Enantioselective conjugate addition of N-heterocycles to α,β-unsaturated ketones catalyzed by chiral primary amines

Article abstract of DOI:10.1055/s-0029-1216636

A new organocatalytic enantioselective conjugate addition reaction of nitrogen-centered heterocycles with α,β-unsaturated ketones has been developed. Promoted by a chiral cinchona alkaloid derived primary amine, the reaction affords the adducts in moderat

Full text of DOI:10.1055/s-0029-1216636

1564
SPECIAL TOPIC
Enantioselective Conjugate Addition of N-Heterocycles to a,b-Unsaturated
Ketones Catalyzed by Chiral Primary Amines
Conjugate
A
dditio
u
n
of
N
-Heter
a
ocycles to
a
n
,
b
-Unsatura
g
ted
K
etonesshun Luo,a Shilei Zhang,a Wenhu Duan,*a,b Wei Wang*a,c
a
b
c
Department of Pharmaceutical Sciences, School of Pharmacy, East China University of Science and Technology,
Shanghai 200237, P. R. of China
Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences,
Graduate School of the Chinese Academy of Sciences, Shanghai 201203, P. R. of China
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131-0001, USA
Fax +1(505)2772609; E-mail: wwang@unm.edu
Received 29 January 2009
were screened for a model aza-Michael addition reaction
of 1H-benzotriazole (2) with (E)-4-phenylbut-3-en-2-one
(3a) (Table 1). The reaction was initially carried out in the
presence of 20 mol% catalyst at room temperature in chlo-
roform. The results of this investigation revealed that ami-
nocatalysts 1a–h differed significantly with regard to
catalytic activity and stereo- and regiocontrol of the pro-
cess. 1,1,1-Trifluoro-N-[(S)-pyrrolidin-2-ylmethyl]meth-
anesulfonamide (1a) and cinchona alkaloid derived
thiourea 1f were good promoters for the process, provid-
ing the products in high yields but with poor enantioselec-
tivities and moderate regioselectivities (Table 1, entries 1
and 6). The use of chiral cyclohexane-1,2-diamine-based
thioureas 1b, 1c, and 1e resulted in sluggish reactions (en-
tries 2, 3, and 5), whereas catalyst 1d gave good yields
(4a, 13%; 5a, 60%) and moderate ee values (4a, 49% ee;
5a, 54% ee) (entry 4). Among the catalysts probed, the
cinchona alkaloid derived primary amines 1g and 1h
showed superior activities (reaction time only 3 h; >98%
total yield of 4a and 5a; entries 7 and 8),11 but with 1g giv-
ing a much higher enantioselectivity.
Abstract: A new organocatalytic enantioselective conjugate addi-
tion reaction of nitrogen-centered heterocycles with a,b-unsaturat-
ed ketones has been developed. Promoted by a chiral cinchona
alkaloid derived primary amine, the reaction affords the adducts in
moderate to high enantioselectivities.
Key words: primary amines, N-heterocycles, enones, conjugate
addition, catalysis
Recently, much attention has been focused on the devel-
opment of new protocols for the asymmetric synthesis of
nitrogen-containing heterocycles because of their broad
utility in organic synthesis and medicinal chemistry.1,2
The conjugate addition of appropriate nitrogen-centered
heterocycles to electron-poor alkenes (e.g., aza-Michael)
represents one of the most efficient approaches to their
synthesis.3,4 Surprisingly, only a handful of catalytic
asymmetric versions of the processes can be identified in
the literature. Jacobsen and co-workers disclosed an ele-
gant chiral salen–aluminum-catalyzed conjugate addition
of a range of aromatic N-heterocyclic compounds to a,b-
unsaturated ketones and imides with high enantioselectiv-
ities.5 Sibi and co-workers also reported chiral-organome-
tallic-mediated highly enantioselective conjugate addition
of nitrogen species to a,b-unsaturated systems.6
Jørgensen and co-workers described an organocatalytic
conjugate addition of aromatic N-heterocycles to a,b-un-
saturated aldehydes using a chiral secondary amine.7 Re-
cently we and other groups have successfully developed
the hydrogen-bond-mediated asymmetric catalytic conju-
gation of N-heterocycles to nitroolefins and enones with
moderate to good enantioselectivities.8–10 Nevertheless,
the utilization of chiral amine covalently catalyzed conju-
gate addition of N-heterocycles to enones has not been re-
ported. Herein we wish to disclose an unprecedented
promotion of such a process by a chiral primary amine, re-
sulting in good regioselectivities and moderate to high
enantioselectivities.
S
S
NHTf
Ph
Ar
N
H
N
H
N
N
H
N
H
H
NMe2
NMe2
1a
1b
1c
S
Ph
S
S
HN
N
H
Ar
Ph
N
N
N
N
H
N
H
H
H
NH2
NH2
N
1d
1e
MeO
1f
NH2
NH2
N
N
N
N
In the exploratory studies, aimed at seeking optimal reac-
tion conditions, eight aminocatalysts 1a–h (Figure 1)
MeO
1g
1h
Ar = 3,5-(F3C)2C6H3
SYNTHESIS 2009, No. 9, pp 1564–1572
x
x
.
x
x
.2
0
0
9
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0029-1216636; Art ID: C00409SS
Figure 1 Structures of screened organocatalysts
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of N-Heterocycles to a,b-Unsaturated Ketones
1565
Table 1 Results of Exploratory Studies of Catalytic Asymmetric
Conjugate Addition Reactions of 1H-Benzotriazole (2) with (E)-4-
Phenylbut-3-en-2-one (3a)a
Table 2 Optimization of Reaction Conditions for Catalytic Asym-
metric Conjugate Addition Reactions of 1H-Benzotriazole (2) with
(E)-4-Phenylbut-3-en-2-one (3a)a
N
N
N
1g (20 mol%)
catalyst
O
N
N
N
N
O
N
N
N
additive
N
(20 mol%)
N
N
N
+
O
O
O
O
2
N
+
2
N
+
+
solvent, r.t.
Ph
Ph
NH1
CHCl3, r.t.
NH1
Ph
Ph
Ph
Ph
2
3a
4a
5a
5a
2
3a
4a
Catalyst Time (h) Yieldb (%)
eec,d,e (%)
Entry Solvent Additive
Time (h)Yieldb (%) eec,d (%)
Entry
4a
33
<5
<5
<5
<5
43
30
23
<5
26
23
<5
<5
42
<5
38
36
<5
5a
66
88
88
84
99
56
57
45
30
68
64
19
38
42
23
60
62
39
4a
5a
4a
5a
4a
5a
12
–32
n.d.
1
2
3
4
5
6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
AcOH
TFA
3
3
88
44
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
72
168
168
72
30
70
21
–3.5
n.d.
n.d.
49
n.d. 15
n.d. 17
trace
trace
13
PTSA
3
trace
60
d-CSA
HCl (2 N)
H3PO4
H3PO4
H3PO4
H3PO4
3
n.d.
8
54
28
3
n.d. 21
168
96
trace
27
57
n.d.
12.5
86
3
90
95
85
n.d.
95
75
62
75
19
0
63
0
7e CHCl3
8e i-PrOH
9e DMF
17
36
36
36
36
36
36
48
68
17
17
1g
1h
3
31
69
53
3
40
58
–70
–17
a Reaction conditions: 2 (1 equiv), 3a (2 equiv), cat. (20 mol%),
CHCl3, r.t.
10e toluene H3PO4
76
9
b Isolated yield.
c The ee values were determined by chiral HPLC analysis (Chiralpak
11e brine
12e THF
13e EtOAc
H3PO4
H3PO4
H3PO4
H3PO4
H3PO4
AS-H).
d n.d. = not determined.
n.d. 64
n.d. 52
e Negative ee values indicate that the opposite enantiomer of 4a was
formed in excess.
14f
15g CHCl3
CHCl3
97
76
The effect of an acid additive, reaction medium, catalyst
loading, and reaction temperature on the catalytic effi-
ciency of 1g was evaluated next. As indicated in Table 2,
the various different acid additives gave very diverse re-
sults (entries 1–6). Stronger Brønsted acids such as tri-
fluoroacetic acid, p-toluenesulfonic acid, and hydrochlo-
ric acid (entries 2–5) resulted in excellent regioselectivi-
ties, to give the Michael N1-adduct 5a exclusively, but the
enantioselectivities were disappointing (8–17%). When
acetic acid was used as additive, the ee of the major prod-
uct 5a was slightly lower (44%, Table 2, entry 1) than
without the use of additive (53%, Table 1, entry 7). The
use of phosphoric acid as additive and a lower tempera-
ture of 0 °C resulted in significantly higher enantioselec-
tivities of both 4a and 5a (95% and 75% respectively)
n.d. 76
16e,h toluene H3PO4
95
95
79
84
17e,i toluene (S)-binol
18e toluene
L-N-Boc-phenyl- 34
glycine
n.d. 82
a Reaction conditions: 2 (1 equiv), 3a (2 equiv), 1g (20 mol%), sol-
vent, r.t.
b Isolated yield.
c The ee values were determined by chiral HPLC analysis (Chiralpak
AS-H).
d n.d. = not determined.
e The reaction was performed at 0 °C.
f The reaction was performed at –14 °C.
(entry 7). Probing solvent effects showed that increasing g The reaction was performed at –30 °C.
the polarity of the reaction medium resulted in decreased
ee values, yields, and reaction activities, for example with
propan-2-ol (entry 8), N,N-dimethylformamide (entry 9),
h Catalyst 1g (10 mol%) and H3PO4 (20 mol%) were used.
i Catalyst 1g (20 mol%) and (S)-binol (20 mol%) were used.
brine (entry 11), tetrahydrofuran (entry 12), and ethyl enantioselectivity of 4a being sacrificed. Asymmetric
acetate (entry 13). A further lowering of the reaction tem- counterion-directed catalysis (ACDC)12 has recently been
perature to –14 °C and –30 °C resulted in prolonged reac- recognized as an attractive strategy for improving enanti-
tion times without an improvement in enantioselectivity oselective transformations. We therefore probed the effect
and yield (entries 14 and 15). Lowering the catalyst load- of (S)-binol and L-N-Boc-phenylglycine on the enantiose-
ing to ten mol% 1g resulted in an enhanced enantioselec- lectivity of the reaction, and found that the enantioselec-
tivity of 5a (79% ee, entry 16 vs 10) without the tivity was improved, although the yield was poor with L-
Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York

1566
G. Luo et al.
SPECIAL TOPIC
N-Boc-phenylglycine (entries 17 and 18). The absolute values of products 5 were observed with enones 3 bearing
configuration of 4a and 5a was determined to be S.13
electron-neutral (entry 1), electron-withdrawing (entries
2–6), as well as electron-donating (entries 7–10) substitu-
ents. A low yield was obtained with unsaturated ketone 3i,
even after a long reaction time (110 h), because of its poor
solubility in toluene at 0 °C (entry 9). However, when
chloroform was used as the solvent, a significantly higher
total yield of up to 99% resulted, with a slight decrease in
the ee value for 5i (74%), but high ee for 4i (94%) (entry
10). It seems that steric effects influence the regioselectiv-
ity of the conjugate addition. The more hindered 2-substi-
tuted substrates gave dominant N1-addition products
(entries 4–6 and 8). The 1g-catalyzed enantioselective
conjugate addition processes were also applicable to het-
erocyclic (entries 11 and 12) and aliphatic (entries 13 and
Having established the optimized reaction conditions, we
then probed the scope and limitations of 1g-promoted
enantioselective conjugate addition of 1H-benzotriazole
(2) to a range of a,b-unsaturated ketones 3 in the presence
of L-N-Boc-phenylglycine as additive in toluene. The re-
sults are summarized in Table 3. Under the reaction con-
ditions, the processes proceeded smoothly to give adduct
5 as the major product, with 4 as a minor one, in moderate
to high enantioselectivities for both regioisomers. The
conjugate processes are tolerant of significant structural
variations of R1 and R2 in enones 3. The electronic effects
of the aromatic system R1 in enones 3 have limited influ-
ence on the reaction outcome. Generally, good to high ee
Table 3 Scope of Catalytic Asymmetric Conjugate Addition Reactions of 1H-Benzotriazole (2) with Enones 3a
N
1g (20 mol%)
L-N-Boc-phenylglycine
(40 mol%)
N
O
N
N
N
N
O
N
2
N
+
O
+
R1
R2
NH1
R1
R2
toluene, 0 °C
R1
R2
2
3a–q
4
5
Entry
3
R1
R2
Time (h)
Yieldb (%)
eec,d (%)
4
5
4
5
1e
2
3a
3b
3c
3d
3e
3f
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
17
63
63
63
63
63
63
63
110
34
110
64
64
64
64
64
72
72
36
16
18
<5
<5
<5
10
7
62
83
81
92
98
60
87
90
14
87
86
60
60
69
62
79
21
29
95
84
81
69
78
86
77
81
78
88
74
38
67
79
75
63
78
75
83
4-BrC6H4
4-FC6H4
95
3
92
4
2-BrC6H4
2-IC6H4
n.d.
n.d.
n.d.
95
5
6
2-O2NC6H4
4-MeOC6H4
2-MeOC6H4
1,3-benzodioxol-5-yl
1,3-benzodioxol-5-yl
2-furyl
7
3g
3h
3i
8
92
9
<5
12
13
21
16
11
<5
20
<5
<5
n.d.
94
10f
11
12
13
14
15
16
17f
18f
3i
3j
71
3k
3l
2-thienyl
Bn
88
91
3m
3n
3o
3p
3q
styryl
83
n-C5H11
n.d.
97
Ph
4-MeOC6H4
Ph
Ph
n.d.
n.d.
Ph
a Reaction conditions: 2 (1 equiv), 3 (2 equiv), 1g (20 mol%), L-N-Boc-phenylglycine (40 mol%), toluene, 0 °C.
b Isolated yield.
c The ee values were determined by chiral HPLC analysis (see experimental section).
d n.d. = not determined.
e (S)-binol (20 mol%) was used as additive instead of L-N-Boc-phenylglycine.
f CHCl3 was used as solvent.
Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of N-Heterocycles to a,b-Unsaturated Ketones
1567
15) enones. Variation of the R2 moieties gave mixed re-
sults. Aliphatic R2 substituents behaved similarly to the
methyl group (entry 16). However, low yields were ob-
tained for both products (entries 17 and 18), with moder-
ate to good enantioselectivities for the major products,
when the R2 groups are aromatic. Again, as a result of the
poor solubilities of 3p and 3q in toluene, chloroform was
used instead.
1:5) to afford adducts 4b [yield: 17 mg (16%)] and 5b [yield: 86 mg
(83%)].
(S)-4-(2H-Benzotriazol-2-yl)-4-phenylbutan-2-one (4a)5e (Table
3, entry 1)
Compound 4a was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 36%; [a]D28 –29 (c 0.9, CHCl3).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 60:40, flow rate 0.5 mL/
min, l = 254 nm): tR (minor) = 16.39 min, tR (major) = 11.65 min,
97% ee.
In further investigations, we examined the reactivity of
other nitrogen heterocycles in this aza-Michael addition
(Scheme 1). 5-Phenyl-1H-tetrazole (6) served as an effec-
tive Michael donor in reaction with (E)-4-phenylbut-3-en-
2-one (3a), giving product 7 in 53% yield, 88% ee, and ex-
cellent regioselectivity. Unfortunately, however, the pro-
cess for 1H-[1,2,4]triazole was sluggish (<5% yield even
after 5 d).
(S)-4-(1H-Benzotriazol-1-yl)-4-phenylbutan-2-one (5a)5e,9b (Ta-
ble 3, entry 1)
Compound 5a was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 62%; [a]D27 –20 (c 1.0, CHCl3).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 60:40, flow rate 1 mL/
min, l = 254 nm); tR (major) = 5.79 min (major), tR (minor) = 6.48
min, 84% ee.
Ph
N
N
1g (20 mol%)
L-N-Boc-phenylglycine
(40 mol%)
O
N
N
N
N
N
O
(S)-4-(2H-Benzotriazol-2-yl)-4-(4-bromophenyl)butan-2-one
(4b)5e (Table 3, entry 2)
Compound 4b was prepared according to the typical procedure de-
+
Ph
N
H
Ph
toluene–CHCl3 (5:1)
0 °C, 3 d
Ph
53%, 88% ee
6
3a
7
scribed above for 4b and 5b.
Yield: 16%; [a]D30 +72 (c 0.95, CHCl3).
Scheme 1 Conjugate addition of heterocycle 6 to (E)-4-phenylbut-
3-en-2-one (3a) promoted by catalyst 1g
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 6.85 min, tR (major) = 8.74 min,
95% ee.
In summary, motivated by the broad synthetic utility of ni-
trogen-containing heterocycles and the lack of efficient
asymmetric methods for their preparation, we have devel-
oped a new catalytic conjugate addition reaction of N-het-
erocycles with a,b-unsaturated ketones. The process,
efficiently catalyzed by cinchona alkaloid derived prima-
ry amine 1g, provides the corresponding adducts in good
to high enantiomeric excesses. A range of unsaturated ke-
tones and N-heterocycles can be applied in the reaction.
Further investigations aimed at expanding the scope of the
conjugate addition process and its applications in biologi-
cal studies are underway in our laboratory.
(S)-4-(1H-Benzotriazol-1-yl)-4-(4-bromophenyl)butan-2-one
(5b)5e (Table 3, entry 2)
Compound 5b was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 83%; [a]D30 +9.5 (c 1.0, CHCl3).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254): tR (minor) = 7.50 min, tR (major) = 10.07 min, 81%
ee.
(S)-4-(2H-Benzotriazol-2-yl)-4-(4-fluorophenyl)butan-2-one
(4c) (Table 3, entry 3)
Compound 4c was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Commercially obtained reagents were used as received, unless
Yield: 18%; [a]D31 +97 (c 0.75, CHCl3).
1
specified otherwise. H and 13C NMR spectra were recorded on
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 6.23 min, tR (major) = 7.88 min,
92% ee.
1H NMR (400 MHz, CDCl3): d = 7.85–7.87 (dd, J = 3.1, 6.6 Hz, 2
H), 7.36–7.41 (m, 4 H), 7.00–7.04 (t, J = 8.7 Hz, 2 H), 6.51–6.55
(dd, J = 5.3, 9.1 Hz, 1 H), 4.10–4.16 (dd, J = 9.1, 17.8 Hz, 1 H),
3.32–3.38 (dd, J = 5.3, 17.8 Hz, 1 H), 2.25 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.9, 163.9, 161.5, 144.2, 134.5,
134.4, 128.8, 128.7, 126.5, 118.2, 116.0, 115.8, 64.9, 48.5, 30.3.
ESI-HRMS: m/z [M + Na]+ calcd for C16H14FN3NaO: 306.1019;
Bruker Avance-400 spectrometers. Chemical shifts are reported rel-
ative to TMS or the solvent resonances as internal standard. Optical
rotations were measured on a Rudolph Research Analytical Autopol
III automatic polarimeter. MS was performed on a Micromass GCT
CA055 spectrometer. Mass spectra (ESI) were obtained from the
University of New Mexico mass spectral facility. TLC was per-
formed on glass plates precoated with silica gel GF254, and spots
were visualized with UV light. Flash column chromatography was
performed on silica gel. HPLC was carried out on an Agilent 1100
HPLC system with Daicel columns.
found: 306.1021.
Conjugate Addition of N-Heterocycle 2 to Enone 3b (Table 3,
entry 2); Typical Procedure
(S)-4-(1H-Benzotriazol-1-yl)-4-(4-fluorophenyl)butan-2-one
(5c) (Table 3, entry 3)
Compound 5c was prepared according to the typical procedure de-
scribed above for 4b and 5b.
1H-Benzotriazole (2; 36 mg, 0.3 mmol, 1 equiv) was added to a soln
of 3b (135 mg, 0.6 mmol, 2 equiv), 9-epi-9-aminoquinine (1g; 19
mg, 0.06 mmol, 20 mol%), and L-N-Boc-phenylglycine (30 mg,
0.12 mmol, 40 mol%) in toluene (1 mL), and the resulting mixture
was stirred for 63 h at 0 °C. The reaction mixture was directly puri-
fied by column chromatography (silica gel, EtOAc–hexane, 1:10 to
Yield: 81%; [a]D31 +49 (c 3.95, CHCl3).
Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York

1568
G. Luo et al.
SPECIAL TOPIC
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.00 min, tR (major) = 8.36 min,
69% ee.
1H NMR (400 MHz, CDCl3): d = 8.05–8.07 (d, J = 8.3 Hz, 1 H),
7.43 (s, 2 H), 7.36–7.39 (m, 1 H), 7.30–7.33 (dd, J = 5.2, 8.6 Hz, 2
H), 7.00–7.04 (t, J = 8.5 Hz, 2 H), 6.31–6.35 (dd, J = 4.9, 8.9 Hz, 1
H), 4.22–4.29 (dd, J = 9.0, 17.8 Hz, 1 H), 3.32–3.38 (dd, J = 4.9,
17.8 Hz, 1 H), 2.27 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 204.4, 163.8, 161.3, 146.0, 134.6,
134.6, 132.8, 128.5, 128.4, 127.5, 127.2, 124.3, 119.8, 116.1, 115.9,
109.9, 57.6, 48.7, 30.3.
ESI-HRMS: m/z [M + Na]+ calcd for C16H14FN3NaO: 306.1019;
found: 306.1025.
1H NMR (400 MHz, CDCl3): d = 8.04–8.06 (d, J = 8.3 Hz, 1 H),
8.01–8.03 (d, J = 7.9 Hz, 1 H), 7.43–7.54 (m, 4 H), 7.31–7.39 (m, 2
H), 7.09–7.12 (dd, J = 4.2, 9.3 Hz, 1 H), 4.24–4.30 (dd, J = 9.3, 18.0
Hz, 1 H), 3.47–3.53 (dd, J = 4.2, 18.0 Hz, 1 H), 2.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.2, 147.9, 145.9, 134.0, 133.9,
133.1, 129.4, 128.9, 128.0, 124.9, 124.6, 119.8, 109.9, 52.9, 48.4,
29.9.
ESI-HRMS: m/z [M + Na]+ calcd for C16H14N4NaO3: 333.0964;
found: 333.0970.
(S)-4-(2H-Benzotriazol-2-yl)-4-(4-methoxyphenyl)butan-2-one
(4g) (Table 3, entry 7)
Compound 4g was prepared according to the typical procedure de-
scribed above for 4b and 5b.
(S)-4-(1H-Benzotriazol-1-yl)-4-(2-bromophenyl)butan-2-one
(5d) (Table 3, entry 4)
Compound 5d was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 10%; [a]D29 +30 (c 1.1, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 8.14 min, tR (major) = 10.28 min,
95% ee.
1H NMR (400 MHz, CDCl3): d = 7.84–7.87 (dd, J = 3.1, 6.6 Hz, 2
H), 7.34–7.37 (m, 4 H), 6.84–6.87 (dd, J = 2.0, 6.7 Hz, 2 H), 6.48–
6.52 (dd, J = 5.2, 9.2 Hz, 1 H), 4.09–4.16 (dd, J = 9.2, 17.7 Hz, 1
H), 3.76 (s, 3 H), 3.32–3.38 (dd, J = 5.2, 7.7 Hz, 1 H), 2.23 (s, 3 H).
Yield: 92%; [a]D31 +166 (c 4.5, CHCl3).
HPLC (Chiralcel OD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.66 min, tR (major) = 6.82 min,
78% ee.
1H NMR (400 MHz, CDCl3): d = 8.04–8.06 (d, J = 8.3 Hz, 1 H),
7.61–7.64 (dd, J = 1.7, 7.6 Hz, 1 H), 7.49–7.51 (d, J = 8.3 Hz, 1 H),
7.42–7.45 (m, 1 H), 7.34–7.38 (dt, J = 1.0, 7.0 Hz, 1 H), 7.14–7.22
(m, 2 H), 7.02–7.04 (dd, J = 2.1, 7.4 Hz, 1 H), 6.81–6.85 (dd,
J = 3.2, 10.7 Hz, 1 H), 4.24–4.31 (dd, J = 10.7, 17.8 Hz, 1 H), 3.20–
3.26 (dd, J = 3.2, 17.8 Hz, 1 H), 2.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.8, 145.9, 137.9, 133.2, 133.1,
130.0, 128.4, 128.1, 127.7, 124.4, 122.0, 119.7, 110.1, 57.3, 47.3,
30.1.
13C NMR (100 MHz, CDCl3): d = 204.3, 159.7, 144.1, 130.7, 128.2,
126.3, 118.2, 114.3, 65.1, 55.3, 48.5, 30.3.
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO2: 318.1218;
found: 318.1227.
(S)-4-(1H-Benzotriazol-1-yl)-4-(4-methoxyphenyl)butan-2-one
(5g) (Table 3, entry 7)
Compound 5g was prepared according to the typical procedure de-
scribed above for 4b and 5b.
ESI-HRMS: m/z [M + Na]+ calcd for C16H14BrN3NaO: 368.0218;
found: 368.0211.
Yield: 87%; [a]D29 +42 (c 0.35, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 8.62 min, tR (major) = 10.11 min,
81% ee.
1H NMR (400 MHz, CDCl3): d = 8.00–8.02 (d, J = 8.2 Hz, 1 H),
7.23–7.42 (m, 5 H), 6.81–6.83 (d, J = 8.5 Hz, 2 H), 6.26–6.29 (dd,
J = 4.8, 9.0 Hz, 1 H), 4.19–4.26 (dd, J = 9.1, 17.6 Hz, 1 H), 3.74 (s,
3 H), 3.29–3.35 (dd, J = 4.8, 17.6 Hz, 1 H), 2.23 (s, 3 H).
(S)-4-(1H-Benzotriazol-1-yl)-4-(2-iodophenyl)butan-2-one (5e)
(Table 3, entry 5)
Compound 5e was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 98%; [a]D31 +226.5 (c 5.9, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 60:40, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.92 min, tR (major) = 6.49 min,
86% ee.
1H NMR (400 MHz, CDCl3): d = 8.04–8.06 (d, J = 8.3 Hz, 1 H),
7.89–7.91 (m, 1 H), 7.43 (s, 2 H), 7.36–7.39 (m, 1 H), 7.30–7.33
(dd, J = 5.2, 8.6 Hz, 2 H), 7.00–7.04 (t, J = 8.5 Hz, 2 H), 6.31–6.35
(dd, J = 4.9, 8.9 Hz, 1 H), 4.22–4.29 (dd, J = 9.0, 17.8 Hz, 1 H),
3.32–3.38 (dd, J = 4.9, 17.8 Hz, 1 H), 2.27 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.7, 146.0, 140.9, 139.9, 133.1,
130.2, 129.3, 127.6, 124.4, 119.7, 110.3, 97.3, 62.4, 47.5, 30.1.
ESI-HRMS: m/z [M + Na]+ calcd for C16H14IN3NaO: 414.0079;
found: 414.0071.
13C NMR (100 MHz, CDCl3): d = 204.7, 159.6, 146.1, 132.9, 130.8,
127.9, 127,3, 124.1, 119.7, 114.4, 110.1, 57.9, 55.3, 48.8, 30.4.
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO2: 318.1218;
found: 318.1228.
(S)-4-(2H-Benzotriazol-2-yl)-4-(2-methoxyphenyl)butan-2-one
(4h) (Table 3, entry 8)
Compound 4h was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 7%; [a]D29 +159 (c 0.3, CHCl3).
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1
mL/min, l = 254 nm): tR (minor) = 6.14 min, tR (major) = 9.41 min,
92% ee.
1H NMR (400 MHz, CDCl3): d = 7.87–7.89 (dd, J = 3.1, 6.6 Hz, 2
H), 7.36–7.39 (dd, J = 3.1, 6.6 Hz, 2 H), 7.24–7.28 (m, 1 H), 7.01–
7.05 (dd, J = 3.7, 10.6 Hz, 1 H), 6.92–6.94 (d, J = 8.2 Hz, 1 H),
6.81–6.85 (t, J = 7.7 Hz, 1 H), 6.77–6.79 (dd, J = 1.7, 7.7 Hz, 1 H),
4.05–4.12 (dd, J = 10.6, 17.7 Hz, 1 H), 3.91 (s, 3 H), 3.20–3.26 (dd,
J = 3.7, 7.7 Hz, 1 H), 2.25 (s, 3 H).
(S)-4-(1H-Benzotriazol-1-yl)-4-(2-nitrophenyl)butan-2-one (5f)
(Table 3, entry 6)
Compound 5f was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 60%; [a]D30 +361 (c 2.15, CHCl3).
HPLC (Chiralcel OD-H, hexane–i-PrOH, 60:40, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 10.52 min, tR (major) = 7.67 min,
77% ee.
13C NMR (100 MHz, CDCl3): d = 204.7, 155.6, 144.1, 129.4, 127.6,
126.7, 126.2, 120.9, 118.3, 110.8, 60.0, 55.7, 47.5, 30.1.
Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of N-Heterocycles to a,b-Unsaturated Ketones
1569
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO2: 318.1218;
(S)-4-(1H-Benzotriazol-1-yl)-4-(2-furyl)butan-2-one (5j) (Table
found: 318.1223.
3, entry 11)
Compound 5j was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 86%; [a]D30 –23 (c 1.2, CHCl3).
(S)-4-(1H-Benzotriazol-1-yl)-4-(2-methoxyphenyl)butan-2-one
(5h) (Table 3, entry 8)
Compound 5h was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 90%; [a]D30 +110 (c 1.0, CHCl3).
HPLC (Chiralcel OD-H, hexane–i-PrOH, 60:40, flow rate 0.5 mL/
min, l = 254 nm): tR (minor) = 13.94 min, tR (major) = 13.16 min,
38% ee.
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm); tR (minor) = 6.65 min, tR (major) = 7.22 min,
78% ee.
1H NMR (400 MHz, CDCl3): d = 7.99–8.01 (d, J = 8.2 Hz, 1 H),
7.48–7.50 (d, J = 8.3 Hz, 1 H), 7.36–7.40 (m, 1 H), 7.30–7.33 (m, 1
H), 7.22–7.27 (m, 1 H), 6.96–6.98 (d, J = 7.6 Hz, 1 H), 6.89–6.91
(d, J = 8.3 Hz, 1 H), 6.80–6.83 (m, 1 H), 4.21–4.28 (ddd, J = 1.9,
10.5, 17.7 Hz, 1 H), 3.90 (s, 3 H), 3.22–3.28 (dd, J = 3.5, 7.7 Hz, 1
H), 2.22 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.01–8.04 (d, J = 8.4 Hz, 1 H),
7.58–7.60 (d, J = 8.4 Hz, 1 H), 7.45–7.49 (m, 1 H), 7.33–7.37 (m, 2
H), 6.47–6.51 (dd, J = 5.3, 8.8 Hz, 1 H), 6.30 (s, 2 H), 4.04–4.11
(dd, J = 8.8, 17.8 Hz, 1 H), 3.52–3.58 (dd, J = 5.3, 17.8 Hz, 1 H),
2.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.8, 150.6, 145.9, 142.9, 132.9,
127.6, 124.2, 119.8, 110.7, 110.0, 108.2, 51.8, 45.6, 30.2.
ESI-HRMS: m/z [M + Na]+ calcd for C14H13N3NaO2: 278.0905;
found: 278.0898.
13C NMR (100 MHz, CDCl3): d = 204.8, 155.8, 145.9, 133.2, 129.5,
127.2, 127.1, 126.9, 124.0, 121.1, 119.5, 110.7, 110.3, 55.6, 51.8,
47.1, 30.3.
(S)-4-(2H-Benzotriazol-2-yl)-4-(2-thienyl)butan-2-one (4k) (Ta-
ble 3, entry 12)
Compound 4k was prepared according to the typical procedure de-
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO2: 318.1218;
found: 318.1230.
scribed above for 4b and 5b.
Yield: 21%; [a]D31 +42 (c 0.85, CHCl3).
(S)-4-(1,3-Benzodioxol-5-yl)-4-(1H-benzotriazol-1-yl)butan-2-
one (5i) (Table 3, entry 9)
Compound 5i was prepared according to the typical procedure de-
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.49 min, tR (major) = 8.92 min,
88% ee.
scribed above for 4b and 5b.
1H NMR (400 MHz, CDCl3): d = 7.85–7.88 (dd, J = 3.1, 6.6 Hz, 2
H), 7.36–7.39 (dd, J = 3.1, 6.6 Hz, 2 H), 7.25–7.27 (dd, J = 1.0, 5.1
Hz, 1 H), 7.16–7.17 (d, J = 3.4 Hz, 1 H), 6.94–6.96 (dd, J = 3.6, 5.1
Hz, 1 H), 6.80–6.84 (dd, J = 5.4, 9.0 Hz, 1 H), 4.12–4.19 (dd,
J = 9.0, 17.7 Hz, 1 H), 3.48–3.54 (dd, J = 5.4, 7.8 Hz, 1 H), 2.24 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 203.5, 144.2, 140.8, 126.9, 126.5,
126.4, 126.1, 118.3, 61.0, 48.9, 30.3.
ESI-HRMS: m/z [M + Na]+ calcd for C14H13N3NaOS: 294.0677;
found: 294.0687.
Yield: 14%; [a]D31 +56 (c 0.75, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 9.44 min, tR (major) = 10.78 min,
88% ee.
1H NMR (400 MHz, CDCl3): d = 8.05–8.07 (d, J = 8.1 Hz, 1 H),
7.36–7.49 (m, 3 H), 6.83–6.85 (dd, J = 1.6, 8.0 Hz, 1 H), 6.78 (d,
J = 1.6 Hz, 1 H), 6.74–6.76 (d, J = 8.0 Hz, 1 H), 6.23–6.27 (dd,
J = 4.7, 9.0 Hz, 1 H), 5.92–5.95 (d, J = 9.3 Hz, 2 H), 4.20–4.27 (dd,
J = 9.2, 17.7 Hz, 1 H), 3.30–3.35 (dd, J = 4.8, 17.7 Hz, 1 H), 2.27
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 204.7, 148.3, 147.8, 146.0, 132.9,
132.5, 127.4, 127.2, 124.2, 120.3, 119.7, 110.1, 108.5, 107.0, 101.4,
58.2, 48.7, 30.4.
(S)-4-(1H-Benzotriazol-1-yl)-4-(2-thienyl)butan-2-one (5k) (Ta-
ble 3, entry 12)
Compound 5k was prepared according to the typical procedure de-
scribed above for 4b and 5b.
ESI-HRMS: m/z [M + Na]+ calcd for C17H15N3NaO3: 332.1011;
found: 332.1007.
Yield: 60%; [a]D31 –14.5 (c 2.3, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 8.48 min, tR (major) = 7.67 min,
67% ee.
(S)-4-(2H-Benzotriazol-2-yl)-4-(2-furyl)butan-2-one (4j) (Table
3, entry 11)
Compound 4j was prepared according to the typical procedure de-
1H NMR (400 MHz, CDCl3): d = 8.02–8.05 (d, J = 8.3 Hz, 1 H),
7.56–7.58 (d, J = 8.3 Hz, 1 H), 7.44–7.48 (m, 1 H), 7.33–7.37 (m, 1
H), 7.22–7.23 (d, J = 5.1 Hz, 1 H), 7.03–7.04 (d, J = 3.4 Hz, 1 H),
6.90–6.92 (m, 1 H), 6.60–6.62 (dd, J = 5.0, 8.9 Hz, 1 H), 4.21–4.27
(dd, J = 8.9, 17.8 Hz, 1 H), 3.48–3.54 (dd, J = 5.0, 17.8 Hz, 1 H),
2.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 204.0, 145.9, 141.3, 132.8, 127.6,
127.0, 126.0, 125.9, 124.3, 119.9, 109.9, 53.6, 49.2, 30.3.
ESI-HRMS: m/z [M + Na]+ calcd for C14H13N3NaOS: 294.0677;
found: 294.0682.
scribed above for 4b and 5b.
Yield: 13%; [a]D31 –15 (c 0.5, CHCl3).
HPLC (Chiralcel OD-H, hexane–i-PrOH, 60:40, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 6.36 min, tR (major) = 5.59 min,
71% ee.
1H NMR (400 MHz, CDCl3): d = 7.85–7.88 (dd, J = 3.1, 6.6 Hz, 2
H), 7.36–7.39 (m, 3 H), 6.61–6.65 (dd, J = 5.6, 8.7 Hz, 1 H), 6.43–
6.44 (d, J = 3.3 Hz, 1 H), 6.34–6.36 (dd, J = 1.9, 3.3 Hz, 1 H), 4.03–
4.10 (dd, J = 8.7, 17.8 Hz, 1 H), 3.51–3.57 (dd, J = 5.6, 7.8 Hz, 1
H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.5, 150.3, 144.2, 143.1, 126.5,
(R)-4-(2H-Benzotriazol-2-yl)-5-phenylpentan-2-one (4l) (Table
3, entry 13)
Compound 4l was prepared according to the typical procedure de-
118.3, 110.6, 108.7, 59.0, 45.6, 30.2.
ESI-HRMS: m/z [M + Na]+ calcd for C14H13N3NaO2: 278.0905;
found: 278.0910.
scribed above for 4b and 5b.
Yield: 16%; [a]D31 +66.5 (c 0.65, CHCl3).
Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York

1570
G. Luo et al.
SPECIAL TOPIC
HPLC (Chiralcel OD-H, hexane–i-PrOH, 80:20, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 6.68 min, tR (major) = 6.16 min,
91% ee.
1H NMR (400 MHz, CDCl3): d = 7.84–7.86 (dd, J = 3.1, 6.5 Hz, 2
H), 7.37–7.39 (dd, J = 3.1, 6.5 Hz, 2 H), 7.21–7.24 (m, 3 H), 7.07–
7.09 (m, 2 H), 5.64–5.71 (m, 1 H), 3.51–3.58 (dd, J = 8.4, 17.7 Hz,
1 H), 3.45–3.50 (dd, J = 7.0, 13.7 Hz, 1 H), 3.24–3.30 (dd, J = 7.4,
13.7 Hz, 1 H), 3.02–3.07 (dd, J = 5.3, 17.7 Hz, 1 H), 2.14 (s, 3 H).
J = 8.4, 17.8 Hz, 1 H), 3.30–3.36 (dd, J = 5.3, 17.7 Hz, 1 H), 2.24
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 204.5, 145.9, 135.4, 133.2, 133.0,
128.7, 128.4, 127.5, 126.7, 126.1, 124.3, 119.8, 110.1, 56.6, 47.4,
30.5.
ESI-HRMS: m/z [M + Na]+ calcd for C18H17N3NaO: 314.1269;
found: 314.1271.
13C NMR (100 MHz, CDCl3): d = 204.7, 144.0, 136.4, 129.1, 128.7,
127.1, 126.3, 118.1, 63.8, 46.6, 41.8, 30.3.
(R)-4-(1H-Benzotriazol-1-yl)nonan-2-one (5n) (Table 3, entry
15)
Compound 5n was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 62%; [a]D31 +5 (c 2.4, CHCl3).
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO: 302.1269;
found: 302.1270.
(R)-4-(1H-Benzotriazol-1-yl)-5-phenylpentan-2-one (5l) (Table
3, entry 13)
Compound 5l was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 60%; [a]D31 +57.5 (c 2.5, CHCl3).
HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH, 60:40, flow rate
0.5 mL/min, l = 254 nm): tR (minor) = 9.61 min, tR (major) = 9.03
min, 63% ee.
1H NMR (400 MHz, CDCl3): d = 8.04–8.06 (d, J = 8.4 Hz, 1 H),
7.64–7.66 (d, J = 8.4 Hz, 1 H), 7.49–7.53 (m, 1 H), 7.35–7.39 (m, 1
H), 5.25–5.29 (m, 1 H), 3.54–3.61 (dd, J = 8.3, 17.9 Hz, 1 H), 3.10–
3.16 (dd, J = 5.0, 17.9 Hz, 1 H), 2.15–2.12 (m, 1 H), 2.12 (s, 3 H),
1.91–2.00 (m, 1 H), 1.20–1.22 (m, 5 H), 1.00–1.03 (m, 1 H), 0.79–
0.82 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.3, 145.6, 133.5, 127.2, 123.9,
119.8, 109.8, 54.5, 48.2, 35.3, 31.1, 30.4, 25.6, 22.3, 13.8.
ESI-HRMS: m/z [M + Na]+ calcd for C15H21N3NaO: 282.1582;
found: 282.1595.
HPLC (Chiralcel OD-H, hexane–i-PrOH, 60:40, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.26, min, tR (major) = 5.89 min,
79% ee.
1H NMR (400 MHz, CDCl3): d = 7.97–7.99 (m, 1 H), 7.29–7.34 (m,
2 H), 7.26–7.28 (dd, J = 1.9, 5.1 Hz, 1 H), 7.12–7.13 (m, 3 H), 7.43–
7.54 (m, 4 H), 6.94–6.96 (m, 2 H), 5.40–5.43 (m, 1 H), 3.66–3.73
(dd, J = 8.3, 18.0 Hz, 1 H), 3.29–3.33 (m, 2 H), 3.20–3.26 (dd,
J = 5.0, 18.0 Hz, 1 H), 2.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.1, 145.4, 136.6, 133.5, 128.9,
128.6, 127.1, 127.0, 123.8, 119.5, 109.6, 56.2, 47.3, 41.8, 30.4.
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO: 302.1269;
found: 302.1268.
(S)-1-(2H-Benzotriazol-2-yl)-1-phenylpentan-3-one (4o) (Table
3, entry 16)
Compound 4o was prepared according to the typical procedure de-
scribed above for 4b and 5b.
(S,E)-4-(2H-Benzotriazol-2-yl)-6-phenylhex-5-en-2-one (4m)
(Table 3, entry 14)
Compound 4m was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 20%; [a]D31 +90 (c 0.85, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.19 min, tR (major) = 9.47 min,
97% ee.
1H NMR (400 MHz, CDCl3): d = 7.85–7.87 (dd, J = 3.1, 6.6 Hz, 2
H), 7.28–7.40 (m, 7 H), 6.57–6.61 (dd, J = 5.1, 9.4 Hz, 1 H), 4.10–
4.17 (dd, J = 9.4, 17.5 Hz, 1 H), 3.30–3.36 (dd, J = 5.1, 17.5 Hz, 1
H), 2.45–2.62 (m, 2 H), 1.03–1.07 (t, J = 7.3 Hz, 3 H).
Yield: 11%; [a]D31 +31.5 (c 0.5, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.51 min, tR (major) = 9.23 min,
83% ee.
1H NMR (400 MHz, CDCl3): d = 7.87–7.90 (dd, J = 3.1, 6.6 Hz, 2
H), 7.40–7.41 (d, J = 2.8 Hz, 1 H), 7.35–7.40 (m, 3 H), 7.25–7.32
(m, 3 H), 6.66–6.70 (d, J = 5.8 Hz, 1 H), 6.45–6.51 (dd, J = 7.8,
15.8 Hz, 1 H), 6.12–6.18 (m, 1 H), 3.78–3.85 (dd, J = 8.2, 17.6 Hz,
1 H), 3.26–3.32 (dd, J = 5.8, 17.6 Hz, 1 H), 2.24 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.9, 144.2, 138.8, 128.9, 128.5,
126.8, 126.3, 118.2, 65.7, 47.4, 36.4, 7.53.
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO: 302.1269;
found: 302.1278.
13C NMR (100 MHz, CDCl3): d = 204.0, 144.2, 135.6, 133.9, 128.9,
128.6, 128.4, 127.3, 126.8, 126.4, 126.0, 118.2, 64.2, 47.6, 30.5.
(S)-1-(1H-Benzotriazol-1-yl)-1-phenylpentan-3-one (5o) (Table
3, entry 16)
Compound 5o was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 79%; [a]D32 +43.5 (c 3.3, CHCl3).
ESI-HRMS: m/z [M + Na]+ calcd for C18H17N3NaO: 314.1269;
found: 314.1266.
(S,E)-4-(1H-Benzotriazol-1-yl)-6-phenylhex-5-en-2-one (5m)
(Table 3, entry 14)
Compound 5m was prepared according to the typical procedure de-
scribed above for 4b and 5b.
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 6.93 min, tR (major) = 7.64 min,
78% ee.
1H NMR (400 MHz, CDCl3): d = 8.02–8.04 (d, J = 8.3 Hz, 1 H),
7.39–7.43 (m, 2 H), 7.27–7.34 (m, 6 H), 6.34–6.38 (dd, J = 4.8, 9.4
Hz, 1 H), 4.21–4.28 (dd, J = 9.4, 17.5 Hz, 1 H), 3.28–3.34 (dd,
J = 4.8, 17.5 Hz, 1 H), 2.32–2.65 (m, 2 H), 2.01–1.05 (t, J = 7.3 Hz,
3 H).
Yield: 69%; [a]D31 –62 (c 2.7, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 7.76 min, tR (major) = 9.59 min,
75% ee.
1H NMR (400 MHz, CDCl3): d = 8.06–8.09 (d, J = 8.4 Hz, 1 H),
7.65–7.67 (d, J = 8.4 Hz, 1 H), 7.47–7.51 (m, 1 H), 7.36–7.40 (m, 1
H), 7.25–7.34 (m, 5 H), 6.53–6.57 (d, J = 5.9 Hz, 1 H), 6.41–6.47
(dd, J = 7.2, 15.9 Hz, 1 H), 5.96–6.02 (m, 1 H), 3.91–3.97 (dd,
13C NMR (100 MHz, CDCl3): d = 207.4, 146.0, 138.9, 133.0, 129.1,
128.6, 127.4, 126.6, 124.2, 119.8, 110.0, 58.5, 47.7, 36.5, 7.45.
ESI-HRMS: m/z [M + Na]+ calcd for C17H17N3NaO: 302.1269;
found: 302.1263.
Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of N-Heterocycles to a,b-Unsaturated Ketones
1571
(S)-3-(1H-Benzotriazol-1-yl)-3-(4-methoxyphenyl)-1-phenyl-
propan-1-one (5p)9b (Table 3, entry 17)
Compound 5p was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Synthesis 2001, 171. (b) Sibi, M.; Manyem, S. Tetrahedron
2001, 56, 8033. (c) Berner, O. M.; Tedeschi, L.; Enders, D.
Eur. J. Org. Chem. 2002, 1877. (d) Christoffers, J.; Baro, A.
Angew. Chem. Int. Ed. 2003, 42, 1688. (e) Xu, L.-W.; Xia,
C.-G. Eur. J. Org. Chem. 2005, 633. (f)Almasi, D.;Alonso,
D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299.
(5) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 8959. (b) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem.
Soc. 2003, 125, 4442. (c) Taylor, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 2003, 125, 11204. (d) Vanderwal, C. D.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 14724.
(e) Gandelman, M.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2005, 44, 2393.
(6) (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am.
Chem. Soc. 1998, 120, 6615. (b) Sibi, M. P.;Prabagaran, N.;
Ghorpades, S. G.; Jasperse, C. P. J. Am. Chem. Soc. 2003,
125, 11796. For other selected examples, see: (c) Fadini, L.;
Togni, A. Chem. Commun. 2003, 30. (d) Palomo, C.;
Oiarbide, M.; Halder, R.; Kelso, M.; Gómez-Bengoa, E.;
Garcia, J. M. J. Am. Chem. Soc. 2004, 126, 9188.
(e) Yamagiwa, N.; Qin, H.; Matunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 13419; and references cited
therein.
Yield: 21%; [a]D31 –12 (c 1.25, CHCl3).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 70:30, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 21.78 min, tR (major) = 29.72 min,
74% ee.
1H NMR (400 MHz, CDCl3): d = 8.03–8.05 (d, J = 8.3 Hz, 1 H),
7.99–8.01 (dd, J = 1.4, 8.5 Hz, 2 H), 7.54–7.60 (m, 2 H), 7.42–7.49
(m, 3 H), 7.34–7.38 (m, 3 H), 6.85–6.87 (d, J = 8.8 Hz, 2 H), 6.53–
6.57 (dd, J = 5.2, 8.5 Hz, 1 H), 4.79–4.85 (dd, J = 8.5, 17.9 Hz, 1
H), 3.89–3.95 (dd, J = 5.2, 17.9 Hz, 1 H), 3.76 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 198.0, 196.1, 159.6, 158.1, 146.2,
136.3, 135.9, 133.6, 133.0, 132.9, 131.3, 131.1, 129.1, 128.7, 128.6,
128.2, 128.1, 128.0, 127.3, 124.0, 119.8, 114.4, 113.6, 110.0, 58.0,
55.3, 55.1, 44.5.
ESI-HRMS: m/z [M + Na]+ calcd for C22H19N3NaO: 380.1375;
found: 380.1389.
(S)-3-(1H-Benzotriazol-1-yl)-1,3-diphenylpropan-1-one (5q)9b
(Table 3, entry 18)
Compound 5q was prepared according to the typical procedure de-
scribed above for 4b and 5b.
(7) Diner, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2007, 46, 1983.
(8) For recent reviews on asymmetric organocatalysis, see:
(a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis –
From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 2005. (b) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(c) Special Issue on Asymmetric Organocatalysis:Acc.
Chem. Res. 2004, 37, 487. (d) Guillena, G.; Ramon, D. J.
Tetrahedron: Asymmetry 2006, 17, 1465. (e) Marcelli, T.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed.
2006, 45, 7496. (f) Guillena, G.; Najera, C.; Ramon, D. J.
Tetrahedron: Asymmetry 2007, 18, 2249. (g) Connon, S. J.
Org. Biomol. Chem. 2007, 5, 3407. (h) Marion, N.; Diez-
Gonzalez, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46,
2988. (i) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
Chem. Int. Ed. 2007, 46, 1570. (j) Takemoto, Y.; Miyabe,
H. Chimia 2007, 61, 269. (k) Longbottom, D.;
Yield: 29%; [a]D31 –19.5 (c 1.5, CHCl3).
HPLC (Chiralcel OD-H, hexane–i-PrOH, 80:20, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 12.55 min, tR (major) = 11.35 min,
83% ee.
(S)-4-Phenyl-4-(5-phenyl-2H-tetrazol-2-yl)butan-2-one (7)
Compound 7 was prepared according to the typical procedure de-
scribed above for 4b and 5b.
Yield: 53%; [a]D32 +51 (c 3.3, CHCl3).
HPLC (Chiralcel OD-H, hexane–i-PrOH, 80:20, flow rate 1 mL/
min, l = 254 nm): tR (minor) = 16.45 min, tR (major) = 13.47 min,
88% ee.
1H NMR (400 MHz, CDCl3): d = 8.14–8.16 (m, 2 H), 7.46–7.50 (m,
3 H), 7.34–7.39 (m, 5 H), 6.48–6.51 (dd, J = 5.1, 9.3 Hz, 1 H), 4.02–
4.09 (dd, J = 9.3, 17.9 Hz, 1 H), 3.32–3.38 (dd, J = 5.0, 17.9 Hz, 1
H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.5, 165.0, 137.4, 130.3, 129.1,
128.9, 128.8, 127.4, 126.9, 126.8, 63.1, 48.1, 30.3.
ESI-HRMS: m/z [M + Na]+ calcd for C17H16N4NaO: 315.1222;
found: 315.1226.
Franckevicius, A. V.; Ley, S. V. Chimia 2007, 61, 247.
(l) Yu, X.-H.; Wang, W. Chem. Asian J. 2008, 3, 516.
(m) Yu, X.-H.; Wang, W. Org. Biomol. Chem. 2008, 6,
2037. (n) Kotsuki, H.; Ikishima, H.; Okuyama, A.
Heterocycles 2008, 75, 493. (o) Kotsuki, H.; Ikishima, H.;
Okuyama, A. Heterocycles 2008, 75, 757.
(9) (a) Wang, J.; Li, H.; Zu, L.-S.; Wang, W. Org. Lett. 2006, 8,
1391. (b) Wang, J.; Zu, L.; Li, H.; Xie, H.; Wang, W.
Synthesis 2007, 2576.
(10) (a) Miller, S. J. Acc. Chem. Res. 2004, 37, 601. (b) Guerin,
D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134.
(c) Hortsmann, T. E.; Guerin, D. J.; Miller, S. J. Angew.
Chem. Int. Ed. 2000, 39, 3635. (d) Guerin, D. J.;
Acknowledgment
We are grateful for financial support from the School of Pharmacy,
East China University of Science & Technology and the National
Science Foundation of China (0801031005), and the National Sci-
ence Foundation (CHE-0704015).
Horstmann, T. E.; Miller, S. J. Org. Lett. 1999, 1, 1107.
(e) Chen, Y. K.; Yishida, M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 9328. (f) Vesely, J.; Ibrahem, I.;
Rios, R.; Zhao, G.-L.; Xu, Y.; Córdova, A. Tetrahedron Lett.
2007, 48, 2193. (g) Vesely, J.; Ibrahem, I.; Zhao, G.-L.;
Rios, R.; Xu, Y.; Córdova, A. Angew. Chem. Int. Ed. 2007,
46, 778.
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Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York

1572
G. Luo et al.
SPECIAL TOPIC
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(13) Determined by measurement of the optical rotations of the
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Synthesis 2009, No. 9, 1564–1572 © Thieme Stuttgart · New York