1-Aza-2-siloxybutadiene: Structure and synthetic application as a piperidinone synthon

Article abstract of DOI:10.1055/s-2004-829180

Synthesis of 1-aza-2-siloxydienes and their structural analysis by multinuclear NMR are described. Moreover, the cycloaddition reaction of the isolated 1-aza-2-siloxydienes with dienophiles to synthesize piperidin-2-ones was explored.

Full text of DOI:10.1055/s-2004-829180

2222
SPECIAL TOPIC
1-Aza-2-siloxybutadiene: Structure and Synthetic Application as a
Piperidinone Synthon
1
-Aza-2-siloxybut
i
a
diene:
y
S
tructure
a
n
o
d Synthetic
A
s
pplicatio
e
n
i Takasu,* Naoko Nishida, Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)2176879; E-mail: mihara@mail.pharm.tohoku.ac.jp
Received 21 May 2004
amide to give cyclic acryl amide dimer. In this communi-
Abstract: Synthesis of 1-aza-2-siloxydienes and their structural
cation, we wish to report the structural determination of
silylated a,b-unsaturated amide and their reactivity with
acrylate to synthesize piperidinones from acrylamides.
analysis by multinuclear NMR are described. Moreover, the cy-
cloaddition reaction of the isolated 1-aza-2-siloxydienes with di-
enophiles to synthesize piperidin-2-ones was explored.
Key words: silicon, amides, piperidines, cycloadditions, tandem
reactions
O
TBSOTf, NEt3
R2
CO2R
N
+
H
(R1 = H)
R1
1
Cycloaddition reactions of dienyl substrates and olefins
by concerted pericyclic reactions or non-concerted step-
wise cyclizations are one of the most useful methods to
prepare 6-membered cyclic compounds in organic syn-
thetic chemistry.1 It is well known that the cycloaddition
reactions extend to the synthesis of 6-membered heterocy-
cles by employing heteroatom-containing dienes or ole-
fins as substrates.2 The reactions have attracted a great
deal of interest to synthesize naturally occurring alkaloids,
biologically active synthetic molecules, and organic fine
chemicals.
R2
O
O
N
CO2R
N
R2
CO2R
R1
R1
2
Scheme 1
SiR3
O
N
O
R2
R2
N
a,b-Unsaturated amides are readily available from a,b-
unsaturated acids, and are utilized as monomers in the
preparation of polymers. However, they have been used
SiR3
R1
R1
B
A
less often as building blocks in the cycloaddition reaction Figure 1 Structures of N-silyl amide (A) and O-silyl imidate (B)
leading to heterocyclic compounds.3,4 Recently, we have
demonstrated that a,b-unsaturated amides act as N-
We have attempted to isolate silylated intermediate 3 from
C(=O)-C-C synthons of piperidinones (Scheme 1).5 The
a,b-unsaturated amide
1 by two different ways
reaction of a,b-unsaturated amide 1 with acrylate is pro-
moted by the assistance of silyl triflate and amine to give
multi-substituted piperidin-2-one 2. In our previous com-
munication,5 we have proposed the reaction proceeds
through a stepwise double Michael addition, because an
intermediacy of mono-Michael adduct has been obtained.
During the further exploration of the cycloaddtion of a,b-
unsaturated amide, the following problems are arising.
First puzzle is the structure of an initial reaction interme-
diate. Treatment of a,b-unsaturated amide with silyl tri-
flate and amine would cause either N- or O-silylation to
give N-silyl amide A or O-silyl imidate (1-aza-2-siloxydi-
ene) B, respectively (Figure 1). To best of our knowledge,
only fragmental studies have been reported for the struc-
tural analysis of silylated a,b-unsaturated amide.6,7 Sec-
ond, acryl amide possessing no b-substituent does not
react with acrylate but with another molecule of acryl
(Scheme 2); treatment of 1 with TBSOTf and NEt3 in
CH2Cl2 (method 1), and deprotonation of 1 with NaH fol-
lowed by addition of TBSCl in THF (method 2). In spite
of many efforts, no desired compound was obtained from
N-alkyl acrylamides and cinnamamides because of their
poor stability. On the other hands, N-phenyl acrylamide
(1a) affords crude silylated product with reasonable sta-
1
bility under both methods. The H and 13C NMR spectra
of the products, formed by both methods, are identical, but
O
OTBS
R2
R2
method 1 or 2
N
N
1
TBS
R1
R1
3
a; R1 = H, R2 = Ph
69%
85%
0%
b; R1 = Ph, R2 = Ph
c; R1 = Ph, R2 = Bn
d; R1 = H, R2 = p-MeOPh
52%
Scheme 2 (method 1) TBSOTf (1.2 equiv), Et3N (0.7–1.5 equiv),
CH2Cl2, r.t.; (method 2) NaH (1.0 equiv), THF, r.t., then TBSCl (1.0
equiv). All chemical yields were based on method 2.
SYNTHESIS 2004, No. 13, pp 2222–2225
Advanced online publication: 30.07.2004
DOI: 10.1055/s-2004-829180; Art ID: C04404SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4

SPECIAL TOPIC
1-Aza-2-siloxybutadiene: Structure and Synthetic Application
2223
removal of the impurity was rather difficult in the case of Next, the cycloaddition reaction of 1-aza-2-siloxydiene 3
method 1. Accordingly, silylated compounds 3 were pre- was explored. When an equimolar of 3a and methyl acry-
pared by method 2 in the following synthesis.
late is treated with TBSOTf (1.0 equiv) in dichloroethane
at room temperature, the desired 2-piperidinone 2a (cyclic
hetero-dimmer) was obtained in 37% yield (Table 2, entry
1). Under the conditions cyclic homo-dimer 4a, acyclic
hetero-dimer 5a and acyclic homo-dimer 6a were pro-
duced as by-products. The formation of acyclic 5 and 6
suggests that the cycloaddition reaction takes place
through a sequential pathway. We have found the reac-
tions performed using of 3 equivalents of TBSOTf or un-
der neat conditions result in better chemical yield of
desired 2a (entries 2 and 3). Piperidinone 2d was also ob-
tained in the reaction with p-methoxyphenyl substrate 3d
in 50% yield, but cinnamamide derivative 3b resulted in
no reaction (entries 4 and 5).
For the NMR study, we have prepared 15N-labelled (98%
enriched) a,b-unsaturated amides 1a*, 1b* and their silyl-
ated derivatives 3a*, 3b*. Their spectral data of selected
atoms (1H, 13C, 15N and 29Si) are summarized in Table 1.8
When the spectra of amides 1* are compared with the ones
of silylated 3*, the chemical shifts are significantly
changed. Especially, chemical shifts of aromatic carbon at
ipso position [C(1¢)] and the nitrogen atom move to ca 10
ppm and ca 130 ppm downfield, respectively. Although
the isolation of pure silylated derivative 3c from N-benzyl
cinnamamide (1c) (unlabeled) was unsuccessful, 15N
NMR of in situ generated 3c by the method 1 resulted in
ca 90 ppm downfield shift (dN 115.7 ppm for 1c, 204.2
ppm for 3c). The phenomenon would indicate the conju- Next, we surveyed another Lewis acids [MgCl2, MeAlCl2,
gation system of 3* is elongated by silylation of 1*. No Zn(OTf)2, Cu(OTf)2, Sn(OTf)2, Yb(OTf)3, Ti(OiPr)4,
29Si-15N spin-spin coupling of 3* is observed, which indi- FeCl3] in the reaction of 3a and 3d with methyl acrylate.
cates that there exists no covalent bonding between nitro- Among them, only FeCl3 afforded the desired 2a and 2d
gen and silicon atoms. Moreover, a single peak in the 29Si in a medium yield (entries 6 and 7). No reaction proceed-
NMR is detected at 23.5 ppm for 3*. The expected 29Si ed without catalyst even at higher temperature, but 3a was
chemical shifts for an O-silyl imidate and N-silyl amide recovered (entries 8 and 9). Cycloaddition of 3a promoted
are 19.6 ppm and 8.7 ppm, respectively.9 Judging from by TBSOTf with a,b-unsaturated ketone, such as methyl
whole NMR studies, the structure of silylated species 3* is vinyl ketone, give cyclic hetero-dimer 2e (entry 10), but
concluded to be O-silyl imidate, 1-aza-2-siloxydiene. Ob- only homo-dimers 4a and 5a were produced with maleic
servation of a bathochromic (blue shift) effect in the UV anhydride or styrene (entries 11 and 12).
spectrum of 3 compared to 1 also supports the O-silyl im-
idate structure (lmax = 268.5 nm for 1a, 297.0 nm for 3a).
In addition, the geometry of 3a and 3b could be deter-
In conclusion, we describe here the structural analysis of
1-aza-2-siloxydienes by multinuclear NMR analysis. Fur-
thermore, their synthetic application towards 5-substitut-
ed piperidin-2-ones was reported. Although it will be
mined as (E)-imidate by NOE observation.
required to improve the chemical yield, this study is, to
Table 1 NMR Spectral Data of Selected Atoms of 1* and 3*a
1'
O
2'
1'
N *
1
*
N
H
1
t
2
3
2'
SiMe2 Bu
NOE
O
2
R1
3
R1
3*
1*
Atom
C(1)
C(2)
C(3)
C(1¢)
H(2)
H(3trans
H(3cis)
H(2¢)
N
1a*
3a*
1b*
3b*
163.9 (d, JC-N = 14.5 Hz)
131.3 (d, JC-N = 10.1 Hz)
127.5 (s)
156.3 (d, JC-N = 12.9 Hz)
125.4 (s)
164.1 (br s)
156.7 (d, JC-N = 12.9 Hz)
N.A.b
120.9 (s)
125.2 (s)
142.4 (s)
N.A.b
137.8 (d, JC-N = 15.8 Hz)
6.36 (dd, J = 16.8, 10.5 Hz)
5.69 (dd, J = 10.5, 2.4 Hz)
6.39 (dd, J = 16.8, 2.4 Hz)
7.60 (d, J = 6.6 Hz)
133.9 (d, JN-H = 90.0 Hz)
–
148.0 (d, JC-N = 2.9 Hz)
6.09 (dd, J = 15.0, 8.4 Hz)
5.53 (dd, J = 8.4, 4.0 Hz)
6.10 (dd, J = 15.0, 4.0 Hz)
6.76 (d, J = 7.7 Hz)
265.5 (s)
138.0 (d, JC-N = 14.5 Hz)
6.59 (d, J = 15.6 Hz)
–
148.2 (s)
6.43 (d, J = 15.3 Hz)
–
)
7.5 (d, J = 115.6 Hz)
7.64 (br d)
7.42 (d, J = 15.3 Hz)
6.84 (d, J = 7.7 Hz)
259.0 (s)
133.8 (d, JN-H = 90.0 Hz)
–
Si
23.5 (s)
23.5 (s)
a 13C, 1H and 29 Si chemical shifts: relative to TMS (d = 0 ppm); 15N chemical shifts: relative to CH3NO2 (d = 379.6 ppm).
b N.A. means not assigned.
Synthesis 2004, No. 13, 2222–2225 © Thieme Stuttgart · New York

2224
K. Takasu et al.
SPECIAL TOPIC
Table 2 Lewis Acid-Mediated Cycloaddition of 3 with Dienophile
R2
N
R2
N
O
O
O
O
O
Lewis acid
COR3
N
R2
NHR2
N
R2
3
NHR2
R3
O
O
2
4
5
6
Entry Substrate
Dienophile (R3)a
Lewis acid (equiv)
Solventa
Temp.
Yield (%)a
2
4
5
6
1
2
3a
3a
3a
3b
3d
3a
3d
3a
3a
3a
3a
3a
MA (OMe)
MA (OMe)
MA (OMe)
MA (OMe)
MA (OMe)
MA (OMe)
MA (OMe)
MA (OMe)
MA (OMe)
MVK (Me)
maleic anhydride
styrene
TBSOTf (1 equiv)
TBSOTf (3 equiv)
TBSOTf (1 equiv)
TBSOTf (1 equiv)
TBSOTf (1 equiv)
FeCl3 (1 equiv)
FeCl3 (1 equiv)
none
DCE
DCE
neat
r.t.
r.t.
r.t.
37
48
47
0
18
nd
10
0
trace
3
6
nd
0
3
0
4
DCE
DCE
DCE
DCE
DCE
toluene
DCE
DCE
DCE
r.t.–60 °C
r.t.
0
0
5
50
38
45
0
nd
21
17
0
nd
trace
trace
0
nd
trace
8
6
r.t.
7
r.t.
8
r.t.
0
9
none
110 °C
r.t.
0
0
0
0
10
11
12
TBSOTf (1 equiv)
TBSOTf (1 equiv)
TBSOTf (1 equiv)
30
0
nd
ca 20
ca 20
nd
0
nd
ca 10
ca 10
r.t.
r.t.–60 °C
0
0
a Abbreviations; MA = methyl acrylate, MVK = methylvinylketone, DCE = 1,2-dichloroethane, nd = not determined.
our best knowledge, the first demonstration for the cy-
cloaddition of the isolated 1-aza-2-siloxydienes. Piperi-
Compound 2a
Colorless oil.
din-2-ones, which would be obtained by the above
IR (neat): 1709, 1651 cm–1.
reaction, would be useful as synthetic building blocks for
1H NMR (400 MHz, CDCl3): d = 7.41–7.37 (m, 2 H), 7.28–7.24 (m,
3 H), 3.88 (dd, J = 12.4, 9.0 Hz, 1 H), 3.70 (dd, J = 12.4, 5.1 Hz, 1
H), 3.06–2.99 (m, 1 H), 2.65–2.60 (m, 2 H), 2.30–2.03 (m, 2 H),
2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.4, 169.5, 142.5, 129.2, 127.0,
126.2, 52.3, 52.2, 39.1, 30.8, 23.8.
a variety of biologically active substances. We suppose
further investigation would reveal the possibility of 1-aza-
2-siloxydiene as a new synthon of various heterocyclic
compounds.
All reactions were carried out under an inert atmosphere. Anhy-
drous dichloroethane and toluene were distilled from CaH2 under
atmospheric or reduced pressure. 15N-enriched aniline was pur-
chased from Aldrich Chemical Co., Inc. 1H, 13C, 15N and 29Si NMR
spectra were recorded on a JEOL ECP 600 (600 MHz, 150 MHz, 60
MHz and 120 MHz for 1H, 13C, 15N and 29Si, respectively) or JEOL
AL400 (400 MHz and 100 MHz for 1H and 13C) apparatus in CDCl3.
Chemical shifts were reported in ppm downfield from TMS (d = 0)
for the 1H and 29Si NMR, MeNO2 (d = 379.60) for the 15N NMR and
relative to the central CDCl3 resonance (d = 77.00) for the 13C NMR
measurements.
HRMS: m/z [M+] calcd for C13H15NO3: 233.1052; found: 233.1045.
Compound 4a
Colorless oil.
IR (neat): 1632, 1605 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.94 (br s, 1 H), 7.45 (d, J = 7.8
Hz, 2 H), 7.38 (t, J = 7.8 Hz, 2 H), 7.31–7.24 (m, 5 H), 7.11 (t, J =
7.3 Hz, 1 H), 4.01 (dd, J = 12.3, 9.9 Hz, 1 H), 3.74 (dd, J = 12.3, 4.1
Hz, 1 H), 2.89–2.85 (m, 1 H), 2.76–2.68 (m, 1 H), 2.60–2.51 (m, 1
H), 2.26–2.12 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 169.9, 169.1, 142.2, 137.5, 134.2,
Cycloaddition Reaction of 3; Typical procedure
129.2, 129.0, 127.1, 126.1, 124.5, 119.8, 53.0, 42.2, 31.6, 25.1.
To a solution of methyl acrylate (0.1 mmol) and TBSOTf (0.3
mmol) in dichloroethane (0.4 mL) was added a solution of 3 (0.1
mmol) in dichloroethane (0.1 mL) at 0 °C. After being stirred for 24
h at ambient temperature, the resulting mixture was quenched with
sat. NaHCO3. The resultant was extracted with EtOAc, washed with
brine, dried over MgSO4, and concentrated. The residue was puri-
fied by flash column chromatography.
HRMS: m/z [M+] calcd for C18H18N2O2: 294.1368; found:
294.1364.
Compound 6a
Colorless oil.
IR (neat): 3310, 1651cm–1.
Synthesis 2004, No. 13, 2222–2225 © Thieme Stuttgart · New York

SPECIAL TOPIC
1-Aza-2-siloxybutadiene: Structure and Synthetic Application
2225
1H NMR (400 MHz, CDCl3): d = 8.82 (br s, 1 H), 7.60–7.07 (m, 10
H), 6.41 (dd, J = 16.6, 1.7 Hz, 1 H), 6.00 (dd, J = 16.6, 10.2 Hz, 1
H), 5.57 (dd, J = 10.2, 1.7 Hz, 1 H), 4.19 (t, J = 6.7 Hz, 2 H), 2.73
(t, J = 6.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 168.4, 166.5, 140.9, 138.1, 129.8,
128.8, 128.6, 128.3, 128.2, 128.0, 124.0, 119.8, 46.0, 36.6.
Acknowledgment
This work was financially supported by the Fujisawa Foundation
and a Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
HRMS: m/z [M+] calcd for C18H18N2O2: 294.1368; found:
References
294.1367.
(1) (a) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990.
Compound 3a* (98% 15N-enriched)
(b) Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S.; Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, 2002.
IR (neat): 2939, 1652, 1598 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.26 (t, J = 7.7 Hz, 2 H), 7.03 (t,
J = 7.7 Hz, 1 H), 6.76 (d, J = 7.7 Hz, 2 H), 6.09 (d, J = 4.0 Hz, 1 H),
6.08 (d, J = 8.4 Hz, 1 H), 5.53 (dd, J = 8.4, 4.0 Hz, 1 H), 1.01 (s, 9
H), 0.35 (s, 6 H).
13C NMR (150 MHz, CDCl3): d = 156.3 (d, JC-N = 12.9 Hz), 148.0
(d, JC-N = 2.9 Hz), 128.8, 125.4, 125.2, 122.9, 121.3, 25.9, 18.1,
–4.6.
(2) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: San
Diego, 1987. (b) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M.
P. Tetrahedron 2002, 58, 379.
(3) Synthesis of piperidines by intermolecular
cyclodimerization of acrylamide equivalents: (a) Lorente,
A.; Navio, J. L. G.; Perez, J. C. L.; Soto, J. L. Synthesis 1985,
89. (b) Elliott, M. C.; Galea, N. M.; Long, M. S.; Willock, D.
J. Tetrahedron Lett. 2001, 42, 4937.
15N NMR (60 MHz, CDCl3): d = 258.1.
29Si NMR (120 MHz): d = 23.5.
(4) Synthesis of piperidines by intramolecular cycloaddition of
a,b-unsaturated amides: (a) Ihara, M.; Ishida, Y.; Tokunaga,
Y.; Kabuto, C.; Fukumoto, K. J. Chem. Soc., Chem.
Commun. 1995, 2085. (b) Toyota, M.; Komori, C.; Ihara, M.
J. Org. Chem. 2000, 65, 7110. (c) Mekouar, K.; Genisson,
Y.; Leue, S.; Greene, A. E. J. Org. Chem. 2000, 65, 5212.
(5) Takasu, K.; Nishida, N.; Ihara, M. Tetrahedron Lett. 2003,
44, 7429.
UV–Vis (CH3CN): lmax = 297 nm.
Compound 3b* (98% 15N-enriched)
IR (KBr): 1661, 1626, 1595 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.42 (d, J = 15.3 Hz, 1 H), 7.36–
7.30 (m, 7 H), 7.08 (t, J = 7.8 Hz, 1 H), 6.84 (t, J = 7.7 Hz, 2 H),
6.43 (d, J = 15.3 Hz, 1 H), 1.07 (s, 9 H), 0.41 (s, 6 H).
(6) Jones, K.; Wilkinson, J.; Ewin, R. Tetrahedron Lett. 1994,
35, 7673.
(7) For comparable examples, structural analysis of silylated
benzamides: (a) Klebe, J. F. Acc. Chem. Res. 1970, 3, 299.
(b) Misaki, T.; Kurihara, M.; Tanabe, Y. Chem. Commun.
2001, 2478.
(8) Levy, G. C.; Lichter, R. L. Nitrogen-15 Nuclear Magnetic
Resonance Spectroscopy; John Wiley & Sons: New York,
1979.
13C NMR (150 MHz, CDCl3): d = 156.7 (d, JC-N = 13.0 Hz), 148.2,
139.4, 135.5, 129.0, 128.8, 128.6, 127.7, 122.9, 121.6, 115.7, 26.0,
–4.5.
15N NMR (60 MHz, CDCl3): d = 259.0.
29Si NMR (120 MHz, CDCl3): d = 23.6.
UV–Vis (CH3CN): lmax = 326 nm.
(9) Jancke, H.; Engelhardt, G.; Wagner, S.; Dirnens, W.;
Herzog, G.; Tieme, E.; Rühlmann, K. J. Organomet. Chem.
1977, 134, 21.
Synthesis 2004, No. 13, 2222–2225 © Thieme Stuttgart · New York