DOI: 10.1002/chem.201404668

Full Paper

& Asymmetric Catalysis

Copper-Catalyzed Propargylic Substitution of Dichloro Substrates: Enantioselective Synthesis of Trisubstituted Allenes and Formation of Propargylic Quaternary Stereogenic Centers Hailing Li,[a] David Grassi,[a] Laure Gune,[b] Thomas Brgi,[c] and Alexandre Alexakis*[a]

Abstract: An easy and versatile Cu-catalyzed propargylic substitution process is presented. Using easily prepared prochiral dichloro substrates, readily available Grignard reagents together with catalytic amount of copper salt and chiral ligand, we accessed a range of synthetically interesting trisubstituted chloroallenes. Substrate scope and nucleophile scope are broad, providing generally high enantioselectivity for the desired 1,3-substitution products. The enantio-

enriched chloroallenes could be further transformed into the corresponding trisubstituted allenes or terminal alkynes bearing all-carbon quaternary stereogenic centers, through the copper-catalyzed enantiospecific 1,1/1,3-substitutions. The two successive copper-catalyzed reactions could be eventually combined into a one-pot procedure and different desired allenes or alkynes were obtained respectively with high enantiomeric excesses.

Introduction Since their discovery by Jacobus H. van’t Hoff, allene compounds have drawn more and more attention owing to their interesting properties and synthetic utility; one of the most highlighted characteristics is their potential axial chirality.[1] Regarding their synthetic importance, and in order to gain more insight on this family of compounds, their asymmetric synthesis has become a must to access enantiomerically enriched axially chiral allenes.[2] Although the introduction of central chirality can be achieved by asymmetric allylic substitution,[3] the asymmetric propargylic substitution are often performed to generate the chiral allenes (Scheme 1).[4] To synthesize chiral allenes, most strategies to date have been based on the chirality transfer from enantioenriched propargyl compounds [Scheme 2, eq. (A)].[5] Recently, the groups of Woodward[6] and Knochel[7] reported respectively the use of propargyl diacetates and propargyl dichlorides as prochiral substrates for allene synthesis [Scheme 2, eq. (B)]. However, in both studies, stoichiometric amounts of copper salts were employed and no example of an asymmetric version has

Scheme 1. Comparison of asymmetric allylic (a) and propargylic (b) substitution. a) Asymmetric allylic substitution introduces central chirality; b) asymmetric propargylic substitution introduces axial chirality.

been reported. Inspired by these studies, we intended to combine these two approaches, namely to use prochiral substrates and to perform the reaction under catalytic conditions. In a previous study, our group reported the first enantioselective synthesis of chiral chloroallenes under the copper-catalyzed conditions [Scheme 2, eq. (C)]. A simple and useful application of this allene synthesis was demonstrated in the stereospecific copper-catalyzed 1,1/1,3 substitutions [Scheme 2, eq. (D)].[8] Owing to the facile racemization in the presence of copper salt and relative instability of this family of molecules, the scope of an asymmetric allene synthesis is highly important and worth extensive study. Herein we aim at further extending the scope of substrates and nucleophiles. The investigation of further transformations and limitations are equally presented. By simply placing different substituents (R1) on the prochiral substrate, introducing different alkyl groups (R2) by Grignard reagents, we can obtain diverse substitution patterns on the chloroallenes and further substitution can install R3 groups in a 1,1- or 1,3-regioselective manner, affording the correspond-

[a] Dr. H. Li, Dr. D. Grassi, Prof. Dr. A. Alexakis Department of Organic Chemistry, University of Geneva Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland) Fax: (+ 41) 22-379-32-15 E-mail: [email protected] [b] Dr. L. Gune Laboratory of Crystallography, University of Geneva Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland) [c] Prof. Dr. T. Brgi Department of Physical Chemistry, University of Geneva Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404668. Chem. Eur. J. 2014, 20, 1 – 14

These are not the final page numbers! ÞÞ

1

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

&

Full Paper First of all, the substrate 1 a was subjected to the conventional conditions for the coppercatalyzed asymmetric allylic alkylation (AAA) using chiral phosphoramidite ligand L1.[9] We observed exclusive formation of the 1,3-substituion product, namely the desired chloroallene 2 a, with 48 % ee (Table 1, entry 1). No trace of other regioisomer was detected. Based on this preliminary result, we continued to study the ligand effect. Several different phosphoramidite ligands were tested, as well as the chiral catalyst-substrate “match/mismatch effect” (Table 1, entries 1–4). The enantiomeric excess was limited to 59 % (Table 1, entry 9) as the highest value for this family of ligands (Table 1, entries 5–12). The ferrocene-based phosphorus ligands[10] were taken into consideration. Different sub-families were investigated, such as Josiphos (Table 1, entries 14 and 15),[11] Taniaphos (Table 1, entry 13),[11] Mandyphos, and Walphos (see the Supporting Information). The best result was obtained with Josiphos L14, which gave 56 % ee (Table 1, entry 15). Among the available ferrocene-based ligands, no further improvement could be obtained. Inspired by the work of asymmetric allylic alkylation using N-heterocyclic carbenes (NHCs) as ligands, several NHCs were used as ligands in the

Scheme 2. Proposed approach for enantioselective allene synthesis.

ing trisubstituted allenes or terminal alkynes (Scheme 2). In short, this study represents a versatile and tunable synthesis of chiral allenes and alkynes bearing quaternary carbon centers at propargylic position.

Results and Discussion Optimization of the reaction conditions The optimization started with an extensive screening of chiral ligands under copper-catalyzed conditions (Figure 1).

Figure 1. Chiral ligands used in this optimization.

&

&

Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

2

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper ed from one of the simplest air-stable SimplePhos ligands L19 (Table 1, entry 25), and screened several different ligands, which are illustrated by replacing the two phenyl groups on the phosphorus atom by other substituents (L20, L21, L22; Table 1, entries 26–30), or replacing the phenyl groups on the chiral amine moiety by 2-naphthyl groups (L23, L24, L25, L26; Table 1, entries 31–36). Knowing that toluene could be used as a decent nonpolar solvent that was known to sometimes promote high enantioselectivity in conjugate addition processes,[17] our reaction was tested in toluene to see the influence (Table 1, entries 34 and 36). A series of ligands that have previously been used for the asymmetric conjugate addition reactions were also studied here (Table 1, entries 31–37). Finally, we managed to increase the ee to 75 % with ligand L26 and toluene as solvent (Table 1, entry 36). We have also adjusted the copper salt/ligand ratio from 1:1.1 to 1:2, whereby ee decreased from 75 % to 70 % (Table 1, entry 37). For a complete list of the tested ligands, see the Supporting Information. Screening of the copper source (Table 2) further increased the ee to 79 % by using copper iodide (Table 2, entry 8). Reducing the catalyst loading led to a reasonable drop in enantioselectivity (Table 2, entry 10). The influence of copper source on this transformation was relatively minor. All of the tested cases gave ee values higher than 70 %, with only one exception (53 % ee with Cu(OAc)2 ; Table 2, entry 4).

Table 1. Preliminary ligand screening.

Entry[a] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37[d]

Ligand L*

Cu salt

Solvent

ee [%][b]

L1 L2 L3 L4 L5 L6 L7 L8 L9 L9 L10 L11 L12 L13 L14 L15 L16 L16 L16 L17 L17 L17 L17 L18 L19 L20 L20 L21 L21 L22 L23 L24 L25 L25 L26 L26 L26

CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC No Cu CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Et2O Et2O CH2Cl2 THF Et2O toluene CH2Cl2 CH2Cl2 CH2Cl2 toluene CH2Cl2 toluene toluene CH2Cl2 CH2Cl2 CH2Cl2 toluene CH2Cl2 toluene toluene

48 50 8 51 44 40 14 51 59 38 13 55 –[c] 7 56 5 65 10 28 55 0 20 18 43 46 48 26 61 0 0 54 47 57 20 66 75 70

Table 2. Copper source screening.

[a] Reaction conditions: The substrate (0.25 mmol) was added to a solution of copper salt and chiral ligand in dry solvent at 78 8C. The ethereal solution of Grignard reagent (1.2 equiv) was added dropwise and the reaction mixture was stirred at 78 8C for 2 h. The desired product was confirmed by 1H NMR spectroscopy and not isolated; [b] determined by GC analysis using a chiral stationary phase; [c] no conversion; [d] copper salt/chiral ligand ratio = 1:2.

www.chemeurj.org

These are not the final page numbers! ÞÞ

Cu salt

ee [%][b]

1 2 3 4 5 6 7 8 9 10[c]

CuTC CuBr CuCl Cu(OAc)2 Cu(OTf)2 (CuOTf)2·C7H8 (CuOTf)2·C6H6 CuI CuNaph CuI

75 70 71 53 78 76 70 79 78 73

[a] Reaction conditions: The substrate (0.10 mmol) was added to a solution of copper salt and ligand L26 in dry toluene at 78 8C. The ethereal solution of Grignard reagent (1.2 equiv) was added dropwise and the reaction mixture was stirred at 78 8C for 2 h. The desired product was confirmed by 1H NMR spectroscopy and not isolated; [b] determined by GC analysis using a chiral stationary phase; [c] 5 mol % catalyst loading.

copper-catalyzed process (Table 1, entry 16, 17, and 19)[12] as well as the copper-free conditions (Table 1, entry 18),[13] giving a maximum of 65 % ee (Table 1, entry 17); however this ee is still not enough for an efficient synthetic methodology. We then turned to biphenyl/binaphthyl-based ligands (Table 1, entries 20 and 24), the best result, 55 % ee obtained with simple (R)-BINAP L17, was promising. However, solvent screening brought no improvement (Table 1, entries 20–23). Finally, we focused our attention on another family of phosphorus ligands, SimplePhos,[14] which is not commonly used for substitution reactions,[15] but has been extensively studied in the copper-catalyzed conjugate addition system.[14a, 16] We startChem. Eur. J. 2014, 20, 1 – 14

Entry[a]

Subsequently, solvent screening was carried out, retaining the combination of L26 and CuI (Table 3). Different mixtures of solvents with different ratios were studied (Table 3, entries 2– 7), as well as the polar ethereal solvents (Table 3, entries 8–10). Toluene remained the best choice among all tested cases. After ligand screening, copper salt screening and solvent screening, under the preliminarily optimized conditions (CuI/ L26 in toluene) a modest level of enantioselectivity (79 % ee) 3

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

&

Full Paper isolated, but, according to the previous synthesis procedure, it was air sensitive and readily decomposed on silica gel. Finally, we found that flash column chromatography on Al2O3 could easily afford the desired ligand, and it decomposed much more slowly in diethyl ether than in dichloromethane when we extracted the solution and purified it by column chromatography. With this knowledge, we have managed to isolate the ligand L27 in a practical yield of 60 % and been able to study its influence on the catalysis. However, for further optimization, we decided to change the model substrate from 1 a to 1 b, to decrease the volatility, for easier isolation and purification. The results for this final stage formal optimization are assembled in Table 4. A set of two diastereomers of phosphoramidite ligands L1 and L2 were tested (Table 4, entries 1 and 2). The ee values were relatively low. SimplePhos ligand L25 and ent-L26 were studied in both CH2Cl2 and toluene as solvent (Table 4, entries 3–6). The enantioselectivity could be improved to 82 % ee with ent-L26 (Table 4, entry 6). The use of ligand L27 led to a major improvement in terms of enantioselectivity (89 % ee; Table 4, entry 8). A simple representative screening of the copper source (Table 4, entries 9 and 10) established the final optimized conditions to be the combination of cheap salt CuBr with easily prepared chiral ligand L27 in toluene and the catalyst loading could be further decreased to 5 mol % while retaining the same enantiomeric excess (Table 4, entry 11).

Table 3. Solvent screening.

Entry[a]

Solvent

ee [%][b]

1 2 3 4 5 6 7 8 9 10

toluene toluene/CH2Cl2 4:1 toluene/CH2Cl2 1:1 toluene/hexane 1:1 toluene/pentane 1:2 Et2O/pentane 1:1 toluene/hexane 1:2 Et2O THF MTBE

79 76 70 79 38 44 72 –[c] 0 58

[a] Reaction conditions: The substrate (0.10 mmol) was added to a solution of CuI and ligand L26 in dry solvent at 78 8C. The ethereal solution of Grignard reagent (1.2 equiv) was added dropwise and the reaction mixture was stirred at 78 8C for 2 h. The desired product was confirmed by 1H NMR spectroscopy and not isolated; [b] determined by GC analysis using a chiral stationary phase; [c] no conversion.

for the allene synthesis was achieved. As there was still much room for optimization, we tried to understand the trend in SimplePhos ligand screening and intended to replace the two ethyl groups on L26 by methyl groups. This ligand, L27 (Table 4), was previously generated in situ and used for the ring-opening of polycyclic hydrazines.[15a,c] L27 could also be

Scope of Grignard reagents Under the optimized conditions, a broad range of Grignard reagents was used as nucleophile to install different alkyl groups on the chloroallenic moiety. This methodology benefits from the large availability and easy preparation of Grignard reagents, and showed a substantial diversity in terms of nucleophiles. The primary alkyl Grignard reagents generally led to high enantioselectivities, with ee values ranging between 90 % and 94 % (Table 5, entries 1–5). We introduced different-sized aliphatic alkyl chains (Table 5, entries 1, 2 and 4) and an alkyl group bearing a phenyl ring (Table 5, entry 3) or a terminal double bond (Table 5, entry 5). As widely known for coppercatalyzed asymmetric allylic alkylation reactions, the allyl group may cause regioselectivity issues and a similar trend was also observed here (Table 5, entry 6). The use of allyl Grignard’s chloride analogue further lowered both regio- and enantioselectivities (Table 5, entry 7). Unexpectedly, the benzyl group, which should behave similarly to allyl in copper-catalyzed substitution, worked relatively well, providing exclusive SN2’ product with a practical ee of 71 % (Table 5, entry 8). Secondary alkyl groups could also be introduced, with even higher enantioselectivities regardless of their increased bulkiness (Table 5, entries 9 and 10). Comparison of entries 10 and 11 clearly shows an influence of the counterion in the Grignard reagent, which was also the case for entries 6 and 7. The use of cyclopentyl magnesium chloride (Table 5, entry 11) instead of bromide (Table 5, entry 10) decreased the ee by 20 %. The methodology was also applied to the conventionally challenging reagent MeMgBr and it was remarkable to obtain high enantio-

Table 4. Final stage formal optimization.

Entry[a] 1 2 3 4 5 6 7 8 9 10 11

Ligand L*

Cu salt

Solvent

Catalyst loading [%]

ee [%][b]

L1 L2 L25 L25 ent-L26 ent-L26 L27 L27 L27 L27 L27

CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuTC CuI CuBr CuBr

CH2Cl2 CH2Cl2 CH2Cl2 toluene CH2Cl2 toluene CH2Cl2 toluene toluene toluene toluene

10 10 10 10 10 10 10 10 10 10 5

39 40 50 4 58 82 58 89 91 92 92

[a] Reaction conditions: The substrate (0.25 mmol) was added to a solution of copper salt and chiral ligand in dry solvent at 78 8C. The ethereal solution of Grignard reagent (1.2 equiv) was added dropwise during 20 min and the reaction mixture was stirred at 78 8C for 2 h. The desired product was confirmed by 1H NMR spectroscopy and not isolated; [b] determined by GC analysis using a chiral stationary phase. Cy = cyclohexyl.

&

&

Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

4

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper Table 5. Scope of Grignard reagents.

Entry[a]

RMgX or RLi

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

EtMgBr nBuMgBr PhCH2CH2MgBr iBuMgBr CH2 = C(CH3)CH2CH2MgBr allylMgBr allylMgCl benzylMgBr iPrMgBr cPentylMgBr cPentylMgCl MeMgBr tBuMgBr PhMgBr nBuLi

Product 2b 2c 2d 2e 2f 2g 2g 2h 2i 2j 2j 2k – – 2c

Yield [%]

ee [%][b]

84 92 84 84 92 n.d.[c] n.d.[d] 85 88 84 92 82 n.d. n.d.[e] n.d.[f]

92 94 90 93 94 58 12 71 96 96 76 91 0 – 23

Scheme 3. Synthetic pathway for substrate preparation.

[a] Reaction conditions: the substrate (0.25 mmol) was added to a solution of CuBr and chiral ligand L27 in dry toluene at 78 8C. The ethereal solution of Grignard reagent (1.2 equiv) was added dropwise over 20 min and the reaction mixture was stirred under 78 8C for 2 h. Full conversion and the desired products were confirmed by 1H NMR spectroscopy; [b] determined by GC analysis using a chiral stationary phase; [c] regioisomer g/a = 1:1.3; [d] regioisomer g/a = 1:2.1; [e] unidentified mixture; [f] full conversion, desired product not isolated.

control on this type of propargylic substrate (Table 5 entry 12). Attempts with tert-butyl or phenyl reagents were unsuccessful (Table 5, entries 13 and 14). One more example, using a organolithium reagent as nucleophile,[18] gave full conversion with the desired allene as major product, although the enantiomeric excess was quite poor (Table 5, entry 15). Substrate scope The generality of this enantioselective allene synthesis method was exploited by extending the scope of 1,1-dichloropropargylic substrates. The advantage of this family of prochiral substrates is their easy preparation;[7] a two-step synthetic sequence from commercially available alkynes, with only one purification by flash column chromatography, can afford different propargyl dichlorides in moderate to good yields (Scheme 3). The first step was the formation of corresponding conjugated ynal from the alkyne, without purification, the second step involved a double chlorination of the crude ynal using PCl5 and provided the desired dichloro substrate 1. These propargyl dichlorides were then subjected to coppercatalyzed substitution reactions under the previously established conditions, leading to the formation of the corresponding chloroallenes in most cases. Various linear aliphatic alkyl groups could be present in the substrate and showed good selectivities (Scheme 4, 2 l, 2 m). Similar substrate 1 d, bearing a terminal chlorine atom, was also tolerated. The resulting allene 2 n, which bears two halogens, would be potentially synthetically useful. Cases where the R group was a secondary Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

These are not the final page numbers! ÞÞ

Scheme 4. Substrate scope.

alkyl afforded the desired allenes with very good ee values (Scheme 4, 2 c, 2 o, ent-2 j), whereas further increasing the steric bulk to tertiary alkyl (tBu) slightly decreased the ee to 84 % (Scheme 4, 2 p). Silyl-substituted allenes imply interesting and important synthetic potential.[5d, 19] Through our methodology, the trimethylsilyl (TMS)-substituted chloroallene 2 q could be obtained with good yield and a decent ee of 85 %. Increasing the size of the silyl group from TMS to triethylsilyl (TES) in the substrate negatively influenced the enantioselectivity and the ee value decreased to 72 % (Scheme 4, 2 r). The bulkier triisopropylsilyl (TIPS) group greatly decreased the reactivity under these conditions. We had to warm up the reaction to 5

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

&

Full Paper room temperature to achieve some conversion; however, the resulting product 2 s was racemic. The phenyl-substituted substrate led to only moderate enantioselectivity (Scheme 4, 2 t). We then tested the influence of substituents on the aromatic ring with different electronic effects. Electron-donating groups, such as para-methyl, had no influence on enantiomeric excess (Scheme 4, 2 u), whereas the electron-withdrawing group paratrifluoromethyl improved the ee value from 64 % to 82 % (Scheme 4, 2 v). An example with protected alcohol functionality was also studied; an a-alkoxyallenylic compound was obtained, albeit with moderate ee (Scheme 4, 2 w). Finally, one more substrate 1 m was prepared for the synthesis of vinylallenic compound 2 x in good yield and good enantioselectivity.

Table 6. Copper-catalyzed transformation of chloroallenes.

Further transformations of chiral chloroallenes By employing this synthetic method, we could easily prepare trisubstituted chiral allenic compounds bearing a chlorine atom, which renders the resultant molecules ready for further transformations. To demonstrate the application and importance of the synthetic system, we performed some simple metal-catalyzed reactions on the reactive allenic chloride moiety. First of all, we tried palladium-catalyzed coupling reactions (Scheme 5). Under the conventional conditions, we carried out Suzuki[13f] and Sonogashira[20] couplings on 2 k aimed at installing phenyl and trimethylsilylethynyl respectively on the allene by replacing the chlorine atom. In the case of the Suzuki coupling, total racemization was observed in the desired product

Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

Solvent

Product

Yield [%]

ee [%][b]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

PhMgBr PhMgBr 2-Naphtyl nBuMgBr nBuMgBr nBuMgCl nBuMgCl vinylMgCl vinylMgCl vinylMgBr ethynylMgBr iPrZnBr iPrZnBr nBuLi nBuLi

THF CH2Cl2 THF CH2Cl2 THF THF CH2Cl2 CH2Cl2 THF THF THF THF CH2Cl2 CH2Cl2 THF

3a 3a 3e 4b 3f 3f 4b Ratio 3/5 1/0.18 Ratio 3/5 1/1.35 Ratio 3/5 1/0.48 – – – – –

91 87 < 80 89 58 n.d. n.d. Low conv. Low conv. Low conv. No conv. No conv. No conv. No conv. No conv.

90 60 80 90 87 88 87.5 n.d. n.d. n.d. – – – – –

by a 1,1-substitution in THF keeping the same level of enantiopurity as the starting chloroallene (Table 6, entry 1). The bulkier 1-naphthyl group could also be installed on the same starting material, albeit with a slightly lower ee (Table 6, entry 3). The preliminary attempt to introduce the alkyl group under the same conditions failed to afford the desired alkylated allene compound 3 as successfully as in previous arylation cases. Instead, a substantial amount of dechlorinated nonchiral allene 5 was detected when performing the reaction with n-butyl Grignard reagent. However, when we simply changed the solvent from THF to CH2Cl2, under similar conditions, the reaction led to almost exclusive formation of 1,3-substitution product 4. Therefore, the nBu group was installed in a 1,3-substitution manner using CH2Cl2 as solvent affording terminal alkyne 4 b with a propargylic quaternary carbon center (Table 6, entry 4). When we subjected the phenyl Grignard to chloroallene in CH2Cl2, no trace of the corresponding alkyne was detected. The reaction still formed exclusively the aryl allene 3 a, albeit partially racemized. The ee value dropped from 90 % to 60 % (Table 6, entry 2). Furthermore, efforts were made to enable 1,1-alkylation. We found that slow addition and careful control of the amount of nucleophile substantially minimzed the side reaction, namely the formation of reduced allene 5. Product formation could then be easily controlled by a simple change of solvent; alkyne 4 b in CH2Cl2 (Table 6, entry 4) and alkylated allene 3 f in THF (Table 6, entry 5). The ee values always remained at high levels in these transformations. We also studied the halogen effect of the Grignard reagents in the substitution

3 a and the reaction provided a complex mixture. The tested Sonogashira coupling afforded the desired product 3 b in 82 % yield, albeit partially racemized. The ee value decreased from 90 % in the starting material 2 k to 36 % in the resulting allene 3 b. Without having obtained promising results from the preliminary tests on Pd-catalyzed coupling systems, we turned to copper-catalyzed substitution reactions of these enantioenriched chloroallenes. Based on the previous report on the copper-catalyzed substitution of racemic chloroallenes by Knochel et al.,[7] we applied this simple and quickly accessible procedure to our enantiomerically enriched allenes. The phenyl group could be introduced to the allene 2 k (90 % ee) &

Nucleophile

[a] Reaction conditions: The substrate (0.10 mmol) was added to a mixture of CuCN and dry solvent at 0 8C. The ethereal solution of Grignard reagent was added dropwise, the reaction mixture was warmed up to room temperature and stirred during 2 h or overnight. The desired products were confirmed by 1H NMR spectroscopy; [b] determined by GC analysis using a chiral stationary phase.

Scheme 5. Pd-catalyzed coupling reactions on chloroallene.

&

Entry[a]

6

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper reaction using nBuMgCl instead of nBuMgBr in both solvents (Table 6, entries 6 and 7). Similar enantioselectivities were obtained, suggesting that the counterion of the Grignard reagent was not crucial in this case. Attempts to install challenging groups by means of the Grignard reagent, such as vinyl (Table 6, entries 8–10) and ethynyl (Table 6, entry 11), were unsuccessful. Other organometallic reagents, such as organozinc reagent (Table 6, entries 12 and 13) and organolithium reagent (Table 6, entries 14 and 15) were tested in both THF and CH2Cl2 respectively, although almost no conversion took place in all of these cases. With the systematic study, we established a relatively tunable enantioselective synthesis for trisubstituted aryl allenes, trisubstituted alkylated allenes, and terminal alkynes with quaternary stereogenic carbon centers (see examples in Figure 2).[21] Different aryl groups with different steric or electronic effects could be introduced highly enantiospecifically (3 a, 3 c–e). Primary, secondary, and tertiary alkyl groups were installed by 1,1-substitution in THF providing the corresponding allenes (3 f–i) while primary and secondary alkyls could also go through 1,3-substitution on chloroallenes in CH2Cl2 to form alkynes (4 b–d). Allyl Grignard worked well in this reaction, with good yield and total chirality transfer (3 j). We could even synthesize highly bulky compounds with a sterically congested quaternary carbon center, such as 4 e. Versatile and synthetically useful moieties, such as propargyl silyl 4 a and allenyl silyl 3 k,[22] were readily prepared from the common chloroallene 2 q. A simple change of solvents, from CH2Cl2 to THF, led to the formation of both compounds 4 a and 3 k respectively.

Copper-catalyzed one-pot sequence Considering that the enantioselective synthesis of chloroallenes and the 1,1-arylation or 1,1/1,3-alkylation of chloroallenes were both under copper-catalyzed conditions, we intended to combine these two steps into a one-pot sequence. For this one-pot process, we could start with the allene synthesis reaction in toluene using an alkyl Grignard reagent, then add the necessary solvent and another Grignard reagent to promote the follow-up alkylation or arylation. Three representative examples are shown in Scheme 6. We subjected substrate 1 b to the previously optimized conditions, leading to the in situ generation of chiral allene 2 k. In the same reaction medium, a second solvent (THF or CH2Cl2) was introduced to promote the following substitution step, giving rise to 3 a, 3 f, or 4 b (depending on choice of solvent or Grignard reagent; Scheme 6). The switch of solvents allowed access to the trisubstituted aryl/alkyl allenes or terminal alkyne in high enantiopurity levels. This methodology provides an easy access to chiral allene and alkyne synthesis, with flexible choice of different substituents pattern in the products. Determination of the absolute configuration X-ray crystallography approach To gain more insight into these products, 4 b was subjected to “click chemistry”. Under Sharpless’ conditions, using a catalytic amount of CuSO4,[23] the terminal alkyne 4 b underwent Huisgen cycloaddition with para-bromophenyl azide to form the corresponding 1,2,3-triazole 6 (Scheme 7). X-ray diffraction on the resulting crystalline product 6 allowed the determination of the absolute configuration of the stereogenic carbon center, which was defined as S (Figure 3). Supposing that this quaternary carbon center was intact during the Huisgen cycloaddition process, the quaternary carbon center in the alkyne 4 b was established as S as well. According to the previous work of Corey[24] and Caporusso[25] on the substitution reactions of bromoallenes, we assumed that, in our case, the nucleophilic attack still followed the reported anti-SN’ manner (Scheme 7). In this way, we attributed the absolute configuration of the axially chiral chloroallene compound 2 k as R. In the case of 1,1-substitution, knowing also that nucleophiles have a preference for anti-type substitutions, we pre-

Figure 2. Formation of enantioenriched allenes and alkynes. Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

These are not the final page numbers! ÞÞ

7

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

&

Full Paper vertical axis uppermost, the more polarizable substituent in the horizontal axis is to the right, then a clockwise screw pattern of polarizability will obtain and the enantiomer should be dextrorotatory; if the more polarizable substituent in the horizontal axis is to the left, then an anticlockwise screw pattern of polarizability will obtain and the enantiomer should be laevorotatory.”[26] Two reported examples are shown in the Table 7, entries 1 and 2. Based on the previously established relative polarizability order, the molecules were placed accordingly with the view along the orthogonal axes, and the screw patterns corresponded well with the sign of optical rotation. Therefore, we selected several representative examples

Scheme 6. Copper-catalyzed one-pot sequence.

Scheme 7. Formation of the 1,2,3-triazole 6.

Table 7. Absolute configuration prediction by Lowe’s extension of Brewster’s rules. Entry[a] Absolute config- Polarizability uration order

Figure 3. X-ray crystal structure of 6.

sumed that the aryl allenes 3 a and alkyl allene 3 f have the depicted stereochemistry, while the other chiral allene compounds and alkynes are assigned by inference (Figure 2).

View along the orthogonal axes

Sign of ½aD

1[a]

Cl > Me > tBu > H

()

2[a]

Me > tBu > H

()

3[b]

Cl > Cy > Me > H

()

4[b]

Cl > nBu > tBu > H

(+)

5[b]

Cl > Cy > nBu > H

()

6[b]

Ph > Cy > Me > H

(+)

7[b]

Cy > Me, Cy > nBu > H

()

Lowe’s empirical approach [a] Previously reported; [b] synthesized in our study.

Based on Lowe’s extension of Brewster’s rules,[26] the absolute configuration of allenes could be predicted according to the relative polarizability of the substituents and the signs of optical rotation (Table 7): “If the allenes are viewed along their orthogonal axes, then the handedness of the screw pattern of polarizability is determined as follows. If by placing the more polarizable substituent in the &

&

Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

which were synthesized in our study, and illustrated them in the same manner. The predicted absolute configurations matched well with the results obtained from X-ray crystallography (Table 7, entries 3–7). 8

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper Vibrational circular dichroism spectra approach

ate would bias a certain conformation in the presence of the chiral phosphorus ligand (Figure 5). Upon the anti-selective oxidative addition process, the CuIII intermediate C would be formed, which could then undergo a reductive elimination to obtain the desired chloroallene P and regenerate the CuI species A. The proposed transition state models for intermediate B are shown in Figure 5. The two naphthyl groups intend to present

The infrared (IR) spectra and vibrational circular dichroism (VCD) spectra[27] of the chloroallene 2 k and phenyl allene 3 a were measured respectively to establish the absolute configurations by comparing the measured spectra with their calculated counterparts (Figure 4). The IR spectra are very well reproduced by the calculations. For the chloroallene 2 k, knowing that the S-enantiomer was used for calculation, based on the comparison, the opposite absolute configuration R can be assigned for 2 k. As for phenyl allene 3 a, the absolute configuration can be assigned as S, which is the same enantiomer used in the calculation (see the Supporting Information for detailed discussion). Overall, the results are in good agreement with what we expected according to previous approaches and further confirmed the absolute configurations of the molecules synthesized in this study.

Proposed mechanism for chloroallene formation We propose a possible mechanism for this enantioselective propargylic substitution. In the case of halogen atoms as leaving group, an anti-SN’/reductive elimination sequence was envisaged (Scheme 8).[4c, 28] The complexation of the initial copper(I) species A with the propargylic substrate S led to the formation of copper coordination intermediate B. This intermedi-

Scheme 8. Proposed mechanism.

Figure 4. Experimental (lower) and calculated (upper) IR and VCD spectra. Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

These are not the final page numbers! ÞÞ

9

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

&

Full Paper over alumina previously activated at 350 8C during 12 h under nitrogen before use. Reaction progress was monitored by thin-layer chromatography (TLC) or GC-MS Hewlett Packard (EI mode) HP6890–5973. TLC was performed using silica gel precoated aluminum plates purchased from Sigma–Aldrich and visualized by UV fluorescence or KMnO4 staining. Flash column chromatography was performed using silica gel 32–63 mm, 60 . 1H (400 MHz), 13C (101 MHz), 31P (162 MHz) and 19F (376 MHz) NMR spectra were recorded on a Bruker 400F NMR in CDCl3 or C6D6, and chemical shifts (d) are given in ppm relative to residual CHCl3 or C6HD5. Multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doublets of doublets), br s (broad singlet). Coupling constants are reported in Hertz (Hz). Optical rotations were recorded on a PerkinElmer 241 polarimeter at 25 8C in a 10 cm cell in the stated solvent; ½aD values are given in 101 deg cm2 g1 (concentration c given as g per 100 mL). Enantiomeric excesses were determined by chiral GC measurement either on a HP6890 (H2 as vector gas) or HP6850 (H2 as vector gas) with the stated column. Temperature programs are described as follows: initial temperature (8C)— initial time (min)—temperature gradient (8C min1)—final temperature (8C); retention times (tR) are given in minutes. Enantiomeric excesses were also determined by Chiral SFC measurement on a Berger SFC with the stated column. The chiral phosphoramidite ligands[9, 29] NHC ligands,[13h, 30, 31] and Simplephos ligands[14] were prepared according to the reported procedures. Josiphos, Taniaphos, Mandyphos, and Walphos ligands were provided by Solvias as a gift. CuTC, CuCN, CuBr, CuI, Cu(OAc)2, Cu(OTf)2, (CuOTf)2·C7H8, (CuOTf)2·C6H6 was purchased from FrontierScientific, Sigma–Aldrich or Alfa-Aesar and used as received. Copper(II) naphthenate (77 % in mineral spirits; 8 % Cu) was purchased from Strem and used as a solution in pentane (3.2 g of the green viscous oil was dissolved in 50 mL pentane).

Figure 5. Models for enantiodiscrimination.

a parallel conformation in order to favor p–p stacking interaction, the conformation of the gem-chloro carbon center would favor transition state TS1 due to lower steric hindrance. In the meantime, the methyl group on the phosphorus atom could also influence the enantioselectivity as we can see the interaction between the front methyl group on the P atom with the upper H or Cl atom in this model. This could be an explanation for the fact that during ligand optimization process, replacing the methyl groups by bulkier alkyls (ethyl or n-butyl) lowered the enantiomeric excesses.

Conclusions In conclusion, we have reported a versatile and tunable synthetic methodology for the enantioselective synthesis of chiral allenes and terminal alkynes. The copper-catalyzed 1,3-propargylic substitution employed a catalytic amount of the cheap copper source CuBr and an easily accessible SimplePhos ligand L27, with a range of readily available Grignard reagents as nucleophiles. The prochiral propargyl dichloride substrates were easily synthesized in two steps from commercially available alkynes with only one purification. The 1,3-substitutions were observed exclusively to afford the chloroallenes with high enantioselectivities up to 96 % ee. A simple and useful application of this chiral allene synthesis was demonstrated in the stereospecific copper-catalyzed 1,1/1,3-substitution. By simply changing the nucleophiles or the solvents, we could gain access to different trisubstituted aryl or alkyl allenes (by 1,1substitution in THF) and terminal alkynes (by 1,3-substitution in CH2Cl2). Synthetically valuable allenyl and propargyl silanes were synthesized in high optical purity through this methodology. The value of this study was further amplified by combining the two copper-catalyzed reactions into a one-pot process and the enantioinduction remained high for this sequence. In summary, this work represents an important contribution to the asymmetric syntheses of allenes and terminal alkynes.

Representative procedure for SimplePhos ligand synthesis 1,1-Dimethyl-N,N-bis((R)-1-(naphthalen-2-yl)ethyl)phosphanamine (L27): To a 100 mL flask was added (R)-bis[(R)-1-(naphthalen-2-yl)ethyl]amine (1.59 g, 4.8 mmol, 1.0 equiv) and THF (15 mL). The solution was cooled down to 78 8C under nitrogen in an acetone/dry ice bath. nBuLi was added dropwise to the solution at 78 8C (the color of the solution turned from yellow to red orange). Once addition had finished, the reaction mixture was stirred at the same temperature for a further 10 min (longer time would lead to the decomposition of the deprotonated amine) before adding PCl3 (0.42 mL, 4.8 mmol, 1.0 equiv). An aliquot of reaction mixture was collected for analysis by 31P NMR spectrocopy (in [D6]benzene). Upon full consumption of PCl3, MeLi solution (1.6 m in Et2O, 6.9 mL, 11.04 mmol, 2.3 equiv) was introduced to the flask, and the reaction mixture was allowed to warm back to 0 8C and stirred for a further 20–30 min. Excess of the organolithium reagent was neutralized by adding several drops of MeOH. The resulting solution was quenched by water and the aqueous phase was extracted with Et2O (3  25 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. A fast column chromatography purification on Al2O3 (eluent = 9:1 pentane/Et2O; Rf = 0.85) provided the desired product L27 (1.13 g, 60 % yield) as a white solid. 1H NMR (400 MHz, CDCl3): d = 7.73–7.71 (m, 2 H), 7.58–7.55 (m, 4 H), 7.44–7.37 (m, 6 H), 7.15 (dd, J = 8.6, 1.8 Hz, 2 H), 4.58–4.50 (m, 2 H), 1.76 (d, J = 6.9 Hz, 6 H), 1.33 (d, J = 6.2 Hz, 3 H), 1.21 ppm (d, J = 5.9 Hz, 3 H); 13C NMR (101 MHz, CDCl3): d = 142.0, 133.2, 132.4, 128.0, 127.5, 127.3, 127.2, 126.0, 125.7, 125.5, 53.5 (d, J = 6.5 Hz), 21.5 (d, J = 9.1 Hz), 17.7 (d, J = 18.2 Hz), 17.1 ppm (d, J =

Experimental Section General remarks: All reactions were carried out under argon atmosphere with flame-dried glasswares. Solvents were dried by filtration

&

&

Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

10

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper 14.5 Hz); 31P NMR (162 MHz, CDCl3): d = 13.47 ppm. The spectral data are in full agreement with those reported in the literature.[14b]

124.8, 90.0, 41.7, 32.1, 32.0, 26.46, 26.42, 26.3, 24.6, 12.1 ppm; HRMS (EI) calcd for C11H17Cl [M] + 184.1013, found 184.1011.

Representative procedure for substrate synthesis

Representative procedure for the copper-catalyzed 1,1-arylation of chloroallenes

(3,3-Dichloroprop-1-yn-1-yl)cyclohexane (1 b): To a solution of cyclohexylacetylene (2.61 mL, 20 mmol, 1.0 equiv) in Et2O (16 mL) at 40 8C was added dropwise nBuLi solution (1.6 m in hexane, 12.5 mL, 20 mmol, 1 equiv) followed by the addition of anhydrous DMF (2.4 mL, 30 mmol, 1.5 equiv) in one portion. The clear reaction mixture was allowed to warm up to room temperature and stirred for 30 min. The solution was then poured into a biphasic mixture of aqueous 10 % KH2PO4 solution (100 mL) and Et2O (80 mL) at 0 8C. The mixture was stirred vigorously, and layers were partitioned. The aqueous phase was extracted with Et2O (3  50 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude 3-cyclohexylpropiolaldehyde obtained was used in the following chlorination step without further purification. The crude aldehyde (calculated as 20 mmol, 1.0 equiv) was dissolved in dry CH2Cl2 (40 mL) and cooled to 20 8C. PCl5 (6.2 g, 30 mmol, 1.5 equiv) was added portionwise and the reaction mixture was stirred overnight. It was quenched by solid NaHCO3 (8.4 g, 100 mmol, 5.0 equiv) at 20 8C followed by water. The mixture was allowed to warm back to room temperature. Additional NaHCO3 was added to completely neutralize the solution. The aqueous phase was extracted with CH2Cl2 (3  50 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluent = pentane; Rf = 0.83) provided the desired compound 1 b (3.01 g, 79 % overall yield over 2 steps) as a slightly yellow liquid. 1H NMR (400 MHz, CDCl3): d = 6.28 (d, J = 1.8 Hz, 1 H), 2.54–2.48 (m, 1 H), 1.84–1.77 (m, 2 H), 1.74–1.66 (m, 2 H), 1.54–1.43 (m, 3 H), 1.38–1.29 ppm (m, 3 H); 13 C NMR (101 MHz, CDCl3): d = 96.2, 76.6, 56.3, 31.9, 29.2, 25.8, 24.8 ppm; HRMS (EI) calcd for C9H12Cl2 [M] + 190.0311, found 190.0306.

(S)-(3-Cyclohexylbuta-1,2-dien-1-yl)benzene (3 a): A dried argonflushed Schlenk tube was charged with CuCN (2.7 mg, 15 mol %) and the chloroallene 2 k (34.1 mg, 0.2 mmol, 1.0 equiv) in THF (2 mL) at 0 8C. PhMgBr (1 m in THF, 0.4 mL, 0.4 mmol, 2.0 equiv) was added dropwise to the solution. The reaction mixture was allowed to warm back to room temperature and the reaction progress was monitored by TLC. Once full conversion had been achieved, the reaction mixture was quenched by saturated aqueous NH4Cl solution and the aqueous phase was extracted with Et2O (2  5 mL). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluent = pentane; Rf = 0.69). Product 3 a was obtained as a colorless oil (0.0385 g, 91 % yield, S-enantiomer, 90 % ee). The enantiomeric excess was determined by GC on a chiral stationary phase (column: Hydrodex b-6-TBDMS, method: 60-0-1-170-5, tR = 86.81, 87.19 min). ½a20 D = + 233.3 (c = 0.53 in CHCl3 ; 1H NMR (400 MHz, CDCl3): d = 7.32–7.26 (m, 4 H), 7.20–7.14 (m, 1 H), 6.08 (p, J = 2.8 Hz, 1 H), 1.94–1.85 (m, 3 H), 1.82 (d, J = 2.8 Hz, 3 H), 1.77–1.73 (m, 2 H), 1.69–1.63 (m, 1 H), 1.35–1.11 ppm (m, 5 H); 13C NMR (101 MHz, CDCl3): d = 202.4, 136.3, 128.63, 128.61, 126.47, 126.43, 109.1, 94.6, 42.3, 32.3, 32.1, 26.6, 26.4, 17.4 ppm; HRMS (EI) calcd for C16H20 [M] + 212.1560, found 212.1560.

Representative procedure for the copper-catalyzed 1,1-alkylation of chloroallenes (S)-Octa-2,3-dien-2-ylcyclohexane (3 f): A dried argon-flushed Schlenk tube was charged with CuCN (2.7 mg, 15 mol %) and the chloroallene 2 k (34.1 mg, 0.2 mmol, 1.0 equiv) in THF (2 mL) at 0 8C. nBuMgBr (3.2 m in Et2O, 0.08 mL, 0.24 mmol, 1.2 equiv) was added dropwise to the solution during 30 min. The reaction mixture was allowed to warm back to room temperature and the reaction progress was monitored by TLC. Once full conversion had been achieved, the reaction mixture was quenched by saturated aqueous NH4Cl solution and the aqueous phase was extracted with Et2O (2  5 mL). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluent = pentane; Rf = 0.63). Product 3 f was obtained as a colorless oil (0.0222 g, 58 % yield, S-enantiomer, 87 % ee). The enantiomeric excess was determined by GC on a chiral stationary phase (column: Hydrodex b-3P, method : 60-0-1-110-0-20-170-5, tR = 46.73, 48.23 min). ½a20 D = + 44.9 (c = 0.60 in pentane); 1H NMR (400 MHz, CDCl3): d = 5.02 (tp, J = 5.6, 2.8 Hz, 1 H), 1.95 (q, J = 6.5 Hz, 2 H), 1.82–1.68 (m, 5 H), 1.67 (d, J = 2.8 Hz, 3 H), 1.40–1.02 (m, 9 H), 0.90 ppm (t, J = 7.1 Hz, 3 H); 13 C NMR (101 MHz, CDCl3): d = 200.7, 104.6, 90.9, 41.8, 32.2, 32.1, 31.6, 29.3, 26.7, 26.6, 22.4, 17.9, 14.1 ppm; HRMS (EI) calcd for C14H24 [M] + 192.1873, found 192.1870.

Representative procedure for the copper-catalyzed propargylic substitution of 1,1-dichloro substrates (R)-(1-Chloropenta-1,2-dien-3-yl)cyclohexane (2 b): A dried Schlenk tube was charged with CuBr (1.8 mg, 5 mol %) and the chiral ligand L27 (5.4 mg, 5.5 mol %) in toluene (2 mL). The mixture was stirred at room temperature for 10 min. The 1,1-dichloroalkyne 1 b (47.8 mg, 0.25 mmol, 1.0 equiv) was introduced dropwise and the reaction mixture was stirred at room temperature for a further 5 min before being cooled to 78 8C in an acetone/dry ice cold bath. The ethyl Grignard reagent (3 m in Et2O, 0.1 mL, 0.30 mmol, 1.2 equiv) was added manually during 20 min. Once the addition was complete the reaction mixture was stirred at 78 8C for 2 h. The reaction was quenched by adding saturated aqueous solution of NH4Cl. Et2O was added and the aqueous phase was separated and extracted with diethyl ether (3  2 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using (eluent = pentane; Rf = 0.76), and the desired product 2 b was isolated as a colorless oil. (0.039 g, 84 % yield, R-enantiomer, 92 % ee). The enantiomeric excess was determined by GC on a chiral stationary phase (column: Hydrodex b-3P, method: 60-0-1110-0-20-170-5, tR = 48.20, 49.14 min). ½a20 D = 86.3 (c = 0.50 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 6.08–6.06 (m, 1 H), 2.13–2.06 (m, 2 H), 1.90–1.73 (m, 5 H), 1.67–1.63 (m, 1 H), 1.31–1.10 (m, 5 H), 1.03 ppm (t, J = 7.3 Hz, 3 H); 13C NMR (101 MHz, CDCl3): d = 198.2, Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

These are not the final page numbers! ÞÞ

Representative procedure for the copper-catalyzed 1,3-alkylation of chloroallenes (S)-(3-methylhept-1-yn-3-yl)cyclohexane (4 b): A dried argon-flushed Schlenk tube was charged with CuCN (2.7 mg, 15 mol %) and the chloroallene 2 k (34.1 mg, 0.2 mmol, 1.0 equiv) in CH2Cl2 (2 mL) at 0 8C. nBuMgBr (3.9 m in Et2O, 0.1 mL, 0.4 mmol, 2.0 equiv) was added dropwise to the solution. The reaction mixture was allowed to warm back to room temperature and the reaction progress was

11

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

&

Full Paper monitored by TLC. Once full conversion had been achieved, the reaction mixture was quenched by saturated aqueous NH4Cl solution and the aqueous phase was extracted with Et2O (2  5 mL). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluent = pentane; Rf = 0.95). Product 4 b was obtained as a colorless oil (0.0342 g, 89 % yield, S-enantiomer, 90 % ee). The enantiomeric excess was determined by GC on a chiral stationary phase (column: Hydrodex b-6-TBDMS: method 60-0-1-110-0-20-170-5, tR = 47.34, 47.86 min). ½a20 D = + 2.7 (c = 0.49 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 2.07 (s, 1 H), 1.93–1.89 (m, 1 H), 1.80–1.76 (m, 3 H), 1.68–1.63 (m, 1 H), 1.49–1.05 (m, 15 H), 0.92 ppm (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): d = 91.4, 69.1, 45.6, 38.8, 38.3, 28.2, 27.4, 27.0, 26.98, 26.9, 26.7, 23.5, 23.46, 14.3 ppm. HRMS (EI) calcd for C11H17 [MC3H7] + 149.1325, found 149.1323.

concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluent = pentane; Rf = 0.95). Product 4 b was obtained as a colorless oil (0.0431 g, 90 % yield).

Acknowledgements This work is supported by the Swiss National Research Foundation (grant No. 200020-126663). The authors warmly thank Dr. D. Mller (Univ. of Geneva) for preparation of useful chemicals, Solvias for generous gift of chiral ligands, BASF for the generous gift of chiral amines and Prof. P. Knochel (L. Maximilian Univ., Munich, Germany) for fruitful discussion. Keywords: allenes · asymmetric catalysis · copper · Grignard reagents · P ligands

Representative procedure for the one-pot copper-catalyzed sequence to generate chiral allenes

[1] Reviews and highlights on allenes: a) Modern Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2005; b) A. HoffmannRçder, N. Krause, Angew. Chem. 2004, 116, 1216 – 1236; Angew. Chem. Int. Ed. 2004, 43, 1196 – 1216; c) A. Hoffmann-Rçder, N. Krause, Angew. Chem. 2002, 114, 3057 – 3059; Angew. Chem. Int. Ed. 2002, 41, 2933 – 2935; d) S. Ma, Acc. Chem. Res. 2003, 36, 701 – 712; e) S. Ma, Chem. Rev. 2005, 105, 2829 – 2871; f) S. Ma, E.-i. Negishi, J. Am. Chem. Soc. 1995, 117, 6345 – 6357; g) A. S. K. Hashmi, Angew. Chem. 2000, 112, 3737 – 3740; Angew. Chem. Int. Ed. 2000, 39, 3590 – 3593; h) S. Yu, S. Ma, Angew. Chem. 2012, 124, 3128 – 3167; Angew. Chem. Int. Ed. 2012, 51, 3074 – 3112. [2] For selected reviews on allene synthesis: a) N. Krause, A. HoffmannRçder, Tetrahedron 2004, 60, 11671 – 11694; b) K. M. Brummond, J. E. DeForrest, Synthesis 2007, 795 – 818; c) S. Yu, S. Ma, Chem. Commun. 2011, 47, 5384 – 5418. For recent advances in catalytic allene synthesis, see: d) R. K. Neff, D. E. Frantz, ACS Catal. 2014, 4, 519 – 528, and the references therein. [3] a) Transition Metal Catalyzed Enantioselective Allylic Substitution in Organic Synthesis Vol. 38 (Ed.: U. Kazmaier), Springer, Berlin Heidelberg, 2012 and the references therein. For selected reviews on copper-catalyzed asymmetric allylic alkylation (AAA), see: b) A. Alexakis, C. Malan, L. Lea, K. Tissot-Croset, D. Polet, C. Falciola, Chimia 2006, 60, 124 – 130; c) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824 – 2852; d) A. Alexakis, J. E. Bckvall, N. Krause, O. Pamies, M. Dieguez, Chem. Rev. 2008, 108, 2796 – 2823; e) O. Basl, A. Denicourt-Nowicki, C. Crvisy, M. Mauduit in Copper-Catalyzed Asymmetric Synthesis (Eds.: A. Alexakis, N. Krause, S. Woodward), WileyVCH, Weinheim, 2014, pp. 85 – 126. [4] a) A. Alexakis, A. CommerÅon, C. Coulentianos, J. F. Normant, Tetrahedron 1984, 40, 715 – 731; b) C. J. Elsevier, P. Vermeer, J. Org. Chem. 1989, 54, 3726 – 3730; c) A. Alexakis, I. Marek, P. Mangeney, J. F. Normant, J. Am. Chem. Soc. 1990, 112, 8042 – 8047; d) J. D. Buynak, D. Khasnis, B. Bachmann, K. Wu, G. Lamb, J. Am. Chem. Soc. 1994, 116, 10955 – 10965; e) Z. Wan, S. G. Nelson, J. Am. Chem. Soc. 2000, 122, 10470 – 10471; f) R. K. Dieter, H. Yu, Org. Lett. 2001, 3, 3855 – 3858; g) K. M. Brummond, A. D. Kerekes, H. Wan, J. Org. Chem. 2002, 67, 5156 – 5163; h) C. Zelder, N. Krause, Eur. J. Org. Chem. 2004, 3968 – 3971; i) X. Tang, S. Woodward, N. Krause, Eur. J. Org. Chem. 2009, 2836 – 2844; j) J. Ye, S. Li, B. Chen, W. Fan, J. Kuang, J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q. Yu, W. Yuan, S. Ma, Org. Lett. 2012, 14, 1346 – 1349; k) A. Nakatani, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2012, 14, 2586 – 2589. [5] For recent examples of copper-catalyzed asymmetric allene synthesis, see: a) H. Ohmiya, U. Yokobori, Y. Makida, M. Sawamura, Org. Lett. 2011, 13, 6312 – 6315; b) M. R. Uehling, S. T. Marionni, G. Lalic, Org. Lett. 2012, 14, 362 – 365; c) M. Yang, N. Yokokawa, H. Ohmiya, M. Sawamura, Org. Lett. 2012, 14, 816 – 819; d) U. Yokobori, H. Ohmiya, M. Sawamura, Organometallics 2012, 31, 7909 – 7913. For a palladium-catalyzed asymmetric allene synthesis from racemic substrates, see: e) Y. Wang, W. Zhang, S. Ma, J. Am. Chem. Soc. 2013, 135, 11517 – 11520.

(S)-(3-Cyclohexylbuta-1,2-dien-1-yl)benzene (3 a): A dried Schlenk tube was charged with CuBr (1.8 mg, 5 mol %) and the chiral ligand L27 (5.4 mg, 5.5 mol %) in toluene (2 mL). The mixture was stirred at room temperature for 10 min. The 1,1-dichloro alkyne 1 b (47.8 mg, 0.25 mmol, 1.0 equiv) was introduced dropwise and the reaction mixture was stirred at room temperature for a further 5 min before being cooled to 78 8C in an acetone/dry ice cold bath. The methyl Grignard reagent (3.2 m in Et2O, 0.09 mL, 0.30 mmol, 1.2 equiv) was added manually during 20 min. Once the addition was complete the reaction mixture was stirred at 78 8C for 2 h. The reaction was monitored by TLC to achieve full conversion of the starting material. THF (1 mL) was introduced and PhMgBr (2.8 m in THF, 0.18 mL, 0.5 mmol, 2.0 equiv) was added dropwise to the solution. The reaction mixture was allowed to warm back to room temperature and the reaction progress was monitored by TLC. Once full conversion had been achieved, the reaction mixture was quenched by saturated aqueous NH4Cl solution and the aqueous phase was extracted with Et2O (2  5 mL). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel using (eluent = pentane; Rf = 0.69). Product 3 a was obtained as a colorless oil (0.0376 g, 71 % yield).

Representative procedure for the one-pot copper-catalyzed sequence to generate chiral alkynes A dried Schlenk tube was charged with CuBr (1.8 mg, 5 mol %) and the chiral ligand L27 (5.4 mg, 5.5 mol %) in toluene (2 mL). The mixture was stirred at room temperature for 10 min. The 1,1-dichloro alkyne 1 b (47.8 mg, 0.25 mmol, 1.0 equiv) was introduced dropwise and the reaction mixture was stirred at room temperature for a further 5 min before being cooled to 78 8C in an acetone/dry ice cold bath. The methyl Grignard reagent (3.2 m in Et2O, 0.09 mL, 0.30 mmol, 1.2 equiv) was added manually during 20 min. Once the addition was complete the reaction mixture was stirred at 78 8C for 2 h. The reaction was monitored by TLC to achieve full conversion of the starting material. CH2Cl2 (1.5 mL) was introduced and nBuMgBr (3.2 m in THF, 0.16 mL, 0.5 mmol, 2.0 equiv) was added dropwise to the solution. The reaction mixture was allowed to warm back to room temperature and the reaction progress was monitored by TLC. Once full conversion had been achieved, the reaction mixture was quenched by saturated aqueous NH4Cl solution and the aqueous phase was extracted with Et2O (2  5 mL). The combined organic phases were dried over Na2SO4,

&

&

Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

12

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper [6] M. Asikainen, W. Lewis, A. J. Blake, S. Woodward, Tetrahedron Lett. 2010, 51, 6454 – 6456. [7] M. A. Schade, S. Yamada, P. Knochel, Chem. Eur. J. 2011, 17, 4232 – 4237. [8] H. Li, D. Mller, L. Gune, A. Alexakis, Org. Lett. 2012, 14, 5880 – 5883. [9] a) K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. 2004, 116, 2480 – 2482; Angew. Chem. Int. Ed. 2004, 43, 2426 – 2428; b) H. Li, A. Alexakis, Angew. Chem. 2012, 124, 1079 – 1082; Angew. Chem. Int. Ed. 2012, 51, 1055 – 1058. [10] For selected examples using ferrocene-based phosphorus ligands in the copper-catalyzed AAA, see: a) F. Dbner, P. Knochel, Angew. Chem. 1999, 111, 391 – 393; Angew. Chem. Int. Ed. 1999, 38, 379 – 381; b) F. Dbner, P. Knochel, Tetrahedron Lett. 2000, 41, 9233 – 9237; c) H. K. Cotton, J. Norinder, J.-E. Bckvall, Tetrahedron 2006, 62, 5632 – 5640. [11] For selected examples using Josiphos or Taniaphos in the copper-catalyzed AAA with Grignard reagents, see: a) F. Lpez, A. W. van Zijl, A. J. Minnaard, B. L. Feringa, Chem. Commun. 2006, 409 – 411; b) M. Giannerini, M. FaÇan s-Mastral, B. L. Feringa, J. Am. Chem. Soc. 2012, 134, 4108 – 4111. [12] For selected examples using NHC ligands in copper-catalyzed AAA, see a) S. Tominaga, Y. Oi, T. Kato, D. K. An, S. Okamoto, Tetrahedron Lett. 2004, 45, 5585 – 5588; b) A. O. Larsen, W. Leu, C. N. Oberhuber, J. E. Campbell, A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 11130 – 11131; c) J. J. Van Veldhuizen, J. E. Campbell, R. E. Giudici, A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127, 6877 – 6882; d) Y. Lee, K. Akiyama, D. G. Gillingham, M. K. Brown, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130, 446 – 447; e) T. Jennequin, J. Wencel-Delord, D. Rix, J. Daubignard, C. Crvisy, M. Mauduit, Synlett 2010, 1661 – 1665. [13] For selected examples using NHC carbene ligands under copper-free AAA conditions, see: a) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128, 15604 – 15605; b) Y. Lee, B. Li, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 11625 – 11633; c) C. M. Latham, A. J. Blake, W. Lewis, M. Lawrence, S. Woodward, Eur. J. Org. Chem. 2012, 699 – 707; d) J.-N. Levy, C. M. Latham, L. Roisin, N. Kandziora, P. D. Fruscia, A. J. P. White, S. Woodward, M. J. Fuchter, Org. Biomol. Chem. 2012, 10, 512 – 515; e) O. Jackowski, A. Alexakis, Angew. Chem. 2010, 122, 3418 – 3422; Angew. Chem. Int. Ed. 2010, 49, 3346 – 3350; f) D. Grassi, A. Alexakis, Org. Lett. 2012, 14, 1568 – 1571; g) D. Grassi, H. Li, A. Alexakis, Chem. Commun. 2012, 48, 11404 – 11406; h) D. Grassi, C. Dolka, O. Jackowski, A. Alexakis, Chem. Eur. J. 2013, 19, 1466 – 1475. [14] a) L. Palais, I. S. Mikhel, C. Bournaud, L. Micouin, C. A. Falciola, M. Vuagnoux-d’Augustin, S. Rosset, G. Bernardinelli, A. Alexakis, Angew. Chem. 2007, 119, 7606 – 7609; Angew. Chem. Int. Ed. 2007, 46, 7462 – 7465; b) D. Mller, L. Gune, A. Alexakis, Eur. J. Org. Chem. 2013, 6335 – 6343. [15] a) C. Bournaud, C. Falciola, T. Lecourt, S. Rosset, A. Alexakis, L. Micouin, Org. Lett. 2006, 8, 3581 – 3584; b) R. Millet, L. Gremaud, T. Bernardez, L. Palais, A. Alexakis, Synthesis 2009, 2101 – 2112; c) L. Palais, C. Bournaud, L. Micouin, A. Alexakis, Chem. Eur. J. 2010, 16, 2567 – 2573.

Chem. Eur. J. 2014, 20, 1 – 14

www.chemeurj.org

These are not the final page numbers! ÞÞ

[16] For selected examples, see : a) D. Mller, A. Alexakis, Chem. Commun. 2012, 48, 12037 – 12049; b) L. Palais, A. Alexakis, Chem. Eur. J. 2009, 15, 10473 – 10485; c) D. Mller, A. Alexakis, Org. Lett. 2012, 14, 1842 – 1845; d) D. Mller, A. Alexakis, Chem. Eur. J. 2013, 19, 15226 – 15239. [17] D. Mller, M. Tissot, A. Alexakis, Org. Lett. 2011, 13, 3040 – 3043. [18] For the example using organolithium as nucleophile in the copper-catalyzed allylic substitution, see M. Prez, M. FaÇan s-Mastral, P. H. Bos, A. Rudolph, S. R. Harutyunyan, B. L. Feringa, Nat. Chem. 2011, 3, 377 – 381. [19] For recent examples of chiral allenylsilane synthesis, see ref. [5d] and: a) D. J. Vyas, C. K. Hazra, M. Oestreich, Org. Lett. 2011, 13, 4462 – 4465; b) C. K. Hazra, M. Oestreich, Org. Lett. 2012, 14, 4010 – 4013; and references therein. [20] T. J. J. Mller, M. Ansorge, Chem. Ber./Recueil 1997, 130, 1135 – 1139. [21] J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593 – 4623. [22] a) C. E. Masse, J. S. Panek, Chem. Rev. 1995, 95, 1293 – 1315; b) M. J. C. Buckle, I. Fleming, S. Gil, K. L. C. Pang, Org. Biomol. Chem. 2004, 2, 749 – 769; c) L. Carroll, M. C. Pacheco, L. Garcia, V. Gouverneur, Chem. Commun. 2006, 4113 – 4115. [23] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708 – 2711; Angew. Chem. Int. Ed. 2002, 41, 2596 – 2599. [24] E. J. Corey, N. W. Boaz, Tetrahedron Lett. 1984, 25, 3059 – 3062. [25] a) A. M. Caporusso, C. Polizzi, L. Lardicci, Tetrahedron Lett. 1987, 28, 6073 – 6076; b) A. M. Caporusso, C. Polizzi, L. Lardicci, J. Org. Chem. 1987, 52, 3920 – 3923; c) C. Polizzi, C. Consoloni, L. Lardicci, A. M. Caporusso, J. Organomet. Chem. 1991, 417, 289 – 304; d) A. M. Caporusso, S. Filippi, F. Barontini, P. Salvadori, Tetrahedron Lett. 2000, 41, 1227 – 1230; e) A. M. Caporusso, L. A. Aronica, R. Geri, M. Gori, J. Organomet. Chem. 2002, 648, 109 – 118; f) A. M. Caporusso, A. Zampieri, L. A. Aronica, D. Banti, J. Org. Chem. 2006, 71, 1902 – 1910. [26] a) J. H. Brewster, J. Am. Chem. Soc. 1959, 81, 5475 – 5483; b) G. Lowe, Chem. Commun. 1965, 411 – 413. [27] T. B. Freedman, X. L. Cao, R. K. Dukor, L. A. Nafie, Chirality 2003, 15, 743 – 758. [28] I. Marek, P. Mangeney, A. Alexakis, J. F. Normant, Tetrahedron Lett. 1986, 27, 5499 – 5502. [29] A. Alexakis, D. Polet, S. Rosset, S. March, J. Org. Chem. 2004, 69, 5660 – 5667. [30] H. Clavier, L. Coutable, L. Toupet, J.-C. Guillemin, M. Mauduit, J. Organomet. Chem. 2005, 690, 5237 – 5254. [31] D. Martin, S. Kehrli, M. d’Augustin, H. Clavier, M. Mauduit, A. Alexakis, J. Am. Chem. Soc. 2006, 128, 8416 – 8417.

Received: July 31, 2014 Published online on && &&, 0000

13

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

&

Full Paper

FULL PAPER & Asymmetric Catalysis H. Li, D. Grassi, L. Gune, T. Brgi, A. Alexakis* && – && Copper-Catalyzed Propargylic Substitution of Dichloro Substrates: Enantioselective Synthesis of Trisubstituted Allenes and Formation of Propargylic Quaternary Stereogenic Centers

&

&

Chem. Eur. J. 2014, 20, 1 – 14

A range of chiral allenes and terminal alkynes are synthesized highly enantioselectively. Starting from prochiral dichloro substrate bearing substituent R1, different alkyl groups R2 are introduced

providing chiral chloroallenes. Further substitution reaction installs R3 groups highly stereospecifically and demonstrates diverse substitution patterns.

14

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

ÝÝ These are not the final page numbers!

Copper-catalyzed propargylic substitution of dichloro substrates: enantioselective synthesis of trisubstituted allenes and formation of propargylic quaternary stereogenic centers.

An easy and versatile Cu-catalyzed propargylic substitution process is presented. Using easily prepared prochiral dichloro substrates, readily availab...
1MB Sizes 0 Downloads 8 Views

Recommend Documents


Highly enantioselective copper-catalyzed propargylic substitution of propargylic acetates with 1,3-dicarbonyl compounds.
A chiral tridentate ketimine P,N,N-ligand has been successfully applied in the copper-catalyzed enantioselective propargylic substitution of propargylic acetates with a variety of β-dicarbonyl compounds, in which excellent enantioselectivities (up to

Borylation of propargylic substrates by bimetallic catalysis. Synthesis of allenyl, propargylic, and butadienyl Bpin derivatives.
Bimetallic Pd/Cu and Pd/Ag catalytic systems were used for borylation of propargylic alcohol derivatives. The substrate scope includes even terminal alkynes. The reactions proceed stererospecifically with formal SN2' pathways to give allenyl boronate

phosphoramide hybrid catalysts.
The diastereo- and enantioselective propargylic alkylation of propargylic alcohols with E-enecarbamates in the presence of a catalytic amount of thiolate-bridged diruthenium complexes bearing an optically active phosphoramide moiety gives the corresp

Enantioselective synthesis of boron-substituted quaternary carbon stereogenic centers through NHC-catalyzed conjugate additions of (pinacolato)boron units to enones.
The first examples of Lewis base catalyzed enantioselective boryl conjugate additions (BCAs) that generate products containing boron-substituted quaternary carbon stereogenic centers are disclosed. Reactions are performed in the presence of 1.0-5.0 m

Assembly of Fluorinated Quaternary Stereogenic Centers through Catalytic Enantioselective Detrifluoroacetylative Aldol Reactions.
A Cu-catalyzed asymmetric detrifluoroacetylative aldol addition reaction of 2-fluoro-1,3-diketones/hydrates to aldehydes in the presence of base and chiral bidentate ligand was developed. The reaction was carried out under convenient conditions and t

Enantioselective Synthesis of Tertiary Propargylic Alcohols under N-Heterocyclic Carbene Catalysis.
A straightforward procedure to carry out the enantioselective benzoin reaction between aldehydes and ynones by employing a chiral N-heterocyclic carbene (NHC) as catalyst was developed. Under the optimized reaction conditions, these ynones undergo a

Nonenzymatic enantioselective synthesis of all-carbon quaternary centers through desymmetrization.
The asymmetric desymmetrization of meso or prochiral compounds containing an all-carbon quaternary center is an attractive alternative to classical synthetic approaches aimed at the asymmetric formation of a new C-C bond. This review focuses on nonen

Stereoselective formation of quaternary stereogenic centers via alkylation of α-substituted malonate-imidazolidinones.
A new stereoselective alkylation methodology is presented for formation of chiral, nonracemic quaternary centers via a chiral auxiliary protocol involving α-alkylated malonate imidazolidinones. Based on two X-ray structures of quaternized products, t

Catalytic, asymmetric synthesis of phosphonic γ-(hydroxyalkyl)butenolides with contiguous quaternary and tertiary stereogenic centers.
A procedure that enables high yielding access to phosphonic γ-(hydroxyalkyl)butenolides with excellent regio-, diastereo- and enantiocontrol is reported. The simultaneous construction of up to two adjacent quaternary stereogenic centers by a catalyti