B(C6F5)3 as versatile catalyst: An efficient and mild protocol for the one-pot synthesis of functionalized piperidines and 2-substituted benzimidazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.10.074

An efficient, mild and environmentally benign protocol has been developed for the diastereoselective one-pot synthesis of functionalized piperidines via tandem reactions of aromatic aldehydes, amines and acetoacetic esters in the presence of a catalytic amount of tris(pentafluorophenyl)borane. Furthermore, B(C₆F₅)₃ was successfully used to catalyze the synthesis of benzimidazole and its derivatives from various aldehydes and o-phenylenediamine. In addition, the applicability of the present protocol was extended for the synthesis of benzoxazoles and benzothiazoles.

Full text of DOI:10.1016/j.tetlet.2015.10.074

Accepted Manuscript
B(C6F5)3 as versatile catalyst: An efficient and mild protocol for the one-pot
synthesis of functionalized piperidines and 2-substituted benzimidazole deriv-
atives
Santosh Kumar Prajapti, Atulya Nagarsenkar, Sravanthi Devi Guggilapu,
Bathini Nagendra Babu
PII:
S0040-4039(15)30271-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.074
TETL 46903
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 September 2015
22 October 2015
23 October 2015
Please cite this article as: Prajapti, S.K., Nagarsenkar, A., Guggilapu, S.D., Babu, B.N., B(C6F5)3 as versatile catalyst:
An efficient and mild protocol for the one-pot synthesis of functionalized piperidines and 2-substituted
benzimidazole derivatives, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.074
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Graphical Abstract
B(C6F5)3 as versatile catalyst: An efficient
and mild protocol for the one-pot synthesis
of functionalized piperidines and 2-
Leave this area blank for abstract info.
substituted benzimidazole derivatives
Santosh Kumar Prajaptiɠ, Atulya Nagarsenkarɠ, Sravanthi Devi Guggilapu and Bathini Nagendra Babu

1
Tetrahedron Letters
B(C6F5)3 as versatile catalyst: An efficient and mild protocol for the one-pot
synthesis of functionalized piperidines and 2-substituted benzimidazole
derivatives
Santosh Kumar Prajaptiɠ, Atulya Nagarsenkarɠ, Sravanthi Devi Guggilapu and Bathini Nagendra Babu
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500037, India
ARTICLE INFO
ABSTRACT
An efficient, mild and environmentally benign protocol has been developed for the
diastereoselective one-pot synthesis of functionalized piperidines via tandem reactions of
aromatic aldehydes, amines, and acetoacetic esters in presence of catalytic amount of
tris(pentafluorophenyl)borane. Furthermore, B(C6F5)3 was successfully used to catalyze the
synthesis of benzimidazole and its derivatives from various aldehydes and o-phenylenediamine.
In addition, the applicability of the present protocol was extended for the synthesis of
benzoxazoles and benzothiazoles.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Piperidine
Benzimidazole
Benzoxazole
2015 Elsevier Ltd. All rights reserved.
Benzothiazole
Tris(pentafluorophenyl)borane
The piperidine ring system is one of the most regular motifs
found in many drugs, drug candidates and natural products such
as alkaloids.1 Compounds bearing this ring exhibit a wide range
of biological activities such as antibacterial,2 anticonvulsant,3
antihypertensive,4 anti-inflammatory3 and antimalarial.5 Also
substituted piperidines have been recognized as an important
class of therapeutic agents in the treatment of cancer metastasis,6
influenza infection,7 viral infections including AIDS,8 and
diabetes.9 Accordingly, the development of efficient methods for
the synthesis of this class of compounds owing to their medicinal
properties is a subject of significant practical importance.
our studies in development of novel synthetic methodologies,12g
herein we wish to report a mild and efficient method for
diastereoselective one-pot synthesis of functionalized piperidines
(Scheme 1).
In order to investigate catalytic efficiency of B(C6F5)3 and to
determine the most appropriate reaction conditions for the
synthesis of substituted piperidines; a model reaction was
performed comprising a mixture of benzaldehyde, aniline, and
methyl acetoacetate under various reaction conditions and the
In recent times, very limited methods have been reported
describing the one-pot multicomponent synthesis of
functionalized piperidines in high diastereoselectivity, based on
catalysts such as tetrabutylammonium tribromide (TBATB),10a L-
proline/TFA,10b molecular iodine,10c bromodimethylsulfonium
bromide (BDMS),10d L-Proline nitrate,10e InCl3,11a CAN,11b
ZrOCl2.8H2O,11c bismuth nitrate,11d BF3.SiO2,11e picric acid,11f
LiClO4,11g MgBr2 (in the presence of tertiary amine),11g and
BF3⋅Et2O11g from the reaction of aromatic aldehyde, amine, and
acetoacetic ester. Furthermore, these methods have limitations in
terms of the use of excess amount of catalysts, product-diversity,
and yields. Hence, the development of a facile and high-yielding
environmentally benign protocol for the one-pot multicomponent
synthesis of densely functionalized piperidine scaffolds is still
necessary.
Tris(pentafluorophenyl)borane
[B(C6F5)3]
has
been
significantly acknowledged as non-conventional, less-toxic, air-
stable, water-tolerant and thermal abiding Lewis acid.12a-e
Recently, it was reported that B(C6F5)3 can be used in the
conversion of polyols into chiral synthons.12f In furtherance of
———
ɠ Authors with equal contribution;  Corresponding author. Tel.: +91-40-23073740; fax: +91-40-23073751; e-mail: bathini.niperhyd@gov.in

2
Tetrahedron
results are summarized in Table 1.
the reaction was attempted by using 3-((1-benzyl-2,3-dihydro-
1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde and the product was
obtained with very good yield (Figure 1, 4o). All the known
synthesized compounds and their relative anti-confirmation were
confirmed by careful comparison of their spectral data and
physical properties with the reported literatures.10-11
In the absence of the catalyst, the reaction did not proceed
satisfactorily. Even after prolonged reaction time only traces of
desired product was obtained (entry 1, Table 1). However, when
5 mol% of B(C6F5)3 was added, the reaction went smoothly and
the desired product was obtained in 85% yield after 16h of
stirring at room temperature (entry 2, Table 1). The yields got
decreased when the quantity of B(C6F5)3 was reduced from 5
mol% to 3 mol% (entry 3, Table 1). Further reduction in the
amount of catalyst led to longer reaction time and further
decreased yield (entry 4, Table 1). The significant increment in
the yield of product was not observed with 10 mol% of the
catalyst (entry 5, Table 1). Next, we examined the effect of
different solvents, which included MeOH, THF, CH3CN and
CH3COOC2H5 under same reaction conditions (entries 6-9, Table
1). Among various solvent tested, EtOH was found to be the best
solvent for the reaction, in terms of rapid conversion, eco-
friendliness and quantified yields. Hence, 5 mol% of B(C6F5)3
and EtOH were selected as the optimized reaction condition for
synthesis of piperidines (entry 2, Table 1)
A plausible mechanistic pathway for this multicomponent
reaction is outlined in Scheme 2, which is in similarity to the
established mechanism as reported in the literature.10,11 B(C6F5)3
can serve as a Lewis acid catalyst for the reaction of aniline and
β-ketoester or aromatic aldehyde to give the corresponding
enamine A or imine B, respectively. The consequent attack of
enamine on the activated imine, followed by inter- and intra-
molecular Mannich-type reactions under the reaction conditions,
would ultimately afford the final functionalized piperidine
scaffold G. B(C6F5)3 is likely to enhance the rate of this multi-
step reaction.
A variety of aldehydes were screened under the present
reaction conditions, and very good results were obtained (Figure
1). Reactions involving aldehydes substituted with electron
donating groups, such as 4-methyl, 4-methoxy, 4-OH and (3,4,5)-
trimethoxy resulted in increased product yields (Figure 1, 4b-e).
Reaction using benzo[d][1,3]dioxole-5-carbaldehyde furnished
moderate yield with increased reaction time (Figure 1, 4f).
Aldehyde substituted with electron withdrawing groups such as
2-nitro and 4-cyano gave moderate yields (Figure 1, 4g-h).
Reaction using aldehyde substituted with 4-methyl ester group
offered somewhat less yield and required more reaction time for
the completion (Figure 1, 4i). Substrate scope of present method
was tested by using the bulky aldehyde such as 3-((1-benzyl-2,3-
dihydro-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde. To our
delight, expected product was formed in very good yield in
absence of any diastereomeric impurities (Figure 1, 4j).
Encouraged with the successful synthesis of functionalized
piperidines, our attention was shifted towards the synthesis of
benzimidazoles. Benzimidazole and its derivatives represent one
of the most important classes of heterocycles, possessing an
assortment of pharmacological activities, such as antimicrobial,
antihypertensive, antibiotic, anticancer and antiparkinson
properties.13 Therefore, preparation of these molecules attracted
considerable attention. There are two common methods for the
preparation of 2-substituted benzimidazole. One is condensation
of o-phenylenediamines and carboxylic acids14a or its derivatives
(nitriles, imidates or orthoesters),14b which often require strong
acidic conditions, and sometimes combines with very high
temperature or microwave-irradiation.14c The other technique
involves the oxidative cyclodehydrogenation of Schiff bases,
which is generated from o-phenylenediamine and aldehydes.
Several reagents and catalyst such as nitrobenzene,15a DDQ,15b
BF3.OEt2,15c I2,15d ammonium metavanadate,15e FeCl3·6H2O,15f
benzofuroxan,15g
MnO2,16a
Pb(OAc)4,16b
In(OTf)3,16c
Yb(OTf)3,16d Sc(OTf)3,16e oxone,17a NaHSO3,17b DMP,17c
17d
P2O5/SiO2
and p-TsOH17e have been employed for the
synthesis of benzimidazoles. Furthermore, solid-supported
catalyst, ionic liquid and microwave-promoted reactions have
also been reported in literature.18a-c Unfortunately, some of the
reported procedures endure limitations such as harsh reaction
conditions, stoichiometric amounts of catalysts, tedious workup
procedure, low yields, eco-hazardous, prolonged reaction times
and co-occurrence of side reactions. As a consequence, the
Next, the reactions were kept using EAA (Figure 1, 3b) and a
diverse range of amines were screened under the present
protocol. Reactions involving anilines substituted with alkyl
moieties, such as methoxy resulted in increased product yield
(Figure 1, 4k). Reactions using anilines with 4-F and 4-Cl
substitutions resulted in increment in the yield of desired
products (Figure 1, 4l and 4m). Reaction with aliphatic amine
such as n-butylamine gave moderate yield (Figure 1, 4n). Again

3
introduction of a mild, efficient, and eco-friendly protocol is still
needed to overcome these limitations.
similar reaction conditions; the corresponding derivatives of
benzimidazole were achieved in high yields, however 3,5-
dimethyl-1-phenyl-1H-pyrazole-4-carbaldehyde required longer
reaction time for the completion of reaction (Figure 2, 6o-s). We
also explored the reactions of aliphatic aldehydes with o-
phenylenediamine under similar reaction conditions, which
proceeded smoothly to afford desired product in good yields
(Figure 2, 6t-v). It is noteworthy that the present method is
compatible with a wide range of functional groups such as
hydroxyl, alkoxy, nitro and nitrile as well as with acid-labile
protecting groups.
Under the optimized present reaction conditions, we kept the
reaction using a mixture benzaldehyde (1 mmol) and o-
phenylenediamine (1 mmol). The reaction went smoothly and the
desired benzimidazole was obtained in 94% yield after 30
minutes of stirring at room temperature. The same reaction was
repeated in the absence of the catalyst but poor yield of the
desired product was obtained along with starting materials
(Figure 2, 6a).
To demonstrate the generality and scope of this protocol in the
synthesis of different substituted benzimidazoles, we evaluated a
variety of aromatic aldehydes under the optimal reaction
conditions and the results are specified in Figure 2. In all the
cases, the reaction proceeded smoothly to afford the
corresponding benzimidazole derivatives (Figure 2, 6a-v) in good
to excellent yields (80-96%) in short reaction times. It was
observed that the aromatic aldehydes bearing electron donating
groups provided the corresponding 2-aryl benzimidazoles in
excellent yields (Figure 2, 6b-e). However, the aromatic
aldehydes tethered with electron withdrawing groups decreased
the rate of reaction and afforded desired product in less yields
relatively (Figure 2, 6f-j). The catalyst was also found to be very
active in the synthesis of benzimidazoles using aldehyde
substrate containing alkyne and bulky aldehyde, 2-
napthaldehyde. Interestingly, no detrimental effect was observed
in alkyne containing substrates and high yield of desired products
(Figure 2, 6k) and (Figure 2, 6l) were observed after 50 min
respectively.
Encouraged by these results and in order to extend the
generality and scope of this method, the reaction was carried out
successfully between o-aminophenol/o-aminothiophenol (Figure
2, 5b and 5c) with aromatic aldehydes, under the same reaction
condition to afford the corresponding benzoxazoles and
benzothiazoles, in moderate to excellent yield (Figure 2, 6w-z),
although prolonged reaction time was required to afford desired
products in high yields.
In conclusion, we have developed a mild and efficient
protocol for the diastereoselective synthesis of functionalized
piperidines
and
benzimidazole
derivatives
using
tris(pentafluorophenyl)borane [B(C6F5)3] as a catalyst at room
temperature. Notably, the advantages of this methodology are
mild reaction conditions, short reaction time, high yields,
environment friendly catalyst, simple work-up procedure,
tolerance with substrates bearing acid labile protecting groups
namely TBDMS and TBDPS, stability of heterocycles such as
triazole, pyrazole and thiazole in the present reaction conditions,
broad applicability to various substrates and avoiding discharge
of toxic volatile solvents. Among synthesized piperidine
derivatives 4j and 4o are densely functionalized and could hold
biological importance. Also, this methodology is useful for the
synthesis of benzoxazoles and benzothiazoles.
Acknowledgments
We thank the Department of Pharmaceuticals (Ministry of
Chemicals and Fertilizers) for providing funds.
References and notes
1. (a) Elbein, A. D.; Molyneux, R. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S.W., Ed.; John Wiley & Son: New York, NY,
1987; Vol. 57; (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435; (c) Daly,
J.W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556.
2. Zhou, Y.; Gregor, V. E.; Ayida, B. K.; Winters, G. C.; Sun, Z.; Murphy,
D.; Haley, G.; Bailey, D.; Froelich, J. M.; Fish, S.; Webber, S. E.;
Hermann, T.; Wall, D. Bioorg. Med. Chem. Lett. 2007, 17, 1206.
3. Bin, H.; Crider, A. M.; Stables, J. P. Eur. J. Med. Chem. 2001, 36, 265.
4. Petit, S.; Nallet, J. P.; Guillard, M.; Dreux, J.; Chermat, R.; Poncelet,
M.; Bulach, C.; Simon, P.; Fontaine, C.; Barthelmebs,M.; Imbs, J. L.
Eur. J. Med. Chem. 1991, 26, 19.
5. Misra, M.; Pandey, S. K.; Pandey, V. P.; Pandey, J.; Tripathi, R.;
Tripathi, R. P. Bioorg. Med. Chem. 2009, 17, 625.
6. (a) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer
Res. 1995, 1, 935; (b) Nishimura, Y.; Satoh, T.; Adachi, H.; Kondo, S.;
Takeuchi, T.; Azetaka, M.; Fukuyasu, H.; Iizuka, Y. J. Med. Chem.
1997, 40, 2626; (c) Zitzmann, N.; Mehta, A. S.; Carrouee, S.; Butters,
T. D.; Platt, F. M.; McCauley, J.; Blumberg, B. S.; Dwek, R. A.; Block,
T. M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11878.
7. (a) Von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason, J.
C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.;
Colman, P. M.; Varghese, J. N.; Ryan, D. M.; Woods, J. M.; Bethell, R.
C.; Hothman, V. J.; Camreon, J. M.; Penn, C. R. Nature 1993, 363, 418;
(b) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai,
C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681.
To check the compatibility and prove the mildness of the
present method, we have studied the substrates bearing with acid
sensitive protecting groups such as TBDMS and TBDPS, which
underwent smooth conversion to afford corresponding
benzimidazoles in 92% and 88% yields respectively, without
affecting the protecting group (Figure 2, 6m-n). Furthermore, we
investigated the reaction of various heterocyclic aldehydes under

4
Tetrahedron
8. (a) Karlsson, G. B.; Butters, T. D.; Dwek, R. A.; Platt, F. M. J. Biol.
mol%]. After completion of reaction, as indicated by TLC analysis, the
solid obtained was filtered, washed with ethanol, dried and re-crystallize
from ethanol to give pure product (4a). The assigned structures of the
products were established from their spectral and physical properties
and also by comparison with available literature data.
Chem. 1993, 268, 570; (b) Groopman, J. E. Rev. Infect. Dis. 1990, 12,
931.
9. (a) Treadway, J. L.; Mendys, P.; Hoover, D. J. Expert Opin. Invest.
Drugs 2001, 10, 439; (b) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5,
605.
20. Typical experimental procedure for the synthesis of benzimidazole
10. (a) Khan, A. T.; Lal, M.; Khan, M. M. Tetrahedron Lett. 2010, 51,
4419; (b) Misra, M.; Pandey, S. K.; Pandey, V. P.; Pandey, J.; Tripathi,
R.; Tripathi, R. P. Bioorg. Med. Chem. 2009, 17, 625; (c) Khan, A. T.;
Khan, M. M.; Bannuru, K. K. R. Tetrahedron 2010, 66, 7762; (d) Khan,
A. T.; Parvin, T.; Choudhury, L. H. J. Org. Chem. 2008, 73, 8398; (e)
Agrawal, N. R.; Bahekar, S. P.; Sarode, P. B.; Zade, S. S.; Chandak, H.
S. RSC Adv. 2015, 5, 47053.
11. (a) Clarke, P. A.; Zaytzev, A. V.; Whitwood, A. C. Tetrahedron Lett.
2007, 48, 5209; (b) Wang, H.-J.; Mo, L.-P.; Zhang, Z.-H. ACS Comb.
Sci. 2011, 13, 181; (c) Mishra, S.; Ghosh, R. Tetrahedron Lett. 2011,
52, 2861; (d) Brahmachari, G.; Das, S. Tetrahedron Lett. 2012, 53,
1479; (e) Dindulkar, S. D.; Parthiban, P.; Jeong, Y. T. Monatsh. Chem.
Chem. Mon. 2012, 143, 113; (f) Mukhopadhyay, C.; Rana, S.; Butcher,
R. J.; Schmiedekamp, A. M. Tetrahedron Lett. 2011, 52, 5835; (g)
Leonova, E.; Makarov, M.; Klemenkova, Z.; Odinets, I. Helv. Chim.
Acta 2010, 93, 1990.
12. (a) Prajapti, S. K.; Nagarsenkar, A.; Babu, B. N. Tetrahedron Lett.
2014, 55, 3507; (b) Prajapti, S. K.; Nagarsenkar, A.; Babu, B. N.
Tetrahedron Lett. 2014, 55, 1784; (c) Nagarsenkar, A.; Prajapti, S. K.;
Babu, B. N. J. Chem. Sci. 2015, 127, 711; (d) Prajapti, S. K.; Gupta, K.
K.; Babu, B. N. J. Chem. Sci. 2015, 127, 1047; (e) Guggilapu, S. D.;
Prajapti, S. K.; Babu, B. N. Tetrahedron Lett. 2015, 56, 889; (f) Adduci,
L. L.; Bender, T. A.; Dabrowski, J. A.; Gagné, M. R. Nature Chem.
2015, 7, 576. (g) Nagarsenkar, A.; Prajapti, S. K.; Guggilapu, S. D.;
Babu, B. N. Org. Lett. 2015, 17, 4592.
derivatives:
A
mixture of benzaldehyde
1
(1 mmol), o-
phenylenediamine 5a (1 mmol) in EtOH (10 mL) was stirred
magnetically at room temperature in the presence of B(C6F5)3 [5 mol%].
After completion of reaction, as indicated by TLC analysis, the solid
obtained was filtered, washed with ethanol, dried and re-crystallize from
ethanol to give pure product (6a). The assigned structures of the
products were established from their spectral and physical properties
and also by comparison with available literature data.
21. Spectroscopic data of representative novel compounds: Methyl 2,6-
bis(3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4j):
Off
yellow solid, mp 80-82 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.14
(1H, s), 8.22 (1H, s), 8.20 (1H, s), 7.38-7.28 (11H, m), 7.24-7.20 (3H,
m), 7.17-7.09 (3H, m), 7.02-6.98 (2H, m), 6.95-6.89 (2H, m), 6.85-6.83
(1H, m), 6.76-6.71 (1H, m), 6.54-6.50 (1H, m), 6.43-6.39 (3H, m), 6.27
(1H, s), 5.62-5.56 (6H, m), 5.07-4.98 (4H, m), 3.84 (3H, s), 2.94-2.89
(1H, m), 2.80-2.74 (1H, m); 13C NMR (125 MHz, DMSO-d6) 167.4,
158.1, 157.9, 154.8, 146.0, 145.7, 144.5, 142.8, 142.7, 137.4, 135.8,
129.4, 129.4, 128.8, 128.8, 128.7, 128.6, 128.0, 127.8, 127.8, 125.4,
124.9, 124.5, 124.5, 124.4, 118.6, 115.7, 112.8, 112.6, 112.1, 111.7,
97.1, 60.8, 60.7, 59.6, 56.3, 54.6, 52.7, 51.0, 39.6; IR (KBr)vmax 3321,
2925, 1651, 1592, 1498, 1251, 1034, 694 cm-1; HRMS m/z calcd. for
C51H46N8O4 [M+H]+: 835.3720; found: 835.3731. Ethyl 2,6-bis(3-((1-
benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4o):
Off
13. (a) Yildiz-Oren, I.; Yalcin, I.; Aki-Sener, E.; Ucarturk, N. Eur. J. Med.
Chem. 2004, 39, 291; (b) Li, X. C.; Widdop, R. E. Hypertension 1995,
26, 989; (c) Evans, D. A.; Sacks, C. E.; Kleschick, W. A.; Taber, T. R.
J. Am. Chem. Soc. 1979, 101, 6789; (d) Kumar, D.; Jacob, M. R.;
Reynolds, M. B.; Kerwin, S. M. Bioorg. Med. Chem. 2002, 10, 3997;
(e) Benazzou, A.; Boraund, T.; Dubedat, P.; Boireau, J.M.; Stutzmann,
C. Eur. J. Pharmcol. 1995, 284, 299.
14. (a) Middleton, R.W.; Wibberley, D. G. J. Heterocycl. Chem. 1980, 17,
1757; (b) Czarny, A.; Wilson, W. D.; Boykin, D. W. J. Heterocycl.
Chem. 1996, 33, 1393; (c) Bourgrin, K.; Loupy, A.; Soufiaoui, M.
Tetrahedron 1998, 54, 8055.
15. (a) Yadagiri, B.; Lown, J. W. Synth. Commun. 1990, 20, 955; (b)
Vanden Eynde, J. J.; Delfosse, F.; Lor, P.; Van Haverbeke, Y.
Tetrahedron 1995, 51, 5813; (c) Nagawade, R. R.; Shinde, D. B. Chin.
Chem. Lett. 2006, 17, 453; (d) Gogoi, P.; Konwar, D. Tetrahedron Lett.
2006, 47, 79; (e) Jadhav, G. R.; Shaikh, M. U.; Kale, R. P.; Gill, C. H.
Chin. Chem. Lett. 2009, 20, 292; (f) Singh, M. P; Sasmal, S.; Lu, W.;
Chatterjee, M. N. Synthesis, 2000, 1380; (g) Patzold, F.; Zeuner, F.;
Heyer, T. H.; Niclas, H. J. Synth. Commun. 1992, 22, 281.
16. (a) Bhatnagar, I.; George, M. V. Tetrahedron 1968, 24, 1293; (b)
Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971; (c) Trivedi, R.;
De, S. K.; Gibbs, R. A. J. Mol. Catal. A: Chem. 2006, 245, 8; (d)
Massimo C.; Francesco E.; Francesca M. Synlett 2004, 1832.
17. (a) Beaulieu, P. L.; Hache, B.; Von Moos, E. Synthesis 2003, 1683; (b)
Austen, S. C.; Kane, J. M. J. Heterocycl. Chem. 2001, 38, 979; (c)
Dabhade, S. K.; Bora, R. O.; Farooqui, M.; Gill, C. H. Chin. Chem. Lett.
2009, 20, 893; (d) Shaterian, H. R.; Fahimi, N.; Azizi, K. Chin. J.
Chem. 2011, 29, 2389; (e) Xiangming, H.; Huiqiang, M.; Yulu, W.
Arkivoc 2007, 13, 150.
18. (a) Surpur, M. P.; Singh, P. R.; Patil, S. B.; Samant, S. D. Synth.
Commun. 2007, 37, 1375; (b) Nadaf, R. N.; Siddiqui, S. A.; Daniel T.;
Lahoti R. J.; Srinivasan K. V. J. Mol. Catal. A 2004, 214, 155; (c) Wu,
C. H.; Sun, C. M. Tetrahedron Lett. 2006, 47, 2601.
yellow solid, mp 72-74 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.23
(1H, s), 8.24-8.20 (2H, m), 7.39-7.27 (11H, m), 7.26-7.08 (2H, m),
7.03-6.86 (7H, m), 6.82-6.72 (2H, m), 6.55-6.49 (1H, m), 6.44-6.39
(4H, m), 6.27 (1H, s), 5.62-5.55 (6H, m), 5.08-4.98 (4H, m), 4.38-4.33
(1H, m), 4.29-4.23 (1H, m), 2.97-2.92 (1H, m), 2.80-2.74 (1H, m), 1.33
(3H, t, J = 7.1 Hz); 13C NMR (125 MHz, DMSO-d6) 167.0, 158.1,
157.9, 154.8, 146.1, 145.9, 144.6, 142.8, 142.7, 137.4, 135.8, 129.5,
129.4, 128.8, 128.7, 128.6, 128.0, 127.8, 125.3, 124.7, 124.5, 124.5,
118.6, 118.6, 115.7, 112.7, 112.7, 112.6, 112.2, 111.8, 97.3, 60.8, 60.7,
59.3, 56.2, 52.7, 39.6, 14.5; IR (KBr)vmax 3345, 2933, 1648, 1592,
1497, 1245, 1033, 693 cm-1; HRMS m/z calcd. for C52H48N8O4
[M+Na]+:
871.3696;
found:
871.3707.
2-(3-((Tert-
butyldimethylsilyl)oxy)phenyl)-1H-benzo[d]imidazole (6m): White
1
solid, mp 251-253 °C; H NMR (300 MHz, DMSO-d6) δ 7.76 (1H, d, J
= 7.9 Hz), 7.63 (1H, t, J = 1.8 Hz), 7.57 (2H, dd, J = 3.0, 6.0 Hz), 7.31
(1H, t, J = 7.9 Hz), 7.17 (2H, dd, J = 3.2, 6.0 Hz), 6.86 (1H, m), 0.93
(9H, s), 0.16 (6H, s); 13C NMR (75 MHz, DMSO-d6) 155.4, 150.8,
138.3, 130.5, 129.4, 129.3, 122.0, 121.9, 121.2, 121.2, 121.0, 119.4,
117.9, 114.4, 25.1, 17.5, -5.4; IR (KBr)vmax 3422, 3055, 2929, 2857,
1600, 1448, 1241, 935, 835, 744 cm-1; HRMS m/z calcd. for
C19H24N2OSi [M+H]+: 325.1736; found: 325.1750. 2-(3-((Tert-
butyldiphenylsilyl)oxy)phenyl)-1H-benzo[d]imidazole (6n): Off white
solid, mp 212-214 °C; 1H NMR (300 MHz, CDCl3) δ 7.91 (1H, m), 7.76
(2H, dd, J = 3.2, 6.2 Hz), 7.7.0 (4H, m), 7.43 (10H, m), 6.71(1H, dd, J =
1.7, 8.1 Hz), 1.06 (9H, s); 13C NMR (75 MHz,CDCl3) 156.1, 151.1,
137.9, 135.4, 135.3, 135.2, 132.4, 129.9, 130.0, 127.8, 127.7, 123.2,
121.7, 119.8, 118.3, 114.9, 26.3, 19.3; IR (KBr)vmax 3432, 3050, 2928,
2855, 1585, 1446, 1427, 1232, 1105, 931, 736, 700 cm-1; HRMS m/z
calcd. for C29H29N2OSi [M+H]+: 449.2044; found: 449.2040. 2-(4-
Phenylthiophen-2-yl)-1H-benzo[d]imidazole (6r): Off white solid, mp
1
245-246 °C; H NMR (300 MHz, DMSO-d6) δ 8.26 (1H, s), 8.05 (1H,
s), 7.75 (2H, d, J = 7.36 Hz), 7.60 (2H, t, J = 4.15 Hz), 7.51 (2H, t, J =
7.36 Hz), 7.38 (1H, m), 7.22 (2H, m); 13C NMR (75 MHz, DMSO-d6)
146.7, 141.9, 134.5, 134.3, 128.9, 127.4, 125.7, 125.2, 123.4, 122.2; IR
(KBr)vmax 3430, 2936, 1448, 1426, 1406, 1226, 742 cm-1; HRMS m/z
calcd. for C17H12N2S [M+H]+: 277.0794; found: 277.0796.
19. Typical experimental procedure for the synthesis of functionalized
piperidines: A mixture of benzaldehyde 1 (1 mmol), aniline 2a (1
mmol), and methyl acetoacetate 3a (0.5 mmol) in EtOH (10 mL) was
stirred magnetically at room temperature in the presence of B(C6F5)3 [5