Formation of tertiary amides and dihydrogen by dehydrogenative coupling of primary alcohols with secondary amines catalyzed by ruthenium bipyridine-based pincer complexes

Article abstract of DOI:10.1002/adsc.201300620

Dehydrogenative coupling of primary alcohols with secondary amines to form tertiary amides and dihydrogen (H₂) is efficiently catalyzed by bipyridyl-based ruthenium pincer complexes (0.2-1 mol%) under neutral conditions (in case of the dearomatized complexes), or with added catalytic amount of base. The reaction is sensitive to steric hindrance; in the case of amidation of bulky secondary amines a less sterically hindered complex is more efficient. Selective acylation of primary amines in the presence of secondary amines was also demonstrated. Copyright

Full text of DOI:10.1002/adsc.201300620

COMMUNICATIONS
DOI: 10.1002/adsc.201300620
Formation of Tertiary Amides and Dihydrogen by
Dehydrogenative Coupling of Primary Alcohols with
Secondary Amines Catalyzed by Ruthenium Bipyridine-Based
Pincer Complexes
Dipankar Srimani,a Ekambaram Balaraman,a,b Peng Hu,a Yehoshoa Ben-David,a
and David Milsteina,*
a
Department of Organic Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel
Fax : (+972)-8-934-6569; e-mail: david.milstein@weizmann.ac.il
Present address: Catalysis Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune – 411008, India
b
Received: July 16, 2013; Published online: && &&, 0000
This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the 40th anniversary of the Mukaiya-
ma aldol rection.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300620.
Abstract: Dehydrogenative coupling of primary al-
cohols with secondary amines to form tertiary
amides and dihydrogen (H2) is efficiently catalyzed
by bipyridyl-based ruthenium pincer complexes
(0.2–1 mol%) under neutral conditions (in case of
the dearomatized complexes), or with added cata-
lytic amount of base. The reaction is sensitive to
steric hindrance; in the case of amidation of bulky
secondary amines a less sterically hindered complex
is more efficient. Selective acylation of primary
amines in the presence of secondary amines was
also demonstrated.
Figure 1. PNN- and PNP-type ruthenium pincer complexes.
Keywords: alcohols; amidation; amines; dehydro-
genation; oxidative coupling; ruthenium pincer
complexes
lyzed by 0.1 mol% of the ruthenium pincer complex
4[4] (Figure 1); this reaction has been used in the prep-
aration of polyamides by Guan and co-workers[5a] and
by us[5b] and in the preparation of peptides.[5c] Follow-
ing publication of our work, examples of acceptorless
Amide bond formation is one of the most fundamen- amide formation by other ruthenium catalysts were
tal reactions in organic chemistry because of its wide- reported, although using higher catalyst loading (2.5–
spread occurrence in peptides, polymers and many 5 mol%).[6] In our initial report,[4] diethylenetriamine,
natural products and pharmaceuticals.[1] The conven- having both primary and secondary amine groups, un-
tional approach for the synthesis of amides is the cou- derwent selective acylation at the primary amine
pling of activated carboxylic acid derivatives with groups; this turned out to be an advantage in the
amines.[2] Alternative approaches of amide synthesis preparation of polyamides bearing free secondary
were reported;[3] however, most of these methods re- amine groups in the backbone, as reported by Guan
quire an equimolar amount of various reagents and and co-workers.[5a] We now report the dehydrogena-
often produce toxic chemical waste with tedious asso- tive coupling of secondary amines with alcohols, to
ciated procedures. In 2007, we reported a new reac- form tertiary amides, using 0.2–1 mol% of Ru pincer
tion, namely the coupling of alcohols and amines to catalyst. Such a reaction using 5 mol% of N-heterocy-
form amides and H2, with no waste, efficiently cata- clic carbine (NHC) Ru complex and 15–35 mol%
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Dipankar Srimani et al.
COMMUNICATIONS
yl)ethanACTHNUTRGNEUGoN ne in 88% isolated yield (Table 1, entry 2).
Studying the scope of this reaction with regard to acy-
clic secondary amines, the reaction of 2-methoxyetha-
nol with N-benzylmethylamine in the presence of
0.2 mol% of 5 resulted after 24 h reflux in toluene in
the formation of N-benzyl-2-methoxymethylacet-
Scheme 1. Dehydrogenative coupling of primary alcohols
with secondary amines.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
recently Glorious and co-workers reported the dehy- the catalyst loading from 0.2 to 0.4 mol%, increased
drogenative coupling of primary and secondary the yield of the desired amide to 93% (Table 1,
amines with methanol to generate formamides cata- entry 4). The same trend was also observed with the
lyzed by a ruthenium-NHC complex.[7c]
reaction of 1-hexanol and N-methylbenzylamine
Our group has demonstrated several environmen- (Table 1, entries 5 and 6). Considering the steric effect
tally benign, atom economical, sustainable reactions, in the amidation reaction, we prepared a less bulky
catalyzed by pincer complexes of ruthenium based on ligand, replacing the two tert-butyl groups by phenyl
pyridine[4,5b,c,8] and acridine[9] backbones. Recently we groups. The hydrido chloride pincer complex 3 was
have developed dearomatized bipyridine-based prepared by reaction of the new tridentate ligand, 6-
Ru(II)pincer complex 5 (Figure 1) and explored its diphenylphosphinomethyl-2,2’-bipyridine
catalytic activity[10] toward the hydrogenation of ami- [BPy(Ph)PNN] (see the Supporting Information for
des,[10a] biomass-derived cyclic diesters,[10b] and urea its preparation) with [RuHCl
ACHTNUTRGNEG(UN PPh3)3(CO)] in THF at
derivatives[10c] as well as organic carbonates, carba- 658C for 12 h, resulting in substitution of the PPh3 li-
mates and formates.[10d] The parent hydrido chloride gands to yield the fully characterized complex 3. This
pincer complex 2 catalyzes in the presence of catalytic complex gives rise to a singlet at 69.44 ppm in the
base (in situ generation of complex 5) several unique 31P{1H} NMR spectrum, and the hydride ligand ap-
environmentally benign reactions including the dehy- pears as a doublet at À14.09 ppm (2JP, H =25.5 Hz) in
1
drogenative transformation of alcohols to carboxylic the H NMR spectrum. The “arm” methylene protons
acid salts using water as the oxygen atom source,[10e] appear as a multiplet in the region of 4.38–4.50 ppm.
dehydrogenative cross-esterification reaction between The carbonyl ligand appears as
a doublet at
primary and secondary alcohols,[10f] direct synthesis of 206.5 ppm (JP, C =7.5 Hz) in the 13C{1H} NMR spec-
pyrroles, pyridines and quinoline by dehydrogenative trum. We believe that the corresponding dearomat-
coupling of amino alcohols with secondary alco- ized complex was generated in situ, by the reaction of
hols,[10g,h] catalytic deuteration of a and b-CH bonds catalyst 3 and 1.1 equivalents of KO-t-Bu, in analogy
of primary and secondary alcohols[10i] and catalytic to complexes 4 and 5 which were generated from
coupling of nitriles with amines to selectively form complexes 1 and 2, respectively, by the treatment with
imines under mild hydrogen pressure.[10j]
an equimolar amount of base.[8a,10a] Employing com-
Herein we communicate the dehydrogenative cou- plex 3 in the amidation reaction, a toluene solution
pling of primary alcohols with secondary amines cata- containing 1-hexanol (5 mmol), N-methylbenzylamine
lyzed by bipyridine-based pincer complexes under (5.5 mmol), 0.01 mmol of complex 3 and 0.011 mmol
mild conditions (Scheme 1).
of KO-t-Bu was refluxed for 24 h under an argon at-
Exploring the feasibility of the amidation reaction mosphere, resulting in complete consumption of 1-
with secondary amines and primary alcohols we ini- hexanol as observed by GC and GC-MS, forming N-
tially examined the reaction of the sterically non-hin- benzyl-N-methylhexanamide in 86% yield (Table 1,
dered amine N-methylpiperazine with alcohols. Thus, entry 7). To our delight, the phenyl complex (3)
when
a
toluene solution containing 1-hexanol showed excellent catalytic activity even with a low
(5 mmol), N-methylpiperazine (5.5 mmol) and catalyst loading (0.2 mol%), which is substantially
0.01 mmol of complex 5[11] was refluxed for 24 h lower than in the previously reported procedure by
under an argon atmosphere, complete consumption of Hong et al (5 mol%).[7a] Crabtree et al. reported the
1-hexanol took place and the product 1-(4-methylpi- dehydrogenative coupling of piperidine (6-fold
perazin-1-yl)hexan-1-one was obtained in 99% yield excess) with benzyl alcohol and with 1-phenethanol
as indicated by GC and confirmed by GC-MS forming the corresponding amides in 89% and 55%
(Table 1, entry 1). The pure amide was isolated in yields, respectively, using
90% yield by chromatographic purification. Encour- (4 mol%) and KOH (15 mol%).[7b]
aged by this result we reacted 2-methoxyethanol Studying the scope of this reaction with regard to
under the same conditions. Thus, refluxing 2-methoxy- other acyclic secondary amines, the reaction of 1-hex-
ethanol and N-methylpiperazine in the presence of anol with N-methylbutylamine in the presence of
0.2 mol% complex 5 gave quantitative formation of 0.5 mol% of catalyst 3 and 0.55 mol% KO-t-Bu result-
a diamine-Ru catalyst
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
the
desired
2-methoxy-1-(4-methylpiperazin-1- ed after 12 h reflux in toluene in the formation of the
2
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Formation of Tertiary Amides and Dihydrogen by Dehydrogenative Coupling of Primary Alcohols
Table 1. Direct synthesis of tertiary amides from primary alcohols and secondary amines catalyzed by Ru-bipyridine
pincer complexes.[a,b]
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Dipankar Srimani et al.
COMMUNICATIONS
[a]
Complex (0.2–1 mol%), primary alcohol (5 mmol), secondary amine (5.5 mmol) and toluene (2 mL) were re-
fluxed under argon.
[b]
The dearomatized complexes 4, 5[11] or a mixture of equivalent catalytic amounts of complex 3 and KO-t-Bu
were used.
[c]
[d]
[e]
[f]
Yields of products were determined by GC using m-xylene as an internal standard.
Isolated yields after purification.
1.5 equiv. of amine were used (with respect to the alcohol).
1ꢁ-Hexanol was completely converted to hexyl hexanoate while the dibenzylamine remained unchanged.
desired amide in 35% yield and the rest of the alcohol zin-1-yl)butan-1-one in 56% yield together with 44%
was converted to hexyl hexanoate, while under the yield of hexyl hexanoate (Table 1, entry 12). On in-
same conditions complex 4 gave a somewhat lower creasing the bulkiness of both the alcohol and the
yield (25%), together with 75% of hexyl hexanoate amine, the reaction of 2-methylbutanol and N-methyl-
(Table 1, entries 8 and 9). Using 1 mol% of catalyst 3 benzylamine catalyzed by 1 mol% complex 3 and
and 1.1 mol% KO-t-Bu for 24 h the yield of desired 1.1 mol% KO-t-Bu gave a 50% yield of the desired
amide was further improved to 88% (Table 1, amide.
entry 10).
It was of interest to us to explore the reactivity and
Expanding the scope of the reaction with respect to selectivity difference between primary and secondary
more bulky secondary amines, a toluene solution con- amines in the dehydrogenative amidation with pri-
taining N-ethylbenzylamine, 1-hexanol, 1 mol% cata- mary alcohols (Scheme 2). For this purpose, 1-hexanol
lyst 3 and 1.1 mol% KO-t-Bu was refluxed for 24 h re- (1 equiv.) was reacted with a toluene solution contain-
sulting in 55% yield of N-benzyl-N-ethylhexanamide ing 1-heptylamine (2 equiv.), N-methylpiperazine
together with 45% of hexyl hexanoate (Table 1, (2 equiv.), 0.2 mol% of catalyst 2 and 0.22 mol%
entry 11). Retardation of the amidation reaction is af- KO-t-Bu or a mixture of 0.2 mol% catalyst 3 and
fected not only by the steric bulk of the amine group, 0.22 mol% KO-t-Bu. After 24 h reflux in toluene, N-
but also by a substituent at the b-position of the alco- heptylhexanamide and 1-(4-methylpiperazin-1-yl)hex-
hol. Thus, the reaction between 2-methyl-1-butanol an-1-one were formed in a ratio of 63:37 and 60:40,
and N-methylpiperazine using 1 mol% catalyst 3 and respectively, with the complete consumption of 1-hex-
1.1 mol% KO-t-Bu gave 2-methyl-1-(4-methylpipera- anol, as indicated by GC and GC-MS. Refluxing a tol-
Scheme 2. Competitive amidation reactions between primary and secondary amines in reactions with 1-hexanol.
4
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Formation of Tertiary Amides and Dihydrogen by Dehydrogenative Coupling of Primary Alcohols
uene solution containing 1-hexanol (1 equiv.), 1-hep- Acknowledgements
tylamine (2 equiv.) and N-ethylbenzylamine (2 equiv.)
This research was supported by the European Research
with 0.2 mol% of catalyst 2 and 0.22 mol% KO-t-Bu
or a mixture of 0.2 mol% catalyst 3 and 0.22 mol%
KO-t-Bu gave 95:5 or 94:6 mixtures of N-heptylhexa-
namide and N-benzyl-N-ethylhexanamide, respective-
ly. Similarly under the same conditions 1-hexanol
(1 equiv.), 1-heptylamine (2 equiv.) and N-methylbu-
tylamine (2 equiv.) gave selectively N-heptylhexan-
Council under the FP7 framework (ERC No 246837), by the
Israel Science Foundation, by the Helen and Martin Kimmel
Center for Molecular Design and by the Bernice and Peter
Cohn Catalysis Research Fund. D.M. has the Israel Matz
Professorial Chair of Organic Chemistry.
ACHTUNGTRENNUNG
References
(Scheme 2), the less bulky primary amine reacts faster
than the cyclic secondary amine, and almost complete
selectivity to primary amide formation is obtained in
the reaction of 1:1 mixtures of linear primary and sec-
ondary amines.
[1] a) T. Cupido, J. Tulla-Puche, J. Spengler, F. Albericio,
Curr. Opin. Drug Discovery Dev. 2007, 10, 768; b) J. W.
Bode, Curr. Opin. Drug Discovery Dev. 2006, 9, 765;
c) J. M. Humphrey, A. R. Chamberlin, Chem. Rev.
1997, 97, 2243.
A possible catalytic cycle for the amidation of pri-
mary alcohol and secondary amines involves O H ac-
[2] a) R. C. Larock, Comprehensive Organic Transforma-
tions, VCH, New York, 1999; b) S.-Y. Han, Y.-A. Kim,
Tetrahedron 2004, 60, 2447.
[3] For recent reviews, see: a) C. A. G. N. Montalbetti, V.
Falque, Tetrahedron 2005, 61, 10827; b) E. Valeur, M.
Bradley, Chem. Soc. Rev. 2009, 38, 606; c) V. R Patta-
biraman, J. W. Bode, Nature 2011, 480, 471; d) S. Lang,
J. A. Murphy, Chem. Soc. Rev. 2006, 35, 146.
À
tivation of the primary alcohol followed by H2 elimi-
nation to give an intermediate aldehyde, which forms
a hemiaminal by reaction with the secondary amine.
Dehydrogenation of the hemiaminal yields the amide.
The self-esterification product of the primary alcohol,
if formed, can be converted to the desired amide by
reaction of the ester with the amines.[8b]
[4] C. Gunanathan, Y. Ben-David, D. Milstein, Science
2007, 317, 790.
In conclusion, an efficient approach for the synthe-
sis of tertiary amides by the direct amidation of alco-
hols with challenging secondary amines was devel-
oped with a well-defined PNN-bipyridyl ruthenium
complex, using a catalyst loading as low as 0.2%. In
the case of amidation of sterically hindered secondary
amines involvement of ester intermediates was ob-
served.
[5] a) H. Zeng, Z. Guan, J. Am. Chem. Soc. 2011, 133,
1159; b) B. Gnanaprakasam, E. Balaraman, C. Gunana-
than, D. Milstein, J. Poly. Sci. Part A: Polymer Chem.
2012, 50, 1755; c) B. Gnanaprakasam, E. Balaraman, Y.
Ben-David, D. Milstein, Angew. Chem. 2011, 123,
12448; Angew. Chem. Int. Ed. 2011, 50, 12240.
[6] a) L. U. Nordstrøm, H. Vogt, R. Madsen, J. Am. Chem.
Soc. 2008, 130, 17672; b) J. H. Dam, G. Osztrovszky,
L. U. Nordstrøm, R. Madsen, Chem. Eur. J. 2010, 16,
6820; c) S. Muthaiah, S. C. Ghosh, J.-E. Jee, C. Chen, J.
Zhang, S. H. Hong, J. Org. Chem. 2010, 75, 3002;
d) A. J. A. Watson, A. C. Maxwell, J. M. J. Williams,
Org. Lett. 2009, 11, 2667.
Experimental Section
[7] a) C. Chen, Y. Zhang, S. H. Hong, J. Org. Chem. 2011,
76, 10005; b) N. D. Schley, G. E. Dobereiner, R. H.
Crabtree, Organometallics 2011, 30, 4174; c) N. Ortega,
C. Richter, F. Glorius, Org. Lett. 2013, 15, 1776.
[8] a) C. Gunanathan, D. Milstein, Acc. Chem. Res. 2011,
44, 588; b) B. Gnanaprakasam, D. Milstein, J. Am.
Chem. Soc. 2011, 133, 1682; c) C. Gunanathan, D. Mil-
stein, Science 2013, 341, DOI: 10.1126/science.1229712.
[9] a) C. Gunanathan, L. J. W. Shimon, D. Milstein, J. Am.
Chem. Soc. 2009, 131, 3146; b) C. Gunanathan, D. Mil-
stein, Angew. Chem. 2008, 120, 8789; Angew. Chem.
Int. Ed. 2008, 47, 8661; c) J. R. Khusnutdinova, Y. Ben-
David, D. Milstein, Angew. Chem. 2013, 125, 6389;
Angew. Chem. Int. Ed. 2013, 52, 6269.
[10] a) E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon,
D. Milstein, J. Am. Chem. Soc. 2010, 132, 16756; b) E.
Balaraman, E. Fogler, D. Milstein, Chem. Commun.
2012, 48, 1111; c) E. Balaraman, Y. Ben-David, D. Mil-
stein, Angew. Chem. 2011, 123, 11906; Angew. Chem.
Int. Ed. 2011, 50, 11702; d) E. Balaraman, C. Gunana-
than, J. Zhang, L. J. W. Shimon, D. Milstein, Nat.
Chem. 2011, 3, 609; e) E. Balaraman, E. Khaskin, G.
General Procedure for the Amidation Reaction
Complex 3 (0.01 mmol), KO-t-Bu (0.011 mmol) primary al-
cohol (5 mmol), secondary amine (5.5 mmol) and toluene
(2 mL) were added to a Schlenk flask under an atmosphere
of nitrogen in a Vacuum Atmospheres glovebox. The flask
was equipped with a condenser and the solution was re-
fluxed with stirring in an open system under argon for the
specified time (Table 1) at 1358C (oil bath temperature).
The reaction products were analyzed by GC-MS. After cool-
ing to room temperature, m-xylene (1 mmol) was added as
an internal standard to the reaction mixture and the prod-
ucts were quantitatively analyzed by GC using a Carboxen
1000 column on an HP690 series GC system or HP-5 cross
linked 5% PH ME Siloxane column (30 m, 0.32 mm,
0.25 mm film thickness) on an HP 6890 series GC system.
Pure amides were isolated by silica gel chromatography.
Characterization data are available in the Supporting Infor-
mation.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Dipankar Srimani et al.
COMMUNICATIONS
Leitus, D. Milstein, Nat. Chem. 2013, 5, 122; f) D. Sri-
mani, E. Balaraman, B. Ganaprakasam, Y. Ben-David,
D. Milstein, Adv. Synth. Catal. 2012, 354, 2403; g) D.
Srimani, Y. Ben-David, D. Milstein, Angew. Chem.
2013, 125, 4104; Angew. Chem. Int. Ed. 2013, 52, 4012;
h) D. Srimani, Y. Ben-David, D. Milstein, Chem.
Commun. 2013, 49, 6632; i) E. Khaskin, D. Milstein,
ACS Catal. 2013, 3, 448; j) D. Srimani, M. Feller, Y.
Ben-David, D. Milstein, Chem. Commun. 2012, 48,
11853.
[11] The reaction was performed using complex 5 as cata-
lyst, or the catalyst was generated in situ by use of
a mixture of complex 2 and 1.1 equiv. KO-t-Bu. Both
gave the same yield of the desired amide.
6
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
Formation of Tertiary Amides and Dihydrogen by
Dehydrogenative Coupling of Primary Alcohols with
Secondary Amines Catalyzed by Ruthenium Bipyridine-
Based Pincer Complexes
7
Adv. Synth. Catal. 2013, 355, 1 – 7
Dipankar Srimani, Ekambaram Balaraman, Peng Hu,
Yehoshoa Ben-David, David Milstein*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!