Potent triazine-based dehydrocondensing reagents substituted by an amido group

Article abstract of DOI:10.3762/bjoc.12.179

This study describes the synthesis of triazine-based dehydrocondensing reagents substituted by amido substituents and demonstrates their efficiency for dehydrocondensing reactions in MeOH and THF. N-Phenylbenzamido-substituted chlorotriazine is readily converted to a stable, non-hygroscopic triazinylammonium-based dehydrocondensing reagent that is superior to 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) in terms of its reactivity in dehydrocondensing reactions.

Full text of DOI:10.3762/bjoc.12.179

Potent triazine-based dehydrocondensing reagents
substituted by an amido group
Munetaka Kunishima*1, Daiki Kato1, Nobu Kimura1, Masanori Kitamura1, Kohei Yamada1
and Kazuhito Hioki2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1897–1903.
1Faculty of Pharmaceutical Sciences, Institute of Medical,
Pharmaceutical, and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan and 2Faculty of
Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima
Chuo-ku, Kobe 655-8586, Japan
doi:10.3762/bjoc.12.179
Received: 31 May 2016
Accepted: 05 August 2016
Published: 24 August 2016
Email:
Associate Editor: R. Sarpong
Munetaka Kunishima* - kunisima@p.kanazawa-u.ac.jp
© 2016 Kunishima et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
amide-forming reactions; amido substituents; dehydrocondensing
reactions; Fischer-type esterification; triazines
Abstract
This study describes the synthesis of triazine-based dehydrocondensing reagents substituted by amido substituents and demon-
strates their efficiency for dehydrocondensing reactions in MeOH and THF. N-Phenylbenzamido-substituted chlorotriazine is
readily converted to a stable, non-hygroscopic triazinylammonium-based dehydrocondensing reagent that is superior to 4-(4,6-
dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) in terms of its reactivity in dehydrocondensing reac-
tions.
Introduction
We previously reported that dehydrocondensing reactions be- the recovery of hydrolyzed carboxylic acids and the formation
tween carboxylic acids 1 and amines 2 to give amides 3 effi- of corresponding esters. DMT-MM is quantitatively synthe-
ciently proceed in water or alcohols in the presence of the dehy- sized from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and
drocondensing reagent, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- N-methylmorpholine (NMM). Related triazinylammonium salts
methylmorpholinium chloride (DMT-MM) (Scheme 1a,b) (DMT-Am) can be prepared from other tertiary amines 5
[1-5]. The mechanism of the reaction shown in Scheme 1b instead of NMM (Scheme 1c) [6].
involves the acyloxytriazine intermediate 4, which has appro-
priate reactivity and sufficient stability to hydrolysis or alcohol- Since the direct reaction of carboxylates with CDMT is very
ysis. This feature enables the use of DMT-MM for dehydrocon- slow, the formation of DMT-Am is essential for the conversion
densing reactions in water or alcohols to give amides without of carboxylates into 4 [7]. Therefore, we developed catalytic
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Scheme 1: Dehydrocondensing reactions using DMT-MM or DMT-Am, and a catalytic amide-forming reaction.
amide-forming reactions in water using triazinylammonium result may indicate that the tuning of the π-electron density
salts (DMT-Am) generated in situ from CDMT and a catalytic within the triazine ring is important in either enhancing or sup-
amount of tertiary amines 5 (Scheme 1d). Most notably, by pressing its reactivity. To find a novel triazine-based dehydro-
introducing various functional groups into 5, it was possible to condensing reagent, we are focusing on the effect of substitu-
develop a cyclodextrin-based artificial acyltransferase [7], a ents on the triazine ring. In this paper, we report the synthesis
crown-ether-based cyclotransferase [8], membrane fusion of and reactivity of triazine-based dehydrocondensing reagents
small unilamellar vesicles to form giant unilamellar vesicles [9], that have an amido group in place of the methoxy groups of
modular methods for the affinity labeling of targeting proteins CDMT or DMT-MM.
[10-12], and reaction acceleration on micelle interfaces [13,14].
Thus, various types of molecular recognitions of carboxylic Results and Discussion
acids were affected by fuctionalized DMT-Am. However, once We decided to use an amido group as a substituent on the
the reaction with 1 takes place, the functionalized tertiary triazine ring instead of a methoxy group based on Hammett sub-
amines 5 liberated, no longer affect the following reaction stituent constants, which indicate that an acetamido group is a
(Scheme 1d). As a consequence, the resulting acyloxyatriazine more electron-withdrawing group (σm = 0.31 for –NMeCOMe,
intermediate 4, which is the same intermediate in Scheme 1b, 0.21 for –NHCOMe, and 0.12 for –OMe [19]). In addition, we
basically shows the same reactivity for aminolysis and expected that the appropriate substitution pattern of amido
alcoholysis regardless of which tertiary amine 5 was used groups (R3 and R4 in Figure 1) would enable the precise control
(Scheme 1b,d). Therefore, it is reasonable to modify the activi- of the reactivity of triazines in dehydrocondensing reactions.
ty of the 1,3,5-triazine ring that is involved in both steps shown We therefore synthesized various secondary or tertiary amide-
in Scheme 1b by introducing another substituent in place of the type chlorotriazines (I–VI) by the substitution of only one me-
methoxy groups.
thoxy group of CDMT because it is straightforward to evaluate
the effect of a single amido substituent. For the design and syn-
To date, several triazine derivatives possessing phenoxy thesis of I–VI, acetamido and benzamido groups were selected
[15,16], 2,2,2-trifluoroethoxy [17], or N-ethylamino groups [18] as the amido substituents (R3 = Me or Ph), and the methyl,
in place of the methoxy groups have been prepared, and the re- phenyl, or hydrogen substituent was placed at R4.
activity of these compounds in amide-forming reactions has
been examined. The reactivity of triazine was found to slightly Tertiary amide-type compounds III–VI were prepared in one
increase following the introduction of electron-withdrawing step from the well-known commercially available 2,4-dichloro-
phenoxy or 2,2,2-trifluoroethoxy groups and decrease upon the 6-methoxy-1,3,5-triazine (6) [20] (Scheme 2). In contrast,
inclusion of an electron-donating N-ethylamino group. This attempts to prepare the secondary amide-type I and II using the
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Beilstein J. Org. Chem. 2016, 12, 1897–1903.
same method resulted in low yields mainly because of the sub-
stitution of the methoxy group of 6 by amido anions (Support-
ing Information File 1). Thus, these compounds were success-
fully synthesized using an alternative method starting from
cyanuric chloride via an intermediate 7 (Scheme 2).
Single-crystal X-ray structure analysis, two-dimensional NMR
spectroscopy, or derivatization of I–VI was performed to unam-
biguously determine their structures, i.e., whether the N- or
O-substituted derivative was prepared from the amido anion
(Supporting Information File 1).
To evaluate the reactivity of these chlorotriazines in amide-
forming reactions, one-pot reactions were performed (Table 1a),
i.e., the chlorotriazines were added to a mixture of carboxylic
acid 1a, amine 2a, and NMM in MeOH or THF at room temper-
ature. The amide-forming reaction in the absence of NMM did
not proceed, meaning that triazinylmorpholinium salts are the
actual reactive species (Supporting Information File 1). To
permit an accurate comparison between the chlorotriazines, all
amide-forming reactions presented in Table 1 were conducted
for 3 h.
Compared with CDMT, low yields of the amide 3a were ob-
tained using the secondary amide-type I and II, possibly
because of the low solubilities of I and II in the reaction sol-
vents owing to the acidic proton of the secondary amide. When
using III–VI, which were soluble in reaction solvents, the
yields of 3a in both MeOH and THF, particularly the high yield
of 3a obtained using benzamido-substituted VI, were compa-
rable with those obtained using CDMT.
Figure 1: Structures of amido-substituted chlorotriazines.
Scheme 2: Synthesis of amido-substituted chlorotriazines.
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Table 1: Amide-forming reactions using chlorotriazines (I–VI) or triazinylammonium salts (VII–X).
(a) in situ amidation
yield (%)
(b) preparation of condensing reagents (VII–X)
(c) amidation using
VII–X
yield (%)
in MeOH
88
in THF
81
additive
–
yield (%)
100
in MeOH
98
in THF
84
chlorotriazine
CDMT
DMT-MM
I
70
86
95
90
91
93
55
80
60
73
72
79
–a
–a
–a
–a
98
91
90
80
–a
–a
75
88
75
95
–a
–a
50
84
81
89
II
–a
–a
III
IV
V
VII (Y =ClO4)b
VIII (Y = ClO4)b
IX (Y = Cl)b
X (Y = Cl)b
LiClO4 (1.1 equiv)
LiClO4 (1.1 equiv)
–
–
VI
aThe reaction was not conducted. bThe counter anions were shown in parentheses.
From these results, dehydrocondensing reagents (VII–X, (THF solvent, Table 1c) and identified N-acetyl-2-phenylethyl-
Table 1) were prepared from III–VI and NMM (Table 1b). Al- amine in 29% and 25% yields, respectively. This byproduct was
though benzamido-substituted IX and X could be readily syn- formed by the aminolysis of the N-methylacetamido group on
thesized, acetamido-substituted triazines were hygroscopic, and the triazine ring by 2a. A similar phenomenon was observed for
therefore, VII and VIII were prepared as stable, non-hygro- IV or VIII in THF. Notably, such a byproduct was not ob-
scopic reagents by counterion exchange in the presence of tained in the case of V, IX, VI, and X. In MeOH, no such
LiClO4 [6].
byproduct resulting from aminolysis was observed in all the
cases.
Amide-forming reactions using the dehydrocondensing reagents
VII–X were then examined (Table 1c). While X afforded a We employed X to further study the synthesis of various amides
good yield (95% in MeOH and 89% in THF) of the amide 3a in with a particular focus on the stability and non-hygroscopic
both solvents, slightly low yields (75–88% in MeOH and property of the reagent (Table 2). In most cases, X exhibited
50–84% in THF) for VII and VIII were obtained, possibly similar reactivity in MeOH compared with DMT-MM, and the
because of the low solubilities of these reagents in the investi- amides 3 were obtained with negligible formation of the corre-
gated solvents (perchlorate salts have generally low solubili- sponding methyl ester 8 (Table 2, entries 1, 5, 7, and 9). In the
ties).
case of the sterically hindered secondary amine 2c, methyl ester
8 was obtained as a byproduct in 31% and 24% yields for X and
We then analyzed the NMR spectra of crude mixtures obtained DMT-MM (Table 2, entry 3), respectively. In contrast, the
from the reactions using III (THF solvent, Table 1a) or VII yields obtained in THF using X were superior to those obtained
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Beilstein J. Org. Chem. 2016, 12, 1897–1903.
Table 2: Substrate scope of carboxylic acids 1 and amines 2.
X
DMT-MM
yield (%)a
yield (%)a
entry
carboxylic acid
amine
2b
amide
solvent time (h)
3
8
time (h)
3
8
1
2
MeOH
THF
6
6
80
75
(1)
–
24
24
73
16
(0)
–
3b
1a
1a
3
4
MeOH
THF
6
4
65
85
(31)
–
9
4
56
24
–
3c
3d
68b
2c
5
6
MeOH
THF
6
3
(87)
(90)
(3)
–
6
3
(89)
(86)
(0)
–
1b
2a
2a
7
8
MeOH
THF
4
4
97
95
(8)
–
3
4
90
(1)
–
3e
3f
81b
1c
1d
9
MeOH
THF
4
4
91
96
(2)
–
3
3
86
(4)
–
2a
10
82b
aIsolated yields. 1H NMR yields are given in parentheses. bFrom reference [2].
using DMT-MM (Table 2, entries 4, 6, 8, and 10), especially for Conclusion
the poorly nucleophilic aniline 2b (Table 2, entry 2).
We prepared triazine-based dehydrocondensing reagents bear-
ing amido substituents and demonstrated their efficiency for
To elucidate the reactivities of X and DMT-MM, time courses their use in dehydrocondensing reactions in both MeOH and
of amide-forming reactions using sterically hindered pivalic THF. The tertiary amide-type chlorotriazines III–VI gave better
acid (1b) and 2-phenylethylamine (2a) in MeOH and THF were yields of the product 3a compared with the secondary amide-
investigated by 1H NMR spectroscopy (Figure 2a,b, respective- type chlorotriazines I and II, possibly because of the reduced
ly). The steric hindrance of 1b was suitable to investigate the solubilities of I and II in the reaction solvents. VI is readily
reaction rates for X and DMT-MM. Although the final yields of converted to a triazinylammonium-based dehydrocondensing
the amide were almost the same for both triazines, the rate of reagent as a chloride salt (X), which is stable and non-hygro-
the reaction with X was faster than that with DMT-MM, partic- scopic. The dehydrocondensing reagent X is superior to DMT-
ularly in THF.
MM in terms of reactivity in dehydrocondensing reactions. Al-
though DMT-MM is the appropriate reagent for dehydrocon-
Similarly, time courses of the basic Fischer-type esterification densing reactions in large-scale synthesis, X have advantage for
of 3-phenylpropanoic acid (1a) in neat MeOH were studied dehydrocondensing reactions in aprotic solvents such as THF,
(Figure 3). Although X was shown to exist as a dihydrate by especially when low nucleophilic starting materials such as
elemental analysis and single-crystal X-ray structure analysis, aniline were used. This study contributes to the development of
the yield of methyl 3-phenylpropanoate was quantitative. The novel functionalized triazine-based dehydrocondensing reagents
rate of esterification with X was faster than that with DMT- that are effective for aminolysis or alcoholysis shown in the
MM.
second step of Scheme 1b.
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Beilstein J. Org. Chem. 2016, 12, 1897–1903.
Figure 2: Time courses of the amide-forming reactions.
Supporting Information
General information, synthesis of triazines I–X and
structure determination, spectral data of amides 3,
attempted synthesis of I from 6, amide-forming reaction
with VI in the absence of NMM, and copies of 1H and
13C NMR spectra of unknown compounds are given.
Supporting Information File 1
Experimental and characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-179-S1.pdf]
Acknowledgements
This work was supported by JSPS KAKENHI Grant (No.
26293003).
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4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. In
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