B. M. Babu et al. / Tetrahedron Letters 55 (2014) 1868–1872
1871
OMe
after stretching the reaction time up to 24 h (Table 1, entry 7). Next
MeO
the effect of solvents was also tested by screening different sol-
vents like DCE, THF, toluene, and DCM (Table 1, entries 3, 4, 5,
and 6, respectively). The result demonstrated that DCM was a
highly effective solvent in terms of reaction time and yield. It is
worthy to mention that, the reaction worked very well in BF3ÁOEt2
without using harsh reaction conditions and gave the correspond-
ing TRAMs in a very high yield within very shorter reaction time at
rt as compared to the previous methods.14,15
OMe
BF3.OEt2
CH2Cl2
O
OMe
OMe
OH
Me
H
5 min, rt
OMe
Me
96%
(isolated yield)
OTBS
MeO
OMe
OMe
1x
2b
(-) - tatarinoid C
To determine the scope of this reaction, various methoxy ben-
zenes and substituted aldehydes were examined under optimized
conditions. We were delighted to find that the reaction of dime-
thoxybenzene and substituted aryl aldehydes resulted in high yield
of product in very short time. There was no substantial effect of
aryl aldehydes bearing electron withdrawing as well as electron
donating substituents at various positions on the reaction (Table 2,
entries 1–10, 14, and 15). The present reaction conditions tolerate
various groups like nitrile, boronic acid for example 4-cyanobenz-
aldehyde and 4-formylphenylboronic acid reacted rapidly with
1,3-dimethoxybenzene to furnish high yield of corresponding tri-
arylmethanes (Table 2, entries 11 and 16). Hindered aldehyde like
naphthaldehyde also underwent smooth reaction with dimethoxy-
benzene and resulted in good yield of product (Table 2, entry 13).
The generality of this protocol was further strengthened by
examining a variety of aldehydes. Furan-2-carboxaldehyde reacted
with 1,3-dimethoxybenzene in standard conditions to afford de-
sired TRAM in high yield (Table 2, entry 20). Similarly, 2,2-dimeth-
ylpropanal, 6-bromo-1,3-benzodioxole-4-carboxaldehyde, and
cyclohexanecarboxaldehyde reacted analogously with dimethoxy-
benzene and resulted in triarylmethanes, respectively (Table 2, en-
tries 17–19). The selectivity of the reaction was also established by
screening dialdehydes like phthalaldehyde which afforded selec-
tively the desired product 3ua (Table 2, entry 21). The method is
amenable for the synthesis of new compounds which are not pre-
pared earlier. It is worthy to mention that the present method is
relatively clean and isolation of product from reaction mixture is
only by filter column.
To further extend the scope of the method we were keen to ex-
plore other substituted arenes in this reaction under the optimized
reaction conditions. In this context we performed the reaction of
other di-substituted arenes like 1,2-dimethoxybenzene and 1,4-
dimethoxybenzene with different substituted aldehydes under
standard reaction conditions and found the formation of desired
products 3vc, 3wc, 3ve, and 3we (Table 3, entries 3, 4, 7, and 8).
Similar results were obtained with tri-substituted arenes like
1,2,4-trimethoxybenzene (Table 3, entries 1 and 2) and 1,3,5-tri-
methoxybenzene (Table 3, entries 5 and 6). We presumed that BF3-
ÁOEt2 promoted that present protocol may be a useful and alternate
addition to the rapid and efficient synthesis of new diversely func-
tionalized triarylmethane scaffolds in very high yield under mild
reaction conditions.
Scheme 2. Rapid and efficient synthesis of (À)-tatarinoid C.
functionalized triarylmethane scaffolds by the Friedel–Crafts alkyl-
ation of substituted benzenes with aldehydes in the presence of
BF3ÁOEt2. Moreover, the developed method is general and applica-
ble for variety of aldehydes and arenes. The discovery and develop-
ment of this protocol led to the rapid and straightforward access to
biologically important phenylpropanoid natural product (À)-
tatarinoid C. This method ought to be of great value as a mild, ra-
pid, efficient, and a general procedure for the synthesis of diversely
functionalized triarylmethanes from readily available starting
materials. Further studies on the application of this methodology
for the synthesis of biologically important natural products is
currently ongoing in our laboratory and results will be published
elsewhere in due course.
Acknowledgments
The authors B.M.B., P.B.T., N.N.R., and G.S.K. thank CSIR-UGC for
the award of a fellowship and to Dr. Ahmed Kamal, Outstanding
Scientist and Head, MCP Division, IICT, for his support and
encouragement.
The authors thank CSIR, New Delhi for financial support as part
of XII Five Year plan programme under title ORIGIN (CSC-0108).
References and notes
The developed protocol was successfully applied to rapid and
straightforward synthesis of phenylpropanoid natural product
(À)-tatarinoid C.19 When we treated chiral aldehydes 1x prepared
by reported method20 with 1,2,4-trimethoxybenzene under opti-
mized reaction conditions,21 we directly obtained the (À)-tatari-
noid C in very high yield within short reaction time (Scheme 2).
It is important to note that, under our conditions, two processes
Friedel–Crafts reactions and deprotection of the hydroxy group
were taking place rapidly in one pot which resulted in the very
high isolated yield of biologically important natural product (À)-
tatarinoid C. The 1H NMR and 13C NMR spectral data of (À)-tatari-
noid C were in good agreement with the data previously reported
in the literature.15
10. Ellsworth, B. A.; Ewing, W. R.; Jurica, E.; U.S. Patent Application 2011/
0082165A1, Apr 7 2011.
In conclusion, we have demonstrated operationally simple,
highly efficient, and rapid protocol for the synthesis of diversely
Babu, B. Madhu
