Direct aminoalkylation of α-branched aldehydes with in situ generated glycine cation equivalents

Article abstract of DOI:10.1055/s-2004-829536

The efficient synthesis of β-formyl-α-aminocarboxylates 4 by direct aminoalkylation of aldehydes with in situ generated ternary iminium salts from inexpensive starting materials is described. These compounds are easily transformed into α-amino-β;,β-dialkyl-γ-butyrolactones 10 and α,α-dialkyl-β-dialkylamino-butane-1,4-diols 11 and can be used as versatile building blocks.

Full text of DOI:10.1055/s-2004-829536

LETTER
1489
Direct Aminoalkylation of a-Branched Aldehydes with in situ Generated
Glycine Cation Equivalents
D
irec
t
A
minoa
t
lkylati
e
on of
a
-Bra
f
nche
d
A
a
ldehyde
s
n Piper, Nikolaus Risch*
Department Chemie, Fakultät für Naturwissenschaften, Universität Paderborn, Warburger Straße 100, 33098 Paderborn, Germany
Fax +49(5251)603245; E-mail: nr@chemie.uni-paderborn.de
Received 14 January 2004
curing and cross linking agents.1 Modern alternatives of
the Mannich reaction allow the aminoalkylation of struc-
turally different nucleophiles.2d We have disclosed that
the aminoalkylation of enamines, imines, alkyl vinyl
Abstract: The efficient synthesis of b-formyl-a-aminocarboxylates
4 by direct aminoalkylation of aldehydes with in situ generated ter-
nary iminium salts from inexpensive starting materials is described.
These compounds are easily transformed into a-amino-b,b-dialkyl-
g-butyrolactones 10 and a,a-dialkyl-b-dialkylamino-butane-1,4- ethers and aromatic compounds with ternary iminium
diols 11 and can be used as versatile building blocks.
salts containing alkyl, aryl and carboxylate groups pro-
vides the corresponding Mannich bases in good to excel-
lent yields.2 Ternary iminium salts generated in situ from
substituted ethyl glyoxylate aminals enable the direct
aminoalkylation of ketones.3
Key words: b-formyl-a-aminocarboxylate, ternary iminium salts,
1,4-butanediols, Mannich bases, butyrolactones
Mannich bases and their derivatives afford a variety of in-
teresting applications, among which the preparation of
pharmaceuticals and natural products is of particular im-
portance. In addition, they are used in plant-protection,
coatings, polymers, dyes, as surface active compounds,
Our interest is currently directed towards aminoalkylation
of such nucleophiles which have either not, or just restrict-
edly, been used under the conditions of the classical
Mannich reaction. Our main goal is the efficient synthesis
of valuable key components for the preparation of phar-
maceuticals and natural products. Inexpensive and readily
available starting materials should be used.
NR2
EtO
N
This paper describes a very promising improvement and
extends the methodologies of the modern Mannich reac-
tion, namely the reaction of aldehydes with in situ gener-
ated iminium salts 3 (method A) and 6 (method B) under
mild reaction conditions (Scheme 1, Table 1). The results
are shown in Table 2.
O
N
N
2
a
method A
O
O
NR2
NR2
R2
b
OEt
Previously, aldehydes have been aminoalkylated by us
employing the appropriate enamines using preformed
iminium salts derived from aromatic aldehydes.2a,d These
free bases are quite unstable and prone to elimination.
Aminoalkylation of aldehydes with in situ generated gly-
cine cation equivalents have so far not been described.
+
EtO
TiCl4
Bt
R1 R2
R1
O
O
1
3
4
e
O
NR2
Cl
O
NHR2 Cl
OEt
d
R2
+
EtO
Table 1 Reaction of Aldehydes with in situ Generated Iminium
Salts 3 (Method A) and 6 (Method B) under Mild Reaction Conditions
R1
R1 R2
O
O
7
1
6
1
a
b
c
d
e
f
R1
R2
3
a
b
c
d
e
f
6
a
b
c
R
R
method B
c
Me
Me
Me
Me
NR2
]-(CH2)5-[
Me
]-(CH2)5-[
EtO
NR2
O
Et
]-(CH2)2-O-(CH2)2-[
5
Et
Bu
Ph
Me
CH2-Ph
CH2-Ph
Et
Scheme 1 Reagents and conditions: a) TiCl4, CH2Cl2, –80 °C, 1 h
(method A); b) –80 °C to 20 °C, 10 h (method A); c) CH3COCl,
CH2Cl2, 0 °C, 1 h (method B); d) 0 °C to 20 °C, 6 h (method B); e)
aq NaHCO3, CH2Cl2, 20 °C, 5 min (method B).
Me
CH2-Ph
Et
Me
O
O
SYNLETT 2004, No. 9, pp 1489–1496
Advanced online publication: 29.06.2004
2
2.
0
7.
2
0
0
4
g
Et
H
DOI: 10.1055/s-2004-829536; Art ID: G53204ST
© Georg Thieme Verlag Stuttgart · New York

1490
S. Piper, N. Risch
LETTER
We strived for a direct aminoalkylation of aldehydes, es-
pecially of a-branched aldehydes. For sterical reasons the
analogous aminoalkylation of tetra-substituted enamines
is not successful.2d
Ph
Ph
O
O
O
N
O
a
O
O
O
The iminium salts 3 are generated in situ by electrophilic
attack of a Lewis acid on the ethyl benzotriazol-1-yl-di-
alkylaminoacetates 2.4 Best results were achieved using
TiCl4 in dichloromethane at –80 °C. We started our stud-
ies using 2-methyl-propanaldehyde (1a) and butyralde-
hyde (1g) as models for a-branched and unbranched
aldehydes. The reaction of 1a with iminium salt 3a, 3b,
and 3e provides the racemic aminoalkylated products 4a,
4b, and 4e,5 respectively in good yields (Table 2, entries
8
1g
Scheme 2 a) 3e, CH2Cl2, –80 °C to 20 °C, 10 h.
remarkable that product 4o can be obtained as a single
diastereoisomer (99% ds, Table 2, entry 20) in moderate
yield. On the other hand, no products were isolated in
other cases (e.g. Table 2, entries 18, 24).
1, 3 and 8). In the case of 1g reacting with iminium salt 3e At this point, we used the alternative method B for the
a single product identified as 3-formyl-pent-2-enoic acid preparation of glycine cation equivalents.7 The iminium
ethyl ester (8) was isolated (Scheme 2, yield 72%, salts 6 are generated in situ by electrophilic attack of
E:Z = 85:15).6 The reaction of 1g with 3a or 3b gives acetyl chloride on the ethyl bis-dialkylaminoacetates 5
complex mixtures.
(Scheme 1). With this method the aminoalkylated prod-
ucts can be isolated as hydrochlorides 78 in preponderant
good yields. Due to hygroscopic properties of 7b, the
yield of this product is moderate and it was not possible to
obtain the aminoalkylated product 4 by this method
(Table 2, entry 2).
The results obtained so far encouraged us to extend our in-
vestigations. The reaction of aldehydes 1a–d with imini-
um salts 3 affords the aminoalkylated products in good
yields without exception. Reacting the unsymmetrically
substituted aldehydes 1c and 1d mixtures of diastereoiso-
mers were isolated. But we generally failed to amino-
alkylate aldehydes 1e und 1f by method A. It is
Table 2 Aminoalkylation of Aldehydes 1 Using Iminium Salts 3 or 6
Entry
1
Aldehyde
Iminium salt
b-Formyl-a-amino-carboxylate (4), hydrochloride 7 Method
Yield (%)a
78
1a
3a
A
O
N
CO2Et
4a
2
3
1a
1a
6a
3b
7a, 4a
B
A
59, –
86
O
N
CO2Et
4b
4
5
1a
1a
6b
3c
7b, 4b
B
A
75, 51
56
O
O
N
CO2Et
4c
6
7
1a
1a
6c
7c, 4c
B
A
86, 52
88
3d
Ph
O
N
CO2Et
4d
Synlett 2004, No. 9, 1489–1496 © Thieme Stuttgart · New York

LETTER
Direct Aminoalkylation of a-Branched Aldehydes
1491
Table 2 Aminoalkylation of Aldehydes 1 Using Iminium Salts 3 or 6 (continued)
Entry
8
Aldehyde
Iminium salt
b-Formyl-a-amino-carboxylate (4), hydrochloride 7 Method
Yield (%)a
86
1a
3e
A
Ph
Ph
O
N
N
CO2Et
4e
9
1b
3a
A
61
O
CO2Et
4f
10
11
1b
1b
6a
3b
7f, 4f
B
A
72, 99
71
O
N
CO2Et
4g
12
1b
3f
A
52
O
N
N
CO2Et
4h
13
14
1c
1c
3a
3b
A
A
56
57
O
CO2Et
4ic
O
N
CO2Et
4jc
15
16
1c
3d
3a
A
A
65
58
Ph
O
N
O
CO2Et
4kc
1d
N
CO2Et
4lb
Synlett 2004, No. 9, 1489–1496 © Thieme Stuttgart · New York

1492
S. Piper, N. Risch
LETTER
Table 2 Aminoalkylation of Aldehydes 1 Using Iminium Salts 3 or 6 (continued)
Entry
17
Aldehyde
Iminium salt
b-Formyl-a-amino-carboxylate (4), hydrochloride 7 Method
Yield (%)a
56
1d
3b
A
O
N
CO2Et
4mb
18
1e
3a
A
–
O
N
CO2Et
4n
19
20
1e
1e
6a
3b
7n, 4nc
B
A
77, 92
49
O
N
CO2Et
4od
21
22
1e
1e
6b
6c
7o, 4od
B
B
80, 76
67, 99
O
N
O
CO2Et
7p, 4pd
23
24
1f
1f
6a
3b
B
A
85, 90
O
O
N
O
CO2Et
O
7q, 4qb
–
N
O
O
CO2Et
4r
25
26
1f
1f
6b
6c
7r, 4rb
B
B
87, 99
55, 85
O
N
O
O
CO2Et
O
7s, 4sb
a Yields of isolated products.
b Diastereomeric ratio 1:1.
c Diastereomeric ratio 3:2.
d The NMR and GC spectra only show the signals of a single diastereoisomer (≥99% ds).
Synlett 2004, No. 9, 1489–1496 © Thieme Stuttgart · New York

LETTER
Direct Aminoalkylation of a-Branched Aldehydes
1493
Table 3 Reduction of b-Formyl-a-amino-carboxylates 4 or Hydro-
chlorides 7 with Sodium Borohydride
We were very pleased to observe that aldehydes 1e and 1f
can be aminoalkylated easily by method B. Again, prod-
ucts 7o and 7p were obtained as single diastereoisomers
(99% ds, Table 2, entries 21 and 22) in good yields. In all
other cases mixtures of diastereoisomers were isolated.
Especially, the aminoalkylated products 7 starting from
aldehydes 1e and 1f are not susceptible to moisture and
can be stored easily. Hydrochlorides 7 can be transformed
simply to the b-formyl-a-aminocarboxylates 4 in high
yields.
Entry Mannich base a-Amino-b,b-dialkyl-
4 or hydro- g-butyrolactone (10)
chloride 7
Method Yield
(%)a
1
4a
A
59
O
O
O
N
N
10a
So far, a-branched aldehydes have not been aminoalkylat-
ed by using modern alternatives of the Mannich reaction.
These products are only barely mentioned in literature al-
though they can be used as versatile building blocks.9
2
4b
A
82
O
In contrast to Mannich bases derived from ketones, ami-
noalkylated aldehydes are non-sensitive to elimination of
the amino group. Therefore, these products can be
purified by column chromatography. Whether or not the
aminoalkylation reaction with ternary iminium salts is
successful can easily be proven by the characteristic NMR
spectroscopic data of the CHN-group.
10b
3
4
4e
4i
A
A
73
47
O
O
Ph
Ph
N
10c
O
O
Reduction of the b-formyl-a-aminocarboxylates 4 synthe-
sized in that way leads to products of interest. The g-hy-
droxy-a-amino acid unit is of importance in biologically
active products.10
N
10db
O
O
NR2
5
6
7
4l
A
B
B
67
99
89
O
R2
a
O
OEt
R1 R2
R1
1
N
O
b
4
10e
O
OH NR2
7n
7o
O
O
NHR2 Cl
OEt
O
c
OEt
O
NR2
R1 R2
R1 R2
N
R1
R2
O
O
7
9
10
Scheme 3 a) 3, CH2Cl2, –80 °C to 20 °C, 10 h (method A);
b) NaBH4, EtOH, 20 °C, 5 h (method A); c) NaBH4, EtOH, 20 °C,
5 h (method B).
10fc
O
O
N
The reduction can be performed in two ways. On the one
hand, the aminoalkylated products 4 starting from imini-
um salts 3 can be reduced in good yields employing sodi-
um borohydride in situ (Scheme 3, method A).
Furthermore, the reduction of hydrochlorides 7 gives the
a-amino-b,b-dialkyl-g-butyrolactones 1011 in high yields
(Scheme 3, method B). The results are shown in Table 3.
10gd
8
9
7q
7r
B
B
99
92
O
O
O
O
N
N
O
10hb
By dint of lithium aluminum hydride both the ester and al-
dehyde group can be reduced in one step (Scheme 4). The
reaction succeeds in good to high yields and the diastereo-
meric ratios of products 1113 are equal to those of the
corresponding hydrochlorides 7 (Table 4).
O
O
O
10ib
In summary, the aminoalkylation of a-branched alde-
hydes with ternary iminium salts generated in situ from
substituted ethyl glyoxylate aminals extends the diversity
in the chemistry of Mannich bases. This method affords a
a Yields of isolated products.
b Diastereomeric ratio 1:1.
c Diastereomeric ratio 3:2.
d Diastereomeric ratio 9:1.
Synlett 2004, No. 9, 1489–1496 © Thieme Stuttgart · New York

1494
S. Piper, N. Risch
LETTER
References
OH NR2
O
NHR2 Cl
OEt
a
OH
(1) (a) Tramontini, M.; Angiolino, L. Chemistry and Uses;
CRC: Boca Raton FL, 1994. (b) Kleinman, E. F. In
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991, 893. (c) Overmann, L. E.;
Ricca, D. J. In Comprehensive Organic Synthesis, Vol. 2;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991, 1007.
(d) Tramontini, M.; Angiolino, L. Tetrahedron 1990, 46,
1791. (e) Dimmock, J. R.; Sidhu, K. K.; Chen, M.; Reid, R.
S.; Allen, T. M.; Kao, G. Y.; Truitt, G. A. Eur. J. Med. Chem.
1993, 28, 313. (f) Traxler, P.; Trinks, U.; Buchdunger, E.;
Mett, H.; Meyer, T.; Müller, M.; Regenaß, U.; Rösel, J.;
Lydon, N. J. Med. Chem. 1995, 38, 2441.
R1 R2
R1 R2
O
5
11
Scheme 4 a) LiAlH4, THF, 20 °C, 10 h.
Table 4 Reduction of b-Formyl-a-amino-carboxylate Hydro-
chlorides 7 with Lithium Aluminum Hydride
Entry Hydrochloride 7 a,a-Dialkyl-b-dialkylamino-
butane-1,4-diol (11)
Yield (%)a
(2) (a) Arend, M.; Risch, N. Angew. Chem., Int. Ed. Engl. 1994,
33, 2422; Angew. Chem. 1994, 106, 2531. (b) Arend, M.;
Risch, N. Angew. Chem., Int. Ed. Engl. 1995, 34, 2639;
Angew. Chem. 1995, 107, 2861. (c) Grumbach, H.-J.;
Arend, M.; Risch, N. Synthesis 1996, 883. (d) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37,
1044; Angew. Chem. 1998, 110, 1096. (e) Grumbach, H.-J.;
Merla, B.; Risch, N. Synthesis 1999, 1027. (f) Merla, B.;
Risch, N. J. Prakt. Chem. 1999, 341(5), 472. (g) Piper, S.;
Risch, N. Arkivoc 2003, 1, 86.
1
7n
72
OH
N
OH
11ac
2
7o
99
OH
N
(3) (a) Merla, B.; Grumbach, H.-J.; Risch, N. Synthesis 1998,
1609. (b) Delbos-Krampe, J.; Risch, N.; Flörke, U. Z.
Naturforsch., B: Chem. Sci 2004, 59, 414.
OH
(4) Katritzky, A. R.; Urogdi, L.; Mayence, A. Synthesis 1989,
323.
11bd
(5) Preparation of b-Formyl-a-aminocarboxylates 4a–m.
Method A: All reactions were conducted under argon. To
generate the iminium salt 3, a solution of ethyl glyoxylate
aminal 24 (2.5 mmol) in anhyd CH2Cl2 (10 mL) was cooled
to –80 °C. TiCl4 (2.5 mmol, 0.28 mL) was added in one
portion under stirring. After a reaction time of 1 h at this
temperature, the aldehyde 1 (2.5 mmol) was added. The
temperature was then allowed to rise slowly to 20 °C. The
mixture was quenched with HCl (6 N) and the aqueous layer
was washed with Et2O several times. The aqueous layer was
basified by the addition of aq sat. NaHCO3 solution and
NaOH (2 N) to pH 10–12. The product was extracted with
Et2O, the combined organic layers were dried (Na2SO4) and
the solvent was removed in vacuo. The aminoalkylated
aldehydes 4 were isolated as yellowish oily products without
further purification. Analytical data of some representative
synthesized compounds (* minor diastereoisomer):
2-Dibenzylamino-3,3-dimethyl-4-oxo-butyric Acid Ethyl
Ester (4e): 1H NMR (200 MHz, CDCl3): d = 1.08 (s, 3 H),
1.14 (s, 3 H), 1.43 (t, 3 H, J = 7.1 Hz), 3.68 (s, 1 H),
(dA = 3.57, dB = 3.98, 4 H, J = 13.7 Hz), 4.25–4.44 (m, 2 H),
7.24–7.46 (m, 10 H), 9.35 (s, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): d = 15.08, 20.39, 20.51 (q), 49.46 (s), 57.41, 60.98
(t), 66.17, 127.83, 128.82, 129.65 (d), 139.28, 170.99 (s),
205.02 (d) ppm. IR (neat): 3062, 3030, 2978, 2935, 2848,
1728, 1603, 1495, 1454, 1367, 1203, 1134, 1028, 970, 939,
748, 700 cm–1. MS (80 eV): m/z (%) = 353 (10) [M]+, 282
(100), 280 (26), 253 (49), 159 (47), 117 (20), 106 (32), 91
(50), 65 (11), 42 (9).
3
4
7q
7r
82
72
OH
OH
N
O
OH
OH
O
11cb
N
O
O
11db
a Yields of isolated products.
b Diastereomeric ratio 1:1.
c Diastereomeric ratio 3:2.
d The NMR and GC spectra only show the signals of a single
diastereoisomer (99% ds).
simple synthesis of b-formyl-a-aminocarboxylates and
their derivatives employing inexpensive, readily available
starting materials. As far as we know, this methodology
allows for the first time the systematic synthesis of such
products. Most of them are new to the literature.
Acknowledgment
We would like to thank the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie and the Grünenthal GmbH for
supporting this research.
(1-Formyl-cyclohexyl)-piperidin-1-yl-acetic Acid Ethyl
Ester (4g): 1H NMR (200 MHz, CDCl3): d = 1.28 (t, 3 H,
J = 7.1 Hz), 1.32–1.64 (m, 14 H), 1.88–2.21 (m, 2 H), 2.28–
2.42 (m, 2 H), 2.59–2.73 (m, 2 H), 3.22 (s, 1 H), 4.16 (dq, 2
H, J = 7.1 Hz, J = 1.7 Hz), 9.80 (s, 1 H) ppm. 13C NMR (50
MHz, CDCl3): d = 14.96 (q), 22.82, 22.95, 24.49, 25.96,
27.02, 29.42, 30.10 (t), 52.65 (s), 53.88, 60.54 (t), 76.34 (d),
170.29 (s), 207.68 (d) ppm. IR (neat): 2933, 2854, 2810,
1726, 1452, 1389, 1369, 1333, 1178, 1151, 1117, 1097, 860,
Synlett 2004, No. 9, 1489–1496 © Thieme Stuttgart · New York

LETTER
750 cm–1. MS (80 eV): m/z (%) = 281 (23) [M]+, 251 (3), 207
Direct Aminoalkylation of a-Branched Aldehydes
1495
J = 2.4 Hz), 4.05 (s, 1 H), 7.20–7.45 (m, 5 H), 9.64 (s, 1 H)
ppm. 13C NMR (50 MHz, CDCl3): d = 14.71, 16.90, 24.55,
27.07, 54.44 (q), 57.55 (s), 60.27 (t), 72.87, 127.72, 128.56,
128.63 (d), 137.99, 169.81 (s), 202.18 (d)ppm. IR (neat):
2937, 2858, 1730, 1655, 1598, 1446, 1396, 1211, 1066,
1028, 764, 702 cm–1. MS (70 eV): m/z (%) = 303 (1) [M]+,
230 (5), 201 (10), 170 (13), 133 (28), 105 (93), 98 (100), 91
(16), 77 (38), 43 (29), 28 (11).
(19), 170 (100), 133 (4), 96 (9), 55 (1), 41 (6).
2-(Benzyl-methyl-amino)-3-formyl-3-methyl-pentanoic
Acid Ethyl Ester (4k): 1H NMR (200 MHz, CDCl3): d =
0.80, 0.81* (t, 3 H, J = 7.6 Hz), 1.22, 1.28* (s, 3 H), 1.36*,
1.37 (t, 3 H, J = 7.1 Hz), 1.57–1.90 (m, 2 H), 2.33, 2.34* (s,
3 H), 3.63*, 3.65 (s, 1 H), (dA = 3.63, dB = 3.85, 2 H, J = 13.4
Hz), 4.26*, 4.27 (q, 2 H, J = 7.1 Hz), 7.18–7.44 (m, 5 H),
9.63, 9.74* (s, 1 H) ppm. 13C NMR (50 MHz, CDCl3): d =
8.48, 8.58*, 15.01, 15.80, 16.65* (q), 27.28, 27.93* (t),
40.63, 40.87* (q), 52.90, 53.23* (s), 60.73, 60.82*, 61.58,
61.73* (t), 71.09*, 71.17, 127.55*, 127.60, 128.73, 129.00*,
129.06, 129.18* (d), 139.40, 139.67*, 170.40, 171.22* (s),
204.74, 206.32* (d) ppm. IR (neat): 2974, 2939, 2806, 1728,
1454, 1369, 1223, 1186, 1146, 1026, 741, 698 cm–1. MS (80
eV): m/z (%) = 291 (18) [M]+, 217 (18), 206 (100), 152 (2),
131 (5), 120 (10), 91 (9), 65 (2), 56 (3), 42 (20).
4-(1-Ethoxycarbonyl-2-methyl-3-oxo-2-phenyl-propyl)-
morpholin-4-ium Chloride (7p): 1H NMR (200 MHz,
CDCl3): d = 1.85 (br s, 3 H), 2.29 (d, 3 H), 3.03–4.14 (m, 8
H), 4.77 (s, 1 H), 7.14–7.47 (m, 5 H), 9.41 (d, 1 H) ppm. 13
C
NMR (50 MHz, CDCl3): d = 13.81, 15.06 (q), 55.84 (s),
63.22, 63.52 (q), 66.74 (t), 72.40, 128.71, 129.68 (d), 132.62,
164.50 (s), 197.96 (d) ppm. IR (KBr): 2950, 2784, 2727,
2517, 2451, 1741, 1722, 1446, 1425, 1335, 1282, 1269,
1217, 1196, 1132, 1097, 1059, 1012, 885, 842, 769, 702, 631
cm–1. MS (70 eV): m/z (%) = 306 (94) [M – HCl + 1]+, 292
(2), 232 (5), 172 (100), 130 (6), 100 (3), 88 (7), 57 (45), 43
(21).
2-Dimethylamino-3-ethyl-3-formyl-heptanoic Acid
Ethyl Ester (4l): 1H NMR (200 MHz, CDCl3): d = 0.71*,
0.73 (t, 3 H, J = 7.6 Hz), 0.84 (t, 3 H, J = 6.8 Hz), 0.90–1.19
(m, 4 H), 1.24 (t, 3 H, J = 7.1 Hz), 1.40–1.77 (m, 4 H), 2.24*,
2.25 (s, 6 H), 3.28 (s, 1 H), 4.14*, 4.16 (q, 2 H, J = 7.1 Hz),
9.84*, 9.85 (s, 1 H) ppm. 13C NMR (50 MHz, CDCl3): d =
7.78, 8.05*, 14.14, 14.33*, 14.87 (q), 21.11, 23.04*, 23.59,
23.70*, 25.47*, 25.66, 27.67*, 29.65 (t), 43.96, 44.00* (q),
54.72, 54.83* (s), 60.57 (t), 72.65, 72.72* (d), 170.23,
170.26* (s), 206.83*, 206.90 (d) ppm. IR (neat): 2960, 2939,
2873, 2788, 1724, 1460, 1381, 1186, 1151, 1097, 1032, 944,
867, 766 cm–1. MS (80 eV): m/z (%) = 257 (28) [M]+, 215
(2), 184 (6), 155 (4), 130 (100), 102 (8), 83 (2), 58 (17).
(6) Laugraud, S.; Guingant, A.; d’Angelo, J. J. Org. Chem.
1987, 52, 4788.
3-Methyl-2-morpholin-4-yl-4-oxo-3-phenyl-butyric Acid
Ethyl Ester (4p): 1H NMR (200 MHz, CDCl3): d = 1.02 (dt,
3 H, J = 7.1 Hz, J = 2.5 Hz), 1.70 (d, 3 H, J = 2.5 Hz), 2.36–
2.50 (m, 2 H), 2.53–2.68 (m, 2 H), 3.48–3.61 (m, 4 H), 3.82–
3.96 (m, 2 H), 3.95 (d, 1 H, J = 2.5 Hz), 7.15–7.34 (m, 5 H),
9.48 (d, 1 H, J = 2.5 Hz) ppm. 13C NMR (50 MHz, CDCl3):
d = 14.64, 16.70, 53.42 (q), 57.59 (s), 60.55 (t), 67.83 (q),
72.10, 128.01, 128.63, 128.78 (d), 137.17, 169.32 (s),
201.70 (d) ppm. IR (neat): 2976, 2852, 1726, 1651, 1446,
1259, 1186, 1117, 1030, 1012, 868, 762, 700 cm–1. MS (70
eV): m/z (%) = 305 (1) [M]+, 281 (9), 232 (7), 201 (25), 172
(100), 144 (57), 105 (57), 100 (60), 91 (11), 58 (31), 28 (13).
(9) (a) Bretschneider, T.; Miltz Münster, W. P.; Steglich, W.
Tetrahedron 1988, 44, 5403. (b) Shipov, A. G.;
(7) Merla, B.; Grumbach, H.-J.; Risch, N. Synthesis 1998, 1609.
(8) Preparation of b-Formyl-a-aminocarboxylates 4n–s and
Hydrochlorides 7. Method B: The reactions were
Zheltonogova, E. A.; Kobzareva, V. P.; Orlova, N. A.;
Baukov, I. Yu J. Gen. Chem. USSR 1991, 61, 2142; Zh.
Obshch. Khim. 1991, 61, 2308. (c) Kobayashi, S.; Ishitani,
H. J. Chem. Soc., Chem. Commun. 1995, 1379. (d)Ferraris,
D.; Young, B.; Dudding, T.; Drury, W. J.; Lectka, T.
Tetrahedron 1999, 55, 8869.
conducted under argon. To generate the iminium salt 6, a
solution of ethyl glyoxylate aminal 56 (2.5 mmol) in anhyd
CH2Cl2 (5 mL) was cooled to 0 °C. Acetyl chloride (2.5
mmol, 0.18 mL) was added in one portion under stirring.
After stirring the mixture for 1 h at this temperature, the
aldehyde 1 (2.5 mmol) was added and the temperature was
allowed to rise to 20 °C. The solvent was removed in vacuo
and the crude product was diluted with Et2O or EtOAc and
filtered. Hydrochlorides 7 were isolated as colorless solids,
dried in high vacuum and stored under argon. Hydrochloride
7 (2.0 mmol) was dissolved in CH2Cl2 (5 mL) and treated
with cold aq sat. NaHCO3 solution. The organic layer was
washed with water and dried (Na2SO4). The solvent was
removed in vacuo to yield b-formyl-a-aminocarboxylates 4.
Analytical data of some representative synthesized
(10) (a) König, W. A.; Hass, W.; Dehler, W.; Fiedler, H. P.;
Zähner, H. Liebigs Ann. Chem. 1980, 622. (b) Raffauf, R.
F.; Zennie, T. M.; Onan, K. D.; Le Quesne, P. W. J. Org.
Chem. 1984, 49, 2714. (c) Helms, G. L.; Moore, R. E.;
Niemczura, W. P.; Patterson, G. M. L.; Tomer, K. B.; Gross,
M. L. J. Org. Chem. 1988, 53, 1298. (d) Thodo, K.;
Hamada, Y.; Shiori, T. Synlett 1994, 105.
(11) Reduction with NaBH4 to Yield a-Amino-b,b-dialkyl-g-
butyrolactones 10a–e. Method A: b-Formyl-a-
aminocarboxylate (4) is synthesized by aminoalkylation of
aldehyde 1 with iminium salt 3 as described above. To this
reaction mixture a solution of NaBH4 (3.0 mmol, 0.11 g) in
anhyd EtOH (5 mL) was added and stirring was continued.
After a reaction time of 5 h at 20 °C, the mixture was
quenched with HCl (6 N) and the aqueous layer was washed
with Et2O several times. The aqueous layer was basified by
the addition of aq sat. NaHCO3 solution and NaOH (2 N) to
pH 10–12. The product was extracted with Et2O, the
combined organic layers were dried (Na2SO4) and the
solvent was removed in vacuo.
Reduction with NaBH4 to Yield a-Amino-b,b-dialkyl-g-
butyrolactones 10f–i. Method B: Hydrochloride 7 (1.0
mmol) was dissolved in anhyd EtOH (10 mL), NaBH4 (2.5
mmol, 0.10 g)12 was added and the mixture was stirred for 5
h at 20 °C. Workup follows as described in method A.
Analytical data of some representative synthesized
compounds (* minor diastereoisomer):
compounds:
1-(1-Ethoxycarbonyl-2-methyl-3-oxo-2-phenyl-propyl)-
piperidinium Chloride (7o): 1H NMR (200 MHz, CDCl3):
d = 0.87 (t, 3 H, J = 7.1 Hz), 1.54–1.99 (q, 6 H), 2.32 (s, 3
H), 2.48–2.85 (m, 2 H), 3.04–3.26 (m, 2 H), 3.59–3.93 (m, 2
H), 4.80 (s, 1 H), 7.23–7.44 (m, 5 H), 9.44 (s, 1 H) ppm. 13
C
NMR (50 MHz, CDCl3): d = 13.74, 14.88, 21.97, 22.59,
44.82 (q), 55.72 (s), 62.86 (t), 71.47, 128.61, 129.38, 129.49
(d), 132.98, 164.78 (s), 198.01 (d) ppm. IR (KBr): 2950,
2841, 2733, 2629, 2525, 1740, 1714, 1450, 1414, 1331,
1264, 1207, 1021, 700 cm–1. MS (70 eV): m/z (%) = 303(1)
[M – HCl]+, 230 (3), 216 (9), 190 (29), 170 (35), 133 (38),
105 (100), 77 (25), 57 (12), 43 (23), 29 (45).
3-Methyl-4-oxo-3-phenyl-2-piperidin-1-yl-butyric Acid
Ethyl Ester (4o): 1H NMR (200 MHz, CDCl3): d = 1.13 (t,
3 H, J = 7.1 Hz), 1.32–1.58 (q, 6 H), 1.77 (s, 3 H), 2.38–2.52
(m, 2 H), 2.58–2.72 (m, 2 H), 4.00 (dq, 2 H, J = 7.1 Hz,
Synlett 2004, No. 9, 1489–1496 © Thieme Stuttgart · New York

1496
S. Piper, N. Risch
LETTER
3-Dimethylamino-4,4-dimethyl-dihydro-furan-2-one
(10a): 1H NMR (200 MHz, CDCl3): d = 1.09 (s, 3 H), 1.13
(s, 3 H), 2.44 (s, 6 H), 2.93 (s, 1 H), (dA = 3.80, dB = 3.88, 2
H, J = 8.9 Hz) ppm. 13C NMR (50 MHz, CDCl3): d = 20.85,
27.09 (q), 40.96 (s), 44.51 (q), 72.72 (d), 78.36 (t), 175.43 (s)
ppm. IR (neat): 2962, 2925, 2362, 2341, 1770, 1736, 1456,
1432, 1261, 1081, 1018, 798 cm–1. MS (80 eV): m/z
(%) = 157 (100) [M]+, 141 (10), 128 (9), 112 (10), 102 (46),
82 (17), 58 (18), 49 (88), 42 (60).
THF (4.0 mmol, 4 mL)12 at 20 °C. After a reaction time of
10 h, the mixture was quenched very slowly with H2O and
HCl (6 N). The aqueous layer was washed with Et2O several
times and basified by the addition of aq sat. NaHCO3
solution and NaOH (2 N) to pH 10–12. The product was
extracted with CH2Cl2, the combined organic layers were
dried (Na2SO4) and the solvent was removed in vacuo.
Analytical data of some representative synthesized
compounds (* minor diastereoisomer):
3-Dibenzylamino-4,4-dimethyl-dihydro-furan-2-one
(10c): 1H NMR (200 MHz, CDCl3): d = 0.66 (s, 3 H), 1.07
(s, 3 H), 3.16–3.29 (m, 5 H), 4.12–4.32 (m, 2 H), 7.12–7.40
(m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): d = 20.80,
24.19 (q), 38.93 (s), 57.70 (t), 66.46 (d), 71.79 (t), 127.96,
129.01, 129.79 (d), 139.27 (s), 170.99 (s) ppm. IR (neat):
2958, 1763, 1736, 1493, 1448, 1365, 1130, 1026, 741, 696
cm–1. MS (80 eV): m/z (%) = 309 (100) [M]+, 281 (12), 253
(49), 217 (62), 195 (20), 105 (10), 91 (42), 65 (5), 53 (3), 41
(5).
3-Dimethylamino-2-methyl-2-phenyl-butane-1,4-diol
(11a): 1H NMR (200 MHz, CDCl3): d = 1.12*, 1.36 (s, 3 H),
2.08*, 2.50 (s, 6 H), 3.02–3.25 (m, 2 H), 3.57–4.11 (m, 3 H),
7.06–7.55 (m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): d =
16.04*, 24.58, 43.19, 44.31* (q), 44.61*, 45.00 (s), 59.96*,
60.59, 73.75*, 74.15 (t), 74.74*, 74.83, 126.11, 126.85*,
127.05, 128.49, 128.96* (d), 144.37*, 145.08 (s) ppm. IR
(neat): 3350, 2947, 2881, 2843, 2252, 1498, 1466, 1444,
1385, 1026, 910, 737, 650 cm–1. MS (70 eV): m/z (%) = 223
(5) [M]+, 192 (88), 176 (11), 162 (87), 147 (39), 118 (74),
115 (76), 102 (67), 88 (94), 70 (96), 58 (95) 44 (97), 28
(100).
4-Piperidin-1-yl-2-oxa-spiro[4.5]decan-3-one (10e): 1H
NMR (200 MHz, CDCl3): d = 0.98–1.55 (m, 16 H), 2.24–
2.45 (m, 2 H), 2.45–2.60 (m, 2 H), 2.74 (s, 1 H), (dA = 3.73,
dB = 3.82, 2 H, J = 9.2 Hz) ppm. 13C NMR (50 MHz,
CDCl3): d = 22.85, 23.06, 24.18, 25.63, 26.84, 29.20, 36.43
(t), 42.76 (s), 53.19 (t), 71.86, 77.28 (d), 175.42 (s) ppm. IR
(KBr): 2931, 2852, 1772, 1450, 1169, 1144, 1099, 1012
cm–1. MS (80 eV): m/z (%) = 237 (100) [M]+, 192 (2), 150
(8), 141 (56), 122 (8), 110 (11), 96 (9), 84 (10), 53 (3), 41 (5).
3-Dimethylamino-4-methyl-4-phenyl-dihydro-furan-2-
one (10f): 1H NMR (200 MHz, CDCl3): d = 1.44, 1.46* (s, 3
H), 2.07, 2.44* (s, 6 H), 3.36, 3.59* (s, 1 H), (dA = 4.19,
dB = 4.62, 2 H, J = 9.2 Hz), (dA = 4.12, dB = 4.24, 2 H,
J = 9.0 Hz, CH2O)*, 7.12–7.43 (m, 5 H) ppm. 13C NMR (50
MHz, CDCl3): d = 22.34*, 29.41, 43.13, 44.93* (q), 46.82,
48.26* (s), 72.14*, 72.76 (d), 76.83*, 77.43 (t), 125.74*,
127.20, 127.43*, 127.55, 128.81, 129.27* (d), 141.48*,
144.84, 174.54*, 174.92 (s) ppm. IR (film): 2974, 2943,
2904, 2877, 2841, 2789, 2254, 1770, 1498, 1446, 1163,
1024, 910, 737, 650 cm–1. MS (80 eV): m/z (%) = 219 (60)
[M]+, 159 (6), 143 (4), 130 (4), 116 (11), 102 (100), 91 (4),
58 (24), 42 (31).
4-Methyl-4-phenyl-3-piperidin-1-yl-dihydro-furan-2-
one; Compound with Methane (10g): 1H NMR (200 MHz,
CDCl3): d = 1.12–1.26 (m, 4 H), 1.43, 1.44* (s, 3 H), 1.47–
1.60 (m, 2 H), 2.12–2.27 (m, 2 H), 2.31–2.49 (m, 2 H), 3.31,
3.53* (s, 1 H), (dA = 4.19, dB = 4.64, 2 H, J = 9.3 Hz),
(dA = 4.18, dB = 4.31, 2 H, J = 9.0 Hz)*, 7.11–7.35 (m, 5 H)
ppm. 13C NMR (50 MHz, CDCl3): d = 22.77*, 29.20 (q),
24.17, 24.47*, 26.71, 27.20* (t), 46.68, 48.01* (s), 51.96,
53.69* (t), 72.87*, 73.78 (d), 76.45*, 77.56 (t), 125.47*,
127.23, 127.35, 128.42, 129.16* (d), 141.43, 145.68*,
174.73*, 175.05 (s) ppm. IR (neat): 2939, 2856, 2252, 1759,
1626, 1446, 1169, 1107, 1024, 910, 737, 650 cm–1. MS (80
eV): m/z (%) = 259 (29) [M]+, 142 (100), 117 (12), 96 (7), 68
(7), 55 (8), 41 (20).
2-Methyl-2-phenyl-3-piperidin-1-yl-butane-1,4-diol
(11b): 1H NMR (200 MHz, CDCl3): d = 1.36 (s, 3 H), 1.41–
1.64 (m, 6 H), 2.11–2.52 (m, 2 H) 2.67–2.84 (m, 2 H), 2.89–
3.01 (m, 2 H), 3.08 (t, 1 H, J = 11.9 Hz), (dA = 3.66,
dB = 4.04, 2 H, J = 9.9 Hz), 7.04–7.26 (m, 5 H) ppm. 13
C
NMR (50 MHz, CDCl3): d = 16.27 (q), 24.64, 27.49 (t),
45.21 (s), 54.86, 60.43, 74.65 (t), 76.60, 126.07, 126.93,
128.89 (d), 144.34 (s) ppm. IR (KBr): 3361, 2937, 2854,
2252, 1468, 1454, 1442, 1039, 1026, 908, 733, 650 cm–1. MS
(70 eV): m/z (%) = 263 (8) [M]+, 232 (87), 210 (33), 201
(40), 142 (92), 128 (92), 118 (87), 112 (100), 98 (91), 84
(91), 69 (71), 55 (90), 41 (98), 28 (73).
2-Benzo[1,3]dioxol-5-ylmethyl-3-dimethylamino-2-
methyl-butane-1,4-diol (11c): 1H NMR (200 MHz,
CDCl3): d = 0.52, 0.88* (s, 3 H), 2.45*, 2.51 (s, 6 H), 2.59–
2.73 (m, 2 H), 3.11–3.57 (m, 3 H), 3.82–4.07 (m, 2 H), 5.83,
5.84* (s, 2 H), 6.44–6.75 (m, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): d = 17.93*, 21.65 (q), 36.30 (t), 41.29*, 41.49 (s),
44.39, 44.68* (q), 59.41*, 59.68, 70.27, 71.37* (t), 72.65*,
75.65 (d), 101.09, 101.23* (t), 108.04, 108.18*, 111.35*,
111.56, 123.97*, 124.08 (d), 131.15*, 131.78, 146.13,
146.39*, 147.51, 147.62* (s) ppm. IR (KBr): 3329, 2945,
2879, 2252, 1504, 1489, 1442, 1248, 1095, 1041, 906, 733,
650 cm–1. MS (80 eV): m/z (%) = 281 (70) [M]+, 249 (5), 134
(6), 113 (1), 98 (7), 88 (100), 58 (31), 44 (4).
2-Benzo[1,3]dioxol-5-ylmethyl-2-methyl-3-piperidin-1-
yl-butane-1,4-diol (11d): 1H NMR (200 MHz, CDCl3): d
= 0.50, 0.87* (s, 3 H), 1.27–1.63 (m, 6 H), 2.24–2.46 (m, 2
H), 2.54–2.78 (m, 2 H), 2.84–3.05 (m, 6 H), 3.08–3.55 (m, 3
H), 3.75–4.07 (m, 2 H), 5.81, 5.82* (s, 2 H), 6.42–6.75 (m,
3 H) ppm. 13C NMR (50 MHz, CDCl3): d = 18.25*, 21.86,
24.65*, 26.04, 27.47 (q), 36.45 (t), 41.36*, 41.55 (s), 44.57*
(t), 53.32*, 54.88 (q), 59.47*, 59.68, 70.38, 71.27*(t),
74.27*, 77.56 (d), 101.06, 101.21* (t), 108.00, 108.15*,
111.35*, 111.55, 123.95* 124.05 (d), 131.27*, 131.86,
146.10, 146.36*, 147.50, 147.60* (s) ppm. IR (film): 3352,
2937, 2854, 2252, 1504, 1489, 1442, 1246, 1097, 1041, 910,
733, 650 cm–1. MS (80 eV): m/z (%) = 321 (12) [M]+, 287
(52), 257 (5), 206 (5), 175 (9), 151 (18), 134 (100), 128 (78),
98 (92), 77 (30), 41 (48).
(12) The hydrochlorides may also be deprotonated with aq sat.
NaHCO3 before reduction. However, the deprotonation with
the reducing agent is useful for small quantity of the b-
formyl-a-aminocarboxylate hydrochlorides.
(13) Reduction with LiAlH4 to Yield a,a-Dialkyl-b-
dialkylamino-butane-1,4-diols 11. To hydrochlorides 7
(1.0 mmol) in anhyd THF (10 mL) was added 1 M LiAlH4 in
Synlett 2004, No. 9, 1489–1496 © Thieme Stuttgart · New York