A Sakurai-Prins-Ritter reaction sequence for the diastereoselective synthesis of 4-amidotetrahydropyrans catalyzed by bismuth triflate

Article abstract of DOI:10.1016/j.tetlet.2008.07.079

The synthesis of 4-amidotetrahydropyrans has been achieved by a single-step Sakurai-Prins-Ritter reaction sequence in a domino fashion by the reaction of an aldehyde and allyltrimethylsilane in acetonitrile using Bi(OTf)₃ as catalyst. The prese

Full text of DOI:10.1016/j.tetlet.2008.07.079

Tetrahedron Letters 49 (2008) 5727–5731
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A Sakurai–Prins–Ritter reaction sequence for the diastereoselective synthesis
of 4-amidotetrahydropyrans catalyzed by bismuth triflate
a
a
a
b
b
Gowravaram Sabitha a, , M. Bhikshapathi , Sambit Nayak , J. S. Yadav , R. Ravi , A. C. Kunwar
*
a Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b N M R Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 4-amidotetrahydropyrans has been achieved by a single-step Sakurai–Prins–Ritter reac-
tion sequence in a domino fashion by the reaction of an aldehyde and allyltrimethylsilane in acetonitrile
using Bi(OTf)3 as catalyst. The present synthesis is highly efficient and diastereoselective.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 May 2008
Revised 11 July 2008
Accepted 12 July 2008
Available online 17 July 2008
Keywords:
Tetrahydropyrans
Diastereoselectivity
Aldehydes
Allyltrimethylsilane
Bi(OTf)3ꢀ4H2O
Sakurai–Prins–Ritter
Functionalized tetrahydropyrans constitute key structural
motifs of a large number of biologically active natural products.1
They have been constructed in a wide variety of ways, with the
most common strategies involving cyclizations onto oxacarbenium
ions or epoxides, hetero Diels–Alder cyclizations, conjugate addi-
tion reactions, and the reduction of cyclic hemiketals.2 Of the large
range of permutations available, the 2,4,6-substitution pattern has
been the most widely studied.2,3 We have investigated the con-
struction of trisubstituted tetrahydropyrans possessing a 4-halo
substituent.4 The synthetic utility of these cyclizations would be
greatly extended if functional groups other than a halide could
be introduced at C-4. Amino tetrahydropyrans are important struc-
tural motifs of a wide range of natural products5 such as ambrutic-
ins, oligomers of glucoamino acids, sialic acid, and desyherbaine.
These compounds are also used in photographic films6 and host-
guest chemistry.7 Examples of the Sakurai–Prins–Ritter (three
reactions) in a single step, for the synthesis of symmetric 2,6-
disubstituted-4-acetamidotetrahydropyrans are limited8 and it
has not been explored extensively. Recently, BF3ꢀOEt2 mediated
synthesis of symmetrically substituted 4-aminotetrahydropyrans
was reported, but stoichiometric amounts of catalyst and long
reaction times it required (8–36 h).9 Hence, there is still great
demand for a new catalytic system with high efficiency and low
catalytic loading.
We report herein an expedient direct synthesis of all cis 2,4,6-
trisubstituted tetrahydropyrans via a Sakurai–Prins–Ritter reaction
sequence mediated by Bi(OTf)3ꢀ4H2O. Bismuth compounds have
attracted recent attention due to their low toxicity, low cost, and
high stability.10 Bismuth salts have been reported as catalysts for
opening of epoxides,11 Mannich-type reactions,12 formation and
deprotection of acetals,13 Friedel–Crafts reactions,14 and Fries and
Claisen rearrangements.15 Bi(OTf)3 is particularly attractive
because it is commercially available or can be prepared easily from
commercially available starting materials.16,17
Initially, 2 equiv of benzaldehyde was treated with 1 equiv of
allyltrimethylsilane in acetonitrile in the presence of 10 mol %
Bi(OTf)3ꢀ4H2O at room temperature, resulting in 4-acetamido-
2,4-diphenyl tetrahydropyran in 85% yield with high diastereo-
selectivity (Scheme 1). The reaction was found to be very fast
and was complete within 45 min. Under similar conditions, various
NHCOCH3
Bi(OTf)3.4H2O (10 mol%)
Si(CH3)3
RCHO
+
CH3CN/ rt
R
O
R
1
2
3
R = alkyl, aryl
* Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.079

5728
G. Sabitha et al. / Tetrahedron Letters 49 (2008) 5727–5731
other aldehydes were reacted to afford the corresponding 4-ace-
tamidotetrahydropyrans (Table 1). In all the cases studied, ali-
phatic aldehydes were found to react rapidly furnishing the
corresponding products in excellent yields, whereas aromatic alde-
hydes reacted slowly. Among these, aromatic aldehydes containing
electron withdrawing groups gave higher yields of products,
compared to those having electron donating groups on the ring.
Electron-rich o-methoxybenzaldehyde led to the desired product
in moderate yield (Table 1, entry g). All the reactions are highly
diastereoselective, and from the 1H and 13C NMR spectra it was
apparent that a single product had been isolated in each reaction.
From NOE studies, it was confirmed that all three substituents
occupied equatorial positions on the tetrahydropyranyl ring (Fig-
ure 1). For tetrahydropyrans 3a and 3i, 1H NMR experiments were
performed at 500 MHz in CDCl3 solution. Assignments were made
using DQFCOSY experiments. The presence of a plane of symmetry
Table 1
Bi(OTf)3ꢀ4H2O-catalyzed synthesis of 4-amidotetrahydropyransa,b
Entry
Aldehyde
Product
Time (h)
0.75
Yield (%)
NHCOCH3
O
CHO
a
859
NHCOCH3
CHO
b
1.5
709
O
H3C
H3C
CH3
NHCOCH3
CHO
c
1.0
88
O
F
F
F
NHCOCH3
CHO
Cl
Cl
Cl
d
1.0
869
O
NHCOCH3
O
CHO
e
1.0
849
O2N
O2N
O2N
NO2
NO2
NHCOCH3
O
CHO
f
1.25
809
NO2
NHCOCH3
OMe
CHO
O
O
g
3.0
60
O
OMe
O
O

G. Sabitha et al. / Tetrahedron Letters 49 (2008) 5727–5731
5729
Table 1 (continued)
Entry
Aldehyde
Product
Time (h)
0.5
Yield (%)
NHCOCH3
h
989
CHO
O
NHCOCH3
i
0.5
0.5
96
CHO
O
NHCOCH3
j
CHO
94
O
NHCOCH3
k
0.5
95
CHO
O
a
All products were characterized by spectral data and confirmed by NOE studies.
Isolated pure products.
b
6
2b
H
H
2b
H
H
5
O
O
4'
4
H
H
2b'
2a
H
H
H3COC
N
2b'
2a
6'
H3COC
N
5'
H 2a'
H 2a'
1
H
1
H
3
H
1'
H
3
H
1'
H
3a
3i
Figure 1. Schematic nOe diagram of 3a and 3i.
Table 2
Bi(OTf)3ꢀ4H2O-catalyzed synthesis of 4-amidotetrahydropyrans using different nitrilesa,b
Entry
Aldehyde
Nitrile
Product
Time (h)
0.75
Yield (%)
NHCOPh
CN
CN
a
84
CHO
CHO
O
NHCOPh
b
1.5
80
O
(continued on next page)

5730
G. Sabitha et al. / Tetrahedron Letters 49 (2008) 5727–5731
Table 2 (continued)
Entry
Aldehyde
Nitrile
Product
Time (h)
0.75
Yield (%)
82
NHCO-C6H4-CH3
CN
CN
c
CHO
H3C
O
NHCO-C6H4-CH3
CHO
d
1.25
78
O
H3C
F
F
F
NHCOCH(CH3)2
e
CHO
CN
0.75
84
C7H15
O
H15C7
NHCOCH(CH3)2
CHO
f
CN
2.0
64
O
H3C
H3C
CH3
a
All products were characterized by spectral data and confirmed by NOE studies.
Isolated pure products.
b
in the molecules was evident from the 1H NMR spectra. We noticed
that dH1 = dH10, dH2a = dH2a0, and dH2b = dH2b0. For 3a, an nOe
cross peak between CH1/CH3 (CH10/CH3) revealed that H1(H10)
and H3 are on the same side of the ring and adopt a diaxial orien-
tation. The proposed structure of 3a was further supported by the
coupling constants 3JCH1/CH2a = 1.8, 3JCH1/CH2b = 11.7, 3JCH2a/CH3 = 4.3,
References and notes
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3
and JCH2b/CH3 = 11.7 Hz. Thus, CH2b (CH2b0) is antiperiplanar to
both CH1(CH10), and C3H. Interestingly, we also observed a
x cou-
pling of ꢁ2 Hz between H2a and H2a0, further supporting their
equatorial orientation. All these findings confirm that the pyran
ring adopts a chair conformation, where the substituents at C1,
C10 and C3 are present in equatorial positions. The spectral param-
eters and nOes for 3i are very similar to those for 3a and imply a
similar structure.
Similarly, the one-pot Sakurai–Prins–Ritter reaction of alde-
hydes and allyltrimethylsilane proceeded in the presence of other
nitriles such as benzonitrile, 4-methylbenzonitrile, and iso-butyro-
nitrile providing the corresponding products in good yields with
high diastereoselectivity as determined from the 1H NMR spectra
of the crude products. In all cases, the three substituents occupied
equatorial positions. The results are indicated in Table 2. This
catalytic (10 mol %) method offers several advantages including
mild conditions, rapidity, no formation of byproducts and does
not require an inert atmosphere.
In conclusion, we have developed an efficient one-pot, Sakurai–
Prins–Ritter reaction mediated by bismuth triflate to furnish 4-
amidotetrahydropyrans.
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8373–8397.
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Acknowledgment
M.B., S.N., and Ravi thank CSIR, New Delhi, for the award of
fellowships.

G. Sabitha et al. / Tetrahedron Letters 49 (2008) 5727–5731
5731
Eguillon, J.-C. Adv. Synth. Catal. 2006, 348, 2080–2084; (d) Ollevier, T.; Nadeau,
E. Synlett 2006, 219–222; (e) Ollevier, T.; Nadeau, E.; Guay-Begin, A.-A.
Tetrahedron Lett. 2006, 47, 8351–8354.
N1-(2,6-Dipropyltetrahydro-2H-4-pyranyl)acetamide 3i (Table 1): semi solid; IR
(KBr): cmꢃ1 3287, 2929, 2869, 1647, 1561, 1146; 1H NMR (CDCl3, 500 MHz): d
5.32 (d, J = 8.4, 1H), 4.00 (ttd, J = 4.3, 11.7, 8.4 Hz, 1H), 3.32 (m, 2H), 1.94 (s, 3H),
1.91 (dddd, J = 1.8, 2.0, 4.3, 13.0 Hz, 2H), 0.97 (td, J = 11.7, 13.0 Hz, 2H), 1.50 (m,
2H), 1.45 (m, 2H), 1.36 (m, 2H), 1.35 (m, 2H), 0.90 (m, 6H, CH3); 13C NMR
(CDCl3, 100 MHz): d 168.5, 76.2, 47.1, 38.8, 37.1, 22.8, 15.2, 13.7; HRMS (m/z)
calcd: 250.1782; found: 250.1782 (M++Na).
13. (a) Leonard, N. M.; Oswald, M. C.; Freiberg, D. A.; Nattier, B. A.; Smith, R. C.;
Mohan, R. S. J. Org. Chem. 2002, 67, 5202–5207; (b) Carrigan, M. D.; Sarapa, D.;
Smith, R. C.; Wieland, L. C.; Mohan, R. S. J. Org. Chem. 2002, 67, 1027–1030.
14. (a) Le Roux, C.; Dubac, J. Synlett 2002, 181–200; (b) Desmurs, J. R.; Labrouillere,
M.; Le Roux, C.; Gaspard, H.; Laporterie, A.; Dubac, J. Tetrahedron Lett. 1997, 38,
8871–8874; (c) Repichet, S.; Le Roux, C.; Dubac, J.; Desmurs, J. R. Eur. J. Org.
Chem. 1998, 2743–2746.
15. (a) Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794–2796;
(b) Ollevier, T.; Mwene-Mbeja, T. M. Synthesis 2006, 3963–3966; (c) Ollevier,
T.; Mwene-Mbeja, T. M. Tetrahedron Lett. 2006, 47, 4051–4055.
N1-(2,6-Dipentyltetrahydro-2H-4-pyranyl)acetamide 3j (Table 1): white solid,
mp: 80–82 °C; (KBr): cmꢃ1 3287, 3089, 2928, 2855, 1643, 1556; 1H NMR
(CDCl3, 300 MHz): d 5.60 (d, J = 7.5 Hz, 1H), 4.02–3.88 (m, 1H), 3.33–3.24 (m,
2H), 1.93 (s, 3H), 1.92–1.85 (m, 2H), 1.53–1.24 (m, 16H), 1.01–0.86 (m, 8H); 13
C
NMR (CDCl3, 75 MHz): d 169.2, 76.0, 46.4,38.6, 36.1, 31.7, 25.2, 23.5, 22.6, 14.0;
HRMS (m/z) calcd: 306.2408; found: 306.2421 (M++Na).
16. (a) Komatsu, N.; Uda, M.; Suzuki, H.; Takahashi, T.; Domae, T.; Wada, M.
Tetrahedron Lett. 1997, 38, 7215–7218; (b) Wieland, L. C.; Zerth, H. M.;
Mohan, R. S. Tetrahedron Lett. 2002, 43, 4597–4600; (c) Ollevier, T.; Ba, T.
Tetrahedron Lett. 2003, 44, 9003–9005; (d) Leroy, B.; Marko, I. E. Org. Lett.
2002, 4, 47–50; (e) Sreekanth, P.; Park, J. K.; Kim, J. W.; Hyeon, T.; Kim, B.
M. Catal. Lett. 2004, 96, 201–204; (f) Choudary, B. M.; Chidara, S.; Raja
Sekhar, C. V. Synlett 2002, 1694–1696; (g) Ollevier, T.; Li, Z. Org. Biomol.
Chem. 2006, 4, 4440–4443.
N1-(2,6-Diisopropyltetrahydro-2H-4-pyranyl)acetamide 3k (Table 1): semi solid;
(KBr): cmꢃ1 3283, 3091, 2943, 2879, 1644, 1556; 1H NMR (CDCl3, 300 MHz): d
5.62 (d, J = 7.5 Hz, 1H), 3.98–3.85 (m, 1H), 3.03–2.95 (m, 2H), 1.94 (s, 3H), 1.93–
1.87 (m, 2H), 1.67–1.59 (m, 2H), 0.95–0.86 (m, 14H); HRMS (m/z) calcd:
250.1782; found: 250.1787 (M++Na).
N1-(2,6-Dipropyltetrahydro-2H-4-pyranyl)benzamide 3a (Table 2): white solid,
mp: 126–128 °C; (KBr): cmꢃ1 3281, 3065, 2956, 2865, 1629, 1543; 1H NMR
(CDCl3, 300 MHz):
d 7.71 (dd, J = 8.0, 1.4 Hz, 2H), 7.43 (m, 3H), 5.84 (d,
17. (a) Repichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J. Tetrahedron Lett.
2002, 43, 993–995; (b) Labrouillere, M.; Le Roux, C.; Gaspard, H.; Laporterie, A.;
Dubac, J.; Desmurs, J. R. Tetrahedron Lett. 1999, 40, 285–286; (c) Peyronneau,
M.; Arrondo, C.; Vendier, L.; Roques, N.; Le Roux, C. J. Mol. Catal. A 2004, 211,
89–91; (d) Bi(OTf)3ꢀ4H2O was prepared from Bi2O3 according to Ref. 17a.
J = 8.8 Hz, 1H), 4.21–4.15 (m, 1H), 3.42–3.35 (m, 2H), 2.09–1.97 (m, 2H), 1.60–
1.30 (m, 8H), 1.17–0.97 (m, 2H), 0.93 (t, J = 7.3 Hz, 6H); HRMS (m/z) calcd:
312.1939; found: 312.1950 (M++Na).
N1-(2,6-Diphenyltetrahydro-2H-4-pyranyl)benzamide 3b (Table 2): white solid,
mp: 202–204 °C; (KBr): cmꢃ13282, 3081, 2923, 2843, 1634, 1546; 1H NMR
(e) General procedure: Allyltrimethylsilane
2
(0.6 mmol) was added to
a
(CDCl3, 300 MHz): d 7.65 (d, J = 7.5 Hz, 2H), 7.48–7.42 (m, 6H), 7.35 (t,
mixture of aldehyde 1 (1.0 mmol) and Bi(OTf)3ꢀ4H2O (10 mol %) in nitrile
(5 mL), and the reaction mixture was stirred at room temperature for the
specified time. After completion of the reaction (as indicated by TLC), the
reaction mixture was quenched with water and extracted with ethyl acetate
(2 ꢂ 5 mL), the combined organics were washed with brine and water, dried
(anhyd NaSO4), and concentrated to leave a crude compound which was
subjected to flash column chromatography using 4:1 hexane, ethyl acetate
solvent as eluent to afford a pure compound 3.
N1-(2,6-Diphenyltetrahydro-2H-4-pyranyl)acetamide 3a (Table 1): white solid;
mp: 220–222 °C; IR (KBr): cmꢃ1 3279, 3069, 2927, 2842, 1643, 1552, 747; 1H
NMR (CDCl3, 500 MHz): d 7.41 (m, 4H), 7.34 (m, 4H), 7.26 (m, 2H), 5.43 (d,
J = 8.4 Hz, 1H), 4.66 (dd, J = 1.8, 11.7 Hz, 2H), 4.39 (ttd, J = 4.3, 11.7, 8.4 Hz, 1H),
2.29 (dddd, J = 1.8, 2.0, 4.3, 13.0 Hz, 2H), 1.96 (s, 3H), 1.42 (td, J = 11.7, 13.0 Hz,
2H); 13C NMR (CDCl3, 100 MHz): d 168.3, 142.2, 128.8, 128.2, 126.2, 78.7, 46.0,
41.9, 23.9; HRMS (m/z): calcd: 318.1469; found: 318.1458 (M++Na).
N1-[2,6-Di(4-fluorophenyl)tetrahydro-2H-4-pyranyl]acetamide 3c (Table 1):
Brown solid, mp: 176–178 °C; (KBr): cmꢃ1 3275, 3082, 2947, 2925, 2840,
1643, 1603, 835; 1H NMR (CDCl3, 300 MHz): d 7.65 (d, J = 7.5 Hz, 2H), 7.34–
7.25 (m, 4H), 7.23–7.16 (m, 2H), 5.21 (d, J = 8.3 Hz, 1H), 5.02 (d, J = 9.8 Hz, 2H),
4.48–4.34 (m, 1H), 2.51–2.44 (m, 2H), 1.93 (s, 3H), 1.32–1.18 (m, 2H); 13C NMR
(CDCl3, 75 MHz): d 167.0, 161.3, 136.6, 125.8, 113.2, 112.9, 75.3, 44.1, 20.9;
HRMS (m/z) calcd: 354.1281; found: 354.1270 (M++Na).
J = 8.3 Hz, 4H), 7.30–7.26 (m, 3H) 5.95 (d, J = 8.3 Hz, 1H), 4.76 (d, J = 10.5 Hz,
2H), 4.67–4.53 (m, 1H), 2.50–2.42 (m, 2H), 1.61–1.48 (m, 2H); 13C NMR (CDCl3,
75 MHz): d 163.9, 140.6, 132.7, 129.1, 126.3, 126.2, 123.7, 75.8, 44.7.; HRMS
(m/z) calcd: 380.1626; found: 380.1632 (M++Na).
N1-(2,6-Diethyltetrahydro-2H-4-pyranyl)-4-methylbenzamide 3c (Table 2):
white solid, mp: 172–174 °C; (KBr): cmꢃ1 3290, 3037, 2959, 2920, 2875,
1632, 1541; 1H NMR (CDCl3, 300 MHz): d 7.60 (d, J = 8.3 Hz, 2H), 7.19 (d,
J = 8.3 Hz, 2H), 5.81 (d, J = 8.3 Hz, 1H), 4.24–4.09 (m, 1H), 3.36–3.26 (m,
2H),2.41 (s, 3H), 2.09–2.01 (m, 2H), 1.62–1.42 (m, 4H), 1.12–0.99 (m, 2H), 0.93
(t, J = 7.5 Hz, 6H); HRMS (m/z) calcd: 298.1782; found: 298.1795 (M++Na).
N1-[2,6-Di(4-fluorophenyl)tetrahydro-2H-4-pyranyl]-4-methylbenzamide
3d
(Table 2): white solid, mp: 212–214 °C; (KBr): cmꢃ1 3294, 3044, 2925, 2850,
1630, 1534; 1H NMR (CDCl3, 300 MHz): d 7.62 (d, J = 7.5 Hz, 2H), 7.43–7.37 (m,
4H), 7.22 (d, J = 8.3 Hz, 2H), 7.08–7.01 (m, 4H), 5.88 (d, J = 7.5 Hz, 1H), 4.72 (d,
J = 11.3 Hz, 2H), 4.63–4.50 (m, 1H), 2.47–2.39 (m, 5H), 1.57–1.43 (m, 2H);
HRMS (m/z) calcd: 430.1594; found: 430.1594 (M++Na).
N1-(2,6-Diheptyltetrahydro-2H-4-pyranyl)-2-methylpropanamide 3e (Table 2):
white solid, mp: 103–105 °C; (KBr): cmꢃ1 3283, 2924, 2853, 1646, 1551; 1H
NMR (CDCl3, 200 MHz): d 5.10 (d, J = 8.0 Hz, 1H), 4.03–3.89 (m, 1H), 3.37–3.24
(m, 2H), 2.33–2.14 (m, 1H), 1.96–1.84 (m, 2H), 1.50–1.24 (m, 24H), 1.13 (d,
J = 6.5 Hz, 6H), 0.98–0.85 (m, 8H); HRMS (m/z) calcd: 390.3347; found:
390.3353 (M++Na).
N1-[2,6-Di(2,6-dimethoxyphenyl)tetrahydro-2H-4-pyranyl]acetamide 3g (Table
1): Brown solid, mp: 226–228 °C; (KBr): cmꢃ1 3282, 3078, 2956, 2914, 2872,
1636, 1608; 1H NMR (CDCl3, 300 MHz): d 7.16 (d, J = 2.2 Hz, 2H), 6.72–6.70 (m,
4H), 5.22 (d, J = 8.3 Hz, 1H), 4.96 (d, J = 10.5 Hz, 2H), 4.45–4.34 (m, 1H), 3.81 (s,
12H), 2.43–2.33 (m, 2H), 1.95 (s, 3H), 1.26–1.13 (m, 2H); HRMS (m/z) calcd:
438.1892; found: 438.1824 (M++Na).
N1-[2,6-Di(4-methylphenyl)tetrahydro-2H-4-pyranyl]-2-methylpropanamide 3f
(Table 2): white solid, mp: 254–256 °C; (KBr): cmꢃ1 3284, 3089, 2932,
28640, 1648, 1556; 1H NMR (CDCl3, 300 MHz): d 7.29 (d, J = 8.3 Hz, 4H), 7.13
(d, J = 8.3 Hz, 4H), 5.22 (d, J = 7.5 Hz, 1H), 4.64 (d, J = 10.5 Hz, 2H), 4.41–4.28 (m,
1H), 2.36 (s, 6H), 2.32–2.25 (m, 3H) 1.44–1.31 (m, 2H), 1.15 (d, J = 6.8 Hz, 6H).;
HRMS (m/z) calcd: 374.2095; found: 374.2099 (M++Na).