In-water dehydrative alkylation of ammonia and amines with alcohols by a polymeric bimetallic catalyst

Article abstract of DOI:10.1021/ol201422s

An in-water dehydrative alkylation with a novel heterobimetallic polymeric catalyst is described. Thus, a boron-iridium heterobimetallic polymeric catalyst was prepared by ionic convolution of a poly(catechol borate) and an iridium complex. The alkylation of ammonia and amines with alcohols, alkylating agents, was performed with 1 mol % Ir of the heterogeneous catalyst in water without the use of organic solvents under aerobic conditions to give the corresponding alkylated amines.

Full text of DOI:10.1021/ol201422s

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3892–3895
In-Water Dehydrative Alkylation of
Ammonia and Amines with Alcohols by a
Polymeric Bimetallic Catalyst
Hidetoshi Ohta,† Yoshinari Yuyama,† Yasuhiro Uozumi,*,†,‡ and
Yoichi M. A. Yamada*,†
RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan, and Institute for
Molecular Science (IMS), and the Graduate University for Advanced Studies, Okazaki,
Aichi 444-8787, Japan
ymayamada@riken.jp; uo@ims.ac.jp
Received May 26, 2011
ABSTRACT
An in-water dehydrative alkylation with a novel heterobimetallic polymeric catalyst is described. Thus, a boronꢀiridium heterobimetallic
polymeric catalyst was prepared by ionic convolution of a poly(catechol borate) and an iridium complex. The alkylation of ammonia and amines
with alcohols, alkylating agents, was performed with 1 mol % Ir of the heterogeneous catalyst in water without the use of organic solvents under
aerobic conditions to give the corresponding alkylated amines.
An in-water dehydration reaction is a paradox under
equilibrium conditions, also known as “water paradox”.1
But enzymes in living things promote such reactions with
extremely high efficiency. For example, nucleic acids
(DNA and RNA) are prepared from mononucleotides
by forming phosphate ester bonds. Proteins are syn-
thesized from amino acids by an amidation. N-methyl-
tranferases are enzymes for methylation of terminal amines
to form N-methylated amines.2 Consequently, development
of enzyme-mimic catalysts for the in-water dehydration
reaction system has attracted interest:3 The esterification
of carboxylic acids with alcohols4 and the dehydrative
Mannich-type reaction5 are typical examples. Also, an
in-water hydrogen-transfer dehydrative N-alkylation of
amines with alcohols is a fundamental and straightforward
method for the synthesis of N-alkylated amines as well as
nitrogen-containing bioactive compounds, drug molecules,
and agrochemicals.6,7 In this reaction, alcohols are used as
alkylating agents in place of harmful and toxic alkyl halides.
Several researchers have carried out pioneering studies on the
† RIKEN Advanced Science Institute.
‡ Institute for Molecular Science (IMS), and the Graduate University for
Advanced Studies.
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Synthesis II; Wiley-VCH: Weinheim, 2003.
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Walter, P. Molecular Biology of the Cell, 5th ed.; Garland Science: 2008.
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ꢀ
r
10.1021/ol201422s
Published on Web 06/29/2011
2011 American Chemical Society

N-alkylation of amines with alcohols using a homogeneous
catalyst of Ir, Ru, Rh, and Pt;8,9 Madsen, Milstein, Williams,
Fujita, and Yamaguchi independently developed the in-
water alkylation reactions of amines with alcohols by using
homogeneous catalysts.10 In the development stage of this
reaction, construction of an aqueous and heterogeneous11
fusion system, a reaction that would satisfy green chemistry
requirements, still remains a major challenge.
We previously developed a new method for the prepara-
tion of highly active and reusable polymer-supported
catalysts.12 In this method, a soluble linear polymer having
multiple ligand groups is convoluted with neutral metals or
anionic metal salts via coordinate or ionic complexation to
obtain an insoluble polymer/metal composite in a single
step. We paid attention to a dicationic iridium complex
and a catechol borate polymer as a heterobimetallic multi-
functional catalyst;13,14 An iridium species should work not
only as a cross-linker of borate polymers but also as a
catalytic species. A catechol borate polymer should be a
main-chain polymer backbone as well as a Brønsted base.
Herein, we report the preparation of a novel convoluted
polymeric heterobimetallic catalyst for the in-water hydro-
gen-transfer dehydrative N-alkylation of amines with alco-
hols. In this catalytic system, aqueous ammonia, as well as
amines, was efficiently alkylated in water under aerobic
conditions.
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R. Org. Lett. 2002, 4, 2691. (b) Cami-Kobeci, G.; Slatford, P. A.;
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Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J.
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Madsen, R. Chem. Commun. 2007, 5034. (b) Gunanathan, C.; Milstein,
D. Angew. Chem., Int. Ed. 2008, 47, 8661. (c) Kawahara, R.; Fujita, K.;
Yamaguchi, R. J. Am. Chem. Soc. 2010, 132, 15108. (d) Saidi, O.;
Blacker, A. J.; Farah, M. M.; Marsden, S. P.; Williams, J. M. J. Chem.
Commun. 2010, 46, 1541. (e) Saidi, O.; Blacker, A. J.; Lamb, G. W.;
Marsden, S. P.; Taylor, J. E.; Williams, J. M. J. Org. Process Res. Dev.
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Figure 1. ATR-IR spectra of 3 (line a), 1 (line b), and 2 (line c)
(left), and XPS spectra of 3 (B 1s and Ir 4f7/2) (right).
A linear polymer of catechol borate 1 was prepared from
1,2-dimethoxybenzene 4 and dodecanedioyl dichloride5 in
four steps (see Supporting Information).15 The polymer 1
was a white powder that was soluble in DMSO, DMF,
MeOH, MeCN, DME, THF, and acetone. The 11B{1H}
NMR spectrum of 1 in DMSO-d6 showed a broad singlet
peak that could be assigned to catechol borate at 14.7
ppm.16 Self-assembly of the borate polymer and an iridium
species was carried out by our convolution method based
on Danjo and Yamaguchi’s process of the self-assembled
D3-symmetric tris(spiroborate) cyclophaneꢀIr complex.17
Thus, an ionic convolution of 1 and Cp*Ir(κ2-CO3)(IPr)18
(2) (brownish orange) was carried out in a DMEꢀMeCN
mixture at 50 °C for 24 h to give 3 as a brown precipitate,
(11) For heterogeneous catalysis in organic solvents, see: (Review) (a)
Narayanan, S.; Deshpande, K. Applied Catal A: General 2000, 199, 1.
(Examples) (b) Valotl, F.; Fachel, F.; Jacquot, R.; Spagnol, M.; Lemairel,
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M. Tetrahedron Lett. 1999, 40, 3689. (c) Martınez, R.; Ramon, D. J.; Yus,
M. Org. Biomol. Chem. 2009, 7, 2176. (d) Kim, J. W.; Yamaguchi, K.;
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Bosco, W.; Chidrala, R. K.; Park, J. J. Org. Chem. 2009, 74, 2877.
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12, 4540. (b) Yamada, Y. M. A.; Watanabe, T.; Torii, K.; Uozumi, Y.
Chem. Commun. 2009, 5594. (c) Yamada, Y. M. A.; Guo, H.; Uozumi,
Y. Org. Lett. 2007, 9, 1501. (d) Yamada, Y. M. A.; Uozumi, Y.
Tetrahedron 2007, 63, 8492. (e) Uozumi, Y.; Yamada, Y. M. A.; Beppu,
T.; Fukuyama, N.; Ueno, M.; Kitamori, T. J. Am. Chem. Soc. 2006, 128,
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4259. (g) Yamada, Y. M. A.; Uozumi, Y. Org. Lett. 2006, 8, 1375.
(13) For reviews of Shibasaki’s homogeneous heterobimetallic multi-
functional catalysts, see: (a) Shibasaki, M.; Kanai, M.; Matsunaga, S.;
Kumagai, N. Acc. Chem. Res. 2009, 42, 1117. (b) Shibasaki, M.; Kanai,
M.; Funabashi, K. Chem. Commun. 2002, 1989. (c) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187. (d) Shibasaki, M.; Sasai,
H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236. (e) Wheatley,
N.; Kalck, P. Chem. Rev. 1999, 99, 3379. (f) van den Beuken, E. K.;
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Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 4925. (h) Iwata, M.; Yazaki, R.; Suzuki, Y.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 18244. (i)
Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 13860.
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Wang, Z.; Chen, G.; Ding, K. Chem. Rev. 2009, 109, 322. (b) Lu, J.; Toy,
P. H. Chem. Rev. 2009, 106, 815. For examples, see: (c) Takizawa, S.;
Somei, H.; Jayaprakash, D.; Sasai, H. Angew. Chem., Int. Ed. 2003, 42,
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Eur. J. 2006, 12, 5188. For an example of catalyst analogue concept, see:
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Chem., Int. Ed. 2003, 42, 2144.
€
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Anorg. Allg. Chem. 1997, 623, 901. (b) Chikkali, S. H.; Gudat, D.;
Lissner, F.; Nieger, M.; Schleid, T. Dalton Trans. 2007, 3906.
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K. J. Am. Chem. Soc. 2009, 131, 1638.
(18) See the Supporting Information for the preparation of 2.
Org. Lett., Vol. 13, No. 15, 2011
3893

which had poor solubility in H2O, MeOH, MeCN, DME,
THF, Et2O, acetone, toluene, and hexane. In the ATR-IR
spectrum of 3, the absorption peaks corresponding to the
hydroxy group in 1 and the carbonate group in 2 disap-
peared, indicating the formation of 3 (Figure 1). The XPS
spectrum of 3 showed five characteristic peaks attributed to
C, B, O, N, and Ir (Figures 1 and S1, Supporting Informa-
tion). The B 1s binding energy in the case of 3 was 192.2 eV,
which was close to that of the tetravalent ate 1•Et3N complex
(192.4 eV)19 and was lower than that of the trivalent 1 (193.0
eV), indicating the formation of a tetravalent borate anion
species. The Ir 4f7/2 binding energy in 3 was 62.7 eV that
could be assigned as an Ir(2þ) species. ICP-AES analysis of 3
revealed that the loading ratio of Ir was 12.06 wt %. These
results clearly indicated that the precipitate 3 comprised
Table 1. In-Water Dehydrative N-Alkylation of Amines with
Alcohols Promoted by 3a
anionic spiroborate polymer species and dicationic Cp*Ir2þ
-
(IPr) species, as shown in Scheme 1. This result was also
supported by elementary analysis.
Scheme 1. Preparation of Ionically Convoluted Poly-
(spiroborate)iridium Catalyst PB-Cp*Ir(IPr) 3
After the successful preparation of the convoluted poly-
meric heterobimetallic catalyst 3, we carried out the in-water
hydrogen-transfer dehydrative alkylation of a variety of
amines by using alcohols as the alkylating reagents. The
reaction was carried out in water without employing addi-
tional bases, and the corresponding N-alkylated amines were
obtained. The representative results are summarized in Table
1. Thus, the reaction of aniline (9a) with benzyl alcohol (10a)
proceeded smoothly in the presence of 3(1 mol % Ir) in water
(100 °C, 24 h) to afford N-benzylaniline (11a) in 85% yield
(entry 1). It is noteworthy that the reaction was carried out
under aerobic conditions. The reaction of electron-rich
(entries 2 and 3) and electron-poor (entries 4 and 5) anilines
9bꢀe with 10a was carried out under similar conditions to
afford the corresponding N-alkylated anilines 11bꢀe in
63ꢀ93% yield. Alkylation of 1-naphthylamine (9f) with
10a afforded N-benzylated amine 11f in 89% yield (entry
6). The catalyst was recovered by decantation, and ICP-AES
a All reactions were carried out using 9 (0.5 mmol), 10 (0.6 mmol),
and 3 (1 mol % Ir) in water (0.5 mL) at 100 °C for 24 h under aerobic
conditions. b Isolated yield. c Second use of 3. d Third use of 3. e 150 °C,
microwave in pH 4 buffer aqueous solution in a sealed tube. f 10 (2.5 mmol).
analysis indicated 95% recovery of the Ir species.20 The
recovered catalyst was reused twice without loss of activity
to afford 11f in stable chemical yield (second use: 87%, third
use: 87%; entries 7ꢀ8). Substituted benzylic alcohols were
found to be suitable alkylating agents for this reaction. Thus,
the reaction of 9a with 2-methylbenzyl, 4-methoxybenzyl,
(20) In the reaction mixture, iridium species were detected (0.008%;
ICP-AES analysis).
(19) See the Supporting Information for the preparation of 1•NEt3.
3894
Org. Lett., Vol. 13, No. 15, 2011

4-chloro, and 3,5-dimethoxybenzyl alcohols 10bꢀe afforded
the corresponding N-alkylated amines 11gꢀj in 78ꢀ86%
yield (entries 9ꢀ12). The alkylation of 9f with a less reactive
aliphatic alcohol 10f under similar conditions also proceeded
smoothly to afford an octylated amine 11k in 86% yield
(entry 13). When the reaction of an aliphatic primary amine
9g was carried out in a pH 4 standard buffer aqueous solution
under microwave conditions in a sealed tube, the alkylation
proceeded to give tribenzylamine (11l) in 83% yield (entry
14).21 The reaction of an aliphatic secondary amine 9h also
gave 11l in 83% yield (entry 15). An alicyclic amine 9i was
also reacted under similar conditions to afford N-benzyl
morpholine (11m) in 83% yield. N-Benzyl 4-piperidine-
methanol (11n), a substrate for the synthesis of an Alzhei-
mer’s disease drug Aricept (donepezil hydrochloride),22 was
given from 4-piperidinemethanol 9j in 61% yield (entry 17).
Aqueousammonia islessreactivethanotheramines, sothe
in-water alkylation of ammonia with alcohols is challen-
ging. Recently, Yamaguchi and Fujita et al. reported the
reaction of aqueous ammonium with alcohols by homo-
geneous catalysts in water.10c Milstein et al. reported the
preparation of amines from alcohols and NH3 gas (7.5
atm) by a homogeneous ruthenium complex in toluene and
water.10b Beller23 and Vogt24 reported amination of alco-
hols with liquid ammonia in organic solvents. We were
pleased to find that the reaction of aq. NH3 and benzyl
alcohol (10a) proceeded in the presence of the heteroge-
neous catalyst 3 (1 mol % Ir) in a pH 4 standard buffer
aqueous solution under microwave conditions to give
tribenzyl amine (11l) in 84% yield (entry 1). The reaction
with both electron-sufficient and -deficient (methoxy,
chloro, trifluoromethyl, and methyl) benzylic alcohols
was also carried out under the similar conditions to afford
the corresponding tribenzylic amines 11oꢀr in 68ꢀ95%
yield (entries 2ꢀ5).
Table 2. In-Water Dehydrative N-Alkylation of Aqueous Am-
monia Promoted by 3a
In conclusion, we have developed a convoluted poly-
meric novel heterobimetallic iridium boron catalyst that
promoted the in-water alkylation of amines, in particular
aqueous ammonia, with alcohols without the use of or-
ganic solvents under aerobic conditions to meet green
chemical requirements.
Acknowledgment. Weacknowledgethepartial financial
support extended by JSPS (Grant-in-Aid for Scientific
Research, No. 20655035), MEXT (Science Research on
Priority Areas, No. 460), JST (CREST Project), and
METI/NEDO (Green-Sustainable Chemical Process project).
We also thank RIKEN Advanced Science Institute
Advanced Technology Support Division for their assis-
tance in XPS and ICP measurements.
a All reactions were carried out using 9 (0.5 mmol), 10 (3.4 mmol),
and 3 (1 mol % Ir) in pH 4 buffer aqueous solution (0.5 mL) at 150 °C for
24 h under microwave conditions in a sealed tube under air. b Isolated
yield. c 48 h.
Supporting Information Available. Experimental de-
tails and NMR data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Furthermore, the catalyst was applied to the in-water
reaction of aqueous ammonia as a substrate (Table 2).
(21) The reaction in water at 100ꢀ150 °C without the use of a
microwave was sluggish.
€
(23) Imm, S.; Bahn, S.; Neubert, L.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2010, 49, 8126.
(22) Abe, T.; Haga, T.; Negi, S.; Morita, Y.; Takayanagi, K.;
Hamamura, K. Tetrahedron 2001, 57, 2701.
€
(24) Pingen, D.; Muller, C.; Vogt, D. Angew. Chem., Int. Ed. 2010, 49,
8130.
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