Cleavage of unactivated amide bonds by ammonium salt-accelerated hydrazinolysis

Article abstract of DOI:10.1039/c4cc02014f

Hydrazinolysis of unactivated amide bonds is significantly accelerated by the addition of ammonium salts. The reactions proceed at 50-70 °C to give amines with broad substrate scope that outperforms existing amide bond cleavage reactions. Application to peptide and amino sugar derivatives is also demonstrated. This journal is

Full text of DOI:10.1039/c4cc02014f

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Cleavage of unactivated amide bonds by
ammonium salt-accelerated hydrazinolysis†
Cite this:DOI: 10.1039/c4cc02014f
Yuhei Shimizu, Megumi Noshita, Yuri Mukai, Hiroyuki Morimoto* and
Takashi Ohshima*
Received 18th March 2014,
Accepted 23rd May 2014
DOI: 10.1039/c4cc02014f
www.rsc.org/chemcomm
Hydrazinolysis of unactivated amide bonds is significantly acceler- and readily cleavable formamides,10 and has not been recognized
ated by the addition of ammonium salts. The reactions proceed at as a general method to cleave simple, unactivated amide bonds
50–70 8C to give amines with broad substrate scope that out- because of the limited reactivity of hydrazinolysis under the
performs existing amide bond cleavage reactions. Application to reported reaction conditions (vide infra). To improve the applic-
peptide and amino sugar derivatives is also demonstrated.
ability of hydrazinolysis, we hypothesized that the addition of
ammonium salts would activate amide bonds and promote
An amide is a ubiquitous structural motif found in various organic hydrazinolysis at a lower reaction temperature similar to the
molecules such as peptides, natural products, and pharmaceuticals, transamidation reaction using ethylenediamine.11,12 Herein, we
because of the high stability of amide bonds.1 The recent develop- report ammonium salt-accelerated hydrazinolysis of unactivated
ment of catalytic methods, such as C–H activation,2 hydrogenation,3 amides using readily available hydrazine monohydrate as the
and kinetic resolution,4 expands the utility of amides as useful cleaving agent. The reactions proceeded at 50–70 1C to provide
directing/protecting groups in organic reactions. In contrast to the amines in good yields with broad substrate scope that out-
utility of amides in organic synthesis, cleavage of amide bonds is less performs that of existing amide bond cleavage reactions.
explored due to the high stability of amide bonds, and the most
To test our hypothesis, we first explored the reaction conditions
general method to cleave amide bonds is conventional hydrolysis using hydrazine hydrate at 60 1C for 6 h under conventional
under harsh acidic/basic conditions with limited functional group heating conditions (Table 1). The reactions proceeded only slug-
tolerance.5 Recent efforts to circumvent the problem have provided gishly under the conditions reported in the previous literature
several elegant solutions,6 but these reactions still require anhydrous (entries 110a and 210b).13 By contrast, the addition of ammonium
conditions and/or high reaction temperatures and have limited salts significantly accelerated the reaction to provide amine 2a, and
functional group tolerance. To expand the utility of simple, the addition of ammonium iodide showed the highest reactivity
unactivated amides for the synthesis of organic molecules, the
development of general and practical methods to cleave amide
Table 1 Optimization of reaction conditions
bonds under mild conditions is necessary.7
To overcome these limitations, we were interested in the
hydrazinolysis of amide bonds. Hydrazinolysis of activated amide
bonds is widely utilized, especially for the removal of phthaloyl
groups under mild conditions in Gabriel amine synthesis.8
Hydrazinolysis of simple unactivated amides is generally very
difficult, however, because of the lack of intramolecular assistance
during cleavage of the amide bonds, and a high temperature and
long reaction time are necessary to provide amine 2 in a reason-
able yield in most cases.9 Hydrazinolysis of simple amide bonds
under mild conditions was limited to only amino acid derivatives
Entry
Ammonium salt
Temp. (1C)
t (h)
Yielda (%)
1
2
3
4
5
6
7
8
9e
None
60
60
60
60
60
60
60
50
50
6
6
6
6
6
n.d.b
7
35
H2NNH2ÁAcOHc
NH4Cl
NH4Br
NH4I
45
52
nBu4NI
NH4I
NH4I
6
n.d.b
90d
89d
90d
24
48
5
NH4I
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582,
Japan. E-mail: ohshima@phar.kyushu-u.ac.jp, hmorimot@phar.kyushu-u.ac.jp
† Electronic supplementary information (ESI) available: Experimental details and
characterization data. See DOI: 10.1039/c4cc02014f
a
Yield was determined by 1H NMR analysis of the crude mixture. b Not
c
detected. 3.0 equiv. of H2NNH2ÁH2O and AcOH were used in EtOH (1.0 M).
d Isolated yield. e Under microwave irradiation conditions.
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Table 2 Scope and limitations of hydrazinolysis of amides
(entries 3–5). No reaction proceeded with tetrabutylammonium
iodide, suggesting that ammonium salt functions as a proton
source (entry 6). Prolonging the reaction time to 24 h gave
satisfactory results (entry 7), and the reaction proceeded even at
50 1C in 89% yield (entry 8). Although the conventional heating
conditions were sufficient to promote amide bond cleavage as
described above, a significant acceleration of the amide bond
cleavage was observed under microwave irradiation conditions to
give 2a in 90% yield for 5 h at 50 1C (entry 9).14
Entry
1
Temp. (1C) t (h) Yielda (%)
Amide 1
1b 60
36
78
With the optimized conditions in hand, we performed hydr-
azinolysis of various amides 1 (Table 2). The reactions proceeded
at 50–70 1C even under conventional heating conditions to give
amine 2 in 78–99% yield. Some of the reactions were performed
under microwave irradiation conditions to provide amines in a
shorter reaction time (entries 3, 5 and 8). Various secondary and
tertiary amides were also reacted, and broad functional groups
were tolerant under the current hydrazinolysis conditions. Amides
1b, 1c, and 1d having acetonide, tert-butoxycarbonyl, and benzyl-
oxycarbonyl functionalities, respectively, also gave products in
good yields, indicating the mildness of the current reaction
conditions.13 It is noted that the cleavage of sterically congested
formamide 1i was slow without addition of ammonium iodide
(entry 8 in the parenthesis), indicating the importance of ammo-
nium iodide as an additive to accelerate reactions.
The broad functional group tolerance under the current
reaction conditions was further confirmed for amide 1p, which
has an acid- and base-sensitive tert-butyldimethylsilyloxy group
(Scheme 1). As expected, the desired product 2p was obtained
in 89% yield with retention of the TBS group under our reaction
conditions. On the other hand, undesired desilylated product 1l
and 2l were obtained as major products under conventional
acidic and basic hydrolysis conditions.
Finally, we applied our reaction conditions to cleave peptide and
amino sugar amide bonds (Scheme 2). Selective deacetylation of
alanine derivative 1q was realized under the current conditions.
Furthermore, selective cleavage of the Gly–Phe bond was realized
when peptide 1r and 1s were exposed to the current reaction
conditions to give amine 2r in 84% and 74% yields (92% based
on recovered starting material), respectively, without racemization
at the a-position of the phenylalanine residue.13 The observed site-
selectivity was presumably affected by both steric and electronic
nature of amide bonds.13 In addition, this reaction condition was
also applied to cleavage of an N-acetyl group from the amino sugar
derivative 1t. Without the addition of ammonium salt, a high
temperature and long reaction time were required to obtain 2t,9a
but with ammonium iodide the reaction proceeded at 60 1C in a
shorter reaction time under microwave irradiation conditions to
give the desired product 2t in 81% yield.
2b
3c
4
1c 70
1d 60
1e 60
1f 70
1g 50
45
4
85
79
92
84
83
48
10
36
5c
6
7b
1h 50
1i 70
18
5
85
8b,c
92 (26)d
9b
1j 60
1k 70
42
48
97
84
10
11
1l 50
1m 60
18
45
94
94
12b
In summary, we developed ammonium salt-accelerated hydraz-
inolysis of unactivated amides. The reactions proceeded by using
readily available ammonium iodide and hydrazine monohydrate
under mild conditions (50–70 1C without strong acids and bases)
with broad substrate generality, including protic functional groups,
which is superior to the conventional acidic/basic hydrolysis condi-
tions and recently reported amide bond cleavage reactions. Applica-
13
1n 50
1o 50
12
12
97
99
14
a
b
c
Isolated yield. Reaction was performed in EtOH. Under microwave
d
tion to peptide and amino sugar derivatives further confirmed the irradiation conditions. Without addition of NH4I.
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Takasago Award in Synthetic Organic Chemistry, Japan and Y.S.
thanks JSPS Research Fellowships for Young Scientists. We
thank the research group of Prof. Hiroshi Suemune at Kyushu
University for the use of a polarimeter and Dr Yoshimasa
Matsushima of Takasago Int. Co. for DSC analysis.
Notes and references
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Scheme 1 Comparison with conventional acidic/basic hydrolysis conditions.
´
4 Review of kinetic resolution: (a) E. Busto, V. Gotor-Fernandez and
V. Gotor, Chem. Rev., 2011, 111, 3998; (b) C. E. Mu¨ller and
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5 P. G. M. Wuts and T. W. Greene, Protective Groups in Organic
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C. P. Vandenbossche, H. Zhao, P. Mousaw, S. P. Singh and
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7 For selected recent examples of facile cleavage of strained amide
´
bonds, see: (a) J. Aube, Angew. Chem., Int. Ed., 2012, 51, 3063;
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C. J. Hamilton, Org. Biomol. Chem., 2008, 6, 385; (b) K. Fukatsu,
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12 Although addition of hydrazinium sulfate have been reported for
the analysis of peptide sequences, these reaction conditions require
anhydrous hydrazine and not widely utilized in the field of organic
synthesis; see: J. H. Bradbury, Nature, 1956, 178, 912.
Scheme 2 Application to peptide and amino sugar derivatives.
13 See ESI† for detail.
applicability of our method. Further experiments are underway in
our laboratory to gain a detailed understanding of the reaction
mechanism and to determine further applications.15
This work was supported by the Grant-in-Aid for Scientific
Research (B) (#24390004), the Scientific Research on Innovative
Areas (#24106733) and Platform for Drug Discovery, Informatics,
and Structural Life Science from MEXT, CREST from JST, Uehara
Memorial Foundation, and the Naito Foundation. H.M. thanks
14 Safety testing consisting of DSC testing of reaction mixtures was
performed. No significant barriers were found to progression of the
reaction (50–70 1C) and an exothermic process started at about 160 1C
(calorific value: o100 J gÀ1, activation energy: ca. 700 kJ molÀ1).
15 (a) Our preliminary results for the application of hydrazinolysis of amide
bonds to the removal of directing groups were presented: Y. Shimizu,
M. Noshita, Y. Mukai, H. Morimoto and T. Ohshima, 104th Symposium
on Organic Synthesis, Japan, O-12, November 6–7, 2013; (b) The pre-
sented method was applied and cited in the very recent publication:
K. S. Kanyiva, Y. Kuninobu and M. Kanai, Org. Lett., 2014, 16, 1968.
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