Mannich-type reaction of N,O-acetals with ketones mediated by a combination of TiCl4 and PhSiCl3

Article abstract of DOI:10.3987/COM-09-S(E)2

A combination of TiCl₄ and PhSiCl₃ efficiently conducts the Mannich-type reaction of N,O-acetals with ketones to afford α-substituted cyclic amine derivatives in good yields. This method was applicable to preparation of azabicyclo co

Full text of DOI:10.3987/COM-09-S(E)2

HETEROCYCLES, Vol. 82, No. 1, 2010
325
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 325 - 332. © The Japan Institute of Heterocyclic Chemistry
Received, 9th December, 2009, Accepted, 19th February, 2010, Published online, 22nd February, 2010
DOI: 10.3987/COM-09-S(E)2
MANNICH-TYPE REACTION OF N,O-ACETALS WITH KETONES
†
MEDIATED BY A COMBINATION OF TiCl4 AND PhSiCl3
Satoshi Kamogawa, Takashi Ikeda, Masami Kuriyama, Yoshihiro
Matsumura, and Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14,
Bunkyo-machi, Nagasaki 852-8521, Japan. E-mail: onomura@nagasaki-u.ac.jp
Abstract – A combination of TiCl4 and PhSiCl3 efficiently conducts the
Mannich-type reaction of N,O-acetals with ketones to afford -substituted cyclic
amine derivatives in good yields. This method was applicable to preparation of
azabicyclo compounds by the intramolecular Mannich-type reaction.
INTRODUCTION
Lewis acid mediated Mannich-type reaction between N,O-acetals 2 prepared by electrochemical
oxidation1 of amine derivatives 1 and carbon nucleophiles (NuH) is one of powerful methods for
syntheses of -substituted amine derivatives 3 (Eq. 1).2,3 We have already reported that some active
methylene compounds such as malonates, acetoacetates, and some modified ketones such as enol ethers
and enol esters reacted well with 2 as the carbon nucleophiles to form the corresponding -substituted
amine derivatives with high yields.4,5 However, similar reactions between 2 and unmodified ketones did
not proceed with good yields. For example, as shown in Eq. 2, although the reaction of N,O-acetal 4 with
isopropenyl acetate (5) gave the desired -acetonylated product 7 in 86% yield, the yield of 7 from
acetone (6) was only 23%. We report herein one of the most powerful protocols for TiCl4-mediated
Mannich-type reaction of 2 with unmodified ketones promoted by co-existing PhSiCl3.
R2
R2
R2
R1
O
R1
R1
2e
Lewis acid
NuH
OR3
X
N
Nu
N
N
(1)
R3OH
R
O
R
R
O
3
2
1 (X=H, CO2H, or CR2OH)
†
Dedicated to Professor Dr. Albert Eschenmoser, ETH Zürich, on his 85th birthday.

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HETEROCYCLES, Vol. 82, No. 1, 2010
O
O
OAc
TiCl4 (1.5 equiv)
+
or
OMe
(2)
N
N
in CH2Cl2
78ºC to rt
12 h
CO2Me
6
5
CO2Me
4
(2.5 equiv)
7
86% yield from 5
23% yield from 6
RESULTS AND DISCUSSION
Since one reason of the low yield of 7 from 6 seemed to be that 6 hardly enolized under the reaction
conditions, we tested combinations of TiCl4 and some chlorosilanes6,7 which might accelerate enolization
of 6 (Eq. 3). These results are summarized in Table 1. Although in the case of using mono- and
di-chlorosilanes the yields of 7 were low (entries 1 and 2), using trichlorosilanes and tetrachlorosilane
improved the yields (entries 3-6).
O
TiCl4 (1.5 equiv)
O
+
RnSiCl(4-n) (1.5 equiv)
OMe
N
N
(3)
in CH2Cl2
12 h
78 ºC to rt
CO2Me
6
CO2Me
4
(2.5 equiv)
7
Table 1. Effect of some chlorosilanes on the reaction of 4 with 6.
Entry
RnSiCl(4-n)
Me3SiCl
Me2SiCl2
MeSiCl3
PhSiCl3
HSiCl3
Yield (%) of 7
1
2
3
4
5
6
17
35
66
61
65
68
SiCl4
Next, we carried out some experiments to optimize amounts of TiCl4 and PhSiCl3 as a representative
combination (Eq. 4), since the yields of 7 promoted by three trichlorosilanes and tetrachlorosilane were
almost same (Table 1). The results are shown in Table 2. A combination of a catalytic (0.15 equiv) or an
equimolar (1.5 equiv) amount of TiCl4 and an equimolar amount of PhSiCl3 could work well (entries 3
and 6).8 On the other hand, a combination of an equimolar amount of TiCl4 and a catalytic amount of
PhSiCl3 did not improve the yield (entry 5).
TiCl4 + PhSiCl3
+
4
7
6
(4)
in CH2Cl2
78 ºC to rt 12 h
(2.5 equiv)

HETEROCYCLES, Vol. 82, No. 1, 2010
327
Similarly this combination of TiCl4 (0.1 equiv) and PhSiCl3 (1.5 equiv) could efficiently mediate the
Mannich-type reaction of 4 with acetophenone 8 or cyclopentanone 10 to improve the corresponding
products 9 and 119 (Eqs. 5 and 6).
Table 2. Effect of amount of TiCl4 and PhSiCl3 on the reaction of 4 with 6.
Entry Equiv of TiCl4
Equiv of PhSiCl3
Yield (%) of 7
1
2
3
4
5
6
0
1.5
0.15
1.5
0
0.15
1.5
3
2
61
23
34
61
0.15
0.15
1.5
1.5
1.5
O
O
in CH2Cl2
-78 ºC to rt
12 h
(5)
N
+
4
CO2Me
equiv
8
PhSiCl3
9
TiCl4
(2.5 equiv)
1.5
0.15
0
1.5
34% yield
68% yield
O
in CH2Cl2
O
78 ºC to rt
12 h
(6)
+
4
N
equiv
CO2Me
11
10
PhSiCl3
TiCl4
(2.5 equiv)
1.5
0.15
0
1.5
36% yield
80% yield
Similar improvement was accomplished in the case of using TiCl2(O-i-Pr)2 as a Lewis acid. Although
using only TiCl2(O-i-Pr)2 did not proceed a reaction of 4 with 10, a combination of TiCl2(O-i-Pr)2 and
PhSiCl3 could mediate the reaction of 4 with 10 to afford 11 in moderate yield (Eq. 7).
in CH2Cl2
equiv
78 ºC to rt
12 h
+
(7)
4
10
11
(2.5 equiv)
PhSiCl3
TiCl2(O-i-Pr)2
0.15
0.15
0
1.5
0% yield
65% yield
The yields of the reaction of 4 with 10 using a combination of Lewis acid and PhSiCl3 shown in Eqs. 6
and 7 exceeded that of the reaction of 4 with trimethylsilyl enol ether 12 (Eq. 8).

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HETEROCYCLES, Vol. 82, No. 1, 2010
OSiMe3
Lewis acid (0.15 equiv)
+
4
(8)
11
in CH2Cl2
78 ºC to rt 12 h
12
(2.5 equiv)
76% yield
17% yield
TiCl4
TiCl2(O-i-Pr)2
Also, the Mannich-type reaction of N-benzyloxycarbonylated pyrrolidines 13 with 10 was effectively
mediated by a combination of TiCl4 and PhSiCl3 to afford the corresponding product 148 (Eq. 9).
O
in CH2Cl2
12 h
O
78 ºC to rt
(9)
+
OMe
N
N
equiv
Cbz
14
Cbz
10
PhSiCl3
TiCl4
(2.5 equiv)
13
0.15
0.15
0
1.5
13% yield
63% yield
Piperidine derivative 15 reacted with 10 in the presence of PhSiCl3 to give the corresponding coupling
product 16 with moderate yield (Eq. 10). The diastereomer ratio 66:34 of 16 was almost same as that of
16 obtained from t-butyldimethylsilyl enol ether 17, while that of 16 obtained from 12 was opposite (Eq.
11).10
in CH2Cl2
O
78 ºC to rt
12 h
(10)
+
10
N
N
OMe
(2.5 equiv)
CO2Me
CO2Me
equiv
16
15
PhSiCl3
TiCl4
1.5
0.15
0
1.5
10% yield (dr=62:38)
46% yield (dr=66:34)
OSiMe2R
TiCl4 (0.15 equiv)
in CH2Cl2
+
15
16
(11)
12 h
78 ºC to rt
(2.5 equiv)
67% yield (dr=30:70) from 12
51% yield (dr=65:35) from 17
12: R=Me
17: R=t-Bu
Furthermore, a combination of TiCl4 and PhSiCl3 effectively mediated the intramolecular Mannich-type
reaction of N-methoxycarbonylated pyrrolidines 18a (n=1) and its piperidine analogue 18b (n=2) to form
tropinone skeleton 19a and its [3.3.1] analogue 19b which is a precursor for alkaloid and redox-catalysts
(Eq. 12).11

HETEROCYCLES, Vol. 82, No. 1, 2010
329
CO2Me
N
O
in CH2Cl2
12 h
TiCl4 (0.15 equiv)
-78 ºC to rt
( )n
(12)
OMe
CO2Me
N
( )n
PhSiCl3 (1.5 equiv)
O
19a: n=1; 58% yield
19b: n=2; 40% yield
18a: n=1
18b: n=2
The role of the trichlorosilanes and tetrachlorosilane in the present system is not clarified at present. We
presume that trichlorosilanes and tetrachlorosilane facilitates smooth enolate generation. Another
possibility is that they may facilitate intermediary formations of enol silyl ethers.5,6 However, this
speculation could be ruled out, because these species can hardly be generated under the present acidic
conditions.
CONCLUSION
In conclusion, a combination of TiCl4 and PhSiCl3 conducts the Mannich type reaction of N,O-acetals
with ketones, wherein PhSiCl3 acts as an efficient promoter. Although mechanistic details are still not
clear, this reaction is a very promising method in organic synthesis.
EXPERIMENTAL
All commercial materials were used without further purification unless otherwise stated. Analytical thin
layer chromatography was performed on Merck silica gel 60 F254 plates (0.25mm). Compounds were
visualized by deeping in anisaldehyde followed by heating. Liquid chromatography was performed using
indicated solvent on silica gel 60 (200-300 mesh). IR spectra were obtained on a Shimadzu FTIR-8100A.
1H NMR spectra were obtained on Varian Gemini 300 and 400 MHz spectrometer and are reported in
parts per million () with tetramethylsilane (TMS) as the internal standard. The coupling constants are
recorded in hertz.
A combination of TiC4- and PhSiCl3-mediated Mannich-type reaction: Typical procedure
Under a nitrogen atmosphere, TiCl4 (12 L, 0.15 mmol) and phenyltrichlorosilane (240 L, 1.5 mmol)
were added dropwise to the solution of 4 (159 mg, 1.0 mmol) and acetone (183 L, 2.5 mmol) in CH2Cl2
(5 mL) at 78 oC. The resulting mixture was stirred for 12 h and allowed to stand until it warmed to room
temperature. The solution was poured in ice water (10 mL) and extracted with CHCl3 (10 mL x 3). The
combined organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The

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residue was purified by silica gel column chromatography (n-hexane : AcOEt = 10 : 1) to afford 7 as a
colorless oil (112 mg, 61%). Compounds 7,4 9,4 19a,4 and 19b12 are known.
1-Methoxycarbonyl-2-(2-oxocyclopentyl)pyrrolidine (11)
1H-NMR (300 MHz, CDCl3)  1.40-2.50 (m, 10H), 2.70-3.05 (m, 1H), 3.25-3.50 (m, 2H), 3.65 and 3.68
13
(2s, 3H), 4.10-4.30 (m, 1H); C-NMR (100 MHz, CDCl3)  218.49 (1C), 155.11 (1C), 56.71, 56.94,
51.82, 51.48, 46.86, 46.54 , 38.42, 34.10, 32.34, 30.33, 27.51, 24.62, 20.25; IR (neat) 2974, 2880, 1747,
1713, 1464, 1396, 1207, 1124, 747 cm1. Anal. Calcd for C11H17NO3: C, 62.54, H, 8.11; N, 6.63. Found:
C, 62.62, H, 8.11; N, 6.37.
1-Benzyloxycarbonyl-2-(2-oxocyclopentyl)pyrrolidine (14)
1H-NMR (300 MHz, CDCl3)  1.40-2.40 (m, 11H), 3.30-3.63 (m, 2H), 4.10-4.30 (m, 1H), 5.00-5.18 (m,
2H), 7.20-7.42 (m, 5H); 13C-NMR (100 MHz, CDCl3)  218.88, 218.75, 154.82, 154.59, 136.51, 128.23,
66.38, 56.93, 56.12, 51.98, 51.59, 46.79, 46.70, 38.60, 38.26, 30.50, 28.43, 27.69, 25.48, 24.81, 20.36,
20.15; IR (neat) 3374, 3090, 2963, 2880, 1736, 1705, 1597, 1498, 1454, 1419, 1288, 1134 cm1. HRMS.
Calcd for C17H21NO3: 287.1522. Found: 287.1525.
1-Methoxycarbonyl-2-(2-oxocyclopentyl)piperidine (16)
1
More polar diastereomer (minor isomer in Eq. 10): H-NMR (300 MHz, CDCl3)  1.30-2.60 (m, 13H),
13
2.99 (t, J=9.9Hz, 1H), 3.65 and 3.68 (2s, 3H), 3.95-4.30 (m, 1H); C-NMR (75 MHz, CDCl3)  218.56,
156.93, 52.10, 51.62, 45.19, 39.85, 38.48, 28.16, 26.81, 24.74, 20.39, 18.54; IR (neat) 2947, 2864, 1732,
1693, 1446, 1263, 1180, 767 cm1. Anal. Calcd for C12H19NO3: C, 63.98, H, 8.50; N, 6.22. Found: C,
64.00, H, 8.46; N, 6.19.
1
Less polar diastereomer (major isomer in Eq. 10): H-NMR (300 MHz, CDCl3)  1.30-2.40 (m, 12H),
2.53-2.80 (m, 2H), 3.68 (s, 3H), 3.93-4.40 (m, 2H); 13C-NMR (75 MHz, CDCl3)  219.03, 155.76, 52.18,
50.30, 46.81, 39.57, 38.51, 26.61, 26.08, 24.85, 19.78, 18.47; IR (neat) 2939, 2864, 1732, 1693, 1446,
1410, 1263, 1186, 1153, 767 cm1. Anal. Calcd for C12H19NO3: C, 63.98, H, 8.50; N, 6.22. Found: C,
64.19, H, 8.42; N, 6.33.
ACKNOWLEDGEMENT
This work was supported by the president’s discretion fund of Nagasaki University and Linking
mechanism of research results to practical application of Japan Science and Technology Agency.

HETEROCYCLES, Vol. 82, No. 1, 2010
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HETEROCYCLES, Vol. 82, No. 1, 2010
1
was observed by H-NMR analyses shown below, enolization of acetone could not be proved.
1H-NMR (300 MHz, CDCl3)  2.18 for acetone; 2.24 for acetone with TiCl4 (1.0 equiv); 2.17 for
acetone with PhSiCl3 (1.0 equiv); 2.66 for acetone with a combination of TiCl4 (1.0 equiv) and
PhSiCl3 (1.0 equiv).
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ratio of 14 could not be determined.
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