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An efficient approach to gem-difluorocyclopropylstannanes via highly regio- and stereoselective hydrostannylation of gem-difluorocyclopropenes and their unique ring-opening reaction to afford β-fluoroallylic alcohols† T. Nihei, T. Hoshino and T. Konno* Treatment of various gem-difluorocyclopropenes with 1.2 equiv. of n-Bu3SnH in the presence of 20 mol% of Et3B at 80 °C for 4 h led to the quantitative formation of the hydrostannylated products in a highly regioand trans-selective manner. Additionally, the prepared trans-gem-difluorocyclopropylstannanes were
Received 9th January 2015, Accepted 6th February 2015
treated with 1.5 equiv. of MeLi in THF at −78 °C for 5 min, followed by quenching the reaction with various agents, such as H2O, alcohols, carboxylic acids, and tosylamide, to give the corresponding
DOI: 10.1039/c5ob00046g
β-fluoroallylic alcohols, ethers, esters, and amides respectively with exclusive Z selectivity in acceptable
www.rsc.org/obc
yields.
Introduction Cyclopropanes are the smallest saturated cycloalkanes and one of the most important synthetic units.1 The origin of their use in synthetic organic chemistry may be ascribed to the very unique structural features of cyclopropanes: owing to their significant ring strains, π-character of the carbon–carbon bond was remarkably enhanced, and as a result, the reaction behaviour is analogous to an alkene in certain cases. For such reasons, cyclopropanes have been paid much attention by many synthetic chemists from the viewpoint of their syntheses as well as synthetic applications.2 Incorporation of fluorine atom(s) into organic molecules often alters their structure, stability, and reactivity, which frequently leads to the discovery of their unexpected physical, chemical, and biological properties.3 Therefore, fluorine-containing substances have recently gained great interest in various fields, such as materials, medicinal, agricultural, and pharmaceutical sciences.4 Consequently, it is not surprising that much effort has been paid to the development of new synthetic methods for the preparation of various gem-difluorocyclopropanes.5–7
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585 Japan. E-mail: [email protected] † Electronic supplementary information (ESI) available: NMR spectra. See DOI: 10.1039/c5ob00046g
This journal is © The Royal Society of Chemistry 2015
Scheme 1
The present work.
In this article we wish to describe a novel synthesis of various gem-difluorocyclopropanes via a highly regio- and stereoselective radical hydrostannylation reaction of gemdifluorocyclopropenes (Scheme 1). In addition, we would also like to report a very unique ring-opening reaction involving defluorination of the gem-difluorocyclopropylstannanes to afford the corresponding β-monofluoroallylic alcohol derivatives in an exclusively Z-selective manner.8
Results and discussion Hydrostannylation of various gem-difluorocyclopropenes The various gem-difluorocyclopropenes 1a–j as starting materials were easily prepared through the reaction of various alkynes with commercially available TMSCF3 in the presence of NaI according to a reported procedure.9 Thus, treatment of 1.0 equiv. of alkynes with 2.0 equiv. of TMSCF3 and 2.2 equiv. of NaI in THF at 110 °C for 2 h in a sealed tube gave the corres-
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Organic & Biomolecular Chemistry
Scheme 2
Entry
X/mol%
Temp./°C
Yielda/% of 2a-trans
Recoverya/% of 1a
1 2 3 4 5 6b 7c 8c
20 20 20 10 0 20 20 20
0 rt 80 80 80 80 rt 60
81 81 Quant. (Quant.) 91 20 Quant. 0 0
19 19 0 9 80 0 Quant. 0
Determined by 19F NMR. The value in parentheses is of the isolated yield. b AIBN was used instead of Et3B. c Pd(PPh3)4 was used instead of Et3B.
was also obtained quantitatively (entry 6). In all cases, the product was trans adduct only, and no other stereoisomers could be detected at all. As shown in entry 7, palladiumcatalyzed hydrostannylation did not proceed at all and resulted in quantitative recovery of starting material 1a. In the palladium-catalyzed reaction at 60 °C, the desired hydrostannylated adduct was not detected at all, although 1a was completely consumed (entry 8). Having the optimized reaction conditions in hand, we examined the scope of this hydrostannylation using a variety of gem-difluorocyclopropenes as shown in Table 2. The hydrostannylation of symmetrical 1,2-diaryl-substituted gem-difluorocyclopropene 1b took place very smoothly to give the corresponding adduct 2b-trans in a highly stereoselective manner (entry 2). However, disappointingly, there was considerable deterioration of stereoselectivity in the case of symmetrical 1,2-dialkyl-substituted gem-difluorocyclopropene 1c (entry 3). In unsymmetrical 1,2-diaryl-substituted gem-difluoro-
Hydrostannylation of various types of gem-difluorocyclopropene derivatives
Entry
R1
R2
1 2 3 4 5 6 7 8 9 10
C6H5 p-MeC6H4 BnOCH2 p-MeC6H4 p-NCC6H4 C6H5 C6H5 C6H5 n-C10H21 BnOCH2
C6H5 p-MeC6H4 BnOCH2 C6H5 C6H5 Me BnOCH2 H H H
a
Hydrostannylation of gem-difluorocyclopropene 1a
a
Preparation of various gem-difluorocyclopropenes.
ponding gem-difluorocyclopropene derivatives 1 in good to excellent yields (Scheme 2). Initial studies on the hydrostannylation of gem-difluorocyclopropenes began with the reaction of 1a with n-Bu3SnH in the presence of Et3B, as shown in Table 1. Thus, treatment of 1.0 equiv. of 1a with 1.2 equiv. of n-Bu3SnH in the presence of 20 mol% of Et3B in toluene at 0 °C for 4 h gave the corresponding adduct 2a-trans in 81% yield with recovery of 1a in 19% yield (entry 1). Although raising the reaction temperature from 0 °C to room temperature did not result in any dramatic change (entry 2), when the reaction was conducted at 80 °C, on the other hand, the starting material 1a was completely consumed, and 2a-trans was obtained quantitatively (entry 3). As shown in entry 4, decreasing the amount of Et3B from 20 mol% to 10 mol% slightly influenced the yield; however the desired adduct was still obtained in 91% yield. It should be noted that the reaction proceeded even in the absence of a radical initiator to afford 2a-trans in 20% yield but with a large amount of unreacted starting material 1a (entry 5). When AIBN was used as a radical initiator instead of Et3B, 2a-trans Table 2
Table 1
a b c d e f g h i j
Yielda,b/% of 2
2 (trans : cis) : 3 (trans : cis)
Quant. (Quant.) 98 (96) 74 (65) 99 (99) 86 (80) 92 (76) Quant. (89) Quant. (78) Quant. (86) 78 (76)
(100 : 0) : — (100 : 0) : — (66 : 34) : — 55 (100 : 0) : 45 (100 : 0) 50 (100 : 0) : 50 (100 : 0) 100 (85 : 15) : 0 100 (90 : 10) : 0 100 (84 : 16) : 0 100 (50 : 50) : 0 100 (50 : 50) : 0
Determined by 19F NMR. b Values in parentheses are of isolated yields.
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cyclopropenes 1d and 1e, it was also revealed that the reaction proceeded in a highly stereoselective manner but in a low regioselective manner (entries 4 and 5). It should be noted that the use of monoarylated gem-difluorocyclopropenes – 1f, 1g and 1h – brought about a high regio- and stereoselection (entries 6–8). However, unsymmetrical monoalkyl-substituted gem-difluorocyclopropenes 1i and 1j underwent a stereorandom hydrostannylation reaction, although the regioselectivity was very high (entries 9 and 10). Stereochemical assignment of gem-difluorocyclopropylstannanes The stereochemical assignment of hydrostannylated products 2 and 3 was performed as follows. In both 2h-trans (major isomer) and 2h-cis (minor isomers), a signal of the Ha proton appears at 2.5–3.0 ppm, which is a much lower field than in the case of 1,1-difluorocyclopropane (
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PAPER
Cite this: Org. Biomol. Chem., 2015, 13, 3721
View Journal | View Issue
An efficient approach to gem-difluorocyclopropylstannanes via highly regio- and stereoselective hydrostannylation of gem-difluorocyclopropenes and their unique ring-opening reaction to afford β-fluoroallylic alcohols† T. Nihei, T. Hoshino and T. Konno* Treatment of various gem-difluorocyclopropenes with 1.2 equiv. of n-Bu3SnH in the presence of 20 mol% of Et3B at 80 °C for 4 h led to the quantitative formation of the hydrostannylated products in a highly regioand trans-selective manner. Additionally, the prepared trans-gem-difluorocyclopropylstannanes were
Received 9th January 2015, Accepted 6th February 2015
treated with 1.5 equiv. of MeLi in THF at −78 °C for 5 min, followed by quenching the reaction with various agents, such as H2O, alcohols, carboxylic acids, and tosylamide, to give the corresponding
DOI: 10.1039/c5ob00046g
β-fluoroallylic alcohols, ethers, esters, and amides respectively with exclusive Z selectivity in acceptable
www.rsc.org/obc
yields.
Introduction Cyclopropanes are the smallest saturated cycloalkanes and one of the most important synthetic units.1 The origin of their use in synthetic organic chemistry may be ascribed to the very unique structural features of cyclopropanes: owing to their significant ring strains, π-character of the carbon–carbon bond was remarkably enhanced, and as a result, the reaction behaviour is analogous to an alkene in certain cases. For such reasons, cyclopropanes have been paid much attention by many synthetic chemists from the viewpoint of their syntheses as well as synthetic applications.2 Incorporation of fluorine atom(s) into organic molecules often alters their structure, stability, and reactivity, which frequently leads to the discovery of their unexpected physical, chemical, and biological properties.3 Therefore, fluorine-containing substances have recently gained great interest in various fields, such as materials, medicinal, agricultural, and pharmaceutical sciences.4 Consequently, it is not surprising that much effort has been paid to the development of new synthetic methods for the preparation of various gem-difluorocyclopropanes.5–7
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585 Japan. E-mail: [email protected] † Electronic supplementary information (ESI) available: NMR spectra. See DOI: 10.1039/c5ob00046g
This journal is © The Royal Society of Chemistry 2015
Scheme 1
The present work.
In this article we wish to describe a novel synthesis of various gem-difluorocyclopropanes via a highly regio- and stereoselective radical hydrostannylation reaction of gemdifluorocyclopropenes (Scheme 1). In addition, we would also like to report a very unique ring-opening reaction involving defluorination of the gem-difluorocyclopropylstannanes to afford the corresponding β-monofluoroallylic alcohol derivatives in an exclusively Z-selective manner.8
Results and discussion Hydrostannylation of various gem-difluorocyclopropenes The various gem-difluorocyclopropenes 1a–j as starting materials were easily prepared through the reaction of various alkynes with commercially available TMSCF3 in the presence of NaI according to a reported procedure.9 Thus, treatment of 1.0 equiv. of alkynes with 2.0 equiv. of TMSCF3 and 2.2 equiv. of NaI in THF at 110 °C for 2 h in a sealed tube gave the corres-
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Scheme 2
Entry
X/mol%
Temp./°C
Yielda/% of 2a-trans
Recoverya/% of 1a
1 2 3 4 5 6b 7c 8c
20 20 20 10 0 20 20 20
0 rt 80 80 80 80 rt 60
81 81 Quant. (Quant.) 91 20 Quant. 0 0
19 19 0 9 80 0 Quant. 0
Determined by 19F NMR. The value in parentheses is of the isolated yield. b AIBN was used instead of Et3B. c Pd(PPh3)4 was used instead of Et3B.
was also obtained quantitatively (entry 6). In all cases, the product was trans adduct only, and no other stereoisomers could be detected at all. As shown in entry 7, palladiumcatalyzed hydrostannylation did not proceed at all and resulted in quantitative recovery of starting material 1a. In the palladium-catalyzed reaction at 60 °C, the desired hydrostannylated adduct was not detected at all, although 1a was completely consumed (entry 8). Having the optimized reaction conditions in hand, we examined the scope of this hydrostannylation using a variety of gem-difluorocyclopropenes as shown in Table 2. The hydrostannylation of symmetrical 1,2-diaryl-substituted gem-difluorocyclopropene 1b took place very smoothly to give the corresponding adduct 2b-trans in a highly stereoselective manner (entry 2). However, disappointingly, there was considerable deterioration of stereoselectivity in the case of symmetrical 1,2-dialkyl-substituted gem-difluorocyclopropene 1c (entry 3). In unsymmetrical 1,2-diaryl-substituted gem-difluoro-
Hydrostannylation of various types of gem-difluorocyclopropene derivatives
Entry
R1
R2
1 2 3 4 5 6 7 8 9 10
C6H5 p-MeC6H4 BnOCH2 p-MeC6H4 p-NCC6H4 C6H5 C6H5 C6H5 n-C10H21 BnOCH2
C6H5 p-MeC6H4 BnOCH2 C6H5 C6H5 Me BnOCH2 H H H
a
Hydrostannylation of gem-difluorocyclopropene 1a
a
Preparation of various gem-difluorocyclopropenes.
ponding gem-difluorocyclopropene derivatives 1 in good to excellent yields (Scheme 2). Initial studies on the hydrostannylation of gem-difluorocyclopropenes began with the reaction of 1a with n-Bu3SnH in the presence of Et3B, as shown in Table 1. Thus, treatment of 1.0 equiv. of 1a with 1.2 equiv. of n-Bu3SnH in the presence of 20 mol% of Et3B in toluene at 0 °C for 4 h gave the corresponding adduct 2a-trans in 81% yield with recovery of 1a in 19% yield (entry 1). Although raising the reaction temperature from 0 °C to room temperature did not result in any dramatic change (entry 2), when the reaction was conducted at 80 °C, on the other hand, the starting material 1a was completely consumed, and 2a-trans was obtained quantitatively (entry 3). As shown in entry 4, decreasing the amount of Et3B from 20 mol% to 10 mol% slightly influenced the yield; however the desired adduct was still obtained in 91% yield. It should be noted that the reaction proceeded even in the absence of a radical initiator to afford 2a-trans in 20% yield but with a large amount of unreacted starting material 1a (entry 5). When AIBN was used as a radical initiator instead of Et3B, 2a-trans Table 2
Table 1
a b c d e f g h i j
Yielda,b/% of 2
2 (trans : cis) : 3 (trans : cis)
Quant. (Quant.) 98 (96) 74 (65) 99 (99) 86 (80) 92 (76) Quant. (89) Quant. (78) Quant. (86) 78 (76)
(100 : 0) : — (100 : 0) : — (66 : 34) : — 55 (100 : 0) : 45 (100 : 0) 50 (100 : 0) : 50 (100 : 0) 100 (85 : 15) : 0 100 (90 : 10) : 0 100 (84 : 16) : 0 100 (50 : 50) : 0 100 (50 : 50) : 0
Determined by 19F NMR. b Values in parentheses are of isolated yields.
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cyclopropenes 1d and 1e, it was also revealed that the reaction proceeded in a highly stereoselective manner but in a low regioselective manner (entries 4 and 5). It should be noted that the use of monoarylated gem-difluorocyclopropenes – 1f, 1g and 1h – brought about a high regio- and stereoselection (entries 6–8). However, unsymmetrical monoalkyl-substituted gem-difluorocyclopropenes 1i and 1j underwent a stereorandom hydrostannylation reaction, although the regioselectivity was very high (entries 9 and 10). Stereochemical assignment of gem-difluorocyclopropylstannanes The stereochemical assignment of hydrostannylated products 2 and 3 was performed as follows. In both 2h-trans (major isomer) and 2h-cis (minor isomers), a signal of the Ha proton appears at 2.5–3.0 ppm, which is a much lower field than in the case of 1,1-difluorocyclopropane (
