Palladium-Catalyzed One-Pot Conversion of Aldehydes and Ketones

Article pubs.acs.org/joc

Palladium-Catalyzed One-Pot Conversion of Aldehydes and Ketones into 4‑Substituted Homopropargyl Alcohols and 5‑En-3-yn-1-ols† Christian A. Umaña and Jorge A. Cabezas* Escuela de Química, Universidad de Costa Rica, San José, 2060, Costa Rica S Supporting Information *

ABSTRACT: Sequential treatment of 2,3-dichloropropene with magnesium and n-BuLi generated the equivalent of 1,3dilithiopropyne, which adds regiospecifically to aldehydes and ketones to produce homopropargyl alcohols. The lithium acetylide intermediate formed in this protocol can be further reacted with aromatic and vinyl halides, under palladium catalysis, to produce 4-substituted homopropargyl alcohols and 5-en-3-yn-1-ols, respectively, in one-pot with good overall yields.

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INTRODUCTION Homopropargyl alcohols are useful building blocks in the synthesis of a wide variety of organic compounds of natural1 and synthetic origin.2 Their synthesis usually involves reaction of monoanionic propargyl (1) or allenyl (2) organometallic reagents, with a carbonyl compound. The major drawback of this methodology comes from the tendency of such ambident nucleophiles to produce mixtures of both homopropargyl (3) and allenic (4) alcohols, which are difficult to separate (Scheme 1). These mixtures are normally obtained because, the allenic (2) and propargylic (1) organometallic species generally coexist in equilibrium.3

Zinc and magnesium propargylic derivatives couple with aromatic or aliphatic aldehydes to produce mixtures of allenic and homopropargyl alcohols.7a Addition of 1-trimethylsilylpropyne-3-zinc bromide to aldehydes and ketones produces mainly homopropargyl alcohols, but addition of the corresponding aluminum derivative produces the allenyl alcohol.7b The regiochemistry of the reaction using propargylic titanium reagents is highly dependent upon the substitution of the organometallic.4g,8 Propargylation, a three-carbon homologation, is a very useful chemical transformation often employed in isoprenoid-related syntheses.9 However, it is frequently difficult to accomplish cleanly, and mixtures of allenic and acetylenic products are generally obtained.10 An indirect procedure employing 3-lithio1-trimethylsilylpropyne initially produces the trimethylsilylprotected acetylene, from which the required homologated alkyne is liberated by reaction with ethanolic silver nitrate followed by sodium cyanide.11 We previously reported12 the preparation of the operational equivalent of the propargyl dianion (5) from treatment of allene (6) with 2 equiv of n-BuLi (Scheme 2). This dianion (5) regiospecifically reacted with aromatic aldehydes and ketones to produce homopropargyl alcohols (3) in very good yields (Scheme 2, method A).13 An additional advantage of this methodology is that the initially formed lithium acetylide intermediate (7) may be further transformed, in situ, into other derivatives (8) by adding electrophiles such as paraformaldehyde, iodomethane, trimethylsilyl chloride, and ethyl chloroformate.12,14 When this methodology was used with aliphatic aldehydes or ketones, mixtures of allenic and acetylenic isomers, favoring the latter (2:8), were obtained. Fortunately, we found that these mixtures of allenyl and homopropargyl alcohols can be

Scheme 1. Generation of Mixtures of 3 and 4 from Organometallics 1 or 2

Numerous methods for the synthesis of homopropargyl alcohols have been developed using organometallic reagents,4 based on metals such as Zn,4a,b Al,4c Mg,4d Sn,4e,f Ti,4g,h Zr,4i Sm,4j Ba,4k In,4l Pd,4m and Li,4n and metalloids, such as Si5a,b and B;5c−e however, in many of these methodologies, the regiochemistry of the product is highly dependent upon steric hindrance and substitution of the organometallic, as well as solvation and the nature of the metal. Allenyllithium reagents, for example, react with aliphatic ketones, producing mainly allenyl alcohols,4n whereas reaction with aromatic carbonyl compounds generates homopropargyl alcohols in poor yields.6 © 2017 American Chemical Society

Received: June 20, 2017 Published: August 25, 2017 9505

DOI: 10.1021/acs.joc.7b01529 J. Org. Chem. 2017, 82, 9505−9514

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The Journal of Organic Chemistry Scheme 2. Our Previous Methods for the Synthesis of Homopropargyl Alcohols

Scheme 3. Preliminary Cross-Coupling Reactions between 11 and 12

and bishomopropargyl alcohols,15 1,5-diynes,21 and insect pheromones.21 One of our interests has been to use lithium acetylide intermediate 7 to perform, in situ, palladium-catalyzed crosscoupling chemistry. Thus, reaction of intermediate 7 with aromatic or vinyl halides, under palladium catalysis, would produce 4-substituted homopropargyl alcohols in a one-pot reaction. We report herein a modified procedure for a small-scale synthesis of allene (6), the development of a new protocol for the preparation of dianion 5, its highly regioselective reaction with aldehydes and ketones to produce homopropargyl alcohols (3), and the efficient palladium cross-coupling reaction of lithium acetylide intermediate 7 to produce acetylenesubstituted homopropargyl alcohols (8) in very good yields and in a one-pot reaction.

quantitatively converted to the corresponding homopropargyl alcohols by a zipper reaction.15 Although this method (Scheme 2, method A) produces homopropargyl alcohols, 3, in very good yields, the high cost of allene (6) restricts its use. To overcome this inconvenience, we developed a new procedure14 for the preparation of dianion 5. We envisioned that 1,3-dilithiopropyne (5) (or its equivalent) could be prepared from reaction of propargyl bromide (9) with n-butyllithium at −78 °C; thus, the acid−base reaction of the acetylenic proton of 9, followed by halogen−metal exchange, would produce 5 (Scheme 2, method B). We found that this halogen−metal exchange requires the presence of tetramethylethylenediamine (TMEDA). We prepared a series of homopropargyl alcohols by this methodology (method B)14 and found that results were comparable with those previously obtained by method A.13 This procedure (method B)14 has been successfully applied by others in the synthesis of biologically active compounds such as amphidinol 3,16 landomycin A,17,18 coenzyme Q-10,19 and other pharmacologically active compounds. 20 We have successfully used this methodology to prepare homopropargyl14

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RESULTS AND DISCUSSION Initial palladium cross-coupling reactions were performed with acetylide intermediate 11 (Scheme 3). Thus, benzophenone 9506


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The Journal of Organic Chemistry Table 1. Preparation of 1,1,4-Triphenyl-3-butyn-1-ol (13) from 11

a

entry

preparation of 11

time (h)

13 (%)

14 (%)

1 2 3 4 5 6

9 + n-BuLi (2 equiv) + TMEDA (method B) 9 + n-BuLi (2 equiv) + TMEDA (method B) 14 + n-BuLi (2 equiv) + TMEDA 14 + n-BuLi (2 equiv) 14 + PhBr, Pd(PPh3)4, CuI, Et3Na 14 + n-BuLi (2 equiv) + PhBr, Pd(PPh3)4

18 72 18 18 18 18

27 25 0 13 20 0

73 75 100 87 80 100

Sonogashira conditions.

Scheme 4. Preparation of Dianion 5 from 2,3-Dihalopropenes 15 and 16

with n-BuLi (2 equiv) to generate lithium acetylide intermediate 11, and this was reacted sequentially with copper iodide, bromobenzene (12), and Pd(PPh3)4 (Scheme 3) in the presence of TMEDA, with overnight stirring at room temperature (Table 1, entry 3). After aqueous workup, the unreacted alcohol 14 was recovered. In another reaction, intermediate 11 was prepared from alcohol 14 as described, and the above cross-coupling reaction (Table 1, entry 3) was repeated in the absence of TMEDA. After stirring at room temperature overnight and aqueous workup, 1,1,4-triphenyl-3butyn-1-ol (13) was obtained in 13% yield (Table 1, entry 4). We alternatively explored synthesizing alcohol 13 through a classical Sonogashira approach. Thus, reaction of acetylenic alcohol 14 with bromobenzene (12) generated product 13 in only 20% yield (Table 1, entry 5). By comparison, reaction of intermediate 11 (prepared by treatment of 14 with 2 equiv of nBuLi) with bromobenzene (12) and Pd(PPh3)4, in absence of CuI, failed to yield product 13, and only homopropargyl alcohol 14 was recovered (Table 1, entry 6). From these experiments (Table 1, entries 1−4), it was concluded that palladium-catalyzed cross-coupling reaction of intermediate 11 was not clean because of the tendency of TMEDA to form a chelate with palladium. Furthermore, it was noticed that a catalytic amount of CuI is needed for the crosscoupling to occur (Table 1, entries 5 and 6).

(10) was reacted with dianion 5, generated from propargyl bromide (9) and n-BuLi in the presence of TMEDA, at −78 °C (method B),14 and the reaction mixture was warmed to room temperature to obtain intermediate 11 (Scheme 3). A THF solution of bromobenzene (12) and tetrakis(triphenylphosphine)palladium(0) was added to this reaction mixture, followed by addition of copper iodide, and the mixture stirred overnight at room temperature. After stirring for 18 h, a mixture of the desired cross-coupling product 13 (27%) and the homopropargyl alcohol 14 (73%) was obtained (Scheme 3, Table 1, entry 1). The reaction was repeated using a longer reaction time for the palladium cross-coupling, and after stirring at room temperature for 72 h, the yield of product 13 did not improve (25%) (Table 1, entry 2). Several examples of chelate complexes between palladium and TMEDA and its derivatives have been reported.22 In our case, it is possible that TMEDA coordinates so strongly with palladium that the latter is not able to undergo an efficient oxidative addition with bromobenzene (12). In fact, a chelate complex between palladium(II) chloride with 1 equiv of TMEDA is commercially available: dichloro(N,N,N′,N′tetramethylethylenediamine)palladium(II). To determine if the presence of TMEDA was adversely affecting the palladium cross-coupling reaction, model reactions were performed. First, homopropargyl alcohol 14 was treated 9507


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The Journal of Organic Chemistry

Table 2. Production of Homopropargyl Alcohol 14, from 2,3-Dihalopropenes 15 and 16 by Treatment with t-BuLi and n-BuLi

yield (%) entry

dihalopropene (equiv)

1 2 3 4 5 6 7

15 16 16 16 16 16 16

t-BuLi (equiv)

n-BuLi (equiv)

PhCOPh, 10 (equiv)

14

21

22

5.70 2.85 5.70 5.70 11.76 2.86 5.71

2.00 0 0 1.00 4.12 1.00 2.00

1.00 1.00 1.00 1.00 1.00 1.00 1.00

2 0 5 0 7 18 21

68 98 91 85 44 48 60

24 0 0 10 36 24 12

(2.85) (2.85) (2.85) (2.85) (5.88) (2.85) (2.85)

Table 3. Preparation of Homopropargyl Alcohol 14, from 2,3-Dihalopropenes 15 and 16

yield (%) entry 1 2 3 4 5 6 7 8 9

dihalopropene (equiv) 16 16 16 15 15 15 15 15 15

(6.1) (5.9) (33.3) (36.4) (36.4) (121.0) (45.4) (15.3) (33.3)

Mg (equiv)

n-BuLi (equiv)

PhCOPh, 10 (equiv)

ratio 5/10

14

21a

22a

18.2 17.6 20.0 60.6 60.6 388.0 193.9 50.4 106.7

4.2 4.1 4.7 8.4 8.4 8.4 4.2 2.1 2.8

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

2.1 2.1 2.3 4.2 4.2 4.2 2.1 1.1 1.4

4 20 22 18 52 95 100 98 100

54 48 63 60 33 0 0 0 0

42 32 15 22 15 0 0 0 0

a

Compounds 21 and 22 were not isolated. They were identified by comparison with authentic samples. Yields were calculated by 1H NMR and capillary GC analysis.

incomplete metal−halogen exchange of 16 (or 15) with t-BuLi, which would result in a low yield of allene (6) (Scheme 4). Using different amounts of t-BuLi and n-BuLi did not improve the yield of alcohol 14 beyond 21% (Table 2, entry 7). Surprisingly, treatment of 16, with 1 or 2 equiv of t-BuLi, followed by addition of benzophenone (10), did not produce alcohol 14 in appreciable amounts (Table 2, entries 2 and 3). Increasing amounts of n-BuLi slightly improved the yield of alcohol 14 (Table 2, entries 4 and 5). In almost all reactions, unidentified byproducts were obtained in yields ranging from 2 to 13% (by GC). The lithiation of 2,3-dihalopropenes 15 and 16 with t-BuLi was complex. Apparently the use of TMEDA is needed for complete metalation.23 An alternative metal−halogen exchange methodology might be use of an excess of lithium powder with a catalytic amount of an arene, such as naphthalene24 or 4,4′-ditert-butylbiphenyl (DTBB).25 It is known that allene (6) can be prepared from 2,3dichloropropene (15) and excess zinc dust in refluxing ethanol.26 In this procedure,26 2,3-dichloropropene was added dropwise over a refluxing suspension of zinc dust in 95% ethanol and water in a 5:1 ratio. The same report26 indicated that allene, prepared by this methodology, contained up to 3% of 2-chloropropene. In an alternative method, 2,3-dichloropro-

To overcome this difficulty, a new protocol for the preparation of dianion 5, without the presence of TMEDA, was developed. New Protocol for Preparation of Dianion 5. It was envisioned that a 2,3-dihalopropene (15 or 16) could be a starting material for the preparation of dianion 5. Thus, 2,3dibromopropene (16) [or 2,3-dichloropropene (15)] was treated with tert-BuLi, at −78 °C, to promote metal−halogen exchange and generate 2-bromo-3-lithiopropene (17) (or 3bromo-2-lithiopropene) that could undergo 1,2-elimination to generate allene (6), the treatment of which with n-BuLi was expected to produce 1,3-dilithiopropyne (5) as in method A (Scheme 2). The efficiency of this procedure was indirectly corroborated by reacting intermediate 5 with benzophenone (10) to obtain the corresponding homopropargyl alcohol 14 (Scheme 4) This protocol was performed under different conditions, all of which produced alcohol 14 in very poor yields (Table 2). In all cases, reduction of benzophenone (10) produced benzhydrol (21) as a major byproduct (Table 2). An additional common byproduct was 1,1-diphenylpentan-1-ol (22) obtained from the addition of remnant n-BuLi to benzophenone (10). The presence of the latter compound (22) was an indication of the incomplete metalation of allene (6) with n-BuLi or the 9508


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The Journal of Organic Chemistry pene was reacted with tellurium in the system hydrazine hydrate−KOH.27 We did not use the above procedure due to the possibility of generating allene containing traces of water and ethanol. In our protocol, the allene is reacted with n-BuLi, and thus, presence of water and ethanol would be detrimental. Moreover, the presence of high levels of 2-chloropropene as an impurity is likely to generate side products under our reaction conditions. Rather, we decided to use a more simple approach employing magnesium, instead of zinc, and dry tetrahydrofuran as solvent. We envisioned that Grignard reagent 19 (or 20) could undergo a β-elimination to produce allene (6) (Scheme 4), which in turn could be directly metalated with n-BuLi, as in our previous procedure.12 The starting Grignard reagent can be easily prepared at room temperature without any external heating. Initial reactions of 2,3-dibromopropene (16) with magnesium, to form Grignard 19, followed by treatment with n-BuLi and addition of benzophenone (10) (Scheme 4) resulted in formation of alcohol 14, in 4% yield (Table 3, entry 1) accompanied by several unidentified byproducts. This reaction was performed in the same flask, equipped with a dry ice condenser to avoid loss of allene. We decided to prepare allene (6) by this procedure but bubbling this gas into a different flask containing a mixture of n-BuLi in diethyl ether, at −78 °C, and follow this by addition of benzophenone (10). Using these conditions, the yield of homopropargyl alcohol 14 increased to 20% (Table 3, entry 2). A large excess of 2,3-dibromopropene (16) did not improve the yield of 14, instead benzhydrol (21) was obtained in 63% (Table 3, entry 3). Formation of Grignard 19 from 2,3-dibromopropene (16) was a vigorous and exothermic reaction; therefore, to prevent loss of allene (6), we used a less reactive starting material, 2,3dichloropropene (15) to form related Grignard 20. When dichloropropene (15) was treated sequentially with magnesium, n-BuLi, and benzophenone (10), homopropargyl alcohol 14 was obtained in 18% yield (Table 3, entry 4). It was surprising that a significant amount of 1,1diphenylpentan-1-ol (22) was obtained in all previous reactions (15−42%, Table 3, entries 1−4). We initially presumed that a large excess of allene (6) was being generated from 2,3-dihalopropenes 15 and 16, but significant amounts of n-BuLi were unreacted by the time benzophenone (10) was added (yield of 22 = 15−42%, Table 3, entries 1−4). We then considered it likely that allene (6) might either not be formed in significant amounts or was being lost. To corroborate the formation of allene (6), a gas sample was taken from the allene generation flask and analyzed by GC− MS. This analysis showed the presence of allene (6) (M+ = 40.1) (Figure 1), which gave a spectrum in agreement with the NIST database.28 The peak at m/z 32.1 corresponds to molecular oxygen. In the previous reactions (Table 3, entries 1−4), allene (6) generated from the 2,3-dihalopropenes (15 and 16) was bubbled into a second flask, containing n-BuLi in a mixture hexanes:ether at −78 °C, and this flask was equipped with a dry ice condenser connected to a vacuum manifold and a glycerin bubbler. The reaction was repeated under identical conditions used in entry 4 (Table 3), but the dry ice condenser was connected to a balloon, instead of a manifold. The balloon inflated due to allene generation and as allene was bubbled into the n-BuLi solution. The reaction was stirred at −78 °C for 1 h, by which time the balloon deflated. Benzophenone (10),

Figure 1. Mass spectrum of the gas sample taken from the allene generator.

dissolved in ether, was added to this reaction mixture, followed by warming to room temperature, as in all previous experiments. In this case, the yield of 14 marginally improved to 52% (Table 3, entry 5). When the reaction was repeated using larger amounts of magnesium and the ratio between dianion 5 and benzophenone (10) was lowered, the homopropargyl alcohol 14 was obtained in excellent yields (95−100%, Table 3, entries 6−9). The most reproducible results were obtained when a ratio 5/10 of 1.4 was used (Table 3, entry 9). Homopropargyl Alcohols. To demonstrate the reproducibility of this methodology (method C) and to compare its efficiency against the previous protocols (methods A and B), several homopropargyl alcohols were prepared (Table 4). Alcohols prepared by this procedure were obtained in comparable (Table 4, entries 3 and 4) or higher (Table 4, entries 1 and 2) yields than with our previous methods. When dianion 5 was reacted with hexanal (31), a mixture of the corresponding homopropargyl 32 (91%) and allenyl 33 (9%) alcohols was obtained (Table 4, entry 6). This result is in agreement with our previous findings13,15 that as the carbonyl group of the aldehyde or ketone becomes “harder” (aromatic vs aliphatic), a significant amount of allenic derivative is obtained, presumably as a result of the nucleophilic addition from the harder end of the isomeric form of the ambident dianion 5 (Scheme 5). Fortunately, when this crude reaction was treated with potassium 3-aminopropylamide (KAPA), allenyl alcohol 33 was completely isomerized to homopropargyl alcohol 32. This result validates the mechanism of the “zipper” reaction,29 where isomerization of internal acetylenes to terminal acetylenes proceeds via a series of deprotonation and allenyl−propargyl rearrangements, and an allenyl species has been proposed as an intermediate30 (Scheme 6). As previously established, the advantage of this methodology is that the initially formed lithium acetylide (11) can be further reacted with a second electrophile. Thus, addition of a second electrophile, such as paraformaldehyde, to the lithium acetylide intermediate 11 resulted in the formation of 69% of diol 34 in a one-pot reaction (Table 4, entry 7). In Situ Synthesis of Substituted Homopropargyl Alcohols. The main objective of this project was to use lithium acetylide intermediates (e.g., 11) to perform, in situ, palladium-catalyzed cross-coupling chemistry and to prepare 4(substituted) homopropargyl alcohols in a one-pot reaction. Thus, benzophenone (10) was reacted at −78 °C with 1,3dilithiopropyne (5) prepared from 2,3-dichloropropene (15) as previously described (method C). The reaction was allowed to warm to room temperature and a THF solution of bromobenzene (12) and Pd(PPh3)4 was added, followed by addition of copper iodide. The reaction was stirred at room temperature overnight, and after aqueous workup and column 9509


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To show the wide applicability of this protocol, tolerance to diverse functional groups, and its application to the synthesis of highly substituted homopropargyl alcohols, several compounds were prepared (Table 5). To favor the palladium oxidative addition step, we used aromatic iodides. Thus, addition of 1,3dilithiopropyne (5) (prepared by method C, Tables 3 and 4) to acetophenone (23) followed by the addition of o-iodotoluene (36), PdCl2(PPh3)2, and CuI resulted in, after stirring overnight and column chromatography, the production of 5-(o-tolyl)-2phenyl-4-pentyn-2-ol (37), in 80% yield (Table 5, entry 3). Treatment of acetophenone (23) under identical conditions and using 2-iodoanisole (38) as electrophile and Pd(PPh3)4 resulted in the formation of 5-(o-methoxyphenyl) 2-phenyl-4pentyn-2-ol (39) in 96% yield in a one-pot reaction (Table 5, entry 4). Reaction of acetophenone (23) with dianion 5, followed by treatment with p-iodonitrobenzene (40) and palladium catalysis, generated 5-(p-nitrophenyl)-2-phenyl-4pentyn-2-ol (41) in 89% yield (Table 5, entry 5). Particularly interesting was the preparation of highly substituted 4-(4′,4′-diphenyl-4′-hydroxy-1′-butynyl)acetophenone (43) in 63% overall yield (Table 5, entry 6). In this case, the cross-coupling reaction of acetylide intermediate 11 with 4′-iodoacetophenone (42) was very successful and no addition to the carbonyl group was observed. Reaction of lithium acetylide intermediate 11 with 2iodothiophene (44) under palladium catalysis yielded 4-(2′thiophenyl)-1,1-diphenyl-3-butyn-1-ol (45) in 69% overall yield (Table 5, entry 7). This procedure is particularly useful in the synthesis of highly functionalized conjugated enynes. Palladium-catalyzed coupling of intermediate 11 with trans-1-iodo-1-pentene (46) yielded trans-1,1-diphenyl-5-nonen-3-yn-1-ol (47) in 55% overall yield from benzophenone (Table 5, entry 8). Coupling of acetophenone (23) with 5, followed by treatment with cisdichloroethene (48) under palladium catalysis, led to the formation of cis-7-chloro-2-phenyl-6-hepten-4-yn-2-ol (49) in 62% yield (Table 5, entry 9).

Table 4. Conversion of Aldehydes and Ketones into Homopropargyl Alcohols

Scheme 5. Ambident Character of Dianion 5

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CONCLUSIONS

In summary, we have further developed and improved a method for the synthesis of allene, from treatment of 2,3dichloropropene with magnesium in dry THF. In contrast to the previous method,26 our preparation of allene can be executed easily, under milder conditions and dry atmosphere. Thus, the allene generated through our methodology can be metalated without any further purification. This represents a vast improvement on the previously reported26 procedure, which is performed under aqueous conditions. We then used the allene, generated using our protocol, to develop a new TMEDA-free procedure for the preparation of one operational equivalent of propargyl dianion 5 that can be used for the

chromatography, 1,1,4-triphenyl-3-butyn-1-ol (13) was obtained, in 45% yield (Table 5, entry 1). As expected, the use of chlorobenzene (35) gave a lower yield (33%, Table 5, entry 2). When the above palladium-catalyzed cross-coupling between intermediate 11 and bromobenzene (12) was attempted without CuI, product 13 was obtained in only 7% yield and alcohol 14 was recovered in 81% yield. This result is consistent with the previous cross-coupling attempted without copper (Table 1, entry 6). Scheme 6. Isomerization of 33 into 32

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The Journal of Organic Chemistry Table 5. One-Pot Conversion of Aldehydes and Ketones into 4-Substituted-Homopropargyl Alcohols

with stainless-steel needles. All reactions were carried out under a positive pressure of nitrogen. Nitrogen was passed through a Drierite gas-drying unit prior to use. Diethyl ether and tetrahydrofuran were refluxed and freshly distilled from sodium and potassium/benzophenone ketyl, respectively, under nitrogen atmosphere. Hexane was distilled from sodium and collected and kept over activated molecular sieves. n-Butyllithium was titrated according to the method of Watson and Eastham.31 Pd(PPh3)4, PdCl2(PPh3)2, and CuI were transferred in a glovebox. 1H NMR and 13C NMR spectra were recorded on a 400 MHz Bruker spectrometer. Low-resolution mass spectra were obtained on a Agilent Technologies 7820A GC coupled to a mass spectrometer 5977E unit using electron impact at 70 eV. Hig-resolution mass spectra were measured on a Waters Synapt HMDS G1, Q-TOF. Infrared spectra were recorded on a PerkinElmer FT-IR Spectrum 1000. General Procedure for the Synthesis of 4-(Substituted) Homopropargyl Alcohols. Preparation of 1,3-Dilithiopropyne (5). An oven-dried, 100 mL, three-necked, round-bottomed flask was equipped with a magnetic stirring bar and a Liebig condenser bearing a glycerin bubbler at the top. The exit of the glycerin bubbler was connected, by means of Tygon tubing, to a double-tipped needle. The other end of this needle was inserted, through a rubber septum, into a single-necked flask equipped with a magnetic stirring bar and capped

conversion of aldehydes and ketones into homopropargyl alcohols (method C). This new procedure has an economic advantage over our previous method A, which uses allene gas to prepare dianion 5. Preparation of 5 using method C is about 2.5 times cheaper than using method A. Furthermore, our new method C represents an improvement over our previous method B because it is TMEDA-free, enabling further palladium-catalyzed functionalization of lithium acetylide intermediates. Thus, the lithium acetylide intermediates obtained in this procedure can be further reacted, under palladium catalysis, to obtain highly functionalized disubstituted homopropargyl alcohols in a one-pot reaction. This synthetic methodology tolerates the presence of different functionalities, such as ether, carbonyl, or nitro groups, in the palladium crosscoupling reaction. This procedure can also be applied in the one-pot synthesis of highly substituted enynes.

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EXPERIMENTAL SECTION

General Information. All glassware and syringes were dried in an oven overnight at 140 °C and flushed with nitrogen immediately prior to use. Transfers of reagents were performed with syringes equipped 9511


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HRMS (ESI, V+): m/z [M + H]+ calcd for C12H16NO 190.1232, found 190.1232. 5,5-Diphenyl-2-pentyn-1,5-diol (34). Yield: 0.104 g, 69%. IR (KBr): νmax 3338, 3257, 2916, 1446, 1188, 1049, 1009 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.44 (m, 4H), 7.33 (m, 4H), 7.26 (m, 2H), 4.17 (dd, J = 2.0 Hz, 2H), 3.20 (t, J = 2.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 145.5, 128.2, 127.3, 126.1, 82.7, 82.2, 77.4, 51.4, 33.8. MS (EI): m/z (rel intensity) 39.1 (4), 77.1 (47), 105.0 (95), 183.1 (100). HRMS (ESI, V+): m/z [M + Na]+ calcd for C17H16O2Na 275.1048, found 275.1052. Mp = 82−83 °C. 1-Nonyn-4-ol (32). Yield: 0.083, 99%. IR (film): vmax 3349, 3311, 2931, 2119, 1460, 1425, 1078, 1037 cm−1. 1H NMR (400 MHz, CDCl3): δ 3.66 (m, 1H), 2.42 (ddd, J = 2.7, 4.7, 16.8 Hz, 1H), 2.31 (ddd, J = 2.7, 6.8, 16.8 Hz, 1H), 2.04 (t, 1H), 1.53 (m, 2H), 1.40−1.25 (m, 6H), 0.88 (t, 3H). 13C NMR (100 MHz, CDCl3): δ 81.1, 70.9, 70.0, 36.3, 31.9, 27.5, 25.4, 22.7, 14.1. MS (EI): m/z (rel intensity) 39.0 (27), 41.1 (47), 55.0 (96), 83.1 (100), 101.0 (38). HRMS (ESI, V+): m/z [M + H]+ calcd for C9H17O 141.1279, found 141.1279. 2-Phenyl-5-(o-tolyl)-4-pentyn-2-ol (37). Yield: 0.120 g, 80%. IR (film): νmax 3554, 3429, 2222, 1601, 1485, 1446, 1069 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.55 (m, 2H), 7.38 (m, 2H), 7.32 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 3.06 (d, 1H, J = 16.6 Hz), 2.96 (d, 1H, J = 16.6 Hz), 2.51 (s, 1H), 2.26 (s, 3H), 1.71 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 146.7, 140.3, 132.1, 129.5, 128.4, 128.1, 127.2, 125.6, 125.0, 123.1, 89.8, 82.9, 73.8, 36.0, 29.6, 20.8. MS (EI): m/z (rel intensity) 43.1 (78), 77.1 (15), 115.1 (10), 121.1 (100), 130 (57). HRMS (ESI, V+): m/z [M + H]+ calcd for C18H18O 250.1358, found 250.1352. 5-(o-Methoxyphenyl)-2-phenyl-4-pentyn-2-ol (39). Yield: 0.153 g, 96%. IR (film): νmax 3504, 2233, 1492, 1463, 1102 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.55 (m, 2H), 7.37 (m, 2H), 7.30 (m, 1H), 7.27 (m, 1H), 7.24 (m, 1H), 6.88 (m, 1H), 6.85 (m, 1H), 3.87 (s, 3H), 3.00 (d, 1H, J = 16.6 Hz), 2.94 (d, 1H, J = 16.6 Hz), 1.72 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.4, 146.8, 133.0, 129.5, 128.3, 127.0, 124.9, 120.5, 112.5, 110.6, 90.5, 80.6, 73.6, 55.9, 36.3, 29.4. MS (EI): m/z (rel intensity) 43.1 (78), 77.1 (21), 115.1 (20), 121.1 (95), 131.1 (33), 146.1 (100). HRMS (ESI, V+): m/z [M + H]+ calcd for C18H19O2 267.1385, found 267.1390. 5-(p-Nitrophenyl)-2-phenyl-4-pentyn-2-ol (41). Yield: 0.150 g, 89%. IR (KBr): νmax 3546, 3412, 2223, 1593, 1493, 1446, 1107 cm−1. 1 H NMR (400 MHz, CDCl3): δ 8.13 (m, 2H), 7.53 (m, 1H), 7.45 (m, 2H), 7.39 (m, 2H), 7.30 (m, 1H), 3.02 (d, 1H, J = 16.9 Hz), 2.94 (d, 1H, J = 16.9 Hz), 2.34 (br s, 1H), 1.73 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 147.0, 146.3, 132.5, 130.4, 128.5, 127.4, 124.9, 123.6, 92.3, 82.3, 73.9, 36.0, 29.4. MS (EI): m/z (rel intensity) 43.1 (58), 77.1 (10), 121.1 (100), 161.1 (5), 122.1 (10). HRMS (ESI, V+): m/z [M + H]+ calcd for C17H16NO3 282.1130, found 282.1125. p-(4-Hydroxy-4,4-diphenyl-1-butynyl)acetophenone (43). Yield: 0.129 g, 63%. IR (KBr): νmax 3498, 2225, 1670, 1598, 1267 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, 2H, J = 8.4 Hz), 7.49 (m, 4H), 7.35 (m, 4H), 7.32 (d, 2H, J = 8.4 Hz), 7.28 (m, 2H), 3.40 (s, 2H), 2.56 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.3, 145.5, 136.1, 131.8, 128.2, 128.1, 128.0, 127.4, 126.2, 89.5, 83.3, 77.6, 34.6, 26.6. MS (EI): m/z (rel intensity) 43.1 (9), 77.1 (48), 105.1 (85), 158.1 (28), 183.1 (100), 322.2 (M+ − H2O, 10). HRMS (ESI, V+): m/z [M + H]+ calcd for C24H21O2 341.1542, found 341.1541; m.p = 123−124 °C. (E)-1,1-Diphenyl-5-en-3-nonyn-1-ol (47). Yield: 0.095 g, 55%. IR (film): νmax 3500, 3082, 1968, 1599, 1447 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.45 (m, 4H), 7.32 (m, 4H), 7.24 (m, 2H), 6.00 (m, 1H, J = 1.6, 7.1, 16.0 Hz), 5.37 (m, 1H, J = 1.7, 7.1, 16.0 Hz), 3.25 (d, 2H, J = 1.7 Hz), 2.61 (s, 1H), 2.02 (m, 2H, J = 1.6, 7.1, 16.0 Hz), 1.37 (m, 2H), 0.88 (t, 3H). 13C NMR (100 MHz, CDCl3): δ 145.9, 144.8, 128.2, 127.3, 126.3, 109.4, 83.7, 83.6, 77.4, 35.1, 34.5, 22.0, 13.8. MS (EI): m/z (rel intensity) 51.1 (10), 77.1 (5), 108.1 (20), 183.1 (85), 262.1 (100). HRMS (ESI, V+): m/z [M + H]+ calcd for C22H25O 305.1905, found 305.1905. 1,1-Diphenyl-4-(2-thiophenyl)-3-butyn-1-ol (45). Yield: 0.126 g, 69%. IR (KBr): νmax 3525, 3470, 2219, 1447, 1425, 1341 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.49 (m, 4H), 7.35 (m, 4H), 7.27 (m, 2H), 7.17 (dd, 1H, J = 1.2, 5.2 Hz), 7.05 (dd, 1H, J = 1.2, 3.7 Hz), 6.90

by a rubber septum bearing a needle attached to a balloon. The threenecked flask was charged with magnesium turnings (1.55g, 64 mmol), a small crystal of iodine, and THF (25 mL). A small amount (∼0.5 mL) of a THF solution (3 mL) of 2,3-dichloropropene (2.22 g, 20 mmol) was added to the magnesium, the mixture was stirred for about 10 min, and a very exothermic reaction ensued after slightly warming the reaction flask. The allene gas generated was bubbled into a solution of n-BuLi (0.65 mL, 1.70 mmol) in dry diethyl ether (5 mL) and dry hexanes (4.35 mL),32 at −78 °C, in a single-necked flask, under nitrogen atmosphere. The remaining THF solution of 2,3-dichloropropene was added in small portions, in order to maintain a vigorous generation of allene. After generation of allene stopped, the canula was removed from the single-necked flask, and the n-BuLi-allene mixture was stirred at −78 °C for 1 h. Synthesis of 5-[(o-Methoxy)phenyl]-2-phenyl-4-pentyn-2-ol (39). An ether solution (3 mL) of acetophenone (23) (0.085 g, 0.60 mmol) was added to a cold (−78 °C) solution of 1,3-dilithiopropyne (5) prepared as above and assumed to be 0.85 mmol of 5 (prepared from 1.70 mmol of n-BuLi). The mixture was slowly warmed to room temperature over 3 h, and a mixture of 2-iodoanisole (38) (0.210 g, 0.90 mmol) and Pd(PPh3)4 (0.069 g) in THF (5 mL) was added, followed by addition of a suspension of CuI (0.006 g) in THF (3 mL), and the resulting mixture stirred at room temperature for 18 h. The reaction was quenched by addition of 10% ammonium acetate (3 mL) and extracted with ether (2 × 20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (Et2O:hexanes, 1:4) to give 0.152 g (96%) of alcohol 39. 1,1-Diphenyl-3-butyn-1-ol (14). Yield: 0.132 g, 99%. IR (KBr): νmax 3410, 3292, 1493, 1448, 1168, 1054 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.45 (m, 4H), 7.33 (m, 4H), 7.25 (m, 2H), 3.16 (d, J = 2.7 Hz, 2H), 2.04 (t, J = 2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 145.4, 128.2, 127.3, 126.1, 80.2, 77.1, 72.5, 33.4. MS (EI): m/z (rel intensity) 39.1 (5), 77.1 (72), 105.2 (100), 183.2 (85). HRMS (ESI, V+): m/z [M + H]+ calcd for C16H15O 223.1121, found 223.1121. Mp = 58−59 °C. 2-Phenyl-4-pentyn-2-ol (24). Yield: 0.091 g, 95%. IR (film): νmax 3411, 3295, 2119, 1495, 1446, 1375, 1101 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.49 (m, 2H), 7.36 (m, 2H), 7.30 (m, 1H), 2.77 (dd, J = 2.6, 16.6 Hz, 1H), 2.69 (dd, J = 2.6, 16.6 Hz, 1H), 2.43 (br s, 1H), 2.06 (t, J = 2.6, 1H), 1.65 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 146.3, 128.4, 127.2, 124.8, 80.5, 73.2, 71.7, 34.6, 29.2. MS (EI): m/z (rel intensity) 43.1 (92), 77.1 (35), 105.1 (25), 121.1 (100). HRMS (ESI, V+): m/z [M + H]+ calcd for C11H13O 161.0966, found 161.0969. 1-Cyclopropyl-1-phenyl-3-butyn-1-ol (26). Yield: 0.105 g, 94%. IR (film): νmax 3548, 3467, 3294, 1493, 1447, 1050 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.52 (m, 2H), 7.38 (m, 2H), 7.30 (m, 1H), 2.93 (dd, J = 2.6, 16.6 Hz, 1H), 2.85 (dd, J = 2.6, 16.6 Hz, 1H), 2.21 (s, 1H), 2.00 (t, J = 2.6 Hz, 1H), 1.40−1.33 (m, 1H), 0.59−0.50 (m, 2H), 0.44−0.38 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 145.0, 128.0, 127.1, 125.5, 80.3, 73.7, 71.1, 33.2, 21.2, 1.5, 0.9. MS (EI): m/z (rel intensity) 39.1 (15), 77.1 (52), 105.1 (98), 147.1 (100). HRMS (ESI, V+): m/z [M + H]+ calcd for C13H15O 187.1123, found 187.1126. 1-Phenyl-3-butyn-1-ol (28). Yield: 0.082 g, 94%. IR (film): νmax 3367, 3310, 2121, 1493, 1453, 1053 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.41−7.35 (m, 4H), 7.33−7.28 (m, 1H), 4.87 (ddd, J = 3.2, 6.3, 6.3 Hz, 1H), 2.65 (ddd, J = 2.7, 6.3, 6.3 Hz, 2H), 2.47 (s, J = 3.2 Hz, 1H), 2.09 (t, J = 2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 142.4, 128.5, 128.0, 125.7, 80.6, 72.3, 71.0, 29.4. MS (EI): m/z (rel intensity) 39.1 (5), 41.1 (5), 77.1 (42), 79.1 (75), 107.1 (100). HRMS (ESI, V+): m/z [M + H]+ calcd for C10H11O 147.0810, found 147.0810. 1-[4-(Dimethylamino)phenyl]-3-butyn-1-ol (30). Yield: 0.112 g, 99%. IR (film): νmax 3370, 3311, 2119, 1955, 1465, 1348, 1163, 1048 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.26 (m, 2H), 6.72 (m, 2H), 4.80 (dd, J = 5.6, 7.3 Hz, 1H), 2.96 (s, 6H), 2.70−2.63 (ddd, J = 2.7, 7.2, 16.1 Hz, 1H), 2.65−2.58 (ddd, J = 2.7, 5.6, 16.1 Hz, 1H), 2.26 (br s, 1H), 2.07 (t, J = 2.7, 1H). 13C NMR (100 MHz, CDCl3): δ 150.6, 130.5, 126.7, 112.4, 81.2, 72.2, 70.5, 40.6, 29.1. MS (EI): m/z (rel intensity) 39.1 (5), 77.1 (18), 150.1 (100), 171.0 (65), 189.0 (M+, 16). 9512


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The Journal of Organic Chemistry (dd, 1H, J = 3.7, 5.2 Hz), 3.39 (s, 2H), 2.96 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 145.7, 131.9, 128.3, 127.4, 126.9, 126.8, 126.4, 123.2, 89.9, 77.9, 77.6, 34.9. MS (EI): m/z (rel intensity) 51.0 (8), 77.0 (50), 105.0 (82), 122.0 (14), 183.0 (100), 286.0 (M+ − H2O, 10). HRMS (ESI, V+): m/z [M + H]+ calcd for C20H17OS 305.1000, found 305.1005. m.p = 68−70 °C. 1,1,4-Triphenyl-3-butyn-1-ol (13). Yield: 0.059 g, 33%. IR (KBr): νmax 3560, 1487, 1446, 1347, 1278, 1167 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.49 (m, 4H), 7.34 (m, 4H), 7.28−7.24 (m, 7H), 3.37 (s, 2H), 3.00 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 145.8, 131.8, 128.3, 128.3, 128.2, 127.4, 126.4, 34.6. MS (EI): m/z (rel intensity) 51.0 (8), 77.0 (43), 105.0 (78), 115.0 (13), 183.0 (100), 280.0 (M+ − H2O, 10). HRMS (ESI, V+): m/z [M + H]+ calcd for C22H19O 299.1436, found 299.1431. (Z)-7-Chloro-2-phenyl-6-en-4-heptyn-2-ol (49). Yield: 0.104 g, 62%. IR (KBr): νmax 3401, 2214, 1601, 1494, 1446, 1098 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.51 (m, 2H), 7.36 (m, 2H), 7.27 (m, 1H), 6.34 (d, 1H, J = 7.4 Hz), 5.83 (dt, 1H, J = 2.2, 7.4 Hz), 2.95 (dd, 1H, J = 2.2, 16.9 Hz), 2.89 (dd, 1H, J = 2.2, 16.9 Hz), 2.50 (s, 1H), 1.69 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 146.5, 128.4, 128.3, 127.2, 124.9, 112.1, 94.8, 78.1, 73.6, 36.1, 29.4. MS (EI): m/z (rel intensity) 43.1 (76), 77.1 (15), 99.0 (4), 105.1 (8), 121.1 (100), 183.2 (M+ − HCl, 10) HRMS (ESI, V+): m/z [M+ − HCl]+ calcd for C13H13O 185.0966, found 185.0968.

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(3) Yamamoto, H. In Comprehensive Organic Synthesis, 2nd ed.; Trost, B. M., Fleming, I., Eds.; Pergamon, Oxford, U.K., 1991; Vol. 2, Chapter 1.3, p 81. (4) (a) Lee, A. S. Y.; Chu, S. F.; Chang, Y. T.; Wang, S. H. Tetrahedron Lett. 2004, 45 (7), 1551. (b) Trost, B. M.; Ngai, M. Y.; Dong, G. Org. Lett. 2011, 13 (8), 1900. (c) Hahn, G.; Zweifel, G. Synthesis 1983, 1983, 883. (d) Shinokubo, H.; Miki, H.; Yokoo, T.; Oshima, K.; Utimoto, K. Tetrahedron 1995, 51, 11681. (e) Marshall, J. A.; Perkins, J. J. Org. Chem. 1994, 59, 3509. (f) Marshall, J. A. Chem. Rev. 1996, 96, 31. (g) Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Org. Chem. 1982, 47, 2225. (h) Justicia, J.; Sancho-Sanz, I.; AlvarezManzaneda, E.; Oltra, J. E.; Cuerva, J. M. Adv. Synth. Catal. 2009, 351, 2295. (i) Stec, J.; Henderson, A. R.; Whitby, R. J. Tetrahedron Lett. 2012, 53, 1112. (j) Tabuchi, T.; Inanaga, J.; Yamaguchi, M. Chem. Lett. 1987, 16, 2275. (k) Yanagisawa, A.; Suzuki, T.; Koide, T.; Okitsu, S.; Arai, T. Chem. - Asian J. 2008, 3 (10), 1793. (l) Loh, T. P.; Lin, M. J.; Tan, K. L. Tetrahedron Lett. 2003, 44 (3), 507. (m) Tamaru, Y.; Goto, S.; Tanaka, A.; Shimizu, M.; Kimura, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 878. (n) Clinet, J. C.; Linstrumelle, G. Synthesis 1981, 1981, 875. (5) (a) Chen, J.; Captain, B.; Takenaka, N. Org. Lett. 2011, 13 (7), 1654. (b) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem. 1986, 51, 3870. (c) Brown, H. C.; Khire, U. R.; Narla, G.; Racherla, U. S. J. Org. Chem. 1995, 60 (3), 544. (d) Kohn, B. L.; Ichiishi, N.; Jarvo, E. R. Angew. Chem., Int. Ed. 2013, 52, 4414. (e) For a recent review on the propargylation of aldehydes and ketones using boron reagents, see the following: Thaima, T.; Zamani, F.; Hyland, C. J. T.; Pyne, S. G. Synthesis 2017, 49, 1461. (6) Michelot, D. Synth. Commun. 1989, 19, 1705. (7) (a) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Org. Chem. 1989, 54 (22), 5198. (b) Daniels, R. G.; Paquette, L. A. Tetrahedron Lett. 1981, 22, 1579. (8) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda, n.; Yamamoto, h. Bull. Chem. Soc. Jpn. 1984, 57, 2768. (9) (a) Corey, E. J.; Achiwa, K. Tetrahedron Lett. 1970, 11, 2245. (b) Corey, E. J.; Katzenellenbogen, J. A.; Gilman, N. W.; Roman, S. A.; Erickson, B. W. J. Am. Chem. Soc. 1968, 90, 5618. (c) Johnson, W. S.; Li, T.; Harbert, C. A.; Bartlett, W. R.; Herrin, T. R.; Staskun, B.; Rich, D. H. J. Am. Chem. Soc. 1970, 92, 4461. (10) Ghosh, P.; Chattopadhyay. Tetrahedron Lett. 2012, 53, 5202. (11) Corey, E. J.; Kirst, H. A. Tetrahedron Lett. 1968, 9, 5041. (12) Hooz, J.; Cabezas, J.; Musmanni, S.; Calzada, J. Org. Synth. 1990, 69, 120. (13) Cabezas, J. A.; Alvarez, L. X. Tetrahedron Lett. 1998, 39, 3935. (14) Cabezas, J. A.; Pereira, A. R.; Amey, A. Tetrahedron Lett. 2001, 42, 6819. (15) Vásquez, S.; Cabezas, J. A. Tetrahedron Lett. 2014, 55, 1894. (16) Hicks, J. D.; Roush, W. R. Org. Lett. 2008, 10, 681. (17) Roush, W. R.; Neitz, J. J. Org. Chem. 2004, 69 (15), 4906. (18) Bensoussan, C.; Rival, N.; Hanquet, G.; Colobert, F.; Reymond, S.; Cossy, J. Nat. Prod. Rep. 2014, 31 (4), 468. (19) Lipshutz, B. H.; Lower, A.; Berl, V.; Schein, K.; Wetterich, F. Org. Lett. 2005, 7 (19), 4095. (20) Gomtsyan, A.; Schmidt, R. G.; Bayburt, E. K.; Gfesser, G. A.; Voight, E. A.; Daanen, J. F.; Schmidt, D. L.; Cowart, M. D.; Liu, H.; Altenbach, R. J.; Kort, M. E.; Clapham, B.; Cox, P. B.; Shrestha, A.; Henry, R.; Whittern, D. N.; Reilly, R. M.; Puttfarcken, P. S.; Brederson, J.; Song, P.; Li, B.; Huang, S. M.; McDonald, H. A.; Neelands, T. R.; McGaraughty, S. P.; Gauvin, D. M.; Joshi, S. K.; Banfor, P. N.; Segreti, J. A.; Shebley, M.; Faltynek, C. R.; Dart, M. J.; Kym, P. R. J. Med. Chem. 2016, 59, 4926. (21) Pereira, A.; Cabezas, J. A. J. Org. Chem. 2005, 70, 2594. (22) (a) Bandi, S.; Debata, N. B.; Ramkumar, V.; Chand, D. K. Inorg. Chem. Commun. 2014, 39, 75. (b) Hughes, R. P.; Overby, J. S.; Williamson, A.; Lam, K. C.; Concolino, T. E.; Rheingold, A. L. Organometallics 2000, 19, 5190. (c) Gogoll, A.; Oernebro, J.; Grennberg, H.; Backvall, J. E. J. Am. Chem. Soc. 1994, 116, 3631. (d) Meek, D. W. Inorg. Chem. 1965, 4 (2), 250.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01529. Diagram of the glassware used and copies of 1H NMR and 13C NMR spectra of all compounds reported in Tables 4 and 5 are provided (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Jorge A. Cabezas: 0000-0002-7571-6914 Notes

The authors declare no competing financial interest. † Preliminary results were presented at the Third Iberoamerican Symposium on Organic Chemistry (SIBEAQO-III), Porto, Portugal, September 2016.

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ACKNOWLEDGMENTS We thank the University of Costa Rica for financial support, Sistema de Estudios de Posgrado (SEP-UCR) for a stipend to C.U., CIPRONA-UCR for high-resolution mass spectra determination, Prof. Cam Oehlschlager for reading the manuscript and useful suggestions, and Dr. Albán Pereira for useful suggestions.

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REFERENCES

(1) (a) Kim, J.; Jeong, W.; Rhee, Y. H. Org. Lett. 2017, 19 (1), 242. (b) Foley, C. N.; Leighton, J. L. Org. Lett. 2015, 17 (23), 5858. (c) Francais, A.; Leyva, A.; Etxebarria-Jardi, G.; Ley, S. V. Org. Lett. 2010, 12 (2), 340. (d) Watanabe, T.; Imaizumi, T.; Chinen, T.; Nagumo, Y.; Shibuya, M.; Usui, T.; Kanoh, N.; Iwabuchi, Y. Org. Lett. 2010, 12 (5), 1040. (2) (a) Hosseyni, S.; Wojtas, L.; Li, M.; Shi, X. J. Am. Chem. Soc. 2016, 138 (12), 3994. (b) Gao, P.; Li, H. X.; Hao, X. H.; Jin, D. P.; Chen, D. Q.; Yan, X. B.; Wu, X. X.; Song, X. R.; Liu, X. Y.; Liang, Y. M. Org. Lett. 2014, 16 (24), 6298. (c) Shu, C.; Liu, M. Q.; Sun, Y. Z.; Ye, L. W. Org. Lett. 2012, 14 (18), 4958. (d) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125 (25), 7482. 9513


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The Journal of Organic Chemistry (23) (a) Klein, J.; Medlik-Balan, A. J. Chem. Soc., Chem. Commun. 1975, 877. (b) Bhanu, S.; Scheinmann, F. J. Chem. Soc., Chem. Commun. 1975, 0, 817. (24) Yus, M.; Ramón, D. J. J. Chem. Soc., Chem. Commun. 1991, 398. (25) Guijarro, A.; Yus, M. Tetrahedron Lett. 1993, 34 (12), 2011. (26) Cripps, H. N.; Kiefer, E. F. Organic Syntheses; Wiley: New York, 1973; Collect. Vol. 5, p 22. (27) Levanova, E. P.; Vshivtsev, V. Yu.; Grabel'nykh, V. A.; Sukhomazova, E. N.; Russavskaya, N. V.; Albanov, A. I.; Tarasova, O. A.; Korchevin, N. A. Russ. J. Gen. Chem. 2008, 78 (10), 1980. (28) NIST Chemistry WebBook (http://webbook.nist.gov/ chemistry). (29) (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891. (b) Brown, C. A.; Yamashita, A. J. Chem. Soc., Chem. Commun. 1976, 959. (30) Negishi, E. In Organometallics in Organic Synthesis; John Wiley & Sons: New York, 1980; Vol. 1, p 252. (31) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165. (32) In the current procedure, a solvent ratio (v/v) of ether:hexanes of 1:1 was used, as previously reported.12

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