First application of air-stable and reusable phosphine-containing calix[4]arene in catalytic aza-morita-baylis-hillman reaction

Article abstract of DOI:10.1055/s-0030-1259068

For the first time, the aza-Morita-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone was catalyzed by 5,11,17,23-tetrabutyl-25- (diphenylphosphinomethoxy)-26,27,28-trihydroxycalix[4]arene (LB1), an air-stable, easily isolated and reu

Full text of DOI:10.1055/s-0030-1259068

LETTER
3057
First Application of Air-Stable and Reusable Phosphine-Containing
Calix[4]arene in Catalytic Aza-Morita–Baylis–Hillman Reaction
C
alix[4]arene in Catalyt
e
ic
A
za-Mor
i
ita–Ba
h
ylis–Hillman
u
R
eaction i Zhong,* Yemin Zheng, Jiadi Zhou, Yanyan Shen
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320752; E-mail: pharmlab@zjut.edu.cn
Received 2 September 2010
ified at both their lower and their upper rims, which make
Abstract: For the first time, the aza-Morita–Baylis–Hillman reac-
them useful in the synthesis of a variety of derivatives
tion of N-sulfonated imines with methyl vinyl ketone was catalyzed
by 5,11,17,23-tetrabutyl-25-(diphenylphosphinomethoxy)-26,27,28-
with selected groups and desired properties.3
trihydroxycalix[4]arene (LB1), an air-stable, easily isolated and re-
usable catalyst. Great acceleration of the reaction was observed and
the aza-Morita–Baylis–Hillman adducts were produced in excellent
calix[4]arene (LB1) as a catalyst, the aza-MBH reaction
yields within short reaction time.
Herein we wish to report that by using 5,11,17,23-tetrabu-
tyl-25-(diphenylphosphinomethoxy)-26,27,28-trihydroxy-
of N-sulfonated imines with methyl vinyl ketone (MVK)
Key words: calix[4]arene, organocatalyst, phosphine, reusable,
proceeded efficiently and the aza-MBH adducts were af-
aza-Morita–Baylis–Hillman
forded in excellent yields under mild conditions
(Scheme 1).
The aza-Morita–Baylis–Hillman (aza-MBH) reaction is
O
TsNH
O
one of the most useful and interesting carbon–carbon
bond-forming reactions since it affords enriched b-amino
carbonyl compounds with an a-alkylidene group and has
enormous potential for synthetic utility under mild reac-
tion conditions.1 Over the past decade, great progress has
been made in the development of catalytic versions of this
reaction and several good multifunctional organocatalysts
for the aza-MBH reaction have been reported.2 Neverthe-
less, the development of a more effective, less expensive,
recoverable and reusable catalyst system remains a great
challenge. For example, a series of great chiral phosphines
based on 1,1¢-binaphthyl-2,2¢-diol were demonstrated by
Shi,2d–2l but the preparation of most of them were compli-
cated and tedious. Besides, the phosphines were easily ox-
idized during the reaction, which made the reaction
become very costly. Following these reports, the biphe-
nyl-2-ol-derived bifunctional phosphanes catalyzing aza-
MBH reaction were also reported.2m However, these cata-
lysts caused the formation of unusual side products. Re-
cently, the growing interest has been focused on
calixarene chemistry, as these systems can be easily mod-
LB (10 mol%)
Ar
+
NTs
Ar
solvent
1
2
3
Scheme 1 Aza-MBH reaction of N-sulfonated imines with MVK
Catalyst LB1 was prepared according to the known
methods4 (Scheme 2) and its catalytic activities for the
aza-MBH reaction were evaluated by performing a model
reaction
between
N-benzylidene-4-methylbenzene-
sulfonamide (1a) and MVK in the presence of 10 mol% of
LB1 (Table 1). The influence of solvent and temperature
on this reaction was investigated and the results are sum-
marized in Table 1. It was found that lower temperature
resulted in slightly better yield but the reaction proceeded
with much slower rate (Table 1, entries 1–4), while higher
temperature caused a slight drop in the yield (Table 1, en-
try 9). Among various solvents, dichloromethane was
found to be the best solvent in terms of yield and reaction
rate. For other solvents such as EtOAc, 2-methyltetrahy-
drofuran (2-MeTHF), toluene and THF, the yield was not
1) Ph2P(O)CH2Cl
NaH, KI, toluene
2) MeSiHCl2
71%
HO
OH
O
OH
HO
OH
OH
OH
PPh2
LB1
Scheme 2 Preparation of LB1
SYNLETT 2010, No. 20, pp 3057–3060
x
x
.x
x
.2
0
1
0
Advanced online publication: 24.11.2010
DOI: 10.1055/s-0030-1259068; Art ID: W13510ST
© Georg Thieme Verlag Stuttgart · New York

3058
W. Zhong et al.
LETTER
Table 1 Aza-MBH Reactions of 1a with MVK Catalyzed by LB1
Table 2 Aza-MBH Reactions of 1 with MVK Using LB1 (10
mol%) at 40 °C in CH2Cl2
NHTs O
O
Entry Ar
Time (h) Products (3) Yield (%)a
LB (10 mol%)
NTs
+
solvent
1
2
Ph
16
40
3a
3b
3c
3d
3e
3f
86
89
88
85
96
95
98
98
96
96
88
1a
2
3a
p-MeOC6H4
Entry Solvents
Temp (°C) Time (h) Yield (%)a
3
2,4-(OMe)2C6H3 72
3,4-(OMe)2C6H3 72
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
2-MeTHF
THF
10
20
30
40
30
30
30
30
50
30
60
48
24
16
27
29
30
27
16
48
87
88
86
85
85
82
80
83
78
0
4
5
m-FC6H4
o-FC6H4
3.5
2
3
6
4
7
p-ClC6H4
o-ClC6H4
p-BrC6H4
o-BrC6H4
2-thiophenyl
8
3g
3h
3i
5
8
6
6
9
5
7
10
11
8
3j
8
toluene
toluene
DMF
15
3k
9
a Isolated yields of 3 from reaction of 1 (1.0 mmol) and MVK (2.0
mmol).
10
a Isolated yield of 3a.
Table 3 Aza-MBH Reactions of 1f (1.0 mmol) with MVK Using
LB1 (10 mol%) at 40 °C in CH2Cl2
appreciably different from that in dichloromethane (en-
tries 5–8). Surprisingly, when DMF was applied as the
solvent, the expected product was not detected by TLC
even after prolonging the reaction time (entry 10). Unlike
other methods,5 various additives such as benzoic acid,
acetic acid, ammonium chloride did not provide any im-
provement in yield and reaction rate.
NHTs O
NTs
LB1 (10 mol%)
+
O
CH2Cl2, 40 °C
F
F
2
1f
3f
Entry
MVK
(equiv)
Time (h) LB1 recovered Adduct yield
yield (%)a
(%)a
95
95
96
95
94
89
95
96
92
95
94
With optimized conditions in hand (40 °C in CH2Cl2 in the
presence of 10 mol% of LB1), the catalytic aza-MBH re-
action of a variety of N-sulfonated aldimines 1 with MVK
was examined (Table 2). In general, introducing an elec-
tron-donating group on the aromatic ring of the N-sul-
fonated imines slowed down the reaction rate and the
corresponding aza-MBH adducts 3 were obtained in low-
er yields (85–89%) under standard conditions (Table 2,
entries 2–4). For substrates with electron-donating
groups, a longer reaction time was needed to achieve a
practical yield. In contrast, electron-withdrawing groups
speeded up the reaction rate and produced products in ex-
cellent yields (>94%; Table 2, entries 5–10). Substituents
at the ortho, meta, or para positions of the aromatic ring
in the employed imines did not affect the outcome of the
reactions (Table 2, entries 5–10). Thiophene-2-carbalde-
hyde gave the corresponding aza-MBH adduct 3k in a
good yield (Table 2, entry 11).
1
2
2.0
1.5
1.3
1.2
1.1
1.0
1.1
1.1
1.1
1.1
1.1
2
80
86
90
92
95
95
93
95
95
96
94
2
3
2
4
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
6
7b
8c
9d
10e
11f
a Isolated yields based on 1f.
It should be pointed out that the calixarene organocatalyst
LB1 was stable at room temperature and no noticeable
changes could be observed within one month. Besides, it
could be easily recovered by adding cold methanol and
filtration after the reaction. The filtrate was then purified
by flash column chromatography to give the correspond-
ing aza-MBH adduct 3 in high to excellent yields. The
recovered LB1 was used in the reaction of N-(2-fluo-
b LB1 was recovered from entry 6.
c LB1 was recovered from entry 7.
d LB1 was recovered from entry 8.
e LB1 was recovered from entry 9.
f LB1 was recovered from entry 10.
robenzylidene)-4-methylbenzenesulfonamide (1f) and
MVK as a model reaction (Table 3). From the results list-
Synlett 2010, No. 20, 3057–3060 © Thieme Stuttgart · New York

LETTER
Calix[4]arene in Catalytic Aza-Morita–Baylis–Hillman Reaction
3059
1) NaH, EtI, toluene
2) MeSiHCl2
67%
EtO
OEt
O
OEt
HO
OH
O
OH
PPh2
P(O)Ph2
LB2
Scheme 3 Preparation of LB2
O
Michael reaction
+
O
O
O
O
H
HO
OH
OH
O
H
H
Ph2P
PPh2
O
LB1
A
TsNH
O
Ar
aldol reaction
NTs
O
Ar
O
O
O
H
H
LB1
H
Ph2P
N
Ts
Ar
O
B
Scheme 4 A plausible reaction mechanism
ed in Table 3, it could be concluded that the reactions em- LB2 as the catalyst afforded the corresponding adduct 3f
ploying different ratios of the substrates proceeded in only 42% yield after 48 hours (Table 4, entry 1).
smoothly and the product 3f was obtained in an almost Whereas in the presence of 10% of phenol, compound 3f
constant yield. An exception came with the run where a was isolated in 88% yield within six hours (Table 4, entry
decreased dosage of MVK (1.0 equiv) led to a slightly de- 2), proving that the phenolic hydroxy groups are essential
creased yield (89%). However, it was interesting to note for this reaction.
that with the dosage of MVK being reduced from two
equivalents to one equivalent, the recovered yield of LB1
increased to as high as 95%. Therefore, the ratio of 1:1.1
Table 4 Aza-MBH Reaction of 1f (1.0 mmol) with MVK (1.5
mmol) Using LB2 (10 mol%) at 40 °C in CH2Cl2
was selected as the best ratio of the substrates for both the
product yield and the recovered yield of the catalyst. Us-
ing the optimized ratio, most of the catalyst was recovered
and reused in the aza-MBH reaction. To our delight, the
catalytic activity of LB1 did not show significant decrease
after being reused five times.
Entry
Phenol additive (mol%)
Time (h) Yield (%)a
1
2
0
48
6
42
88
10
a Isolated yields based on 1f.
It was reported that the hydroxy group of the catalyst for
aza-MBH reaction was considered to be essential to
achieve good yield in short time.6 To have an understand-
ing of the mechanism of this reaction, we further prepared
catalyst LB2 by replacing the hydroxy groups in LB1
with ethoxy groups (Scheme 3). Again, N-(2-fluoroben-
zylidene)-4-methylbenzenesulfonamide (1f) and MVK
were used as model substrates and the results are summa-
rized in Table 4. It should be noted that the reaction using
Based on our results and earlier reports,5e,f,7 we have pro-
posed a plausible mechanism as shown in Scheme 4.
Compound LB1 can be considered as a bifunctional cata-
lyst in this reaction.8 The phosphine in LB1 acts as a
Lewis base to initiate the aza-MBH reaction and the hy-
droxy groups act as Brønsted acid through hydrogen
bonding to stabilize the reaction transition state to accel-
erate the reaction. Thus, Michael addition of LB1 to MVK
Synlett 2010, No. 20, 3057–3060 © Thieme Stuttgart · New York

3060
W. Zhong et al.
LETTER
J. Org. Chem. 2008, 2150. (j) Zhao, L.-J.; Kwong, C.-K.;
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afforded an enolate intermediate A, followed by a Man-
nich reaction with imine 1 to give a hydrogen-bonding-
stabilized intermediate B. Subsequently the intermediate
B undergoes proton transfer and elimination to give the
aza-MBH product. Whereas in the case of LB2, the
ethoxy groups do not donate hydrogens to stabilize the in-
termediate anions and therefore longer reaction time was
needed and lower yield was obtained.
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In summary, for the first time, 5,11,17,23-tetrabutyl-25-
(diphenylphosphinomethoxy)-26,27,28-tri-hydroxycalix-
[4]arene (LB1) has been shown to be an efficient, air-sta-
ble and reusable catalyst in aza-MBH reaction. Excellent
yields of aza-Morita–Baylis–Hillman adducts were pro-
duced within short reaction times under mild conditions.
More efforts are underway to develop other derivatives of
calix[4]arene as organocatalysts.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the National Key Technology R&D Program (No.
2007BAI34B00) and the National Natural Science Foundation of
China (21076194) for financial support.
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