Diastereoselective Pd-Catalyzed C-H Arylation of Ferrocenylmet

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Diastereoselective Pd-Catalyzed C-H Arylation of Ferrocenylmetaneamines with Arylboronic Acids or Pinacol Esters Kristina Plevova, Brigita Mudrakova, Erik Rakovsky, and Radovan Sebesta J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00953 • Publication Date (Web): 01 May 2019 Downloaded from http://pubs.acs.org on May 2, 2019

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The Journal of Organic Chemistry

Diastereoselective Pd-Catalyzed C-H Arylation of Ferrocenylmet-aneamines with Arylboronic Acids or Pinacol Esters Kristína Plevová,a Brigita Mudráková,a Erik Rakovský,b and Radovan Šebesta*a Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovak Republic. a

Comenius University in Bratislava, Faculty of Natural Sciences, Department of Inorganic Chemistry, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovak Republic. b

Table of Contents Graphics H Fe H

Pd(OAc)2 (R)-Boc-Ala-OH Me ArB(OH)2, or ArBpin NMe2 K CO , TBAB, DMAc, air 2 3 diastereoselective C-H activation

Me

H

NMe2 Fe Ar

yields 27-83%, d.r. 5:1 up to 20:1 (11 examples)

Abstract An efficient diastereoselective synthesis of planar chiral ferrocenes via Pd(II)-catalyzed direct C-H activation with arylboronic acids or pinacol esters is presented. The reaction was performed under mild conditions using commercially available achiral or chiral amino acids as ligands. The best results were obtained with (R)-Boc-alanine, which yielded products in 27-83% yield with diastereoselectivities ranging from 5:1 to 20:1 (11 examples). Diastereoisomeric products can also be obtained using (S)-Boc-alanine as a ligand. Stereoinduction of the reaction was explained by DFT calculations of possible transition states.

Introduction Ferrocene and its derivatives have a diverse array of uses in chemistry, catalysis, material science or in medicine.1-2 Ferrocene moiety is one of the privileged scaffolds present in a number of ligands, which are efficient in transition metal catalysis.3 Owing to its 3D-structure, many ferrocene derivatives possess planar stereogenic moiety (planar chirality), which often in combination with the central stereogenic unit, is an advantageous feature in many chiral ferrocene ligands. The standard method for synthesis of this type of compounds is enantioselective or diastereoselective ortho-metalation.4 However, direct enantioselective C-H activation might be more efficient for the synthesis of this kind of compounds. Metal-catalyzed C-H activations proved useful way to obtain structurally complex compounds from simple stating materials.5-9 Even more importantly, enantioselective C-H activations 1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 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 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

provided many chiral compounds.10-15 Furthermore, it gives access to planar chiral ferrocene derivatives as well.16-17 Seminal advance in the enantioselective C-H activation was the work of Yu and coworkers, who identified Pd-monoprotected amino acid catalytic system for performing efficient enantioselective C-H functionalizations of arenes.18-20 In 2007, You et al. described the direct C-H activation of ferrocenyl oxazolines with arenes allowing the synthesis of planar chiral ferrocene derivatives.21 Later, they also developed the enantioselective arylation of ferrocenyl methylamines with arylboronic acids using simple N-Boc protected amino acids as chiral ligands.22 The methodology was then further developed to intramolecular C-H activation independently by You and Gu.23-24 Pdcatalyzed intramolecular C−H arylation of N-(2-bromoaryl)ferrocenecarboxamides was efficiently catalyzed also with TADDOL-based phosphoramidite or O-PINAP ligands.25-26 An intramolecular enantioselective C−H arylation of ferrocenyl aryl sulfides was realized, which afforded planarly chiral ferrocenyl thiophene derivatives.27 Gu, You and coworkers also accomplished Pd-catalyzed C-H alkenylation.28 Even oxidative C-H/C-H activation was showed with heteroarenes, and azoles.29-30 The removable 8‑aminoquinoline directing group was also effective in mediating oxidative C(sp2)– H/C(sp3)−H cross-coupling of ferrocene with toluene derivatives.31 Transient ketimine formation was effective in promoting C-H activation of ferrocenyl ketones.32 Other coupling partners, such as diaryl ketones,33 were also compatible with this approach. Annulations with alkynes also worked well.34-36 Effective C-H activations need chelation assistance and most of them so far proceeded via nitrogenbased functionalities. Recently, You and coworkers showed that ferrocenyl thioketones could be arylated using arylboronic acids.37 Apart from palladium, ferrocene C-H functionalizations were studied with a range of other metals, such as Ir, Pt, Co, Au, Rh, and recently Cu.38-49 Many chiral ferrocene ligands, including those employed in industry, such as Josiphos, Xyliphos, Walphos, or Taniaphos, possess a combination of planar and central chirality.50 For this reason, we decided to study chiral ligand enhanced diastereoselective Pd-catalyzed C-H arylation of chiral ferrocenyl amines. Here we would like to present a synthesis of planar chiral ferrocenes via diastereoselective direct C-H activation catalyzed by Pd(II)-amino acid complexes (Scheme 1).

Results and Discussion

2 ACS Paragon Plus Environment

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Previous work Diastereoselective ortho-metalation ODG* Fe H You et al. NMe2 Fe H

ODG*

1. Strong base 2. E+

Fe E

Pd/chiral amino acid ArB(OH)2

NMe2 Fe Ar

This work Chiral-ligand-enhanced diastereoselective C-H activation R R Pd/chiral or achiral * * amino acid NR2 NR2 ArB(OH) or ArBpin 2 Ar Fe H Fe

Scheme 1.

Inspired by You´s experimental conditions,22 we have started to investigate the arylation reaction on (R)-Ugi amine (1) and phenylboronic acid (Scheme 2). Direct C-H activation was carried out in the presence of 10 mol% Pd(OAc)2, 20 mol% of Boc-protected glycine as ligand, K2CO3 (1 equiv.) and tetrabutylammonium bromide (TBAB, 0.25 equiv.) in N,N-dimethylacetamide (DMAc, 0.05M) at 60°C in the presence of air oxygen (open flask). The reaction afforded a mixture of diastereomeric monoarylated products (R,Rp)- and (R,Sp)-3a and a diarylated compound (R)-4a. Ph Pd(OAc)2 (10 mol%) NMe2 Ligand (20 mol%) Fe

PhB(OH)2 (2 equiv.) K2CO3, DMAc 1 (0.25 mmol) TBAB (0.25 equiv.) air, temp., 24 h

NMe2 Fe Ph + (R,Rp)-3a

Ph NMe2

Fe (R,Sp)-3a

+

NMe2 Fe Ph (R)-4a

Scheme 2.

At first, we have optimized the reaction conditions for maximum diastereoselectivity and monoarylation/diarylation ratio. The reaction without a chiral ligand afforded a mixture of monosubstituted products with dr (R,Rp)-3a/(R, Sp)-3a 6:1 (Table 1, entry 1). Formation of disubstituted product (R)-4a was also observed. Achiral amino acid ligand Boc-Gly-OH afforded the corresponding products 3a with higher d.r. 10:1 (Table 1, entry 2). If racemic ligand (rac)-Boc-Val-OH was used in the reaction, diastereoselectivity decreased to 2:1 (Table 1, entry 3). With the aim to increase the diastereoselectivity via chiral-ligand-enhanced diastereoselective arylation, several chiral amino acids were assessed. When (S)-Boc-Val-OH was used as a ligand in this transformation, the diastereomeric ratio decreased to 1:1. The same result was also obtained, if the reaction temperature was lowered from 60 °C to r.t. (Table 1, entries 4,5). These results indicated chirality mismatch between the ligand 3 ACS Paragon Plus Environment


and the substrate, (R)-Ugi amine ((R)-1). If ligand with opposite configuration was used ((R)-Boc-ValOH), diastereomeric purity of the target product 3a increased to 14:1 (Table 1, entry 9). Eventually, less sterically hindered ligand (R)-Boc-Ala-OH afforded the products 3a with an excellent diastereomeric ratio (R,Rp)-3a/(R,Sp)-3a 20:1 (Table 1, entry 11). Interesting result was obtained, if reaction was carried out under 40°C (Table 1, entry 6). The reaction showed reversed diastereoselectivity and isomer (R,Sp)-3a was the major one. Using of more sterically hindered (S)-Boc-Phe-OH did not alter diastereoselectivity of the arylation (Table 1, entries 7,8). Another noteworthy feature is a positive influence of trace amounts of water on this transformation. The reaction under anhydrous conditions afforded product 3a with d.r. 1:1 (Table 1, entry 10).

Table 1. Screening of protected amino acids in view of diastereoselectivity.a d.r.b (3a)

Ratiob of

Rp:Sp

3a:4a

n.d.

6:1

17:1

60

47

10:1

22:1

(rac)-Boc-Val-OH

60

n.d.

2:1

30:1

4

(S)-Boc-Val-OH

60

43

1:1

20:1

5

(S)-Boc-Val-OH

r.t.

n.d.

1:1

18:1

6

(S)-Boc-Val-OH

40

n.d.

1:2

38:1

7

(S)-Boc-Phe-OH

40

n.d.

1:2

14:1

8

(S)-Boc-Phe-OH

60

n.d.

1:1.6

>99:1

9

(R)-Boc-Val-OH

60

69

14:1

27:1

10c

(R)-Boc-Val-OH

60

n.d.

1:1

>99:1

11

(R)-Boc-Ala-OH

60

83

20:1

>99:1

Entry

Ligand

Temp. (°C)

Yield (%)

1

-

60

2

Boc-Gly-OH

3

Reaction conditions: 1 (0.25 mmol), 2a (0.5 mmol), Pd(OAc)2 (10 mol%), ligand (20 mol%), K2CO3 (1 equiv.), TBAB (0.25 equiv.) stirring in DMAc at 60°C in open flask for 24 h; b Determined by 1H NMR analysis of crude; c Reaction was performed under anhydrous conditions.

a

Having the best conditions for diastereoselectivity in hand, we focused our attention to a screening of possible influence of additives on yield and diastereoselectivity of the reaction (Table 2). For the optimization, standard conditions presented in Table 1 were used and different amounts of additives tetrabutylammonium bromide (TBAB) or pivalic acid (PivOH)25-26,51 was evaluated. The best result in view of yield and diastereoselectivity was obtained with 0.4 equiv. of TBAB (Table 2, entry 2).

Table 2. Screening of additive influence on yield.


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NMe2 Fe

Pd(OAc)2 (10 mol%) (R)-Boc-Ala-OH (20 mol%)

NMe2 Fe

ArB(OH)2 (2d) (2 equiv.) K2CO3 (1 equiv.) additive (X equiv.) DMAc (0.05M), air, 60°C, 48h

(R)-1

Cl (R,Rp)-3d

d.r.a (3d)

Yield [%]

Rp:Sp

(R,Rp)-3d/(R,Sp)-3d

TBAB (25)

10:1

36/-

2

TBAB (40)

12.5:1

61/-

3b

TBAB (100)

10:1

54/7c

4

TBAB (100)

12.5:1

34/12c

5b

PivOH (100)

-

Entry

Additive (mol%)

1

a Determined

by

1H

-/-

NMR analysis of crude. Reaction was stirred for 24 h. c Product isolated as a complex with b

boronic acid.

Next, we investigated scope and limitations of the reaction. Using optimized reaction conditions, we have screened several aryl and heteroaryl boronic acids. The obtained results are summarized in Scheme 3. Both electron-donating, as well as electron-withdrawing groups on the phenyl ring of arylboronic acids 2b-2i (Scheme 3), were well tolerated in the reaction and corresponding products 3b-3i were isolated in good yields (27-61%) and high diastereomeric ratios. Reaction also tolerated sterically demanding arylboronic acids (2-naphthyl and 2-anthracenyl) and the corresponding products 3j-k were isolated in good yields (44% and 72%) and in high diastereomeric purities (Scheme 3). The reaction did not work with sterically hindered 2-methoxyphenyl boronic acid. The C-H activation reaction did not proceed with heteroaryl boronic acids 2-furane, and 3-pyridine; with 2-thiophene boronic acid only trace amounts of the corresponding C-H activation product was detected. We have found out that this reaction works well also with corresponding pinacol esters of boronic acid. Compound 3b was obtained in 36% using the corresponding pinacol boronote. As there is good availability of pinacol boronate esters, products 3g-k were obtained from corresponding pinacol esters. Traces or no C-H activation products were obtained also with pinacol esters of vinylboronic, (phenylethynyl)boronic, 4-nitrophenylboronic, and 4-dimethylaminophenylboronic acids. Pinacol esters of alkylboronic acids (methyl, and hexyl) were also unreactive. In these cases, only the formation of boronic acid homocoupling products were observed. We have briefly assessed also ferrocenyl amines with bulkier amines instead of dimethylamine. In these cases, however, mainly homocoupling of boronic acid and decomposition of starting material was observed, even under higher temperatures. The reaction of (R)-1 with phenylboronic acid 2a was also performed in a gram-scale (3.9 mmol) and afforded (R,Rp)-3a in 63% yield and product (R,Sp)-3a in 4% yield (diastereoselectivity of reaction was 16.6:1).



Pd(OAc)2 (10 mol%) Boc-(R)-Ala-OH (20 mol%)

NMe2 Fe

ArB(OH)2 or ArBpin (2 equiv.) K2CO3 (1 equiv.) TBAB (0.4 equiv.) DMAc (0.05M), air, 60°C, time

(R)-1

OMe 3b, 58% (with ArB(OH)2) d.r. 12.5:1 (36% with ArBpin)

3a, 83% d.r.20:1

NMe2 CN 3f, 27% d.r. 14.3:1

3d, 61% d.r. 15.5:1

3c, 46% d.r. 5.2:1

NMe2 Fe

tBu

3g, 49% (with ArBpin) 3h, 56% (with ArBpin) d.r. 7.1:1 only one diastereomer (6% 2,5-disubstituted) NMe2 Fe

3e, 54% d.r. 16.6:1

NMe2

Ph

F

Cl

Me

Fe

Fe

NMe2 Fe

Fe

NMe2

Fe

(R,Rp)-3a-j

NMe2

Fe

Fe

Fe

NMe2 + (R,Sp)-3a-k

Fe Ar

NMe2

NMe2

NMe2

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OMe 3i, 49% (with ArBpin) d.r. 16.6:1 (17% 2,5-disubstituted)

NMe2 Fe

3j, 72% (with ArBpin) d.r. 20:1

3k, 44% (with ArBpin) d.r. 10:1

Scheme 3

Relative configurations of arylation products were determined by NOESY NMR (see SI). Suitable X-ray crystals were obtained by layering technique of dichloromethane and hexane. Crystallographic analysis showed that absolute configuration of arylation product is (R,Rp). The absolute configuration of arylation products was also determined by comparison of experimental and DFT calculated CD spectra (TPSS/def2-TZVP and B3LYP/def2-SV(P)). Calculated CD spectra for (R,Rp)-3c agree with experimental CD (for details see SI). CD spectra of several other obtained derivatives 3a, 3e, and 3f have the same character, supporting configuration assignment in the whole compound 3 series (Figure 1b).


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a)

b)

Figure 1. a) X-ray structure of (R,Rp)-3a, complex with phenol; b) CD spectra for compounds (R,Rp)-3a, 3c, 3e, 3f.

Relative and absolute (R,Rp)-configuration is also supported by DFT calculations of the possible diastereomeric transition states. Calculations using long-range corrected hybrid density ωB97X-D functional52 and LACVP basis set showed that transition state Pro-R-TS leading to major (R,Rp)-3a diastereoisomer is indeed energetically more favored to Pro-S-TS by 26.6 kJ/mol (Figure 2). The reason for this difference is likely a non-bonding interaction between α-methyl group and the ferrocene moiety in Pro-S-TS. Tentative mechanism comprises initial coordination of amine 1 to Pd2+ forming Pdcomplex I. This step is then likely followed by diastereoselective C-H activation, which affords palladacyclic complex II. This complex then undergoes transmetallation with arylboronic acid or pinacol ester to provide complex III, which then affords the product 3 by reductive elimination (Figure 2).



N

N

Ar Fe

Fe

(R,Rp)-3

1

PdL2

L2BO

OAc

Pd

N

O

Boc N

N

Pd BocN

O O

BocHN O

Fe

Ar

Fe

Page 8 of 16

I

O O O

N Pd H

Fe

Pro-S-TS Grel = 26.6 kJ.mol-1

III

O

ArB(OR)2

N Pd Fe

N

O O

Pd

O

NHBoc

H O

BocN II

O

Fe

Pro-R-TS Grel = 0 kJ.mol-1

Figure 2. Tentative mechanism of the C-H arylation of ferrocenyl amine 1 (left); DFT calculated (ωB97X-D/LACVP) diastereomeric transitions states for ortho-palladation (right).

Conclusion In conclusion, we have developed chiral-ligand-enhanced diastereoselective C-H arylation of chiral ferrocenyl amines. Using Pd(II)/(R)-Boc-alanine as a catalyst, (R,Rp)-arylated amines were obtained in high diastereomeric purities. Using a range of arylboronic acid or pinacol esters arylated products were obtained in yields up to 83%. On the other hand, with (S)-Boc-valine, (R,Sp)-diastereomers were major products. DFT calculations of the diastereomeric transition states revealed reason for stereoinduction.

Experimental Section General Information 1H

and 13C NMR spectra were recorded at 600 or 300 MHz for 1H nuclei, 150 or 75 MHz for 13C nuclei. Chemical shifts are reported in in δ units, parts per million (ppm) using; signals are referenced to TMS as an internal standard. Coupling constants (J) are given in Hz and multiplicity is abbreviated as: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), m (multiplet). HRMS were measured using electronspray ionization (ESI). Specific optical rotations ([α]D20) values are reported in degrees; concentration (c) is in g/100 mL, if not stated otherwise. Reactions were monitored by thin8 ACS Paragon Plus Environment

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layer chromatography (TLC) carried out on silica or alumina plates, visualized by irradiation with UV light. Commercially available reagents were used without further purification.

General procedure for diastereoselective synthesis of planar chiral ferrocenes 3a-k To a solution of boronic acid 2a-k (0.5 mmol) in DMAc (5 mL) was at room temperature added stepwise 20 mol% Boc-(R)-ALA-OH (9.5 mg, 0.05 mmol), 10 mol% Pd(OAc)2 (5.6 mg, 0.025 mmol), K2CO3 (30 mg, 0.25 mmol), TBAB (20 mg, 0.06 mmol or 32 mg, 0.10 mmol) and amine (R)-1 (64 mg, 0.052 ml, 0.25 mmol). Then the reaction mixture was stirred at 60°C for time specified for each compound. Once reaction was completed, it was quenched with saturated NaHCO3 solution (20 mL) and extracted with Et2O (3×15 mL). Collected organic layers were washed with distillated water (3×20 mL), brine (20 mL) and then filtrated through pad of Celite. Obtained organic phase was then dried over anhydrous Na2SO4, filtrated and evaporated under reduced pressure. The crude product was purified by chromatography on SiO2 to afford target products. Characterization data for planar chiral ferrocenes 3a-k. (R,Rp)-N,N-dimethyl-1-(2-phenylferrocenyl)ethan-1-amine ((R,Rp)-3a). Following general procedure (using 20 mg TBAB (0.06 mmol, 0.25 eq), stirring 24h), product (R,Rp)-3a was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (69 mg, 83%). RF = 0.31 (hexane/EtOAc 2:1 + 2% Et3N). Reaction leads to formation of products in d.r. 20:1. 1H NMR (600 MHz, CDCl3): δ 7.60 (dd, J = 8.1 Hz, 1.1 Hz, 2H), 7.32 (dd, J = 7.6 Hz, 7.6 Hz, 2H), 7.25 – 7.22 (m, 1H), 4.43 (dd, J = 2.4 Hz, 1.5 Hz, 1H), 4.29 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 4.25 (dd, J = 2.2 Hz, 1.5 Hz, 1H), 4.09 (s, 5H), 3.88 (q, J = 6.8 Hz, 1H), 1.90 (s, 6H), 1.58 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 139.3, 130.1 (2×CPh), 127.9 (2×CPh), 126.2, 88.4, 87.4, 70.2 (5×CCp), 68.6, 67.5, 66.8, 55.4, 40.8 (2×CH3), 17.0 ppm. IR (ATR; cm-1): 1189, 1155, 1105, 1077, 1045, 1001, 809, 764, 731, 701, 545, 488. [α]D20= -52.0 (c 0.5, CH3CN). HRMS (ESI) calcd. for [M+H+] C20H24FeN+ m/z 334.1253, found: 334.1259. (R,Sp)-N,N-dimetyl-1-(2-phenylferrocenyl)ethan-1-amine ((R,Sp)-3a). Following general procedure (using 20 mg TBAB (0.06 mmol, 0.25 eq), stirring 24h), product (R,Sp)-3a was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (5 mg, 6%). RF = 0.34 (hexane/EtOAc 2:1 + 2% Et3N). 1H NMR (600 MHz, CDCl3): δ 7.68 (dd, J = 8.0 Hz, 1.0 Hz, 2H), 7.31 (dd, J = 7.5 Hz, 7.5 Hz, 2H), 7.25 – 7.23 (m, 1H), 4.33 (dd, J = 2.2 Hz, 1.7 Hz, 1H), 4.24 – 4.23 (m, 1H), 4.21 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 4.14 (s, 5H), 3.40 (q, J = 6.8 Hz, 1H), 2.37 (s, 6H), 1.11 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 139.4, 130.4 (2×CPh), 127.7 (2×CPh), 126.2, 91.9, 87.8, 70.3 (5×CCp), 69.8, 69.2, 66.2, 59.0, 43.3 (2×CH3), 17.4 ppm. IR (ATR; cm-1): 1155, 1106, 1082, 1034, 1001, 814, 763, 700, 572, 529, 483. [α]D20= -3.44 (c 0,5, CH3CN). HRMS (ESI) calcd. for [M+H+] C20H24FeN+ m/z 334.1253, found: 334.1253.



(R)-N,N-dimetyl-1-(2,5-phenylferrocenyl)ethan-1-amine ((R)-4a). Following general procedure (using 20 mg TBAB (0.06 mmol, 0.25 eq), stirring 24h), product (R)-4a was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (4 mg, 4%). RF = 0.63 (hexane/EtOAc 2:1 + 2% Et3N). 1H NMR (600 MHz, CDCl3): δ 8.01 – 7.98 (m, 2H), 7.54 – 7.51 (m, 2H), 7.35 (dd, J = 7.5 Hz, 7.5 Hz, 2H), 7.31 – 7.27 (m, 3H), 7.24 – 7.22 (m, 1H), 4.47 (d, J = 2.4 Hz, 1H), 4.44 (d, J = 2.4 Hz, 1H), 4.18 (s, 5H), 3.43 (q, J = 6.8 Hz, 1H), 1.87 (s, 6H), 1.59 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 139.6, 139.2, 131.4 (2×CPh), 131.3 (2×CPh), 127.7 (2×CPh), 127.3 (2×CPh), 126.5, 126.2, 91.0, 88.7, 72.4, 71.5 (5×CCp), 66.9, 57.4, 44.0 (2×CH3), 20.8 ppm. IR (ATR; cm-1): 1155, 1069, 1029, 816, 763, 730, 698, 574, 529, 482. [α]D20= -115 (c 1, CH3CN). HRMS (ESI) calcd. for [M+H+] C26H28FeN+ m/z 410.1566, found: 410.1571. (R,Rp)-N,N-dimethyl-1-[2-(4-methoxyphenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3b). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 48h), product (R,Rp)-3b was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (53 mg, 58%). RF = 0.26 (hexane/EtOAc 2:1 + 2% Et3N). Reaction leads to formation of products in d.r. 12.5:1. 1H NMR (600 MHz, CDCl3): δ 7.53 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.39 (dd, J = 2.2 Hz, 1.4 Hz, 1H), 4.26 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 4.21 – 4.19 (m, 1H), 4.08 (s, 5H), 3.85 (q, J = 6.8 Hz, 1H), 3.83 (s, 3H), 1.90 (s, 6H), 1.57 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 158.1, 131.3, 131.1 (2×CPh), 113.3 (2×CPh), 88.4, 87.0, 70.1 (5×CCp), 68.6, 67.2, 65.5, 55.5, 55.4, 40.8 (2×CH3), 16.8 ppm. IR (ATR; cm-1): 1519, 1241, 1105, 1078, 1035, 1001, 808, 728, 546, 495. [α]D20= -155 (c 0.25, CH3CN). HRMS (ESI) calcd. for [M+H+] C21H26FeNO+ m/z 364.1358, found: 364.1366. (R,Rp)-N,N-dimethyl-1-[2-(4-methylphenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3c). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 72h), product (R,Rp)-3c was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (56 mg, 46%). RF = 0.32 (hexane/EtOAc 2:1 + 2% Et3N). Reaction leads to formation of products in d.r. 5.2:1. 1H NMR (600 MHz, CDCl3): δ 7.49 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 4.41 (dd, J = 2.3 Hz, 1.5 Hz, 1H), 4.27 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 4.23 – 4.21 (m, 1H), 4.08 (s, 5H), 3.86 (q, J = 6.8 Hz, 1H), 2.36 (s, 3H), 1.89 (s, 6H), 1.58 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 136.2, 135.8, 130.0 (2×CPh), 128.6 (2×CPh), 88.5, 87.7, 70.2 (5×CCp), 68.5, 67.3, 66.6, 55.4, 40.9 (2×CH3), 21.3, 17.0 ppm. IR (ATR; cm-1): 2919, 2852, 2827, 2773, 1521, 1450, 1365, 1256, 1187, 1106, 1078, 1046, 1001, 927, 816, 731, 578, 543, 493. [α]D20= -59.5 (c 1, CH3CN). HRMS (ESI) calcd. for [M+H+] C21H26FeN+ m/z 348.1409, found: 348.1413. (R,Rp)-N,N-dimethyl-1-[2-(4-chlorophenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3d). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 48h), product (R,Rp)-3d was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (56 mg, 61%). RF = 0.22 (hexane/EtOAc 2:1 + 2% Et3N). Reaction leads to 10 ACS Paragon Plus Environment

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formation of products in d.r. 15.5:1. 1H NMR (600 MHz, CDCl3): δ 7.61 – 7.59 (m, 2H), 7.29 – 7.26 (m, 2H), 4.41 (dd, J = 2.4 Hz, 1.5 Hz, 1H), 4.29 (dd, J = 2.5 Hz, 2.5 Hz, 1H), 4.26 (dd, J = 2.4 Hz, 1.5 Hz, 1H), 4.07 (s, 5H), 3.82 (q, J = 6.8 Hz, 1H), 1.94 (s, 6H), 1.54 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl ): δ 138.1, 131.8, 131.2 (2×CPh), 128.0 (2×CPh), 87.7, 86.8, 70.3 3 (5×CCp), 68.9, 67.8, 67.0, 55.6, 40.6 (2×CH3), 15.5 ppm. IR (ATR; cm-1): 2931, 2817, 2773, 1500, 1449, 1365, 1257, 1187, 1091, 1001, 926, 817, 731, 547, 521, 476, 451. [α]D20= -108 (c 1, CH3CN). HRMS (ESI) calcd. for [M+H+] C20H23ClFeN+ m/z 368.0863, found: 368.0867. (R,Rp)-N,N-dimethyl-1-[2-(4-fluorophenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3e). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 24h), product (R,Rp)-3e was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (47 mg, 54%). RF = 0.20 (hexane/EtOAc 2:1 + 2% Et3N). Reaction leads to formation of products in d.r. 16.6:1. 1H NMR (600 MHz, CDCl3): δ 7.61 (dd, JHF = 8.3 Hz, JHH = 5.9 Hz, 2H), 7.00 (dd, JHH, HF = 8,7 Hz, 2H), 4.40 (br d, J = 0.8 Hz, 1H), 4.28 (br s, 1H), 4.24 (br s, 1H), 4.07 (s, 5H), 3.81 (q, J = 6.8 Hz, 1H), 1.93 (s, 6H), 1.55 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 161.5 (q, JCF = 245.2 Hz), 135.1 (d, JCF = 3.2 Hz), 131.3 (d, JCF = 7.6 Hz, 2×CPh), 114.6 (d, JCF = 21.1 Hz, 2×CPh), 87.6, 87.4, 70.2 (5×CCp), 68.9, 67.5, 66.7, 55.2, 40.7 (2×CH3), 15.9 ppm. 19F NMR (564 MHz, CDCl3): δ -116.79 (s) ppm. IR (ATR; cm-1): 2933, 2818, 2774, 1516, 1450, 1365, 1258, 1219, 1188, 1158, 1106, 1078, 1048, 1001, 927, 837, 811, 779, 576, 543, 493, 460. [α]D20= -66.1 (c 1, CH3CN). HRMS (ESI) calcd. for [M+H+] C20H23FFeN+ m/z 352.1158, found: 352.1166. (R,Rp)-4-(2-(1-(dimethylamino)ethyl)ferrocen-1-yl)benzene carbonitrile ((R,Rp)-3f). Following general procedure (using 20 mg TBAB (0.06 mmol, 0.25 eq), stirring 6 days), product (R,Rp)-3f was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange oil (24 mg, 27%). RF = 0.20 (hexane/EtOAc 2:1 + 2% Et3N). Reaction leads to formation of products in d.r. 14.3:1. 1H NMR (600 MHz, CDCl3): δ 7.83 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 4.50 (dd, J = 2.5 Hz, 1.5 Hz, 1H), 4.36 (dd, J = 2.5 Hz, 2.5 Hz, 1H), 4.34 – 4.33 (m, 1H), 4.06 (s, 5H), 3.83 (q, J = 6.7 Hz, 1H), 2.00 (s, 6H), 1.51 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 145.9, 131.7 (2×CPh), 130.1 (2×CPh), 119.5, 109.3, 88.5, 85.2, 70.6 (5×CCp), 69.7, 68.8, 67.7, 55.8 (2×CH3), 40.2, 13.6 ppm. IR (ATR; cm-1): 2929, 2818, 2775, 2222, 1604, 1513, 1450, 1365, 1257, 1186, 1106, 1078, 1049, 1000, 927, 820, 782, 585, 556, 487, 446. [α]D20= -254 (c 0.5, CH3CN). HRMS (ESI) calcd. for [M+H+] C21H23FeN2+ m/z 359.1205, found: 359.1211. (R,Rp)-N,N-dimethyl-1-[2-(4-biphenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3g). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 48h), product (R,Rp)-3g was isolated after silica gel chromatography (eluent hexane/EtOAc 3:1 + 2% Et3N) as an orange oil (50 mg, 49%). RF = 0.34 (hexane/EtOAc 3:1 + 2% Et3N). Reaction leads to formation of products in d.r. 7.1:1. 1H NMR (600 MHz, CDCl3): δ 7.71 – 7.70 (m, 2H), 7.66 – 7.64 (m, 2H), 7.57 – 7.56 (m, 2H), 7.46 (dd, J = 7.7 Hz, J = 7.7 Hz, 2H), 7.35 (dd, J = 7.4 Hz, J = 7.4 Hz, 1H), 4.48 (dd, J = 2.3 Hz, 1.5 Hz, 1H), 4.32 (dd, J = 2.5 Hz, 2.5 Hz, 1H), 4.29 – 4.26 (m, 1H), 4.11 (s, 5H), 3.93 (q, J = 6.8 Hz, 1H), 1.95 (s, 6H), 1.59 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 11 ACS Paragon Plus Environment


MHz, CDCl3): δ 141.0, 138.8, 138.6, 130.4 (2×CPh), 128.9 (2×CPh), 127.2, 127.0 (2×CPh), 126.5 (2×CPh), 87.7, 70.3 (5×CCp), 68.8, 67.7, 66.9, 55.5, 40.8 (2×CH3), 29.8, 16.3 ppm. IR (ATR; cm-1): 1489, 1448, 1257, 1105, 1077, 1040, 1000, 926, 807, 764, 729, 695, 584, 534, 499, 447. [α]D20= - 167 (c 0.5, CH3CN). HRMS (ESI) calcd. for [M+] C26H27FeN+ m/z 409.1493, found: 409.1477. (R,Rp)-N,N-dimethyl-1-[2-(4-(tert-butyl)phenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3h). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 48h), product (R,Rp)-3h was isolated after silica gel chromatography (eluent hexane/EtOAc 3:1 + 2% Et3N) as an orange oil (56 mg, 56%). RF = 0.20 (hexane/EtOAc 3:1 + 2% Et3N). Reaction leads to diastereoselective formation of major product (R,Rp)-3h. 1H NMR (600 MHz, CDCl3): δ 7.54 – 7.50 (m, 2H), 7.34 – 7.30 (m, 2H), 4.41 (dd, J = 2.3 Hz, 1.5 Hz, 1H), 4.27 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 4.22 – 4.20 (m, 1H), 4.09 (s, 5H), 3.87 (q, J = 6.8 Hz, 1H), 1.89 (s, 6H), 1.57 (d, J = 6.9 Hz, 3H), 1.35 (s, 9H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 149.1, 136.0, 129.7 (2×CPh), 124.8 (2×CPh), 88.4, 87.3, 70.1 (5×CCp), 68.6, 67.3, 66.6, 55.3, 40.8 (2×CH3), 34.6, 31.5 (3×CH3), 16.8 ppm. IR (ATR; cm-1): 3598, 2996, 2952, 2856, 2816, 2772, 1610, 1521, 1450, 1401, 1362, 1259, 1188, 1106, 1075, 1000, 964, 927, 814, 720, 663, 618, 589, 557, 530, 491, 456. [α]D20= -82.9 (c 0.5 CH3CN). HRMS (ESI) calcd. for [M+] C24H31FeN+ m/z 389.1800, found: 389.1786. (R,Rp)-N,N-dimethyl-1-[2-(3-methoxyphenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3i). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 48h), product (R,Rp)-3i was isolated after silica gel chromatography (eluent hexane/EtOAc 3:1 + 2% Et3N) as an orange oil (44 mg, 49%). RF = 0.30 (hexane/EtOAc 3:1 + 2% Et3N). Reaction leads to formation of products in d.r. 16.6:1. 1H NMR (600 MHz, CDCl3): δ 7.31 – 7.26 (m, 3H), 6.83 – 6.81 (m, 1H), 4.47 – 4.47 (m, 1H), 4.31 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 4.27 – 4.27 (m, 1H), 4.12 (s, 5H), 3.94 (q, J = 6.8 Hz, 1H), 3.87 (s, 3H), 1.97 (s, 6H), 1.59 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 159.2, 140.9, 128.8, 122.8, 115.9, 111.4, 88.1, 87.6, 70.2 (5×CCp), 68.9, 67.6, 66.7, 55.5, 55.3, 40.8 (2×CH3), 16.1 ppm. IR (ATR; cm-1): 2932, 1598, 1576, 1497, 1459, 1364, 1286, 1258, 1238, 1205, 1178, 1156, 1105, 1076, 1044, 935, 819, 786, 702, 528, 494. [α]D20= -82.8 (c 0.5, CH3CN). HRMS (ESI) calcd. for [M+] C21H25FeNO+ m/z 363.1286, found: 363.1289. (R,Rp)-N,N-dimethyl-1-[2-(naphthyl)ferrocenyl]ethan-1-amine ((R,Rp)-3j). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 24h), product (R,Rp)-3j was isolated after silica gel chromatography (eluent hexane/EtOAc 10:1 + 2% Et3N) as an orange solid (69 mg, 72%) with m.p.: 76.2 – 78.2°C. RF = 0.33 (hexane/EtOAc 3:1 + 2% Et3N). Reaction leads to formation of products in d.r. 20:1. 1H NMR (600 MHz, CDCl3): δ 8.15 – 8.15 (m, 1H), 7.84 – 7.80 (m, 4H), 7.48 – 7.44 (m, 2H), 4.56 (dd, J = 2.4 Hz, 1.5 Hz, 1H), 4.34 (dd, J = 2.5 Hz, 2.5 Hz, 1H), ), 4.31 (dd, J = 2.3 Hz, 1.5 Hz, 1H), 4.10 (s, 5H), 3.98 (q, J = 6.8 Hz, 1H), 1.99 (s, 6H), 1.59 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 137.0, 133.4, 132.1, 128.8, 127.9, 127.9, 127.7, 127.1, 126.1, 125.5, 88.0, 87.8, 70.2 (5×CCp), 69.1, 67.9, 67.0, 55.7, 40.7 (2×CH3), 15.5 ppm. IR (ATR; cm-1): 2969, 2932, 2815, 2468, 1626, 1598, 1507, 1445, 1365, 1261, 1197, 1104, 1045, 999, 861, 818, 749, 546. [α]D20= -24.4 (c 0.5, CH3CN). HRMS (ESI) calcd. for [M+] C24H25FeN+ m/z 383.1331, found: 383.1338. 12 ACS Paragon Plus Environment

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(R,Rp)-N,N-dimethyl-1-[2-(anthracenyl)ferrocenyl]ethan-1-amine ((R,Rp)-3k). Following general procedure (using 32 mg TBAB (0.10 mmol, 0.40 eq), stirring 48h), product (R,Rp)-3k was isolated after silica gel chromatography (eluent hexane/EtOAc 3:1 + 2% Et3N) as an orange solid (47 mg, 44%) with m.p.: 52.9 – 54.4°C. RF = 0.22 (hexane/EtOAc 3:1 + 2% Et3N). Reaction leads to formation of products in d.r. 10:1. 1H NMR (600 MHz, CDCl3): δ 8.40 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.00 (dd, J = 6.4 Hz, J = 3.3 Hz, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 7.48 – 7.42 (m, 2H), 4.61 (dd, J = 2.3 Hz, 1.5 Hz, 1H), 4.37 (dd, J = 2.5 Hz, 2.5 Hz, 1H), 4.35 – 4.33 (m, 1H), 4.13 (s, 5H), 4.05 (q, J = 6.7 Hz, 1H), 2.05 (s, 6H), 1.60 (d, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 136.4, 132.1, 131.9, 131.6, 130.6, 128.7, 128.3, 128.1, 127.4, 127.3, 126.0, 125.9, 125.4, 125.2, 88.0, 87.6, 70.2 (5×CCp), 69.1, 68.1, 67.2, 55.9, 40.6 (2×CH3), 15.0 ppm. IR (ATR; cm-1): 3090, 3048, 2967, 2930, 2854, 2814, 2773, 2204, 2106, 1920, 1627, 1449, 1365, 1259, 1187, 1155, 1105, 1076, 1047, 1001, 941, 872, 807, 738, 643, 623, 538, 492, 468. [α]D20= 63.6 (c 0.5, CH3CN). HRMS (ESI) calcd. for [M+] C28H27FeN+ m/z 433.1487, found: 433.1490. (R,Rp)-N,N-dimethyl-1-(2-phenylferrocenyl)ethan-1-amonium phenylboronate (2a.PhB(OH)2). Following general procedure (using 0.5 mmol of (R)-Ugi amine, stirring 48h), complex C1 was isolated after silica gel chromatography (eluent hexane/EtOAc 6:1 + 2% Et3N) as an orange solid (130 mg, 57%) with m.p.: 88.1-90.3°C. RF = 0.26 (hexane/EtOAc 2:1 + 2% Et3N). 1H NMR (600 MHz, CDCl3): δ 7.56 (dd, J = 7.2 Hz, 1.3 Hz, 2H), 7.32 (dd, J = 7.6 Hz, 7.6 Hz, 2H), 7.26 – 7.24 (m, 1H), 7.21 (dd, J = 7.8 Hz, 7.8 Hz, 2H), 6.87 (dd, J = 7.4 Hz, 7.4 Hz, 1H), 6.75 (d, J = 7.7 Hz, 2H), 4.43 (dd, J = 2.3 Hz, 1.5 Hz, 1H), 4.32 (dd, J = 2.5 Hz, 2.5 Hz, 1H), 4.27 – 4.25 (m, 1H), 4.10 (s, 5H), 3.95 (q, J = 6.8 Hz, 1H), 1.86 (s, 6H), 1.65 (d, J = 6.9 Hz, 3H) ppm. 13C{1H} NMR (150 MHz, CDCl3): δ 156.7, 139.1, 130.2 (2×CPh), 129.6 (2×CPh), 128.0 (2×CPh), 126.4 (2×CPh), 119.9, 115.7, 88.8, 86.5, 70.2 (5×CCp), 68.3, 67.9, 67.0, 55.3, 40.8 (2×CH3), 17.9 ppm.

Author Information Corresponding author E-mail: [email protected]

Acknowledgments This work was supported by the Slovak Grant Agency VEGA, grant nos. VEGA 1/0595/17 and VEGA 1/0507/17. We thank Dr. Ján Moncoľ from the Slovak University of Technology, Faculty of Chemical and Food Technology, for the X-ray measurement on a Cu microsource equipped diffractometer.



Accession Codes The deposition number CCDC 1895092 ((R,Rp)-3a-PhOH) contains the supplementary crystallographic data for this paper (including structure factors). These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif or Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Supporting Information: additional optimization results, CD spectra, X-ray analysis data, picture of 1H and 13C NMR spectra, NOESY spectra, computational details.

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Diastereoselective Pd-Catalyzed C-H Arylation of Ferrocenylmet

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