Organocatalytic enantioselective aza-Michael additions of N-heterocycles to α,β-unsaturated enones

Article abstract of DOI:10.1002/ejoc.200901227

A procedure for enantioselective organocatalytic conjugate additions of a variety of N-heterocycles to α,β-unsaturated enone systems is presented. The reactions are efficiently catalyzed by salts of 9-amino-9-deoxy-epiquinine (3d). Cyclic, acyclic, and aromatic enones can be used in reactions with 1H-benzotriazole (1a) or 5-phenyltetrazole derivatives 12, providing the Michael addition products in high yields and with good to excellent enantioselectivities.

Full text of DOI:10.1002/ejoc.200901227

FULL PAPER
DOI: 10.1002/ejoc.200901227
Organocatalytic Enantioselective aza-Michael Additions of N-Heterocycles to
α,β-Unsaturated Enones
Jian Lv,[a] Hao Wu,[a] and Yongmei Wang*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Nitrogen heterocycles / aza-Michael addition
A procedure for enantioselective organocatalytic conjugate
additions of a variety of N-heterocycles to α,β-unsaturated
enone systems is presented. The reactions are efficiently cat-
alyzed by salts of 9-amino-9-deoxy-epiquinine (3d). Cyclic,
acyclic, and aromatic enones can be used in reactions with
1H-benzotriazole (1a) or 5-phenyltetrazole derivatives 12,
providing the Michael addition products in high yields and
with good to excellent enantioselectivities.
ditions of 5-phenyltetrazole to α,β-unsaturated aldehydes
with high enantioselectivity. Zhong and co-workers[9] have
developed a novel, practical, and highly enantio- and dia-
stereoselective domino reaction based on the use of -pro-
line for the synthesis of functionalized tetrahydro-1,2-oxaz-
ines (THOs).
Chiral primary amines are also effective catalysts for
enantioselective β-additions to α,β-unsaturated carbonyl
compounds.[10] In the case of these α,β-unsaturated systems,
the catalyst activates the substrate through the iminium ion
mechanism, thereby facilitating the addition of the nucleo-
phile to the β-carbon atom. This reaction protocol has been
developed in its organocatalytic version for a number of
different reactions such as Michael additions,[11] Diels–
Alder reactions,[12] cyclopropanation reactions,[13] epoxid-
ation reactions,[14] and aziridination reactions.[15]
Here we wish to describe a more general and efficient
enantioselective process for organocatalytic conjugate ad-
ditions of a broad spectrum of nucleophilic heterocycle spe-
cies to enones, catalyzed by a primary amine organocatalyst
derived from a cinchona alkaloid.[16] The reactions afford
good yields and enantioselectivities with 1H-benzotriazole
and tetrazole as nucleophiles and a diverse array of cyclic,
acyclic, or aromatic enones as electrophiles.
Introduction
Nitrogen-containing heterocycles and their derivatives
have broad application in synthetic, materials, and bio-
logical chemistry, and as a result their synthesis and reactiv-
ity are subjects of considerable interest.[1] Conjugate ad-
dition reactions of nitrogen-centered heterocyclic nucleo-
philes to electron-deficient olefins serve as a powerful pre-
parative method in the area of heterocyclic chemistry. An
asymmetric version of this Michael addition process would
furnish enantiomerically enriched adducts, but to date re-
ports of this reaction are sparse. Jacobsen and Gandel-
man,[2] for example, accomplished additions of a range of
different aromatic N-heterocyclic compounds to unsatu-
rated ketones and imides with high enantioselectivities with
the aid of a chiral Al-salen catalyst, and Miller and co-
workers[3] have described the use of peptides as catalysts for
asymmetric conjugations of azide to unsaturated imides
with moderate to good enantioselectivity. In another report,
Wang and co-workers[4] used 6Ј-hydroxyquinine as a cata-
lyst for asymmetric additions of 1H-benzotriazole to ni-
troolefins and quinine-derived thiourea[5] for addition to
aromatic enones with moderate enantioselectivities. Mac-
Millan and co-worker[6] demonstrated the enantioselective
formation of β-amino aldehydes through additions of O-
(tert-butyldimethylsilyl)-protected carbamates to α,β-unsat-
urated aldehydes, Jørgensen and co-workers[7] succeeded in
additions of 1,2,4-triazoles to α,β-unsaturated aldehydes
with high enantioselectivities with the aid of a chiral 2-
[bis(3,5-bis-trifluoromethylphenyl)(trimethylsilanyloxy)-
methyl]pyrrolidine catalyst, and Vicario and co-workers[8]
used a chiral imidazolidinone as catalyst for asymmetric ad-
Results and Discussion
In an exploratory study, a series of chiral amines were
screened as bifunctional organocatalysts for their ability to
promote the Michael addition reaction between 1H-benzo-
triazole (1a) and cyclohex-2-en-1-one (2a) in PhCH3 at
room temperature (Table 1). The results of this investigation
revealed that the aminocatalysts 3a–f differed significantly
with regard to catalytic activity and stereo- and regiocon-
trol of the process. Interestingly, secondary amines such as
3a (Table 1, Entry 1) afforded poor results. Because the rela-
[a] Department of Chemistry, the Key Laboratory of Elemento-
Organic Chemistry, Nankai University,
97 Weijin Road, Tianjin 300071, Republic of China
Fax: +86-22-23502654
E-mail: ymw@nankai.edu.cn
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J. Lv, H. Wu, Y. Wang,
Table 1. Catalytic asymmetric Michael addition reaction between 1H-benzotriazole (1a) and cyclohex-2-en-1-one (2a).[a]
FULL PAPER
Entry
Cat.
Additive
Time
[h]
Yield [%][b]
ee [%][c]
4a
5a
4a
5a
1
2
3
3a
3b
3c
3d
3d
3d
3d
3d
3d
3d
3e
3f
PhCO2H
PhCO2H
–
24
24
24
4
4
3
12
24
4
4
4
30
30
50
60
67
72
72
42
66
60
70
75
10
20
25
30
33
28
24
15
33
40
30
25
0
–74
0
0
–61
0
4
–
38
73
86
90
75
55
45
–80
55
40
72
83
90
80
65
81
–78
58
5[d]
6
PhCO2H
PhCO2H
PhCO2H
PhCO2H
TFA[g]
7[e]
8[f]
9
10
11
12
TMA[g]
PhCO2H
PhCO2H
4
[a] Reaction conditions: 1a (0.125 mmol), 2a (0.60 mmol), 3 (20 mol-%), and additive (40 mol-%) in PhCH3 (1.25 mL) were stirred at room
temperature. [b] Isolated yield. [c] Determined by HPLC analysis. [d] PhCOOH: 20 mol-%. [e] Reaction temperature: 0 °C. [f] Reaction
temperature: –20 °C. [g] TFA = trifluoroacetic acid; TMA = p-methylmandelic acid.
tive bulkiness of secondary amines might be unfavorable for Table 2. Effect of solvent on the catalytic asymmetric Michael ad-
dition reaction between 1H-benzotriazole (1a) and cyclohex-2-en-
the formation of iminium ions with α,β-unsaturated
ketones, we wondered whether primary amines might be
1-one (2a).[a]
more suitable for enone activation as a result of their re-
duced steric requirements.
Preliminary studies confirmed that the primary amine 3b
was able to promote the reaction with moderate catalytic
efficiency, enantioselectivity, and regioselectivity (Table 1,
Entry 2). Subsequently we found that 9-amino-9-deoxy-
epiquinine (3d) provided the products in high yields (reac-
tion time only 4 h; 90% total yield of 4a and 5a) but with
poor enantioselectivities (38% ee, Entry 4). Of the systems
Entry Solvent
Yield [%][b]
ee [%][c]
tested, a combination of PhCOOH (40 mol-%) and 3d
(20 mol-%), which was very recently described as an effec-
tive catalyst for enone activation, has the most favorable
characteristics in terms of reaction time (4 h) and enantio-
selectivity with respect both to 4a and to 5a (86% and 83%,
respectively) at room temperature (Table 1, Entry 6). We
also found that lowering the temperature to 0 °C resulted
in an improved enantioselectivity without any significant
lowering of yield, although with an increase in reaction time
(Table 1, Entry 7). A much longer reaction time (24 h) was
required when the reaction temperature was –20 °C
(Table 1, Entry 8) and enantioselectivity was reduced. Sol-
4a
5a
4a
5a
1
2
3
4
5
6
PhCH3
CH2Cl2
CHCl3
THF
CH3OH
H2O
72
70
75
69
30
20
24
30
25
31
30
60
90
56
63
83
0
90
64
70
72
21
0
–10
[a] Reaction conditions: 1a (0.125 mmol), 2a (0.60 mmol), 3d
(20 mol-%), and PhCOOH (40 mol-%) in solvent (1.25 mL) were
stirred at 0 °C. [b] Isolated yield. [c] Determined by HPLC analysis.
Parts a and b of Figure 1 show the effects of the concen-
vent effects were also examined and it was found that tration of the reaction mixture and the mol ratio of cyclo-
PhCH3 was ideal for this process (Table 2). hexenone 2a to 1H-benzotriazole (1a), respectively, on the
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Enantioselective aza-Michael Additions of N-Heterocycles
enantioselectivity for the Michael addition between 1H- Table 3. 1,4-Additions between 1H-benzotriazole (1a) and cyclic
α,β-unsaturated enones 2.[a]
benzotriazole and cyclohexenone. As can be seen from Fig-
ure 1 (a), an increase in the enantioselectivity (from 67 to
90% ee for 4a and from 65 to 90% ee for 5a) was observed
with decreasing concentration of the reaction mixture (Fig-
ure 1, a), whereas at higher concentrations the enantio-
selectivity decreased. In addition, it was found that the
enantioselectivity could be increased to 90% ee if the 2a/1a
mol ratio were increased to 4.8. In this regard, optimum
conditions were found to depend significantly on the
amount of 2a and the concentration of 1a.
[a] Reaction conditions: 1a (0.125 mmol),
2 (0.60 mmol), 3d
(20 mol-%), and PhCO2H (40 mol-%) were stirred at 0 °C in
PhCH3 (1.25 mL). [b] Isolated yield. [c] Determined by HPLC
analysis.
enantioselectivities generally comparable with those ob-
tained with the cyclohex-2-en-1-one systems 2. Oct-3-en-2-
one (6b, Entry 2) and oct-2-en-3-one (6c, Entry 3) worked
just as well as the truncated linear enone pent-3-en-2-one
(6a, Entry 1), all with very good yields and enantio-
selectivities. Furthermore, the branched example 6d (En-
Figure 1. a) Enantioselectivity with respect to 4a and 5a against the
concentration of 1a in the Michael addition between 1H-benzotri-
azole (1a, 1 equiv.) and cyclohexenone 2a (4.8 equiv.). b) Enantio-
selectivity with respect to 4a and 5a against the mol ratio of cyclo-
hexenone 2a to 1H-benzotriazole (1a); the concentration of 1a is
0.1 molL–1.
Enantioselective organocatalytic Michael additions were try 4) also worked well and was obtained in good yields
first investigated with cyclic enones (Table 3). It was pleas- (75% for 7d and 25% for 8d), with retention of the high
ing to find that as well as the known compounds 4a and enantioselectivities (94% ee for 7d and 97% ee for 8d).
5a, the seven-membered congeners (Table 3, Entry 2) were
To explore the scope of the reactions further, a series of
also formed with similarly high yields (60% for 4b and 30% aromatic E-α,β-unsaturated enones (Table 5) were used as
for 5b) and enantioselectivities (95% ee for 4b and 97% ee substrates in 1,4-additions with 1H-benzotriazole (1a). As
for 5b). Moreover, 4,4-dimethylcyclohex-2-en-1-one (2c) a result of the poor solubilities of 9d and 9f, PhCH3/CHCl3
also served as an effective Michael acceptor with 1H-benzo- (7:3) was used instead. Because H2O would be generated
triazole (1a), giving the major product 4c in 83% yield and during the formation of an active iminium intermediate, the
with 90% ee and excellent regioselectivity (Entry 3). In fact, expected hydrogen-bonding interaction might be affected.
only the five-membered cyclopent-2-en-1-one (Entry 4) gave Consequently, molecular sieves (4 Å) were added to remove
only moderate enantioselectivity (63% ee for 4d and 35% ee the trace amounts of water. In this way, the ee value for the
for 5d), but retained the high yields (75% for 4d and 15% major product 10a was raised from 86% to 90%, although
for 5d).
the reaction time had to be extended, probably because the
1H-Benzotriazole (1a) was next applied in additions with hydrolysis of the iminium salt to release the catalyst would
linear E-enones (Table 4). Again, it was most encouraging be retarded after the completion of Michael addition (En-
to see that they did indeed react with high yields and try 2). It was pleasing to find that these reactions also
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J. Lv, H. Wu, Y. Wang,
FULL PAPER
Table 4. 1,4-Additions between 1H-benzotriazole (1a) and the lin-
ear α,β-unsaturated enones 6.[a]
Table 5. 1,4-Additions between 1H-benzotriazole (1a) and the aro-
matic α,β-unsaturated enones 9.[a]
[a] Reaction conditions: 1a (0.125 mmol),
6 (0.60 mmol), 3d
(20 mol-%), and PhCO2H (40 mol-%) were stirred at 0 °C in
PhCH3 (1.25 mL). [b] Isolated yield. [c] Determined by HPLC
analysis.
worked very well and that the Michael adducts were all
formed in moderate yields and with generally excellent
enantioselectivities. Both electron-withdrawing (Cl, En-
tries 5 and 7) and electron-donating (Me, Entries 4 and 6)
substituents can be introduced on the aromatic ring without
deterioration in yield or enantioselectivity.
[a] Reaction conditions: 1a (0.125 mmol),
9 (0.60 mmol), 3d
(20 mol-%), PhCO2H (40 mol-%), and mol. sieves (4 Å, 10 mg)
were stirred at 0 °C in PhCH3 (1.25 mL). [b] Isolated yield. [c] De-
termined by HPLC analysis. [d] Without mol. sieves. [e] PhCH3/
CHCl3 (7:3) as solvent.
Determination of the absolute configurations of the
newly generated stereogenic centers was performed by
chemical correlation as follows: the aza-Michael reaction
between 9d and 1H-benzotriazole, under the conditions
very recently reported by Wang,[5] furnished levorotatory
(R)-3-(1H-benzotriazol-1-yl)-3-(4-chlorophenyl)-1-phenyl-
propan-1-one {10d, [α]D25 = + 9.7 (c = 0.6, CHCl3)}, whereas
adduct 10d as obtained by us in the presence of catalyst 3d
was in the form of the levorotatory isomer {[α]2D5 = + 26.8
(c = 0.6, CHCl3)}. For the reaction between 9 and 1a we
thus propose a plausible, albeit very naive, catalytic mode
based on the absolute and relative configurations of the N-
heterocycle derivative 10d (Scheme 1). The ketiminium cat-
ion formed between 3d and enone 9d might adopt a trans
conformation, and a hydrogen bond could be formed from
the bridgehead nitrogen of 3d and the NH group of 1H-
benzotriazole (1a) to produce concerted communication. As
a result of the steric hindrance and bifunctional effect, re-
face selectivity would be enforced to give the desired
Michael addition products 10d and 11d.
Scheme 1. Proposed mode of Michael addition between 1a and 9d
with catalysis by the multifunctional salt of 3d.
giving products 13 in 85–95% yields and with 90–98% ee
In further investigations, we examined the reactivities of values and excellent regioselectivities. Both electron-with-
other nitrogen heterocycles in these aza-Michael additions. drawing (Cl, Entry 8) and electron-donating (Me, Entries 5–
The 5-phenyl-1H-tetrazole derivatives 12 served as effective 7) substituents can be introduced on the aromatic ring of
Michael donors in reactions with α,β-unsaturated (E)-en- 5-phenyl-1H-tetrazole without deterioration in yield or
ones at lower temperatures (from 0 °C to –20 °C, Table 6), enantioselectivity. Moreover, the position of the substituent
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Enantioselective aza-Michael Additions of N-Heterocycles
Table 6. 1,4-Additions of 5-phenyltetrazole derivatives to α,β-unsaturated enones.[a]
[a] Reaction conditions: 12 (0.125 mmol), enone (0.60 mmol), 3d (20 mol-%), and PhCO2H (40 mol-%) were stirred at –20 °C in PhCH3
(1.25 mL). [b] Isolated yield. [c] Determined by HPLC analysis. [d] Reaction temperature 0 °C. [e] PhCH3/CHCl3 (7:3) as the solvent and
mol. sieves (4 Å, 10 mg) as additives.
(a methyl group, for example) on the aromatic ring seems veloped. The reactions are efficiently catalyzed by salts of 9-
to have no influence except when in the ortho-position (En- amino-9-deoxy-epiquinine (3d). Cyclic, acyclic, and aromatic
try 7). Furthermore, we found that the use of mol. sieves enones can be used and the reactions with 1H-benzotriazole
(4 Å) as additives and PhCH3/CHCl3 (7:3) as the solvent (1a) provide the Michael addition products in high yields and
were crucial in order to obtain high enantioselectivities in with good to excellent enantioselectivities. We found strong
the Michael addition between 5-phenyl-1H-tetrazole (12a) effects of the concentration of the reaction mixture and the
and (E)-4-phenylbut-3-en-2-one (9a).
ratio of cyclohexenone 2a to 1H-benzotriazole (1a) on the
enantioselectivity for the Michael addition between 1H-
benzotriazole and cyclohexenone 2a. Moreover, the 5-
phenyl-1H-tetrazole derivatives 12 also served as effective
Michael donors in reactions with α,β-unsaturated (E)-en-
ones, giving products 13 in 85–95% yields and with 90–
98% ee values and excellent regioselectivities.
Conclusions
In summary, a procedure for enantioselective organocata-
lytic conjugate additions between a variety of N-heterocyclic
compounds and α,β-unsaturated enone systems has been de-
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J. Lv, H. Wu, Y. Wang,
FULL PAPER
124.1, 120.3, 109.3, 56.4, 49.3, 44.0, 37.0, 26.5, 23.6 ppm. HRMS
(ESI): calcd. for C13H16N3O: 230.1288 [M + H]+; found 230.1286;
HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 85:15, 1.0 mL
min–1): tR (4b minor) = 14.5, tR (4b major) = 16.6 min (95% ee).
Experimental Section
General: Commercial reagents were used as received, unless other-
wise stated. Catalysts 3c, 3d, and 3f were synthesized by literature
procedures.[17] 1H and 13C NMR spectra were recorded with Bruker
DPX 300 or 400 spectrometers. Chemical shifts are reported in
ppm from tetramethylsilane with the solvent resonance as the in-
ternal standard. Accurate mass data were obtained with an Agilent
Technologies 6520 Accurate-Mass Q-TOF LC/MS instrument by
electrospray ionization (ESI). Optical rotations were measured with
a Perkin–Elmer 341 polarimeter at 20 °C. HPLC analysis was per-
formed with a Shimadzu CTO-10AS instrument and a Chi-
ralpak AD-H column purchased from Daicel Chemical Industries,
LTD.
(S)-3-(2H-Benzotriazol-2-yl)cycloheptanone (5b): The title com-
pound was obtained by the General Procedure described above,
from 1a and 2b. Yield 30% (8.6 mg). [α]2D0 = +4.0 (c = 0.5, CH2Cl2).
3
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.86 [dd, J(H,H)
= 3.1, 6.6 Hz, 2 H, Ar-H], 7.40 [dd, 3J(H,H) = 3.1, 6.6 Hz, 2 H, Ar-
H], 5.23–5.16 (m, 1 H, N–CH), 3.56 [dd, 3J(H,H) = 10.8, 15.1 Hz, 1
H, CH2], 3.08 [dd, 3J(H,H) = 2.5, 15.1 Hz, 1 H, CH2], 2.75–2.57
(m, 2 H, CH2), 2.47–2.42 (m, 2 H, CH2), 2.08–1.96 (m, 2 H, CH2),
1.90–1.79 (m, 1 H, CH2), 1.76–1.66 (m, 1 H, CH2) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 209.4, 144.0, 126.4, 118.1, 63.3,
49.3, 44.2, 37.5, 26.6, 23.7 ppm. HRMS (ESI): calcd. for
C13H15N3ONa: 252.1107; found 252.1109 [M + Na]+; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 mL min–1): tR (5b
minor) = 16.6, tR (5b major) = 17.0 min (97% ee).
Typical Procedure for Additions of 1H-Benzotriazole to Cyclic α,β-
Unsaturated Enones: PhCOOH (40 mol-%) was added to a stirred
solution of catalyst 3d (20 mol-%) in PhCH3 (1.25 mL), and the
solution was stirred for 5 minutes at room temperature. After ad-
dition of enone 2 (0.60 mmol), the mixture was stirred for 10 min-
utes. The benzotriazole 1a (0.125 mmol) was added at 0 °C, and
stirring was continued for the indicated time, resulting in a mixture
of regioisomers. The crude reaction mixture was then loaded onto
a silica gel column for purification (EtOAc/hexane, 1:5), to afford
the Michael adduct.
(R)-3-(1H-Benzotriazol-1-yl)-4,4-dimethylcyclohexanone (4c): The
title compound was obtained by the General Procedure described
above, from 1a and 2c. Yield 83% (25.2 mg). [α]2D0 = +6.1 (c = 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.08 [d,
3J(H,H) = 8.4 Hz, 1 H, Ar-H], 7.50 [d, 3J(H,H) = 3.6 Hz, 2 H, Ar-
3
H], 7.40–7.36 (m, 1 H, Ar-H), 4.78 [dd, J(H,H) = 5.1, 10.0 Hz, 1
H, N–CH], 3.46 [ddd, 3J(H,H) = 1.0, 10.0, 15.6 Hz, 1 H, CH2],
(S)-3-(1H-Benzotriazol-1-yl)cyclohexanone (4a): The title com-
pound was obtained by the General Procedure described above,
from 1a and 2a. Yield 72% (19.4 mg). [α]2D0 = + 21 (c = 0.5 in
3
2.84 [ddd, J(H,H) = 1.6, 5.1, 15.7 Hz, 1 H, CH2], 2.75–2.67 (m, 1
H, CH2), 2.57–2.49 (m, 1 H, CH2), 2.10–2.03 (m, 1 H, CH2), 1.83–
1.75 (m, 1 H, CH2), 1.34 (s, 3 H, CH3), 1.10 (s, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 207.1, 145.2, 133.8,
127.5, 124.0, 120.1, 109.5, 64.1, 43.6, 37.5, 36.2, 36.0, 28.0,
21.9 ppm. HRMS (ESI): calcd. for C14H18N3O: 244.1444 [M +
H]+; found 244.1447; HPLC (Chiralpak AD-H, hexanes/propan-2-
ol, 85:15, 1.0 mL min–1): tR (4c minor) = 12.0, tR (4c major) =
14.1 min (89% ee).
1
CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.10 [d,
3J(H,H) = 8.3 Hz, 1 H, Ar-H], 7.54–7.52 (m, 2 H, Ar-H), 7.44–
7.38 (m, 1 H, Ar-H), 5.10–5.00 (m, 1 H, N–CH), 3.32 [dd, 3J(H,H)
3
= 10.9, 14.4 Hz, 1 H, CH2], 2.97 [dd, J(H,H) = 4.5, 14.4 Hz, 1 H,
CH2], 2.59-2.39 (m, 4 H, CH2), 2.27–2.16 (m, 1 H, CH2), 1.93–1.77
(m, 1 H, CH2) ppm. 13C NMR (75 MHz, CDCl3 25 °C, TMS): δ =
206.7, 146.0, 132.1, 127.5, 124.3, 120.3, 109.0, 56.9, 47.1, 40.6, 31.0,
22.0 ppm. HRMS (ESI): calcd. for C12H14N3O: 216.1131 [M + H]
+; found 216.1129; HPLC (Chiralpak AD-H, hexanes/propan-2-ol,
85:15, 1.0 mL min–1): tR (4a minor) = 13.6, tR (4a major) =
17.4 min (90% ee).
(S)-3-(1H-Benzotriazol-1-yl)cyclopentanone (4d): The title com-
pound was obtained by the General Procedure described above,
from 1a and 2d. Yield 81% (20.3 mg). [α]2D0 = +5.0 (c = 0.2,
1
CH2Cl2). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.10 [d,
3J(H,H) = 8.4 Hz, 1 H, Ar-H], 7.58–7.52 (m, 2 H, Ar-H), 7.44–
(S)-3-(2H-Benzotriazol-2-yl)cyclohexanone (5a): The title com-
pound was obtained by the General Procedure described above,
from 1a and 2a. Yield 24% (6.4 mg). [α]2D0 = +28.1 (c = 0.5 in
7.40 (m, 1 H, Ar-H), 5.50-5.44 (m, 1 H, N–CH), 3.12 [dd, 3J(H,H)
3
= 18.5, 5.9 Hz, 1 H, CH2], 2.94 [dd, J(H,H) = 7.7, 18.6 Hz, 1 H,
CH2], 2.51-2.44 (m, 1 H, CH2) ppm. 13C NMR (100 MHz, CDCl3
25 °C, TMS): δ = 214.0, 146.2, 132.5, 127.7, 124.4, 120.3, 109.1,
55.9, 44.1, 36.7, 29.7 ppm. HPLC (Chiralpak AD-H, hexanes/pro-
pan-2-ol, 85:15, 1.0 mL min–1): tR (4d minor) = 13.9, tR (4d major)
= 17.0 min (34% ee).
1
CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.78 [dd,
3J(H,H) = 2.7, 6.4 Hz, 2 H Ar-H], 7.31 [dd, 3J(H,H) = 2.7, 6.4 Hz,
3
2 H, Ar-H], 5.23–5.10 (m, 1 H, N–CH), 3.18 [dd, J(H,H) = 9.6,
14.6 Hz, 1 H, CH2], 2.92 [dd, J(H,H) = 4.5, 14.6 Hz, 1 H, CH2],
3
2.46–2.36 (m, 4 H, CH2), 2.03–1.96 (m, 1 H, CH2), 1.83–1.71 (m,
1 H, CH2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
206.7, 144.1, 126.5, 118.1, 64.1, 46.7, 40.5, 31.5, 21.4 ppm. HRMS
(ESI): calcd. for C12H13N3ONa: 238.0951; found 238.0947 [M +
Na]+; HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 95:5,
1.0 mL min–1): tR (5a major) = 15.8, tR (5a minor) = 18.0 min
(90% ee).
(S)-3-(2H-Benzotriazol-2-yl)cyclopentanone (5d): The title com-
pound was obtained by the General Procedure described above,
from 1a and 2d. Yield 10% (2.5 mg). [α]2D0 = +15.0 (c = 0.2,
1
CH2Cl2). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.86 [dd,
3J(H,H) = 3.1, 6.6 Hz, 2 H, Ar-H], 7.86 [dd, 3J(H,H) = 3.1, 6.6 Hz,
2 H, Ar-H], 5.69–5.63 (m, 1 H, N–CH), 3.01 [ddd, 3J(H,H) = 6.19,
18.65, 26.28 Hz, 2 H, CH2], 2.72–2.66 (m, 3 H, CH2), 2.42–2.35
(m, 1 H, CH2) ppm. 13C NMR (100 MHz, CDCl3 25 °C, TMS):
δ = 214.5, 144.3, 126.6, 118.1, 63.3, 44.7, 36.2, 30.3 ppm. HPLC
(Chiralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 mL min–1): tR
(5a major) = 12.3, tR (5a minor) = 13.9 min (60% ee).
(S)-3-(1H-Benzotriazol-1-yl)cycloheptanone (4b): The title com-
pound was obtained by the General Procedure described above,
from 1a and 2b. Yield 60% (17.2 mg). [α]2D0 = –20.2 (c = 0.5,
1
CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.08 [d,
3J(H,H) = 8.3 Hz, 1 H, Ar-H], 7.57–7.48 (m, 2 H, Ar-H), 7.42–
7.37 (m, 1 H, Ar-H), 5.05–4.96 (m, 1 H, N–CH), 3.64 [dd, 3J(H,H) Typical Procedure for Additions of 1H-Benzotriazole to Linear α,β-
= 11.4, 14.1 Hz, 1 H, CH2], 2.97 [ddd, 3J(H,H) = 2.1, 3.9, 13.8 Hz,
Unsaturated Enones: PhCOOH (40 mol-%) was added to a stirred
1 H, CH2], 2.83–2.33 (m, 4 H, CH2), 2.16–2.05 (m, 2 H, CH2), solution of catalyst 3d (20 mol-%) in PhCH3 (1.25 mL) and the
1.97–1.84 (m, 1 H, CH2), 1.70–1.59 (m, 1 H, CH2) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 209.7, 146.1, 131.8, 127.4,
solution was stirred for 5 minutes at room temperature. After ad-
dition of the enone 6 (0.60 mmol), the mixture was stirred for 10
2078
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Eur. J. Org. Chem. 2010, 2073–2083

Enantioselective aza-Michael Additions of N-Heterocycles
minutes. The benzotriazole 1a (0.125 mmol) was added at 0 °C, and
stirring was continued for the indicated time, resulting in a mixture
of regioisomers. The crude reaction mixture was then loaded onto
a silica gel column for purification (EtOAc/hexane, 1:5), to afford
the Michael adduct.
(S)-2-(1H-Benzotriazol-2-yl)octan-4-one (7c): The title compound
was obtained by the General Procedure described above, from 1a
and 6c. Yield 66% (20.2 mg). [α]2D0 = +7.9 (c = 0.7, CH2Cl2). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.02 [d, 3J(H,H) =
8.4 Hz, 1 H, Ar-H], 7.62 [d, 3J(H,H) = 8.4 Hz, 1 H, Ar-H], 7.48 [t,
3
3J(H,H) = 7.3 Hz, 1 H, Ar-H], 7.34 [t, J(H,H) = 7.6 Hz, 1 H, Ar-
(S)-4-(1H-Benzotriazol-1-yl)pentan-2-one (7a): The title compound
was obtained by the General Procedure described above, from 1a
3
H], 5.44–5.36 (m, 1 H, N–CH), 3.55 [dd, J(H,H) = 7.8, 17.7 Hz,
1 H, COCH2], 3.09 [dd, 3J(H,H) = 5.7, 17.7 Hz, 1 H, COCH2],
2.45–2.30 (m, 2 H, CH2), 1.66 [d, 3J(H,H) = 6.8 Hz, 3 H, CH3],
1.49–1.42 (m, 2 H, CH2), 1.24–1.15 (m, 2 H, CH2), 0.82 [t, 3J(H,H)
= 7.3 Hz, 3 H] ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ
= 207.8, 145.8, 132.6, 127.2, 123.9, 119.8, 109.7, 50.2, 48.3, 43.1,
25.5, 22.1, 21.2, 13.7 ppm. HRMS (ESI): calcd. for C14H20N3O:
246.1601 [M + H]+; found 246.1603; HPLC (Chiralpak AD-H, hex-
anes/propan-2-ol, 95:5, 1.0 mL min–1): tR (7c minor) = 12.7, tR (7c
major) = 15.7 min (95% ee).
1
and 6a. Yield 75% (19.0 mg). [α]2D0 = +15.4 (c = 0.5, CH2Cl2). H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.04 [d, 3J(H,H) =
8.4 Hz, 1 H, Ar-H], 7.64 [d, 3J(H,H) = 8.4 Hz, 1 H, Ar-H], 7.50 [t,
3
3J(H,H) = 7.6 Hz, 1 H, Ar-H], 7.36 [t, J(H,H) = 7.6 Hz, 1 H, Ar-
3
H], 5.45–5.33 (m, 1 H, N–CH), 3.60 [dd, J(H,H) = 7.7, 18.0 Hz,
3
1 H, CH2], 3.15 [dd, J(H,H) = 5.7, 18.0 Hz, 1 H, CH2], 2.15 (s, 3
H, COCH3), 1.68 [d, 3J(H,H) = 6.8 Hz, 3 H, CH3] ppm. 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 205.2, 145.8, 132.6, 127.2,
124.0, 119.8, 109.7, 50.2, 49.1, 30.4, 21.2 ppm. HRMS (ESI): calcd.
for C11H14N3O: 204.1131 [M + H]+; found 204.1133; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 90:10, 1.0 mL min–1): tR (7a
minor) = 11.1, tR (7a major) = 11.8 min (90% ee).
(S)-2-(2H-Benzotriazol-2-yl)octan-4-one (8c): The title compound
was obtained by the General Procedure described above, from 1a
1
and 6c. Yield 33% (10.1 mg). [α]2D0 = –22.7 (c = 0.8, CH2Cl2). H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.85 [dd, 3J(H,H) =
(S)-4-(2H-Benzotriazol-2-yl)pentan-2-one (8a): The title compound
was obtained by the General Procedure described above, from 1a
and 6a. Yield 18% (4.5 mg). [α]2D0 = +16.1 (c = 0.5, CH2Cl2). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.77 [dd, 3J(H,H) =
3
3.1, 6.5 Hz, 2 H, Ar-H], 7.37 [dd, J(H,H) = 3.1, 6.6 Hz, 2 H, Ar-
3
H], 5.57–5.44 (m, 1 H, N–CH), 3.49 [dd, J(H,H) = 7.1, 17.5 Hz,
1 H, COCH2], 3.04 [dd, 3J(H,H) = 6.6, 17.5 Hz, 1 H, COCH2],
3
3
2.43 [t, J(H,H) = 7.4 Hz, 2 H, CH2], 1.70 [d, J(H,H) = 6.7 Hz, 3
H, COCH3], 1.53 [td, 3J(H,H) = 7.4, 15.2 Hz, 2 H, CH2], 1.32–1.20
(m, 2 H, CH2), 0.86 [t, 3J(H,H) = 7.3 Hz, 3 H, CH3] ppm. 13C
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 207.2, 144.0, 126.2,
118.2, 58.5, 48.3, 43.0, 25.6, 22.2, 21.4, 13.9 ppm. HRMS (ESI):
calcd. for C14H19N3ONa: 268.1420 [M + Na]+; found 268.1418;
HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 m min–1):
tR (8c minor) = 7.6, tR (8c major) = 9.0 min (99% ee).
3
3.1, 6.6 Hz, 2 H, Ar-H], 7.29 [dd, J(H,H) = 3.1, 6.6 Hz, 2 H, Ar-
3
H], 5.50–5.38 (m, 1 H, N–CH), 3.46 [dd, J(H,H) = 7.2, 17.7 Hz,
1 H, COCH2], 2.99 [dd, 3J(H,H) = 6.4, 17.7 Hz, 1 H, COCH2],
3
2.11 (s, 3 H, COCH3), 1.63 [d, J(H,H) = 6.8 Hz, 3 H, CH3] ppm.
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 204.7, 144.0, 126.2,
118.0, 58.4, 49.2, 30.4, 21.4 ppm. HRMS (ESI): calcd. for
C11H13N3ONa: 226.0951 [M + Na]+; found 226.0947; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 90:10, 1.0 mL min–1): tR (8a
minor) = 6.5, tR (8a major) = 6.9 min (93% ee).
(R)-4-(1H-Benzotriazol-1-yl)-5-methylhexan-2-one (7d): The title
compound was obtained by the General Procedure described
above, from 1a and 6d. Yield 75% (21.7 mg). [α]2D0 = –25.0 (c = 0.6,
(S)-4-(1H-Benzotriazol-1-yl)octan-2-one (7b): The title compound
was obtained by the General Procedure described above, from 1a
and 6b. Yield 70% (21.4 mg). [α]2D0 = +9.3 (c = 0.6, CH2Cl2). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.03 [d, 3J(H,H) =
8.4 Hz, 1 H, Ar-H], 7.65 [d, 3J(H,H) = 8.4 Hz, 1 H, Ar-H], 7.49 [t,
1
CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.02 [d,
3J(H,H) = 8.3 Hz, 1 H, Ar-H], 7.64 [d, 3J(H,H) = 8.4 Hz, 1 H, Ar-
H], 7.49 [t, 3J(H,H) = 7.5 Hz, 1 H, Ar-H], 7.35 [t, 3J(H,H) =
3
3
3J(H,H) = 7.6 Hz, 1 H, Ar-H], 7.36 [t, J(H,H) = 7.6 Hz, 1 H, Ar-
8.1 Hz, 1 H, Ar-H], 5.06–5.00 (m, 1 H, N–CH), 3.75 [dd, J(H,H)
3
3
= 9.9, 17.8 Hz, 1 H, COCH2], 3.10 [dd, J(H,H) = 3.5, 17.8 Hz, 1
H], 5.29–5.20 (m, 1 H, N–CH), 3.57 [dd, J(H,H) = 8.4, 18.0 Hz,
3
H, COCH2], 2.44–2.32 (m, 1 H, CH), 2.09 (s, 3 H, COCH3), 1.00
1 H, OCH2], 3.13 [dd, J(H,H) = 5.0, 18.0 Hz, 1 H, OCH2], 2.24–
3
3
[d, J(H,H) = 6.8 Hz, 3 H, CH3], 0.79 [d, J(H,H) = 6.7 Hz, 3 H,
CH3] ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 205.5,
145.4, 134.1, 127.2, 123.9, 119.8, 110.0, 59.9, 45.1, 33.3, 30.5, 19.6,
19.0 ppm. HRMS (ESI): calcd. for C13H18N3O: 232.1444 [M +
H]+; found 232.1440; HPLC (Chiralpak AD-H, hexanes/propan-2-
ol, 90:10, 1.0 mL min–1): tR (7d minor) = 8.8, tR (7d major) =
9.2 min (96% ee).
2.13 (m, 1 H, CH2), 2.01 (s, 3 H, COCH3), 2.01–1.89 (m, 1 H,
CH2), 1.31–1.13 (m, 3 H, CH2CH2), 1.01–0.91 (m, 1 H, CH2), 0.79
(t, J = 7.2 Hz, 3 H, CH2CH2) ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 205.3, 145.6, 133.5, 127.2, 123.9, 119.8, 109.8,
54.5, 48.2, 45.1, 30.4, 28.0, 22.1, 13.8 ppm. HRMS (ESI): calcd. for
C14H20N3O: 246.1601 [M + H]+; found 246.1600; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 mL min–1): tR (7b
minor) = 15.8, tR (7b major) = 16.9 min (94% ee).
(R)-4-(2H-Benzotriazol-2-yl)-5-methylhexan-2-one (8d): The title
compound was obtained by the General Procedure described
above, from 1a and 6d. Yield 20% (5.8 mg). [α]2D0 = –5.6 (c = 0.6,
(S)-4-(3H-Benzotriazol-2-yl)octan-2-one (8b): The title compound
was obtained by the General Procedure described above, from 1a
and 6b. Yield 20% (6.1 mg). [α]2D0 = +17.4 (c = 0.6, CH2Cl2). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.86 [dd, 3J(H,H) =
1
CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.84 [dd,
3J(H,H) = 3.1, 6.6 Hz, 2 H, Ar-H], 7.34 [dd, 3J(H,H) = 3.1, 6.6 Hz,
3
3
3.1, 6.5 Hz, 2 H, Ar-H], 7.37 [dd, J(H,H) = 3.1, 6.5 Hz, 2 H, Ar-
2 H, Ar-H], 5.44–5.35 (m, 1 H, N–CH), 3.49 [dd, J(H,H) = 7.8,
3
H], 5.42–5.30 (m, 1 H, N–CH), 3.49 [dd, J(H,H) = 7.8, 17.6 Hz,
17.6 Hz, 1 H, COCH2], 3.08 [dd, 3J(H,H) = 5.8, 17.6 Hz, 1 H,
1 H, COCH2], 3.08 [dd, 3J(H,H) = 5.8, 17.6 Hz, 1 H, COCH2], COCH2], 2.14 (s, 3 H, COCH3), 2.11–1.90 (m, 2 H, CH2), 1.35–
2.14 (s, 3 H, COCH3), 2.11–1.91 (m, 1 H, CH2), 1.31–0.97 (m, 4 1.23 (m, 3 H, CH3), 1.09–0.95 (m, 1 H, CH), 0.82 [t, 3J(H,H) =
H, CH2CH2), 0.82 [t, 3J(H,H) = 7.0 Hz, 3 H, CH3] ppm. 13C NMR
7.02, 7.0 Hz, 3 H, CH3] ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
(75 MHz, CDCl3, 25 °C, TMS): δ = 204.8, 143.9, 126.2, 118.1, 62.8, TMS): δ = 204.8, 143.9, 126.2, 118.1, 62.85, 48.1, 35.4, 30.3, 27.8,
48.1, 35.4, 30.3, 27.8, 22.1, 13.8 ppm. HRMS (ESI): calcd. for
C14H19N3ONa: 268.1420 [M + Na]+; found 268.1416; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 mL min–1): tR (8b
minor) = 5.8, tR (8b major) = 6.4 min (97% ee).
22.1, 13.8 ppm. HRMS (ESI): calcd. for C13H17N3ONa: 254.1264
[M + Na]+; found 254.1261; HPLC (Chiralpak AD-H, hexanes/
propan-2-ol, 95:5, 1 mL min–1): tR (8d minor) = 7.8, tR (8d major)
= 9.7 min (97% ee).
Eur. J. Org. Chem. 2010, 2073–2083
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2079

J. Lv, H. Wu, Y. Wang,
FULL PAPER
Typical Procedure for Additions of 1H-Benzotriazole to Aromatic
302.1267; HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 90:10,
α,β-Unsaturated Enones: PhCOOH (40 mol-%) and MS (4 Å, 1.0 mL min–1): tR (11b minor) = 10.5, tR (11b major) = 12.0 min
10 mg) were added to a stirred solution of catalyst 3d (20 mol-%)
in PhCH3 (1.25 mL) and the solution was stirred for 5 minutes at
room temperature. After addition of an enone 9 (0.60 mmol), the
mixture was stirred for 10 minutes. The benzotriazole 1a
(0.125 mmol) was added at 0 °C, and stirring was continued for the
indicated time, resulting in a mixture of regioisomers. The crude
reaction mixture was then loaded onto a silica gel column for puri-
fication (EtOAc/hexane, 1:5), to afford the Michael adduct.
(97% ee).
(R)-3-(1H-Benzotriazol-1-yl)-1,3-diphenylpropan-1-one (10c): The
title compound was obtained by the General Procedure described
above, from 1a and 9c. Yield 65% (21.2 mg). [α]2D0 = +23.1 (c = 0.6,
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.03 [d,
3J(H,H) = 7.9 Hz, 2 H, Ar-H], 7.88–7.32 (m, 12 H, Ar-H), 6.83 (m,
1 H, N–CH), 4.76 [dd, 3J(H,H) = 9.0, 18.0 Hz, 1 H], 3.91 [dd,
3J(H,H) = 5.0, 18.0 Hz, 1 H] ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 195.9, 146.2, 139.1, 136.3, 133.6, 133.0, 129.1,
128.7, 128.5, 128.3, 127.4, 126.8, 124.1, 119.9, 110.0, 58.4,
44.3 ppm. HRMS (ESI): calcd. for C21H17N3ONa: 350.1624; found
350.1627 [M + Na]+; HPLC (Chiralpak AD-H, hexanes/propan-2-
ol, 70:30, 1.0 mL min–1): tR (10c minor) = 16.0, tR (10c major) =
19.1 min (94% ee).
(R)-4-(1H-Benzotriazol-1-yl)-4-phenylbutan-2-one (10a): The title
compound was obtained by the General Procedure described
above, from 1a and 9a. Yield 70% (23.2 mg). [α]2D0 = +24.1 (c = 0.6,
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.02 [d,
3J(H,H) = 8.1 Hz, 1 H, Ar-H], 7.41–7.29 (m, 8 H, Ar-H), 6.31 [dd,
3J(H,H) = 4.6, 9.4 Hz, 1 H, N–CH], 4.27 [dd, 3J(H,H) = 9.4,
17.7 Hz, 1 H, COCH2], 3.31 [dd, 3J(H,H) = 4.6, 17.7 Hz, 1 H,
COCH2], 2.24 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 204.6, 146.3, 138.8, 133.0, 129.1, 128.5, 127.3,
126.6, 124.1, 119.8, 110.0, 58.3, 48.8, 30.4 ppm. HRMS (ESI):
calcd. for C16H15N3ONa: 288.1107 [M + Na]+; found 288.1110;
HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 90:10, 1 m min–1):
tR (10a minor) = 19.8, tR (10a major) = 20.8 min (90% ee).
(R)-3-(2H-Benzotriazol-2-yl)-1,3-diphenylpropan-1-one (11c): The
title compound was obtained by the General Procedure described
above, from 1a and 9c. Yield 10% (4.1 mg). [α]2D0 = +137.5 (c = 0.4,
1
CHCl3). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.02–7.30
(m, 14 H, Ar-H), 6.78 [dd, 3J(H,H) = 5.0, 9.0 Hz, 1 H, Ar-H], 4.73
[dd, 3J(H,H) = 9.0, 18.0 Hz, 1 H, COCH2], 3.89 [dd, 3J(H,H) =
5.0, 18.0 Hz, 1 H, COCH2] ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 195.5, 144.1, 138.8, 136.2, 133.5, 130.9, 128.9,
128.7, 128.2, 126.8, 126.2, 118.2, 65.7, 44.1 ppm. HRMS (ESI):
calcd. for C21H17N3ONa: 350.1624; found 350.1626 [M + Na]+;
HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 m min–1):
tR (11c minor) = 36.8, tR (11c major) = 45.2 min (97% ee).
(R)-4-(2H-Benzotriazol-2-yl)-4-phenylbutan-2-one (11a): The title
compound was obtained by the General Procedure described
above, from 1a and 9a. Yield 25% (8.3 mg). [α]2D0 = +35 (c = 0.6,
1
CHCl3). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.84 [dd,
3J(H,H) = 3.1, 6.5 Hz, 2 H, Ar-H], 7.37–7.29 (m, 7 H, Ar-H), 6.53
3
3
[dd, J(H,H) = 4.9, 9.5 Hz, 1 H, N–CH], 4.16 [dd, J(H,H) = 9.6,
17.9 Hz, 1 H, COCH2], 3.32 [dd, 3J(H,H) = 4.9, 17.8 Hz, 1 H,
COCH2], 2.23 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 204.2, 144.3, 138.6, 128.9, 128.6, 126.8, 126.3,
118.2, 65.6, 48.5, 30.3 ppm. HRMS (ESI): calcd. for
C16H15N3ONa: 288.1107 [M + Na]+; found 288.1119; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 90:10, 1 mL min–1): tR (11a
minor) = 13.6, tR (11a major) = 18.2 min (96% ee).
(R)-3-(1H-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-phenylpropan-1-
one (10d): The title compound was obtained by the General Pro-
cedure described above, from 1a and 9d. Yield 70 % (31.6 mg).
[α]2D0 = +26.8 (c = 0.85, CHCl3). 1H NMR (400 MHz, CDCl3,
3
25 °C, TMS): δ = 8.03 [d, J(H,H) = 8.3 Hz, 1 H, Ar-H], 7.94 [d,
3J(H,H) = 8.4 Hz, 2 H, Ar-H], 7.51–7.29 (m, 10 H, Ar-H), 6.54
3
3
[dd, J(H,H) = 4.8, 8.9 Hz, 1 H, N–CH], 4.85 [dd, J(H,H) = 9.0,
17.8 Hz, 1 H, COCH2], 3.81 [dd, 3J(H,H) = 4.8, 17.8 Hz, 1 H,
COCH2] ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ =
195.7, 146.5, 140.5, 137.6, 136.1, 134.5, 133.8, 133.0, 129.3, 128.8,
128.3, 17.6, 124.2, 120.0, 109.7, 57.7, 44.4 ppm. HRMS (ESI):
calcd. for C21H17ClN3O: 362.1055 [M + H]+; found 362.1058;
HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 70:30,
1.0 mL min–1): tR (10d minor) = 18.7, tR (10d major) = 31.3 min
(93% ee).
(R)-4-(1H-Benzotriazol-1-yl)-4-(4-methylphenyl)butan-2-one (10b):
The title compound was obtained by the General Procedure de-
scribed above, from 1a and 9b. Yield 80% (27.9 mg). [α]2D0 = +11.7
1
(c = 0.65, CHCl3). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
3
8.01 [d, J(H,H) = 8.3 Hz, 1 H, Ar-H], 7.40–7.28 (m, 3 H, Ar-H),
3
3
7.18 [d, J(H,H) = 8.1 Hz, 2 H, Ar-H], 7.10 [d, J(H,H) = 8.0 Hz,
2 H, Ar-H], 6.27 [dd, 3J(H,H) = 4.8, 9.3 Hz, 1 H, N–CH], 4.25 [dd,
3J(H,H) = 9.3, 17.7 Hz, 1 H, COCH2], 3.30 [dd, 3J(H,H) = 4.8,
17.7 Hz, 1 H, COCH2], 2.28 (s, 3 H, CH3), 2.24 (s, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 204.7, 146.2, 138.4,
138.4, 135.8, 132.9, 129.7, 127.3, 126.5, 124.1, 119.8, 110.1, 58.2,
48.8, 30.5, 21.1 ppm. HRMS (ESI): calcd. for C17H17N3ONa:
302.1264 [M + Na]+; found 302.1266; HPLC (Chiralpak AD-H,
hexanes/propan-2-ol, 90:10, 1.0 mL min–1): tR (11b minor) = 15.8,
tR (11b major) = 22.3 min (89% ee).
(R)-3-(2H-Benzotriazol-2-yl)-3-(4-chlorophenyl)-1-phenylpropan-1-
one (11d): The title compound was obtained by the General Pro-
cedure described above, from 1a and 9d. Yield 15% (6.8 mg). [α]2D0
= +89.7 (c = 0.9, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C,
3
TMS): δ = 8.00 [d, J(H,H) = 7.8 Hz, 2 H, Ar-H], 7.83 [d, 3J(H,H)
3
= 7.4 Hz, 2 H, Ar-H], 7.6 [t, J(H,H) = 7.3 Hz, 1 H, Ar-H], 7.59
3
3
[t, J(H,H) = 7.5 Hz, 1 H, Ar-H], 7.42 [d, J(H,H) = 7.5 Hz, 2 H,
3
3
Ar-H], 7.35 [d, J(H,H) = 7.2 Hz, 2 H, Ar-H], 7.30 [d, J(H,H) =
7.6 Hz, 2 H, Ar-H], 6.75 [t, J(H,H) = 6.8 Hz, 1 H, N–CH], 4.65
3
(R)-4-(2H-Benzotriazol-2-yl)-4-(4-methylphenyl)butan-2-one (11b):
The title compound was obtained by the General Procedure de-
scribed above, from 1a and 9b. Yield 16% (5.6 mg). [α]2D0 = +8.2 (c
= 0.65, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
7.83 [dd, 3J(H,H) = 3.1, 6.6 Hz, 2 H, Ar-H], 7.35–7.11 (m, 6 H,
Ar-H), 6.49 [dd, 3J(H,H) = 5.1, 9.4 Hz, 1 H, N–CH], 4.13 [dd,
3J(H,H) = 9.4, 17.7 Hz, 1 H, COCH2], 3.31 [dd, 3J(H,H) = 5.1,
17.7 Hz, 1 H, COCH2], 2.29 (s, 3 H, CH3), 2.22 (s, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 204.3, 114.2, 138.5,
[dd, 3J(H,H) = 8.3, 18.0 Hz, 1 H, COCH2], 3.92 [dd, 3J(H,H) = 5.4,
18.0 Hz, 1 H, COCH2] ppm. 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ = 195.3, 144.2, 137.3, 136.2, 134.5, 133.7, 129.1, 128.7,
128.4, 128.2, 126.5, 118.2, 65.1, 44.0 ppm. HRMS (ESI): calcd. for
C21H16N3ONa: 384.0874 [M + Na]+; found 384.070; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 70:30, 1.0 mL min–1): tR (11d
minor) = 11.7, tR (11d major) = 14.7 min (96% ee).
(R)-3-(1H-Benzotriazol-1-yl)-3-(4-methylphenyl)-1-phenylpropan-1-
135.7, 129.6, 126.7, 126.3, 118.2, 65.4, 48.4, 30.4, 21.1 ppm. HRMS one (10e): The title compound was obtained by the General Pro-
(ESI): calcd. for C17H17N3ONa: 302.1264 [M + Na]+; found
cedure described above, from 1a and 9e. Yield 52 % (22.2 mg).
2080
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2073–2083

Enantioselective aza-Michael Additions of N-Heterocycles
[α]2D0 = +76.4 (c = 0.95, CHCl3). 1H NMR (400 MHz, CDCl3,
minutes. The 5-phenyltetrazole derivative 12 (0.125 mmol) was
added at –20 °C, and stirring was continued for the indicated time,
resulting in a single of regioisomers. The crude reaction mixture
3
25 °C, TMS): δ = 8.00 [t, J(H,H) = 8.8 Hz, 3 H, Ar-H], 7.59–7.28
3
(m, 8 H, Ar-H), 7.12 [d, J(H,H) = 7.9 Hz, 2 H, Ar-H], 6.54 [dd,
3J(H,H) = 5.0, 8.6 Hz, 1 H, N–CH], 4.83 [dd, 3J(H,H) = 8.7, was then loaded onto a silica gel column for purification (EtOAc/
17.8 Hz, 1 H, COCH2], 3.88 [dd, 3J(H,H) = 5.0, 17.9 Hz, 1 H, hexane, 1:5), to afford the Michael adduct.
COCH3], 2.29 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ = 196.0, 146.2, 138.4, 136.3, 136.1, 133.6, 133.1,
129.7, 128.7, 128.3, 127.3, 126.7, 124.0, 119.9, 110.0, 58.2, 44.5,
(S)-4-(5-Phenyl-2H-tetrazol-2-yl)pentan-2-one (13a): The title com-
pound was obtained by the General Procedure described above,
from 12a and 6a. Yield 88% (20.2 mg). [α]2D0 = –15 (c = 1.5,
21.1 ppm. HRMS (ESI): calcd. for C22H20N3O: 342.1601 [M +
1
CH2Cl2). H NMR (300 MHz, CDCl3 25 °C, TMS): δ = 8.07–8.04
H]+; found 342.1604; HPLC (Chiralpak AD-H, hexanes/propan-2-
(m, 2 H, Ar-H), 7.42–7.39 (m, 3 H, Ar-H), 5.45–5.33 (m, 1 H, N–
ol, 65:35, 1.0 mL min–1): tR (10e minor) = 15.8, tR (10e major) =
CH), 3.39 [dd, 3J(H,H) = 7.0, 17.9 Hz, 1 H, COCH2], 2.97 [dd,
23.2 min (95% ee).
3J(H,H) = 6.6, 17.8 Hz, 1 H, COCH2], 2.14 (s, 3 H, COCH3), 1.61
[d, 3J(H,H) = 6.8 Hz, 3 H, CH3] ppm. 13C NMR (75 MHz, CDCl3,
(R)-3-(2H-Benzotriazol-2-yl)-3-(4-methylphenyl)-1-phenylpropan-1-
25 °C, TMS): δ = 204.1, 164.9, 130.2, 128.8, 127.5, 126.8, 55.9, 48.4,
30.3, 20.9 ppm. HRMS (ESI): calcd. for C12H15N4O: 231.1240 [M
+ H]+; found 231.1244; HPLC (Chiralpak AD-H, hexanes/propan-
2-ol, 95:5, 1.0 mL min–1): tR (13a minor) = 13.7, tR (13a major) =
14.3 min (90% ee).
one (11e): The title compound was obtained by the General Pro-
cedure described above, from 1a and 9e. Yield 12% (5.1 mg). [α]2D0
= +99.5 (c = 0.4, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C,
3
TMS): δ = 8.00 [d, J(H,H) = 7.7 Hz, 2 H, Ar-H], 7.82 [d, 3J(H,H)
3
= 8.6 Hz, 2 H, Ar-H], 7.57 [t, J(H,H) = 7.3 Hz, 1 H, Ar-H], 7.46
3
[t, J(H,H) = 7.5 Hz, 2 H, Ar-H], 7.37–7.32 (m, 4 H, Ar-H), 7.14
(S)-4-(5-Phenyl-2H-tetrazol-2-yl)octan-2-one (13b): The title com-
pound was obtained by the General Procedure described above,
from 12a and 6b. Yield 93% (43.5 mg). [α]2D0 = +1.4 (c = 1.1,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.09–8.06
(m, 2 H, Ar-H), 7.41–7.40 (m, 3 H, Ar-H), 5.36–5.27 (m, 1 H, N–
CH), 3.34 [dd, 3J(H,H) = 7.7, 17.9 Hz, 1 H, COCH2], 3.00 [dd,
3J(H,H) = 5.84, 17.9 Hz, 1 H, COCH2], 2.12 (s, 3 H, COCH3),
1.99-1.81 (m, 2 H, CH2), 1.26–1.14 (m, 2 H, CH2), 0.78 [t, 3J(H,H)
= 6.9 Hz, 3 H, CH3] ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 204.2, 164.8, 130.3, 128.8, 127.5, 126.8, 60.1, 47.2, 34.7,
30.3, 27.6, 22.09, 13.8 ppm. HRMS (ESI): calcd. for C15H21N4O:
3
3
[d, J(H,H) = 7.7 Hz, 2 H, Ar-H], 6.74 [dd, J(H,H) = 5.4, 8.5 Hz,
1 H, N–CH], 4.70 [dd, 3J(H,H) = 8.8, 17.9 Hz, 1 H, COCH2], 3.89
[dd, 3J(H,H) = 5.1, 17.9 Hz, 1 H, COCH2], 2.30 (s, 3 H, Ar-
CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 195.6,
144.2, 138.5, 136.4, 135.9, 133.5, 129.6, 128.7, 128.2, 126.9, 126.2,
118.3, 65.6, 44.1, 21.1 ppm. HRMS (ESI): calcd. for
C22H19N3ONa: 364.1420 [M + Na]+; found 364.1418; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 65:35, 1.0 mL min–1): tR (11e
minor) = 10.1, tR (11e major) = 10.8 min (95% ee).
(R)-3-(1H-Benzotriazol-1-yl)-1-(4-chlorophenyl)-3-phenylpropan-1-
one (10f): The title compound was obtained by the General Pro-
cedure described above, from 1a and 9f. Yield 43 % (19.4 mg).
[α]2D0 = +21.2 (c = 0.85, CHCl3). 1H NMR (400 MHz, CDCl3,
273.1710 [M
+
H]+; found 273.1707; HPLC analysis (Chi-
ralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 mL min–1): tR (13b
minor) = 11.2, tR (13b major) = 12.3 min (96% ee).
3
25 °C, TMS): δ = 8.03 [t, J(H,H) = 8.3 Hz, 1 H, Ar-H], 7.94 [d,
(S)-2-(5-Phenyl-2H-tetrazol-2-yl)octan-4-one (13c): The title com-
pound was obtained by the General Procedure described above,
from 12a and 6c. Yield 95% (32.3 mg). [α]2D0 = –20.4 (c = 1.3,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.15–8.12
(m, 2 H, Ar-H), 7.49–7.46 (m, 3 H, Ar-H), 5.54-5.45 (m, 1 H, N–
CH), 3.43 [dd, 3J(H,H) = 7.1, 17.7 Hz, 1 H, COCH2], 3.02 [dd,
3J(H,H) = 8.4 Hz, 2 H, Ar-H], 7.51–7.29 (m, 10 H, Ar-H), 6.54
3
3
[dd, J(H,H) = 4.8, 8.9 Hz, 1 H, N–CH], 4.85 [dd, J(H,H) = 9.0,
17.8 Hz, 1 H, COCH2], 3.81 [dd, 3J(H,H) = 4.8, 17.8 Hz, 1 H,
COCH2] ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ =
194.8, 146.2, 140.2, 138.9, 134.6, 129.7, 129.2, 129.1, 128.6, 127.5,
126.7, 124.2, 119.9, 114.1, 109.9, 58.4, 44.4 ppm. HRMS (ESI):
calcd. for C21H17ClN3O: 362.1055 [M + H]+; found 362.1058;
HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 70:30,
1.0 mL min–1): tR (10f minor) = 20.6, tR (10f major) = 23.7 min
(93% ee).
3
3J(H,H) = 6.6, 17.7 Hz, 1 H, COCH2], 2.47 [t, J(H,H) = 7.4 Hz,
2 H, COCH2], 1.68 [d, 3J(H,H) = 6.7 Hz, 3 H, CH3], 1.59–0.87 (m,
7 H, CH2CH2CH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 206.6, 164.8, 130.2, 128.8, 127.5, 126.8, 56.0, 47.6, 43.0,
25.6, 22.2, 20.9, 13.8 ppm. HRMS (ESI): calcd. for C15H21N4O:
273.1710 [M + H]+; found 273.1709; HPLC (Chiralpak AD-H, hex-
anes/propan-2-ol, 90:10, 1.0 mL min–1): tR (13c minor) = 8.1, tR
(13c major) = 8.8 min (92% ee).
(R)-3-(2H-Benzotriazol-2-yl)-1-(4-chlorophenyl)-3-phenylpropan-1-
one (11f): The title compound was obtained by the General Pro-
cedure described above, from 1a and 9f. Yield 8% (3.61 mg). [α]2D0
= +117.5 (c = 0.6, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C,
(S)-4-(5-Phenyl-2H-tetrazol-2-yl)-5-methylhexan-2-one (13d): The
title compound was obtained by the General Procedure described
above, from 12a and 6d. Yield 90% (29.0 mg). [α]2D0 = –5.8 (c = 1.3,
CH2Cl2). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.16–8.14
(m, 2 H, Ar-H), 7.49–7.46 (m, 3 H, Ar-H), 5.28–5.23 (m, 1 H, N–
CH), 3.59 [dd, 3J(H,H) = 9.8, 17.9 Hz, 1 H, COCH2], 3.00 [dd,
3J(H,H) = 3.9, 17.9 Hz, 1 H, COCH2], 2.38–2.40 (m, 1 H, CH),
3
3
TMS): δ = 8.03 [t, J(H,H) = 8.3 Hz, 1 H, Ar-H], 7.94 [d, J(H,H)
= 8.4 Hz, 2 H, Ar-H], 7.51–7.29 (m, 10 H, Ar-H), 6.54 [dd, 3J(H,H)
3
= 4.8, 8.9 Hz, 1 H, N–CH], 4.85 [dd, J(H,H) = 9.0, 17.8 Hz, 1 H,
COCH2], 3.81 [dd, 3J(H,H) = 4.8, 17.8 Hz, 1 H, COCH2] ppm. 13
C
NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 194.5, 144.2, 140.1,
138.7, 134.6, 129.7, 129.1, 129.0, 128.7, 126.8, 126.3, 118.3, 65.7,
44.1 ppm. HRMS (ESI): calcd. for C21H16N3ONa: 384.0874 [M +
Na]+; found 384.077; HPLC (Chiralpak AD-H, hexanes/propan-2-
ol, 70:30, 1.0 mL min–1): tR (10f minor) = 11.5, tR (10f major) =
14.6 min (97% ee).
3
2.21 (s, 3 H, COCH3), 0.97 [d, J(H,H) = 6.8 Hz, 3 H, CH3], 0.90
[d, 3J(H,H) = 6.8 Hz, 3 H, CH3] ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 204.4, 164.5, 130.2, 128.8, 127.5, 126.8,
65.0, 43.4, 32.9, 30.4, 18.6, 18.4 ppm. HRMS (ESI): calcd. for
C14H19N4O: 259.1553 [M + H]+; found 259.1557; HPLC (Chi-
ralpak AD-H, hexanes/propan-2-ol, 95:5, 1.0 mL min–1): tR (13d
minor) = 9.8, tR (13d major) = 10.3 min (98% ee).
Typical Procedure for Additions of 5-Phenyltetrazole Derivatives to
α,β-Unsaturated Enones: PhCOOH (40 mol-%) was added to a
stirred solution of catalyst 3d (20 mol-%) in PhCH3 (1.25 mL) and
the solution was stirred for 5 minutes at room temperature. After
addition of an enone 2 (0.60 mmol), the mixture was stirred for 10
(S)-4-(5-p-Tolyl-2H-tetrazol-2-yl)octan-2-one (13e): The title com-
pound was obtained by the General Procedure described above,
Eur. J. Org. Chem. 2010, 2073–2083
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2081

J. Lv, H. Wu, Y. Wang,
FULL PAPER
from 12b and 6b. Yield 87% (25.0 mg). [α]2D0 = –5.2 (c = 0.65,
1.25 mL) and the solution was stirred for 5 minutes at room tem-
perature. After addition of enone 9a (0.60 mmol), the mixture was
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.03 [d,
3
3J(H,H) = 7.92 Hz, 2 H Ar-H], 7.29 [d, J(H,H) = 7.92 Hz, 2 H, stirred for 10 minutes. 5-Phenyltetrazole (12a, 0.125 mmol) was
Ar-H], 5.40–5.34 (m, 1 H, N–CH), 3.40 [dd, 3J(H,H) = 7.6,
17.8 Hz, 1 H, COCH2], 3.06 [dd, 3J(H,H) = 6.0, 17.9 Hz, 1 H,
COCH2], 2.41 (s, 3 H, Ar-CH3), 2.19 (s, 3 H, COCH3), 2.08–1.88
(m, 2 H, CH2), 1.38–1.06 (m, 4 H, CH2CH2), 0.85 [t, 3J(H,H) =
added at –20 °C, and stirring was continued for the indicated time,
resulting in a single regioisomer. The crude reaction mixture was
then loaded onto a silica gel column for purification (EtOAc/hex-
ane, 1:5), to afford the Michael adduct. Yield 95% (43.9 mg).
7.03, 3 H, CH3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): [α]2D0 = +58.2 (c = 1.3, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C,
δ = 204.2, 164.9, 140.4, 129.5, 126.8, 124.8, 60.0, 47.2, 34.7, 30.4,
27.6, 22.1, 21.5, 13.8 ppm. HRMS (ESI): calcd. for C16H23N4O:
287.1866 [M + H]+; found 287.1869; HPLC (Chiralpak AD-H, hex-
anes/propan-2-ol, 95:5, 1.0 mL min–1): tR (13e minor) = 13.2, tR
(13e major) = 16.0 min (96% ee).
TMS): δ = 8.14–8.11 (m, 2 H, Ar-H), 7.46–7.45 (m, 3 H, Ar-H),
7.41–7.32 (m, 5 H, Ar-H), 6.47 [dd, 3J(H,H) = 5.0, 9.4 Hz, 1 H,
3
N–CH], 4.04 [dd, J(H,H) = 9.4, 18.0 Hz, 1 H, COCH2], 3.33 [dd,
3J(H,H) = 5.0, 18.0 Hz, 1 H, COCH2], 2.38 (s, 3 H, COCH3) ppm.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 203.6, 165.0, 137.4,
130.3, 129.1, 129.0, 128.8, 126.9, 126.8, 63.1, 48.1, 30.3 ppm.
HRMS (ESI): calcd. for C17H17lN4O: 293.1397 [M + H]+; found
293.1400; HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 90:10,
1.0 mL min–1): tR (13i major) = 17.2, tR (13i minor) = 18.0 min
(91% ee).
(S)-4-(5-m-Tolyl-2H-tetrazol-2-yl)octan-2-one (13f): The title com-
pound was obtained by the General Procedure described above,
from 12c and 6b. Yield 91% (32.5 mg). [α]2D0 = –2.4 (c = 0.85,
1
CHCl3). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.97 (s, 1
3
3
H, Ar-H), 7.94 [d, J(H,H) = 7.7 Hz, 1 H, Ar-H], 7.37 [t, J(H,H)
= 7.6 Hz, 1 H, Ar-H], 7.27 [d, 3J(H,H) = 8.3 Hz, 1 H, Ar-H], 5.40–
5.34 (m, 1 H, N–CH), 3.40 [dd, 3J(H,H) = 7.6, 17.8 Hz, 1 H,
3
Acknowledgments
COCH2], 3.06 [dd, J(H,H) = 6.0, 17.9 Hz, 1 H, COCH2], 2.41 (s,
3 H, Ar-CH3), 2.19 (s, 3 H, COCH3), 2.08-1.88 (m, 2 H, CH2),
1.38–1.06 (m, 4 H, CH2CH2), 0.85 [t, 3J(H,H) = 7.03 Hz, 3 H,
CH3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 204.2,
165.0, 138.6, 131.0, 128.8, 127.4, 127.3, 124.0, 60.1, 47.2, 34.7, 30.4,
27.6, 22.1, 21.4, 13.8 ppm. HRMS (ESI): calcd. for C16H23N4O:
287.1866 [M + H]+; found 287.1869; HPLC (Chiralpak AD-H, hex-
anes/propan-2-ol, 95:5, 1.0 mL min–1): tR (13f minor) = 9.9, tR (13f
major) = 10.8 min (97% ee).
The work was financially supported by the National Natural Sci-
ence Foundation of China (Grant No. 20672061), the Chinese 863
Project (no. 2007AA05Z102), and the Chinese 973 Program (no.
2010CB833301). We also thank Nankai University State Key Labo-
ratory of Elemento-Organic Chemistry for support.
[1] A. R. Katritzky, A. F. Pozharskii, Handbook of Heterocyclic
Chemistry, 2nd ed., Pergamon, Oxford, 2002.
(S)-4-(5-o-Tolyl-2H-tetrazol-2-yl)octan-2-one (13g): The title com-
pound was obtained by the General Procedure described above,
from 12d and 6b. Yield 85% (30.4 mg). [α]2D0 = –4.2 (c = 0.85,
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.01 [d,
3J(H,H) = 7.2 Hz, 1 H, Ar-H], 7.38–7.29 (m, 3 H, Ar-H), 5.44–
5.34 (m, 1 H, N–CH), 3.43 [dd, 3J(H,H) = 7.7, 17.8 Hz, 1 H,
[2] M. Gandelman, E. N. Jacobsen, Angew. Chem. Int. Ed. 2005,
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T. E. Hortsmann, D. J. Guerin, S. J. Miller, Angew. Chem. Int.
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[5] J. Wang, L. Zu, H. Li, H. Xie, W. Wang, Synthesis 2007, 2576–
2580.
[6] Y. K. Chen, M. Yoshida, D. W. C. MacMillan, J. Am. Chem.
Soc. 2006, 128, 9328–9329.
[7] P. Dinér, M. Nielsen, M. Marigo, K. A. Jørgensen, Angew.
Chem. Int. Ed. 2007, 46, 1983–1987.
3
COCH2], 3.07 [dd, J(H,H) = 5.9, 17.8 Hz, 1 H, COCH2], 2.62 (s,
3 H, Ar-CH3), 2.20 (s, 3 H, COCH3), 2.09–1.91 (m, 2 H, CH2),
1.43–1.11 (m, 4 H, CH2CH2), 0.86 [t, 3J(H,H) = 7.1 Hz, 3 H,
CH3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 204.2,
165.2, 137.4, 131.3, 129.8, 129.4, 126.6, 126.0, 59.9, 47.2, 34.7, 30.4,
27.6, 22.1, 21.7, 13.8 ppm. HRMS (ESI): calcd. for C16H23N4O:
287.1866 [M + H]+; found 287.1868; HPLC (Chiralpak AD-H, hex-
anes/propan-2-ol, 95:5, 1.0 mL min–1): tR (13g minor) = 9.5, tR (13g
major) = 10.6 min (93% ee).
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2007, 27, 2509–2511.
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Chem. Int. Ed. 2008, 47, 10187–10191.
(S)-4-[5-(p-Bromophenyl)-2H-tetrazol-2-yl]octan-2-one (13h): The
title compound was obtained by the General Procedure described
above, from 12e and 6b. Yield 89% (34.2 mg). [α]2D0 = –1.2 (c = 0.85,
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.08 [d,
3J(H,H) = 8.4 Hz, 2 H, Ar-H], 7.46 [d, 3J(H,H) = 8.4 Hz, 2 H, Ar-
[10] a) H. Kim, C. Yen, P. Preston, J. Chin, Org. Lett. 2006, 8, 5239–
5242; b) J.-W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J.-G. Deng,
Y.-C. Chen, Org. Lett. 2007, 9, 413–415; c) S. B. Tsogoeva, S. B.
Jagtap, Synlett 2004, 2624–2626; d) N. J. A. Martin, B. List, J.
Am. Chem. Soc. 2006, 128, 13368–13369.
[11] a) J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C.
Chen, Y. Wu, J. Zhu, J.-G. Deng, Angew. Chem. Int. Ed. 2007,
46, 389–392; b) G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli,
L. Sambri, P. Melchiorre, Org. Lett. 2007, 9, 1403–1405; c)
S. H. McCooey, S. J. Connon, Org. Lett. 2007, 9, 599–602; d)
Y.-Q. Yang, G. Zhao, Chem. Eur. J. 2008, 14, 10888–10891; e)
X. Lu, L. Deng, Angew. Chem. Int. Ed. 2008, 47, 7710–7710;
f) B. Tan, P. J. Chuan, X. Zeng, M. Lu, G. Zhong, Org. Lett.
2008, 10, 3489–3492.
3
H], 5.41–5.35 (m, 1 H, N–CH), 3.41 [dd, J(H,H) = 7.8, 17.9 Hz,
1 H, COCH2], 3.07 [dd, 3J(H,H) = 5.8, 17.9 Hz, 1 H, COCH2],
2.19 (s, 3 H, CH3), 2.07–1.86 (m, 2 H, CH2), 1.38–1.21 (m, 4 H,
CH2CH2), 0.86 [t, 3J(H,H) = 7.1 Hz, 3 H, CH3] ppm. 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 204.2, 164.0, 136.2, 129.1,
128.1, 126.1, 60.2, 47.1, 34.7, 30.3, 27.6, 22.0, 13.8 ppm. HRMS
(ESI): calcd. for C15H20ClN4O: 307.1320 [M + H]+; found
307.1320; HPLC (Chiralpak AD-H, hexanes/propan-2-ol, 95:5,
1.0 mL min–1): tR (13h minor) = 12.5, tR (13h major) = 14.1 min
(95% ee).
[12] P. R. Singh, K. Bartelso, Y. Wang, H. Su, X. Lu, L. Deng, J.
Am. Chem. Soc. 2008, 130, 2422–2423.
[13] J. Lv, J. Zhang, Zh. Lin, Y. Wang, Chem. Eur. J. 2009, 15, 972–
979.
(R)-4-Phenyl-4-(5-phenyl-2H-tetrazol-2-yl)butan-2-one
(13i):
PhCOOH (40 mol-%) and mol. sieves (4 Å, 10 mg) were added to
a stirred solution of catalyst 3d (20 mol-%) in PhCH3/CHCl3 (7:3,
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Eur. J. Org. Chem. 2010, 2073–2083

Enantioselective aza-Michael Additions of N-Heterocycles
[14] a) X. Wang, C. M. Reisinger, B. List, J. Am. Chem. Soc. 2008,
130, 6070–6071; b) X. Lu, Y. Liu, B. Sun, B. Cindric, L. Deng,
J. Am. Chem. Soc. 2008, 130, 8134–8135.
[15] F. Pesciaioli, F. D. Vincentiis, P. Galzerano, G. Bencivenni, G.
Bartoli, A. Mazzanti, P. Melchiorre, Angew. Chem. Int. Ed.
2008, 47, 8703–8706.
[16] After our original submission, enantioselective conjugate ad-
ditions of N-heterocycles to α,β-unsaturated ketones in the
presence of the -N-Boc-phenylglycine salt of a primary amine
derived from a chiral cinchona alkaloid (20 mol-%), affording
moderate to good levels of enantioselectivity (ee values ranging
from 38–88% for Michael N1 adducts), were reported; see: G.
Luo, S. Zhang, W. Duan, W. Wang, Synthesis 2009, 1564–1572.
B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7,
1967–1969.
[17]
Received: October 28, 2009
Published Online: February 25, 2010
Eur. J. Org. Chem. 2010, 2073–2083
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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