Molecular and Crystal Structures of Three Berberine Derivatives

Berberine azide, berberine thiocyanate, and 8-cyano-8H-berberine were prepared from berberine chloride, a quaternary protoberberine alkaloid. The molecular and crystal structures of all compounds are reported and discussed.


Introduction
Berberine (1) is a yellow quaternary protoberberine alkaloid occuring in many plant species of the Berberidaceae and other families. Berberine is known as an antimicrobial agent for the treatment of eye infections, gastrointestinal disorders, and other diseases [1,2]. The chemistry of berberine and related alkaloids may deal either with side chains alterations to form structural analogs [3] or with nucleophile attack on the iminium C=N + bond [4,5]. Continuing our research on the conversions of isoquinoline alkaloids with nucleophiles we investigated the reactions of berberine chloride with azide, thiocyanate, and cyanide ions.

Results and Discussion
The protoberberine skeleton is derived from 5,6-dihydrodibenzo[a,g]quinolizinium. Berberine (1) is a tetrasubstituted alkaloid with a methylenedioxy group at C2 and C3, and two methoxy groups at C9 and C10. The susceptibility of berberine to nucleophilic attack at carbon C8 is known and several adducts are described in literature, especially those with oxygen-and carbon-nucleophiles [4,5]. An early example is the reaction with cyanide which provides 8-cyano-8H-berberine (2) (8cyanodihydroberberine, berberine pseudocyanide) [6]. Little is known about reactions of berberine with nitrogen-and sulfur-nucleophiles.
We tried to prepare berberine adducts by rection with azide and thiocyanate ions. Under the described experimental conditions, berberine chloride (1a) did not give expected adducts. An excess of sodium azide led to a mere exchange of counter-anions so that we isolated berberine azide (1b) as a principal product. The IR spectrum of 1b indicated an intensive band of the antisymmetric valence vibration of azide ion [N=N=N]at 2035 cm -1 . The reaction of 1a with sodium thiocyanate proceeded similarly to yield berberine thiocyanate (1c). On the other hand, the reaction of berberine chloride with NaCN, performed according to literature [7], gave 8-cyano-8H-berberine (2). After slow recrystallizations, all the three products afforded crystals suitable for X-ray data collection.

Syntheses
Berberine azide (1b).-Berberine chloride (100 mg, 0.23 mmol) was suspended in water and sodium azide (500 mg, 7.7 mmol) was added. The mixture was refluxed for 1 h. After cooling to room temperature a yellow precipitate was collected, washed with water and dried. Yield: 76 mg (74 %  6 ) was in agreement with that of berberine chloride [13]. Slow evaporation of saturated aqueous solution afforded a single crystal for X-ray diffraction analysis.
8-Cyano-8H-berberine (2).-Sodium cyanide (160 mg, 2.5 mmol) dissolved in water was added to a solution of berberine chloride (100 mg, 0.23 mmol) in methanol. The mixture was refluxed for 15 min. After slow cooling to 5 °C a brown precipitate was separated and recrystallized from diethyl ether.