Electrophilic Aminations

These methods proved to be succesful in most cases, therefore representing an extremely valuable tool for synthetic chemistry. Nevertheless, all procedures mentioned so far, are based on a nucleophilic nitrogen source. Given the high electronegativity of nitrogen such a behaviour appears to be obvious, though limits the scope of all these reactions, since many amines have only limited nucleophilic character. This could either originate from aromatic residues, which delocalize the electron density of the nitrogen into the ring-system, or simply from sterical hinderance. These difficulties may be overcome with the aid of an “umpolung strategy”, utilizing an electrophilic nitrogen source of type [NR2]⁺. There are different approaches to change the electronic character of a nitrogen atom, of which the usage of nitrenoid intermediates for C-N bond forming reactions is rather less explored.⁴¹ The following chapter will focus on various examples of transition-metal catalyzed reactions using an electrophilic nitrogen source containing a weak N-X bond (X is an equally or more electronegative atom than nitrogen) and an organometallic species.

3.3.1 Early Examples

The first example of a transition metal catalyzed electrophilic amination of an organometallic species was reported by Narasaka in 1997.⁴² O-Methylsulfonyloximes were utilized as electrophilic nitrogen source, which after treatment with an alkyl Grignard reagent in the presence of a copper-catalyst reacted to the corresponding substituted imine. After hydrolysis and benzoylation the desired amide was obtained in 96% yield (Scheme 15). This method was succesful for primary as well as for secondary and tertiary magnesium reagents. The presence of the copper catalyst proved to be essential for this transformation, as without this transition metal, no product formation was observed.

Scheme 15. Electrophilic amination of alkyl Grignard reagents in the presence of a copper-catalyst, using O-methylsulfonyloximes.⁴²

41 a) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417–424; b) P. Mueller, C. Fruit, Chem. Rev. 2003, 103,

3.3.2 Electrophilic Aminations Using N-Hydroxylamine Benzoates

A frequently used electrophilic nitrogen source are N-hydroxylamine benzoates, which have been introduced by Johnson and co-workers.⁴³ Similar to the oximes mentioned above, the electronegativity difference between nitrogen and oxygen leads to a positively polarized nitrogen atom. In addition to this electronic umpolung on the nitrogen atom, the N-O bond is rather weak and OCOPh an excellent leaving group. This combination enabled a smooth transformation with various diorganozinc reagents in the presence of a copper-catalyst. Thus, dipyridylzinc (0.6 equiv) is readily aminated using morpholino benzoate and [Cu(OTf)]2·C6H6

(1.25 mol%) under mild conditions (25 °C, 1 h), providing the 4-(pyridin-2-yl)morpholine in 71% yield (Scheme 16).⁴³

Scheme 16. Copper-catalyzed electrophilic amination of diarylzincs using N-hydroxylamine benzoates.⁴³

The scope and the mechanism of this transformation was further investiagted in the following years.⁴⁴ Due to the usage of a mild organozinc species, various functional groups, such as esters were tolerated. However, the limited scope of diorganozinc reagents as well as of polyfunctionalized hydroxylamine benzoates still represented major drawbacks. Later, this method was extended to secondary hydroxylamine benzoates and Grignard reagents (Scheme 17).^44,45 Interstingly, the attack of the Grignard reagent at the carbonyl position of the benzoate was easily suppressed by employing a slow addition of the metallic species.

43 a) A. M. Berman, J. S. Johnson, J. Org. Chem. 2005, 70, 364–366; b) A. M. Berman, J. S. Johnson, J. Am.

Chem. Soc. 2004, 126, 5680–5681.

44 M. Campbell, J. S. Johnson, Org. Lett. 2007, 9, 1521–1524.

45 A. M. Berman, J. S. Johnson, J. Org. Chem. 2006, 71, 219–224.

Scheme 17. Electrophilic amination of Grignard reagents in the presence of a copper-catalyst.⁴⁴

To enhance the scope of suitable nucleophiles, Wang and co workers showed that using a slightly alterated procedure, highly functionalized aryl and heteroaryl diorganozinc reagents obtained from directed metalation with TMP2Zn can engage in electrophilic amination.⁴⁶ Therefore, various heterocyclic scaffolds, such as caffeine or 1,3,4-oxadiazole have been metalated using the bis-base TMP2Zn (0.6 equiv, 25 °C) and subsequently aminated using morpholino benzoate in the presence of Cu(OAc)2 (10 mol%) affording the corresponding aminated products in 82–91% yield (Scheme 18).⁴⁶

Scheme 18. Metalation of caffeine and substituted 1,3,4-oxadiazole using TMP2Zn and subsequent electrophilic amination using morpholino benzoate.⁴⁶

3.3.3 Electrophilic Aminations Using N-Chloroamines

Another widely used source of electrophilic nitrogen are N-chloroamines. In the past, these rather labile substrates have been used to generate aminyl radicals, which then undergo for example cyclization reactions.⁴⁷ These radical based reactions, however, lack of selectivity due to the high reactivity of the aminyl radicals. Nevertheless, the basic prerequisite for a transition metal-catalyzed electrophilic amination with an organometallic reagent is given. Although the electronegativity of chlorine and nitrogen is almost identical, the slight polarization engaged with the weak N-Cl bond and chloride as a good leaving group, provides a highly suitable precursor. Lei and co-workers showed the utility of N-chloroamines in the copper-catalyzed coupling with boronic acids.⁴⁸ A wide range of arylboronic acids was successfully amidated with acetylated aniline derivatives, providing the corresponding teriary amides in high yields (Scheme 19). Suprisingly, a radical mechanism was ruled out by experimental studies. The proposed mechanism is based on an oxidative insertion into the N-Cl bond followed by transmetalation with the boronic acid.

Scheme 19. Amidation of boronic acids using N-chloroamines in the presence of a copper-catalyst.⁴⁸

This method, however, was limited to acetylated substrates, therefore leading to amides only.

Later, Jarvo and co-workers extended this method and developed a nickel-catalyzed cross-coupling between N-chloroamines and diphenylzinc.⁴⁹ Thus, the diarylzinc species (2.0 equiv) was readily aminated in the presence of Ni(cod)2 (5.0 mol%) and bipyridine (10 mol%) using N-chloro dibutylamine, leading to the corresponding tertiary amine in 60%

yield (Scheme 20). Remarkably, electron-donating as well as electron-withdrawing substituents were tolerated. This method was further extended to a one-pot procedure, generating the N-chloroamine in-situ using NCS (1.1 equiv).

47 a) R. Göttlich, M. Noack, Tetrahedron Lett. 2001, 42, 7771–7774; b) L. Stella, Angew. Chem. Int. Ed. 1983, 22, 337–350.

48 C. He, C. Chen, J. Cheng, C. Liu, W. Liu, Q. Li, A. Lei, Angew. Chem. Int. Ed. 2008 , 47 , 6414–6417.

49 T. J. Barker, E. R. Jarvo, J. Am. Chem. Soc. 2009, 131, 15598–15599.

Scheme 20. In-situ generation of N-chloroamines and subsequent electrophilic amination of diorganozinc reagents in the presence of a nickel-catalyst.⁴⁹

Another development of this protocol was reported by Gosmini and co-workers.⁵⁰ They showed, that this transformation is also efficiently achieved using a cobalt-catalyst.

Interstingly, the cobalt-catalyst was used prior to generate the organozinc species by a radical cobalt-catalyzed insertion,⁵¹ and then reused for the electrophilic amination reaction. Thus, 1-bromo-3,5-bis(trifluoromethyl)benzene was smoothly converted into the corresponding organozinc reagent using this CoBr2-catalyzed insertion, and subsequently aminated with 3-(benzylchloroamino)propanenitrile, leading to the desired tertiary amine in 61% yield (Scheme 21).

Scheme 21. Cobalt-catalyzed zinc insertion into a carbon-bromine bond and subsequent amination with a N-chloramine, reusing the cobalt-catalyst.⁵⁰

50 X. Qian, Z. Yu, A. Auffrant, C. Gosmini, Chem. Eur. J. 2013, 19, 6225–6229.

3.3.4 Electrophilic Aminations Using other Nitrogen Sources

The basic idea of utilizing a polarized, weak nitrogen-heteroatom bond for electrophilic aminations has been further developed by Kürti and co-workers. So far, no direct synthesis of primary amines using an electrophilic amination has been developed. The difficulty presented by this task, is to find a suitable aminating agent, which can transfer the electrophilic nitrogen, yet will not undergo deprotonation by the basic organometallic species. The approach to overcome this undesired sidereaction, was to utilize a sterically hindered nitrogen source.⁵² Thus, bulky NH-oxaziridines represent excellent electrophilic nitrogen transfer reagents, which after ring-opening provide the desired primary amines in excellent yields (Scheme 22).⁵³

Scheme 22. Electrophilic amination of aryl and heteroaryl Grignard reagents using NH-oxaziridine,

leading to primary aniline derivatives.⁵³

This reaction utilizes aryl and heteroaryl Grignard reagents and proceeds smoothly without the presence of a transition metal. Remarkably, strained oxaziridines could also be used to prepare phenoles derivatives under similar conditions. For unprotected NH-oxaziridines, exclusively the attack on the nitrogen atom was observed. However, when attaching a sterically hindered group, such as a benzyl moiety, the attack on the nitrogen is blocked and a selective oxygenation of the magnesium reagent was observed (Scheme 23).⁵³

52 E. J. Corey, A. W. Gross, J. Org. Chem. 1985, 50, 5391–5393.

53 a) H. Gao, Z. Zhou, D.-H. Kwon, J. Coombs, S. Jones, N. E. Behnke, D. H. Ess, L. Kürti, Nat. Chem. 2017, 9, 681–688; b) Z. Zhou, Z. Ma, N. E. Behnke, H. Gao, L. Kürti, J. Am. Chem. Soc. 2017, 139, 115–118.

Scheme 23. Electrophilic oxygenation of arylmagnesium halides with N–benzyl oxaziridine.⁵³