Chemo and enantioselective addition of grignard reagents to ketones and enolizable
ketimines
Ortiz, Pablo
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Publication date: 2017
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Ortiz, P. (2017). Chemo and enantioselective addition of grignard reagents to ketones and enolizable ketimines. University of Groningen.
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Non gogoa, han zangoa
[Where the mind goes the body follows] Basque proverb
N-sulfonyl imines are widely used as substrates for a range of transformations. Access to N-sulfonyl aldimines is straightforward through direct condensation between the parent aldehyde and the sulfonamide. However, this approach is not efficient for the synthesis of enolizable N-sulfonyl ketimines. This chapter describes a rapid and facile methodology for obtaining these products using microwave irradiation.
Chapter 6:
Direct Synthesis of Enolizable N-Sulfonyl Ketimines
Under Microwave Irradiation
Part of this chapter has been published:
6.1. Introduction
The carbonyl group is arguably the most important functional group in synthetic chemistry due to the numerous transformations it can undergo. Its analogous C=N bond is not less relevant, especially considering the widespread applications of imines in organic synthesis. However, contrary to their carbonyl counterparts (aldehydes and ketones), imines are less stable and seldom commercially available, and therefore they usually have to be synthesized.
Among the various types, N-sulfonyl imines are the most commonly used because of the strong activating power provided by the sulfonyl moiety.[1] As a consequence,
N-sulfonyl imines, in particular N-tosyl imines, are ubiquitous in organic transformations. To name but a few, they have been used as substrates for cycloadditions,[2–6] aziridines[7] and oxazolines[8] preparations, as well as nucleophilic
additions[9–12] and reductions.[13,14]
Due to their widespread use, several methodologies for preparing N-sulfonyl imines have been described. There are a myriad of methods reported for the synthesis of N-sulfonyl aldimines by (Lewis) acid-catalyzed reactions of aldehydes with sulfonamides (Scheme 1, a).[15] These methodologies, however, are generally
not efficient when applied to enolizable ketimines.[16] The lower electrophilicity of the
ketone compared to the aldehyde, together with the relatively low nucleophilic power of sulfonamide, make this transformation difficult (Scheme 1, b).
Scheme 1. Direct synthesis of N-sulfonyl aldimines (a) and ketimines (b).
To overcome the reactivity problem, different strategies have been applied (Scheme 2). Regarding the ketone partner, its transformation into oximes has allowed successful reactions with both sulfinyl chlorides[17,18] and sulfonyl cyanides[19] to
yield N-sulfonyl ketimines (Scheme 2, left). Examples of the opposite approach, involving the modification of the nucleophile, have also been reported:
Sulfinamides, which are more nucleophilic than sulfonamides, have been condensed with the carbonyl group, followed by oxidation to the desired N-sulfonyl ketimine (Scheme 2, top).[20,21] This latter method, developed by Ruano et al., is
generally considered the most reliable method for the synthesis of N-sulfonyl ketimines.[13,14,22–24] Although trustworthy, the method has some significant
drawbacks. It involves the handling of peracids and peroxy compounds and is time consuming, since it requires several synthetic operations such as: 1) the preparation of the sulfinamide (only the enantiopure compound is commercially available) 2) the condensation with the corresponding ketone, requiring 36 h of reflux, and finally 3) the oxidation of the N-sulfinyl imine with m-CPBA.[20,21] In fact, Ruano et
al. acknowledge that “In theory, the ideal procedure for obtaining N-sulfonylimines would involve the condensation of carbonyl compounds with sulfonamides.” [20]
Scheme 2. Strategies for the synthesis of enolizable ketimines. m-CPBA = meta-Chloroperoxybenzoic acid. MWI = Microwave irradiation.
Other routes for the preparation of N-sulfonyl ketimines, such as palladium-catalyzed isomerization of N-tosyl aziridines[25] or an aza-pinacol rearrangement,[26]
have been reported as well (Scheme 2, right). However, these methods are based on starting materials that are not commercially available and require prior synthesis.
6.1. Introduction
The carbonyl group is arguably the most important functional group in synthetic chemistry due to the numerous transformations it can undergo. Its analogous C=N bond is not less relevant, especially considering the widespread applications of imines in organic synthesis. However, contrary to their carbonyl counterparts (aldehydes and ketones), imines are less stable and seldom commercially available, and therefore they usually have to be synthesized.
Among the various types, N-sulfonyl imines are the most commonly used because of the strong activating power provided by the sulfonyl moiety.[1] As a consequence,
N-sulfonyl imines, in particular N-tosyl imines, are ubiquitous in organic transformations. To name but a few, they have been used as substrates for cycloadditions,[2–6] aziridines[7] and oxazolines[8] preparations, as well as nucleophilic
additions[9–12] and reductions.[13,14]
Due to their widespread use, several methodologies for preparing N-sulfonyl imines have been described. There are a myriad of methods reported for the synthesis of N-sulfonyl aldimines by (Lewis) acid-catalyzed reactions of aldehydes with sulfonamides (Scheme 1, a).[15] These methodologies, however, are generally
not efficient when applied to enolizable ketimines.[16] The lower electrophilicity of the
ketone compared to the aldehyde, together with the relatively low nucleophilic power of sulfonamide, make this transformation difficult (Scheme 1, b).
Scheme 1. Direct synthesis of N-sulfonyl aldimines (a) and ketimines (b).
To overcome the reactivity problem, different strategies have been applied (Scheme 2). Regarding the ketone partner, its transformation into oximes has allowed successful reactions with both sulfinyl chlorides[17,18] and sulfonyl cyanides[19] to
yield N-sulfonyl ketimines (Scheme 2, left). Examples of the opposite approach, involving the modification of the nucleophile, have also been reported:
Sulfinamides, which are more nucleophilic than sulfonamides, have been condensed with the carbonyl group, followed by oxidation to the desired N-sulfonyl ketimine (Scheme 2, top).[20,21] This latter method, developed by Ruano et al., is
generally considered the most reliable method for the synthesis of N-sulfonyl ketimines.[13,14,22–24] Although trustworthy, the method has some significant
drawbacks. It involves the handling of peracids and peroxy compounds and is time consuming, since it requires several synthetic operations such as: 1) the preparation of the sulfinamide (only the enantiopure compound is commercially available) 2) the condensation with the corresponding ketone, requiring 36 h of reflux, and finally 3) the oxidation of the N-sulfinyl imine with m-CPBA.[20,21] In fact, Ruano et
al. acknowledge that “In theory, the ideal procedure for obtaining N-sulfonylimines would involve the condensation of carbonyl compounds with sulfonamides.” [20]
Scheme 2. Strategies for the synthesis of enolizable ketimines. m-CPBA = meta-Chloroperoxybenzoic acid. MWI = Microwave irradiation.
Other routes for the preparation of N-sulfonyl ketimines, such as palladium-catalyzed isomerization of N-tosyl aziridines[25] or an aza-pinacol rearrangement,[26]
have been reported as well (Scheme 2, right). However, these methods are based on starting materials that are not commercially available and require prior synthesis.
Another multi-step procedure includes the palladium-catalyzed cross-coupling reaction between organoboronic acids and tosylbenzimidoyl chlorides, which is limited to the synthesis of diaryl tosylimines.[27]
A quick survey of the available methodologies for the synthesis of enolizable N-sulfonyl ketimines makes it apparent that this still remains challenging.[28] As part of
our work on nucleophilic additions to N-sulfonyl ketimines (see chapter 7), we required a reliable and quick procedure for their preparation. Direct condensation of sulfonamides with ketones requires acid catalysis and long reaction times under reflux, due to the overall low reactivity of the reagents. Moreover, this approach generally results in low yields, owing to the kinetic instability and ease of enolization of N-sulfonyl ketimines under harsh reaction conditions. In fact, with the reported methodologies we struggled to get minute amounts of the condensation product 2a (vide infra). We reasoned that microwave irradiation (MWI) could be an alternative strategy to address the issues related to the reactivity of the reagents and the low yields (Scheme 2, bottom). MWI has previously been used for the synthesis of N-sulfinyl imines,[29,30] using the relatively more
nucleophilic sulfinamides. MWI has also been used for the synthesis of N-sulfonyl aldimines starting from the more reactive aldehydes.[31,32]
6.2. Results and discussion
We began our investigation on a model reaction, namely the condensation between acetophenone 1a and p-toluensulfonamide (Ts-NH2), using Ti(OEt)4 as both Lewis
acid and drying agent. Titanium ethoxide was chosen rather than the commonly used chlorides in order to avoid the HCl formed upon quenching, which can catalyze imine hydrolysis. Some of the reported microwave-assisted methods for the synthesis of N-sulfonyl aldimines are run solvent free, [29,31,32] and so was our first
attempt (Table 1, entry 1). In this case the reaction crude was highly viscous and revealed less than 50% conversion to the desired N-sulfonyl imine 2a. Therefore we decided to run the reaction with a solvent (Table 1, entries 2-4). Results were slightly better with dicholoroethane (DCE) than with toluene. However, the environmental impact outweighed the benefits, so the latter was chosen as the reaction solvent for the subsequent studies.
Table 1. Optimization of Reaction Conditions
Reaction conditions: 1a (1 mmol), p-toluensulfonamide, dry solvent (0.5 mL) and Lewis acid (2 equiv.), stirred under microwave irradiation (60 W). [a] Conversion was estimated by 1H
NMR. [b] BF3·OEt2, AlCl3 and ZnCl2 were independently tested. [c] MgSO4 was added. [d] 1
equiv. of Ti(OEt)4 was used.
Next, the effect of different ratios of the reagents on the reaction conversion was tested. Using two equivalents of Ts-NH2 had only a slight, positive impact on the
conversion, (Table 1, entry 5) and further optimization revealed 1.2 equivalent as the optimal excess of the reagent. On the other hand, an excess of 1a had no effect on the conversion. As expected, the reaction outcome was strongly dependent on the temperature at which it was carried out. The conversion rose from to 64% to 80%, and peaked at 92% when running the reaction at 100 oC, 125 oC and 150 oC
respectively (Table 1, entries 6, 7 and 8 respectively). It is worth noting that it takes less than two minutes to reach 150 oC, which is not possible with a standard reflux
Entry Equiv. Ts-NH2 Time (min) Temp. (oC) Lewis acid Solvent Conv.(%)[a]
1 1 120 100 Ti(OEt)4 - 49 2 1 120 100 Ti(OEt)4 Toluene 59 3 1 120 100 Ti(OEt)4 DCE 61 4 1 120 100 Ti(OEt)4 DCM 49 5 2 120 100 Ti(OEt)4 Toluene 64 6 1.2 120 100 Ti(OEt)4 Toluene 64 7 1.2 120 125 Ti(OEt)4 Toluene 80 8 1.2 120 150 Ti(OEt)4 Toluene 92 9 1.2 240 150 Ti(OEt)4 Toluene 94 10 1.2 60 150 Ti(OEt)4 Toluene 93 11 1.2 30 150 Ti(OEt)4 Toluene 89 12 1.2 120 150 Ti(OiPr)4 Toluene 50 13 1.2 120 150 B, Al, Zn[b] Toluene 0 14[c] 1.2 60 150 Ti(OEt)4 Toluene 93 15[d] 1.2 60 150 Ti(OEt)4 Toluene 93
Another multi-step procedure includes the palladium-catalyzed cross-coupling reaction between organoboronic acids and tosylbenzimidoyl chlorides, which is limited to the synthesis of diaryl tosylimines.[27]
A quick survey of the available methodologies for the synthesis of enolizable N-sulfonyl ketimines makes it apparent that this still remains challenging.[28] As part of
our work on nucleophilic additions to N-sulfonyl ketimines (see chapter 7), we required a reliable and quick procedure for their preparation. Direct condensation of sulfonamides with ketones requires acid catalysis and long reaction times under reflux, due to the overall low reactivity of the reagents. Moreover, this approach generally results in low yields, owing to the kinetic instability and ease of enolization of N-sulfonyl ketimines under harsh reaction conditions. In fact, with the reported methodologies we struggled to get minute amounts of the condensation product 2a (vide infra). We reasoned that microwave irradiation (MWI) could be an alternative strategy to address the issues related to the reactivity of the reagents and the low yields (Scheme 2, bottom). MWI has previously been used for the synthesis of N-sulfinyl imines,[29,30] using the relatively more
nucleophilic sulfinamides. MWI has also been used for the synthesis of N-sulfonyl aldimines starting from the more reactive aldehydes.[31,32]
6.2. Results and discussion
We began our investigation on a model reaction, namely the condensation between acetophenone 1a and p-toluensulfonamide (Ts-NH2), using Ti(OEt)4 as both Lewis
acid and drying agent. Titanium ethoxide was chosen rather than the commonly used chlorides in order to avoid the HCl formed upon quenching, which can catalyze imine hydrolysis. Some of the reported microwave-assisted methods for the synthesis of N-sulfonyl aldimines are run solvent free, [29,31,32] and so was our first
attempt (Table 1, entry 1). In this case the reaction crude was highly viscous and revealed less than 50% conversion to the desired N-sulfonyl imine 2a. Therefore we decided to run the reaction with a solvent (Table 1, entries 2-4). Results were slightly better with dicholoroethane (DCE) than with toluene. However, the environmental impact outweighed the benefits, so the latter was chosen as the reaction solvent for the subsequent studies.
Table 1. Optimization of Reaction Conditions
Reaction conditions: 1a (1 mmol), p-toluensulfonamide, dry solvent (0.5 mL) and Lewis acid (2 equiv.), stirred under microwave irradiation (60 W). [a] Conversion was estimated by 1H
NMR. [b] BF3·OEt2, AlCl3 and ZnCl2 were independently tested. [c] MgSO4 was added. [d] 1
equiv. of Ti(OEt)4 was used.
Next, the effect of different ratios of the reagents on the reaction conversion was tested. Using two equivalents of Ts-NH2 had only a slight, positive impact on the
conversion, (Table 1, entry 5) and further optimization revealed 1.2 equivalent as the optimal excess of the reagent. On the other hand, an excess of 1a had no effect on the conversion. As expected, the reaction outcome was strongly dependent on the temperature at which it was carried out. The conversion rose from to 64% to 80%, and peaked at 92% when running the reaction at 100 oC, 125 oC and 150 oC
respectively (Table 1, entries 6, 7 and 8 respectively). It is worth noting that it takes less than two minutes to reach 150 oC, which is not possible with a standard reflux
Entry Equiv. Ts-NH2 Time (min) Temp. (oC) Lewis acid Solvent Conv.(%)[a]
1 1 120 100 Ti(OEt)4 - 49 2 1 120 100 Ti(OEt)4 Toluene 59 3 1 120 100 Ti(OEt)4 DCE 61 4 1 120 100 Ti(OEt)4 DCM 49 5 2 120 100 Ti(OEt)4 Toluene 64 6 1.2 120 100 Ti(OEt)4 Toluene 64 7 1.2 120 125 Ti(OEt)4 Toluene 80 8 1.2 120 150 Ti(OEt)4 Toluene 92 9 1.2 240 150 Ti(OEt)4 Toluene 94 10 1.2 60 150 Ti(OEt)4 Toluene 93 11 1.2 30 150 Ti(OEt)4 Toluene 89 12 1.2 120 150 Ti(OiPr)4 Toluene 50 13 1.2 120 150 B, Al, Zn[b] Toluene 0 14[c] 1.2 60 150 Ti(OEt)4 Toluene 93 15[d] 1.2 60 150 Ti(OEt)4 Toluene 93
system, and the power required for this corresponds to that needed for an office light bulb (60W). Higher temperatures were also tested in an attempt to reach full conversion, but side products became predominant due to decomposition. Extending the reaction time from the standard 2 h to 4 h was not beneficial either. Further optimization indicated that even one hour is sufficient to reach the maximum conversion (Table 1, entries 9 and 10 respectively), but shortening it further had a deleterious effect (Table 1, entry 11).
Finally, we investigated the last reaction parameter remaining, the Lewis acid. The crucial role of Ti(OEt)4 was exemplified when Ti(OiPr)4 and BF3·OEt2 were used
instead. Ti(OiPr)4 resulted in significantly reduced conversion (50% vs 92%, Table 1,
entries 12 and 8). Significantly, with Lewis acids derived from other metals, such as BF3, AlCl3 or ZnCl2, only starting material was recovered (Table 1, entry 13). Adding
extra dehydrating agent (MgSO4) did not have any influence on the conversion.
Importantly, we could lower the number of equivalents of Ti(OEt)4 from 2 to 1
without any impact on the conversion(Table 1, entry 15).
Having solved one of the major issues in the synthesis of enolizable ketimines, namely the conversion, we moved to the next problem: product isolation. The kinetic instability of imines often causes low isolated yields even when the conversion is high. [21,33] Purification by column chromatography using either silica
or neutral aluminium oxide as well as their passivated analogues led to partial hydrolysis of the ketimine product. To overcome this problem we attempted crystallization. Unfortunately, the traces of remaining Ts-NH2 prevented selective
product crystallization. Despite these difficulties encountered in the purification, the acetophenone-derived N-tosyl imine 2a could be obtained with 75% yield after fast column chromatography (Table 2, entry 1).
Next we investigated the scope of the reaction. In order to compare our method with those previously reported, both yields are presented in Table 2. It should be noted that, unfortunately, many of the reports using ketimines do not report the actual yields for their synthesis. We compare our methodology against the reported direct condensation yields (one-step reaction between the ketone and the sulfonamide) as well as against multi-step synthesis protocols, most of which can be attributed to Ruano’s method.[20]
The initial substrate scope involved the synthesis of aryl alkyl ketimines. The presence of electron donating groups (EDG) in the aromatic ring resulted in relatively lower yields of the imine, due to ketone deactivation. Hence, imines 2b and 2c with p-Me and p-OMe substituents, respectively, were isolated in 67% and 62% yields (Table 2, entries 2 and 3 respectively). N-tosyl imine 2d with a more electron rich aromatic ring, such as thiophene, was isolated in a good 70% yield (Table 2, entry 4). Surprisingly, introducing an electron withdrawing group in the aromatic ring did not enhance the conversion. In fact, product 2e was obtained with slightly lower conversion (78%) than in the case of ketones with EDG (Table 2, entry 5). An additional drawback of the activated substrate was more rapid hydrolysis of the corresponding ketimine, leading to only 44% of isolated yield.
To examine the role of sterics, both substrates with ortho substituents in the aromatic ring as well as substrates with bulky alkyl groups, were tested. A methyl group in ortho position was tolerated, providing product 2f with 62% of isolated yield (Table 2, entry 6). The bulkiness of the alkyl moiety had a stronger impact on the reaction outcome. The imine 2g, with a tert-butyl group instead of the methyl of the benchmark acetophenone-derived 2a, was formed in 57% conversion (Table 2, entry 7). Interestingly, isopropyl bearing imine 2h could not be obtained, due to complete tautomerisation to the enamide product. The trend towards enamide formation was also observed when the R2 was Et. The enamide product (15%) was formed next to
the desired product 2i, which was obtained with 42% isolated yield (Table 2, entry 9).
Next we applied the methodology to the synthesis of dialkyl ketimines. N-tosyl imine 2j was obtained in 54% isolated yield (Table 2, entry 10). The product 2k with the bulkier tert-butyl group was obtained in higher yield, 60%, probably due to the less pronounced enolization pathway (Table 2, entry 11). Synthesis of diaryl ketimine was also attempted. N-tosyl imine 2l, derived from benzophenone, was obtained with an excellent yield of 84% (Table 2, entry 12).
system, and the power required for this corresponds to that needed for an office light bulb (60W). Higher temperatures were also tested in an attempt to reach full conversion, but side products became predominant due to decomposition. Extending the reaction time from the standard 2 h to 4 h was not beneficial either. Further optimization indicated that even one hour is sufficient to reach the maximum conversion (Table 1, entries 9 and 10 respectively), but shortening it further had a deleterious effect (Table 1, entry 11).
Finally, we investigated the last reaction parameter remaining, the Lewis acid. The crucial role of Ti(OEt)4 was exemplified when Ti(OiPr)4 and BF3·OEt2 were used
instead. Ti(OiPr)4 resulted in significantly reduced conversion (50% vs 92%, Table 1,
entries 12 and 8). Significantly, with Lewis acids derived from other metals, such as BF3, AlCl3 or ZnCl2, only starting material was recovered (Table 1, entry 13). Adding
extra dehydrating agent (MgSO4) did not have any influence on the conversion.
Importantly, we could lower the number of equivalents of Ti(OEt)4 from 2 to 1
without any impact on the conversion(Table 1, entry 15).
Having solved one of the major issues in the synthesis of enolizable ketimines, namely the conversion, we moved to the next problem: product isolation. The kinetic instability of imines often causes low isolated yields even when the conversion is high. [21,33] Purification by column chromatography using either silica
or neutral aluminium oxide as well as their passivated analogues led to partial hydrolysis of the ketimine product. To overcome this problem we attempted crystallization. Unfortunately, the traces of remaining Ts-NH2 prevented selective
product crystallization. Despite these difficulties encountered in the purification, the acetophenone-derived N-tosyl imine 2a could be obtained with 75% yield after fast column chromatography (Table 2, entry 1).
Next we investigated the scope of the reaction. In order to compare our method with those previously reported, both yields are presented in Table 2. It should be noted that, unfortunately, many of the reports using ketimines do not report the actual yields for their synthesis. We compare our methodology against the reported direct condensation yields (one-step reaction between the ketone and the sulfonamide) as well as against multi-step synthesis protocols, most of which can be attributed to Ruano’s method.[20]
The initial substrate scope involved the synthesis of aryl alkyl ketimines. The presence of electron donating groups (EDG) in the aromatic ring resulted in relatively lower yields of the imine, due to ketone deactivation. Hence, imines 2b and 2c with p-Me and p-OMe substituents, respectively, were isolated in 67% and 62% yields (Table 2, entries 2 and 3 respectively). N-tosyl imine 2d with a more electron rich aromatic ring, such as thiophene, was isolated in a good 70% yield (Table 2, entry 4). Surprisingly, introducing an electron withdrawing group in the aromatic ring did not enhance the conversion. In fact, product 2e was obtained with slightly lower conversion (78%) than in the case of ketones with EDG (Table 2, entry 5). An additional drawback of the activated substrate was more rapid hydrolysis of the corresponding ketimine, leading to only 44% of isolated yield.
To examine the role of sterics, both substrates with ortho substituents in the aromatic ring as well as substrates with bulky alkyl groups, were tested. A methyl group in ortho position was tolerated, providing product 2f with 62% of isolated yield (Table 2, entry 6). The bulkiness of the alkyl moiety had a stronger impact on the reaction outcome. The imine 2g, with a tert-butyl group instead of the methyl of the benchmark acetophenone-derived 2a, was formed in 57% conversion (Table 2, entry 7). Interestingly, isopropyl bearing imine 2h could not be obtained, due to complete tautomerisation to the enamide product. The trend towards enamide formation was also observed when the R2 was Et. The enamide product (15%) was formed next to
the desired product 2i, which was obtained with 42% isolated yield (Table 2, entry 9).
Next we applied the methodology to the synthesis of dialkyl ketimines. N-tosyl imine 2j was obtained in 54% isolated yield (Table 2, entry 10). The product 2k with the bulkier tert-butyl group was obtained in higher yield, 60%, probably due to the less pronounced enolization pathway (Table 2, entry 11). Synthesis of diaryl ketimine was also attempted. N-tosyl imine 2l, derived from benzophenone, was obtained with an excellent yield of 84% (Table 2, entry 12).
Table 2. Substrate scope
Entry Product 2 Yield (Conv.) (%)[a]
Rep. yield of direct condensation (%) [b] Rep. yield of multistep synthesis (%) 1 75 (93) 15-65[15,32,34–37] 75[20] 2 67 (82) - - 3 62 (82) - 61[20] 4 70 (87) - - 5 44 (78) - - 6 62 (79) -[c] -[c] 7 35 (57) -[c] -[c] 8 -[d] -[e] -[e]
Entry Product 2 Yield (Conv.) (%)[a]
Rep. yield of direct condensation (%) [b] Rep. yield of multistep synthesis (%) 9 42 (56) [f] - 45[27] 10 54 (74) - 58[20] 11 60 (84) - 43,[20] 51[26] 12 84 (91) 42-83 [16,35,37,38] 69[20] 13 54 (68) - 63[20] 14 37 (79) -[c] -[c] 15 27 (61) 18[12] -
Reaction conditions: ketone 1a-l (1 mmol), sulfonamide (1.2 mmol), dry toluene (0.5 mL) and Ti(OEt)4 (1 mmol) stirred under microwave irradiation (60 W). [a] Conversion to the imine
product was estimated by 1H NMR. [b] Direct condensation refers to the reaction between the
ketone and the sulfonamide. [c] New compound. [d] Enamide product 2h* was formed and isolated in 61% yield. [e] Not described in the literature. [f] 15% of enamide product was formed.
Table 2. Substrate scope
Entry Product 2 Yield (Conv.) (%)[a]
Rep. yield of direct condensation (%) [b] Rep. yield of multistep synthesis (%) 1 75 (93) 15-65[15,32,34–37] 75[20] 2 67 (82) - - 3 62 (82) - 61[20] 4 70 (87) - - 5 44 (78) - - 6 62 (79) -[c] -[c] 7 35 (57) -[c] -[c] 8 -[d] -[e] -[e]
Entry Product 2 Yield (Conv.) (%)[a]
Rep. yield of direct condensation (%) [b] Rep. yield of multistep synthesis (%) 9 42 (56) [f] - 45[27] 10 54 (74) - 58[20] 11 60 (84) - 43,[20] 51[26] 12 84 (91) 42-83 [16,35,37,38] 69[20] 13 54 (68) - 63[20] 14 37 (79) -[c] -[c] 15 27 (61) 18[12] -
Reaction conditions: ketone 1a-l (1 mmol), sulfonamide (1.2 mmol), dry toluene (0.5 mL) and Ti(OEt)4 (1 mmol) stirred under microwave irradiation (60 W). [a] Conversion to the imine
product was estimated by 1H NMR. [b] Direct condensation refers to the reaction between the
ketone and the sulfonamide. [c] New compound. [d] Enamide product 2h* was formed and isolated in 61% yield. [e] Not described in the literature. [f] 15% of enamide product was formed.
Finally, to assess the viability of the method for the synthesis of other N-sulfonyl imine derivatives, the influence of the substituent in the sulfonamide (R3) moiety
was investigated. Replacing the aryl with an alkyl group in the sulfonamide decreased the reactivity of the corresponding Ts-NH2, and the
acetophenone-derived tert-butyl N-sulfonyl imine 2m, as well as methyl N-sulfonyl imine 2n, were obtained in 54% and 37% yields, respectively (Table 2, entries 13 and 14). As expected, the synthesis of N-sulfonylmesityl imine 2o provided the product with a modest 27% yield, but this is nevertheless significantly higher than what is possible with the previously reported method (Table 2, entry 15). [12]
Although broader than other reported methodologies, there were still some substrates that proved unreactive towards the formation of p-toluensulfonyl imines (Figure 1). Very activated ketones, for their very same nature, were too reactive and would give a messy crude or, if the desired compound could was formed, it would decompose back to the starting materials during the purification. The “most” activated substrate that we were able to use was para-Cl acetophenone 1e, as mentioned above (table 2). Conjugated ketones gave very little conversion, probably due to the competing reactivity of the conjugated double bond (Figure 1). Finally, N,N-dimethylsulfamoyl protected imine could not be synthesized.
Figure 1. Problematic substrates.
Most yields lie in the moderate to good range, but it should be noted that these surpass the yields of all previous methods based on direct condensations. When compared to Ruano’s[20] and other multistep syntheses,[26,27] this one-step synthesis
provides similar yields, using an operationally far simpler procedure, reduced amounts of reagents, and remarkably shorter reaction times (Scheme 2). To further prove the synthetic utility of the methodology we scaled up the synthesis to 6.5 mmol of acetophenone 1a which afforded 1.2 g of N-tosyl imine product 2a (66% yield).
6.3. Conclusion
In summary, we have developed a simple and rapid method for the synthesis of N-sulfonyl ketimines, via direct condensation of ketones and sulfonamides, assisted by MWI. Microwave-assisted synthesis of imines from the commercially available ketones and sulfonamides allows to complete the transformation in one hour, with minimal environmental impact, both in terms of energy and solvent use: no chlorinated solvents and no reflux. The formation of N-sulfonyl ketimines reported here represents the first alternative to multistep procedures based on the formation of N-sulfinyl imines, furnishing the products in similar yields, with the additional advantages of using commercially available reagents, a one-step procedure, lower energy consumption and shorter reaction times.
6.4. Experimental section 6.4.1. General information
Reagents and substrates were purchased from commercial sources and used as received. Titanium (IV) ethoxide technical grade was used. Dry solvents were collected from a dry solvent purification system. Microwave reactions were performed with a CEM Discover SP W/Activent Unit (CEM Corp., Matthews, NC) with a continuous focused microwave power delivery system in a pressure glass vessel (10 or 35 mL) closed with an Activent™ cap under magnetic stirring. Reactions were temperature controlled, for which the MW unit adjusted the power used (maximum 60 W). The temperature of the reaction mixture was monitored using a calibrated infrared temperature control under the reaction vessel, and the pressure was controlled with Activent™ pressure control system. The experiments were carried out without the need of inert atmosphere. Reactions were monitored by 1H NMR. Purification of the products, when necessary, was performed by
column chromatography using Merck 60 Å 230-400 mesh silica gel. NMR data was collected on Varian VXR400 (1H at 400.0 MHz; 13C at 101 MHz), equipped with a 5
mm z-gradient broadband probe. Chemical shifts are reported in parts per million (ppm) relative to residual solvent peak (CDCl3, 1H: 7.26 ppm; 13C: 77.16 ppm).
Coupling constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, d: doublet, dd: doublet of doublets, t: triplet, q: quartet, m:
Finally, to assess the viability of the method for the synthesis of other N-sulfonyl imine derivatives, the influence of the substituent in the sulfonamide (R3) moiety
was investigated. Replacing the aryl with an alkyl group in the sulfonamide decreased the reactivity of the corresponding Ts-NH2, and the
acetophenone-derived tert-butyl N-sulfonyl imine 2m, as well as methyl N-sulfonyl imine 2n, were obtained in 54% and 37% yields, respectively (Table 2, entries 13 and 14). As expected, the synthesis of N-sulfonylmesityl imine 2o provided the product with a modest 27% yield, but this is nevertheless significantly higher than what is possible with the previously reported method (Table 2, entry 15). [12]
Although broader than other reported methodologies, there were still some substrates that proved unreactive towards the formation of p-toluensulfonyl imines (Figure 1). Very activated ketones, for their very same nature, were too reactive and would give a messy crude or, if the desired compound could was formed, it would decompose back to the starting materials during the purification. The “most” activated substrate that we were able to use was para-Cl acetophenone 1e, as mentioned above (table 2). Conjugated ketones gave very little conversion, probably due to the competing reactivity of the conjugated double bond (Figure 1). Finally, N,N-dimethylsulfamoyl protected imine could not be synthesized.
Figure 1. Problematic substrates.
Most yields lie in the moderate to good range, but it should be noted that these surpass the yields of all previous methods based on direct condensations. When compared to Ruano’s[20] and other multistep syntheses,[26,27] this one-step synthesis
provides similar yields, using an operationally far simpler procedure, reduced amounts of reagents, and remarkably shorter reaction times (Scheme 2). To further prove the synthetic utility of the methodology we scaled up the synthesis to 6.5 mmol of acetophenone 1a which afforded 1.2 g of N-tosyl imine product 2a (66% yield).
6.3. Conclusion
In summary, we have developed a simple and rapid method for the synthesis of N-sulfonyl ketimines, via direct condensation of ketones and sulfonamides, assisted by MWI. Microwave-assisted synthesis of imines from the commercially available ketones and sulfonamides allows to complete the transformation in one hour, with minimal environmental impact, both in terms of energy and solvent use: no chlorinated solvents and no reflux. The formation of N-sulfonyl ketimines reported here represents the first alternative to multistep procedures based on the formation of N-sulfinyl imines, furnishing the products in similar yields, with the additional advantages of using commercially available reagents, a one-step procedure, lower energy consumption and shorter reaction times.
6.4. Experimental section 6.4.1. General information
Reagents and substrates were purchased from commercial sources and used as received. Titanium (IV) ethoxide technical grade was used. Dry solvents were collected from a dry solvent purification system. Microwave reactions were performed with a CEM Discover SP W/Activent Unit (CEM Corp., Matthews, NC) with a continuous focused microwave power delivery system in a pressure glass vessel (10 or 35 mL) closed with an Activent™ cap under magnetic stirring. Reactions were temperature controlled, for which the MW unit adjusted the power used (maximum 60 W). The temperature of the reaction mixture was monitored using a calibrated infrared temperature control under the reaction vessel, and the pressure was controlled with Activent™ pressure control system. The experiments were carried out without the need of inert atmosphere. Reactions were monitored by 1H NMR. Purification of the products, when necessary, was performed by
column chromatography using Merck 60 Å 230-400 mesh silica gel. NMR data was collected on Varian VXR400 (1H at 400.0 MHz; 13C at 101 MHz), equipped with a 5
mm z-gradient broadband probe. Chemical shifts are reported in parts per million (ppm) relative to residual solvent peak (CDCl3, 1H: 7.26 ppm; 13C: 77.16 ppm).
Coupling constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, d: doublet, dd: doublet of doublets, t: triplet, q: quartet, m:
multiplet). Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI.
6.4.2. Procedure for the synthesis of N-sulfonyl imines
A 10 mL microwave vial equipped with a stirrer was charged with the ketone (1 mmol), the sulfonamide (1.2 mmol), dry toluene (0.5 mL) and Ti(OEt)4 (1 mmol). The
vial was closed and heated at 150±C for 1 hour using microwave irradiation (60W). After completion, it was let to cool down to room temperature, diluted with 5 mL of AcOEt, quenched with 1 mL of NaHCO3, and filtered through a pad of celite. The
solvent was evaporated in vacuo and the crude was analysed by 1H NMR.
Conversion was estimated by comparing the integration of signals corresponding to the product and to the unreacted ketone. In the case of volatile ketones the comparison was done against the remaining p-toluensulfonamide. The crude product was purified by flash chromatography on silica gel using mixtures of pentane and AcOEt as the eluent. Except from 2m and 2n, which are oils, the other compounds are white or off-yellow solids. If an oil was obtained after purification, the solid could be obtained by precipitation in Et2O/pentane mixture. For the large
scale reaction, the same procedure was followed using 6.5 mmol of ketone, 7.8 mmol (1.2 equiv.) of p-toluensulfonamide, 6.5 mL of dry toluene and 7.8 mmol (1.2 equiv.) of Ti(OEt)4 reacted in a 35 mL vial.
4-Methyl-N-(1-phenyl-ethylidene)-benzenesulfonamide (2a)
The product was isolated in 75% yield (0.75 mmol, 205.5 mg, starting from 1 mmol of ketone 1a) and 66% yield (4,27 mmol, 1.168 g, starting from 6.5 mmol of ketone 1a) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical data were found to be in
accordance with those reported in the literature.[13,20]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 7.9 Hz, 2H), 7.54 (t,
J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 2.99 (s, 3H), 2.45 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 180.0, 143.7, 138.9, 137.7, 133.3, 129.6, 128.8,
128.4, 127.2, 21.8, 21.3.
4-Methyl-N-(1-(p-tolyl)ethylidene)-benzenesulfonamide (2b)
The product was isolated in 67% yield (0.67 mmol, 193.7 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[13]
1H NMR (CDCl3, 400 MHz): δ d 7.92 (d, J = 8.0 Hz, 2H), 7.79 (d, J= 8.1 Hz, 2H), 7.31
(d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 2.94 (s, 3H), 2.41 (s, 3H), 2.36 (s, 3H). 13C
NMR (CDCl3, 101 MHz): δ 179.6, 144.2, 143.4, 138.8, 134.7, 129.4, 129.3, 128.3, 126.9,
21.5, 21.5, 20.9.
N-[1-(4-Methoxy-phenyl)-ethylidene]-4-methylbenzenesulfonamide (2c)
The product was isolated in 62% yield (0.62 mmol, 189.6 mg) after column chromatography (SiO2, pentane:AcOEt
6:1). The analytical data were found to be in accordance with those reported in the literature.[13,20]
1H NMR (CDCl3, 400 MHz): δ 7.93-7.89 (m, 4H), 7.33 (d, J = 7.9 Hz, 2H), 6.88 (d, J =
9.0 Hz, 2H), 3.84 (s, 3H), 2.93 (s, 3H), 2.43 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ
178.8, 164.0, 143.4, 139.2, 130.8, 130.1, 129.5, 127.1, 114.0, 55.7, 21.7, 20.9.
N-(1-(thiophen-2-yl)ethylidene)-4-methylbenzenesulfonamide (2d)
The product was isolated in 70% yield (0.70 mmol, 194.7 mg) after column chromatography (SiO2, pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[14]
1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 3.7 Hz, 1H), 7.58 (d,
J = 4.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 7.10-7.07 (m, 1H), 2.91 (s, 3H), 2.41 (s, 3H), 13C
NMR (CDCl3, 101 MHz): δ 173.1, 144.0, 143.5, 138.6, 135.1, 133.8, 129.5, 128.6, 127.0,
multiplet). Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI.
6.4.2. Procedure for the synthesis of N-sulfonyl imines
A 10 mL microwave vial equipped with a stirrer was charged with the ketone (1 mmol), the sulfonamide (1.2 mmol), dry toluene (0.5 mL) and Ti(OEt)4 (1 mmol). The
vial was closed and heated at 150±C for 1 hour using microwave irradiation (60W). After completion, it was let to cool down to room temperature, diluted with 5 mL of AcOEt, quenched with 1 mL of NaHCO3, and filtered through a pad of celite. The
solvent was evaporated in vacuo and the crude was analysed by 1H NMR.
Conversion was estimated by comparing the integration of signals corresponding to the product and to the unreacted ketone. In the case of volatile ketones the comparison was done against the remaining p-toluensulfonamide. The crude product was purified by flash chromatography on silica gel using mixtures of pentane and AcOEt as the eluent. Except from 2m and 2n, which are oils, the other compounds are white or off-yellow solids. If an oil was obtained after purification, the solid could be obtained by precipitation in Et2O/pentane mixture. For the large
scale reaction, the same procedure was followed using 6.5 mmol of ketone, 7.8 mmol (1.2 equiv.) of p-toluensulfonamide, 6.5 mL of dry toluene and 7.8 mmol (1.2 equiv.) of Ti(OEt)4 reacted in a 35 mL vial.
4-Methyl-N-(1-phenyl-ethylidene)-benzenesulfonamide (2a)
The product was isolated in 75% yield (0.75 mmol, 205.5 mg, starting from 1 mmol of ketone 1a) and 66% yield (4,27 mmol, 1.168 g, starting from 6.5 mmol of ketone 1a) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical data were found to be in
accordance with those reported in the literature.[13,20]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 7.9 Hz, 2H), 7.54 (t,
J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 2.99 (s, 3H), 2.45 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 180.0, 143.7, 138.9, 137.7, 133.3, 129.6, 128.8,
128.4, 127.2, 21.8, 21.3.
4-Methyl-N-(1-(p-tolyl)ethylidene)-benzenesulfonamide (2b)
The product was isolated in 67% yield (0.67 mmol, 193.7 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[13]
1H NMR (CDCl3, 400 MHz): δ d 7.92 (d, J = 8.0 Hz, 2H), 7.79 (d, J= 8.1 Hz, 2H), 7.31
(d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 2.94 (s, 3H), 2.41 (s, 3H), 2.36 (s, 3H). 13C
NMR (CDCl3, 101 MHz): δ 179.6, 144.2, 143.4, 138.8, 134.7, 129.4, 129.3, 128.3, 126.9,
21.5, 21.5, 20.9.
N-[1-(4-Methoxy-phenyl)-ethylidene]-4-methylbenzenesulfonamide (2c)
The product was isolated in 62% yield (0.62 mmol, 189.6 mg) after column chromatography (SiO2, pentane:AcOEt
6:1). The analytical data were found to be in accordance with those reported in the literature.[13,20]
1H NMR (CDCl3, 400 MHz): δ 7.93-7.89 (m, 4H), 7.33 (d, J = 7.9 Hz, 2H), 6.88 (d, J =
9.0 Hz, 2H), 3.84 (s, 3H), 2.93 (s, 3H), 2.43 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ
178.8, 164.0, 143.4, 139.2, 130.8, 130.1, 129.5, 127.1, 114.0, 55.7, 21.7, 20.9.
N-(1-(thiophen-2-yl)ethylidene)-4-methylbenzenesulfonamide (2d)
The product was isolated in 70% yield (0.70 mmol, 194.7 mg) after column chromatography (SiO2, pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[14]
1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 3.7 Hz, 1H), 7.58 (d,
J = 4.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 7.10-7.07 (m, 1H), 2.91 (s, 3H), 2.41 (s, 3H), 13C
NMR (CDCl3, 101 MHz): δ 173.1, 144.0, 143.5, 138.6, 135.1, 133.8, 129.5, 128.6, 127.0,
N-[1-(4-Chloro-phenyl)-ethylidene]-4-methylbenzenesulfonamide (2e)
The product was isolated in 44% yield (0.44 mmol, 134.1 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[13]
1H NMR (CDCl3, 400 MHz): δ 7.91 (d, J =8.3 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H),
7.38-7.33 (m, 4H), 2.95 (s, 3H), 2.44 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 178.5, 143.8,
139.8, 138.5, 135.9, 129.7, 129.6, 129.0, 127.2, 21.7, 21.1.
4-methyl-N-(1-(o-tolyl)ethylidene)benzenesulfonamide (2f)
The product was isolated in 62% yield (0.62 mmol, 178.9 mg) after column chromatography (SiO2,pentane:AcOEt 10:1).
1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.3 Hz, 2H), 7.40 (d, J =
7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.25-7.18 (m, 3H), 2.93 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 184.2, 143.7, 139.5, 138.4, 136.2, 131.7, 130.7,
129.6, 128.0, 127.2, 126.1, 25.2, 21.7, 20.8. HRMS (ESI+, m/z) calc. for 288.10528 [M+H]+, found 288.10507. M.p. 118-119 ±C.
HRMS (ESI+, m/z) calc. for
N-(2,2-dimethyl-1-phenyl-propylidene)-4-methylbenzenesulfonamide (2g)
The product was isolated in 35% yield (0.35 mmol, 109.0 mg) after column chromatography (SiO2,pentane:AcOEt 10:1).
1H NMR (CDCl3, 400 MHz): δ 7.68 (d, J = 8.3 Hz, 2H), 7.41-7.33 (m,
3H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (dd, J = 7.8, 1.8 Hz, 2H), 2.39 (s, 3H), 1.19 (s, 9H). 13C
NMR (CDCl3, 101 MHz): δ 193.2, 143.2, 138.4, 135.5, 129.3, 128.9, 127.5, 127.2, 126.3,
43.0, 27.9, 21.6. HRMS (ESI+, m/z) calc. for 316.13658[M+H]+, found 316.13612. M.p.
151-152 ±C.
HN SO2p-Tol
4-Methyl-N-(1-phenyl-propylidene)benzenesulfonamide (2i)
The product was isolated in 42% yield (0.42 mmol, 121.6 mg) after column chromatography (SiO2, pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[13]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 7.9 Hz, 2H), 7.53 (t,
J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.47-3.40 (m, 2H), 2.44 (s, 3H), 1.37 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 184.7, 143.5, 139.0,
136.2, 133.1, 129.6, 128.9, 128.7, 127.2, 27.7, 21.7, 13.0.
N-(1,2-Dimethylpropylidine)-p-toluenesulfonamide (2j)
The product was isolated in 54% yield (0.54 mmol, 128.1 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical
data were found to be in accordance with those reported in the literature.[20]
1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.60
(sept, J = 6.8 Hz, 1H), 2.53 (s, 3H), 2.42 (s, 3H), 1.11 (d, J = 6.8 Hz, 6H). 13C NMR
(CDCl3, 101 MHz): δ 193.8, 143.5, 138.7, 129.5, 127.1, 41.6, 22.1, 21.7, 19.4.
N-(1,2,2-Trimethylpropylidine)-p-toluenesulfonamide (2k)
The product was isolated in 60% yield (0.60 mmol, 152.2 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical
data were found to be in accordance with those reported in the literature.[26]
1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.7 Hz, 2H), 2.54 (s,
3H), 2.42 (s, 3H), 1.15 (s, 9H). 13C NMR (CDCl3, 101 MHz): δ 195.3, 143.3, 139.0, 129.5,
N-[1-(4-Chloro-phenyl)-ethylidene]-4-methylbenzenesulfonamide (2e)
The product was isolated in 44% yield (0.44 mmol, 134.1 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[13]
1H NMR (CDCl3, 400 MHz): δ 7.91 (d, J =8.3 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H),
7.38-7.33 (m, 4H), 2.95 (s, 3H), 2.44 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 178.5, 143.8,
139.8, 138.5, 135.9, 129.7, 129.6, 129.0, 127.2, 21.7, 21.1.
4-methyl-N-(1-(o-tolyl)ethylidene)benzenesulfonamide (2f)
The product was isolated in 62% yield (0.62 mmol, 178.9 mg) after column chromatography (SiO2,pentane:AcOEt 10:1).
1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.3 Hz, 2H), 7.40 (d, J =
7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.25-7.18 (m, 3H), 2.93 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 184.2, 143.7, 139.5, 138.4, 136.2, 131.7, 130.7,
129.6, 128.0, 127.2, 126.1, 25.2, 21.7, 20.8. HRMS (ESI+, m/z) calc. for 288.10528 [M+H]+, found 288.10507. M.p. 118-119 ±C.
HRMS (ESI+, m/z) calc. for
N-(2,2-dimethyl-1-phenyl-propylidene)-4-methylbenzenesulfonamide (2g)
The product was isolated in 35% yield (0.35 mmol, 109.0 mg) after column chromatography (SiO2,pentane:AcOEt 10:1).
1H NMR (CDCl3, 400 MHz): δ 7.68 (d, J = 8.3 Hz, 2H), 7.41-7.33 (m,
3H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (dd, J = 7.8, 1.8 Hz, 2H), 2.39 (s, 3H), 1.19 (s, 9H). 13C
NMR (CDCl3, 101 MHz): δ 193.2, 143.2, 138.4, 135.5, 129.3, 128.9, 127.5, 127.2, 126.3,
43.0, 27.9, 21.6. HRMS (ESI+, m/z) calc. for 316.13658[M+H]+, found 316.13612. M.p.
151-152 ±C.
HN SO2p-Tol
4-Methyl-N-(1-phenyl-propylidene)benzenesulfonamide (2i)
The product was isolated in 42% yield (0.42 mmol, 121.6 mg) after column chromatography (SiO2, pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[13]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 7.9 Hz, 2H), 7.53 (t,
J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.47-3.40 (m, 2H), 2.44 (s, 3H), 1.37 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 184.7, 143.5, 139.0,
136.2, 133.1, 129.6, 128.9, 128.7, 127.2, 27.7, 21.7, 13.0.
N-(1,2-Dimethylpropylidine)-p-toluenesulfonamide (2j)
The product was isolated in 54% yield (0.54 mmol, 128.1 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical
data were found to be in accordance with those reported in the literature.[20]
1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.60
(sept, J = 6.8 Hz, 1H), 2.53 (s, 3H), 2.42 (s, 3H), 1.11 (d, J = 6.8 Hz, 6H). 13C NMR
(CDCl3, 101 MHz): δ 193.8, 143.5, 138.7, 129.5, 127.1, 41.6, 22.1, 21.7, 19.4.
N-(1,2,2-Trimethylpropylidine)-p-toluenesulfonamide (2k)
The product was isolated in 60% yield (0.60 mmol, 152.2 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical
data were found to be in accordance with those reported in the literature.[26]
1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.7 Hz, 2H), 2.54 (s,
3H), 2.42 (s, 3H), 1.15 (s, 9H). 13C NMR (CDCl3, 101 MHz): δ 195.3, 143.3, 139.0, 129.5,
N-(Diphenylmethylene)-p-toluenesulfionamide (2l)
The product was isolated in 84% yield (0.84 mmol, 281.7 mg) after column chromatography (SiO2, pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[16,20]
1H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 8.2 Hz, 2H), 7.62-7.35 (m, 10H), 7.29 (d, J =
8.1 Hz, 2H), 2.43 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 178.9, 143.5, 138.7, 129.5,
128.3, 127.5, 21.7.
N-(1-Phenylethylidine)-t-butanesulfonamide (2m)
The product was isolated in 54% yield (0.54 mmol, 129.9 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical
data were found to be in accordance with those reported in the literature.[14,20]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.6, 2H), 2.91 (s, 3H), 1.55 (s, 9H). 13C NMR (CDCl3, 101 MHz): δ 180.5, 137.7, 133.0,
128.7, 128.0, 59.1, 24.0, 21.2.
N-(1-Phenylethylidene)methanesulfonamide (2n)
The product was isolated in 37% yield (0.37 mmol, 73.7 mg) after column chromatography (SiO2,pentane:AcOEt 5:1).
1H NMR (CDCl3, 400 MHz): δ7.92 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.4
Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 3.22 (s, 3H), 2.88 (s, 3H). 13C NMR (CDCl3, 101 MHz):
δ 180.3, 137.3, 133.3, 128.7, 128.2, 43.2, 21.3. HRMS (ESI+, m/z) calc. for 198.05833 [M+H]+, found 198.05843.
N-(1-Phenylethylidene)-2,4,6-trimethylphenylsulfonamide (2o)
The product was isolated in 27% yield (0.27 mmol, 81.1 mg) after column chromatography (SiO2, pentane:AcOEt 5:1). The
analytical data were found to be in accordance with those reported in the literature.[12]
1H NMR (CDCl3, 400 MHz): δ 7.91 (d, J = 7.4 Hz, 2H), 7.53 (t, J =
7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 6.98 (s, 2H), 2.95 (s, 3H), 2.69 (s, 6H) 2.32 (s, 3H).
13C NMR (CDCl3, 101 MHz): δ 179.1, 142.3, 139.0, 137.8, 135.8, 133.1, 131.7, 128.7,
128.3, 22.9, 21.1, 21.1.
4-methyl-N-(2-methyl-1-phenylprop-1-en-1-yl)benzenesulfonamide (2h*)
The product was isolated in 61% yield (0.61 mmol, 182.7 mg) after column chromatography (SiO2,pentane:AcOEt 10:1).
1H NMR (CDCl3, 400 MHz): δ7.47 (d, J = 8.2 Hz, 2H), 7.17-7.7.09
(m, 7 H), 6.48 (s, 1H), 2.36 (s, 3H), 1.71 (s, 3H), 1.66 (s, 3H). 13C NMR (CDCl3, 101
MHz): δ 143.0, 137.6, 137.1, 129.9, 129.8, 129.2, 128.3, 127.7, 127.2, 21.5, 21.3, 20.0. HRMS (ESI+, m/z) calc. for 302.12093 [M+H]+, found 302.1067. M.p. 102-103±C.
6.5. References
[1] A. B. Charette in Chiral Amine Synthesis (Ed.: T. C. Nugent), Wiley-VCH, Weinheim, 2010, pp 1–49.
[2] D. Xie, L. Yang, Y. Lin, Z. Zhang, D. Chen, X. Zeng, G. Zhong, Org. Lett. 2015, 17, 2318-2321.
[3] H.-M. Zhang, W.-Q. Jia, Z.-Q. Liang, S. Ye, Asian J. Org. Chem. 2014, 3, 462-465. [4] B. M. Trost, S. M. Silverman, J. Am. Chem. Soc. 2012, 134, 4941-4954.
[5] B. M. Trost, S. M. Silverman, J. Am. Chem. Soc. 2010, 132, 8238-8240.
[6] A. Kondoh, K. Odaira, M. Terada, Angew. Chem. Int. Ed. 2015, 54, 11240-1244.
[7] N. Giubellina, S. Mangelinckx, K. W. Törnroos, N. De Kimpe, J. Org. Chem. 2006, 71, 5881-5887.
[8] X.-T. Zhou, Y.-R. Lin, L.-X. Dai, J. Sun, L.-J. Xia, M.-H. Tang, J. Org. Chem. 1999, 64, 1331-1334.
[9] S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626-2704. [10] C. Tan, X. Liu, L. Wang, J. Wang, X. Feng, Org. Lett. 2008, 10, 5305-5308.
N-(Diphenylmethylene)-p-toluenesulfionamide (2l)
The product was isolated in 84% yield (0.84 mmol, 281.7 mg) after column chromatography (SiO2, pentane:AcOEt 10:1). The
analytical data were found to be in accordance with those reported in the literature.[16,20]
1H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 8.2 Hz, 2H), 7.62-7.35 (m, 10H), 7.29 (d, J =
8.1 Hz, 2H), 2.43 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 178.9, 143.5, 138.7, 129.5,
128.3, 127.5, 21.7.
N-(1-Phenylethylidine)-t-butanesulfonamide (2m)
The product was isolated in 54% yield (0.54 mmol, 129.9 mg) after column chromatography (SiO2,pentane:AcOEt 10:1). The analytical
data were found to be in accordance with those reported in the literature.[14,20]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.6, 2H), 2.91 (s, 3H), 1.55 (s, 9H). 13C NMR (CDCl3, 101 MHz): δ 180.5, 137.7, 133.0,
128.7, 128.0, 59.1, 24.0, 21.2.
N-(1-Phenylethylidene)methanesulfonamide (2n)
The product was isolated in 37% yield (0.37 mmol, 73.7 mg) after column chromatography (SiO2,pentane:AcOEt 5:1).
1H NMR (CDCl3, 400 MHz): δ7.92 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.4
Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 3.22 (s, 3H), 2.88 (s, 3H). 13C NMR (CDCl3, 101 MHz):
δ 180.3, 137.3, 133.3, 128.7, 128.2, 43.2, 21.3. HRMS (ESI+, m/z) calc. for 198.05833 [M+H]+, found 198.05843.
N-(1-Phenylethylidene)-2,4,6-trimethylphenylsulfonamide (2o)
The product was isolated in 27% yield (0.27 mmol, 81.1 mg) after column chromatography (SiO2, pentane:AcOEt 5:1). The
analytical data were found to be in accordance with those reported in the literature.[12]
1H NMR (CDCl3, 400 MHz): δ 7.91 (d, J = 7.4 Hz, 2H), 7.53 (t, J =
7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 6.98 (s, 2H), 2.95 (s, 3H), 2.69 (s, 6H) 2.32 (s, 3H).
13C NMR (CDCl3, 101 MHz): δ 179.1, 142.3, 139.0, 137.8, 135.8, 133.1, 131.7, 128.7,
128.3, 22.9, 21.1, 21.1.
4-methyl-N-(2-methyl-1-phenylprop-1-en-1-yl)benzenesulfonamide (2h*)
The product was isolated in 61% yield (0.61 mmol, 182.7 mg) after column chromatography (SiO2,pentane:AcOEt 10:1).
1H NMR (CDCl3, 400 MHz): δ7.47 (d, J = 8.2 Hz, 2H), 7.17-7.7.09
(m, 7 H), 6.48 (s, 1H), 2.36 (s, 3H), 1.71 (s, 3H), 1.66 (s, 3H). 13C NMR (CDCl3, 101
MHz): δ 143.0, 137.6, 137.1, 129.9, 129.8, 129.2, 128.3, 127.7, 127.2, 21.5, 21.3, 20.0. HRMS (ESI+, m/z) calc. for 302.12093 [M+H]+, found 302.1067. M.p. 102-103±C.
6.5. References
[1] A. B. Charette in Chiral Amine Synthesis (Ed.: T. C. Nugent), Wiley-VCH, Weinheim, 2010, pp 1–49.
[2] D. Xie, L. Yang, Y. Lin, Z. Zhang, D. Chen, X. Zeng, G. Zhong, Org. Lett. 2015, 17, 2318-2321.
[3] H.-M. Zhang, W.-Q. Jia, Z.-Q. Liang, S. Ye, Asian J. Org. Chem. 2014, 3, 462-465. [4] B. M. Trost, S. M. Silverman, J. Am. Chem. Soc. 2012, 134, 4941-4954.
[5] B. M. Trost, S. M. Silverman, J. Am. Chem. Soc. 2010, 132, 8238-8240.
[6] A. Kondoh, K. Odaira, M. Terada, Angew. Chem. Int. Ed. 2015, 54, 11240-1244.
[7] N. Giubellina, S. Mangelinckx, K. W. Törnroos, N. De Kimpe, J. Org. Chem. 2006, 71, 5881-5887.
[8] X.-T. Zhou, Y.-R. Lin, L.-X. Dai, J. Sun, L.-J. Xia, M.-H. Tang, J. Org. Chem. 1999, 64, 1331-1334.
[9] S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626-2704. [10] C. Tan, X. Liu, L. Wang, J. Wang, X. Feng, Org. Lett. 2008, 10, 5305-5308.
[11] Z. Hou, J. Wang, X. Liu, X. Feng, Chem. Eur. J. 2008, 14, 4484-4486.
[12] S. Nakamura, M. Hayashi, Y. Hiramatsu, N. Shibata, Y. Funahashi, T. Toru, J. Am. Chem. Soc. 2009, 131, 18240-18241.
[13] Q. Yang, G. Shang, W. Gao, J. Deng, X. Zhang, Angew. Chem. Int. Ed. 2006, 45, 3832-3835. [14] S. H. Kwak, S. A. Lee, K.-I. Lee, Tetrahedron Asymmetry 2010, 21, 800-804.
[15] M. A. Zolfigol, M. Tavasoli, A. R. Moosavi-Zare, P. Arghavani-Hadi, A. Zare, V. Khakyzadeh, RSC Adv. 2013, 3, 7692-7696 and references 10-22 therein.
[16] Non enolizable ketimines, such as diaryl ketimines, can be synthesized in good yields: R. N. Ram, A. A. Khan, Synth. Commun. 2001, 31, 841-846.
[17] D. L. Boger, W. L. Corbett, T. T. Curran, A. M. Kasper, J. Am. Chem. Soc. 1991, 113, 1713-1729.
[18] G. D. Artman III, A. Bartolozzi, R. W. Franck, S. M. Weinreb, Synlett 2001, 2001, 232-233. [19] D. L. Boger, W. L. Corbett, J. Org. Chem. 1992, 57, 4777-4780.
[20] J. L. García Ruano, J. Alemán, M. B. Cid, A. Parra, Org. Lett. 2005, 7, 179-182. [21] J. L. García Ruano, J. Alemán, M. B. Cid, A. Parra, Org. Synth. 2007, 84, 129-138. [22] R. Shintani, M. Takeda, Y.-T. Soh, T. Ito, T. Hayashi, Org. Lett. 2011, 13, 2977-2979. [23] R. Shintani, M. Takeda, T. Tsuji, T. Hayashi, J. Am. Chem. Soc. 2010, 132, 13168-13169. [24] A. A. Mikhailine, M. I. Maishan, R. H. Morris, Org. Lett. 2012, 14, 4638-4641. [25] J. P. Wolfe, J. E. Ney, Org. Lett. 2003, 5, 4607-4610.
[26] Y. Sugihara, S. Iimura, J. Nakayama, Chem. Commun. 2002, 134-135.
[27] L.-Y. Fan, F.-F. Gao, W.-H. Jiang, M.-Z. Deng, C.-T. Qian, Org. Biomol. Chem. 2008, 6, 2133-2137.
[28] There is an unoptimized procedure without reported yields (1.5 equiv. of Ts-NH2, and 1.5
equiv. of Ti(OiPr) at toluene reflux for 12 h, together with catalytic ZnCl2) X. Huang, J.
Huang, Y. Wen, X. Feng, Adv. Synth. Catal. 2006, 348, 2579-2584.
[29] J. F. Collados, E. Toledano, D. Guijarro, M. Yus, J. Org. Chem. 2012, 77, 5744-5750. [30] J. Qin, L. Huang, Y. Cao, Z. Sun, RSC Adv. 2014, 5, 7291-7296.
[31] A. Vass, J. Dudás, R. S. Varma, Tetrahedron Lett. 1999, 40, 4951-4954. [32] T. Jin, G. Feng, M. Yang, T. Li, Synth. Commun. 2004, 34, 1277-1283. [33] R. W. Layer, Chem. Rev. 1963, 63, 489-510.
[34] A. Zare, A. R. Moosavi-Zare, A. Hasaninejad, A. Parhami, A. Khalafi-Nezhad, M. H. Beyzavi, Synth. Commun. 2009, 39, 3156-3165.
[35] A. Khalafi-Nezhad, A. Parhami, A. Zare, A. N. Shirazi, A. R. Moosavi Zare, A. Hassaninejad, Can. J. Chem. 2008, 86, 456-461.
[36] R. Matsubara, F.Berthiol, S. Kobayashi, J. Am. Chem. Soc. 2008, 130, 1804-1805.
[37] A. R. Moosavi-Zare, M. A. Zolfigol, E. Noroozizadeh, V. Khakyzadeh, A. Zare, M. Tavasoli, Phosphorus Sulfur Silicon Relat. Elem. 2014, 189, 149-156.
[11] Z. Hou, J. Wang, X. Liu, X. Feng, Chem. Eur. J. 2008, 14, 4484-4486.
[12] S. Nakamura, M. Hayashi, Y. Hiramatsu, N. Shibata, Y. Funahashi, T. Toru, J. Am. Chem. Soc. 2009, 131, 18240-18241.
[13] Q. Yang, G. Shang, W. Gao, J. Deng, X. Zhang, Angew. Chem. Int. Ed. 2006, 45, 3832-3835. [14] S. H. Kwak, S. A. Lee, K.-I. Lee, Tetrahedron Asymmetry 2010, 21, 800-804.
[15] M. A. Zolfigol, M. Tavasoli, A. R. Moosavi-Zare, P. Arghavani-Hadi, A. Zare, V. Khakyzadeh, RSC Adv. 2013, 3, 7692-7696 and references 10-22 therein.
[16] Non enolizable ketimines, such as diaryl ketimines, can be synthesized in good yields: R. N. Ram, A. A. Khan, Synth. Commun. 2001, 31, 841-846.
[17] D. L. Boger, W. L. Corbett, T. T. Curran, A. M. Kasper, J. Am. Chem. Soc. 1991, 113, 1713-1729.
[18] G. D. Artman III, A. Bartolozzi, R. W. Franck, S. M. Weinreb, Synlett 2001, 2001, 232-233. [19] D. L. Boger, W. L. Corbett, J. Org. Chem. 1992, 57, 4777-4780.
[20] J. L. García Ruano, J. Alemán, M. B. Cid, A. Parra, Org. Lett. 2005, 7, 179-182. [21] J. L. García Ruano, J. Alemán, M. B. Cid, A. Parra, Org. Synth. 2007, 84, 129-138. [22] R. Shintani, M. Takeda, Y.-T. Soh, T. Ito, T. Hayashi, Org. Lett. 2011, 13, 2977-2979. [23] R. Shintani, M. Takeda, T. Tsuji, T. Hayashi, J. Am. Chem. Soc. 2010, 132, 13168-13169. [24] A. A. Mikhailine, M. I. Maishan, R. H. Morris, Org. Lett. 2012, 14, 4638-4641. [25] J. P. Wolfe, J. E. Ney, Org. Lett. 2003, 5, 4607-4610.
[26] Y. Sugihara, S. Iimura, J. Nakayama, Chem. Commun. 2002, 134-135.
[27] L.-Y. Fan, F.-F. Gao, W.-H. Jiang, M.-Z. Deng, C.-T. Qian, Org. Biomol. Chem. 2008, 6, 2133-2137.
[28] There is an unoptimized procedure without reported yields (1.5 equiv. of Ts-NH2, and 1.5
equiv. of Ti(OiPr) at toluene reflux for 12 h, together with catalytic ZnCl2) X. Huang, J.
Huang, Y. Wen, X. Feng, Adv. Synth. Catal. 2006, 348, 2579-2584.
[29] J. F. Collados, E. Toledano, D. Guijarro, M. Yus, J. Org. Chem. 2012, 77, 5744-5750. [30] J. Qin, L. Huang, Y. Cao, Z. Sun, RSC Adv. 2014, 5, 7291-7296.
[31] A. Vass, J. Dudás, R. S. Varma, Tetrahedron Lett. 1999, 40, 4951-4954. [32] T. Jin, G. Feng, M. Yang, T. Li, Synth. Commun. 2004, 34, 1277-1283. [33] R. W. Layer, Chem. Rev. 1963, 63, 489-510.
[34] A. Zare, A. R. Moosavi-Zare, A. Hasaninejad, A. Parhami, A. Khalafi-Nezhad, M. H. Beyzavi, Synth. Commun. 2009, 39, 3156-3165.
[35] A. Khalafi-Nezhad, A. Parhami, A. Zare, A. N. Shirazi, A. R. Moosavi Zare, A. Hassaninejad, Can. J. Chem. 2008, 86, 456-461.
[36] R. Matsubara, F.Berthiol, S. Kobayashi, J. Am. Chem. Soc. 2008, 130, 1804-1805.
[37] A. R. Moosavi-Zare, M. A. Zolfigol, E. Noroozizadeh, V. Khakyzadeh, A. Zare, M. Tavasoli, Phosphorus Sulfur Silicon Relat. Elem. 2014, 189, 149-156.
Life is not easy for any of us. But what of that? We must have perseverance and above all confidence in ourselves. We must believe that we are gifted for something and that this thing must be attained.
Marie Curie
This chapter describes the catalytic enantioselective alkylation of enolizable N-sulphonyl ketimines using inexpensive and readily available organomagnesium reagents. The low reactivity and competing enolization of the ketimines is overcome by the use of a Cu-phosphine chiral catalyst, which also renders the transformation highly chemoselective and enantioselective for a broad range of ketimine substrates.
Chapter 7:
Copper-Catalyzed Enantioselective Alkylation of
Enolizable Ketimines with Organomagnesium
Reagents
Part of this chapter has been published:
P. Ortiz, J. F. Collados, R. P. Jumde, E. Otten, S. R. Harutyunyan, Angew. Chem. Int. Ed. 2017, 56, 3041-3044.
J. Rong, J. F. Collados, P. Ortiz, R. P. Jumde, E. Otten, S. R. Harutyunyan, Nat. Commun. 2016, 7, 13780.
