Cerium(IV) sulfate catalyzed one-pot threecomponent diastereo selective synthesis of 4-amidotetrahydropyrans

Article abstract of DOI:10.1139/V09-050

A convenient and diastereoselective one-pot synthesis of cis-4-amidotetrahydropyrans is described. This simple protocol involves Prins cyclization of homoallylic alcohol and aldehydes, followed by Ritter reaction of acetonitrile leading to the formation o

Full text of DOI:10.1139/V09-050

698
Cerium(IV) sulfate catalyzed one-pot three-
component diastereo selective synthesis of 4-
amidotetrahydropyrans
Nagarajan Panneer Selvam and Paramasivan T. Perumal
Abstract: A convenient and diastereoselective one-pot synthesis of cis-4-amidotetrahydropyrans is described. This simple
protocol involves Prins cyclization of homoallylic alcohol and aldehydes, followed by Ritter reaction of acetonitrile lead-
ing to the formation of cis-4-acetamidopyrans in good yields.
Key words: cerium(IV) sulfate, diastereoselective, tetrahydroamidopyrans, Prins–Ritter reaction.
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Resume : On decrit une methode de synthese monotope commode et diastereoselective des cis-4-amidotetrahydropyranes.
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Ce protocole simple implique des reactions de cyclisation de Prins entre l’alcool homoallylique et divers aldehydes, suivies
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d’une reaction de Ritter avec de l’acetonitrile qui conduit a la formation des cis-4-acetamidopyranes avec de bons rende-
ments.
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Mots-cles : sulfate de cerium(IV), diastereoselective, tetrahydroamidopyranes, reaction de Prins–Ritter.
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[Traduit par la Redaction]
Introduction
Results and discussion
Multicomponent one-pot syntheses are highly important
because of their wide range of applications in pharmaceuti-
cal chemistry for the production of structural scaffolds and
combinatorial libraries for drug discovery.1 The tetrahydro-
pyran ring has attracted significant attention in recent years,
as it is part of the backbone of many natural products.2 It is
featured widely in many natural products, such as phorboxa-
zole A, psymberin, and (–)-centrolobine. The 4-amino tetra-
hydropyran ring system is a core unit in a number of natural
products, such as ambruticin VS, glycamino acid, and
others3 (Fig. 1). Because of their prevalence, there are multi-
ple strategies for the construction of these six-membered
ring systems, including Prins cyclization,4 hetero Diels–Alder
reactions,5 and intramolecular nucleophilic reactions.6
Among the several methods available, Prins cyclization7
offers one of the most versatile methods for the construc-
tion of the tetrahydropyran ring. A few reports on the use
of the Ritter reaction to terminate Prins cyclizations;8 the
scope of this process has not been explored extensively.
Recently, Yadav et al. described the synthesis of substi-
tuted tetrahydroamidopyran derivatives using CeCl3Á7H2O/
acetyl chloride,9 phosphomolybdic acid10 catalyst. Because of
the unique pharmacological, biological, and industrial impor-
tance, simple and efficient protocols for the synthesis of these
compounds are highly desirable.
In continuation of our work on the development of useful
synthetic methodologies using cerium(IV) sulfate,11 we
herein describe an efficient Prins–Ritter reaction sequence
for the direct synthesis of 4-acetamidotetrahydropyrans from
homoallylic alcohols, carbonyl compounds, and acetonitrile.
First, we carried out a three-component coupling reaction of
4-chlorobenzaldehyde with but-3-en-1-ol in acetonitrile in
the presence of 20 mol% Ce(SO4)2 at room temperature.
The reaction proceeded to completion in 6.5 h, and the prod-
uct, 4-acetamidotetrahydropyran (3a), was obtained in 93%
yield with cis-selectivity (Scheme 1).
Other Lewis acid catalysts, such as zinc(II) chloride,
ferric chloride hexahydrate, stannous chloride dihydrate, po-
tassium hydrogen sulfate, cerium(IV) sulfate, and phospho-
tungstic acid, were tested, but Ce(SO4)2 was found to be the
most efficient in terms of conversion.
Thus encouraged, we examined various substituted aryl
aldehydes and homoallylic alcohols for the synthesis of 4-
acetamidotetrahydropyrans under optimized reaction condi-
tions. 4-Chlorobenzaldehyde, 2,4-dichlorobenzaldehyde, 4-
nitrobenzaldehyde, 3-nitrobenzaldehyde, 4-methylbenzalde-
hyde, 4-bromobenzaldehyde, and 4-methoxybenzaldehyde
reacted well with 3-buten-1-ol and acetonitrile to produce the
corresponding 4-acetamidotetrahydropyrans in high yields
(Table 1, entries 1–8). An aliphatic aldehyde (propionalde-
hyde) also reacted with 3-buten-1-ol and acetonitrile to afford
the product in 82% yield (Table 1, entry 9). Furthermore, sub-
stituted homoallylic alcohols, such as 1-phenyl-but-3-en-1-ol,
1-(3-nitrophenyl)-but-3-en-1-ol, 1-(4-chlorophenyl)but-3-en-1-ol,
and 1-(2,4-dichlorophenyl)-but-3-en-1-ol also participated in this
transformation (Table 1, entries 10–15). Ketones, such as
cyclohexanone and cyclopentanone, reacted comparably
Received 18 November 2008. Published on the NRC Research
Press Web site at canjchem.nrc.ca on 8 May 2009.
N.P. Selvam and P.T. Perumal.1 Organic Chemistry Division,
Central Leather Research Institute, Chennai 600 020, India.
1Corresponding author (e-mail: ptperumal@gmail.com).
Can. J. Chem. 87: 698–705 (2009)
doi:10.1139/V09-050
Published by NRC Research Press

Selvam and Perumal
699
Scheme 1. Synthesis of 4-acetamidotetrahydropyran derivatives.
Scheme 2. Synthesis of spirocyclic 4-acetamidotetrahydropyrans.
Fig. 1. Examples of tetrahydropyran derivatives.
ments. The structure of 3j was also established by NOE ex-
periments (Fig. 2).
A rationale for the cis selectivity could be explained by
assuming the formation of an (E)-oxocarbenium ion via a
chair-like transition state, which has an increased stability
relative to the open oxocarbenium ion due to delocalization.
The optimal geometry for this delocalization places the hy-
drogen atom at C4 in a pseudo-axial position, which favours
equatorial attack of the nucleophiles.12
The structure 3j shown in Fig. 2 was deduced from the
NMR data, where the two substituents were shown to be cis
to each other. The H2 and H6 protons have a large coupling
of J = 10.0 Hz. Presence of the large coupling indicates that
it is in axial position, with large diaxial coupling with H3a
and H5a, which implies an equatorial position for the aro-
matic group at C2. Similarly, the equatorial orientation of
the substituent at C4 is suggested by the multiplicities of
H3a and H5a protons. The equatorial orientation of the sub-
stituents at C2 and C4 was also confirmed by NOESY cross
peaks for H2 with H4 and H6. This structure was further
confirmed by NOESY cross peaks for NH/H3a, NH/H3e,
NH/H5a, NH/H5e, Ar/H3a, and Ar/H3e.
giving spirocyclic 4-acetamidotetrahydropyrans in good
yields (Table 1, entries 16 and 17; Scheme 2).
The reactions were clean, and the products were obtained
in excellent yields with high diastereoselectivity as deter-
mined from the NMR spectra of the products. In all cases,
cis-isomer were obtained exclusively, and the structure of
which was confirmed by NOE experiments. The formation
of the products can be explained by hemi-acetal formation
followed by Prins cyclization and subsequent Ritter amida-
tion (Scheme 3).
In summary, we have described an efficient Prins–
Ritter reaction
to
produce
highly
substituted
4-acetamidotetrahydropyrans in high yields with all cis
selectivity. The use of inexpensive and readily available cer-
ium(IV) sulfate makes this procedure simple, convenient,
and practical. In addition to its simplicity, efficiency, and
milder reaction conditions, this method provides an easy ac-
cess for 4-acetamidotetrahydropyran derivatives with diverse
chemical structures.
The structures of compounds 3a–3q were characterized by
spectral and elemental analyses. Compound 3j showed peaks
at 3282, 3071, 1638, and 1114 cm–1, indicating the presence
of –NH–, –CH, –CO, and –C–O–C– groups in the IR
spectrum. A singlet at d 1.96 and a doublet at 5.49 (D2O
Experimental
1
exchangeable) in the H NMR and signals at d 22.7 and
168.5 in the 13C NMR spectrum confirmed the presence of
acetamido group in the molecule. The mass spectral data
and elemental analysis also supported the structural assign-
Materials and methods
Zinc(II) chloride, ferric chloride hexahydrate, stannous
chloride dihydrate, and potassium hydrogen sulfate were ob-
Published by NRC Research Press

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Can. J. Chem. Vol. 87, 2009
Table 1. Synthesis of 4-acetamidotetrahydropyrans via Prins–Ritter reaction.
Published by NRC Research Press

Selvam and Perumal
701
Table 1. Concluded.
Published by NRC Research Press

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Can. J. Chem. Vol. 87, 2009
Scheme 3. Plausible mechanism.
lowed by purification on silica gel (Merck, 100–200 mesh,
ethyl acetate – hexane, 4:6) gave pure 4-acetamidotetrahy-
dropyran.
Fig. 2. Characteristic NOE of 3j.
N-[2-(4-Chlorophenyl)tetrahydropyran-4-yl]acetamide 3a
(Table 1, entry 1)
White solid. Isolated yield: 93%, mp 177–179 8C. 1H
NMR (500 MHz, DMSO-d6) d: 1.16 (q, 1H, J = 11.5 Hz),
1.37 (m, 1H), 1.70 (m, 4H), 1.91 (d, 1H, J = 13.0 Hz), 3.49
(t, 1H, J = 12.3 Hz), 3.89 (m, 2H), 4.34 (d, 1H, J =
10.7 Hz), 7.28 (m, 4H), 7.84 (d, 1H, J = 7.65 Hz, D2O ex-
changeable). 13C NMR (125 MHz, DMSO-d6) d: 23.2, 32.6,
42.0, 46.0, 66.8, 77.4, 122.7, 128.6, 132.1, 142.1, 168.9. IR
nmax (KBr): 3287, 2930, 2845, 1643, 1563, 1362, 1148,
1090, 830 cm–1. Mass (ESI): 254 (M + 1). Anal. calcd. for
C13H16NO2Cl: C, 61.54; H, 6.36; N, 5.52%. Found: C,
61.75; H, 6.40; N, 5.58%.
tained from S.D. Fine Chemicals. Cerium(IV) sulfate and
phosphotungstic acid were purchased from Aldrich. Re-
agent-grade acetonitrile was used. All melting points are un-
corrected. IR spectra were recorded on a PerkinElmer FTIR
N-(2-Naphthalen-2-yl-tetrahydropyran-4-yl)acetamide 3b
(Table 1, entry 2)
Pale yellow solid. Yield: 90%, mp 154–156 8C. H NMR
1
1
spectrophotometer. H and 13C NMR spectra were recorded
(500 MHz, CDCl3) d: 1.52 (m, 2H), 1.89 (s, 3H), 2.03 (m,
1H), 2.32 (m, 1H), 3.76 (m, 1H), 4.23 (m, 1H), 4.24 (m,
1H), 4.56 (dd, 1H, J1 = 3.4 Hz, J2 = 13.0 Hz), 5.46 (d, 1H,
J = 8.4 Hz, D2O exchangeable), 7.47 (m, 3H), 7.59 (m,
4H).13C NMR (125 MHz, CDCl3) d: 23.2, 32.9, 40.3, 47.1,
67.4, 78.7, 124.1, 124.6, 125.9, 126.8, 127.4, 128.3, 133.0,
134.1, 139.8, 169.9. IR nmax (KBr): 3276, 3048, 2943, 1639,
1550, 1372, 1250, 1145, 1089, 964 cm–1. Mass (ESI): 270
(M + 1). Anal. calcd. for C17H19NO2: C, 75.81; H, 7.11; N,
5.20%. Found: C, 76.09; H, 7.16; N, 5.17%.
in DMSO-d6 and CDCl3 using TMS as an internal standard
on a JEOL and Bruker spectrometers at 500 MHz and
125 MHz, respectively. Mass spectra were recorded on a
Thermo Fennign mass spectrometer using electrospray ion-
ization method. Elemental analyses were recorded using a
Thermo Finnigan FLASH EA 1112 CHN analyzer. Column
chromatography was performed on silica gel (100–200
mesh, SRL, India). Analytical TLC was performed on pre-
coated plastic sheets of silica gel G/UV-254 of 0.2 mm
thickness (Macherey-Nagel, Germany).
N-[2-(2,4-Dichlorophenyl)tetrahydropyran-4-yl]acetamide
3c (Table 1, entry 3)
General procedure for the synthesis of 4-
acetamidotetrahydropyrans (3a–3q)
White solid. Isolated yield: 94%, mp 153–155 8C. 1H
NMR (500 MHz, DMSO-d6) d: 1.07 (q, 1H, J = 12.2 Hz),
1.41 (m, 1H), 1.72 (m, 4H), 1.99 (m, 1H), 3.54 (t, 1H, J =
11.5 Hz), 3.91 (m, 1H), 4.01 (m, 1H), 4.56 (d, 1H, J =
10.7 Hz), 7.38 (d, 1H, J = 8.4 Hz), 7.44 (d, 1H, J =
8.4 Hz), 7.51 (s, 1H), 7.86 (d, 1H, J = 6.9 Hz, D2O ex-
changeable). 13C NMR (125 MHz, DMSO-d6) d: 23.7, 32.5,
39.0, 45.77, 67.1, 74.8, 127.5, 128.4, 129.7, 131.8, 133.1,
139.3, 169.1. IR nmax (KBr): 3299, 2934, 2864, 1642, 1540,
A mixture of homoallylic alcohol (1.0 mmol), carbonyl
compound (1.0 mmol), and cerium(IV) sulfate (20 mol%) in
acetonitrile (5 mL, used as a solvent) was stirred at room
temperature for a specified time (Table 1). After completion
of the reaction as indicated by TLC, the reaction mixture
was quenched with ice water (10 mL) and extracted with
ethyl acetate (2 Â 15 mL). The combined organic layers
were dried over anhydrous Na2SO4. Removal of solvent fol-
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Selvam and Perumal
703
1366, 1145, 1086, 817, 714 cm–1. Mass (ESI): 288 (M + 1).
Anal. calcd. for C13H15NO2Cl2: C, 54.18; H, 5.25%; N, 4.86.
Found: C, 54.39; H, 5.29; N, 4.81%.
N-[2-(4-Methoxyphenyl)tetrahydropyran-4-yl]acetamide
3h (Table 1, entry 8)
1
Pale green solid. Yield: 88%, mp 182–184 8C. H NMR
(500 MHz, CDCl3) d: 1.36 (q, 1H, J = 12.5 Hz), 1.39 (m,
1H), 1.98 (s, 3H), 2.10 (m, 1H), 2.16 (m, 1H), 3.69 (m,
1H), 3.78 (s, 3H), 4.17 (m, 2H), 4.33 (dd, 1H, J1 = 2.2 Hz,
J2 = 11.8 Hz), 5.36 (d, 1H, J = 7.7 Hz, D2O exchangeable),
6.96 (d, 2H, J = 8.4 Hz), 7.18 (m, 2H). 13C NMR
(125 MHz, CDCl3) d: 23.1, 41.4, 43.1, 46.7, 54.7, 59.6,
74.1, 114.8, 129.1, 134.3, 156.8, 169.4. IR nmax (KBr):
3341, 2956, 2937, 1649, 1561, 1371, 1079, 1043, 814,
733 cm–1. Mass (ESI): 250 (M + 1). Anal. calcd. for
C14H19NO3: C, 67.45; H, 7.68; N, 5.62%. Found: C,67.63;
H,7.71; N, 5.66%.
N-[2-(4-Nitrophenyl)tetrahydropyran-4-yl]acetamide 3d
(Table 1, entry 4)
White solid. Isolated yield: 92%, mp 164–166 8C. 1H
NMR (500 MHz, DMSO-d6) d: 1.14 (q, 1H, J = 11.5 Hz),
1.40 (m, 1H), 1.71 (m, 4H), 1.99 (d, 1H, J = 12.2 Hz), 3.52
(t, 1H, J = 12.2 Hz), 3.93 (m, 1H), 4.02 (dd, 1H, J1
=
3.85 Hz, J2 = 11.5 Hz), 4.52 (d, 1H, J = 10.0 Hz), 7.55 (d,
2H, J = 8.4 Hz) 7.97 (d, 1H, J = 7.7 Hz), 8.14 (d, 2H, J =
8.4 Hz, D2O exchangeable). 13C NMR (125 MHz, DMSO-
d6) d: 23.8, 32.6, 39.3, 44.8, 68.4, 74.3, 126.8, 129.7, 132.9,
139.6, 168.4. IR nmax (KBr): 3288, 2922, 2858, 1672, 1519,
1425, 1345, 1148, 1084, 854 cm–1. Mass (ESI): 265 (M +
1). Anal. calcd. for C13H16N2O4: C, 59.08; H, 6.10; N,
10.60%. Found: C, 58.87; H, 6.16; N, 10.56%.
N-(2-Ethyltetrahydropyran-4-yl)acetamide 3i (Table 1,
entry 9)
1
White solid, Isolated yield: 82%, mp 80–83 8C. H NMR
(500 MHz, CDCl3) d: 0.96 (t, 3H, J = 7.5 Hz), 1.26 (m, 4H),
1.86 (m, 2H), 1.97 (s, 3H), 3.28 (m, 1H), 3.47 (m, 1H), 3.96
(m, 2H), 5.46 (d, 1H, J = 8.4 Hz, D2O exchangeable) . 13C
NMR (125 MHz, CDCl3) d: 9.9, 23.6, 29.3, 33.1, 39.3, 47.3,
68.9, 77.7, 169.3. IR nmax (KBr): 3288, 3097, 2956, 2936,
2847, 1648, 1560, 1439, 1374, 1156, 1096, 978, 738 cm–1.
Mass (ESI): 194 (M + Na). Anal. calcd. for C9H17NO2: C,
63.13; H, 10.01; N, 8.18%. Found: C, 63.37; H, 10.08; N,
8.21%.
N-[2-(3-Nitrophenyl)-tetrahydropyran-4-yl]acetamide 3e
(Table 1, entry 5)
White solid. Isolated yield: 92%, mp 186–188 8C. 1H
NMR (500 MHz, DMSO-d6) d: 1.17 (q, 1H, J = 12.3 Hz),
1.41 (m, 1H), 1.73 (m, 4H), 2.03 (m, 1H), 3.54 (t, 1H, J =
11.5 Hz), 3.92 (m, 1H), 4.03 (m, 1H), 4.52 (d, 1H, J =
11.5 Hz), 7.57 (t, 1H, J = 8.4 Hz) 7.73 (d, 1H, J = 7.7 Hz),
7.86 (d, 1H, J = 7.7 Hz), 8.07 (d, 1H, J = 8.4 Hz, D2O ex-
changeable), 8.11 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
d: 23.2, 32.5, 41.6, 45.9, 66.9, 76.8, 120.5, 122.6, 130.3,
133.5, 145.3, 148.2, 169.2. IR nmax (KBr): 3288, 2930,
2855, 1635, 1536, 1345, 1148, 1090, 735 cm–1. Mass (ESI):
265 (M + 1). Anal. calcd. for C13H16N2O4: C, 59.08; H,
6.10; N, 10.60%. Found: C, 59.31; H, 6.16; N, 10.58%.
N-(2,6-Diphenyltetrahydropyran-4-yl)acetamide 3j
(Table 1, entry 10)
Pale yellow solid. Isolated yield: 85%, mp: 220–222 8C.
1H NMR (500 MHz, CDCl3) d: 1.38 (q, 2H, J = 12.2 Hz),
1.96 (s, 3H), 2.26 (m, 2H), 4.35 (m, 1H), 4.64 (d, 2H, J =
10.0 Hz), 5.49 (d, 1H, J = 8.4 Hz, D2O exchangeable), 7.27
(m, 2H), 7.32 (t, 4H, J = 6.9 Hz), 7.40 (d, 4H, J = 6.9 Hz).
13C NMR (125 MHz, DMSO-d6) d: 22.7, 45.8, 77.3, 125.6,
127.2, 128.2, 142.5, 168.5. IR nmax (KBr): 3282, 3071, 2832,
1638, 1547, 1438, 1290, 1114, 738 cm–1. Mass (ESI): 296
(M + 1). Anal. calcd. for C19H21NO2: C, 77.26; H, 7.17; N,
4.74%. Found: C, 77.47; H, 7.21; N, 4.69%.
N-(2-p-Tolyltetrahydropyran-4-yl)acetamide 3f (Table 1,
entry 6)
White solid. Yield: 88%, mp 163–165 8C. 1H NMR
(500 MHz, CDCl3) d: 1.43 (m, 2H), 1.90 (s, 3H), 1.98 (m,
1H), 2.21 (m, 1H), 2.36 (s, 3H), 3.65 (m, 1H), 4.17 (m,
2H), 4.37 (dd, 1H, J1 = 3.1 Hz, J2 = 12.6 Hz), 5.46 (d, 1H,
J = 8.4 Hz, D2O exchangeable), 7.73 (m, 4H). 13C NMR
(125 MHz, CDCl3) d: 21.6, 21.9, 23.4, 26.1, 34.0, 40.6,
42.8, 126.3, 128.3, 134.8, 136.3, 169.3. IR nmax (KBr):
3286, 2957, 2938, 1651, 1556, 1371, 1096, 1042, 871,
730 cm–1. Mass (ESI): 256 (M + Na). Anal. calcd. for
C14H19NO2: C, 72.07; H, 8.21; N, 6.00%. Found: C, 72.37;
H, 8.26; N, 6.02%.
N-[2-(4-Bromophenyl)-6-phenyltetrahydropyran-4-
yl]acetamide 3k (Table 1, entry 11)
Pale yellow solid. Yield: 87%, mp 169–172 8C. H NMR
1
(500 MHz, CDCl3) d: 1.30 (m, 2H), 1.79 (s, 3H), 2.36 (m,
2H), 4.39 (m, 1H), 4.62 (m, 2H), 5.39 (d, 1H, J = 7.7 Hz,
D2O exchangeable), 7.30 (m, 5H), 7.46 (m, 2H), 7.52 (m,
2H). 13C NMR (125 MHz, CDCl3) d: 23.2, 40.8, 42.6, 47.8,
77.9, 79.3, 125.8, 128.3, 129.6, 130.6, 132.1, 141.6, 142.9,
143.2, 169.3. IR nmax (KBr): 3321, 2956, 2846, 1656, 1548,
1363, 1078, 946, 813, 736 cm–1. Mass (ESI): 375 (M + 1).
Anal. calcd. for C19H20BrNO2: C, 60.97; H, 5.39; N, 3.74%.
Found: C, 61.10; H, 5.40; N, 3.76%.
N-[2-(4-Bromophenyl)tetrahydropyran-4-yl]acetamide 3g
(Table 1, entry 7)
White solid. Yield: 90%, mp 176–178 8C. 1H NMR
(500 MHz, CDCl3) d: 0.96 (t, 3H, J = 7.5 Hz), 1.61 (m,
4H), 2.19 (m, 4H), 3.69 (m, 1H), 4.10 (m, 2H), 4.36 (dd,
1H, J1 = 2.2 Hz, J2 = 11.6 Hz), 5.21 (d, 1H, J = 7.7 Hz,
D2O exchangeable), 7.19 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H,
J = 8.4 Hz).13C NMR (125 MHz, CDCl3) d: 22.7, 32.8,
39.6, 47.1, 69.1, 77.9, 122.3, 128.4, 132.6, 142.1, 173.2. IR
nmax (KBr): 3296, 2956, 2849, 1648, 1560, 1268, 1096,
741 cm–1. Mass (ESI): 327 (M + 1). Anal. calcd. for
C15H20BrNO2: C, 55.23; H, 6.18; N, 4.29%. Found: C,
55.46; H, 6.23; N, 4.32%.
N-[2-(3-Nitrophenyl)-6-phenyltetrahydropyran-4-
yl]acetamide 3l (Table 1, entry 12)
Off-white solid. Isolated yield: 87%, mp 178–180 8C. H
1
NMR (500 MHz, DMSO-d6) d: 1.35 (m, 2H), 1.89 (s, 3H),
2.09 (m, 2H), 4.15 (m, 1H), 4.65 (m, 2H), 7.23 (m, 9H),
8.74 (d, 1H, J = 7.5 Hz, D2O exchangeable). 13C NMR
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Can. J. Chem. Vol. 87, 2009
(125 MHz, DMSO-d6) d: 22.7, 24.0, 33.4, 45.6, 56.9, 77.5,
120.1, 120.8, 122.3, 125.6, 127.2, 129.9, 132.3, 142.1,
144.6, 147.8, 168.9. IR nmax (KBr): 3301, 1663, 1533, 1347,
1096, 698 cm–1. Mass (ESI): 341 (M + 1). Anal. calcd. for
C19H20N2O4: C, 67.05; H, 5.92; N, 8.23%. Found: C, 67.29;
H, 5.98; N, 8.27%.
(ESI): 198 (M + 1). Anal. calcd. for C11H19NO2: C, 66.97;
H, 9.71; N, 7.10%. Found: C, 67.21; H, 9.77; N, 7.06%.
N-(1-Oxaspiro[5.5]undec-4-yl)acetamide 3q (Table 1,
entry 17)
White solid. Yield: 83%, mp 146–148 8C. 1H NMR
(500 MHz, CDCl3) d: 1.27 (m, 12H), 1.87 (m, 1H), 1.98 (s,
3H), 2.00 (m, 1H), 3.71 (m, 1H), 3.69 (m, 1H), 4.16 (m,
1H), 5.21 (d, 1H, J = 7.2 Hz, D2O exchangeable). 13C
NMR (125 MHz, CDCl3) d: 21.3, 23.8, 27.6, 33.4, 36.4,
41.8, 47.9, 68.4, 79.8, 169.4. IR nmax (KBr): 3346, 2958,
2931, 2847, 1648, 1536, 1349, 1208, 1098, 746 cm–1. Mass
(ESI): 234 (M + Na). Anal. calcd. for C12H21NO2: C, 68.21;
H, 10.02; N, 6.63%. Found: C, 68.43; H, 10.07; N, 6.59%.
N-[2-(4-Chlorophenyl)-6-(4-fluorophenyl)-
tetrahydropyran-4-yl]acetamide 3m (Table 1, entry 13)
1
Pale brown solid. Yield: 86%, mp 108–111 8C. H NMR
(500 MHz, CDCl3) d: 1.35 (m, 2H), 1.96 (s, 3H), 2.23 (m,
2H), 4.35 (m, 1H), 4.59 (d, 2H, J = 10.7 Hz), 5.61 (d, 1H,
J = 7.7 Hz, D2O exchangeable), 6.99 (t, 2H, J = 8.4 Hz),
7.30 (m, 6H). 13C NMR (125 MHz, CDCl3) d: 24.0, 36.3,
40.3, 46.2, 62.4, 78.3, 115.6, 126.5, 127.9, 129.3, 133.3,
137.7, 140.4, 162.7 (JC–F = 210.2 Hz), 169.6. IR nmax
(KBr): 3314, 2924, 1639, 1545, 1372, 1219, 1075, 828,
579 cm–1. Mass (ESI): 348 (M + 1). Anal. calcd. for
C19H19NO4FCl: C, 65.61; H, 5.51; N, 4.03%. Found: C,
65.73; H, 5.52; N, 4.06%.
Supplementary data
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca) or may be purchased
from the Depository of Unpublished Data, Document Deliv-
ery, CISTI, National Research Council Canada, Ottawa, ON
K1A 0R6, Canada. DUD 3929. For more information on ob-
taining material, refer to cisti-icist.nrc-cnrc.gc.ca/cms/
unpub_e.shtml.
N-[2-(2,4-Dichlorophenyl)-6-(3-
nitrophenyl)tetrahydropyran-4-yl]acetamide 3n (Table 1,
entry 14)
White solid. Yield: 88%, mp 128–131 8C. 1H NMR
(500 MHz, DMSO-d6) d: 1.24 (q, 1H, J = 11.5 Hz), 1.37 (q,
1H, J = 11.5 Hz), 1.76 (s, 3H), 2.09 (t, 2H, J = 13.8 Hz),
4.17 (m, 1H), 4.88 (t, 2H, J = 10.0 Hz), 7.46 (d, 1H, J =
8.4 Hz), 7.57 (s, 1H), 7.62 (m, 2H), 7.85 (d, 1H, J =
7.7 Hz), 7.91 (d, 1H, J = 7.7 Hz), 8.11 (d, 1H, J = 8.4 Hz,
D2O exchangeable), 8.20 (s, 1H). 13C NMR (125 MHz,
CDCl3) d: 23.2, 38.6,, 40.3, 45.8, 74.7, 77.1, 121.1, 122.1,
123.6, 128.1, 129.1, 129.9, 131.2, 132.2, 133.6, 138.9,
144.7, 148.3, 169.1. IR nmax: 3277, 2926, 2849, 1634, 1535,
1473, 1346, 1128, 1098, 815 cm–1. Mass (ESI): 409 (M +
1). Anal. calcd. for C19H18N2O4Cl2: C, 55.76; H, 4.43; N,
6.84. Found: C, 55.96; H, 4.46; N, 6.80%.
Acknowledgement
One of the authors, N.P., thanks the Council of Scientific
and Industrial Research, New Delhi, for the research fellow-
ship.
References
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N-[2-(2,4-Dichlorophenyl)-6-(4-
nitrophenyl)tetrahydropyran-4-yl]acetamide 3o (Table 1,
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White solid. Yield: 86%, mp 118–120 8C. 1H NMR
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1
Pale yellow solid. Yield: 85%, mp 148–150 8C. H NMR
(500 MHz, CDCl3) d: 1.26 (m, 12H), 1.89 (s, 3H), 3.47 (m,
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