Selective alkylation of (Hetero)aromatic amines with alcohols catalyzed by a ruthenium pincer complex

Article abstract of DOI:10.1021/ol3001969

A readily available pincer ruthenium(II) complex catalyzes the selective monoalkylation of (hetero)aromatic amines with a wide range of primary alcohols (including pyridine-, furan-, and thiophene-substituted alcohols) with high efficiency when used in low catalyst loadings (1 mol %). Tertiary amine formation via polyalkylation does not occur, making this ruthenium system an excellent catalyst for the synthesis of sec-amines.

Full text of DOI:10.1021/ol3001969

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1456–1459
Selective Alkylation of (Hetero)Aromatic
Amines with Alcohols Catalyzed by a
Ruthenium Pincer Complex
ꢀ
Santosh Agrawal, Maud Lenormand, and Belen Martın-Matute*
´
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University,
SE 106 91 Stockholm, Sweden
belen@organ.su.se
Received January 25, 2012
ABSTRACT
A readily available pincer ruthenium(II) complex catalyzes the selective monoalkylation of (hetero)aromatic amines with a wide range of primary
alcohols (including pyridine-, furan-, and thiophene-substituted alcohols) with high efficiency when used in low catalyst loadings (1 mol %).
Tertiary amine formation via polyalkylation does not occur, making this ruthenium system an excellent catalyst for the synthesis of sec-amines.
Aromatic amines are important building blocks used in
the synthesis of a wide range of pharmaceuticals, agro-
chemicals and bioactive molecules.1 They also play an
important role in organometallic and coordination che-
mistry.2 The alkylation of amines with alcohols to give
higher order amines and water as sole byproduct is a very
attractiveand environmentally friendlyalternative toother
methods, such as alkylation of amines by alkyl halides under
basic conditions,3 hydroamination of alkenes4 or reductive
amination of carbonyl compounds.5 The principle govern-
ing the use of alcohols as alkylating reagents involves their
oxidation by a transition metal complex; after in situ
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r
10.1021/ol3001969
Published on Web 02/27/2012
2012 American Chemical Society

reaction with an amine, the imine formed is reduced by the
transition metal hydride formed in the first step, yielding a
higher order amine.6 Since the early 80s, transition metal
complexes,7ꢀ18 in particular iridium and ruthenium, have
been shown to be active for this transformation. We have
recently used this method to synthesize nitrogen-containing
pseudodisaccharides.16 In general, iridium8e,13,14,18 complexes
are more reactive than ruthenium-based catalysts, making
possible the use of iridium loadings as low as 0.1 mol %.18e
Recently, Williams, Beller and co-workers8f were able
to obtain good yields in the N-alkylation of indoles by using
0.2ꢀ0.5 mol % of the dimeric Shvo’s ruthenium catalyst
(0.4ꢀ1 mol % Ru) at 110 °C. Also, Madsen and co-workers
reported an elegant synthesis of substituted indoles using
readily available RuCl3 (1 mol %) at 170 °C.15b Williams
also reported that small loadings of [Ru(p-cymene)Cl2]2
(1 mol % Ru) afford excellent results in the N-alkylation
of sec-amines, forming tert-amines.8c
Figure 1. CNN-Ruthenium complexes 1 and 2.
neither 1 nor the methylated derivative complex 2 have been
used in the reduction of imines. Here, we communicate that
the readily available Ru(II)-CNN pincer complex 2(Figure1)
is, however, an excellent catalyst for the alkylation of
amines by alcohols, which is thought to proceed by reduction
of imine intermediates. Ruthenium complex 2 catalyzes the
alkylation of anilines and heteroaromatic amines by alcohols
(including pyridine-, furan-, and thiophene-substituted
alcohols) with high efficiency, using low catalyst loadings
(1 mol %). A large substrate scope is demonstrated, and
products derived from polyalkylation are not detected,
making this ruthenium system an excellent catalyst for the
synthesis of sec-amines.
Aniline (3a) and benzyl alcohol (4) were chosen as model
substrates. In the presence of K2CO3 (30 mol %), neither 1
nor 2 (2.5 mol %) afforded the desired product in good
yield. However, when KOt-Bu was used instead of K2CO3,
complex 2 catalyzed the formation of amine 5 in excellent
yield, while only moderate yields were obtained with 1.
This is in high contrast with the results obtained by Baratta
and co-workers, who found complex 1 to be significantly
more reactive than 2 in the reduction of ketones under
hydrogen transfer conditions.19 Further optimization al-
lowed us to use catalyst loadings as low as 1 mol % when
combined with stoichiometric amounts of KOt-Bu
(Scheme 1a, and Table S1, Supporting Information).
Similarly, 2-amino pyridine 6a gave the corresponding
alkylated amine (7) in quantitative yield (91% isolated,
Scheme 1b). In all cases, higher yields were obtained when
MS 4 A were added to the reaction mixture.
Having established the optimal reaction conditions we
turned our attention to the use of a ferrocenyl-substituted
alcohol (8) as alkylating reagent. Quantitative yields of the
corresponding sec-amines were obtained from a range of
substituted anilines (3aꢀf) as well as heteroaromatic amines
(6aꢀc) with different electronic properties (Scheme 2). The
secondary amines obtained (9aꢀf, 10aꢀc) were isolated in
good to excellent yields.
The catalyst system [Ru 2 (1 mol %)/KOt-Bu] is highly
selective and yielded monoalkylated products exclusively,
even when excess of alcohol was used (see Supporting
Information). Hence, it was of interest to explore whether
diamines could be N,N0-dialkylated (i.e., introduction of
one substituent on each nitrogen). Few reports on the
synthesis of such types of compounds are available in the
literature,20 and most of them yield a mixture of products
Baratta and co-workers have communicated that Ru-
(II)-CNN (C = carbon; N = nitrogen) pincer complex 1
affords impressive TONs (1.7 ꢁ 105) in the reduction of
ketones under hydrogen transfer conditions.19 However,
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Org. Lett., Vol. 14, No. 6, 2012
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Scheme 1. Ru (2) Catalyzed Alkylation of 3a and 6a by Alcohol 4a
Scheme 3. Selective Mono N,N0-Dialkylation of 11a
a Isolated yields.
a Isolated yields.
Scheme 2. N-Alkylation of Anilines and Heteroaromatic Aminesa
Table 1. N-Alkylation of 3a and 6a by Heteroaromatic Alcohols
14ꢀ16a
a Isolated yields.
due to mono, di, tri and tetra-alkylation. When 2,6-
diamino pyridine 11 was treated with either alcohol 4 or
8 (2 equiv) in the presence of complex 2 (1 mol %) and
KOt-Bu (1 equiv), N,N0-dialkylation took place exclu-
sively, affording diamines 12 and 13, respectively, in ex-
cellent yields (Scheme 3). Interestingly, although two CꢀN
bonds are formed, the catalyst loading could be kept as low as
1 mol %.
a All reactions were carried out using Ru (2, 4 mg, 1 mol %), amine
(0.5 mmol), alcohol (0.5 mmol), MS 4 A, KOt-Bu (0.5 M in THF, 1 mL,
0.5 mmol) in dry toluene (0.5 mL), 24 h, 110 °C. b Isolated yield.
The use of heteroaromatic alcohols as latent electro-
philes is also a challenging goal. Kempe and co-workers18a
have reported that their iridium-based catalyst afforded
from moderate to low yields of higher order amines when
using alcohols such as furfuryl alcohol (14) or 2-thiophene-
methanol (15). Ruthenium complex 2 is highly active when
heteroaromatic alcohols are used as alkylating reagents.
Table 1 shows the results obtained in the N-alkylation of
aniline 3a and heteroaromatic amine 6a by heteroaromatic
alcohols [i.e., furfuryl alcohol (14), 2-thiophenemethanol (15)
and 2-pyridinemethanol (16)] using 1 mol % of Ru com-
plex 2. The sec-amines obtained were isolated in good
yields (71ꢀ86%).
We also tested the alkylation of amines such as benzy-
lamine and hexylamine under the optimized reaction con-
ditions. However, these substrates afforded the products in
trace amounts. Neither the use of amines that cannot be
oxidized to imines (e.g., 1-tert-octylamine) gave the desired
product (see Supporting Information, Table S2). On
the other hand, the lack of reactivity of aliphatic amines
under the reaction conditions opens the possibility of using
aliphatic amino alcohols18c (20ꢀ22) as alkylating reagents.
(20) (a) Sprinzak, Y. J. Am. Chem. Soc. 1956, 78, 3207. (b) Sibert,
J. W.; Hundt, G. R.; Sargent, A. L.; Lynch, V. Tetrahedron 2005, 61,
ꢁ
ꢀ
12350. (c) Margalef-Catala, R.; Claver, C.; Salagre, P.; Fernandez, E.
Tetrahedron Lett. 2000, 41, 6583.
1458
Org. Lett., Vol. 14, No. 6, 2012

excellent yield (Table 2, entry 1). Branched amino alcohols
21 and 22 also afforded excellent yields (entries 2ꢀ3). The
reaction was also successful for the N-alkylation of hetero-
aromatic amine 6a with amino alcohols 20ꢀ22 (Table 2,
entries 4ꢀ6).
Table 2. N-Alkylation of 3a and 6a by Heteroaromatic Alcohols
14ꢀ16a
In conclusion, ruthenium 2 is able to achieve excellent
results, and can be compared with those obtained with
the highly reactive iridium catalysts under homogeneous
conditions in the alkylation of amines with alcohols.
(Hetero)aromatic amines could be alkylated with alco-
hols, such as ferrocenyl methanol, heteroaromatic alco-
hols and amino alcohols. Furthermore, selective N,N0-
dialkylation occurred when aromatic diamines were
subjected to the reaction conditions. In this way, struc-
tural variants of N-substituted aminoferrocenes, N,N0-
dialkylamines and N-arylated diamines can be synthe-
sized selectively in excellent yields. We are currently
investigating the mechanism and our results will be
communicated in due course.
Acknowledgment. Financial support from the Swedish
Research Council (Vetenskapsradet), the Wenner-Gren
Foundation, the Swedish Governmental Agency for In-
novation Systems (VINNOVA), and the Berzelii Center
EXSELENT is gratefully acknowledged. We thank Prof.
W. Baratta (Dipartimento di Chimica, Fisica e Ambiente,
ꢁ
Universita di Udine, Via Cotonificio 108, I-33100, Udine,
Italy) for helpful discussions.
a All reactions were carried out using Ru (2, 4 mg, 1 mol %), amine
(0.5 mmol), amino alcohol (0.5 mmol), MS 4 A, KOt-Bu (0.5 M in THF,
1 mL, 0.5 mmol) in dry toluene (0.5 mL) for 24 h at 110 °C. b Isolated yield.
Supporting Information Available. Detailed experi-
mental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Indeed, reaction of aniline 3a with amino alcohol 20
afforded N-arylated diamine 23a, which was isolated in
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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