Practical synthesis of ethyl 1-(tert-butoxycarbonyl)-4-(1-pyrrolidinyl)-4- piperidineacetate, an intermediate of a novel antiarteriosclerotic, utilizing aza-michael addition promoted by LiBr

Article abstract of DOI:10.1246/cl.2012.1703

The aza-Michael addition of pyrrolidine to β,β-dialkylated unsaturated ester 6 utilizing LiBr proceeded smoothly to give the inaccessible ethyl 1-(tert-butoxycarbonyl)-4-(1-pyrrolidinyl)-4-piperidineacetate (7), which is an intermediate of novel antiarter

Full text of DOI:10.1246/cl.2012.1703

doi:10.1246/cl.2012.1703
Published on the web December 8, 2012
1703
Practical Synthesis of Ethyl 1-(tert-Butoxycarbonyl)-4-(1-pyrrolidinyl)-4-piperidineacetate,
an Intermediate of a Novel Antiarteriosclerotic, Utilizing Aza-Michael Addition Promoted by LiBr
Akira Iida,* Naohiro Onodera, and Tatsuro Yasukata
Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd.,
1-3 Kuise Terajima 2-Chome, Amagasaki, Hyogo 660-0813
(Received September 21, 2012; CL-120986; E-mail: akira.iida@shionogi.co.jp)
The aza-Michael addition of pyrrolidine to ¢,¢-dialkylated
unsaturated ester 6 utilizing LiBr proceeded smoothly to give the
inaccessible ethyl 1-(tert-butoxycarbonyl)-4-(1-pyrrolidinyl)-4-
piperidineacetate (7), which is an intermediate of novel
antiarteriosclerotic 1.
ognized as a simple and useful method for preparing ¢-
aminocarbonyl derivatives.4 Much effort has been invested in
the development of efficient methods; e.g., using lanthanoid
triflate,5 InCl3,6 FeCl3,7 KF/Al2O3,8 CeCl3/NaI,9 silica gel,10
lipase,11 clay,12 ultrasound,13 and microwave.14 Recently, envi-
ronmentally benign protocols using water solvent were report-
ed.15 These methods, however, are limited to reactions of ¢-non
or monoalkylated unsaturated ester substrates and cannot be
applied to ¢,¢-dialkylated unsaturated esters as a Michael
acceptor because this reaction is susceptible to steric factors.16
As far as we know, the use of high pressure is the only effective
way to achieve the aza-Michael addition of this type.5a,17
However, the need remains for a method offering improved
efficiency for pilot plant preparation from the recently recog-
nized standpoint of process chemistry.
Novel antiarteriosclerotic 1 was discovered by IMMD Inc.
and Shionogi & Co., Ltd.1 Recently, our group developed a pilot
plant preparation method for tert-butyl 4-(2-hydroxyethyl)-4-(1-
pyrrolidinyl)-1-piperidinecarboxylate (5), which is an intermedi-
ate of 1, via unstable iminium salt 3 by a Reformatsky-type
reaction (Scheme 1).2 However, scale-up of the Reformatsky
reaction lacks reproducibility because agglomeration of the zinc
powder is likely to occur. In fact, our first trial pilot production
was unsuccessful (500 L scale).
In this study, we investigated the aza-Michael addition
between ¢,¢-dialkylated unsaturated ester 6 and pyrrolidine
using various additives (PdCl2, Pd(OAc)2, TMSOTf, MnSO4,
Bu4NI, Sc(OTf)3, Yb(OTf)3, ZrCl4, Al(Oi-Pr)3, CuI, Bi(OTf)3,
BF3-Et2O, MgBr2, FeCl3, CeCl3, LiClO4, B(OH)3, NiCl2,
AgOTf, ZnCl, TiCl4, Ti(Oi-Pr)4, AlCl3, Cu(OTf)2, HClO4,
Mg(ClO4)2, CsF, SmI2, Sn(OTf)2, SnCl4, In(OTf)3, Eu(hfc)3,
GaCl3, FeCl2, CoCl2, MS4A, SiO2, and H2O) (Scheme 3).
Among the 38 additives screened, LiClO4 promoted the desired
addition, although the yield was low (31%). The main by-
products in this reaction were ester 8 (migration of the double
bond of starting material 6) and amide 9 (1,2-adduct from 8).
The 1,2-adduct of 6 was not observed. Based on this result, we
attempted optimization of the reaction conditions. The use of
1.0 equiv of LiClO4 at 20-25 °C gave the desired ester 7 in good
yield (82%). Although the LiClO4-promoted aza-Michael addi-
tion was reported by Saidi and co-wokers, the use of ¢,¢-
dialkylated unsaturated ester as a Michael acceptor has not been
described.18
Here we report a new practical synthetic route to key
intermediate ester 7 via the aza-Michael addition of pyrrolidine
to ¡,¢-unsaturated ester 6 (Scheme 2). The practical preparation
of ester 6 from ketone 2 using the Horner-Wadsworth-Emmons
reaction was reported by the Merck group.3
The aza-Michael addition, that is, addition of nitrogen
nucleophilies to ¡,¢-unsaturated carbonyl compounds, is rec-
AcO-
N
N+
O
BocN
H
BocN
AcOH
2
3
O
RO
RO2C
Zn
Br
HO
Red-Al
NBoc
NBoc
O
N
N
4
5
N
HO2C
N
From the viewpoint of process chemistry, a safer and more
inexpensive reagent than LiClO4 is needed. We focused on the
ability of the Li salt to promote the reaction. Table 1 lists the
N
S
N
CF3
Cl
1
Scheme 1.
N
H
additive
O
O
O
EtO
EtO
(3 vol.)
(EtO)2P(O)CH2CO2Et
HWE-Reaction
(0.2 equiv)
EtO
O
BocN
NBoc
NBoc
NBoc
20 - 25 °C, 24 h
N
2
6
6
7
O
O
O
EtO
N
EtO
N
NBoc
H
1
NBoc
NBoc
N
aza-Michael addition
8
9
7
Scheme 3.
Scheme 2.
Chem. Lett. 2012, 41, 1703-1705
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1704
Table 1. Screening of Li salts
aza-Michael addition between cycloalkylidenic ester 10 and
amine had a poor yield due to the generation of by-products
(double bond isomer and 1,2-adduct). Although the low yield of
¢-amino ester is not well understood yet, optimization of the
reaction conditions needs to be attempted. In contrast to cases in
which ¢,¢-dimethyl acrylate 12 was used, the desired ¢-amino
ester 13 was obtained in good yield (80%).
In conclusion, we developed a safe, practical, and robust
synthesis of less accessible ethyl 1-(tert-butoxycarbonyl)-4-(1-
pyrrolidinyl)-4-piperidineacetate (7), which is an intermediate
of novel antiarteriosclerotic 1, utilizing the aza-Michael addition
promoted by LiBr.
Ratio
Entry
Li salta
Yield/%b
7/8/9b
1
2
3
4
5
6
7
8
9
LiClO4
LiClc
82
76
84/2/14
76/1/23
82/1/17
78/4/18
76/3/21
27/69/4
26/70/4
25/72/3
®
LiBr
LiIc
81
76
LiOTf
LiOAc
Li2CO3
Li2SO4
LiPF6
LiBr¢H2O
LiBr (54% aq.)
b
73
16
15
14
trace
71
51
10
11
72/3/25
53/4/43
c
References and Notes
1
2
3
A. Itai, S. Muto, R. Tokuyama, H. Fukasawa, T. Ohara, T.
Kato, WO2007/023882.
a1.0 equiv was used. Determined by HPLC analysis. Reac-
tion time was 30 h.
H. Osato, M. Osaki, T. Oyama, Y. Takagi, T. Hida, K. Nishi,
M. Kabaki, Org. Process Res. Dev. 2011, 15, 1433.
M. S. Ashwood, A. W. Gibson, P. G. Houghton, G. R.
Humphrey, D. C. Roberts, S. H. B. Wright, J. Chem. Soc.,
Perkin Trans. 1 1995, 641.
O
EtO
HO
Red-Al
NBoc
NBoc
N
N
toluene, 5 °C, 2 h
4
a) G. Cardillo, C. Tomasini, Chem. Soc. Rev. 1996, 25, 117.
b) N. Asao, T. Shimada, T. Sudo, N. Tsukada, K. Yazawa,
Y. S. Gyoung, T. Uyehara, Y. Yamamoto, J. Org. Chem.
1997, 62, 6274. c) N. Srivastava, B. K. Banik, J. Org. Chem.
2003, 68, 2109. d) S. Kobayashi, K. Kakumoto, M. Sugiura,
Org. Lett. 2002, 4, 1319. e) T. C. Wabnitz, J. B. Spencer,
Org. Lett. 2003, 5, 2141. f) L. Yang, L.-W. Xu, C.-G. Xia,
Tetrahedron Lett. 2007, 48, 1599. g) D. Pettersen, F. Piana,
L. Bernardi, F. Fini, M. Fochi, V. Sgarzani, A. Ricci,
Tetrahedron Lett. 2007, 48, 7805. h) D. Enders, C. Wang,
J. X. Liebich, Chem.®Eur. J. 2009, 15, 11058. i) Q. Kang,
Y. Zhang, Org. Biomol. Chem. 2011, 9, 6715. j) L.-W. Xu,
C.-G. Xia, Eur. J. Org. Chem. 2005, 633, and other
references cited therein.
7
5
(82%, purity: >99%)
Scheme 4.
amine
(6 vol.)
LiBr
O
O
EtO
EtO
(1.0 equiv)
20 - 25 °C, 24 h
R2N
10
11
amine; Et2NH
morpholine (trace)
pyrrolidine (23% yield)
(trace)
LiBr
(1.0 equiv)
5
a) G. Jenner, Tetrahedron Lett. 1995, 36, 233. b) S.
Matsubara, M. Yoshioka, K. Utimoto, Chem. Lett. 1994,
827.
N
H
O
O
EtO
(6 vol.)
EtO
N
20 - 25 °C, 24 h
6
7
T.-P. Loh, L.-L. Wei, Synlett 1998, 975.
12
13
(80% yield)
a) J. Cabral, P. Laszlo, L. Mahé, M.-T. Montaufier, S. L.
Randriamahefa, Tetrahedron Lett. 1989, 30, 3969. b) M.
Pérez, R. Pleixats, Tetrahedron 1995, 51, 8355.
L. Yang, L.-W. Xu, C.-G. Xia, Tetrahedron Lett. 2005, 46,
3279.
Scheme 5.
8
9
results of the screening of Li salts. We found that LiBr was as
effective as LiClO4 (Entry 3). The selectivity and reaction
velocity of LiCl and LiI were somewhat inferior to LiBr (Entries
2 and 4). The use of LiBr has some merits, i.e., it is, safe, easy to
handle, inexpensive, and easily available.
These results prompted us to synthesize the amino alcohol
5, which is an intermediate of 1. The amino ester 7 was prepared
using the present aza-Michael addition as crude product (78%,
7:8:9 = 98:0:2).19 By-product isomer 8 and amide 9 could
mostly be removed by extraction. The obtained ester 7 was
subjected to the subsequent Red-Al reduction (Scheme 4). The
reduction proceeded successfully with 95% conversion. After
crystallization, the desired amino alcohol 5 was obtained in 82%
yield without purification via silica gel column chromatography
(purity, >99% by HPLC analysis).20
G. Bartoli, M. Bosco, E. Marcantoni, M. Petrini, L. Sambri,
E. Torregiani, J. Org. Chem. 2001, 66, 9052.
10 B. Basu, P. Das, I. Hossain, Synlett 2004, 2630.
11 K. P. Dhake, P. J. Tambade, R. S. Singhal, B. M. Bhanage,
Tetrahedron Lett. 2010, 51, 4455.
12 N. S. Shaikh, V. H. Deshpande, A. V. Bedekar, Tetrahedron
2001, 57, 9045.
13 J.-M. Yang, S.-J. Ji, D.-G. Gu, Z.-L. Shen, S.-Y. Wang,
J. Organomet. Chem. 2005, 690, 2989.
14 K. M. Amore, N. E. Leadbeater, T. A. Miller, J. R. Schmink,
Tetrahedron Lett. 2006, 47, 8583.
15 a) K. Surendra, N. S. Krishnaveni, R. Sridhar, K. R. Rao,
Tetrahedron Lett. 2006, 47, 2125. b) M. K. Chaudhuri, S.
Hussain, M. L. Kantam, B. Neelima, Tetrahedron Lett. 2005,
46, 8329. c) B. C. Ranu, S. Banerjee, Tetrahedron Lett. 2007,
48, 141.
Finally, we investigated the substrate generality of the
present aza-Michael addition (Scheme 5). Unexpectedly, the
Chem. Lett. 2012, 41, 1703-1705
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1705
16 M. Pfau, Bull. Soc. Chim. Fr. 1967, 1117.
crude product (2.67 g, 78%).
17 a) A. Y. Rulev, S. Azad, H. Kotsuki, J. Maddaluno, Eur. J.
Org. Chem. 2010, 6423. b) A. Y. Rulev, N. Yenil, A.
Pesquet, H. Oulyadi, J. Maddaluno, Tetrahedron 2006, 62,
5411.
20 Red-Al 70% in toluene (3.11 g, 10.8 mmol) was added to a
stirred solution of ester 7 (2.67 g) in toluene (10.0 mL) at
0-5 °C, followed by being stirred at the same temperature for
3 h. Acetone (0.7 mL) was added to the reaction mixture,
which was then poured into aqueous 10% citric acid
(35.0 mL). The pH of the aqueous layer was adjusted to 10
with aqueous 48% NaOH, which was extracted with ethyl
acetate (15.0 mL). The organic layer was washed with water
(10.0 mL) and evaporated. After MeOH (8.0 mL) was added
to the residue, water (15.0 mL) was added slowly to the
solution at 20-25 °C, and precipitation of the amino alcohol
5 was observed. This slurry was cooled to 5 °C and aged for
1 h. The crystals were obtained by filtration, washed with
water and dried. By this procedure, the desired amino
alcohol 5 was obtained (1.91 g, 82%).
18 N. Azizi, M. R. Saidi, Tetrahedron 2004, 60, 383.
19 Unsaturated ester 6 (2.69 g, 10.0 mmol) was added to a
stirred solution of LiBr (868 mg, 10.0 mmol) in pyrrolidine
(8.1 mL) at 20-25 °C, followed by being stirred at the same
temperature for 24 h. After removing pyrrolidine from the
reaction mixture of amino ester 7 by evaporation, toluene
(35.0 mL) and aqueous 10% citric acid (40.0 mL) were added
to the residue at 0-5 °C. The pH of the aqueous layer was
adjusted to 10 with aqueous 20% NaOH, which was
extracted with toluene (30.0 mL). The organic layer was
washed with aqueous 1% NaOH (14.0 mL) and water
(14.0 mL). The desired amino ester 7 was obtained as a
Chem. Lett. 2012, 41, 1703-1705
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/