Stereoselective synthesis of β-amino ketones via direct Mannich-type reactions, catalyzed with ZrOCl2·8H2O under solvent-free conditions

Article abstract of DOI:10.1002/ejoc.200600493

At room temperature, zirconium oxychloride (ZrOCl₂· 8H₂O) efficiently catalyzes the direct Mannich-type reaction of a variety of in situ generated aldimines using aldehydes and anilines with ketones in a three-component reaction under solvent-free conditions. The reaction proceeds rapidly and affords the corresponding β-amino ketones in good to high yields with good to excellent stereoselectivities. The catalyst can be recycled for subsequent reactions without any appreciable loss of efficiency. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600493

FULL PAPER
DOI: 10.1002/ejoc.200600493
Stereoselective Synthesis of β-Amino Ketones via Direct Mannich-Type
Reactions, Catalyzed with ZrOCl2·8H2O under Solvent-Free Conditions
Bagher Eftekhari-Sis,[a] Amir Abdollahifar,[a] Mohammed M. Hashemi,*[a] and
Maryam Zirak[b]
Keywords: Direct Mannich-type reaction / β-Amino ketones / Zirconium oxychloride / Solvent-free conditions
At room temperature, zirconium oxychloride (ZrOCl2·8H2O)
efficiently catalyzes the direct Mannich-type reaction of a
variety of in situ generated aldimines using aldehydes and
anilines with ketones in a three-component reaction under
solvent-free conditions. The reaction proceeds rapidly and
affords the corresponding β-amino ketones in good to high
yields with good to excellent stereoselectivities. The catalyst
can be recycled for subsequent reactions without any ap-
preciable loss of efficiency.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
transthioacetylization of acetals,[8b] deoxygenation of het-
erocyclic N-oxides,[8c] reduction of nitro compounds,[8d]
conversion of carbonyl compounds to 1,3-oxathiolanes,[8e]
synthesis of nitriles from O-arylaldoximes,[8f] Michael reac-
tions of 1,3-dicarbonyl compounds and enones,[8g] opening
of epoxide rings by amines,[8h] reactions of indole, 1-meth-
ylindole, and pyrrole with α,β-unsaturated ketone,[8i] and
other organic transformations.[8j–8w] There have been only a
few reports on metal-oxysalt-based organic reactions.[9]
Recently, we have reported[10] that ZrOCl2·8H2O sup-
ported on montmorillonite K10 catalyzes the synthesis of
β-amino esters and ketones via the conjugated addition of
amines to α,β-unsaturated carbonyl compounds. The results
encouraged us to work on the synthesis of β-amino ketones
via three-component Mannich reactions catalyzed with
ZrOCl2·8H2O.
As part of our research on chemical transforma-
tions,[10,11] in this paper we report a simple and environmen-
tally benign methodology for the stereoselective synthesis of
β-amino ketones via direct Mannich-type reactions between
aldehydes, anilines, and ketones under neutral, solvent-free
conditions at room temp. using ZrOCl2·8H2O as the cata-
lyst. We report herein that excellent anti selectivity was ob-
served in ZrOCl2·8H2O-catalyzed direct Mannich-type re-
actions of cyclic ketones and aldimines under solvent-free
conditions.
Introduction
Multi-component reactions (MCRs) performed either in
the solid phase or in solution,[1] have emerged as powerful
tools in combinatorial chemistry for the generation of
small-molecule libraries. The goal is to aid the discovery of
new leads for drug development and optimization of pro-
cesses or to identify novel biologically active substrates.
β-Amino carbonyl compounds are attractive targets for
chemical synthesis because of their wide use as biologically
active molecules.[2] Therefore, the development of new syn-
thetic methods leading to β-amino carbonyl compounds or
their derivatives has attracted much attention in organic
synthesis. The Mannich reaction is a classical method for
the preparation of β-amino ketones and aldehydes,[2,3] and
has been one of the most important basic reactions in or-
ganic chemistry for its use in natural product and pharma-
ceutical syntheses. However, due to the drastic reaction con-
ditions and the long reaction times, the classical intermo-
lecular Mannich reaction is plagued by a number of serious
disadvantages.[3] However, catalytic Mannich reactions have
been reported by several groups as an efficient method to
prepare β-amino carbonyl compounds.[4]
Due to the ease of availability,[5] and low toxicity,[6] ZrIV
salts have recently attracted much attention.[7] This has been
reflected in their applications in several organic transforma-
tions such as electrophilic amination of activated arenes,[8a]
[a] Department of Chemistry, Sharif University of Technology,
P. O. Box 11365-9516, Tehran, Iran
Results and Discussion
Fax: +98-21-600-5718
The ZrOCl2·8H2O-catalyzed Mannich reaction was first
studied using imines. N-Benzylideneaniline and cyclohexa-
none were treated with 15 mol% ZrOCl2·8H2O under sol-
vent-free conditions for 25 min at room temp. The corre-
sponding β-amino ketone was isolated in high yield (95%),
E-mail address: mhashemi@sharif.edu
[b] Department of Organic Chemistry, Faculty of Chemistry, Tab-
riz University,
P. O. Box 51664, Tabriz, Iran
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Stereoselective Synthesis of β-Amino Ketones
FULL PAPER
with 100% anti selectivity. Consequently, a one-pot se- Table 1. Mannich reactions of benzaldehyde (1 mmol), aniline
(1 mmol), and cyclohexanone under different conditions.
quence involving the formation of the imine and its in situ
Mannich reaction was investigated. The overall reaction is
shown in Scheme 1.
ZrOCl2·8H2O
Entry
Solvent
Yield [%]
anti/syn
[mol-%]
1a
1b
1c
1d
1e
1f
1g
1h
1i
MeCN
MeOH
EtOAc
H2O
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
15
15
15
15
15
10
20
0
68[a]
45[a]
70[a]
58:42
53:47
61:39
–
[a][b]
–
93, 86, 80[a][c] 100:0
57[a]
95[a]
5[a]
98:2
100:0
–
82:18
99:1
15
15
43[d]
92[e]
1j
[a] 3 equiv. of cyclohexanone was used. [b] Main product was imine.
[c] Catalyst was used over three runs. [d] 1 equiv. of cyclohexanone
was used. [e] 5 equiv. of cyclohexanone was used.
Table 2. Direct Mannich-type reactions of aromatic aldehydes, ani-
lines, and cyclic ketones (see also Scheme 1).[a]
Scheme 1. Direct Mannich-type reaction between aldehydes of type
1, anilines, and cyclic ketones.
n
X
XЈ
Time
[min] [mg]
Yield[b]
anti/syn[c]
[%]
To examine the optimal conditions for the Mannich reac-
tion of benzaldehyde, aniline, and cyclohexanone using
ZrOCl2·8H2O as the catalyst, to afford the corresponding
β-amino carbonyl adduct, we carried out experiments 1a–
1j. A summary of the results is provided in Table 1. Entries
1a–1e show the effect of various solvents and solvent-free 2f
conditions on the yield and stereoselectivity of the reaction.
Interestingly, the Mannich reaction exhibited an intriguing
solvent effect; excellent anti selectivity was observed under
solvent-free conditions, whereas the reaction in aqueous or
organic solvent showed low stereoselectivity. Therefore, we
chose solvent-free conditions for high yield and high anti
selectivity of the reaction and environmental acceptability.
Entry 1e describes the yields of three consecutive additions
leading to the corresponding β-amino ketones. In these ex-
periments the product was isolated by filtration, the solid
residues were washed with dichloromethane, and the re-
maining catalyst reloaded with fresh reagents for further
runs after reactivation (35 °C, vacuum). No considerable
decrease in the yield was observed demonstrating that
ZrOCl2·8H2O can be reused as a catalyst in direct Man-
nich-type reactions. The optimum amount of catalyst
2a
2b
2c
2d
2e
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
H
H
H
H
H
H
4-MeO
3-Me
4-Cl
3-Me
3-Me
4-Cl
H
4-Me
4-Cl
H
4-Cl
4-NO2
furfural
H
6
7
220
239
259
257
298
223
262
240
247
317
252
206
219
245
233
79
80
93
88
92
83
85
82
79
94
77
63
75
75
76
99:1
97:3
100:0
99:1
74:26
92:8
20
15
25
10
15
15
12
20
15
15
50
45
55
2g
2h
99:1
H
H
85:15
81:19
72:28
100:0
87:13
94:6
2i
2j
2k
2l
2m
2n
2o
4-NO2
4-Cl
4-Me
H
4-Cl
H
H
3-Me
83:17
89:11
[a] Reaction conditions: To aniline (1 mmol), aldehyde (1 mmol),
cycloalkanone (3 equiv.), and ZrOCl2·8H2O (0.05 g, 15 mol-%)
were added successively at room temp. and stirred for the time
listed in Table 2. [b] Yields refer to isolated products. [c] Dia-
stereomeric ratio measured by H-NMR spectroscopic analysis of
the crude reaction mixture.
1
As shown in Table 2, high anti selectivity is obtained with
(0.15 mmol of ZrOCl2·8H2O) was determined from experi- various substituted benzaldehydes except for nitro-substi-
ments corresponding to entries 1e–1g. Entry 1h shows the tuted benzaldehydes (see compounds 2e, 2j).
catalytic effect of ZrOCl2·8H2O in the three-component
The proposed mechanism involves the attack of in-situ-
Mannich reaction of benzaldehyde, aniline, and cyclohexa- generated enolate a on the in-situ-generated aldimine b as
none. The optimum amount of cyclohexanone was deter- shown in Scheme 2. ZrOCl2, used in catalytic amounts, is
mined to be 3 equiv. as shown in entries 1e, 1i, and 1j. recycled in the reaction and can be reused for subsequent
The reaction of benzaldehyde, aniline, and cyclohexa- reactions.
none in the presence of ZrOCl2·8H2O gives the β-amino
Four possible transition states are shown in Scheme 3.
ketone adduct in high yield over a short reaction time with Transition states I and IV provide the anti isomer, whereas,
excellent anti selectivity. Details of this reaction are summa- the syn isomer forms via II and III. In III and IV the two
rized in Table 2. The data in Table 2 clearly show that the phenyl groups of aldimine are syn to each other, so they are
reaction of different aromatic aldehydes of type 1, anilines, unfavorable. Also in III and IV steric repulsion exists be-
and cyclic ketones give the corresponding β-amino ketones tween the hydrogen atoms of cyclohexanone’s methylene
in good to high yield with good to excellent anti selectivity groups and phenyl and hydroxy (or chloro) groups, respec-
at room temp. without using any solvent.
tively. Steric repulsion in IV is less than in III; therefore,
Eur. J. Org. Chem. 2006, 5152–5157
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M. M. Hashemi et al.
FULL PAPER
of cyclohexanone and phenyl group on the carbon atom
and the hydroxy (or chloro) on the Zr atom causes II to be
less favorable. I is the most stable transition state that pro-
duces the anti isomer.
As shown in VI and VII, the phenyl group on carbon is
syn to the methylene group of cyclohexanone, in which the
steric repulsion between the phenyl group on the carbon
atom and cyclohexanone methylene group causes VI and
VII to be unfavorable.
Mannich reactions of hexanal and anilines with cyclo-
hexanone were investigated, Scheme 4 clearly shows that the
reaction of the aliphatic aldehyde, anilines, and cyclohexa-
none afford the corresponding β-amino ketones in low
yields over long reaction times.
1
The anti/syn ratio was determined by H NMR, using
the intensity of the Ha (Scheme 5). JHa,Hb signal of the anti
isomer which is higher than that of the syn isomer. Accord-
ing to the H NMR spectrum, the Ha signal for the anti
1
Scheme 2. Proposed reaction mechanism for Mannich reactions of
benzaldehyde, anilines, and cyclohexanone.
isomer has a lower δ value than that for the syn isomer. For
instance, in the 1H NMR spectra of 2-[(p-chlorophen-
ylamino)phenylmethyl]cyclohexanone (2i), the signal at δ =
4.58 ppm (J = 6.9 Hz) is contributed by the anti isomer,
while the one at 4.87 ppm (J = 3.7 Hz) is contributed by
the syn isomer.
since IV leads to the anti isomer, this contributes to product
formation more than in III. The phenyl groups of aldimine
Similarly, Mannich reactions of aldehydes and anilines
in I and II are anti to each other, therefore I and II should with acyclic ketones such as acetone and acetophenone
be more stable than III and IV. However, the existence of were investigated, the overall reaction is best formulated in
greater steric repulsion in II between the methylene groups Scheme 6.
Scheme 3. Four possible transition states.
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Stereoselective Synthesis of β-Amino Ketones
FULL PAPER
Table 3. Mannich reaction of aromatic aldehydes, anilines, and acy-
clic ketones (see also Scheme 6).
R
Ar
ArЈ
Time
[h]
Yield[a]
[mg]
[%]
3a
3b
3c
3d
3e
Me
Me
Ph
Ph
Ph
3-MeC6H4 Ph
4-ClC6H4 Ph
0.75
0.75
4
4
4
189
205
195
211
221
65
93
65
63
66
Ph
4-ClC6H4 Ph
Ph 4-ClC6H4
Ph
[a] Yields refer to isolated products, and products are characterized
1
using H NMR and 13C NMR spectroscopy.
Another characteristic feature of the present protocol is
the high chemoselectivity of cyclohexanone toward aldimi-
nes, in preference to aldehydes, prepared in situ from the
reaction of aldehydes and amines as shown in Scheme 7.
Scheme 4. Reaction conditions: to aniline (1 mmol), hexanal
(1 mmol), cyclohexanone (3 equiv.), and ZrOCl2·8H2O (0.05 g)
were added successively at room temp. and stirred for 4 h.
1
Scheme 5. Identification of anti and syn isomer by H NMR spec-
troscopy.
Scheme 7. Chemoselectivity of cyclohexanone toward aldimine in
preference to aldehydes.
Although conventional Lewis acids activate aldehydes
preferentially, in this media, aldehydes do not undergo an
aldol reaction by means of ZrOCl2·8H2O at room temp.
under solvent-free conditions. The high chemoselectivity is
rationalized by considering the higher basicity of nitrogen
over oxygen. A related phenomenon was recently reported
for the difference in the reactivity between aldimines and
aldehydes by the use of proline, HBF4, and dibutyltin di-
methoxide.[12]
The following features are noteworthy in these reactions.
i. A 1:1:3 mixture of benzaldehyde, p-anisidine, and cyclo-
hexanone with 15 mol% of ZrOCl2·8H2O gives the Man-
nich adduct in 85% yield in 15 min under solvent-free con-
ditions (2g). This is in contrast to 84% yield for a reaction
performed in water (1 day), catalyzed by HCl/40 mol-%
SDS (sodium dodecyl sulfate).[13]
ii. It is known that the Mannich reaction of cyclohexanone
tends to exhibit high anti stereoselectivity, but these meth-
ods have some disadvantages such as long reaction ti-
mes.[4b,13] In the present work we obtained Mannich ad-
Scheme 6. Mannich reaction of aromatic aldehydes, anilines, and
acyclic ketones.
The reaction of aldehydes, anilines, and acyclic ketones ducts in good to excellent anti selectivity in short reaction
in the presence of ZrOCl2·8H2O gives the β-amino ketone times without using any solvent.
adducts in good yields over short reaction times at room iii. Anilines substituted with electron-withdrawing groups
temp. without using any solvent. The required time for the and aldehydes substituted with electron-donating groups
completion of the reaction in the case of acetophenone is give only low yields (2l).
longer than for acetone. The results are summarized in iv. Not only benzaldehyde, but also heteroaromatic alde-
Table 3.
hydes, such as furfural, work well (2f).
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M. M. Hashemi et al.
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CDCl3): δ = 1.70–1.79 (m, 2 H, CH2), 1.93–1.99 (m, 2 H, CH2),
2.10–2.17 (m, 1 H, CH2), 2.35–2.40 (m, 1 H, CH2), 2.45–2.48 (m,
v. For the reactions of cyclic ketones and acetone, 3 equiv.
of the ketone are needed to avoid polyaminoalkylation.
vi. Increase in ring size leads to an increase in the reaction
times (2b, 2d, 2n).
vii. Mannich reactions of aliphatic aldehydes and anilines
with ketones are not interesting due to low yields and long
reaction times.
3
1 H, CH), 4.53 (d, JH,H = 7.31 Hz, 1 H, CH, anti isomer), 5.18
3
(br. s, 1 H, NH), 6.49 (d, JH,H = 7.88 Hz, 2 H, CHAr), 6.68 (t,
3JH,H = 7.30 Hz, 1 H, CHAr), 7.07 (t, 3JH,H = 8.35 Hz, 2 H, CHAr),
7.30–7.41 (m, 4 H, CHAr) ppm. C18H18ClNO (299.79): calcd. C
72.11, H 6.05, N 4.67; found C 72.33, H 6.24, N 4.41.
2-[(p-Nitrophenyl)(phenylamino)methyl]cyclohexanone (2e): IR
(KBr): ν = 3373 (NH), 3032, 2948, 2858 (CH), 1699 (CO), 1601
˜
1
(C=C), 1515, 1346 (NO2), 1287 (NH) cm–1. H NMR (500 MHz,
Conclusion
CDCl3): δ = 1.59–1.68 (m, 1 H, CH2), 1.78–1.87 (m, 2 H, CH2),
1.99–2.00 (m, 1 H, CH2), 2.06–2.08 (m, 2 H, CH2), 2.34–2.38 (m,
1 H, CH), 2.41–2.49 (m, 1 H, CH2), 2.84–2.88 (m, 1 H, CH), 4.71
In summary, three-component Mannich reactions of al-
dehydes, anilines, and ketones are efficiently catalyzed by
ZrOCl2·8H2O under solvent-free conditions. Aromatic and
heteroaromatic aldehydes can be successfully used as the
aldehyde component. Also, we have found that good to ex-
cellent anti selectivity was observed in the ZrOCl2·8H2O-
3
3
(d, JH,H = 4.84 Hz, 0.74 H, CH, anti isomer), 4.83 (d, JH,H
=
3.42 Hz, 0.26 H, CH, syn isomer), 4.93 (s, 1 H, NH), 6.48 (d, 3JH,H
= 7.77 Hz, 2 H, CHAr), 6.67 (d, 3JH,H = 7.37 Hz, 1 H, CHAr), 7.07
3
3
(t, JH,H = 8.09 Hz, 2 H, CHAr), 7.58 (t, JH,H = 8.49 Hz, 2 H,
3
CHAr), 8.17 (d, JH,H = 8.64 Hz, 2 H, CHAr) ppm. C19H20N2O3
catalyzed Mannich reactions of cyclic ketones and aromatic (324.37): calcd. C 70.35, H 6.21, N 8.64; found C 70.56, H 5.98, N
8.49.
aldimines in very short times, at room temp. under solvent-
free conditions.
2-[Phenyl(m-tolylamino)methyl]cyclohexanone (2h): IR (KBr): ν =
˜
3351 (NH), 3038, 2944 (CH), 1702 (CO), 1602, 1538 (C=C), 1306
1
(NH) cm–1. H NMR (500 MHz, CDCl3): δ = 1.74–1.82 (m, 2 H,
CH2), 1.92–2.01 (m, 4 H, CH2), 2.25 (s, 3 H, CH3), 2.37–2.39 (m,
1 H, CH2), 2.46–2.49 (m, 1 H, CH2), 2.74–2.78 (m, 1 H, CH), 4.63
Experimental Section
3
3
General: All chemicals were purchased and used without any fur-
ther purification. NMR spectra were recorded at 500 MHz for pro-
ton and at 125 MHz for carbon nuclei in (CDCl3/CCl4). Elemental
analyses were carried out using a Vario EL III, Elementar. The
products were purified by column chromatography carried out on
silica gel using ethyl acetate/petroleum ether mixtures. All com-
pounds were characterized by their spectroscopic data (IR, NMR)
by comparison with those reported in the literature. Reactions were
carried out at room temp. All aldehydes, ketones, and amines em-
ployed are commercially available.
(d, JH,H = 6.96 Hz, 0.85 H, CH, anti isomer), 4.77 (d, JH,H
=
3.47 Hz, 0.15 H, CH, syn isomer), 4.70 (br. s, 1 H, NH), 6.31 (d,
3
3JH,H = 6.37 Hz, 1 H, CHAr), 6.38 (s, 1 H, CHAr), 6.46 (d, JH,H
=
7.34 Hz, 1 H, CHAr), 6.95 (t, JH,H = 7.66 Hz, 1 H, CHAr), 7.25 (t,
3
3JH,H = 7.15 Hz, 1 H, CHAr), 7.34 (t, 3JH,H = 7.42 Hz, 2 H, CHAr),
7.40 (d, JH,H = 7.70 Hz, 2 H, CHAr) ppm. C20H23NO (293.40):
3
calcd. C 81.87, H 7.90, N 4.77; found C 82.01, H 7.69, N 4.88.
2-[(p-Nitrophenyl)(m-tolylamino)methyl]cyclohexanone (2j): IR
(KBr): ν = 3373 (NH), 2948, 2858 (CH), 1699 (CO), 1601 (C=C),
˜
1516, 1345 (NO2), 1300, 1100 (NH) cm–1. 1H NMR (500 MHz,
CDCl3): δ = 1.59–1.67 (m, 1 H, CH2), 1.78–1.89 (m, 2 H, CH2),
1.99–2.01 (m, 1 H, CH2), 2.08–2.11 (m, 2 H, CH2), 2.24 (s, 3 H,
CH3), 2.34–2.37 (m, 1 H, CH2), 2.41–2.46 (m, 1 H, CH2), 2.84–
General Reaction Procedure: To aniline derivative (1 mmol), benzal-
dehyde derivative (1 mmol), cyclohexanone (3 equiv.), and
ZrOCl2·8H2O (0.05 g, or 15 mol-%) were added successively at
room temp. (20–25 °C) and stirred at the same temperature for
20 min. After completion of the reaction, ethyl acetate (15 mL) was
added, and catalyst was removed by filtration. Filtrates were
washed with a saturated aqueous NaHCO3 solution and brine,
dried with anhydrous Na2SO4, and concentrated to dryness. The
crude mixture was washed with hexane to afford the 2-[phenyl-
(phenylamino)methyl]cyclohexanone in (259 mg) 93% as a 100:0
anti/syn mixture. Products 2 were obtained almost in pure form.
Further purification carried out by column chromatography on sil-
ica gel using petroleum ether/ethyl acetate.
3
2.88 (m, 1 H, CH), 4.69 (d, JH,H = 5.1 Hz, 0.72 H, CH, anti iso-
3
mer), 4.81 (d, JH,H = 4.47 Hz, 0.28 H, CH, syn isomer), 4.85 (br.
3
s, 1 H, NH), 6.25 (t, JH,H = 7.77 Hz, 1 H, CHAr), 6.33 (s, 1 H,
3
3
CHAr), 6.49 (t, JH,H = 7.69 Hz, 1 H, CHAr), 6.94 (t, JH,H
=
7.75 Hz, 1 H, CHAr), 7.59 (d, JH,H = 8.51 Hz, 2 H, CHAr), 8.18
(d, 3JH,H = 8.54 Hz, 2 H, CHAr) ppm. C20H22N2O3 (338.40): calcd.
C 70.99, H 6.55, N 8.28; found C 80.20, H 6.32, N 8.51.
3
2-[(p-Chlorophenyl)(m-tolylamino)methyl]cyclohexanone (2k): IR
(KBr): ν = 3349 (NH), 3045, 2939, 2865 (CH), 1703 (CO), 1603,
˜
1531 (C=C), 1487, 1300 (NH), 710 (C–Cl) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.72–1.85 (m, 3 H, CH2), 1.96–2.01 (m, 3
H, CH2), 2.64 (s, 3 H, CH3), 2.35–2.36 (m, 1 H, CH2), 2.43–2.47
2-[(Phenylamino)(p-tolyl)methyl]cyclopentanone (2a): IR (KBr): ν =
˜
3393 (NH), 3039, 2955, 2871 (CH), 1724 (CO), 1603, 1510 (C=C),
1
1313 (NH) cm–1. H NMR (500 MHz, CDCl3): δ = 1.73–1.81 (m,
3
(m, 1 H, CH2), 2.72–2.75 (m, 1 H, CH), 4.60 (d, JH,H = 6.18 Hz,
3
2 H, CH2), 1.93–1.95 (m, 2 H, CH2), 2.09–2.17 (m, 1 H, CH2),
2.32–2.36 (m, 1 H, CH2), 2.38 (s, 3 H, CH3), 2.45–2.50 (m, 1 H,
1 H, CH, anti isomer), 4.74 (s, 1 H, NH), 6.29 (d, JH,H = 7.98 Hz,
3
1 H, CHAr), 6.35 (s, 1 H, CHAr), 6.48 (d, JH,H = 7.43 Hz, 1 H,
3
3
3
CHAr), 6.96 (t, JH,H = 7.72 Hz, 1 H, CHAr), 7.31 (d, JH,H
=
CH), 4.05 [d, J(H,H) = 7.44 Hz, 1 H, CH, anti isomer], 5.12 (s, 1
3
3
H, NH), 6.51 (d, JH,H = 7.69 Hz, 2 H, CHAr), 6.64 (t, JH,H
=
8.35 Hz, 2 H, CHAr), 7.35 (d, JH,H = 8.46 Hz, 2 H, CHAr) ppm.
C20H22ClNO (327.85): calcd. C 73.27, H 6.76, N 4.27; found C
73.49, H 6.56, N 4.46.
3
7.31 Hz, 1 H, CHAr), 7.04 (t, JH,H = 7.43 Hz, 2 H, CHAr), 7.13
3
3
3
(d, JH,H = 7.89 Hz, 2 H, CHAr), 7.27 (d, JH,H = 7.98 Hz, 2 H,
CHAr) ppm. C19H21NO (279.38): calcd. C 81.68, H 7.58, N 5.01;
found C 81.47, H 7.71, N 4.92.
2-[Phenyl(m-tolylamino)methyl]cycloheptanone (2o): IR (KBr): ν =
˜
3344 (NH), 3029, 2944, 2872 (CH), 1702 (CO), 1597, 1531 (C=C),
2-[(p-Chlorophenyl)(phenylamino)methyl]cyclopentanone (2b): IR
1501, 1322 (NH) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.31–1.37
(KBr): ν = 3358 (NH), 3032, 2959, 2868 (CH), 1725 (CO), 1602, (m, 2 H, CH2), 1.49–1.63 (m, 2 H, CH2), 1.73–1.75 (m, 1 H, CH2),
˜
1518 (C=C), 1310 (NH), 761 (C–Cl) cm–1. 1H NMR (500 MHz,
1.93–1.95 (m, 3 H, CH2), 2.26 (s, 3 H, CH3), 2.35–2.39 (m, 1 H,
5156
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Stereoselective Synthesis of β-Amino Ketones
FULL PAPER
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CH2), 2.50–2.56 (m, 1 H, CH2), 2.90–2.95 (m, 1 H, CH), 4.52 (d,
3
3JH,H = 7.47 Hz, 0.89 H, CH, anti isomer), 4.64 (d, JH,H
=
4.53 Hz, 0.11 H, CH, syn isomer), 4.94 (br. s, 1 H, NH), 6.34 (d,
3
3JH,H = 8.24 Hz, 1 H, CHAr), 6.41 (s, 1 H, CHAr), 6.47 (d, JH,H
=
7.47 Hz, 1 H, CHAr), 6.97 (t, JH,H = 7.72 Hz, 2 H, CHAr), 7.25–
7.27 (m, 1 H, CHAr), 7.30–7.39 (m, 4 H, CHAr) ppm. 13C NMR
(125 MHz, CDCl3): δ = 22.1, 25.4, 28.4, 29.6, 29.8, 42.9, 58.9, 60.7,
110.7, 110.9, 114.8, 118.8, 127.5, 127.6, 128.8, 128.9, 129.3, 138.9,
142.0, 147.3, 215.4 ppm. C21H25NO (307.43): calcd. C 82.04, H
8.20, N 4.56; found C 81.83, H 8.43, N 4.34.
3
4-Phenyl-4-(m-tolylamino)butan-2-one (3a): IR (KBr): ν = 3358
˜
(NH), 3038, 2959 (CH), 1700 (CO), 1602, 1538 (C=C), 1308 (NH)
cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.14 (s, 3 H, CH3), 2.27
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3
(s, 3 H, CH3), 2.90 (d, JH,H = 6.25 Hz, 2 H, CH2), 4.42 (s, 1 H,
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3
NH), 4.81 (t, 3JH,H = 6.21 Hz, 1 H, CH), 6.28 (d, JH,H = 8.27 Hz,
3
1 H, CHAr), 6.35 (s, 1 H, CHAr), 6.52 (d, JH,H = 7.37 Hz, 1 H,
3
CHAr), 6.97 (t, JH,H = 7.73 Hz, 1 H, CHAr), 7.21–7.35 (m, 5 H,
[7] P. J. Moles, http://www.zrchem.com.
CHAr) ppm. 13C NMR (125 MHz, CDCl3): δ = 30.5, 30.9, 31.1,
31.5, 51.3, 54.0, 54.2, 110.8, 111.5, 114.5, 114.8, 115.3, 115.5, 119.1,
119.6, 120.1, 128.0, 129.3, 129.7, 133.4, 138.9, 141.6, 146.7,
205.9 ppm. C17H19NO (253.34): calcd. C 80.60, H 7.56, N 5.53;
found C 80.32, H 7.29, N 5.78.
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4-(p-Chlorophenylamino)-4-phenylbutan-2-one (3b): IR (KBr): ν =
˜
3349 (NH), 3030, 2940, 2876 (CH), 1706 (CO), 1597, 1535 (C=C),
1
1497, 1320 (NH), 726 (C–Cl) cm–1. H NMR (500 MHz, CDCl3):
3
δ = 2.11 (s, 3 H, CH3), 2.92 (d, JH,H = 5.64 Hz, 2 H, CH2), 4.60
3
3
(s, 1 H, NH), 4.76 (t, JH,H = 6.11 Hz, 1 H, CH), 6.45 (d, JH,H
=
8.83 Hz, 1 H, CHAr), 7.03 (d, JH,H = 8.85 Hz 2 H, CHAr), 7.24–
7.30 (m, 1 H, CHAr), 7.34–7.36 (m, 4 H, CHAr) ppm. 13C NMR
(125 MHz, CDCl3): δ = 30.7, 51.2, 54.8, 55.0, 114.7, 115.2, 115.7,
123.1, 126.5, 127.9, 129.2, 129.4, 142.4, 145.6, 206.3 ppm.
C16H16ClNO (273.76): calcd. C 70.20, H 5.89, N 5.12; found C
69.92, H 6.08, N 5.60.
3
Supporting Information (see also the footnote on the first page of
this article): IR, 1H and 13C NMR spectroscopic data of com-
pounds 2c, 2d, 2f, 2g, 2i, 2l, 2m, 2n, 3d, and 3e.
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Received: August 6, 2006
Published Online: September 18, 2006
2082; b) Y.-S. Wu, J. Cai, Z.-Y. Hu, G.-X. Lin, Tetrahedron
Eur. J. Org. Chem. 2006, 5152–5157
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5157