Selective synthesis of secondary and tertiary amines by Cp*iridium-catalyzed multialkylation of ammonium salts with alcohols

Article abstract of DOI:10.1021/ol702522k

(Chemical Equation Presented) The efficient selective synthesis of secondary and tertiary amines has been achieved by means of Cp*Ir- catalyzed multialkylation of ammonium salts with alcohols without solvent: the reactions of ammonium acetate with alcohols gave tertiary amines exclusively, while those of ammonium tetrafluoroborate afforded secondary amines selectively. Using this method, secondary 5- and 6-membered cyclic amines were synthesized from ammonium tetrafluoroborate and diols in one pot.

Full text of DOI:10.1021/ol702522k

ORGANIC
LETTERS
2008
Vol. 10, No. 2
181-184
Selective Synthesis of Secondary and
Tertiary Amines by Cp*Iridium-Catalyzed
Multialkylation of Ammonium Salts with
Alcohols
Ryohei Yamaguchi,* Shoko Kawagoe, Chiho Asai, and Ken-ichi Fujita*
Graduate School of Human and EnVironmental Studies, Kyoto UniVersity, Yoshida,
Sakyo-ku, Kyoto 606-8501, Japan
yama@kagaku.mbox.media.kyoto-u.ac.jp; fujitak@kagaku.mbox.media.kyoto-u.ac.jp
Received October 16, 2007
ABSTRACT
The efficient selective synthesis of secondary and tertiary amines has been achieved by means of Cp*Ir-catalyzed multialkylation of ammonium
salts with alcohols without solvent: the reactions of ammonium acetate with alcohols gave tertiary amines exclusively, while those of ammonium
tetrafluoroborate afforded secondary amines selectively. Using this method, secondary 5- and 6-membered cyclic amines were synthesized
from ammonium tetrafluoroborate and diols in one pot.
Acyclic and cyclic amines have been of great importance in
many fields of organic chemistry, including biological,
medicinal, agrochemical, dyes, and material chemistry. Thus,
the development of versatile and efficient methods for the
synthesis of amines has attracted much attention and is still
occupying an active area of research.1
Ammonia or simple salts are attractive nitrogen sources
for the synthesis of amines. Recently, there have been some
reports on homogeneous catalytic systems using it as the
substrate:2 palladium-catalyzed telomerization of butadiene
and ammonia giving primary alkylamines,3 rhodium- and
iridium-catalyzed reductive aminations of carbonyl com-
pounds with ammonium formate and ammonia affording
primary alkylamines,4 and copper- and palladium-catalyzed
coupling reactions of ammonia with aryl hailides producing
arylamines.5 While most of them described the synthesis of
primary alkyl- and arylamines, Buchwald et al. reported very
recently selective palladium-catalyzed arylation of ammonia
affording di- and triarylamines.5c However, to the best of
(3) Prinz, T.; Driessen-Ho¨lscher, B. Chem. Eur. J. 1999, 5, 2069.
(4) (a) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M.
J. Org. Chem. 2002, 67, 8685. (b) Gross, T.; Seayad, A. M.; Ahmad, M.;
Beller, M. Org. Lett. 2002, 4, 2055. (c) Ogo, S.; Makihara, N.; Kaneko,
Y.; Watanabe, Y. Organometallics 2001, 20, 4903.
(5) (a) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron
Lett. 2001, 42, 3251. (b) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 10028. (c) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 10354 and references cited therein.
(1) For example: (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W.
Tetrahedron 2001, 57, 7785. (b) Chiappe, C.; Pieraccini, D. Green Chem.
2003, 5, 193.
(2) Earlier review concerning the use of ammonia in catalytic reactions:
Roundhill, D. M. Chem. ReV. 1992, 92, 1.
10.1021/ol702522k CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/13/2007

our knowledge, there has been no report on selective
synthesis of di- and trialkylamines from ammonia or its
simple salts.
better results (entries 7 and 8). It is noted that ammonia itself
gave rather poor yields (entries 13 and 14)8 and that the
reaction using an Ir(I) complex such as [IrCl(cod)]2 resulted
in no reaction (entry 4). The reactions using Ru catalysts9
required a higher temperature (140 °C) but gave lower yields
of the product (entries 5 and 6). The yields were improved
when a slight excess (3.6 equiv) of benzyl alcohol and a
higher temperature (130 °C) were employed (entry 15).
We have reported an atom-economical catalytic system
for the synthesis of secondary and tertiary amines by the
N-alkylation of primary and secondary amines with alcohols
catalyzed by a Cp*Ir complex,6 in which the high catalytic
performance of Cp*Ir complexes for hydrogen transfer
reactions is essential.7 Since the utilization of ammonia or
its simple salts as nitrogen sources has been one of the
important objectives in catalytic organic chemistry as
mentioned above, we report here an efficient selective
synthesis of secondary and tertiary alkylamines by the Cp*Ir
complex-catalyzed multialkylation of ammonium salts with
primary and secondary alcohols without solvent.
The results of the present catalytic trialkylation reactions
of ammonium acetate with a variety of primary alcohols are
shown in Table 2. In the case of benzylic alcohols, the yields
Table 2. Cp*Ir-Catalyzed Trialkylation of NH4OAc with
Various Primary Alcohols Affording Trialkylaminesa
We started to investigate the N-alkylation of a variety of
ammonium salts with alcohols because ammonium salts are
more easily and safely handled than ammonia itself (Table
1). When the reaction of ammonium chloride with benzyl
Table 1. Cp*Ir-Catalyzed Trialkylation of Ammonium Salts
with Benzyl Alcohola
entry
catalyst
ammonium salt
yieldb (%)
1
2
3
[Cp*IrCl2]2
[Cp*IrCl2]2
none
NH4Cl
NH4OAc
NH4OAc
13
72
0
4
5
6
7
8
9
10
11
12
13
14
15d
[Ir(cod)Cl]2
RuCl2(PPh3)3
RuH2(PPh3)4
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
NH4OAc
NH4OAc
NH4OAc
NH4HCO3
(NH4)2CO3
NH4NO3
(NH4)2SO4
(NH4)H2PO4
(NH4)2HPO4
NH3 (aq)
0
0 (45)c
0 (16)c
43
66
31
3
4
20
10
0
a The reactions were carried out with ammonium salt (1.0 mmol) and
alcohol (3.6 mmol). b Isolated yield. c Toluene (1.0 mL) was added as
solvent. d The reactions were conducted with 5.0 mmol of alcohols at higher
temperature (140 °C). e GC yield.
NH3 (dioxane)
NH4OAc
87
a The reactions were carried out with ammonium salt (1.0 mmol) and
benzyl alcohol (3.0 mmol). b GC yield. c The yield of the reaction conducted
at 140 °C is in parentheses. d The reaction was carried out with NH4OAc
(1.0 mmol), PhCH2OH (3.6 mmol), [Cp*IrCl2]2 (0.5 mol % Ir), and NaHCO3
(1.0 mol %) at 130 °C for 17 h.
were good to high, and several kinds of functional groups
were unaffected (entries 1-9). In the case of aliphatic
alcohols, 5 equiv of alcohols and a reaction temperature of
140 °C were needed to obtain good yields of the products
(entries 10-13).
The present catalytic reactions would proceed through
triple N-alkylations in which three elementary steps (dehy-
drogenation, imine or iminium ion formation, and hydroge-
nation) are involved. Based on the proposed mechanism for
alcohol (3 equiv) in the presence of [Cp*IrCl2]2 (3.0 mol %
Ir) was carried out at 110 °C for 17 h without solvent,
tribenzylamine was obtained in 13% yield (entry 1, Table
1). However, we have found that use of ammonium acetate
greatly improved the yield to 72% (entry 2). The results of
the reactions of other ammonium salts are summarized in
Table 1. As is seen, ammonium salts of weak acids gave
(8) The poor results might be attributed to the diluted conditions.
(9) (a) Watanabe, Y.; Tsuji, Y.; Ohsugi, Y. Tetrahedron Lett. 1981, 22,
2667. (b) Murahashi, S.-I.; Kondo, K.; Hakata, T. Tetrahedron Lett. 1982,
23, 229.
(6) Fujita, K.; Li, Z.; Ozeki, N.; Yamaguchi, R. Tetrahedron Lett. 2003,
44, 2687.
(7) Fujita, K.; Yamaguchi, R. Synlett 2005, 560.
182
Org. Lett., Vol. 10, No. 2, 2008

Cp*Ir-catalyzed N-alkylation of amines,6,7 a possible mech-
anism for the first monoalkylation cycle is depicted in
Scheme 1.10-12 Thus, it is apparent that each of the
of ammonium tetrafluoroborate resulted in such high selec-
tivity and yield as shown in Scheme 2.
The reactions of ammonium tetrafluoroborate with other
primary alcohols also gave secondary amines very selec-
tively. The results are summarized in Table 3.
Scheme 1
Table 3. Cp*Ir-Catalyzed Dialkylation of NH4BF4 with
Various Primary Alcohols Affording Dialkylaminesa
N-alkylation reactions must take place very smoothly to
obtain the good to high yields of products.
As is shown above, ammonium acetate is a good ammonia
source for the triple N-alkylations affording tertiary amines.
However, it is very difficult to obtain a secondary amine
even using 2 equiv of alcohol: the reaction of ammonium
acetate with 1-hexanol (2.2 equiv) gave trihexylamine in 35%
yield along with a trace amount of dihexylamine (Scheme
2). On the other hand, we have found that the reaction of
a The reactions were carried out with NH4BF4 (1.0 mmol), alcohol (2.2
mmol), and NaHCO3 (30 mol %). b GC yield.
In the reactions with secondary alcohols, complete selec-
tivity for the formation of secondary amines was observed
probably due to steric hindrance. The results are summarized
in Table 4.
Scheme 2
Table 4. Cp*Ir-Catalyzed Dialkylation of NH4BF4 with
Various Secondary Alcohols Affording Dialkylaminesa
ammonium benzoate with 1-hexanol (2.2 equiv) gave di-
hexylamine (42%) as a major product and a small amount
of trihexylamine (12%). Thus, after several experiments using
other ammonium salts,13 it is remarkable that the reaction
(10) In the present reaction, catalytic intermediates would be Ir(III)
species. There are many examples of Cp*Ir-catalyzed hydrogen transfer
reactions in which catalytic intermediates are trivalent iridium species. (a)
Suzuki, T.; Yamada, T.; Watanabe, K.; Katoh, T. Bioorg. Med. Chem. Lett.
2005, 15, 2583. (b) Hanasaka, F.; Fujita, K.; Yamaguchi, R. Organometallics
2005, 24, 3422. (c) Ogo, S.; Makihara, N.; Watanabe, Y. Organometallics
1999, 18, 5470. (d) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1201.
(11) According to a suggestion of one of the referees, we carried out the
reactions using cationic Ir(III) complexes, such as [Cp*Ir(MeCN)3](BF4)2
and [Cp*Ir(MeCN)3](PF6)2, to give tribenzylamine in 57% and 21% yields,
respectively. These results also support that Ir(III) complexes could be
catalytically active species.
(12) We conducted the similar reaction of ammonium acetate with
benzaldehyde (3 equiv) using 2-propanol (5 equiv) as hydrogen donor in
the presence of [Cp*IrCl2]2 (5 mol %) and NaHCO3 (30 mol %) at 110 °C
for 17 h to give tribenzylamine (21%) and dibenzylamine (15%), supporting
the possible mechanism.
a The reaction was carried out with NH4BF4 (1.0 mmol), alcohol (3.0
mmol), [Cp*IrCl2]2 (3.0 mol % Ir), and NaHCO3 (30 mol %). b Isolated
yield (GC yield in parentheses). c A mixture of diastereomers. d NH4OAc
1
was used instead of NH4BF4. e Meso/dl ) 62:38 by H NMR.
Furthermore, this catalytic system for facile formation of
secondary amines can be extended to the one-pot synthesis
(13) The reactions of other ammonium salts such as NH4PF6 and NH4-
SO3CF3 gave trace amount of the product.
Org. Lett., Vol. 10, No. 2, 2008
183

of cyclic amines from an ammonium salt and diols.14 Thus,
the reactions of ammonium tetrafluoroborate with 1-phenyl-
1,5-pentanediol and 1-phenyl-1,4-butanediol afford 2-phe-
nylpiperidine and 2-phenylpyrrolidine in 85% and 62%
yields, respectively (Scheme 3).
nol (1 equiv) under the similar conditions as above
(Scheme 5). There-action of hexylammonium acetate with
Scheme 5
Scheme 3
1-hexanol gave trihexylamine predominantly, indicating that
the reaction did not stop at the dialkyaltion step B, probably
due to relatively weak acidity of acetic acid. On the other
hand, the same reaction of hexylammonium tetrafluorobofrate
afforded dihexylamine selectively, demonstrating that the
reaction did stop at step B, probably due to stronger acidity
of tetrafluoroboric acid. Thus, acidity of a counter acid of
an ammonium salt might be one of the factors responsible
for the present selectivity.15
While the precise reason for the present selectivity has
not been clear yet, we have assumed the following equilib-
riums between produced amines and their salts and that the
N-alkylation could occur toward free amines (Scheme 4).
In summary, we have developed a new atom-economical
catalytic system for the selective synthesis of secondary and
tertiary amines by means of Cp*Ir-catalyzed multi-alkylation
of ammonium salts with alcohols without solvent. Further-
more, this catalytic system can be extended to the efficient
one-pot synthesis of cyclic amines from ammonium tet-
rafluoroborate and diols.
Scheme 4
Acknowledgment. This work was supported by KA-
KENHI (No. 19550106).
According to the assumption, we have carried out
the reactions of hexylammonium salts with 1-hexa-
Supporting Information Available: General experimen-
tal procedures and characterization data of products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) We have reported the Cp*Ir-catalyzed synthesis of cyclic tertiary
amines by the reaction of primary amines with diols. See: (a) Fujita, K.;
Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525. (b) Fujita, K.; Enoki,
Y.; Yamaguchi, R. Org. Synth. 2006, 83, 217.
(15) We have not succeeded in selective synthesis of primary amines
yet.
OL702522K
184
Org. Lett., Vol. 10, No. 2, 2008