N-heterocyclic carbene-catalyzed aza-michael addition

Article abstract of DOI:10.1039/c1ob05429e

Aza-Michael addition of amines, including aromatic and aliphatic amines, with α, β-unsaturated ketones was realized employing N-Heterocyclic Carbene (NHC) as organocatalyst, yielding β-amino ketones with up to 98% yield.

Full text of DOI:10.1039/c1ob05429e

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PAPER
N-Heterocyclic carbene-catalyzed aza-Michael addition†
Qiang Kang and Yugen Zhang*
Received 18th March 2011, Accepted 23rd June 2011
DOI: 10.1039/c1ob05429e
Aza-Michael addition of amines, including aromatic and aliphatic amines, with a, b-unsaturated
ketones was realized employing N-Heterocyclic Carbene (NHC) as organocatalyst, yielding b-amino
ketones with up to 98% yield.
Table 1 Catalyst Screeninga
Introduction
b-Aminocarbonyl compounds have been used as building blocks
for nitrogen-containing natural products and biologically active
drugs.1 Aza-Michael addition2 is one of the most direct approaches
for construction of these prevalent structure motifs. It represents a
valuable synthetic alternative to the established Mannich reaction.
Most aza-Michael reaction protocols are often promoted by
Lewis acidic catalysts or Brønsted acids. However, the latter
have suffered some drawbacks such as metal contaminations,
harsh reaction conditions as well as oligomerization of Michael
acceptors.3 Therefore, developing new efficient and robust catalytic
system for aza-Michael addition is important for their broad
application in organic synthesis. Recently, N-heterocyclic carbenes
(NHCs) have emerged as powerful organocatalysts which realized
numerous Umpolung reactions4 via “Breslow intermediate”5 or the
homoenolate equivalent species.6 However, the reaction catalyzed
by NHCs empolying other substrates, except aldehydes,5,8–10 was
quite limited.7 As part of our effort focused on application
of NHCs as organocatalysts,11 herein we report an alternative
protocol for aza-Michael addition of amines to a,b-unsaturated
ketones catalyzed by N-heterocylic carbenes.
Entry
Catalyst
Base
Time
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
—
1b
1c
1d
1e
1f
—
20 h
20 h
10 min
20 h
20 h
20 h
20 h
20 h
42
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
75
0c
44
Trace
Trace
69
37
a Reaction conditions: 10 mol% of 1, 10 mol% of KOtBu, 1.2 equiv of 3a,
0.25 mol L-1 of 2a at 23 ◦C. b Yield of isolated product. c 3a decomposed.
Mes = 2,4,6-trimethylphenyl.
Results and discussion
The initial investigation was carried out between aniline 2a and
a,b-unsaturated ketone 3a in the presence of 10 mol% imidazolium
salt 1a, which afforded the desired addition product 4a in moderate
yield (42%, Table 1, entry 1). The yield could be significantly
improved by introducing 10 mol% KOtBu (75% yield, Table 1,
entry 2) into the reaction system. It should be noted that without
imidazolium salt ketone 3a undergoes quick oligomerization
and polymerization in the presence of a catalytic amount of
KOtBu (Table 1, entry 3). Catalyst optimization using different
imidazolium and imidazolinium salts indicated that sterically
more demanding imidazolium salt 1b provided the lower yield of
4a (44% yield, Table 1, entry 4) and alkyl substituted imidazolium
salts 1c and 1d only gave trace amounts of desired product (Table
1, entries 5 and 6). The reaction catalyzed by 1e went smoothly to
afford 4a in 69% yield (Table 1, entry 7). Compared to imidazolium
salt 1a, imidazolinium salt 1f gave much lower yield (37%, Table
1, entry 8).
Investigations with respect to the effect of bases indicated that
bases which were examined generally had no significant effect on
reaction yield (Table 2, entries 1–4). The reaction time was short-
ened as n-butyl lithium (nBuLi) was used. The byproduct, oligomer
of Michael acceptor 3a, could be minimized in the reaction
system by using 10 mol% of potassium bis(trimethylsilyl)amide
(KHMDS) as the base.
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The
Nanos, Singapore, 138669, Singapore. E-mail: ygzhang@ibn.a-star.edu.sg;
Fax: (+65)-6478-9020
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra. See DOI: 10.1039/c1ob05429e
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Table 2 Condition optimizationa
Table 3 Amine scopea
Yield (%)b
Entry
Base
Solvent
Time/h
Yield (%)b
Entry
RNH2
Time/h
Product
1
2
3
4
5
6
7
KOtBu
KHMDS
LiHMDS
nBuLi
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
THF
THF
THF
THF
CH2Cl2
Toluene
Et2O
MeCN
Toluene
Toluene
20
24
24
4
24
20
18
20
40
48
75
1
2
3
4
5
6
C6H5 NH2 (2a)
20
22
41
20
18
18
4a
4b
4c
4d
4e
4f
92
98
69
92
88
84
76 (0c)
67
4-OMe-C6H4 NH2 (2b)
4-Cl-C6H4 NH2 (2c)
4-ethynyl-C6H4 NH2 (2d)
3,5-(Me)2-C6H3 NH2 (2e)
59
35
92
84
33
72
67
8
9d
10e
7
22
4g
83
a Reaction conditions: 10 ◦mol % of 1a, 10 mol% of base, 1.2 equiv of 3a,
0.25 mol L-1 of 2a at 23 C. b Yield of isolated prodcut. c Without 1a. d 5
mol% of 1a was used. e 2 mol% of 1a was used. KHMDS = Potassium
bis(trimethylsilyl)amide. LiHMDS = lithium bis(trimethylsilyl)amide.
8
9
10
11
12
Benzylamine (2h)
Cyclohexylamine (2i)
Allylamine (2j)
5
5
5
5
4
4h
4i
87
82
83
84
91
4j
Propargylamine (2k)
4k
4l
Several solvents were examined for the reaction by employing
10 mol% of imidazonium salt 1a and 10 mol% KHMDS at 23 ◦C.
Aza-Michael reaction went smoothly in several common solvents
such as THF (76%), CH2Cl2 (35%), toluene (92%), Et2O (84%),
MeCN (33%). The reaction performed better in less polar solvents
as compared to that in polar solvents. Toluene was chosen as
the optimal solvent since the reaction in toluene led to complete
conversion in 20 h and did not afford oligomerization byproduct.
Further studies on the catalyst loading disclosed that less catalyst
loading (5 mol% and 2 mol%, respectively) afforded lower yields
(72% and 67%, Table 2, entries 9 and 10), even when the reaction
time was prolonged to 40 or 48 h.
A wide range of amines, including aromatic and aliphatic
amines, were screened under optimized reaction conditions (1.0
equiv of amine, 1.2 equiv of 3a, 10 mol% of 1a and 10 mol% of
KHMDS in toluene at 23 ◦C). The results were summarized in
Table 3. Several substituted aromatic amines were examined in the
reaction with enone 3a. For aromatic amines with an electron-
donating group, such as 2b and 2f, the reaction went smoothly,
affording the desired products with high yields (98% yield for 2b,
84% yield for 2f, Table 3, entries 2 and 6). For an aromatic amine
with electron-withdrawing group, the reaction needed a longer
time (41 h) to achieve a good yield (69%, Table 3, entry 3). In the
case of 2d (4-ethynylaniline) and 2e (3,5-dimethylaniline), products
4d (92%) and 4e (88%) were obtained in good yields (Table 3,
entries 4 and 5). Hetero-aromatic amine 2g was also examined
and a high yield was obtained (83%, entry 7).
a Reaction conditions: 10 mol % of 1a◦, 10 mol% of KHMDS, 1.2 equiv of
3a, 0.25 mol L-1 of 2 in toluene at 23 C. b Yield of isolated product.
Table 4 Conjugate acceptor scopea
Entry
R1
R2
R3
product
Yield (%)b
1
2
3
4
5
6
7
8
H
H
H
H
H
Me
H
H
H
Me
Et
4m
4n
4o
4p
4q
4r
49
56
72
69
75
0
CH3(CH2)3
H
CH3(CH2)3
CO2Et
Me
C6H5
Me
C6H5
C6H5
C6H5
C6H5
C6H5
OBn
4s
29
0
4t
a Reaction conditions: 10 mol % of 1a, 1.2 equiv of 3, 10 mol% of KHMDS,
0.25 mol L-1 of 2a in toluene at 23 ◦C. b Yield of isolated product.
in good yield (entry 3), whereas Michael acceptors with an alkyl
(entry 4) or ester group (entry 5) in the b-position gave acceptable
yields. b,b-Disubtituted enone employed could not afford the
desired addition product (entry 6). However, the reaction was
sluggish when an enone with aryl substituted in the b-position was
employed, affording a yield of 29% (entry 7). Unfortunately, efforts
for aza-Michael addition of aniline 2a to an a,b-unsaturated ester
(entry 8), cyclohexenone and cyclopentenone have not been proven
successful so far.
Aliphatic amines such as benzylamine 2h, cyclohexylamine 2i,
allylamine 2j and propargylamine 2k were readily tolerated in this
reaction and good yields were obtained (82–87% yield, Table 3,
entries 8–11). Addition of phenylethylamine 2l to enone 3a is also
successful but with low diastereoselectivity (1.4 : 1 dr, Table 3, entry
12).
The possible utilization of various conjugate enones was
investigated, as shown in Table 4. Alkyl ketones such as methyl
vinly ketone (entry 1), and hexene ethyl ketone (entry 2) are well
tolerated under optimized conditions. Michael acceptors without
substituted group in the b-position afforded the desired product
As shown in Scheme 1, the addition of 2-aminoethanol to a,b-
unsaturated ketones was examined in the presence of 10 mol%
NHC catalyst and 10 mol% KHMDS in toluene. In contrast
to K. A. Scheidt’s conjugate addition of alcohols to activated
alkene reaction,7f only nitrogen attached addition product 4u was
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stated. Reagents were purchased at the highest commercial quality
and used without further purification, unless otherwise stated.
Yields refer to chromatographically and spectroscopically (1H
NMR) homogeneous materials, unless otherwise stated. Reactions
were monitored by thin-layer chromatography (TLC) carried out
on 0.25 mm E. Merck silica gel plates (60F-254) using UV light
as visualizing agent and an ethanolic solution of ammonium
molybdate and anisaldehyde and heat as developing agents. E.
Merck silica gel was used for flash column chromatography.
NMR spectra were recorded on a Bruker AV-400 instrument. The
following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m =
multiplet, pent = pentet, hex = hexet, br = broad.
Scheme 1
detected in 74% yield and product in which the oxygen side acted
as nucleophile was not observedat all.
Based on the results we obtained, the mechanism of this reaction
is speculated as shown in Scheme 2. N-heterocyclic carbene,
generated from imidazonium salt upon treatment with base, reacts
with amine to form an NHC-amine complex. This complex might
activate the enone and expedite the 1,4-addition of amine to enone,
affording b-amino ketone and regenerating the N-heterocyclic
carbene.12
General procedure
To a solution of imidazolium salt (0.05 mmol) in toluene (1 mL)
was added KHMDS (75 mL, 15% w/w solution in toluene, 0.05
mmol) at 23 ◦C under Ar atmosphere. The resulting mixture was
stirred at that temperature for 1 h before the solution of a, b-
unsaturated ketone (0.6 mmol) and amine (0.5 mmol) in toluene
(1 mL) was added. The reaction was stirred at 23 ◦C (monitored
by TLC) before it was quenched with NH4Cl (4 mL, sat. aq.). The
layers were separated and the aqueous layer was extracted with
EtOAc (3 ¥ 5 mL). The combined organic layers were washed
with brine (5 mL), dried (Na2SO4) and concentrated in vacuo.
Flash column chromatography (silica gel, hexanes : EtOAc = 30 : 1
~ 2 : 1) afforded b-amino ketone.
1-Phenyl-3-(phenylamino)butan-1-one (4a). 92% yield as col-
orless oil. IR (film) nmax 3390, 1676, 1597, 1495, 1001, 688 cm-1;
1H NMR (400 MHz, CDCl3): d = 7.96–7.93 (m, 2 H), 7.59–7.55
(m, 1 H), 7.49–7.44 (m, 2 H), 7.20–7.16 (m, 2 H), 6.73–6.69 (m,
1 H), 6.65–6.63 (m, 2 H), 4.19–4.14 (m, 1 H), 3.82 (br, 1 H), 3.33
(dd, J = 4.0, 16.4 Hz, 1 H), 3.07 (dd, J = 7.6, 16.4 Hz, 1 H), 1.33
ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 199.2,
146.7, 137.0, 133.2, 129.3, 128.6, 128.0, 117.5, 113.4, 45.5, 44.3,
20.9 ppm; HRMS (ESI): calcd for C16H18NO+ [M + H+]240.1383,
found 240.1374.
Scheme 2 Proposed mechanism.
Conclusions
In summary, we have identified an N-heterocyclic carbene as
catalyst for aza-Michael addition of amines with a,b-unsaturated
ketones to afford b-amino ketones. The reaction features a
metal-free approach, high yields, mild reaction conditions, as
well as an operationally simple and environmentally benign
procedure. These features, together with the tolerability of both
aromatic and aliphatic amines, warrant the wide application of
the current methodology for the synthesis of b-amino ketones.
Further investigation of the mechanism of this reaction and
potential application of the catalytic system is ongoing in our
group.
3-(4-Methoxyphenylamino)-1-phenylbutan-1-one
(4b). 98%
yield as colorless oil. IR (film) nmax 1677, 1508, 1448, 1232, 1035,
819, 689 cm-1; 1H NMR (400 MHz, CDCl3): d = 7.96–7.93 (m, 2
H), 7.60–7.55 (m, 1 H), 7.48–7.45 (m, 2 H), 6.79 (d, J = 8.8 Hz,
2 H), 6.64 (d, J = 8.8 Hz, 2 H), 4.12–4.04 (m, 1 H), 3.75 (s, 3 H),
3.57 (br, 1 H), 3.31 (dd, J = 4.0, 16.4 Hz, 1 H), 3.05 (dd, J = 7.6,
16.4 Hz, 1 H), 1.31 ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100
MHz, CDCl3): d = 199.3, 152.2, 140.8, 137.0, 133.1, 128.5, 127.9,
115.3, 114.8, 55.6, 46.7, 44.3, 20.9 ppm; HRMS (ESI): calcd for
C17H20NO2 [M + H+] 270.1489, found 270.1485.
+
Experimental
3-(4-Chlorophenylamino)-1-phenylbutan-1-one (4c). 69% yield
as colorless oil. IR (film) nmax 3390, 1676, 1597, 1495, 1290, 1001,
814, 751 cm-1; 1H NMR (400 MHz, CDCl3): d = 7.96–7.93 (m, 2
H), 7.61–7.56 (m, 1 H), 7.49–7.46 (m, 2 H), 7.12 (d, J = 8.8 Hz, 2
H), 6.56 (d, J = 8.8 Hz, 2 H), 4.15–4.08 (m, 1 H), 3.88 (br, 1 H),
3.28 (dd, J = 4.0, 16.8 Hz, 1 H), 3.09 (dd, J = 7.2, 16.8 Hz, 1 H),
1.33 ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =
199.1, 145.4, 137.0, 133.3, 129.2, 128.7, 128.0, 122.0, 114.6, 45.8,
44.1, 20.9 ppm; HRMS (ESI): calcd for C16H17ClNO+ [M + H+]
274.0993, found 274.0982.
General method
Reactions were carried out under nitrogen or argon atmosphere
with dry solvents under anhydrous conditions, unless otherwise
noted. Dry tetrahydrofuran (THF), diethyl ether (Et2O), toluene,
methylene chloride (CH2Cl2) and acetonitrile (MeCN) were pur-
chased in anhydrous form and used without further purification.
Ethyl acetate (EtOAc), diethyl ether (Et2O), methylene chloride
(CH2Cl2), and hexanes were purchased at the highest commercial
quality and used without further purification, unless otherwise
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3-(4-Ethynylphenylamino)-1-phenylbutan-1-one
(4d). 92%
(dd, J = 6.0, 16.4 Hz, 1 H), 2.97 (dd, J = 6.4, 16.4 Hz, 1 H), 2.56–
2.49 (m, 1 H), 1.94–1.85 (m, 2 H), 1.74–1.70 (m, 2 H), 1.62–1.57
(m, 1 H), 1.28–0.98 (m, 5 H), 1.14 ppm (d, J = 6.0 Hz, 3 H), N–H
yield as colorless oil. IR (film) nmax 3284, 2098, 1677, 1606, 1513,
1
1325, 1173, 1001, 823, 688 cm-1; H NMR (400 MHz, CDCl3):
1
d = 7.95–7.92 (m, 2 H), 7.60–7.56 (m, 1 H), 7.49–7.45 (m, 2 H),
7.33–7.31 (m, 2 H), 6.56–6.53 (m, 2 H), 4.17–4.12 (m, 2 H), 3.28
(dd, J = 6.0, 16.8 Hz, 1 H), 3.09 (dd, J = 7.2, 16.8 Hz, 1 H), 2.99
(s, 1 H), 1.33 ppm (d, J = 6.0 Hz, 3 H); 13C NMR (100 MHz,
CDCl3): d = 199.0, 147.2, 136.9, 133.6, 133.4, 128.7, 128.0, 112.8,
110.0, 84.7, 74.9, 45.3, 44.1, 20.9 ppm; HRMS (ESI): calcd for
C18H18NO+ [M + H+] 264.1383, found 264.1387.
is not observed in H NMR; 13C NMR (100 MHz, CDCl3): d =
199.7, 137.2, 133.0, 128.5, 128.0, 53.4, 46.2, 46.0, 34.4, 33.5, 26.1,
25.2, 25.1, 21.2 ppm; HRMS (ESI): calcd for C16H24NO+ [M +
H+] 246.1852, found 246.1859.
3-(Allylamino)-1-phenylbutan-1-one (4j). 83% yield as pale
yellow oil. IR (film) nmax 2970, 1679, 1448, 1211, 1001, 916, 752,
1
689 cm-1; H NMR (400 MHz, CDCl3): d = 7.97–7.95 (m, 2 H),
3-(3,5-Dimethylphenylamino)-1-phenylbutan-1-one (4e). 88%
yield as colorless oil. IR (film) nmax 2970, 1738, 1678, 1597, 1183,
1001, 822, 752 cm-1; 1H NMR (400 MHz, CDCl3): d = 7.98–7.95
(m, 2 H), 7.61–7.57 (m, 1 H), 7.50–7.46 (m, 2 H), 6.40 (s, 1 H),
6.30 (s, 2 H), 4.20–4.13 (m, 1 H), 3.72 (br, 1 H), 3.35 (dd, J =
4.0, 16.4 Hz, 1 H), 3.06 (dd, J = 3.6, 16.4 Hz, 1 H), 2.25 (s, 6 H),
1.33 ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =
199.4, 146.8, 139.0, 137.1, 133.2, 128.6, 128.1, 119.6, 111.4, 45.5,
44.6, 21.5, 21.1 ppm; HRMS (ESI): calcd for C18H22NO+ [M +
H+] 268.1696, found 268.1699.
7.59–7.55 (m, 1 H), 7.49–7.45 (m, 2 H), 5.97–5.87 (m, 1 H), 5.20
(d, J = 17.2 Hz, 1 H), 5.10 (d, J = 10.4 Hz, 1 H), 3.40–3.14 (m, 3
H), 3.17 (dd, J = 6.4, 16.8 Hz, 1 H), 3.01 (dd, J = 6.0, 16.8 Hz, 1
H), 1.8 (br, 1 H), 1.18 ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100
MHz, CDCl3): d = 199.6, 137.1, 136.7, 133.2, 128.6, 128.0, 116.0,
49.8, 49.1, 45.6, 20.5 ppm; HRMS (ESI): calcd for C13H18NO+ [M
+ H+] 204.1383, found 204.1377.
1-Phenyl-3-(prop-2-ynylamino)butan-1-one (4k). 84% yield as
colorless oil. IR (film) nmax 2970, 1738, 1679, 1448, 1372, 1215,
1002, 753, 689, 661 cm-1; 1H NMR (400 MHz, CDCl3): d = 7.96–
7.93 (m, 2 H), 7.57–7.54 (m, 1 H), 7.47–7.43 (m, 2 H), 3.57–3.49
(m, 1 H), 3.47 (dd, J = 2.4, 8.0 Hz, 2 H), 3.13 (dd, J = 6.8, 16.8
Hz, 1 H), 3.02 (dd, J = 5.6, 16.8 Hz, 1 H), 2.21 (t, J = 2.4 Hz, 1
H), 1.90 (br, 1 H), 1.16 ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100
MHz, CDCl3): d = 199.3, 136.9, 133.2, 128.6, 128.0, 81.9, 71.4,
48.1, 45.4, 35.5, 20.0 ppm; HRMS (ESI): calcd for C13H16NO+ [M
+ H+] 202.1226, found 202.1229.
3-(Benzo[d][1,3]dioxol-5-ylamino)-1-phenylbutan-1-one
(4f).
84% yield as colorless oil. IR (film) nmax 2970, 1738, 1503, 1488,
1
1365, 1202, 1038, 753 cm-1; H NMR (400 MHz, CDCl3): d =
7.95–7.93 (m, 2 H), 7.60–7.56 (m, 1 H), 7.49–7.45 (m, 2 H), 6.66
(d, J = 8.4 Hz, 1 H), 6.30 (d, J = 2.4 Hz, 1 H), 6.10 (dd, J = 2.4,
8.4 Hz, 1 H), 5.86 (s, 2 H), 4.08–4.00 (m, 1 H), 3.61 (br, 1 H),
3.29 (dd, J = 4.4, 16.4 Hz, 1 H), 3.05 (dd, J = 6.4, 16.4 Hz, 1 H),
1.31 ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3):
d = 199.3, 148.4, 142.4, 139.8, 137.1, 133.2, 128.6, 128.0, 108.7,
105.7, 100.6, 97.0, 46.8, 44.2, 20.9 ppm; HRMS (ESI): calcd for
3-((R)-1-Phenylethylamino)-1-phenylbutan-1-one
(4l). 91%
yield (2 diastereomers, dr = 1.4 : 1) as colorless oil. IR (film) nmax
2970, 1738, 1679, 1448, 1370, 1216, 754, 700, 691 cm-1; 1H NMR
(400 MHz, CDCl3): d = 7.91–7.86 (m, 4.8 H), 7.56–7.52 (m, 2.4
H), 7.45–7.40 (m, 4.8 H), 7.34–7.29 (m, 9.6 H), 7.27–7.21 (m, 2.4
H), 3.98–3.92 (m, 2.4 H), 3.27–2.85 (m, 7.2 H), 1.82 (br, 2.4 H),
1.36 (d, J = 6.8 Hz, 3 H), 1.35 (d, J = 6.8 Hz, 4.2 H), 1.13 (d, J
= 6.0 Hz, 4.2 H), 1.08 ppm (d, J = 6.0 Hz, 3 H); 13C NMR (100
MHz, CDCl3): d = 199.9, 199.8, 146.0, 145.2, 137.1, 137.0, 133.0,
128.5, 128.5, 128.4, 128.1, 128.0, 126.9, 126.8, 126.6, 126.5, 55.3,
55.0, 47.8, 46.6, 46.6, 45.2, 25.3, 24.6, 21.6, 19.9 ppm; HRMS
(ESI): calcd for C18H22NO+ [M + H+] 268.1696, found 268.1706.
C17H18NO3 [M + H+] 284.1281, found 284.1283.
+
1-Phenyl-3-(pyridin-3-ylamino)butan-1-one (4g). 83% yield as
pale yellow oil. IR (film) nmax 3970, 1738, 1681, 1482, 1448, 1216,
1002, 795, 753 cm-1; 1H NMR (400 MHz, CDCl3): d = 8.03 (d, J
= 2.8 Hz, 1 H), 7.95–7.92 (m, 3 H), 7.60–7.56 (m, 1 H), 7.49–7.45
(m, 2 H), 7.09–7.06 (m, 1 H), 6.93–6.90 (m, 1 H), 4.19–4.12 (m, 1
H), 4.01 (br, 1 H), 3.29 (dd, J = 4.4, 16.4 Hz, 1 H), 3.12 (dd, J =
6.8, 16.4 Hz, 1 H), 1.34 ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100
MHz, CDCl3): d = 198.9, 142.9, 138.8, 136.9, 136.7, 133.4, 128.7,
128.0, 123.8, 119.1, 45.4, 44.0, 20.8 ppm; HRMS (ESI): calcd for
C15H17N2O+ [M + H+] 241.1335, found 241.1342.
4-(Phenylamino)butan-2-one (4m). 49% yield as colorless oil.
1
IR (film) nmax 3396, 1707, 1601, 1505, 1168, 748, 693 cm-1; H
3-(Benzylamino)-1-phenylbutan-1-one (4h). 87% yield as col-
orless oil. IR (film) nmax 2925, 1677, 1599, 1504, 1291, 1001, 747,
NMR (400 MHz, CDCl3): d = 7.26–7.15 (m, 2 H), 6.73–6.71 (m,
1 H), 6.62–6.59 (m, 2 H), 3.96 (br, 1 H), 3.41 (T, J = 6.4 Hz, 2
H), 2.75 (T, J = 6.0 Hz, 2 H), 2.16 ppm (s, 3 H); 13C NMR (100
MHz, CDCl3): d = 208.1, 147.6, 129.2, 117.5, 112.9, 42.5, 38.2,
30.2 ppm; HRMS (ESI): calcd for C10H14NO+ [M + H+] 164.1070,
found 164.1065.
1
688 cm-1; H NMR (400 MHz, CDCl3): d = 7.97–7.94 (m, 2 H),
7.59–7.54 (m, 1 H), 7.48–7.44 (m, 2 H), 7.36–7.30 (m, 4 H), 7.27–
7.22 (m, 2 H), 3.88 (d, J = 13.2 Hz, 1 H), 3.80 (d, J = 13.2 Hz,
1 H), 3.44–3.37 (m, 1 H), 3.19 (dd, J = 6.8, 16.8 Hz, 1 H), 3.04
(dd, J = 5.6, 16.8 Hz, 1 H), 1.95 (br, 1 H), 1.23 ppm (d, J = 6.0
Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 199.6, 140.3, 137.1,
133.1, 128.6, 128.4, 128.1, 128.0, 126.9, 51.4, 49.3, 45.7, 20.6 ppm;
HRMS (ESI): calcd for C17H20NO+ [M + H+] 254.1539, found
254.1535.
5-(Phenylamino)nonan-3-one (4n). 56% yield as colorless oil.
1
IR (film) nmax 2932, 1707, 1602, 1504, 1259, 749, 693 cm-1; H
NMR (400 MHz, CDCl3): d = 7.17–7.13 (m, 2 H), 6.69–6.66 (m,
1 H), 6.60–6.58 (m, 2 H), 3.85–3.79 (m, 1 H), 3.67 (br, 1 H), 2.67
(dd, J = 4.8, 16.0 Hz, 1 H), 2.56 (dd, J = 6.8, 16.0 Hz, 1 H), 2.41
(q, J = 14.4 Hz, 2 H), 1.57–1.51 (m, 2 H), 1.41–1.27 (m, 4 H), 1.02
(t, J = 7.2 Hz, 3 H), 0.88 ppm (t, J = 7.2 Hz, 3 H); 13C NMR
(100 MHz, CDCl3): d = 210.9, 147.2, 129.3, 117.3, 113.2, 49.7,
3-(Cyclohexylamino)-1-phenylbutan-1-one (4i). 82% yield as
colorless oil. IR (film) nmax 2925, 1680, 1448, 1216, 1002, 752,
1
690 cm-1; H NMR (400 MHz, CDCl3): d = 7.96–7.94 (m, 2 H),
7.58–7.54 (m, 1 H), 7.48–7.44 (m, 2 H), 3.52–3.44 (m, 1 H), 3.12
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46.6, 36.8, 34.9, 28.4, 22.5, 14.0, 7.5 ppm; HRMS (ESI): calcd for
C15H24NO+ [M + H+] 234.1852, found 234.1859.
7991; (d) G. Cardillo and C. Tomasini, Chem. Soc. Rev., 1996, 25,
117.
2 (a) N. Sokoloff and P. Latschinoff, Ber. Dtsch. Chem. Ges., 1874,
7, 1384; (b) W. Heintz, N. Sokoloff and P. Latschinoff, Ber. Dtsch.
Chem. Ges., 1874, 7, 1518; (c) M. E. Jung, Comprehensive Organic
SynthesisB. M. Trost, Ed. Pergamon, New York, NY, 1991; Vol. 4,
pp 30; (d) P. Perlmutter, Conjugate Addition Reactions in Organic
SynthesisPergamon, New York, NY, 1992, pp 114; (e) N. Asao,
T. Shimada, T. Sudo, N. Tsukada, K. Yazawa, Y. S. Gyoung, T.
Uyehara and Y. Yamamoto, J. Org. Chem., 1997, 62, 6274; (f) D.
Enders, C. Wang and J. X. Liebich, Chem.–Eur. J., 2009, 15,
11058.
3 (a) G. Jenner, Tetrahedron Lett., 1995, 36, 233; (b) T. P. Loh and L. L.
Wei, Synlett, 1998, 975; (c) G. Bartoli, M. Bosco, E. Marcantoni, M.
Petrini, L. Sambri and E. Torregiani, J. Org. Chem., 2001, 66, 9052;
(d) T. C. Wabnitz and J. B. Spencer, Tetrahedron Lett., 2002, 43, 3891;
(e) S. Kobayashi, K. Karumoto and M. Sugiura, Org. Lett., 2002, 4,
1319; (f) N. Srivastava and B. K. Banik, J. Org. Chem., 2003, 68, 2109;
(g) R. Varala, M. M. Alam and S. R. Adapa, Synlett, 2003, 720; (h) N.
Azizi and M. R. Saidi, Tetrahedron, 2004, 60, 383; (i) L.-W. Xu, L. Li
and C.-G. Xia, Helv. Chim. Acta, 2004, 87, 1522; (j) M. K. Chaudhuri,
S. Hussain, M. L. Kantam and B. Neelima, Tetrahedron Lett., 2005,
46, 8329; (k) I. Reboule, R. Gil and J. Collin, Tetrahedron Lett., 2005,
46, 7761.
1-Phenyl-3-(phenylamino)heptan-1-one (4p). 69% yield as col-
orless oil. IR (film) nmax 3390, 2955, 1677, 1599, 1505, 1214, 748,
1
690 cm-1; H NMR (400 MHz, CDCl3): d = 7.95–7.93 (m, 2 H),
7.59–7.56 (m, 1 H), 7.49–7.45 (m, 2 H), 7.20–7.15 (m, 2 H), 6.72–
6.63 (m, 3 H), 4.08–4.02 (m, 1 H), 3.79 (br, 1 H), 3.26 (dd, J =
4.8, 16.8 Hz, 1 H), 3.15 (dd, J = 7.2, 16.8 Hz, 1 H), 1.73–0.92
(m, 7 H), 0.92 ppm (t, J = 6.4 Hz, 3 H); 13C NMR (100 MHz,
CDCl3): d = 199.5, 147.2, 137.2, 133.2, 129.4, 128.6, 128.0, 117.3,
113.2, 49.9, 42.7, 35.1, 28.5, 22.6, 14.0 ppm; HRMS (ESI): calcd
for C19H24NO+ [M + H+] 282.1852, found 282.1860.
Ethyl 4-oxo-4-phenyl-2-(phenylamino)butanoate (4q). 75%
yield as colorless oil. IR (film) nmax 2970, 1738, 1602, 1368, 751,
1
690 cm-1; H NMR (400 MHz, CDCl3): d = 7.96–7.93 (m, 2 H),
7.60–7.56 (m, 1 H), 7.48–7.44 (m, 2 H), 7.21–7.16 (m, 2 H), 6.77–
6.73 (m, 1 H), 6.71–6.69 (m, 2 H), 4.65–4.60 (m, 1 H), 4.56–4.54
(m, 1 H), 4.19 (q, J = 7.2 Hz, 2 H), 3.59–3.57 (m, 2 H), 1.21 ppm
(t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 197.2,
172.8, 146.3, 136.3, 133.4, 129.3, 128.6, 128.0, 118.4, 113.6, 61.5,
4 (a) D. Seebach, Angew. Chem., Int. Ed. Engl., 1979, 18, 239; (b) J. J.
Eisch, J. Organomet. Chem., 1995, 500, 101; (c) M. Pohl, B. Lingen and
M. Muller, Chem.–Eur. J., 2002, 8, 5288.
+
5 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
52.9, 40.7, 14.0 ppm; HRMS (ESI): calcd for C18H20NO3 [M +
6 (a) C. Burstein, S. Tschan, X. Xie and F. Glorius, Synthesis, 2006, 2418;
(b) C. Burstein and F. Glorius, Angew. Chem., Int. Ed., 2004, 43, 6205;
(c) M. He, J. R. Struble and J. W. Bode, J. Am. Chem. Soc., 2006, 128,
8418.
H+] 298.1438, found 298.1444.
1,3-Diphenyl-3-(phenylamino)propan-1-one (4s). 29% yield as
colorless solid. IR (film) nmax 3385, 1738, 1671, 1600, 1506, 1365,
1291, 1217, 689 cm-1; 1H NMR (400 MHz, CDCl3): d = 7.94–7.91
(m, 2 H), 7.60–7.56 (m, 1 H), 7.48–7.44 (m, 4 H), 7.36–7.32 (m,
2 H), 7.27–7.23 (m, 1 H), 7.12–7.08 (m, 2 H), 6.99–6.66 (m, 1
H), 6.59–6.56 (m, 2 H), 5.04–5.00 (m, 1 H), 4.57 (br, 1 H), 3.53
(dd, J = 5.2, 16.0 Hz, 1 H), 3.43 ppm (dd, J = 7.6, 16.0 Hz, 1
H); 13C NMR (100 MHz, CDCl3): d = 198.2, 146.9, 142.9, 136.6,
133.4, 129.1, 128.8, 128.7, 128.2, 127.3, 126.3, 117.7, 113.7, 54.7,
46.3 ppm; HRMS (ESI): calcd for C21H20NO+ [M + H+] 302.1539,
found 302.1539.
7 (a) M. Movassaghi and M. A. Schmidt, Org. Lett., 2005, 7, 2453; (b) C.
Fischer, S. W. Smith, D. A. Powell and G. C. Fu, J. Am. Chem. Soc.,
2006, 128, 1472; (c) L. He, T. Y. Jian and S. Ye, J. Org. Chem., 2007,
72, 7466; (d) T. Boddaert, Y. Coquerel and J. Rodriguez, Adv. Synth.
Catal., 2009, 351, 1744; (e) K.-S. Lee, A. R. Zhugralin and A. H.
Hoveyda, J. Am. Chem. Soc., 2009, 131, 7253; (f) E. M. Phillips, M.
Riedrich and K. A. Scheidt, J. Am. Chem. Soc., 2010, 132, 13179; (g) J.
M. O’Brien and A. H. Hoveyda, J. Am. Chem. Soc., 2011, 133, 7712;
(h) T. Boddaert, Y. Coquerel and J. Rodriguez, Chem.–Eur. J., 2011, 17,
2266.
8 For the review, see: (a) A. Enders and T. Balensiefer, Acc. Chem.
Res., 2004, 37, 534; (b) A. Berkessel and H. Gro¨ger, Asymmetric
Organocatalysis, Wiley-VCH, Weinheim, 2005; (c) K. Zeitler, Angew.
Chem., Int. Ed., 2005, 44, 7506; (d) D. Enders, O. Niemeier and A.
Henseler, Chem. Rev., 2007, 107, 5606 and references therein; (e) N.
3-(2-Hydroxyethylamino)-1-phenylbutan-1-one (4u). 74% yield
as colorless oil. IR (film) nmax 3304, 2928, 1680, 1448, 1359, 1266,
1054, 755, 689, 587 cm-1; 1H NMR (400 MHz, CDCl3): d = 7.97–
7.95 (m, 2 H), 7.60–7.56 (m, 1 H), 7.49–7.45 (m, 2 H), 3.77–
3.69 (m, 4 H), 3.54–3.47 (m, 1 H), 3.34 (dd, J = 6.8, 16.4 Hz,
1 H), 3.17 (dd, J = 6.4, 16.4 Hz, 1 H), 3.01–2.84 (m, 2 H), 1.29
ppm (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =
198.9, 136.6, 133.5, 128.7, 128.1, 59.9, 49.8, 48.1, 44.3, 19.5 ppm;
Marion, S. D
´ıez-Gonza´lez and S. P. Nolan, Angew. Chem., Int. Ed.,
2007, 46, 2988 and references therein; (f) V. Nair, S. Vellalath and B. P.
Babu, Chem. Soc. Rev., 2008, 37, 2691; (g) E. M. Phillips, A. Chan and
K. A. Scheidt, Aldrichimica Acta, 2009, 42, 55; (h) J. L. Moore and T.
Rovis, Top. Curr. Chem., 2010, 291, 77.
9 (a) M. S. Kerr, J. R. de Alaniz and T. Rovis, J. Am. Chem. Soc., 2002,
124, 10298; (b) D. Enders and U. Kallfass, Angew. Chem., Int. Ed.,
2002, 41, 1743; (c) K. Y.-K. Chow and J. W. Bode, J. Am. Chem. Soc.,
2004, 126, 8126; (d) N. T. Reynolds, J. R. de Alaniz and T. Rovis, J.
Am. Chem. Soc., 2004, 126, 9518; (e) S. S. Sohn, E. L. Rosen and J.
W. Bode, J. Am. Chem. Soc., 2004, 126, 14370; (f) N. T. Reynold and
T. Rovis, J. Am. Chem. Soc., 2005, 127, 16406; (g) S. S. Sohn and J.
W. Bode, Org. Lett., 2005, 7, 3873; (h) A. Chan and K. A. Scheidt,
Org. Lett., 2005, 7, 905; (i) K. Zeitler, Org. Lett., 2006, 8, 637; (j) V.
Nair, S. Vellalath, M. Poonoth and E. Suresh, J. Am. Chem. Soc., 2006,
128, 8736; (k) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2007, 129,
13796; (l) G.-Q. Li, Y. Li, L.-X. Dai and S.-L. You, Org. Lett., 2007,
9, 3519; (m) J. W. Bode and S. S. Sohn, J. Am. Chem. Soc., 2007, 129,
13798.
+
HRMS (ESI): calcd for C12H18NO2 [M + H+] 208.1332, found
208.1334.
Acknowledgements
This work is funded by the Institute of Bioengineering and Nan-
otechnology (Biomedical Research Council, Agency for Science,
Technology and Research, Singapore).
10 Very recent examples: (a) S. P. Lathrop and T. Rovis, J. Am. Chem. Soc.,
2009, 131, 13628; (b) K. Hirano, A. T. Biju, I. Piel and F. Glorius, J.
Am. Chem. Soc., 2009, 131, 14190; (c) Y. Kawanaka, E. M. Phillips and
K. A. Scheidt, J. Am. Chem. Soc., 2009, 131, 18028; (d) D. E. A. Raup,
B. Cardinal-David, D. Holte and K. A. Scheidt, Nat. Chem., 2010, 2,
766; (e) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2010, 132, 2860;
(f) B. Cardinal-David, D. E. A. Raup and K. A. Scheidt, J. Am. Chem.
Soc., 2010, 132, 5345; (g) A. T. Biju, N. E. Wurz and F. Glorius, J. Am.
Chem. Soc., 2010, 132, 5970; (h) J. Kaeobamrung, M. C. Kozlowski1
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©