University of Groningen
Catalytic asymmetric carbon-carbon bond forming methodologies for synthesis of chiral N-containing heterocycles and chiral carboxamides
Guo, Yafei DOI:
10.33612/diss.147535855
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Publication date: 2020
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Guo, Y. (2020). Catalytic asymmetric carbon-carbon bond forming methodologies for synthesis of chiral N-containing heterocycles and chiral carboxamides. University of Groningen.
https://doi.org/10.33612/diss.147535855
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Chapter 5: Lewis acid-driven control of regio- and
enantioselectivities of Cu-catalyzed conjugate additions of
Grignard reagents to bifunctional Michael acceptors.
In this chapter, the asymmetric conjugate addition of Grignard reagents to olefins bearing two conjugated functional groups, each on one side, has been studied. It was demonstrated that Lewis acid/base interactions could be used to control/override the reactivity of the dominant functional group, thus allowing regioselective reactions with the less reactive functional group in the presence of a more reactive one without the need for protecting groups. Different modes of selectivity are accessed by directing the LA to the desired functional group, exploiting either its strength or functional group affinity.
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5.1 Introduction
Small organic molecules that contain multiple reactive functional groups are highly attractive synthetic building blocks for constructing complex molecular structures. However, the reactive functional groups that make these molecules so attractive for chemical synthesis also cause major problems associated with chemo- and regioselectivity. Typically, the result is a mixture of compounds, dominated by the product derived from the most reactive functional group. Before moving to our work, progress in asymmetric conjugate additions (ACA) to bifunctional Michael acceptors are reviewed.
Conjugate addition of organometallics is one of the powerful methods for the C-C forming reactions in organic synthesis.1-3 While in recent years, many examples of ACA have been
reported, including unsaturated esters, ketones, amides, carboxylic acids, pyridines and several heterocyclic substrates,4-10 most of these reports are related to substrates with one
functional group. Only a handful methods are known involving substrates bearing doubly activated olefines, such as fumaric or maleic compounds.11 As highlighted above, reactions
with such systems are challenging, because of regioselectivity issues. In addition, obtaining enantiopure products is troublesome, as outcompeting the background reaction is difficult and requires a very reactive and selective catalyst.
One of the few successful examples makes use of organozinc and trialkyl aluminum reagents for the ACA to nitroacrylates as substrates. Here (Scheme 1), the nitro group is the most activating one and therefore allows substrate controlled regioselectivityduring the addition reaction. Phosphoramidite-derived copper(I) catalysts employed in this reaction afforded chiral2-substituted 3-nitro propionic acid esters with up to 92% yield and 92%
ee. These chiral products are very useful, as they can be transformed into a range of other
functional groups, including amines, aldehydes, acid moieties and 2-amino acids and its
derivatives.12-13
Scheme 1: The ACA reaction of organozinc and trialkyl aluminium reagents to nitro acrylates.
In 2003, the highly enantioselective conjugate addition of dialkylzinc reagents to another class of nitroalkenes was reported (Scheme 2). As with previous, various kinds of organozinc reagents were examined, yielding products with high enantioselectivities.14
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Scheme 2: The ACA reaction of organozinc reagents to acyclic nitroalkenes.
The -keto ester is another example of substrate class bearing two activating functional groups. Hoveyda and co-workers disclosed the ACA of organozinc reagents to -keto esters (5- and 6-membered methyl and t-butyl ester substrates) (Scheme 3), which was promoted by a chiral N-heterocyclic carbene (NHC) ligand and a copper based catalytic system. Interestingly, these transformations gave rise to the formation of chiral all-carbon quaternary stereogenic centers that bear a readily functionalizable carboxylic ester substituent with up to 98% yield and 95% ee. It is noteworthy that the two challenging nucleophiles Me2Zn and Ph2Zn displayed good reactivity. These results were further
improved by using PhLi and ZnCl2.15
Scheme 3: The ACA reaction of organozinc reagents to -keto ester.
Optically active 2-substituted succinic acid derivatives are valuable and important building blocks for the syntheses of various biologically active compounds and natural products. In recent years, large amounts of work was reported for the preparation of chiral 2-substituted succinic acid derivatives. However, the reported methodologies are still limited to arylations. For example, the groups of Hayashi and Wu described rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic esters (Scheme 4). It was found that phosphorus-based chiral ligands fail to induce high stereodifferentiation. However, chiral norbornadiene ligands were proven to be effective to obtain high enantioselectivity in these 1,4-addition reactions.16-17
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Scheme 4: The ACA reaction of arylboronic acids to fumaric esters.
Maleimide is a very common acceptor used in organic synthesis. The groups of Korenaga and Hayashi showed that phosphorus based chiral ligands are effective in the Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to maleimides leading to products with yields and ees up to 99% (Scheme 5).18-19
Scheme 5. The ACA reaction of arylboronic acids to maleimides.
Tedrow and co-workers devised conjugate addition of arylboronic acids to 4-oxobutenamides (Scheme 6). Using rhodium catalysis, they managed to reach high regio- and enantioselectivities (>99:1 regioselectivity and >99% ee) and excellent yields (up to 99%). The key to high selectivity is the use of sterically demanding P-chiral diphosphines (Duanphos). The chiral products can be converted into alternate targets by selective derivatization of either the amide or ketone functional group.20
Scheme 6: The ACA reaction of arylboronic acids to 4-oxobutenamides.
All these examples are based on the reactivity of the most reactive functional group or make use of identical functional groups. Making reactions with multiple functional groups
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selective, as well as being able to control/override the reactivity of the dominant functional group, is one of the holy grails in organic synthesis. The most common strategy in this context employs temporary protection of the reactive functional group, allowing the desired reaction with the weaker functional group to occur. Although effective, this approach leads to two additional synthetic steps (protection and deprotection), which is detrimental for the efficiency and sustainability of the transformation.
In this work, we aimed to use Lewis acid/base interactions to control the selectivity in addition reactions to substrates carrying multiple functional groups (Figure 1). While such molecules have various reactive sites (indicated with arrows), in theory the preferred selectivity can be controlled by directing the Lewis acid (LA) to the desired functional group, by either exploiting the strength (Lewis acidity) or the functional group affinity of the LA (Figure 1). The power of this strategy is the ability to provide protecting group free transformations with multifunctional organic synthons, where the functional groups in question are conjugated and non-conjugated systems.
Figure 1: Preferred Lewis acid (LA) activation and site blocking based on Lewis acidity and affinity.
For this work, we chose four substrates with different functional groups - ester, amide, acid and pyridine - and studied its ACA of Grignard reagents and the possibility to control/override the reactivity of the dominant functional group (Scheme 7). To achieve this, different Lewis acids were used in combination with various copper/ligand catalysts.
Scheme 7: The work in this chapter.
5.2 Result and discussion
To explore the optimal reaction conditions a model reaction was selected comprising of substrate 1 (bearing an amide and an ester functional group) as the starting material and EtMgBr as the nucleophile (Table 1). In the absence of any catalyst and LA, the 1,4-adduct with respect to the most reactive ester group, product 3 was obtained with 100% regioselectivity and 78% yield (entry 1). Interestingly, when catalyst L1/Cu was introduced in the reaction, both ACA products 2 and 3 were obtained with a ratio of 10:90 and 40% ee for the major product (entry 2). Next, we studied the effect of Lewis acids in this reaction (TMSOTf, TMSBr, TMSCl, TMSI, BF3·Et2O and BEt3, entries 5-10). The formation of the
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product 2 derived from ACA with respect to the less activating carboxamide group increased when different Lewis acids were used. Noteworthy is the regioselectivity of 83:17 (2:3) obtained when BF3·Et2O was used as a Lewis acid. In addition, 17% ee could be
obtained in the presence of a chiral copper catalyst (entry 9). Several ligands (depicted in Scheme 8) in combination with BF3·Et2O were tested to improve further the
enantioselectivity of the reaction (entries 11-16). Unfortunately, in most cases racemic product 2 was obtained. Enantioselectivity of the reaction was slightly improved when using copper salt in combination with either ligand L5 and L6 (30-35% ee). Thus as a result of different reactivities of an ester and an amide functional groups, the regioselectivity of the addition reaction can significantly be affected by Lewis aci, however the enantioselctivity couldn’t be improved further.
Scheme 8: Chiral ligands explored in this chapter.
Table 1: Optimization of reaction conditions for addition of EtMgBr to substrate 1.a
Entry Ligand/Cu LA Ratio Yield (%)b ee (%)c
1 - - 0:100 78 0 2 L1 - 10:90 66 40 3 L2 - 2：98 65 0 4 L3 - - <5 nd 5 L1 TMSOTf 18:82 58 0 6 L1 TMSCl 0:100 86 0 7 L1 TMSBr 8:92 76 0 8 L1 TMSI 28:72 63 0 9 L1 BF3·Et2O 83:17 72 17 10 L1 BEt3 45:55 18 nd 11 L4 BF3·Et2O 93:7 78 0 12 L2 BF3·Et2O 87:13 63 0 13 L5 BF3·Et2O 90:10 79 35 14 L6 BF3·Et2O 92:8 76 30 15 L7 BF3·Et2O 90:10 <5 nd 16 L8 BF3·Et2O 91:9 35 nd
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aReaction conditions: 1 (0.2 mmol), EtMgBr (2.0 equiv.), Ligand L (6 mol%), CuBr·SMe2 (5 mol%) in solvent (2
mL), -78 oC, 2h. bIsolated yields. cThe enantiomeric excess was determined by HPLC on a chiral stationary
phase.
A reasonable cause for the low enantioselectivity is the inability of the chiral catalyst to outcompete the non-catalysed addition pathway. The apparent evidence for this is the result obtained when using the least reactive Grignard reagent, MeMgBr: in the presence of BF3·Et2O and L1/Cu only the ACA product 4 was obtained with 96% ee and 81% isolated
yield (Scheme 9).
Scheme 9: Methylation of substrate 1 by using MeMgBr.
Delighted by this result, we next explored substrate 6 with conjugated carboxamide and carboxylic acid functionalities: both functional groups exhibited similar reactivity towards CA of Grignard reagents. More specifically, the reaction in the absence of a LA and a copper catalyst resulted in a mixture of products 7 and 8 with 46:54 ratio and a total of 38% yield (Table 2, entry 1). Similar ratio of products 7 and 8 (45:55, entry 2) was obtained in the presence of Cu/L1 catalyst. Next we screened the reaction in the presence of Cu/L1 and various Lewis acids (TMSOTf, TMSBr, TMSCl, BF3·Et2O and BCl3) (entries 3-7).
Table 2: Optimization of reaction conditions for addition of EtMgBr to substrate 6.a
Entry Ligand LA Solvent Ratio(7:8)b Yield(%)c ee (%)d
1 - - DCM 46:54 38 0 2 L1 - DCM 45:55 42 0 3 L1 TMSOTf DCM 35:65 72 0 4 L1 TMSBr DCM 10:90 82 0 5 L1 TMSCl DCM 33:66 51 0 6 L1 BF3·Et2O DCM 65:35 52 0 7 L1 BCl3 DCM 38:62 58 0 8 - TMSBr DCM 45:55 68 0 9 L1 BF3·Et2O MTBE - 0 - 10 L1 TMSBr MTBE 53:47 16 - 11 L1 TMSOTf MTBE 51:49 10 - 12 L4 TMSBr DCM 8:92 78 0 13 L5 TMSBr DCM 5:95 88 35 14 L6 TMSBr DCM 9:91 83 0 15 L5 TMSBr DCM 10:90 87 0 16 L7 TMSBr DCM 15:85 68 0 17 L9 TMSBr DCM 12:88 78 0
aReaction conditions: 6 (0.2 mmol), EtMgBr (2.0 equiv.), Ligand L (6 mol%), CuBr·SMe2 (5 mol%) in solvent (2
mL), -78 oC, overnight. bThe conversion was determined by 1H NMR. cIsolated yields. dThe enantiomeric excess
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We were pleased to find that using TMSBr as a LA, product 8 could be obtained with regioselectivity of 90% and 82% yield (entry 4). In contrast, in the presence of BF3·Et2O as
the LA the major product was compound 7 (ratio 7:8 = 65:35, entry 6). Interestingly, in the sence of Cu/L1, using TMSBr resulted in a mixture of products (45:55, entry 8). This stresses the important cooperative role of the Lewis acid and the catalyst in controlling the regioselectivity of the reaction. Changing the solvent to MTBE did not result in improved results (entries 9-11). Screening of various ligands with TMSBr indicated to Tol-BINAP (L5) as an optimal chiral ligand for this reaction providing product 8 with 95% of regioselectivity and 35% ee (entries 12-17).
In our previous work, we have reported Lewis acid promoted catalytic asymmetric addition of Grignard reagents to relatively unreactive alkenyl-substituted aromatic N-heterocycles as well as conjugated carboxamides.8-9 This is why we were interested in the reactivity and
selectivity associated with substrate 9, in which the double bond is conjugated to pyridine and carboxamide functional groups. Upon reaction addition of EtMgBr to 9, product 10 resulting from conjugate addition with respect to amide functional group was obtained in 92% yield (Table 3, entry 1). As a result of Lewis acid screening (TMSOTf, TMSBr, TMSCl, BF3·Et2O and BCl3, entries 2-6) in the absence of Cu-catalyst, it was found that TMSBr can
selectively activate the substrate and reverse the regioselectivity, yielding mainly the product 11 (99%, entry 3). When catalyst (L1/Cu) was introduced into the reaction in combination with different Lewis acids (entries 7-9), the best result was obtained with BF3·Et2O providing product 90% of product 10 with moderate enantiomeric excess (67%,
entry 9). Interestingly, the product 11 which the major product when using sillyl based Lewis acids has been always obtained as a racemic mixture despite various chiral ligands used.
Table 3: Optimization of reaction conditions for addition of EtMgBr to substrate 9.a
Entry ligand LA Ratio
10:11 Yield (%) b ee (%)c 1(-20oC) - - 100:0 92 - 2 - TMSOTf 25:75 68 - 3 - TMSBr 1:99 92 - 4 - TMSCl 28:72 38 - 5 - BF3·Et2O 65:32 72 - 6 - BCl3 17:83 43 - 7 L1 TMSOTf 75:25 82 0 8 L1 TMSBr 5:95 90 0 9 L1 BF3·Et2O 90:10 68 67 10 L4 TMSBr 4:96 88 0 11 L6 TMSBr 5:95 86 0 12 L10 TMSBr 4:96 68 0 13 L7 TMSBr 5:95 86 0 14 L9 TMSBr 2:98 92 0
aReaction conditions: 9 (0.2 mmol), EtMgBr (2.0 equiv.), Ligand L (6 mol%), CuBr·SMe2 (5 mol%) in solvent (2
mL), -78 oC, overnight. bIsolated yields. cThe enantiomeric excess was determined by HPLC on a chiral
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To summarize, the regioselectivity in the addition reaction to the bifunctional substrate 9, can be well tuned by the use of Lewis acids (TMSBr and BF3·Et2O), however, the
enantioselectivities require further improvement.
5.3 Conclusions
In this chapter, we have demonstrated that Lewis acid/base interactions can be used to control the selectivity in conjugate addition reactions to bifunctional Michael acceptors. Different modes of selectivities can be accessed by directing the LA to the desired functional group, exploiting either its strength or functional group affinity. While this is a promising approach to provide protecting group free transformations with multifunctional organic synthons, further experiments are required to establish full scope of these approach. Also, thorough investigations are needed to achieve such transformations with high enantioselectivities.
5.4 Experimental section
5.4.1 General experimental information
All reactions were carried out with anhydrous solvents (vide infra) under a nitrogen atmosphere using oven-dried glassware and standard Schlenk techniques. Reactions were monitored by 1H NMR. Purification of the products was performed by column
chromatography using Merck 60 A 230-400 mesh silica gel. Components were visualized by UV and KMnO4 staining (TLC). NMR data was collected on Varian VXR400 (1H at 400.0 MHz; 13C at 100.58 MHz) equipped with a 5 mm z-gradient broadband probe. Chemical shifts are
reported in parts per million (ppm) relative to residual solvent peak (CDCl3, 1H: 7.26 ppm; 13C: 77.16 ppm). Coupling constants are reported in Hertz. Multiplicity is reported with the
usual abbreviations. Enantiomeric excesses (ee) were determined by chiral HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.
Unless otherwise indicated, reagents and substrates were purchased from commercial sources and used as received. Solvents not required to be dry were purchased as technical grade and used as received. Dry solvents were freshly collected from a dry solvent purification system prior to use. Inert atmosphere experiments were performed with standard Schlenk techniques with dried (P2O5) nitrogen gas. Grignard reagents were
purchased from Sigma-Aldrich EthylMgBr, MethylMgBr (3.0 M in Et2O). Chiral ligands were
purchased from Sigma Aldrich and Strem Chemicals. All reported compounds were characterized by 1H and 13C NMR, HRMS and compared with literature data.
5.4.2 General procedure for synthesis of substrates (E)-3-dimethylcarbamoylpropenoic acid ethyl ester (1)
To a solution of the monoethyl fumarate (6.94 mmol) in 10 mL of DCM at -20 °C was added N-methylmorpholine (NMM, 6.94 mmol) followed by isobutyl chloroformate (iBCF, 6.94 mmol). After the reaction mixture was allowed to stir for 30 min, anhydrous dimethylamine (2.0 M in THF, 6.94 mmol) was added to the mixture. After 30 min the mixture was stirred for 4 h at room temperature. The solvent was evaporated, and the residue was redissolved in EtOAc. The organic layer was washed with HCl 2 M, saturated NaHCO3, saturated NaCl, dried over MgSO4, and concentrated. The crude
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afford product 1 as a colorless oil [86% yield]. 1H NMR (CDCl3, 400 MHz): δ 7.40 (d, J = 15.4
Hz, 1H), 6.78 (d, J = 15.4 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.13 (s, 3H), 3.04 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 166.9, 164.8, 133.8, 131.2, 61.2, 37.6, 35.9, 14.3.
HRMS (ESI+, m/Z): calcd for C8H14NO3 [M+H]+: 172.0968, found: 172.0966. (E)-4-(dimethylamino)-4-oxobut-2-enoic acid (6)
To a solution of 1 (1 mmol) in MeOH 5 mL was add 5 mL NaOH solution (2 M). The combined solution was stirred at room temperature for 1 h. Then, extract the reaction mixture with ethyl acetate (3 x 5 mL) and dry the combined organic layers over MgSO4. Filter the combined organic
under reduced pressure. Purify the acid by chromatography using CH2Cl2-MeOH (9:1) to
obtain the final product with 60% yield. 1H NMR (CDCl3, 400 MHz) δ 10.07 (s, 1H), 7.42 (d, J
= 15.4 Hz, 1H), 6.76 (d, J = 15.4 Hz, 1H), 3.12 (s, 3H), 3.03 (s, 3H). 13C NMR (CDCl3,101 MHz)
δ 171.85, 167.66, 137.57, 133.53, 40.30, 38.60. HRMS (ESI+, m/Z): calcd for C6H9NO3
[M+H]+: 144.0661, found: 144.0668.
(E)-N, N-dimethyl-3-(pyridine-4-yl)acrylamide (9)
To a cold 0 °C solution of trans-3-(4-pyridyl)acrylic acid (2.31 mmol) in DCM (4 mL) was added thionyl chloride (2.77 mmol) and dry DMF (14 L). The solution was then stirred at room temperature for 2 h and concentrated under reduced pressure to remove residual thionyl chloride. The resulting residue was re-dissolved in DCM (4 mL), cooled at 0 °C and dimethylamine solution (2.0 M THF, 3.69 mmol) was added. Dry triethylamine (4.62 mmol) was added and stirring was continued at ambient temperature (3 h). The solvent was removed under reduced pressure and DCM (14 mL) was added. The organic phase was washed with saturated Na2CO3 solution (2 mL × 2), water (3 mL × 2),
and brine (4 mL), and dried over MgSO4. After removal of the solvent, the product 9 was
obtained obtained as a white solid in 91 % yield. 1H NMR (CDCl3, 400 MHz): δ 8.68-8.60 (m,
2H), 7.56 (d, J = 15.5 Hz, 1H), 7.38-7.37 (m, 2H), 7.06 (d, J = 15.5 Hz, 1H), 3.18 (s, 3H), 3.08 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 166.7, 150.5, 142.7, 139.5, 122.1, 121.8, 37.5, 36.0.
HRMS (ESI+, m/Z): calcd for C10H13N2O [M+H]+: 177.1022, found: 177.1024. 5.4.3 General procedure for asymmetric addition
In a flame-dried Schlenk tube equipped with septum and magnetic stirring bar, CuBr·SMe2
and ligand were dissolved in dry solvent and stirred under nitrogen atmosphere for 20 min. The substrate was added at once. After stirring for 5 min. at room temperature, the reaction mixture was cooled down (see the details per substrate), followed by addition of Lewis acid. After 20 min., RMgBr was added by hand in about 1 min. After stirring for 2 h, the reaction was quenched with MeOH followed by addition of saturated aqueous NH4Cl
solution and warming up to room temperature. The reaction mixture was extracted with DCM (3×3 mL). Combined organic phases were dried over MgSO4, filtered and solvents
were evaporated. The crude was purified by flash chromatography on silica gel.
Ethyl 4-(dimethylamino)-2-ethyl-4-oxobutanoate (2)
The reaction was performed with 0.2 mmol 1, CuBr.SMe2 (0.01 mmol,
5 mol%), ligand L5 (0.012 mmol, 6 mol%), BF3·Et2O (0.025 mL, 1.0 mmol), EtMgBr (0.3
mmol, 3.0 M in Et2O), 2.0 mL of DCM 2 h at -78 oC. The crude product, a mixture 83:17 of
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1:1). The product 2 was obtained as a colorless oil (79% yield, 35% ee). 1H NMR (CDCl3,
400 MHz): δ 4.18 (dq, J = 10.5, 7.0 Hz, 1H), 4.12 (dq, J = 10.5, 7.0 Hz, 1H), 3.01 (s, 3H), 2.92 (s, 3H), 2.90-2.83 (m, 1H), 2.75 (dd, J = 16.0, 9.5 Hz, 1H), 2.34 (dd, J = 16.0, 4.5 Hz, 1H), 1.71-1.54 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ
176.0, 171.3, 60.5, 42.9, 37.2, 35.6, 34.9, 25.5, 14.4, 11.7. HRMS (ESI+, m/Z): calcd for C10H19NO3Na [M+Na]+: 224.1257, found: 224.1257. HPLC: Chiracel-ADH, n-heptane/i-PrOH
98:2, 0.5 mL/min, 40 °C, detection at 208 nm. Retention time (min): 34.9 (major) and 38.6 (minor).
Figure 1: 1H-13C-HMBC spectrum of the isolated compound 2. Ethyl 3-(dimethylcarbamoyl)pentanoate (3)
The reaction was performed with 0.2 mmol 1, EtMgBr (0.3 mmol, 3.0 M in Et2O), 2.0 mL of DCM 2 h at -78 oC. The crude product was
purified by column chromatography on silica gel (SiO2, pentane:Et2O
1:1). Product 3 was obtained as a colorless oil (75% yield, racemic).
1H NMR (CDCl3, 400 MHz): δ 4.14-4.05 (m, 2H), 3.13 (s, 3H), 3.13-3.06
(m, 1H), 2.97 (s, 3H), 2.84 (dd, J = 16.9, 9.8 Hz, 1H), 2.39 (dd, J = 16.8, 4.5 Hz, 1H), 1.68-1.55 (m, 1H), 1.53-1.42 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz) δ 175.08, 172.96, 60.54, 38.67, 37.57, 36.67, 35.89, 25.75,
14.26, 11.61. HRMS (ESI+, m/Z): calcd for C10H19NO3Na [M+Na]+: 224.1257, found:
224.1259. HPLC: Chiracel-ADH, n-heptane/i-PrOH 98:2, 0.5 mL/min, 40 °C, detection at 208 nm. Retention time (min): 29.0 (minor) and 34.4 (major).
Ethyl 4-(dimethylamino)-2-methyl-4-oxobutanoate (4)
The reaction was performed with 0.2 mmol 1, CuBr.SMe2 (0.01 mmol,
5 mol%), ligand L1 (0.012 mmol, 6 mol%), BF3·Et2O (1.0 mmol),
MeMgBr (0.3 mmol, 3.0 M in Et2O), 2.0 mL of DCM 2 h at -78 oC. Product 4 was obtained as
a colorless oil after column chromatography (SiO2, pentane:Et2O 1:3) [81% yield, 96% ee]. 1H NMR (CDCl3, 400 MHz): δ 4.15 (dq, J = 10.9, 7.0 Hz, 1H), 4.11 (dq, J = 10.9, 7.0 Hz, 1H),
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3.03-2.93 (m, 1H), 3.00 (s, 3H), 2.92 (s, 3H), 2.77 (dd, J = 16.2, 8.4 Hz, 1H), 2.30 (dd, J = 16.2, 5.5 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.20 (d, J = 7.0 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ
176.0, 171.3, 60.5, 42.9, 37.2, 35.6, 34.9, 25.5, 14.4, 11.7. HRMS (ESI+, m/Z): calcd for C9H17NO3 [M+H]+:188.1287, found: 188.1290. HPLC: Chiracel-ADH, n-heptane/i-PrOH 98:2,
0.5 mL/min, 40 °C, detection at 208 nm. Retention time (min): 39.6 (major) and 43.3 (minor).
3-(dimethylcarbamoyl)pentanoic acid
The reaction was performed with 0.2 mmol 6, CuBr.SMe2 (0.01 mmol, 5
mol%), ligand L5 (0.012 mmol, 6 mol%), TMSBr (0.4 mmol), EtMgBr (0.4 mmol, 3.0 M in Et2O), 2.0 mL of DCM overnight at -78 oC. Product 8
was obtained as a colorless oil after column chromatography (SiO2,
pentane:Et2O 1:3) [88% yield, 35% ee]. 1H NMR (CDCl3, 400 MHz) δ 3.13
(s, 4H), 2.98 (s, 3H), 2.83 (dd, J = 16.8, 9.6 Hz, 1H), 2.39 (dd, J = 16.8, 4.0 Hz, 1H), 1.73-1.55 (m, 1H), 1.54-1.39 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz) δ 175.50,
164.41, 63.08, 39.24, 32.33, 28.30, 16.80, 14.17. HRMS (ESI+, m/Z): calcd for C8H15NO3
[M+H]+:174.1130, found: 174.1135.
N,N-dimethyl-3-(pyridin-4-yl)pentanamide
The reaction was performed with 0.2 mmol 9, EtMgBr (0.4 mmol, 3.0 M in Et2O), 2.0 mL of DCM overnight at -20 oC. The crude product was
purified by column chromatography on silica gel (SiO2, pentane:Et2O
1:1). Product 10 was obtained as a colorless oil (92% yield, racemic).
1H NMR (CDCl3, 400 MHz) δ 8.48 (d, J = 3.8 Hz, 2H), 7.14 (d, J = 5.6 Hz,
2H), 3.19-3.03 (m, 1H), 2.88 (s, 3H), 2.84 (s, 3H), 2.57 (d, J = 7.0 Hz, 2H), 1.85-1.67 (m, 1H), 1.67-1.48 (m, 1H), 0.77 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101
MHz) δ 173.53, 156.72, 152.33, 125.86, 45.86, 41.94, 39.87, 38.08, 31.09, 14.54. HRMS (ESI+, m/Z): calcd for C12H18NO2 [M+H]+:207.1497, found: 207.1491.
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N,N-dimethyl-2-(pyridin-4-ylmethyl)-23-butanamide
The reaction was performed with 0.2 mmol 9, CuBr.SMe2 (0.01 mmol, 5
mol%), ligand L1 (0.012 mmol, 6 mol%), TMSBr (0.4 mmol), EtMgBr (0.4 mmol, 3.0 M in Et2O), 2.0 mL of DCM overnight at -78 oC. Product 11 was obtained as a colorless oil after column chromatography (SiO2,
pentane:Et2O 1:1) [68% yield, 67% ee]. 1H NMR (CDCl3, 400 MHz) δ
8.45 (d, J = 4.6 Hz, 2H), 7.09 (d, J = 5.8 Hz, 2H), 2.95 (dd, J = 12.5, 9.6 Hz, 1H), 2.90-2.81 (m, 4H), 2.75 (s, 3H), 2.67 (dd, J = 12.6, 4.6 Hz, 1H), 1.82-1.65 (m, 1H), 1.63-1.43 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz) δ 174.47, 149.67, 149.61, 124.43, 44.55, 38.31,
37.32, 35.70, 26.35, 11.92. HRMS (ESI+, m/Z): calcd for C12H18NO2 [M+H]+:207.1497, found:
207.1489.
Figure 3: 1H-13C-HMBC spectrum of the isolated compound 11.
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