2-(Diphenylphosphino)benzoyl-substituted calix[4]arene: Efficient organocatalyst in aza-Morita-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone

Article abstract of DOI:10.1055/s-0031-1290358

A novel bifunctional organocatalyst 5,11,17,23-tetra-butyl-25-[2- (diphenylphosphino)benzoate]-26,27,28-trihydroxycalix-[4]arene (LB3) was synthesized and applied to promote the aza-Morita-Baylis-Hillman (aza-MBH) reaction of N-sulfonated im-ines with met

Full text of DOI:10.1055/s-0031-1290358

LETTER
741
2-(Diphenylphosphino)benzoyl-Substituted Calix[4]arene:
Efficient Organocatalyst in Aza-Morita–Baylis–Hillman Reaction of
N-Sulfonated Imines with Methyl Vinyl Ketone
2
-(Diphenylphosph
a
ino)benzoy
n
l-Substituted
y
C
alix[4]are
a
ne n Shen, Qian Tang, Chenchen Zhang, Weihui Zhong*
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)88871087; E-mail: weihuizhong@zjut.edu.cn
Received 16 October 2011
The synthetic route to LB3 is shown in Scheme 1. Treat-
ment of calix[4]arene with 2-(diphenylphosphino)benzoic
acid in dichloromethane at room temperature in the pres-
ence of dicyclohexylcarbodiimide (DCC) and 4-(N,N-
Abstract: A novel bifunctional organocatalyst 5,11,17,23-tetra-
butyl-25-[2-(diphenylphosphino)benzoate]-26,27,28-trihydroxycalix-
[4]arene (LB3) was synthesized and applied to promote the aza-
Morita–Baylis–Hillman (aza-MBH) reaction of N-sulfonated im-
ines with methyl vinyl ketone. It was found that in the presence of dimethylamino)pyridine (DMAP) afforded the corre-
acidic additives the reaction rate could be accelerated to give aza-
MBH adducts in good to excellent yields. Compared to our previous
phosphine-containing calix[4]arene LB1, the novel catalyst was
solvents and temperatures. The results are summarized in
more effective.
sponding bifunctional organocatalyst LB3 with good
yields. To optimize the reaction, we screened a series of
Table 1. As shown in Table 1, the solvents employed sig-
Key word: phosphine-containing calix[4]arene, organocatalysis,
aza-Morita–Baylis–Hillman
The aza-Morita–Baylis–Hillman (aza-MBH) reaction is
one of the most powerful methods for carbon–carbon
bond formations in organic synthesis.1 It provides a sim-
HO
OH
EtO
O
OEt
O
OH
OEt
ple and convenient method for the synthesis of interesting
classes of densely functionalized molecules in operation-
ally simple, one-pot and economical procedures.2 The de-
velopment of catalysts has attracted considerable interest
in recent years.3 Various organocatalysts including quini-
dine derivatives,4a–d BINOL derivatives,4e–h (S)-proline,4i
bis(thio)ureas,4j–l bifunctional aminothiourea4m and bi-
functional phosphinothiourea4n,o have been developed for
the MBH reaction. Recently, growing interest has been fo-
cused on calixarene chemistry, as this system can be eas-
ily modified at both lower and upper rims, which make
them useful in the synthesis of various derivatives with se-
lected groups and desired properties.5
PPh2
PPh2
LB1
LB2
HO
OH
O
OH
O
PPh2
LB3
In our pervious work, the phosphine-containing organo-
catalyst 5,11,17,23-tetrabutyl-25-(diphenylphosphinometh-
oxy)-26,27,28-trihydroxycalix[4]arene (LB1; Figure 1)
showed high catalytic activity in the aza-MBH reaction of
N-sulfonated imines with methyl vinyl ketone (MVK),
while LB2 (Figure 1) was less efficient which indicated
that the hydroxy group was essential in the aza-MBH re-
action.6 In continuation of our interest to develop more ef-
ficient bifunctional organocatalysts in the aza-MBH
reaction, a novel phosphine-containing organocatalyst
5,11,17,23-tetrabutyl-25-[2-(diphenylphosphino)benzoate]-
26,27,28-trihydroxycalix[4]arene (LB3) was synthesized
and its efficacy in aza-MBH reaction was investigated.
Figure 1 Substituted calix[4]arenes as organocatalyst for aza-MBH
reaction developed by our group
COOH
PPh2
DCC, DMAP
+
HO
OH
O
OH
solvent
O
PPh2
LB3
SYNLETT 2012, 23, 741–746
Advanced online publication: 24.02.2012
x
x.
x
x.
2
0
1
1
HO
OH
OH
OH
DOI: 10.1055/s-0031-1290358; Art ID: W56211ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Preparation of LB3

742
Y. Shen et al.
LETTER
ly, the reaction proceeded slowly and inefficiently.
Several research groups have reported that water and oth-
er protic additives can enhance the reaction rate.4e,7 In our
reaction, we found that the reaction rate could be acceler-
ated significantly when 10 mol% of benzoic acid was add-
ed to the reaction system. A comparison study of LB3 and
LB16 is presented in Table 2. In comparison with LB1,
the reaction was completed in a shorter time using LB3 as
the catalyst in the presence of benzoic acid (entries 1–8).
The addition of benzoic acid did not accelerate the reac-
tion catalyzed by LB1. When the aza-MBH reaction was
carried out in dichloromethane, 1,2-dichloroethane
(DCE), toluene, THF, 1,4-dioxane or ethyl acetate, the
reactions proceeded smoothly to give the corresponding
adduct 3a in moderate to good yields (entries 1–10). The
most promising yield was obtained when the reaction was
carried out in CH2Cl2 at 40 °C (entry 1). It was found that
at lower reaction temperature the corresponding aza-
MBH adduct 3a was obtained in higher yield but the reac-
tion proceeded with considerably slower rate (entries 1–
4). In the case of acetonitrile (MeCN), the product was
provided in very poor yield (entry 11).
Table 1 Preparation of LB3
Entry
Solvent
CH2Cl2
DCE
Temp (°C) Time (h) Yield (%)a
1
2
3
4
5
6
7
8
9
40
40
40
40
40
r.t.
60
80
120
7
49
55
62
15
20
58
72
68
57
6.5
6
toluene
MeCN
THF
14
10
18
toluene
toluene
toluene
toluene
5.5
5
5
a Isolated yields based on calix[4]arene.
nificantly affect the reaction. For example, 62% of the
corresponding product LB3 was obtained in toluene (en-
try 3), compared to only 15% in acetonitrile (entry 4). The
highest yield was achieved when the reaction was carried
out in toluene at 60 °C for 5.5 hours (entry 7).
Based on the above results, LB3 was determined to be an
effective catalyst. Therefore, the reaction conditions in-
cluding the amount of catalyst and Brønsted acidic were
investigated (Table 3). A slightly higher yield of the prod-
uct 3a was obtained when the amount of catalyst and ben-
zoic acid was increased to 20 mol% (entry 4), whereas
reducing the amount of catalyst and benzoic acid to 5
mol% or 1 mol%, led to longer reaction times (entries 1
To investigate the catalytic activities of this novel bifunc-
tional catalyst in aza-MBH reactions, an initial examina-
tion was carried out by using N-benzylidene-4-
methylbenzenesulfonamide (1a) and MVK as the sub-
strates in the presence of 10 mol% of LB3. Disappointed-
Table 2 Aza-MBH Reaction of 1a with MVK Organocatalyzed by LB3 or LB1
O
NHTs O
LB1 or LB3
+
Ph
NTs
Ph
solvent
1a
2
3a
Entry
Solvent
Temp (°C)
LB3 (10 mol%), PhCO2H (10 mol%)
LB1 (10 mol%)a
Time (h)
Yield (%)
Time (h)
Yield (%)b
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
EtOAc
THF
40
30
20
0
4
7
88
88
89
91
85
87
86
82
87
75
35
16
24
48
60
27
16
27
30
–
85
86
88
87
83
78
85
80
–
3
8
4
12
4.5
6
5
30
50
40
40
40
40
40
6
7
7
8
8
9
DCE
5
10
11
1,4-dioxane
MeCN
10
14
–
–
–
–
a No obvious improvement was observed when additive PhCO2H was used.
b Isolated yields based on 1a.
Synlett 2012, 23, 741–746
© Thieme Stuttgart · New York

LETTER
2-(Diphenylphosphino)benzoyl-Substituted Calix[4]arene
743
acid, phenol, 4-methylbenzenesulfonamide, water or
ethanol showed that the reaction rate was moderately de-
creased compared to that observed with benzoic acid (en-
tries 2–6). Similar phenomenon was also observed by
using more acidic additive such as L-proline and trifluoro-
acetic acid (entries 8 and 9). In contrast, no aza-MBH ad-
duct 3a was obtained even after 100 hours with
trifluoromethanesulfonic acid (entry 10).
Table 3 Screening of Catalyst and PhCO2H Loading for the Reaction
of 1a and 2 Catalyzed by LB3
NHTs O
LB3
PhCO2H
O
NTs
+
CH2Cl2, 40 °C
1a
2
3a
Entry
LB3
(mol%)
PhCO2H
(mol%)
Time
(h)
Yield
(%)a
85
86
88
90
82
85
53
With the optimal reaction conditions identified, we next
turned our attention to examine the scope of these catalyt-
ic aza-MBH reactions using a variety of N-sulfonated im-
ines with MVK. The results are summarized in Table 5.
Substrate generality for this catalytic reaction is satisfac-
tory and the reaction can tolerate various electron-donat-
ing or electron-withdrawing groups on the aromatic ring.
All reactions proceeded smoothly to give the correspond-
ing adducts 3 in high yields. Electron-withdrawing groups
could enhance the rate of the aza-MBH reactions (entries
8–11), however the substrates with electron-donating
groups gave the aza-MBH adducts in slightly lower yields
with prolonged reaction time (entries 2–7). Imines of
thiophene-2-carbaldehyde, furan-2-carbaldehyde, nicotin-
aldehyde, and 1-naphthaldehyde gave the corresponding
1
2
3
4
5
6
7
1
5
1
5
12
7
10
20
10
10
10
10
20
2
4
4
6
20
50
4.5
15
a Isolated yields based on 1a.
Table 4 The Effect of Various Additives in aza-MBH Reaction of 1a
with MVK Catalyzed by LB3
NHTs O
Table 5 Aza-MBH Reactions of 1 with MVK using LB3 (10 mol%)
LB3 (10 mol%)
additive (10 mol%)
O
and PhCO2H (10 mol%) at 40 °C in CH2Cl2
NTs
+
LB3 (10 mol%)
O
NHTs O
CH2Cl2, 40 °C
PhCO2H (10 mol%)
+
Ar
NTs
1a
2
3a
Ar
CH2Cl2, 40 °C
Entry
Additive
–
pKa
Time (h) Yield (%)a
1
2
3
Entry
1
Ar
Ph
Time (h) Product 3 Yield (%)a
1
2
–
100
20
70
78
88
85
84
88
87
69
0
4
6
3a
3b
3c
3d
3e
3f
88
86
82
84
87
84
82
93
94
93
95
90
96
88
85
EtOH
15.97
14.00
10.17
10.89
4.74
25
20
10
12
2
p-MeOC6H4
o-MeOC6H4
p-MeC6H4
3
H2O
3
11
5
4
p-TsNH2
phenol
AcOH
PhCO2H
L-proline
4
5
5
3,4-(Me)2C6H3
3,4-(OMe)2C6H3
2,4-(OMe)2C6H3
p-BrC6H4
5
6
4.5
6
35
28
7
4.20
4
5
7
3g
3h
3i
8
1.95
8
2.5
9
CF3CO2H
CF3SO3H
0.23
19
9
o-ClC6H4
3
10
–15.00
100
a Isolated yields based on 1a.
10
11
12
13
14
15
p-FC6H4
1
3j
and 2). We then conducted experiments to assess the in-
fluence of Brønsted acidic additives with different load-
ings of benzoic acid ranging from 2 mol% to 50 mol%. It
was found that the highest yield was obtained in the pres-
ence of 10 mol% of benzoic acid (entry 3). Various addi-
tives with different acidic strength were also examined,
and the results are shown in Table 4. A 25-fold rate en-
hancement was observed with benzoic acid (pKa 4.20) as
compared to the reaction conducted without any additive
(entries 1 and 7). Less acidic compounds such as acetic
o-FC6H4
0.5
9
3k
3l
2-thiophenyl
2-furanyl
0.5
2
3m
3n
3o
3-pyridynil
1-naphthalenyl
5
a Isolated yields of 3 from reaction of 1 (1.0 mmol) and MVK (1.5
mmol).
© Thieme Stuttgart · New York
Synlett 2012, 23, 741–746

744
Y. Shen et al.
LETTER
Table 6 Aza-MBH Reactions of 1k (1.0 mmol) with MVK using
LB3 (10 mol%) and PhCO2H (10 mol%) at 40 °C in CH2Cl2
Table 7 Aza-MBH Reaction of 1a with MVK Organocatalyzed by
LB3 or LB4 in the Presence of PhCO2H (10 mol%)
NHTs O
NHTs O
O
LB3 (10 mol%)
LB3 or LB4
O
PhCO2H (10 mol%)
NTs
PhCO2H
NTs
+
+
CH2Cl2, 40 °C
CH2Cl2, 40 °C
F
F
1k
2
3k
1a
2
3a
Entry
Time
(h)
Recovered yield of Yield of
Entry
Catalyst
PhCO2H
(mol%)
Time
(h)
Yield of
LB3 (%)a
3k (%)a
3aa (%)
1
0.5
0.5
0.5
0.5
0.5
0.5
95
96
93
94
93
92
95
1
2
3
4
LB3
LB3
LB4
LB4
0
10
0
100
4
20
2b
3c
4d
5e
6f
96
88
92
150
20
11
93
10
60
91
a Isolated yields based on 1a.
90
reaction system catalyzed by LB4, the reaction gave the
corresponding adduct 3a in moderate yield after 20 hours
(entry 4). Whereas in the presence of 10 mol% of benzoic
acid in the reaction system catalyzed by LB3, compound
3a was isolated in 88% yield within four hours (entry 2),
proving that the hydroxy groups are essential for this re-
action.
a Isolated yields based on 1k.
b LB3 was recovered from entry 1.
c LB3 was recovered from entry 2.
d LB3 was recovered from entry 3.
e LB3 was recovered from entry 4.
f LB3 was recovered from entry 5.
According to the above observation and earlier re-
ports,4g,n,8 we propose a plausible mechanism shown in
Scheme 3. LB3 acts as a bifunctional organocatalyst in
this reaction. The phosphine serves as a nucleophile to ini-
tiate the reaction and the hydroxy groups serve as a hydro-
gen bond donor to stabilize the generated intermediate.
Firstly, Michael addition of LB3 to MVK affords enolate
intermediate A, which is protonated by benzoic acid. Sub-
sequently, the intermediate A undergoes a Mannich reac-
tion with imine to give the hydrogen bond stabilized
intermediate B, which followed by proton transfer and
elimination affords the desired aza-MBH product. Brøn-
sted acidic additives lead to substantial rate enhancements
through two steps. Firstly, Brønsted acidic additives pro-
vide a proton to form intermediate A and the anion acts as
a hydrogen bond accepter to give further stabilization.
Secondly, the proton transfer is accelerated by the addi-
tive, which enhances the rate of the elimination step to
form the aza-MBH product.
aza-MBH adducts (3l–3o) in good yields within practical
reaction time (entries 12–15).
Calix[4]arene organocatalyst LB3 was stable at room
temperature and could be easily isolated by adding cold
methanol and filtration after reaction, which is similar to
the workup procedure used for LB1. Therefore we believe
that a major practical advantage of 1,3-calixdiphosphines
is their high stability towards oxidation. The recovered
LB3 gave the product 3k in almost a constant yield in only
half an hour (Table 6, entry 2). The catalytic activity of
LB3 did not show significant decrease after being reused
five times (entries 3–6).
To examine the role of hydroxy group, we further pre-
pared catalyst LB4 by replacing the hydroxy groups in
LB3 with propyl group (Scheme 2). It should be noted
that when LB4 was used solely, the product was obtained
in only 11% yield after 150 hours (Table 7, entry 3). Fur-
thermore, when 10 mol% of benzoic acid was added to the
1) n-PrBr, Ba(OH)2/BaO, DMF
2)
, DCC, DMAP
COOH
O
O
O
O
O
HO
OH
OH
OH
PPh2
PPh2
LB4
Scheme 2 Preparation of LB4
Synlett 2012, 23, 741–746
© Thieme Stuttgart · New York

LETTER
2-(Diphenylphosphino)benzoyl-Substituted Calix[4]arene
745
O
HO
O–
HO
OH
OH
O
O
OH
OH
PhCO2H
O
O
O
H
O
+
PPh2
P
Ph
PH2
LB3
A
NHTs O
PhCH NTs
Ph
OH
H
OH
O
OH
O
LB3
O
Ph2
P
O
N
O
Ts
Ph
Ph
B
Scheme 3 A plausible reaction mechanism
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521.
In conclusion, we have developed a new organocatalyst
5,11,17,23-tetrabutyl-25-[2-(diphenylphosphino)benzoate]-
26,27,28-trihydroxycalix[4]arene (LB3)9 to promote the
aza-MBH reactions of N-sulfonated imines with MVK
under mild conditions in the presence of acidic addi-
tives.10 The corresponding aza-MBH adducts can be ob-
tained in good to excellent yields (up to 96%). Efforts are
in progress to develop other derivatives of calix[4]arene
as organocatalysts and to explore other applications of
these new organocatalysts.
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Acknowledgment
We thank the National Natural Science Foundation of China
[21076194] for financial support.
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© Thieme Stuttgart · New York
Synlett 2012, 23, 741–746

746
Y. Shen et al.
2009, 7, 1272.
LETTER
6 H, ArH), 7.29 (t, J = 5.6 Hz, 9 H, ArH), 7.66 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 162.1, 148.5, 148.1, 144.0,
143.1, 140.9, 140.6, 138.0, 137.9, 137.6, 137.5, 134.1 (2 ×
C), 133.9, 133.8, 133.5, 133.4, 132.9 (2 × C), 131.9 (2 × C),
131.6 (2 × C), 131.0, 130.8, 128.4 (2 × C), 128.3 (3 × C),
128.2 (4 × C), 126.8 (2 × C), 126.1 (2 × C), 125.9, 125.7,
125.3, 124.9, 124.8, 34.0, 33.9, 31.6 (9 × C), 31.3 (2 × C),
31.2 (2 × C), 31.1 (4 × C), 29.8. MS (ESI): m/z = 936.6 [M –
1]–. HRMS (ESI): m/z [M – 1]– calcd for C63H69O5P:
936.4883; found: 935.4756.
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(d) Matsui, K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H.
Tetrahedron: Asymmetry 2006, 17, 578. (e) Garnier, J. M.;
Anstiss, C.; Liu, F. Adv. Synth. Catal. 2009, 351, 331.
(f) Takizawa, S.; Inoue, N.; Hirata, S.; Sasai, H. Angew.
Chem. Int. Ed. 2010, 49, 9725. (g) Wei, Y.; Shi, M. Acc.
Chem. Res. 2010, 43, 1005. (h) Zhong, F.; Wang, Y.; Han,
X.; Huang, K.; Lu, Y. Org. Lett. 2011, 13, 1310.
(10) Typical Procedure for the Aza–Morita–Baylis–Hillman
Reaction of N-Sulfonated Imines 1 with MVK in the
Presence of LB3 (10 mol%): To N-(2-fluorobenzylidene)-
4-methylbenzenesulfonamide (1a; 0.259 g, 1.0 mmol), LB3
(0.094 g, 0.10 mmol) and PhCO2H (0.012 g, 0.10 mmol) in
CH2Cl2 (3.0 mL) was added MVK (0.105 g, 1.5 mmol) at r.t.
Then the temperature was raised to 40 °C with stirring for 4
h. The solution was extracted with CH2Cl2 (20 mL) and then
washed with H2O (2 × 15 mL). The organic layer was dried
with Na2SO4 and evaporated to afford a white solid that was
purified by flash chromatography (eluent: EtOAc–PE, 1:4)
to give the corresponding aza-Morita–Baylis–Hillman
adduct 3a (0.289 g, 88%); mp 120.2–121.3 °C (lit.,3g 120–
121 °C). 1H NMR (400 MHz, CDCl3): d = 2.15 (s, 3 H, Me),
2.42 (s, 3 H, Me), 5.27 (d, J = 8.7 Hz, 1 H, CH2), 5.71 (d,
J = 8.7 Hz, 1 H, CH2), 6.07 (s, 1 H, CH), 6.09 (s, 1 H, NH),
7.08 (m, 2 H, ArH), 7.17–7.22 (m, 5 H, ArH), 7.64 (d, J =
8.0 Hz, 2 H, ArH). MS (ESI): m/z = 328.2 [M – 1]–.
(9) Typical Procedure for the Preparation of LB3: A
suspension of para-tert-butylcalix[4]arene (1.30 g, 2.0
mmol) in toluene (45 mL) was cooled to 0 °C. Then 2-
(diphenylphosphino)benzoic acid (0.92 g, 3.0 mmol),
dicyclohexylcarbodiimide (DCC, 0.699 g, 3.4 mmol) and 4-
(N,N-dimethylamino)pyridine (DMAP; 0.041 g, 0.34 mmol)
were added. After stirring at 60 °C for 12 h, the suspension
was filtrated and extracted with CH2Cl2 (100 mL) and then
washed with H2O (2 × 50 mL). The organic layer was dried
with anhyd Na2SO4 and evaporated to afford a white solid
that was purified by flash chromatography (EtOAc–PE,
1:30) to afford LB3; yield 60%; mp 181.0–182.1 °C. 1H
NMR (400 MHz, CDCl3): d = 0.88 (s, 15 H, Me), 1.08 (s, 15
H, Me), 1.25 (s, 6 H, Me), 3.72 (m, 8 H, CH2), 6.10 (br, 1 H,
OH), 6.49 (br, 2 H, OH), 6.68 (s, 2 H, ArH), 6.88 (s, 1 H,
ArH), 7.01 (s, 1 H, ArH), 7.08 (s, 2 H, ArH), 7.17–7.23 (m,
Synlett 2012, 23, 741–746
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