Microwave-assisted solventless reaction of iridium-catalyzed alkylation of amines with alcohols in the absence of base

Article abstract of DOI:10.1021/ol202281h

Microwave-assisted iridium catalyzed alkylation of amines with alcohols was undertaken under solvent-free and base-free conditions. Such alkylation reactions are green, atom-economic, and effective for mono-, di-, and triaklyation of amines. Good isolated yields were obtained for mono- and dialkylated amines using stoichiometric amounts of amines and alcohols, in the presence of 1 mol % [Cp*IrCl₂]₂. Reasonable yields of trialkylated products were obtained using 4 equiv of alcohols.

Full text of DOI:10.1021/ol202281h

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5386–5389
Microwave-Assisted Solventless Reaction
of Iridium-Catalyzed Alkylation of Amines
with Alcohols in the Absence of Base
Weixing Zhang,† Xiaochun Dong,*,† and Weili Zhao*,†,‡
School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China, and Key
Laboratory for Special Functional Materials of the Ministry of Education, Henan
University, Kaifeng, 475004, P. R. China
xcdong@shmu.edu.cn; zhaoweili@fudan.edu.cn
Received August 23, 2011
ABSTRACT
Microwave-assisted iridium catalyzed alkylation of amines with alcohols was undertaken under solvent-free and base-free conditions. Such
alkylation reactions are green, atom-economic, and effective for mono-, di-, and triaklyation of amines. Good isolated yields were obtained for
mono- and dialkylated amines using stoichiometric amounts of amines and alcohols, in the presence of 1 mol % [Cp*IrCl2]2. Reasonable yields of
trialkylated products were obtained using 4 equiv of alcohols.
Amines are a very important family of compounds in the
pharmaceutical and chemical industries as well as in biol-
ogy. The classic alkylation reaction of amines is achieved
either by reaction with an alkyl halide or by reductive
amination of an aldehyde and ketone. The former proce-
dure can be problematic due to overalkylation and the toxic
nature of many alkyl halides and related alkylating agents.
The latter method requires the use of strong reducing
reagents or dangerous hydrogen gas.1 Very recently, direct
catalytic alkylation with alcohols using a borrowed hydro-
gen concept emerged as an attractive green and atom-
economical chemistry solution which generates only water
as a byproduct.2 Early examples of homogeneous catalyzed
alkylations of amines by alcohols were published indepen-
dently by Grigg3 and Watanabe,4 in 1981. Ruthenium5 and
(4) Watanabe, Y.; Tsuji, Y.; Ige, H.; Ohsugi, Y.; Ohta, T. J. Org.
Chem. 1984, 49, 3359.
† Fudan University.
(5) (a) Watanabe, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T.-A. J.
Org. Chem. 1996, 61, 4214. (b) Ganguly, S.; Roundhill, D. M. Poly-
hedron 1990, 20, 2517. (c) Huh, K.-T.; Tsuji, Y.; Kobayashi, M.; Okuda,
F.; Watanabe, Y. Chem. Lett. 1988, 449. (d) Naskar, S.; Bhattacharjee,
M. Tetrahedron Lett. 2007, 48, 3367. (e) Hamid, M. H. S. A.; Williams,
J. M. J. Chem. Commun. 2007, 725. (f) Hamid, M. H. S. A.; Williams,
J. M. J. Tetrahedron Lett. 2007, 48, 8263. (g) Hollmann, D.; Tillack, A.;
Michalik, D.; Jackstell, R.; Beller, M. Chem.;Asian J. 2007, 2, 403.
(h) Tillack, A.; Hollmann, D.; Michalik, D.; Beller, M. Tetrahedron Lett.
2006, 47, 8881. (i) Del Zotto, A.; Baratta, W.; Sandri, M.; Verardo, G.;
Rigo, P. Eur. J. Inorg. Chem. 2004, 524. (j) Gunanathan, V; Milstein, D.
‡ Henan University.
(1) Lawrence, S. A. Amines: Synthesis, Properties and Applications;
Cambridge University Press: Cambridge, 2005.
(2) For recent reviews on borrowing hydrogen, see: (a) Guillena, G.;
ꢀ
Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46, 2358.
(b) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv. Synth.
Catal. 2007, 349, 1555. (c) Nixon, T. D.; Whittlesey, M. K.; Williams,
J. M. J. Dalton Trans. 2009, 38, 753. (d) Dobereiner, G. E.; Crabtree,
R. H. Chem. Rev. 2010, 110, 681. (e) Guillena, G.; Ramon, D. J.; Yus, M.
Chem. Rev. 2010, 110, 1611.
(3) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. J.
ꢀ
€
Angew. Chem., Int. Ed. 2008, 47, 8661. (k) Imm, S.; Bahn, S.; Neubert,
Chem. Soc., Chem. Commun. 1981, 611.
L.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 8126.
r
10.1021/ol202281h
Published on Web 09/12/2011
2011 American Chemical Society

Table 1. Optimization of Conditionsa
Table 2. Alkylation of Amines with Diols To Form N-Hetero-
cyclesa
entry
sol.
base
conditions
140 °C, 1 h
convb
yieldc
1d
2d
3
H2O
None
None
1%
10%
90%
80%
80%
0%
5%
H2O
140 °C, 10 h
80%
70%
70%
0%
H2O
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 140 °C, 1 h
110 °C, 1 h
4
H2O
None
None
None
None
None
None
None
None
1%
5e
6
H2O
H2O
85%
trace
50%
5%
75%
trace
30%
trace
5%
7d
8d
9
None
None
None
None
None
None
None
110 °C, 10 h
MW, 110 °C, 1 h
MW, 130 °C, 0.5 h
MW, 140 °C, 1 h
MW, 140 °C, 1 h
MW, 140 °C, 1 h
10
11
12
13
10%
100%
80%
75%
91%
70%
65%
10%
a Reaction conditions: benzylamine (1 mmol), 1,5-pentanediol
(1 mmol), [Cp*IrCl2]2 (1 mol %), K2CO3 (0À10 mol %). b Conversion
based on benzylamine. c Yield determined by HPLC. d Under conven-
tional heating. e In the absence of iridium catalyst.
iridium catalysts6,7 were subsequently reported as the most
frequently used catalysts for the alkylation of amines by
alcohols. Additionally, rhodium8 and platinum9 were also
reported to be effective. [Cp*IrCl2]210 was discovered to be a
very efficient catalyst for alkylation of amines with alcohols.
Other iridium catalysts such as [Cp*IrI2]2,11 [IrCl(cod)]2,12
and [Cp*Ir(NH3)3][Cl]213 were also reported to be efficient
catalysts for iridium catalyzed alkylation of amines. These
reactions are typically run in toluene under reflux for a long
period of heating and require addition of base, e.g. potas-
sium carbonate, which may form the iridium carbonate
complex during the reaction. Although no base was needed
in a few cases, a polar solvent and an extended period of
heating were generally required.11,13
We are very interested in a green and atom-economical
method for the preparation of amine. Recently, iridium
catalysts were reported to be active in the solvent-free and
microwave-assisted alkylation of CÀC bond formation.
Ruthenium catalyzed amine synthesis with alcohols
under solvent-freemicrowaveconditions was documented;
however, extra ligand and an excess of alcohols were
required. Herein we report an efficient, green, and atom-
a Reaction conditions: amine (1 mmol), diol (1 mmol), [Cp*IrCl2]2
(1 mol %), MW, 140 °C, 1 h. b Isolated yield. c MW, 160 °C, 1 h.
economical alkylation of amines with alcohols under
solvent-free, base-free, and microwave conditions.
Iridium complexes are generally more stable than rho-
dium complexes. [Cp*IrCl2]2 was selected as the catalyst,
and the N-alkylation of benzylamine with 1,5-pentanediol
was employed as the model reaction for optimization of
reaction conditions. The results are summarizedin Table 1.
(8) Tanaka, N.; Hatanaka, M.; Watanabe, Y. Chem. Lett. 1992, 575.
(9) Tsuji, R.; Takeuchi, Y.; Ogawa, H.; Watanabe, Y. Chem. Lett.
1986, 293.
(10) (a) Fujita, K.; Li, Z.; Yamaguchi, R. Tetrahedron Lett. 2003, 44,
2687. (b) Fujita, K.-I.; Yamaguchi, R. Synlett 2005, 4, 560. (c) Fujita,
K.-I.; Enoki, Y.; Yamaguchi, R. Org. Synth. 2006, 83, 217. (d) Fujita,
K.-I.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943.
(e) Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K.-I. Org. Lett.
2008, 10, 181. (f) Yamaguchi, R.; Mingwen, Z.; Kawagoe, S.; Asai, C.;
Fujita, K.-I. Synthesis 2009, 1220. (g) Nordstrøm, L. U.; Madsen, R.
Chem. Commun. 2007, 5034.
(11) (a) Saidi, O.; Blacker, A. J.; Lamb, G. W.; Marsden, S. P.;
Taylor, J. E.; Williams, J. M. J. Org. Process Res. Dev. 2010, 14, 1046.
(b) Saidi, O.; Blacker, A. J.; Farah, M. M.; Marsden, S. P.; Williams,
J. M. J. Chem. Commun. 2010, 1541.
(12) (a) Blank, B.; Madalska, M; Kempe, R. Adv. Synth. Catal. 2008,
350, 749. (b) Blank, B.; Michlik, S.; Kempe, R. Chem.;Eur. J. 2009, 15,
3790.
(6) For a very recent review, see: Suzuki, T. Chem. Rev. 2011, 111,
1825 and references cited therein.
(13) Kawahara, R.; Fujita, K.-I.; Yamaguchi, R. J. Am. Chem. Soc.
2010, 132, 15108.
(14) (a) Grigg, R.; Whitney, S.; Sridharan, V.; Keep, A.; Derrick, A.
(7) (a) Cami-Kobeci, G.; Williams, J. M. J. Chem. Commun. 2004,
1072. (b) Cami-Kobeci, G.; Slatford, P. A.; Whittlesey, M. K.; Williams,
J. M. J. Bioorg. Med. Chem. Lett. 2005, 15, 535. (c) Nordstrøm, L. U.;
Madsen, R. Chem. Commun. 2007, 5034. (d) Blank, B.; Madalska, M.;
Kempe, R. Adv. Synth. Catal. 2008, 350, 749. (e) Gunanathan, C.;
Milstein, D. Angew. Chem., Int. Ed. 2008, 47, 8661. (f) Prades, A.;
€
Tetrahedron 2009, 65, 4375. (b) Lofberg, C.; Grigg, R.; Whittaker,
M. A.; Keep, A.; Derrick, A. J. Org. Chem. 2006, 71, 8023.
(c) Anxionnat, B.; Pardo, D. G.; Ricci, G.; Cossy, J. Org. Lett. 2011,
13, 4084. (d) Lubinu, M. C.; De Luca, L.; Giacomelli, G.; Porcheddu, A.
Chem.;Eur. J. 2011, 17, 82.
(15) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. J. Org.
Chem. 2011, 76, 2328. Iridium has been mentioned in the footnote to be
effective; however, no details have been reported.
ꢀ
Corberan, R.; Poyatos, M.; Peris, E. Chem.;Eur. J. 2008, 14, 11474.
(g) Gnanamgari, D.; Sauer, E. L. O.; Schley, N. D.; Butler, C.; Incarvito,
C. D.; Crabtree, R. H. Organometallics 2009, 28, 321. (h) Blank, B.;
Michlik, S.; Kempe, R. Chem.;Eur. J. 2009, 15, 3790. (i) Michlik, S.;
Kempe, R. Chem.;Eur. J. 2010, 16, 13193.
Org. Lett., Vol. 13, No. 19, 2011
5387

When water was used as solvent, under conventional
heating, we observed that 1-benzylpiperidine was gener-
ated in about 5% yield at 140 °C for 1 h in the absence of
base (entry 1, Table 1). Good conversion and yield were
reached after 10 h of heating (entry 2, Table 1). The
effectiveness of [Cp*IrCl2]2 for the alkylation of amine
encouraged us to test the microwave irradiated conditions.
Good conversion and yield can be reached under micro-
wave irradiation at 130 °C for 1 h both in the presence and
in the absence of base (entries 3 and 4, Table 1). However,
without the iridium catalyst, no desired product was
generated (entry 5, Table 1). Improved conversion and
yield were realized at 140 °C under microwave conditions.
The promising results promoted us to try a neat reaction
under microwave conditions based on the assumption that
a reduced amount ofwater will favor the conversion. When
the reaction was undertaken in neat conditions at a
relatively low reaction temperature (e.g., below 130 °C),
neither conventional heating nor microwave irradiation
afforded significant conversion (entries 7À10, Table 1).
The optimized conditions for the iridium catalyzed amina-
tion was discovered to be a neat reaction without base at
140 °C for 1 h under microwave heating (entry 11, Table 1).
In comparison, the addition of base was not beneficial
(entries 12, and 13, Table 1). After suitable reaction
conditions had been established, we wished to examine
the scope and reliability of the synthesis of N-heterocycles
by the reaction of different amines with suitable diols.16
The results are summarized in Table 2. We were pleased to
obtain good conversions and reasonable isolated yields of
the corresponding N-benzyl-piperidine derivatives for
both electron-rich and -deficient benzyl amines (entries
1À4, Table 2). For 7- and 5-membered N-heterocycles, a
higher reaction temperature (160 °C) was required to reach
complete conversion (entries 5 and 6, Table 2).
Table 3. Alkylation of Amines with Various Alcoholsa
Table 4. Trialkylation of Amine Using NH4OAc with Various
Primary Alcoholsa
a Reaction conditions: ammonium acetate (1 mmol), alcohol (4 mmol),
[Cp*IrCl2]2 (1 mol %), MW, 160 °C, 1 h. b Isolated yield.
With the success of dialkylation of amines with diols, we
are very much interested in the possibility of monoalkyla-
tion of an amine with alcohol. To further evaluate the
scope of the microwave-assisted neat reaction of the
iridium catalyzed alkylation of amines with alcohols under
base-free condition, a variety of amines and alcohols were
exploited as the coupling partners. To ensure fast and
complete conversion, the optimum reaction conditions
a Reaction conditions: amine (1 mmol), alcohol (1 mmol),
(16) (a) Fujita, K.-I.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2004,
ꢀ
6, 3525. (b) Prades, A.; Corberan, R.; Poyatos, M.; Peris, E. Chem.;
[Cp*IrCl2]2 (1 mol %), MW, 160 °C, 1 h. b Isolated yield.
Eur. J. 2008, 14, 11474.
5388
Org. Lett., Vol. 13, No. 19, 2011

were discovered tobemicrowave irradiationat160°C for 1
h. The results are collected in Table 3. Good isolated yields
were obtained for the monoalkylation of alkylamine,
arylamine, benzylamine, and heterocyclic amine, with a
wide range of alcohols (Table 3).
Our focus next turned toward whether trialkylation of
an amine was feasible. We examined the trialkylation of an
amine with a benzyl alcohol using ammonium acetate as
the amine source.10e,f Thereactions were undertakenunder
microwave irradiation at 160 °C for 1 h. The results are
summarized in Table 4. To ensure complete conversion
and reasonable yields of the desired trialkylated products,
4 equiv of the primary alcohols were required.
CÀN bond forming reactions provide high efficiency and
easy manipulation, possibly resulting in a superior process
for the chemical and pharmaceutical industries.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20872026),
the Hi-Tech Research and Development Program of China
(863 Plan, 2009AA02Z308), Shanghai Pujiang Talent Plan
Project (09PJD008), National Basic Research Program of
China (973 Program) No. 2010CB912600, and Sino Swiss
Science and Technology Cooperation (SSSTC, EG
30-032010). We are also grateful to Roche R&D Center
(China) Ltd. for support.
In summary, we have communicated here an iridium
catalyzed alkylation of amines with alcohols under micro-
wave irradiation, solvent-free, and base-free conditions.
[Cp*IrCl2]2 is effective for mono-, di-, and trialkylation of
amines with alcohols. Such green and atom-economical
Supporting Information Available. Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5389