Dehydrogenative amide synthesis: Azide as a nitrogen source

Article abstract of DOI:10.1021/ol302915g

A new atom-economical strategy to amide linkage from an azide and alcohol liberating hydrogen and nitrogen was developed with an in situ generated ruthenium catalytic system. The reaction has broad substrate generality including diols for the synthesis of cyclic imides.

Full text of DOI:10.1021/ol302915g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Dehydrogenative Amide Synthesis: Azide
as a Nitrogen Source
Zhenqian Fu,‡,§ Jeongbin Lee,†,§ Byungjoon Kang,† and Soon Hyeok Hong*,†
Center for Nanoparticle Research, Institute for Basic Science, and Department
of Chemistry, College of Natural Sciences, Seoul National University,
Seoul 151-747, Korea, and Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
soonhong@snu.ac.kr
Received October 23, 2012
ABSTRACT
A new atom-economical strategy to amide linkage from an azide and alcohol liberating hydrogen and nitrogen was developed with an in situ
generated ruthenium catalytic system. The reaction has broad substrate generality including diols for the synthesis of cyclic imides.
Atom-economical amide synthesis is one of the top
challenges in synthetic organic chemistry.1 The amide bond
is the key backbone of all natural peptides in biological
systems and is also a favorable functional group in all
branches of organic chemistry.2 Traditionally, amides have
been synthesized by reactions of carboxylic acids and their
derivatives with amines,3 which suffers from harsh conditions
and a large amount of byproduct. Over the past few years,
chemists have extensively addressed new methodologies to
amide linkage, aiming at a more efficient and environmentally
benign pathway. Interesting approaches include native chemi-
cal ligation;4 oxidative amidation of alcohols,5,9 aldehydes,6 or
alkynes;7 and oxidative coupling of an R-bromonitroalkane8
(Scheme 1). All these systems utilize amine, mostly primary
amine, as an “N” atom source of amide.
During our studies on the atom-economical and envi-
ronmentally benign amidation from an alcohol with an
amine prompted by a ruthenium catalytic system,9 we en-
visioned that amidation of alcohols could be achieved with
azides in place of amines. Herein, we report an in situ
generated catalyst based on RuH2(PPh3)4 for the direct
amide synthesis from azide and alcohol. To the best of our
knowledge, this is the first example of a transition-metal-
based catalytic system that transforms an azide and alcohol
directly into an amide in a single step.
† Seoul National University.
‡ Nanyang Technological University.
§ These authors contributed equally to this work.
(1) (a) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey,
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The reaction of 2-phenylethanol (1a) and benzyl azide
(2a) was chosen to investigate the catalytic conditions to
realize the amidation of an alcohol with an azide (Table 1).
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W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064. (c) Tamaru, Y.;
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r
10.1021/ol302915g
XXXX American Chemical Society

Table 1. Catalyst Screeninga
Scheme 1. Different Strategies of Amide Synthesis
time
(h)
yield
(%)b
entry
2a/1a
[Ru]
1
1.1
[Ru(benzene)Cl2]2
[Ru(p-cymene)Cl2]2
RuCl3
Shvo’s complexc
RuH2(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuH2(PPh3)4
24
24
24
24
24
24
24
48
48
48
48
48
0
2
1.1
<5
<5
<5
23
29
33
73
78
84
76
100
3
1.1
4
1.1
5
1.1
6
1.1
7
1.1
8
1.1
RuH2(PPh3)4
9
1.5
RuH2(PPh3)4
10
11
12
2.0
RuH2(PPh3)4
1:1.1
1:1.2
RuH2(PPh3)4
RuH2(PPh3)4
a Reaction conditions: 2a (0.5 mmol scale), 1a, Ru complex (5 mol %), 4
(5mol%),NaH(20mol%), CH3CN(5mol%),toluene(0.6mL), reflux, 48
h. b Yields were determined by GC using dodecane as an internal standard.
c Shvo’s complex = (1-hydroxytetraphenyl cyclopentadienyl-(tetraphenyl-
2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II)
A series of ruthenium complexes with the help of the
N-heterocyclic carbene (NHC) ligand generated from
1,3-diisopropylimidazolium bromide (4) and NaH, well-
known catalysts for the oxidative amide synthesis from
alcohols,9 were selected as the precatalyst complexes. The
role of NaH has been suggested to activate the precata-
lyst as well as to generate the NHC ligand from 4.9 The
[Ru(benzene)Cl2]2-based catalyst did not exhibit any
activity for the target reaction (Table 1, entry 1). A trace
amount of amide was detected with catalytic systems
using [Ru(p-cymene)Cl2]2, RuCl3, and Shvo’s complex
(Table 1, entries 2ꢀ4). Then we noticed that several
ruthenium hydride complexes exhibited improved activ-
ities (Table 1, entries 5ꢀ7). Among them, RuH2(PPh3)4
displayed the best activity for this transformation. The
desired amide product 3aa was obtained in 33% yield for 24
h (Table 1, entry 7). When the reaction time was prolonged
to 48 h, the yield of amide 3aa reached up to 73% (Table 1,
entry 8). The reaction efficiency was sensitive to the ratio of
azide and alcohol. We found that the reaction with a slightly
higher amount of alcohol 1a than that of 2a (2a:1a = 1:1.2)
provided the amide product 3aa in quantitative GC yield and
92% isolated yield (Table 1, entry 12).
With the optimized conditions in hand, we examined the
generality of this protocol. First, the feasibility of this
method was evaluated by the reaction of benzyl azide with
a range of alcohols (Table 2). Benzyl alcohol generated the
corresponding amide with an excellent yield of 94%, and
aliphatic alcohols also showed excellent activity (entries
1ꢀ3). Sterically hindered alcohols led to formation of the
corresponding amides withlowered yields (entries 4 and 5).
2-Furanmethanol (1f) also provided the amide 3fa in 80%
yield (entry 6). When using 5-hexen-1-ol as a starting
material, the reduction of the unsaturated double bond in
the alcohol occurred with the formation of the correspond-
ing amide in 73% yield (entry 7).
chemoselectivity of our catalytic system, we chose the reac-
tion with an alcohol possessing an alkyne functional group.
When 5-hexyn-1-ol and benzyl azide were employed,
the corresponding amide 3ca was obtained in 27% yield
along with 1,4-disubstituted 1,2,3-triazole compound
3ha (entry 8).11
Next, another noticeable result was obtained, based on
our recent work including efficient synthesis of cyclic
imides from amines and diols under the same catalytic
system.12 Various cyclic imides were synthesized from
benzyl azide and diols in 40% to 75% yields (entries
9ꢀ12). Syntheses of five-membered succinimides (entries
9 and 11), a six-membered glutarimide (entry 10), and a
phthalimide derivative (entry 12) were demonstrated.
The scope of azide components was expanded using
2-phenylethanol (Table 3). Both electron-donating and
-withdrawing substituents on the aromatic ring furnished
the corresponding amides with good to excellent yields
(entries 2ꢀ4). The electron-withdrawing fluoro group led
to a reduced yield of 3ad (entry 4). Sterically hindered
azides also generated the corresponding amides in moder-
ate yields (entries 7 and 8). Aromatic azides such as phenyl
azide gave the amide in a significantly low yield of 22%
(entry 9). Sensitivity to sterics and N-nucleophilicity have
(10) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565.
(11) (a) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.;
Zhao, H. T.; Lin, Z. Y.; Jia, G. C.; Fokin, V. V. J. Am. Chem. Soc. 2008,
130, 8923. (b) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams,
I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127,
15998.
(12) (a) Zhang, J.; Senthilkumar, M.; Ghosh, S. C.; Hong, S. H.
Angew. Chem., Int. Ed. 2010, 49, 6391. (b) Senthilkumar, M.; Hong,
S. H. Synlett 2011, 1481.
One of the most significant uses of azide is in the [3 þ 2]
cycloaddition reaction with alkyne.10 To investigate the
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Synthesis of Amide and Imides from Benzyl Azide 2a
and Alcoholsa
Table 3. Synthesis of Amide from 2-Phenylethanol 1aa
a Reaction conditions: Azide (0.5 mmol, 1.0 equiv), 1a (1.2 equiv),
RuH2(PPh3)4 (5mol%),4(5 mol %), NaH (20 mol %), CH3CN(5mol%),
toluene (0.6 mL), reflux, 48 h. b Yields are of the isolated product and
represent the average of at least two runs. c NaH (40 mol %), toluene
(0.3 mL). d Mesitylene (0.6 mL) at reflux.
we explored the utility of the reaction by performing an 15N-
isotope labeling experiment. The reaction of 2-phenylethanol
and 15N-labeled 3-phenylpropylazide under the optimized
conditions gave the desired amide 3aj in 73% yield. 15N-
labeled cyclohexylazide also gave the corresponding amide
3ak in 46% yield (Scheme 2). As easily manageable 15N-
labeled azides are readily accessible in one step from alkyl
halides and commercially available 15N-labeled NaN3, facile
access to 15N-labeled amides bearing various functional
groups could be realized with this methodology.
Next, we investigated the mechanism of this direct
amidation from an azide and alcohol. Initially, we suspected
the involvement of an aza-ylide for the transformation. It
has been well reported that an organoazide ligates car-
boxylic acid or an ester to give an amide in the presence of
triphenylphosphine.14 Therefore, we applied the same reac-
tion conditions to (benzylimino)triphenylphosphorane 4a,
which is independently prepared by the Staudinger reaction
of benzyl azide and triphenylphosphine, with 2-phenyletha-
nol. However, no reaction occurred. This result excluded the
possibility of aza-ylide involvement in the reaction.
a Reaction conditions: 2a (0.5 mmol, 1.0 equiv), alcohol (1.2 equiv),
RuH2(PPh3)4 (5mol%),4(5 mol %), NaH (20 mol %), CH3CN(5mol%),
toluene (0.6 mL), reflux, 48 h. b Yields are of the isolated product and
represent the average of at least two runs. c NaH (40 mol %), toluene
(0.3 mL). d Toluene (0.3 mL).
been also well reported in the direct amidation from
alcohols and amines.5,9
Considering the importance of isotope labeled pep-
tides and proteins in medical and biological studies,13
(13) (a) Baillie, T. A. Pharmacol. Rev. 1981, 33, 81. (b) Baillie, T. A.;
Rettenmeier, A. W. J. Clin. Pharmacol. 1986, 26, 481. (c) Mutlib, A. E.
Chem. Res. Toxicol. 2008, 21, 1672. (d) Pregosin, P. S.; Randall, E. W.;
White, A. I. J. Chem. Soc., Perkin Trans. 2 1972, 513. (e) Ruck, R. T.;
Bergman, R. G. Angew. Chem., Int. Ed. 2004, 43, 5375. (f) Kelly,
N. M.; Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 1997, 14, 205.
(g) Lankiewicz, L.; Grehn, L.; Ragnarsson, U. J. Label. Compd. Radio-
pharm. 1993, 33, 551.
(14) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
€
(b) Kohn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004, 43, 3106.
(c) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2, 1939.
Org. Lett., Vol. XX, No. XX, XXXX
C

dehydrogenation. The reason why the reaction proceeded
better with a slightly higher amount of alcohols could be
related to the increased transfer hydrogenation efficiency
by providing an increased amount of hydrogen. The next
steps followed the same reaction mechanism suggested
in the oxidative amide synthesis from an alcohol and
amine.5,9 The generated aldehyde intermediate was subse-
quently attacked by the amine to form the hemiaminal
intermediate. Finally, further dehydrogenation of the
hemiaminal gave the amide product.
Scheme 2. Isotope Labeling Study
Scheme 3. Proposed Mechanism of Amide Synthesis Directly
from Azide and Alcohol
In conclusion, we have demonstrated for the first time
that direct amide synthesis from an azide and alcohol is
possible. This fundamental but important transformation
allows atom economical and direct synthesis of amide
bond producing hydrogen and nitrogen gas as the sole
byproducts. The reaction has broad substrate generality
including diols for the synthesis of cyclic imides. In addi-
tion, 15N-labeled amides could be prepared in one step
using readily available 15N-labeled azides and alcohols.
This expansion of the N-source for the atom-economical
amide syntheses will be a step forward toward achieving
environmentally benign amide synthesis.
Figure 1. Reaction profiles showing the changes in amount of
substrate and product. Azide (2b, 0.10 mmol, 1.0 equiv), alcohol
(1a, 1.2 equiv), RuH2(PPh3)4 (5 mol %), 4 (5 mol %), NaH (20
mol %), CH3CN (5 mol %), toluene (0.12 mL), reflux. Average
of three runs. The reaction progress was monitored by GC.
Acknowledgment. This research was supported by the
Research Center Program of IBS (Institute for Basic
Science) in Korea and the Basic Science Research Program
through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science,
and Technology (2012004077).
Kinetic studies, performed by monitoring the reaction
progress between 2-phenylethanol (1a) and p-methoxy-
benzyl azide (2b), gave a conclusive idea regarding the me-
chanism (Figure 1). At the very initial stage of the reaction,
p-methoxybenzyl amine (5b) was detected along with the
rapid consumption of 2b. The concentration of 5b was
slowly decreased while that of amide 3ab increased. These
results strongly led us to conclude the reaction mechanism
shown in Scheme 3. First, an azide was mainly reduced
to an amine by hydrogen transferred from alcohol
Supporting Information Available. Details of experi-
mental procedure and characterization data. This material
is free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX