Dehydrative amination of alcohols in water using a water-soluble calix[4]resorcinarene sulfonic acid

Article abstract of DOI:10.1055/S-2008-1078416

A protocol for the dehydrative amination of alcohols in water using a water-soluble calix[4]resorcinarene sulfonic acid as a reusable multifunctional catalyst was developed.

Full text of DOI:10.1055/S-2008-1078416

CLUSTER
1539
Dehydrative Amination of Alcohols in Water Using a Water-Soluble
Calix[4]resorcinarene Sulfonic Acid
Dehydrative
A
e
minationin
i
W
ate
r
ji Shirakawa, Shoichi Shimizu*
Department of Applied Molecular Chemistry and High Technology Research Center, College of Industrial Technology, Nihon University,
Narashino, Chiba 275-8575, Japan
Fax +81(47)4742579; E-mail: s5simizu@cit.nihon-u.ac.jp
Received 5 January 2008
soluble calixarenes, to solve this dilemma.11,12 More re-
Abstract: A protocol for the dehydrative amination of alcohols in
cently, our group found that a water-soluble calix[4]resor-
water using a water-soluble calix[4]resorcinarene sulfonic acid as a
cinarene sulfonic acid 1 works as an efficient reusable
reusable multifunctional catalyst was developed.
catalyst for three-component Mannich-type reactions in
Key words: aminations, calixarenes, green chemistry, host–guest
systems, phase-transfer catalysis
water.13,14 In the reaction system, 1 functions not only as a
Brønsted acid catalyst, but also as an inverse phase-trans-
fer catalyst, due to its ability to form supramolecular host–
guest complexes. In this context, carbon–nitrogen bond-
The development of efficient methods for forming car-
forming reactions in water using a water-soluble
bon–nitrogen bonds has received considerable attention in
calix[4]resorcinarene sulfonic acid 1 have been a focus of
organic synthesis due to the importance of nitrogen-con-
our research. This paper presents a method for metal-free
taining compounds in the production of pharmaceuticals
dehydrative amination of alcohols in water15,16 catalyzed
and fine chemicals.1 Substitution reactions of alkyl ha-
by 1, and it describes the reusability of catalyst 1
lides, alkyl acetates, or related compounds with amine nu-
(Scheme 1).
cleophiles are one of the most useful types of carbon–
nitrogen bond-forming reactions.2 The atomic efficiency
of substitution reactions may be further enhanced when
Ts
HN
OH
R2
catalyst 1
Ts–NH2
H2O
+
+
alcohols, instead of alkyl halides or alkyl acetates, are
used as substrates, as is the case when water is the sole by-
product of the reaction.3 Therefore, the development of a
procedure for the catalytic amination of alcohols is highly
desirable. Consequently, a number of methods using met-
al catalysts in organic solvent systems have recently been
reported.4,5
R1
R2
H2O
R1
SO3H
OH
HO
HO
OH
OH
Me
Me
Me
Me
HO3S
Reducing the use of hazardous solvents is one of the most
important challenges presented by the effort to minimize
pollution and risks associated with the production of
chemicals. Accordingly, organic reactions in water with-
out the use of organic solvents have attracted a great deal
of interest in both academic and industrial research.6
Among such reaction systems, aqueous biphasic systems
using water-soluble catalysts have the additional advan-
tage of catalyst recycling after simple decantation or ex-
traction of the organic products.7 However, because of the
low solubility of many organic substrates in water, aque-
ous biphasic systems often exhibit insufficient reaction
rates. To circumvent this problem, polar, water-miscible
co-solvents8 or surfactants9 are frequently used. However,
use of these additives may complicate workup proce-
dures; in particular, product separation and catalyst recov-
ery may be difficult. Recently, our research group
developed a new reaction system, which is based on the
inverse phase-transfer catalysis10 of functionalized water-
SO3H
HO
HO
HO3S
OH
1
Scheme 1 Dehydrative amination of alcohols in water catalyzed
by 1
Initially, various Brønsted acids were examined as cata-
lysts for the amination reaction of trans-1,3-diphenyl-2-
propen-1-ol with p-toluenesulfonamide in water
(Table 1). Common Brønsted acids, such as AcOH, TFA,
MsOH, TsOH, and TfOH, were not effective catalysts of
this reaction (entries 2–6). However, a water-soluble
calix[4]resorcinarene sulfonic acid 1 (10 mol%) was
found to efficiently catalyze the reaction, giving the prod-
uct 2a in excellent yield (entry 7). Moreover, using only 1
mol% of catalyst 1 in the reaction gave the product 2a in
good yield (entry 9). These results suggest that catalyst 1
bearing the hydrophobic cavity forms host–guest com-
plexes with substrates; these complexes are important for
efficient catalysis of the reaction in water. Furthermore, in
SYNLETT 2008, No. 10, pp 1539–1542
x
x
.x
x
.2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1078416; Art ID: Y00108ST
© Georg Thieme Verlag Stuttgart · New York

1540
S. Shirakawa, S. Shimizu
CLUSTER
addition to the sulfonamide, the carboxamide and carbam-
ate also could serve as the amine source in the present re-
action system, giving the synthetically useful benzoyl-
and benzyloxycarbonyl-protected amines 2b and 2c in ex-
cellent yields (entries 10 and 11).
Table 2 Amination of Alcohols in Water
Ts
OH
HN
1 (10 mol%)
H2O, 60 °C, 24 h
Ts–NH2
+
R1
R2
R1
R2
(1.5 equiv)
3
Entry
1
Alcohol
Yield (%)a
Table 1 Effect of Catalysts
PG
OH
OH
HN
97 (2a)
catalyst
+
PG–NH2
Ph
Ph
Ph
Ph
Ph
H2O, 60 °C, 24 h
Ph
Ph
(1.5 equiv)
OH
2
2
87 (3a)
63 (3b)
99 (3c)
99 (3d)
97 (3e)
(PG = Ts, Bz, or Cbz)
Yield (%)a
0 (2a)
Me
OH
Entry
Catalyst (mol%)
none
PG
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Bz
Cbz
3
1
2
OH
4b
5b
6
AcOH (10)
TFA (10)
MsOH (10)
TsOH (10)
TfOH (10)
1 (10)
0 (2a)
Ph
Ph
OH
3
3 (2a)
4
2 (2a)
4-FC6H4
4-FC6H4
OH
5
5 (2a)
6
3 (2a)
4-MeOC6H4
4-MeOC6H4
OH
7
97 (2a)
96 (2a)
84 (2a)
92 (2b)
98 (2c)
7
50 (3f)
S
Ph
8
1 (2)
9
1 (1)
OH
8b
9
80 (3g)
96 (3h)
10
11
1 (10)
2-naphthyl
Me
OH
1 (10)
a Isolated yield.
4-MeOC6H4
Me
OH
Next, the substrate generality of the amination reaction in 10
water catalyzed by 1 was examined using various allyl
and benzyl alcohols (Table 2).17 Both acyclic and cyclic
60 (3i)
a Isolated yield.
allyl alcohols could be used as substrates in this reaction
system (entries 1–3). Also, amination of benzyl alcohols
containing electron-donating or -withdrawing groups oc-
curred cleanly and the corresponding products 3c–3i were
obtained in moderate to excellent yields (entries 4–10).
Substrates containing heteroaromatic alcohols also
worked well in this reaction (entry 7).
b Reaction temperature: 100 °C.
Table 3 Reusability of Catalyst 1
Ts
OH
HN
1 (10 mol%)
+
Ts–NH2
Ph
Ph
H2O, 60 °C, 24 h
Ph
Ph
(1.2 equiv)
2a
The reusability of a calix[4]resorcinarene sulfonic acid
catalyst 1 was examined (Table 3). After each reaction,
the resulting organic products were extracted using ethyl
acetate; the aqueous solution containing the catalyst was
recovered and reused directly in the next cycle. Activity of
catalyst 1 was retained after being recycled multiple
times. Even after recycling the catalyst 1 five times, the
yields were practically identical to those observed when
fresh catalyst was used.
Recycle number
Fresh 1st
2nd
94
3rd
95
4th
93
5th
94
Yield of 2a (%)a
93
92
a Isolated yield.
with 1-methylindole occurred cleanly and afforded the de-
sired product 4a in good yield. The substitution reaction
using an active methylene compound also proceeded
smoothly to give the product 4b. The present reaction sys-
tem has been applied to carbon–sulfur bond formation,16b
giving the desired compound 4c in good yield.
The utility and applicability of the present reaction system
was extended to nucleophilic substitution reactions of al-
cohols with carbon nucleophiles (Scheme 2).16a,18 The
Friedel–Crafts-type substitution reaction of benzhydrol
Synlett 2008, No. 10, 1539–1542 © Thieme Stuttgart · New York

CLUSTER
Dehydrative Amination in Water
1541
(2) (a) Tsuji, J. Transition Metal Reagents and Catalysts:
OH
Nu
1 (10 mol%)
+
NuH
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H2O, 80 °C, 24 h
Ph
Ph
Ph
Ph
4
O
O
NMe
Ph
Ph
S
(3) For reviews of palladium-catalyzed amination of allylic
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Eur. J. Org. Chem. 2005, 2647.
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a: 87%
(1.2 equiv NuH)
4c: 80%
(2 equiv NuH)
4b: 88%
(3 equiv NuH)
(4) For recent examples of metal-catalyzed amination of
alcohols, see: (a) Qin, H.; Yamagiwa, N.; Matsunaga, S.;
Shibasaki, M. Angew. Chem. Int. Ed. 2007, 46, 409.
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M.; Prim, D. Adv. Synth. Catal. 2006, 348, 2063.
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(5) A few examples of Brønsted acid catalyzed amination of
alcohols were reported, see: (a) Motokura, K.; Nakagiri, N.;
Mori, K.; Mizugaki, T.; Ebitani, K.; Jitsukawa, K.; Kaneda,
K. Org. Lett. 2006, 8, 4617. (b) Sanz, R.; Martínez, A.;
Álvarez-Gutiérrez, J. M.; Rodríguez, F. Eur. J. Org. Chem.
2006, 1383.
Scheme 2 Nucleophilic substitution reaction of benzhydrol in water
The proposed mechanism for the calix[4]resorcinarene
sulfonic acid 1-catalyzed dehydrative amination of alco-
hols is shown in Scheme 3. The water-soluble catalyst 1
forms host–guest complexes with alcohols in the organic–
aqueous interfacial layer. The dehydration reaction is pro-
moted by the sulfonic acid moieties on catalyst 1. The re-
sulting allylic or benzylic cation18 undergoes nucleophilic
attack by the amide, giving the amination product 3 with
regeneration of the catalyst 1.
organic phase
H
R2 OH
R2
N
Ts
R1
R1
(6) (a) Li, C.-J. Chem. Rev. 2005, 105, 3095. (b) Kobayashi, S.;
Manabe, K. Acc. Chem. Res. 2002, 35, 209. (c) Organic
Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
and Professional: London, 1998. (d) Li, C.-J.; Chan, T.-H.
Organic Reactions in Aqueous Media; Wiley: New York,
1997. (e) Li, C.-J. Chem. Rev. 1993, 93, 2023.
3
Ts–NH2
R2
R2 OH
O3S
SO3H
HO3S
HO3S
R1
R1
– H2O
(7) (a) Aqueous-Phase Organometallic Catalysis: Concepts and
Applications, 2nd, Completely Revised and Enlarged
Edition; Cornils, B.; Herrmann, W. A., Eds.; Wiley-VCH:
Weinheim, 2004. (b) Aqueous-Phase Organometallic
Catalysis: Concepts and Applications; Cornils, B.;
Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 1998.
(8) For examples, see: (a) Bradley, D.; Williams, G.; Lombard,
H.; Holzapfel, C. W. Synth. Commun. 2001, 31, 2077.
(b) Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.;
Uemura, S. J. Org. Chem. 1999, 64, 5593. (c) Purwanto, P.;
Delmas, H. Catal. Today 1995, 24, 135. (d) Kobayashi, S.;
Hachiya, I.; Yamanoi, Y. Bull. Chem. Soc. Jpn. 1994, 67,
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Chem. 1994, 480, 177.
(9) For examples, see: (a) Hamada, T.; Manabe, K.; Kobayashi,
S. Chem. Eur. J. 2006, 12, 1205. (b) Mori, Y.; Manabe, K.;
Kobayashi, S. Angew. Chem. Int. Ed. 2001, 40, 2815.
(c) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martín-
Matute, B. J. Am. Chem. Soc. 2001, 123, 5358. (d) Tian,
H.-Y.; Chen, Y.-J.; Wang, D.; Bu, Y.-P.; Li, C.-J.
Tetrahedron Lett. 2001, 42, 1803. (e) Tian, H.-Y.; Chen, Y.-
J.; Wang, D.; Zeng, C.-C.; Li, C.-J. Tetrahedron Lett. 2000,
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Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
7202.
aqueous phase
SO3H
HO3S
catalyst 1
Scheme 3 Proposed mechanism
In summary, a method for calix[4]resorcinarene sulfonic
acid 1-catalyzed dehydrative amination of alcohols in wa-
ter was developed.19 In the reaction system developed in
the present study, catalyst 1 worked, not only as a Brønst-
ed acid catalyst, but also as an inverse phase-transfer cat-
alyst. That is to say, 1 performs dual-function catalysis. It
is noteworthy that the present reaction proceeded under
nonmetallic conditions in water and, furthermore, the
aqueous phase containing catalyst 1 could be readily recy-
cled. This reaction system offers an efficient and green
method for the synthesis of nitrogen-containing com-
pounds.
References and Notes
(10) For reviews, see: (a) Starks, C. M.; Liotta, C. L.; Halpern,
M. In Phase-Transfer Catalysis: Fundamentals,
Applications, and Industrial Perspectives; Chapman:
London, 1994, 179–183. (b) Goldberg, Y. In Phase-
Transfer Catalysis: Selected Problems and Applications;
Gordon: Berkshire, 1992, 359–366.
(1) (a) Lawrence, S. A. Amines: Synthesis, Properties and
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Chemistry for Organic Synthesis, Vol. 1; Negishi, E.-I., Ed.;
Wiley-Interscience: New York, 2002, 1051–1096.
Synlett 2008, No. 10, 1539–1542 © Thieme Stuttgart · New York

1542
S. Shirakawa, S. Shimizu
CLUSTER
Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161.
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(19) General Experimental Procedure for Dehydrative
Amination in H2O (Table 2): Alcohol (0.30 mmol) and p-
toluenesulfonamide (0.45 mmol) were added to a solution of
water-soluble calix[4]resorcinarene sulfonic acid 113,20
(0.030 mmol) in H2O (1 mL) with stirring, and the reaction
mixture was vigorously stirred at 60 °C for an additional 24
h. After the addition of sat. aq NaHCO3 solution (3 mL), the
resulting mixture was extracted with EtOAc (3 × 3 mL). The
combined extracts were dried over anhyd Na2SO4 and
evaporated. The products were purified by flash
(12) (a) Maksimov, A. L.; Buchneva, T. S.; Karakhanov, E. A. J.
Mol. Catal. A: Chem. 2004, 217, 59. (b) Karakhanov, E.;
Buchneva, T.; Maximov, A.; Zavertyaeva, M. J. Mol. Catal.
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Schildbach, F. Tetrahedron 2001, 57, 6985.
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608.
(14) For other examples of Brønsted acid catalyzed three-
component Mannich-type reactions in water, see:
(a) Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8, 4939.
(b) Akiyama, T.; Takaya, J.; Kagoshima, H. Adv. Synth.
Catal. 2002, 344, 338. (c) Manabe, K.; Mori, Y.;
chromatography on silica gel to yield the amination product.
Recycling Experiments (Table 3): Alcohol (0.90 mmol)
and p-toluenesulfonamide (1.08 mmol) were added to a
solution of water-soluble calix[4]resorcinarene sulfonic acid
1 (0.090 mmol) in H2O (3 mL) with stirring, and the reaction
mixture was vigorously stirred at 60 °C for an additional 24 h.
After each reaction, EtOAc (3 mL) was added to the reaction
mixture, and the solution was stirred for 5 min. The resulting
mixture was allowed to stand for 5 min and then the organic
phase was removed via a syringe. This extraction procedure
was repeated twice. The remaining aqueous catalyst solution
was reused directly in the next cycle. Isolation of the
amination product 2a was performed in a manner similar to
that described above.
Kobayashi, S. Tetrahedron 2001, 57, 2537.
(15) For palladium-catalyzed amination of allylic alcohols in
water, see: (a) Yang, S.-C.; Hsu, Y.-C.; Gan, K.-H.
Tetrahedron 2006, 62, 3949. (b) Kinoshita, H.; Shinokubo,
H.; Oshima, K. Org. Lett. 2004, 6, 4085.
(16) For surfactant-type Brønsted acid catalyzed dehydrative
reactions in water, see: (a) Shirakawa, S.; Kobayashi, S.
Org. Lett. 2007, 9, 311. (b) Manabe, K.; Iimura, S.; Sun, X.-
M.; Kobayashi, S. J. Am. Chem. Soc. 2002, 124, 11971.
(17) The reactions using simple aliphatic alcohols such as
hexanol and cyclohexanol gave no amination product.
(18) For recent examples of dehydrative nucleophilic substitution
reactions of alcohols with carbon nucleophiles, see:
(a) Motokura, K.; Nakagiri, N.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Org. Chem. 2007, 72, 6006. (b) Noji, M.;
(20) Kazakova, E. K.; Makarova, N. A.; Ziganshina, A. U.;
Muslinkina, L. A.; Muslinkin, A. A.; Habicher, W. D.
Tetrahedron Lett. 2000, 41, 10111.
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