Polonovski-type Reaction Induced by O-Silylated Acetals

Full text of DOI:10.1021/jo971057f

8
268
J . Org. Chem. 1997, 62, 8268-8270
P olon ovsk i-typ e Rea ction In d u ced by
Sch em e 1. Sp ecu la tion of Rea ction Mech a n ism
O-Silyla ted Keten e Aceta ls
Yasuyuki Kita,* Kentoku Gotanda, Chino Fujimori,
Kenji Murata, Ryutaro Wakayama, and Masato Matsugi
Faculty of Pharmaceutical Sciences, Osaka University,
1
-6 Yamada-oka, Suita, Osaka 565, J apan
Received J une 11, 1997
In 1927, Max and Michael Polonovski reported that the
treatment of a tertiary amine N-oxide with acetic anhy-
dride results in a rearrangement in which one of the alkyl
groups attached to nitrogen is cleaved, and the N-acetyl
derivative of the corresponding secondary amine and
aldehyde are obtained.1 This reaction has been widely
used in alkaloid chemistry to create a carbon-carbon
bond on the R-carbon to the nitrogen through an iminium
ion intermediate.2 On the other hand, it is known that
the Polonovski-type reaction is induced by a silicon-
activator (TBDMSOTf) and nucleophiles, but it is neces-
sary to use a strong base such as alkyllithium.3
4 (path A). It is thought that 5 is formed by nucleophilic
addition of acetonitrile activated by ZnI
2
through path
B. The formation of 5 was inhibited by the use of another
solvent such as propionitrile. A convenient explanation
of the control of this reaction course by the difference in
the silyl part is depicted in Scheme 1. Namely, we
suggest that the attack of the siloxy anion on the
unreacted SKA is depressed by the steric repulsion in
the case of using SKA 2b whose silyl part is bulky.
Consequently the enolate anion derived from SKA as a
nucleophile is not formed (Scheme 1).
As can be seen in Table 1, SKA 2b only acts during
the activation of the N-oxide to the iminium ion inter-
mediate, and the nucleophilic attack by the enolate anion
does not occur. Therefore, we thought that it would be
feasible to introduce various nucleophilic species on the
R-carbon to the nitrogen by employing this remarkable
feature. Consequently, we could achieve a regioselective
carbon-carbon bond formation on the R-carbon atom of
the heterocyclic nitrogen in the N-oxide 6 in good yields
by addition of only the expected nucleophile (Table 2).
Finally, we could obtain the ring closed products 9a
and 9b by way of intramolecular carbon-carbon bond
formation of the N-oxides (8a and 8b) by employing the
4
We have reported that O-silylketene acetal (SKA) is
an excellent reagent for the silicon-induced Pummerer-
type rearrangement of various sulfoxides which under
nearly neutral conditions gives high yields of R-siloxy
sulfides.5 A similar silicon-induced Polonovski-type reac-
tion with tertiary amine N-oxides using the SKA treat-
ment would provide a useful method for carbon-carbon
bond formation to the R-carbon of the nitrogen of N-
oxides. Therefore, we first examined the silicon-induced
Polonovski reaction of N-oxides having an N-protected
6
indole (1) using SKA. Treatment of 1 with SKA (2a -c)
2
(5 equiv) in the presence of a catalytic amount of ZnI at
6
0 °C in acetonitrile gave carbon-carbon bond forming
compounds, the (methoxycarbonyl)methyl adduct 4 and
the cyanomethyl adduct 5 (Table 1). It has become
apparent that the choice of silyl moiety in SKA influences
the course of the reaction. Specifically, in the case of SKA
bulky activator 2b in the presence of trifluoroacetic acid
(2a ), bearing a tert-butyldimethylsilyl group, 4 was
or toluenesulfonic acid (Table 3).7 The participation of
preferentially converted to 5 (Table 1, entry 1), whereas
in the case of SKA (2b), bearing a tert-butyldiphenylsilyl
group, only the cyanomethyl compound 5 was obtained
SKA 2b in this reaction is apparent from the fact that
9
a and 9b are not formed by treatment only with
trifluoroacetic acid (5 equiv) at 60 °C in propionitrile.
In conclusion, it has been found that the reaction of
N-oxides and SKA 2b shows a regioselective carbon-
carbon bond formation on the R-carbon to the nitrogen
of the tertiary amine N-oxide. The present silicon-
induced Polonovski-type reaction provides a very useful
carbon-carbon bond forming method due to the mild
reaction conditions and simple procedure such as only
mixing the desired nucleophile and SKA 2b in propioni-
trile at 60 °C.
(Table 1, entry 2). On the other hand, in the case of SKA
(2c), bearing a trimethylsilyl group, no reaction occurred
(Table 1, entry 3).
The following mechanism is proposed to account for
these interesting behaviors. The oxygen atom of the
N-oxide is first silylated by SKA, and then the hydrogen
atom on the R-carbon to the nitrogen is removed by the
in situ generated ester anion. The nucleophilic addition
of SKA to the iminium intermediate 3 forms the adduct
(
1) (a) Polonovski, M.; Polonovski, M. C. R. Hebd. Seances Acad. Sci.
927, 184, 331 and 1333. (b) Polonovski, M.; Polonovski, M. Bull. Soc.
Chim. Fr. 1927, 41, 1190. (c) Polonovski, M. Bull. Soc. Chim. Belg.
974, 39, 1507.
2) See a review for synthetic applications of Polonovski reaction:
Grierson, D. Organic React. 1990, 39, 85.
3) (a) Tokitoh, N.; Okazaki, R. Tetrahedron Lett. 1984, 25, 4677.
b) Tokitoh, N.; Okazaki, R. Chem. Lett. 1985, 241. (c) Tokitoh, N.;
1
Exp er im en ta l Section
1
Gen er a l P r oced u r e. All reactions were carried out under
(
a positive atmosphere of dry nitrogen. Melting points are
uncorrected. 1H NMR spectra were measured in CDCl
on 200,
4
50, and 500 MHz spectrometers with SiMe as the internal
3
(
2
(
Okazaki, R. Chem. Lett. 1984, 937. (d) Okazaki, R.; Tokitoh, N. J .
Chem. Soc., Chem. Commun. 1984, 192. (e) Tokitoh, N.; Okazaki, R.
Bull. Chem. Soc. J pn. 1987, 60, 3291.
standard. E. Merck silica gel 60 (70-230 mesh ASTM) for
column chromatography and E. Merck precoated TLC plates
(
4) Kita, Y.; Yasuda, H.; Sugiyama, Y.; Fukata, F.; Haruta, J .;
Tamura, Y. Tetrahedron Lett. 1983, 24, 1273.
(7) Results from a 1H NMR study suggested that silylation on the
nitrogen atom in the indole ring will occur with 5a and 5b. Therefore,
the ring closure reactions successfully proceeded by the addition of
acids that are not adequately nucleophilic (TFA or TsOH) to cleave
the N-Si bond.
(
5) A review see: Kita, Y.; Shibata, N. Synlett 1996, 289.
(6) (a) Lounasmaa, M.; Karvinen, E. Tetrahedron 1991, 47, 6371.
(
1
b) Lounasmaa, M.; Karvinen, E.; Koskinen, A.; J okela, R. Tetrahedron
987, 43, 2135.
S0022-3263(97)01057-8 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 23, 1997 8269
Ta ble 1. P olon ovsk i Rea ction In d u ced by SKA 2
Ta ble 2. Regioselective C-C Bon d F or m a tion on a
Ta ble 3. In tr a m olecu la r Nu cleop h ilic Cycliza tion
In d u ced by SKA 2b
Ca r bon Atom of th e Nitr ogen Heter ocycle
+
(
%): 282 (M , 2), 195 (100). HRMS calcd for C24
H
28
N
2
O
3
3
92.2100; found 392.2098.
3
-[2-(5-(Ben zyloxy)-3,6-d ih yd r o-2H -p yr id in io]et h yl]-5-
1
m eth oxy-1H-in d ole N′-oxid e (8b): yellow oil.
H
NMR
(
CDCl ) δ: 2.23 (m, 1 H), 2.68 (m, 1 H), 3.25-3.61 (m, 6 H),
3
3
1
7
.78 (s, 3 H), 3.86 (s, 2 H), 4.69 (dd, 2 H, J ) 11.5 Hz), 4.86 (bs,
H), 6.79 (dd, 1 H, J ) 8.9, 2.5 Hz), 6.98 (s, 1 H), 7.13-7.62 (m,
+
H), 9.75 (bs, 1 H). MS m/z (%): 282 (M , 2), 195 (100). HRMS
calcd for C23
Meth oxyca r bon yl)m eth yl Ad d u ct 4 a n d Cya n om eth yl
Ad d u ct 5. A mixture of N-oxide 1 (196 mg, 0.5 mmol), SKA 2b
470 mg, 2.5 mmol), and zinc iodide (15.9 mg, 10 mol %) in dry
acetonitrile (7.3 mL) was stirred for 2 h at 60 °C. After
concentration of the reaction mixture under reduced pressure,
the residue was purified by flash column chromatography
26 2 3
H N O 378.1943; found 378.1963.
(
with silica gel F254 for preparative TLC (PLC) were used. The
known N-oxide 63 and 8a were prepared by the reported
methods.
6
(
ter t-Bu tyl[(1-m eth oxyvin yl)oxy]d ip h en ylsila n e(2b). This
4
is prepared essentially following the published method: pale
1
yellow oil. H NMR (CDCl
3
3
) δ: 0.92 (s, 9 H), 2.94 (d, 1 H, J )
(
4
AcOEt/hexane, 1:1) to give the (methoxycarbonyl)methyl adduct
(148 mg, 66%) and cyanomethyl adduct 5 (14.3 mg, 7%).
3-(Ben zyloxy)-1-[2-[1-(m eth oxym eth yl)-1H-in d ol-3-yl]-
eth yl]-1,2,5,6-tetr a h yd r op yr id in -2-yl}a cetic a cid m eth yl
3
) δ: 1.95 (m, 1 H),
.35 (m, 1 H), 2.66-2.80 (m, 4 H), 2.85-2.99 (m, 4 H), 3.23 (s,
.3 Hz), 3.05 (d, 1 H, J ) 3.3 Hz), 3.26 (s, 3 H), 7.23-7.30 (m, 6
H), 7.55-7.60 (m, 4 H). MS m/z (%): 282 (M , 2), 195 (100).
HRMS calcd for C19 Si 312.1546; found 312.1561.
+
{
24 2
H O
N-Oxid e 1 a n d N-Oxid e 8b. These were prepared es-
1
ester (4): pale yellow oil. H NMR (CDCl
2
6
sentially following a published method.
3
-[2-[5-(Ben zyloxy)-3,6-d ih yd r o-2H -p yr id in io]et h yl]-1-
3 H), 3.56 (s, 3 H), 3.74 (bs, 1 H), 4.68 (d, 1H, J ) 6.5 Hz), 4.75
1
(
m eth oxym eth yl)-1H-in d ole N′-oxid e (1): yellow oil.
H
(d, 1H, J ) 6.5 Hz), 4.82 (bs, 1H), 5.40 (s, 2 H), 7.02 (s, 1 H),
-
1
NMR (CDCl
3
) δ: 2.38 (m, 1 H), 2.75 (m, 1 H), 3.22 (s, 3 H), 3.30-
7.14-7.61 (m, 8 H). IR (KBr) cm : 1738. MS m/z (%): 448
+
3
1
.61 (m, 6 H), 3.94 (s, 2 H), 4.79 (dd, 2 H, J ) 11.5 Hz), 4.92 (bs,
H), 5.40 (s, 2 H), 7.07 (s, 1 H), 7.13-7.62 (m, 9 H). MS m/z
(M , 13), 91 (100). HRMS calcd for C27
448.2357.
32 2 4
H N O 448.2359; found

8
270 J . Org. Chem., Vol. 62, No. 23, 1997
Notes
{
3-(Ben zyloxy)-1-[2-[1-(m eth oxym eth yl)-1H-in d ol-3-yl]-
isomers of 73:27): white crystals. Mp 136-140 °C. 1H NMR
eth yl]-1,2,5,6-tetr a h yd r op yr id in -2-yl}a ceton itr ile (5): pale
3
(CDCl ) δ: 2.28 (s, 3 H 27/100), 2.46 (s, 3 H 73/100), 2.56 (bdd,
1
yellow oil. H NMR (CDCl
.68 (m, 2 H), 2.71-3.08 (m, 6 H), 3.26 (s, 3 H, J ) 2.5 Hz), 3.39
t, 1 H), 4.78 (s, 2 H), 4.99 (bs, 1 H), 5.41 (s, 2 H), 7.15-7.62 (m,
3
) δ: 2.14 (m, 1 H), 2.34 (m, 1 H),
2 H 73/100, J ) 16.5, 5.5 Hz), 2.60-2.63 (m, 1 H 27/100), 2.81-
2.90 (m, 1H), 2.96 (ddd, 1 H 27/100, J ) 16.5, 11.0, 6.1 Hz), 3.13
(ddd, 1 H 27/100, J ) 12.8, 9.2, 5.0 Hz), 3.49 (ddd, 1H 73/100, J
) 13.4, 11.0, 5.0 Hz), 3.83 (d, 1 H 73/100, J ) 11.0 Hz), 3.89 (d,
1 H 27/100, J ) 9.8 Hz), 4.12 (d, 1 H 73/100, J ) 11.0 Hz), 4.31
(d, 1 H 27/100, J ) 9.8 Hz), 5.96 (d, 1 H 73/100, J ) 7.9 Hz),
6.64 (bt, 1 H 73/100, J ) 7.0 Hz), 6.98-7.40 (m, 7 H). IR (KBr)
2
(
1
+
0 H). MS m/z (%): 415 (M , 23), 91 (100). HRMS calcd for
415.2257; found 415.2251.
26 29 3 2
C H N O
C-C Bon d F or m ed P r od u cts 7a -d . General procedure:
A mixture of N-oxide 6 (16.3 mg, 0.100 mmol), SKA 2b (96.3
mg, 0.308 mmol), and O-methyl-O-(trimethylsilyl)ketene acetal
-1
+
cm : 1736. HRMS(FAB ) calcd for C19H22NO 296.1650; found
2
(
58.9 mg, 0.403 mmol) in propionitrile (2 mL) was stirred for 2
296.1632. Anal. Calcd for C19H21NO : C,77.26; H, 7.17; N, 4.74.
2
h at 60 °C. After concentration of the reaction mixture under
reduced pressure, the residue was purified by flash column
chromatography on silica gel (hexane/AcOEt, 1:1) to give the
C-C bond formed products 7a (14.4 mg, 66%). The physical data
for 7a -d are summarized below.
found: C, 77.15; H, 7.14; N, 4.66.
1
-(Ben zyloxy)-3,4,6,7,12b-h exa h yd r oin d olo[2,3-a ]qu in o-
lizin e (9a ). A mixture of N-oxide 8a (38.5 mg, 0.11 mmol), SKA
b (175 mg, 0.56 mmol), and trifluoroacetic acid (3 µL: 35 mol
against 8a ) in propionitrile (4 mL) was stirred for 19 h at 60
C. After concentration of the reaction mixture under reduced
pressure, the residue was purified by preparative TLC (CH Cl
MeOH, 10:1) to give the ring closure product 9a (4.4 mg, 12%):
2
%
°
(
2-Meth yl-1,2,3,4-tetr a h yd r oisoqu in olin -1-yl)a cetic a cid
1
m eth yl ester (7a ): pale yellow oil. H NMR (CDCl
(
3
) δ: 2.48
2
2
/
s, 3 H), 2.61 (dd, 1 H, J ) 15.6, 5.3 Hz), 2.84 (dd, 1 H, J ) 15.6,
7
5
(
.9 Hz), 2.59-3.19 (m, 4 H), 3.71 (s, 3 H), 4.15 (dd, 1 H, J ) 7.9,
1
dark orange oil. H NMR (CDCl
3
) δ: 2.18 (m, 1 H), 2.34 (m, 1
-
1
.3 Hz), 7.05-7.17 (m, 4 H). IR (KBr) cm : 1736. MS m/z
H), 2.63 (m, 1 H), 2.74 (m, 1 H), 2.90 (m, 1 H), 3.01 (m, 1 H),
+
%): 282 (M , 2), 195 (100). HRMS calcd for C13H17NO
2
3
1
.16 (m, 1 H), 3.30 (m, 1 H), 4.65 (s, 1 H), 4.88 (s, 2 H), 4.94 (bs,
H), 7.03-7.47 (m, 9 H), 8.42 (bs, 1 H).
2
2
19.1259; found 219.1264. Anal. Calcd for C13H17NO : C, 71.21;
H, 7.81; N, 6.39. found: C, 71.61; H, 7.85; N, 6.11.
-(2-Meth yl-1,2,3,4-tetr a h yd r oisoqu in olin -1-yl)p r op ion -
ic a cid m eth yl ester (7b) (as a mixture of diastereomeric
1
-(Ben zyloxy)-9-m et h oxy-3,4,6,7,12b-h exa h yd r oin d olo-
2
[
2,3-a ]qu in olizin e (9b). A mixture of N-oxide 8b (5.0 mg, 0.013
1
mmol), SKA 2b (20 mg, 0.064 mmol), and trifluoroacetic acid (1
µL: ca. 1 equiv against 8b) in propionitrile (1 mL) was stirred
for 12 h at 60 °C. After concentration of the reaction mixture
under reduced pressure, the residue was purified by preparative
isomers of 53:47): pale yellow oil. H NMR (CDCl
3
(
3
) δ: 1.03 (d,
H 53/100, J ) 7.0 Hz), 1.17 (d, 3 H 47/100, J ) 7.0 Hz), 2.41
s, 3 H 47/100), 2.43 (s, 3 H 53/100), 2.63-2.84 (m, 4 H), 3.13-
3
1
7
.31 (m, 1 H), 3.60 (s, 3 H 47/100), 3.74 (s, 3 H 53/100), 3.78 (d,
TLC (CH
2 2
Cl /MeOH, 10:1) to give the ring closure product 9b
H 53/100, J ) 8.1 Hz), 3.87 (d, 1 H 47/100, J ) 6.6 Hz), 6.95-
1
.17 (m, 4 H). IR (KBr) cm- : 1736. HRMS(FAB ) calcd for
1
+
(1.6 mg, 34%): dark orange oil. H NMR (CDCl ) δ: 2.19 (m, 1
3
H), 2.34 (m, 1 H), 2.60 (m, 1 H), 2.75 (m, 1 H), 2.92-2.98 (m, 2
C
NO
5
14
H
2
20NO
2
234.1494; found 234.1490. Anal. Calcd for C14
: C, 72.07; H, 8.21; N, 6.00. found: C, 72.15; H, 8.32; N,
.85.
Meth oxy(2-m eth yl-1,2,3,4-tetr ah ydr oisoqu in olin -1-yl)ace-
tic a cid m eth yl ester (7c) (as a mixture of diastereomeric
19
H -
H), 3.16 (m, 1 H), 3.30 (m, 1 H), 3.84 (s, 3 H), 4.64 (bs, 1 H),
4
.87 (s, 2 H), 4.96 (bs, 1 H), 6.76 (dd, 1 H, J ) 8.8, 2.5 Hz), 6.93
(d, 1 H, J ) 2.5 Hz), 7.07 (d, 1 H, J ) 8.8 Hz), 7.23-7.41 (m, 5
+
H), 8.31 (bs, 1 H). MS m/z (%): 360 (M , 31.2), 79 (100). HRMS
1
calcd for C23
H
24
N
2
O
2
360.1836; found 360.1834.
isomers of 69:31): pale yellow oil. H NMR (CDCl
H 69/100), 2.45 (s, 3 H 31/100), 2.61-2.74 (m, 2 H), 2.83-2.92
m, 1 H), 3.15-3.18 (m, 1 H), 3.28 (s, 3 H 31/100), 3.32 (s, 3 H
3
) δ: 2.44 (s,
3
(
1
Su p p or tin g In for m a tion Ava ila ble: H NMR spectra of
2b, 4, 5, 7a , and 9a ; HRMS spectra of 2b, 4, 5, and 7a ; IR
spectra of 4 and 7a . (16 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
6
6
3
9/100), 3.63 (s, 3 H 31/100), 3.77 (s, 3 H 69/100), 3.81 (d, 1H
9/100, J ) 5.5 Hz), 3.93 (d, 1H 69/100, J ) 5.5 Hz), 3.99 (d, 1H
1/100, J ) 4.0 Hz), 4.06 (d, 1H 31/100, J ) 4.0 Hz), 7.09-7.24
-
1
+
(
9
m, 4 H). IR (KBr) cm : 1751. FABMS m/z (%): 250 (M + 1,
+
2), 146 (100). HRMS(FAB ) calcd for C14
found 250.1439.
2-Meth yl-1,2,3,4-tetr a h yd r oisoqu in olin -1-yl)p h en yla ce-
tic a cid m eth yl ester (7d ) (as a mixture of diastereomeric
3
H20NO 250.1443;
(
J O971057F