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S.-P. Tan et al. / Tetrahedron xxx (2017) 1e6
of CH2Cl2 at room temperature, and found that a novel dimeric
product 4 (40%) could be isolated (Table 1, entry 2). Recovery of
starting material 1 was detected in 20% after a careful column
chromatographic separation. In order to understand the influence
of FeCl3 as catalyst, the reaction was performed in the absence of
FeCl3 and no reaction was observed (Table 1, entry 1). This result
clearly indicated that the FeCl3 played a significant role in the
transformation process. Several attempts have also been tried to
improve the yield of cross-coupling product 4 and to reduce the
recovery of starting material 1 by modification of the amount of
FeCl3, the reaction time and temperature with different solvent
systems. However, none of these gave significant improvement.
Contrarily, either with a higher amount of FeCl3 or a larger reaction
temperature reduced the yield of 4. The best yield of 4 (43%) was
obtained in acetonitrile, along with 14% of 1 after chromatography
(Table 1, entry 11). In view of the synthetic efficiency, the starting
material 1 in acetonitrile treated with anhydrous FeCl3 (5 mol%) for
60 min at 25 ꢁC were identified as the optimum conditions for this
approach. The full assignment for all the 1H and 13C signals of 4 was
accomplished by 1D and 2D NMR. Based on the above analysis,
compound 4 was assigned as murrabicine, a novel dimeric carba-
zole of murrayacine 1 (see Supporting Information for a complete
NMR data).
Encouraged by the afore-mentioned findings, we envisaged the
potential in developing more novel coupling products from other
pyrano[3,2-a]carbazole derivatives. Thus, we started our investi-
gation on girinimbine 2 and mahanimbine 3. In a similar prepara-
tion manner, girinimbine 2 (0.10 mmol) and mahanimbine 3
(0.10 mmol) were separately treated with 5 mol% anhydrous FeCl3
in 10 mL of CH2Cl2. Murranimbine 5 (27%) was isolated from the
FeCl3-catalyzed cross-coupling of 2 (Table 2, entry 2), which was
previously isolated as natural products from M. euchrestifolia.50 This
compound has also been synthesized by Chakraborty et al. via one-
pot Lewis acid (BF3-Et2O) mediated reaction.11 Again, the unreacted
starting material 2 was recovered along with product 5 after col-
umn chromatography (Table 2). However, the treatment of maha-
nimbine 3 with FeCl3 as catalyst, unexpectedly, furnished with a
stereoselective cycloadduct 6 in 42% isolated yield (Table 3). This
cycloadduct, also known as bicyclomahanimbine, is a natural pyr-
ano[3,2-a]carbazole alkaloid from the genus of Murraya.49,51
Dimeric carbazole alkaloid was not isolated from this approach.
Optimization towards the transformation of compound 5 and 6
were achieved by using anhydrous FeCl3 as catalyst with suitable
reaction conditions (Tables 2 and 3).
Based on the above experimental results, a plausible mechanism
of a direct FeCl3-catalyzed intermolecular cross-coupling reaction
towards the formation of 4 and 5 has been proposed as depicted in
Scheme 1.
Our route to dimeric 4 began from its monomer 1 which had
involved a direct activation of CꢀH and NꢀH bonds by one step
FeCl3-catalyzed cross-coupling reaction was suggested. Initial co-
ordination of FeCl3 enhanced the electrophilicity of the pyran ring
of 1 gives complexes 1a. The complexation enhances the inter-
molecular nucleophilic addition by the amine group of 1a to the
pyran double bond of the remaining compound 1, and results in a
sequential formation of a CꢀN bond and a CꢀC bond to give in-
termediate 1b. A consequent FeCl3-catalyzed reaction promoted an
opening of the pyran ring via intramolecular proton transfer, fol-
lowed by proto-demetalation to give 1c. Subsequently, another
formyl group of 1c is activated by FeCl3 to give more electrophilicity
at the carbonyl carbon and promoted an opening of the remaining
pyran ring to give carbenium ion 1d. Successively, this reaction
proceeded with another NꢀH bond activation led to a second CꢀN
bond formation between the remaining carbazole amine group and
the carbenium ion, followed by proton transfer and regeneration of
FeCl3 in situ to give the desired regiospecific dimeric product 4
(Scheme 1). A total of three bonds (two CꢀN bonds and one CꢀC
bond) were formed through this approach. Comparison of the 1H of
compound 1 and 4, two sets of unsubstituted ring-C and two
deshielded proton signals for H-4, which showed long range
coupling with their respective formyl proton signals were observed
in 4. Compound 4 consists of two units of 1 was suggested. The
1H-1H COSY correlations between the proton at C-9 at the first unit
and C-100 of the second unit of 4, indicated that the two units of 1
were linked with a CꢀC linkage between C-9 and C-100 (Fig. 2). In
NOESY experiment, correlations between H-9/H-100, H-10'/H-90
and H-10/H-10 at the
b
-orientation were observed. Meanwhile, H-
9'/H-100 was correlated with 110-CH3 at the
b-position and unam-
biguously determined the relative stereochemistry of 4 (Fig. 3).
Owing to the lack of an electron withdrawing effect of the formyl
group in the carbazole nucleus of 2, the transformation stopped at
the formation of the dimeric compound 5, and the desired product
was not formed. The similar mechanism has been proposed as
depicted in Scheme 1. The reaction involved an initial coordination
of FeCl3 enhanced the electrophilicity of the pyran ring of 2 gives
complexes 2a. The complexation enhances a bimolecular nucleo-
philic addition by a lone pair of NꢀH group of the first molecule to
the electron deficient pyran double bond of 2, resulted a sequential
forming of a CꢀN and a CꢀC bond between the molecules of 2,
followed by the loss of FeCl3 generated compound 5 (Scheme 1).
The spectroscopic data of our synthetic carbazole alkaloid 5 are in
full agreement with those reported by Ito et al. from the natural
products.50
Consequently, we investigated a stepwise FeCl3-catalyzed route
of mahanimbine 3 to a cyclized monoterpenoid pyrano[3,2-a]
carbazole alkaloid, bicyclomahanimbine 6. Due to the presence of
FeCl3 as catalyst, the probable mechanism of the formation of 6 was
suggested to be a FeCl3-catalyzed stereoselective intramolecular
Fig. 1. Structures of naturally occurring pyrano[3,2-a]carbazole alkaloids 1e3 and the
corresponding dimeric carbazoles 4e5 and cycloadduct 6.
Please cite this article in press as: Tan S-P, et al., A direct FeCl3-catalyzed cross-coupling and cyclization reactions: A new approach to the
Tan, Siow-Ping
