Reductive aminopropylation of ketene silyl (thio)acetals leading to the synthesis of δ-amino esters

Article abstract of DOI:10.1016/j.tetlet.2011.08.054

In the presence of silica gel or titanium tetrachloride, ketene silyl acetals or ketene silyl thioacetals underwent 1,4-addition with α,β unsaturated aldimines which possess a large triphenylmethyl group at the imino nitrogens followed by reduction with s

Full text of DOI:10.1016/j.tetlet.2011.08.054

Tetrahedron Letters 52 (2011) 5388–5391
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reductive aminopropylation of ketene silyl (thio)acetals leading
to the synthesis of d-amino esters
⇑
Isao Mizota, Shun Agatani, Iwao Hachiya, Makoto Shimizu
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of silica gel or titanium tetrachloride, ketene silyl acetals or ketene silyl thioacetals under-
Received 10 July 2011
Revised 3 August 2011
Accepted 8 August 2011
Available online 16 August 2011
went 1,4-addition with
a,b unsaturated aldimines which possess a large triphenylmethyl group at the
imino nitrogens followed by reduction with sodium cyanoborohydride to give aminopropylated products,
d-amino esters, in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aminopropylation
Ketene silyl acetal
Ketene silyl thioacetal
a,b-Unsaturated aldimine
d-Amino esters
In connection with unusual helix types in oligomers of d-amino
were subjected to the aminopropylation reaction, and Table 2 sum-
marizes the results.6
acids (d-peptides) and their stabilities, d-amino acids have received
considerable attention from the standpoints of dipeptide isosteres
and reversal of turn mimetics.1 Although we have already reported
new synthetic methods for d-amino esters of type A using double
As shown in Table 2, tetra-substituted ketene silyl acetals
underwent aminopropylation reaction to give the products 3 in
good yields in which methoxy derivative gave the best result (en-
tries 1–8). Although tri-substituted ketene silyl acetals did not give
the adducts in good yields, their sulfur analogs gave the amino-
propionated products in moderate yields (entries 9–11), in which
cyclohexylthio derivative recorded the best result (entry 9). In
the cases with di-substituted ketene silyl acetals, the reaction did
not give the desired product, either, where only the hydrolysis of
ketene silyl acetals was observed. However, use of ketene silyl
thioacetals gave the aminopropylated products in moderate yields
nucleophilic addition to a
,b-unsaturated aldimines,2 there still re-
mains an important problem for the selective synthesis of d-amino
esters of type B using the double addition tactic, in other words,
reductive aminopropylation (Scheme 1). This kind of transforma-
tion is not trivial due to the instability of an intermediary enamino
or imino compound against hydrolysis or isomerization.3 The
ready second 1,2-addition of the same 1,4-nucleophiles has also
been found to be quite problematic.4 We would like to describe
herein an easy access to d-amino esters of type B by reductive
aminopropylation of ketene silyl (thio)acetals, in which use of
a,b-unsaturated aldimines having a large trityl group at the imino
nitrogens is crucial.
The initial examination was carried out using aminopropylation
of the ketene silyl acetal 2a derived from ethyl isobutyrate with
allylideneamine 1, and results are summarized in Table 1.
As shown in Table 1, the addition reaction of the ketene silyl
acetal 2a in the presence of SiO2 (5.00 g/mmol) as previously re-
ported5 gave an intermediary 1,4-addition product which in turn
was reduced with NaCNBH3 (4.0 equiv) at À40 °C to rt to afford
the desired aminopropylated product 3a in 75% yield (entry 9). Un-
der the optimum conditions a variety of ketene silyl (thio)acetals 2
⇑
Corresponding author. Tel./fax: +81 59 231 9413.
E-mail address: mshimizu@chem.mie-u.ac.jp (M. Shimizu).
Scheme 1. Double nucleophilic addition to a,b-unsaturated aldimine.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.054

I. Mizota et al. / Tetrahedron Letters 52 (2011) 5388–5391
5389
Table 1
Reductive aminopropylation of ketene silyl acetal-comparison of reaction conditions.a
OTMS
SiO2
NaCNBH3
(y equiv)
OEt
2a
(1.5 equiv)
H
N
(x g / mmol)
N
EtO2C
Trityl
Trityl
MeOH, -78 oC - rt, 30 min
MeOH
Temp., 17 h
3a
1
Trityl = Triphenylmethyl
Entry
SiO2 (g/mmol)
NaCNBH3 (equiv)
Temp (oC)
Yield of 3ab (%)
1
2
3
4
5
6
7
8
9
2.50
2.50
2.50
1.25
5.00
6.25
5.00
5.00
5.00
4.0
4.0
1.0
4.0
4.0
4.0
4.0
4.0
4.0
À78 to rt
À78 to rt
À78 to rt
À78 to rt
À78 to rt
À78 to rt
0 to rt
41
49
33
22
68
52
66
71
75
À20 to rt
À40 to rt
a
The reaction was carried out according to the typical procedure.
Isolated yield.
b
Table 2
Reductive aminopropylation of ketene silyl (thio)acetalsa
R1
R2
OTMS
XR3
SiO2
NaCNBH3
2
R1 R2
H
N
(5.0 g / mmol) (1.5 equiv) (4.0 equiv)
MeOH, -78 oC - rt, 30 min
N
R3X
Trityl
Trityl
-40 oC - rt, 17 h
O
1
3
R2 OTMS
R1 XR3
R2 OTMS
R1 XR3
Entry
Yield of 3b (%)
Entry
Yield of 3b (%)
OTMS
OnPr
OTMS
OiPr
OTMS
OMe
OTMS
2b
2h
1
3b, 54
3c, 70
3a, 75
3d, 78
3e, 38
3f, 51
3g, 33
8
3h, 60
3i, 49
3j, 46
3k, 31
3l, 42
3m, 52
2c
2i
2
9
SCy
OTMS
OTMS
2a
2j
2k
2l
3
10
11
12
13
OEt
OTMS
SPh
OTMS
2d
4
OMe
OTMS
SEt
OTMS
StBu
OTMS
2e
5
SEt
OTMS
EtS
2f
2m
6
7
EtS
EtO
OMe
OTMS
SCy
2g
EtO
OMe
a
The reaction was carried out according to the typical procedure.
Isolated yield.
b
(entries 12 and 13). We next examined use of b-phenyl
urated aldimine 4a, and Table 3 summarizes the results.
In contrast to allylideneamine 1 the initial addition reaction did
not proceed with b-phenyl ,b-unsaturated aldimine 4a in the
presence of silica gel (entry 1), whereas other Lewis acids exam-
ined here promoted the reductive aminoalkylation reaction to give
the adduct 5a in moderate to good yields. Among the Lewis acids
screened titanium tetrachloride promoted the desired transforma-
tion most efficiently to give the product 5a in 77% yield (entry 6).
a
,b-unsat-
tuted a,b-unsaturated aldimines 4 besides the cinnamylidene
derivative 4a could also be used for the present aminoalkylation
reaction to give the adducts 5 in moderate to good yields (entries
5–9). However, at present time use of tri- and di-substituted ke-
tene silyl acetals or their thio analogs did not give satisfactory
yields of the aminoalkylated products presumably due to the com-
peting hydrolysis of the ketene silyl (thio)acetals and/or intermedi-
ary imines or enamines under the present reaction conditions.8
In conclusion, the present reductive aminoalkylation of ketene
silyl (thio)acetals provides an easy access to d-amino esters which
are useful molecules in drug discovery as well as for new func-
tional materials. Although some limitation of the nucleophiles is
a
Under these conditions a series of b-substituted
a,b-unsaturated
aldimine 4 was used for the present aminoalkylation reaction
and Table 4 summarizes the results.7
Regarding the alkoxy part of the ketene silyl acetal, ethoxy
derivative 2a recorded the best result (entries 1–4). Other b-substi-
involved in the cases with b-substituted
mines, use of a large trityl group at the imino nitrogen has
a,b-unsaturated aldi-

5390
I. Mizota et al. / Tetrahedron Letters 52 (2011) 5388–5391
Table 3
Reductive aminoalkylation of ketene silyl acetal-comparison of reaction conditionsa
OTMS
NaCNBH3
(1.5 equiv) (4.0 equiv)
Promoter
(1.0 equiv)
OEt
H
N
Ph
N
EtO2C
Trityl
Trityl
CH2Cl2, -78 oC - rt, 30 min
MeOH
Ph
4a
5a
-40 oC - rt, 17 h
Entry
Promoter
Yield of 5ab (%)
c
1
2
3
4
5
6
SiO2
–
SnCl2
SnCl4
AlCl3
TiCl4
27
61
52
72
77
d
TiCl4
a
b
c
The reaction was carried out according to the typical procedure.
Isolated yield.
SiO2 (5.0 g/mmol) was used.
d
The initial 1,4-addition was conducted for 1 h.
Table 4
Reducive aminoalkylation of ketene silyl acetalsa
OTMS
OR2
TiCl4,
NaCNBH3
(1.0 equiv)
H
N
(1.0 equiv) (1.1 equiv)
R1
N
R2O2C
Trityl
Trityl
CH2Cl2, -78 oC - rt, 1 h
MeOH
R1
4
-40 oC - rt, 18 h
5
Entry
R1
R2
Yield of 5b (%)
1
2
3
4
5
6
7
8
9
4a: Ph
4a: Ph
4a: Ph
4a: Ph
4b: Me
4c: Et
2a, Et
5a, 77
5d, 71
5b, 66
5c, 63
5e, 59
5f, 60
5g, 55
5h, 59
5i, 46
2d, Me
2b, nPr
i
2c, Pr
2a, Et
2a, Et
2a, Et
2a, Et
2a, Et
4d: nPr
4e: nBu
4f: Cy
a
The reaction was carried out according to the typical procedure.
Isolated yield.
b
T. Tetrahedron Lett. 2001, 42, 5463–5466; (l) Shimizu, M.; Morita, A.; Kaga, T.
Tetrahedron Lett. 1999, 40, 8401–8405.
provided new environment for the control of the double nucleo-
philic addition reaction to use only small second nucleophiles for
the 1,2-addition.
3. It has been reported that several imines are readily hydrolyzed to the parent
carbonyl compounds. See: (a) Saggiomo, V.; Lüning, U. Tetrahedron Lett. 2009,
50, 4663–4665; (b) Godoy-Alcántar, C.; Yatsimirsky, A. K.; Lehn, J.-M. J. Phys. Org.
Chem. 2005, 18, 979–985; (c) Onaka, M.; Ohno, R.; Yanagiya, N.; Izumi, Y. Synlett
1993, 141–142; (d) Dash, A. C.; Dash, B.; Panda, D. J. Org. Chem. 1985, 50, 2905–
2910.
Acknowledgments
4. For a review, see: Shimizu, M.; Hachiya, I.; Mizota, I. Chem. Commun. 2009, 874–
889.
5. Shimizu, M.; Kawanishi, M.; Itoh, A.; Mizota, I.; Hachiya, I. Chem. Lett. 2011, 40,
862–863. See also, Ref. 2a.
This work was supported by Grant-in-Aids for Scientific Re-
search (B) and on Innovative Areas ‘Organic Synthesis Based on
Reaction Integration. Development of New Methods and Creation
of New Substances’ from JSPS and MEXT.
6. Under
an
argon
atmosphere,
a
suspension
of
N-allylidene-
triphenylmethaneamine
1
(59.0 mg, 0.20 mmol) in CH3OH (1.4 mL) was
stirred at room temperature for 10 min. Dried silica gel (500 mg) and CH3OH
(0.30 mL) were added to it. The reaction mixture was cooled to À78 °C. A
solution of (1-ethoxy-2-methylprop-1-enyloxy)-trimethylsilane (56.0 mg,
0.30 mmol) in CH3OH (1.2 mL) was added to the mixture. After the mixture
was allowed to warm up to room temperature during 30 min with stirring,
sodium cyanoborohydride (50.0 mg, 0.80 mmol) was added to the resulting
mixture at À40 °C. The mixture was gradually warmed to room temperature
during 16 h. Saturated aq NaHCO3 (10 mL) was added to quench the reaction.
The mixture was filtered with suction through a Celite pad and washed with
ethyl acetate. The mixture was extracted with ethyl acetate (3 Â 5.0 mL). The
combined extracts were dried over Na2SO4 and concentrated in vacuo to give a
crude product. Purification on silica gel TLC (n-hexane/EtOAc = 6:1 as an eluent)
gave the aminopropylated compound 3a (62.2 mg, 75%) as a pale yellow oil.
Rf = 0.30 (n-Hex/EtOAc = 6:1); 1H NMR (500 MHz, CDCl3) d 1.14 (s, 6H), 1.23 (t,
J = 7.0 Hz, 3H), 1.38–1.45 (m, 2H), 1.49–1.53 (m, 2H), 2.09 (t, J = 6.7 Hz, 2H), 4.09
(q, J = 7.0 Hz, 2H), 7.16–7.19 (m, 3H), 7.24–7.28 (m, 6H), 7.45–7.47 (m, 6H); 13C
NMR (125 MHz, CDCl3) d 14.2, 25.1, 26.4, 38.3, 42.0, 44.0, 60.2, 70.9, 126.2,
References and notes
1. (a) Garrido, N. M.; García, M.; Díez, D.; Sánchez, M. R.; Sanz, F.; Urones, J. G. Org.
Lett. 2008, 10, 1687–1690; (b) Trabocchi, A.; Menchi, G.; Danieli, E.; Guarna, A.
Amino Acids 2008, 35, 37–44; (c) Baldauf, C.; Günther, R.; Hofmann, H.-J. J. Org.
Chem. 2004, 69, 6214–6220.
2. (a) Shimizu, M.; Kawanishi, M.; Mizota, I.; Hachiya, I. Org. Lett. 2010, 12, 3571–
3573; (b) Takahashi, A.; Kawai, S.; Hachiya, I.; Shimizu, M. Eur. J. Org. Chem.
2010, 191–200; (c) Mizota, I.; Matsuda, Y.; Hachiya, I.; Shimizu, M. Eur. J. Org.
Chem. 2009, 4073–4084; (d) Mizota, I.; Matsuda, Y.; Hachiya, I.; Shimizu, M. Org.
Lett. 2008, 10, 3977–3980; (e) Shimizu, M.; Takahashi, A.; Kawai, S. Org. Lett.
2006, 8, 3585–3587; (f) Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2005, 34,
1456–1457; (g) Shimizu, M.; Kurokawa, H.; Takahashi, A. Lett. Org. Chem. 2004,
1, 353–356; (h) Shimizu, M.; Yamauchi, C.; Ogawa, T. Chem. Lett. 2004, 33, 606–
607; (i) Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2003, 32, 606–607; (j)
Shimizu, M.; Nishi, T. Chem. Lett. 2002, 46–47; (k) Shimizu, M.; Ogawa, T.; Nishi,

I. Mizota et al. / Tetrahedron Letters 52 (2011) 5388–5391
5391
127.7, 128.6, 146.3, 177.9; IR (neat) 3085, 3053, 3022, 2975, 2935, 2854, 1724,
1590, 1484, 1450, 1388, 1316, 1266, 1180, 1142, 1098, 1029, 902, 770, 745,
705 cmÀ1; HRMS (EI): calcd for C28H33NO2 (M+) 415.2511, found 415.2520.
washed with ethyl acetate. The mixture was extracted with ethyl acetate
(3 Â 5.0 mL). The combined extracts were dried over Na2SO4 and concentrated
in vacuo to give a crude product. Purification on silica gel TLC (n-hexane/
EtOAc = 6:1 as an eluent) gave the aminopropylated compound 5a (75.7 mg,
77%) as a colorless oil.
7. Under
propylidene)triphenylmethaneamine 4a (76.0 mg, 0.20 mmol) in CH2Cl2
(1.4 mL) was stirred at room temperature for 10 min. solution of TiCl4
(0.20 mL, 0.20 mmol) in CH2Cl2 (0.30 mL) was added to it. The reaction mixture
solution of (1-ethoxy-2-methylprop-1-
an
argon
atmosphere,
a
suspension
of
N-(3-phenyl-
A
Rf = 0.50 (n-Hex/EtOAc = 6:1); 1H NMR (500 MHz, CDCl3) d 1.01 (s, 3H), 1.12 (s,
3H), 1.21 (t, J = 7.0 Hz, 3H), 1.60–1.66 (m, 1H), 1.94–2.04 (m, 3H), 3.16–3.20 (m,
1H), 4.05–4.13 (m, 2H), 7.09–7.33 (m, 20H); 13C NMR (100 MHz, CDCl3) d 14.2,
20.6, 24.6, 31.3, 41.7, 46.5, 50.4, 60.4, 70.7, 126.0, 126. 5, 127.6, 127.7, 128.5,
129.8, 140.0, 146.1, 177.7; IR (neat) 3085, 3058, 3028, 2977, 2935, 2860, 1723,
1597, 1490, 1450, 1387, 1366, 1244, 1128, 1028, 903, 768, 744, 704 cmÀ1; HRMS
(EI): calcd for C34H37NO2 (M+) 491.2824, found 491.2832.
was cooled to À78 °C, and
a
enyloxy)trimethylsilane 2a (37.0 mg, 0.22 mmol) in CH2Cl2 (1.20 mL) was
added to the mixture. After the mixture was allowed to warm up to room
temperature during 60 min with stirring,
a
solution of sodium
cyanoborohydride (12.0 mg, 0.20 mmol) in CH3OH (0.40 mL) was added to the
resulting mixture at À40 °C. The mixture was gradually warmed to room
temperature during 17 h. Saturated aq NaHCO3 (10 mL) was added to quench
the reaction. The mixture was filtered with suction through a Celite pad and
8. Ketene silyl (thio)acetals are readily hydrolyzed under the influence of Brønsted
acids in protic solvents. Related side reactions, see: Ref. 5.