Stereoselective one-pot, three-component synthesis of 4- amidotetrahydropyran

Article abstract of DOI:10.1021/jo7023366

(Chemical Equation Presented) The reaction of aldehyde with allylsilane in acetonitrile mediated by boron trifluoride etherate generated 4-aminotetrahydropyrans in good yields. The product is highly stereoselective.

Full text of DOI:10.1021/jo7023366

synthesis of 4-halo-,7 4-thio-,8 4-azido-,9 4-aryl-,10 and 4-hydroxy-
tetrahydropyran,5e,f,7d,11 methods for the synthesis of 4-ami-
notetrahydropyran are limited.12 In this paper, an efficient
method for the synthesis of 4 aminotetrahydropyran from
aldehyde, trimethylallylsilane, and acetonitrile mediated by BF3‚
Et2O is disclosed (Scheme 1). Thus, when benzaldehyde was
subjected to react with allyltrimethylsilane in acetonitrile in the
presence of boron trifluoride etherate, 4-acetamido-2,6-diphe-
nyltetrahydrofuran was obtained in 70% yield.
Stereoselective One-Pot, Three-Component
Synthesis of 4-Amidotetrahydropyran
U. C. Reddy, B. Rama Raju, E. K. Pramod Kumar, and
Anil K. Saikia*
Department of Chemistry, Indian Institute of Technology
Guwahati, Guwahati 781039, India
asaikia@iitg.ernet.in
SCHEME 1. Synthesis of 4-Acetamidotetrahydropyran
ReceiVed October 30, 2007
The reaction is generalized in Table 1. In all of the cases
studied, 4-acetamidotetrahydropyrans 1b-11b could be obtained
in high purity without any side products. Both aliphatic and
aromatic aldehydes give good yields with high diasteroselectivity
as determined from the 1H and 13C NMR spectrum of the crude
product. The substituent on the aromatic ring has a promising
effect on this reaction. The electron-withdrawing and simple
aldehydes gave good yields compared to electron-donating
groups on the ring. On the other hand, aliphatic aldehydes are
better substituents than the aromatic aldehydes. Only a single
diastereomer was obtained from each reaction, which was
determined by 1H and 13C NMR and comparison of the authentic
samples.11a The conformations of the compounds are in the chair
form, and all three substituents are in the equatorial position.
This was confirmed by NOE experiments and single-crystal
X-ray analysis (ORTEP diagram of 1b in the Supporting
Information).13
The reaction of aldehyde with allylsilane in acetonitrile
mediated by boron trifluoride etherate generated 4-aminotet-
rahydropyrans in good yields. The product is highly stereo-
selective.
Multicomponent reactions are gaining interest in organic
synthesis due to its ability to form multiple bonds in a single
step.1 Substituted tetrahydropyrans are important targets because
of their presence in many natural products.2 These tetrahydro-
pyrans are prepared by hetero-Diels-Alder methods,3 manipula-
tion of carbohydrates,4 Prins cyclization,5 and intramolecular
Michael reactions.6 Although there are a few methods for the
Other nitriles such as dichloroacetonitrile and bezonitrile also
gave the corresponding protected 4-aminotetrahydropyrans 1d-
6d in good yields (Table 2).
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10.1021/jo7023366 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/17/2008
1628
J. Org. Chem. 2008, 73, 1628-1630

SCHEME 2. Mechanism of the Reaction
TABLE 1. Synthesis of 4-Aminotetrahydropyran
TABLE 2. Synthesis of 4-dichloroacetamido- and
4-benzamidotetra-hydropyran
a Yields refer to isolated yield. Compounds are characterized by 1H, 13
NMR and IR spectra.
C
clization, and (iii) Ritter, can be performed without any
difficulties. To our knowledge, this is the first single-step method
for the synthesis of symmetric 2,6-disubstituted 4-acetamidot-
etrahydropyran. The mechanism of the reaction can be explained
as follows. In the presence of Lewis acid, allyltrimethylsilane
1 reacts with aldehyde to afford intermediate 2 (Scheme 2). The
intermediate 2 reacts with another molecule of aldehyde to give
tetrahydropyranyl cation 3, which in the presence of neucleo-
phile, CH3CN, gives intermediate 4. The species 4 upon
hydrolysis gives the 4-acetamidotetrahydropyran 5.
This method will be of immense importance in organic
synthesis, as the 4-aminotetrahydropyran skeleton is a core
structure in a number of bioactive molecules14 and natural
products such as ambruticins VS, glycamino acid, sialic acid,
(14) (a) Gopalsamy, A.; Moore, W. J.; Kern, J. C.; Molinari, A. J.; Shi,
M.; Welmaker, G. S.; Wilson, M. A.; Krishnamurthy, G.; Commons, T. J.;
Webb, M. B.; Woodworth, R. P. PCT. Int. Appl. WO 2006124875 A2,
2006, 516 pp. (b) Braun, A.; Courtemanche, G.; Crespin, O.; Fett, E.; Pascal,
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Decicco, C.; Maduskuie, T. P.; Voss, M. E. US Patent Appl. US 2004072802
A1, 2004, 150 pp.
a Yields refer to isolated yield. Compounds are characterized by 1H, 13
NMR and IR spectra.
C
The major advantage of this reaction is that in a single step,
three reactions, primarily (i) Sakurai-Hosomi, (ii) Prins cy-
J. Org. Chem, Vol. 73, No. 4, 2008 1629

and others.15 This type of skeleton is also used in photographic
films16 and host-guest chemistry.17
70%) as a crystalline solid with mp 223-224 °C. The product 1b
1
is characterized by spectrometric methods. H NMR (400 MHz,
CDCl3): δ 1.38-1.48 (m, 2 H), 1. 96 (s, 3 H), 2.25-2.30 (m, 2
H), 4.32-4.44 (m, 1 H), 4.65 (dd, J)11.2 and 2.0 Hz, 2 H), 5.60
(d, J) 8.0 Hz, 1 H), 7.25-7.43 (m, 10 H). 13C NMR (100 MHz,
CDCl3): δ 23.6, 40.6, 46.9, 78.5, 125.9, 127.7, 128.5, 142.2, 169.6.
IR: 3296, 2922, 2846, 1640, 1543, 1493, 1446, 1282, 1114, 1064
cm-1. Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 77.42; H, 7.20; N, 4.69.
In summary, an efficient, highly diastereoselective one-pot
method for the synthesis of 2,6-disubtituted 4-amidotetrahy-
dropyran in good yields has been developed. The scope and
synthetic applications of this novel reaction are under investiga-
tion in our laboratory.
N-[2,6-Bis-(4-nitrophenyl)tetrahydr-pyran-4-ylbenzamide (2d,
Table 2). To a mixture of nitrobenzaldehyde, 2c (151 mg, 1.0
mmol), allyltrimethylsilane (0.10 mL, 0.6 mmol.), and benzonitrile
(5.0 mL) was added borontrifluoride etherate (0.15 mL, 1.2 mmol)
drop by drop at rt. The reaction mixture was strirred at rt for 12 h.
Progress of the reaction was monitored by TLC using ethyl acetate
and hexane as eluents. After completion of the reaction, the product
was extracted with ethyl acetate and washed with brine and water.
The organic layer was dried (Na2SO4) and evaporated to leave the
crude product, which was purified by short column chromatography
over silica gel to give N-[2,6-bis(4-nitrophenyl)tetrahydropyran-4-
ylbenzamide 2d (300 mg, 67%) as a crystalline solid with mp 263-
264 °C. The product 2d was characterized by spectrometric
Experimental Section
General Procedure. To a mixture of aldehyde (1.0 equiv),
allyltrimethylsilane (0.6 equiv), and nitrile (5.0 mL) was added
borontrifluoride etherate (1.2 equiv) drop by drop at rt. The reaction
mixture was strirred at rt for specified time. The progress of the
reaction was monitored by TLC using ethyl acetate and hexane as
eluents. After completion of the reaction, the product was extracted
with ethyl acetate and washed with brine and water. The organic
layer was dried (Na2SO4) and evaporated to leave the crude product,
which was purified by short column chromatography over silica
gel to give the title compounds.
4-Acetamido-2,6-diphenyltetrahydropyran (1b, Table 1). To
a mixture of benzaldehyde, 1a (0.10 mL, 1.0 mmol), allyltrimeth-
ylsilane (0.10 mL, 0.6 mmol), and acetonitrile (5.0 mL) was added
boron trifluoride etherate (0.15 mL, 1.2 mmol) drop by drop at rt.
The reaction mixture was strirred at rt for 24 h. Progress of the
reaction was monitored by TLC using ethyl acetate and hexane as
eluents. After completion of the reaction, the product was extracted
with ethyl acetate and washed with brine and water. The organic
layer was dried (Na2SO4) and evaporated to leave the crude product,
which was purified by short column chromatography over silica
gel to give 4-acetamido-2,6-diphenyltetrahydropyran 1b (207 mg,
1
methods. H NMR (400 MHz, CDCl3/DMSO-d6): δ 1.52-1.61
(m, 2 H), 2.31-2.35 (m, 2 H), 4.30-4.45 (m, 1 H), 4.84-4.86
(m, 2 H), 6.10 (s, 1 H), 7.65-7.67(d, J ) 8.8 Hz, 2 H), 8.24-8.25
(d, J ) 8.8 Hz, 2 H), 8.35 (d, J ) 6.4 Hz, 1 H). 13C NMR (100
MHz, CDCl3/DMSO-d6): δ 37.8, 46.1, 65.7, 76.2, 122.6, 125.7,
146.2, 148.1, 162.7. IR: 3274, 3087, 2923, 2840, 1673, 1602, 1558,
1516, 1350, 1284, 1207, 1127, 1084, 850, 809, 746 cm-1. Anal.
Calcd for C19H17Cl2N3O6: C, 50.24; H, 3.77; N, 9.25. Found: C,
50.35; H, 3.81; N, 9.18.
Acknowledgment. A.K.S. and C.M.R. are grateful to the
Council of Scientific & Industrial Research (CSIR), New Delhi,
for financial support (Grant No. 01(1809)/02/EMR II) and a
fellowship, respectively.
(15) (a) Michelet, V.; Genet, J.-P. Curr. Org. Chem. 2005, 9, 405. (b)
Hoefle, G.; Steinmetz, H.; Gerth, K.; Reichenbach, H. Liebigs Ann. Chem.
1991, 941. (c) Suhara, Y.; Yamaguchi, Y.; Collins, B.; Schnaar, R. L.;
Yanagishita, M.; Hildreth, J. E. K.; Shimada, I.; Ichikawa, Y. Bioorg. Med.
Chem. 2002, 10, 1999. (d) Dondoni, A.; Boscarato, A.; Marra, A.
Tetrahedron: Asymmetry 1994, 5, 2209. (e) Ciccotosto, S.; von Itzstein,
M. Tetrahedrom Lett. 1995, 36, 5405. (f) Sabesan, S.; Neira, S.; Wasserman,
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Supporting Information Available: Experimental procedures
and full characterization data for all compounds, 1H and 13C NMR
spectra of all compounds and X-ray crystallographic data and
ORTEP diagram of 1b are included. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO7023366
1630 J. Org. Chem., Vol. 73, No. 4, 2008