Mild Amide-Cleavage Reaction Mediated by Electrophilic Benzylation

Article abstract of DOI:10.1002/chem.201603120

An extremely mild method for amide-cleavage by using the triazine-based benzylating reagent 4-(4,6-diphenoxy-1,3,5-triazin-2-yl)-4-benzylmorpholinium trifluoromethanesulfonate (DPT-BM), which spontaneously releases benzyl cation species when being dissolved at room temperature, has been developed. O-Benzylation of the amide with DPT-BM and the subsequent hydrolysis of the resulting intermediate benzyl imidate salt afford the corresponding amine and benzyl ester, which can be converted by hydrogenolysis into a carboxylic acid under neutral conditions. O-Benzylation proceeds depending on both steric and electronic factors around the amide group. Thus, some amides have been selectively cleaved over other amides. Furthermore, intramolecular chemoselective cleavage of an amide group in the presence of an ester group was achieved. Such selective hydrolytic reactions cannot be performed with Meerwein reagents as well as under acidic or basic hydrolytic conditions.

Full text of DOI:10.1002/chem.201603120

DOI: 10.1002/chem.201603120
Full Paper
&
Reaction Mechanisms
Mild Amide-Cleavage Reaction Mediated by Electrophilic
Benzylation
Kohei Yamada, Yukiko Karuo, Yuichi Tsukada, and Munetaka Kunishima*[a]
Abstract: An extremely mild method for amide-cleavage by
using the triazine-based benzylating reagent 4-(4,6-diphe-
noxy-1,3,5-triazin-2-yl)-4-benzylmorpholinium trifluorometha-
nesulfonate (DPT-BM), which spontaneously releases benzyl
cation species when being dissolved at room temperature,
has been developed. O-Benzylation of the amide with DPT-
BM and the subsequent hydrolysis of the resulting inter-
mediate benzyl imidate salt afford the corresponding amine
and benzyl ester, which can be converted by hydrogenolysis
into a carboxylic acid under neutral conditions. O-Benzyla-
tion proceeds depending on both steric and electronic fac-
tors around the amide group. Thus, some amides have been
selectively cleaved over other amides. Furthermore, intramo-
lecular chemoselective cleavage of an amide group in the
presence of an ester group was achieved. Such selective hy-
drolytic reactions cannot be performed with Meerwein re-
agents as well as under acidic or basic hydrolytic conditions.
cleavage by using the Schwartz reagent,[8] and formation of re-
active intermediates, such as imidoyl chlorides,[9a,b] imidoyl tri-
flates,[9c] and alkyl imidates[9d–m] followed by alcoholysis or hy-
drolysis. It is reasonable to assume that amides can be more
efficiently cleaved by using an electrophilic reagent than by
using a nucleophilic one. Due to the p-electron-donating prop-
erty of the nitrogen atom, the electrophilicity of the carbonyl
carbon atom of amides is lower than that of other carbonyl
compounds. The order of the electrophilicity of the carbonyl
carbon atoms is aldehyde>ketone>ester>amide, whereas
the basicity of the carbonyl oxygen atoms, which is significant-
ly related to the nucleophilicity, is in the inverse order, that is,
amide>ester>ketone>aldehyde.[10] Therefore, an approach
by using electrophilic reagents should be favorable for mild
amide-cleavage.
Introduction
Amides are very important components in natural products,
such as proteins, sugars, and lipids, as well as in artificial com-
pounds, including drugs, agricultural chemicals, and polymers.
Therefore, many efficient and mild methods for the condensa-
tion of carboxylic acids and amines in order to afford amides
have been developed.[1] In this context, we have previously de-
veloped a distinctive dehydrocondensing reagent, that is, 4-
(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlo-
ride (DMT-MM) that can produce amides in protic solvents,
such as methanol and water, as well as in aprotic solvents.[2] In
contrast to the fact that such mild conditions are available for
amide-forming reactions, the reverse reaction, that is, hydroly-
sis of amides to carboxylic acids and amines, is usually con-
ducted under strongly acidic or basic conditions due to the
high stability of amides.[3] Consequently, the hydrolysis of
amidic compounds containing acid- or base-labile functional
groups is a very difficult task to achieve. Apart from the direct
hydrolysis involving nucleophilic addition of water or a hydrox-
ide ion to the carbonyl carbon atom of the amide, several
methods for the cleavage of amides under milder conditions
have been reported; this includes microwave-assisted transa-
midation,[4] intramolecular N–O acyl migration,[5a,b] serine-selec-
tive oxidative cleavage,[6] conversion of amides to tert-butoxy-
carbamates through tert-butoxycarbonylamides,[7] reductive
We have previously developed a novel O-benzylating re-
agent, that is, 4-(4,6-diphenoxy-1,3,5-triazin-2-yl)-4-benzylmor-
pholinium trifluoromethanesulfonate (DPT-BM),[11] which gener-
ates benzyl cation equivalents upon dissolving in a solvent
under non-acidic conditions at room temperature. The benzy-
lation of various alcohols possessing acid- or base-labile func-
tional groups proceeded to give the benzyl ethers in good
yields. Moreover, DPT-BM is a non-hygroscopic, stable solid,
which can be handled under open air at room temperature
without any detectable decomposition. The reaction of an
amide with DPT-BM would proceed leading to the formation
of a benzyl imidate salt, with subsequent hydrolysis of the re-
sulting salt giving the corresponding benzyl ester and amine
(Figure 1).[12] The resulting benzyl ester can be converted into
the corresponding carboxylic acid by hydrogenolysis under
neutral conditions.
[a] Dr. K. Yamada, Y. Karuo, Y. Tsukada, Prof. Dr. M. Kunishima
Faculty of Pharmaceutical Sciences
Institute of Medical, Pharmaceutical, and Health Sciences
Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan)
E-mail: kunisima@p.kanazawa-u.ac.jp
A similar strategy for the O-alkylation of amides by using
Meerwein reagents has been developed for the deacetylation
of acetamide,[9d] and many applications of this methodology
Supporting information and ORCIDs numbers of the authors for this article
are available on the WWW under http://dx.doi.org/10.1002/
chem.201603120.
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amide 1 f gave a slightly decreased yield of 69% (Table 1,
entry 6). In contrast, secondary amides of tri-substituted car-
boxylic acids did not undergo cleavage; the adamantanecar-
boxamide 1g possessing a bulky group at the carbonyl carbon
did not participate in the reaction (Table 1, entry 7). The reac-
tions of the non- and mono-substituted lactams 1h and 1i af-
forded the corresponding benzyl esters in 87 and 89% yields,
respectively (Table 1, entries 8 and 9). However, the a,a-disub-
stituted lactam 1j was cleaved in only 10% yield (Table 1,
entry 10). In the case of the tertiary amide 1k, possessing
a straight acyl chain, the reaction proceeded in 83% yield
(Table 1, entry 11), whereas the reaction of the more hindered
di- or tri-substituted amides 1l and 1m resulted in quantitative
recovery of the starting amides (Table 1, entries 12 and 13). In-
terestingly, the aromatic secondary amides 1o and 1p hardly
reacted at all (Table 1, entries 15 and 16), whereas the primary
amide 1n and the tertiary amide 1q gave the esters in 81 and
92% yields, respectively (Table 1, entries 14 and 17). The anilide
1r was inert to benzylation by this method (Table 1, entry 18).
The reaction of the cinnamyl amide 1s gave compound 3s in
a moderate yield (Table 1, entry 19).
Figure 1. Amide-cleavage reaction through benzyl imidate salt intermedi-
ates.
have been reported.[9d–m] In 1997 and 2000, certain investiga-
tions into the scope of the reaction for primary,[9l] secondary,[9l]
and tertiary amides[9m] were reported. However, insights and
considerations into the relation between the structure and the
reactivity were not explored completely. Thus, even since then
(i.e., after 2000), to the best of our knowledge, applications of
the method by using Meerwein reagents were virtually limited
to substituted benzamides and cyclic amides (i.e., diketopiper-
azines and lactams).[13] The O-alkylation strategy for amide
cleavage shows great promise. However, it has only found lim-
ited application because of both the lack of a systematic study
into the substrate scope of the reaction and the major draw-
backs of using Meerwein reagents, that is, 1) Meerwein re-
agents need to be carefully handled and stored because of
their sensitivity to moisture and heat, and 2) the transforma-
tion of methyl or ethyl ester into the carboxylic acid is usually
performed under either acidic or basic conditions (e.g., by
using aqueous solutions of HCl or NaOH). However, the new
strategy described above would solve these problems. Herein,
we report a practical method based on electrophilic benzyla-
tion of the amide by using DPT-BM, which can be conducted
under nearly neutral conditions.
Discussion for the hydrolysis of the benzyl imidate salts
Although the imidate salts 2 are difficult to isolate without any
decomposition due to their instability, the crude mixtures re-
1
sulting from the O-benzylation could be analyzed by H NMR
spectroscopy.[15] Thus, we were able to determine the ratio of
the starting amides 1 and the imidate salts 2. In the case of
acyclic amides, the ratio of 2 to 1 is comparable to the yield of
the benzyl esters obtained. Interestingly, the lactam 1j was
completely converted into the imidate salt, indicating that the
70% yield of the recovered amide was regenerated from com-
pound 2j (Table 1, entry 10). O-Debenzylation would be re-
sponsible for the regeneration of the starting amides.[9m,16,17]
The same reaction was partially indicated in other cases, partic-
ularly in those where sterically hindered compounds were
used such as compounds 1b, 1o, 1p, and 1s (Table 1, en-
tries 2, 15, 16, and 19, respectively).
Results and Discussion
Investigation of the reaction scope
Upon treatment with DPT-BM in 1,2-dimethoxyethane (DME) at
room temperature, the mono-substituted primary amide 1a,
which has no substituent on the amide nitrogen atom, quanti-
tatively underwent O-benzylation to give the corresponding
imidate salt 2a as an intermediate, which is then converted
into the corresponding benzyl ester 3a in 95% yield by hydrol-
ysis in DME/water (1:1) (Table 1, entry 1).[14] Encouraged by this
result, we investigated the scope of the reaction for a series of
amides. As summarized in Table 1, the reaction is affected by
substituents on both the nitrogen atom and the carbonyl
group of the amide bond. Reactions with other primary
amides (i.e., compounds 1b, 1c, and 1d) similarly proceeded
(Table 1, entries 2–4), and the reaction yields slightly decreased
with an increase in the number of substituents at the a-posi-
tion. No racemization occurred during the benzylation and
subsequent hydrolysis of compound 1c (Table 1, entry 3). In
the case of secondary amides having an N-phenethyl group,
the mono-substituted amide 1e was converted to the benzyl
ester in 81% yield (Table 1, entry 5), and the di-substituted
The hydrolysis of the imidate salt can proceed by the addi-
tion of a water molecule to the iminium carbon (Scheme 1,
path a). This reaction would be slower for highly substituted
imidate salts derived from bulky amides. In addition, the O-
benzyl group will be positioned perpendicular to the p plane
of the iminium to lessen steric repulsion from other substitu-
ents. In this case, the CÀO s orbital of the benzyloxy group is
parallel to the iminium p orbital; therefore, water or other nu-
Scheme 1. Proposed hydrolysis mechanisms and debenzylation mechanisms
of benzyl imidate salts.
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Table 1. Amide-cleavage reaction of several amides.
Entry
1
Yield of 3[b]
[%] ([% ee[h]])
Ratio 2/1[a]
Entry
1
Yield of 3[b]
[%] ([% ee[h]])
Ratio 2/1[a]
1
2
3
4
5
95
99: 1[c]
11
12
13
14
15
83
90: 10[d]
0: 100[d]
0: 100[d]
92:8[d]
81
100: 0[c]
100: 0[d]
84: 16[d,e]
83: 17[d]
0, recovered 1l: quant.
0, recovered 1m: 95%
81
91 (99)
77
81
9, recovered 1o: 84%
17: 83[d]
6
7
69
78: 22[d]
16
17
0, recovered 1p: quant.
19: 81[d]
100:0[d]
0, recovered 1g: quant.
0: 100[d,f]
92%
8
87[g]
100: 0[d]
100: 0[d]
100: 0[d]
18
19
0, recovered 1r: 70%
56, recovered 1s: 43%
0: 100[d]
81: 19[d]
9
89[g]
10
10,[g] recovered 1j: 70%
[a] The ratios of 2/1 were calculated by using the crude 1H NMR spectra. [b] Yield of isolated product. [c] DPT-BM (1.5 equiv) was used. [d] DPT-BM
(2.0 equiv) was used. [e] A CHCl3/diglyme (11:2) mixture was employed as solvent. [f] A CH2Cl2/DME (1:1) mixture was employed as solvent. [g] Isolated as
the Boc-protected product. [h] Enantiomeric excess.
cleophiles can competitively attack the benzylic carbon atom,
leading to the regeneration of the starting amide (Scheme 1,
path b). The hydrolysis uneventfully proceeded with the highly
hindered compound 2q (Table 1, entry 17), whereas debenzyla-
tion competed with hydrolysis in the case of the less hindered
compounds 2o and 2p (Table 1, entries 15 and 16). Due to the
conjugation between the phenyl group and the iminium p
plane, the O-benzyl group of compounds 2o and 2p will be
positioned perpendicular to the iminium p plane to avoid
steric repulsion with the aromatic ortho proton and the phe-
nethyl group. Conversely, the O-benzyl group of compound
2q need not be oriented in such a direction because the
phenylÀCN bond of compound 2q will be twisted as the
phenylÀCO bond of compound 1q (see below), thus, debenzy-
lation no longer occur.
Conformational discussion for the O-benzylation step
The O-benzylation of amides is strongly affected by steric hin-
drance around the carbonyl lone pairs. The lone pairs, both
syn and anti to the nitrogen atom, can be involved in benzyla-
tion reactions by using DPT-BM (Figure 2).[18]
Due to the conjugation between the nitrogen atom and the
carbonyl group, substituents at the nitrogen atom are posi-
tioned as either syn or anti to the carbonyl group. Thus, a suffi-
ciently bulky syn substituent on the nitrogen atom would pre-
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to Meerwein reagents in most cases. For some exceptions, a,a-
di-substituted lactams, secondary aromatic amides, and di-sub-
stituted tertiary amides can be cleaved by Meerwein reagents,
although longer reaction times (12 h to 4 d) were needed per-
haps due to a poor reactivity of these amides. These results in-
dicate that DPT-BM exhibits milder reactivity than Meerwein re-
agents.
Figure 2. Conformation of amides showing the lone pairs.
vent the syn lone pair from participating in the benzylation.
Conversely, when a sufficiently bulky substituent on the a-
carbon atom is positioned as syn or synclinal to the carbonyl
oxygen atom, benzylation involving the anti lone pair is hin-
dered. In the case of primary amides, O-benzylation can take
place through the unhindered syn lone pair (i.e., compounds
1a–1d and 1n, Table 1, entries 1–4 and 14). Reaction of a di-
substituted secondary amide can proceed through conforma-
tions with either the N-alkyl group being anti to the carbonyl
oxygen atom, or the acyl substituents being anti or anticlinal
to the carbonyl oxygen atom (see compound 1 f, Table 1,
entry 6). Here, the tri-substituted secondary amide was inert to
O-benzylation because both lone pairs are blocked (see com-
pound 1g, Table 1, entry 7), with the N-alkyl group occupying
the position syn to the carbonyl oxygen atom because of the
buttressing effect of the bulky adamantyl group. Conversely,
the syn lone pair in a lactam can react with DPT-BM because
the N-alkyl group constituting the lactam ring is locked in the
anti conformation (see compound 1j, Table 1, entry 10). In the
case of tertiary amides, di-substituted amides such as com-
pound 1l were inert to the benzylation with DPT-BM (Table 1,
entry 12), because the acyl substituents occupy positions syn
or synclinal to the carbonyl oxygen atom owing to the but-
tressing effect of the N-alkyl group. The O-benzylation of the
secondary aromatic amides 1o and 1p hardly occurred owing
to the steric effects of ortho hydrogen atoms of the benzoyl
group (Table 1, entries 15 and 16). Due to the coplanarity of
the benzoyl moiety, the hydrogen atoms not only hinder the
anti lone pair directly, but also push the N-phenethyl group
into a position syn to the carbonyl oxygen atom by a buttress-
ing effect. This steric effect seems to be predominant over the
electronic effect of the substituents on the phenyl group of
the benzoyl moiety because compound 1p, whose electron
density at the carbonyl oxygen atom is increased by the para-
methoxy group, gave compound 2p in a yield similar to that
of compound 2o. In the case of the tertiary aromatic amide
1q (Table 1, entry 17), because the carbonyl group can conju-
gate with the amide nitrogen atom more strongly than with
the phenyl group, the COÀNR bond in the amide group retains
its coplanarity; therefore, the phenylÀCO bond is preferentially
twisted.[19] NMR chemical shift analysis supports this conforma-
tional change; the chemical shift of the aromatic ortho protons
of compound 1q (d=7.41–7.38 ppm) appears at a higher
magnetic field than those of the non-twisted secondary amide
1o (d=7.72–7.66 ppm). The reaction of the anilide 1r did not
proceed probably because of its electron deficiency (Table 1,
entry 18). The observed reactivity and substrate selectivity of
DPT-BM in the amide cleavage seem to be similar to that of
Meerwein reagents (see Table S2 in the Supporting informa-
tion). Thus, DPT-BM can be considered as a useful alternative
Selective amide-cleavage reactions
In order to show the synthetic advantages of DPT-BM by ex-
ploiting its milder reactivity, we have achieved chemoselective
amide-cleavage reactions with different types of amides. In
a competitive reaction between the aliphatic amide 1e and
the aromatic amide 1o, compound 1e preferentially reacted
over compound 1o at a ratio of 93:7 (Scheme 2A). It is worth
noting that the regioselective amide cleavage of 2-methyl-glu-
taramide (1t) proceeded to give the mono-ester-mono-amide
3t in 92% yield, and neither the regioisomer nor the diester
was detected (Scheme 2B). The single a-methyl group of com-
pound 1t is responsible for the regioselectivity of the reaction.
Chemoselective conversion of an amide into a carboxylic acid
in the presence of an ester moiety is challenging, because the
ester group is usually more reactive than the amide group
under basic or acidic conditions. The conversion of compound
1u possessing an ethyl ester moiety into the benzyl imidate
salt, and the subsequent hydrolysis proceeded to give the
benzyl ester 3u and the phenethylamine 4 in 89 and 70%
yields, respectively (Scheme 2C). Hydrogenolysis of the result-
ing benzyl ester 3u gave the carboxylic acid 5 in 95% yield
without affecting the ethyl ester moiety. These results illustrate
the outstanding reactivity and selectivity of DPT-BM.
Scheme 2. Chemoselective amide-cleavage reactions.
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rification unless otherwise noted. The benzamide 1n, solvent
grade diglyme, chloroform, and dichloromethane were purchased
from commercial sources, and 1,2-dimethoxyethane was purchased
from commercial sources and distilled over metal sodium before
use. All reactions sensitive to oxygen or moisture were conducted
under a N2 atmosphere.
Interestingly, DPT-BM still has the ability to produce amides
from carboxylic acids and amines, because DPT-BM has a struc-
ture similar to the dehydrocondensing reagent, DMT-MM.[11]
Reaction of 3-phenylpropionic acid (6) and the phenethyl
amine 4 with 1.1 equivalents of DPT-BM proceeded to give the
amide 1e in 21% yield (Scheme 3).[20] Thus, DPT-BM is able to
effect both amide-cleaving and amide-forming reactions as en-
zymes do. However, in contrast to enzymes, which often cata-
lyze a reversible reaction through the same pathway, DPT-BM
effects the reactions through different reaction pathways.
Procedure for the synthesis of 4-(4,6-diphenoxy-1,3,5-triazin-2-
yl)-4-benzylmorpholinium trifluoromethanesulfonate (DPT-BM)
4,6-Diphenoxy-2-trifluoromethanesulfonyloxy-1,3,5-triazine (the pre-
cursor of DPT-BM): Sodium acetate (3.31 g, 40.4 mmol) and 4-meth-
ylmorpholine (4.44 mL, 40.4 mmol) were added to a solution of 2-
chloro-4,6-diphenoxy-1,3,5-triazine (11.0 g, 36.7 mmol) in methanol
(120 mL) at room temperature. After stirring for 30 min, the reac-
tion mixture was filtered through a pad of celite. The solvent was
concentrated in vacuo and chloroform was added to the residue.
The mixture was washed with a 1m aqueous solution of HCl and
brine. The organic layer was dried over Na2SO4, the solvent was
concentrated in vacuo to afford 2-hydroxy-4,6-diphenoxy-1,3,5-tria-
zine (9.8 g) as a white solid, which was used in the next reaction
step without further purification. Trifluoromethanesulfonic anhy-
dride (6.79 mL, 40.4 mmol) and N,N-diisopropylethylamine
(7.06 mL, 40.4 mmol) were added to a solution of 2-hydroxy-4,6-di-
phenoxy-1,3,5-triazine (9.8 g) in dichloromethane (91 mL) at 08C.
After stirring for 1.5 h, the reaction mixture was washed with a satu-
rated aqueous solution of NH4Cl and brine. The organic layer was
dried over Na2SO4 and the solvent was concentrated in vacuo. The
residue was purified by column chromatography (hexane/EtOAc=
9:1) to give the title compound (9.9 g, 65%) as a white solid. M.p.
78–808C; 1H NMR (400 MHz, CDCl3): d=7.46–7.38 (m, 4H), 7.34–
7.27 (m, 2H), 7.19–7.12 ppm (m, 4H); 13C NMR (100 MHz, CDCl3):
d=173.8, 167.9, 151.1, 129.7, 126.8, 121.0, 118.3 ppm (q, J=
319 Hz, CÀF); HRMS (FAB): m/z calcd for C16H11F3N3O5S: 414.0372
[M+H]+; found: 414.0371; elemental analysis calcd (%) for
C16H10F3N3O5S: C 46.49, H 2.44, N 10.17; found: C 46.43, H 2.48, N
10.40.
Scheme 3. Dehydrocondensation reaction of a carboxylic acid and an amine
by using DPT-BM.
Conclusion
In conclusion, we successfully developed a new amide-cleav-
age reaction based on the electrophilic benzylation of amides
by using DPT-BM, which is a highly practical, and therefore,
a useful alternative to Meerwein reagents because it is an air-
stable benzylating reagent that generates benzyl cation equiv-
alents under neutral conditions at room temperature. We sys-
tematically elucidated the relationship between the structure
and the reactivity of amides undergoing cleavage with DPT-BM
and conclude that it is dependent on the steric and electronic
characteristics of the amides. On the basis of these reactivity
characteristics, regio- or chemoselective cleavage reactions
were achieved; in particular an amide containing an ester
moiety—a functional group with which conventional amide-
cleavage methods are incompatible—was cleaved without af-
fecting the ester group.
4-(4,6-Diphenoxy-1,3,5-triazin-2-yl)-4-benzylmorpholinium trifluorome-
thanesulfonate (DPT-BM): 4-Benzylmorpholine (3.50 mL, 20.9 mmol)
was added to a solution of 4,6-diphenoxy-2-trifluoromethanesulfo-
nyloxy-1,3,5-triazine (7.86 g, 19.0 mmol) in THF/Et2O (1:1 v/v,
38 mL) at À408C. After stirring for 13 h, Et2O (100 mL) was added
to the mixture. The formed precipitate was filtered and washed
with cold Et2O to afford DPT-BM (10.3 g, 92%) as a white solid.
Experimental Section
1
M.p.: 82–848C; H NMR (400 MHz, CDCl3, at À308C): d=7.60–7.50
Nuclear magnetic resonance (1H NMR (400 MHz), 13C NMR
(100 MHz)) spectra were determined on a JEOL JNM-ECS400 spec-
trometer. Chemical shifts are reported as d values relative to tetra-
methylsilane as the internal standard and coupling constants are
given in [Hz]. The following abbreviations are used for spin multi-
plicity: s=singlet, d=doublet, t=triplet, m=multiplet, br=broad.
Chemical shifts for 13C NMR spectroscopy were reported in [ppm]
relative to the center line of a triplet at 77.16 ppm for deuterio-
chloroform. Mass spectra were measured on JMS-SX102A (FAB),
JMS-T100TD (ESI, DART). Chiral HPLC was performed on a JASCO
LC-2000 series by using Daicel CHIRALPAK IB-3. Analytical thin layer
chromatography (TLC) was performed on Merck precoated analyti-
cal plates, 0.25 mm thick, silica gel 60 F254. Preparative TLC separa-
tions were performed on Merck analytical plates (0.25 or 0.50 mm
thick) precoated with silica gel 60 F254. Flash chromatography sep-
arations were performed on KANTO CHEMICAL silica gel 60 N
(spherical, neutral, 40–100 mesh) unless otherwise noted. Recycling
preparative HPLC was performed with Japan Analytical Industry
LC-928 equipped with the GPC columns Jaigel-1H and 2H. Re-
agents were of commercial grade and were used without any pu-
(m, 1H), 7.45–7.33 (m, 6H), 7.32–7.25 (m, 2H), 7.12–7.00 (m, 6H),
5.03 (s, 2H), 4.30–4.19 (m, 2H), 4.18–4.10 (m, 2H), 3.99–3.89 (m,
2H), 3.78–3.66 ppm (m, 2H); 13C NMR (100 MHz, CDCl3, at À308C):
d=173.6, 168.9, 150.8, 132.0, 131.5, 129.9, 129.4, 127.2, 125.3,
120.8, 120.5 (q, J=315 Hz, CÀF), 74.5, 62.0, 57.9 ppm; HRMS (FAB):
m/z calcd for C26H25N4O3: 441.1927 [MÀCF3O3S]+; found: 441.1929;
elemental analysis calcd (%) for C27H25F3N4O6S: C 54.91, H 4.27, N
9.49; found: C 54.78, H 4.32, N 9.53.
General procedure for the amide-cleavage reaction: DPT-BM
(0.68 mmol, 2.0 equiv) was added to
a solution of amide
1 (0.34 mmol) and activated MS5ꢁ (33.5 mg) in DME (335 mL) at
room temperature. After stirring for 2 h, the reaction mixture was
concentrated in vacuo. The ratio of starting amides 1 and the imi-
1
date salts 2 was analyzed by H NMR spectroscopy. After that, the
hydrolysis reaction was conducted in DME/H2O (1:1 v/v, 2 mL) at
room temperature for 0.5 h. The reaction mixture was diluted with
EtOAc and washed with brine. The organic phase was dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography (hexane/EtOAc) to afford the
benzyl esters 3.
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C. K. McClure, Synth. Commun. 1997, 27, 923; m) G. E. Keck, M. D.
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Acknowledgements
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2014, 20, 12274.
This work was partially supported by JSPS KAKENHI Grant
Number 25460012.
[12] Similar method by using benzyl trichloroacetimidate and trimethylsilyl
trifluoromethanesulfonate have been investigated. However, this
method was only applied to lactams. See references [9g,i,k].
[13] Reported amide-cleavage reactions after reference [9m] was published,
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S. Yoshida, H. Hashimoto, S. Hosokawa, Tetrahedron Lett. 2012, 53, 422;
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[14] Several combinations of organic solvents and water for the hydrolysis
were tested by using compound 2e. See Table S1 in the Supporting In-
formation.
[15] The ratio of compound 2 to compound 1 was calculated based on the
benzylic protons of compound 2 and the appropriate protons of com-
pound 1 by using 1H NMR spectroscopy in CDCl3. See the Supporting
Information.
[16] CarbonÀoxygen bond cleavage in the hydrolysis of imidate under
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DPT-BM in nucleophilic attack by carboxylates due to the steric hin-
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O-benzylation of carboxylates. M. Kunishima, T. Ujigawa, Y. Nagaoka, C.
Kawachi, K. Hioki, M. Shiro, Chem. Eur. J. 2012, 18, 15856.
Keywords: amide cleavage · benzylation · carbocations ·
electrophilic addition
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Received: June 30, 2016
Published online on && &&, 0000
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ÝÝ These are not the final page numbers!

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FULL PAPER
Cleave it: A mild method for amide-
cleavage by using 4-(4,6-diphenoxy-
1,3,5-triazin-2-yl)-4-benzylmorpholinium
trifluoromethanesulfonate (DPT-BM),
which generates benzyl cation species
at room temperature, has been devel-
oped (see scheme). O-Benzylation of
amides with DPT-BM and subsequent
hydrolysis of the resulting benzyl imi-
date salts give the corresponding
amines and benzyl esters.
&
Reaction Mechanisms
K. Yamada, Y. Karuo, Y. Tsukada,
M. Kunishima*
&& – &&
Mild Amide-Cleavage Reaction
Mediated by Electrophilic Benzylation
Chem. Eur. J. 2016, 22, 1 – 7
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7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ