Direct α-alkylation of ketones with primary alcohols catalyzed by iridium–CNP complex
3
Direct a-alkylation of ketones with primary alcohols catalyzed by iridium–CNP complex Dawei Wang ⇑ , Keyan Zhao, Piming Ma, Chongying Xu, Yuqiang Ding ⇑ The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, China article info Article history: Received 22 August 2014 Revised 4 November 2014 Accepted 9 November 2014 Available online 15 November 2014 Keywords: Alkylation Solvent-free CAC coupling Iridium complexes Dehydrogenation aldol condensation abstract The a-alkylation of ketones with primary alcohols was realized by CAC cross-coupling with iridium–CNP complexes as catalyst. This reaction proceeds via dehydrogenation reactions, aldol condensation, and hydrogenation using the borrowed hydrogen atoms from alcohols. The pyridyl methanols and other het- erocyclic substituted methanols, especially alkyl alcohols, were also suitable for this transformation. Ó 2014 Elsevier Ltd. All rights reserved. Introduction The direct a-alkylation of ketones with alcohols has been receiving much attention as an efficient method to form CAC bonds. 1 Compared to alkylation using alkyl halides as coupling reagents, the use of alcohols is an atom-economical process and green chemistry solution in which water is the only byproduct. 2,3 The reaction proceeds through: (1) oxidation of alcohols to the cor- responding carbonyl compounds; (2) alkylation of ketones to form unsaturated carbonyl compounds; and (3) reduction of the CAC bonds using the borrowed hydrogen atoms from alcohols (Scheme 1). 4,5 Therefore, the use of alcohols as alternative alkylat- ing agents sounds reasonable and interesting. 6 However, an often overlooked fact is that transfer hydrogenation is an important competitive reaction. It is a famous, well-studied reaction, but it drastically limits the development of alkylation (Scheme 2). 2i,5a,7 Despite the aforementioned shortcomings, scientists have put in a lot of efforts into this area. Hitherto, Ru and Ir have proved to be the most effective catalysts for the a-alkylation of ketones with alcohols. 8 Our interest in developing new catalysts to adjust transition metal reactivity 9,10 has led to the recent discovery of CNP iridium complexes. We have synthesized the CNP iridium complexes with phosphine ligand and non-coordinating anion (Scheme 3). 11 Here we reported that a-alkylation of ketones with alcohols was real- ized by using iridium–CNP complexes as catalysts through borrow- ing hydrogen reaction with good yields. Compared to the literatures (especially Zhang’s work with [RuCl 2 (p-Cymene)] 2 as catalyst), this method does not need the expensive Xantphos as ligand but slightly enhanced yields obtained. Also, the experiments showed that no transfer hydrogenation product was detected and iridium–CNP complexes are effective catalysts for borrowing hydrogen reaction without any interference from transfer hydrogenation. Given such considerations, the reaction of acetophenone with benzyl alcohol was chosen as a model reaction by which to evaluate the influence of various benzothienyl skeleton phosphine ligand iridium(III) catalysts. First we examined the iridium complexes with toluene as a solvent. The results showed that the yield of the product with catalyst 2b was slightly higher than other cationic iridium(III) compounds, but the yield was not satisfactory in toluene (Table 1, http://dx.doi.org/10.1016/j.tetlet.2014.11.034 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. Tel./fax: +86 510 85917763. E-mail addresses: [email protected] (D. Wang), [email protected] (Y. Ding). OH R 1 O R 1 Alkylation O R 2 R 1 O R 2 R 1 [M] [M]H 2 O R 2 Scheme 1. a-Alkylation of ketones with alcohols using the borrowing hydrogen strategy. Tetrahedron Letters 55 (2014) 7233–7235 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Transcript of Direct α-alkylation of ketones with primary alcohols catalyzed by iridium–CNP complex
Tetrahedron Letters 55 (2014) 7233–7235
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier .com/ locate/ tet le t
Direct a-alkylation of ketones with primary alcohols catalyzedby iridium–CNP complex
http://dx.doi.org/10.1016/j.tetlet.2014.11.0340040-4039/� 2014 Elsevier Ltd. All rights reserved.
⇑ Corresponding authors. Tel./fax: +86 510 85917763.E-mail addresses: [email protected] (D. Wang), [email protected]
(Y. Ding).
OHR1
OR1Alkylation O
R2 R1
O
R2 R1
[M]
[M]H2
O
R2
Scheme 1. a-Alkylation of ketones with alcohols using the borrowing hydrogenstrategy.
Dawei Wang ⇑, Keyan Zhao, Piming Ma, Chongying Xu, Yuqiang Ding ⇑The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, China
a r t i c l e i n f o
Article history:Received 22 August 2014Revised 4 November 2014Accepted 9 November 2014Available online 15 November 2014
Keywords:AlkylationSolvent-freeCAC couplingIridium complexesDehydrogenation aldol condensation
a b s t r a c t
The a-alkylation of ketones with primary alcohols was realized by CAC cross-coupling with iridium–CNPcomplexes as catalyst. This reaction proceeds via dehydrogenation reactions, aldol condensation, andhydrogenation using the borrowed hydrogen atoms from alcohols. The pyridyl methanols and other het-erocyclic substituted methanols, especially alkyl alcohols, were also suitable for this transformation.
� 2014 Elsevier Ltd. All rights reserved.
Introduction ing agents sounds reasonable and interesting.6 However, an often
The direct a-alkylation of ketones with alcohols has beenreceiving much attention as an efficient method to form CACbonds.1 Compared to alkylation using alkyl halides as couplingreagents, the use of alcohols is an atom-economical process andgreen chemistry solution in which water is the only byproduct.2,3
The reaction proceeds through: (1) oxidation of alcohols to the cor-responding carbonyl compounds; (2) alkylation of ketones to formunsaturated carbonyl compounds; and (3) reduction of the CACbonds using the borrowed hydrogen atoms from alcohols(Scheme 1).4,5 Therefore, the use of alcohols as alternative alkylat-
overlooked fact is that transfer hydrogenation is an importantcompetitive reaction. It is a famous, well-studied reaction, but itdrastically limits the development of alkylation (Scheme 2).2i,5a,7
Despite the aforementioned shortcomings, scientists have put ina lot of efforts into this area. Hitherto, Ru and Ir have proved tobe the most effective catalysts for the a-alkylation of ketones withalcohols.8
Our interest in developing new catalysts to adjust transitionmetal reactivity9,10 has led to the recent discovery of CNP iridiumcomplexes. We have synthesized the CNP iridium complexes withphosphine ligand and non-coordinating anion (Scheme 3).11 Herewe reported that a-alkylation of ketones with alcohols was real-ized by using iridium–CNP complexes as catalysts through borrow-ing hydrogen reaction with good yields. Compared to theliteratures (especially Zhang’s work with [RuCl2(p-Cymene)]2 ascatalyst), this method does not need the expensive Xantphos asligand but slightly enhanced yields obtained. Also, the experimentsshowed that no transfer hydrogenation product was detected andiridium–CNP complexes are effective catalysts for borrowinghydrogen reaction without any interference from transferhydrogenation.
Given such considerations, the reaction of acetophenone withbenzyl alcohol was chosen as a model reaction by which to evaluatethe influence of various benzothienyl skeleton phosphine ligandiridium(III) catalysts. First we examined the iridium complexes withtoluene as a solvent. The results showed that the yield of the productwith catalyst 2b was slightly higher than other cationic iridium(III)compounds, but the yield was not satisfactory in toluene (Table 1,
O
R1 OHR2O
R1 R2
+
OH
R1 OR2+
Alkylation
TransferhydrogenationR3
R3
R3
Scheme 2. Transfer hydrogenation versus a-alkylation of ketones with alcohols.
Table 2Alkylation of acetophenonea,b
R1 OH+2b 1 mol%, Cs2CO3
t-amyl alcohol, 120 oC3 4 5
O O
R1
5a, 92%
O
5b, 98%
O
5c, 81%
O
O Cl
5d, 81%
ON
5e, 86%
O
N
5f, 83%
O
N
5g,78%
OO
5h, 76%
OS
5i, 63% c
O
5l, 61% c
O
5j, 49% c
O
5k, 42% c
O
a Reagents and conditions: 3 (1.0 mmol), 4 (1.1 mmol), 2b loading (1 mol %),Cs2CO3 (1.0 mmol), tert-amyl alcohol (2 mL), 120 �C, 24 h, N2.
b Isolated yield.c 4 (3.0 mmol).
Table 3Alkylation of ketonesa,b
OH+
2b 1 mol%, Cs2CO3
t-amyl alcohol, 120 oC
3 4 5
O O
R1R1R2 R2
5m, 75%
O
N
Cl5n, 87%
O
N
O 5o, 84%
O
N
5p, 83%
O
NO
5q, 81%
O
N
5r, 57%
O
F3C
5s, 69%
ON
O
ON
OCl
ON
O5t, 63% 5u, 73%
O O O
5v, 81% 5w, 83% 5x, 68%
a Reagents and conditions: 3 (1.0 mmol), 4 (1.1 mmol), 2b loading (1 mol %),Cs2CO3 (1.0 mmol), tert-amyl alcohol (2 mL), 120 �C, 24 h, N2.
b Isolated yield.
Table 1Screening of optimized reaction conditions for acetophenone with benzyl alcohola
OH+[Ir], Cs2CO3solvent, 120 oC
3a 4a 5a
O O
Entry Catalyst Solvent Yieldb (%)
1 None Toluene Trace2 [Ir⁄(Bt)2Cl]2 Toluene 173 1a Toluene 424 1b Toluene 515 2a Toluene 696 2b Toluene 797 2c Toluene 778 2d Toluene 769 2b DMSO 3210 2b 1,4-Dioxane 5111 2b tert-Amyl alcohol 9212 2a tert-Amyl alcohol 8513 2c tert-Amyl alcohol 8714 2d tert-Amyl alcohol 8815c 2b tert-Amyl alcohol 92
a Reagents and conditions: acetophenone (1.0 mmol), benzyl alcohol (1.1 mmol),Cat [Ir] loading (1 mol %), Cs2CO3 (1.0 mmol), solvent (2 mL), 120 �C, 24 h, N2.
b Isolated yield.c Cat [Ir] loading (2 mol %).
IrPR3
Cl
S N
2
IrPR3S N
2
X
1 2
1a: R = PPh31b: R = n-Bu2a: R = PPh3, X = OTf2b: R = n-Bu, X = OTf2c: R = n-Bu, X = BF42d: R = n-Bu, X = SbF6
Scheme 3. Benzothienyl skeleton Ir(III)–CNP complexes.
7234 D. Wang et al. / Tetrahedron Letters 55 (2014) 7233–7235
entries 3–8). Other solvents, such as DMSO, 1,4-dioxane were foundto have no promise, but fortunately the yield was increased whiletert-amyl alcohol added to the reaction (Table 1, entries 9–11). Itshould be noted that nearly all the catalysts with coordination aniongave excellent yields (Table 1, entries 12–14).
Encouraged by the promising results, we further employed theabove methods to acetophenone and various alcohols. Theobtained results are summarized in Table 2. The effect of substitu-ents on the aromatic ring of alcohol has also been explored, andacetophenone with benzyl alcohols with an electron-donating oran electron-withdrawing substituent proceeded in moderate togood yield (Table 2, see 5a–c). It was found that the substitutionpatterns of pyridyl methanol substrates have little influence onthe formation of desired products (Table 2, see 5d–f). And furyl-,thienyl-heterocyclic alcohols could react under the optimal reac-tion conditions with gratifying yield (Table 2, see 5g–h).
In addition to the aromatic alcohol employed, linear andbranched chain aliphatic alcohols were also employed for the a-alkylation reactions. We have chosen iso-octyl alcohol, isobutanol,1-pentanol, and n-propanol as representatives (Table 2, see 5i–5l).
The corresponding target products were all separated smoothly,while the yields were significantly lower than those of aromaticalcohol. It should be noted that excess aliphatic alcohols are usu-ally needed in the reaction, which is probably caused by their easyvolatility.
Table 4The alkylation of acetophenone with alcohol under solvent-free conditionsa,b
R1 OH+2b (1 mol%)
3 4 5
O O
R1Cs2CO3, reflux
5g, 74%
OO
5a, 86%
O
5i, 65%
O
5l, 73%
O
5j, 61%
O
5k, 52%
O
a Reagents and conditions: 3 (1.0 mmol), 4 (2 mL), 2b loading (1 mol %), Cs2CO3
(1.0 mmol), reflux, 24 h, N2.b Isolated yield.
D. Wang et al. / Tetrahedron Letters 55 (2014) 7233–7235 7235
The reaction of different substituted aromatic ketones with aro-matic alcohols was studied (Table 3). The results showed that dif-ferent alkylated ketones were obtained in good yields by using thecatalyst 2b. The reaction had good substituent tolerance. The sub-stituents having different electronic properties on the aryl ring ofacetophenones significantly affected the reaction yields. Generally,acetophenones possessing electron-donating groups gave the cor-responding products in higher yields (Table 3, see 5n, 5o, 5p, 5q,and 5u) as compared to electron-poor ones (Table 2, see 5m, and5t). Notably benzyl alcohol with 1-[4-(trifluoromethyl)phenyl]eth-anol afforded only 57% yield of the desired product. We attributedthis result to the trifluoromethyl strong electron withdrawal(Table 3, see 5r). A similar trend was also observed by Zhanggroup,8g and they figured out that it was due to the decompositionof ketone starting materials.
Moreover, the borrowing hydrogen reaction of acetophenonewith alcohols was also examined under solvent-free conditions.To our surprise, all the acetophenones were converted to their cor-responding ketones with moderate to good yields (Table 4). Thisreaction under solvent-free conditions provides an effective, greenmethod for the alkylation of ketones with alcohols.
Conclusions
In conclusion, a highly efficient CAC bond formation was devel-oped through the a-alkylation of ketones with primary alcohols.The corresponding functionalized ketones were obtained with irid-ium–CNP complex as a catalyst through borrowing hydrogen reac-tion, and the substrate scope was wide. The pyridyl methanols andother heterocyclic substituted methanols, especially alkyl alcohols,were also suitable for this transformation. The present methodol-ogy provides an easy alternative route to aldol reaction derivatives.
Acknowledgments
We gratefully acknowledge financial support of this work by theNational Natural Science Foundation of China (21401080,21371080), the Natural Science Foundation of Jiangsu Province ofChina (BK20130125), China Postdoctoral Science Foundation(2014M550262) and MOE & SAFEA for the 111 Project (B13025).
Supplementary data
Supplementary data associated with this article can be found, in theonline version, at http://dx.doi.org/10.1016/j.tetlet.2014.11.034.
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