Catalytic, asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with activated olefins by quinidine-derived chiral amines

Article abstract of DOI:10.1002/chem.200400872

The chiral nitrogen Lewis base, tricyclic cinchona alkaloid derivative TQO, is an effective promoter in the catalytic, asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines Ar-CH=NR′ 1 (R′ = Ts, Ms, Ns, SES) with various activated olefins such as

Full text of DOI:10.1002/chem.200400872

Catalytic, Asymmetric Aza-Baylis–Hillman Reaction of N-Sulfonated Imines
with Activated Olefins by Quinidine-Derived Chiral Amines
Min Shi,* Yong-Mei Xu, and Yong-Ling Shi[a]
Abstract: The chiral nitrogen Lewis
base, tricyclic cinchona alkaloid deriva-
tive TQO, is an effective promoter in
the catalytic, asymmetric aza-Baylis–
Hillman reaction of N-sulfonated
yields with good to high ee (up to
99%) at À308C or 458C in various sol-
vents, including DMF/MeCN (1:1, v/v).
The first such reaction of 1 with the
simplest Michael acceptor MVK and
methyl acrylate has been achieved with
excellent enantioselectivity. The ad-
ducts derived from MVK and EVK
had the opposite absolute configuration
to those from acrolein, methyl acrylate,
phenyl acrylate, and a-naphthyl acry-
late. A plausible mechanism has been
proposed on the basis of previous re-
ports and the authorsꢀ investigations.
An effective bifunctional chiral nitro-
gen Lewis base–Brønsted acid system
has been revealed in this type of aza-
Baylis–Hillman reaction.
À
imines Ar CH=NR’ 1 (R’ = Ts, Ms,
Ns, SES) with various activated olefins
such as methyl vinyl ketone (MVK),
ethyl vinyl ketone (EVK), acrolein,
methyl acrylate, phenyl acrylate, or a-
naphthyl acrylate to give the corre-
sponding adducts in moderate to good
Keywords: betaines · Lewis bases ·
asymmetric catalysis · aza-Baylis–
Hillman
reaction
·
enantio-
selectivity
Introduction
acceptors such as MVK or methyl acrylate with a Lewis
base promoter.
Great progress has been made in development of the
Baylis–Hillman (BH) reaction,[1] including several catalytic,
asymmetric versions,[2] since Baylis and Hillman first report-
ed the reaction of acetaldehyde with ethyl acrylate and
acrylonitrile in the presence of catalytic amounts of a strong
Lewis base such as 1,4-diazabicyclo[2.2.2]octane (DABCO)
in 1972.[3] However, the catalytic, asymmetric BH reaction is
still not fruitful, because until now it has been limited to the
specialized a,b-unsaturated ketones or acrylates such as
ethyl vinyl ketone (EVK) (71% ee),[2a] 2-cyclohexen-1-
During our investigations,[4] we have found that the reac-
tions with MVK or methyl acrylate of arylaldehydes bearing
electron-donating groups such as Et or MeO on the phenyl
ring were either sluggish or did not occur at all under the
traditional BH conditions. We therefore used N-tosylated
imines (N-arylmethylidene-4-methylbenzenesulfonamides,
ArCH=NTs) instead of arylaldehydes in the traditional BH
reaction with MVK or methyl acrylate,[5] because we expect-
ed the tosylated imino group to have high reactivity toward
nucleophilic attack, even when the phenyl ring bears elec-
tron-donating groups. Indeed, such reactions, promoted by a
catalytic amount of a Lewis base such as DABCO or 4-(di-
methylamino)pyridine (DMAP), give exclusively the normal
aza-BH adducts in good yields for many N-arylmethylidene-
4-methylbenzenesulfonamides.[5b,c] As a suitable chiral nitro-
gen Lewis base for a catalytic, asymmetric version of this re-
action, we chose 4-(3-ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]dec-
one[2b]
or
1,1,1,3,3,3-hexafluoroisopropyl
acrylate
(99% ee)[2c] and naphthyl acrylate (91% ee).[2d] For the sim-
plest methyl vinyl ketone (MVK), 81% ee has been attained
in the presence of a special nucleophile-loaded peptide and
l-proline.[2e] High enantioselectivity (>90% ee) has not so
far been reported in BH reactions involving simple Michael
5-yl)quinolin-6-ol (TQO) (10 mol%)[2c,g,6]
, because it is
[a] Prof. M. Shi, Dr. Y.-M. Xu, Y.-L. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
easily prepared from (+)-quinidine[2c,g,6] and high enantio-
meric excesses were achieved in the reac-
tions of 1,1,1,3,3,3-hexafluoroisopropyl acry-
late with arylaldehydes.[2c] We have previ-
ously reported an unprecedented catalytic,
asymmetric aza-BH reaction of N-tosylated
imines 1 with MVK and methyl acrylate uti-
354 Fenglin Lu, Shanghai 200032 (P. R. China)
Fax : (+86)21-6416-6128
E-mail: mshi@pub.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200400872
Chem. Eur. J. 2005, 11, 1794 – 1802

FULL PAPER
lizing TQO to achieve >90% ee in good yield under mild
conditions.[5d] This was the first case in which a high ee
(>90%) could be realized using the simplest Michael ac-
ceptor, MVK. The structure of TQO plays a very important
role in achieving high ee in this reaction.[2c,5d] Exploration
for a novel and highly efficient chiral Lewis base for catalyt-
ic, asymmetric BH reactions is a very attractive and compet-
itive field. Here, we report in full detail such a reaction of
N-sulfonated imines with various activated olefins, including
ethyl vinyl ketone (EVK), acrolein, phenyl acrylate, and a-
naphthyl acrylate. An interesting inversion of absolute con-
figuration between the adducts derived from MVK and
EVK and those from acrolein, methyl acrylate, phenyl acry-
late and a-naphthyl acrylate has also been revealed.
at À308C in MeCN. To obtain the aza-BH adducts 2 with
high ee values and yields, we next investigated the reaction
of N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide 1e
with MVK in MeCN/DMF at À308C (Table 2). The best re-
Table 2. Aza-Baylis–Hillman reactions of N-(4-chlorobenzylidene)-4-
methylbenzenesulfonamide 1e (1.0 equiv) with methyl vinyl ketone
(2.0 equiv) in the presence of TQO (10 mol%).
Entry
MeCN/DMF
(v/v)
Yield of
ee [%]
Absolute
configuration
2e [%][a]
1
2
3
4
5:1
4:1
1:1
1:2
76
78
71
66
78
90
93
93
R
R
R
R
Results and Discussion
[a] Yield of isolated product.
Catalytic, asymmetric aza-Baylis–Hillman reaction of N-sul-
fonated imines
action conditions were obtained with MeCN/DMF = 1:1
(v/v) at À308C, which gave 2e in 71% yield with 93% ee
(Table 2, entry 3). The absolute configuration of 2e was de-
termined by X-ray crystallography to be R-enriched
(Figure 1).[7]
Reactions with MVK and EVK: The results with N-tosylated
imines 1 such as N-(4-ethylbenzylidene)-4-methylbenzene-
sulfonamide 1c and N-(4-chlorobenzylidene)-4-methylben-
zenesulfonamide 1e as substrates for the reaction with
MVK in the presence of TQO are summarized in Table 1.
Table 1. Aza-Baylis–Hillman reactions of N-(4-ethylbenzylidene)-4-
methylbenzenesulfonamide 1c or N-(4-chlorobenzylidene)-4-methylben-
zenesulfonamide 1e (1.0 equiv) with methyl vinyl ketone (2.0 equiv) in
the presence of TQO (10 mol%).
Entry Ar
1
Solvent Time Temp.
2
Yield ee
[h]
[8C]
[%][a] [%]
1
2
3
4
5
6
7
8
9
p-EtC6H4 1c THF
p-EtC6H4 1c THF
p-EtC6H4 1c MeCN
p-EtC6H4 1c MeCN
p-EtC6H4 1c DMF
p-EtC6H4 1c DMF
p-ClC6H4 1e THF
p-ClC6H4 1e THF
p-ClC6H4 1e MeCN
p-ClC6H4 1e DMF
36
24
24
24
24
24
24
24
24
24
20
À25
0
À20
À20
À40
0
À20
À30
À30
2c 30
2c 33
2c 50
2c 64
2c 55
2c 50
2e 71
2e 65
2e 80
2e 51
62
76
78
86
93
96
42
63
81
95
Figure 1. Crystal structure of 2e (ORTEP drawing).
In the reaction of other N-tosylated imines 1 with MVK
in the presence of TQO as a chiral nitrogen Lewis base, sim-
ilar results were obtained under the optimized reaction con-
ditions (Table 3). Aza-BH adducts of 1 were obtained with
high ee values (90–99%) and moderate to good yields (58–
80%; Table 3, entries 1–5). N-(p-Nitrobenzylidene)-4-meth-
ylbenzenesulfonamide (1g), N-furan-2-ylmethylene-4-meth-
ylbenzenesulfonamide (1h), and 4-methyl-N-(3-phenylallyli-
dene)benzenesulfonamide (1i) with MVK under the same
reaction conditions gave 2g–2i with moderate ee values
(Table 3, entries 6–8). No adduct 2g was observed in DMF
at À408C, because N-(4-nitrobenzylidene)-4-methylbenzene-
sulfonamide decomposes rapidly in DMF under these condi-
tions. The ee of 2 can reach over 99% after one recrystalli-
zation from CH2Cl2/hexane (1:6, v/v) in most cases.
10
[a] Yield of isolated product.
At 08C~208C (room temperature), moderate enantioselec-
tivities (42–78% ee) for the corresponding adducts 2c and
2e were achieved in THF or MeCN (Table 1, entries 1, 3,
and 7). Moreover, at lower temperatures (À20 to À308C),
the ee values of 2c and 2e could reach 86% and 81%, with
64% and 80% yield, respectively (Table 1, entries 4 and 9).
The highest ee values (96% and 95%) for 2c and 2e were
achieved in DMF at À30 to À408C with 50% and 51%
yield (Table 1, entries 6 and 10). Thus, the highest ee value
was attained at À308C in DMF, but the best chemical yield
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M. Shi et al.
Table 3. Aza-Baylis–Hillman reactions of N-tosylated imines
(1.0 equiv) with methyl vinyl ketone (2.0 equiv) in the presence of TQO
(10 mol%) under the optimized reaction conditions.
1
tained in only 20% ee with 60% yield of isolated product
(Scheme 1). Use of sulfone-protected imine as substrate is
Entry Ar
1
2
Yield [%][a] ee [%]
Absolute
configuration
Scheme 1. Baylis–Hillman reaction of p-nitrobenzaldehyde with MVK in
the presence of TQO (10 mol%).
1
2
3
4
5
6
C6H5
p-MeC6H4
p-EtC6H4
p-MeOC6H4
p-NO2C6H4
p-EtC6H4
1a 2a 80
1b 2b 80
1c 2c 74
1d 2d 67
1 f 2 f 58
1g 2g 60
97[b]
96
R
R
R
R
R
R
96
important for achieving high enantioselectivity in BH reac-
tions with MVK as acceptor, although high enantiomeric ex-
cesses have been achieved in the reactions of 1,1,1,3,3,3-
hexafluoroisopropyl acrylate with aldehydes.[2c]
The results for optimized reaction conditions with N-tosy-
lated imine 1a and with EVK as the substrate at À308C are
summarized in Table 5. In MeCN or THF, the corresponding
adduct 4a was obtained in 42% and 49% yield with 86%
and 55% ee, respectively, with an R-enriched configuration
99[c,e]
90
74[d]
7
8
1h 2h 61
73[e]
46[e]
R
R
À
C6H5 CH=CH 1i 2i 54
[a] Yield of isolated product. [b] In DMF, yield: 57%; 96% ee. [c] In
DMF, yield: 59%; 99% ee. [d] In DMF, no imine BH adduct was formed
because the imine decomposed quickly. [e] The reaction mixture was stir-
red for 36 h.
Table 5. Aza-Baylis–Hillman reactions of N-tosylated imines 1 (1.0 equiv) with ethyl vinyl ketone (2.0 equiv)
in the presence of TQO (10 mol%).
For
other
N-sulfonated
imines such as N-mesylated
À
imine 1j (ArCH=N Ms) and
N-SES-protected imine 1l
(b-trimethylsilylethanesulfon-
amide: Me3SiCH2CH2SO2N=
CHAr), this catalytic, asym-
metric aza-BH reaction pro-
ceeded smoothly under the
same conditions to give the
corresponding adducts 3a and
3c in good yields with 89%
Entry
Ar
1
Solvent
Time
[h]
4
Yield
[%][a]
ee
[%]
Absolute
configuration
1
2
3
4
5
6
7
C6H5
C6H5
C6H5
C6H5
p-MeC6H4
p-FC6H4
p-ClC64
1a
1a
1a
1a
1b
1e
1m
MeCN
THF
DMF
84
84
48
22
41
22
22
4a
4a
4a
4a
4b
4c
4d
42
49
44
54
49
54
46
86
55
90
R
R
R
R
R
R
R
MeCN/DMF (1:1)
MeCN/DMF (1:1)
MeCN/DMF (1:1)
MeCN/DMF (1:1)
94
87[b]
84
82
and
80% ee,
respectively
[a] Yield of isolated product. [b] After one recrystallization from CH2Cl2/hexane, the ee can reach 99.9%.
(Table 4, entries 1 and 3).
However, we found that N-4-
À
nitrobenzenesulfonated imine 1k (ArCH=N Ns), which
should be the most active electrophile in this aza–BH reac-
tion, decomposed rapidly under the same reaction condi-
tions and the corresponding aza-BH adduct 3b was not
formed (Table 4, entry 2).
(Table 5, entries 1 and 2). In DMF, adduct 4a was obtained
in 44% yield with 90% ee (Table 5, entry 3). When this re-
action was carried out in MeCN/DMF (1:1 (v/v) at À308C,
94% ee could be achieved after 22 h in 54% yield (Table 5,
entry 4). These should be the best conditions for this reac-
tion. For several other N-tosylated imines (1b, 1e, and 1m),
similar results were obtained (Table 5, entries 5–7). The re-
crystallization of 4 gave a higher ee. For example, after one
recrystallization of 4b from CH2Cl2/hexane (1:3, v/v), the ee
of 4b reached 99.9% (Table 5, entry 5). In general, this type
of aza-BH reaction is more sluggish than that of MVK
under the same conditions, although high enantioselectivity
could still be achieved.
In the traditional BH reaction of p-nitrobenzaldehyde
with MVK under the same conditions, the adduct was ob-
Table 4. Aza-Baylis–Hillman reactions of other N-sulfonated imines 1
(1.0 equiv) with methyl vinyl ketone (2.0 equiv) in the presence of TQO
(10 mol%).
Reactions with acrolein, methyl acrylate, phenyl acrylate, a-
naphthyl acrylate, and acrylonitrile: We found that the cata-
lytic, asymmetric aza-BH reaction of N-tosylated imines 1
with acrolein proceeded smoothly in the presence of TQO.
The solvent survey showed that THF was the best solvent
for this reaction (Table 6). The ee achieved reached 85% in
58% yield at À258C, and 72% in 71% yield at room tem-
Entry C6H5CH=NR
1
3
Yield ee
Absolute
[%][a] [%] configuration
1
2
3
C6H5CH=N Ms
1j 3a 58
1k 3b
89[b]
–
–
[c]
À
À
C6H5CH=N Ns
0
–
[c]
80[b]
–
À
4-MeC6H4CH=N SES 1l 3c 71
[a] Yield of isolated product. [b] Determined by chiral HPLC. [c] The
sign of specific rotation.
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Asymmetric Aza-Baylis–Hillman Reaction
FULL PAPER
Table 6. Aza-Baylis–Hillman reactions of N-(benzylidene)-4-methylben-
zenesulfonamide 1a (1.0 equiv) with acrolein (2.0 equiv) in the presence
of TQO (10 mol%).
Table 8. Aza-Baylis–Hillman reactions of N-(benzylidene)-4-methylben-
zenesulfonamide 1a (1.0 equiv) with methyl acrylate (2.0 equiv) in the
presence of TQO (10 mol%).
Entry Solvent
Temp. Time Yield of ee
Absolute
Entry
Solvent
Temp. Time Yield of ee
[8C] [h]
Absolute
6a [%][a] [%] configuration
5a[%][a] [%] configuration
[8C]
[h]
1
2
3
4
5
6
7
MeCN/DMF (1:1) À20
24
72
36
55
72
36
72
NR[b]
33
–
60
62
60
65
–
52
–
67
83
83
75
–
S
S
S
S
S
S
1
THF
THF
CH2Cl2
À25 10
À25 24
À25 96
58
57
20
24
71
85
85
78
71
72
S
S
S
S
S
2[b]
3
MeCN
DMF
RT
0
[c]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
RT
0
0
À20
4
5
CH3CN/DMF (1:1) À25
THF RT
4
4
[a] Yield of isolated product. [b] 0.25 mol% of TQO was employed.
[a] Yield of isolated product. [b] No reaction. [c] Starting material imine
1a decomposed.
perature (208C), with an S-enriched configuration (Table 6,
entries 1 and 5). In MeCN/DMF (1:1, v/v), the ee achieved
was 71% at À258C (Table 6, entry 4). This reaction is fairly
effective in THF in the presence of TQO because a shorter
reaction time is required than with MVK or EVK. Using
0.25 mol% TQO as a chiral nitrogen Lewis base, a similar
result was obtained after 24 h (Table 6, entry 2). Under the
optimized conditions, we next examined the aza–BH reac-
tion of other N-tosylated imines 1 with acrolein (Table 7).
The adducts 5b–f were obtained in 83–89% ee with moder-
ate to good yields (Table 7, entries 1–5.
with 70–83% ee (Table 9). N-Mesylated imine 1j and N-ni-
trobenzenesulfonated imine 1k produced the corresponding
adducts 6j and 6k in the similar yields and ee (Table 9, en-
tries 9 and 10). In general, this type of aza-BH reaction is
relatively sluggish in comparison to that with MVK or acro-
lein.
Table 9. Aza-Baylis–Hillman reactions of N-sulfonated imines
(1.0 equiv) with methyl acrylate (2.0 equiv) in the presence of TQO
(10 mol%).
1
Table 7. Asymmetric aza-Baylis–Hillman reaction of N-tosylated imines
1 with acrolein (2.0 equiv) in the presence of TQO (10 mol%).
Entry Ar
1
Time
[h]
6
Yield ee
Absolute
[%][a] [%] configuration
Entry
Ar
1
Time
[h]
5
Yield
[%][a]
ee
[%]
Absolute
configuration
1
2
3
4
5
6
7
8
9
C6H5
p-MeC6H4
p-EtC6H4
p-MeOC6H4
p-ClC6H4
m-FC6H4
p-NO2C6H4
2,3-Cl2C6H3
C6H5CH=N Ms 1j 68
1a 72
1b 72
1c 72
1d 72
1e 36
1 f 32
1g 35
1i 38
6a 62
6b 67
6c 62
6d 64
6e 60
6 f 87
6g 60
6i 58
6j 72
6k 60
83
80
82
70
77
83
72
71
77
83
S
S
S
S
S
S
S
S
S
S
1
2
3
4
5
p-MeC6H4
p-ClC6H4
p-FC6H4
m-ClC6H4
p-BrC6H4
1b
1e
1m 10
1n
1o
20
10
5b 55
5c 62
5d 61
5e
5 f
83
87
88
89
89
S
S
S
S
S
4.5
5
65
72
[a] Yield of isolated product.
À
À
10
C6H5CH=N Ns 1k 72
[a] Yield of isolated product.
However, the reactions of N-tosylated imines 1 with
methyl acrylate in MeCN/DMF (1:1, v/v) at À208C, MeCN
at room temperature, or DMF at 08C were sluggish, and
most N-tosylated imines decomposed during the reaction in
DMF or MeCN (Table 8, entries 1–3). However, we had
found previously that, with DABCO as a Lewis base in di-
chloromethane at 08C, the reaction proceeded smoothly to
give the adducts 6 in good yields.[5e] Moreover, in the pres-
ence of TQO, adduct 6a was obtained with 67–83% ee in
60–65% yields with an S-enriched configuration in the reac-
tion of 1a with methyl acrylate in dichloromethane (Table 8,
entries 4–7). At 08C, the highest ee was achieved after 36 or
72 h. Similar enantioselectivity was obtained from this reac-
tion at À208C. For other N-tosylated imines 1 in the pres-
ence of TQO, products 6 were obtained in 58–87% yields
Chen and co-workers reported previously that using
À
phenyl acrylate, CH=CH C(O)OPh, or a-naphthyl acrylate,
À
CH=CH C(O)O(a-Nap), as a Michael acceptor, the BH re-
action with aldehydes can be significantly accelerated in the
presence of DABCO (30 mol%).[8] Encouraged by this
result, we exchanged methyl acrylate for the more reactive
phenyl acrylate as a Michael acceptor (2.0 equiv) for the cat-
alytic, asymmetric aza-BH reaction with N-sulfonated
imines 1 (1.0 equiv). The solvent effects and reaction tem-
peratures were first examined similarly to those described in
Table 8. We found that the best conditions were reaction in
acetonitrile at À208C. The results with phenyl acrylate are
summarized in Table 10. The adducts 7 were obtained with
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M. Shi et al.
Table 10. Aza-Baylis–Hillman reactions of N-sulfonated imines
1
(1.0 equiv) with phenyl acrylate (2.0 equiv) in the presence of TQO
(10 mol%).
Scheme 3. Catalytic, asymmetric aza-Baylis–Hillman reaction of N-sulfo-
nated imine 1a (1.0 equiv) with a-naphthyl acrylate (2.0 equiv).
Entry Ar
1
Time
[h]
7
Yield
ee
Absolute
[%][a] [%] configuration
1
2
3
4
5
C6H5
1a 24
1b 72
7a 67
7b 68
74
69
74
82
67
S
S
S
S
S
for phenyl acrylate were obtained in the reaction of N-sulfo-
nated imines 1 with a-naphthyl acrylate.
p-MeC6H4
m-MeC6H4
m-FC6H4
1c
1 f
1i
72
8
20
7c
84
In addition, aza-BH reaction of 1a with acrylonitrile af-
forded adduct 9a in 35% yield with 55% ee in CH2Cl2, and
in 34% yield with 68% ee in THF, under the same condi-
tions as for methyl acrylate. Another N-tosylated imine, 1b,
gave a similar result (Scheme 4).
7d 83
7e 81
2,3-Cl2C6H3
[a] Yield of isolated product.
67–82% ee in 67–84% yields (Table 10, entries 1–5). Using
N-tosylated imine 1e as substrate and a-naphthyl acrylate as
a Michael acceptor under the same conditions, this reaction
was sluggish and the corresponding adduct 8e was obtained
with 46% ee in 40% yield (Scheme 2). We examined this re-
Scheme 2. Catalytic, asymmetric aza-Baylis–Hillman reaction of N-sulfo-
nated imine 1e (1.0 equiv) with a-naphthyl acrylate (2.0 equiv).
Scheme 4. Aza-Baylis–Hillman reaction of N-(benzylidene)-4-methylben-
zenesulfonamide 1a (1.0 equiv) with acrylonitrile (2.0 equiv).
action at 08C in various solvents; in MeCN for 12 h, 78% ee
can be achieved in 67% yield (Table 11, entry 1). In DMF,
the yield of 8e reached 81% with 45% ee after 22 h
(Table 11, entry 5). The mixed solvent did not improve the
ee or yield (Table 11, entries 7 and 8). The best result was
obtained in MeCN at 08C. Under the optimized conditions,
we also examined its general applicability to other N-sulfo-
nated imines through the aza–BH reaction of 1a with a-
naphthyl acrylate (Scheme 3). Adduct 8a was obtained in
85% yield with 80% ee. In general, similar results to that
To extend the scope and explore the limitations of this
novel reaction, we tried to synthesize aliphatic N-tosylated
imines as starting materials. However, we found that many
of these are very labile, even when stored below À208C. We
used literature procedures to prepare the aliphatic N-tosy-
lated imines 1o and 1p,[9] which must be used immediately
for the reaction. The attempted catalytic, asymmetric aza-
BH reaction of 1o and 1p with MVK in the presence of
TQO under the same conditions gave many unidentified
products, and the aza-BH adduct was not formed
(Scheme 5).
Table 11. Aza-Baylis–Hillman reactions of N-(4-chlorobenzylidene)-4-
methylbenzenesulfonamide 1e (1.0 equiv) with a-naphthyl acrylate
(2.0 equiv) in the presence of TQO (10 mol%).
Scheme 5. Aza-Baylis–Hillman reaction of aliphatic imines with MVK in
the presence of TQO (10 mol%).
Entry
Solvent
Time
[h]
Yield of
ee
[%]
Absolute
configuration
8e [%][a]
In this systematic investigation of the aza-BH reaction of
N-sulfonated imines 1 with the simplest Michael acceptors
such as MVK, EVK, acrolein, methyl acrylate, and acrylo-
nitrile, and with sterically large Michael acceptors such as
phenyl acrylate and a-naphthyl acrylate, moderate to excel-
lent enantioselectivities have been achieved, depending on
the Michael acceptors employed. The reaction rate and the
ee achieved are fairly sensitive to the solvents and reaction
1
2
3
4
5
6
7
8
MeCN
THF
CH2Cl2
dioxane
DMF
12
17
22
21
22
47
12
12
67
65
46
77
81
64
72
65
78
72
73
56
45
65
70
74
S
S
S
S
S
S
S
S
acetone
DMF/CH2Cl2 (1:1)
DMF/MeCN (1:1)
[a] Yield of isolated product.
1798
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Asymmetric Aza-Baylis–Hillman Reaction
FULL PAPER
temperatures employed. Careful examination of these condi-
tions is required to achieve higher yields and ee values.
Determination of absolute configuration: The absolute con-
figuration of adducts 2, which have negative specific rota-
tion, recrystallized from dichloromethane and hexane, was
found by X-ray diffraction to be R-enriched (Supporting In-
formation).[5d] The absolute configuration of adducts 3 and
4, which also have negative specific rotation, can be assigned
as R-enriched by comparison of their sign of specific rota-
tion with those we reported previously.[5d,h] We found ad-
ducts 5 and 6 to have positive specific rotation and their ab-
solute configurations can be assigned as S-enriched by com-
parison of their sign of specific rotation with those reported
by Hatakeyama.[2g,5h] It is therefore necessary to determine
their absolute configurations unambiguously. We attempted
to determine the absolute configuration of 6 by X-ray dif-
fraction similarly to the adduct 2e. The single crystal of 6d
was indeed obtained by recrystallization from dichlorome-
thane and hexane (1:4, v/v). However, the X-ray data indi-
cated that the crystal structure of 6d (Figure 2) is a race-
Scheme 6. Determination of absolute configuration of 5–8.
Scheme 7. The absolute configuration of adducts.
Figure 2. Crystal structure of 6d (ORTEP drawing).
protons, the adducts are produced in R-enriched configura-
tion, and otherwise the configuration is S-enriched. This
result suggests that the steric bulkiness of activated olefins
may play a key role in the resulting absolute stereochemis-
try of the adducts in this reaction.
mate (see Supporting Information). Our careful examination
revealed that recrystallization of adducts 6, 7, and 8 with a
variety of solvents, such as toluene, ethyl acetate, dichloro-
methane, and acetonitrile, lead to a decrease in ee in the re-
sulting crystals and an increase in ee in the mother liquors.
Therefore, adducts 6, 7, and 8 could not be recrystallized to
an enantiopure form, and it is impossible to determine their
absolute configurations by X-ray diffraction. To clarify this
interesting inversion of stereochemistry further, the absolute
configurations of 5–7 were confirmed unambiguously to be
S-enriched by the method reported by Li and Hatakeya-
ma,[2g,10] namely, by transforming the products to the corre-
sponding phenylglycine derivatives and comparing them to
authentic samples prepared from (R)-phenylglycine
(Scheme 6).[11] The absolute configurations of adducts 8 and
9 have been assigned as S-enriched by the same method
(Scheme 6).
Mechanistic explanation: (+)-Quinidine or (À)-quinine
showed no catalytic activity for this reaction. The hydroxyl
group on the quinolyl ring is also crucial, because the reac-
tion became sluggish and gave the product with only about
10% ee in very low yield when O-methylated TQO was
used as the chiral Lewis base (Scheme 8). Thus, the structure
of the Lewis base plays an important role in this reaction.
We further confirmed that when 10–30 mol% TQO was
used in the aza-BH reaction of 1e with MVK, the adducts
2e were formed with similar ee values (Table 12). In the re-
action of 1e with methyl acrylate, similar results were ob-
tained. This result suggests that this asymmetric aza–BH re-
action catalyzed by chiral nitrogen Lewis base TQO is a un-
imolecular process.
We have elucidated this inversion of absolute configura-
tion; Scheme 7 shows that if the Michael acceptors have a-
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M. Shi et al.
chael acceptors MVK and EVK, two betaine intermediates
B and C are in an equilibrium which is stabilized by intra-
molecular hydrogen bonding between the amidate ion and
the phenolic OH, and are nearly ideal for the subsequent
E2 or E1cb elimination for stereoelectronic reasons,[2c,g] as
indicated in Newman projection D (Scheme 10) according
Scheme 8. Catalytic activity in the aza-BH reaction.
Table 12. Aza-Baylis–Hillman reactions of N-(4-chlorobenzylidene)-4-
methylbenzenesulfonamide 1e (1.0 equiv) with methyl vinyl ketone in
the presence of TQO (10–30 mol%).
Entry
TQO [mol%]
Yield of
ee
[%]
Absolute
configuration
2e [%][a]
1
2
3
4
10
15
20
30
77
78
75
76
93
92
93
93
R
R
R
R
[a] Yield of isolated product.
A key intermediate of the reaction (Scheme 9) is based
on the mechanism proposed by Hatakeyama and on our
own results reported above.[2c,g] We believe that the key
Scheme 10. A plausible reaction mechanism for the catalytic, asymmetric
aza-Baylis–Hillman reaction of imines with MVK.
to the generally accepted mechanism of the BH reaction,[1,3]
which was strongly consolidated by Santosꢀs findings based
on an ESI/MS/MS spectroscopic investigation recently.[12]
Since MVK and EVK have a-protons in their structures,
they are sterically larger than methyl acrylate (OMe) and
phenyl acrylate (OPh).[13] The intermediate B suffers from
severe steric interactions between the Ar and the methyl
group in the MVK and TQO moieties (Newman projection
D). On the other hand, intermediate C has only the steric
interaction between the aromatic group and the N-sulfonat-
ed group (Scheme 10). Conversely, the intermediate C suf-
fers from fewer steric interactions. Therefore, intermediate
C undergoes facile elimination to furnish R-enriched ad-
ducts and regenerates the nitrogen Lewis base.
For Michael acceptors acrolein, methyl acrylate, phenyl
acrylate, a-naphthyl acrylate, and acrylonitrile, which do not
have a-protons, the ammonium enolate E formed reacts
with N-sulfonated imines to give two betaine intermediates
F and G in a similar equilibrium through Mannich reaction;
these are stabilized by intramolecular hydrogen bonding be-
tween the amidate ion and the phenolic OH group
(Scheme 11). Since methyl acrylate and phenyl acrylate do
not have a-protons in their structures, they are sterically
smaller than MVK and EVK.[13] The steric interaction of the
Scheme 9. Key intermediate for the catalytic, asymmetric aza-Baylis–Hill-
man reaction of N-sulfonated imines with activated olefins.
factor is the intramolecular hydrogen bonding between the
phenolic OH group and the nitrogen-centered anion, stabi-
lized by a sulfonyl group to give a relatively rigid transition
state in this reaction.
The following mechanistic explanation could rationalize
the outcome of the absolute configuration of the adducts
(Schemes 10 and 11). Michael addition of TQO to a a,b-un-
saturated ketone or ester gives enolate A equilibrated with
enol A’, or E equilibrated with enol E’, which in turn under-
goes Mannich reaction with N-sulfonated imine to furnish
an equilibrium mixture of several diastereomers. For Mi-
1800
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Asymmetric Aza-Baylis–Hillman Reaction
FULL PAPER
Experimental Section
General: Melting points were obtained with a Yanagimoto micro melting
point apparatus and are uncorrected. 1H NMR spectra were recorded on
a Bruker AM-300 spectrometer for solutions in CDCl3 with tetramethyl-
silane (TMS) as internal standard; J values are in Hz. Mass spectra were
recorded with an HP-5989 instrument. N-Tosylimines were prepared ac-
cording to the literature.[15] All the solid compounds reported in this
paper gave satisfactory CHN microanalyses with a Carlo-Erba 1106 ana-
lyzer. Commercially obtained reagents were used without further purifi-
cation. All reactions were monitored by TLC with Huanghai GF254 silica
gel coated plates. Flash column chromatography was carried out using
200–300-mesh silica gel at increased pressure. The optical purities of the
BH adducts were determined by HPLC analysis using a chiral stationary
phase column (column, Daicel Co. Chiralcel OD, AS and OJ; eluent,
hexane/2-propanol (95:5, v/v); flow rate, 1.0 mLminÀ1; detection, 254 nm
light). The absolute configuration of the major enantiomer of 2e, recrys-
tallized from dichloromethane/hexane (1:4, v/v), was determined from its
X-ray crystal structure and the others were subsequently assigned by
comparing the sign of the specific rotation with that of an authentic
sample.
Typical reaction procedure for TQO-catalyzed aza-Baylis–Hillman reac-
tion of methyl vinyl ketone with N-(p-ethylbenzenesulfonyl)benzaldimine
1c: To
a solution of 1c (72 mg, 0.25 mmol) and TQO (8.0 mg,
0.025 mmol) in CH3CN/DMF (1:1, v/v) (1.0 mL) was added methyl vinyl
ketone (41 mL, 0.5 mmol) at À308C. The reaction mixture was stirred at
À308C for 24 h. After the reaction was completed, the solvent was re-
moved under reduced pressure and the residue was purified by flash
column chromatography (SiO2; eluent, EtOAc/petroleum ether, 1:5, v/v)
to yield 2c (66 mg, 74%) as a colorless solid.
Scheme 11. A plausible reaction mechanism for the catalytic, asymmetric
aza-Baylis–Hillman reaction of N-sulfonated imines with methyl acrylate.
N-sulfonated group with the aromatic group in this stabi-
lized transition state G is more severe than that of the ester
moiety and aromatic group in intermediate F, and causes
the formation of the aza–BH adduct with an S configura-
tion.[2c,g]
N-[1-(4-Ethylphenyl)-2-methylene-3-oxobutyl]-4-methylbenzenesulfona-
mide (2c): Yield 66 mg (74%); colorless solid (96% ee), m.p. 114–1158C;
[a]2D5 = À46.98 (c = 1.00 in CHCl3); 1H NMR (CDCl3, TMS, 300 MHz):
d = 1.23 (t, 3J(H,H) = 7.6 Hz, 3H; Me), 2.15 (s, 3H; Me), 2.39 (s, 3H;
Me), 2.54 (q, 3J(H,H) = 7.6 Hz, 2H; CH2), 5.20 (d, 3J(H,H) = 8.4 Hz,
1H; NH), 5.51 (d, 3J(H,H) = 8.4 Hz, 1H; CH), 6.09 (s, 2H), 6.97 (d,
Overall, we believe that TQO acts as a bifunctional chiral
ligand promoter in this reaction.[14] The nitrogen atom in the
quinuclidine moiety acts as a Lewis base (LB) to initiate the
BH reaction and the phenolic OH group acts as a Lewis
acid through hydrogen bonding (BA = Brønsted acid as a
Lewis acid) to stabilize the key enolate intermediate and
the reaction intermediate. Thus, this is an LBBA bifunction-
al chiral ligand catalytic system. The key factor is the intra-
molecular hydrogen bonding between the phenolic OH and
the nitrogen anion stabilized by the sulfonyl group. More-
over, the use of N-sulfonated imines, instead of aldehydes,
can drive the reaction forward and perhaps cut down on the
reversibility shown in Schemes 9–11 which usually erodes
the enantioselectivity in the BH reaction.
We have achieved the highest ee values so far for the aza–
BH reaction involving MVK, EVK, acrolein, methyl acry-
late, phenyl acrylate, or a-naphthyl acrylate as a Michael ac-
ceptor. Moreover, this is the first case of a highly enantiose-
lective aza-Baylis–Hillman reaction of imines with a,b-unsa-
turated ketones or esters to be reported. An interesting in-
version of stereochemistry between MVK or EVK and acro-
lein, methyl acrylate, phenyl acrylate, or a-naphthyl acrylate
has been revealed. A plausible mechanism has been pro-
posed on the basis of previous reports and our own results.
Continuing efforts are under way to elucidate the mechanis-
tic details of this reaction and to discover its scope and limi-
tations.
3
3J(H,H) = 6.1 Hz, 2H; Ar), 6.98 (d, J(H,H) = 6.1 Hz, 2H; Ar), 7.21 (d,
3J(H,H)
= = 8.4 Hz, 2H; Ar);
8.4 Hz, 2H; Ar), 7.63 (d, 3J(H,H)
13C NMR (CDCl3, TMS, 75 MHz): d = 15.51, 21.42, 26.25, 28.29, 58.29,
126.44, 127.22, 127.89, 129.08, 129.38, 136.09, 137.44, 143.16, 143.54,
146.66, 198.26; IR (CHCl3): n˜ =1674 cmÀ1 (C=O); MS (70 eV): m/z (%):
358 (0.5) [M++1], 288 (5.6) [M+À69], 202 (100) [M+À155]; elemental
analysis calcd (%) for C20H23NO3S: C 67.20, H 6.49, N 3.92; found: C
67.04, H 6.42, N 3.74.
HPLC conditions: OD-H column, 258C, 2-propanol/n-hexane
= 3:97
(v/v), 1.0 mLminÀ1, major peak: 43.22 min; minor peak: 50.06 min.
Typical reaction procedure for TQO-catalyzed aza-Baylis–Hillman reac-
tion of methyl acrylate with N-benzenesulfonyl benzaldimine 1a: To a so-
lution of 1a (130 mg, 0.5 mmol) and TQO (16 mg, 0.05 mmol) in CH2Cl2
(0.5 mL) was added methyl acrylate (90 mL, 1 mmol) at 08C. The reaction
was stirred at 08C for 36 h. After the reaction was completed, the solvent
was removed under reduced pressure and the residue was purified by
flash column chromatography (SiO2; eluent, EtOAc/petroleum ether, 1:5,
v/v) to yield 6a (107 mg, 62%) as a colorless solid.
Methyl 2-[phenyl(toluene-4-sulfonylamino)methyl]acrylate (6a): Yield
107 mg, 62%; colorless solid (83% ee); m.p. 76–788C; [a]2D5 = +19.58 (c
= 0.88 in CHCl3); 1H NMR (CDCl3, TMS, 300 MHz): d = 2.40 (s, 3H;
Me), 3.60 (s, 3H; Me), 5.29 (d, 3J(H,H) = 9.2 Hz, 1H; NH), 5.65 (d,
3J(H,H) = 9.2 Hz, 1H; CH), 5.83 (s; 1H), 6.22 (s; 1H), 7.13–7.18 (m,
2H; Ar), 7.21–7.33 (m, 5H; Ar), 7.67 (d, 3J(H,H) = 8.6 Hz, 2H; Ar);
13C NMR (CDCl3, TMS, 75.4 MHz): d = 21.4, 51.8, 58.6, 126.4, 127.0,
127.5, 127.6, 128.4, 129.3, 137.4, 138.4, 138.5, 143.2, 165.6; IR (CHCl3): n˜
= 1708 cmÀ1 (C=O), 1633 cmÀ1 (C=C); MS (70 eV): m/z (%): 314 (1.94)
[M+À31], 190 (100.00) [M+À155], 155 (67.94) [MeC6H4SO2+]; HRMS:
calcd for C17H16NO3S: 314.0859 [M+ÀOCH3]; found: 314.0890; elemental
analysis calcd (%) for C18H19NO4S: C 62.59, H 5.54, N 4.06; found: C
62.57, H 5.68, N 3.92.
Chem. Eur. J. 2005, 11, 1794 – 1802
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M. Shi et al.
HPLC conditions: AS column, 258C, 2-propanol/n-hexane = 40:60 (v/v),
4737–4739; h) M. Shi, L. H. Chen, Chem. Commun. 2003, 1310–
1311; i) Baylis–Hillman reaction of methyl acrylate with imines: P.
Perlmutter, C. C. Teo, Tetrahedron Lett. 1984, 25, 5951–5952; j) M.
Takagi, K. Yamamoto, Tetrahedron 1991, 47, 8869–8882; k) Baylis–
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0.6 mLminÀ1; major peak: 20.90 min; minor peak: 25.91 min.
Acknowledgements
We thank the State Key Project of Basic Research (Project 973) (No.
G2000048007), Shanghai Municipal Committee of Science and Technolo-
gy, and the National Natural Science Foundation of China for financial
support (20025206, 203900502, and 20272069).
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[7] Crystal data of 2e: empirical formula: C18H18ClNO3S; formula
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space group: P21; unit cell dimensions: a = 8.513(3), b = 12.076(4),
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=
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Received: August 25, 2004
Revised: November 28, 2004
Published online: January 25, 2005
1802
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Chem. Eur. J. 2005, 11, 1794 – 1802