Palladium-catalysed amination of aromatic rings

You’ve seen that palladium catalysis helps form carbon–carbon bonds that are difficult to make using conventional reactions. It can also help form carbon–heteroatom bonds that are difficult to make, and you have already seen some examples in the reactions of π-allyl complexes. Work starting in the 1990s by Buchwald and Hartwig has shown that Pd can be used to promote nucleophilic substitution at a vinylic or aromatic centre—a reaction which would not normally be possible. For example, aromatic amines can be prepared directly from the corresponding bromides, iodides, or triflates and the required amine in the presence of palladium (0) and a strong alkoxide base.

The mechanisms and catalysts used in this ‘Buchwald–Hartwig’ chemistry mirror those of coupling reactions involving oxidative addition, transmetallation, and reductive elimination. The fi rst step, as usual, is oxidative insertion of Pd(0) into the aryl–halogen bond. The Pd (II) complex now adds the amine so that both coupling partners find themselves bonded to the same palladium atom. The base eliminates H–I from the complex and reductive elimination forms the Ar–N bond.

Various bases, such as t-BuONa, MeONa, LiN (TMS)2, or K₂CO₃, have been successful and some of the most successful ligands (coordinating groups shown in brown) are shown below. The fourth structure is a preformed complex used in catalytic amounts.

The range of compounds which can be made is very great: both electron-withdrawing and electron-donating substituents are acceptable; hindered compounds or those with acidic hydrogens such as phenols are tolerated. Even aryl chlorides, which are much cheaper than bromides or iodides, can also be successful.

Aromatic heterocyclic halides also work well whether they are electron-deficient or electron-rich. These couplings use the more hindered ligand shown in the margin.

It is tempting to view the amine as the ‘nucleophile’ in these reactions but it is clear that nucleophilicity has little to do with it as amides also couple to aromatic rings under similar conditions. The ability to act as a ligand for palladium is the important thing. The ligand xantphos (see above) is used in these reactions and again the nature of the substituents on the benzene ring is of little account. Even strained azetidines react well.

These reactions have been very widely used in the pharmaceutical industry in the making of medicinal compounds. When Sepracor wanted to make their anti-fungal compound itraconazole, it was obvious that they should make the two ends with stereochemistry and join them together with a central achiral section. Right in the middle is a piperazine ring joined to two different benzene rings, one connected through O and one through N. The C–N coupling chemistry of Buchwald and Hartwig could have been made for this problem.

We have already seen that p-bromophenol can be joined to an amine with palladium catalysis, so it should be easy to join it to piperazine. However, there is a potential problem of selectivity: we want to add this benzene ring just once, and the way to do this is to protect one nitrogen atom by reductive amination with benzaldehyde. The remaining NH group can then be coupled to the aromatic ring and the benzyl group removed by hydrogenation.

The workers at Sepracor then added the left-hand end of the molecule (we shall call this R1) to the free OH group. The other aromatic ring, already functionalized with the right-hand end of the molecule (we shall call this R2) was coupled as its bromide to the free NH group by a second Buchwald–Hartwig amination reaction process. It’s easy to see how this chemistry simplifies the assembly of such a large and complex molecule.

اخر الاخبار

اخبار العتبة العباسية المقدسة

في المثنى.. المجمع العلمي يواصل إقامة مشروع تعليم القراءة الصحيحة على طريق زائري الأربعين

تعزيزًا لخطتها الطبية.. العتبة العباسية المقدسة تنشر أكثر من 13 سيارة إسعاف و100 مسعف بزيارة الأربعين

ضمن برنامج بيوت النعيم.. قسم الشؤون الفكرية ينظم مجلسًا حسينيًّا في بابل

تهيئة مساحة إضافية في مجمع أبي الفضل العباس (عليه السلام) خدمةً لزائري الأربعين

المزيد

الآخبار الصحية

العلاقة بين الجهاز الهضمي والمزاج

7 علامات على القدمين.. مؤشر لمشاكل صحية خطيرة

9 عادات يومية بسيطة تجعلك أكثر ذكاء وإبداعا

هل يجب تناول مكملات "فيتامين الشمس" في فصل الصيف؟

المزيد

الآخبار التكنلوجية

أسرع الطرق لتبريد سيارتك بعد الوقوف تحت أشعة الشمس الحارقة

مشاكل ناقل الحركة CVT وأسباب عدم رضا السائقين عنه ؟

دراسة تكشف تأثيرا خطيرا لـ"تشات جي بي تي" على سلوك المراهقين ؟

أول مفاعل نووي على سطح القمر.. سباق محفوف بالمخاطر بين 3 دول

المزيد

مواضيع ذات صلة

Oxypalladation and the Wacker oxidation

Alkenes coordinated to palladium (II) are attacked by nucleophiles

Intramolecular alkylations make rings

Vinyl epoxides provide their own alkoxide base

Allylic electrophiles are activated by palladium (0)

Coupling to alkynes: the Sonogashira reaction

The Suzuki coupling couples boronic acids to halides

The Suzuki coupling couples boronic acids to halides

Hydropalladation–dehydropalladation

Palladium is the most widely used metal in homogeneous catalysis

Insertion reactions are reversible

Carbon monoxide incorporation extends the carbon chain