Metal-free hydration of ynamides: Convenient approach to amides

Article abstract of DOI:10.1016/j.tetlet.2016.03.052

The trifluoroacetic acid (TFA) mediated hydration of ynamides was developed, which is an efficient approach for the synthesis of N-monosubstituted amides. This convenient method is effective with a wide range of substrates under room temperature condition, and the products are obtained in high to excellent yields through an easy work-up process.

Full text of DOI:10.1016/j.tetlet.2016.03.052

Tetrahedron Letters 57 (2016) 1873–1876
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Metal-free hydration of ynamides: convenient approach to amides
⇑
Hai Huang, Luning Tang, Yang Xi, Guangke He, Hongjun Zhu
Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
The trifluoroacetic acid (TFA) mediated hydration of ynamides was developed, which is an efficient
approach for the synthesis of N-monosubstituted amides. This convenient method is effective with a wide
range of substrates under room temperature condition, and the products are obtained in high to excellent
yields through an easy work-up process.
Received 18 January 2016
Revised 16 March 2016
Accepted 17 March 2016
Available online 18 March 2016
Ó 2016 Published by Elsevier Ltd.
Keywords:
Metal-free
Hydration
Ynamides
Amide bond
Room temperature
Introduction
Bi and co-workers13 reported a convenient approach to the prepa-
ration of imides that involves the reaction of ynamides with HOAc/
Amides have been paid much attention in both biological and
chemical studies for a long time.1 On the one hand, benefitting
from the special properties (e.g., stability, polarity, conformational
diversity, etc.) of the amide moiety, amides and their derivatives
are widely applied as biologically active compounds, such as Ator-
vastain,2 Lisinopril,3 Valsartan,4 and Diltiazem.5 On the other hand,
amides act as especially useful and versatile building blocks for
organic synthesis,6 especially open a wide access to the synthesis
of nitrogen-contained heterocyclic compounds, for examples, the
synthesis of benzoxazoles,7 quinolinones,8 and phenanthridi-
nones.9 To date, various methods for the synthesis of amides have
been developed, in which amidation of carboxylic acid derivatives
is the traditional method for the synthesis of amides. However, the
lability of those functional carboxylic acid derivatives often
restricts its wide applications.10 In addition, this procedure pro-
duces a stoichiometric amount of waste products and thus innately
faces serious environmental problems.11 Therefore, developing
alternative, efficient, and convenient methods to synthesize
amides at mild reaction conditions is highly attractive.12
Acetone/H2O at 100 °C (Scheme 1, a). Using Sn-W mixed oxide,
Mizuno and co-workers14 have successfully achieved the goal of
hydration of ynamides for synthesis imides (Scheme 1, b). Thus,
as part of the functionalization of ynamides, as well as a lack of sys-
tematic studies on hydration of ynamides, developing efficient and
convenient methods to synthesize amides through hydration of
ynamides is still of great value. We herein report a convenient
and straightforward method based on the TFA-mediated hydration
of ynamides for synthesizing N-monosubstituted amides
(Scheme 1, c). To the best of our knowledge, this is the first exam-
ple of metal-free hydration of ynamides giving N-monosubstituted
amides under room temperature.
Results and discussions
Recently we have developed the iodine-mediated oxidation of
ynamides to synthesize varied
a
-keto-amides.15 In the course of
our study, we noticed the hydration of ynamide 1a was trans-
formed into amide 2a in 76% isolated yield under TFA/CH3CN/
H2O condition (Table 1, entry 1). Thus, we started this synthesis
by conducting the reaction of tert-butyl N-phenyl- N-(phenyl-
ethynyl) carbamate (1a) as the model case for condition
optimization. The use of TFA allowed the direct conversion of
benzyl-phenylethynyl-carbamic acid tert-butyl ester (1a) into the
corresponding N-monosubstituted phenylacetamides 2a in the
yield of 65–80% under mild condition (Table 1, entries 1–3), and
DCM was superior to CH3CN (76%), THF (65%). The addition of
3.0 equiv TFA produced the highest yield of 2a (Table 1, entries
Ynamides have thus emerged as versatile building blocks in
organic synthesis, while an impressive number of transformations
from ynamides have been reported in recent years. Compared with
other methods for synthesis of amides, the hydration of ynamides
is a straightforward method to produce amides. However, only two
literatures described such a hydration systematically. For instance,
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2016.03.052
0040-4039/Ó 2016 Published by Elsevier Ltd.

1874
H. Huang et al. / Tetrahedron Letters 57 (2016) 1873–1876
Bi's wrok:
EWG
EWG
R2
HOAc (2.0 equiv)
N
R1
N
R1
R2
a
100 o
C
H2O/Acetone,
O
imides (EWG = Ts, COR)
Mizuno 's wrok:
EWG
N
Sn-W oxide
EWG
R1
R2
R1
N
b
c
100 o
C
R2
H2O/mesitylene,
O
imides (EWG = Ts, COR)
This wrok:
H
N
Boc
R2
TFA
hydration
R1
NH
R2
R1
N
C
N
R1
R2
R1
R2
r.t.
DCM,
O
N-monosubstituted amides
Scheme 1. TFA-mediated hydration of ynamides.
3–5). Other acids, such as acetic acid, HCl (5.0%), failed to provide
the corresponding amides (Table 1, entries 6–7).
Table 1
Optimization of reaction conditionsa
With the optimized conditions in hand (Table 1, entry 5), we
examined the scope and generality of various ynamides in this
transformation. The results are summarized in Table 2. Groups
such as methyl, methoxy that are substituted in the aryl ring were
tolerated and readily produced high yields of the corresponding
phenylacetamides (Table 2, 2b–2c). The structure of 2a was further
confirmed via single-crystal X-ray diffraction (Table 2).16 Under the
optimized reaction conditions, various substrates bearing ortho,
meta, and para substitutions in the N-aryl ring were converted
(moderate to high yields) into the corresponding N-monosubsti-
tuted amides (Table 2, 2d–2m). The yields decreased when having
an electron-withdrawing group in the meta position of N-aryl ring
(Table 2, 2k vs 2j). Ynamides with different N-substituted groups,
such as benzyl, 2-naphthyl, were also used to this reaction to
produce the corresponding N-monosubstituted amides with good
yield (Table 2, 2n–2o). In addition, an excellent yield of alkyl-
substituted ynamide 1p was obtained under the reaction
H+
solvent, air, r.t.
Boc
H
N
Ph
N
Ph
Ph
Ph
O
1a
2a
Entry
Solvent
H+ (equiv)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8b
CH3CN
THF
TFA (1.0)
TFA (1.0)
TFA (1.0)
TFA (2.0)
TFA (3.0)
TFA (6.0)
CH3COOH (3.0)
HCl (3.0)
12
12
12
5
3
3
76
65
80
81
85
86
0
DCM
DCM
DCM
DCM
DCM
DCM
24
24
0
a
Reaction conditions: 1a (0.3 mmol), TFA or other acids, H2O (5.0 equiv) and
solvent (2.0 mL) at rt under air atmosphere.
b
5.0 wt% (m/v) of HCl in H2O was used, and unidentified mixture was given.
Table 2
TFA-mediated hydration of ynamidesa
H
Boc
R2
TFA (3.0equiv)
N
R1
N
R1
R2
DCM, air, r.t.
O
1
2
H
H
N
H
N
N
Bn
R
O
O
O
R
Br
(2n, 3h, 80%)
2a: R = H, 3h, 85%
2b: R = Me, 3h, 82%
2d: R = 2-Me, 3h, 56%
H
N
2e
: R = 3-Me, 3h, 83%
2f: R = 4-Me, 3h, 77%
2g
2c
: R = MeO, 3h, 83%
: R = 3-F, 3h, 85%
O
2h: R = 3-Cl, 3h, 81%
2i: R = 3-Br, 3h, 83%
2j
: R = 3-MeO, 3h, 95%
(2o, 5h, 78%)
H
N
2a
2k: R = 3-CF3, 5h, 76%
H
N
2l
: R = 4-Cl, 3h, 79%
2m: R = 4-Br, 3h, 82%
O
O
(2q, 3h, 89%)
(2p, 3h, 93%)
a
Reaction conditions: 1 (0.3 mmol), TFA (3.0 equiv), H2O (5.0 equiv) and DCM (2.0 mL) at rt under air
atmosphere.

H. Huang et al. / Tetrahedron Letters 57 (2016) 1873–1876
1875
Table 3
Gram-scale experimentsa
H
N
Boc
R2
TFA (3.0 equiv)
DCM, air, r.t.
R1
N
R1
R2
O
2
1
H
N
H
N
H
N
Br
O
O
O
O
2a, yield: 91%
2c, yield: 90%
2i, yield: 95%
H
N
H
N
H
N
O
O
O
Br
2q, yield: 98%
2p, yield: 93%
2m, yield: 96%
a
Reaction conditions: Ynamides 1 (6.0 mmol), H2O (5.0 equiv), TFA (1.5 mL), DCM (30 mL), rt, 5 h.
Table 4
One-pot preparation of amides from bromoalkynesa
1) Cu Cat.
2) TFA
H
H
N
N
O
R1
Br
R2
R1
R2
+
O
O
H
N
H
H
N
N
Br
O
O
O
O
2i
, total yield: 48%
, total yield: 56%
2a
, total yield: 62%
2c
a
Reaction conditions: 1) tert-butyloxycarbamates (0.6 mmol), bromoalkynes (0.72 mmol), CuSO4ꢀ5H2O
(0.06 mmol), 1,10-Phenanthroline (0.12 mmol), K3PO4 (1.2 mmol), and toluene (2 mL), 85 °C, 18 h. 2) TFA
(0.2 mL), toluene, rt, 5 h; isolated yield was given.
O
TFA (3.0 equiv)
H2O (5.0 equiv)
O
O
O
N
N
DCM, air, r.t.
O
O
1r
TFA (3.0 equiv)
H2O (5.0 equiv)
Ts
Ts
N
N
Bn
DCM, air, r.t.
Bn
1s
O
N
TFA (3.0 equiv)
H2O (5.0 equiv)
O
O
O
H
N
N
or
DCM, air, r.t.
O
O
1t
Scheme 2. TFA-mediated hydration of ynamides without Boc group.
conditions (Table 2, 2p). Finally, terminal ynamide was also tested,
that N-phenylacetamide was obtained in 89% yield (Table 2, 2q).
To demonstrate the synthetic potential of this strategy, scale-up
experiments were carried out for several substrates. To our delight,
the reactions all proceeded well and the corresponding amides
could be isolated in excellent yield via simple work-up process
(Table 3).17 For example, an excellent yield (91%) of product 2a
was obtained when 1a was employed in the gram-scale reaction
condition.
Further application of our method was extended in developing a
one-pot method for synthesis of amides employing bromoalkynes
as starting materials. And the procedure is very simple as follows:
CuSO4ꢀ5H2O and K3PO4 are filtered off after completion of the
cross-coupling of bromoalkynes and tert-butyloxycarbamates,

1876
H. Huang et al. / Tetrahedron Letters 57 (2016) 1873–1876
R1
NH
R2
Supplementary data
TFA
A
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.03.
052.
Boc
R2
C N
R1
N
R1
R2
A'
1
References and notes
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Different ynamides derivatives without the Boc group were also
investigated (Scheme 2). Ether 3-(phenylethynyl)-oxazolidin-2-
one 1r or ynesulfonamide 1s was unable to convert into the corre-
sponding amides. Additionally, hydration of ynamides containing
ethyl on the ester moiety (1t) also did not take place. These results
reveal the important role of Boc group in this hydration system.
By employing our experimental results and literature reports,
we have proposed a mechanism for this hydration (Scheme 3).
After deprotection of the Boc group under TFA condition, ynamides
1 can afford the intermediate A, which are also characterized by
keteniminium forms A0 increasing their electrophilicity and regios-
electivity.18 The addition of H2O to intermediate A0 would lead to
the formation of enol intermediate B.15 Through a keto/enol
tautomerism, intermediate B can then form the corresponding
amides 2.
Conclusion
16. Crystal date of 2a: C14H13NO; M = 211.25; Monoclinic’; space group P21/n; final
In conclusion, a novel and efficient method has been developed
for the construction of N-monosubstituted amides through TFA-
mediated hydration of ynamides. This protocol takes place at room
temperature and utilizes readily available starting materials under
metal-free conditions, which provides a convenient and highly
attractive route to various amides. Further studies on exploring
the reactivity and application of ynamides are underway.
R indices [I > 2r(I)]: R1 = 0.0379, wR2 = 0.0915, R indices(all data): R1 = 0.0536,
wR2 = 0.1017, a = 5.6832(5) Å, b = 25.278(2) Å, c = 8.0124(7) Å; b = 91.916(2)°,
V = 1150.44(17) Å3; T = 296 K; Z = 4; reflection measured/independent: 6372/
2032 (Rint = 0.022), number of observations [I > 2r(I)]: 1561, parameters: 145.
CCDC-1447766 contains the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
17. General procedure for the preparation of amides: To a mixture of ynamides
(6.0 mmol) and DCM (30 mL) in a reaction vial was added TFA (18.0 mmol).
The reaction mixture was stirred at rt for 4 h while being monitored with TLC
analysis. Upon completion, the reaction mixture was concentrated in vacuum
to give directing products.
Acknowledgments
18. (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P.
Chem. Rev. 2010, 110, 5064–5106; (b) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840–2859; (c) Wang, X. N.; Yeom, H. S.; Fang, L. C.; He,
S.; Ma, Z. X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560–578.
The authors greatly acknowledge the financial support in part
by Provincial Natural Science Foundation of Jiangsu, China
(No. BK20140937), and Postgraduate Innovation Fund of Jiangsu
Province, China (2015, KYLX15_0797).