Development of Triazinone-Based Condensing Reagents for Amide Formation

Article abstract of DOI:10.1021/acs.joc.9b01261

Novel triazinone-based condensing reagents have been developed. The palladium-catalyzed O-N allylic rearrangement of 2-(allyloxy)-4,6-dichloro-1,3,5-triazine and subsequent regioselective substitution using alcohols and an amine afforded chlorotriazinones, which can be readily converted using N-methylmorpholine into the corresponding condensing reagents. The condensation of carboxylic acids and amines using these reagents proceeded to afford the desired amides in good yields. In comparison with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, the newly synthesized triazinone-based condensing reagents exhibited higher reactivity.

Full text of DOI:10.1021/acs.joc.9b01261

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Development of Triazinone-Based Condensing Reagents for Amide
Formation
Kohei Yamada, Mika Kota, Kensuke Takahashi, Hikaru Fujita, Masanori Kitamura,
and Munetaka Kunishima*
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan
S
* Supporting Information
ABSTRACT: Novel triazinone-based condensing reagents have been developed.
The palladium-catalyzed O−N allylic rearrangement of 2-(allyloxy)-4,6-dichloro-
1,3,5-triazine and subsequent regioselective substitution using alcohols and an amine
afforded chlorotriazinones, which can be readily converted using N-methylmorpho-
line into the corresponding condensing reagents. The condensation of carboxylic
acids and amines using these reagents proceeded to afford the desired amides in
good yields. In comparison with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmor-
pholinium chloride, the newly synthesized triazinone-based condensing reagents exhibited higher reactivity.
Previously, we reported a triazine-based acid-catalyzed
benzylating reagent, 2,4,6-tris(benzyloxy)-1,3,5-triazine (Tri-
BOT), and its derivatives (Figure 1A).5 Additionally, we have
also developed highly reactive triazinedione-based benzylating
reagents, 6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
(MonoBOT) and N,N′-dimethylated 6-(benzyloxy)-1,3,5-
triazine-2,4-(1H,3H)-dione (DMBOT).6 DMBOT is more
reactive than TriBOT and can thus benzylate alcohols in the
presence of 2,6-di-tert-butylpyridinium trifluoromethanesulfo-
nate, a relatively weak acid catalyst, which is not effective for
the benzylation using TriBOT. With regard to the calculation
study of the sequential tautomerization of cyanuric acid to
isocyanuric acid,7 the difference in the reactivity of these
benzylating reagents can be explained as follows: the enthalpy
change from MonoBOT (DMBOT) to isocyanuric acid is
considered to be larger than that from TriBOT to 4,6-bis-
(benzyloxy)-1,3,5-triazin-2(1H)-one.5c Accordingly, the triazi-
nedione- and triazinone-based condensing reagents 1 and 2,
respectively, are also expected to be highly reactive despite the
absence of a strong electron-withdrawing group (Figure 1B).
Indeed, the lowest unoccupied molecular orbital (LUMO)
energy levels of CDMT, chlorotriazinone 3, and chlorotriazi-
nedione 4 were calculated as −1.13, −1.54, and −1.55 eV,
respectively (B3LYP/6-31G* level of theory, Figure 1C).
These results indicate that with regard to the formation of
acyloxytriazines, which is the rate-determining step in the
condensation,3g the triazinone- and triazinedione-based
condensing reagents 1 and 2, respectively, are more reactive
than DMT-MM.
INTRODUCTION
■
A triazine-based condensing reagent, 4-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM),
which is synthesized from 2-chloro-4,6-dimethoxy-1,3,5-
triazine (CDMT) and N-methylmorpholine (NMM), has
been widely used for the synthesis of amides from carboxylic
acids and amines in alcohols or water (eqs 1 and 2).1N-
Methylmorpholino group of DMT-MM can be replaced by
other trialkylammonio groups using alternative tert-amines as
long as they satisfy the steric and electronic requirements for
the formation of triazinylammonium salts.2 Therefore, using
functionalized tert-amines, we previously developed substrate-
selective amidations via molecular recognition.3 Moreover, the
synthesis of several chlorotriazines possessing substituents,
such as phenoxy, trifluoroethoxy, N-ethylamino, amido, and
imido was reported for the control of reactivity.4 It appears
reasonable that the replacement of the methoxy group at the
triazine ring by more electron-withdrawing functionality would
result in more reactive condensing reagents. However, a strong
electron-withdrawing group bonded to triazine via a
heteroatom, such as oxygen or nitrogen, may also serve as an
eliminating group, which makes the corresponding condensing
reagent unstable. Therefore, new highly reactive stable triazine
derivatives devoid of a strong electron-withdrawing group are
required to address this issue.
Herein, we report the synthesis and reactivity of new
condensing reagents possessing these promising core skeletons.
Received: May 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b01261
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The Journal of Organic Chemistry
Article
Figure 1. Concept and design of new condensing reagents.
Scheme 1. Attempt for the Synthesis of the Triazinedione- and Triazinone-type Condensing Reagents
OMe isomer in a 61:39 ratio (Scheme 1C). The reaction of
this regioisomeric mixture with NMM selectively produced
triazinylammonium salt 1-OMe; the 12-OMe isomer was inert
to the reaction with NMM due to the steric hindrance of the
adjacent N-allyl group.9
RESULTS AND DISCUSSION
■
Preliminary studies have revealed that the synthesis of N-
methylated cholorotriazinone 3 by N-alkylation using methyl
iodide was unsuccessful possibly because of the low
nucleophilicity of the anion intermediate 6 (Scheme 1A).
After extensive efforts, the formation of N,N-dialkylated
cholorotriazinedione and N-alkylated cholorotriazinone struc-
tures was achieved via the O−N allylic rearrangement of
allyloxytriazines.8 The reaction of 2,4-diallyloxy-6-chloro-1,3,5-
triazine (7) in the presence of a palladium catalyst smoothly
proceeded to afford the corresponding 1,3-diallyl-6-chloro-
1,3,5-triazine-2,4(1H,3H)-dione (8) (Scheme 1B). However,
when compound 8 was treated with NMM for 24 h, the
corresponding triazinylammonium salt (9) was not obtained.
Instead, the unreacted compound 8 and several decomposed
compounds, such as N-deallylated compound 10, were formed
as a result of the nucleophilic attack of the chloride
counteranion. The reaction of 2-(allyloxy)-4-chloro-6-me-
thoxy-1,3,5-triazine (11) with a palladium catalyst afforded a
mixture of regioisomeric chlorotriazinones 12-OMe and 12-
Further efforts led to the regioselective synthesis of 12-OMe
in 75% (three steps from cyanuric chloride; Scheme 2A) via
the O−N rearrangement of 2-(allyloxy)-4,6-dichloro-1,3,5-
triazine (13), followed by regioselective substitution at the
sixth position of the resulting 1-allyl-4,6-dichloro-1,3,5-triazin-
2(1H)-one (14) with MeOH.10 With a reliable procedure in
hand, we prepared the alkoxy derivatives 12-OEt and 12-OiPr
using EtOH and i-PrOH, respectively. Moreover, the amino-
substituted triazinone 12-NMe2 can be synthesized by
employing dimethylamine as a nucleophile. The treatment of
these synthesized chlorotriazinones with NMM afforded the
corresponding condensing reagents 1-OMe, 1-OEt, 1-OiPr,
and 1-NMe2 in good yields (Scheme 2B).11
We previously reported that DMT-MM in CH2Cl2 is
decomposed by demethylation at the morphonium nitrogen.
To investigate the stability of the new condensing reagents in
B
DOI: 10.1021/acs.joc.9b01261
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Scheme 2. Successful Synthesis of Triazinone-type Condensing Reagents
an aprotic solvent, NMR experiments were performed in
CDCl3. Demethylation at the nitrogen atom and/or deal-
kylation at the oxygen atom occurred to generate X and Y,
respectively (Table 1). From the viewpoint of stability of these
The substrate scope of a series of carboxylic acids 15 and
amines 16 was evaluated (Table 3). While the reactions of the
secondary amine 16b using either 1-OiPr or 1-NMe2 in
MeOH resulted in moderate yields (56 and 59% yields,
respectively, entries 1 and 3), the reactions in THF afforded
the product 17ab in good yields (86 and 88% yields,
respectively, entries 2 and 4). On the contrary, dibenzylamine
16c in either MeOH or THF afforded a tertiary amide 17ac in
excellent yields (entries 5 and 6). The coupling of sterically
bulky pivalic acid 15b with 16a produced 17ba in moderate
yields (entries 7−10). Next, several aromatic acids were used
as starting materials. Similar to the reaction using aliphatic acid
15a, the reaction of benzoic acid 15c with 16a using 1-OiPr
for 10 min afforded benzamide 17ca in excellent yields (entries
11 and 12). The condensation between 15c and 16a using 1-
NMe2 also gave good yields (91%, entries 13 and 14), although
prolonged reaction times (7 h in MeOH, and 3 h in THF)
were required. The reaction was amenable to both electron-
rich (entries 15−18) and electron-poor benzoic acids (entries
19−22). As in the case of the reactions of aliphatic acids and
secondary amines (entries 1−6), the coupling of benzoic acid
15c with secondary amines 16b and 16c in THF afforded the
corresponding products in high yields (entries 24, 26, and 28),
while the reaction in MeOH exhibited inferior results when 1-
OiPr was used (entries 23 and 27). Compared to DMT-MM,
1-OiPr and/or 1-NMe2 gave higher yields in THF, although
DMT-MM often afforded good yields in MeOH. Users can
select from these reagents depending on the purpose.
Table 1. Stability of the Condensing Reagents in CDCl3
1 (%)
X (%)
Y (%)
1-OMe
1-OEt
1-OiPr
1-NMe2
25
69
78
95
19
24
21
5
56
7
1
condensing reagents in a nonpolar solvent, 1-OiPr and 1-
NMe2 were found to be relatively stable; thus, they were used
for further investigation.
The treatment of 3-phenylpropionic acid 15a and phenethyl-
amine 16a with the condensing reagent 1-OiPr in tetrahy-
drofuran (THF) at room temperature for 2 h afforded the
corresponding amide 17aa in a modest yield (78%, entry 1,
Table 2). Since the protonation of 16a by an imide proton of
the coproduct, triazinedione, was considered responsible for
this moderate yield, we investigated the effect of the addition
of a proton capture agent. The addition of 1.1 equiv of
triethylamine was effective for the reaction (entries 3 and 4),
while the addition of NMM moderately increased the yield
(85%, entry 2). When MeOH was used as a solvent, amide
17aa was obtained in 87% yield (entry 5). The reaction in
MeOH in the presence of NMM increased the yield to 93%
(entry 6). The yields were maintained even at shortened
reaction time (10 min, entries 7 and 8). Similarly, in the case of
1-NMe2, the reaction in the presence of triethylamine in THF
and that in the presence of NMM in MeOH afforded the
amide in excellent yields (entries 9−13).
To evaluate the utility of the reagent, we conducted the
peptide synthesis. Amidations of Cbz-L-Phe-OH (15f) and
Cbz-D,L-Phe-OH (D,L-15f) with L-Ala-OMe (16d) using 1-
OiPr proceeded to give 17fd and D,L-17fd in 91 and 89%
yields, respectively (Scheme 3). Racemization at α-position of
phenylalanine moiety of 17fd was not observed (Supporting
Information, Figure S1). These results indicate that 1-OiPr is
superior to a triazine-type condensing reagent, DMT-MM-
(TsO) (77, 98% de),12 and comparable with other recently
reported Oxyma-type condensing reagents, such as HOTU
C
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Table 2. Screening of Reaction Conditions
a
entry
condensing reagent
solvent
proton capture agent
yield (%)
1
2
3
4
5
6
1-OiPr
1-OiPr
1-OiPr
1-OiPr
1-OiPr
1-OiPr
1-OiPr
1-OiPr
1-NMe2
1-NMe2
1-NMe2
1-NMe2
THF
THF
THF
THF
MeOH
MeOH
THF
MeOH
THF
THF
THF
MeOH
MeOH
none
78
85
NMM (1.1 equiv)
Et3N (1.1 equiv)
Et3N (0.5 equiv)
none
NMM (1.1 equiv)
Et3N (1.1 equiv)
NMM (1.1 equiv)
none
c
95 (95%)
84
87
93
91
95
67
86
95
64
87
b
7
8
b
9
10
11
12
13
NMM (1.1 equiv)
Et3N (1.1 equiv)
none
1-NMe2
NMM (1.1 equiv)
a
b
c
NMR yield. Reaction time: 10 min. Isolated yield.
(100, >99% de),13 o-NosylOXY (91, >99% de),14 and TsOXY
(93, 97% de).15
EXPERIMENTAL SECTION
■
General Methods. Nuclear magnetic resonance (1H NMR (400
MHz), 13C NMR (100 MHz)) spectra or nuclear magnetic resonance
(1H NMR (600 MHz), 13C NMR (150 MHz)) spectra were
determined on a JEOL JNM-ECS400 spectrometer or a JEOL JNM-
ECA600 spectrometer. Chemical shifts for 1H NMR are reported as δ
values relative to tetramethylsilane as the internal standard and
coupling constants are in hertz (Hz). The following abbreviations are
used for spin multiplicity: s = singlet, d = doublet, t = triplet, m =
multiplet, and br = broad. Chemical shifts for 13C NMR were
reported in ppm relative to the center line of a triplet at 77.16 ppm for
deuteriochloroform and 49.00 ppm for CD3OD. Mass spectra were
measured on JMS-T100TD, JMS−SX102A. Analytical thin-layer
chromatography (TLC) was performed on Merck precoated analytical
plates, 0.25 mm thick, silica gel 60 F254. Preparative TLC separations
were performed on Merck analytical plates (0.25 or 0.50 mm thick)
precoated with silica gel 60 F254. Flash chromatography separations
were performed on KANTO CHEMICAL Silica Gel 60 N (spherical,
neutral, 40−100 mesh) unless otherwise noted. Reagents were
commercial grades and were used without any purification unless
otherwise noted. All reactions sensitive to oxygen or moisture were
conducted under a N2 atmosphere. All calculations were performed
using Spartan’14. LUMO energy was obtained by density functional
theory calculations with the B3LYP/6-31G* basis set in vacuum.
General Procedure for the Synthesis of Chlorotriazinones.
To a solution of cyanuric chloride (461 mg, 2.5 mmol) in CH2Cl2 (5
mL) was added a mixture of diisopropylethylamine (479 μL, 2.75
mmol) and allylalcohol (187 μL, 2.75 mmol) at −10 °C. After stirring
for 18 h, reaction mixture was warmed up to room temperature. After
6 h, the reaction mixture was washed with 1 M HCl, water, and brine.
The organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure to give the crude allyloxytriazine 13, which
was used in the next reaction without further purification. A solution
of allyloxytriazine 13, NaHCO3 (630 mg, 7.5 mmol), and
Pd(PhCN)2Cl2 (29 mg, 0.075 mmol) in chloroform (10.5 mL) was
heated at reflux. After 3 h, the reaction mixture was cooled to −20 °C
and added MS3A (1.35 g). iPrOH (3.8 mL, 50 mmol) was added
dropwise over 40 min. After 1.5 h, the reaction mixture was warmed
to −10 °C. After 2 h, reaction mixture was gradually wormed to rt.
After 36 h, reaction mixture was filtered through celite pad and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane/AcOEt = 4:1) to give chlorotria-
zinone 12-OiPr (470 mg, 82% yield) as a white solid.
Based on the comparison of the reaction times for
synthesizing aromatic amide 17ca using 1-OiPr (10 min,
entry 11 in Table 2), 1-NMe2 (7 h, entry 13 in Table 2), and
DMT-MM (2 h),1c the order of reactivity of these condensing
reagents was 1-OiPr > DMT-MM > 1-NMe2. As in the case of
DMT-MM,3g the rate-determining step of the reaction using 1-
OiPr and 1-NMe2 was expected to be the formation of
acyloxytriazinone intermediates. To compare the relative
electrophilicity among these condensing reagents, substitution
reaction experiments were conducted (Scheme 4). Upon
treatment of the condensing reagents 1-OiPr, 1-NMe2, and
DMT-MM with triethylamine (1.0 equiv) in CD3OD for 10
min, the substitutions of the N-methylmorpholino group with
the deuterated methoxy group proceeded to afford 18-OiPr,
18-NMe2, and 19 in 89, 45, and 78% yields, respectively. These
results revealed that 1-OiPr is a more reactive condensing
reagent than DMT-MM and that the reactivity of triazinone-
type reagents can be modulated by replacement of the
substituent at the triazinone ring.
CONCLUSIONS
■
We successfully developed new triazinone-type reagents. The
formation of a triazinone skeleton via the palladium-catalyzed
O−N allylic rearrangement of allyloxytriazine, followed by
regioselective substitution using nucleophiles, such as alcohols
and an amine, provided the desired chlorotriazinones 12-OMe,
12-OEt, 12-OiPr, and 12-NMe2. The corresponding condens-
ing reagents 1-OMe, 1-OEt, 1-OiPr, and 1-NMe2 were readily
prepared. The condensations of several carboxylic acids and
amines including protected amino acids using 1-OiPr and 1-
NMe2 proceeded to give the desired amides in good yields.
The comparison of electrophilicity measured via substitution
reaction with CD3OD and calculation of LUMO energy levels
revealed that 1-OiPr is more reactive than DMT-MM.
D
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a
Table 3. Substrate Scope for Condensation Using 1-OiPr and 1-NMe2
a
b
From ref 1c. From ref 1b.
1-Allyl-4-chloro-6-methoxy-1,3,5-triazin-2(1H)-one (12-OMe).
White solid (380 mg, 75%); H NMR (400 MHz, CDCl3): δ 5.85
(ddt, J = 17, 11, 6.0 Hz, 1H), 5.29 (ddt, J = 17, 1.4, 1.4 Hz, 1H), 5.29
(ddt, J = 11, 1.4, 1.4 Hz, 1H), 4.55 (ddd, J = 6.0, 1.4, 1.4 Hz, 2H),
1
E
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Scheme 3. Synthesis of Dipeptides Using 1-OiPr
(d, J = 17 Hz, 1H), 5.32 (d, J = 11 Hz, 1H), 4.87 (s, 3H), 4.72 (q, J =
6.9 Hz, 2H), 4.62 (d, J = 6.4 Hz, 2H), 4.48−4.40 (m, 2H), 4.10−4.02
(m, 2H), 3.96−3.86 (m, 2H), 3.87−3.77 (m, 2H), 3.52 (s, 3H), 1.49
(t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD): δ 168.5,
166.7, 156.3, 130.8, 120.5, 70.7, 63.3, 61.2, 55.8, 46.9, 14.3; HRMS
(ESI-TOF) calcd for C13H21N4O3 (M − Cl+): 281.1614, found:
281.1629.
Scheme 4. Substitution Reaction of the Condensing
Reagents Using Triethylamine in CD3OD
4-(5-Allyl-6-isopropoxy-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-4-
methylmorpholinium chloride (1-OiPr). White solid (876 mg, 88%);
1H NMR (400 MHz, CD3OD): δ 5.92 (ddt, J = 17, 10, 6.0 Hz, 1H),
5.52 (sep, J = 6.4 Hz, 1H), 5.40 (dd, J = 17, 1.4 Hz, 1H), 5.32 (dd, J =
10, 1.4 Hz, 1H), 4.89 (s, 3H), 4.61 (ddd, J = 6.0, 1.4, 1.4 Hz, 2H),
4.47−4.38 (m, 2H), 4.11−4.01 (m, 2H), 3.96−3.86 (m, 2H), 3.86−
3.76 (m, 2H), 3.51 (s, 3H), 1.48 (d, J = 6.4 Hz, 6H); 13C{1H} NMR
(100 MHz, CD3OD): δ 168.6, 166.2, 156.4, 130.8, 120.4, 80.4, 63.3,
61.2, 55.7, 46.9, 21.9; HRMS (ESI-TOF) calcd for C14H23N4O3 (M −
Cl+): 295.1770, found: 295.1788.
4-(5-Allyl-6-(dimethylamino)-4-oxo-4,5-dihydro-1,3,5-triazin-2-
yl)-4-methylmorpholin-4-ium chloride (1-NMe2). White solid (709
mg, 96%); 1H NMR (400 MHz, CD3OD): δ 6.11 (ddt, J = 17, 11, 5.0
Hz, 1H), 5.28−5.41 (m, 2H), 4.56−4.64 (m, 2H), 3.64−4.47 (m,
8H), 3.46 (s, 3H), 3.28 (s, 6H); 13C{1H} NMR (100 MHz, CD3OD):
δ 166.8, 164.8, 159.6, 133.8, 118.4, 63.5, 60.8, 56.1, 52.2, 42.3; HRMS
(FAB-TOF) calcd for C19H19N4O3 ([M + H]+): 351.1457, found:
351.1456.
4.16 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.1, 162.8,
153.8, 129.4, 120.0, 57.9, 45.0; HRMS (DART-TOF) calcd for
C7H9ClN3O2 ([M + H]+): 202.0383, found: 202.0400; anal. calcd for
C7H8ClN3O2: C, 41.70; H, 4.00; N, 20.84. Found: C, 41.62; H, 4.01;
N, 20.83.
1-Allyl-4-chloro-6-ethoxy-1,3,5-triazin-2(1H)-one (12-OEt). Col-
orless oil (451 mg, 84%); 1H NMR (600 MHz, CDCl3): δ 5.85 (ddt, J
= 17, 10, 6.2 Hz, 1H), 5.29 (ddt, J = 17, 1.0, 1.0 Hz, 1H), 5.29 (ddt, J
= 10, 1.0, 1.0 Hz, 1H), 4.61 (q, J = 7.2 Hz, 2H), 4.55 (ddd, J = 6.2,
1.0, 1.0 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.0, 162.1, 153.8, 129.5, 119.8, 67.9, 44.8, 14.0; HRMS
(DART-TOF) calcd for C8H11ClN3O2 ([M + H]+): 216.0540, found:
216.0527; anal. calcd for C8H10ClN3O2: C, 44.56; H, 4.67; N, 19.49.
Found: C, 44.73; H, 4.71; N, 19.41.
1-Allyl-4-chloro-6-isopropoxy-1,3,5-triazin-2(1H)-one (12-OiPr).
General Procedure for Amidation. To the solution of acid 15c
(48.8 mg, 0.4 mmol), amine 16a (55 μL, 0.44 mmol), and N-
methylmorpholine (48 μL, 0.44 mmol) in MeOH (2 mL) was added
1-OiPr (146 mg, 0.44 mmol) at room temperature. After stirring for
10 min, the reaction mixture was quenched with 1 M aq. KHSO4 and
was concentrated under reduced pressure. The mixture was diluted
with CH2Cl2 and washed with 1 M HCl, sat. aq. NaHCO3, and brine.
The organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (hexane/AcOEt 7:3) to afford 17ca (87.5 mg,
97%) as a white solid.
1
White solid (470 mg, 82%); H NMR (400 MHz, CDCl3): δ 5.84
(ddt, J = 17, 11, 6.0 Hz, 1H), 5.48 (sep, J = 6.4 Hz, 1H), 5.28 (ddt, J =
16, 1.4, 1.4 Hz, 1H), 5.28 (ddt, J = 11, 1.4, 1.4 Hz, 1H), 4.53 (ddd, J =
6.0, 1.4, 1.4 Hz, 1H), 1.43 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3): δ 170.3, 161.8, 154.1, 129.7, 120.0, 77.0, 44.9, 21.8;
HRMS (DART-TOF) calcd for C9H13ClN3O2 ([M + H]+):
230.0696; found: 230.0713; anal. calcd for C9H12ClN3O2: C, 47.07;
H, 5.27; N, 18.30. Found: C, 46.97; H, 5.30; N, 18.50.
1-Allyl-4-chloro-6-(dimethylamino)-1,3,5-triazin-2(1H)-one (12-
1
NMe2). White solid (1.38 g, 64%); H NMR (600 MHz, CDCl3): δ
6.02 (ddt, J = 17, 11, 5.2 Hz, 1H), 5.31−5.37 (m, 1H), 5.20−5.26 (m,
1H), 4.51−4.55 (m, 2H), 3.17 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 168.9, 162.5, 156.2, 131.9, 118.3, 50.3, 41.5; HRMS (ESI+-
TOF) calcd for C8H12ClN4O ([M + H]+): 215.0700, found:
215.0703; anal. calcd for C8H11N4OCl: C, 44.76; H, 5.17; N, 26.10.
Found: C, 44.67; H, 5.15; N, 25.98.
General Procedure for the Synthesis of Condensing
Reagents. To a solution of chlorotriazinone 12-OiPr (689 mg, 3.0
mmol) in Et2O was added N-methylmorpholine (495 μL, 4.5 mmol)
dropwise at 0 °C. After stirring for 1 h, a precipitate was filtered and
washed with Et2O to give 1-OiPr (876 mg, 88% yield) as a white
solid.
N-Phenethyl-3-phenylpropanamide (17aa).1b,4a White solid
1
(96.4 mg, 95%); H NMR (400 MHz, CDCl3): δ 7.30−7.26 (m,
4H), 7.24−7.17 (m, 4H), 7.09 (d, J = 1.8 Hz, 2H), 5.30 (s, 1H), 3.48
(q, J = 4.6 Hz, 2H), 2.95 (t, J = 5.0 Hz, 2H), 2.74 (t, J = 4.6 Hz, 2H),
2.42 (t, J = 5.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.1,
140.9, 140.0, 139.0, 128.8, 128.7, 128.6, 128.5, 126.6, 126.3, 40.7,
38.6, 35.7, 31.8; LRMS (DART-TOF): 254 ([M + H]+).
N,N-Diethyl-3-phenylpropanamide (17ab).1b,4a Colorless oil
1
(70.3 mg, 86%); H NMR (400 MHz, CDCl3): δ 7.32−7.16 (m,
5H), 3.38 (q, J = 7.3 Hz, 2H), 3.22 (q, J = 7.3 Hz, 2H), 2.98 (t, J = 8.3
Hz, 2H), 2.59 (t, J = 8.3 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H), 1.10 (t, J =
7.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.3, 141.7,
128.5, 126.1, 42.0, 40.3, 35.2, 31.7, 14.3, 13.2; LRMS (DART-TOF):
206 ([M + H]+).
4-(5-Allyl-6-methoxy-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-4-
methylmorpholinium chloride (1-OMe). White solid (225 mg,
75%); 1H NMR (400 MHz, CD3OD): δ 5.92 (ddt, J = 17, 11, 6.0 Hz,
1H), 5.41 (ddt, J = 17, 1.4, 1.4 Hz, 1H), 5.32 (ddt, J = 11, 1.4, 1.4 Hz,
1H), 4.62 (ddd, J = 6.0, 1.4, 1.4 Hz, 2H), 4.50−4.40 (m, 2H), 4.26 (s,
3H), 4.10−4.01 (m, 2H), 3.95−3.86 (m, 2H), 3.86−3.76 (m, 2H),
3.51 (s, 3H); 13C{1H} NMR (CD3OD): δ 168.5, 167.4, 156.2, 130.8,
120.4, 63.3, 61.2, 59.7, 55.9, 47.0; HRMS (ESI-TOF) calcd for
C12H19N4O3 ([M − Cl]+): 267.1457, found: 267.1442.
N,N-Dibenzyl-3-phenylpropanamide (17ac).16 White solid (120
mg, 91%); 1H NMR (400 MHz, CDCl3): δ 7.37−7.14 (m, 13H), 7.07
(d, J = 7.4 Hz, 2H), 4.60 (s, 2H), 4.37 (s, 2H), 3.05 (t, J = 7.8 Hz,
2H), 2.72 (t, J = 7.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
172.8, 141.3, 137.4, 136.5, 129.0, 128.7, 128.6, 128.6, 128.4, 127.7,
127.5, 126.4, 126.2, 49.9, 48.4, 35.1, 31.7; LRMS (DART-TOF): 330
([M + H]+).
4-(5-Allyl-6-ethoxy-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-4-meth-
N-Phenethylpivalamide (17ba).4a White solid (66.4 mg, 81%);
1H NMR (600 MHz, CDCl3): δ 7.33−7.16 (m, 5H), 5.66 (brs, 1H),
1
ylmorpholinium chloride (1-OEt). White solid (138 mg, 84%); H
NMR (400 MHz, CD3OD): δ 5.93 (ddt, J = 17, 11, 6.4 Hz, 1H), 5.41
F
DOI: 10.1021/acs.joc.9b01261
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The Journal of Organic Chemistry
Article
3.50 (dt, J = 6.9, 7.8 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H), 1.14 (s, 9H);
13C{1H} NMR (600 MHz, CDCl3): δ 178.4, 139.2, 128.9, 128.7,
126.6, 40.7, 38.7, 35.8, 27.6.
Munetaka Kunishima: 0000-0002-3296-490X
Notes
The authors declare no competing financial interest.
N-Phenethylbenzamide (17ca).1,4 White solid (87.5 mg, 97%);
1H NMR (400 MHz, CDCl3): δ 7.71−7.66 (m, 2H), 7.53−7.45 (m,
1H), 7.45−7.7.38 (m, 2H), 7.37−7.30 (m, 2H), 7.29−7.22 (m, 3H),
6.10 (s, 1H), 3.73 (q, J = 6.9 Hz, 2H), 2.95 (t, J = 6.9 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 167.6, 139.0, 134.7, 131.5,
128.9, 128.8, 128.6, 126.9, 126.6, 41.3, 35.8; LRMS (DART-TOF):
226 ([M + H]+).
ACKNOWLEDGMENTS
This work was partially supported by JSPS KAKENHI Grant
Nos. 17H03970, 26293003, and 16K08160.
■
REFERENCES
■
N-Phenethyl-4-methoxybenzamide (17da).1b White solid (95.6
mg, 94%); 1H NMR (400 MHz, CDCl3): δ 7.69−7.62 (m, 2H),
7.36−7.30 (m, 2H), 7.28−7.22 (m, 3H), 6.93−6.87 (m, 2H), 6.02 (s,
1H), 3.84 (s, 3H), 3.71 (q, J = 6.9 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 167.1, 162.2, 139.1, 128.9,
128.8, 128.7, 127.0, 126.6, 113.8, 55.5, 41.2, 35.9; LRMS (DART-
TOF): 256 ([M + H]+).
(1) (a) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S.
Synthesis and characterization of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-
4-methylmorpholinium chloride. Tetrahedron Lett. 1999, 40, 5327−
5330. (b) Kunishima, M.; Kawachi, C.; Monta, J.; Terao, K.; Iwasaki,
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relationship with the nitrogen lone pair of tert-amines blocks the
approach of CDMT to nitrogen (gauche β-alkyl effect): Kunishima,
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N-Phenethyl-4-nitrobenzamide (17ea).1,4 White solid (101 mg,
1
94%); H NMR (400 MHz, CDCl3): δ 8.29−8.25 (m, 2H), 7.85−
7.81 (m, 2H), 7.37−7.33 (m, 2H), 7.30−7.23 (m, 3H), 6.13 (s, 1H),
3.76 (q, J = 4.4 Hz, 2H), 2.97 (t, J = 4.4 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 165.6, 149.6, 140.3, 138.6, 128.9, 128.9, 128.1,
126.9, 123.9, 41.5, 35.6; LRMS (DART-TOF): 271 ([M + H]+).
N,N-Diethyl-benzamide (17cb).17 Colorless oil (67.9 mg, 96%);
1H NMR (400 MHz, CDCl3): δ 7.41−7.34 (m, 5H), 3.62−3.47 (m,
2H), 3.32−3.18 (m, 2H), 1.30−1.18 (m, 3H), 1.17−1.03 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 171.3, 137.4, 129.1, 128.4,
126.3, 43.3, 39.3, 14.3, 13.0; LRMS (DART-TOF): 178 ([M + H]+).
N,N-Dibenzyl-benzamide (17cc).18 White solid (117 mg, 97%);
1H NMR (400 MHz, CDCl3): δ 7.53−7.46 (m, 2H), 7.42−7.26 (m,
11H), 7.19−7.09 (m, 2H), 4.70 (s, 2H), 4.40 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 172.4, 137.0, 136.5, 136.3, 129.8, 129.0, 128.8,
128.7, 128.5, 127.8, 127.6, 127.1, 126.8, 51.6, 46.9; LRMS (DART-
TOF): 302 ([M + H]+).
Methyl ((Benzyloxy)carbonyl)-L-phenylalanyl-L-alaninate
(17fd).14 White solid (35 mg, 91%); H NMR (400 MHz, CDCl3):
1
δ 7.39−7.13 (m, 10H), 6.49−6.31 (m, 1H), 5.44−5.31 (m, 1H), 5.08
(s, 2H), 4.50 (dq, J = 7.3, 7.3 Hz, 1H), 4.38−4.50 (m, 1H), 3.70 (s,
3H), 3.10 (dd, J = 6.4, 13.8 Hz, 1H), 3.05 (dd, J = 6.9, 13.8 Hz, 1H),
1.32 (d, J = 7.3 Hz, 3H).
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1
δ 7.39−7.13 (m, 10H), 6.56−6.41 (m, 0.5H), 6.41−6.25 (m, 1H),
5.59−5.48 (m, 0.5H), 5.48−5.32 (m, 10.5), 5.07 (s, 2H), 4.50 (dq, J
= 7.3, 7.3 Hz, 0.5H), 4.49 (dq, J = 7.3, 7.3 Hz, 0.5H), 4.52−4.39 (m,
1H), 3.70 (s, 1.5H), 3.68 (s, 1.5H), 3.15−2.96 (m, 2H), 1.32 (d, J =
7.3 Hz, 1.5H), 1.21 (d, J = 7.3 Hz, 1.5H).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b01261.
■
S
Amidation using 12-OiPr in the presence of diisopro-
pylethylamine: racemization test of 17fd; calculations;
1H and 13C NMR spectra for compounds 12-OMe, 12-
OEt, 12-OiPr, 12-NMe2, 1-OMe, 1-OEt, 1-OiPr, and 1-
1
NMe2; H NMR spectra for compounds 17aa−17fd
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: kunisima@p.kanazawa-u.ac.jp.
■
ORCID
Kohei Yamada: 0000-0002-7857-1474
Hikaru Fujita: 0000-0002-0430-9705
Masanori Kitamura: 0000-0002-8087-1855
G
DOI: 10.1021/acs.joc.9b01261
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DOI: 10.1021/acs.joc.9b01261
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