Reactions of N-Acyl imines with dihydropyrans

Article abstract of DOI:10.1055/s-2008-1032209

A series of dihydropyranyl acetamides was synthesized by the TFA-catalyzed reaction of dihydropyrans with N-acyl imines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032209

PAPER
871
Reactions of N-Acyl Imines with Dihydropyrans
R
eactionof N-
i
A
cyl Im
d
ines
w
ith D
i
ihydro
k
pyrans a Polat Cakir, Keith T. Mead*
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Fax +1(662)3251618; E-mail: kmead@ra.msstate.edu
Received 17 September 2007; revised 13 December 2007
*RO
O
Ph
*RO
O
Ph
O
Ph
*RO
Abstract: A series of dihydropyranyl acetamides was synthesized
by the TFA-catalyzed reaction of dihydropyrans with N-acyl imi-
nes.
+
+
N
N
N
Ph
Ph
Ph
Key words: N-acyl imines, dihydropyrans, dihydropyranyl aceta-
mides, Mannich reaction, cycloaddition
endo
exo
Equation 1
O
R
O
Ph
There has been a renewed interest in the use of N-acyl imi-
nes as intermediates for stereoselective synthesis.1 Perti-
nent to our own work, we noted that a number of groups
have studied the reactions of N-acyl imines and related de-
rivatives with electron-rich olefins, with varying out-
comes.2–7 Until recently, only a handful of examples of
[4+2]-cycloaddition reactions had been reported. Schmidt
was an early pioneer of this work, and reported the isola-
tion of cycloadducts in high yield from the reaction of vi-
nyl acetates with in situ generated N-acyl imines.7
Extending this concept, Dujardin and co-workers recently
reported the [4+2] cycloadditions of N-acyl imines with
chiral vinyl ethers as an enantioselective route to b-amido
aldehydes (Equation 1).3–5 Interestingly, it was observed
that the stereochemistry, as well as the mechanism of for-
mation, of the 1,3-oxazine cycloadducts was found to be
heavily influenced by the choice of Lewis acid used to
promote cycloaddition. In the presence of SnCl4, reactions
proceeded by a stepwise mechanism leading to the selec-
tive formation of exo products, whereas Yb(fod)3 favored
endo product formation via a concerted mechanism. In
contrast, Kobayashi has reported that when a silyl ether is
used as the donor, a Mannich-type reaction appears to be
the favored route (Equation 2).6
Me3SiO
Ph
+
NHCOR
CO2Et
N
CO2Et
Equation 2
no-1,3-oxazines II8 and study their behavior towards
nucleophilic ring cleavage. Ikeda has reported the reaction
of 2,3-dihydropyran with an N-methyl-N-acyl immonium
ion, generated in situ from 1,3,5-trimethyl[1,3,5]triazin-
ane under basic conditions.9 However, the bicyclic cy-
cloadduct in this case was an unstable immonium ion
which did not survive the reaction conditions. We thought
that the alternative use of an N-acyl imine would circum-
vent this problem and allow the isolation of the cycload-
duct. To our surprise, however, the only product we
observed in each case was the dihydropyranyl acetamide
I.
As Table 1 shows, this reaction is general for a variety of
donor–acceptor combinations, and showed a remarkable
degree of stereoselectivity. In all cases involving a 4-phe-
nyl substituted dihydropyran (entries 4–7), a single iso-
meric product formed, generally as a crystalline material.
The relative stereochemistries assigned to products 4c–f is
based on the X-ray crystal structure analysis of compound
4d (Figure 1). Not surprisingly, the reaction of dihydropy-
ran 1d10 (entry 8) gave a diastereomeric mixture of prod-
ucts 4g.
Independent work in our laboratory prompted us to study
related reactions of N-acyl imines with dihydropyrans as
a route to some novel bicyclic acetals (Scheme 1). Our in-
terest in this area stemmed from a broad focus on devel-
oping new methodologies for constructing polycyclic
structures of interest in natural product synthesis. Specif-
ically, our goal was to prepare a series of tetrahydropyra-
Two different procedures were employed in this study. In
the first of these, the N-acyl imine was generated in situ
R2
O
O
R2
NH
O
R2
O
O
O
R1
R1
R1
+
N
N
I
Ph
Ph
Ph
II
Scheme 1
SYNTHESIS 2008, No. 6, pp 0871–0874
x
x
.
x
x
.2
0
0
8
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032209; Art ID: M06207SS
© Georg Thieme Verlag Stuttgart · New York

872
S. P. Cakir, K. T. Mead
PAPER
Table 1 Reactions of N-Acyl Imines with Dihydropyrans
Entry
1
DHP
Reagent
O
Conditionsa
A
Productb
Yield (%)c
Ph
O
O
Ph
O
72
MeO
NH
NH
NH
NH
NH
1a
Ph
Ph
O
2a
4a
2
3
4
5
6
A
A
A
A
A
42
O
O
O
O
MeO
1a
Ph
Ph
Ph
O
2b
O
4b
4a
4c
4d
76
65
62
72
Ph
Ph
O
N
1a
Ph
O
Ph
3a
O
Ph
O
O
N
NH
NH
Ph
3a
O
Ph
1b
Ph
O
Ph
O
O
N
Ph
3b
O
Ph
Ph
Ph
Ph
Ph
1b
Ph
OMe
OMe
Ph
N
O
O
H
N
Ph
3a
Ph
Ph
O
1c
4e
4f
7
8
B
A
77
O
N
OMe
OMe
O
O
H
N
Ph
3b
Ph
Ph
O
1c
68e
O
N
Ph
O
O
O
Ph
BnO
BnO
BnO
NH
BnO
1dd
Ph
Ph
3a
4g
a Conditions A: TFA (0.2 equiv), CH2Cl2, 0 °C to r.t., 12 h; Conditions B: BF3·OEt2 (0.2 equiv), CH2Cl2, 0 °C to r.t., 12 h.
b All products were identified by 1H and 13C NMR spectroscopy.
c Yields are based on isolated and purified materials.
d Synthesized according to the published procedure.10
e Diastereomeric ratio is 1:1.5 as determined by 1H NMR spectroscopy.
from its N,O-acetal precursor in the presence of the donor other initiators such as SnCl4 generally gave lower yields
component (entries 1 and 2). In the second approach, the of the same products, as did the use of stoichiometric
N-acyl imine was separately prepared following literature amounts of TFA. In contrast to the findings of Dujardin,
procedures4,11 and immediately reacted with the dihydro- when Yb(fod)3 was used, no reaction was observed. The
pyran without purification (entries 3–8). Highest yields use of photolysis and ultrasound resulted in an equal lack
were found when catalytic TFA was employed. The use of of success. Predictably, yields increased slightly when
Synthesis 2008, No. 6, 871–874 © Thieme Stuttgart · New York

PAPER
Reaction of N-Acyl Imines with Dihydropyrans
873
4a
Crystalline white solid; mp 121–122 °C.
1H NMR (600 MHz, CDCl3): d = 7.80 (d, J = 7.4 Hz, 2 H), 7.79 (t,
J = 7.4 Hz, 1 H), 7.36 (t, J = 7.7 Hz, 2 H), 7.32–7.22 (m, 5 H), 6.65
(d, J = 8.0 Hz, 1 H), 6.41 (s, 1 H), 5.70 (d, J = 8.2 Hz, 1 H), 3.89–
3.87 (m, 2 H), 1.94–1.90 (m, 2 H), 1.81–1.78 (m, 2 H).
13C NMR (150 MHz, CDCl3): d = 166.6, 142.6, 140.1, 134.4, 131.5,
128.5, 127.8, 127.3, 126.9, 112.1, 65.5, 56.0, 22.0, 21.0.
4b
Crystalline white solid; mp 142–144 °C.
1H NMR (600 MHz, CDCl3): d = 7.21–7.30 (m, 5 H), 6.70 (d,
J = 7.9 Hz, 1 H), 6.35 (s, 1 H), 5.47 (d, J = 8.6 Hz, 1 H), 3.88–3.90
(m, 2 H), 1.97 (s, 3 H), 1.84–1.78 (m, 4 H).
13C NMR (150 MHz, CDCl3): d = 169.2, 142.1, 140.3, 128.3, 127.0,
126.8, 112.2, 65.3, 55.4, 23.0, 21.9, 20.7.
Figure 1 ORTEP diagram of compound 4d
LA
O
O
Me
4c
Crystalline white solid; mp 168–170 °C.
N
1H NMR (600 MHz, CDCl3): d = 7.42–7.25 (m, 15 H), 6.50 (s, 1 H),
6.12 (d, J = 7.4 Hz, 1 H), 5.60 (d, J = 7.5 Hz, 1 H), 4.00–3.95 (m, 1
H), 3.91 (dt, J = 2.0, 10.9 Hz, 1 H), 3.27 (br s, 1 H), 2.21–2.15 (m,
1 H), 1.78–1.75 (m, 1 H).
Ph
Ph
Figure 2 A zwitterion intermediate
13C NMR (150 MHz, CDCl3): d = 166.1, 144.6, 143.1, 140.3, 131.3,
electron-donating groups were present on the 2-position
of the dihydropyran (entries 6 and 7).
128.8, 128.3, 127.9, 127.2, 126.7, 112.6, 61.7, 56.2, 38.4, 31.1.
4d
Based on prior discussions of related reactions,5 it is high-
ly likely that these reactions proceed in a nonconcerted
fashion via a zwitterion intermediate (Figure 2), which
then loses a proton faster than ring-closure can occur. Un-
fortunately, attempts to trap this oxocarbenium ion with
added nucleophiles (e.g., anisole, allylsilane) were unsuc-
cessful.
Crystalline white solid; mp 130–131 °C.
1H NMR (600 MHz, CDCl3): d = 7.34–7.19 (m, 8 H), 7.16 (d,
J = 6.8 Hz, 2 H), 6.55 (s, 1 H), 5.83 (d, J = 7.7 Hz, 1 H), 5.39 (d,
J = 8.0 Hz, 1 H), 3.94–3.91 (m, 1 H), 3.87 (dt, J = 2.2, 10.8 Hz, 1
H), 3.12 (t, J = 4.1 Hz, 1 H), 2.14–2.07 (m, 1 H), 1.73 (s, 4 H).
13C NMR (150 MHz, CDCl3): d = 168.6, 144.1, 142.3, 140.4, 128.6,
128.4, 128.3, 127.7, 127.6, 126.4, 112.9, 61.7, 55.1, 38.2, 31.2,
22.8.
Crystallographic Data:14 C20H21NO2, M = 307.38, monoclinic,
space group P21/c, a = 15.7685 (8) Å, b = 8.9293 (5) Å,
c = 24.4424 (13) Å, a = 90.00°, b = 105.38 (2)°, g = 90.00°,
V = 3318.30 (3) Å3, Z = 8, F(000) = 1312, crystal size =
0.33 × 0.17 × 0.02 mm. The crystals were very thin and conse-
quently, diffraction was far too weak for a standard diffractometer.
Crystallographic data were collected on a Bruker-Nonius X8 Pro-
teum diffractometer equipped with multilayer-optic focused CuK
(a) radiation (l = 1.54178 Å) at 90 K (‘CryoCool LN2’, CryoIndus-
tries of America.) The structure was solved by direct methods
(SHELXS-97)15 and refined by full-matrix least-squares against F2
(SHELXS-97).15 Hydrogen atoms were found in difference maps
and refined using the appropriate riding model for each type of H
atom.
In summary, a Mannich-type reaction was observed in the
TFA-catalyzed reaction of dihydropyrans with N-acyl
imines. Related beta substitution reactions of dihydropyr-
ans have been documented.12 However, we are aware of
only one example of the use of a Michael acceptor in this
context.13
1H NMR: Bruker AMX 600 spectrometer (600 MHz); d values in
ppm relative to tetramethylsilane signal as internal reference; cou-
pling constants J in Hz; 13C NMR: Bruker AMX 600 spectrometer
(150 MHz); d values in ppm relative to the residual 13C solvent sig-
nal (CDCl3: d = 77.0) as internal reference. The progress of all reac-
tions was monitored by TLC, which was carried out on Merck silica
gel plates with fluorescent indicator. Flash column chromatography
was performed using 230–400 mesh silica gel. All commercially
available reagents were used as received unless otherwise reported.
Melting points are uncorrected. N-Acyl imines and N,O-acetal 2a
were prepared by using the reported procedures.4,10
4e
Crystalline white solid; mp 64–66 °C.
1H NMR (600 MHz, CDCl3): d = 7.52 (d, J = 8.5 Hz, 2 H), 7.42–
7.38 (m, 5 H), 7.33–7.21 (m, 6 H), 7.13 (d, J = 7.6 Hz, 2 H), 7.07
(d, J = 7.6 Hz, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 6.20 (s, 1 H), 4.20 (dt,
J = 2.5, 10.7 Hz, 1 H), 4.15–4.12 (m, 1 H), 3.80 (s, 3 H), 3.37 (br t,
J = 4.8 Hz, 1 H), 2.31–2.15 (m, 1 H), 1.85–1.80 (m, 1 H).
13C NMR (150 MHz, CDCl3): d = 165.2, 159.9, 154.1, 145.7, 141.4,
133.9, 131.2, 130.0, 129.3, 128.8, 128.4, 128.1, 127.0, 126.7, 126.1,
113.9, 107.3, 62.6, 55.7, 55.2, 37.0, 31.8.
Dihydropyranylacetamides 4a–g; General Procedure
To a solution of either N-acyl imine 3a/3b or N,O-acetal 2a (1.1
equiv) in CH2Cl2 was added dihydropyran 1a–d (1.0 equiv) at 0 °C
followed by trifloroacetic acid (0.2 equiv), unless otherwise indicat-
ed. The mixture was stirred overnight and then quenched with few
drops of H2O and dried (MgSO4). After filtration and evaporation of
CH2Cl2 in vacuo, the crude product was purified by flash column
chromatography using hexane–EtOAc mixtures.
Synthesis 2008, No. 6, 871–874 © Thieme Stuttgart · New York

874
S. P. Cakir, K. T. Mead
PAPER
4f
Oil.
(4) Gizecki, P.; Dhal, R.; Poulard, C.; Gosselin, P.; Dujardin, G.
J. Org. Chem. 2003, 68, 4338.
(5) Gizecki, P.; Dhal, R.; Toupet, L.; Dujardin, G. Org. Lett.
2000, 2, 585.
1H NMR (600 MHz, CDCl3): d = 7.50 (d, J = 8.0 Hz, 2 H), 7.39 (t,
J = 7.1 Hz, 2 H), 7.34–7.22 (m, 6 H), 7.12 (d, J = 7.5 Hz, 2 H), 6.90
(d, J = 8.0 Hz, 2 H), 5.97 (d, J = 8.6 Hz, 1 H), 5.31 (d, J = 8.4 Hz, 1
H), 4.20–4.11 (m, 2 H), 3.78 (s, 3 H), 3.30 (br s, 1 H), 2.29–2.20 (m,
1 H), 1.84–1.77 (m, 1 H), 1.47 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 168.5, 159.8, 153.8, 145.4, 141.2,
130.0, 128.8, 128.5, 128.3, 126.9, 126.8, 126.1, 113.7, 113.3, 106.8,
62.3, 55.1, 54.7, 37.0, 31.6, 22.7.
(6) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.;
Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507.
(7) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 602.
(8) Chmielewski has reported the formation of related bicyclic
structures from the reactions of glycals with trichloroacetyl
isocyanate, see: Chmielewski, M.; Kaluza, Z. J. Org. Chem.
1986, 51, 2395.
(9) Ikeda, K.; Morimoto, T.; Sekiya, M. Chem. Pharm. Bull.
1980, 28, 1178.
(10) Oguri, H.; Oomura, A.; Tanabe, S.; Hirama, M. Tetrahedron
Lett. 2005, 46, 2179.
4g
Isomeric mixture; oil.
1H NMR (600 MHz, CDCl3): d (major isomer) = 7.28 (t, J = 6.9 Hz,
2 H), 7.48–7.22 (m, 18 H), 6.50 (s, 1 H), 6.42 (d, J = 8.1 Hz, 1 H),
5.74 (d, J = 8.5 Hz, 1 H), 4.63–4.46 (m, 4 H), 3.97–3.91 (m, 1 H),
3.89–3.82 (m, 1 H), 3.79–3.74 (m, 2 H), 2.32 (td, J = 5.0, 16.0 Hz,
1 H), 2.03 (dd, J = 7.0, 16.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 166.5, 142.0, 141.4, 139.7, 138.0,
137.9, 137.88, 134.3, 131.6, 128.7, 128.6, 128.3, 127.74, 127.67,
127.6, 127.0, 126.9, 109.6, 76.5, 73.5, 71.1, 70.0, 68.7, 55.2, 27.8.
(11) Kupfer, R.; Meier, S.; Würthwein, E. U. Synthesis 1984,
688.
(12) (a) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
(b) Lellouche, J.-P.; Koeller, S. J. Org. Chem. 2001, 66,
693. (c) Unterhalt, B.; Bause, G. Pharmazie 1998, 53, 231.
(d) Moriguchi, T.; Endo, T.; Takata, T. J. Org. Chem. 1995,
60, 3523. (e) Hojo, M.; Masuda, R.; Sakaguchi, S.;
Takagawa, M. Synthesis 1986, 1016. (f) Barrett, A. G. M.;
Betts, M. J.; Fenwick, A. J. Org. Chem. 1985, 50, 169.
(13) Takaki, K.; Yamada, M.; Negoro, K. J. Org. Chem. 1982,
47, 5246.
Acknowledgment
We thank the National Institutes of Health, through NCI Grant No.
R15 CA122083-01, for financial support of this research.
(14) Crystallographic data (excluding structure factors) for
structure 4d reported in this paper have been deposited with
the Cambridge crystallographic Data Centre as
supplementary publication number CCDC 657468. Copies
of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44
(1223)336 033; E-mail: deposit@ccdc.cam.ac.uk].
(15) Sheldrick, G. M. SHELXS-97; University of Göttingen:
Göttingen, 1997.
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Synthesis 2008, No. 6, 871–874 © Thieme Stuttgart · New York