Sulfonyl hydrazine as new functionality in organocatalysis: Camphorsulfonyl hydrazine catalyzed enantioselective Aza-Michael addition

Article abstract of DOI:10.1055/s-0029-1216639

Sulfonyl hydrazine is a new functionality for the Lewis base organocatalysis. N^α-substituted camphorsulfonyl hydrazines (CaSH) are effective organocatalysts for the asymmetric aza-Michael addition to α,β-unsaturated aldehydes with enantioselectivity of up to 90%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216639

SPECIAL TOPIC
1573
Sulfonyl Hydrazine as New Functionality in Organocatalysis: Camphor-
sulfonyl Hydrazine Catalyzed Enantioselective Aza-Michael Addition
E
nantioselective
i
Aza-M
n
ichael
A
dd
gition -Yan Chen, Hao He, Bao-Jian Pei, Wing-Hong Chan, Albert W. M. Lee*
Department of Chemistry, Hong Kong Baptist University, Hong Kong, P. R. of China
Fax +852 34117438; E-mail: alee@hkbu.edu.hk
Received 10 February 2009
Abstract: Sulfonyl hydrazine is a new functionality for the Lewis
base organocatalysis. Na-substituted camphorsulfonyl hydrazines
(CaSH) are effective organocatalysts for the asymmetric aza-
Michael addition to a,b-unsaturated aldehydes with enantioselec-
tivity of up to 90%.
NH
NH
S
N
N
O
R
O
R
O
1
2
Key words: sulfonyl hydrazine, camphorsulfonyl hydrazine, orga-
nocatalysis, aza-Michael addition, a,b-unsaturated aldehyde
Figure 1 Hydrazide 1 and sulfonyl hydrazine (CaSH) 2
The use of homochiral small organic molecules to cata-
lyze enantioselective transformations has been a highly
dynamic and productive research area since the turn of the
century.1 The catchy term organocatalysis was coined by
David MacMillan in 2000.1b,2 In less than a decade, orga-
nocatalysis has become the third pillar, after biocatalysis
and organometallic catalysis, for modern asymmetric ca-
talysis. According to Benjamin List, there are essentially
four types of organocatalysts, Lewis bases, Lewis acids,
Brønsted bases, and Brønsted acids.3 Among the Lewis
base catalysts, they are dominated by primary or second-
ary amines,1d,4,5 and many of them are derived from amino
acids. In this paper, we would like to discuss our efforts of
using sulfonyl hydrazine as a new Lewis base functional-
ity in organocatalysis, in particular, the enantioselective
aza-Michael addition.
NH2NH2⋅H2O
N
AcOH–MeOH
92%
S
O
N
H
O
SO2X
X = Cl 3
X = OH (1S)-(+)-CSA
O
4
SOCl2
NaBH3CN
RX (X = Cl, Br or I)
NH
N
S
S
TFA, MeOH
80–96%
N
R
NaOH, TBAB, THF
92–97%
N
R
O
O
O
O
2a R = Me
2b R = Et
2c R = Bn
5
Scheme 1 CaSHs from CSA
monohydrate, camphorsulfonyl chloride 3 cyclized readi-
ly into cyclic sulfonyl hydrazone 4. Alkylation under
phase transfer conditions followed by NaBH3CN reduc-
tion afforded Na-alkylated CaSH 2 in excellent overall
yield. It is worth noting that both enantiomers of CaSH
can be readily prepared as both (+) and (–)-CSA are com-
mercially available.
The concept behind the design of this series of sulfonyl
hydrazines as effective organocatalysts is the a-heteroat-
om effect.6,7 It is well argued that the nucleophilicity and
hence the catalytic effect of an amine will be greatly en-
hanced by attaching a heteroatom to it. To put this concept
into practice, Ogilvie developed cyclic hydrazide (carbo-
nyl hydrazine) 1 as a new scaffold in enantioselective or-
ganocatalytic Diels–Alder reaction.8 Recently, we
reported our efforts of developing camphorsulfonyl hy-
drazine 2 (CaSH) (Figure 1) as an effective organocata-
lyst. In CaSH-catalyzed Diels–Alder reactions in brine,
good chemical yields and up to 96% ee could be
achieved.9 Coincidentally, almost at the same time,
Langlois and co-workers also reported their findings of
using 2 as organocatalyst in Diels–Alder reactions.10
Michael addition reaction of nitrogen nucleophiles to a,b-
unsaturated carbonyl systems is an important transforma-
tion, which could lead to the synthesis of amino acids,
amino alcohols, and many virtual building blocks for nat-
ural products and bioactive compounds.11 Besides asym-
metric metal-catalyzed methodolgies,12 analogous
organocatalytic Michael addition is also an attractive ap-
proach.13 For example, the pioneering work of MacMillan
and co-workers used chiral imidazolidinones as organo-
catalysts to activate a,b-unsaturated aldehydes for highly
enantioselective aza-Michael reactions with N-siloxycar-
bamates.14
The synthesis of Na-alkylated CaSHs from readily avail-
able optically pure camphorsulfonic acid (CSA) is out-
lined in Scheme 1.9 Upon treatment with hydrazine
We first chose doubly Cbz substituted hydroxylamine 6 as
the nitrogen nucleophile for the initial studies. Bis-Cbz
hydroxylamine 6 can be readily prepared via the reaction
SYNTHESIS 2009, No. 9, pp 1573–1577
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0029-1216639; Art ID: C00609SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

1574
L.-Y. Chen et al.
SPECIAL TOPIC
Table 1 Aza-Michael Addition of Carbamate 6a to (E)-Crotonalde-
hyde (7a)
Table 2 Na-Alkylated CaSH-Catalyzed Aza-Michael Addition
O
NH
O
2b
7a
S
N
R
Cbz
OCbz
NH
Et
, TCA
O
7a
N
O
S
+
Cbz
OCbz
N
O
N
(20 mol%)
Cbz
OCbz
O
N
H
+
O
2a R = Me
2b R = Et
2c R = Bn
CHCl3, r.t.
O
Cbz
OCbz
N
H
6a
8a
8a
6a
Cbz
N
OCbz
Cbz
OCbz
N
MeOH
NaBH4
MeOH
NaBH4
OH
OH
9a
9a
Entry
Additivea
Time (h)
Yieldb (%) ee (%)c
Entry Catalysta Solvent
Temp
Time
(h)
Yield
(%)b
ee
(°C)
r.t.
r.t.
r.t.
r.t.
0
(%)c
1
2
3
4
5
6
none
96
48
4
60
46
71
46
61
60
51
55
52
5
1
2
3
4
5
6
7d
8
9
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2c
2c
CHCl3
CH2Cl2
brine
24
24
24
24
24
24
24
24
48
4
61
84
59
60
trace
80
70
65
60
84
45
73
78
63
34
88
n.d.
84
84
88
90
89
21
45
PhCO2H
TsOH
TfOH
TCA
24
24
24
Et2O
78
53
Et2O
TFA
toluene
toluene
toluene
toluene
toluene
CHCl3
toluene
r.t.
r.t.
0
a Amount used: 20 mmol%.
b Isolated yield of 8a.
c Enantiomeric excess was determined by chiral HPLC analysis on the
corresponding amino alcohol 9a. Assignment of absolute configura-
tion was based on literature precedents.15
–10
r.t.
r.t.
r.t.
of hydroxylamine hydrochloride with excess benzyl chlo-
roformate. Direct Michael addition of 6 to (E)-crotonalde-
hyde (7a) using 20 mol% Na-ethyl CaSH 2b as catalyst
was a rather slow reaction with only moderate enantiose-
lectivity (Table 1, entry1). Therefore, we explored the use
of acid additive to speed up the reaction. The results are
summarized in Table 1. When weak acid PhCO2H was
used, there was not much improvement in the reaction
(Table 1, entry 2). When we shifted to a stronger acid
TsOH, the reaction went faster with slightly improved
yield. However, the % ee remained low (Table 1, entry 3).
As for triflic acid (TfOH), % ee was sharply decreased to
5% (Table 1, entry 4). Eventually, we found that trichlo-
roacetic acid (TCA) gave satisfactory result with moder-
ated yield of 8a and up to 78% ee (Table 1, entry 5). With
a stronger trifluoroacetic acid (TFA), the chemical yield
remained the same, but the % ee dropped (Table 1, entry
6).
10
11
12
24
24
a Amount used = 20 mmol% of CaSH and 20 mmol% TCA except for
entry 7.
b Isolated yield of 8a.
c Enantiomeric excess was determined by chiral HPLC analysis on the
corresponding amino alcohol; n.d. = not determined.
d Amount of catalyst used = 10 mmol% of CaSH and 10 mmol% of
TCA.
In the hope of enhancing the enantioselectivity, we carried
out the reactions at lower temperature. The reaction sharp-
ly slowed down at 0 °C in Et2O and only trace amount of
the desired product 8a could be detected after 24 hours
(Table 2, entry 5). With toluene as the solvent at 0 or –10
°C, we found that the ee could be increased to 88% and
90% respectively (Table 2, entries 8 and 9). Finally, when
the loading of the catalyst and TCA was reduced to 10
mol%, good chemical yield (70%) and enantioselectivity
(84% ee) could also be obtained (Table 2, entry 7).
Other Na-alkylated CaSHs like 2a and 2c were also stud-
ied. Na-Methyl CaSH 2a is also a rather effective catalyst.
The reaction rate was much accelerated with good yield
(84%) and enantioselectivity (89%) (Table 2, entry 10).
However, as compared to 2b, Na-methyl CaSH 2a is not
too stable at ambient temperature and has to be freshly
With these preliminary results, we further investigated the
solvent and temperature effect as well as the catalytic ef-
fect of different Na-alkylated CaSHs. Results are summa-
rized in Table 2.
In comparison with CHCl3, better reactivity and enantio-
selectivity were obtained in Et2O and toluene (Table 2,
entries 4 and 6). For other solvent systems like CH2Cl2
and brine, the results were not quite satisfactory (Table 2,
entries 2 and 3). In alcoholic solvent like MeOH, the reac-
tions did not proceed.
Synthesis 2009, No. 9, 1573–1577 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Aza-Michael Addition
1575
Table 3 CaSH-Catalyzed Aza-Michael Addition to a,b-Unsaturated Aldehydes
X
OY
X
OY
MeOH
NaBH4
N
R1
X
OY
N
2a or 2b (20 mol%)
+
O
N
H
7a–g
TCA (20 mol%)
toluene
R1
OH
R1
O
6a–d
8a–l
9a–l
6a X, Y = Cbz
6c X = Boc, Y = Cbz
6b X = Cbz, Y = Me 6d X = Boc, Y = Bn
Entry
1
R1 (7)
X
Y
Catalyst
Product
8a
Time (h)
4
Yield (%)a
ee (%)b
Me (a)
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Me
Me
Me
Cbz
Bn
2a
2a
2b
2a
2b
2b
2b
2b
2b
2b
2b
2b
84
40
45
40
40
–
90
66
82
85
84
–
2
Et (b)
8b
8c
24
3
n-Pr (c)
n-Bu (d)
EtCH=CH(CH2)2 (e)
Ph (f)
48
4
8d
8e
48
5
24
6
8f
24
7
2-furyl (g)
Me (a)
8g
24
–
–
8
8h
8i
20
70
51
50
70
78
38
40
41
56
24
9
Et (b)
20
10
11
12
n-Pr (c)
Me (a)
8j
48
8k
8l
18
Me (a)
24
a Isolated yields of 8a–l.
b Enantiomeric excess was determined by chiral HPLC analysis on the corresponding amino alcohol.
13C NMR spectra were recorded on a Bruker AV400 spectrometer
(at 400 and 100 MHz, respectively) in CDCl3. Chemical shifts were
registered relatively to Me4Si (in ppm). Optical rotations were taken
on a JASCO DIP-1000 digital polarimeter. FT-IR was recorded on
a PerkinElmer Spectrum 100 FT/IR spectrometer. High-resolution
mass spectra were recorded on a QSTAR Pulsar/LC/MS/MS Sys-
tem, ESI-QTOF instrument (Applied Biosystem) or Bruker Auto-
flex MALDI-TOF MS instrument. HPLC analysis was performed
on a Hewlett Packard Series 1050 HPLC, using Chiralpak AD-H
(0.46 cm × 25 cm) with 15% i-PrOH in n-hexane as eluent and 1
mL/min flow rate.
prepared. While Na-benzyl CaSH 2c is an effective cata-
lyst in Diels–Alder reactions,10 it is not a good catalyst in
this Michael addition reaction (Table 2, entries 11 and
12).
The scope of the reaction for different a,b-unsaturated al-
dehydes was investigated with either 2a or 2b as the cata-
lyst. From the results summarized in Table 3, it can be
seen that both CaSH 2a and 2b are effective organocata-
lysts for the aza-Michael addition of aliphatic aldehydes
(Table 3, entries 1–5). However, they are ineffective to-
wards aromatic aldehydes15 (Table 3, entries 6 and 7). Hy-
droxylamines of different substitution pattern 6b–d were
also tested. However, the enantioselectivities were poorer.
Na-Alkylated Cyclic Camphorsulfonyl Hydrazines 2a–c; Gen-
eral Procedure
To a solution (1S)-(+)-10-camphorsulfonyl chloride (3; 2.5 g, 10
mmol) in MeOH (20 mL) was added hydrazine monohydrate (0.97
mL, 20 mmol) and AcOH (0.29 mL, 5 mmol). The mixture was
stirred at 80 °C to reflux for 4 h. The reaction was cooled down. Af-
ter removal of the organic solvent on a rotary evaporator, the result-
ing mixture was dissolved in a small amount of H2O (4 mL) and
extracted with EtOAc (3 × 15 mL). The aqueous phase was basified
with NaOH pellets to pH 9–10 and extracted with EtOAc (3 × 15
mL). The combined organic layers were washed with brine (5 mL)
and dried (Na2SO4), followed by filtration and concentration to ob-
tain 2.1 g of a white solid of cyclic camphorsulfonyl hydrazone 4 in
92% yield. Then, to a solution of 4 (1.14 g, 5 mmol) in THF (20 mL)
was added NaOH (400 mg, 10 mmol) and Bu4NBr (645 mg, 2
mmol), followed by alkyl halide (10 mmol). The reaction mixture
was stirred at r.t. After consumption of the starting material (tracked
In summary, we have demonstrated that sulfonyl hydra-
zine is a new Lewis base functionality in organocatalysis.
Camphorsulfonyl hydrazines (CaSH), which can be syn-
thesized in good overall yield from camphorsulfonic acid
(CSA), is an effective organocatalyst for the asymmetric
aza–Michael addition of a,b-unsaturated aldehydes with
good enantioselectivity. Further investigations of other
CaSH-catalyzed transformations are in progress.
Progress of all reactions was monitored by TLC; visualization was
effected by exposure to UV light or I2. Purification was effected by
silica gel column chromatography (100–200 mesh silica gel) using
mixtures of petroleum ether (bp 60–80 °C)–EtOAc as eluent. 1H and
Synthesis 2009, No. 9, 1573–1577 © Thieme Stuttgart · New York

1576
L.-Y. Chen et al.
SPECIAL TOPIC
by TLC), H2O (4 mL) was added and the THF was removed by
evaporation. The resulting mixture was extracted with EtOAc (3 ×
15 mL) and the combined organic layers were washed with brine (5
mL) and dried (Na2SO4), followed by further purification via col-
umn chromatography to give 5a–c in 92–97% yield. To a solution
of 5 (1 mmol) in MeOH (2 mL) was added trifluoroacetic acid (2
mL). The mixture was stirred at 0 °C and NaBH3CN (0.628 g, 10
mmol) was added in portions. The reaction was then allowed to stir
at r.t. After consumption of the starting material (tracked by TLC),
MeOH was removed on a rotary evaporator. H2O (2 mL) was added
to the resulting mixture and NaOH pellets were used to basify the
solution to pH 9–10. Then the mixture was extracted with EtOAc (3
× 10 mL). The combined organic layers were washed with brine (3
mL) and dried (Na2SO4), followed by further purification via col-
umn chromatography to give 2a–c.
stirring for another 30 min, the carbamate 6 (0.2 mmol) was added.
The resulting solution was stirred until complete consumption of
carbamate 6 as determined by TLC. The reaction mixture was then
quenched with aq NaHCO3 (0.3 mL) and extracted with EtOAc (3
× 5 mL). The combined organic solutions were dried (Na2SO4). The
product 8a–l was purified by silica gel chromatography (Table 3).
Then, 8 was diluted with MeOH (2 mL) at 0 °C followed by the ad-
dition of NaBH4 (0.6 mmol). The mixture was stirred for 10 min,
quenched with aq sat. NH4Cl (0.5 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic extracts were washed with brine
(5 mL). The organic layer was separated, dried (Na2SO4) and the
solvent was removed. The crude product was purified by the silica
gel chromatography.
8a
1H NMR (400 MHz, CDCl3): d = 1.25 (d, J = 6.8 Hz, 3 H), 2.51 (dd,
J = 6.0, 16.4 Hz, 1 H), 2.77 (dd, J = 6.0, 16.4 Hz, 1 H), 4.09–4.15
(m, 1 H), 5.24 (s, 4 H), 7.26–7.35 (m, 10 H), 9.71 (s, 1 H).
2a
Mp 81–83 °C; [a]D20 –78.8 (c = 1.05, CHCl3).
IR (neat): 3294, 2961, 2880, 1334, 1145 cm–1.
13C NMR (100 MHz, CDCl3): d = 14.1, 21.0, 51.3, 60.3, 68.5, 71.3,
127.8, 128.3, 128.5, 128.6, 128.9, 134.1, 135.2, 154.3, 199.2.
1H NMR (400 MHz, CDCl3): d = 3.31 (dd, J = 9.4, 5.8 Hz, 1 H),
3.26 (d, J = 14.4 Hz, 1 H), 3.16 (d, J = 14.8 Hz, 1 H), 2.83 (s, 3 H),
1.80–1.69 (m, 3 H), 1.64–1.57 (m, 2 H), 1.33 (s, 3 H), 1.26–1.20 (m,
1 H), 1.18–1.11 (m, 1 H), 0.94 (s, 3 H).
HRMS (MALDI-TOF): m/z calcd for C20H21NO6 + Na (M + Na)+:
394.1261; found: 394.1274.
9a
13C NMR (100 MHz, CDCl3): d = 62.6, 51.6, 50.2, 46.9, 45.5, 37.4,
34.6, 34.4, 26.1, 21.4, 20.8.
1H NMR (400 MHz, CDCl3): d = 1.77–1.86 (m, 1 H), 1.23 (d, J =
6.4 Hz, 3 H), 2.05–2.11 (m, 1 H), 4.17–4.20 (m, 2 H), 4.29–4.34 (m,
1 H), 5.07–5.19 (m, 4 H), 7.26–7.36 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 17.4, 31.8, 51.6, 65.3, 68.0, 69.6,
127.8, 128.2, 128.3, 128.5, 128.6, 135.1, 135.9, 155.1, 157.4.
HRMS (MALDI-TOF): m/z calcd for C20H23NO6 + Na (M + Na)+:
396.1418; found: 396.1416.
HRMS (ESI): m/z calcd for C11H21N2O2S (M + H)+: 245.1323;
found: 245.1320.
2b
Mp 105 °C; [a]D20 –111.3 (c = 1.05, CHCl3).
IR (neat): 3359, 2956, 2878, 1333, 1176, 1143 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.00 (br, 1 H), 3.42–3.34 (m, 1 H),
3.23 (d, J = 14.4 Hz, 1 H), 3.23–3.19 (m, 1 H), 3.13 (d, J = 14.4 Hz,
1 H), 3.05–2.96 (m, 1 H), 1.78–1.68 (m, 3 H), 1.65–1.56 (m, 2 H),
1.33 (s, 3 H), 1.24–1.10 (m, 2 H), 1.19 (t, J = 7.0 Hz, 3 H), 0.93 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 62.9, 51.3, 50.6, 46.5, 45.1, 41.4,
37.0, 34.1, 25.9, 21.1, 20.5, 12.3.
9b
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 7.3 Hz, 3 H), 1.42–
1.47 (m, 2 H), 1.69–1.78 (m, 1 H), 1.83–3.14 (m, 1 H), 4.09–4.11
(m, 1 H), 4.16–4.20 (m, 2 H), 5.06–5.19 (m, 4 H), 7.29–7.37 (m, 10
H).
13C NMR (100 MHz, CDCl3): d = 10.6, 25.0, 30.5, 57.3, 65.3, 67.9,
69.6, 127.9, 128.2, 128.4, 128.5, 128.6, 135.1, 135.9, 155.0, 157.5.
HRMS (MALDI-TOF): m/z calcd for C21H25NO6 + Na (M + Na)+:
410.1574; found: 410.1565.
HRMS (ESI): m/z calcd for C12H23N2O2S (M + H)+: 259.1480;
found: 259.1477.
Anal. Calcd for C12H22N2O2S: C, 55.78; H, 8.58; N, 10.84; S, 12.41.
Found: C, 55.61; H, 8.76; N, 10.86; S, 12.42.
9c
1H NMR (400 MHz, CDCl3): d = 0.853 (t, J = 7.2 Hz, 3 H), 1.19–
1.39 (m, 4 H), 1.7–1.83 (m, 1 H), 1.94–2.09 (m, 1 H), 4.16–4.19 (m,
1 H), 4.16–4.19 (m, 2 H), 5.06–5.19 (m, 4 H), 7.26–7.38 (m, 10 H).
2c
Mp 69–70 °C; [a]D20 –87.4 (c = 1.1, CHCl3).
13C NMR (100 MHz, CDCl3): d = 13.7, 19.1, 30.7, 33.9, 55.4, 65.2,
67.8, 69.5, 127.8, 128.1, 128.3, 128.4, 128.5, 135.1, 135.9, 155.0,
157.5.
HRMS (MALDI-TOF): m/z calcd for C22H27NO6 + Na (M + Na)+:
424.1731; found: 424.1713.
IR (neat): 3359, 2958, 2881, 1324, 1143 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39–7.29 (m, 5 H), 4.58 (d,
J = 14.8 Hz, 1 H), 4.06 (d, J = 14.8 Hz, 1 H), 3.31 (d, J = 14.4 Hz,
1 H), 3.22 (d, J = 14.4 Hz, 1 H), 3.16 (dd, J = 8.8, 5.6 Hz, 1 H),
1.76–1.51 (m, 5 H), 1.32 (s, 3 H), 1.23–1.17 (m, 1 H), 1.13–1.07 (m,
1 H), 0.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 136.0, 128.6, 128.4, 127.6, 62.5,
51.3, 50.7, 50.4, 46.7, 45.2, 37.2, 34.2, 25.9, 21.1, 20.6.
9d
1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 6.8 Hz), 1.14–1.42 (m,
6 H), 1.68–1.81 (m, 1 H), 1.95–2.09 (m, 1 H), 4.14–4.19 (m, 3 H),
5.06–5.27 (m, 4 H), 7.29–7.36 (m, 10 H).
HRMS (MALDI-TOF): m/z calcd for C17H25N2O2S (M + H)+:
321.1631; found: 321.1628.
13C NMR (100 MHz, CDCl3): d = 14.0, 22.4, 28.1, 30.7, 31.6, 55.8,
65.3, 67.9, 69.6, 127.9, 128.2, 128.4, 128.5, 128.6, 135.1, 135.9,
155.0, 157.5.
HRMS (MALDI-TOF): m/z calcd for C23H29NO6 + Na (M + Na)+.
438.1887; found: 438.1898.
Aza-Michael Addition and Subsequent Reduction; General
Procedure
Na-Ethyl CaSH 2b (10 mg, 0.04 mmol) and TCA (6.5 mg, 0.04
mmol) were mixed in anhyd toluene (0.6 mL) for 30 min. The re-
spective a,b-unsaturated aldehyde 7 (0.6 mmol) was added. After
Synthesis 2009, No. 9, 1573–1577 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Aza-Michael Addition
1577
9e
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Rev. 2007, 107, 5744. (i) Akiyama, T.; Itoh, J.; Fuchibe, K.
Adv. Synth. Catal. 2006, 348, 999. (j) Lygo, B.; Andrews,
B. I. Acc. Chem. Res. 2004, 37, 518. (k) Shirakawa, S.;
Yamamoto, K.; Kitamura, M.; Ooi, T.; Maruoka, K. Angew.
Chem. Int. Ed. 2005, 44, 625. (l) Ooi, T.; Maruoka, K.
Angew. Chem. Int. Ed. 2007, 46, 4222. (m) Hashimoto, T.;
Maruoka, K. Chem. Rev. 2007, 107, 5656. (n) Merino, P.;
Marques-Lopez, E.; Herrera, R. P. Adv. Synth. Catal. 2008,
350, 1195. (o) Dondoni, A.; Massi, A. Angew. Chem. Int.
Ed. 2008, 47, 2.
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H), 1.75–
1.84 (m, 2 H), 1.92–2.1 (m, 6 H), 4.15–4.20 (m, 1 H), 4.16–4.19 (m,
2 H), 5.24–5.35 (m, 2 H), 7.29–7.34 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 14.26, 20.4, 23.7, 30.7, 31.9,
55.5, 65.2, 67.9, 69.6, 127.8, 128.2, 128.3, 128.4, 128.5, 128.6,
132.5 135.1, 135.9.
HRMS (ESI): m/z calcd for C25H31NO6 + Na (M + Na)+: 464.2049;
found: 464.2046.
9h
1H NMR (400 MHz, CDCl3): d = 1.26 (d, J = 6.8 Hz, 3 H), 1.64–
1.71 (m, 1 H), 1.79–1.81 (m, 1 H), 2.38 (s, 1 H), 3.51 (dd,
J = 5.2, 10.0 Hz, 1 H), 3.57 (dd, J = 5.2, 10.0 Hz, 1 H), 3.72 (s, 3 H),
4.31–4.37 (m, 1 H), 5.14–5.25 (m, 2 H), 7.26–7.39 (m, 5 H).
(2) A similar term ‘organic catalysis’ had first appeared in the
German literature: Langenbeck, W. Fortschr. Chem.
Forsch. 1966, 6, 301.
13C NMR (100 MHz, CDCl3): d = 18.1, 36.2, 52.2, 59.0, 64.5, 67.9,
128.1, 128.3, 128.6, 135.9, 158.2.
HRMS (ESI): m/z calcd for C13H19NO4 + Na (M + Na)+: 276.1211;
found: 276.1212.
(3) List, B. Chem. Rev. 2007, 107, 5413.
(4) For an excellent review on iminium ion activation, see:
(a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006,
39, 79. (b) Ref. 1e.
(5) For selected examples, see: (a) Brandes, S.; Niess, B.; Bella,
M.; Prieto, A.; Overgaard, J.; Jorgensen, K. A. Chem. Eur. J.
2006, 12, 6039. (b) Halland, N.; Braunton, A.; Bachmann,
S.; Marigo, M.; Jorgensen, K. A. J. Am. Chem. Soc. 2004,
126, 4790. (c) Bertelsen, S.; Halland, N.; Bachmann, S.;
Marigo, M.; Braunton, A.; Jorgensen, K. A. Chem.Commun.
2005, 4821. (d) Wang, J.; Li, H.; Mei, Y.; Lou, B.; Xu, D.;
Xie, D.; Gou, H.; Wang, W. J. Org. Chem. 2005, 70, 5678.
(e) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167.
(f) Ibrahem, I.; Cordova, A. Chem. Commun. 2006, 1760.
(g) Yua, X.-H.; Wang, W. Org. Biomol. Chem. 2008, 6,
2037. (h) Ye, L.-W.; Zhou, J.; Shao, Z.-H. J. Mol. Catal. A:
Chem. 2008, 285, 1.
9i
1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 7.2 Hz, 3 H), 1.49–
1.55 (m, 2 H), 1.68–1.81 (m, 2 H), 2.0 (s, 1 H), 3.50–3.53 (m, 1 H),
3.58–3.76 (m, 1 H), 4.07–4.09 (m, 1 H), 5.22 (s, 2 H), 7.32–7.41 (m,
5 H).
13C NMR (100 MHz, CDCl3): d = 18.0, 23.7, 36.1, 52.1, 59.0, 64.4,
67.8, 128.1, 128.3, 128.6, 135.9, 158.2.
HRMS (MALDI-TOF): m/z calcd for C14H21NO4 + Na (M + Na)+:
290.1363; found: 290.1356.
9k
(6) Sander, E. G.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90,
6154.
1H NMR (400 MHz, CDCl3): d = 1.24 (d, J = 7.2 Hz, 3 H), 1.41 (s,
9 H), 1.67–1.79 (m, 2 H), 3.42–3.78 (m, 2 H), 4.32–4.48 (m, 1 H),
5.24 (d, J = 17.6 Hz, 2 H), 7.34–7.41 (m, 5 H).
(7) (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 1172. (b) Cavill, J. L.; Elliott, R. L.; Evans, G.;
Jones, I. L.; Platts, J. A.; Ruda, A. M.; Tomkinson, N. C. O.
Tetrahedron 2006, 62, 410. (c) Cavill, J. L.; Peters, J.-U.;
Tomkinson, N. C. O. Chem. Commun. 2003, 728.
(d) Dirksen, A.; Hackeng, T. M.; Dawson, P. E. Angew.
Chem. Int. Ed. 2006, 45, 7581.
13C NMR (100 MHz, CDCl3): d = 14.2, 17.3, 17.6, 27.9, 36.3, 60.4,
71.1, 83.2, 128.6, 128.7, 128.9, 134.4, 155.5.
HRMS (ESI): m/z calcd for C17H25NO6 + Na (M + Na)+: 362.1579;
found: 362.1582.
(8) (a) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141.
(b) Lemay, M.; Ogilvie, W. W. J. Org. Chem. 2006, 71,
4663. (c) Lemay, M.; Aumand, L.; Ogilvie, W. W. Adv.
Synth. Catal. 2007, 349, 441.
9l
1H NMR (400 MHz, CDCl3): d = 1.30 (d, J = 6.8 Hz, 3 H), 1.54 (s,
9 H), 1.62–1.70 (m, 1 H), 1.76–1.84 (m, 1 H), 2.65 (s, 1 H), 3.41–
3.60 (m, 2 H), 4.33–4.37 (m, 1 H), 4.86 (q, J = 9.2 Hz, 2 H), 7.35–
7.40 (m, 5 H).
(9) He, H.; Pei, B.-J.; Chou, H. H.; Tian, T.; Chan, W. H.; Lee,
A. W. M. Org. Lett. 2008, 10, 2421.
13C NMR (100 MHz, CDCl3): d = 18.4, 28.3, 36.3, 51.3, 58.9, 78.6,
81.8, 128.4, 128.6, 129.2, 135.3, 158.0.
HRMS (MALDI-TOF): m/z calcd for C16H25NO4 + Na (M + Na)+:
318.1676; found: 318.1663.
(10) Langlois, Y.; Petit, A.; Rémy, P.; Scherrmann, M. C.;
Kouklovsky, C. Tetrahedron Lett. 2008, 49, 5576.
(11) (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(b) Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(12) For reviews of the Michael addition catalyzed by metallic
complexes, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron
2000, 56, 8033. (b) Krause, N.; Hoffmann-Roder Synthesis
2001, 171. (c) Christoffers, J.; Koripelly, G.; Rosiak, A.
Synthesis 2007, 1279. (d) Ikariya, T.; Murata, K.; Noyori, R.
Org. Biomol. Chem. 2006, 4, 393.
(13) (a) Marigo, M.; Jorgensen, K. A. Chem. Commmun. 2006,
2001. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 18,
1701. (c) Almasi, D.; Alonso, D. A.; Najera, C.
Tetrahedron: Asymmetry 2007, 18, 299. (d) Vicario, J. L.;
Badia, D.; Carrillo, L. Synthesis 2007, 2065.
(14) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 9328.
Acknowledgment
Financial support from Faculty Research Grant (FRG/07-08/04)
and General Research Fund of the Research Grant Council is grate-
fully acknowledged.
References
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Synthesis 2009, No. 9, 1573–1577 © Thieme Stuttgart · New York