DE102009055183B3 - Preparing aryl-substituted nitroalkane derivatives comprises arylation of nitroalkene derivative with boroaryl compound in presence of palladium salt or palladium complex in water or in mixture of water and water miscible organic solvent - Google Patents

Abstract

Preparing aryl-substituted nitroalkane derivatives (II) comprises arylation of nitroalkene derivatives (I) with boroaryl compounds in the presence of 0.1-10 mol.% of palladium salts or palladium complexes in water or in a mixture of water and water miscible organic solvent. Preparing aryl-substituted nitroalkane derivatives of formula (O 2N-CH 2-CH(Ar1)-X) (II) comprises arylation of nitroalkene derivatives of formula (O 2N-CH=CH-X) (I) with boroaryl compounds in the presence of 0.1-10 mol.% of palladium salts or palladium complexes in water or in a mixture of water and water miscible organic solvent. X : CR2OR1, CR(OR2) 2, C(=O)-Y1-R3 n, CN or CR4 3; R : H, optionally branched 1-12C-alkyl, 2-12C-alkenyl, 1-12C-alkynyl, 6-12C-aryl or 7-13C-alkylaryl; R1 : H, optionally branched 1-6C-alkyl, 3-6C-alkenyl, 3-6C-cycloalkyl, 6-10C-aryl, 7-11C-alkylaryl, tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl or isobutyloxycarbonyl; either R2 : optionally branched 1-6C-alkyl, 3-6C-alkenyl, 3-6C-cycloalkyl, 6-10C-aryl, 7-11C-alkylaryl, 4-methoxybenzyl, 2-nitrobenzyl, 2,2,2-trichloroethyl, 2-bromoethyl or 2-trimethylsilylethyl; or R2+R2 : optionally saturated ring; Y1 : O (where n is 1) or N (where n is 2); either R3 : H, optionally branched 1-12C-alkyl, 6-10C-aryl or 7-11C-alkylaryl (optionally substituted by one or more halo, methoxy or nitro); or R3+R3 : optionally saturated ring that optionally additionally contains O or N atoms; R4 : H or halo, where at least one R4 is halo; Ar1 : aryl group comprising 6-14C-aryl or 3-14C-heteroaryl, having one or more heteroatom(s) comprising O, N or S, where the aryl group is optionally substituted with one or more halo, OR5, NR5R6, SR5, NO, NO 2, S(=O)-R5, SO 2R5, NSO 2N R5R6, SO 2NR5R6, COOR5, CHO, C(=O)R5, C(=O)NR5R6, Si(R5) 3, CN, OR7, NR5R8 or SR9, and the optionally branched 1-6C-alkyl, 2-6C-alkenyl, 6-10C-aryl, 3-10C-heteroaryl, 7-11C-alkylaryl, 4-11C-alkyl heteroaryl, 3-6C-cycloalkyl or 3-6C-cycloheteroalkyl groups are optionally together forms a optionally saturated ring, and optionally substituted by one or more halo, OR5, NR5R6, SR5, NO, NO 2, S(=O)-R5, SO 2-R5, NSO 2NR5R6, SO 2NR5R6, COOR5, CHO, C(=O)R5, C(=O)NR4R5, Si(R5) 3, CN, OR7, NR5R8 or SR9; R5, R6 : H, or 1-6C-alkyl, 2-6C-alkenyl, 6-10C-aryl, 3-10C-heteroaryl, 7-11C-alkylaryl, 4-11C-alkyl heteroaryl, 3-6C-cycloalkyl or 3-6C-cycloheteroalkyl, where the above groups are optionally together forms a optionally saturated ring; R7 : tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl or isobutyloxycarbonyl; R8 : methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, formyl, acetyl, benzoyl, 4-methoxybenzyl, benzenesulfonyl or 4-methylbenzenesulfonyl; R9 : tetrahydropyranyl, 4-methoxybenzyl, fluorenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, benzyloxycarbonyl or tert-butyloxycarbonyl; and n : 1 or 2. Independent claims are included for aryl substituted nitroalkane derivatives of formula (O 2N-CH 2-CH(Ar1)-C(=O)-N(R3) 2) (IV) (representative of (II)) and/or their enantiomers.

Description

The invention relates to a process for the economical preparation of aryl-substituted nitroalkane derivatives by arylation of nitroalkene derivatives with boraryl compounds with the addition of palladium catalysts.

The aryl-substituted nitroalkane derivatives which can be prepared by the process according to the invention are suitable, for example, as intermediates for the preparation of active pharmaceutical ingredients and thus of great technical and commercial interest. In particular, the nitro group can be converted in a conventional manner by reduction into an amino group, which results in a very easy access to aryl-substituted derivatives of beta-amino acids, beta-amino aldehydes, beta-amino ketones and beta-amino alcohols.

It is known in principle that various structural classes of nitroalkenes can be converted into the corresponding arylated nitroalkane derivatives in the sense of a 1,4-addition with boraryl compounds in the presence of rhodium catalysts. To name a few, here is the German patent DE 10 2004 062 640 B4 which is based on the reaction of 3,3-dimethoxynitropropene with arylboronic acids in the presence of rhodium (I) salts with or without the addition of chiral or achiral ligands.

Disadvantage of all these methods is the use of rhodium, which is extremely expensive compared to other catalyst metals. Furthermore, the required reaction conditions are relatively harsh, so that there is no broad applicability to sensitive nitroalkenes.

The prior art further includes a number of methods for, in part, also enantioselective, palladium-catalyzed 1,4-addition of boraryl compounds to alpha-beta-unsaturated aldehydes, ketones, carboxylic esters, nitriles and amides and N-tosyl-arylimines ( Lu et al., J. Org. Chem., 2005, pp. 9651-9653; Minaard et al., Org. Lett., 2005, pp. 5309-5312; Miyaura et al., Chem. Lett., 2007, p. 1442- Miyaura et al., Synlett, 2008, pp. 2487-2490; Satoh et al., J. Org. Chem., 2008, pp. 1590-1592).

Furthermore, individual examples of palladium-catalyzed 1,4-additions of boraryl compounds to selected nitroalkenes are known.

Uemura et al. (Bull. Chem. Soc. Jpn., 2003, pp. 1423-1431) describe the PdCl ₂ -catalyzed 1,4-addition of sodium tetraphenylborate to a few selected nitroalkenes. The process has the disadvantage that the addition products are obtained racemically and only in moderate yields up to 62%. On the other hand, the much cheaper arylboronic acids than the tetraaryl borates can not be used in this process.

Lu et al. (J. Org. Chem., 2005, pp. 9651-9653 and Tet. Lett., 2006, pp. 7167-7170) describe the 1,4-addition of phenylboronic acid to nitrostyrene. A Pd (OAc) ₂ / bipyridine catalyst system in aqueous media is used. Disadvantages of the process are the relatively harsh reaction conditions (48 h 60 ° C and 72 h 40 ° C), under which sensitive nitroalkenes can easily decompose. Accordingly, the yield here is only 55%. Furthermore, it was not possible to use chiral ligands. Therefore, only racemic products are accessible with this method.

Miyaura et al. ( JP 2004315457 A ) describe a process for the enantioselective palladium-catalyzed 1,4-addition of boraryl compounds to alpha-beta-unsaturated aldehydes, ketones, esters, nitriles and carboxylic acid amides. In addition to a large number of other educts, nitroalkenes are also abstractly listed as possible substrates in this process. However, more specific details are only in relation to nitroethylene, 1-nitropropylene and 2-nitropropylene, with no examples being formulated for nitroalkenes. Since nitroalkenes, depending on their substitution patterns, sometimes have extreme differences in properties and reactivity, it can not be assumed that these processes are generally applicable to all nitroalkenes.

As expected, a direct transfer of the reaction conditions JP 2004315457 A in some cases very unsatisfactory results on the nitroalkenes according to the invention, since various side reactions occur with these sensitive substrates. In general, the addition of water to the hydrate and substitution of the nitro group by the aryl radical are observed. Furthermore, higher molecular weight by-products occur, which could not be further elucidated.

The object of the present invention was therefore to provide a process for the arylation of nitroalkenes, which overcomes the disadvantages mentioned above, ie uses more economical catalysts instead of the rhodium-based catalysts and is applicable to a wide range of nitroalkenes, including sensitive nitroalkenes. In particular, the process should be technically simple and economically feasible and provide the desired products with high enantiomeric excesses at high yields.

This object is achieved by a method according to claim 1. Further preferred embodiments emerge from the subclaims.

worin
X für CR₂OR¹, CR(OR²)₂, C(=O)-Y-R_n ³, CN oder CR₃ ⁴ steht, wobei die Reste R, R¹, R² jeweils unabhängig voneinander ausgewählt sind aus
R Wasserstoffatom, jeweils verzweigter oder unverzweigter
C₁-C₁₂-Alkyl-Gruppe, C₂-C₁₂-Alkenyl-Gruppe, C₁-C₁₂-Alkinyl-Gruppe, C₆-C₁₂-Aryl-Gruppe und C₇-C₁₃-Alkylaryl-Gruppe
R¹ Wasserstoffatom jeweils verzweigter oder unverzweigter
C₁-C₆-Alkyl-Gruppe, C₃-C₆-Alkenyl-Gruppe, C₃-C₆-Cycloalkyl-Gruppe, C₆-C₁₀-Aryl-Gruppe, C₇-C₁₁-Alkylaryl-Gruppe, Tetrahydropyranyl-, Tetrahydrofuranyl-, 4-Methoxybenzyl-, 3,4-Dimethoxybenzyl-, 2-Nitrobenzyl-, 4-Nitrobenzyl-, Trimethylsilyl-, Triethylsilyl-, Triisopropylsilyl-, tert-Butyldimethylsilyl-, tert-Butyldiphenylsilyl-, Diphenylmethylsilyl-, Acetyl-, Pivaloyl-, Benzoyl-, Methoxycarbonyl-, Ethoxycarbonyl-, Benzyloxycarbonyl-, 4-Methoxybenzyloxycarbonyl-, Fluorenylmethyloxycarbonyl-, Trichlorethyloxycarbonyl-, Isobutyloxycarbonyl-Gruppe;
R² jeweils verzweigter oder unverzweigter
C₁-C₆-Alkyl-Gruppe, C₃-C₆-Alkenyl-Gruppe, C₃-C₆-Cycloalkyl-Gruppe, C₆-C₁₀-Aryl-Gruppe, C₇-C₁₁-Alkylaryl-Gruppe, 4-Methoxybenzyl-, 2-Nitrobenzyl-, 2,2,2-Trichlorethyl-, 2-Bromethyl-, 2-Trimethylsilylethyl-Gruppe, wobei die Reste R² gleich oder unterschiedlich sind und gegebenenfalls miteinander einen gesättigten oder ungesättigten Ring bilden;
Y Sauerstoff (n = 1) oder Stickstoff (n = 2) ist;
und
R³ ausgewählt ist aus Wasserstoffatom, jeweils verzweigter oder unverzweigter
C₁-C₁₂-Alkyl-Gruppe, C₆-C₁₀-Aryl-Gruppe und C₇-C₁₁-Alkylaryl-Gruppe, wobei die C₇-C₁₁-Alkylaryl-Gruppe unsubstituiert oder substituiert durch ein oder mehrere Halogenatome, Methoxy- oder Nitro-Gruppen ist,
wobei für n = 2 die Reste R³ gleich oder unterschiedlich sind, und diese gegebenenfalls miteinander einen gesättigten oder ungesättigten Ring bilden und dieser Ring gegebenenfalls zusätzlich ein Sauerstoff- oder Stickstoffatom enthält;
R⁴ Wasserstoff oder ein Halogenatom (F, Cl, Br, I) ist, wobei mindestens ein R⁴ ein Halogenatom ist;
und worin
Aryl für eine Arylgruppe steht, welche ausgewählt ist aus C₆-C₁₄-Arylgruppen oder C₃-C₁₄-Heteroarylgruppen mit einem oder mehreren Heteroatom(en), ausgewählt aus Sauerstoff, Stickstoff und Schwefel,
wobei die C₆-C₁₄-Arylgruppen oder C₃-C₁₄-Heteroarylgruppen unsubstituiert oder gleich oder unterschiedlich substituiert sind durch eine oder mehrere Halogenatome (F, Cl, Br, I), OR⁵-, NR⁵R⁶-, SR⁵-, NO-, NO₂-, S(=O)-R⁵-, SO₂-R⁵-, NSO₂N R⁵R⁶-, SO₂N R⁵R⁶-, COOR⁵-, CHO-, C(=O)R⁵-, C(=O)N R⁵R⁶-, Si(R⁵)₃-, CN-, OR⁷-, NR⁵R⁶- oder SR⁹-Gruppen, jeweils verzweigte oder unverzweigte
C₁-C₆-Alkylgruppen, C₂-C₆-Alkenylgruppen, C₆-C₁₀-Arylgruppen, C₃-C₁₀-Heteroarylgruppen, C₇-C₁₁-Alkylarylgruppen, C₄-C₁₁-Alkylheteroarylgruppen, C₃-C₆-Cycloalkylgruppen oder C₃-C₆-Cycloheteroalkylgruppen,
wobei die genannten Gruppen gegebenenfalls miteinander einen gesättigten oder ungesättigten Ring bilden und unsubstituiert oder gleich oder unterschiedlich substituiert sind durch ein oder mehrere Halogenatome (F, Cl, Br, I), OR⁵-, NR⁵R⁶-, SR⁵-, NO-, NO₂-, S(=O)-R⁵-, SO₂-R⁵-, NSO₂N R⁵R⁶-, SO₂N R⁵R⁶-, COOR⁵-, CHO-, C(=O)R⁵-, C(=O)N R⁴R⁵-, Si(R⁵)₃-, CN-, OR⁷-, NR⁵R⁸- oder SR⁹-Gruppen
und
wobei R⁵ und R⁶ gleich oder unterschiedlich sind und ausgewählt sind aus Wasserstoffatom, jeweils verzweigten oder unverzweigten
C₁-C₆-Alkylgruppen, C₂-C₆-Alkenylgruppen, C₆-C₁₀-Arylgruppen, C₃-C₁₀-Heteroarylgruppen, C₇-C₁₁-Alkylarylgruppen, C₄-C₁₁-Alkylheteroarylgruppen, C₃-C₆-Cycloalkylgruppen und C₃-C₆-Cycloheteroalkylgruppen,
wobei die genannten Gruppen gegebenenfalls miteinander einen gesättigten oder ungesättigten Ring bilden;
R⁷ ausgewählt ist aus Tetrahydropyranyl-, Tetrahydrofuranyl-, 4-Methoxybenzyl-, 3,4-Dimethoxybenzyl-, 2-Nitrobenzyl-, 4-Nitrobenzyl-, Trimethylsilyl-, Triethylsilyl-, Triisopropylsilyl-, tert-Butyldimethylsilyl-, tert-Butyldiphenylsilyl-, Diphenylmethylsilyl-, Acetyl-, Pivaloyl-, Benzoyl-, Methoxycarbonyl-, Ethoxycarbonyl-, Benzyloxycarbonyl-, 4-Methoxybenzyloxycarbonyl-, Fluorenylmethyloxycarbonyl-, Trichlorethyloxycarbonyl-, Isobutyloxycarbonyl-Gruppe;
R⁸ ausgewählt ist aus Methoxycarbonyl-, Ethoxycarbonyl-, tert-Butyloxycarbonyl-, Allyloxycarbonyl-, Benzyloxycarbonyl-, 4-Methoxybenzyloxycarbonyl-, Fluorenylmethyloxycarbonyl-, Formyl-, Acetyl, Benzoyl-, 4-Methoxybenzyl-, Benzensulfonyl-, 4-Methylbenzensulfonyl-Gruppe;
und
R⁹ ausgewählt ist aus Tetrahydropyranyl-, 4-Methoxybenzyl-, Fluorenylmethyl-, Trimethylsilyl-, Triethylsilyl-, Triisopropylsilyl-, tert-Butyldimethylsilyl-, tert-Butyldiphenylsilyl-, Diphenylmethylsilyl-, Benzyloxycarbonyl-, tert-Butyloxycarbonyl-Gruppe;
durch Arylierung von Nitroalkenderivaten der allgemeinen Formel (I)

worin X die oben genannte Bedeutung hat,
mit einer Borarylverbindung, wobei die Aryl-Gruppe die oben genannte Bedeutung hat, in Gegenwart von 0,1 mol% bis 10 mol%, bezogen auf das Nitroalkenderivat, eines Palladiumsalzes oder eines Palladiumkomplexes in Wasser oder in Mischungen aus Wasser und einem mit Wasser mischbaren organischen Lösungsmittel.In other words, the object is achieved by a process for preparing aryl-substituted nitroalkane derivatives of the general formula (II),

wherein
X is CR ₂ OR ¹ , CR (OR ² ) ₂ , C (= O) -YR _n ³ , CN or CR ₃ ⁴ , wherein the radicals R, R ¹ , R ^{2 are} each independently selected from
R is hydrogen, in each case branched or unbranched
C ₁ -C ₁₂ alkyl group, C ₂ -C ₁₂ alkenyl group, C ₁ -C ₁₂ alkynyl group, C ₆ -C ₁₂ aryl group and C ₇ -C ₁₃ alkylaryl group
R ¹ hydrogen atom each branched or unbranched
C ₁ -C ₆ -alkyl group, C ₃ -C ₆ -alkenyl group, C ₃ -C ₆ -cycloalkyl group, C ₆ -C ₁₀ -aryl group, C ₇ -C ₁₁ -alkylaryl group, Tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, Acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl group;
R ² each branched or unbranched
C ₁ -C ₆ -alkyl group, C ₃ -C ₆ -alkenyl group, C ₃ -C ₆ -cycloalkyl group, C ₆ -C ₁₀ -aryl group, C ₇ -C ₁₁ -alkylaryl group, 4-methoxybenzyl, 2-nitrobenzyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-trimethylsilylethyl group, wherein the radicals R ^{2 are the} same or different and optionally together form a saturated or unsaturated ring;
Y is oxygen (n = 1) or nitrogen (n = 2);
and
R ^{3 is} selected from hydrogen, each branched or unbranched
C ₁ -C ₁₂ -alkyl group, C ₆ -C ₁₀ -aryl group and C ₇ -C ₁₁ -alkylaryl group, where the C ₇ -C ₁₁ -alkylaryl group is unsubstituted or substituted by one or more halogen atoms, Is methoxy or nitro groups,
where, for n = 2, the radicals R ^{3 are} identical or different, and these optionally together form a saturated or unsaturated ring and this ring optionally additionally contains an oxygen or nitrogen atom;
R ^{4 is} hydrogen or a halogen atom (F, Cl, Br, I), wherein at least one R ^{4 is} a halogen atom;
and in which
Aryl is an aryl group which is selected from C ₆ -C ₁₄ aryl groups or C ₃ -C ₁₄ heteroaryl groups with one or more heteroatom (s) selected from oxygen, nitrogen and sulfur,
wherein the C ₆ -C ₁₄ -aryl or C ₃ -C ₁₄ -heteroaryl groups are unsubstituted or substituted identically or differently by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ , C (= O) NR ⁵ R ⁶ , Si (R ⁵ ) ₃ , CN, OR ⁷ , NR ⁵ R ⁶ or SR ⁹ , each branched or unbranched
C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups or C ₃ -C ₆ -cycloheteroalkyl groups,
wherein said groups optionally together form a saturated or unsaturated ring and are unsubstituted or substituted identically or differently by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO -, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O ) R ⁵ , C (= O) NR ⁴ R ⁵ , Si (R ⁵ ) ₃ , CN, OR ⁷ , NR ⁵ R ⁸ or SR ⁹ groups
and
wherein R ⁵ and R ^{6 are the} same or different and are selected from hydrogen, each branched or unbranched
C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups and C ₃ -C ₆ -cycloheteroalkyl groups,
wherein said groups optionally together form a saturated or unsaturated ring;
R ^{7 is} selected from tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl -, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl group;
R ^{8 is} selected from methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, formyl, acetyl, benzoyl, 4-methoxybenzyl, benzenesulfonyl, 4-methylbenzenesulfonyl Group;
and
R ^{9 is} selected from tetrahydropyranyl, 4-methoxybenzyl, fluorenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, benzyloxycarbonyl, tert-butyloxycarbonyl;
by arylation of nitroalkene derivatives of the general formula (I)

where X has the meaning given above,
with a boraryl compound, wherein the aryl group has the abovementioned meaning, in the presence of 0.1 mol% to 10 mol%, based on the nitroalkene derivative, a palladium salt or a palladium complex in water or in mixtures of water and a water-miscible organic solvents.

The process is outlined in Scheme 1 below.

Schema 1

Scheme 1

The compounds of the general formula (II) which can be prepared by the process according to the invention contain a carbon atom (marked with a star), which represents a center of chirality. Each compound can therefore exist in two different forms, so-called enantiomers, which behave spatially like image and mirror image (Scheme 2).

Schema 2

Scheme 2

On the one hand, the racemic products (ratio of enantiomers = 50:50) can be produced very easily with the new process. In particular, the method also offers the possibility of a To produce enantiomer in large excess. Ie. the ratio of the enantiomers is> 85:15 (enantiomeric excess ≥70% ee), preferably> 90:10 (enantiomeric excess ≥80% ee).

Palladium salts or complexes are significantly more economical catalysts compared to, for example, rhodium catalysts. Furthermore, the palladium-catalyzed reaction according to the invention can be applied to a very broad spectrum of nitroalkenes, in particular also to sensitive nitroalkenes. The desired products are obtained with high enantiomeric excesses at high yields.

The nitroalkenes of the general formula (I) to be used for the process can be prepared very easily and economically by known processes.

Preferably, the radical R in the general formula (I) and correspondingly then also in the aryl-substituted nitroalkane of the general formula (II) is a hydrogen atom.

Preferred nitroalkene derivatives of the general formula (I) are derivatives from the group consisting of 3-nitroacrylamide, 3-nitroacrylic acid dimethylamide, 3-nitroacrylic acid methyl ester, 3-nitroacrylic acid ethyl ester, 3,3-dimethoxy-1-nitropropene and 3-benzyloxy-1-nitropropene preferably 3,3-dimethoxy-1-nitropropene, 3-nitroacrylic acid amide or 3-nitroacrylic acid dimethylamide used.

Nitroalkenes of the general formula (I) in which the group X is a carboxylic acid, a carboxylic acid ester, a carboxylic acid amide or a carbonitrile (for example 3-nitroacrylamide, 3-nitroacrylic acid dimethyl, 3-nitroacrylates or 3-nitroacrylates), provide alkenes having two electron-withdrawing groups It is known from the prior art that boraryl compounds react under palladium catalysis with alpha-beta-unsaturated carboxylic acid esters, nitriles and amides in the sense of a 1,4-addition (J. Org. Chem., 2005, p. Org. Lett., 2005, pp. 5309-5312; Chem. Lett., 2007, pp. 1442-1443; Synlett, 2008, pp. 2487-2490; J. Org. Chem., 2008, pp. 9651-9653; 1590-1592).

In this respect, two different addition products (A and B) are possible with these nitroalkenes, which are shown in Scheme 3 (example of X = carboxylic acid methyl ester).

Schema 3

Scheme 3

It was surprisingly found that when using the method according to the invention only the product type B is formed. The reaction proceeds very regioselectively in the sense of a 1,4-addition to the nitroalkene structure.

The palladium salt used is preferably Pd (OAc) ₂ , Pd (acac) ₂ or PdCl ₂ . The palladium complex has palladium in the oxidation state 0 or +2, preferably +2.

It has been described in the literature that palladium (II) chloride PdCl ₂ does not catalyze the 1,4-addition of arylboronic acids to selected nitroalkenes (Uemura et al., Bull. Chem. Soc. Jpn., 2003, p. 1423- 1431).

Surprisingly, therefore, was the finding that simple palladium (II) salts such as palladium (II) acetate Pd (OAc) ₂ , palladium (II) acetylacetonate Pd (acac) ₂ and also PdCl _2, the 1,4-addition Of arylboronic acids to the inventive nitroalkenes of the general formula (I) well catalyze. This is particularly advantageous for the preparation of the racemic aryl-substituted nitroalkane derivatives of the general formula (II), since the costs for the use of ligands are eliminated.

A certain exception is dichloro (1,5-cyclooctadiene) palladium (II) Pd (cod) Cl ₂ , which does not catalyze the reaction according to the invention.

Palladium complexes containing certain chiral or achiral phosphorus ligands catalyze the reaction very well. The complexes can either be prefabricated or in situ from Pd salt and ligand are prepared. In the case of an in-situ generation, the use of Pd (cod) Cl ₂ as a salt is advantageous because then no racemic background reaction can occur due to uncomplexed residues of Pd salt.

Otherwise, a slight excess of ligand based on the palladium salt is advantageous in order to ensure complete complexation of the Pd salt.

The use of chiral ligands or chiral palladium complexes leads to products in which one enantiomer is present in excess over the other enantiomer (enantiomeric excess). It makes sense to use chiral ligands which themselves have a high enantiomeric excess (eg> 98% ee). Studies using various ligands with the various substrates gave products with enantiomeric excess of ≥ 70% ee, preferably ≥ 80% ee. By known operations, such as recrystallization, the ee value can be increased to> 98%.

As ligands of the palladium complex, or as added ligands both chiral and achiral ligands were used. Preferably, chiral ligands were used, as in this way enantiomerically enriched products were accessible.

These ligands preferably contain phosphorus (III), more preferably at least 2 atoms of phosphorus (III), most preferably at least 2 atoms of phosphorus (III), which are linked via a C-C bridge.

1,2-Bis (diphenylphosphino) ethane (dppe), (2,3) bis (diphenylphosphino) butane (Chiraphos), 1,2-bis [(2-methoxyphenyl) - (phenyl) phosphino] ethane were examples of examples of ligands (Dipamp), 2,3-bis (diphenylphosphino) bicyclo [2.2.1] hept-5-ene (norphos), 1,2-bis ((2R, 5R) -2,5-diphenylphospholano) ethane (Ph) BPE), 3,4-bis (diphenylphosphino) -1-benzylpyrrolidine (catASium ^® D), 1,2-bis (diphenylphosphino) propane (prophos) and 2,2'-Binaphtyldiphenyldiphosphin (BINAP) were used.

Examples of prefabricated palladium complexes were [Pd (dppe) (PhCN) ₂ ] (SbF ₆ ) ₂ , [Pd (chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ and [Pd ((R, R) -Dipamp) (PhCN ) ₂ ] (SbF ₆ ) ₂ .

oder das Enantiomer oder das Racemat oder ein entsprechendes Derivat als Ligand des Palladiumkomplexes oder als zugesetzter Ligand verwendet.In preferred embodiments, chiraphos has been prepared according to formula (III)

or the enantiomer or the racemate or a corresponding derivative used as a ligand of the palladium complex or as a ligand added.

Chiraphos-type derivatives are, in particular, bis-phosphinylalkanes, as described in the German patent application DE 10 2005 036 340 A1 to be named. The bis-phosphinylalkanes mentioned there are expressly incorporated herein by reference. Examples which may be mentioned are chiraphos derivatives which have longer and optionally substituted carbon chains on the carbon atoms of the CC bridge or derivatives in which the phenyl rings carry further substituents.

When using optimized reaction conditions, only 0.25 mol% of catalyst based on the nitroalkene used are necessary. It is in principle even possible to reduce the amount of catalyst to only 0.1 mol%, based on the nitroalkene used. However, decreases with decreasing amount of catalyst, the reaction rate and side reactions such. As the hydrate formation are favored.

As boraryl compounds, it is possible in principle to use all compounds which contain a carbon-boron bond in which the carbon atom is a member of an aromatic or heteroaromatic ring or ring system.

Preference is given to using boraryl compounds selected from arylboronic acids, arylboronic acid esters, arylboronic acid anhydrides, arylboronic acid trifluoroborates and tetraarylborates, as shown by way of example in Scheme 4. Particularly preferred are arylboronic acids.

Schema 4

Scheme 4

"Aryl" in particular represents a phenyl group which is unsubstituted or identical or differently substituted by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ -, C (= O) NR ⁵ R ⁶ -, Si (R ⁵ ) ₃ , CN, OR ⁷ -, NR ⁵ R ⁶ - or SR ⁹ groups, in each case branched or unbranched
C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups or C ₃ -C ₆ -cycloheteroalkyl groups,
wherein said groups optionally together form a saturated or unsaturated ring and are unsubstituted or substituted identically or differently by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO -, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O ) R ⁵ , C (= O) NR ⁴ R ⁵ , Si (R ⁵ ) ₃ , CN, OR ⁷ , NR ⁵ R ⁶ or SR ⁹ groups
and
wherein R ⁵ and R ^{6 are the} same or different and are selected from hydrogen, each branched or unbranched
C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups and C ₃ -C ₆ -cycloheteroalkyl groups,
wherein said groups optionally together form a saturated or unsaturated ring;
R ^{7 is} selected from tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl -, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl group;
R ^{8 is} selected from methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, formyl, acetyl, benzoyl, 4-methoxybenzyl, benzenesulfonyl, 4-methylbenzenesulfonyl Group;
and
R ^{9 is} selected from tetrahydropyranyl, 4-methoxybenzyl, fluorenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, benzyloxycarbonyl, tert-butyloxycarbonyl group

Particular preference is given to using boraryl compounds in which aryl is a phenyl group which is unsubstituted or identical or differently substituted by one or more, preferably one, two or three halogen atoms (F, Cl, Br, I), methyl groups, unsubstituted or with one or more halogen atoms a plurality of halogens, methoxy groups, ethoxy groups, amino groups, hydroxy groups, thiol groups, thiomethyl groups, Si (CH ₃ ) ₃ groups, COOH groups, COOCH ₃ groups, phenyl groups, oxyphenyl groups, SO ₂ CH ₃ groups, SOCH ₃ groups, CN groups, NO ₂ groups, CH ₂ CH (NH ₂ ) COOH groups, NCOOC (CH ₃ ) ₃ groups, NCOOCH ₂ -phenyl groups, NHSO ₂ CH ₃ groups, SO ₂ NH ₂ groups, CON (CH ₃ ) ₂ groups, cyclopropyl groups, pyrazole groups, N (CH ₂ -phenyl) ₂ groups, CHO groups, CH = CH ₂ - Groups, CH ₂ OH groups, N (CH ₃ ) ₂ groups, OCF ₃ groups, O-CH ₂ -phenyl groups, O-Si (CH ₃ ) ₃ groups, O-Si (CH (CH ₃ ) ₂ ) _3- groups or O-Si (CH ₃ ) ₂ C (CH ₃ ) ₃ groups.

In a further preferred embodiment, aryl is a heteroaryl group which is selected from pyrrole, pyrazole, imidazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, indole, benzopyrazole, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, Pyridine, quinoline and isoquinoline and which is unsubstituted or the same or different substituted by one or more, preferably one, two or three
Halogen atoms (F, Cl, Br, I), methyl groups, unsubstituted or substituted by one or more halogens, benzyl groups, COOC (CH ₃ ) ₃ groups, COOCH ₂ -phenyl groups, methoxy groups, ethoxy groups, amino groups, hydroxy groups, thiol groups, Thiomethyl, Si (CH ₃ ) ₃ , COOH, COOCH ₃ , phenyl, oxyphenyl, SO ₂ CH ₃ , SOCH ₃ , CN, NO ₂ , CH ₂ CH (NH ₂ ) COOH groups, NCOOC (CH ₃ ) ₃ groups, NCOOCH ₂ phenyl groups, NHSO ₂ CH ₃ groups, SO ₂ NH ₂ groups, CON (CH ₃ ) ₂ groups, cyclopropyl groups, N (CH ₂ -phenyl) ₂ groups, CHO groups, CH = CH ₂ groups, CH ₂ OH groups, N (CH ₃ ) ₂ groups, OCF ₃ groups, O-CH ₂ -phenyl groups, O-Si (CH ₃ ) ₃ groups, O-Si (CH (CH ₃ ) ₂ ) ₃ groups or O-Si (CH ₃ ) ₂ C (CH ₃ ) ₃ groups.

Particularly preferably, the heteroaryl group is selected from pyrrole, pyrazole, imidazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, indole, benzopyrazole, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole, unsubstituted or the same or different substituted by one or more, preferably one, two or three of the other substituents mentioned above.

1.0 to 1.5 equivalents of the boraryl compound, based on the nitroalkene derivative, are used.

As the solvent, water or mixtures of water and a water-miscible organic solvent are used, and the organic solvents are not further limited and used alone or in admixture with each other. Polar aprotic and polar protic organic solvents are preferably used.

By "mixtures of water and a water-miscible organic solvent" is preferably understood mixtures of water and at least one organic solvent which mix completely to form a single homogeneous phase. However, mixtures are also included in which at least 5% (v / v) of the organic solvent (s) are soluble in water, and which subsequently form a two-phase system with the aqueous phase.

Pure organic solvents can not be used, i. H. the presence of water is required in any case. The mixing ratio (V / V) can be varied between 1:10 and 10: 1. The optimum mixing ratio depends on the substrate used and the boraryl compound used. Eligible is a high water content, however, a certain degree of organic solvent is necessary for the solubility of the educts. For relatively readily water-soluble starting materials, such as. For example, 3-nitroacrylamide and phenylboronic acid pure water can be used as the solvent, but the reaction rate is relatively low here. The enantioselectivities are hardly dependent on the solvent used.

Using the process according to the invention, the hydrolysis of the boraryl compounds used can occur as a side reaction (proton boronation, Scheme 5).

Schema 5

Scheme 5

Side reaction means that more than 30% of the boraryl compound used enter into this reaction and thus are not available for the actual desired arylation reaction according to the invention.

By way of example, it has been found that when using 3,3-dimethoxy-1-nitropropene and acetone or tetrahydrofuran (THF) as the solvent, more than 60% of the boraryl compound used is subjected to protodeboronation. Even when using 3 equivalents of boraryl compound based on 3,3-dimethoxy 1-nitropropene does not completely run off the arylation reaction according to the invention. From an economic point of view, however, it is not acceptable to use more than 1.5 equivalents of boraryl compound, based on the nitroalkene used.

Surprisingly, it has been found that the protodeboration can be reduced to less than 30% if the water-miscible organic solvent is a polar aprotic, strongly coordinating solvent. Preferably, N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), tetramethylurea, N-methyl-2-pyrolidone (NMP), 2-pyrrolidinone, acetonitrile or derivatives of these solvents are used the solvents are used alone or in mixture.

By "derivatives of these solvents" is meant that instead of the methyl group (s) one or more, optionally different, C1-C6 alkyl chains are present.

The use of said polar aprotic, strongly coordinating solvent leads compared to z. As acetone or THF to a moderate to significant reduction in the reaction rate.

worin R³ die oben genannte Bedeutung hat, die unerwünschte Protodeboronierung zurückgedrängt wird, selbst wenn kein polares aprotisches, stark koordinierendes Lösungsmittel verwendet wird. „Zurückgedrängt” bedeutet, dass die Nebenreaktion zu weniger als 30% auftrat. Dies hat den Vorteil, dass die mit dem Einsatz dieser polaren aprotischen, stark koordinierenden Lösungsmittel verbundene Verringerung der Reaktionsgeschwindigkeit vermieden werden kann.It has also been found, completely surprisingly, that when using the nitroalkenes, 3-nitroacrylic acid dimethylamide or of 3-nitroacrylic acid esters of the formula (Ia) and formula (Ib)

wherein R ^{3 has} the meaning given above, the unwanted Protodeboronierung is suppressed, even if no polar aprotic, strongly coordinating solvent is used. "Back-pushed" means that the side reaction occurred to less than 30%. This has the advantage that the reduction in reaction rate associated with the use of these polar aprotic, strongly coordinating solvents can be avoided.

The arylation can in principle be carried out at temperatures between 0 ° C. and the boiling point of the solvent or of the mixture. However occur at temperatures above 40 ° C increased side reactions such. As the decomposition of the substrate and hydrate formation. Preferably, the reaction is between 10 ° C and 40 ° C, most preferably between 15 ° C and 30 ° C. The reaction temperature has little influence on the achievable enantiomeric excesses. From a technical point of view, it is particularly advantageous that the reaction without energy input, d. H. without heating or cooling, can be carried out at room temperature.

Special acids such as HBF ₄ or HPF ₆ , preferably HBF ₄ , accelerate the reaction and surprisingly lead to a complete suppression of the formation of relatively high molecular weight by-products. Based on the nitroalkene derivative, 1-20, preferably 1-10, most preferably 1-5 equivalents of HBF ₄ or HPF ₆ , preferably HBF ₄ , are added.

An addition of silver salts accelerates the reaction. According to analogue literature, however, 10 mol% of silver salt, based on substrate, are required for this purpose. In the context of the present invention, based on the nitroalkene derivative, 0.1 to 1.0 mol% of a silver salt, preferably AgBF ₄ or AgSbF ₆ , most preferably AgBF ₄ , was added. It was surprisingly found that even 0.4 mol% of silver salt are sufficient to achieve a comparably positive effect.

Acid and silver salt can be used together.

Most of the aryl-substituted nitroalkane derivatives obtainable by this process are already known.

wobei
Aryl für eine Arylgruppe steht, welche ausgewählt ist aus C₆-C₁₄-Arylgruppen oder C₃-C₁₄-Heteroarylgruppen mit einem oder mehreren Heteroatom(en), ausgewählt aus Sauerstoff, Stickstoff und Schwefel,
wobei die C₆-C₁₄-Arylgruppen oder C₃-C₁₄-Heteroarylgruppen unsubstituiert oder gleich oder unterschiedlich substituiert sind durch eine oder mehrere Halogenatome (F, Cl, Br, I), OR⁵-, NR⁵R⁶-, SR⁵-, NO-, NO₂-, S(=O)-R⁵-, SO₂-R⁵-, NSO₂N R⁵R⁶-, SO₂N R⁵R⁶-, COOR⁵-, CHO-, C(=O)R⁵-, C(=O)N R⁵R⁶-, Si(R⁵)₃-, CN-, OR⁷-, NR⁵R⁸- oder SR⁹-Gruppen, jeweils verzweigte oder unverzweigte
C₁-C₆-Alkylgruppen, C₂-C₆-Alkenylgruppen, C₆-C₁₀-Arylgruppen, C₃-C₁₀-Heteroarylgruppen, C₇-C₁₁-Alkylarylgruppen, C₄-C₁₁-Alkylheteroarylgruppen, C₃-C₆-Cycloalkylgruppen oder C₃-C₆-Cycloheteroalkylgruppen,
wobei die genannten Gruppen gegebenenfalls miteinander einen gesättigten oder ungesättigten Ring bilden und unsubstituiert oder gleich oder unterschiedlich substituiert sind durch ein oder mehrere Halogenatome (F, Cl, Br, I), OR⁵-, NR⁵R⁶-, SR⁵-, NO-, NO₂-, S(=O)-R⁵-, SO₂-R⁵-, NSO₂N R⁵R⁶-, SO₂N R⁵R⁶-, COOR⁵-, CHO-, C(=O)R⁵-, C(=O)N R⁴R⁵-, Si(R⁵)₃-, CN-, OR⁷-, NR⁵R⁸- oder SR⁹-Gruppen
und
wobei R⁵ und R⁶ gleich oder unterschiedlich sind und ausgewählt sind aus Wasserstoffatom, jeweils verzweigten oder unverzweigten
C₁-C₆-Alkylgruppen, C₂-C₆-Alkenylgruppen, C₆-C₁₀-Arylgruppen, C₃-C₁₀-Heteroarylgruppen, C₇-C₁₁-Alkylarylgruppen, C₄-C₁₁-Alkylheteroarylgruppen, C₃-C₆-Cycloalkylgruppen und C₃-C₆-Cycloheteroalkylgruppen,
wobei die genannten Gruppen gegebenenfalls miteinander einen gesättigten oder ungesättigten Ring bilden;
R⁷ ausgewählt ist aus Tetrahydropyranyl-, Tetrahydrofuranyl-, 4-Methoxybenzyl-, 3,4-Dimethoxybenzyl-, 2-Nitrobenzyl-, 4-Nitrobenzyl-, Trimethylsilyl-, Triethylsilyl-, Triisopropylsilyl-, tert-Butyldimethylsilyl-, tert-Butyldiphenylsilyl-, Diphenylmethylsilyl-, Acetyl-, Pivaloyl-, Benzoyl-, Methoxycarbonyl-, Ethoxycarbonyl-, Benzyloxycarbonyl-, 4-Methoxybenzyloxycarbonyl-, Fluorenylmethyloxycarbonyl-, Trichlorethyloxycarbonyl-, Isobutyloxycarbonyl-Gruppe;
R⁸ ausgewählt ist aus Methoxycarbonyl-, Ethoxycarbonyl-, tert-Butyloxycarbonyl-, Allyloxycarbonyl-, Benzyloxycarbonyl-, 4-Methoxybenzyloxycarbonyl-, Fluorenylmethyloxycarbonyl-, Formyl-, Acetyl, Benzoyl-, 4-Methoxybenzyl-, Benzensulfonyl-, 4-Methylbenzensulfonyl-Gruppe;
und
R⁹ ausgewählt ist aus Tetrahydropyranyl-, 4-Methoxybenzyl-, Fluorenylmethyl-, Trimethylsilyl-, Triethylsilyl-, Triisopropylsilyl-, tert-Butyldimethylsilyl-, tert-Butyldiphenylsilyl-, Diphenylmethylsilyl-, Benzyloxycarbonyl-, tert-Butyloxycarbonyl-Gruppe
und
wobei
beide Reste R³ gleich oder unterschiedlich sind und ausgewählt sind aus Wasserstoffatom, jeweils verzweigter oder unverzweigter
C₁-C₁₂-Alkyl-Gruppe, C₆-C₁₀-Aryl-Gruppe und C₇-C₁₁-Alkylaryl-Gruppe, wobei die C₇-C₁₁-Alkylaryl-Gruppe unsubstituiert oder substituiert durch ein oder mehrere Halogenatome, Methoxy- oder Nitro-Gruppen ist,
und die Reste R³ gegebenenfalls miteinander einen gesättigten oder ungesättigten Ring bilden und dieser Ring gegebenenfalls zusätzlich ein Sauerstoff- oder Stickstoffatom enthält.However, aryl-substituted nitroalkane derivatives of the general formula (IV) are unknown and therefore accessible for the first time on this route.

in which
Aryl is an aryl group which is selected from C ₆ -C ₁₄ aryl groups or C ₃ -C ₁₄ heteroaryl groups with one or more heteroatom (s) selected from oxygen, nitrogen and sulfur,
wherein the C ₆ -C ₁₄ -aryl or C ₃ -C ₁₄ -heteroaryl groups are unsubstituted or substituted identically or differently by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ , C (= O) NR ⁵ R ⁶ , Si (R ⁵ ) ₃ , CN, OR ⁷ , NR ⁵ R ⁸ or SR ⁹ , each branched or unbranched
C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups or C ₃ -C ₆ -cycloheteroalkyl groups,
wherein said groups optionally together form a saturated or unsaturated ring and are unsubstituted or substituted identically or differently by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO -, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O ) R ⁵ , C (= O) NR ⁴ R ⁵ , Si (R ⁵ ) ₃ , CN, OR ⁷ , NR ⁵ R ⁸ or SR ⁹ groups
and
wherein R ⁵ and R ^{6 are the} same or different and are selected from hydrogen, each branched or unbranched
C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups and C ₃ -C ₆ -cycloheteroalkyl groups,
wherein said groups optionally together form a saturated or unsaturated ring;
R ^{7 is} selected from tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl -, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl group;
R ^{8 is} selected from methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, formyl, acetyl, benzoyl, 4-methoxybenzyl, benzenesulfonyl, 4-methylbenzenesulfonyl Group;
and
R ^{9 is} selected from tetrahydropyranyl, 4-methoxybenzyl, fluorenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, benzyloxycarbonyl, tert-butyloxycarbonyl group
and
in which
both radicals R ^{3 are the} same or different and are selected from hydrogen, in each case branched or unbranched
C ₁ -C ₁₂ -alkyl group, C ₆ -C ₁₀ -aryl group and C ₇ -C ₁₁ -alkylaryl group, where the C ₇ -C ₁₁ -alkylaryl group is unsubstituted or substituted by one or more halogen atoms, Is methoxy or nitro groups,
and the radicals R ³ optionally together form a saturated or unsaturated ring and this ring optionally additionally contains an oxygen or nitrogen atom.

vor.The enantiomerically enriched or enantiomerically pure aryl-substituted nitroalkane derivative of the general formula (IV) is in the optical configuration of the general formula (IVa) or (IVb)

in front.

"Enantiomerically enriched" means that the respectively desired enantiomer is present in> 50%, preferably ≥ 60%, most preferably ≥ 70%. "Enantiomerically pure" means ≥ 98% ee.

The invention will be explained in more detail below by means of examples without being limited thereto.

Examples

Example 1 Reaction Without Ligand / Synthesis of 3-nitro-2-phenylpropionamide

0.02 mmol of a palladium salt is added to a solution of 0.116 mg of nitroacrylamide (1 mmol), 183 mg of phenylboronic acid (1.5 mmol) and 19 mg of silver tetrafluoroborate (0.1 mmol) in a mixture of 4 ml of tetrahydrofuran, 2 ml of water and 0.375 ml of tetrafluoroboric acid. The mixture is stirred for 22 hours at 19 ° C. After aqueous workup, the product is isolated by column chromatography. ¹ H-NMR (400 MHz, CDCl _3): 7:29 to 7:45 (m, 5H), 5:55 (s., Br, 1H), 5:44 (s., Br, 1H), 5.19 (dd, 1H), 4:54 ( dd, 1H), 4.35 (dd, 1H). used palladium salt yield Pd (acac) ₂ 86% PdCl ₂ 91% Pd (OAc) ₂ 69% Pd (cod) Cl ₂ 0% acac = acetylacetonate; OAc = acetate, cod = 1,5-cyclooctadiene

Example 2: Testing of Various Ligands / Synthesis of 3-nitro-2-phenylpropionamide

464 mg of nitroacrylamide (4 mmol) and 732 mg of phenylboronic acid (6 mmol) are added to a solution of 0.08 mmol palladium salt, 0.084 mmol ligand and 0.4 mmol AgBF ₄ in a mixture of 16 ml tetrahydrofuran, 8 ml water and 1495 ml tetrafluoroboric acid. The reaction mixture is stirred at the indicated reaction conditions. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. palladium salt ligand reaction conditions yield ee Pd (OAc) ₂ (S, S) -chiraphos 7 h, 19 ° C 77% 87% Pd (cod) Cl ₂ (S, S) -chiraphos 7 h, 19 ° C 80% 86% Pd (cod) Cl ₂ (R, R) -Norphos 7 h, 19 ° C 0% 0% 65 h, 50 ° C 0% 0% Pd (cod) Cl ₂ (R, R) -Ph-BPE 72 h, 23 ° C 19% 42% Pd (cod) Cl ₂ (R) -Catasium ^® D 48 h, 23 ° C 42% 87% Pd (cod) Cl ₂ (R) -Prophos 8 h, 23 ° C 83% 63% Pd (acac) ₂ (R) -BINAP 8 h, 60 ° C 51% 0% acac = acetylacetonate; OAc = acetate, cod = 1,5-cyclooctadiene

Example 3: Test various solvents / synthesis of 3-nitro-2-phenylpropionamide

To a solution of 1.161 g of nitroacrylamide (10 mmol) and 1829 g of phenylboronic acid (15 mmol) in a mixture of 40 ml of the relevant solvent, 20 ml of water and 3.74 ml of 50% HBF ₄ are added 8 mg of AgBF ₄ (0.04 mmol). and 30 mg of [Pd ((S, S) -chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ (0.025 mmol). The reaction mixture is stirred for 21 hours at 24 ° C. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. solvent yield ee methanol 76% 77% ethanol 81% 81% isopropanol 84% 82% tert-butanol 88% 83% tetrahydrofuran 87% 84% acetone 72% 81% dimethylacetamide 85% 81%

Example 4: Testing different temperatures / synthesis of 3-nitro-2-phenyl-propionic acid amide

A solution of 14 mg of dichloro (1,5-cyclooctadiene) palladium (II) (0.05 mmol), 22 mg (S, S) -chiraphos (0.051 mmol) and 39 mg of AgBF ₄ (0.2 mmol) in a mixture of 20 ml of isopropanol, 10 ml of water and 1868 ml of tetrafluoroboric acid is stirred for 30 min at 22 ° C. The solution is then brought to the corresponding reaction temperature and 580 mg of nitroacrylamide (5 mmol) and 914 mg of phenylboronic acid (7.5 mmol) are added. The reaction mixture is stirred at the indicated reaction conditions. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. reaction temperature reaction conditions yield ee 0 ° C 48 h, 0 ° C 63% 84% 10 ° C 30 h, 10 ° C 76% 83% 22 ° C 16 h, 22 ° C 84% 82% 30 ° C 3 h, 30 ° C 78% 80% 40 ° C 2.5 hours, 40 ° C 86% 80%

Example 5: Use of various boronic acids / synthesis of 2- (4-fluorophenyl) -3-nitro-propionic acid amide

To a solution of 2,772 g of nitroacrylamide (23.9 mmol) and 5,012 mg of 4-fluoro-phenylboronic acid (35.8 mmol) in a mixture of 96 ml of tetrahydrofuran, 48 ml of water and 8.9 ml of 50% HBF ₄ are added 72 mg of [Pd (( S, S) -chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ (0.0597 mmol) and 19 mg of AgBF ₄ (0.0955 mmol). The reaction mixture is stirred for 42 hours at 23 ° C. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. This gives 3.417 g of the target compound (yield 67%) as a yellow oil with an enantiomeric excess of 87%. ¹ H-NMR (400 MHz, CDCl ₃ ): 7.18-7.30 (m, 2H), 6.97-7.02 (m, 2H), 5.89 (s, br., 1H), 5.59 (s, br., 1H), 5.07 (dd, 1H), 4.43 (dd, 1H), 4.27 (dd, 1H)
analogously were prepared:

3-Nitro-2- (4-tolyl) -propionsäureamid

• Yield 71%, enantiomeric excess 82%, ¹ H-NMR (400 MHz, CDCl _3): (. S, br, 1H) 7.17 (m, 4H), 6:03, 5.67 (s., Br, 1H), 5.13 (dd , 1H), 4.49 (dd, 1H), 4.31 (dd, 1H), 2.33 (s, 3H)

2- (4-methoxy-phenyl) -3-nitro-propionamide

• Yield 44%, enantiomeric excess 73%, ¹ H-NMR (400 MHz, CDCl _3): (. S, br, 1H) 7:19 to 7:23 (m, 2H), 6.87-6.93 (m, 2H), 5.80, 5:55 ( s, br., 1H), 5.13 (dd, 1H), 4.50 (dd, 1H), 4.29 (dd, 1H), 3.79 (s, 3H)

Example 6: Ethyl nitroacrylate as substrate / synthesis of 2- (4-chlorophenyl) -3-nitro-propionic acid ethyl ester

To a solution of 619 mg of 3-nitro-acrylic acid ethyl ester (4.3 mmol) and 1 g of 4-chlorophenylboronic acid (6.4 mmol) in a mixture of 17.4 ml of N, N-dimethylacetamide, 8.3 ml of water and 1.6 ml 50% HBF ₄ 83 mg of AgBF ₄ (0.43 mmol) and 101 mg of [Pd (dppe) (PhCN) ₂ ] (SbF ₆ ) ₂ (0.085 mmol) are added. The Reaction mixture is stirred for 25 hours at 23 ° C. After aqueous workup, the product is isolated by column chromatography. This gives 284 mg of the target compound (yield 26%) as a yellow oil. ¹ H-NMR (400 MHz, CDCl _3): 7.25 (m, 2H), 7.11 (m, 2H), 4.96 (dd, 1H), 4:44 (dd, 1H), 4.29 (dd, 1H), 4:00 to 4:19 (m, 2H), 1.12 (t, 3H).
analogously were prepared:

2- (4-fluorophenyl) -3-nitro-propionic acid ethyl ester

• Yield 29%, ¹ H-NMR (400 MHz, CDCl _3): 7.26 (m, 2H), 7:07 (m, 2H), 5:07 (dd, 1H), 4:54 (dd, 1H), 4:41 (dd, 1H) , 4.10-4.28 (m, 2H), 1.23 (t, 3H).

3-Nitro-2- (4-trifluoromethyl-phenyl) -propionic acid ethyl ester

• Yield 25%, ¹ H-NMR (400 MHz, CDCl _3): 7.64 (m, 2H), 7:42 (m, 2H), 5.11 (dd, 1H), 4:58 (dd, 1H), 4.45 (dd, 1H) , 4.10-4.32 (m, 2H), 1.23 (t, 3H).

3-Nitro-2- (4-tolyl) propionic acid ethyl ester

• Yield 18%, ¹ H-NMR (400 MHz, CDCl _3): 7.16 (m, 4H), 5:07 (dd, 1H), 4:52 (dd, 1H), 4:38 (dd, 1H), 4:08 to 4:28 (m, 2H), 2.34 (s, 3H), 1.22 (t, 3H).

2- (4-methoxy-phenyl) -3-nitro-propionic acid ethyl ester

• Yield 19%, ¹ H-NMR (400 MHz, CDCl _3): 7.19 (m, 2H), 6.89 (m, 2H), 5:06 (dd, 1H), 4:53 (dd, 1H), 4:36 (dd, 1H) , 4.10-4.28 (m, 2H), 4.00 (s, 3H), 1.22 (t, 3H).

Example 7: Methyl nitroacrylate as substrate / synthesis of methyl 3-nitro-2-phenyl-propionate

To a solution of 262 mg of 3-nitro-acrylic acid methyl ester (2 mmol) and 487 mg of phenylboronic acid (4 mmol) in a mixture of 8 ml of N, N-dimethylacetamide, 4 ml of water and 0.75 ml of 50% HBF ₄ are added 39 mg of AgBF ₄ (0.2 mmol) and 48 mg of [Pd ((S, S) -chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ (0.02 mmol). The reaction mixture is stirred for 27 hours at 23 ° C. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. This gives 38 mg of the target compound (yield 9%) as a yellow oil with an enantiomeric excess of 22%. ¹ H-NMR (400 MHz, CDCl _3): 7.28 (m, 3H), 7.19 (m, 2H), 5:04 (dd, 1H), 4:48 (dd, 1H), 4:37 (dd, 1H), 3.66 (s , 3H).

When [Pd ((R, R) -dipamp) (PhCN) ₂ ] (SbF ₆ ) _{2 is used} as the catalyst, the target compound is obtained in 15% yield and with an enantiomeric excess of 49%.

Example 8: 3,3-Dimethoxy-nitropropene as substrate

To a solution of 294 mg of 3,3-dimethoxy-1-nitropropene (2 mmol) and 488 mg of phenylboronic acid (4 mmol) in a mixture of 8 ml of acetone and 4 ml of water is added 48 mg of [Pd ((S, S) Chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ (0.02 mmol). The reaction mixture is stirred for 5 hours at 21 ° C. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. This gives 214 mg of the target compound (yield 47%) as a yellow oil with an enantiomeric excess of 85%. ¹ H-NMR (400 MHz, CDCl _3): 7:25 to 7:39 (m, 5H), 4.87 (dd, 1H), 4.68 (dd, 1H), 4:47 (d, 1H), 3.81 (m, 1H), 3:38 (s, 3H), 3.36 (s, 3H).

When dimethylacetamide is used instead of acetone as the solvent, the target compound is obtained after a reaction time of 23 hours in 67% yield and with an enantiomeric excess of 83%.

Potassium phenyltrifluoroborate as Borarylverbindung

When potassium phenyltrifluoroborate is used instead of phenyl boronic acid and [Pd (dppe) (PhCN) ₂ ] (SbF ₆ ) ₂ instead of [Pd ((S, S) -chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ , the result is 21 h at 15 ° C, the target compound in 59% yield.

Example 9: 3-Benzyloxy-1-nitropropene as substrate / synthesis of 3-benzyloxy-2-phenyl-1-nitropropane

To a solution of 386 mg of 3-benzyloxy-1-nitropropene (2 mmol) and 488 mg of phenylboronic acid (4 mmol) in a mixture of 8 ml of N, N-dimethylacetamide and 4 ml of water is added 39 mg of AgBF ₄ (0.2 mmol) and 24 mg [Pd (dppe) (PhCN) ₂ ] (SbF ₆ ) ₂ (0.02 mmol). The reaction mixture is stirred for 25 hours at 27 ° C. After aqueous workup, the product is isolated by column chromatography. This gives 362 mg of the target compound (yield 67%) as a pale yellowish oil. ¹ H-NMR (400 MHz, CDCl _3): 7:25 to 7:40 (m, 10H), 4.87 (dd, 1H), 4.61 (dd, 1H), 4:52 (m, 2H), 3.91 (dd, 1H), 3.84 (dd, 1H), 3.70 (m, 1H)

Example 10: Nitroacrylic acid as substrate / synthesis of 2-phenyl-3-nitro-propionic acid

To a solution of 120 mg of nitroacrylic acid (1 mmol) and 250 mg of phenylboronic acid (2.1 mmol) in a mixture of 4.2 ml of N, N-dimethylacetamide, 2.1 ml of water and 0.4 ml of 50% HBF ₄ are added 25 mg of [Pd (( R, R) -Dipamp) (PhCN) ₂ ] (SbF ₆ ) ₂ (0.02 mmol). The reaction mixture is stirred for 24 hours at 21 ° C. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. This gives 25 mg of the target compound (yield 12%) as a viscous oil with an enantiomeric excess of 29%. ¹ H-NMR (400 MHz, CDCl ₃ ): 8.71 (s, br. 1H), 7.20-7.35 (m, 5H), 5.00 (dd, 1H), 4.48 (dd, 1H), 4.41 (m, 1H)

Example 11: Nitroacrylic acid dimethylamide as substrate / synthesis of 3-nitro-2-phenylpropionic acid dimethylamide

To a solution of 144 mg of nitroacrylic acid dimethylamide (1 mmol) and 244 mg of phenylboronic acid (2 mmol) in a mixture of 4 ml of the relevant solvent, 2 ml of water and 0.374 ml of 50% HBF ₄ are added (0.02 mmol) of the relevant palladium complex. The reaction mixture is stirred at the indicated reaction conditions. After aqueous workup, the product is isolated by column chromatography and the enantiomeric excess determined by HPLC. ¹ H-NMR (400 MHz, CDCl _3): 7:18 to 7:35 (m, 5H), 5.11 (dd, 1H), 4:55 (dd, 1H), 4:36 (dd, 1H), 2.90 (s, 3H), 2.86 (s, 3H). palladium complex solvent reaction conditions yield ee (Pd (dppe) (PhCN) ₂ ] (SbF ₆ ) ₂ dimethylacetamide 16 h, 19 ° C 94% 0% [Pd ((S, S) chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ acetone 4.5 h, 19 ° C 76% 85% [Pd ((S, S) chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ dimethylacetamide 7 h, 19 ° C 81% 84% [Pd ((R, R) -Dipamp) (PhCN) ₂ ] (SbF ₆ ) ₂ dimethylacetamide 72 h, 23 ° C 68% 61%

Example 12: Synthesis of (+) - 2- (4-chloro-phenyl) -3-nitro-propionic acid amide

In a 6 liter 3-necked flask with mechanical stirrer, 71.4 g of nitroacrylamide (615.1 mmol), 125 g of 4-chlorophenylboronic acid (799.3 mmol), 1.861 g of [Pd ((R, R) - (+) chiraphos) (PhCN) ₂ ] (SbF ₆ ) ₂ (1.54 mmol) and 0.479 g of silver tetrafluoroborate (2.46 mmol) with a mixture of 2500 ml of tetrahydrofuran, 1250 ml of deionized water and 324.068 g of tetrafluoroboric acid (50% in water, 1845.3 mmol). The slightly turbid mixture is stirred at 22 ° C until complete reaction of the nitroacrylamide. The progress of the reaction can be monitored by thin-layer chromatography on silica gel (eluent mixture of ethyl acetate: petroleum ether: methanol 95:95:10) and staining with iodine (nitroacrylamide Rf = 0.39; 2- (4-chlorophenyl) -3-nitro-propionamide Rf = 0.6, 4-chlorophenylboronic acid Rf = 0.74). After 25 hours, the conversion is about 95%, after 50 hours, the reaction is complete. The tetrahydrofuran is removed on a rotary evaporator at 50 ° C cycling temperature in vacuo. The residue is extracted with 1500 ml and 600 ml of dichloromethane. The combined organic phases are dried over sodium sulfate. It is filtered off from the sodium sulfate and the solvent removed at 50 ° C in a vacuum on a rotary evaporator. This gives 133.25 g of crude product (crude yield 94.7%) with an enantiomeric excess of 85% (determined by HPLC, Daicel Chiralpak AS, eluent heptane: isopropanol = 30:70, flow 0.7 ml / min, UV detection at 254 nm). The crude product is recrystallized from a mixture of 100 ml of ethyl acetate and 100 ml of high-boiling petroleum ether. This gives 104.23 g of the target compound with a Enatiomerenüberschuß of 93%. By a further recrystallization from 103 ml of ethyl acetate and 95 ml of high-boiling petroleum ether to obtain 81.39 g (yield 57.9%) of the target compound as light brown crystals with a Enatiomerenüberschuß of 98.7%.
¹ H-NMR (400 MHz, CDCl ₃ ): 7.31 (m, 2H), 7.21 (m, 2H), 5.62 (s, br., 1H), 5.47 (s, br., 1H), 5.09 (dd, 1H), 4.45 (dd, 1H), 4.25 (dd, 1H); ¹³ C-NMR (400 MHz, _CDCl3): 171.17, 135.06, 132.65, 129.80, 129.38, 75.93, 48.91; Melting point 109-111 ° C, specific rotation + 178.8 ° (c = 2 g / 100 ml dichloromethane, 589 nm, 21 ° C).

Claims (17)

Process for the preparation of aryl-substituted nitroalkane derivatives of the general formula (II)

wherein X is CR ₂ OR ¹ , CR (OR ² ) ₂ , C (= O) -YR _n ³ , CN or CR ₃ ⁴ , wherein the radicals R, R ¹ , R ^{2 are} each independently selected from R hydrogen atom , in each case branched or unbranched C ₁ -C ₁₂ -alkyl group, C ₂ -C ₁₂ -alkenyl group, C ₁ -C ₁₂ -alkynyl group, C ₆ -C ₁₂ -aryl group and C ₇ -C ₁₃ Alkylaryl group R ¹ hydrogen atom each branched or unbranched C ₁ -C ₆ alkyl group, C ₃ -C ₆ alkenyl group, C ₃ -C ₆ cycloalkyl group, C ₆ -C ₁₀ aryl group , C ₇ -C ₁₁ -Alkylaryl group, tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl Butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl; R ^{2 are} each branched or unbranched C ₁ -C ₆ -alkyl group, C ₃ -C ₆ -alkenyl group, C ₃ -C ₆ -cycloalkyl group, C ₆ -C ₁₀ -aryl group, C ₇ -C ₁₁ -Alkylaryl group, 4-methoxybenzyl, 2-nitrobenzyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-trimethylsilylethyl group, where the radicals R ^{2 are the} same or different and optionally together with one another saturated or form unsaturated ring; Y is oxygen (n = 1) or nitrogen (n = 2); and R ^{3 is} selected from hydrogen, in each case branched or unbranched C ₁ -C ₁₂ -alkyl group, C ₆ -C ₁₀ -aryl group and C ₇ -C ₁₁ -alkylaryl group, where the C ₇ -C ₁₁ - Alkylaryl group is unsubstituted or substituted by one or more halogen atoms, methoxy or nitro groups, where for n = 2, the radicals R ^{3 are the} same or different, and these optionally together form a saturated or unsaturated ring and this ring optionally additionally Oxygen or nitrogen atom; R ^{4 is} hydrogen or a halogen atom (F, Cl, Br, I), wherein at least one R ^{4 is} a halogen atom; and wherein aryl is an aryl group selected from C ₆ -C ₁₄ aryl groups or C ₃ -C ₁₄ heteroaryl groups having one or more heteroatom (s) selected from oxygen, nitrogen and sulfur, wherein the C ₆ -C ₁₄ -aryl groups or C ₃ -C ₁₄ -heteroaryl groups are unsubstituted or identical or differently substituted by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ , C (= O) NR ⁵ R ⁶ , Si (R ⁵ ) ₃ , CN, OR ⁷ , NR ⁵ R ⁸ or SR ⁹ groups, each branched or unbranched C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ C ₆ -Cycloalkyl groups or C ₃ -C ₆ -cycloheteroalkyl groups, said groups optionally together with one another form a saturated or unsaturated ring and are unsubstituted or identical or different substituted by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ -, C (= O) NR ⁴ R ⁵ -, Si (R ⁵ ) ₃ -, CN-, OR ⁷ -, NR ⁵ R ⁸ - or SR ⁹ groups and wherein R ⁵ and R ^{6 are the} same or different and are selected from hydrogen, respectively branched or unbranched C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups and C ₃ -C ₆ -cycloheteroalkyl groups, wherein said groups optionally together form a saturated or unsaturated ring; R ^{7 is} selected from tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl -, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl group; R ^{8 is} selected from methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, formyl, acetyl, benzoyl, 4-methoxybenzyl, benzenesulfonyl, 4-methylbenzenesulfonyl Group; and R ^{9 is} selected from tetrahydropyranyl, 4-methoxybenzyl, fluorenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, benzyloxycarbonyl, tert -butyloxycarbonyl; by arylation of nitroalkene derivatives of the general formula (I)

wherein X has the abovementioned meaning, with a boroaryl compound, wherein the aryl group has the abovementioned meaning, in the presence of 0.1 mol% to 10 mol%, based on the nitroalkene derivative, a palladium salt or a palladium complex in water or in Mixtures of water and a water-miscible organic solvent. Process according to Claim 1, characterized in that the palladium salt is Pd (OAc) ₂ , Pd (acac) ₂ or PdCl ₂ and the palladium complex has palladium in the oxidation state 0 or +2, preferably +2. A method according to claim 1 or 2, characterized in that the palladium complex comprises chiral or achiral ligands, preferably chiral ligands, wherein the ligands preferably contain phosphorus (III), more preferably at least 2 atoms of phosphorus (III), most preferably at least 2 atoms of phosphorus (III), which are connected via a CC bridge. Method according to one of claims 1 to 3, characterized in that chiral or achiral ligands, preferably chiral ligands, are added, the ligands preferably containing phosphorus (III), more preferably at least 2 atoms of phosphorus (III), most preferably at least 2 atoms Phosphorus (III), which are connected via a CC bridge. Method according to one of claims 1 to 4, characterized in that chiraphos according to formula (III)

or the enantiomer or the racemate or a corresponding derivative is contained or added as a ligand of the palladium complex. Method according to one of claims 1 to 5, characterized in that the radical R is a hydrogen atom. Process according to one of Claims 1 to 6, characterized in that the nitroalkene derivatives of the general formula (I) used are derivatives from the group consisting of 3-nitroacrylamide, 3-nitroacrylic acid dimethylamide, 3-nitroacrylic acid methyl ester, 3-nitroacrylic acid ethyl ester, 3,3-dimethoxy-1-one nitropropene and 3-benzyloxy-1-nitropropene, more preferably 3,3-dimethoxy-1-nitropropene, 3-nitroacrylic acid amide or 3-nitroacrylic acid dimethylamide. Method according to one of claims 1 to 7, characterized in that aryl is a phenyl group which is unsubstituted or identical or differently substituted by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ - , SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO -, C (= O) R ⁵ -, C (= O) NR ⁵ R ⁶ -, Si (R ⁵ ) ₃ , CN, OR ⁷ -, NR ⁵ R ⁸ or SR ⁹ groups, each branched or unbranched C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups or C ₃ -C ₆ -cycloheteroalkyl groups, where the groups mentioned optionally together form a saturated or unsaturated ring and are unsubstituted or identical or differently substituted by one or more halogen atoms (F, Cl, Br, I) , OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ -, C (= O) NR ⁴ R ⁵ -, Si (R ⁵ ) ₃ - , CN, OR ⁷ , NR ⁵ R ⁸ or SR ⁹ groups and wherein R ⁵ and R ^{6 are the} same or different and are selected from hydrogen, each branched or unbranched C ₁ -C ₆ alkyl groups, C ₂ - C ₆ alkenyl groups, C ₆ -C ₁₀ aryl groups, C ₃ -C ₁₀ heteroaryl groups, C ₇ -C ₁₁ alkylaryl groups, C ₄ -C ₁₁ alkyl heteroaryl groups, C ₃ -C ₆ cycloalkyl groups, and C ₃ -C ₆ Cycloheteroalkyl groups, wherein said groups optionally together form a saturated or unsaturated ring; R ^{7 is} selected from tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl -, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl group; R ^{8 is} selected from methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, formyl, acetyl, benzoyl, 4-methoxybenzyl, benzenesulfonyl, 4-methylbenzenesulfonyl Group; and R ^{9 is} selected from tetrahydropyranyl, 4-methoxybenzyl, fluorenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, benzyloxycarbonyl, tert-butyloxycarbonyl group Method according to one of claims 1 to 8, characterized in that aryl is a phenyl group which is unsubstituted or identical or different substituted by one or more, preferably one, two or three halogen atoms (F, Cl, Br, I), methyl groups, unsubstituted or substituted by one or more halogens, methoxy, ethoxy, amino, hydroxy, thiol, thiomethyl, Si (CH ₃ ) ₃ , COOH, COOCH ₃ , phenyl, oxyphenyl, SO ₂ CH _3, groups SOCH ₃ groups, CN groups, NO ₂ groups, CH ₂ CH (NH ₂ ) COOH groups, NCOOC (CH ₃ ) ₃ groups, NCOOCH ₂ -phenyl groups, NHSO ₂ CH ₃ groups, SO ₂ NH ₂ groups, CON (CH ₃ ) ₂ groups, cyclopropyl groups, pyrazole groups, N (CH ₂ -phenyl) ₂ - Groups, CHO groups, CH = CH ₂ groups, CH ₂ OH groups, N (CH ₃ ) ₂ groups, OCF ₃ groups, O-CH ₂ -phenyl groups, O-Si (CH ₃ ) ₃ Groups, O-Si (CH (CH ₃ ) ₂ ) ₃ groups or O-Si (CH ₃ ) ₂ C (CH ₃ ) ₃ groups. Process according to one of claims 1 to 8, characterized in that aryl is a heteroaryl group which is selected from pyrrole, pyrazole, imidazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, indole, benzopyrazole, benzimidazole, benzofuran, benzothiophene, Benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, pyridine, quinoline and isoquinoline and which is unsubstituted or identical or different substituted by one or more, preferably one, two or three halogen atoms (F, Cl, Br, I), methyl groups, unsubstituted or with a or more halogens, benzyl groups, COOC (CH ₃ ) ₃ groups, COOCH ₂ phenyl groups, methoxy groups, ethoxy groups, amino groups, hydroxy groups, thiol groups, thiomethyl groups, Si (CH ₃ ) ₃ groups, COOH groups, COOCH ₃ Groups, phenyl, oxyphenyl, SO ₂ CH ₃ , SOCH ₃ , CN, NO ₂ , CH ₂ CH (NH ₂ ) COOH, NCOOC (CH ₃ ) ₃ , NCOOCH ₂ phenyl groups, NHSO ₂ CH ₃ groups, SO ₂ NH ₂ groups, CON (CH ₃ ) ₂ groups, cyclopropyl groups, N (CH ₂ -phenyl) ₂ groups, CHO groups, CH = CH ₂ groups, CH ₂ OH groups, N (CH ₃ ) ₂ groups, OCF ₃ groups, O-CH ₂ -phenyl groups, O-Si (CH ₃ ) ₃ groups, O-Si (CH (CH ₃ ) ₂ ) ₃ groups or O-Si (CH ₃ ) ₂ C (CH ₃ ) ₃ groups. Method according to one of claims 1 to 10, characterized in that the water-miscible organic solvent, a polar aprotic, strongly coordinating solvent, preferably N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF) , Tetramethylurea, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidinone, acetonitrile or a derivative of any of these solvents, these solvents being used alone or in admixture. Method according to one of claims 1 to 11, characterized in that 1.0 to 1.5 equivalents of the boraryl compound, based on the nitroalkene derivative, are used. Method according to one of claims 1 to 12, characterized in that the boraryl compound is selected from arylboronic acids, Arylboronsäureestern, Arylboronsäureanhydriden, Arylboronsäuretrifluorboraten and Tetraarylboraten, preferably Arylboronsäuren. Method according to one of claims 1 to 13, characterized in that based on the nitroalkene derivative 1-20, preferably 1-10, most preferably 1-5 equivalents of HBF ₄ or HPF ₆ , preferably HBF ₄ , are added. Method according to one of claims 1 to 14, characterized in that based on the nitroalkene derivative 0.1 to 1.0 mol% of a silver salt, preferably AgBF ₄ or AgSbF ₆ , most preferably AgBF ₄ , are added. Aryl-substituted nitroalkane derivatives of the general formula (IV)

wherein aryl is an aryl group selected from C ₆ -C ₁₄ aryl groups or C ₃ -C ₁₄ heteroaryl groups having one or more heteroatom (s) selected from oxygen, nitrogen and sulfur, wherein the C ₆ -C ₁₄ -Arylgruppen or C ₃ -C ₁₄ heteroaryl unsubstituted or substituted the same or different by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO-, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ -, C (= O) NR ⁵ R ⁶ -, Si (R ⁵ ) ₃ , CN, OR ⁷ -, NR ⁵ R ⁸ - or SR ⁹ groups, in each case branched or unbranched C ₁ -C ₆ -alkyl groups C ₂ -C ₆ alkenyl groups, C ₆ -C ₁₀ aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ -C ₆ -cycloalkyl groups or C C ₃ -C ₆ -cycloheteroalkyl groups, where the groups mentioned optionally together form a saturated or unsaturated ring and unsubstitu or identical or different substituents are substituted by one or more halogen atoms (F, Cl, Br, I), OR ⁵ -, NR ⁵ R ⁶ -, SR ⁵ -, NO, NO ₂ -, S (= O) -R ⁵ -, SO ₂ -R ⁵ -, NSO ₂ NR ⁵ R ⁶ -, SO ₂ NR ⁵ R ⁶ -, COOR ⁵ -, CHO-, C (= O) R ⁵ -, C (= O) NR ⁴ R ⁵ , Si (R ⁵ ) ₃ , CN, OR ⁷ , NR ⁵ R ⁸ or SR ⁹ groups and wherein R ⁵ and R ^{6 are the} same or different and are selected from hydrogen, each branched or unbranched C C ₁ -C ₆ -alkyl groups, C ₂ -C ₆ -alkenyl groups, C ₆ -C ₁₀ -aryl groups, C ₃ -C ₁₀ -heteroaryl groups, C ₇ -C ₁₁ -alkylaryl groups, C ₄ -C ₁₁ -alkyl heteroaryl groups, C ₃ - C ₆ -cycloalkyl groups and C ₃ -C ₆ -cycloheteroalkyl groups, wherein said groups optionally together form a saturated or unsaturated ring; R ^{7 is} selected from tetrahydropyranyl, tetrahydrofuranyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl -, diphenylmethylsilyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, trichloroethyloxycarbonyl, isobutyloxycarbonyl group; R ^{8 is} selected from methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, fluorenylmethyloxycarbonyl, formyl, acetyl, benzoyl, 4-methoxybenzyl, benzenesulfonyl, 4-methylbenzenesulfonyl Group; and R ^{9 is} selected from tetrahydropyranyl, 4-methoxybenzyl, fluorenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, benzyloxycarbonyl, tert-butyloxycarbonyl and both Radicals R ^{3 are} identical or different and are selected from hydrogen atom, in each case branched or unbranched C ₁ -C ₁₂ -alkyl group, C ₆ -C ₁₀ -aryl group and C ₇ -C ₁₁ -alkylaryl group, wherein the C ₇ -C ₁₁ -Alkylaryl group is unsubstituted or substituted by one or more halogen atoms, methoxy or nitro groups, and the radicals R ³ optionally together form a saturated or unsaturated ring and this ring optionally additionally contains an oxygen or nitrogen atom. Enantiomerically enriched or enantiomerically pure aryl-substituted nitroalkane derivative of the general formula (IV) according to claim 16, characterized in that it is in the optical configuration of the general formula (IVa) or (IVb)

is present.