Simple synthetic equivalents for the β-(N,N-disubstituted)ethylamino acyl cation synthon and their applications

Article abstract of DOI:10.1055/s-2001-18439

Various N,N-disubstituted-β-amino-N-methoxy-N-methylpropanamides 3a-i were prepared which served as an excellent β-aminoacyl cation equivalents. These were used to prepare β-amino ketones 1, pharmacologically active tertiary 1-(3,3-diarylpropyl)amines 7a-c, and the interesting C-glycoside 8.

Full text of DOI:10.1055/s-2001-18439

PAPER
2239
Simple Synthetic Equivalents for the -(N,N-Disubstituted)ethylamino Acyl
Cation Synthon and their Applications
V
-(
N
,
N
-Disubstitut
.
ed)ethylamin
S
o Acyl Cation
e
Equivalen
l
ts vamurugan, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology, Madras, Chennai 600 036, India
Fax 91(44)2350509; E-mail: isingh@pallava.iitm.ernet.in
Received 26 June 2001; revised 28 August 2001
This paper is dedicated to Professor S. Swaminathan.
Represented in Figure 2 are the two possible routes ensu-
Abstract: Various N,N-disubstituted- -amino-N-methoxy-N-me-
thylpropanamides 3a–i were prepared which served as an excellent
-aminoacyl cation equivalents. These were used to prepare -ami-
no ketones 1, pharmacologically active tertiary 1-(3,3-diarylpro-
pyl)amines 7a–c, and the interesting C-glycoside 8.
ing disconnection C. Katritzky, based on benzotriazole
chemistry developed7 2 as a novel synthetic equivalent of
-aminoacyl anion X towards the synthesis of -aminoet-
hyl ketones. In their work the nature of the electrophile is
restricted to alkyl halide and benzaldehyde. It therefore
cannot be used for the synthesis of 1 where R3 is an aryl
residue.
Keywords: Weinreb amide -amino ketones, Grignard reactions,
alkylations, glycoside
R2
N
+
-Amino ketones 1 are highly attractive substances be-
cause of their value as general synthetic building blocks in
the preparation of pharmaceuticals, plant protection mate-
rials or natural products.1a Of the various disconnections
(Figure 1) possible to arrive at 1, it is disconnection A
which provides one of the most fundamental methods for
the synthesis of 1. It is based on the classical Mannich and
related reactions. Although limited to aminomethylation,1
many variants2 of the Mannich reaction have been ex-
tremely promising. In this context, iminium salts2 and
imines3 have served as valuable substrates for their reac-
tion with enamines and silyl enol ethers, respectively, to
obtain -amino ketones. However, both substrates have
some limitations. Iminium salts are extremely hygroscop-
ic and are prone to hydrolysis. They therefore demand in
situ generation. In addition, the basic nature of imines de-
activates the Lewis acid, and expensive Zr(OTf)4 or
Hf(OTf)4 are required for successful reactions.
O
R3
N
Bt
R1
-
O
O
Cb
R2
N
X
2
C
R3
R1
Bt = benzotriazolyl
Cb = carbazolyl
O
R2
N
-
O
R2
R3
CH3
N
N
R1
+
O
R1
OCH3
O
O
3a-i
Y
Figure 2
With regard to synthon Y, there are few reports8 wherein
the -(N,N-disubstituted)ethylaminoacyl unit in the form
of the corresponding Weinreb amide has served as an
equivalent to synthon Y. However, in these cases the unit
was a fragment of a larger molecule for specific synthetic
needs. With this precedence we aimed at simple and
straightforward synthesis of the reagents equivalent to the
N-protected -aminoacyl cation Y which would be of im-
mense interest and use as valuable reagents. Herein we
disclose our systematic study towards the preparation of
Disconnection B is apparently simple but it demands rel-
atively unstable and reactive aryl vinyl ketones (when
R3 = Aryl) as starting material for the Michael reaction
and hence has not been used much. The approach, howev-
er, has been very useful in preparing -amino esters,4
nitriles5 and amides.6
various
-(N,N-disubstituted)ethylaminoacyl cation
equivalents9 3a–i and their utility to arrive at -aminoeth-
yl ketones. The motivation to this proposal lay in the suc-
cess, in which N-methoxy-N-methylamide functionality,
now popularly called as Weinreb amide, has received to-
wards clean acylation with organometallics.10 Multigram
quantities of the reagent 3a–i are easily and routinely pre-
pared in high yields (75–91%) (Scheme 1, Table 1) by
alkylating various amines 4a–i with N-methoxy-N-meth-
yl-3-bromopropanamide (5) using K2CO3 in acetonitrile
as solvent. The amide 5 is prepared in two high yielding
steps starting from 3-bromopropanoic acid.11 Conversion
R2
B
R3
N
R1
A
O
Figure 1 Possible disconnections A and B of the -amino ketone 1
leading to its synthesis
Synthesis 2001, No. 15, 12 11 2001. Article Identifier:
1437-210X,E;2001,0,15,2239,2246,ftx,en;T05101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2240
V. Selvamurugan, I. S. Aidhen
PAPER
Table 1 Various -(N, N-Disubstituted)ethylamino Acyl Cation
Equivalents 3a–i Prepared
of 3-bromopropanoic acid to the corresponding acid chlo-
ride and its subsequent reaction with N,O-dimethylhy-
droxylamine hydrochloride in the presence of two
equivalents of pyridine furnished N-methoxy-N-methyl-
3-bromopropanamide9 (5) in 76% yield. All the amides
3a–i can be stored indefinitely on shelf without any de-
composition.
Entry Secondary Amine
Prod- Yieldc IR (CHCl3)
ucta,b (%)
(cm–1)
1
2
3
(Bn)2NH
1a
3a
3b
3c
80
79
75
2816, 1676, 1484,
1452,1369
MeNHSO2Ph
1b
2944, 2368, 1673,
1462, 1340
K2CO3, CH3CN
R2
CH3
R2
CH3
N
reflux, 3h
+
Br
N
NH
N
R1
OCH3
3,4-
2901, 1679, 1490,
1434, 1380
R1
OCH3
(MeO)2C6H3CH2
O
O
NHBn
1c
4a-i
5
3a-i
f: R1, R2= -CH=CH-N=CH-
g: R1, R2= -(CH2)2-O-(CH2)2-
h: R1, R2= -CH2(CH2)3CH2-
i: R1=R2= CH3
a: R1=R2= Bn
b: R1= CH3; R2= SO2Ph
c: R1= Bn; R2= 3,4-(MeO)2C6H3CH2
d: R1=R2= CH(CH3)2
e: R1, R2= -(CH2)2-N(Boc)-(CH2)2-
4
5
(Me2CH)2NH
1d
3d
3e
78
78
2960, 2840, 1669,
1450, 1375
2990, 1708, 1676,
1450, 1310
Scheme 1
1e
1f
6
7
8
9
3f
3g
3h
3i
75
91
87
76
3060, 1676, 1600,
1310, 1375
It was observed that substrates 3a,c,d and g underwent
clean reaction with various Grignard reagents at 0 °C
(Scheme 2) forming the corresponding -amino ethyl ke-
tones in good to excellent yields (Table 2). On the other
hand the reaction of phenylmagnesium bromide with 3b at
0 °C was complex. This could be in part due to the
cleavage12 of N-SO2Ph by the attack of Grignard reagent
on the electrophilic sulfur atom and subsequent fragmen-
tation. To avoid the decomposition, the reaction tempera-
ture was systematically lowered and the addition of
phenylmagnesium bromide at various temperatures was
investigated. Finally it was observed that at –40 °C, de-
composition was completely eliminated and a clean reac-
tion ensued affording 1bm in 67% yield. The condition
developed was general and not specific to phenylmagne-
sium bromide as exemplified by succesful reaction with
other Grignard reagents (Table 2). In case of substrates 3e
and 3f the Grignard reagent was added at –40 °C and then
the temperature was allowed to reach 0 °C for successful
reaction. Substrates 3b and 3c are particularly notewor-
thy. In the case of 3b further functionalisation at the nitro-
gen center is possible after desulphonylation13 whereas
the two benzyl groups in 3c are orthogonal and therefore
would allow greater flexibility in manipulating the nitro-
2990, 1679, 1472,
1450, 1375
1g
2990, 2840, 1673,
1440, 1350
1h
Me2NHd
2900, 1679, 1472,
1450, 1375
1i
a Satiafactory microanalyses were obtained for all the new com-
pounds: C 0.30, H 0.27, N 0.31.
b Syrupy liquid.
c Yield of isolated product.
d Reaction conditions: To an excess of 40% aq Me2NH (50 mL) was
added a solution of 5 (2.5 mmol) in CH2Cl2 (75 mL) and stirred for
12 h at 0 °C.
gen center.4 In the case of allylmagnesium bromide (En-
tries 6 and 13 in Table 2) the initially formed , -
unsaturated product isomerised to more stable , -unsat-
urated product during acidic workup and purification us-
ing silica gel chromatography.
R2
R3
THF, 1.5h, -40 °C or 0 °C
N
R1
3a-g
+
R3MgBr
The developed route to -amino ketones was applied to
the synthesis of therapeutically important tertiary 1-(3,3-
diarylpropyl)amines14 7a–c (Figure 3) as depicted in
Scheme 3. This approach is particularly important when
the two aryl residues are not equivalent (Table 3).
O
1
6a-g
a: R3= C6H5
b: R3= 4-(CH3O)C6H4
c: R3= 4-(CH3)C6H4
d: R3= n-C4H9
The elegance of these synthetic equivalents was further
confirmed by its ready use in appending the -(N,N-diben-
zyl)ethylamino acyl fragment at the anomeric carbon of
glycosyl residue. Treatment of 3,4,6-tri-O-benzyl-2-
deoxy- -D-arabino-hexopyranosyllithium15 with 3a re-
e: R3= (CH3)2CH
f: R3= CH2=CH-CH2-
g: R3= 1-naphthyl
Scheme 2
Synthesis 2001, No. 15, 2239–2246 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
β-(N,N-Disubstituted)ethylamino Acyl Cation Equivalents
2241
Table 2 Addition of Grignard Reagent to 3a–g to form Various -(N,N-Disubstituted)ethylamino Ketones 1
Entry
Starting Amide Grignard Re-
agent
Reaction Temp Producta,b
(oC)
Yield (%)c
IR (CHCl3)
(cm–1)
1
2
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
3d
3e
3f
6a
6b
6c
6d
6e
6f
0
1aa
1ab
1ac
1ad
1ae
1af
79
73
74
83
72
68
65
67
68
70
77
74
65
66
71
69
75
70
70
76
70
68
78
2816, 1689, 1491, 1443, 1347
2944, 1676, 1587, 1480, 1456
2861, 1671, 1491, 1443, 1371
2864, 1712, 1488, 1444, 1363
2872, 1714, 1490, 1360, 1210
2912, 1696, 1422, 1491, 1356
2874, 1681, 1483, 1448, 1339
2816, 1683, 1443, 1337, 1180
2955, 1670, 1456, 1340, 1160
2816, 1671, 1450, 1370, 1150
2865, 1714, 1440, 1375, 1176
2860, 1712, 1449, 1368, 1169
2973, 1691, 1430, 1370, 1171
2911, 1690, 1447, 1368, 1169
2888, 1690, 1487, 1443, 1334
3032, 1688, 1587, 1487, 1443
2896, 1678, 1444, 1332, 1371
2998, 1710, 1488, 1465, 1355
2902, 1710, 1490, 1360, 1299
2973, 1690, 1448, 1350, 1175
2990, 1708, 1688, 1443, 1332
3040, 1688, 1611,1313, 1340
2985, 1691, 1485, 1432, 1330
0
3
0
4
0
5
0
6
0
7
6g
6a
6b
6c
6d
6e
6f
0
1ag
1bad
1bbe
1bcf
1bd
1be
1bf
8
–40
9
–40
10
11
12
13
14
15
16
17
18
19
20
21
22
23
–40
–40
–40
–40
6g
6a
6b
6c
6d
6e
6a
6b
6c
6g
–40
1bgg
1ca
1cb
1cc
0
0
0
0
1cd
1ce
0
0
1da
1eb
1fc
–40 to 0
–40 to 0
0
3g
1gg
a Satiafactory microanalyses were obtained for all the new compounds. C 0.26, H 0.29, N 0.22.
b Syrupy liquid, unless otherwise indicated.
c Yield of isolated product.
d Mp 58–60 °C.
e Mp 79–81 °C.
f Mp 91–92 °C.
g Mp 95–97 °C.
i) ArMgX,THF, 0 °C, 2.5h
R2
ii) PTSA, benzene, reflux, 3h
iii) Pd/C, H2, MeOH, RT, 12h
PhMgBr, THF, 0 °C
R2
N
Ph
N
Ph
3g-i
R1
R1
Ar
O
1ga-1ia
7a-c
Scheme 3
sulted in the formation of 8, an interesting C-glycoside
J
1,2ax = 3.4 Hz, H-1).15 The efficiency of the developed ap-
(Scheme 4). The axial addition of the -aminoacyl unit proach to the -amino ketones tempted us to explore the
1
was shown by H NMR spectroscopy; = 4.98 (d, 1 H, synthesis of -amino ketones by replacing 5 with its high-
Synthesis 2001, No. 15, 2239–2246 ISSN 0039-7881 © Thieme Stuttgart · New York

2242
V. Selvamurugan, I. S. Aidhen
PAPER
ing and versatile due to the flexibility that exists in chang-
ing the nature of the substitution at nitrogen centre as per
requirement of the synthetic objective.
CH3
N
Ph
X
H3C
N
Ph
Ar
All the solvents and reagents were distilled before use. Anhyd sol-
vents were prepared according to the standard procedures. Reac-
tions requiring inert atmosphere were carried out under dry N2.
Melting points were determined in capillary using a Toshniwal
melting point apparatus and are uncorrected. NMR spectra were re-
corded on a Bruker (300 MHz 1H, 75 MHz 13C) or a Jeol (400 MHz
1H, 100 MHz 13C) NMR spectrometers using TMS as an internal
standard. IR spectra were recorded on a Shimadzu IR 470 instru-
ment. Elemental analyses were performed on a Heraeus CHN ana-
lyzer. Optical rotation was measured by a Jasco DIP 370
polarimeter. The TLC tests for monitoring the course of the reaction
were performed on silica gel (Merck, TLC grade) coated on a glass
plate (7 cm 2.5 cm) followed by staining in iodine vapors. For col-
umn chromatography, silica gel (100–200 mesh) was used, unless
otherwise indicated.
CH3
7c ( tolpropamine)
7a: X = -O-: Ar = 4-(CH3O)C6H4
7b: X = CH2: Ar = C6H5 (fenpiprane)
Figure 3 Chemical Structures of compounds 7a–c
Table 3 Application of 3g–i Towards the Preparation of 7a–c
Entry Starting -Amino Grignard Reagent , -Dia- Overall
Amide Ketone
(yield %)
(ArMgBr)
rylpropy- Yield
lamine
(%)a
68
1
2
3
3g
3h
3i
1ga (75) Ar = 4-MeOC6H4 7c
1ha (81) Ar = Ph
1ia (80) Ar = 4-MeC6H4
7b
7c
70
3-Bromo-N-methoxy-N-methylpropanamide (5) was prepared ac-
cording to the procedure described in the literature.9 N-Methyl-N-
phenylsulphonyl amine19a and N-benzyl-N-(3,4-dimethoxybenzyl)
amine19b were prepared based on the similar type of procedure de-
scribed in the literature.
69
a Yield of isolated product based on 3g–i.
Alkylation of Amines 4a–i with 5; General Procedure
To a mixture of an appropriate amine (2.5 mmol) and anhyd K2CO3
er homologue 9a. Substrate 9a was, however, found to be
unstable, as substantial amounts of it readily decomposed (1.4 g, 10 mmol) in anhyd MeCN (10 mL) was added 5 (0.5 g, 2.5
mmol) and the mixture was stirred at reflux for 3 h. The mixture was
to -butyrolactone and amine hydrobromide by reaction
cooled to r.t. and filtered through Celite. The solvent was evaporat-
with water during the workup procedure. On the contrary
ed from the filtrate and the resulting residue was purified by column
chromatography (hexane–EtOAc) to afford 3a–i in good yields
(75–91%) (Tables 1 and 4).
the chloro analogue 9b was found to be very stable. Alky-
lation of morpholine with 9b afforded 10 which upon
treatment with 2-naphthylmagnesium bromide resulted in
the formation of 4-morpholino-1-(2-naphthyl)butan-1-
one (11), a valuable -amino ketone found to be a potent
inhibitor of Jak3 kinase (Scheme 4).16 This further illus-
trates the usefulness and the generality associated with the
proposed synthetic equivalents for or -(N,N-disubsti-
tuted)aminoacyl cations.
Addition of Grignard Reagents to 3a–i; General Procedure
To a solution of 3a–i (2.5 mmol) in anhyd THF (20 mL) was added
the appropriate Grignard reagent (7.5 mmol) in anhyd THF (10 mL)
under N2 at a suitable temperature (see Table 2). The mixture was
then stirred for 1.5 h. The hydrolysis was achieved by the cautious
addition of sat. aq NH4Cl solution (30 mL). After returning to r.t.,
the two phases were separated and the aqueous phase was extracted
with EtOAc (3 20 mL). The organic phases were combined,
washed with brine (40 mL) and dried (Na2SO4). Removal of the sol-
vent under reduced pressure gave the crude product, which was pu-
rified by column chromatography (hexane–EtOAc) to afford N-
disubstituted- -amino ketones 1aa–1gg in good yields (65–83%)
(Tables 2 and 5).
In summary, various N-protected- -aminoacyl cation
equivalents have been prepared which undergo a clean re-
action with various Grignard reagents leading to the con-
venient synthesis of -aminoethyl ketones. Given the fact
that there are many reagents available for enantioselective
reduction17 of the aromatic ketone functionality, the de-
veloped approach to N-protected -amino ketone should
also be a valuable starting point for rapid and potential en-
try into -amino alcohol functionality, which is present in
many of the important antidepressents.18 The synthetic
equivalents proposed herein, become even more interest-
Tertiary 1-(3,3-Diarylpropyl)amines 7a–c; General Procedure
N,N-Disubstituted- -amino ketones 1ga–1ia (75–81%) were pre-
pared by the addition of phenylmagnesium bromide [prepared from
bromobenzene (1.17 g, 7.5 mmol) and Mg (0.206 g, 8.5 mmol) in
anhyd THF (20 mL) with stirring at reflux for 1 h under a N2 atm]
to a solution of 3g–i (2.5 mmol) in THF (20 mL) at 0 °C. To a stirred
OBn
CH3
O
H
BnO
X
N
BnO
O
N
X
OCH3
O
O
N(Bn)2
O
9a: X = Br
9b: X = Cl
8
10: X = N(OCH3)CH3
11: X = 2-naphthyl
Scheme 4
Synthesis 2001, No. 15, 2239–2246 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
β-(N,N-Disubstituted)ethylamino Acyl Cation Equivalents
2243
Table 4 NMR Data for Compounds 3a–i
Product
1H NMR (300 MHz, CDCl3/TMS)
13C NMR (75 MHz, CDCl3/TMS)
, J (Hz)
3a
2.60 (t, 2 H, J = 7.3, CH2CO), 2.82 (t, 2 H, J = 7.3,
30.29, 32.01, 49.21, 58.27, 61.02, 126.83, 128.15, 128.71,
NCH2CH2), 3.08 (s, 3 H, NCH3), 3.59 (s, 4 H, NCH2Ph ), 3.64
139.51, 175.10
(s, 3 H, OCH3), 7.1–7.36 (m, 10 H, ArH)
3b
3c
2.75 (t, 2 H, J = 7.3, CH2CO), 2.80 (s, 3 H, NCH3), 3.15 (s, 3
H, NCH3), 3.34 (t, 2 H, J = 7.3, NCH2CH2), 3.68 (s, 3 H,
OCH3), 7.51–7.60 (m, 3 H, ArH), 7.77–7.79 (m, 2 H, ArH)
31.00, 31.47, 35.42, 45.62, 60.75, 126.84, 128.59, 132.10,
137.00, 171.15
2.60 (t, 2 H, J = 7.4, CH2CO), 2.84 (t, 2 H, J = 7.4,
NCH2CH2), 3.11 (s, 3 H, NCH3), 3.53 (s, 2 H, NCH2Ph), 3.55
(s, 2 H, NCH2), 3.59 (s, 3 H, OCH3), 3.84 (s, 3 H, ArOCH3),
3.88 (s, 3 H, ArOCH3), 6.88–7.36 (m, 8 H, ArH)
30.33, 32.55, 49.25, 54.85, 54.92, 58.25, 58.31, 61.05,
114,51, 114.82, 126.81, 128.21, 128.51, 128.72, 140.73,
139.71, 159.61, 159.91, 171.15
3d
3e
1.52 {d, 12 H, J = 7.4, [(CH3)2CH]2}, 2.61 {m, 2 H,
[(CH3)2CH]2}, 2.71 (t, 2 H, J = 7.3, CH2CO), 2.85 (t, 2 H, J
= 7.3, NCH2CH2), 3.10 (s, 3 H, NCH3), 3.59 (s, 4 H,
NCH2Ph), 3.69 (s, 3 H, OCH3)
21.15, 31.25, 38.75, 48.30, 49.31, 61.50, 171.15
1.35 [s, 9 H, (CH3)3C], 2.34 [t, 4 H, J = 6.8, N(CH2)2], 2.54
(t, 2 H, J = 7.3, NCH2), 2.63 (t, 2 H, J = 7.3, CH2CO), 3.08
(s, 3 H, NCH3), 3.33 [t, 4 H, J = 6.8, N(CH2)2], 3.60 (s, 3 H,
OCH3)
28.26, 29.37, 32.00, 43.11, 52.76, 53.30, 61.16, 79.47,
154.55, 170.54
3f
2.88 (t, 2 H, J = 7.3, CH2CO), 3.15 (s, 3 H, NCH3), 3.57 (s, 3
H, OCH3), 4.29 (t, 2 H, J = 7.3, NCH2) 6.98–7.06 (m, 2 H,
ArH), 7.66 (s, 1 H, ArH)
31.92, 33.38, 41.95, 61.11, 121.57, 128.77, 137.14, 170.67
28.83, 31.63, 44.32, 53.09, 60.80,. 66.11, 172.46
3g
3h
2.42 (t, 2 H, J = 6.8, CH2CO), 2.62 (t, 2 H, J = 6.8, NCH2),
2.66 [t, 4 H, J = 7.3, N(CH2)2], 3.11 (s, 3 H, NCH3), 3.63 (s,
3 H, OCH3), 3.64 [t, 4 H, J = 7.3, O(CH2)2]
1.50–1.65 (m, 2 H, CH2CH2CH2), 1.82–1.99 (m, 4 H,
CH2CH2CH2), 2.87 (t, 2 H, J = 7.3, CH2CO), 3.06 (s, 3 H,
NCH3), 2.98–3.10 [m, 6 H, (CH2)2NCH2], 3.63 (s, 3 H,
OCH3)
24.30, 26.33, 30.41, 32.11, 49.31, 56.71, 62.02, 171.30
3i
2.27 [s, 6 H, N(CH3)2], 2.65–2.78 (m, 4 H, CH2CO, NCH2),
31.10, 32.81, 35.40, 45.62, 60.85, 171.82
3.10 (s, 3 H, NCH3), 3.70 (s, 3 H, OCH3)
solution of 1ga–1ia (2.5 mmol) in anhyd THF (20 mL) was added
the appropriate aryl Grignard reagent (7.5 mmol) under N2 at 0 °C
and the mixture was stirred for 2.5 h period. After quenching the ex-
cess of the Grignard reagent with sat. aq NH4Cl (30 mL), the crude
product was extracted with EtOAc (3 20 mL). The solvent was
evaporated from the combined organic layers and the resulting res-
idue was dried in vacuo. The residue was then dissolved in benzene
(10 mL) and a little excess of p-toluenesulphonic acid monohydrate
was added. The mixture was stirred at reflux for 3 h. After cooling
to r.t., the solvent was evaporated under reduced pressure. The re-
sulting material was dissolved in MeOH (20 mL) and a catalytic
amount of Pd 10% (on activated charcoal) was added. The mixture
was stirred at r.t. under a H2 atm (ballon pressure was used). After
12 h, the mixture was filtered through Celite. The solvent was evap-
orated from the filtrate and the resulting residue was purified by col-
umn chromatography (hexane–EtOAc) to afford tertiary 1-(3,3-
diarylpropyl)amines 7a–c as colourless syrups in good yields (68–
70%).
1-[3-(4-Methoxyphenyl)-3-phenylpropyl]morpholine (7a)
Yield: 0.52 g (68%); mp (hydrochloride salt) 58–62 °C.
IR (KBr): 3098, 3032, 2855, 1590, 1432 cm–1.
1H NMR (400 MHz, CDCl3): = 2.11–2.28 (m, 4 H, CH2CH2), 2.30
[t, 4 H, J = 6.8 Hz, N(CH2)2], 3.59 (s, 3 H, ArOCH3), 3.82 [t, 4 H,
J = 6.8 Hz, O(CH2)2], 4.01 (t, 1 H, J = 7.4 Hz, CHCH2), 6.69 (d, 2
H, J = 8.3 Hz, ArH), 7.04 (d, 2 H, J = 8.3 Hz, ArH), 7.10–7.51 (m,
5 H, ArH).
13C NMR (100 MHz, CDCl3): = 33.47, 46.32, 48.83, 53.55, 54.85,
66.81, 114.12, 120.71, 125.51, 128.41, 129.20, 129.55, 137.88,
154.87.
Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C,
77.30; H, 7.98; N, 4.34.
Synthesis 2001, No. 15, 2239–2246 ISSN 0039-7881 © Thieme Stuttgart · New York

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V. Selvamurugan, I. S. Aidhen
PAPER
Table 5 NMR Data for Compounds 1aa–1ia
Product
1H NMR (300 MHz, CDCl3/TMS)
13C NMR (75 MHz, CDCl3/TMS)
, J (Hz)
1aa
2.89 (t, 2 H, J = 7.3, CH2CO), 3.04 (t, 2 H, J = 7.3, NCH2),
3.56 (s, 4 H, NCH2Ph), 7.13–7.41 (m, 13 H, ArH), 7.78–7.89
(d, 2 H, J = 7.2, ArH)
36.21, 47.18, 58.17, 126.81, 128.10, 128.21, 128.40,128.65,
132.91, 134.21, 139.08, 198.31
1ab
2.87 (t, 2 H, J = 6.8, CH2CO), 3.01 (t, 2 H, J = 6.8, NCH2),
3.56 (s, 4 H, NCH2Ph), 3.70 (s, 3 H, ArOCH3 ) 6.80–6.85 (m,
2 H, ArH), 7.13–7.29 (m, 10 H, ArH), 7.71–7.74 (m , 2 H,
ArH)
36.13,49.23,55.41,58.74,117.25,126.69,127.94128.93,129.1
4, 131.87, 129.56, 163.05, 197.56
1ac
1ad
2.35 (s, 3 H, ArCH3), 2.92 (t, 2 H, J = 7.3, CH2CO), 3.06 (t,
2 H, 7.3, NCH2), 3.56 (s, 4 H, NCH2Ph), 6.81–7.01 (m, 2 H,
ArH), 7.21–7.41 (m, 12 H, ArH)
32.31,34.21,47.11,58.21,125.31,126.93,128.21128.43,129.1
1,132.71,133.21,139.05,197.61
0.88 (t, 3 H, J = 7.3, CH3), 1.21–1.27 (m, 2 H, CH2CH3),
1.46–1.50 (m, 2 H, CH2CH2), 2.22 (t, 2 H, J = 7.3, CH2CO),
2.54 (t, 2 H, J = 6.8, CH2CO), 2.76 (t, 2 H, J = 6.8, NCH2),
3.50 (s, 4 H, NCH2Ph), 7.20–7.34 (m, 10 H, ArH)
13.68, 22.11, 25.52, 40.66, 42.10, 48.47, 58.19, 126.78,
128.01, 128.65, 139.08, 209.71
1ae
1af
1.10 [d, 6 H, J = 7.10, (CH3)2CH], 2.50–2.60 (m, 1 H-,
CHCO), 2.60 (t, 2 H, J = 6.8, CH2CO), 2.75 (t, 2 H, J = 6.8,
NCH2) 3.60 (s, 4 H, NCH2Ph), 7.21–7.34 (m, 10 H, ArH)
18.05, 38.36, 40.69, 48.68, 58.41, 126.93, 127.40, 127.90,
139.30, 213.80
1.78 (dd, 3 H, J = 7.8, 1.9, CH3), 2.72 (t, 2 H, J = 6.8,
CH2CO), 2.85 (t, 2 H, J = 6.8, NCH2), 3.56 (s, 4 H, NCH2Ph),
5.99 (d, 1 H, J = 16.3, CH=CHCH3), 6.62–6.75 (m, 1 H,
CH=CHCH3), 7.20–7.34 (m, 10 H, ArH)
19.34, 42.58, 48.64, 58.19, 122.21, 127.78, 128.41, 128.65,
139.08, 141.18, 196.91
1ag
1ba
1bb
1bc
1bd
2.85 (t, 2 H, J = 7.3, CH2CO), 3.04 (t, 2 H, J = 7.3, NCH2),
3.56 (s, 4 H, NCH2Ph), 7.10–7.90 (m, 17 H, ArH)
38.73, 49.71, 59.14, 126.78, 126.81, 127.70, 127.75, 127.77,
127.96, 128.16, 128.79, 129.76, 130.10, 132.79, 132.87,
134.21, 139.08, 199.79
2.81 (s, 3 H, NCH3), 3.30 (t, 2 H, J = 6.8, CH2CO), 3.42 (t, 2
H, J = 6.8, NCH2), 7.42–7.58 (m, 6 H, ArH), 7.77–7.79 (m,
2 H, ArH), 7.91–7.93 (m, 2 H, ArH)
36.33, 38.30, 45.95, 128.22, 128.68, 129.14, 132.61, 133.34,
133.43, 136.54, 137.71, 197.68
2.82 (s, 3 H, NCH3), 3.28 (t, 2 H, J = 7.3, CH2CO), 3.46 (t, 2
H, J = 7.3, NCH2), 3.87 (s, 3 H, ArOCH3), 6.92–6.95 (m, 2
H, ArH), 7.51–7.62 (m, 2 H, ArH), 7.91–8.01 (m, 5 H, ArH)
36.11, 37.70, 46.05, 55.60, 113.76,127.20, 129.09,
129.52,130.20, 132.65, 137.34,163.72, 196.55
2.77 (s, 3 H, ArCH3), 2.80 (d, 3 H, NCH3), 3.21 (t, 2 H, J =
7.3, CH2CO), 3.42 (t, 2 H, J = 7.3, NCH2), 7.2–7.3 (m, 2 H,
ArH), 7.12–7.25 (m, 2 H, ArH), 7.51–7.62 (m, 5 H, ArH)
32.35, 36.33, 38.41, 45.98, 125.81, 126.93, 128.72, 129.56,
132.31, 133.34, 137.71, 139.11, 197.34
0.89 (t, 3 H, J = 7.3, CH3), 1.24–1.34 (m, 2 H, CH2CH3),
1.49–1.56 (m, 2 H, CH2CH2), 2.40 (t, 2 H, J = 7.3, CH2CO),
2.72 (t, 2 H, J = 6.8, CH2CO), 2.73 (s, 3 H, NCH3), 3.24 (t, 2
H, J = 6.8, NCH2), 7.50–7.60 (m, 3 H, ArH), 7.76 (dd, 2 H, J
= 7.3, 1.0, ArH)
13.81, 22.23, 25.63, 36.41, 40.71, 42.41, 46.11, 128.64,
129.56, 133.91, 137.05, 209.81
1be
1bf
1.21 [d, 6 H, J = 7.0, (CH3)2CH], 2.48–2.55 (m, 1 H, CHCO),
2.75 (t, 2 H, J = 6.8, CH2CO), 2.80 (s, 3 H, NCH3), 3.30 (t, 2
H, J = 6.8, NCH2), 7.50–7.70 (m, 5 H, ArH)
18.20, 38.35, 40.75, 42.40, 46.10, 128.56, 129.63, 130.01,
137.10, 210.10
1.75 (dd, 3 H, J = 7.8, 1.9, CH3), 2.72 (t, 2 H, J = 6.8,
CH2CO), 2.78 (s, 3 H, NCH3), 3.26 (t, 2 H, J = 6.8, NCH2),
5.87 (d, 1 H, J = 16.3, CH=CHCH3), 6.68–6.79 (m, 1 H,
CH=CHCH3), 7.50–7.76 (m, 5 H, ArH)
19.37, 36.38, 38.90, 46.15, 122.11, 127.68, 128.60, 129.76,
133.99, 137.15, 199.91
1bg
1ca
2.80 (s, 3 H, NCH3), 3.35 (t, 2 H, J = 6.8, CH2CO), 3.45 (t, 2
H, J = 6.8, NCH2), 7.42–7.90 (m, 12 H, ArH)
36.05, 38.01, 45.84, 127.56, 128.22, 128.68, 128.72, 128.92,
129.14, 129.56, 129.80, 132.61, 133.34, 133.43, 136.54,
137.71, 137.90, 197.96
2.96 (t, 2 H, J = 7.3, CH2CO), 3.14 (t, 2 H, J = 7.3, NCH2),
3.57 (s, 2 H, NCH2Ph), 3.61 (s, 2 H, NCH2), 3.84 [s, 6 H,
Ar(OCH3)2], 6.75–7.95 (m, 13 H, ArH)
36.21, 47.18, 55.88, 58.11, 58.18, 114.17, 114.15, 126.82,
128.16, 128.43, 128.48, 128.76, 129.15, 131.65, 136.65,
139.19, 139.71, 159.90, 159.24, 197.62
Synthesis 2001, No. 15, 2239–2246 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
β-(N,N-Disubstituted)ethylamino Acyl Cation Equivalents
2245
Table 5 NMR Data for Compounds 1aa–1ia (continued)
Product
1H NMR (300 MHz, CDCl3/TMS)
13C NMR (75 MHz, CDCl3/TMS)
, J (Hz)
1cb
2.96 (t, 2 H, J = 6.8, CH2CO), 3.14 (t, 2 H, J = 6.8, NCH2),
3.57 (s, 2 H, NCH2Ph), 3.61 (s, 2 H, NCH2), 3.84 (s, 3 H,
ArOCH3), 3.88 (s, 3 H, ArOCH3), 3.89 (s, 6 H, ArOCH3),
6.81–8.01 (m, 12 H, ArH)
35.89, 49.86, 54.23, 58.11, 58.64, 113.15, 114.15, 114.75,
126.87, 128.21, 128.43, 128.48, 128.76, 129.10, 136.66,
139.78, 158.54, 158.68, 159.10, 198.16
1cc
1cd
2.22 (s, 3 H, ArCH3), 2.78 (t, 2 H, J = 7.3, CH2CO), 3.17 (t,
2 H, J = 7.3, NCH2), 3.56 (s, 2 H, NCH2Ph), 3.59 (s, 2 H,
NCH2), 3.83 [s, 6 H, Ar(OCH3)2], 6.81–7.31 (m, 12 H, ArH) 137.87, 139.19, 154.20, 154.44, 197.62
23.33, 34.43, 46.77, 58.22, 58.63, 114.21, 114.25, 126.78,
128.33, 128.49, 128.58, 128.76, 129.02, 136.65, 136.81,
0.91 (t, 3 H, J = 7.3, CH3), 1.22–1.29 (m, 2 H, CH2CH3),
1.47–1.51 (m, 2 H, CH2CH2), 2.23 (t, 2 H, J = 7.3, CH2CO)
2.55 (t, 2 H, J = 6.8, CH2CO), 2.78 (t, 2 H, J = 6.8, NCH2),
3.50 (s, 2 H, NCH2Ph), 3.54 (s, 2 H, NCH2), 3.85 [s, 6 H,
Ar(OCH3)2], 6.77–7.36 (m, 8 H, ArH)
13.78, 22.78, 25.82, 41.76, 42.70, 48.57, 58.29, 58.63,
113.12, 114.11, 126.82, 128.12, 128.75, 129.34, 139.32,
139.74, 152.76, 152.86, 208.89
1ce
1.11 [d, 6 H, J = 7.1, C(CH3)2], 2.50–2.60 (m, 1 H -, CHCO),
2.62 (t, 2 H, J = 6.8, CH2CO), 2.78 (t, 2 H, J = 6.8, NCH2),
3.52 (s, 2 H, NCH2Ph), 3.56 (s, 2 H, NCH2), 3.86 (s, 3 H,
ArOCH3), 3.89 (s, 3 H, ArOCH3), 6.76–7.40 (m, 8 H, ArH)
18.07, 38.18, 40.69, 48.62, 55.88, 58.11 58.18, 110.87,
112.04, 126.83, 128.25, 128.82, 129.50, 139.23, 139.43,
158.12, 158.45, 201.11
1da
1.55 {d, 12 H, J = 7.4, [(CH3)2CH]2}, 2.65 {m, 2 H,
[(CH3)2CH]2}, 2.81 (t, 2 H, J = 6.9, CH2CO), 3.10 (t, 2 H, J
= 6.9, NCH2), 7.31–7.59 (m, 3 H, ArH), 7.88–8.05 (m, 2 H,
ArH)
21.18, 32.85, 38.78, 48.35, 127.86, 129.18, 131.87, 135.63,
196.16
1eb
1fc
1.50 [s, 9 H, (CH3)3C], 3.25 [m, 6 H, N(CH2)2, CH2CO], 3.40
[br s, 4 H, N(CH2)2], 3.98 (s, 3 H, OCH3), 6.92 (d, 2 H, J =
5.5, ArH), 7.98 (d, 2 H, J = 5.5, ArH)
28.20, 32.30, 43.28, 55.27, 55.45, 55.57, 81.26, 113.71,
129.92, 130.37, 153.90, 163.50, 197.44
2.35 (s, 3 H, ArCH3), 2.92 (t, 2 H, J = 7.3, CH2CO), 4.35 (t,
2 H, J = 7.3, NCH2), 6.98–7.16 (m, 4 H, ArH), 7.41–7.66 (m,
3 H, ArH)
21.30, 32.31, 42.85, 120.30, 125.50, 128.47 129.22, 129.60,
137.85, 138.35, 198.18
1gg
1ga
1ha
2.58 (t, 2 H, J = 7.3, CH2CO), 2.75 (t, 2 H, J = 7.3, NCH2),
2.85 [t, 2 H, J = 6.9, N(CH2)2], 3.68 [t, 4 H, J = 6.9, O(CH2)2],
7.31–7.97 (m, 7 H, ArH)
32.63, 46.32, 53.55, 66.81, 123.32, 127.86,
127.95,128.52,128.82, 129.10, 129.18, 131.10, 131.87,
135.63, 196.17
2.56 (t, 2 H, J = 7.3, CH2CO), 2.75 (t, 2 H, J = 7.3, NCH2),
2.80 [t, 4 H, J = 7.3, N(CH2)2], 3.78 [t, 4 H, J = 7.3, O(CH2)2],
7.36–7.48 (m, 3 H, ArH), 7.59–7.97 (m, 2 H, ArH)
32.65, 45.22, 52.52, 65.80, 128.43, 128.46, 131.65, 136.67,
195.75
1.18–1.27 (m, 2 H, CH2CH2CH2), 1.32–1.58 (m, 4 H,
CH2CH2CH2), 2.16 [m, 4 H, N(CH2)2], 2.49 (t, 2 H, J = 7.3
Hz, NCH2), 2.90 (t, 2 H, CH2CO), 7.07–7.27 (m, 3 H, ArH),
7.68–7.70 (m, 2 H, ArH)
23.54, 25.05, 35.70, 52.77, 53.54, 125.80, 126.33, 131.97,
136.28, 198.36
1ia
2.41 [s, 6 H, N(CH3)2], 2.91 (t, 2 H, NCH2), 3.37 (t, 2 H,
CH2CO), 7.41–7.63 (m, 3 H, ArH), 7.68–7.78 (m, 2 H, ArH)
32.15, 34.32, 46.62, 128.28, 128.34, 132.45, 136.66, 194.65
1-(3,3-Diphenylpropyl)piperidine (7b)
two phases were separated and the aqueous phase was extracted
with EtOAc (3 20 mL). The organic phases were combined,
washed with brine (40 mL) and dried (Na2SO4). Removal of the sol-
vent under reduced pressure gave the crude product which was pu-
rified by column chromatography (hexane–EtOAc) to afford 8 as a
colourless syrup; yield: 61% (0.65 g); [ ]D27 +49.9 (c = 1, CHCl3).
IR (CHCl3): 2933, 2869, 1718, 1611, 1454 cm–1.
1H NMR (400 MHz, CDCl3): = 1.80 (ddd, 1 H, J2ax,2eq = 13 Hz,
Yield: 0.48 g (70%); mp (hydrochloride salt) 216–218 °C (Lit.14 mp
215–216 °C). Spectral properties were in agreement with
literature14 values.
1-[3-(4-Methylphenyl)-3-phenylpropyl]-N,N-dimethylamine
(7c)
Yield: 0.43 g (69%); mp (hydrochloride salt) 154–157 °C (Lit.14 mp
156–158 °C). Spectral properties were in agreement with
literature14 values.
J2ax,3 = 8.5 Hz, J2ax,1 = 3.4 Hz, H-2ax), 2.37 (dd, 1 H, J2eq,2ax = 13.1
Hz, J2eq,3 = 4.8 Hz, H-2eq), 2.97 (t, 2 H, J = 7.3 Hz, CH2CO), 3.15
(t, 2 H, J = 7.3 Hz, NCH2), 3.67–3.72 (m, 5 H, NCH2Ph, H-6), 3.70
(dd, 1 H, J6’,6 = 10.7 Hz, J6’,5 = 3.9 Hz, H-6'), 4.06–4.13 (m, 1 H, H-
5), 4.48 (dd, 1 H, J4,3 = 12.7 Hz, J4,5 = 11.8 Hz, H-4), 4.59–4.69 (m,
6 H, OCH2Ph), 4.86 (dd, 1 H, J3,4 = 12.7 Hz, J2,3 = 8 Hz, H-3), 4.98
(d, 1 H, J1,2ax = 3.4 Hz, H-1), 7.22–7.87 (m, 25 H, ArH).
Reaction of 3,4,6-Tri-O-benzyl-2-deoxy- -D-arabino-hexo-
pyranosyllithium15 with 3a; 3-(N,N-Dibenzyl)-1-(3,4,6-tri-O-
benzyl-2-deoxy- -D-arabino-hexopyranosyl)propan-1-one (8)
To a solution of 3a (0.5 g, 1.6 mmol) in anhyd THF (10 mL) was
added 3,4,6-tri-O-benzyl-2-deoxy- -D-arabino-hexopyranosyllith-
ium (2.0 g, 4.8 mmol) at –78 °C under Ar. The mixture was stirred
for 1.5 h. The hydrolysis was achieved by the cautious addition of
sat. aq NH4Cl solution (30 mL) at –40 °C. After returning to r.t., the
13C NMR (75MHz, CDCl3): = 35.06 (C-2), 36.45 (CH2), 48.84
(CH2), 58.08 (NCH2Ph), 68.45 (C-5), 70.57 (C-6), 71.42 (C-3),
Synthesis 2001, No. 15, 2239–2246 ISSN 0039-7881 © Thieme Stuttgart · New York

2246
V. Selvamurugan, I. S. Aidhen
PAPER
73.06 (C-4), 74.61 (PhCH2O), 77.30 (PhCH2O), 77.88 (PhCH2O),
96.38 (C-1), 126.59–138.79 (several peaks, C6H5), 199.22 (C=O).
Acknowledgement
We are grateful to DST, New Delhi for the financial support (Pro-
ject No: SP/S1/G-06/2000) of this research and RSIC (IIT), Chen-
nai for the spectral data. One of us (VS) thanks IIT, Chennai for the
scholarship and Dr. Jaimala Singh, CLRI, Chennai for constant sup-
port. We also thank Dr. S. Ganesh, Sygene Internationeal (P) Ltd.,
Banglore, for helping with the NMR data.
Anal.Calcd for C44H47NO5: C, 78.89; H, 7.07; N, 2.09. Found: C,
78.78; H, 7.18; N, 2.24.
4-Bromo-N-methoxy-N-methylbutanamide (9a)
To a stirred and cooled solution (0 °C) of 4-bromobutanoyl chloride
(3 g, 16.1 mmol) and N,O-dimethlyhydroxylamine hydrochloride
(1.5 g, 16.1 mmol) in anhyd CH2Cl2 (40 mL), was added dropwise
a solution of anhyd pyridine (2.8 g, 35.4 mmol) dissolved in anhyd
CH2Cl2 (15 mL). The reaction mixture was stirred for 1 h. After re-
turning to r.t., the mixture was washed with 2 N HCl (2 50 mL),
then with sat aq NaHCO3 solution (50 mL) followed by brine (50
mL).The organic phase was dried (Na2SO4) and concentrated to af-
ford 9a as a colourless oil (1.35 g, 40%) which was readily decom-
posed to -butyrolactone and amine hydrobromide. The 1H NMR of
the isolated -butyrolactone was identical with that of the authentic
sample.
References
(1) (a) Tramontini, M.; Angiolini, L. Mannich Bases, Chemistry
and Uses; CRC: Boca Raton, 1994. (b) Tramontini, M.;
Angiolini, L. Tetrahedron 1990, 46, 1791.
(2) Arend, M.; Risch, N. Synlett 1997, 974; and references cited
therein.
(3) (a) Kobayashi, S.; Iwamota, S.; Nagayama, S. Synlett 1997,
1099. (b) Loh, T. P.; Wei, L. L. Tetrahedron Lett. 1998, 39,
323.
(4) Davies, S. G.; Ichihara, O. Tetrahedron Lett. 1998, 39, 6045.
(5) Loh, T. P.; Wei, L. Synlett 1998, 975.
(6) Davies, S. G.; McCarthy, T. D. Synlett 1995, 700.
(7) Katritzky, A. R.; Yang, Z.; Lam, J. N. J. Org. Chem. 1993,
58, 1970.
(8) (a) Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett. 2000,
41, 4339. (b) Yang, C.; Yasuda, N. Bioorg. Med. Chem. Lett.
1998, 8, 255. (c) Lee, J. S.; Pyun, D. K.; Lee, W. K.; Lee, C.
H. Bull. Korean Chem. Soc. 1998, 19, 1294.
4-Chloro-N-methoxy-N-methylbutanamide (9b)
According to the same reaction conditions and workup procedure as
previously described for 9a, compound 9b was obtained as a colour-
less oil from vacuum distilled 4-chlorobutanoyl chloride20 (3 g, 21.2
mmol), N,O-dimethlyhydroxylamine hydrochloride (2 g, 21.2
mmol) in anhyd CH2Cl2 (50 ml), and anhyd pyridine (3.6 g, 46.6
mmol) dissolved in anhyd CH2Cl2 (20 ml). The compound 9b was
directly used without further purification for alkylation with mor-
pholine; yield: 2.8 g (80%).
(9) For an isolated example in the total synthesis of
norsecurinine, see: Jacobi, P. A.; Blum, C. A.; Desimone, R.
W.; Udodong, U. E. S. J. Am. Chem. Soc. 1991, 113, 5384.
(10) For reviews concerning chemistry of Weinreb amide, see:
(a) Sibi, M. P. Org. Prep. Proc. Int. 1993, 25, 15.
(b) Mentzel, M. P.; Hoffmann, H. M. R. J. Prakt. Chem.
1997, 339, 517. (c) Singh, J.; Satyamurthi, N.; Aidhen, I. S.
J. Prakt. Chem. 2000, 342, 340.
(11) Kendall, E. C.; McKenzie, B. Org. Synth. 1951, Coll. Vol. I,
131.
(12) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 3rd ed.; Wiley: NewYork, 1999, Chap. 10.
(13) Sabitha, G.; Reddy, B. V. S.; Abraham, S.; Yadav, J. S.
Tetrahedron Lett. 1999, 40, 1569.
(14) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915; and
references cited therein.
(15) Lancelin, J.-M.; Morin-Allory, L.; Sinay, P. J. Chem.
Soc.,Chem. Commun. 1984, 355.
(16) Brown, G. R.; Bamford, A. M.; Bowyer, J.; James, D. S.;
Rankine, N.; Tang, E.; Torr, V.; Culbert, E. J. Bioorg. Med.
Chem. Lett. 2000, 10, 575.
(17) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 2675.
IR (CHCl3): 2965, 1661, 1442, 1179, 1021 cm–1.
1H NMR (400 MHz, CDCl3): = 2.22 (m, 2 H, CH2CH2CH2), 2.74
(t, 2 H, J = 6.8 Hz, CH2CO), 3.30 (s, 3 H, NCH3), 3.75 (t, 2 H,
J = 6.8 Hz, ClCH2), 3.82 (s, 3 H, OCH3)
13C NMR (75 MHz, CDCl3): = 27.0, 28.4, 44.1, 44.3, 60.9, 172.9.
N-Methoxy-N-methyl-4-morpholinobutanamide 10
Following the general procedure, 10 was prepared as colourless syr-
up from 9b (0.94 g, 5.7 mmol), 1g (0.5 g, 5.7 mmol) and anhyd
K2CO3 in anhyd MeCN (20mL); yield: 1.1 g (89%).
IR (CHCl3): 2990, 1678, 1455, 1478, 1375 cm–1.
1H NMR (400 MHz, CDCl3): = 1.83 (m, 2 H, CH2CH2CH2), 2.38
(t, 2 H, J = 7.3 Hz, CH2CO), 2.47 [m, 6 H, N(CH2)2, NCH2], 3.18
(s, 3 H, NCH3), 3.69 (s, 3 H, OCH3), 3.70 [t, 4 H, J = 6.8 Hz,
O(CH2)2].
13C NMR (100 MHz, CDCl3): = 21.29, 29.52, 32.18, 48.22, 53.58,
61.18, 66.95, 172.10.
Anal. Calcd for C10H20N2O3: C, 55.53; H, 9.32; N, 12.95. Found: C,
55.40; H, 9.48; N, 13.11.
4-Morpholino-1-(2-naphthyl)butan-1-one (11)
(18) (a) Robertson, D. W.; Kruhinski, J. H.; Fuller, R. W.;
Leander, J. D. J. Med. Chem. 1988, 31, 1412. (b) Koenig,
T. M.; Mitchell, D. Tetrahedron Lett. 1994, 35, 1339.
(c) Carlier, P. R.; Lo, K. M.; Lo, M. M.-C.; Williams, I. D.
J. Org. Chem. 1995, 60, 7511.
(19) (a) 3b: Cairns, T. L.; Sauer, J. C. J. Org. Chem. 1955, 20,
627. (b) Compound 3c was prepared by refluxing a mixture
of benzylamine (1 g, 9.33 mmol) and veratraldehyde (1.55 g,
9.33 mmol) in benzene (10 mL) for 2 h. The solvent was
evaporated and dissolved in anhyd EtOH (8 mL), treated
with NaBH4 (0.68 g, 18 mmol) at 0 °C for 1 h to afford 3c as
a colourless oil in quantitative yield (2.5 g, 96%). The
product was directly used for further alkylation.
(20) Goel, O. P.; Seamans, R. E. Synthesis 1973, 538.
Following the general procedure, 11 was prepared as a colourless
solid by the addition of 2-naphthylmagnesium bromide [prepared
from 2-bromonaphthalene (1.71 g, 8.3 mmol) and Mg (0.226 g, 9.3
mmol) in THF (20 mL) with stirring at reflux for 1 h under a N2 atm]
to the stirred solution of 10 (0.6 g, 2.7 mmol) in THF (10 mL) at
0 °C; yield: 0.62 g (82%); mp 76–78 °C (Lit.16 mp 77–80 °C).
IR (CHCl3): 2998, 1690, 1450, 1485, 1380 cm–1.
1H NMR (400 MHz, CDCl3): = 1.94 (m, 2 H, CH2CH2CH2), 2.40
(t, 2 H, J = 7.3 Hz, NCH2), 2.42 [t, 4 H, J = 7.4 Hz, N(CH2)2], 2.99
(t, 2 H, J = 7.3Hz, CH2CO), 3.64 [t, 4 H, J = 7.4 Hz, O(CH2)2],
7.19–7.96 (m, 7 H, ArH).
13C NMR (100 MHz, CDCl3): = 21.32, 31.12, 48.11, 53.18, 65.85,
123.12, 126.76, 127.95 128.50, 128.90, 129.09, 129.28, 131.50,
131.87, 135.56, 193.15.
Synthesis 2001, No. 15, 2239–2246 ISSN 0039-7881 © Thieme Stuttgart · New York