Asymmetric copper-catalyzed alkylations and autocatalysis Pellegrini, Tilde
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Chapter 3
Asymmetric conjugate addition of Grignard reagents to
symmetric bispyridyl alkenes
Chiral pyridines are recurrent structural motives in medicinal compounds and ligands used in organometallic reactions. Herein we report a methodology for the asymmetric addition of Grignard reagents to Lewis acid activated symmetric bispyridyl alkenes. While additions to 4-pyridyl substituted alkenes can be achieved with good yields and excellent ees, additions to 2-pyridyl alkenes can only be achieved in a racemic fashion. Additionally, a comparison between the abilities of the two isomeric pyridines and benzoxazole to activate an alkene towards the CA is made.
Part of this chapter has been published: R. P. Jumde, F. Lanza, T. Pellegrini, S. R. Harutyunyan, Nat. Commun. 2017, 8.
44
3.1. Introduction
3.1.1. Importance of pyridines in medicinal chemistry
Pyridine derivatives are essential in medicinal chemistry. For instance, in the list of FDA approved drugs, pyridine occupies the second place of most present nitrogen containing-heterocycles (62 out of 640 drugs). Furthermore, more than 50% of the drugs containing pyridine moiety has one substituent on the ring.[1]
Figure 3 Chiral pyridine-containing drugs and natural products.
For their frequent recurrence in pharmaceutical and natural compounds, chiral molecules containing pyridine motive are very attractive for medicinal chemists (Figure 1). The stereogenic center is often situated close to the ring: indeed, in many chiral approved drugs, the chiral center is located in α-position respect to the heteroarene.[1,2] In particular, molecules containing two or more pyridine rings,
bonded together by a two-carbon atom alkyl spacer, have displayed biological activity as nervous system agent,[3–5] anti-infective agent[6] and respiratory agents[7] (Figure
2). For these reasons, the development of pharmaceutical compounds would profit from a methodology capable to afford enantiomerically enriched pyridine derivatives.
45
Figure 4 Biologically active molecules containing two or more pyridine rings.
3.1.2. Utilization of bispyridyl compounds in chemistry
Besides their importance in medicinal chemistry, pyridine is a recurring moiety also in organic and inorganic chemistry. The nitrogen of the pyridine ring can be an electron donor and, therefore, pyridines have been widely employed as ligands for transition metal catalysis.[8–13] In literature, multitude of bidentate ligands have been reported,
containing 2-pyridyl units. Among those, bipy (1, Figure 3) is one of the most remarkable and has been applied in homogeneous catalysis[14–16] and metal extraction
from aqueous media[17]. Moreover, metallic complexes with 1 have been used as dyes
for photovoltaic panels.[18] Also a ligand containing four 2-pyridyl substituent, N4Py
(2), has been widely used to chelate transition metals used in redox reactions.[19–21]
Figure 5 Pyridine chelating ligands.
In the series of pyridine containing ligands, bpe (3, Figure 3) has been employed as chelating ligand for metals. Pt(II)·3[22] as well as Pd(II)·3 complexes[23] have been
prepared. Bpe has been proven to dissociate easily in square planar complexes [PtMe2·3]: because of the distortion of 3 caused by the broad bite angle, the complex
has a limited stability and can easily undergo reactions with halogens and HCl.[24]
[PtR2·3] complexes have been tested in the catalysis of hydrophenylation of alkenes
with scarce outcomes.[25]
Nevertheless, the N-oxide of 3, L1, was successfully employed in the copper-catalyzed N-arylation of imidazoles (Scheme 1).[26] L1 has shown increased reactivity in
46
comparison with its precursor and bidentate ligands with a shorter divider between the pyridine moieties.
Scheme 24 Copper-catalyzed N-arylation of imidazoles.[26]
Additionally, 3 is a building block for the synthesis of macrocyclic ligands (for example, 4[27] and 5[28], Figure 4). The tridentate ligand 4 stabilizes d8 metal like Pt(II) and its
oxidative addition intermediate. The complexes Fe(III)Cl·5 and Mn(III)Cl·DMF·5 catalyze the epoxidation of styrenes, displaying higher activities than the ones carrying other acyclic ligands.
Figure 6 Macrocyclic ligands 4[27] and 5[28].
Instead, 6 (Figure 5), bearing 4-pyridine units, cannot chelate the metals because the lone pairs on the nitrogen atoms are too far from each other. Nevertheless, this remarkable molecule can be a linker in binuclear catalysts used in Suzuki coupling[29]
and transfer hydrogenation of ketones[30] (respectively 7 and 9, Figure 5). In the
latter, the higher reactivity of the complex is due to interaction between the two Ru(II)-NNN moieties.[30]
47
Figure 7 1,2-Bis(4-pyridyl)-ethane and catalysts obtained from it.[29,30]
The pyridine 6 is also largely used in the preparation of inorganic-organic assemblies[31]: metal clusters are used to construct porous solids. In organically
functionalized zinc-substituted polyoxyvanadates, the geometry of the ligand plays a key role in the determination of the final structure. In fact, chiral R and L helices as well as a sinuate chain (Figure 6, source: Chang et al., 2007[31]) were prepared and
characterized. Furthermore, this molecule was also utilized in the synthesis of Metal Organic Frameworks (MOFs)[32].
48
Figure 8 Assemblies of zinc-substituted polyoxovanadates and zinc organoamine subunits (Source:
Chang et al., 2007[31]).
3.1.3. Asymmetric conjugate addition to vinyl pyridines
Given the interest in chiral pyridines, different methods for their synthesis have been developed. The most common and straightforward is the direct functionalization of the pyridyl ring, despite its need of superstoichiometric amounts of chiral reagents. A more recent method exploit the ability of pyridyl substitutents can activate olefins towards
49 the addition of nucleophiles.[33,34] In first instance, Melchiorre et al. achieved the
alkylation of vinyl pyridines via the addition of α-amino radicals thanks to the use of Brønsted acids, but only with moderate ee of the product (10, Scheme 2a).[34]
Scheme 25 ACA to vinyl pyridines.
In 2009, the group of Lam reported a highly enantioselective addition of hydrides to β,β-disubstituted pyridines catalyzed by transition metals (Scheme 2b).[35]
Vinyl-pyridines have reduced affinity towards nucleophiles with respect to other α,β-unsaturated compounds, in fact, they can activate the alkene only by induction and no further mesomeric electron withdrawing effect is possible.[36] For this reason, even if
non-enantioselective CA have been reported,[37] the asymmetric addition of carbon
nucleophiles are more difficult to achieve. The first examples consist of addition of arylboronic acids that involves the use of activated electron-deficient pyridines (like 13), rhodium catalysts and high temperature, and proceeds with high enantioselectivities (Scheme 2c).[38,39]
50
In 2017, our group reported a novel strategy for the alkylation of β-substituted heteroaryl olefins via the copper(I)-catalyzed addition of Grignard reagents (Chapter 2, Paragraph 2.1.3.).[40] Although by using of BF3.OEt2 it was possible to activate a
wide range of vinyl heteroarenes, vinyl pyridines proved to be more challenging substrates. However, we observed that both 2-pyridyl and 4-pyridyl alkenes can undergo CA in the presence of higher loadings of LA and Grignard reagents (3.0 equiv. of Lewis acid and 3.0 equiv. of RMgBr, vs . respectively 1.5 and 2.0 equiv. previously reported for other hetereoarenes[41]). Interestingly, the behavior of the two
pyridyl-alkenes are remarkably different from each other (Scheme 3). 4-pyridyl olefins (15) can be converted to the chiral alkane in the presence of TMSOTf (Scheme 3a), while under the same conditions, 2-pyridines (17) require an electron withdrawing substituent to afford the addition product 18. Moreover 2-pyridines generally prefer BF3.OEt2 as additive (Scheme 3b), that denotes a lower reactivity of 2-pyridyl alkenes
compared to 15. With both pyridyl alkenes, excellent yields and enantioselectivities are achieved.[41]
Scheme 26 Reactivity of 4- and 2-pyridyl alkenes towards the asymmetric addition of Grignard
reagents.[41]
In a similar way to what has been reported for the copper-catalyzed asymmetric addition of Grignard reagents to other vinyl heteroarenes,[40] the proposed mechanism
involves:
1) The transmetallation of the organomagnesium reagent by the copper(I) complex.
2) The formation of a π-complex between copper and the olefin. 3) The oxidative addition (Cu(I) oxidizes to Cu(III)).
51 4) The reductive elimination, where catalyst and the enolate of the product are
released.[41]
3.2. Aim
Chiral compounds containing two or more pyridine rings are present in a cornucopia of commercial drugs and natural products. Pyridines are also capable of coordinating transition metals and can be found in bidentate and macrocyclic ligands (2-pyridines) or are utilized in the preparation of multinuclear metallic catalysts, inorganic/organic assemblies and MOFs. The introduction of a chiral center to these compounds can open the possibilities for new ligands for asymmetric catalysis and the control of chirality in supramolecular aggregates.
For this reason, our aim is to develop a methodology for synthesis of highly enantioenriched pyridine derivatives through the asymmetric copper-catalyzed addition of Grignard reagents to symmetric 1,2-bispyridyl substituted olefins (Scheme 4). The achievement of enantioselectivity in the addition of highly reactive organometallic reagents to 1,2-disubstituted alkenes is troublesome, due to the presence of background reaction competing with the catalytic asymmetric pathway.
Scheme 27 Asymmetric addition of organomagnesium reagents to bispyridylalkenes.
3.3. Results and discussion
3.3.1. Asymmetric addition to symmetric 4-pyridyl alkenes
Our investigation began with the addition of ethylmagnesium bromide to 1,2-bis(4-pyridyl)ethene (19). The catalyst CuBr·SMe2/L5 was used first in the initial screening
as it gave the best results in our previous work.[41] In this case, it is important to obtain
the product with good conversion, as it cannot be separated from the starting material via either column chromatography, prep-TLC or crystallization. From the initial solvent screening, CH2Cl2 was found to be the most suitable, as it afforded the product
20a with 82% conversion and 40% ee (entry 1, Table 1). On the contrary, reactions in diethyl ether, MTBE or toluene only led to low conversion (entries 1-6, 8). We observed that 19 was poorly soluble in these solvents, even at room temperature. Curiously, increasing the reaction temperature to ˗50 °C led to a decrease in conversion
52
(entry 4). The reaction in THF as solvent afforded the product in good yield, albeit as a racemate (entry 7).
Table 6 Effect of the solvent on the asymmetric addition of ethylmagnesium bromide to 19.
Entry Solvent T (°C) Conversion (%)a ee (%)b
1 CH2Cl2c -78 82 40 2 Et2O -78 30 rac 3 Et2O d -78 0 - 4 Et2O -50 15 - 5 MTBE -78 0 - 6 Toluene -78 26 - 7 THF -78 89 rac 8 CH2Cl2:Et2O (9:1) -78 49 n.d.
a Conversion to 20a was determined by 1H-NMR. b Determined via CSP-HPLC. c
Performed with 1.1 equiv. of TMSOTf. d Reaction was performed with BF3.OEt2 (1.1
equiv.).
Afterwards, the effect of different Lewis acids in the activation of 19 was studied (Table 2). The strength of the trimethylsilanes used for this purpose was determined by the leaving group ability: TMSOTf>TMSI>TMSBr>TMSCl.
53
Table 7 Effect of the Lewis acid on the asymmetric addition of ethylmagnesium bromide to 19.
Entry LA (equiv.) Equiv. EtMgBr Conversion (%)a Yield (%)b ee (%)c 1 TMSOTf (3.0) 3.0 86 67 9 2d TMSOTf (3.0) 3.0 97 86 rac 3 TMSOTf (1.1) 1.5 89 57 4 4 TMSOTf (2.2) 1.5 27 n.d. n.d. 5 TMSOTf (0.5) 20 0 - - 6 TMSI (3.0) 3.0 83e - - 7 TMSBr (3.0) 3.0 85e 67 33 8f TMSBr (1.5) 2.0 90e 53 46 9 f TMSBr (1.0) 2.0 45e n.d. n.d. 10 TMSCl (3.0) 3.0 48e n.d. 58 11g TMSCl (3.0) 3.0 32e n.d. 71 12 TMSCl (3.0) 1.5 + 1.5 44e n.d. 58 13 TMSCl (1.0) 3.0 <5 - - 14 TMSCl (5.0) 5.0 28e n.d. n.d. 15 BF3.OEt2 (1.1) 2.0 44h n.d. 68 16 BF3.OEt2 (3.0) 3.0 -h - - 17 BF2OTf (1.5) 2.0 14 - - 18 AlMe3 (1.0) 2.0 0 - - 19 Mg(OTf)2 (3.0) 3.0 0 - - 20 None 1.5 0 - -
a Conversion was determined by 1H-NMR. b Isolated yield. c Determined via CSP-HPLC. d EtMgBr was diluited in Et2O and added over 1h. e Product 21 formed f EtMgBr was
diluited in Et2O and added over 2h. g EtMgBr was diluited in Et2O and added over 3h. h Unidentified side products were formed.
Although TMSOTf was the best additive in our previous work[41], its use did not give
good enantioselectivities in this reaction. When using TMSOTf to activate the substrate, the reaction proceeded with loss of enantioselectivity, either with fast or slow addition of the organometallic reagent (entries 1-3, Table 2). When the amount of EtMgBr was lower than the one of TMSOTf, the reaction reached only 27% conversion
54
(entry 4). This suggests the partial degradation of the Grignard reagent with an excess of Lewis acid. The use of a substoichiometric amount of TMSOTf was deleterious for the reaction (entry 5): the substrate required at least one equivalent of Lewis acid to undergo CA. With TMSI, the reaction did not reach full conversion and the β-hydride transfer product was detected (ratio 21:20a = 80:20, entry 6). In the presence of TMSBr, less reduction product was formed (entries 7-9), the least when 3.0 equiv. of Lewis acid were used (ratio 21:20a = 20:80, entry 7). On the other hand, the increase of the quantity of TMSBr caused a loss of ee (33% ee entry 7 vs. 46% entry 8). The low reactivity of TMSCl granted good enantioselectivities (58% when the Grignard was added in one shot and improved to 71% when added over 3h (entries 10 and 11), in both cases with low conversions. The addition of 1.5 equiv. of the organometallic reagent over 2h had no influence on the outcome of the reaction (entry 10 vs. entry 12). No product was obtained when only 1.0 equiv. of TMSCl was used (entry 13). It was found that a large excess of the Lewis acid could inhibit the reaction (entry 14). Instead, BF3.OEt2 (1.1 equiv. or 3.0 equiv.) favored the formation of side products
(entries 15 and 16). On the other hand, BF2OTf, AlMe3 or Mg(OTf)2 were not effective
in the activation of the starting material. Note: BF2OTf, obtained by reaction of
stoichiometric amounts of TMSOTf and BF3.OEt2 is reported to have a superior Lewis
acidity with respect to BF3.[42] AlMe3 was proven to be a valid Lewis acid additive in the
addition of organozinc reagents to aldehydes[43] and in the nickel catalyzed aryl-ether
bond cleavage[44].
Given the dependence of the enantioselectivity on the strength and amount of the Lewis acid, we wondered about the presence of a non-catalyzed reaction. We tested the reaction between substrate, Grignard reagent and Lewis acid in the absence of a catalyst. Indeed, both TMSOTf and TMSBr were able to promote the addition of the Grignard reagent. With TMSBr, the background reaction is slower than with TMSOTf (48% conversion vs. 92%, entries 1 and 2, Table 3). For this reason, it is possible to obtain higher enantioselectivities when using TMSBr and the reaction results were more reproducible as well. Instead, BF3.OEt2 did not favor the racemic addition of
55
Table 8 Background addition of ethylmagnesium bromide to 19.
Entry L.A. (equiv.) Equiv. EtMgBr Conversion (%)a
1 TMSOTf (1.5) 2.0 92
2 TMSBr (1.5) 2.0 48
3 BF3.OEt2 (1.1) 2.0 <10 a Conversion was determined by 1H-NMR.
1.5 Equiv. of TMSBr and 2.0 equiv. of EtMgBr were selected as optimal conditions to continue our screening. The Grignard reagent was diluted and added to the reaction over 2h to avoid the uncatalyzed reaction. Sixteen ligands were tested, including ferrocenyl diphosphines, L3 and L5-15, BINAP (L16), phosphoroamidites (L17-L18) and Tröger’s base L19 (Table 4).
56
57 Entry Ligand Conversion
(%)c Yield 20a (%)b Ratio 20a:21c ee (%)d 1 L3 88 69 100:0 52 2 L6 89 54 89:11 91 3 L7 66 n.d. 100:0 60 4 L8 <10e - - - 5 L9 83 81 100:0 rac 6 L10 92 76 100:0 -13 7 L11 ~80e 29 100:0 rac 8 L12 <10 - - - 9 L13 0 - - - 10 L14 82 68 100:0 -29 11 L15 <5 - - - 12f L16 15 - - - 13 g L17 92e - 0:100 - 14 g L18 >90 - 0:100 - 15h L19 23e n.d. - -
EtMgBr was diluted in Et2O and added over 2h. a Conversion was determined by 1
H-NMR. b Isolated yield c Ratio was determined by 1H-NMR. d Determined via CSP-HPLC.
e Unidentified side products were formed. f Reaction was performed at ˗65 °C. g Reaction was performed with 24 mol% of ligand. h Reaction was performed at rt.
In the presence of the diphosphines L3, L5-8 and L14 the product was formed with good conversion and yield. Using L6, the product 20a was obtained as an 89:11 mixture with 21 with an excellent 91% ee (entry 2, Table 4). The change of one of the phosphine substituents from phenyl to cyclohexyl gave a decrease of enantioselectivity (entry 7). Bulky ligands L9-11 afforded the product either as a racemate or with low ee (entries 5-7). Complexes containing L12-13 and L15-19 were unable to catalyze the addition of the Grignard reagent. Surprisingly, when employing monodentate phosphoroamidites L17 or L18, only the β-hydride transfer product was obtained (entries 13 and 14). In entries 12 and 15, higher temperatures were applied in order to improve the solubility of the complexes CuBr·SMe2/L16 and L19 in the reaction
media, but in both cases no significant amount of product was obtained.
Hence, the scope of the Grignard reagents was studied with the catalyst formed by CuBr·SMe2 and L6, which showed superior performance with respect to the
enantiocontrol of this reaction. To our delight, the addition of organomagnesium reagents with a linear alkyl chain as well as with alkenyl Grignard reagents and γ-branched ones proceeded with excellent enantioselectivities (products 20a, 20b, 20d and 20e Scheme 5). This enantioselectivity is unprecedented for the asymmetric addition of highly reactive nucleophiles to symmetric acyclic alkenes. Also, the addition
58
of CypMgBr to 19 proceeded with good, but lower enantioselectivity (20f, 71% ee). The presence of β-hydride transfer from the organometallic reagent to the substrate as a side reaction affects the final yields (40-66%). As it is possible to get products of addition of both α- and γ-branched Grignard reagents, it is surprising that β-branched i-BuMgBr was found unreactive in this transformation. In addition, methylation and phenylation of 19 were not successful either.
Scheme 28 Organomagnesium reagents scope. EtMgBr diluted in Et2O and added over 2h.
3.3.2. Asymmetric addition to symmetric 2-pyridyl alkenes
2-Pyridyl olefins are characterized by a lower reactivity with respect those bearing a 4-pyridyl ring.[41] Correspondingly, substrate 22 displayed significantly different
reactivity compared to 19. In Table 5, it emerges that only selected Lewis acids, TMSOTf, TMSI and TMSBr, can activate this substrate towards the addition of the Grignard. Full conversion to the product was achieved using TMSOTF in non-coordinating solvents, such as toluene or CH2Cl2. However, under these conditions, the
product was obtained with low ees (0-15%, entries 2-4, Table 5). No conversion to 23a was observed. A possible reason for the poor enantiocontrol is the non-catalyzed addition of the Grignard (entry 5). The use of substoichiometric TMSOTf is not sufficient to form 23a. The conversion decreased when using silyl-based Lewis acid with poorer leaving groups (81% with TMSI and 45% with TMSBr, respectively entries 7 and 8). Using TMSBr in the catalytic reaction, 75% ee was achieved (entry 8). With this Lewis acid it is possible to achieve good enantioselectivity because it is too weak to activate the substrates towards the background reaction (entry 9). Lewis acid additives like TMSCl and BF3.OEt2 are not hard enough to activate 22 towards the
1,4-addition. An increase in the reaction temperature did not cause an increase in the reactivity of the system, but rather inhibited the reaction. We suppose that this is due
59 to a partial degradation of the Grignard reagent caused by the Lewis acid at temperatures above ˗78 °C (entries 5 and 9).
Table 10 Reactivity of substrate 22 towards the asymmetric addition of ethylmagnesium bromide
Entry L.A. (equiv.) T (°C) Conversion (%)a Yield (%)b ee (%)c 1d TMSOTf (1.5) -78 0 - - 2e TMSOTf (1.5) -78 67 n.d. 0 3 TMSOTf (1.5) -78 full 34 15 4 TMSOTf (3.0) -78 full 85 12 5f TMSOTf (3.0) -78 full n.d. - 6 TMSOTf (0.5) -78 0 - - 7 TMSI (3.0) -78 81 53 0 8 TMSBr (3.0) -78 45 19 75 9f TMSBr (3.0) -78 0 - - 10 TMSBr (3.0) -50 0 - - 11 TMSCl (3.0) -78 0 - - 12 BF3.OEt2 (3.0) -78 11 - - 13 BF3.OEt2 (3.0) -50 0 - -
In combination with 1.5 equiv. of LA, 2.0 equiv of EtMgBr were used. With 3.0 equiv. of LA, 3.0 equiv. of EtMgBr. a Conversion was determined by 1H-NMR. b Isolated yield c Determined via CSP-HPLC. d Reaction was performed in Et2O. e Reaction was
performed in toluene. f Reaction was performed in the absence of catalyst.
We further evaluated the catalytic system by changing the copper(I)-source and the ligand. Replacing CuBr·SMe2 with (CuOTf)2•tolueneafforded product23a with 51%
conversion and 5% ee (entry 1, Table 6). With complexes of CuTC/L5 (Structure in Figure 7a; entry 2, Table 5) or CuBr·SMe2 and other chiral ferrocenyl diphosphines
60
Table 11 Catalyst screening in the addition of ethylmagnesium bromide to 22.
Entry Cu(I) source Ligand Conversion (%)a ee (%)b 1 (CuOTf)2•toluene L5 51 5 2 CuTC L5 <5 - 3 CuBr·SMe2 L3 0 - 4 CuBr·SMe2 L6 0 - 5 CuBr·SMe2 L7 0 - 6 CuBr·SMe2 L8 0 - 7 CuBr·SMe2 L14 0 -
a Conversion was determined by 1H-NMR. b Determined via CSP-HPLC.
Figure 9 Structure of CuTc and 1,2-bis(2-quinoyl)ethene.
Our investigations confirmed the difficult reactivity of this compound. In Chapter 2, Paragraph 2.3.3., we discussed the low reactivity of compound 24 (Figure 7b) in the copper catalyzed addition of EtMgBr. In both 22 and 24, the alkenyl substituent is adjacent to the nitrogen on the heteroarene: it is feasible that, the Lewis acid bound to the nitrogen creates an excessive hindrance to allow the coordination of the catalyst to the double bond. On the contrary, the Grignard reagent can add to the alkene faster in a racemic way without a catalyst assistance.
Nonetheless, we had discovered that 23 could be prepared upon simple addition of the organomagnesium reagent to 22 in the presence of TMSOTf. Thus, we developed a catalyst free procedure for the synthesis of racemic compounds 23b-d with yields of
61 84-96% (Scheme 6). Under these conditions, the addition of PhMgBr was achieved as well.
Scheme 29 Synthesis of racemic 1,2-bis(2-pyridyl)ethanes 23b-d.
3.3.3. Selectivity in the addition to 4-pyridyl, 2-pyridyl and 2-benzoxazyl alkenes
Based on the investigations of various alkenyl heteroarene substrates in addition reactions, we could rank different heteroarenes according to their activation of the adjacent olefins towards the CA of Grignard reagents. The proposed reactivity scale is depicted in Figure 8. Benzoxazole is the most effective for this reaction, in fact 1,2-bis(2-benzoxazyl)ethene undergoes conjugate addition even in absence of a Lewis acid (Chapter 2). While 4-pyridine substituted olefins are less reactive than olefins with benzoxazole, they are more reactive than 2-pyridine substituted olefins. This conclusion derives from the fact that compound 19 can only undergo addition in the presence of Lewis acids, however TMSCl is already sufficient for this purpose. Instead, the least reactive substrate 22 necessitates the use of more reactive Lewis acid such as TMSOTf, TMSI or TMSBr to undergo any CA.
Figure 10 Proposed scale of activation of heteroaryl substituents on olefins towards the ACA of
62
However, all these conclusions are based on non-direct experiments. In none of the experiments prior to this study, the reactivity of these moieties has been directly compared. We have designed compound 25, 26 and 27 (Figure 9) to make a direct comparison between the reactivity of different heteroarenes.
Figure 11 Structure of alkenes 25-27, bearing two different heteroaryl substituents in 1,2-position.
Alkene 25 was prepared by condensation reaction of the aldehyde 28 and γ-pinacoline (29) with a low yield, probably due to the degradation of the product at the reflux temperature of DMF. Compounds 26 and 24 were synthesized by condensation of 2-methylbenzoxazol (30) and the pyridine carbaldehyde with LDA at low temperature, to avoid the thermal decomposition of the product, and subsequent elimination with MsCl (Scheme 7).
Scheme 30 Syntheses of 2-(2-(pyridin-4-yl)vinyl)pyridine(25), 2-(2-(pyridin-4-yl)vinyl)benzoxazole (26) and 2-(2-(pyridin-2-yl)vinyl)benzoxazole (27).
The reactivity of alkenes 25, 26 and 27 towards the asymmetric addition of Grignard was studied. The addition of ethylmagnesium bromide to 25 affords selectively 33 as only product with all the Lewis acid tested (TMSOTf, TMSBr and BF3·OEt2, entries
1-4, Table 2). The structure of 33 was confirmed by 1H-13C HMBC NMR spectroscopy
(Figure 10). High enantioselectivities were achieved with TMSBr (90% ee with ligand L5 and 94% with L6 (entries 2 and 4). 1,4-Conjugate addition has occurred with respect to the 4-pyridine moiety. The reaction occurred stereoselectively, meaning that the steric bulk of the 2-pyridine was not sufficient to impede the interaction of the transmetallated catalyst with of the olefin.
63
Table 12 Reactivity of 25 towards the asymmetric conjugate addition of ethylmagnesium bromide.
a Conversion was determined by 1H-NMR. b Isolated yield cDetermined via
CSP-HPLC.
Figure 12 1H-13C-HMBC (1H at 600.0 MHz, 13C at 150.75 MHz, CDCl3), δ. Expansion of the signal
corresponding to 2Je-Hf (blue), 3Je-Hg (blue),3Je-Hk (purple) and 2Jh-Hg (green). The coupling between the
quaternary carbon of the 2-pyridyl (Ce) and the Hk belonging to the ethyl substituent (purple) confirms that ethyl and 2-pyridine moiety are bonded to the same carbon atom. Ch, instead, has a coupling only with Hg and Hf.
Next, the reactivity of the alkenes 26 and 27 towards the copper-catalyzed addition of EtMgBr was studied. A complex mixture of products was obtained when using CuBr·SMe2/L6 and TMSBr as additive in the additions reactions using both
heteroarene substrates. Interestingly, conjugate addition with respect to the pyridyl Entry Ligand LA Yield (%) b ee (%)c
1 L5 TMSOTf 66 39
2 L5 TMSBr 40 90
3 L5 BF3·OEt2 57 26
64
ring is observed when using L14 and TMSBr (entry 2, Table 8). Also here, the structure of the compound was confirmed by 1H-13C HMBC NMR. Instead, addition of
ethylmagnesium bromide to 27, led to the formation of the isomer 35b both in the absence and the presence of Lewis acids (TMSBr or BF3·OEt2, entries 3-5, Table 8).
The structure of 35b was determined by NMR. Based on the results illustrated in Chapter 2 and Chapter 3 (Paragraphs 3.3.1. and 3.3.2.) and on the previous work reported by our group[40,41], the expected order of reactivity is benzoxazylalkenes >
4-pyridylalkenes > 2-pyridyl alkenes. A feasible explanation for the formation of products 34 and 35, is that the pyridine nitrogen is more Lewis basic compared to the benzoxazole nitrogen and therefore Lewis acid activation occurs preferentially on the pyridine. However, the reactivity of the 2-pyridyl-alkenes/Lewis acid adduct is troublesome and the formation of product 35a has been observed only with 3.0 equiv. of TMSBr and rac-L16 as ligand (entry 6, Table 8).
Table 13 Reactivity of 26 and 27 towards the asymmetric conjugate addition of ethylmagnesium
bromide.
a Isolated yield b Determined via CSP-HPLC.
Entry Substrate Ligand LA Product Yield (%) a ee (%)b 1 26 L6 TMSBr 34a 0 - 2 26 L14 TMSBr 34a 53 6 3 27 L14 TMSBr 35b 60 rac 4 27 L14 BF3·OEt2 35b 39 rac 5 27 L14 None 35b 39 rac 6 27 rac-L16 TMSBr (3.0) 35a:34b (1:2) 32 -
65
Figure 13 a) Product 34a, correlation in 13C HMBC NMR (1H at 400 MHz, 13C at 101 MHz, CDCl3), 2JCc-Hd (blue), 3JCb-Hg (blue),) and 3JCd-Hb (green). The correlation between the Cb and Cc with proton Hd
confirms that the pyridyl moiety is binded to the methylene. Likewise, Cd is correlated with Hb of the pyridine ring. b) Product 35b, correlation in 13C HMBC NMR (1H at 600.0 MHz, 13C at 150.75 MHz,
CDCl3), 3JCe-Hg (blue),) and 3JCd-Hf (green). The coupling of the quaternary carbon Ce with the protons of
the ethyl group, and the one of Cf with Hd indicate that the pyridine ring and the ethyl are bonded to the same carbon atom.
3.3.4. Interaction of 1,2-bis(4-pyridyl)ethene (19) with TMSBr
To get more insight in the mode of activation of the substrate by the Lewis acid, the nature of the activated species in solution was studied. The observations done in the catalytic reactions were taken into account:
1) The alkene 19 was not soluble in ether and toluene at room temperature, but soluble in CH2Cl2.
2) A precipitate was formed upon addition of TMSBr to the solution of 19 and the catalyst at -78°C in CH2Cl2.
The color of the catalyst solution (CuBr·L5) changes from orange to bright red when the substrate is introduced. The complex CuBr·L3 was chosen as model catalyst, given that better NMR spectra can be recorded for this complex when compared to that obtained with CuBr·L5 of CuBr·L6 (Figure 12a), and 19 was chosen as substrate.
When 10 equiv. of 19 were added to the solution of CuBr·L3, the doublets in the 31P
spectrum corresponding to the phosphines shifted slightly up field (Figure 12b). To the solution of CuBr·SMe2·L3 and 10 equiv. of 19 in CD2Cl2, 5 equiv. of TMSOTf
were added. The reaction became immediately turbid and the resolution of the spectrum decreased because of the presence of a solid (Figure 12c). The chemical shift of the two doublets remained unchanged, meaning that a significant part of the complex CuBr·L3 was not affected by the addition of TMSOTf, but it rather reacted with 19. On the contrary, when TMSOTf was added to CuBr·SMe2·L3 in
66
Figure 14 Reaction of the complex CuBr·L3 with 19 and TMSOTf, 31P-NMR (162 MHz, CD2Cl2), δ.
From these results, we can assume that substrate 19 protects the catalyst from decomposition. It is reported in literature, treating 4,4’-bipyridine with 2.0 equiv. of TMSOTf, the salt [Me3Si(4,4’-bipyridine)SiMe3]2+(OTf-)2 can be isolated.[45] We
suppose that the TMSOTf interacts with the pyridine moiety to form the salt [Me3Si(19)SiMe3]2+(OTf-)2 or [(19)SiMe3]+OTf- (Figure 14) that precipitates from the
reaction mixture. This salt is a powder, insoluble in organic solvent and crystals could not be grown. It was also not possible to perform NMR spectra because of its poor solubility in organic solvents. However, the fact that [(19)SiMe3]+OTf- is less prone
than its precursor to be attacked by TMSBr and that the surnatant only contains free 19, suggests that the precipitate consists of the monosubstituted salt.
67
3.4. Conclusions
In summary, we have reported the asymmetric synthesis of alkanes bearing 4-pyridine moieties with remarkable ees (70-97%). These compounds are highly valuable for medicinal and supramolecular chemistry. Given the high reactivity of the two Michael-partners used, the addition of the Grignard reagents proceeds with surprisingly high enantioselectivity. Nevertheless, suppression of the β-hydride transfer remains a challenge. The reactivity of an alkene bearing a 2-pyridyl moiety differs significantly from its 4-pyridyl isomer. In this case, it is not possible to achieve good conversion and good ees because of the fast non-catalyzed addition of RMgBr that competes with the catalytic enantioselective pathway. However, it is possible to exploit the high activity of TMSOTf to prepare racemic alkanes bearing two pyridine rings without the use of a catalyst. These compounds could be used as ligands in transition metal catalysis. By submitting alkenes bearing two different heteroaryl substituents to the addition reaction, we compared directly the reactivity of 2-benzoxazyl, 4-pyridyl and 2-pyridyl olefins. It is possible to outline that the reactivity of these heteroaryl olefins towards nucleophilic conjugate addition in the presence of a Lewis acid is 4-pyridyl > 2-benzoxazyl > 2-pyridyl.
We have tried to clarify the substrate activation mode by the Lewis acid. Upon addition of TMSX, a precipitate is formed: we believe that this is the salt formed upon reaction of bis-pyridine substrate and 1.0 equiv. of additive. However, we were not able to characterize this salt due to its insolubility in organic solvents
3.5. Experimental section
3.5.1. General informationAll reactions using oxygen- and/or moisture-sensitive materials 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, when necessary, was performed by flash-column chromatography using Merck 60 Å 230-400 mesh silica gel, Merck 90 active neutral or VWR AnalaR NORMAPUR aluminum oxide basic. NMR data was collected on Bruker Avance NEO 600 (1H at 600.0 MHz; 13C at 150.87MHz), equipped with a
Prodigy Cryo-probe and Varian VXR400 (1H at 400.0 MHz; 13C at 100.58 MHz, 19F at
376.50 MHz, 31P at 161.97 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. CD2Cl2: 1H: 5.32 ppm; 13C: 54.0 ppm). Coupling
constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, bs: broad singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doublet of doublets, t: triplet, td: triplet of doublets, q: quartet, m: multiplet). Exact
68
mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI ionization. Enantiomeric excesses (ees) were determined by Chiral HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector and by Waters Acquity UPC2 system with PDA detector and QDA mass 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 and used as received (EtMgBr (3.0M in Et2O), n-HexMgBr, i-BuMgBr (2.0 M in Et2O), CypMgBr (1.8M in Et2O). All other
Grignard reagents were prepared from the corresponding alkyl bromides and Mg activated with I2 in Et2O and concentration was determine by NMR titration
method[46]. Chiral ligands L3, L5, L6, L9 and L10 - L16 were purchased from Sigma
Aldrich and Solvias. L7-L8 were prepared according to the literature procedure.[47]
L17-L18 were obtained from the laboratory of Ben L. Feringa.[48] L19 was obtained
from the laboratory of Jérôme Lacour.[49]All reported compounds were characterized
by 1H and 13C NMR and compared with literature data. All new compounds were fully
characterized by 1H and 13C NMR and HRMS techniques. The absolute configurations
of products were not assigned.
3.5.2. Synthesis of substrates
(E)-2-(2-(pyridin-4-yl)vinyl)pyridine(25)
In a 250ml three-necked round bottom flask, 4.8 ml (75 mmol, 3 equiv.) of 4-methyl pyridine were dissolved in 65 mL of dry DMF and 4.2 g of freshly mashed KOH pellets (75 mmol 3 equiv.). The reaction was stirred at 60 oC for 1 h. 2.38 g of
2-pyridinecarboxaldehyde (25 mmol, 1 equiv.) were added and the reaction was refluxed for 30 min. Once the reaction had reached room temperature, 20 mL of water were added and the aqueous phase was extracted with 50 mL of CH2Cl2. The organic phase
was washed with water (3 x 20 mL). The organic phase was dried with MgSO4 and the
solvent was removed under reduced pressure. The product was obtained after flash-column chromatography (Neutral Al2O3, pentane:EtOAc, 80:20→ 0:100, v/v) as a
white solid (583 mg, 0.78 mmol, yield 11 %). The NMR data are in agreement with the ones present in literature.[50]
1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.8 Hz, 1H), 8.60 (d, J = 4.9 Hz, 2H), 7.70
(t, 1H), 7.58 (d, J = 16.1 Hz, 1H), 7.44 – 7.38 (m, 3H), 7.33 (d, J = 16.1 Hz, 1H), 7.22 (dd, 1H).
13C NMR (101 MHz, CDCl3) δ 154.4, 150.3, 149.9, 144.0, 136.8, 132.2, 130.0, 123.1,
69
3.5.3. General procedure for the synthesis of 2-(benzoxazol-2-yl)-1-(pyridinyl)ethan-1-ol
In a Schlenk under dry and inert atmosphere, 1.1 mL of iPr2NH (7.2 mmol, 1.2 equiv.)
were dissolved in 18 mL of dry THF. A solution of n-BuLi (2.6 mL, 2.6 M in toluene, 6.6 mmol, 1.1 equiv.) were added dropwise at -78 oC. After 5 minutes, a solution of 0.72
mL of 2-methylbenzoxazole (6.0 mmol, 1.0 equiv.) in 2 mL of THF was added dropwise and the reaction was allowed to stir for 15 min. A solution of the pyridine carboxaldehyde (7.2 mmol, 1.2 equiv.) in 3 mL THF was added dropwise. The solution was allowed to reach room temperature and stirred overnight. The reaction was quenched with 5 mL of saturated aqueous NH4Cl solution and extracted with CH2Cl2
(3 x 10 mL). The organic phase was dried with MgSO4 and the solvent was removed
under reduced pressure. The crude was purified by column chromatography (Neutral Al2O3, CH2Cl2 -> AcOEt -> EtOH -> MeOH).
2-(benzoxazol-2-yl)-1-(pyridin-4-yl)ethan-1-ol (31)
Product was obtained from 0.72 mL of 2-methylbenzoxaole (6.0 mmol ) using 4.5 mL of n-BuLi 1.6 M solution in hexanes. The product was obtained as a yellow solid (1.44 g, 6 mmol, quantitative yield) without need of further purification.
1H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 4.2 Hz, 2H), 7.67 (dd, J = 6.0, 3.2
Hz, 2H), 7.41 – 7.36 (m, 2H), 7.33 (dd, 2H), 5.35 (dd, 1H), 4.76 (bs, 1H), 3.40 – 3.17 (m, 2H).
13C NMR (101 MHz, Chloroform-d) δ 164.2, 151.5, 150.6, 150.1, 140.7, 125.2, 124.7,
120.8, 119.8, 110.7, 69.8, 37.6.
HRMS (ESI+): m/z calcd. for C14H13N2O2 ([M+H+]) 241.09715, found 241.09715.
2-(benzoxazol-2-yl)-1-(pyridin-2-yl)ethan-1-ol (32)
Product was obtained from 0.72 mL of 2-methylbenzoxaole (6.0 mmol ) using a 2.5 mL of n-BuLi 2.6 M solution in toluene and recovered after column chromatography (Al2O3, CH2Cl2 ->
AcOEt -> EtOH -> MeOH) as brown solid (0.892 g, 3.72 mmol, 67% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 4.4 Hz, 1H), 7.75 – 7.61 (m, 2H), 7.53 – 7.41 (m, 2H), 7.36 – 7.13 (m, 3H), 5.39 (m, J = 9.0, 4.7 Hz, 1H), 4.77 (d, J = 5.5 Hz, 1H), 3.51 (dd, J = 15.9, 4.2 Hz, 1H), 3.36 (dd, J = 15.8, 8.4 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 164.7, 160.5, 150.8, 148.8, 137.1, 124.9, 124.4, 122.9, 120.6, 119.8, 110.7, 102.5, 71.0, 37.3.
70
3.5.4. General procedure for the synthesis of (E)-2-((pyridinyl)vinyl)benzoxazoles
In a round bottom flask, 1.44 g (6.0 mmol) of 2-(benzoxazol-2-yl)-1-(pyridinyl)ethan-1-ol were dissolved in 25 mL CH2Cl2 and cooled to 0 oC. First 0,56 mL of MsCl (7.2
mmol) and then 2.00 mL of Et3N (14.4 mmol, 2.4 equiv.) were added dropwise
maintaining the reaction at 0 oC. The reaction was allowed to warm up to rt and stirred
overnight. The reaction was quenched with 10 mL of H2O, extracted with CH2Cl2 (3 x
20 mL). The organic phase was dried with MgSO4 and the solvent was removed under
reduced pressure. The crude was purified by column chromatography (Neutral Al2O3,
CH2Cl2 -> AcOEt).
(
E)-2-(2-(pyridin-4-yl)vinyl)benzoxazole (26)Product was obtained from 1.44 g of 31 (6.0 mmol) as a yellow solid (821 mg, 3.69 mmol, 62% yield).
1H NMR (400 MHz, Chloroform-d) δ 8.71 – 8.65 (m, 2H),
7.78 – 7.73 (m, 2H), 7.71 (d, J = 16.4 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.42 – 7.33 (m, 2H), 7.26 (d, J = 16.4 Hz, 1H).
13C NMR (101 MHz, Chloroform-d) δ 161.7, 150.8, 150.7, 142.4, 142.17, 136.5, 126.1,
125.0, 121.5, 120.5, 118.6, 110.7.
HRMS (ESI+): m/z calcd. for C14H13N2O2 ([M+H+]) 223.08659, found 223.08655. (E)-2-(2-(pyridin-2-yl)vinyl)benzoxazole (27)
Product was prepared from 0.892 g of 32 (3.72 mmol), 0.34 mL of MsCl (4.4 mmol, 1.2 equiv.), 1.23 mL of Et3N ( 8.8
mmol, 2.4 equiv.) in 20 mL of CH2Cl2. 27 was obtained as a
yellow solid (0.576 g, 2.59 mmol, 70% yield).
1H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 4.7 Hz, 1H), 7.81 (d, J = 15.9 Hz,
1H), 7.77 – 7.68 (m, 2H), 7.62 (d, J = 16.0 Hz, 1H), 7.58 – 7.50 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.29 – 7.20 (m, 1H).
13C NMR (101 MHz, Chloroform-d) δ 162.6, 153.6, 150.7, 150.3, 142.4, 138.3, 136.9,
125.7, 124.7, 123.9, 123.9, 120.3, 118.1, 110.6.
HRMS (ESI+): m/z calcd. for C14H13N2O2 ([M+H+]) 223.08659, found 223.08705. 3.5.5. General procedure for the asymmetric addition to 19
In a heat dried Schlenk tube equipped with septum and magnetic stirring bar, the CuBr·SMe2 (10 mol%), and (R,Sp)-L6 (12 mol%) were dissolved in CH2Cl2
(1mL/0.1mmol of substrate) and stirred under nitrogen atmosphere for 15 min. The substrate (0.1 - 0.2 mmol, 1 equiv.) was added at once. After stirring for 5 min. at rt the reaction mixture was cooled to -78 °C and TMSBr(1.5 equiv.) was added followed by
71 RMgBr (2.0 equiv.). After stirring at -78 °C for 16h, the reaction was quenched with MeOH (0.5 mL) followed by saturated aqueous NH4Cl solution and warmed to RT.
Reaction mixture was extracted with CH2Cl2 (3 × 10 mL). Combined organic phases
were dried over MgSO4, filtered and solvents were evaporated on rotary evaporator.
The oily crude was purified by a small chromatography on neutral Al2O3 using a
mixture of pentane and EtOAc (9:1) as eluent to remove the complex, and subsequently pure EtOAc. The product was obtained by filtration through basic Al2O3 using
CH2Cl2:EtOAc (1:1) as an eluent.
4-(1-(pyridin-4-yl)butan-4-yl)pyridine (20a)
The reaction was performed with 0.1 mmol 1,2-bis(4-pyridyl)ethene, EtMgBr (0.2 mmol, 3M in Et2O) diluted in Et2O
(0.6 mL total volume), CuBr·SMe2 (2.1 mg, 0.01 mmol, 10 mol%),
(R,Sp)-L6 (7.7 mg, 0.012 mmol, 12 mol%), TMSBr (0.02 mL, 0.15 mmol, 1.5 equiv.) in 1 mL CH2Cl2. Product 20a was obtained as
pale yellow oil (15.4 mg, 0.075 mmol, yield 75%, 91% ee). The absolute configuration of 20a was not assigned.
1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 6.0 Hz, 2H), 8.41 (dd, J = 5.9 Hz,
2H), 6.99 (d, J = 6.1 Hz, 2H), 6.91 (d, J = 5.8 Hz, 2H), 3.00 – 2.90 (m, 1H), 2.86 – 2.69 (m, 2H), 1.83 – 1.58 (m, 2H), 0.80 (t, J =7.4 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) δ 153.0, 150.0, 149.80, 148.7, 124.5, 123.3, 48.7,
42.0, 28.4, 12.0.
HRMS (ESI+): m/z calcd. for C16H17N2 ([M+H+]) 213.13863, found 213.13841.
CSP-HPLC: (254nm, Chiralcel OD-H, n-heptane:i-PrOH = 90:10, 40 °C, 0.5 mL/min.), tR = 41.96 min (major), tR = 3.21 min (minor).
4,4'-(hexan -1,2-diyl)dipyridine (20b)
The reaction was performed with 0.2 mmol 1,2-bis(4-pyridyl)ethene, (0.2 mmol, 1.8M in Et2O) diluted in Et2O (1.2 mL
total volume), CuBr·(R,Sp)-L6 (16.9 mg, 0.02 mmol, 10 mol%), TMSBr (0.04 mL, 0.30 mmol, 1.5 equiv.) in 2 mL CH2Cl2. Product
20b was obtained as pale yellow oil (27.8 mg, 0.12 mmol, yield 60%, 99% ee). The absolute configuration of 20b was not assigned.
1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 5.6 Hz, 2H), 8.41 (d, J = 5.7 Hz,
2H), 6.98 (d, J = 5.5 Hz, 2H), 6.90 (d, J = 5.5 Hz, 2H), 3.00 – 2.86 (m, 1H), 2.80 (d, J = 8.7 Hz, 2H), 1.77 – 1.62 (m, 2H), 1.36 – 0.98 (m, 4H), 0.82 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) δ 153.3, 150.0, 149.8, 148.7, 124.5, 123.2, 46.9,
42.3, 35.1, 29.6, 22.7, 14.0.
72
CSP-HPLC: (254nm, Chiralcel OJ-H, n-heptane:i-PrOH = 90:10, 40 °C, 0.5 mL/min.), tR = 28.52min (major), tR = 40.76 min (minor).
4-(1-(pyridin-4-yl)octan-4-yl)pyridine (20c)
The reaction was performed with 0.1 mmol 1,2-bis(4-pyridyl)ethene, n-HexMgBr (0.2 mmol, 2M in Et2O) diluted in
Et2O (0.6 mL total volume), CuBr·SMe2 (2.1 mg, 0.01 mmol, 10
mol%), (R,Sp)-L6 (7.7 mg, 0.012 mmol, 12 mol%), TMSBr (0.02 mL, 0.15 mmol, 1.5 equiv.) in 1 mL CH2Cl2. Product 20c was
obtained as pale yellow oil (17.1 mg, 0.064 mmol, yield 64%, 94% ee). The absolute configuration of 20c was not assigned.
1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 6.0 Hz, 2H), 8.41 (d, J = 6.1 Hz, 2H),
6.98 (d, J = 5.8 Hz, 2H), 6.90 (d, J = 6.0 Hz, 2H), 2.93 (m, 1H), 2.85 – 2.71 (m, 2H), 1.74 – 1.56 (m, 2H), 1.31 – 1.07 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) δ 153.3, 150.0 (2C), 149.7 (2C), 148.8, 124.5 (2C),
123.3 (2C), 46.9, 42.3, 35.4, 31.7, 29.8, 27.4, 22.7, 14.1.
HRMS (ESI+): m/z calcd. for C18H25N2 ([M+H+]) 269.20123, found 269.20149.
CSP-HPLC: (254nm, Chiralcel OD-H, n-heptane:i-PrOH = 94:6, 40 °C, 0.5 mL/min.), tR = 46.13 min (major), tRmin = 42,17 min (minor).
4,4'-(hept-6-ene-1,2-diyl)dipyridine (20d)
The reaction was performed with 0.2 mmol 1,2-bis(4-pyridyl)ethene, (0.2 mmol, 2M in Et2O) diluted in Et2O (1.2 mL
total volume), CuBr·(R,Sp)-L6 (16.9 mg, 0.02 mmol, 10 mol%), TMSBr (0.04 mL, 0.30 mmol, 1.5 equiv.) in 2 mL CH2Cl2. Product
20d was obtained as pale yellow oil (19.2 mg, 0.054 mmol, yield 54%, 90% ee). The absolute configuration of 20d was not assigned. 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 5.0 Hz, 2H), 8.41 (d, J = 4.8 Hz, 2H), 6.99 (d, J = 4.9 Hz, 2H), 6.89 (d, J = 4.9 Hz, 2H), 5.78 – 5.53 (m, 1H), 5.02 – 4.83 (m, 2H), 2.98 – 2.86 (m, 1H), 2.86 – 2.71 (m, 2H), 2.12 – 1.88 (m, 2H), 1.77 – 1.56 (m, 2H), 1.48 – 1.11 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 153.0, 150.1 (2C), 149.8 (2C), 148.6, 138.2 (2C), 124.5, 123.3, 115.1 (2C), 46.9, 42.3, 34.8, 33.6, 26.7.
HRMS (ESI+): m/z calcd. for C17H21N2 ([M+H+]) 253.169938, found 253.17021.
CSP-HPLC: (254nm, Chiralcel OD-H, n-heptane:i-PrOH = 90:10, 40 °C, 0.5 mL/min.), tR = 35.68 min (major), tR = 33.40 min (minor).
73 4,4'-(5-methylhexane-1,2-diyl)dipyridine (20e)
The reaction was performed with 0.1 mmol 1,2-bis(4-pyridyl)ethene, (0.2 mmol, 2M in Et2O) diluted in Et2O (0.6 mL
total volume), CuBr·SMe2 (2.1 mg, 0.01 mmol, 10 mol%), (R,Sp )-L6 (7.7 mg, 0.012 mmol, 12 mol%), TMSBr (0.04 mL, 0.30 mmol, 1.5 equiv.) in 1 mL CH2Cl2. Product 20e was obtained as pale
yellow oil (10.3 mg, 0.040 mmol, yield 40%, 94% ee). The absolute configuration of 20e was not assigned.
1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 5.2 Hz, 2H), 8.41 (d, J = 5.1 Hz, 2H), 7.04 – 6.92 (m, 2H), 6.92 – 6.84 (m, 2H), 3.03 – 2.86 (m, 1H), 2.86 – 2.67 (m, 2H), 1.79 – 1.54 (m, 2H), 1.46 (m, 1H), 1.10 (m, 1H), 0.97 (m, 1H), 0.81 (dd, J = 6.6, 5.4 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 153.3, 150.0, 149.8, 148.7, 124.5, 123.3, 47.2, 42.4, 36.6, 33.3, 28.1, 22.8, 22.4.
HRMS (ESI+): m/z calcd. for C17H23N2 ([M+H+]) 255.18558, found 255.18597.
CSP-HPLC: (254nm, Chiralcel OD-H, n-heptane:i-PrOH = 95:5, 40 °C, 0.5 mL/min.), tR = 54.39 min (major), tR = 50.44 min (minor).
4,4'-(5-methylhexane-1,2-diyl)dipyridine (20f)
The reaction was performed with 0.2 mmol 1,2-bis(4-pyridyl)ethene, CypMgBr (0.2 mmol, 1.8 M in Et2O) diluted in
Et2O (1.2 mL total volume), CuBr·(R,Sp)-L6 (16.9 mg, 0.02 mmol, 10 mol%), TMSBr (0.04 mL, 0.30 mmol, 1.5 equiv.) in 2 mL CH2Cl2. Product 20f was obtained as pale yellow oil (33.0 mg, 0.13
mmol, yield 66%, 72% ee). The absolute configuration of 20f was not assigned. 1H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 5.0 Hz, 2H), 8.34 (d, J = 4.9 Hz, 2H), 6.91 (t, J = 6.0 Hz, 2H), 6.79 (d, J = 1151.9 Hz, 2H), 3.16 (dd, J = 13.4, 3.9 Hz, 1H), 2.74 (dd, J = 13.4, 10.8 Hz, 1H), 2.57 (td, J = 10.3, 3.9 Hz, 1H), 2.24 – 2.00 (m, 2H), 1.64 – 1.21 (m, 6H), 1.04 – 0.85 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ 152.8, 149.8, 149.7, 148.9, 124.5, 123.7, 53.6, 45.5, 41.1, 31.9, 31.7, 25.4, 25.2.
HRMS (ESI+): m/z calcd. for C17H21N2 ([M+H+]) 253.16993, found 253.17008.
CSP-HPLC: (254nm, Chiralcel OD-H, n-heptane:i-PrOH = 85:15, 40 °C, 0.5 mL/min.), tR = 15.14 min (major), tR = 35.10 min (minor).
3.5.6. General procedure for the asymmetric addition to 22
In a heat dried Schlenk tube equipped with septum and magnetic stirring bar, CuBr·SMe2 (10 mol%), and (R,Sp)-L5 (12 mol%) were dissolved in CH2Cl2 (0.1M
74
mmol, 1 equiv.) was added at once. After stirring for 5 min. at rt the reaction mixture was cooled to -78 °C and TMSBr or TMSCl (1.5-3.0 equiv.) was added followed by RMgBr (2.0-3.0 equiv.). After stirring at -78 °C for 16h, the reaction was quenched with MeOH (0.5 mL) followed by saturated aqueous NH4Cl solution and warmed to RT.
Reaction mixture was extracted with CH2Cl2 (3 × 10 mL). Combined organic phases
were dried over MgSO4, filtered and solvents were evaporated on rotary evaporator.
The oily crude was purified by flash column chromatography on neutral Al2O3 using a
mixture of pentane and EtOAc (9:1 -> 4:1).
(S)-4-(1-(pyridin-2-yl)butan-4-yl)pyridine (23a)
The reaction was performed with 0.1 mmol 1,2-bis(4-pyridyl)ethene, EtMgBr (0.2 mmol, 3M in Et2O), CuBr·SMe2 (2.1
mg, 0.01 mmol, 10 mol%), (R,Sp)-L5 (7.13 mg, 0.012 mmol, 12 mol%), TMSBr (0.04 mL, 0.3 mmol, 3.0 equiv.) in 1 mL CH2Cl2.
Product 23a was obtained as pale yellow oil (4.0 mg, 0.019 mmol, yield 19%, 75% ee). The absolute configuration of 23a was not assigned.
1H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 4.7 Hz, 1H), 8.51 (d, J = 4.9 Hz, 1H),
7.45 (m, 2H), 7.04 (ddd, 2H), 6.98 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 3.28 – 3.05 (m, 3H), 1.95 – 1.61 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) δ 164.0, 160.8, 149.5, 149.3, 136.0, 136.0, 123.9,
123.8, 121.3, 121.0, 49.9, 44.2, 28.1, 12.2.
HRMS (ESI+): m/z calcd. for C14H16N2 ([M+H+]) 213.13863, found 213.13893.
CSP-HPLC: (254nm, Chiralcel OZ-H, n-heptane:i-PrOH = 95:5, 40 °C, 0.5 mL/min.), tR = 17.81 min (major), tR = 19.78 min (minor).
3.5.7. General procedure for the racemic addition to 22
In a heat dried Schlenk tube equipped with septum and magnetic stirring bar, 1,2-bis(2-pyridyl)-ethylene (0.8-0.89 mmol, 1 equiv) was dissolved in CH2Cl2. After
stirring for 5 min. at rt the reaction mixture was cooled to -78 °C and TMSBr(3.0 equiv.) was added, followed by RMgBr (3.0 equiv.). After stirring at -78 °C for 16h, the reaction was quenched with MeOH (1 mL) followed by saturated aqueous NH4Cl
solution and warmed to rt. The reaction mixture was extracted with CH2Cl2 (3 × 10
mL). The combined organic phases were dried over MgSO4, filtered and solvents were
evaporated on rotary evaporator. The oily crude was purified by column chromatography on neutral Al2O3 using a mixture of pentane and EtOAc (4:1-> 0:1).
75 2,2'-(3-methylbutane-1,2-diyl)dipyridine (23b)
The reaction was performed with 0.8 mmol 1,2-bis(2-pyridyl)ethene, i-PrMgBr (2.4 mmol, 3M in Et2O), TMSOTf (0.45 mL, 2.4 mmol, 3.0
equiv.) in 10 mL CH2Cl2. Product 23b was obtained as colorless oil
(167 mg, 0.74 mmol, yield 93%). 1H NMR (400 MHz, Chloroform-d) δ 8.53 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 5.0 Hz, 1H), 7.39 (dd, J = 7.6 Hz, 1H), 7.32 (dd, J = 8.6, 6.7 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 6.94 (d, J = 5.7 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 3.39 – 3.14 (m, 3H), 2.22 – 2.03 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ (ppm); 163.3, 161.3, 149.21, 149.19, 135.8, 135.6, 124.6, 123.8, 121.1, 120.8, 55.0, 41.1, 32.9, 21.0, 20.9.
HRMS (ESI+): m/z calcd. for C15H19N2 ([M+H+]), 227,15428 found 227,15443.
2,2'-(1-cyclopentylethane-1,2-diyl)dipyridine (23c)
The reaction was performed with 0.89 mmol 1,2-bis(2-pyridyl)ethene, CypMgBr (2.7 mmol, 1.5M in Et2O), TMSOTf (0.51
mL, 2.7 mmol, 3.0 equiv.) in 10 mL CH2Cl2. Product 23c was
obtained as colorless oil (188 mg, 0.75 mmol, yield 84%).
1H NMR (400 MHz, Chloroform-d) δ (ppm); 8.52 (dd, J = 11.0, 3.9 Hz, 1H), 8.44 (d, J = 4.7 Hz, 1H), 7.37 (td, J = 7.6, 1.9 Hz, 1H), 7.31 (td, J = 7.7, 1.9 Hz, 1H), 7.02 – 6.90 (m, 2H), 6.81 (d, J = 7.8, 1.1 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 3.34 – 3.17 (m, 2H), 3.07 (td, J = 10.1, 4.7 Hz, 1H), 2.40 – 2.25 (m, 1H), 2.05 – 1.95 (m, 1H), 1.71 – 1.28 (m, 6H), 1.11 – 0.99 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ (ppm); 166.5 , 163.5 , 151.8 , 151.7 , 138.3 , 138.2 , 126.5 , 126.2, 123.6 , 123.3 , 56.8 , 48.1 , 45.8 , 34.1 , 34.0 , 27.9 , 27.7 .
HRMS (ESI+): m/z calcd. for C17H21N2 ([M+H+]) 253.16993, found 253.17041.
2,2'-(1-phenylethane-1,2-diyl)dipyridine (23d)
The reaction was performed with 0.8 mmol 1,2-bis(2-pyridyl)ethene, CypMgBr (2.4 mmol, 3M in Et2O), TMSOTf (0.45 mL, 2.4 mmol, 3.0
equiv.) in 10 mL CH2Cl2. Product 23d was obtained as colorless oil
(224 mg, 0.86 mmol, yield 96%). 1H NMR (400 MHz, Chloroform-d) δ(ppm); 8.57 (d, J = 4.8 Hz, 1H), 8.50 (d, J = 4.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.05 (t, J = 6.8 Hz, 1H), 7.00 (d, J = 6.0 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 4.72 (d, J = 7.9 Hz, 1H), 3.80 (dd, J = 13.6, 8.0 Hz, 1H), 3.52 (dd, J = 13.6, 7.7 Hz, 1H).
76
13C NMR (101 MHz, Chloroform-d) δ 165.4 , 162.8 , 151.8(2C) , 146.0 , 138.9 , 138.5 ,
131.0 (2C), 130.8 (2C) , 129.0 , 126.6 , 126.1 , 123.9 , 123.6 , 55.9 , 46.2 .
HRMS (ESI+): m/z calcd. for C18H17N2 ([M+H+]) 261.13863, found 261.13880. 3.5.8. General procedure for the asymmetric addition to 25-27
In a heat dried Schlenk tube equipped with septum and magnetic stirring bar, the CuBr·SMe2 (5 mol%), and (R,Sp)-L5, (R,Sp)-L6 or (S,Rp)-L14 (6 mol%) were dissolved in CH2Cl2 (1mL/0.1mmol of substrate) and stirred under nitrogen atmosphere for 15
min. The substrate (0.1 mmol, 1 equiv.) was added at once. After stirring for 5 min at rt the reaction mixture was cooled to -78 °C and EtMgBr (2.0 equiv.) was diluted in CH2Cl2 to a total volume of 0.6 mL and added over 2 h. After stirring at -78 °C for 18
h, the reaction was quenched with MeOH (0.5 mL) followed by saturated aqueous NaHCO3 solution and warmed to rt. The reaction mixture was extracted with CH2Cl2
(3 × 10 mL). Combined organic phases were dried over MgSO4, filtered and solvents were evaporated on rotary evaporator. The oily crude was purified by flash column chromatography on neutral Al2O3 using a mixture of pentane and EtOAc as eluent.
2-(1-(pyridin-4-yl)butan-2-yl)pyridine (33)
The reaction was performed with 0.1 mmol 25, TMSBr (0.15 mmol, 1.5 equiv), EtMgBr (3M in Et2O, 0.2 mmol, 2.0 equiv),
CuBr·SMe2 (0.01 mmol, 10 mol%), ligand (R,Sp)-L6 (0.012 mmol, 12 mol%) in 1mL CH2Cl2. After purification by flash
column chromatography (neutral Al2O3, pentane: EtOAc, 9:1 ->
1:1). Product 33 was obtained as pale-yellow oil (14.9 mg, 0.07 mmol, 70% yield, 92% ee). The absolute configuration of 33 was not assigned.
1H NMR (400 MHz, CDCl3), δ 8.59 – 8.54 (m, J = 5.5 Hz, 1H), 8.40 – 8.31 (d, 2H),
7.53 – 7.44 (m, 1H), 7.12 – 7.05 (m, 1H), 6.96 – 6.86 (m, 3H), 3.11 – 3.00 (m, 2H), 2.99 – 2.86 (m, 2H), 1.87 – 1.67 (m, 1H), 0.84 – 0.74 (t, 3H).
13C NMR (101 MHz, CDCl3), δ 163.1, 149.9, 149.64, 149.58, 136.2, 124.6, 123.6, 121.6,
50.8, 41.1, 28.2, 12.1.
HRMS (ESI+): m/z calcd. for C14H17N2 ([M+H+]) 213,13863, found 213,13883.
CSP-HPLC: (210 nm, Chiralcel OZ-H, n-heptane:i-PrOH = 95:5, 40 °C, 1.0 mL/min.), tR = 19.11 min (major), tR = 21.65 min (minor).
2-(1-(pyridin-4-yl)butan-2-yl)benzoxazole (34a)
The reaction was performed with 0.1 mmol 26, EtMgBr (0.2 mmol, 3.0 M in Et2O) diluted in CH2Cl2 (0.6 mL total volume),
CuBr·SMe2 (1.0 mg, 0.005 mmol, 5 mol%), (S,Rp)-L14 (4.1 mg, 0.006 mmol, 6 mol%), TMSBr (0.02 mL, 0.15 mmol, 1.5 equiv.) in 1 mL CH2Cl2. After purification by flash column
77 chromatography (neutral Al2O3, pentane:EtOAc, 4:1) and filtration on K2CO3, the
product 34a was obtained as colorless oil (13.3 mg, 0.053 mmol, 53% yield, 65% ee).
1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 6.0 Hz, 2H), 7.70 – 7.59 (m, 1H),
7.51 – 7.35 (m, 1H), 7.33 – 7.26 (m, 2H), 7.07 (d, J = 6.0 Hz, 2H), 3.33 – 3.18 (m, 2H), 3.05 (dd, J = 13.1, 6.1 Hz, 1H), 1.99 – 1.76 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) δ 168.3, 150.7, 150.0, 148.2, 141.2, 124.8, 124.4,
124.3 (2C), 119.9, 110.5, 102.5, 42.7, 38.7, 26.6, 11.8.
HRMS (ESI+): m/z calcd. for C16H17N2O ([M+H+]) 253.1335, found 253.1338.
CSP-HPLC: (254nm, Chiralcel AD-H, n-heptane/i-PrOH = 98:2, 40 °C, 0.5 mL/min.), tR = 58.97 min (major), tR = 64.05 min (minor).
2-(2-(pyridin-2-yl)butyl)benzoxazole (35b)
The reaction was performed with 0.1 mmol 27, EtMgBr (0.2 mmol, 3.0 M in Et2O) diluted in CH2Cl2 (0.6 mL total volume),
CuBr·SMe2 (1.0 mg, 0.005 mmol, 5 mol%), (S,Rp)-L14 (4.1 mg, 0.006 mmol, 6 mol%), TMSBr (0.02 mL, 0.15 mmol, 1.5 equiv.) in 1 mL CH2Cl2. After purification by flash column
chromatography (neutral Al2O3, pentane:EtOAc, 25:1 -> 9:1) and filtration on K2CO3,
the product 35b was obtained as colorless oil (13.3 mg, 0.060 mmol, 60% yield, racemic). 1H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 4.2 Hz, 1H), 7.66 – 7.59 (m, 1H), 7.55 (td, J = 7.7, 1.8 Hz, 1H), 7.49 – 7.35 (m, 1H), 7.38 – 7.22 (m, 2H), 7.15 (d, J = 7.8 Hz, 1H), 7.10 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 3.48 – 3.22 (m, 3H), 1.98 – 1.72 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 166.3, 162.7, 150.7, 149.7, 141.5, 136.3, 124.5, 124.1, 123.4, 121.7, 119.7, 110.4, 47.3, 34.1, 28.3, 11.9.
HRMS (ESI+): m/z calcd. for C16H17N2O ([M+H+]) 253.1335, found 253.1336.
CSP-HPLC: (254nm, Chiralcel OB-H, n-heptane:i-PrOH = 99:1, 40 °C, 0.5 ml/min.), tR = 21.44 min, tR = 28.70 min.
3.5.9. Procedure for the NMR studies about interaction between catalyst, 19 and TMSOTf
a) Preparation of Sample A: under inert atmosphere, 7.4 mg of complex Cu·L3 (0.010 mmol) were dissolved in 0.6 mL of CD2Cl2. The complex was transferred
in a dry NMR tube (Sample A) and 1H, 13C and 31P NMR spectra were recorded
(1H at 400.0 MHz; 13C at 100.6 MHz, 31P at 161.9 MHz).
b) Preparation of Sample B: to Sample A, 18.2 mg of 19 (0.1 mmol) were added and 1H, 13C and 31P NMR spectra were recorded (1H at 400.0 MHz; 13C at 100.6
