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Article
Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones Xing-Ping Zeng, Zhong-Yan Cao, Xin Wang, Long Chen, Feng Zhou, Feng Zhu, Cui-Hong Wang, and Jian Zhou J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11476 • Publication Date (Web): 11 Dec 2015 Downloaded from http://pubs.acs.org on December 12, 2015
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Journal of the American Chemical Society
Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones Xing-Ping Zeng,1 Zhong-Yan Cao,1 Xin Wang,2 Long Chen,1 Feng Zhou,1 Feng Zhu,1 Cui-Hong Wang,1 and Jian Zhou*1,3 1
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, P R China; 2College of Chemistry, Sichuan University, Chengdu, 610064, P R China; 3State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China.
ABSTRACT: Phosphoranes 2 are identified as a type of effective Lewis bases to activate chiral (salen)AlCl complex 1 to enhance its electrophilicity. Accordingly, a three-component catalyst system consisting of complex 1, phosphorane 2e and Ph3PO is developed as a powerful tool for asymmetric ketone cyanosilylation. In particular, an unprecedented highly enantioselective cyanosilylation of linear aliphatic ketones is achieved. A tandem Wittig-cyanosilylation sequence starting from phosphorane 2a and enals 10 is further achieved, which internally utilizes byproduct Ph3PO and remaining phosphorane 2a as co-catalysts for cyanosilylation of α,β,γ,δunsaturated enones, providing an atom-efficient access to valuable chiral conjugated dienes and enynes. The high efficiency of the cyanosilylation originates from orthogonal activation of both (salen)AlCl complex 1 and TMSCN by phosphorane and Ph3PO, respectively. This mechanistic insight is supported by NMR, MS, react IR analysis and DFT calculations. Furthermore, the formation of charged complexes through the activation of chiral complex 1 by phosphorane 2a is confirmed by electrical conductivity experiments. ■ INTRODUCTION
To enhance the Lewis acidity of the metal centre of a chiral metal complex often plays an important role in achieving a high catalytic activity for reaction development. In this context, a routine and powerful strategy is to introduce weakly or non-coordinating anions to secure high electrophilicity of a chiral metal complex.1 It is also possible to use an achiral Lewis basic cocatalyst to activate a chiral metal complex, but this conceptually different strategy is much less explored,2 possibly because such a type of ligand-accelerated catalysis 3 contradicts commonly held views that the binding of a Lewis base to a chiral metal complex will lead to reduced Lewis acidity.4 According to the Lewis base catalysis defined by Denmark,5 the activation of a chiral 1 ACS Paragon Plus Environment
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metal complex by a Lewis base may originate from a re-distribution of electron-density in the resulting Lewis adduct, which polarizes adjacent bonds to form a hypervalent species with enhanced Lewis acidity. 6 Given polarization strong enough, ionization may occur to produce cationic species with greatly enhanced electrophilicity. Therefore, it is interesting and rewarding to exploit powerful Lewis bases to effectively activate easily available chiral metal complexes, to improve catalytic activity and enantioselection. In addition, two intriguing beneficial effects may be brought about: (1) Along with the activation of chiral metal complex for better electrophilic activation, it is still possible to use a second co-catalyst to activate the nucleophile. Such an orthogonal activation 7 is promising to develop reactions unattainable by common cooperative catalysis8 in which the chiral catalyst is not activated. (2) It offers the promise to identify new ligand motifs, as the structural feature of a powerful co-catalyst is useful to develop new chiral ligands. Herein, we wish to report that phosphorane 2 can effectively activate chiral (salen)AlCl complex 19, a privileged catalyst 10 easy to prepare and handle, which contributes to a highly enantioselective cyanosilylation of simple ketones and conjugated enones. Since its discovery by Jacobsen et al, chiral catalyst 1 has proved to be valuable in a handful of important reactions,9,11 including Strecker reaction,9 conjugate addition,11a-f Friedel-Crafts11g and Passerini-type reaction11h-j. Despite significant achievements, it is still important to enhance the Lewis acidity of this neutral complex to expand its application. For example, it alone failed to catalyze ketone cyanosilylation.12 With the cooperative activation of TMSCN by Ph3PO to form a more active species Ph3P(OTMS)(N=C:),13 Kim et al used complex 1 to realize an asymmetric ketone cyanosilylation, but the enantioselectivity had ample room to improve.12 Based on this work, we further developed a highly enantioselective tandem Wittig-cyanosilylation sequence, aiming at recycling Ph3PO to cooperate with complex 1 for cyanosilylation of enone 4 (A, Scheme 1).14 However, subsequent studies revealed the high efficiency of cyanosilylation step was attributed to orthogonal activation of chiral complex 1 and TMSCN by phosphorane 2a and Ph3PO, respectively (B, Scheme 1). This not only suggests the potential of phosphoranes as a type of ligand motifs to develop chiral metal catalysts,15 an untrodden path in the chemistry of ylides, but paves the way to a powerful catalyst system consisting of (salen)AlCl complex 1, phosphorane 2e and Ph3PO for asymmetric ketone cyanosilylation. It is worth mentioning that owing to the importance of cyanohydrins as precursors to tetrasubstituted α-hydroxy carbonyl derivatives, much effort has been devoted to cyanation of ketones. 16 However, while several outstanding catalyst systems have been devised for highly enantioselective cyanosilylation of alkyl aryl ketones,17 linear aliphatic ketones still present a challenge as a substrate class, and the newly identified catalyst system first enables the transformation of a number of linear aliphatic ketones to the corresponding cyanohydrins in excellent enantioselectivity (≥90% ee). 2 ACS Paragon Plus Environment
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Journal of the American Chemical Society
Scheme 1. Asymmetric tandem Wittig-cyanosilylation reaction
O Ph3P
+
2a (1.0 equiv)
OTMS
O R
Wittig Reaction
H
Asymmetric Cyanosilylation
R
3 (R = Ar or n-Pr)
R = Ar, 71-97%, 68-93% ee R = n-Pr, 66%, 75% ee
Note: complex 1 and TMSCN were added after the completion of the Wittig step.
N
N Al O Cl O
t-Bu
t-Bu
O 3 (1.0 equiv)
+
R
CH2Cl2, 80 oC
t-Bu
Ph3PO
4
t-Bu
B) Asymmetric orthogonal activation (this work)
R
O t-Bu
Al Cl
R OTMS
O
N
(R,R)-1 (5-10 mol %)
TMSCN (2.0 equiv), -30 oC
A) Previously assumed cooperative activation
t-Bu
CN 5
t-Bu
CN PPh3
N O
t-Bu
t-Bu
Cl
O t-Bu
Al O
Ph3P
OTMS
O
N
CN PPh3
N O
t-Bu
t-Bu
■ RESULTS AND DISCUSSION Mechanistic Studies. The reaction of α,β,γ,δ-unsaturated enone 6a and TMSCN was first undertaken to probe the role of each component of the catalytic system (Table 1). As expected, no reaction took place in the presence of either chiral complex 1 or Ph3PO at 25 oC (entries 1-2). Ph3PO was used in 100 mol % to mimic the condition in tandem Wittig-cyanosilylation reaction. However, it was very surprising that the merging of 10 mol % complex 1 and 100 mol % Ph3PO was also inefficient to promote the cyanosilylation at -30 oC, the previously used condition,14 giving product 7a in less than 5% yield even after 36 h (entry 3). Considering that in the tandem protocol, there might be some phosphorane 2a remaining from the Wittig step, 10 mol % 2a was added, and the reaction was indeed dramatically accelerated to give product 7a in 90% yield and 92% ee (entry 4). To understand the role of phosphorane, more control experiments were conducted. First, it was surprising that the use of 10 mol % phosphorane 2a mediated the reaction efficiently at -30 oC to give 7a in 92% yield (entry 5). To the best of our knowledge, phosphorane as an organic promoter to trigger a reaction is unprecedented.18 Second, without the cooperation of Ph3PO, the merger of complex 1 and 2a (10 mol %, each) catalyzed the reaction inefficiently at 25 oC to give 7a in 43% yield with 65% ee after 36 h, and poorly at -30 oC (entries 6-7). These experiments implied that phosphorane 2a coordinated to complex 1 to form an enhanced chiral aluminum catalyst (R,R)-1/2a (entry 1 vs 6); otherwise, free phosphorane would cause severe 3 ACS Paragon Plus Environment
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racemic background reaction. On the other hand, the presence of Ph3PO was also important to secure high reactivity and enantioselectivity, as the Lewis adduct (R,R)-1/2a was impotent to mediate the reaction efficiently by itself at -30 oC (entries 7). Table 1. Control experiments for asymmetric cyanosilylation of enone 6aa
a
Entry
1 (X)
2a (Y)
Ph3PO (Z)
Temp. (oC)
Yield (%)b
Ee (%)c
1
10
--
--
25
no reaction
--
2
--
--
100
25
no reaction
3
10
--
100
-30
Article
Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones Xing-Ping Zeng, Zhong-Yan Cao, Xin Wang, Long Chen, Feng Zhou, Feng Zhu, Cui-Hong Wang, and Jian Zhou J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11476 • Publication Date (Web): 11 Dec 2015 Downloaded from http://pubs.acs.org on December 12, 2015
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 19
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Journal of the American Chemical Society
Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones Xing-Ping Zeng,1 Zhong-Yan Cao,1 Xin Wang,2 Long Chen,1 Feng Zhou,1 Feng Zhu,1 Cui-Hong Wang,1 and Jian Zhou*1,3 1
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, P R China; 2College of Chemistry, Sichuan University, Chengdu, 610064, P R China; 3State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China.
ABSTRACT: Phosphoranes 2 are identified as a type of effective Lewis bases to activate chiral (salen)AlCl complex 1 to enhance its electrophilicity. Accordingly, a three-component catalyst system consisting of complex 1, phosphorane 2e and Ph3PO is developed as a powerful tool for asymmetric ketone cyanosilylation. In particular, an unprecedented highly enantioselective cyanosilylation of linear aliphatic ketones is achieved. A tandem Wittig-cyanosilylation sequence starting from phosphorane 2a and enals 10 is further achieved, which internally utilizes byproduct Ph3PO and remaining phosphorane 2a as co-catalysts for cyanosilylation of α,β,γ,δunsaturated enones, providing an atom-efficient access to valuable chiral conjugated dienes and enynes. The high efficiency of the cyanosilylation originates from orthogonal activation of both (salen)AlCl complex 1 and TMSCN by phosphorane and Ph3PO, respectively. This mechanistic insight is supported by NMR, MS, react IR analysis and DFT calculations. Furthermore, the formation of charged complexes through the activation of chiral complex 1 by phosphorane 2a is confirmed by electrical conductivity experiments. ■ INTRODUCTION
To enhance the Lewis acidity of the metal centre of a chiral metal complex often plays an important role in achieving a high catalytic activity for reaction development. In this context, a routine and powerful strategy is to introduce weakly or non-coordinating anions to secure high electrophilicity of a chiral metal complex.1 It is also possible to use an achiral Lewis basic cocatalyst to activate a chiral metal complex, but this conceptually different strategy is much less explored,2 possibly because such a type of ligand-accelerated catalysis 3 contradicts commonly held views that the binding of a Lewis base to a chiral metal complex will lead to reduced Lewis acidity.4 According to the Lewis base catalysis defined by Denmark,5 the activation of a chiral 1 ACS Paragon Plus Environment
Journal of the American Chemical Society
1 2 3 4 5 6 7 8 9 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
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metal complex by a Lewis base may originate from a re-distribution of electron-density in the resulting Lewis adduct, which polarizes adjacent bonds to form a hypervalent species with enhanced Lewis acidity. 6 Given polarization strong enough, ionization may occur to produce cationic species with greatly enhanced electrophilicity. Therefore, it is interesting and rewarding to exploit powerful Lewis bases to effectively activate easily available chiral metal complexes, to improve catalytic activity and enantioselection. In addition, two intriguing beneficial effects may be brought about: (1) Along with the activation of chiral metal complex for better electrophilic activation, it is still possible to use a second co-catalyst to activate the nucleophile. Such an orthogonal activation 7 is promising to develop reactions unattainable by common cooperative catalysis8 in which the chiral catalyst is not activated. (2) It offers the promise to identify new ligand motifs, as the structural feature of a powerful co-catalyst is useful to develop new chiral ligands. Herein, we wish to report that phosphorane 2 can effectively activate chiral (salen)AlCl complex 19, a privileged catalyst 10 easy to prepare and handle, which contributes to a highly enantioselective cyanosilylation of simple ketones and conjugated enones. Since its discovery by Jacobsen et al, chiral catalyst 1 has proved to be valuable in a handful of important reactions,9,11 including Strecker reaction,9 conjugate addition,11a-f Friedel-Crafts11g and Passerini-type reaction11h-j. Despite significant achievements, it is still important to enhance the Lewis acidity of this neutral complex to expand its application. For example, it alone failed to catalyze ketone cyanosilylation.12 With the cooperative activation of TMSCN by Ph3PO to form a more active species Ph3P(OTMS)(N=C:),13 Kim et al used complex 1 to realize an asymmetric ketone cyanosilylation, but the enantioselectivity had ample room to improve.12 Based on this work, we further developed a highly enantioselective tandem Wittig-cyanosilylation sequence, aiming at recycling Ph3PO to cooperate with complex 1 for cyanosilylation of enone 4 (A, Scheme 1).14 However, subsequent studies revealed the high efficiency of cyanosilylation step was attributed to orthogonal activation of chiral complex 1 and TMSCN by phosphorane 2a and Ph3PO, respectively (B, Scheme 1). This not only suggests the potential of phosphoranes as a type of ligand motifs to develop chiral metal catalysts,15 an untrodden path in the chemistry of ylides, but paves the way to a powerful catalyst system consisting of (salen)AlCl complex 1, phosphorane 2e and Ph3PO for asymmetric ketone cyanosilylation. It is worth mentioning that owing to the importance of cyanohydrins as precursors to tetrasubstituted α-hydroxy carbonyl derivatives, much effort has been devoted to cyanation of ketones. 16 However, while several outstanding catalyst systems have been devised for highly enantioselective cyanosilylation of alkyl aryl ketones,17 linear aliphatic ketones still present a challenge as a substrate class, and the newly identified catalyst system first enables the transformation of a number of linear aliphatic ketones to the corresponding cyanohydrins in excellent enantioselectivity (≥90% ee). 2 ACS Paragon Plus Environment
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Journal of the American Chemical Society
Scheme 1. Asymmetric tandem Wittig-cyanosilylation reaction
O Ph3P
+
2a (1.0 equiv)
OTMS
O R
Wittig Reaction
H
Asymmetric Cyanosilylation
R
3 (R = Ar or n-Pr)
R = Ar, 71-97%, 68-93% ee R = n-Pr, 66%, 75% ee
Note: complex 1 and TMSCN were added after the completion of the Wittig step.
N
N Al O Cl O
t-Bu
t-Bu
O 3 (1.0 equiv)
+
R
CH2Cl2, 80 oC
t-Bu
Ph3PO
4
t-Bu
B) Asymmetric orthogonal activation (this work)
R
O t-Bu
Al Cl
R OTMS
O
N
(R,R)-1 (5-10 mol %)
TMSCN (2.0 equiv), -30 oC
A) Previously assumed cooperative activation
t-Bu
CN 5
t-Bu
CN PPh3
N O
t-Bu
t-Bu
Cl
O t-Bu
Al O
Ph3P
OTMS
O
N
CN PPh3
N O
t-Bu
t-Bu
■ RESULTS AND DISCUSSION Mechanistic Studies. The reaction of α,β,γ,δ-unsaturated enone 6a and TMSCN was first undertaken to probe the role of each component of the catalytic system (Table 1). As expected, no reaction took place in the presence of either chiral complex 1 or Ph3PO at 25 oC (entries 1-2). Ph3PO was used in 100 mol % to mimic the condition in tandem Wittig-cyanosilylation reaction. However, it was very surprising that the merging of 10 mol % complex 1 and 100 mol % Ph3PO was also inefficient to promote the cyanosilylation at -30 oC, the previously used condition,14 giving product 7a in less than 5% yield even after 36 h (entry 3). Considering that in the tandem protocol, there might be some phosphorane 2a remaining from the Wittig step, 10 mol % 2a was added, and the reaction was indeed dramatically accelerated to give product 7a in 90% yield and 92% ee (entry 4). To understand the role of phosphorane, more control experiments were conducted. First, it was surprising that the use of 10 mol % phosphorane 2a mediated the reaction efficiently at -30 oC to give 7a in 92% yield (entry 5). To the best of our knowledge, phosphorane as an organic promoter to trigger a reaction is unprecedented.18 Second, without the cooperation of Ph3PO, the merger of complex 1 and 2a (10 mol %, each) catalyzed the reaction inefficiently at 25 oC to give 7a in 43% yield with 65% ee after 36 h, and poorly at -30 oC (entries 6-7). These experiments implied that phosphorane 2a coordinated to complex 1 to form an enhanced chiral aluminum catalyst (R,R)-1/2a (entry 1 vs 6); otherwise, free phosphorane would cause severe 3 ACS Paragon Plus Environment
Journal of the American Chemical Society
1 2 3 4 5 6 7 8 9 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
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racemic background reaction. On the other hand, the presence of Ph3PO was also important to secure high reactivity and enantioselectivity, as the Lewis adduct (R,R)-1/2a was impotent to mediate the reaction efficiently by itself at -30 oC (entries 7). Table 1. Control experiments for asymmetric cyanosilylation of enone 6aa
a
Entry
1 (X)
2a (Y)
Ph3PO (Z)
Temp. (oC)
Yield (%)b
Ee (%)c
1
10
--
--
25
no reaction
--
2
--
--
100
25
no reaction
3
10
--
100
-30
