Three-component, one-pot diastereoselective synthesis of 4-amidotetrahydropyrans via the Prins-Ritter reaction sequence

Article abstract of DOI:10.1016/j.tet.2008.01.038

Three-component coupling of carbonyl compounds, homoallylic alcohols, and nitriles has been achieved using 20 mol % of phosphomolybdic acid (PMA) at ambient temperature via the Prins-Ritter sequence to furnish 4-amidotetrahydropyrans in high yields with a

Full text of DOI:10.1016/j.tet.2008.01.038

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3025e3031
www.elsevier.com/locate/tet
Three-component, one-pot diastereoselective synthesis
of 4-amidotetrahydropyrans via the PrinseRitter
reaction sequence
*
J.S. Yadav , B.V. Subba Reddy, S. Aravind, G.G.K.S. Narayana Kumar, C. Madhavi,
A.C. Kunwar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, Andhra Pradesh, India
Received 28 July 2007; received in revised form 21 December 2007; accepted 10 January 2008
Available online 16 January 2008
Abstract
Three-component coupling of carbonyl compounds, homoallylic alcohols, and nitriles has been achieved using 20 mol % of phosphomoly-
bdic acid (PMA) at ambient temperature via the PrinseRitter sequence to furnish 4-amidotetrahydropyrans in high yields with all cis selectivity.
Spirocyclic-4-amidotetrahydropyrans are obtained using cyclic ketones.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: PrinseRitter sequence; Nitriles; Heteropolyacids; Amidotetrahydropyrans
8
1
. Introduction
reactivities. They are non-toxic and allow cleaner reactions in
comparison to conventional catalysts. Also, heteropolyacids are
promisingsolidacidsand act asbifunctional catalystsinhomoge-
The multi-component one-pot synthesis has received great
9
importance because of its wide range of applications in phar-
maceutical chemistry for production of structural scaffolds and
combinatorial libraries for drug discovery. In particular, three-
component coupling (3CC) reactions have proven remarkably
successful in generating molecular complexities in a single
step operation. The 4-aminotetrahydropyran ring system is
a core structure in a number of natural products such as am-
bruticins VS, glycamino acid, and others. Generally, tetra-
hydropyran derivatives are prepared via Prins cyclization
using acid catalysis. However, the use of Ritter amidation
6
to terminate Prins cyclization is scarce, hence an efficient
and practical methodology for the PrinseRitter type reaction
7
would be of great importance for natural product synthesis.
In recent years, heteropolyacids (HPAs) are environmen-
tally friendly and economically viable solid acids owing to
their ease of handling, high catalytic activities, and
neous as well as in heterogeneous conditions. Among various
heteropolyacids, phosphomolybdic acid (PMA, H PMo O )
is one of the less expensive and commercially available solid
acid catalysts. However, there have been no reports on the
useofphosphomolybdicacidforthesynthesisof4-amidotetrahy-
dropyran derivatives via the PrinseRitter sequence.
3
12 40
1
0
1
2
,3
2. Results and discussions
4,5
In this paper, we describe a direct and efficient protocol for
the synthesis of 4-amidotetrahydropyrans by means of Prinse
Ritter sequence using PMA as solid acid catalyst. Initially, we
attempted the coupling of cyclohexanecarboxaldehyde with
but-3-en-1-ol in acetonitrile in the presence of 20 mol % of
phosphomolybdic acid. Surprisingly, the reaction went to com-
pletion over 6.5 h and the product, 4-acetamidotetrahydro-
pyran 3a was obtained, instead of 4-hydroxytetrahydropyran,
in 92% yield with cis selectivity (Scheme 1).
*
Corresponding author. Tel.: þ91 40 27193030; fax: þ91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.038

3026
J.S. Yadav et al. / Tetrahedron 64 (2008) 3025e3031
O
NHCOMe
p-methylbenzaldehyde, p-methoxybenzaldehyde, and p-nitro-
OH
benzaldehyde reacted readily with 3-buten-1-ol and acetonitrile
to produce the corresponding 4-acetamidotetrahydropyrans in
high yields (entries beg, Table 1). The structure of the 2,
H
20 mol% PMA
CH3CN, r.t.
+
O
1
2
3a
4-disubstituted tetrahydropyran was established by NOE exper-
iments (Fig. 1).
Scheme 1.
The structure of 3d shown in Figure 1 was deduced from
the NMR data, where the two substituents are shown to be
cis to each other. The H2 proton has a large and small coupling
of J¼11.2 and 2.2 Hz. Presence of the large coupling indicates
Encouraged by this result, we turned our attention to various
aldehydes, homoallylic alcohols, and nitriles. Interestingly,
propanaldehyde, hydrocinnamaldehyde, 2-naphthaldehyde,
Table 1
Preparation of 4-acetamidotetrahydropyrans via PrinseRitter reaction sequence
a
Time (h)
b
Yield (%)
Entry
Homoallyl alcohol
Carbonyl compound
Nucleophile
Amidopyrans
NHAc
CHO
OH
a
CH
3
CN
6.5
92
O
NHAc
OH
OH
b
c
CHO
CHO
CH
CH
3
CN
CN
7.0
7.0
90
89
O
NHAc
3
O
NHAc
CHO
OH
OH
OH
d
e
f
CH
CH
CH
3
CN
3
CN
3
CN
8.0
7.5
8.5
90
92
82
O
NHAc
CHO
O
Me
Me
NHAc
CHO
O
MeO
MeO
O2N
NHAc
CHO
OH
OH
g
h
CH
CH
3
CN
8.5
8.0
80
88
O
O N
2
NHAc
O
3
CN
O
NHAc
O
O
OH
OH
i
j
CH
CH
3
CN
CN
7.5
8.0
84
85
Ph
Ph
NHAc
O
3
O

J.S. Yadav et al. / Tetrahedron 64 (2008) 3025e3031
3027
Table 1 (continued)
Entry Homoallyl alcohol
a
Time (h)
b
Yield (%)
Carbonyl compound
Nucleophile
Amidopyrans
O
HN
O
CH2CH2CH3
CHO
CHO
OH
OH
k
CH
3
CH
2
CH
2
CN
7.0
7.5
88
Br
Br
O
HN
l
Me
3
CCN
87
O
O
HN
O
Ph
CHO
CHO
OH
m
PhCN
8.5
82
Br
Br
Br
NHAc
O
OH
n
o
p
CH
CH
CH
3
CN
3
CN
3
CN
8.0
7.5
7.5
85
92
91
Br
NHAc
OH
OH
CHO
O
NHAc
CHO
CHO
O
NHAc
OH
q
CH
CH
3
CN
8.0
7.5
84
86
O
Br
Br
NHAc
OH
CHO
r
3
CN
O
Me
Me
a
1
13
All products were characterized by H NMR, C NMR, IR, and mass spectrometry.
Isolated and unoptimized yield.
b
that it is in axial position, with large diaxial coupling with
H3a, which imply an equatorial position for the aromatic
group at C2. Similarly the equatorial orientation of the
substituent at C4 is suggested by the multiplicities of H3a
and H5a protons (H3a (q) with Jw11.9 Hz and H5a (dq)
with J¼4.8, w11.9 Hz). The equatorial orientation of the sub-
stituents at C2 and C4 is also confirmed by NOESY cross
peaks for H2 with H4 and H6. This structure was further con-
firmed by NOESY cross peaks for NH/H3a, NH/H3e, NH/
H5a, NH/H5e, Ar/H3a, and Ar/H3e.
CH3
O
H
3
H
NH
5
4
H
2
H
O
The substituted homoallylic alcohols like 1-phenylbut-en-
-ol, 1-cyclohexylbut-3-en-1-ol, and 1-(4-bromophenyl)-3-
H
1
H
6
1
H
H
buten-1-ol also participated well in this transformation (entries
ner, Table 1). The structure of the 2,4,6-trisubstituted tetrahy-
dropyran was established by NOE experiments (Fig. 2). As
Figure 1. Characteristic NOE’s of product 3d.

3028
J.S. Yadav et al. / Tetrahedron 64 (2008) 3025e3031
CH3
A rationale for the cis selectivity could be explained by as-
O
suming 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 op-
timal geometry for this delocalization places the hydrogen
atom at C4 in a pseudo-axial position, which favors equatorial
H
3
H
H C
NH
5
3
4
H
2
H
H
9
O
8
1
7
H
6
1
1
10
H
12
1
1
attack of the nucleophile. Among other solid acid catalysts
Ò
such as montmorillonite KSF, Amberlyst-15 , and phospho-
Figure 2. Characteristic NOE’s of product 3r.
tungstic acid tested, phosphomolybdic acid was found to be
efficient in terms of conversion. The scope and generality of
this process are illustrated with respect to various carbonyl
compounds, homoallylic alcohols, and nitriles, and the results
are presented in Table 1. It is noteworthy to highlight that both
aromatic and aliphatic substrates worked well for this
transformation.
expected, NMR data suggest that for 3r all the three 2, 4, and 6
substituents are at equatorial position. The H2 and H6 protons
show large vicinal couplings (J¼11.3 Hz), corresponding to
axial orientation of these protons, which was further confirmed
by H2/H6. This implies equatorial orientation of the substitu-
ents at 2 and 6 positions. Equatorial orientation of the substit-
uent at C4 position is confirmed by NOESY cross peak for H2/
H4, and also H4/H6. Further, equatorial position of the aro-
matic group was confirmed by NOESY cross peaks, H-or-
tho/H3e, and also H-ortho/H3a.The structure was further
confirmed by NOESY cross peaks for NH/H3a, NH/H3e,
NH/H5a, NH/H5e, H7/H5a, and H7/H5e.
3. Conclusion
In summary, we have described an efficient PrinseRitter re-
action to produce highly substituted 4-amidotetrahydropyrans
in high yields with all cis selectivity. The use of inexpensive
and readily available phosphomolybdic acid makes this proce-
dure simple, convenient, and practical. In addition to its
simplicity, efficiency, and milder reaction conditions, this
method provides an easy access for 4-amidotetrahydropyran
derivatives with diverse chemical structures.
This reaction was also successful with cyclic ketones such
as cyclohexanone, 4-phenyl-1-cyclohexanone, and cyclopeta-
none to give spirocyclic-4-acetamidotetrahydropyrans compa-
rably in good yields (entries hej, Table 1, Scheme 2).
NHCOCH3
O
OH
2
0 mol% PMA
CH3CN, r.t.
+
4. Experimental section
Ph
O
Ph
4.1. General
Scheme 2.
Melting points were recorded on Buchi R-535 apparatus
and are uncorrected. IR spectra were recorded on a PerkineEl-
The reaction was successful with other nitriles such as
1
mer FT-IR 240-c spectrophotometer using KBr optics. H
n-butyronitrile, tert-butyl nitrile, and benzonitrile (entries
kem, Table 1). In the absence of phosphomolybdic acid, the
reaction did not proceed even after a long reaction time
1
NMR and C spectra were recorded on Gemini-200 and Var-
3
ian Bruker-300 spectrometer in CDCl using TMS as internal
3
(
12 h). The reactions were clean and the products were ob-
standard. Mass spectra were recorded on a Finnigan MAT
1020 mass spectrometer operating at 70 eV.
tained at room temperature in excellent yields with high dia-
stereoselectivity as determined from the NMR spectra of the
crude products. In all cases, cis-isomer was obtained exclu-
sively and the structure of which was confirmed by NOE
experiments. The formation of the products could be explained
by hemi-acetal formation followed by Prins cyclization and
subsequent Ritter amidation (Scheme 3).
General procedure: A mixture of homoallylic alcohol
(1.0 mmol), carbonyl compound (1.0 mmol), and phosphomo-
lybdic acid (20 mol %) in nitrile (5 mL, used as a solvent) was
ꢀ
stirred at 23 C for a specified time (Table 1). After comple-
tion of the reaction as indicated by TLC, the reaction mixture
was quenched with water and extracted with ethyl acetate
+
R'
O
H
'
''''
O
..
R
R'
O
+
R
+
HO
..
R'
R
H
OH
+
2
R''
R''
:
N
OH
NHCOR''
R
N
+
O
R'
R'
R'
R
O
O
R
H
Scheme 3. A plausible reaction mechanism.

J.S. Yadav et al. / Tetrahedron 64 (2008) 3025e3031
3029
(
hydrous Na SO . Removal of solvent followed by purification
2ꢁ10 mL). The combined organic layers were dried over an-
4.1.5. N-[2-(4-Methylphenyl)tetrahydro-2H-4-pyranyl]-
acetamide (3e)
2
4
ꢀ
on silica gel (Merck, 100e200 mesh, ethyl acetateehexane,
:6) gave pure 4-amidotetrahydropyran. The products thus
Pale yellow solid, mp 166e168 C. IR (KBr): n 3294, 2956,
ꢂ1 1
4
2926, 1648, 1553, 1366, 1087, 1042, 802, 730 cm . H NMR
(300 MHz, CDCl ): d 1.30 (q, 1H, J¼12.0 Hz), 1.37 (dq, 1H,
obtained were characterized by NMR, IR, and mass
spectrometry.
3
J¼4.6, 12.4 Hz), 1.94 (s, 3H), 1.96 (ddq, 1H, J¼12.7, 4.4,
2
.2 Hz), 2.16 (ddt, 1H, J¼12.7, 4.6, 2.2 Hz), 2.32 (s, 3H), 3.64
4
.1.1. N-(2-Cyclohexyltetrahydro-2H-4-pyranyl)-
(dt, 1H, J¼2.2, 12.2 Hz), 4.16 (m, 1H), 4.19 (m, 1H), 4.34
(dd, 1H, J¼1.7, 11.3 Hz), 5.23 (d, 1H, J¼7.5 Hz), 7.08 (d, 2H,
acetamide (3a)
Colorless solid, mp 148e150 C. IR (KBr): n 3280, 3089,
ꢀ
13
J¼8.1 Hz), 7.16 (d, 2H, J¼8.1 Hz). C NMR (75 MHz,
2
8
1
944, 2930, 2822, 1648, 1543, 1422, 1373, 1091, 966,
CDCl ): d 169.3, 133.6, 129.4, 128.5, 125.6, 73.0, 59.4, 46.6,
3
ꢂ1
1
04 cm . H NMR (300 MHz, CDCl ): d 0.89e1.38 (m,
42.5, 40.1, 23.3, 21.2. LCMS m/z (%): (MþNa) 256. HRMS
3
0H), 1.56e1.90 (m, 5H), 1.93 (s, 3H), 3.04 (m, 1H), 3.41
calcd for C H NO Na: 256.1313. Found: 256.1320.
1
4
19
2
(
dt, 1H, J¼2.0, 12.0 Hz), 3.86 (m, 1H), 3.90 (m, 1H), 5.36
(d, 1H, J¼7.5 Hz). LCMS m/z (%): (MþNa) 248. HRMS
calcd for C H NO Na: 248.1626. Found: 248.1636.
4.1.6. N-[2-(4-Methoxyylphenyl)tetrahydro-2H-4-pyranyl]-
acetamide (3f)
1
3
23
2
ꢀ
Light green solid, mp 183e185 C. IR (KBr): n 3306, 2946,
ꢂ1
1
2936, 1651, 1548, 1376, 1078, 1042, 814, 720 cm . H NMR
4
.1.2. N-(2-Ethyltetrahydro-2H-4-pyranyl)acetamide (3b)
ꢀ
Colorless solid, mp 82e84 C. IR (KBr): n 3286, 3091,
954, 2930, 2842, 1642, 1559, 1437, 1373, 1155, 1091, 977,
(300 MHz, CDCl ): d 1.32 (q, 1H, J¼12.4 Hz), 1.38 (dq, 1H,
3
2
7
J¼4.5, 12.4 Hz), 1.93 (s, 3H), 2.06 (ddq, 1H, J¼12.6, 4.5,
2.2 Hz), 2.12 (ddt, 1H, J¼12.6, 4.5, 2.2 Hz), 3.63 (dt, 1H,
J¼2.4, 12.2 Hz), 3.77 (s, 3H), 4.06 (m, 1H), 4.11 (m, 1H), 4.32
(dd, 1H, J¼2.0, 11.3 Hz), 5.30 (d, 1H, J¼7.5 Hz), 6.80 (d, 2H,
ꢂ1
1
38 cm
.
H NMR (300 MHz, CDCl ): d 0.92 (t, 3H,
3
J¼7.3 Hz), 1.22e1.59 (m, 4H), 1.82e1.92 (m, 2H), 1.94 (s,
3
1
H), 3.22 (m, 1H), 3.44 (dt, 1H, J¼1.8, 12.0 Hz), 3.99 (m,
1
3
13
H), 3.95 (m, 1H), 5.31 (d, 1H, J¼8.2 Hz). C NMR
J¼8.5 Hz), 7.15e7.26 (m, 2H, J¼8.5 Hz). C NMR (75 MHz,
(
75 MHz, CDCl ): d 169.4, 77.7, 66.3, 46.0, 37.9, 32.6,
3
CDCl ): d 169.2, 156.6, 134.4, 128.5, 114.6, 73.6, 58.4, 54.6,
3
2
for C H NO Na: 194.1156. Found: 194.1165.
8.8, 23.0, 9.5. LCMS m/z (%): (MþNa) 194. HRMS calcd
46.4, 42.6, 40.3, 23.2. LCMS m/z (%): (MþNa) 272. HRMS
calcd for C H NO Na: 272.1262. Found: 272.1270.
14 19 32
9
17
2
4
.1.3. N-(2-Phenethyltetrahydro-2H-4-pyranyl)-
acetamide (3c)
Pale yellow solid, mp 90e92 C. IR (KBr): n 3308, 2923,
4.1.7. N-[2-(4-Nitrophenyl)tetrahydro-2H-4-pyranyl]-
acetamide (3g)
ꢀ
ꢀ
Yellow solid, mp 190e192 C. IR (KBr): n 3294, 2956,
ꢂ1
ꢂ1
1
2
852, 1648, 1543, 1368, 1083, 946, 745 cm
.
H NMR
2926, 1648, 1625, 1515, 1456, 1102, 1032, 812, 726 cm
1
.
(
300 MHz, CDCl ): d 1.26 (m, 2H), 1.31 (dq, 1H, J¼4.2,
H NMR (300 MHz, CDCl ): d 1.22 (q, 1H, J¼12.3 Hz),
3
3
1
1
1
2.2 Hz), 1.36 (q, 1H, J¼12.0 Hz), 1.85 (t, 2H, J¼7.5 Hz),
.93 (s, 3H), 2.66 (ddt, 1H, J¼2.2, 4.2, 12.0 Hz), 2.74 (ddq,
H, J¼2.2, 12.0, 12.0 Hz), 3.28 (m, 1H), 3.44 (dt, 1H,
1.44 (dq, 1H, J¼4.4, 12.3 Hz), 1.95 (s, 3H), 2.20 (ddq, 1H,
J¼12.3, 4.5, 2.4 Hz), 2.26 (ddt, 1H, J¼12.3, 4.5, 2.3 Hz),
3.67 (dt, 1H, J¼1.8, 12.0 Hz), 4.12 (m, 1H), 4.20 (m, 1H),
4.49 (dd, 1H, J¼2.0, 11.2 Hz), 5.23 (d, 1H, J¼7.0 Hz), 7.47
(d, 2H, J¼8.6 Hz), 8.18 (d, 2H, J¼8.6 Hz). LCMS m/z (%):
(MþNa) 287. HRMS calcd for C H N O Na: 287.1007.
J¼1.5, 12.0 Hz), 3.89 (m, 1H), 4.13 (m, 1H), 5.28 (d, 1H,
1
3
J¼8.3 Hz), 7.07e7.26 (m, 5H). C NMR (75 MHz, CDCl ):
3
d 23.1, 31.4, 32.5, 37.7, 38.3, 45.9, 66.3, 75.4, 125.6, 127.8,
1
3 16 2 4
1
calcd for C H NO Na: 270.1469. Found: 270.1478.
28.1, 141.7, 169.5. LCMS m/z (%): (MþNa) 270. HRMS
Found: 287.1015.
1
5
21
2
4
.1.8. N-[1-Oxaspiro[5.5]undec-4-yl]acetamide (3h)
Colorless solid, mp 148e150 C. IR (KBr): n 3350, 2954,
ꢂ1 1
ꢀ
4
.1.4. N-[2-(2-Naphthyl)tetrahydro-2H-4-pyranyl]-
acetamide (3d)
2922, 2851, 1632, 1536, 1367, 1206, 1083, 821, 743 cm . H
NMR (300 MHz, CDCl ): d 1.20e1.71 (m, 12H), 1.85 (dq,
ꢀ
Light yellow solid, mp 155e157 C. IR (KBr): n 3242, 3057,
936, 2851, 1633, 1558, 1363, 1306, 1250, 1145, 1089, 964,
3
2
8
1H, J¼4.6, 12.0 Hz), 1.93 (s, 3H), 2.04 (ddq, 1H, J¼12.0, 4.4,
2.2 Hz), 3.63 (dt, 1H, J¼2.2, 12.0 Hz), 3.68 (m, 1H), 4.11 (m,
ꢂ1
1
21, 738 cm . H NMR (500 MHz, CDCl ): d 7.81 (m, 4H,
3
1
3
Ar), 7.45 (m, 3H, Ar), 5.37 (d, 1H, NH, J¼8.3 Hz), 4.58 (dd,
1H), 5.10 (d, 1H, J¼6.7 Hz). C NMR (75 MHz, CDCl ):
3
1
H, H2, J¼11.2, 2.2 Hz), 4.24 (m, 1H, H4), 4.22 (m, 1H,
d 169.3, 138.4, 137.2, 129.0, 125.6, 78.5, 66.9, 46.4, 40.6,
32.8, 23.4, 21.0. LCMS m/z (%): (MþNa) 234. HRMS calcd
for C H NO Na: 234.1469. Found: 234.1476.
H6e), 3.73 (dt, 1H, H6a, J¼2.4, 12.2 Hz), 2.31 (ddt, 1H, H3e,
J¼12.8, 4.6, 2.2 Hz), 2.01 (ddq, 1H, H5e, J¼12.8, 4.4,
w2.3 Hz), 1.97 (s, 3H, COeMe), 1.55 (dq, 1H, H5a, J¼4.8,
1
2
21
2
1
3
w12.4 Hz), 1.45 (q, 1H, H3a, J w 11.9 Hz). C NMR
4.1.9. N-[9-Phenyl-1-oxaspiro[5.5]undec-4-yl]acetamide
(3i)
(
75 MHz, CDCl ): d 23.4, 32.7, 40.7, 46.5, 67.1, 78.7, 123.9,
3
ꢀ
1
1
24.3, 125.8, 126.1, 127.6, 128.0, 128.1, 132.9, 133.3, 139.4,
69.4. LCMS m/z (%): (MþNa) 292. HRMS calcd for
Colorless solid, mp 172e174 C. IR (KBr): n 3434, 3320,
2926, 2860, 1645, 1543, 1446, 1375, 1078, 971, 759,
ꢂ1
701 cm . H NMR (200 MHz, CDCl ): d 1.13e1.38 (m,
3
1
C H NO Na: 292.1313. Found: 292.1321.
7
1
19
2

3030
J.S. Yadav et al. / Tetrahedron 64 (2008) 3025e3031
þ
3
2
5
7
1
2
H), 1.32e1.77 (m, 6H), 1.84e1.98 (m, 5H), 2.39e2.55 (m,
H), 3.64 (dt, 1H, J¼2.2, 12.0 Hz), 3.77 (ddd, 1H, J¼1.5,
.2, 12.0 Hz), 4.15 (m, 1H), 5.58 (d, 1H, J¼7.5 Hz), 7.08e
172.2. LCMS m/z (%): (MþH ) 361. HRMS calcd for
C H BrNO : 360.0599. Found: 360.0606.
1
8
19
2
1
3
.25 (m, 5H). C NMR (75 MHz, CDCl ): d 169.3, 146.9,
4.1.14. N-[2-(4-Bromophenyl)-6-phenyltetrahydro-2H-4-
pyranyl]acetamide (3n)
Light yellow solid, mp 170e172 C. IR (KBr): n 3316,
2945, 2852, 1643, 1543, 1376, 1077, 942, 812, 735 cm .
1
H NMR (200 MHz, CDCl ): d 1.25e1.39 (m, 2H), 1.94 (m,
3
28.1, 126.7, 125.7, 71.8, 59.3, 43.9, 43.5, 42.4, 39.8, 33.0,
9.4, 28.6, 28.0, 23.3. LCMS m/z (%): (MþNa) 310. HRMS
ꢀ
ꢂ1
calcd for C H NO Na: 310.1782. Found: 310.1793.
2
1
8
25
3
3
H), 2.22e2.32 (m, 2H), 4.33 (m, 1H), 4.56e4.66 (m, 2H),
4
.1.10. N-(6-Oxaspiro[4.5]dec-9-yl)acetamide (3j)
Light yellow solid, mp 112e114 C. IR (KBr): n 3335, 2954,
ꢂ1 1
ꢀ
5.30 (d, 1H, J¼7.5 Hz), 7.21e7.39 (m, 7H), 7.41e7.46 (m,
1
3
2H). C NMR (75 MHz, CDCl ): d 23.4, 40.1, 40.3, 46.7,
3
2922, 2851, 1632, 1536, 1367, 1206, 1083, 821, 743 cm . H
NMR (200 MHz, CDCl ): d 1.24e1.75 (m, 12H), 1.87 (s, 3H),
3
NMR (CDCl , 75 MHz): d 23.1, 24.5, 33.1, 41.1, 42.1, 44.3,
61.0, 83.9, 169.2. LCMS m/z (%): (MþH ) 198. HRMS calcd
for C H NO : 198.1494. Found: 198.1505.
77.7, 78.4, 125.7, 127.4, 127.6, 128.4, 131.5, 140.8, 141.8,
3
1
3
142.0, 169.6. LCMS m/z (%): (MþNa) 397. HRMS calcd
.45e3.71 (m, 2H), 3.91 (m, 1H), 5.81 (d, 1H, J¼8.0 Hz).
C
for C H BrNO Na: 396.0575. Found: 396.0586.
19 20
2
3
þ
4.1.15. N-(2,6-Dicyclohexyltetrahydro-2H-4-pyranyl)-
1
1
20
2
acetamide (3o)
Colorless solid, mp 180e182 C. IR (KBr): n 3288, 3093,
ꢀ
4
.1.11. N-[2-(4-Bromophenyl)-tetrahydro-2H-4-pyranyl]-
butanamide (3k)
Colorless solid, mp 178e180 C. IR (KBr): n 3291, 2958,
2
7
1
3
1
2
956, 2932, 2843, 1644, 1559, 1437, 1373, 1155, 1091, 977,
ꢂ1
1
44 cm . H NMR (300 MHz, CDCl ): d 0.80e1.43 (m,
ꢀ
3
6H), 1.54e1.80 (m, 8H), 1.89e1.92 (m, 2H), 1.93 (s, 3H),
.00 (ddd, 2H, J¼11.0, 6.8, 1.2 Hz), 3.90 (m, 1H), 5.17 (d,
ꢂ1
1
2
924, 2850, 1636, 1549, 1250, 1095 cm
.
H NMR
(
1
200 MHz, CDCl ): d 0.94 (t, 3H, J¼7.55 Hz), 1.23 (m, 1H),
3
13
H, J¼7.9 Hz). C NMR (CDCl , 75 MHz): d 23.5, 26.5,
3
.64 (m, 2H), 1.93 (m, 1H), 2.09 (t, 2H, J¼7.5 Hz), 2.18 (m,
8.8, 29.2, 35.8, 43.2, 46.8, 80.3, 169.2. LCMS m/z (%):
2
H), 3.64 (dt, 1H, J¼2.2, 12.0 Hz), 4.08e4.21 (m, 2H), 4.35
(
MþNa) 330. HRMS calcd for C H NO Na: 330.2408.
1
9
33
2
(
dd, 1H, J¼2.2, 11.3 Hz), 5.19 (d, 1H, J¼7.5 Hz), 7.17 (d, 2H,
Found: 330.27416.
1
3
J¼8.3 Hz), 7.42 (d, 2H, J¼8.3 Hz). C NMR (75 MHz,
CDCl ): d 172.2, 140.9, 131.3, 127.2, 121.1, 77.8, 66.8, 46.0,
3
4
.1.16. N-(2,6-Diphenyltetrahydro-2H-4-pyranyl)-
acetamide (3p)
Light yellow solid, mp 232e234 C. IR (KBr): n 3279, 3070,
40.6, 38.5, 32.5, 19.0, 13.5. LCMS m/z (%): (MþNa) 349.
HRMS calcd for C H BrNO Na: 349.0575. Found: 349.0584.
1
5
20
2
ꢀ
ꢂ1
1
2951, 2842, 1641, 1552, 1373, 1293, 1120, 747, 696 cm . H
4.1.12. N-[2-(2-Naphthyl)tetrahydro-2H-4-pyranyl]-2,2-
dimethylpropanamide (3l)
NMR (300 MHz, CDCl ): d 1.38 (q, 2H, J¼12.0 Hz), 1.94 (s,
3
3
H), 2.29 (td, 2H, J¼2.2, 12.0 Hz), 4.35 (m, 1H), 4.64 (dd, 2H,
ꢀ
Pale brown solid, mp 172e174 C. IR (KBr): n 3422, 3284,
069, 2935, 2847, 1648, 1549, 1491, 1352, 1251, 1145, 1089,
1
25, 700 cm . H NMR (200 MHz, CDCl ): d 1.16 (s, 9H),
J¼1.5, 11.3 Hz), 5.24 (d, 1H, J¼7.5 Hz), 7.20e7.40 (m, 10H).
3
8
1
2
4
4
13
C NMR (CDCl , 75 MHz): d 23.4, 40.4, 46.7, 78.3, 125.7,
3
ꢂ1
þ
3
127.5, 128.3, 142.0, 169.4. LCMS m/z (%): (MþNa ) 318.
.41 (q, 1H, J¼12.0 Hz), 1.53 (dq, 1H, J¼4.6, 12.4 Hz),
.10 (ddq, 1H, J¼2.3, 4.4, 12.6 Hz), 2.34 (ddt, 1H, J¼2.2,
.6, 12.6 Hz), 3.70 (dt, 1H, J¼12.0, 2.4 Hz), 4.24 (m, 1H),
.26 (m, 1H), 4.52 (dd, 1H, J¼2.2, 11.2 Hz), 5.40 (d, 1H,
HRMS calcd for C H NO Na: 318.1469. Found: 318.1479.
2
1
9
21
4
4
.1.17. N-[2-(4-Bromophenyl)-6-cyclohexyltetrahydro-2H-
-pyranyl]acetamide (3q)
Pale yellow solid, mp 186e188 C. IR (KBr): n 3278, 2923,
ꢂ1
1
3
J¼8.3 Hz), 7.42 (m, 3H), 7.79 (m, 4H). C NMR (75 MHz,
ꢀ
CDCl ): d 27.5, 33.0, 38.6, 40.9, 46.3, 67.1, 78.7, 101.6,
3
2848, 1643, 1553, 1488, 1369, 1154, 1085, 1010, 812 cm .
1
H NMR (300 MHz, CDCl ): d 0.95e1.32 (m, 5H), 1.12 (m,
1
1
23.9, 124.2, 125.8, 126.0, 127.6, 128.0, 132.9, 133.3,
39.5, 178.2. LCMS m/z (%): (MþNa) 334. HRMS calcd
3
1
H), 1.24 (m, 1H), 1.49 (m, 1H), 1.63e1.85 (m, 5H), 1.94
(s, 3H), 2.00 (ddt, 1H, J¼2.0, 4.2, 2.0 Hz), 2.16 (ddt, 1H,
J¼12.0, 4.2, 2.0 Hz), 3.30 (ddd, 1H, J¼11.0, 6.2, 2.0 Hz),
4.11 (ddt, 1H, J¼4.4, 8.5, 12.0 Hz), 4.35 (dd, 1H, J¼1.4,
for C H NO Na: 334.1782. Found: 310.1790.
2
0
25
2
4.1.13. N-[2-(4-Bromophenyl)tetrahydro-2H-4-pyranyl]-
benzamide (3m)
11.0 Hz), 5.23 (d, 1H, J¼7.3 Hz), 7.18 (d, 2H, J¼8.5 Hz),
ꢀ
13
7.41 (d, 2H, J¼8.5 Hz). C NMR (CDCl , 75 MHz): d 23.4,
Colouless solid, mp 206e208 C. IR (KBr): n 3278, 3064,
939, 2848, 1632, 1539, 1487, 1399, 1145, 1085, 827,
00 cm
3
2
7
26.2, 26.5, 28.7, 34.8, 40.4, 42.8, 46.7, 77.5, 80.7, 121.0,
þ
ꢂ1
1
.
H NMR (300 MHz, CDCl ): d 1.52 (q, 1H,
3
127.3, 131.3, 141.6, 169.4. LCMS m/z (%): (MþH ) 381.
J¼12.2 Hz), 1.66 (dq, 1H, J¼4.8, 12.2 Hz), 2.16 (ddq, 1H,
HRMS calcd for C H BrNO : 380.1225. Found: 380.1234.
1
9
27
2
J¼2.2, 4.4, 12.0 Hz), 2.32 (ddt, 1H, J¼2.2, 4.6, 12.0 Hz), 3.66
(
(
(
dt, 1H, J¼2.0, 12.2 Hz), 4.16 (m, 1H), 4.24 (m, 1H), 4.50
1
m, 9H). C NMR (75 MHz, CDCl ): d 32.5, 40.8, 46.6, 67.1,
4.1.18. N-[2-Cyclohexyl-6-(4-methylphenyl)-tetrahydro-2H-
4-pyranyl]acetamide (3r)
dd, 1H, J¼2.0, 12.0 Hz), 5.86 (d, 1H, J¼7.5 Hz), 7.11e7.76
3
ꢀ
Pale yellow solid, mp 188e190 C. IR (KBr): n 3314, 2923,
1
3
ꢂ1
7
7.8, 121.2, 126.7, 127.3, 128.5, 128.6, 131.4, 131.5, 140.8,
2852, 1646, 1543, 1368, 1083, 922, 804 cm
.
H NMR

J.S. Yadav et al. / Tetrahedron 64 (2008) 3025e3031
3031
(
(
4
500 MHz, CDCl ): d 7.22 (d, 2H, Ar-ortho, J¼7.9 Hz), 7.12
Bioorg. Med. Chem. 2002, 10, 1999e2013; (b) Hofle, G.; Steim-
netz, H.; Gerth, K.; Reichenbach, H. Liebigs Ann. Chem. 1991,
3
d, 2H, Ar-meta, J¼7.9 Hz), 5.30 (d, 1H, NH, J¼8.3 Hz),
9
41e945.
. (a) Wei, Z. Y.; Li, J. S.; Wang, D.; Chan, T. H. Tetrahedron Lett. 1987, 28,
441e3444; (c) Wei, Z. Y.; Wang, D.; Li, J. S.; Chan, T. H. J. Org. Chem.
.38 (dd, 1H, H2, J¼11.3, 2.0 Hz), 4.16 (dtt, 1H, H4, J¼8.3,
4
w11.9, w4.2 Hz), 3.31 (ddd, 1H, H6, J¼11.3, 6.2, 1.8 Hz),
3
2
2
3
1
.32 (s, 3H, AreMe), 2.19 (ddt, 1H, H3e, J¼12.4, 4.3,
.1 Hz), 2.00 (ddt, 1H, H5e, J¼12.3, 4.2, 2.1 Hz), 1.96 (s,
H, COeMe), 1.92e1.66 (m, 5H, Cy), 1.48 (m, 1H, H7),
.24 (m, 1H, H3a), 1.13 (m, 1H, H5a), 1.29e1.03 (m, 5H,
1989, 54, 5768e5774; (d) Coppi, L.; Ricci, A.; Taddei, M. J. Org. Chem.
1988, 53, 911e913.
. (a) Yang, J.; Viswanathan, G. S.; Li, C. J. Tetrahedron Lett. 1999, 40,
5
1
627e1630; (b) Chan, K.-P.; Loh, T.-P. Tetrahedron Lett. 2004, 45,
387e8390; (d) Miranda, P. O.; Diaz, D. D.; Padron, J. I.; Ramirez,
8
1
3
Cy). C NMR (75 MHz, CDCl ): d 169.2, 133.6, 129.8,
3
1
2
M. A.; Martin, V. S. J. Org. Chem. 2005, 70, 57e62.
6. (a) Al-Mutairi, E. H.; Crosby, S. R.; Darzi, J.; Harding, J. R.; Hughes, R. A.;
King, C. D.; Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem. Commun.
28.8, 125.5, 80.6, 46.8, 42.8, 40.4, 34.9, 28.9, 28.6, 26.5,
6.1, 23.4, 21.0. LCMS m/z (%): (MþNa) 338. HRMS calcd
2001, 835e836; (b) Perron, F.; Albizati, K. F. J. Org. Chem. 1987, 52,
4128e4130; (c) Epstein, O. L.; Rovis, T. J. Am. Chem. Soc. 2006, 128,
16480e16481.
for C H NO Na: 338.2095. Found: 338.2106.
2
0
29
2
Acknowledgements
7
. (a) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Tetrahedron Lett.
006, 47, 4397e4401; (b) Yadav, J. S.; Reddy, M. S.; Prasad, A. R.
2
Tetrahedron Lett. 2006, 47, 4937e4941; (c) Yadav, J. S.; Reddy, M. S.;
Prasad, A. R. Tetrahedron Lett. 2006, 47, 4995e4998.
S.A. and G.G.K.S.N.K. thank CSIR, New Delhi for the
award of fellowships.
8
. Misono, M.; Ono, I.; Koyano, G.; Aoshima, A. Pure Appl. Chem. 2000,
7
2, 1305e1311.
References and notes
9
. Kozhevnikov, I. V. Chem. Rev. 1998, 98, 171e198.
1
0. (a) Saidi, M. R.; Torkiyan, L.; Azizi, N. Org. Lett. 2006, 8, 2079e2082;
(b) Baskaran, S.; Kumar, G. D. K. Chem. Commun. 2004, 1026e1027;
(c) Kita, Y.; Tohma, H.; Kumar, G. A.; Hamamoto, H. Chem.dEur. J.
2002, 8, 5377e5383; (d) Rafiee, E.; Jafari, H. Bioorg. Med. Chem. Lett.
2006, 16, 2463e2466; (e) Okumura, K.; Yamashita, K.; Hirano, M.;
Niva, M. Chem. Lett. 2005, 34, 716e717.
1
. (a) D o¨ mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168e3210; (b)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T. A. Acc. Chem. Res. 1996, 29, 123e131; (c) Ugi, I. Pure Appl. Chem.
2001, 73, 187e191.
2. (a) Snider, B. B.; Hawryluk, N. Org. Lett. 2000, 2, 635e638; (b) Michelet,
V.; Genet, J.-P. Curr. Org. Chem. 2005, 9, 405e418.
11. (a) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002,
124, 4960e4961; (b) Ramesh, J.; Rychnovsky, S. D. Org. Lett. 2006, 8,
2175e2178.
3. (a) Suhara, Y.; Yamaguchi, Y.; Collins, B.; Schnaar, R. L.; Ya-
nagishita, M.; Hildreth, J. E. K.; Shimada, I.; Ichikawa, Y.