N, N -diethylurea-catalyzed amidation between electron-deficient aryl azides and phenylacetaldehydes

Article abstract of DOI:10.1021/ol503655a

Urea structures, of which N,N-diethylurea (DEU) proved to be the most efficient, were discovered to catalyze amidation reactions between electron-deficient aryl azides and phenylacetaldehydes. Experimental data support 1,3-dipolar cycloaddition between DEU-activated enols and electrophilic phenyl azides, especially perfluoroaryl azides, followed by rearrangement of the triazoline intermediate. The activation of the aldehyde under near-neutral conditions was of special importance in inhibiting dehydration/aromatization of the triazoline intermediate, thus promoting the rearrangement to form aryl amides.

Full text of DOI:10.1021/ol503655a

Letter
pubs.acs.org/OrgLett
N,N‑Diethylurea-Catalyzed Amidation between Electron-Deficient
Aryl Azides and Phenylacetaldehydes
Sheng Xie,† Olof Ramstrom,*,† and Mingdi Yan*,†,‡
̈
†Department of Chemistry, KTH - Royal Institute of Technology, Teknikringen 36, Stockholm, Sweden
‡Department of Chemistry, University of Massachusetts Lowell, 1 University Ave., Lowell, Massachusetts 01854, United States
S
* Supporting Information
ABSTRACT: Urea structures, of which N,N-diethylurea
(DEU) proved to be the most efficient, were discovered to
catalyze amidation reactions between electron-deficient aryl
azides and phenylacetaldehydes. Experimental data support
1,3-dipolar cycloaddition between DEU-activated enols and
electrophilic phenyl azides, especially perfluoroaryl azides,
followed by rearrangement of the triazoline intermediate. The activation of the aldehyde under near-neutral conditions was of
special importance in inhibiting dehydration/aromatization of the triazoline intermediate, thus promoting the rearrangement to
form aryl amides.
mide bonds are frequently present as functional and
example, PFAAs react with enamines at room temperature
Astructural units in natural products and synthetic without any catalysts, with cycloaddition rate constants in the
range of 0.01−1.2 M−1 s−1.13
polymers, and as linkers in constructing functional nanoma-
When methyl 4-azido-2,3,5,6-tetrafluorobenzoate (1a) and
phenylacetaldehyde (2a) were mixed in an amide solvent or
DMSO, aryl amide (3aa) was formed (Table 1, Figure S1).
terials and surfaces. Many reaction types lead to this
transformation, of which carboxyl-amine coupling reactions
are arguably the most popular.1 Azides, which can be
considered as a protected form of amines, have recently been
shown to perform well in certain amidation reactions, for
example, Staudinger ligation,2 thioacid−azide amidation,3
alkyne−sulfonyl azide coupling,4 alcohol−azide amide syn-
thesis,5 and azide−aldehyde amidations.6 Of these, the
amidation reaction between aldehydes and azides is redox-
neutral, involving only the release of nitrogen as the side
product and is therefore an attractive process.
The first reported azide−aldehyde amidation reaction dates
back to the 1950s and is known as the Boyer reaction.7 While
intramolecular Boyer amidation proceeds well, intermolecular
reactions between aldehydes and aliphatic azides require
strongly acidic conditions (>1 equiv of TiCl4, TFA, or
TsOH) to give aliphatic amides in very limited yields.8,9 An
alternative approach used a strong base (1−2 equiv of tert-
butoxide salts) to activate special azides to give aryl amides in
moderate to good yields.6a,b Transition-metal-catalyzed alde-
hyde−azide amidation was also recently reported; however, it
had limited substrate scope and slow kinetics.6c,d Herein, we
report a new catalytic azide−aldehyde amidation reaction which
could be carried out under mild conditions to give aryl amides
in good yields.
a
Table 1. Model Reaction and Optimization
b
entry
cat., mol %
solvent
time/temp
yield (%)
86
1
2
3
4
5
6
7
8
9
DEU, 20
DEU, 20
DEU, 20
DEU, 20
DEU, 30
DEU, 10
DEU, 10
DMPU, 130
−
DMSO
DMSO
DMF
2 h/rt
c
4 h/rt
>99 (91 )
2 h/rt
63
49
0
DMPU
2 h/rt
d
other
16 h/60 °C
2 h/rt
DMSO
DMSO
DMSO
DMSO
75
>99
73
7
24 h/rt
16 h/rt
64 h/rt
a
Conditions: 1a (0.5 M, 1 equiv), 2a (0.63 M). rt (≈22 °C).
b
c
d
Determined by 19F NMR. Isolated yield. THF, MeOH, acetone.
After various amide and urea structures were screened, it was
found that N,N-diethylurea (DEU) was the most efficient
(Table S1) and was thus chosen for further studies. The best
conditions included 20 mol % DEU in DMSO, under which the
reaction was completed at room temperature within 4 h to give
the aryl amide in 91% isolated yield (entry 2, Table 1). The
Perfluoroaryl azides (PFAAs) were initially selected to
evaluate the reaction with aldehydes. PFAAs exhibit unique
reactivities, owing to the presence of highly electronegative
fluorine atoms.10 They have been utilized in photoaffinity
labeling,11 and in surface and nanomaterial functionalization.12
PFAAs also show higher reactivities than phenyl azide in 1,3-
dipolar cycloadditions toward activated dipolarophiles. For
Received: December 18, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503655a
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Letter
solvent proved important, and amide or urea solvents such as
DMF or DMPU (1,3-dimethyltetrahydropyrimidin-2(1H)-one)
reduced the catalytic effect resulting in lower conversion
(entries 3, 4). When other solvents such as THF, MeOH, or
acetone were used, no product was formed (entry 5). Reducing
the DEU catalyst to 10 mol % gave slower conversion (entries
6, 7). The catalytic effect of other amides/ureas was more
sluggish. For example, 73% amide formation was observed
when the reaction was carried out in the presence of 1.3 equiv
of DMPU for 16 h (entry 8). Without any catalyst, only 7% of
the product was formed after 64 h (entry 9).
We next conducted a series of experiments to investigate the
mechanism of this transformation. Benzaldehydes did not give
any aryl amide products. When phenylacetaldehyde (2a) was
dissolved in DMPU, a clear transformation was observed for
the aldehyde proton in the 1H NMR spectrum (Figures S2, S3).
Small amounts (15%) of the typical aldol product 4 could also
be isolated from the mixture (Scheme 1a). This conversion was
a
Scheme 1. Control Experiments
Substrate screening was then performed for both the azide
and the aldehyde (Figure 1). Perfluorophenyl azides worked
a
(a) Reaction of phenylacetaldehyde in DMPU in the absence of the
azide. (b) Model reaction carried out in 20:80 D2O/DMSO. (c) DEU-
catalyzed reaction of PFPA 1a and 2-phenylpropanal in 20:80 D2O/
DMSO.
however absent when azide 1a was added. Simply mixing the
azide with DMPU or DEU did not result in any changes in the
NMR spectrum, indicating that the azide was not activated by
the urea, whereas the aldehyde was. When the reaction was
carried out using 20 mol % DEU as the catalyst in D2O/DMSO
(20:80 v/v), one deuterium atom was incorporated at the
benzyl position in the product (Scheme 1b; supported by the
NMR spectrum of the isolated compound 3aa-D). This
suggests that the benzylic proton in the aldehyde was activated
and could exchange with D2O. For 2-phenylpropanal, on the
other hand, no deuteration was observed in the product
(Scheme 1c). These results suggest that one of the benzylic
protons in the amide product emanates from the aldehyde,
accomplished via a hydride shift process.
From the above results, a plausible mechanism can be
envisioned that involves activated enol formation followed by
(3 + 2) cycloaddition with the azide to give the triazoline
intermediate, which subsequently undergoes nitrogen extrusion
and a hydride shift to give the amide product. When methyl
vinyl ether was tested with azide 1a under identical conditions,
the conversion was sluggish (30% after 16 h), indicating that
the unactivated enol was unlikely to be the active species in the
cycloaddition step. This was further supported by the fact that
addition of catalytic amounts of TsOH completely impaired
amide formation. On the other hand, when a base such as
DMAP or DBU was added, the azide conversion was
accelerated and a large amount of triazole was formed together
with the amide (Scheme 2). In the case of DBU, triazole was
formed exclusively.14 The isolation of a small amount of
triazoles (3fa-t, 3ca-t) as byproducts in the DEU-catalyzed
reactions also supports the formation of the triazoline as the
intermediate. However, ureas, including DEU and DMPU, are
generally considered to be superweak Brønsted bases15 and are
unlikely to deprotonate the enol form of phenylacetaldehyde
(pKa = 9.5−9.8).16
Figure 1. Substrate scope. Conditions: 1 (0.5 mmol), 2 (0.63 mmol),
DEU (0.1 mmol), DMSO (1 mL), rt (≈22 °C), 4 h, isolated yields.
b
c
a80 °C, 2 d. Neat DMPU, 80 °C, 2 d. 60 °C, 4 h.
efficiently, and these azides were generally converted to the
corresponding aryl amides (3aa, 3ab, 3ba, 3ca, 3cb) in over
80% isolated yield at room temperature within 4 h. For 4-nitro-
2,3,5,6-tetrafluorophenyl azide, heating at 80 °C for 2 days
(3da) was required, whereas the reaction with pentafluoro-
pyridinyl azide efficiently resulted in amide 3ea in 90% yield.
Other electrophilically activated phenyl azides were also tested.
o-Nitrophenyl- and p-nitrophenyl azides gave aryl amides in
slightly lower but still good yields (3fa, 3fb, 3gb). o-
Bromophenyl azide gave aryl amide 3hb as the major product
in 32% yield together with a large amount of the starting
material. Phenyl azide did not give any amide product even
after extensive optimization of the reaction conditions.
Interestingly, tosyl azide did not lead to any amide product
under these conditions.
α-Substituted phenylacetaldehydes, e.g., 2-phenylpropanal,
generally gave higher yields than phenylacetaldehyde (3aa vs
3ab, 3ca vs 3cb, 3fa vs 3fb). Other aliphatic aldehydes such as
3-phenylpropanal resulted in lower yields where, for example,
20% of product 3ac was isolated after heating the reaction at 80
°C for 2 days. However, when DMPU was used as the solvent,
even without the addition of DEU, the yield of 3ac increased to
70%.
B
DOI: 10.1021/ol503655a
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Letter
but evidence points to a cooperative interaction mode where
both the electronic effect and the geometry of the urea play
important roles. Similar phenomena were observed by Seebach
and co-workers where DMPU was reported to cause increased
nucleophilicity of the reagents and was especially useful for
reactions involving polyanionic species.20
Scheme 2. Catalysis by DEU or Base
Following the formation of the activated enol species (5), (3
+ 2) cycloaddition with the highly electrophilic azide gives the
triazoline intermediate (6). The near-neutral reaction con-
ditions facilitate synchronous rearrangement of the unstable
triazoline intermediate, involving extrusion of nitrogen and a
1,5-hydride shift to give the aryl amide (7) as the final product.
This rearrangement is similar to the cycloaddition reaction of
PFAA with enamines to yield amidines, where the electron-
deficient aryl group promoted the transformation at room
temperature.13 In the presence of a stronger base, the triazoline
instead underwent dehydration to form the 1,4-triazole (8),
which was also reported recently by Ramachary et al.14
In summary, we have demonstrated that DEU in DMSO
acted as an efficient catalyst for the reaction of phenyl-
acetaldehydes with electron-deficient phenyl azides, especially
perfluoroaryl azides. Unlike other aldehyde−azide amidations
that use strong acids, bases, or transition metals, this reaction
uses catalytic amounts of DEU and proceeds under very mild
conditions at room temperature to give the products in high
yield. The ability to form amide structures without using harsh
reagents at elevated temperatures is highly attractive to a wide
range of applications including bioconjugation, surface
functionalization, and nanomaterials synthesis.
Figure 2 summarizes the catalytic effect of various ureas/
amides on the model reaction (Table 1). The fact that thioureas
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 2. Catalytic effects of ureas/amides on the model reaction
(Table 1) in DMSO.
Experimental procedures and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
completely inhibited the reaction ruled out the possibility of
hydrogen bond donation-assisted electrophilic activation of the
carbonyl group as the main mechanism of the reaction.17
Relative weak catalysis was also observed for N,N′-disubstituted
ureas. Ureas have fair hydrogen bond basicities18 and are
therefore likely to interact with, and activate, the enol form of
the aldehyde. The catalytic effect is however also affected by the
urea structure. For example, DMEU displayed a significantly
lower catalytic effect than all other ureas tested, including TMU
and DMPU (Figure S4), despite their similar properties.19
An activated enol-mediated mechanism can be proposed
(Scheme 3), where ureas such as DEU and DMPU stabilize the
enol form and activate the phenylacetaldehyde structure
through hydrogen bonding interactions. DMSO, a strong
hydrogen bond acceptor,18 could also work synergistically with
DEU. The exact nature of the interactions is however complex,
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ramstrom@kth.se.
*E-mail: mingdi_yan@uml.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The study was in part supported by the Royal Institute of
Technology, the National Institutes of Health
(R01GM080295), and the National Science Foundation
(CHE-1112436). S.X. thanks the China Scholarship Council
for a special scholarship award.
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