Aminoalkylations of esters, sulfones, sulfoxides, alkylated pyridines, and nitriles with in situ generated iminium ions

Article abstract of DOI:10.1055/s-2006-949463

N-(α-Aminoalkyl)benzotriazoles, prepared from a variety of aldehydes and secondary amines, react with diverse ester enolates, sulfones, a sulfoxide, alkylated pyridines, and nitriles to provide novel access to β-amino carboxylic esters (55-80% yield), β-aminoalkyl sulfones (42-88% yield), β-aminoalkyl sulfoxides (20-32% yield), α- and γ-(β- aminoalkyl)pyridines (69-90% yield), and β-aminoalkyl cyanides (10-97% yield), respectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949463

PAPER
3377
Aminoalkylations of Esters, Sulfones, Sulfoxides, Alkylated Pyridines, and
Nitriles with in situ Generated Iminium Ions
Aminoalkylations
lwith in
a
situ Gener
a
ted Iminium Ions R. Katritzky,*a Krzysztof R. Idzik,a,b Ashraf A. A. Abdel-Fattah,a,c Jadwiga Soloducho,b Peter J. Steeld
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
E-mail: katritzky@chem.ufl.edu
b
Department of Chemistry, Faculty of Medical Chemistry and Microbiology, Wroclaw University of Technology,
Wybrzeże Wyspianskiego 27, 50-370 Wroclaw, Poland
Department of Chemistry, Benha University, Benha, Egypt
Department of Chemistry, University of Canterbury, Chirstchurch, New Zealand
c
d
Received 13 April 2006; revised 31 May 2006
Dedicated in honor of Miha Tisler’s 80th birthday
nyl)alkyl]amines.11 We recently published preliminary
results of the further application of 1 in the aminoalkyla-
tion of nitriles.12 We now disclose further extensions of
the scope of aminoalkylations mediated by 1 to include
Abstract: N-(a-Aminoalkyl)benzotriazoles, prepared from a vari-
ety of aldehydes and secondary amines, react with diverse ester eno-
lates, sulfones, a sulfoxide, alkylated pyridines, and nitriles to
provide novel access to b-amino carboxylic esters (55–80% yield),
b-aminoalkyl sulfones (42–88% yield), b-aminoalkyl sulfoxides esters, sulfones, and alkylazines. These methods rely on
(20–32% yield), a- and g-(b-aminoalkyl)pyridines (69–90% yield),
and b-aminoalkyl cyanides (10–97% yield), respectively.
the ability of compounds 1 to function as masked iminium
ions in their reactions with the metalated derivatives of
these compound classes, thus providing the corresponding
functionalized Mannich bases.
Key words: benzotriazoles, b-amino esters, b-aminoalkyl sulfones,
pyridines, b-aminoalkyl cyanides
R3
R2
Bt2
R1
R3
R2
Bt–
N+
R3
R2
Bt1
R1
Carbon–carbon bond formation is of fundamental impor-
tance in organic chemistry. The Mannich reaction is a
prominent method for forming C–C bonds and provides a
key step for the synthesis of numerous nitrogen-contain-
ing pharmaceuticals, natural products, polymers, dyes,
and cross-linking agents.1 The classical Mannich reaction
is confined to aminomethylation and is frequently accom-
panied by deamination.2 The use of preformed iminium
salts has advantages, requiring milder conditions, and al-
lowing the aminoalkylation of structurally diverse nucleo-
philes.3 However, iminium salts are frequently thermally
unstable and hygroscopic, and often undergo deprotona-
tion with basic nucleophiles in preference to normal
addition.1b Therefore, novel and advantageous amino-
alkylating reagents are still highly desirable.
N
R1
N
1C
1B
1A
N
N
N
Bt1
=
Bt2
=
N
N
N
Scheme 1 Equilibrium forms of N-(a-aminoalkyl)benzotriazoles
Synthesis of N-(a-Aminoalkyl)benzotriazoles
N-(a-Aminoalkyl)benzotriazoles 1a–i are easily available
by the well-established condensation of benzotriazole, an
aldehyde, and a secondary amine in benzene under Dean–
Stark conditions (for 1a–e),13 in dichloromethane in the
N-(a-Aminoalkyl)benzotriazoles 1 have considerable po-
tential in organic synthesis.4 The methine carbon in 1 is
highly electrophilic due to the mobile equilibrium be-
tween both covalent isomers 1A and 1C with the benzo-
triazolide–iminium ion pair 1B5 (Scheme 1). Our group
has successfully applied this concept in reactions with
Grignard reagents and Reformatsky reagents to provide
an easy access to secondary and tertiary amines.6 N-(a-
Aminoalkyl)benzotriazoles 1 are valuable intermediates
for the aminoalkylation of activated heterocycles to give
(aminoalkyl)heterocycles,7 of nitroalkanes to give b-nitro
amines,8 of ketones to give b-amino ketones,9 of phenols
to give phenolic Mannich bases,10 and of alcohols and thi-
ols to give N-(a-alkoxyalkyl)- and N-[(a-alkylsulfa-
presence of anhydrous magnesium sulfate (for 1f–h), 13 or
in water (for 1i,j)14 (Scheme 2, Table 1). The H and 13
C
1
NMR spectra of N-(a-aminoalkyl)benzotriazoles 1a–j to-
gether with the elemental analyses for the novel com-
pounds 1c,g fully support their proposed structures.
R3
R1R2NH
Bt
BtH
1a–j
+
N
R3CHO
R2
R1
Scheme 2 Synthesis of N-(a-aminoalkyl)benzotriazoles
Synthesis of b-Amino Carboxylic Esters
b-Amino acids and their derivatives are an important class
of organic molecules for the preparation of a variety of bi-
ologically significant molecules.15 Accordingly, in recent
SYNTHESIS 2006, No. 20, pp 3377–3388
Advanced online publication: 10.10.2006
DOI: 10.1055/s-2006-949463; Art ID: M02506SS
1
7.
1
0
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

3378
A. R. Katritzky et al.
PAPER
Table 2 Yields in the Preparation of b-Amino Esters
Table 1 N-(a-Aminoalkyl)benzotriazoles Prepared by Condensa-
tion of Benzotriazole, Aldehydes, and Secondary Amines
Compd R3
NR1R2
R4
R5
Me
Et
Yield (%)
Compd R3
NR1R2
Compd R3
NR1R2
4a
4b
4c
4d
4e
i-Pr
Tol
N(CH2)4O
N(CH2)4O
1-Naph
Bn
55a
80
1a
1b
1c
1d
1e
Tol
N(CH2)4O
N(CH2)4O
N(CH2)5
NBn2
1f
1g
1h
1i
i-Pr
N(CH2)4O
N(CH2)4S
NBn2
4-ClC6H4
1-Naph
Ph
i-Pr
i-Pr
H
CH2t-Bu N(CH2)4S
Et
Et
74b
59
i-Pr
NBn2
(CH2)5Me
Ph
Et
N(CH2)4O
NBnMe
3-py
N(CH2)5
Me
60
2-py
N(CH2)5
1j
H
a Total yield of two isolated diastereomers.
b Mixture of two diastereomers.
years substantial efforts have focused on the development
of stereoselective methods for the synthesis of b-ami-
nocarboxylic esters, including, for example, (i) enantiose-
lective hydrogenations of b-amino acrylates,16 and (ii)
asymmetric additions of different enolate equivalents to
imines.17
Synthesis of b-Aminoalkyl Sulfones and b-Amino-
alkyl Sulfoxides
b-Aminoalkyl sulfones are intermediates in asymmetric
syntheses20 and for saturated nitrogen heterocycles,21
b-lactams,22 cyclic and acylic nonproteinogenic a-amino
acids,23 peptide isosteres,24 b-amino alcohols,25 substitut-
ed uridines and adenosines,26 alkaloids,27 and carbohy-
drates.28 Enantiopure b-aminoalkyl sulfones and
sulfoxides are also valuable precursors to an array of com-
pounds with high potential for diverse pharmacological
properties.29
Although significant advances in the development of
methods for the synthesis of b-amino esters have been
made, a number of challenges in connection with sub-
strate generality persist. Previously, N-(a-amino-
alkyl)benzotriazoles 1 have been treated with ketene silyl
acetals in reactions catalyzed by either lanthanide
triflate18 or methyllithium19 to give the corresponding b-
amino esters. We now report that reaction of esters with 1
in the presence of lithium diisopropylamide provides a
straightforward approach to b-amino esters 4 (Scheme 3).
The various synthetic approaches for the preparation of b-
aminoalkyl sulfones includes (Scheme 4) (i) azirine ring
opening with sulfonyl carbanions,30 (ii) stereoselective
additions of sulfonyl carbanions to chiral N-sulfinyl
imines,31 (iii) intramolecular32 and intermolecular21,33 aza-
Michael additions to alkenyl sulfones, and (iv) direct nu-
cleophilic substitution with sulfonyl carbanions on imi-
doyl halides followed by the chemoselective reductions of
imines.34 Although the reported methods are suitable to
provide certain examples of b-aminoalkyl sulfones, none
can be considered a general method. We now report reac-
tions of 1 with sulfones providing an efficient and general
access to b-aminoalkyl sulfones.
Ester enolates 3a–e were prepared by the lithiation of the
corresponding a-monosubstituted ester 2 with two equiv-
alents of lithium diisopropylamide in tetrahydrofuran at
–78 °C. Treatment of enolates 3 with 1 at –78 °C followed
by stirring of the mixture while it warmed to room temper-
ature gave the expected aminoalkylated products 4. Our
method is experimentally simple, and yields range from
55% to 80% (Scheme 3, Table 2).
The structures of novel compounds 4a–e were supported
1
by their H and 13C NMR spectroscopic data. In the 13C
NMR spectra of 4a–e the peak of the ester carbonyl group
typically appeared in the region of 174.0–175.5 ppm.
R3 = p-Tolylsulfinyl
R
H
R1
N
OR5
OR5
SO2R2
(iii)
R3
LDA
R
R2SO2(R1)CHLi
THF, –78 °C
R4R3NH
R4
R4
OLi
O
R
4 = H
(ii)
2a–e
3a–e
R
N
R1
1
R3
SO2R2
R4
R2SO2(R1)CHLi
R3 = R4 = H
R4
R2
R2SO2(R1)CHLi
4 = H
OR5
(i)
N
R
(iv)
R1
4a–e
R = R5CHR6CH
R
R2
R3
O
N
N
Hal
R3
Scheme 3 Synthesis of b-amino esters from a-monosubstituted
esters and N-(a-aminoalkyl)benzotriazoles
R5
R6
Scheme 4 Synthetic approaches to the preparation of b-aminoalkyl
sulfones
Synthesis 2006, No. 20, 3377–3388 © Thieme Stuttgart · New York

PAPER
Aminoalkylations with in situ Generated Iminium Ions
3379
Our first attempt at the aminoalkylation of sulfones con-
sisted of treating benzyl phenyl sulfone (5a) with two
equivalents of n-butyllithium in tetrahydrofuran at –78 °C
followed by the addition of 1a; this produced the expected
aminoalkylated product 6a in 81% yield. To make the pro-
cedure simpler, the reaction of sulfone 5a with 1a was
also examined in the presence of two equivalents of potas-
sium tert-butoxide in dimethyl sulfoxide at room temper-
ature; this produced b-aminoalkyl sulfone 6a with no
significant change in the yield. In further experiments,
sulfones 5a–f smoothly reacted with various N-(a-ami-
noalkyl)benzotriazoles 1 by any of the aforementioned
procedures, giving in each case the corresponding b-ami-
noalkyl sulfone 6 as the sole product. TLC analysis and
NMR spectra of the crude products showed that the reac-
tions were very clean; benzotriazole was the only byprod-
uct. The pure b-aminoalkyl sulfones 6a–l were isolated in
42–88% yields (Scheme 5, Table 3).
Table 3 Yields in the Preparation of b-Amino Sulfones and
b-Amino Sulfoxides
Producta NR1R2
R3
R4
R5
Yield
(%)
6a
6b
6c
6d
6e
6f
N(CH2)4O
Tol
Ph
Ph
Ph
Ph
81b
65c
79c
42c
73c
78b
70b
67b
66c
70c,d
71b
88b
20b
32b,d
N(CH2)5
N(CH2)4O
N(CH2)4O
N(CH2)4O
N(CH2)4O
N(CH2)4O
N(CH2)4O
N(CH2)4S
N(CH2)4S
NBn2
1-Naph
Tol
4-BrC6H4 Tol
Tol
2-Naph
2-Naph
H
Tol
Tol
Ph
Ph
Ph
Ph
Tol
Ph
Ph
Ph
Ph
4-ClC6H4
i-Pr
6g
6h
6i
i-Pr
Me
Ph
i-Pr
i-Pr
Ph
The structures of novel compounds 6a–l were supported
by NMR spectroscopy and elemental analyses. The 13C
NMR spectra of 6a–l showed the characteristic signal of
the carbon next to the sulfonyl group in the region of
60.2–74.9 ppm and the 1H NMR spectra revealed the char-
acteristic signal of the proton attached to the same carbon
in the region of 3.37–5.06 ppm.
6j
i-Pr
Tol
Me
Ph
6k
6l
i-Pr
NBn2
i-Pr
6me
6ne
N(CH2)4O
NBn2
i-Pr
Ph
Ph
Ph
Inspired by the fact that b-amino sulfoxides are interesting
building blocks in the synthesis of biologically active
compounds,35 we anticipated that the aminoalkylation of
sulfoxides would be an alternative efficient synthetic ac-
cess to b-amino sulfoxides. Indeed, reactions of the lithio
derivative of 5h (prepared in situ by the lithiation of sul-
foxide 5h) with 1d,f gave the corresponding aminoalky-
lated products 6m,n in low yields (20–32%) (Scheme 5,
Table 3).
a n = 2 unless stated otherwise.
b Method A: n-BuLi (2 equiv), THF, –78 °C.
c Method B: t-BuOK (2 equiv), DMSO, r.t.
d Total yield of two isolated diastereomers.
e n = 1.
which a- and g-(b-aminoalkyl)heterocycles have been
prepared by are shown: (i) reductive amination of ethynyl-
heterocycles with amine hydrochloride salts,38 (ii) amina-
tion of vinylheterocycles with secondary amines,38 and
(iii) reactions of lithiated heterocycles with (b-halo-
alkyl)amines.40 However, these methods can only be used
for the synthesis of a- and g-(b-aminoalkyl)pyridines that
are not substituted at the a and b-positions [i.e., only ap-
plicable to the preparation of (b-aminoethyl)heterocy-
cles].
R3
R4
R5
i. A or B
ii. 1
R4
R5
R1
N
S(O)n
R2
S(O)n
6a–n
5a–h
5a: R5 = R4 = Ph, n = 2
5b: R5 = R4 = Tol, n = 2
5c: R5 = Ph, R4 = 2,6-F2C6H3, n = 2
5d: R5 = Ph, R4 = Naph, n = 2
5e: R5 = Tol, R4 = 4-BrC6H4, n = 2
5f: R5 = Ph, R4 = Me, n = 2
We now report that aminoalkylation of alkylpyridines 7
with a series of 1 gives novel access to amine derivatives
8 with a pyridyl moiety at a b-position (Scheme 7,
Table 4). We investigated the feasibility and optimization
5g: R5 = Ph, R4 = H, n = 2
A) n-BuLi, THF, –78 °C
B) t-BuOK, DMSO, r.t.
5h: R5 = R 4 = Ph, n = 1
R3
Het
Scheme 5 Synthesis of b-aminoalkyl sulfones and b-aminoalkyl
sulfoxides
R1R2NH
Het = 2-Py
R
3 = H
(ii)
R3
Het
R3
HetLi
(iii)
R3
(i)
R1
Synthesis of a- and g-(b-Aminoalkyl)pyridines
Het
N
R2
Het = 2-Py
R1R2NH⋅HCl
N
Cl
R1
R2
a- and g-(b-Aminoalkyl)heterocycles are important com-
pounds in medicinal chemistry, e.g. the potent histamine
H1-antagonist is a [b-(2-pyridyl)ethyl]amine,36 and 4-sub-
stituted (b-aminoethyl)-2,3-dihydrobenzimidazoles are
dopaminergic agents.37 In Scheme 6 the methods by
R
3 = H
R1 = R2 = Me
Het = 5-Thienyl
Scheme 6 Methods for the synthesis of a- and g-(b-aminoalkyl)he-
terocycles
Synthesis 2006, No. 20, 3377–3388 © Thieme Stuttgart · New York

3380
A. R. Katritzky et al.
PAPER
of the synthesis of 4-{2-methyl-1-[phenyl(2-pyridyl)- rabutylammonium fluoride, alkali cyanide, or with alkyl
methyl]propyl}morpholine (8a) from the reaction of [phe- or aryl cyanides activated by scandium(III) trifluoro-
nyl(2-pyridyl)methyl]lithium [prepared in situ by stirring methanesulfonate, (iv) addition of bromoacetonitrile to
of 2-benzylpyridine (7a) with 1.1 equivalents n-butyllith- aldimines mediated by tin powder,52 and (v) cyanide an-
ium in tetrahydrofuran at –78 °C for 1 h] with benzotriaz- ion nucleophilic substitution of b-amino halides or tosy-
ole 1f at –78 °C in tetrahydrofuran; after aqueous workup, lates.53 Despite the abundance of preparative procedures
8a was obtained in 69% isolated yield (Scheme 7, for b-amino nitriles, none is both general and convenient.
Table 4).When the lithio derivatives of 7a,b (generated in For instance, method iii is limited by the availability of
situ by the lithiation of benzylpyridine) were quenched aziridine starting materials, and although modern alterna-
with 1a,b,f,h, the corresponding aminoalkylated products tives of the Mannich reaction allow the aminoalkylation
8b–d were obtained in 79–90% yield (Scheme 7). How- of structurally diverse nucleophiles, a common drawback
ever, the reaction of (2-pyridylmethyl)lithium with 1d associated with the use of preformed salts is frequently
gave 2-(3-methylbut-1-enyl)pyridine (9) (65% yield) as preferential deprotonation by basic nucleophiles instead
the result of aminoalkylation followed by deamination of a normal addition.3a We recently communicated the
(Scheme 7) .
preliminary results of quenching the lithio derivatives of
nitriles 10 with benzotriazoles 1 (Scheme 9).12 Indeed,
this approach introduces an efficient and structurally tol-
erant methodology for access to b-aminoalkyl cyanides.
In this paper, we report our full investigations and the ste-
reochemistry of the title compounds possessing two
asymmetric carbons.
7a,b
i. n-BuLi, –78 °C,
THF
R2
R4
N
R1
Ph
Py
7a–c
ii. 1a,b,f,h
Py
R3
8a–d
R
4 = Ph
7c: Het = 2-py,
1f
R
4 = H
Reactions of the lithio derivatives of nitriles 10a–e (gen-
erated in situ by treating the parent nitrile with n-butyllith-
ium at –78 °C) with the appropriate 1 in tetrahydrofuran
at –78 °C provided the corresponding b-aminoalkyl cya-
nides as the mono-aminoalkylated products 11a–i in 66–
97% yields (Scheme 9, Table 5). The structures of 11a–i
were determined from their spectral data together with
elemental analyses and, in some cases, by X-ray crystal-
lography.
N
9
Scheme 7 Aminoalkylation of alkylpyridines
Table 4 Preparation of a- and g-(b-Aminoalkyl)heterocycles
Compd Py
R3
NR1R2
Yield (%)
8a
8b
8c
8d
2-py
i-Pr
N(CH2)4O
NBn2
69
79
65
90a
X = TMS, Na or alkyl
Y = Tolyl or 4-NO2C6H4
4-py
4-py
2-py
i-Pr
R2
N
4-ClC6H4
Tol
N(CH2)4O
N(CH2)4O
R4
R1
R4
R1
H
N
R2 = SO2Y
(iii)
CN
hν
XCN
R3 = H
R4
R2
a Total yield of two isolated diastereomers.
(iv)
Br(R1)CHCN
R1 = R3 = H
R2R3 R5N
R1 = R2 = R3 = Et
(ii)
R4
R1
Synthesis of b-Aminoalkyl Cyanides
R3
N
CN
R2
R1 = R3 = H
b-Aminoalkyl cyanides have wide applications as diverse
as fuel and lubricant additives,41 antimicrobial and anti-
protozoal agents,42 intermediates for foam-generating
agents for fire-extinguishing,43 and curing agents for ep-
oxides.44 Rhodococcus sp. R312 and Rhodococcus eryth-
ropolis NCIMB 11540 biotransformations of b-amino
cyanides45 provide b-amino acids that function as key
components in many peptidic natural products15c and
valuable intermediates for biologically active b-lactams,46
b-peptides,47 and heterocycles.48
R4 = R1= R2 = H
CN-
(i)
R2R3NH
R1
(v)
R1
R4
R4
X
N
R2
R3
CN
Scheme 8 Available synthetic routes for preparing b-aminoalkyl
cyanides
Particularly for the aminoalkylated products 11 contain-
ing two asymmetric carbon atoms, the reaction is ste-
reospecific when an ortho substituent is present in the
nucleophilic center (as in 11a) or a bulky group is present
in the electrophilic center (as in 11b,c) but otherwise dia-
stereomeric mixtures are provided (as in 11d–g). The ex-
isting diastereomers of 11a–c have been assigned anti on
the basis of X-ray crystallography of 11b,c.12 However,
Available synthetic routes for preparing b-aminoalkyl cy-
anides include (Scheme 8): (i) cyanoethylation of primary
amines with acrylonitrile,49 (ii) photoinduced addition of
tertiary amines to the b-position of a,b-unsaturated ni-
triles,50 (iii) nucleophilic ring opening of N-sulfonyl
aziridines51 with trimethylsilyl cyanide triggered by tet-
Synthesis 2006, No. 20, 3377–3388 © Thieme Stuttgart · New York

PAPER
Aminoalkylations with in situ Generated Iminium Ions
3381
Table 5 Yields and Diastereomeric Ratios in Preparation of
b-Amino Nitriles
the diastereomeric mixtures of 11d–g were assigned anti
and syn on the basis of their spectral data. For example,
their 1H NMR spectra display two overlapping sets of sig-
nals and their 13C NMR spectra generally show two sets of
lines. Although the integrated intensities of the a-cyano
Compd NR1R2
R3
R4 R5
anti/syn Yieldd
(%)
2,4-Cl2C6H3 100:0b 89
1
11a
11b
11c
11d
N(CH2)4O Tol
H
H
proton in the H NMR spectra of deuterated chloroform
solutions indicated that the percentage of anti-isomers is
slightly higher (53–62%) than that of syn-isomers in 11d–f,
for 11g the major isomer is syn (69%). The structures of
the anti- and syn-diastereomers of 11f and 11g were defin-
itively ascertained by their X-ray crystal structures, and
N(CH2)5
N(CH2)5
1-Naph
Ph
100:0b 79
100:0b 66
62:38c 94
53:47b,c 97
55:45b,c 93
31:69b,c 88
1-Naph Et Ph
N(CH2)4O Tol
N(CH2)4O i-Pr
N(CH2)4O i-Pr
H
H
H
H
4-BrC6H4
Ph
also the syn-diastereomer of 11d was definitively support- 11e
ed by an X-ray crystal structure (crystallographic data for
11d,f, and g are included in the Supporting Information).
11f
Bena
Bena
Further confirmation of the diastereomeric structures of
11d–g was found in the previously proposed method54 for
correlating relative configuration based on the a-cyano
proton coupling constants. This assumes that the most fa-
vored conformer of both anti- and syn-isomers of the title
compounds should feature the R1R2N and R5 in anti-
periplanar (i.e. q = 180°) relationships. In this conforma-
tion the anti-isomer will have an H–C–C–R4 (R4 = H)
dihedral angle of approximately 60°, giving rise to a small
coupling constant while the syn-isomer will have a dihe-
dral angle of approximately 180°, giving rise to a large
coupling constant. In light of this, analysis of the vicinal
coupling constants allowed us to confirm the stereochem-
ical assignments of 11d–g as previously described. For
example, the anti-isomer of 11d displays a vicinal cou-
pling constant J2–3 = 6.0 Hz, while the syn-isomer shows
for the same proton a J2–3 = 9.8 Hz, values congruent with
those underlined for b-hydroxy nitriles.55
11g
11h
11i
NBn2
i-Pr
H
NBnMe
N(CH2)4O
Et Ph
4-BrC6H4
–
–
93
70
H
H
a Ben = Benzo[1,3]dioxol-4-yl.
b Relative configuration was determined by X-ray crystallography.
c Diastereomeric ratio was evaluated by 1H NMR analysis.
d Yields of pure isolated products.
spectively, with the vicinal coupling constants similar to
those found for the syn isomers of monoalkylated prod-
ucts (type 11) as described above (J = 7.6 Hz). Addition-
ally, the 13C NMR spectrum of 12b shows that the carbons
of the two naphthyl(piperidyl)methyl moieties are equiv-
alent.
R2
N
i. n-BuLi, –78 °C
ii. 1c,j
R2
N
NC
R5
R3
R4
R1
CN
R1
R5
10f,c
R3
R2
12a,b
CN
R4
R1
N
12a: R3 = 1-Naph, R1R2N = (CH2)5N, R5 = H (39%)
12b: R3 = H, R1R2N = NBnMe, R5 = Ph (43%)
R4
i. n-BuLi, –78 °C, THF
ii. 1a,c,f,h–j
R3
R5
CN
+
anti-11
R5
10a-e
Scheme 10 Synthesis of doubly aminoalkylated products from the
reactions of nitriles with benzotriazoles
R2
R1
CN
R4
N
10a: R5 = 2,4-Cl2C6H3, R4 = H
10b: R5 = 4-BrC6H4, R4 = H
10c: R5 = Ph, R4 = H
10d: R5 = Benzo[1,3]dioxol-5-yl, R4 = H
10e: R5 = Ph, R4 = Et
10f: R5 = R4 = H
R3
R5
Exceptionally, the reaction of 1i with the lithio derivative
of 10a provided amino cyanide 13 in 72% yield together
with diamino cyanide 14 in 10% yield (Scheme 11). The
proposed structures of 13 and 14 were supported by their
spectral data and elemental analyses. For example, the 1H
NMR spectrum of 14 revealed two characteristic signals
as doublets at 3.34 and 3.03 ppm with a geminal coupling
constant of ca. 13.7 Hz, assignable to the protons of the
two newly introduced methylene groups attached to the
secondary amine moieties.
syn-11
For designation of R, NR1R2, R3, R3 and R4 in 11 see Table 5
Scheme 9 Synthesis of b-amino nitriles
However, treatment of nitrile 10f with benzotriazole 1c
and nitrile 10c with benzotriazole 1j in stoichiometric ra-
tios provided the corresponding doubly aminoalkylated
products 12a and 12b in 39% and 43% yields, respective-
ly (Scheme 10). The reaction provided 12a as a single dia-
stereomer; this isomer has been assigned syn on the basis
of 1H and 13C NMR spectral data. The two protons next to
the a-cyano proton are equivalent, and their characteristic
signals appear in 1H NMR spectrum in deuterated chloro-
form as a doublet at 4.70 ppm and triplet at 4.35 ppm, re-
In summary, the benzotriazole-assisted aminoalkylations
of esters, sulfones, alkylated heterocycles, and nitriles de-
scribed herein represent convenient and advantageous
protocols for the syntheses of numerous novel functional-
ized amines. Previously we reported good methods for the
preparation of b-amino esters.18,19 However, those meth-
ods usually required the use of ketene silyl acetals, and
now with our new procedure the target molecules can be
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3382
A. R. Katritzky et al.
PAPER
R1
N
(dd, J = 10.1, 2.6 Hz, 1 H), 3.12–3.00 (m, 2 H), 3.00–2.88 (m, 2 H),
2.52–2.45 (m, 2 H), 2,38–2.32 (m, 2 H), 1.99–1.91 (m, 1 H), 1.08
(d, J = 6.9 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 174.0, 134.0, 133.9, 132.0, 129.1,
127.7, 126.9, 126.2, 125.2, 125.0, 122.9, 70.8, 67.3, 52.1, 52.0,
51.5, 32.5, 21.2, 18.9.
CN
R5
13
i. n-BuLi, –78 °C
ii. 1i
R2
R5
CN
+
R4
10a
R1R2N = O(CH2)4N
R5
NC
R
5 = 2,4-Cl2C6H3
R1
R2
R1
N
R2
R4 = H
N
Anal. Calcd. for C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
73.68; H, 8.06; N, 4.01.
14
Second Diastereomer of 4a
Pink microcrystals; yield: 0.068 g (10%); mp 102–103 °C.
Scheme 11 Synthesis of singly and doubly aminoalkylated products
from the reaction of a nitrile with a benzotriazole
1H NMR (300 MHz, CDCl3): d = 8.31 (d, J = 8.5 Hz, 1 H), 7.85 (d,
J = 8.0 Hz, 1 H), 7.79–7.75 (m, 2 H), 7.56 (td, J = 6.9, 1.4 Hz, 1 H),
7.49–7.44 (m, 2 H), 4.89 (d, J = 11.4 Hz, 1 H), 3.71–3.59 (m, 7 H),
3.59–3.47 (m, 1 H), 3.04–2.97 (m, 2 H), 2.89–2.82 (m, 2 H), 1.82–
1.64 (m, 1 H), 0.79 (d, J = 6.9 Hz, 3 H), 0.71 (d, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 174.0, 133.9, 132.5, 131.7, 129.0,
127.8, 126.6, 126.4, 125.4, 125.3, 122.8, 71.7, 68.1, 51.8, 51.0,
29.2, 21.0, 20.4.
provided in yields ranging from 55% to 80% by the se-
quential treatment of the parent ester with lithium diiso-
propylamide and the benzotriazole adduct. In contrast to
the previous routes38–40 to a- and g-(b-aminoalkyl)py-
ridines, the method described herein provides the title
molecules substituted at both a- and b-positions. In addi-
tion, the use of N-(a-aminoalkyl)benzotriazoles for the
aminoalkylations of sulfones and nitriles suggests that
few limitations are to be expected and provides comple-
mentary approaches to the methods reported earlier for b-
aminoalkyl-substituted sulfones and nitriles. The target
molecules are prepared in synthetically useful to excellent
Anal. Calcd. for C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
74.04; H, 8.15; N, 4.00.
Ethyl 2-Benzyl-3-morpholin-4-yl-3-(4-tolyl)propionate (4b)
Colorless microcrystals; yield: 0.588 g (80%); mp 104–105 °C.
1H NMR (300 MHz, CDCl3): d = 7.25–7.12 (m, 5 H), 7.09–7.04 (m,
yields and are unavailable by other methods. In general, 4 H), 4.13–4.05 (m, 2 H), 3.79 (d, J = 11.7 Hz, 1 H), 3.65–3.52 (m,
4 H), 3.38 (td, J = 11.1, 3.2 Hz, 1 H), 2.79–2.70 (m, 1 H), 2.56–2.45
the benzotriazole methods demonstrate good generality,
since N-(a-aminoalkyl)benzotriazoles can be derived
from a variety of secondary amines and aliphatic, aromat-
(m, 3 H), 2.37 (s, 3 H), 2.27–2.25 (m, 2 H), 1.15 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 174.2, 139.4, 137.4, 130.7, 128.9,
128.5, 128.2, 126.2, 71.8, 67.3, 60.0, 50.3, 49.2, 35.9, 21.0, 14.3.
ic, or heterocyclic aldehydes. The easy accessibility and
shelf-stability of N-(a-aminoalkyl)benzotriazoles make
them useful as valuable alternative Mannich reagents.
Anal. Calcd. for C23H29NO3: N, 3.81. Found: N, 3.64.
HRMS: m/z [M + H]+ calcd for C23H29NO3: 368.2220; found:
368.2206.
All melting points are uncorrected. 1H and 13C NMR spectra were
recorded on a Varian Gemini (300 MHz) spectrometer in CDCl3
with TMS as the internal standard. HRMS (ESI) spectrometry was
conducted on a 4.7 T Bruker Bioapex II instrument. Microanalyses
were performed on a Carlo Erba 1106 elemental analyzer. Column
chromatography was performed on silica gel (200–425 mesh). THF
was distilled from sodium–benzophenone ketyl and DMSO was
dried over molecular sieves prior to use.
Ethyl 2-Ethyl-5,5-dimethyl-3-thiomorpholin-4-ylhexanoate (4c)
Compound 4c was obtained as a 2:1 mixture of two diastereomers.
Pink oil; yield: 0.446 g (74%).
1H NMR (300 MHz, CDCl3): d = 4.20–4.08 (m, 2 H), 3.10–3.05 (m,
0.33 H), 2.87–2.84 (m, 3 H), 2.81–2.71 (m, 0.66 H), 2.58–2.50 (m,
4 H), 1.62–1.41 (m, 2 H), 1.32–1.22 (m, 3 H), 1.12–1.05 (m, 1 H),
0.97–0.83 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 175.5, 174.9, 65.3, 64.9, 60.7, 59.8,
51.8, 51.7, 51.5, 50.8, 42.1, 40.4, 30.3, 30.2, 30.0, 29.3, 28.4, 28.3,
24.5, 22.7, 14.3, 14.1, 12.2, 12.1.
b-Amino Esters 4a–e; General Procedure
To a soln of ester 2 (2 mmol) in dry THF (10 mL), LDA (4.0 mmol)
was added at –78 °C. The resultant soln was stirred at –78 °C for 1
h and then benzotriazole 1 (2 mmol) in THF (10 mL) was added.
The mixture was stirred for 12 h while the temperature was allowed
to rise to 20 °C. After quenching with H2O (20 mL) and extraction
with EtOAc (3 × 25 mL), the combined organic layers were washed
with H2O (25 mL) and dried (MgSO4) and the solvent was removed
in vacuo. The resulting oil was subjected to column chromatogra-
phy (silica gel, hexanes–EtOAc, 10:1 then 6:1); this gave the corre-
sponding b-amino ester 4.
Anal. Calcd. for C16H31NO2S: C, 63.74; H, 10.36; N, 4.65. Found:
C, 63.41; H, 10.61; N, 4.38.
Ethyl 2-[1-(Dibenzylamino)-2-methylpropyl]octanoate (4d)
Yellow oil; yield: 0.499 g (59%).
1H NMR (300 MHz, CDCl3): d = 7.35–7.18 (m, 10 H), 4.16–4.02
(m, 2 H), 3.77–3.54 (m, 4 H), 2.85–2.75 (m, 2 H), 1.71–1.66 (m, 1
H), 1.40–1.13 (m, 13 H), 1.02–0.96 (m, 3 H), 0.92–0.85 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 175.5, 140.1, 139.9, 129.2, 129.0,
128.1, 127.9, 126.7, 126.6, 64.9, 63.9, 60.0, 59.9, 55.0, 54.2, 46.6,
45.8, 31.7, 31.6, 31.2, 29.3, 29.2, 28.9, 28.0, 26.0, 22.5, 21.3, 20.8,
19.7, 14.1, 14.0.
Methyl 4-Methyl-3-morpholin-4-yl-2-(2-naphthyl)pentanoate
(4a)
Two diastereomers of 4a were isolated.
First Diastereomer of 4a
Pink microcrystals; yield: 0.307 g (45%); mp 104–105 °C.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 8.4 Hz, 1 H), 7.85 (d,
J = 7.6 Hz, 1 H), 7.77 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 7.1 Hz, 1 H),
7.55–7.43 (m, 3 H), 4.76 (d, J = 10.7 Hz, 1 H), 3.57 (s, 3 H), 3.50
Anal. Calcd. for C28H41NO2: N, 3.31. Found: N, 3.20.
HRMS: m/z [M + H]+ calcd for C28H41NO2: 424.3210; found:
424.3196.
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Aminoalkylations with in situ Generated Iminium Ions
3383
Methyl 2-Phenyl-3-(1-piperidyl)-3-(3-pyridyl)propionate (4e)
Colorless microcrystals; yield: 0.389 g (60%); mp 162–163 °C.
4-[2-(4-Bromophenyl)-2-(4-tolylsulfonyl)-1-(4-tolyl)ethyl]mor-
pholine (6c)
Colorless microcrystals; yield: 0.813 g (79%); mp 221–222 °C.
1H NMR (300 MHz, CDCl3): d = 8.35–8.34 (m, 2 H), 7.37–7.28 (m,
3 H), 7.15–7.06 (m, 4 H), 4.40 (s, 2 H), 3.73 (s, 3 H), 2.65–2.50 (m,
2 H), 2.28–2.15 (m, 2 H), 1.59–1.47 (m, 4 H), 1.31–1.26 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 173.2, 150.3, 148.3, 136.0, 135.0,
129.2, 128.7, 128.4, 127.3, 122.6, 70.2, 53.3, 51.8, 50.4, 26.5, 24.4.
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.2 Hz, 2 H), 7.26–
7.20 (m, 4 H), 7.03 (d, J = 7.7 Hz, 2 H), 6.93 (d, J = 7.7 Hz, 2 H),
6.76 (d, J = 8.0 Hz, 2 H), 4.96 (d, J = 11.8 Hz, 1 H), 4.58 (d, J = 11.8
Hz, 1 H), 3.51–3.44 (m, 2 H), 3.26–3.14 (m, 2 H), 2.46–2.40 (m, 5
H), 2.29–2.19 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 143.8, 138.5, 137.2, 131.4, 130.8,
129.2, 129.1, 128.5, 128.4, 128.3, 122.6, 69.7, 69.4, 66.1, 49.1,
21.5, 20.9 .
Anal. Calcd. for C20H24N2O2: C, 74.04; H, 7.46; N, 8.63. Found: C,
73.94; H, 7.82; N, 8.54.
b-Aminoalkyl Sulfones 6a–l and Sulfoxides 6m,n; General Pro-
cedure
Anal. Calcd. for C26H28BrNO3S: C, 60.70; H, 5.49; N, 2.72. Found:
C, 60.93; H, 5.30; N, 2.57.
Method A: A soln of sulfone or sulfoxide 5 (2 mmol) in anhyd THF
(15 mL) was cooled to –78 °C under N2 and then treated dropwise
with 1.55 M n-BuLi in hexane (2.6 mL, 4 mmol) to afford a clear
soln, which was stirred at this temperature for 1 h. A soln of benzo-
triazole 1 in anhyd THF (10 mL ) was then added dropwise. The re-
action mixture was allowed to warm to r.t. while stirring overnight.
After the reaction had been quenched by the addition of sat. NH4Cl,
the mixture was extracted with EtOAc (3 × 30 mL). The organic ex-
tracts were combined, washed with 10% aq Na2CO3 soln (2 × 30
mL) and brine (2 × 30 mL), and dried (MgSO4). After evaporation
under vacuum, purification of the residue by flash chromatography
(silica gel, hexanes–EtOAc, 5:1) afforded pure 6.
4-[2-(2-Naphthyl)-1-(4-tolyl)-2-(4-tolylsulfonyl)ethyl]morpho-
line (6d)
Colorless microcrystals; yield: 0.398 g (41%); mp 208–209 °C.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 8.1 Hz, 2 H), 7.64–
7.62 (m, 3 H), 7.54 (d, J = 8.5 Hz, 1 H), 7.37–7.34 (m, 3 H), 7.16
(d, J = 7.8 Hz, 2 H), 6.88–6.82 (m, 4 H), 5.18 (d, J = 11.8 Hz, 1 H),
4.80 (d, J = 11.8 Hz, 1 H), 3.56–3.51 (m, 2 H), 3.32–3.20 (m, 2 H),
2.54–2.49 (m, 2 H), 2.38–2.26 (m, 5 H), 2.09 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 143.6, 138.7, 136.9, 132.8, 129.1,
128.7, 128.4, 128.0, 127.9, 127.4, 126.3, 125.9, 70.5, 69.5, 66.2,
49.1, 21.4, 20.8 .
Method B: A mixture of sulfone 5 (2 mmol) and t-BuOK (0.45 g, 4
mmol) in DMSO (10 mL) was stirred at r.t. for 1 h. After addition
of 1 (2 mmol) in DMSO (5 mL), the mixture was stirred for 8 h. The
mixture was diluted with EtOAc (100 mL), poured into H2O (100
mL), and treated with a sat. aq soln of NH4Cl (30 mL). The organic
layer was extracted with EtOAc (2 × 20 mL), washed with H2O (3
× 30 mL), and dried (Na2SO4), and the solvent was removed under
reduced pressure. Purification of the residue by column chromatog-
raphy (silica gel, hexanes–EtOAc, 5:1) gave pure product 6.
Anal. Calcd. for C30H31NO3S: C, 74.20; H, 6.43; N, 2.88. Found: C,
74.30; H, 6.33; N, 2.56.
4-[1-(4-Chlorophenyl)-2-(2-naphthyl)-2-(4-tolylsulfonyl)eth-
yl]morpholine (6e)
Colorless microcrystals; yield: 0.739 g (73%); mp 237–238 °C.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 8.2 Hz, 2 H), 7.66–
7.58 (m, 3 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.42–7.36 (m, 3 H), 7.17
(d, J = 8.1 Hz, 2 H), 7.06 (d, J = 8.4 Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2
H), 5.16 (d, J = 11.8 Hz, 1 H), 4.85 (d, J = 11.8 Hz, 1 H), 3.56–3.50
(m, 2 H), 3.33–3.21 (m, 2 H), 2.53–2.48 (m, 2 H), 2.35–2.29 (m, 5
H).
13C NMR (75 MHz, CDCl3): d = 143.7, 138.5, 133.1, 132.8, 132.79,
130.3, 129.1, 128.8, 128.7, 128.6, 128.3, 128.2, 127.9, 127.8, 127.5,
126.5, 126.1, 70.2, 69.3, 66.1, 49.0, 21.4 .
4-[2-Phenyl-2-(phenylsulfonyl)-1-(4-tolyl)ethyl]morpholine
(6a)
Colorless microcrystals; yield: 0.683 g (81%); mp 239–241 °C.
1H NMR (300 MHz, CDCl3): d = 7.81 (d, J = 7.5 Hz, 2 H), 7.50–
7.39 (m, 3 H), 7.14–7.05 (m, 5 H), 6.92 (d, J = 7.8 Hz, 2 H), 6.79
(d, J = 8.0 Hz, 2 H), 5.06 (d, J = 11.8 Hz, 1 H), 4.72 (d, J = 11.8 Hz,
1 H), 3.53–3.47 (m, 2 H), 3.24 (br s, 2 H), 2.52–2.47 (m, 2 H), 2.29
(br s, 2 H), 2.17 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 163.1, 141.7, 137.0, 132.6, 131.4,
129.2, 128.7, 128.5, 128.4, 128.3, 128.2, 70.4, 69.5, 66.2, 49.1,
20.9.
Anal. Calcd. for C29H28ClNO3S: C, 68.83; H, 5.58; N, 2.77. Found:
C, 68.44; H, 5.76; N, 2.44.
4-{2-Methyl-1-[(phenylsulfonyl)methyl]propyl}morpholine (6f)
Colorless prisms; yield: 0.464 g (78%); mp 106–107 °C.
Anal. Calcd. for C25H27NO3S: C, 71.23; H, 6.46; N, 3.32. Found:
C, 71.00; H, 6.63; N, 3.63.
1H NMR (300 MHz, CDCl3): d = 7.94–7.91 (m, 2 H), 7.65–7.54 (m,
3 H), 3.51–3.34 (m, 5 H), 3.03–2.89 (m, 2 H), 2.49–2.39 (m, 4 H),
1.91–1.80 (m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3
H).
13C NMR (75 MHz, CDCl3): d = 140.8, 133.4, 129.1, 127.8, 66.8,
64.7, 54.3, 48.9, 29.3, 21.1, 19.7.
1-[1-(1-Naphthyl)-2-phenyl-2-(phenylsulfonyl)ethyl]piperidine
(6b)
Colorless microcrystals; yield: 0.592 g (65%); mp 180–181 °C.
1H NMR (300 MHz, CDCl3): d = 8.49 (d, J = 8.7 Hz, 1 H), 7.83 (d,
J = 8.2 Hz, 1 H), 7.67–7.49 (m, 5 H), 7.36–7.34 (m, 3 H), 7.26–7.16
(m, 5 H), 6.98 (t, J = 7.8 Hz, 2 H), 5.81 (d, J = 10.3 Hz, 1 H), 4.98
(d, J = 10.3 Hz, 1 H), 2.30–2.18 (m, 2 H), 2.14–2.03 (m, 2 H), 1.23–
1.11 (m, 2 H), 1.02–0.88 (m, 4 H).
Anal. Calcd. for C15H23NO3S: N, 4.71. Found: N, 4.68.
HRMS: m/z [M + H]+ calcd for C15H23NO3S: 298.1471; found:
298.1461.
13C NMR (75 MHz, CDCl3): d = 139.4, 133.8, 132.8, 132.6, 132.0,
131.1, 130.9, 128.7, 128.1, 128.0, 127.9, 127.7, 126.2, 125.4, 124.1,
123.8, 74.9, 59.8, 50.2, 26.0, 23.9.
4-[1-Isopropyl-2-(phenylsulfonyl)propyl]morpholine (6g)
Colorless microcrystals; yield: 0.436 g (70%); mp 99–101 °C.
1H NMR (300 MHz, CDCl3): d = 7.90 (d, J = 7.4 Hz, 2 H), 7.68–
7.55 (m, 3 H), 3.61 (t, J = 4.5 Hz, 4 H), 3.37 (dq, J = 7.3, 1.9 Hz, 1
H), 3.04 (dd, J = 9.4, 1.9 Hz, 1 H), 2.56–2.49 (m, 2 H), 2.41–2.34
(m, 2 H), 2.00–1.93 (m, 1 H), 1.28 (d, J = 7.3 Hz, 3 H), 1.09 (d,
J = 6.6 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H).
Anal. Calcd. for C29H29NO2S: C, 76.46; H, 6.42; N, 3.07. Found: C,
76.29; H, 6.54; N, 2.73.
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A. R. Katritzky et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 139.4, 133.3, 129.1, 128.3, 66.9,
1H NMR (300 MHz, CDCl3): d = 7.96–7.94 (m, 2 H), 7.71–7.58 (m,
3 H), 7.42–7.21 (m, 10 H), 3.79 (AB system, JAB = 13.3 Hz, 2 H),
3.51 (q, J = 7.1 Hz, 1 H), 3.36 (d, J = 9.2 Hz, 1 H), 3.29 (AB system,
JAB = 13.3 Hz, 2 H), 2.05–1.94 (m, 1 H), 1.39 (d, J = 7.3 Hz, 3 H),
1.10 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H).
66.6, 57.9, 48.9, 26.4, 21.3, 21.0, 11.7.
Anal. Calcd. for C16H25NO3S: C, 61.70; H, 8.09; N, 4.50. Found: C,
61.50; H, 7.94; N, 4.55.
4-{2-Methyl-1-[phenyl(phenylsulfonyl)methyl]propyl}morpho-
line (6h)
13C NMR (75 MHz, CDCl3): d = 139.5, 139.2, 133.4, 129.3, 129.2,
128.6, 128.1, 127.0, 60.2, 59.1, 53.9, 27.1, 21.3.
Colorless microcrystals; yield: 0.500 g (67%); mp 189–190 °C.
Anal. Calcd. for C26H31NO2S: C, 74.07; H, 7.41; N, 3.32. Found: C,
73.74; H, 7.57; N, 3.31.
1H NMR (300 MHz, CDCl3): d = 7.51–7.48 (m, 2 H), 7.39–7.34 (m,
1 H), 7.27–7.14 (m, 7 H), 4.54 (d, J = 10.0 Hz, 1 H), 3.75–3.59 (m,
5 H), 3.05–2.98 (m, 2 H), 2.87–2.80 (m, 2 H), 1.98–1.92 (m, 1 H),
0.99 (d, J = 6.9 Hz, 3 H), 0.68 (d, J = 7.1 Hz, 3 H).
Dibenzyl{2-methyl-1-[phenyl(phenylsulfonyl)methyl]pro-
pyl}amine (6l)
Colorless microcrystals; yield: 0.851 g (88%); mp 162–163 °C.
13C NMR (75 MHz, CDCl3): d = 140.5, 133.1, 132.3, 130.5, 128.4,
128.3, 128.2, 128.1, 71.8, 69.4, 67.1, 50.4, 29.3, 21.0, 20.6.
1H NMR (300 MHz, CDCl3): d = 7.59–7.57 (m, 4 H), 7.47–7.10 (m,
15 H), 4.60 (d, J = 8.0 Hz, 1 H), 4.20 (AB system, JAB = 13.7 Hz, 2
H), 3.98 (dd, J = 8.0, 3.0 Hz, 1 H), 3.83 (AB system, JAB = 13.7 Hz,
2 H), 1.77–1.72 (m, 1 H), 0.67 (d, J = 6.7 Hz, 3 H), 0.62 (d, J = 7.0
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 140.1, 139.6, 133.7, 132.6, 129.8,
128.3, 128.2, 128.1, 128.0, 126.9, 71.7, 61.2, 55.5, 30.2, 21.5, 18.0.
Anal. Calcd. for C21H27NO3S: C, 67.53; H, 7.29; N, 3.75. Found: C,
67.37; H, 7.40; N, 3.68.
4-{2-Methyl-1-[phenyl(phenylsulfonyl)methyl]propyl}thiomor-
pholine (6i)
Yellow microcrystals; yield: 0.514 g (66%); mp 149–150 °C.
1H NMR (300 MHz, CDCl3): d = 7.46–7.37 (m, 4 H), 7.27–7.09 (m,
6 H), 4.34 (d, J = 7.6 Hz, 1 H), 3.63 (dd, J = 5.5, 1.9 Hz, 1 H), 2.87–
2.81 (m, 2 H), 2.74–2.61 (m, 2 H), 2.48–2.30 (m, 5 H), 1.12 (d,
J = 6.6 Hz, 3 H), 1.11 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.9, 132.8, 132.6, 130.8, 128.34,
128.29, 127.9, 71.5, 70.3, 31.8, 28.1, 21.7, 19.3.
Anal. Calcd. for C31H33NO2S: C, 76.98; H, 6.88; N, 2.90. Found: C,
76.69; H, 6.99; N, 2.90.
4-{2-Methyl-1-[phenyl(phenylsulfinyl)methyl]propyl}morpho-
line (6m)
Colorless microcrystals; yield: 0.143 g (20%); mp 125–126 °C.
1H NMR (300 MHz, CDCl3): d = 7.41–7.36 (m, 1 H), 7.31–7.27 (m,
2 H), 7.23–7.21 (m, 1 H), 7.16–7.11 (m, 4 H), 6.70 (d, J = 7.3 Hz, 2
H), 4.48 (d, J = 10.6 Hz, 1 H), 3.85–3.82 (m, 4 H), 3.16–3.09 (m, 2
H), 2.98 (dd, J = 7.7, 2.8 Hz, 1 H), 2.76–2.71 (m, 2 H), 2.17–2.13
(m, 1 H), 0.95 (d, J = 6.9 Hz, 3 H), 0.66 (d, J = 7.1 Hz, 3 H).
Anal. Calcd. for C21H27NO2S2: C, 64.74; H, 6.99; N, 3.60. Found:
C, 64.87; H, 7.09; N, 3.58.
4-{2-Methyl-1-[(4-tolyl)(tosyl)methyl]propyl}thiomorpholine
(6j)
Two diastereomers of 6j were isolated.
13C NMR (75 MHz, CDCl3): d = 141.3, 130.9, 130.6, 128.2, 128.1,
127.4, 125.9, 72.5, 68.1, 67.1, 49.8, 27.3, 22.9, 20.3.
First Diastereomer of 6j
Colorless microcrystals; yield: 0.501 g (60%); mp 152–153 °C.
Anal. Calcd. for C21H27NO2S: C, 70.55; H, 7.61; N, 3.92. Found: C,
70.84; H, 7.85; N, 3.92.
1H NMR (300 MHz, CDCl3): d = 7.35 (d, J = 8.2 Hz, 2 H), 7.04 (d,
J = 8.0 Hz, 3 H), 6.93 (d, J = 7.4 Hz, 3 H), 4.45 (d, J = 9.3 Hz, 1 H),
3.51 (dd, J = 9.3, 4.2 Hz, 1 H), 3.30–3.24 (m, 2 H), 3.11–3.04 (m, 2
H), 2.65 (t, J = 4.5 Hz, 4 H), 2.31 (s, 3 H), 2.25 (s, 3 H), 1.90–1.86
(m, 1 H), 1.00 (d, J = 6.9 Hz, 3 H), 0.69 (d, J = 7.0 Hz, 3 H).
Dibenzyl[1,2-diphenyl-2-(phenylsulfinyl)ethyl]amine (6n)
Two diastereomers of 6n were isolated.
First Diastereomer of 6n
Colorless microcrystals; yield: 0.221 g (22%); mp 148–149 °C.
13C NMR (75 MHz, CDCl3): d = 143.1, 138.2, 137.6, 130.2, 129.0,
128.8, 128.3, 128.26, 71.4, 71.1, 53.1, 30.0, 27.9, 21.5, 21.1, 20.5.
1H NMR (300 MHz, CDCl3): d = 7.65–7.63 (m, 4 H), 7.47–7.42 (m,
3 H), 7.38–7.33 (m, 3 H), 7.27–7.25 (m, 2 H), 7.19–7.10 (m, 4 H),
6.94–6.87 (m, 3 H), 6.84–6.68 (m, 2 H), 6.29 (d, J = 8.1 Hz, 2 H),
4.89 (d, J = 12.4 Hz, 1 H), 4.33 (d, J = 12.4 Hz, 1 H), 4.19 (d, J =
13.3 Hz, 2 H), 3.15 (d, J = 13.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 140.9, 139.1, 133.2, 130.7, 130.2,
130.1, 129.9, 128.6, 127.9, 127.8, 127.4, 127.2, 126.9, 125.0, 75.1,
61.5, 54.2.
Anal. Calcd. for C23H31NO2S2: C, 66.15; H, 7.48; N, 3.35. Found:
C, 66.45; H, 7.66; N, 3.36.
Second Diastereomer of 6j
Colorless microcrystals; yield: 0.084 g (10%); mp 54–55 °C.
1H NMR (300 MHz, CDCl3): d = 7.33 (d, J = 8.2 Hz, 2 H), 7.06 (d,
J = 8.2 Hz, 3 H), 6.96 (d, J = 5.8 Hz, 3 H), 4.26 (d, J = 7.1 Hz, 1 H),
3.57 (dd, J = 5.8, 6.9 Hz, 1 H), 2.87–2.81 (m, 2 H), 2.74–2.59 (m, 2
H), 2.41–2.36 (m, 5 H), 2.32 (s, 3 H), 2.28 (s, 3 H), 1.08 (d, J = 6.7
Hz, 6 H).
Anal. Calcd. for C34H31NO: C, 81.40; H, 6.23; N, 2.79. Found: C,
66.65; H, 5.17; N, 2.16.
Second Diastereomer of 6n
Colorless microcrystals; yield: 0.100 g (10%); mp 174–175 °C.
13C NMR (75 MHz, CDCl3): d = 143.6, 138.2, 136.3, 130.8, 129.4,
129.0, 128.7, 128.4, 71.2, 70.4, 31.5, 28.2, 21.7, 21.6, 21.4, 19.6.
1H NMR (300 MHz, CDCl3): d = 7.63–7.58 (m, 2 H), 7.54–7.49 (m,
3 H), 7.36–7.29 (m, 2 H), 7.26–7.24 (m, 2 H), 7.19–7.16 (m, 9 H),
6.90–6.87 (m, 2 H), 6.84–6.77 (m, 5 H), 4.62 (d, J = 12.4 Hz, 1 H),
4.16 (d, J = 12.4 Hz, 1 H), 3.72 (d, J = 13.2 Hz, 2 H), 3.03 (d, J =
13.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 142.2, 138.8, 134.6, 130.7, 130.3,
129.8, 129.2, 129.1, 128.7, 128.5, 128.3, 128.2, 128.0, 127.8, 127.1,
127.0, 124.0, 74.8, 61.5, 53.5.
Anal. Calcd. for C23H31NO2S2: N, 3.35. Found: N, 3.08.
HRMS: m/z [M + H]+ calcd for C23H31NO2S2: 418.1868; found:
418.1858.
Dibenzyl{2-methyl-1-[1-(phenylsulfonyl)ethyl]propyl}amine
(6k)
Colorless microcrystals; yield: 0.599 g (71%); mp 144–145 °C.
Synthesis 2006, No. 20, 3377–3388 © Thieme Stuttgart · New York

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Aminoalkylations with in situ Generated Iminium Ions
3385
Anal. Calcd. for C34H31NO: C, 81.40; H, 6.23; N, 2.79. Found: C,
76.04; H, 5.97; N, 2.59.
Hz, 1 H), 4.66 (d, J = 12.1 Hz, 1 H), 3.48–3.41 (m, 2 H), 3.67–3.30
(m, 2 H), 2.54–2.49 (m, 2 H), 2.27–2.22 (m, 2 H), 2.21 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 161.5, 149.1, 142.3, 136.2, 136.1,
132.4, 128.9, 128.4, 128.2, 127.9, 126.1, 123.6, 120.9, 71.3, 67.2,
54.8, 49.2, 21.0.
(2-Aminoethyl)pyridines 8a–d; General Procedure
To a soln of 7 (2 mmol) in dry THF (10 mL), 1.6 M n-BuLi in hex-
anes (1.5 mL, 2.2 mmol) was added at –78 °C. The mixture was
stirred at the same temperature for 1 h, and 1 (2 mmol) in THF (10
mL) was added dropwise. The reaction mixture was stirred for 10 h
while the temperature was allowed to rise to 20 °C. After quenching
with H2O (20 mL) and extraction with EtOAc (3 × 25 mL), the com-
bined organic layers were washed with H2O (25 mL) and dried
(MgSO4), and the solvent was removed in vacuo. Column chroma-
tography of the residue (silica gel, hexanes–EtOAc, 10:1, then 6:1)
gave pure product 8.
Anal. Calcd. for C24H26N2O: C, 80.41; H, 7.31; N, 7.81. Found: C,
80.72; H, 7.45; N, 7.84.
Second Diastereomer of 8d
Colorless microcrystals; yield: 0.279 g (39%); mp 151–152 °C.
1H NMR (300 MHz, CDCl3): d = 8.52 (d, J = 4.8 Hz, 1 H), 7.55 (td,
J = 7.7, 1.8 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 3 H), 7.10–6.93 (m, 8 H),
4.83 (d, J = 12.2 Hz, 1 H), 4.61 (d, J = 12.2 Hz, 1 H), 3.42–3.35 (m,
2 H), 3.30–3.26 (m, 2 H), 2.57–2.52 (m, 2 H), 2.25–2.20 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 163.2, 148.8, 140.7, 136.3, 135.9,
131.6, 128.9, 128.6, 128.3, 128.1, 126.1, 122.7, 120.9, 71.7, 67.2,
54.8, 49.1, 20.9.
4-{2-Methyl-1-[phenyl(2-pyridyl)methyl]propyl}morpholine
(8a)
Colorless microcrystals; yield: 0.490 g (79%); mp 121–122 °C.
1H NMR (300 MHz, CDCl3): d = 8.52 (d, J = 4.7 Hz, 1 H), 7.49–
7.42 (m, 3 H), 7.27–7.20 (m, 3 H), 7.14–7.09 (m, 1 H), 6.99–6.95
(m, 1 H), 4.44 (d, J = 11.5 Hz, 1 H), 3.67 (dd, J = 11.5, 2.1 Hz, 1 H),
3.39–3.36 (m, 4 H), 2.61–2.58 (m, 4 H), 1.64–1.59 (m, 1 H), 0.95
(d, J = 6.9 Hz, 3 H), 0.83 (d, J = 6.9 Hz, 3 H).
Anal. Calcd. for: C24H26N2O: C, 80.41; H, 7.31; N, 7.81. Found: C,
80.29; H, 7.42; N, 7.76.
b-Aminoalkyl Cyanides 11a–i, 12a,b, 13, and 14; General Pro-
cedure
13C NMR (75 MHz, CDCl3): d = 163.2, 148.5, 142.3, 135.9, 128.3,
128.2, 126.2, 123.4, 121.0, 70.9, 67.7, 55.3, 51.8, 30.2, 21.3, 17.2.
To a soln of nitrile 10 (2 mmol) in dry THF (10 mL), 1.6 M n-BuLi
in pentane (2.6 mL, 4.2 mmol) was added at –78 °C. After the mix-
ture had stirred for 1 h at the same temperature, benzotriazole 1 (2
mmol) in THF (10 mL) was added. Stirring was continued for 10 h
while the temperature was allowed to rise to 20 °C. The mixture was
quenched with H2O and extracted with EtOAc (3 × 25 mL). The
combined organic layers were washed with H2O (25 mL) and dried
(MgSO4), and the solvent was removed in vacuo. Column chroma-
tography of the resulting oil (silica gel, hexanes–EtOAc, 10:1) gave
pure product.
Anal. Calcd. for C20H26N2O: C, 77.38; H, 8.44; N, 9.02. Found: C,
77.50; H, 8.54; N, 8.98.
Dibenzyl{2-methyl-1-[phenyl(4-pyridyl)methyl]propyl}amine
(8b)
Colorless microcrystals; yield: 0.664 g (79%); mp 159–160 °C.
1H NMR (300 MHz, CDCl3): d = 8.38 (d, J = 5.5 Hz, 2 H), 7.35–
6.94 (m, 17 H), 4.30 (d, J = 11.4 Hz, 1 H), 3.82–13.64 (m, 1 H), 3.57
(AB system, JAB = 11.4 Hz, 2 H), 3.48 (AB system, JAB = 13.3 Hz,
2 H), 2.29–12.20 (m, 1 H), 1.02 (d, J = 6.9 Hz, 3 H), 0.70 (d, J = 7.4
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 153.1, 149.8, 142.9, 139.5, 129.5,
130.0, 128.3, 128.0, 127.9, 126.9, 126.4, 123.9, 61.9, 54.1, 53.1,
26.5, 20.0.
2-(2,4-Dichlorophenyl)-3-morpholin-4-yl-3-(4-tolyl)propio-
nitrile (11a)
Colorless plates; yield: 0.668 g (89%); mp 143–145 °C.
1H NMR (300 MHz, CDCl3): d = 7.39 (d, J = 2.2 Hz, 1 H), 7.26–
6.93 (m, 5 H), 6.58 (d, J = 8.5 Hz, 1 H), 5.02 (d, J = 5.4 Hz, 1 H),
3.77–3.72 (m, 4 H), 3.49 (d, J = 5.4 Hz, 1 H), 2.58–2.55 (m, 4 H),
2.31 (s, 3 H).
Anal. Calcd. for C30H32N2: C, 85.67; H, 7.67; N, 6.66. Found: C,
85.30; H, 7.85; N, 6.68.
13C NMR d = 138.4, 134.7, 133.0, 132.4, 131.7, 130.0, 129.1, 128.9,
128.8, 127.2, 117.9, 70.5, 66.8, 51.7, 37.5, 21.1.
4-[1-(4-Chlorophenyl)-2-phenyl-2-(4-pyridyl)ethyl]morpholine
(8c)
Colorless microcrystals; yield: 0.246 g (65%); mp 212–213 °C.
Anal. Calcd. for C20H20Cl2N2O: C, 64.01; H, 4.37; N, 7.46. Found:
C, 64.22; H, 4.48; N, 7.44.
1H NMR (300 MHz, CDCl3): d = 8.29 (d, J = 5.8 Hz, 2 H), 7.36–
7.20 (m, 7 H), 7.07–7.02 (m, 4 H), 4.54 (d, J = 12.1 Hz, 1 H), 4.32
(d, J = 12.1 Hz, 1 H), 3.45–3.43 (m, 2 H), 3.38–3.33 (m, 2 H), 2.50–
2.45 (m, 2 H), 2.26–2.23 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 149.6, 141.3, 133.3, 133.1,
130.1, 128.3, 128.1, 126.6, 123.7, 71.1, 66.9, 52.1, 49.1.
3-(1-Naphthyl)-2-phenyl-3-(1-piperidyl)propionitrile (11b)
Pale yellow microcrystals; yield: 0.538 g (79%); mp 101–103 °C.
1H NMR (300 MHz, CDCl3): d = 8.07 (d, J = 7.3 Hz, 1 H), 7.78–
7.70 (m, 2 H), 7.44–7.37 (m, 4 H), 7.24–7.20 (m, 2 H), 7.12–7.05
(m, 3 H), 5.03 (d, J = 8.0 Hz, 1 H), 4.53 (d, J = 9.5 Hz, 1 H), 2.50
(br s, 4 H), 1.67–1.53 (m, 4 H), 1.33–1.27 (m, 2 H).
Anal. Calcd. for C23H23ClN2O: C, 72.91; H, 6.12; N, 7.39. Found:
C, 71.52; H, 6.03; N, 7.23.
13C NMR (75 MHz, CDCl3): d = 134.3, 133.7, 132.7, 131.1, 128.8,
128.5, 128.3, 128.1, 127.8, 126.1, 125.4, 124.3, 122.8, 120.6, 100.2,
51.5, 42.1, 26.4, 24.3.
4-[2-Phenyl-2-(2-pyridyl)-1-(4-tolyl)ethyl]morpholine (8d)
Two diastereomers of 8d were isolated.
Anal. Calcd. for C24H24N2: C, 84.67; H, 7.11. Found: C, 84.38; H,
7.50.
First Diastereomer of 8d
Colorless microcrystals; yield: 0.366 g (51%); mp 162–163 °C.
1H NMR (300 MHz, CDCl3): d = 8.36 (d, J = 4.8 Hz, 1 H), 7.52 (d,
J = 7.3 Hz, 2 H), 7.37–7.25 (m, 3 H), 7.22–7.14 (m, 1 H), 7.09–7.05
(m, 3 H), 7.01–6.98 (m, 2 H), 6.87–6.81 (m, 1 H), 4.76 (d, J = 12.1
2-[(1-Naphthyl)(1-piperidyl)methyl]-2-phenylbutyronitrile
(11c)
Colorless needles; yield: 0.486 g (66%); mp 176–177 °C.
1H NMR (300 MHz, CDCl3): d = 8.05 (d, J = 8.2 Hz, 1 H), 7.80 (d,
J = 7.3 Hz, 1 H), 7.74 (d, J = 8.6 Hz, 1 H), 7.58 (d, J = 8.1 Hz, 1 H),
7.50–7.38 (m, 2 H), 7.28–7.23 (m, 3 H), 7.04–6.92 (m, 3 H), 4.99
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3386
A. R. Katritzky et al.
PAPER
(s, 1 H), 3.08–2.93 (m, 3 H), 2.32 (br s, 2 H), 2.06 (sext, J = 7.4 Hz,
1 H), 1.66–1.59 (m, 4 H), 1.29–1.27 (m, 2 H), 0.93 (t, J = 7.4 Hz, 3
2-(1,3-Benzodioxol-4-yl)-3-(dibenzylamino)-4-methylpentane-
nitrile (11g)
H).
Compound 11g was obtained as a mixture of anti and syn diaste-
reomers (31:69).
13C NMR (75 MHz, CDCl3): d = 137.3, 133.5, 132.9, 131.8, 129.0,
128.2, 127.7, 127.6, 126.9, 126.3, 125.8, 125.0, 124.4, 123.1, 123.0,
70.0, 54.2, 54.1, 34.5, 27.1, 24.2, 9.4.
Colorless prisms; yield: 0.726 g (88%); mp 114–115 °C.
1H NMR (300 MHz, CDCl3): d = 7.39–7.24 (m, 10 H), 6.79–6.61
(m, 3 H), 5.99–5.4 (m, 2 H), 4.33 (d, J = 2.3 Hz, 0.69 H), 4.08 (AB
system, JAB = 14.0 Hz, 1.24 H), 4.06 (d, J = 2.3 Hz, 031 H), 3.89
(AB system, JAB = 13.6 Hz, 1.24 H), 3.48 (AB system, JAB = 14.0
Hz, 1.38 H), 2.99 (t, J = 6.7 Hz, 0.31 H), 2.82 (dd, J = 8.8, 2.6 Hz,
0.69 H), 2.54–2.42 (m, 0.69 H), 2.11–2.00 (m, 0.31 H), 1.18 (d, J =
6.6 Hz, 2.07 H), 0.93 (d, J = 6.7 Hz, 0.93 H), 0.92 (d, J = 6.5 Hz,
0.93 H), 0.71 (d, J = 6.6 Hz, 2.07 H).
Anal. Calcd. for C26H28N2: C, 84.74; H, 7.66; N, 7.60. Found: C,
84.82; H, 7.85; N, 7.81.
2-(4-Bromophenyl)-3-morpholin-4-yl-3-(4-tolyl)propionitrile
(11d)
Compound 11d was obtained as a mixture of anti and syn diaste-
reomers (62:38).
Pale yellow plates; yield: 0.724 g (94%); mp 105–107 °C.
13C NMR (75 MHz, CDCl3): d = 148.1, 148.0, 147.4, 146.8, 139.2,
138.8, 129.6, 129.3, 128.8, 128.7, 128.4, 128.1, 127.3, 127.0, 121.9,
121.0, 120.7, 120.0, 108.7, 108.5, 108.2, 107.8, 101.4, 101.3, 68.2,
65.7, 54.8, 53.9, 38.4, 34.3, 29.4, 28.9, 21.7, 20.8.
1H NMR (300 MHz, CDCl3): d = 7.34 (d, J = 8.2 Hz, 2 H), 7.08–
6.96 (m, 4 H), 6.85(dd, J = 10.9, 8.2 Hz, 2 H), 4.48 (d, J = 6 Hz, 0.62
H), 4.37 (d, J = 9.8 Hz, 0.38 H), 3.86 (d, J = 9.9 Hz, 0.38 H), 3.77–
3.71 (m, 8 H), 3.36 (d, J = 6.2 Hz, 0.62 H), 2.58–2.38 (m, 8 H), 2.30
(s, 3.7 H), 2.29 (s, 2.3 H).
Anal. Calcd. for C27H28N2O2: C, 78.61; H, 6.84; N, 6.79. Found: C,
78.63; H, 6.97; N, 6.84.
13C NMR (75 MHz, CDCl3): d = 138.2, 138.1, 132.8, 132.5, 132.1,
131.8, 131.5, 130.1, 130.0, 129.5, 129.0, 128.9, 128.8, 128.6, 122.2,
122.0, 119.6, 118.2, 73.6, 72.9, 67.0, 66.8, 51.6, 50.2, 40.3, 40.1,
21.1, 21.0.
2-{[Benzyl(methyl)amino]methyl}-2-phenylbutyronitrile (11h)
Colorless oil; yield: 0.518 g (93%).
1H NMR (300 MHz, CDCl3): d = 7.45–7.21 (m, 10 H), 3.53 (s, 2 H),
2.98 (AB system, JAB = 13.9 Hz, 1 H), 2.92 (AB system, JAB = 13.9
Hz, 1 H), 2.17 (s, 3 H), 2.23–2.14 (m, 1 H), 1.91–1.84 (m, 1 H), 0.91
(t, J = 7.3 Hz, 3 H).
Anal. Calcd. for C20H21BrN2O: C, 62.34; H, 5.49; N, 7.27. Found:
C, 62.63; H, 5.62; N, 7.14.
4-Methyl-3-morpholin-4-yl-2-phenylpentanenitrile (11e)
Compound 11e was obtained as a mixture of anti and syn diaste-
reomers (53:47).
13C NMR (75 MHz, CDCl3): d = 138.9, 137.4, 128.8, 128.6, 128.1,
127.6, 126.9, 126.5, 122.5, 66.9, 63.7, 50.5, 43.6, 30.6, 9.3.
Anal. Calcd. for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C,
82.32; H, 8.16; N, 10.32.
Colorless plates; yield: 0.501 g (97%); mp 91–92 °C.
1H NMR (300 MHz, CDCl3): d = 7.43–7.29 (m, 5 H), 4.25 (d, J =
2.3 Hz, 0.47 H), 4.10 (d, J = 4.8 Hz, 0.53 H), 3.75–3.64 (m, 2 H),
3.55–3.38 (m, 2 H), 2.89–2.77 (m, 2 H), 2.66 (dd, J = 9.5, 2.5 Hz,
0.47 H), 2.64 (dd, J = 9.5, 2.5 Hz, 0.53 H), 2.56–2.41 (m, 2 H),
2.32–2.17 (m, 1 H), 1.11 (d, J = 6.6 Hz, 1.78 H), 1.05 (d, J = 6.5 Hz,
2.82 H), 0.82 (d, J = 6.6 Hz, 1.40 H).
13C NMR (75 MHz, CDCl3): d = 135.6, 135.1, 128.7, 128.5, 128.1,
127.7, 127.4, 119.9, 119.6, 75.7, 75.1, 67.5, 67.1, 50.7, 49.6, 39.5,
35.3, 29.5, 29.4, 21.3, 21.0, 20.8.
2-(4-Bromophenyl)-3-morpholin-4-ylpropionitrile (11i)
Brown oil; yield: 0.413 g (70%).
1H NMR (300 MHz, CDCl3): d = 7.52 (d, J = 8.5 Hz, 2 H), 7.24 (d,
J = 8.5 Hz, 2 H), 3.92 (dd, J = 9.1, 5.9 Hz, 1 H), 3.72–3.67 (m, 4 H),
2.87 (dd, J = 13.1, 9.1 Hz, 1 H), 2.66 (dd, J = 12.9, 5.8 Hz, 1 H),
2.56–2.53 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 133.2, 132.2, 129.2, 122.4, 119.7,
66.8, 63.0, 53.6, 36.1.
Anal. Calcd. for C16H22N2O: C, 74.38; H, 8.58; N, 10.84. Found: C,
74.77; H, 8.99; N, 10.84.
Anal. Calcd. for C13H15BrN2O: C, 52.90; H, 5.12. Found: C, 52.83;
H, 4.95.
2-(1,3-Benzodioxol-4-yl)-4-methyl-3-morpholin-4-ylpentane-
nitrile (11f)
Compound 11f was obtained as a mixture of anti and syn diaste-
reomers (55:45).
3-(1-Naphthyl)-2-[(1-naphthyl)(1-piperidyl)methyl]-3-
(1-piperidyl)propionitrile (12a)
Colorless prisms; yield: 0.382 g (39%); mp 78–80 °C.
1H NMR (300 MHz, CDCl3): d = 7.91–7.78 (m, 7 H), 7.56–7.34 (m,
7 H), 4.70 (d, J = 7.6 Hz, 2 H), 4.35 (t, J = 8.0 Hz, 1 H), 2.39–2.27
(m, 8 H), 1.62–1.51 (m, 8 H), 1.31–1.28 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 133.8, 133.2, 132.3, 128.8, 128.4,
126.1, 125.7, 125.3, 124.9, 123.7, 120.2, 60.9, 51.4, 37.0, 26.2,
24.4.
Colorless prisms; yield: 0.562 g (93%); mp 102–103 °C.
1H NMR (300 MHz, CDCl3): d = 6.88–6.77 (m, 3 H), 5.99 (s, 1 H),
5.98 (s, 1 H), 4.14 (d, J = 2.7 Hz, 0.55 H), 3.99 (d, J = 5.1 Hz, 0.45
H), 3.73–3.61 (m, 2 H), 3.58–3.44 (m, 2 H), 2.89–2.82 (m, 1 H),
2.79–2.73 (m, 1 H), 2.61 (d, J = 2.7 Hz, 0.45 H), 2.58 (d, J = 2.9 Hz,
0.55 H), 2.56–2.46 (m, 2 H), 2.32–2.09 (m, 1 H), 1.07 (d, J = 6.6
Hz, 1.51 H), 1.03 (d, J = 6.6 Hz, 1.47 H), 1.02 (d, J = 6.6 Hz, 1.23
H), 0.85 (d, J = 6.6 Hz, 1.79 H).
Anal. Calcd. for C34H37N3: C, 83.74; H, 7.65; N, 8.62. Found: C,
83.92; H, 8.01; N, 8.57.
13C NMR (75 MHz, CDCl3): d = 148.0, 147.8, 147.1, 146.9, 129.2,
128.7, 121.5, 120.9, 120.0, 119.8, 108.5, 108.3, 108.2, 107.9, 101.4,
101.3, 75.5, 75.0, 67.6, 67.1, 50.7, 49.7, 39.0, 35.1, 29.5, 29.3, 21.1,
21.0 (2C), 20.9.
3-[Benzyl(methyl)amino]-2-{[benzyl(methyl)amino]methyl}-2-
phenylpropionitrile (12b)
Pale yellow plates; yield: 0.330 g (43%); mp 53–55 °C.
1H NMR (300 MHz, CDCl3): d = 7.79–7.20 (m, 15 H), 3.56 (AB
system, JAB = 13.2 Hz, 2 H), 3.49 (AB system, JAB = 13.2 Hz, 2 H),
3.13 (AB system, JAB = 13.6 Hz, 2 H), 2.87 (AB system, JAB = 13.6
Hz, 2 H), 2.15 (s, 6 H).
Anal. Calcd. for C17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found: C,
67.89; H, 7.63; N, 9.29.
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Aminoalkylations with in situ Generated Iminium Ions
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13C NMR (75 MHz, CDCl3): d = 138.9, 137.3, 129.8, 129.0, 128.9,
128.5, 128.1, 128.0, 127.6, 127.0, 126.7, 125.7, 122.7, 64.2, 63.7,
50.8, 43.7.
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Org. Chem. 1992, 57, 4932.
(14) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Org. Prep. Proced.
Int. 1989, 21, 135.
(15) (a) Ma, J.-A. Angew. Chem. Int. Ed. 2003, 42, 4290.
(b) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25,
117.
Anal. Calcd. for C26H29N3: C, 81.42; H, 7.62; N, 10.96. Found: C,
81.45; H, 7.52; N, 10.71.
2-(2,4-Dichlorophenyl)-3-morpholin-4-ylpropionitrile (13)
(16) (a) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159. (b) Zhou,
Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am.
Chem. Soc. 2002, 124, 4952. (c) Hsiao, Y.; Rivera, N. R.;
Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.;
Armstrong, J. D. III; Grabowski, E. J. J.; Tillyer, R. D.;
Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918.
(17) (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 12964. (b) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
(c) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem. Int. Ed. 2004, 43, 1566.
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Katritzky, A. R. Tetrahedron Lett. 1996, 37, 3731.
(19) Katritzky, A. R.; Shobana, N.; Harris, P. A. Tetrahedron
Lett. 1990, 31, 3999.
(20) (a) Wang, Q.; Dau, M.-E. T. H.; Sasaki, N. A.; Potier, P.
Tetrahedron 2001, 57, 6455. (b) Lehman de Gaeta, L. S.;
Czarniecki, M.; Spaltenstein, A. J. Org. Chem. 1989, 54,
4004.
Colorless prisms; yield: 0.411 g (72%); mp 97–98 °C.
1H NMR (300 MHz, CDCl3): d = 7.56 (d, J = 8.4 Hz, 1 H), 7.43 (d,
J = 1.8 Hz, 1 H), 7.33 (dd, J = 8.4, 1.8 Hz, 1 H), 4.41 (dd, J = 9.2,
4.9 Hz, 1 H), 3.76–3.70 (m, 4 H), 2.84–2.50 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 135.1, 133.3, 130.4, 130.2, 129.7,
128.0, 119.6, 66.8, 61.2, 53.5, 33.5.
Anal. Calcd. for C13H14Cl2N2O: C, 54.75; H, 4.95; N, 9.82. Found:
C, 54.92; H, 4.85; N, 9.79.
2-(2,4-Dichlorophenyl)-3-morpholin-4-yl-2-(morpholin-4-yl-
methyl)propionitrile (14)
Colorless plates; yield: 0.057 g (10%); mp 91–92 °C.
1H NMR (300 MHz, CDCl3): d = 7.78 (d, J = 8.5 Hz, 1 H), 7.38 (d,
J = 2.2 Hz, 1 H), 7.29 (dd, J = 8.5, 2.2 Hz, 1 H), 3.54–3.51 (m, 8 H),
3.34 (d, J = 13.9 Hz, 2 H), 3.03 (d, J = 13.9 Hz, 2 H), 2.61–2.55 (m,
4 H), 2.46–2.39 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 134.6, 133.0, 132.9, 131.6, 131.2,
127.2, 122.5, 66.9, 61.2, 54.6, 52.3.
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Synthesis 2006, No. 20, 3377–3388 © Thieme Stuttgart · New York