Chemo and enantioselective addition of grignard reagents to ketones and enolizable
ketimines
Ortiz, Pablo
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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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If you're going to try, go all the way. Otherwise, don't even start. Charles Bukowski, Factotum
In this chapter a new strategy to access chiral tertiary diarylmethanols through copper-catalyzed direct alkylation of (di)(hetero)aryl ketones by using Grignard reagents is described. The low reactivity and the similarity of the enantiotopic faces of bis-aromatic ketones were partially overcome, which resulted in moderate to good yields and enantioselectivities of the addition products.
Chapter 2:
Catalytic Asymmetric Alkylation of Aryl Heteroaryl
Ketones
Part of this chapter has been published:
2.1. Introduction
Diarylmethanols and aryl heteroarylmethanols with a tetrasubstituted center in the alpha position to the oxygen are extensively present motives in drugs (Figure 1).[1] To name but a few examples: Tiemonium iodide[2] is an antispasmodic and antimuscarinic drug; Chlorphenoxamine[3] is used as antipruritic and antiparkinsonian; Doxylamine[4] is sold as sedative by itself, and together with other drugs for several indications; Clemastine[5] shows antihistaminic and anticholinergic effects and Escitalopram[6] (Lexapro©, Cipralex©) is one of the most important antidepressants.
Figure 1. Selected medicinally important diaryl- and aryl heteroarylmethanols.
Given their high biomedical applications, development of methods for their preparations is of high interest. In contrast to the enantiopure secondary diarylmethanol core, which can be easily accessed either by nucleophilic addition to aromatic aldehydes[7] or the reduction of diaryl ketones,[8] asymmetric synthesis of tertiary diarylmethanol remains a great challenge.[9]
Several approaches have been explored to access chiral tertiary diarylmethanols, including the recently reported stereoselective synthesis.[10] Nevertheless, the catalytic asymmetric addition of organometallic reagents to a ketone remains the most efficient and simplest approach,[11] and has been extensively explored (Scheme 1, acyclic systems shown). The first reports required the use of diphenylzinc.[12,13] Later, methodologies employing phenylboronic acids[13b] and triphenylborane[13c] as the primary source of the phenyl group were developed. Arylboronic acids can also be added, when the reaction is catalyzed by rhodium[14] or palladium.[15] Catalytic enantioselective arylation of ketones has also been accomplished using either triaryl
aluminium reagents[16] or Grignard reagents,[17] both in presence of excess of Ti(OiPr)4 (Scheme 1).
All these methodologies rely on the use of a large excess of expensive or difficult to prepare arylating reagents, and frequently long reaction times are needed. Furthermore, the final structure is limited to the alkyl chain, which is almost invariably methyl, with a few examples of ethyl. And last but not least, heteroaromatic aryls are seldom present, despite their widespread presence in drugs.[18]
Scheme 1. Representative methodologies for enantioselective arylation of acyclic aryl alky
ketones. L* = Chiral ligand.
In theory, the above-mentioned problems would be circumvented if tertiary diarylmethanols could be accessed by the catalytic alkylation of diaryl ketones. This, however, is considerably more challenging: in contrast to aldehydes and ketones, the reactivity of diaryl ketones is significantly diminished. Additional difficulties are associated with competitive reduction via β-H transfer and, above all, decreased enantiodiscrimination due to the negligible steric and electronic differences between the two aryl substituents on the carbonyl moiety.
As mentioned in the introduction, the asymmetric copper-catalyzed addition of Grignard reagents to aryl alkyl ketones and acylsilanes had been developed, which proceeded with high yields and enantioselectivities (Scheme 2a).[19] We were
2.1. Introduction
Diarylmethanols and aryl heteroarylmethanols with a tetrasubstituted center in the alpha position to the oxygen are extensively present motives in drugs (Figure 1).[1] To name but a few examples: Tiemonium iodide[2] is an antispasmodic and antimuscarinic drug; Chlorphenoxamine[3] is used as antipruritic and antiparkinsonian; Doxylamine[4] is sold as sedative by itself, and together with other drugs for several indications; Clemastine[5] shows antihistaminic and anticholinergic effects and Escitalopram[6] (Lexapro©, Cipralex©) is one of the most important antidepressants.
Figure 1. Selected medicinally important diaryl- and aryl heteroarylmethanols.
Given their high biomedical applications, development of methods for their preparations is of high interest. In contrast to the enantiopure secondary diarylmethanol core, which can be easily accessed either by nucleophilic addition to aromatic aldehydes[7] or the reduction of diaryl ketones,[8] asymmetric synthesis of tertiary diarylmethanol remains a great challenge.[9]
Several approaches have been explored to access chiral tertiary diarylmethanols, including the recently reported stereoselective synthesis.[10] Nevertheless, the catalytic asymmetric addition of organometallic reagents to a ketone remains the most efficient and simplest approach,[11] and has been extensively explored (Scheme 1, acyclic systems shown). The first reports required the use of diphenylzinc.[12,13] Later, methodologies employing phenylboronic acids[13b] and triphenylborane[13c] as the primary source of the phenyl group were developed. Arylboronic acids can also be added, when the reaction is catalyzed by rhodium[14] or palladium.[15] Catalytic enantioselective arylation of ketones has also been accomplished using either triaryl
aluminium reagents[16] or Grignard reagents,[17] both in presence of excess of Ti(OiPr)4 (Scheme 1).
All these methodologies rely on the use of a large excess of expensive or difficult to prepare arylating reagents, and frequently long reaction times are needed. Furthermore, the final structure is limited to the alkyl chain, which is almost invariably methyl, with a few examples of ethyl. And last but not least, heteroaromatic aryls are seldom present, despite their widespread presence in drugs.[18]
Scheme 1. Representative methodologies for enantioselective arylation of acyclic aryl alky
ketones. L* = Chiral ligand.
In theory, the above-mentioned problems would be circumvented if tertiary diarylmethanols could be accessed by the catalytic alkylation of diaryl ketones. This, however, is considerably more challenging: in contrast to aldehydes and ketones, the reactivity of diaryl ketones is significantly diminished. Additional difficulties are associated with competitive reduction via β-H transfer and, above all, decreased enantiodiscrimination due to the negligible steric and electronic differences between the two aryl substituents on the carbonyl moiety.
As mentioned in the introduction, the asymmetric copper-catalyzed addition of Grignard reagents to aryl alkyl ketones and acylsilanes had been developed, which proceeded with high yields and enantioselectivities (Scheme 2a).[19] We were
intrigued whether this catalytic system could be applied to diaryl ketones as well (Scheme 2b). It should be noted that no examples of direct catalytic asymmetric alkylation of diarylketones had ever been reported.
Scheme 2. a) Asymmetric alkylation of aryl alky ketones and acylsilanes previously
developed in our group. [19] b) Goal of the project: asymmetric alkylation of aryl
(hetero)aryl ketones. 2.2. Results and discussion
We initially investigated the addition of iBuMgBr to 2-benzoylthiophene 1a in the presence of CuBr·SMe2 (5 mol%), Joshiphos-type ligand L1 (6 mol%) and BF3ÿOEt2/CeCl3 (1/1) in tBuOMe. (Table 1, entry 2). A combination of Lewis acids[20] was required in order to improve the reactivity and to outcompete non-catalytic Meerwein–Ponndorf–Verley-type (MPV) reduction,[21] which leads to the formation of racemic secondary alcohols. The latter is a formidable competitor when Grignard reagents with β-hydrogen are used.[22] Despite the use of Lewis acids, a low conversion and a mixture of the desired addition product 2a and the reduction side product 3a were obtained. However, when no ligand was added only the latter was observed (Table 1, entry 1). Therefore, an extensive chiral ligand screening was performed: Joshiphos-type chiral ligands L2-L4, as well as other ligand classes
L7-L9, showed similar behavior to L1, giving low conversion and a mixture of the
desired addition and reduction side products. Moreover, low or no enantioselectivity was observed in all cases (Table 1, entry 2). Only with ligand L5 the ee surpassed 10%, but abundant reduction product was observed (Table 1, entry 3).
Table 1. Selected screening of reaction conditions.
Entry[a] Ligand Solvent Temp.
(±C) Grignard equiv. Conv. (%)[b] 2a:3a:4a (%) ee (%)[c] 1 - tBuOMe -60 1.3 28 0:28:0 - 2 L1-L4, L7-L9 tBuOMe -60 1.3 <63 <37:0-36:0 <10 3 L5 tBuOMe -60 1.3 60 31:29:0 28 4 L6 tBuOMe -60 1.3 33 33:0:0 42 5[d] L6 tBuOMe -60 1.3 19 0:19:0 - 6 L6 tBuOMe -60 2 49 37:0:12 52 7 L6 Et2O -60 2 75 34:17:22 48 8 L6 Toluene -60 2 88 6:0:82 n.d. 9 L6 tBuOMe -40 2 67 15:46:6 n.d. 10 L6 tBuOMe -78 2 26 9:0:17 62 11[e] L6 tBuOMe -60 2 33 6:0:27 n.d. 12[f] L6 tBuOMe -60 2 42 40:0:2 69
[a] Reaction conditions: 1a (0.1 mmol), CuBrÿSMe2 (5 mol %), ligand (6 mol %), 1 mL dry
solvent, iBuMgBr (0.7 M in tBuOMe), BF3ÿOEt2 (1 equiv.) , CeCl3 (1 equiv.), -60 ±C, 16 h (2-3
h addition). [b] Determined by GC-MS and 1H NMR. [c] Determined by chiral HPLC. [d]
intrigued whether this catalytic system could be applied to diaryl ketones as well (Scheme 2b). It should be noted that no examples of direct catalytic asymmetric alkylation of diarylketones had ever been reported.
Scheme 2. a) Asymmetric alkylation of aryl alky ketones and acylsilanes previously
developed in our group. [19] b) Goal of the project: asymmetric alkylation of aryl
(hetero)aryl ketones. 2.2. Results and discussion
We initially investigated the addition of iBuMgBr to 2-benzoylthiophene 1a in the presence of CuBr·SMe2 (5 mol%), Joshiphos-type ligand L1 (6 mol%) and BF3ÿOEt2/CeCl3 (1/1) in tBuOMe. (Table 1, entry 2). A combination of Lewis acids[20] was required in order to improve the reactivity and to outcompete non-catalytic Meerwein–Ponndorf–Verley-type (MPV) reduction,[21] which leads to the formation of racemic secondary alcohols. The latter is a formidable competitor when Grignard reagents with β-hydrogen are used.[22] Despite the use of Lewis acids, a low conversion and a mixture of the desired addition product 2a and the reduction side product 3a were obtained. However, when no ligand was added only the latter was observed (Table 1, entry 1). Therefore, an extensive chiral ligand screening was performed: Joshiphos-type chiral ligands L2-L4, as well as other ligand classes
L7-L9, showed similar behavior to L1, giving low conversion and a mixture of the
desired addition and reduction side products. Moreover, low or no enantioselectivity was observed in all cases (Table 1, entry 2). Only with ligand L5 the ee surpassed 10%, but abundant reduction product was observed (Table 1, entry 3).
Table 1. Selected screening of reaction conditions.
Entry[a] Ligand Solvent Temp.
(±C) Grignard equiv. Conv. (%)[b] 2a:3a:4a (%) ee (%)[c] 1 - tBuOMe -60 1.3 28 0:28:0 - 2 L1-L4, L7-L9 tBuOMe -60 1.3 <63 <37:0-36:0 <10 3 L5 tBuOMe -60 1.3 60 31:29:0 28 4 L6 tBuOMe -60 1.3 33 33:0:0 42 5[d] L6 tBuOMe -60 1.3 19 0:19:0 - 6 L6 tBuOMe -60 2 49 37:0:12 52 7 L6 Et2O -60 2 75 34:17:22 48 8 L6 Toluene -60 2 88 6:0:82 n.d. 9 L6 tBuOMe -40 2 67 15:46:6 n.d. 10 L6 tBuOMe -78 2 26 9:0:17 62 11[e] L6 tBuOMe -60 2 33 6:0:27 n.d. 12[f] L6 tBuOMe -60 2 42 40:0:2 69
[a] Reaction conditions: 1a (0.1 mmol), CuBrÿSMe2 (5 mol %), ligand (6 mol %), 1 mL dry
solvent, iBuMgBr (0.7 M in tBuOMe), BF3ÿOEt2 (1 equiv.) , CeCl3 (1 equiv.), -60 ±C, 16 h (2-3
h addition). [b] Determined by GC-MS and 1H NMR. [c] Determined by chiral HPLC. [d]
In spite of the intrinsic difficulties of the system, promising results were found when ligand L6 was used (Table 1, entry 4). Complete selectivity toward the addition product and, compared to the other ligands, a remarkable ee were observed.
With the best ligand in hand we turned our attention to the other reaction parameters. An extensive screening of Lewis acids had already been done and also for this catalytic system the BF3ÿOEt2/CeCl3 combination was found to be favored. This mixture increased the reactivity of the substrate and avoided the MPV-type reduction. Our hypothesis is that the catalytic pathway prevails due to the coordination of Lewis acids to the carbonyl moiety, which prevents the coordination of the Grignard reagent. If no Lewis acid was used, a low conversion towards the reduction product was observed (Table 1, entry 5). To investigate the possibility that organocerium species are involved in the reaction, isobutyl organocerium reagent was synthesized[23] and tested. The starting material was recovered, thus indicating that CeCl3 acts as Lewis acid.
Increasing the amount of the Grignard reagent to 2 equivalents rose the conversion, although the elimination product 4a was observed as well (Table 1, entry 6). Further increases led to the predominance of the elimination product. Alternative solvents to tBuOMe were investigated as well. Conversion rose with both Et2O and toluene, but side reactions outcompeted the addition (Table 1, entries 7 and 8). Higher temperature led to higher conversion, yet the reduction product was the major product (Table 1, entry 9). Not surprisingly, the enantiodiscrimination was augmented when performing the reaction at -78 °C, while the conversion dropped (Table 1, entry 10). Doubling the catalyst loading led to an increased elimination product (Table 1, entry 11). A more concentrated reaction resulted in slightly higher conversion while the elimination was kept low (Table 1, entry 12). The table comprises just few selected data from the long optimization process. Dozens of experiments were set up with the hope that we would find the conditions that would deliver the product in good yield and enantioselectivity, but it did not happen. The optimization process revealed a troublesome scenario in which increasing the conversion almost inevitably led to the elimination side product predominating over the addition. As a matter of fact, we found that elimination takes place both during the reaction and during the purification. The predominance
of the elimination product can be rationalized by the formation of very stable conjugated product.
In our efforts to avoid the elimination, trapping of the corresponding alkoxide of the addition product was attempted. Unfortunately, none of the silyl chlorides or methylating agents that we tried had the desired effect. Using a Grignard reagent without β-hydrogens would prevent elimination and thus, we tried to synthesize the unsaturated version of isobutylmagnesium bromide, starting from 1-bromo-2-methylprop-1-ene. To our regret, it could not be prepared in tBuOMe.
For the substrate scope ketones with electron donating and withdrawing groups were synthesized (Figure 2). We were pleased to see that with the activated ketones the addition product increased, while the elimination remained low (2b and 2c). However, lower enantioselectivity was observed. On the other hand, the presence of electron donating group (meta-methyl) in the phenyl ring made the substrate unreactive and no conversion was observed. The effect of halogen substitution was also evaluated. Ketones with bromine in para and meta gave rise to the tertiary aryl heteroaryl methanols 2d and 2e in moderate yields and enantioselectivities. The substitution at ortho position was not tolerated, and only 24% of addition product was detected, while the remaining was reduction product. If instead of bromine methyl or methoxy groups were placed in ortho the substrate became completely unreactive, most likely due to the increased steric hindrance.
Other heteroaromatic rings different to thiophene were also tested. We found that 2-benzopyridine is a suitable substrate for this reaction. Pyridine ring is present in many drugs, and the corresponding tertiary alcohol 2f could be isolated in 39% yield, even if the ee was low. On the other hand, the addition to the furan bearing ketone was highly problematic, although the results slightly improved when BF3ÿOEt2 was not added, allowing us to obtain the product 2g, which was very unstable. The situation was analogous with the diheteroaryl alcohol 2h bearing both thiophene and furan rings. The thiazole containing product 2i was obtained with low ee, even when the reaction was performed at -78 °C. The isomer of the former,
2j, did regrettably give similar results in terms of ee.
Unfortunately we could not determine the absolute configuration of the products. On the one hand, the fact that compounds are oils, together with the low to moderate ee’s prevented us from using X-ray crystallography. On the other,
In spite of the intrinsic difficulties of the system, promising results were found when ligand L6 was used (Table 1, entry 4). Complete selectivity toward the addition product and, compared to the other ligands, a remarkable ee were observed.
With the best ligand in hand we turned our attention to the other reaction parameters. An extensive screening of Lewis acids had already been done and also for this catalytic system the BF3ÿOEt2/CeCl3 combination was found to be favored. This mixture increased the reactivity of the substrate and avoided the MPV-type reduction. Our hypothesis is that the catalytic pathway prevails due to the coordination of Lewis acids to the carbonyl moiety, which prevents the coordination of the Grignard reagent. If no Lewis acid was used, a low conversion towards the reduction product was observed (Table 1, entry 5). To investigate the possibility that organocerium species are involved in the reaction, isobutyl organocerium reagent was synthesized[23] and tested. The starting material was recovered, thus indicating that CeCl3 acts as Lewis acid.
Increasing the amount of the Grignard reagent to 2 equivalents rose the conversion, although the elimination product 4a was observed as well (Table 1, entry 6). Further increases led to the predominance of the elimination product. Alternative solvents to tBuOMe were investigated as well. Conversion rose with both Et2O and toluene, but side reactions outcompeted the addition (Table 1, entries 7 and 8). Higher temperature led to higher conversion, yet the reduction product was the major product (Table 1, entry 9). Not surprisingly, the enantiodiscrimination was augmented when performing the reaction at -78 °C, while the conversion dropped (Table 1, entry 10). Doubling the catalyst loading led to an increased elimination product (Table 1, entry 11). A more concentrated reaction resulted in slightly higher conversion while the elimination was kept low (Table 1, entry 12). The table comprises just few selected data from the long optimization process. Dozens of experiments were set up with the hope that we would find the conditions that would deliver the product in good yield and enantioselectivity, but it did not happen. The optimization process revealed a troublesome scenario in which increasing the conversion almost inevitably led to the elimination side product predominating over the addition. As a matter of fact, we found that elimination takes place both during the reaction and during the purification. The predominance
of the elimination product can be rationalized by the formation of very stable conjugated product.
In our efforts to avoid the elimination, trapping of the corresponding alkoxide of the addition product was attempted. Unfortunately, none of the silyl chlorides or methylating agents that we tried had the desired effect. Using a Grignard reagent without β-hydrogens would prevent elimination and thus, we tried to synthesize the unsaturated version of isobutylmagnesium bromide, starting from 1-bromo-2-methylprop-1-ene. To our regret, it could not be prepared in tBuOMe.
For the substrate scope ketones with electron donating and withdrawing groups were synthesized (Figure 2). We were pleased to see that with the activated ketones the addition product increased, while the elimination remained low (2b and 2c). However, lower enantioselectivity was observed. On the other hand, the presence of electron donating group (meta-methyl) in the phenyl ring made the substrate unreactive and no conversion was observed. The effect of halogen substitution was also evaluated. Ketones with bromine in para and meta gave rise to the tertiary aryl heteroaryl methanols 2d and 2e in moderate yields and enantioselectivities. The substitution at ortho position was not tolerated, and only 24% of addition product was detected, while the remaining was reduction product. If instead of bromine methyl or methoxy groups were placed in ortho the substrate became completely unreactive, most likely due to the increased steric hindrance.
Other heteroaromatic rings different to thiophene were also tested. We found that 2-benzopyridine is a suitable substrate for this reaction. Pyridine ring is present in many drugs, and the corresponding tertiary alcohol 2f could be isolated in 39% yield, even if the ee was low. On the other hand, the addition to the furan bearing ketone was highly problematic, although the results slightly improved when BF3ÿOEt2 was not added, allowing us to obtain the product 2g, which was very unstable. The situation was analogous with the diheteroaryl alcohol 2h bearing both thiophene and furan rings. The thiazole containing product 2i was obtained with low ee, even when the reaction was performed at -78 °C. The isomer of the former,
2j, did regrettably give similar results in terms of ee.
Unfortunately we could not determine the absolute configuration of the products. On the one hand, the fact that compounds are oils, together with the low to moderate ee’s prevented us from using X-ray crystallography. On the other,
comparison with reported molecules was not possible. The derivatization of the diarylmethanols is hampered by their low stability and the reported chiral α-tertiary diarylmethanols do not have the β-branched alkyl chain, required by our catalytic system in order to obtain reasonable enantioselectivities (vide infra). Nevertheless, we compared the HPLC traces of 2a with the analogous diarylmethanol having 3-bromopropane instead of isobutyl as alkyl chain.[16b] Based on this result we can say that, most likely, 2a has R configuration.
Figure 2. Substrate scope. Reaction conditions: 1a-j (0.1 mmol), CuBrÿSMe2 (5 mol %), ligand
L6 (6 mol %), 0.5 mL of dry tBuOMe, iBuMgBr (0. 7M in tBuOMe), BF3ÿOEt2 (1
equiv.) CeCl3 (1 equiv.) -60 ±C, 16h (2-3 h addition). Conversion to the addition
product determined by 1H NMR and 19F NMR. Enantiomeric excess determined by
chiral HPLC. [a] No BF3ÿOEt2 added. [b] The compounds decomposed fast, so only
partial characterisation was possible. [c] Performed at -78 ±C.
The low to moderate ee’s obtained can be rationalized on the basis of progressive difficulty of enantiodiscrimination when going from aldehydes to aryl akyl ketones and finally to diaryl or dialkyl ketones due to increasingly smaller steric and electronic differences between the two substituents at the carbonyl group. In this context, the enantioselectivity of 69% ee obtained with 2-benzoylthiophene, is quite remarkable. Even though there are dozens of reports on the catalytic asymmetric arylation of aryl alkyl ketones, this is the first example of its complementary process, the catalytic asymmetric addition of organometallic reagents to (di)heteroaryl ketones. In fact, we have found just one example in the literature of asymmetric addition of carbon nucleophiles to diaryl ketones, namely the Reformatsky reaction on phenyl(o-tolyl)methanone (Scheme 3a).[24] In this case, the steric hindrance by the methyl in the ortho position is presumably the origin of the enantioselectivity. In addition, DFT calculations showed a 64.5 degree angle between the planes of the two aryls, while it was calculated to be just 37.8 for our substrate (Figure 3). Having said that, we also tried phenyl(o-tolyl)methanone, as well as other diarylketones substituted in ortho, under our reaction conditions, but all proved to be unreactive (Scheme 3b).
comparison with reported molecules was not possible. The derivatization of the diarylmethanols is hampered by their low stability and the reported chiral α-tertiary diarylmethanols do not have the β-branched alkyl chain, required by our catalytic system in order to obtain reasonable enantioselectivities (vide infra). Nevertheless, we compared the HPLC traces of 2a with the analogous diarylmethanol having 3-bromopropane instead of isobutyl as alkyl chain.[16b] Based on this result we can say that, most likely, 2a has R configuration.
Figure 2. Substrate scope. Reaction conditions: 1a-j (0.1 mmol), CuBrÿSMe2 (5 mol %), ligand
L6 (6 mol %), 0.5 mL of dry tBuOMe, iBuMgBr (0. 7M in tBuOMe), BF3ÿOEt2 (1
equiv.) CeCl3 (1 equiv.) -60 ±C, 16h (2-3 h addition). Conversion to the addition
product determined by 1H NMR and 19F NMR. Enantiomeric excess determined by
chiral HPLC. [a] No BF3ÿOEt2 added. [b] The compounds decomposed fast, so only
partial characterisation was possible. [c] Performed at -78 ±C.
The low to moderate ee’s obtained can be rationalized on the basis of progressive difficulty of enantiodiscrimination when going from aldehydes to aryl akyl ketones and finally to diaryl or dialkyl ketones due to increasingly smaller steric and electronic differences between the two substituents at the carbonyl group. In this context, the enantioselectivity of 69% ee obtained with 2-benzoylthiophene, is quite remarkable. Even though there are dozens of reports on the catalytic asymmetric arylation of aryl alkyl ketones, this is the first example of its complementary process, the catalytic asymmetric addition of organometallic reagents to (di)heteroaryl ketones. In fact, we have found just one example in the literature of asymmetric addition of carbon nucleophiles to diaryl ketones, namely the Reformatsky reaction on phenyl(o-tolyl)methanone (Scheme 3a).[24] In this case, the steric hindrance by the methyl in the ortho position is presumably the origin of the enantioselectivity. In addition, DFT calculations showed a 64.5 degree angle between the planes of the two aryls, while it was calculated to be just 37.8 for our substrate (Figure 3). Having said that, we also tried phenyl(o-tolyl)methanone, as well as other diarylketones substituted in ortho, under our reaction conditions, but all proved to be unreactive (Scheme 3b).
Figure 3. Phenyl(o-tolyl)methanone (left) and 2-Benzoylthiophene (right) structure calculated
at the B3LYP/6-311+G(2d, 2p) level. Hydrogen atoms have been omitted for clarity. The relative flatness of diaryl ketones is a handicap for the enantiodiscrimination. Hence, the origin of the significant ee’s obtained must lie in the reagent-catalyst complex, rather than in the substrate. Within this framework, β-branched Grignard reagents are required for the asymmetric addition (Scheme 4, 2b and 3b). When linear Grignard reagents were tested, products with low enantioselectivity were obtained (Scheme 4, 4b). O S * HO S R RMgBr
CuBr.SMe2(5 mol%) L6 (6 mol%) F3C F3C 1b BF3·OEt2(1 equiv.) CeCl3(1 equiv.) tBuOMe , -60 °C R= iBu (2b) 63 %, 50 % ee R= CH2Cy (3b) 61 %, 41 % ee R= nBu (4b) 77 %, 13% ee
Scheme 4. Influence of the Grignard reagent on the enantioselectivity of the reaction.
2.3. Conclusion
In summary, we have demonstrated that it is possible to achieve catalytic asymmetric addition of organometallic reagents to stereochemically challenging diaryl ketones. While the enantioselectivities and conversions are from moderate to good, this new methodology benefits from a) readily available Grignard reagents, b) cost-efficient copper catalysis, c) the ability to have diverse alkyl chains in the final product, and more remarkably, d) allowing the presence of heteroaromatic rings in the structure, widely spread in biologically active products. Nevertheless, this new approach needs improved yields and ee’s to be viable for accessing pharmaceutically valuable molecules.
2.4. Experimental section 2.4.1. General information
Unless otherwise indicated, reagents and substrates were purchased from commercial sources and used as received. Solvents not required to be dry were purchased as technical grade and used as received. Dry solvents were freshly collected from a dry solvent purification system prior to use. Inert atmosphere experiments were performed with standard Schlenk techniques with dried (P2O5) nitrogen gas. 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 or Merck 90 Å 70-230 mesh active neutral aluminium oxide. NMR data was collected on Varian VXR400 (1H at 400.0 MHz; 13C at 101 MHz; 19F at 376 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; 19F are calibrated externally against CFCl3). Coupling constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, bs: broad singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doublet of doublets, t: triplet, td: triplet of doublets, q: quartet, m: multiplet). Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI (positive mode for ketones and negative mode for alcohols). Enantiomeric excesses were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector. Grignard reagents were prepared from the corresponding alkyl bromides and Mg activated with I2 in tBuOMe. Benzoylthiophene 1a, Benzoylpyridine 1f, methoxybenzophenone, 2-methylbenzophenone and 2-(trifluoromethyl)benzophenone are commercially available.
2.4.2. General procedure for the preparation of aryl heteroaryl and diheteroaryl ketones
Following a modified literature procedure,[25] in a flame-dried, nitrogen flushed three-neck round bottom flask the corresponding acyl chloride (3 mmol) and AlCl3 (3.9 mmol) were dissolved in CH2Cl2 (3 mL), and cooled to 0 °C. A solution of thiophene or furan (3 mmol) in CH2Cl2 (3 mL) was added dropwise, and then the
Figure 3. Phenyl(o-tolyl)methanone (left) and 2-Benzoylthiophene (right) structure calculated
at the B3LYP/6-311+G(2d, 2p) level. Hydrogen atoms have been omitted for clarity. The relative flatness of diaryl ketones is a handicap for the enantiodiscrimination. Hence, the origin of the significant ee’s obtained must lie in the reagent-catalyst complex, rather than in the substrate. Within this framework, β-branched Grignard reagents are required for the asymmetric addition (Scheme 4, 2b and 3b). When linear Grignard reagents were tested, products with low enantioselectivity were obtained (Scheme 4, 4b). O S * HO S R RMgBr
CuBr.SMe2(5 mol%) L6 (6 mol%) F3C F3C 1b BF3·OEt2(1 equiv.) CeCl3(1 equiv.) tBuOMe , -60 °C R= iBu (2b) 63 %, 50 % ee R= CH2Cy (3b) 61 %, 41 % ee R= nBu (4b) 77 %, 13% ee
Scheme 4. Influence of the Grignard reagent on the enantioselectivity of the reaction.
2.3. Conclusion
In summary, we have demonstrated that it is possible to achieve catalytic asymmetric addition of organometallic reagents to stereochemically challenging diaryl ketones. While the enantioselectivities and conversions are from moderate to good, this new methodology benefits from a) readily available Grignard reagents, b) cost-efficient copper catalysis, c) the ability to have diverse alkyl chains in the final product, and more remarkably, d) allowing the presence of heteroaromatic rings in the structure, widely spread in biologically active products. Nevertheless, this new approach needs improved yields and ee’s to be viable for accessing pharmaceutically valuable molecules.
2.4. Experimental section 2.4.1. General information
Unless otherwise indicated, reagents and substrates were purchased from commercial sources and used as received. Solvents not required to be dry were purchased as technical grade and used as received. Dry solvents were freshly collected from a dry solvent purification system prior to use. Inert atmosphere experiments were performed with standard Schlenk techniques with dried (P2O5) nitrogen gas. 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 or Merck 90 Å 70-230 mesh active neutral aluminium oxide. NMR data was collected on Varian VXR400 (1H at 400.0 MHz; 13C at 101 MHz; 19F at 376 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; 19F are calibrated externally against CFCl3). Coupling constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, bs: broad singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doublet of doublets, t: triplet, td: triplet of doublets, q: quartet, m: multiplet). Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI (positive mode for ketones and negative mode for alcohols). Enantiomeric excesses were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector. Grignard reagents were prepared from the corresponding alkyl bromides and Mg activated with I2 in tBuOMe. Benzoylthiophene 1a, Benzoylpyridine 1f, methoxybenzophenone, 2-methylbenzophenone and 2-(trifluoromethyl)benzophenone are commercially available.
2.4.2. General procedure for the preparation of aryl heteroaryl and diheteroaryl ketones
Following a modified literature procedure,[25] in a flame-dried, nitrogen flushed three-neck round bottom flask the corresponding acyl chloride (3 mmol) and AlCl3 (3.9 mmol) were dissolved in CH2Cl2 (3 mL), and cooled to 0 °C. A solution of thiophene or furan (3 mmol) in CH2Cl2 (3 mL) was added dropwise, and then the
mixture was stirred at room temperature for two hours. It was quenched with crushed iced, acidified with 37% HCl (0.3 mL) and extracted trice with CH2Cl2. The organic layer wash washed with brine, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using mixtures of pentane and AcOEt as the eluent.
Thiophen-2-yl(4-(trifluoromethyl)phenyl)methanone (1b)
Product 1b was obtained in 52% yield after column chromatography on silica gel (pentane:AcOEt 20:1) The analytical data were found to be in accordance with those reported in the literature.[26]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.1 Hz, 2H), 7.78 – 7.73 (m, 3H), 7.60 (dd, J = 3.8, 0.8 Hz, 1H), 7.17 (dd, J = 4.8, 3.9, 1H). 13C NMR (CDCl3, 101 MHz): δ 187.2, 143.2, 141.4, 135.5, 135.3, 134.0, 129.5, 128.4, 125.7 (q, J = 3.8 Hz).
(3,5-bis(trifluoromethyl)phenyl)(thiophen-2-yl)methanone (1c)
Product 1c was obtained in 30% yield as an orange oil after column chromatography on silica gel (pentane:AcOEt 20:1) 1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 2H), 8.07 (s, 1 H), 7.81 (dd, J = 4.9, 0.9 Hz, 1H), 7.60 (dd, J = 3.8, 1.0 Hz, 1H), 7.21 (dd, J = 4.8, 4.0 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 185.2, 142.3, 140.0, 136.1, 135.6, 132.3 (q, J = 34.0 Hz), 129.3 (m), 128.7, 125.7 (hept, J = 3.6 Hz), 123.1 (q, J = 273.0 Hz). 19F NMR (CDCl3, 376 MHz): δ -63.0. HRMS (ESI+, m/z) calc. for 325.01163 [M+H]+, found 325.01203.
(4-bromophenyl)(thiophen-2-yl) methanone (1d)
Product 1d was obtained in 95% yield after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[27]
1H NMR (CDCl3, 400 MHz): δ 7.74 – 7.69 (m, 3H), 7.64 – 7.63 (m, 1H), 7.62 – 7.59 (m, 2H), 7.15 (dd, J = 4.9, 3.8 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 187.2, 143.5, 137.1, 135.0, 134.8, 131.9, 130.9, 128.3, 127.5.
(3-bromophenyl)(thiophen-2-yl) methanone (1e)
Product 1e was obtained in quantitative yield after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[28]
1H NMR (CDCl3, 400 MHz): δ 7.97 (t, J = 1.7 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.72 – 7.68 (m, 1H), 7.62 (dd, J = 3.8, 1.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.17 (dd, J = 4.9, 3.9 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 186.6, 143.2, 140.1, 135.3, 135.3, 135.0, 132.2, 130.2, 128.4, 127.9, 122.8.
2-benzoylfuran (1g)
Product 1g was obtained in 44% yield after column chromatography on silica gel (pentane:AcOEt 10:1) The analytical data were found to be in accordance with those reported in the literature.[29]
1H NMR (CDCl3, 400 MHz): δ 7.99 – 7.92 (m, 2H), 7.70 – 7.67 (m, 1H), 7.57 (t, J = 7.4 Hz, 1H) 7.47 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 3.6 Hz, 1H), 6.57 (dd, J = 3.5, 1.7 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 182.9, 152.4, 147.4, 137.4, 132.8, 129.5, 128.6, 121.0, 112.4.
Furan-2-yl(thiophen-2-yl)methanone (1h)
Product 1h was obtained in 33% yield after column chromatography on silica gel (pentane:AcOEt 20:1) The analytical data were found to be in accordance with those reported in the literature.[30]
1H NMR (CDCl3, 400 MHz): δ 8.15 (dd, J = 3.8, 1.1 Hz, 1H), 7.68 (dd, J = 5.0, 1.1 Hz, 1H), 7.66 (dd, J = 1.7, 0.8 Hz, 1H), 7.38 (dd, J = 3.6, 0.8 Hz, 1H), 7.17 (dd, J = 4.9, 3.9 Hz, 1H), 6.58 (dd, J = 3.6, 1.7 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 173.6, 152.5, 146.6, 142.3, 134.1, 134.0, 128.4, 119.0, 112.6.
Thiophen-2-yl(5-(trifluoromethyl)pyridin-2-yl)methanone (1j)
Product 1j was obtained in 24% yield as a yellow solid after column chromatography on silica gel (pentane:AcOEt 20:1) 1H NMR (CDCl3, 400 MHz): δ 9.01 (d, J = 2.1 Hz, 1H), 8.40 (dd, J
mixture was stirred at room temperature for two hours. It was quenched with crushed iced, acidified with 37% HCl (0.3 mL) and extracted trice with CH2Cl2. The organic layer wash washed with brine, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using mixtures of pentane and AcOEt as the eluent.
Thiophen-2-yl(4-(trifluoromethyl)phenyl)methanone (1b)
Product 1b was obtained in 52% yield after column chromatography on silica gel (pentane:AcOEt 20:1) The analytical data were found to be in accordance with those reported in the literature.[26]
1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.1 Hz, 2H), 7.78 – 7.73 (m, 3H), 7.60 (dd, J = 3.8, 0.8 Hz, 1H), 7.17 (dd, J = 4.8, 3.9, 1H). 13C NMR (CDCl3, 101 MHz): δ 187.2, 143.2, 141.4, 135.5, 135.3, 134.0, 129.5, 128.4, 125.7 (q, J = 3.8 Hz).
(3,5-bis(trifluoromethyl)phenyl)(thiophen-2-yl)methanone (1c)
Product 1c was obtained in 30% yield as an orange oil after column chromatography on silica gel (pentane:AcOEt 20:1) 1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 2H), 8.07 (s, 1 H), 7.81 (dd, J = 4.9, 0.9 Hz, 1H), 7.60 (dd, J = 3.8, 1.0 Hz, 1H), 7.21 (dd, J = 4.8, 4.0 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 185.2, 142.3, 140.0, 136.1, 135.6, 132.3 (q, J = 34.0 Hz), 129.3 (m), 128.7, 125.7 (hept, J = 3.6 Hz), 123.1 (q, J = 273.0 Hz). 19F NMR (CDCl3, 376 MHz): δ -63.0. HRMS (ESI+, m/z) calc. for 325.01163 [M+H]+, found 325.01203.
(4-bromophenyl)(thiophen-2-yl) methanone (1d)
Product 1d was obtained in 95% yield after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[27]
1H NMR (CDCl3, 400 MHz): δ 7.74 – 7.69 (m, 3H), 7.64 – 7.63 (m, 1H), 7.62 – 7.59 (m, 2H), 7.15 (dd, J = 4.9, 3.8 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 187.2, 143.5, 137.1, 135.0, 134.8, 131.9, 130.9, 128.3, 127.5.
(3-bromophenyl)(thiophen-2-yl) methanone (1e)
Product 1e was obtained in quantitative yield after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[28]
1H NMR (CDCl3, 400 MHz): δ 7.97 (t, J = 1.7 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.72 – 7.68 (m, 1H), 7.62 (dd, J = 3.8, 1.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.17 (dd, J = 4.9, 3.9 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 186.6, 143.2, 140.1, 135.3, 135.3, 135.0, 132.2, 130.2, 128.4, 127.9, 122.8.
2-benzoylfuran (1g)
Product 1g was obtained in 44% yield after column chromatography on silica gel (pentane:AcOEt 10:1) The analytical data were found to be in accordance with those reported in the literature.[29]
1H NMR (CDCl3, 400 MHz): δ 7.99 – 7.92 (m, 2H), 7.70 – 7.67 (m, 1H), 7.57 (t, J = 7.4 Hz, 1H) 7.47 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 3.6 Hz, 1H), 6.57 (dd, J = 3.5, 1.7 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 182.9, 152.4, 147.4, 137.4, 132.8, 129.5, 128.6, 121.0, 112.4.
Furan-2-yl(thiophen-2-yl)methanone (1h)
Product 1h was obtained in 33% yield after column chromatography on silica gel (pentane:AcOEt 20:1) The analytical data were found to be in accordance with those reported in the literature.[30]
1H NMR (CDCl3, 400 MHz): δ 8.15 (dd, J = 3.8, 1.1 Hz, 1H), 7.68 (dd, J = 5.0, 1.1 Hz, 1H), 7.66 (dd, J = 1.7, 0.8 Hz, 1H), 7.38 (dd, J = 3.6, 0.8 Hz, 1H), 7.17 (dd, J = 4.9, 3.9 Hz, 1H), 6.58 (dd, J = 3.6, 1.7 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 173.6, 152.5, 146.6, 142.3, 134.1, 134.0, 128.4, 119.0, 112.6.
Thiophen-2-yl(5-(trifluoromethyl)pyridin-2-yl)methanone (1j)
Product 1j was obtained in 24% yield as a yellow solid after column chromatography on silica gel (pentane:AcOEt 20:1) 1H NMR (CDCl3, 400 MHz): δ 9.01 (d, J = 2.1 Hz, 1H), 8.40 (dd, J
= 3.9 Hz, 1.1, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.13 (dd, J = 8.3, 1.7 Hz, 1H), 7.78 (dd, J = 4.9, 1.1 Hz, 1H), 7.20 (dd, J = 4.9, 4.0 Hz, 1H). 13C NMR (CDCl3, 101 MHz): 182.2, 156.6, 145.44 (q, J = 3.9 Hz), 139.6, 137.3, 137.1, 134.58 (q, J = 3.4 Hz), 129.01 (q, J = 33.3 Hz), 128.0, 123.7, 123.25 (q, J = 273.0 Hz). 19F NMR (CDCl3, 376 MHz): δ -62.7. HRMS (ESI+, m/z) calculated for 258.01950 [M+H]+, found 258.01979. M.p. 59.9-60.8±C
Thiophen-2-yl(o-tolyl)methanone
The product was obtained in quantitative yield as an orange solid after washing the crude mixture with Et2O.The analytical data were found to be in accordance with those reported in the literature. [31] 1H NMR (CDCl3, 400 MHz): δ 7.72 (d, J = 4.9 Hz, 1H), 7.46 – 7.35 (m, 3H), 7.31 – 7.23 (m, 2H), 7.11 (t, J = 4.4 Hz, 1H), 2.39 (s, 3H).
(2-methoxyphenyl)(thiophen-2-yl)methanone
The product was obtained in 40% yield after column chromatography on silica gel (pentane:AcOEt 10:1). The analytical data were found to be in accordance with those reported in the literature.[32]
1H NMR (CDCl3, 400 MHz): δ 7.68 (dd, J = 4.9, 1.3 Hz, 1H), 7.48 – 7.37 (m, 3H), 7.09 (dd, J = 5.0, 3.7 Hz, 1H), 7.05 – 6.98 (m, 2H), 3.79 (s, 3H).
(2-bromophenyl)(thiophen-2-yl)methanone
The product was obtained in 93% yield as a yellow solid after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[33] 1H NMR (CDCl3, 400 MHz): δ 7.68 (d, J = 4.9 Hz, 1H), 7.57 (dd, J = 7.7, 0.8 Hz, 1H), 7.35 – 7.17 (m, 4H), 7.03 (t, J = 4.8 Hz, 1H).
Thiophen-2-yl(m-tolyl)methanone
The product was obtained in quantitative yield after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[28]
1H NMR (CDCl3, 400 MHz): δ 7.71 (dd, J = 4.9, 1.1 Hz, 1H), 7.68 – 7.63 (m, 3H), 7.42 – 7.34 (m, 2H), 7.15 (dd, J = 4.9, 3.8 Hz, 1H), 2.43 (s, 3H).
Thiazol-2-yl(4-(trifluoromethyl)phenyl)methanone (1i)
Thiazol-2-yl(4-(trifluoromethyl)phenyl)methanone (1i) was prepared following a different procedure: in a flame-dried, nitrogen flushed three-neck round bottom flask 2-bromo thiazole (3 mmol) was dissolved in toluene (6 mL), cooled down to -78 °C and butyllithium (3.15 mmol) was added over 30 min, and left stirring for additional 15 min. Then it is cannulated to a flame-dried, nitrogen flushed three-neck round bottom flask containing 4-(trifluoromethyl)benzoyl chloride (3 mmol) in toluene (6 mL). After stirring it for 15 min it is quenched with aqueous NHCO3, washed with brine, dried over MgSO4 and concentrated under vacuum.
The product was obtained as an orange oil in 12% yield after column chromatography on silica gel (pentane:AcOEt 20:1). The analytical data were found to be in accordance with those reported in the literature.[34]
1H NMR (CDCl3, 400 MHz): δ 8.56 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 3.0 Hz, 1H), 7.78 (s, 1H), 7.77 – 7.75 (m, 2H). 13C NMR (CDCl3, 101 MHz): δ183.3, 167.2, 145.3, 138.2, 134.8 (q, J = 32.8 Hz) 131.5, 127.1, 125.5 (q, J = 3.8 Hz), 123.8 (d, J = 272.9 Hz). 19F NMR (CDCl3, 376 MHz): δ -63.3.
2.4.3. General procedure for 1,2-addition of Grignard reagents to diaryl ketones
In a flame-dried, nitrogen flushed Schlenk tube, CuBrÿSMe2 (0.005mmol, 1.03 mg, 5 mol %) and ligand (R, SP)-L6 (0.006 mmol, 6 mol %) is dissolved in dry tBuOMe (0.5 mL) and stirred at room temperature for 15 min. The ketone 1a-j (0.1 mmol) and the CeCl3 (0.1 mmol, 1equiv.) are added, stirred for 15 min. and cooled to to -60±C. The BF3ÿOEt2 (0.1 mmol, 1equiv.) is added, the mixture stirred for 15 min, and then the Grignard reagent (0.2 mmol, 2equiv. in tBuOMe ) is added over 2-3 hours. Once the addition is complete it is left overnight (16h). The reaction is quenched by the addition of MeOH (1 mL) and saturated aqueous NH4Cl (2 mL), and then warmed to room temperature, whereupon it is diluted with AcOEt and the layers are
= 3.9 Hz, 1.1, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.13 (dd, J = 8.3, 1.7 Hz, 1H), 7.78 (dd, J = 4.9, 1.1 Hz, 1H), 7.20 (dd, J = 4.9, 4.0 Hz, 1H). 13C NMR (CDCl3, 101 MHz): 182.2, 156.6, 145.44 (q, J = 3.9 Hz), 139.6, 137.3, 137.1, 134.58 (q, J = 3.4 Hz), 129.01 (q, J = 33.3 Hz), 128.0, 123.7, 123.25 (q, J = 273.0 Hz). 19F NMR (CDCl3, 376 MHz): δ -62.7. HRMS (ESI+, m/z) calculated for 258.01950 [M+H]+, found 258.01979. M.p. 59.9-60.8±C
Thiophen-2-yl(o-tolyl)methanone
The product was obtained in quantitative yield as an orange solid after washing the crude mixture with Et2O.The analytical data were found to be in accordance with those reported in the literature. [31] 1H NMR (CDCl3, 400 MHz): δ 7.72 (d, J = 4.9 Hz, 1H), 7.46 – 7.35 (m, 3H), 7.31 – 7.23 (m, 2H), 7.11 (t, J = 4.4 Hz, 1H), 2.39 (s, 3H).
(2-methoxyphenyl)(thiophen-2-yl)methanone
The product was obtained in 40% yield after column chromatography on silica gel (pentane:AcOEt 10:1). The analytical data were found to be in accordance with those reported in the literature.[32]
1H NMR (CDCl3, 400 MHz): δ 7.68 (dd, J = 4.9, 1.3 Hz, 1H), 7.48 – 7.37 (m, 3H), 7.09 (dd, J = 5.0, 3.7 Hz, 1H), 7.05 – 6.98 (m, 2H), 3.79 (s, 3H).
(2-bromophenyl)(thiophen-2-yl)methanone
The product was obtained in 93% yield as a yellow solid after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[33] 1H NMR (CDCl3, 400 MHz): δ 7.68 (d, J = 4.9 Hz, 1H), 7.57 (dd, J = 7.7, 0.8 Hz, 1H), 7.35 – 7.17 (m, 4H), 7.03 (t, J = 4.8 Hz, 1H).
Thiophen-2-yl(m-tolyl)methanone
The product was obtained in quantitative yield after washing the crude mixture with Et2O. The analytical data were found to be in accordance with those reported in the literature.[28]
1H NMR (CDCl3, 400 MHz): δ 7.71 (dd, J = 4.9, 1.1 Hz, 1H), 7.68 – 7.63 (m, 3H), 7.42 – 7.34 (m, 2H), 7.15 (dd, J = 4.9, 3.8 Hz, 1H), 2.43 (s, 3H).
Thiazol-2-yl(4-(trifluoromethyl)phenyl)methanone (1i)
Thiazol-2-yl(4-(trifluoromethyl)phenyl)methanone (1i) was prepared following a different procedure: in a flame-dried, nitrogen flushed three-neck round bottom flask 2-bromo thiazole (3 mmol) was dissolved in toluene (6 mL), cooled down to -78 °C and butyllithium (3.15 mmol) was added over 30 min, and left stirring for additional 15 min. Then it is cannulated to a flame-dried, nitrogen flushed three-neck round bottom flask containing 4-(trifluoromethyl)benzoyl chloride (3 mmol) in toluene (6 mL). After stirring it for 15 min it is quenched with aqueous NHCO3, washed with brine, dried over MgSO4 and concentrated under vacuum.
The product was obtained as an orange oil in 12% yield after column chromatography on silica gel (pentane:AcOEt 20:1). The analytical data were found to be in accordance with those reported in the literature.[34]
1H NMR (CDCl3, 400 MHz): δ 8.56 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 3.0 Hz, 1H), 7.78 (s, 1H), 7.77 – 7.75 (m, 2H). 13C NMR (CDCl3, 101 MHz): δ183.3, 167.2, 145.3, 138.2, 134.8 (q, J = 32.8 Hz) 131.5, 127.1, 125.5 (q, J = 3.8 Hz), 123.8 (d, J = 272.9 Hz). 19F NMR (CDCl3, 376 MHz): δ -63.3.
2.4.3. General procedure for 1,2-addition of Grignard reagents to diaryl ketones
In a flame-dried, nitrogen flushed Schlenk tube, CuBrÿSMe2 (0.005mmol, 1.03 mg, 5 mol %) and ligand (R, SP)-L6 (0.006 mmol, 6 mol %) is dissolved in dry tBuOMe (0.5 mL) and stirred at room temperature for 15 min. The ketone 1a-j (0.1 mmol) and the CeCl3 (0.1 mmol, 1equiv.) are added, stirred for 15 min. and cooled to to -60±C. The BF3ÿOEt2 (0.1 mmol, 1equiv.) is added, the mixture stirred for 15 min, and then the Grignard reagent (0.2 mmol, 2equiv. in tBuOMe ) is added over 2-3 hours. Once the addition is complete it is left overnight (16h). The reaction is quenched by the addition of MeOH (1 mL) and saturated aqueous NH4Cl (2 mL), and then warmed to room temperature, whereupon it is diluted with AcOEt and the layers are
separated. The aqueous layer is extracted with AcOEt (3µ5 mL) and the combined organic layers are dried with anhydrous MgSO4, filtered, and the solvent is evaporated in vacuo. The crude product is purified by flash chromatography on neutral aluminium oxide using mixtures of pentane and AcOEt as the eluent to obtain alcohols 2a-j.
3-methyl-1-phenyl-1-(thiophen-2-yl)butan-1-ol (2a)
Product 2a was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [24% yield, 42% conversion, 69% ee].
1H NMR (CDCl3, 400 MHz): δ 7.47 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.25 – 7.22 (m, 1H), 7.19 (dd, J = 5.0, 1.3 Hz, 1H), 6.90 (dd, J = 5.0, 3.6 Hz, 1H), 6.87 (dd, J = 3.6, 1.3 Hz, 1H), 2.28 (dd, J = 14.3, 5.4 Hz, 1H), 2.25 (s, 1H), 2.19 (dd, J = 14.4, 6.1 Hz, 1H), 1.75 – 1.64 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 154.3, 146.2, 128.1, 127.1, 126.6, 125.8, 124.8, 123.9, 77.9, 52.3, 24.7, 24.7, 24.6. HRMS (ESI-, m/z) calc. for 245.09946 [M-H]-, found 245.10072. The ee was determined by HPLC analysis (Chiracel-OJH, n-heptane/iPrOH 95:5, 0.5 mL/min). Retention time (min): 15.9 (major) and 17.0 (minor).
3-methyl-1-(thiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)butan-1-ol (2b)
Product 2b was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [64% yield, 88% conversion, 50% ee].
1H NMR (CDCl3, 400 MHz): δ 7.63 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.23 (dd, J = 5.0, 1.3 Hz, 1H), 6.94 (dd, J = 4.9, 3.6 Hz, 1H), 6.91 (dd, J = 3.6, 1.3 Hz, 1H) 2.33 (s, 1H) 2.32 (dd, J = 14.4, 5.3 Hz, 1H), 2.23 (dd, J = 14.4, 6.4 Hz, 1H), 1.76 – 1.61 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 153.41, 150.07, 129.3 (q, J = 32.4 Hz), 126.8, 126.2, 125.2, 125.1 (q, J = 3.8 Hz), 124.3 (d, J = 272.1 Hz), 124.1, 77.6, 52.1, 24.7, 24.6, 24.5. 19F NMR (CDCl3, 376 MHz): δ -62.4. HRMS (ESI-, m/z) calc. for 313.08685 [M-H]-, found 313.08779. The ee was determined by HPLC analysis (Chiracel-OJH, n-heptane/iPrOH 97:3, 0.5 mL/min). Retention time (min): 12.8 (minor) and 16.2 (major).
1-(3,5-bis(trifluoromethyl)phenyl)-3-methyl-1-(thiophen-2-yl)butan-1-ol (2c)
Product 2c was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [47% yield, 68% conversion, 35% ee].
1H NMR (CDCl3, 400 MHz): δ 7.95 (s, 2H), 7.75 (s, 1H), 7.25 (s, 1H), 6.94 (dd, J = 5.0, 3.7 Hz, 1H), 6.91 (dd, J = 3.5, 1.2 Hz, 1H), 2.29 (dd, J = 13.1, 4.2 Hz, 1H), 2.23 (dd, J = 18.7, 4.2 Hz, 1H), 1.70 – 1.59 (m, 1H), 0.95 (t, J = 6.2 Hz, 3H), 0.76 (dd, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 152.4, 149.1, 131.5 (q, J = 33.2 Hz), 127.2, 126.2 (m), 125.8, 124.4, 123.6 (q, J = 272.7 Hz) 121.2 (hept, J = 3.1 Hz), 77.4, 52.2, 24.7, 24.6, 24.6. 19F NMR (CDCl3, 376 MHz): δ -62.8. HRMS (ESI-, m/z) calc. for 381.07423 [M-H]-, found 381.07504. The ee was determined by HPLC analysis (Chiracel-ODH, n-heptane/iPrOH 96:4, 0.5 mL/min). Retention time (min): 9.9 (minor) and 12.5 (major).
1-(4-bromophenyl)-3-methyl-1-(thiophen-2-yl)butan-1-ol (2d)
Product 2d was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [44% yield, 55% conversion, 56% ee].
1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.20 (dd, J = 5.0, 1.2 Hz, 1H), 6.90 (dd, J = 5.0, 3.6 Hz, 1H), 6.87 (dd, J = 3.6, 1.2 Hz, 1H), 2.24 (dd, J = 14.9, 5.8 Hz, 1H), 2.23 (s, 1H), 2.16 (dd, J = 14.4, 6.2 Hz, 1H), 1.72 – 1.62 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H).13C NMR (CDCl3, 101 MHz): 153.8, 145.3, 131.3, 127.8, 126.8, 125.2, 124.0, 121.2, 77.6, 52.2, 24.8, 24.7, 24.6. HRMS (ESI-, m/z) calc. for 323.00997 [M-H]-, found 323.01082. The ee was determined by HPLC analysis (Chiracel-OJH, n-heptane/iPrOH 97:3, 0.5 mL/min). Retention time (min): 18.2 (minor) and 21.3 (major).
1-(3-bromophenyl)-3-methyl-1-(thiophen-2-yl)butan-1-ol (2e)
Product 2e was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 5:1) [38% yield, 53% conversion, 42% ee].
separated. The aqueous layer is extracted with AcOEt (3µ5 mL) and the combined organic layers are dried with anhydrous MgSO4, filtered, and the solvent is evaporated in vacuo. The crude product is purified by flash chromatography on neutral aluminium oxide using mixtures of pentane and AcOEt as the eluent to obtain alcohols 2a-j.
3-methyl-1-phenyl-1-(thiophen-2-yl)butan-1-ol (2a)
Product 2a was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [24% yield, 42% conversion, 69% ee].
1H NMR (CDCl3, 400 MHz): δ 7.47 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.25 – 7.22 (m, 1H), 7.19 (dd, J = 5.0, 1.3 Hz, 1H), 6.90 (dd, J = 5.0, 3.6 Hz, 1H), 6.87 (dd, J = 3.6, 1.3 Hz, 1H), 2.28 (dd, J = 14.3, 5.4 Hz, 1H), 2.25 (s, 1H), 2.19 (dd, J = 14.4, 6.1 Hz, 1H), 1.75 – 1.64 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 154.3, 146.2, 128.1, 127.1, 126.6, 125.8, 124.8, 123.9, 77.9, 52.3, 24.7, 24.7, 24.6. HRMS (ESI-, m/z) calc. for 245.09946 [M-H]-, found 245.10072. The ee was determined by HPLC analysis (Chiracel-OJH, n-heptane/iPrOH 95:5, 0.5 mL/min). Retention time (min): 15.9 (major) and 17.0 (minor).
3-methyl-1-(thiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)butan-1-ol (2b)
Product 2b was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [64% yield, 88% conversion, 50% ee].
1H NMR (CDCl3, 400 MHz): δ 7.63 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.23 (dd, J = 5.0, 1.3 Hz, 1H), 6.94 (dd, J = 4.9, 3.6 Hz, 1H), 6.91 (dd, J = 3.6, 1.3 Hz, 1H) 2.33 (s, 1H) 2.32 (dd, J = 14.4, 5.3 Hz, 1H), 2.23 (dd, J = 14.4, 6.4 Hz, 1H), 1.76 – 1.61 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 153.41, 150.07, 129.3 (q, J = 32.4 Hz), 126.8, 126.2, 125.2, 125.1 (q, J = 3.8 Hz), 124.3 (d, J = 272.1 Hz), 124.1, 77.6, 52.1, 24.7, 24.6, 24.5. 19F NMR (CDCl3, 376 MHz): δ -62.4. HRMS (ESI-, m/z) calc. for 313.08685 [M-H]-, found 313.08779. The ee was determined by HPLC analysis (Chiracel-OJH, n-heptane/iPrOH 97:3, 0.5 mL/min). Retention time (min): 12.8 (minor) and 16.2 (major).
1-(3,5-bis(trifluoromethyl)phenyl)-3-methyl-1-(thiophen-2-yl)butan-1-ol (2c)
Product 2c was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [47% yield, 68% conversion, 35% ee].
1H NMR (CDCl3, 400 MHz): δ 7.95 (s, 2H), 7.75 (s, 1H), 7.25 (s, 1H), 6.94 (dd, J = 5.0, 3.7 Hz, 1H), 6.91 (dd, J = 3.5, 1.2 Hz, 1H), 2.29 (dd, J = 13.1, 4.2 Hz, 1H), 2.23 (dd, J = 18.7, 4.2 Hz, 1H), 1.70 – 1.59 (m, 1H), 0.95 (t, J = 6.2 Hz, 3H), 0.76 (dd, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 152.4, 149.1, 131.5 (q, J = 33.2 Hz), 127.2, 126.2 (m), 125.8, 124.4, 123.6 (q, J = 272.7 Hz) 121.2 (hept, J = 3.1 Hz), 77.4, 52.2, 24.7, 24.6, 24.6. 19F NMR (CDCl3, 376 MHz): δ -62.8. HRMS (ESI-, m/z) calc. for 381.07423 [M-H]-, found 381.07504. The ee was determined by HPLC analysis (Chiracel-ODH, n-heptane/iPrOH 96:4, 0.5 mL/min). Retention time (min): 9.9 (minor) and 12.5 (major).
1-(4-bromophenyl)-3-methyl-1-(thiophen-2-yl)butan-1-ol (2d)
Product 2d was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [44% yield, 55% conversion, 56% ee].
1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.20 (dd, J = 5.0, 1.2 Hz, 1H), 6.90 (dd, J = 5.0, 3.6 Hz, 1H), 6.87 (dd, J = 3.6, 1.2 Hz, 1H), 2.24 (dd, J = 14.9, 5.8 Hz, 1H), 2.23 (s, 1H), 2.16 (dd, J = 14.4, 6.2 Hz, 1H), 1.72 – 1.62 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H).13C NMR (CDCl3, 101 MHz): 153.8, 145.3, 131.3, 127.8, 126.8, 125.2, 124.0, 121.2, 77.6, 52.2, 24.8, 24.7, 24.6. HRMS (ESI-, m/z) calc. for 323.00997 [M-H]-, found 323.01082. The ee was determined by HPLC analysis (Chiracel-OJH, n-heptane/iPrOH 97:3, 0.5 mL/min). Retention time (min): 18.2 (minor) and 21.3 (major).
1-(3-bromophenyl)-3-methyl-1-(thiophen-2-yl)butan-1-ol (2e)
Product 2e was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 5:1) [38% yield, 53% conversion, 42% ee].
1H NMR (CDCl3, 400 MHz): δ 7.67 (t, J = 1.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 5.0, 1.2 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.91 (dd, J = 5.0, 3.6 Hz, 1H), 6.88 (dd, J = 3.6, 1.2 Hz, 1H), 2.24 (dd, J = 14.4, 5.4 Hz, 2H), 2.22 (s, 1H), 2.17 (dd, J = 14.4, 6.1 Hz, 1H), 1.75 – 1.62 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 153.5, 148.7, 130.2, 129.7, 129.0, 126.8, 125.2, 124.7, 124.1, 122.6, 77.5, 52.2, 24.8, 24.6, 24.6. HRMS (ESI-, m/z) calc. for 323.00997 [M-H]-, found 323.01091. The ee was determined by HPLC analysis (Chiracel-OJH, n-heptane/iPrOH 95:5, 0.5 mL/min). Retention time (min): 14.5 (minor) and 15.7 (major).
3-methyl-1-phenyl-1-(pyridin-2-yl)butan-1-ol (2f)
Product 2f was obtained as an yellow oil after column chromatography(silica gel, pentane:AcOEt 40:1) [39% yield, 47% conversion, 22% ee]. 1H NMR (CDCl3, 400 MHz): δ 8.48 (d, J = 4.7 Hz, 1H), 7.61 (td, J = 7.9, 1.7 Hz, 1H), 7.53 (dd, J = 8.4, 1.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.18 (dt, J = 3.8, 1.6 Hz, 1H), 7.16 – 7.11 (m, 1H), 5.98 (s, 1H), 2.28 (dd, J = 14.2, 5.4 Hz, 1H), 2.13 (dd, J = 14.2, 6.2 Hz, 1H), 1.82 – 1.69 (m, 1H), 0.90 (d, J = 6.7 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 164.3, 147.4, 147.3, 137.0, 128.3, 126.9, 126.1, 122.1, 120.9, 77.7, 49.7, 25.0, 24.6, 24.5. HRMS (ESI-, m/z) calc. for 240.13829 [M-H]-, found 240.1394. The ee was determined by HPLC analysis (Chiracel-ADH, n-heptane/iPrOH 98:2, 0.5 mL/min). Retention time (min): 12.5 (major) and 13.4 (minor).
1-(furan-2-yl)-3-methyl-1-phenylbutan-1-ol (2g)
Product 2g was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [28% yield, 50% conversion, 12% ee]. Due to the instability of the compound it could only be partially characterized.
1H NMR (CDCl3, 400 MHz): δ 7.43 – 7.39 (m, 2H), 7.34 – 7.29 (m, 3H), 7.25 – 7.21 (m, 1H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.20 (dd, J = 3.3, 0.8 Hz, 1H), 2.15 (dd, J = 14.4, 6.4 Hz, 1H), 2.07 (dd, J = 14.4, 5.3 Hz, 1H), 1.74 – 1.63 (m, 1H), 0.87 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H). The ee was determined by HPLC analysis (Chiracel-OJH,
n-heptane/iPrOH 95:5, 0.5 mL/min). Retention time (min): 13.4 (minor) and 14.9 (major).
1-(furan-2-yl)-3-methyl-1-(thiophen-2-yl)butan-1-ol (2h)
Product 2h was obtained as an orange oil after column chromatography (neutral aluminium oxide, pentane:AcOEt 10:1) [29% yield, 61% conversion, 16% ee]. Due to the instability of the compound it could only be partially characterized.
1H NMR (CDCl3, 400 MHz): δ 7.36 (dd, J = 1.8, 0.9 Hz, 1H), 7.21 (dd, J = 5.0, 1.3 Hz, 1H), 6.93 (dd, J = 5.0, 3.6 Hz, 1H), 6.90 (dd, J = 3.6, 1.3 Hz, 1H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 6.27 (dd, J = 3.3, 0.8 Hz, 1H), 2.57 (s, 1H), 2.21 (dd, J = 14.3, 6.2, 1H), 2.10 (dd, J = 14.3, 5.5, 1H), 1.81 – 1.70 (m, 1H), 0.85 (d, J = 6.7, 3H), 0.83 (d, J = 6.7, 3H). The ee was determined by HPLC analysis (Chiracel-ODH, n-heptane/iPrOH 99.5:0.5, 0.5 mL/min). Retention time (min): 8.6 (major) and 10.1 (minor).
3-methyl-1-(thiazol-2-yl)-1-(4-(trifluoromethyl)phenyl)butan-1-ol (2i)
Product 2i was obtained as an orange oil after column chromatography(neutral aluminium oxide, AcOEt: MeOH 20:1) [40% yield, 80% conversion, 6% ee].
1H NMR (CDCl3, 400 MHz): δ 7.78 (d, J = 8.2 Hz, 2H), 7.72 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.29 (s, 1H), 3.57 (s, 1H), 2.39 (dd, J = 14.6, 5.3 Hz, 1H), 2.29 (dd, J = 14.7, 6.6 Hz, 1H), 1.78 – 1.67 (m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 177.7, 142.3, 131.5, 129.6 (q, J = 32.6 Hz), 127.1, 125.4 (q, J = 3.7 Hz), 124.3 (q, J = 272.0 Hz), 120.0, 79.1, 51.6, 24.6, 24.6, 24.0. 19F NMR (CDCl3, 376 MHz): δ -62.5. HRMS [M-H]- Calc. for 314.08210, found 323.08305. HRMS (ESI-, m/z) calc. for 314.08210 [M-H]-, found 314.08305. The ee was determined by HPLC analysis (Chiracel-ADH, n-heptane/iPrOH 99:2, 0.5 mL/min). Retention time (min): 26.5 (minor) and 52.8 (major).
