Direct carbon-carbon bond formation from alcohols and active methylenes using NaHSO4/SiO2

Article abstract of DOI:10.1055/s-0031-1290083

A simple and efficient procedure for carbon-carbon bond formation has been developed starting from alcohols and active methylene-containing compounds using silica gel supported sodium hydrogen sulfate (NaHSO₄/SiO ₂) under mild conditions. NaHSO₄/SiO₂ can be reused without loss of catalytic activity at least ten times. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290083

LETTER
2971
Direct Carbon–Carbon Bond Formation from Alcohols and Active Methylenes
using NaHSO4/SiO2
D
irec
t
Carbon–
a
C
arbon Bon
d
d Formation
a
from Alco
s
hols and A
h
ctive
M
ethy
i
lenes Aoyama,*a,b Saki Miyota,a Toshio Takido,a Mitsuo Kodomaric
a
Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University,
Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
Fax +81(3)32590818; E-mail: aoyama.tadashi@nihon-u.ac.jp
The Center for Creative Materials Research, Research Institute of Science and Technology, College of Science and Technology,
Nihon University, Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
b
c
Department of Bioscience and Engineering, Shibaura Institute of Technology, Fukasaku, Minuma-ku, Saitama 337-8570, Japan
Received 8 September 2011
PTS and polymer-supported PTS. Similar reactions have
been reported using Lewis or Brønsted acid as a catalyst
in recent years.4–9 Moreover, Brønsted acid ionic liquid
also catalyzed the reaction of 1,3-dicarbonyl compounds
Abstract: A simple and efficient procedure for carbon–carbon
bond formation has been developed starting from alcohols and
active methylene-containing compounds using silica gel supported
sodium hydrogen sulfate (NaHSO4/SiO2) under mild conditions.
NaHSO4/SiO2 can be reused without loss of catalytic activity at with alcohols.10 However, these reactions require long re-
least ten times.
action times, high temperatures and large amounts of nu-
cleophilic species. In the course of our study of synthetic
methods using inorganic solid-supported reagents, we
have found that NaHSO4/SiO2 catalyzes the direct nucleo-
philic substitution of alcohols. The advantages of the pro-
cedure using inorganic-supported reagents are: (i) the
supported reagents could be separated after use from the
reaction mixture by simple filtration; (ii) used supported
reagents could be regenerated extensively by drying in
vacuo. Similar reactions using supported reagents,
HClO4/SiO2, have been reported very recently,11 however,
excess amounts of material and long reaction times were
needed to complete the reactions. Furthermore, the
HClO4/SiO2 system could not be reused for subsequent re-
actions.
Key words: carbon–carbon coupling, silica gel, alcohol, supported
catalysts
The C–C bond formation reactions are fundamental in or-
ganic synthesis. General procedures for C–C bond for-
mation reactions typically involve using reactive
nucleophiles (NuH) or organometallic compounds (R1M)
and halides (R2X) or related species. These species are of-
ten prepared from active methylenes and alcohols. How-
ever, the general method for C–C bond formation using
R1M and R2X generates stoichiometric amounts of un-
wanted MX. Direct substitution of the hydroxyl group in
an alcohol by nucleophiles could be considered as an ideal
process because of the generation of H2O as an only by-
product and because of the wide availability of starting
materials (Figure 1).
In this paper we describe direct C–C bond formation from
alcohols and active methylenes using a reusable NaHSO4/
SiO2 system (Scheme 1).
general way
R1
R3
R2
R4
NaHSO4/SiO2
OH
R1
M
R2
X
R1 R2
MX
+
+
+
+
R1
R2
+
R3
R4
ideal way
R1
1
2
3
R2 OH
R1 R2
H2O
H
Scheme 1 Direct C–C bond formation using NaHSO4/SiO2
Figure 1
The reaction of acetyl acetone (1a) with benzhydrol (2a)
was investigated as a model reaction to determine the op-
timum reaction conditions for the synthesis of 3; the re-
sults are summarized in Table 1.
Khalaf et al.1 have reported such a transformation using an
excess of H2SO4 and either H3PO4 or a stoichiometric
amount of AlCl3. The catalytic activation of alcohols is
considered to be difficult due to the poor leaving ability of
the OH group. In 2006, Yasuda et al.2 reported C–C bond
formation from alcohols and active methylene-containing
compounds mediated by indium trichloride, and Sanz et
al.3 reported the metal-free catalytic substitution of alco-
hols using a catalytic amount of Brønsted acid such as
When a mixture of 1a (10 mmol), 2a (2 mmol), and
NaHSO4/SiO2 (2.1 mmol) was stirred in dichloroethane
(DCE) at 80 °C for 180 minutes, 3aa was obtained in 95%
yield. Although the amount of 1a was reduced until equiv-
alent to the amount of 2a in the same reaction, the yields
of 3aa did not decrease; however, the yield of 3aa did de-
crease when the reaction time was shortened (Table 1, en-
tries 4 and 5). In the reaction using an equivalent amount
of 1a and 2a, as the reaction temperature was decreased,
SYNLETT 2011, No. 20, pp 2971–2976
x
x
.x
x
.2
0
1
1
Advanced online publication: 28.11.2011
DOI: 10.1055/s-0031-1290083; Art ID: U06611ST
© Georg Thieme Verlag Stuttgart · New York

2972
T. Aoyama et al.
LETTER
the yield of 3aa decreased along with increasing amounts promote the reaction. When granular NaHSO4 was used,
of by-product (Table 1, entries 4 and 6–8). The structure no 3aa was generated, but 8% yield of 4 was isolated. For-
of the by-product was deduced to be dibenzhydryl ether mation of 4 suggests a reaction pathway shown in
(4) on the basis of its NMR spectroscopic data and by Scheme 2. When the reaction was carried out in the ab-
HRMS. When the reaction was carried out with reduced sence of 1a at 0 °C, 4 was quantitatively formed. Reaction
amounts of NaHSO4/SiO2, the yield of 3aa decreased and of 4 with two equivalents of 1a was carried out in the pres-
that of 4 increased (Table 1, entries 9–11). When other ence of NaHSO4/SiO2 at 60 °C to give 3aa (>99%). The
solvents such as toluene, chloroform and cyclohexane coupling probably proceeds through the formation of a
were used instead of DCE for this reaction, each solvent stabilized carbocation, which can react with 1a to produce
gave 3aa in moderate to excellent yields (Table 1, entries 3aa, or with 2a to give 4. Ether 4 could be an intermediate
12–14). Among the acid catalysts tested, NaHSO4/SiO2 of a reaction that proceeds in two steps: formation of car-
was the most effective system.
bocation and alkylation of active methylenes. NaHSO4/
SiO2 accelerates both steps in the reaction of 1a with 2a.
Silica gel supported polyphosphoric acid (PPA/SiO2) and
silica sulfuric acid (SSA)12 also catalyzed this reaction to We checked the reusability of NaHSO4/SiO2 in advance
afford moderate yields of 3aa (Table 1, entries 15–19). of reactions by using a series of various active methy-
The reaction using silica gel supported zinc chloride lenes. NaHSO4/SiO2 was recovered from the reaction
(ZnCl2/SiO2) gave 3aa in good yield. Silica gel did not mixture by filtration, regenerated by drying in vacuo at
Table 1 Optimization of Reaction Conditions for the Reaction of Acetyl Acetone and Benzhydrola
O
O
OH
O
O
catalyst
+
Ph
Ph
Ph
Ph
1a
2a
3aa
Entry
1
1a (mmol) 2a (mmol) Solvent
Catalyst
Amount (g)
1.0
Time (min) Temp (°C) Yield (%)b,c
10
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
DCE
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
PPA/SiO2
180
180
60
30
15
30
30
30
30
30
30
30
30
30
30
30
30
30
30
80
80
80
80
80
60
30
0
95
2
DCE
1.0
94
3
DCE
1.0
93
4
DCE
1.0
98
5
DCE
1.0
87
6
DCE
1.0
98
7
DCE
1.0
43 (25)
2 (36)
92 (4)
76 (11)
39 (19)
98
8
DCE
1.0
9
DCE
0.8
60
60
60
60
60
60
60
60
60
60
60
10
11
12
13
14
15
16
17
18
19
DCE
0.5
DCE
0.1
toluene
CHCl3
cyclohexane
DCE
1.0
1.0
98
1.0
61 (11)
38 (31)
72
1.0
DCE
SSA
1.0
DCE
ZnCl2/SiO2
NaHSO4
1.0
88
DCE
2.1 (mmol)
1.0
0 (8)
0
DCE
SiO2
a In all reactions NaHSO4/SiO2 (2.1 mmol/g, 1.0 g) was used.
b Isolated yield.
c The yield of 4 is given in parentheses.
Synlett 2011, No. 20, 2971–2976 © Thieme Stuttgart · New York

LETTER
Direct Carbon–Carbon Bond Formation from Alcohols and Active Methylenes
2973
not give 3ea, but instead 3ea¢ and an unexpected product
5 were formed in 50 and 40% yields, respectively
(Scheme 3). A more detailed investigation on the pathway
of formation of 5 is underway. Benzoyl acetoacetic acid
ethyl ester 1f gave 3fa in excellent yield at 60 °C for
30 minutes, whereas 4,4-dimethyl-3-oxopentanoic acid
ethyl ester (1g) and 4-chloro-3-oxobutanoic acid ethyl es-
ter (1h) needed longer reaction times and higher tempera-
ture than 1f (1 h and 2 h at 80 °C), to obtain 3ga and 3ha
in excellent yields, respectively (Table 3, entries 6 and 7).
b-Diketones also gave 3 in excellent yields. Benzoyl ace-
tone 1k and dibenzoylmethane 1l gave 3ka and 3la, re-
spectively, quantitatively. In the reaction of 1l, twice the
amount of DCE was used because 3la did not dissolve
completely in 10 mL DCE; the mixture of solidified 3la
and a NaHSO4/SiO2 was separated by filtration.
Ph
Ph
Ph
Ph
OH
NaHSO4/SiO2
O
DCE
0 °C, 30 min
Ph
Ph
2a
4
≥99%
O
O
Ph
Ph
Ph
O
O
NaHSO4/SiO2
+
O
DCE
Ph
60 °C, 30 min
Ph
Ph
1a
4
3aa
≥99%
OH
H2O
Ph
Ph
2a
Ph
Ph
Ph
Ph
OH
H
O
H
Ph
O
Ph
O
Ph
Ph
4
O
O
O
Ph
Ph
2a
+
+
O
O
Ot-Bu
Ph
Ph
1e
3ea'
5
Scheme 3
1a
Ph
Ph
3aa
Reaction of trifluoro acetyl acetone 1j was carried out at
80 °C for two hours to give 3ja in 79% yield. In the reac-
tions of a-methyl-b-diketone 1m and a-methyl-b-keto es-
ter 1i, the latter gave 3ia in 83% yield, whereas the former
did not react under similar conditions (Table 4, entries 8
and 12). b-Ketoamide and cyclic diketone also underwent
a similar reaction. For instance, 1n and 1o reacted with 2a
to give 3na in 97% yield and 3oa in 92%, respectively.
Scheme 2
120 °C for two hours, and used for the subsequent reac-
tion. As can be seen from Table 2, NaHSO4/SiO2 could be
recycled at least ten times without loss of catalytic activi-
ty, and 3aa was obtained in satisfactory yields.
Table 2 Reuse of NaHSO4/SiO2 for the Synthesis of 3aa
Various alcohols were used for the reaction of 1a
(Table 4). The reaction using p-chlorobenzhydrol (2b)
gave 3ab quantitatively (80 °C for 0.5 h), whereas p-
methoxybenzhydrol (2c) gave 3ac in 62% yield along
with the corresponding ether. Compound 2d produced 1-
(2-methyl-4-phenyl-4H-chromen-3-yl)ethanone (6) quan-
titatively, instead of 3ad (Table 4, entry 4 and Scheme 4).
Secondary benzylic alcohol 2e–g also reacted with 1a,
and 3ae–ag were obtained in moderate to good yields. In
these reactions, 1-(4-chlorophenyl)ethanol (2f) required
five hours reaction time to give 3af in satisfactory yield.
When benzyl alcohol 2h was used for the reaction, 3ah
was not formed. In the reactions of allylic alcohols, 3-hy-
droxy-1,3-diphenyl propene (2i) gave 3ai in good yield,
and 3-hydroxy-1-phenyl-1-butene (2j) gave 3aj in moder-
ate yield. Cinnamic alcohol 2k and tert-butyl alcohol 2l,
however, did not yield the expected product 3ak and 3al.
Reaction of tert-butyl alcohol with 2a did not proceed un-
der similar conditions.
NaHSO4/SiO2
1a
2a
3aa
+
DCE
60 °C, 30 min
Reuse
Catalyst
Yield (%)a
0
1
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
98
97
99
99
99
99
98
98
2
3
4
6
8
10
a Isolated yield.
Ph
O
A series of active methylene-containing compounds were
used for this reaction. Reactions of alkyl acetoacetates 1b,
1c, and 1d with 2a gave the corresponding product, 3ba,
3ca, and 3da, in moderate to good yields, respectively
(Table 3, entries 1–3). When these reactions were carried
out at 80 °C, the corresponding products, 3ba–da, were
obtained in excellent yields. tert-Butyl acetoacetate did
NaHSO4/SiO2
1a
+
2d
DCE
60 °C, 30 min
O
6
94%
Scheme 4
Synlett 2011, No. 20, 2971–2976 © Thieme Stuttgart · New York

2974
T. Aoyama et al.
LETTER
In conclusion, we have developed a simple and efficient high yield, simplicity of operation, and utilization of inex-
method for C–C bond formation from alcohols and active pensive and reusable catalyst.
methylene-containing compounds using NaHSO4/SiO2 as
an acid catalyst.13–15 This new method for the formation of
References and notes
C–C bonds has the advantage of mild reaction conditions,
(1) Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1972, 37, 4227.
Table 3 Reaction of 2a with 1 Using NaHSO4/SiO2
R1
Ph
R2
Ph
OH
NaHSO4/SiO2
R1
R2
+
DCE
60 °C, 30 min
Ph
Ph
1
2a
3
Entry
1
Substrate (1)
Temp (°C)
60
Time (h)
0.5
3
Yield (%)a
80 (98)b
O
O
O
O
1b
3ba
OEt
2
1c
60
0.5
3ca
66 (99)b
OAllyl
O
O
O
O
3
4
5
1d
1e
1f
60
80
60
0.5
0.5
0.5
3da
3ea
3fa
84 (92)b
OBn
0c
Ot-Bu
O
O
97
Ph
Cl
OEt
O
O
6
7
8
1g
1h
1i
80
80
80
1
2
1
3ga
3ha
3ia
98
91
83
OEt
O
O
OEt
O
O
OEt
O
O
9
10
11
1j
1k
1l
80
60
60
2
3ja
3ka
3la
79
F3C
O
O
0.5
0.5
99
Ph
O
O
50 (99)d
Ph
Ph
Ph
Ph
O
O
12
13
14
1m
1n
1o
80
80
80
4
3
3
3ma
3na
3oa
–(99)e
97
O
O
NMe2
O
O
92
a Isolated yield.
b Reaction was performed at 80 °C.
c See Scheme 3.
d DCE (20 mL) was used.
e The recovery of 1m is given in parentheses.
Synlett 2011, No. 20, 2971–2976 © Thieme Stuttgart · New York

LETTER
Direct Carbon–Carbon Bond Formation from Alcohols and Active Methylenes
2975
Table 4 Reaction of 1a with 2 using NaHSO4/SiO2
O
O
OH
O
O
NaHSO4/SiO2
DCE
+
R1
R2
R1
R2
1a
2
3
Entry
1
Alcohol (2)
Temp (°C)
60
Time (h)
0.5
Yield (%)a
OH
2a
3aa
3ab
98
99
62
OH
2
2b
80
0.5
Cl
OH
3
4
5
6
2c
2d
2e
2f
80
60
80
80
0.5
0.5
0.5
5
3ac
3ad
3ae
3af
MeO
OH OH
0 (94)b
OH
57
OH
67 (11)c
Cl
OH
7
8
9
2g
2h
2i
80
80
80
0.5
3
3ag
3ah
3ai
79
0
OH
OH
0.5
83
OH
10
2j
80
0.5
3aj
62
OH
11
12
2k
2l
80
80
0.5
3
3ak
3al
0
0
OH
a Isolated yield.
b See Scheme 4.
c The yield of the corresponding ether is given in parentheses.
Synlett 2011, No. 20, 2971–2976 © Thieme Stuttgart · New York

2976
T. Aoyama et al.
LETTER
131.2, 141.1, 141.4, 167.3, 201.6. HRMS (EI): m/z [M]+
(2) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem. Int. Ed.
2006, 45, 793.
calcd for C20H20O3: 308.1412; found: 308.1417. Anal. Calcd
for C20H20O3: C, 77.90; H, 6.54. Found: C, 78.07; H, 6.58.
Compound 3da: White solid; mp 95–97 °C. IR (neat):
1740, 1709 cm–1. 1H NMR (CDCl3): d = 2.05 (s, 3 H), 4.58
(d, J = 12.1 Hz, 1 H), 4.78 (d, J = 12.1 Hz, 1 H), 4.93 (d,
J = 13.7 Hz, 1 H), 4.96 (d, J = 13.7 Hz, 1 H), 7.03–7.29 (m,
15 H). 13C NMR (CDCl3): d = 30.0, 50.9, 65.1, 67.2, 126.8,
127.0, 127.6, 127.8, 128.1, 128.2, 128.5, 128.7, 128.8,
135.0, 141.1, 141.4, 167.5, 201.4. HRMS (EI): m/z [M]+
calcd for C24H22O3: 358.1569; found: 358.1569. Anal. Calcd
for C24H22O3: C, 80.42; H, 6.19. Found: C, 80.16; H, 5.82.
Compound 3ga: White solid; mp 101–102 °C. IR (neat):
1729, 1705 cm–1. 1H NMR (CDCl3): d = 0.91 (s, 9 H), 0.94
(t, J = 7.1 Hz, 3 H), 3.84–3.99 (m, 2 H), 4.86 (d,
(3) Sanz, R.; Martínez, A.; Miguel, D.; Álvarez-Gutiérrez, J. M.;
Rodríguez, F. Adv. Synth. Catal. 2006, 348, 1841.
(4) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Angew. Chem. Int. Ed. 2006, 45, 2605.
(5) Sanz, R.; Miguel, D.; Martínez, A.; Álvarez-Gutiérrez, J. M.;
Rodríguez, F. Org. Lett. 2007, 9, 2027.
(6) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161.
(7) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett.
2007, 9, 825.
(8) Motokura, K.; Nakagiri, N.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Org. Chem. 2007, 72, 6006.
(9) Kischel, J.; Mertins, K.; Michalik, D.; Zapf, A.; Beller, M.
Adv. Synth. Catal. 2007, 349, 865.
(10) Funabiki, K.; Komeda, T.; Kubota, Y.; Matsui, M.
J = 12.1 Hz, 1 H), 4.89 (d, J = 12.1 Hz, 1 H), 7.09–7.37 (m,
10 H). 13C NMR (CDCl3): d = 13.7, 25.9, 45.7, 52.0, 58.8,
61.2, 126.7, 126.8, 128.1, 128.4, 128.5, 141.3, 141.7, 167.6,
207.4. HRMS (EI): m/z [M]+ calcd for C22H26O3: 338.1882;
found: 338.1879. Anal. Calcd for C22H26O3: C, 78.07; H,
7.74. Found: C, 77.96; H, 7.73.
Tetrahedron 2009, 65, 7457.
(11) Liu, P. N.; Dang, L.; Wang, Q. W.; Zhao, S. L.; Xia, F.; Ren,
Y. J.; Gong, X. Q.; Chen, J. Q. J. Org. Chem. 2010, 75, 5017.
(12) Salehi, P.; Zolfigol, M. A.; Shirini, F.; Baghbanzadeh, M.
Curr. Org. Chem. 2006, 10, 2171.
(13) Preparation of NaHSO4/SiO2: SiO2 [Wakogel C-200
(Wako Pure Chemical Ind. Ltd.), 10 g] was added to a
solution of NaHSO4·H2O (30 mmol, 4.14 g) in distilled
water, and the mixture was stirred at room temperature for
0.5 h. The water was removed by rotary evaporation under
reduced pressure, and the resulting reagent was dried in
vacuo (10 mmHg) at 120 °C for 5 h
(14) Typical procedure: A mixture of 1 (2.0 mmol), 2 (2.0
mmol), and NaHSO4/SiO2 (2.1 mmol, 1.0 g) in DCE (10 mL)
was stirred at 60 °C for 0.5 h, and then the used supported
reagent was removed by filtration. The filtrate was
concentrated and dried in vacuo to obtain 3 (>98% by GC).
(15) Compound 3ca: White solid; mp 68–70 °C. IR (neat): 1739,
1707 cm–1. 1H NMR (CDCl3): d = 2.09 (s, 3 H), 4.42 (dt,
J = 6.0, 1.4 Hz, 2 H), 4.56 (d, J = 12.4 Hz, 1 H), 4.78 (d,
J = 12.4 Hz, 1 H), 5.07–5.13 (m, 2 H), 5.57–5.67 (m, 1 H),
7.14–7.36 (m, 10 H). 13C NMR (CDCl3): d = 30.1, 50.9,
65.1, 66.0, 118.7, 126.9, 127.0, 127.7, 127.8, 128.6, 128.8,
Compound 3ja: White solid; mp 99–101 °C. IR (neat):
1769, 1716 cm–1. 1H NMR (CDCl3): d = 1.92 (s, 3 H), 4.83
(d, J = 11.9 Hz, 1 H), 5.16 (d, J = 11.9 Hz, 1 H), 7.17–7.32
(m, 10 H). 13C NMR (CDCl3): d = 31.1, 51.6, 65.9, 115.2 (q,
J = 291.9 Hz, CF3), 127.3, 127.3, 127.6, 128.1, 129.0, 129.1,
139.7, 140.2, 184.2 (q, J = 36.9 Hz, COCF3), 199.0. HRMS
(EI): m/z [M]+ calcd for C18H15F3O2: 320.1024; found:
320.1033. Anal. Calcd for C18H15F3O2: C, 67.50; H, 4.72.
Found: C, 67.27; H, 4.48.
Compound 3na: White solid; mp 138–139 °C. IR (neat):
1704, 1636 cm–1. 1H NMR (CDCl3): d = 2.09 (s, 3 H), 2.77
(s, 3 H), 2.91 (s, 3 H), 4.63 (d, J = 11.9 Hz, 1 H), 4.96 (d,
J = 11.9 Hz, 1 H), 7.13–7.33 (m, 10 H). 13C NMR (CDCl3):
d = 27.7, 36.1, 37.6, 51.5, 63.2, 126.8, 127.0, 127.8, 128.1,
128.5, 128.9, 141.1, 142.0, 167.1, 204.9. HRMS (EI): m/z
[M]+ calcd for C19H21NO2: 295.1572; found: 295.1571.
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 77.34; H, 7.17; N, 4.70
Synlett 2011, No. 20, 2971–2976 © Thieme Stuttgart · New York

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