*b and Stefan Chassaing*a,b a
ITAV, Université de Toulouse, CNRS, Toulouse, France Laboratoire de Synthèse, Réactivité Organique et Catalyse (LASYROC), Institut de Chimie, CNRSUMR7177, Université de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France
b
GRAPHICAL ABSTRACT recyclable
application
O
CuI
Nu X
+
I
Cu R
I
Cu
CuI-USY
X = I, Br Nu = O-, N-, S-, and C-nucleophiles
OH O
Nu R
3-Methylobovatol
> 50 examples
- ligand-free method - wide scope - high functional group tolerance
ABSTRACT The copper(I)-doped zeolite CuI-USY proved to be a versatile, efficient, and recyclable catalyst for various Ullmann-type coupling reactions. Easy-to-prepare and cheap, this catalytic material enables the arylation and heteroarylation of diverse O-, N-, S- and Cnucleophiles under ligand-free conditions, while exhibiting large functional group compatibility. The facility of this catalyst to promote C-O bond formation was further demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether of biological relevance. From a mechanistic viewpoint, two competitive pathways depending on the nature of the nucleophile and consistent with the obtained results have been proposed.
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1-INTRODUCTION – Originally found by Ullmann at the very end of the XIXth century,1 the copper-promoted coupling of aryl halides with various O- and N-nucleophiles has been revamped in the past decades and extended to C- and S-nucleophiles, while becoming a catalytic and useful tool in organic synthesis.2 The original stoichiometric process, performed under harsh conditions, was replaced a century later by one based on palladium complexes used in catalytic amounts under much milder conditions, through the seminal works of Buchwald and Hartwig.3 In an amazing reversal, copper came back again at the beginning of the XXIst century, due to its lower cost and toxicity and to its higher abundance. Various combinations of copper salts and specific ligands have thus been developed to set up mild and useful copper-catalyzed arylation reactions.4 Such reactions allow the arylation of N-, O-, S-, and to a lesser extend C-, nucleophiles such as anilines, amines, amides, alcohols, phenols and thiols as well as some activated methylene compounds, that have led to numerous applications in synthesis, medicinal chemistry, life and materials sciences.5 Although milder and catalytic conditions have been set, mostly relying on specific ligands, not much has so far been done for ‘greening’ further such arylation reactions through heterogeneous catalysis, despite the interest of such catalysis within the Green Chemistry context.6 Cu-nanoparticules, Cu-supported on carbon,7 alumina, titania, kaolin,8 and Cucomplexes grafted on various materials9-12 have been reported, but with variable efficiency and results. Since we are exploring the potential of easy-to-prepare, inexpensive and highly stable CuIzeolites as ligand-free catalysts for organic synthesis,13,14 we have attempted applying CuIzeolites to Ullmann-type arylations.15 We report here that CuI-USY zeolite indeed acted as an efficient ligand-free and recyclable catalyst for various Ullmann-type C-O, C-N, C-S and C-C coupling reactions (Scheme 1) and we also report its application as key step in the total synthesis of a naturally occurring diaryl ether, namely 3-methylobovatol. CuI
X
Nu
+
R
CuI
Nu
CuI
R
CuI-USY X = Halogen Nu = O-, N-, S-, and C-nucleophiles I
Scheme 1 – Cu -USY catalyzed Ullmann-type arylation reactions
2-RESULTS AND DISCUSSION – 2.1- O-, N-, S, and C-arylation reactions – scope and limitations 2.1.1- The C-O case – Simple aryl iodides or bromides readily react with electron-rich phenols, such as 3,5-dimethylphenol, in the presence of CuI-USY and cesium carbonate in toluene at 120 °C.15 However, aryl chlorides do not, as shown here. Indeed, chlorobenzene only gave trace amounts of the expected diaryl ether 1a when submitted to these conditions
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The Journal of Organic Chemistry
with 3,5-dimethylphenol in toluene or DMF and even after heating at 140 °C and prolonged reaction times (Scheme 2). Functionalized aryl bromides and iodides were then engaged in a series of O-arylation with the model 3,5-dimethylphenol. Those carrying strongly electron-withdrawing group efficiently gave the corresponding diaryl ethers 1b,c in high yields (78-83%), as already shown,15 but those carrying carbonyl group gave variable but interesting results. Aryl halides bearing a ketone, such as fluorenone or acetophenone, smoothly reacted to give the diaryl ethers 1d and 1e in comparable yields. Not so surprisingly, aryl halides bearing an aldehyde were more prone to side-reactions, and the expected diaryl ethers were thus obtained in more modest yields (~ 40% for 1f). The latters could nevertheless be improved by performing the coupling reaction in the more polar solvent DMF (up to 60%). As suspected from steric hindrance and as already observed with ortho-methyl substituted derivatives,15 ortho-bromobenzaldehyde gave the expected coupling product 1g in only low yield. Aryl iodide carrying an isopropyl ester group readily reacted, giving 1h in good yield, while its methyl ester analog only led to the expected product 1i in modest yield. Interestingly, the corresponding free carboxylic acid could also be engaged in such coupling, but DMF proved to be a much more suitable solvent than toluene, probably for solubility reasons. Thus, performing the O-arylation in DMF at higher temperature – i.e., 140 °C – led to the formation of 1j in high yield (80%). Other functional groups, including basic amines, ethers and acid-sensitive acetals, were examined and all of them proved fully compatible with the reaction conditions, giving the expected diaryl ethers 1k-p in good to excellent yields. Of particular relevance is the compatibility of the present conditions with the allyl residue and the common acid-sensitive methoxymethyl (MOM) protecting group, providing 1o,p in good to high yields depending on the starting halide. Rewardingly, pyridinyl halides also appeared as suitable aryl sources, despite their strongly coordinating motif. Indeed, 2- and 3-bromopyridines were very efficiently converted into the corresponding pyridyl aryl ethers 1q and 1r, quantitatively for the first and in high yield for the second. In a second series of experiments, the phenol scope was examined further. The electron-rich 3-dimethylaminophenol readily reacted with phenyl iodide, furnishing diaryl ether 1s, while phenols carrying strongly electron-withdrawing group, such as nitro or cyano groups, did not react, no trace of the expected diaryl ethers 1t,u being detected.15 However, 4-chlorophenol did, providing the 4-chlorophenyl phenyl ether 1v in reasonable yield (~60%). Surprisingly, some amounts of the diether 1v’ were also isolated, revealing the possibility of coupling 4chlorophenol with 1v. Despite some hindrance, 2-naphtol reacted with phenyl iodide, giving the expected 2-naphtyl phenyl ether 1w, but DMF was required to reach satisfactory yield, as the reaction proved faster in DMF than in toluene in this case. Interestingly, even aliphatic alcohols, such as ethanol and butan-1-ol, could be engaged with iodobenzene into this coupling reaction, providing in good yields the corresponding aryl alkyl ethers 1x,y (~75%).
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CuI -USY Cs2CO 3
X R
R'
OH
Page 4 of 34
O
a
Ph
O
R
R'
PhCH 3 120 °C, 24 h
85 %: X = I 1a 83 %: X = Br < 5 % (< 5 %b, < 5 %b,c): X = Cl
1a-y
O
O
O
O
NO 2
CN
1d 83 %: X = Br
1c 83 %: X = I 78 %: X = Br
1b 83 %: X = I 83 %: X = Br
O
O
O
H
O O
O H 1e 76 %: X = I 55 %: X = Br
36 % (39 %b): X = I 38 % (60 %b): X = Br
1f
1g 19 %: X = Br
O
O
O O
O O
O 1h 70 %: X = I
1i 41
%d:
1j
80 %c): X = I
O
O
66 %: X = I 74 %: X = Br
1m 84 %: X = I
O
O
(25
%b,
O
O 1l
-e
O
NEt 2 1k 84 %: X = Br
OH
X=I
O
O
O
O
1n 77 %: X = I
O
N
N
O
O O
1p 84 %: X = I 64 %: X = Br
1o 79 %: X = I
N
O
O
Ph
1s 69 %: X = I
O
1w 21 % (62 %b): X = I
O Ph
NC
1t 0 %f: X = I
Ph
O
Ph
O 2N
O
Ph
1x 75 %h: X = I
1r 79 %: X = Br
1q quant.: X = Br
1u 0 %g: X = I
Cl
Ph
1v 58 %g: X = I
/
O
Cl O
Ph
O
Ph
1v' 4 %: X = I
1y 73 %h: X = I
a Reactions run with CuI -USY (10 mol%), ROH (1.5 equiv), aryl halide (1.0 equiv) and Cs CO 2 3 (2.0 equiv), unless otherwise stated. b Reactions run in DMF in place of PhCH 3. c Reactions run at 140 °C. d The 1H NMR analysis of the crude revealed the formation of 1i together with unidentified side products. e No conversion observed in PhCH 3. f No trace of expected product detected by LCMS. g Ph 2O also isolated in a 35 % yield. h Reaction run in the nucleophilic alcohol as solvent. I
Scheme 2 – Cu -USY catalyzed O-arylation reactions
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The Journal of Organic Chemistry
2.1.2- The C-N case – To go further with our CuI-USY arylation tool, we evaluated its potential for C-N bond formation. Various anilines, aliphatic amines and amides as Nnucleophiles were thus submitted to the set-up conditions.16 Rewardingly, the expected Narylated products were produced in most cases (Scheme 3). From our results, the solvent nature and the electronic profile of the N-nucleophiles emerged as crucial factors in governing the reactivity, thus the product yields.
R' R
CuI -USY Cs2CO 3
I R'
NH
R'
a
R
N R'
DMF 120 °C, 24 h
H N
H N
Ph
2a-k H N
F 3C Ph CF3
2a
O 2N
Ph 2d
/ ON 2
2d'
CF3
H N
Ph
2g 0 % (0 %b,c)
X
N Ph
2h: X = CH2 2i: X = O
0%
O
O Ph
O
O 2N
N H
O 2f 75 %e,i
2c'
2e 77 %e,h
H N O 2N
NPh 2
/
2c
NPh 2
e 2d/2d' 88 % : 18 % traces : 72 %c,f
2j
F 3C
32 % : 31 %d (0 %b) 2c/2c' 52 % : 21 %c,e 19 % : 57 %c,f,g
