Development of a triazinedione-based dehydrative condensing reagent containing 4-(dimethylamino)pyridine as an acyl transfer catalyst

Article abstract of DOI:10.1039/d1ob00450f

A new triazinedione-based reagent, (N,N′-dialkyl)triazinedione-4-(dimethylamino)pyridine (ATD-DMAP) was developed for the operationally simple dehydrative condensation of carboxylic acids. This reagent comprises an ATD core and DMAP as the leaving group, which is liberated into the reaction system to accelerate acyl transfer reactions. Upon adding ATD-DMAP to a mixture of carboxylic acids and alcohols in the presence of an amine base, the corresponding esters were formed rapidly at room temperature. Moreover, dehydrative condensation between carboxylic acids and amines using ATD-DMAP proceeded in high yield.

Full text of DOI:10.1039/d1ob00450f

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Development of a triazinedione-based dehydrative
condensing reagent containing 4-(dimethylamino)
pyridine as an acyl transfer catalyst†
Cite this: DOI: 10.1039/d1ob00450f
a
a
b
a
Jie Liu, Hikaru Fujita,
Masanori Kitamura, Daichi Shimada and
a
Munetaka Kunishima
*
A new triazinedione-based reagent, (N,N’-dialkyl)triazinedione–4-(dimethylamino)pyridine (ATD-DMAP)
was developed for the operationally simple dehydrative condensation of carboxylic acids. This reagent
comprises an ATD core and DMAP as the leaving group, which is liberated into the reaction system to
accelerate acyl transfer reactions. Upon adding ATD-DMAP to a mixture of carboxylic acids and alcohols
in the presence of an amine base, the corresponding esters were formed rapidly at room temperature.
Moreover, dehydrative condensation between carboxylic acids and amines using ATD-DMAP proceeded
in high yield.
Received 8th March 2021,
Accepted 30th April 2021
DOI: 10.1039/d1ob00450f
rsc.li/obc
step can be omitted. Thus, the experimental procedure for the
DMAP-mediated esterification is simplified. To date, two dehy-
Introduction
Various esterification reactions have been developed, owing to drative condensing reagents containing DMAP have been
the wide presence of esters in natural products, organic reported. In 1982, Arrieta et al. isolated 4-(dimethylamino)pyri-
materials, and biologically active compounds such as drug dinium chlorosulfite chloride (1, Fig. 1a) as a solid reagent
1
–5
15,16
molecules.
Dehydrative condensing reagents are commonly composed of DMAP and SOCl2.
However, esterification
used for the esterification of carboxylic acids with near-equi- using 1 required a stepwise procedure. Thus, after this reagent
molar amounts of alcohols under mild reaction conditions. activated a carboxylic acid as an acyl chloride in the first step,
Several dehydrative condensing reagents, such as an alcohol and one more equivalent of DMAP were added in
6
,7
8
carbodiimides
and carboxylic anhydrides, enable direct the second step to afford the corresponding ester. In 2014,
esterification without a stepwise procedure that includes the Okuno et al. reported the stable and storable dehydrative con-
pre-activation of carboxylic acids. Indeed, such esterification densing reagent 2,4,6-trichlorobenzoyl chloride–4-(dimethyl-
can be initiated by adding the dehydrative condensing reagent amino)pyridine (TCB-DMAP; Fig. 1b), which was synthesized
to a mixture comprising a carboxylic acid and an alcohol.
from the reaction between TCB (Yamaguchi reagent) and
1
7
4-(Dimethylamino)pyridine (DMAP) is an inexpensive and DMAP. In the general procedure, TCB-DMAP and alcohol
9
–14
effective nucleophilic catalyst for acyl transfer reactions.
This catalyst increases the esterification reaction rate because acid and Pr EtN in toluene. Although this simple procedure
2
were almost simultaneously added to a solution of a carboxylic
i
of the formation of a highly reactive N-acylpyridinium inter- afforded esters in high yield, esterification using TCB-DMAP
mediate in the reaction mixture. Thus, in some cases, even ter- generally required 24 h at room temperature.
tiary alcohols can be converted to the corresponding esters.
In this paper, we describe the development of a new DMAP-
DMAP is therefore widely used in esterification reactions, com- containing reagent for operationally simple dehydrative con-
bined with dehydrative condensing reagents.
densation, based on our previous work, for a series of triazine-
If the DMAP-containing dehydrative condensing reagent
releases this molecule during the reaction, the DMAP addition
a
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
b
Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2, Bunkyo-cho,
Matsuyama 790-8578, Japan
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Previously reported dehydrative condensing reagents containing
d1ob00450f
DMAP.
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1
8–27
based reagents.
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4- the early development stage of the various reagents.
methylmorpholinium chloride (DMT-MM, Fig. 2) is a distinct Unfortunately, esterification using DMT-DMAP (Fig. 2) pro-
2
1
dehydrative condensing reagent because amidation between a ceeded only in low yield. This was attributed to the decreased
carboxylic acid and an amine using DMT-MM proceeds in electrophilicity of the triazine moiety, which was stabilized by
1
8,19
high yield, even in protic solvents.
This is attributed to the strong electron donation from the dimethylamino group in the
mild reactivity of the triazinyl ester intermediates toward DMAP moiety. Our recent alternative approach toward
hydrolysis and alcoholysis. Therefore, esterification of car- DMT-MM modification is the transformation of the triazine
boxylic acids by DMT-MM typically requires an excess amount core. Studies on triazine-based acid-catalyzed alkylating
2
0
of alcohol to complete the alcoholysis of triazinyl esters. We reagents indicated that “isomerization” of the core structure,
recently developed a new esterifying reagent, DMT-3,5-LUT, by from a (dialkoxy)triazine to an (alkoxy)triazinone or triazine-
2
5
modifying the tert-amine moiety in DMT-MM. DMT-3,5-LUT dione, increases the electron deficiency of the triazine
2
8–31
contains 3,5-lutidine as a nucleophilic catalyst for acyl transfer moiety.
Thus, N-alkyl groups were introduced to fix the
instead of the N-methylmorpholine (NMM) in DMT-MM. In isomerized triazinone and triazinedione cores. In particular,
contrast to DMT-MM, DMT-3,5-LUT provided esters from near- the N-allyl group is preferred because of its synthetic accessi-
equimolar amounts of carboxylic acids and alcohols, although bility. Triazinone-based dehydrative condensing reagent 2
moderate yields and long reaction times (>24 h) were observed exhibited higher reactivity than DMT-MM in amide-forming
2
6
for the relatively low-reactive carboxylic acids, such as benzoic reactions. On the other hand, synthesis of triazinedione-
acid. Since DMAP is a superior acyl transfer catalyst to 3,5-luti- based reagent 3 was unsuccessful, despite its predicted potent
dine, we attempted to introduce DMAP into the triazine core at reactivity.
Scheme 1 Synthesis of ATD-DMAP.
Table 1 Screening of bases and solvents for esterification using
ATD-DMAP
a
Entry
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
NMM
NMM
None
CH
CH
CH
CH
CH
CH
CH
CHCl
MeCN
THF
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
98
82
5
98
97
93
b
DMAP
i
2
Pr EtN
DBU
c
NaHCO
NMM
NMM
NMM
NMM
NMM
3
44 (80)
3
99
97
97
96
95
1
1
1
0
1
2
EtOAc
DMF
a
1
Fig. 2 Design of a new triazinedione-based dehydrative condensing
reagent containing DMAP.
Calculated from H NMR spectroscopic analysis using an internal
b
c
standard. NMM (0.6 equiv.) was used. Reaction time of 30 min.
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Results and discussion
A new dehydrative condensing reagent was designed by
merging the two concepts for DMT-MM modification
described in Fig. 2, whereby installation of DMAP to the ATD
core led to ATD-DMAP. ATD-DMAP was synthesized by adding
DMAP (1 equiv.) to a THF solution of chlorotriazinedione 5
(
Scheme 1), which was prepared in a flask via the Pd-catalyzed
O-to-N allylic rearrangement of bis(allyloxy)triazine 4 (1.2
3
1
equiv.) according to our previously described procedure. The
precipitate was collected to afford ATD-DMAP as a stable white
solid in 93% yield. The product can be stored for more than
six months in a refrigerator and handled in open air at room
temperature.
Following the general esterification procedure using
2
5
DMT-3,5-LUT, ATD-DMAP (1.2 equiv.) was added to a solu-
tion of 3-phenylpropionic acid (6a, 1 equiv.), 2-phenylethanol
(
2 2
7a, 1.2 equiv.), and NMM (1.2 equiv.) in CH Cl at room temp-
erature. The reaction was completed within 10 min to afford
the corresponding ester 8aa in 98% yield (entry 1, Table 1).
When the amount of NMM was decreased (0.6 equiv.), the
product was obtained in 82% yield after 10 min (entry 2). The
reaction proceeded very sluggishly in the absence of
NMM (5%, entry 3), indicating that as a base NMM plays an
important role in promoting esterification. Other organic
i
bases such as DMAP, Pr EtN, and DBU afforded ester 8aa in
2
9
4
3–98% yield (entries 4–6). The yield of 8aa decreased to
4% when using NaHCO as a heterogeneous inorganic
3
base; however, a longer reaction time (30 min instead of
0 min) improved the yield to 80% (entry 7). The reactions
1
using NMM (1.2 equiv.) also proceeded in other common
organic solvents, such as CHCl , MeCN, THF, EtOAc, and
3
DMF, without any significant loss in the product yield (entries
8
–12, respectively).
We next carried out esterification reactions between various
carboxylic acids and alcohols using ATD-DMAP (Table 2).
Esterification of 6a with secondary alcohol 7b (entry 1), cyclo-
hexanecarboxylic acid (6b) with 7a (entry 2), and 6b with 7b
(
1
entry 3) under the standard reaction conditions (NMM, rt,
0 min) afforded the corresponding esters in 89, 94, and 83%
yield, respectively. Notably, the yield of 8bb improved to 93%
i
2
when Pr EtN was used as the base (entry 4). The reaction of
sterically hindered 1-adamantanecarboxylic acid (6c) with 7a
afforded 8ca in 36% yield, even after 24 h in the presence of
i
2
Pr EtN (entry 5). A higher yield (83%) was obtained under
microwave irradiation conditions (130 °C, 20 min) using NMM
as the base (entry 6). Both the esterification reactions of 6a
with phenol (7c, entry 7) and benzoic acid (6d) with 7a (entry
8) proceeded in 86–94% yield under the standard reaction con-
ditions. α-Chiral carboxylic acid 6e (entry 9) was converted to
the corresponding benzyl ester 8ed in quantitative yield
without loss in enantiomeric purity. Acetylation of the tertiary
alcohol 7e (1 equiv.) proceeded in 64% yield when using
excess ATD-DMAP (1.5 equiv.) and NMM (2 equiv.) in the pres-
ence of 4A molecular sieves to remove any residual moisture in
the reaction mixture (entry 10).
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ATD-DMAP can also be used for amide-forming coupling entry 13). N-Acetylation of L-phenylalanine methyl ester hydro-
reactions between carboxylic acids and amines (Table 3). The chloride (9f, 1 equiv.) was carried out using sodium acetate
dehydrative condensation of 6a (1 equiv.) and 2-phenylethyl- (6n, 1.1 equiv.) to afford 10nf in quantitative yield (entry 14).
amine (9a, 1.1 equiv.) using ATD-DMAP (1.1 equiv.) in CH
2
Cl
2
Amidation between Cbz-L-Phe-OH (6e) and L-Ala-OMe hydro-
at room temperature afforded the corresponding amide 10aa chloride (9g) in the presence of Et N afforded dipeptide 10eg
3
in 93% yield after 10 min (entry 1). Under the same reaction in 92% yield (entry 15), under slightly modified conditions
conditions, aliphatic (6h), α,β-unsaturated (6i,j), and aromatic [(ATD-DMAP (1.2 equiv.), 15 min)]. Racemization of the phenyl-
1
(
6k,l) carboxylic acids provided the desired amides in 81–98% alanine moiety in 10eg was not detected in H NMR spectrum
yield (entries 2–6, respectively). Although the reaction of of the crude mixture (Fig. S1 and S2†).
pivalic acid (6m) proceeded slowly (28% after 10 min, entry 7),
To compare the effect of the reagent core structure, we next
the yield reached 91% after 3 h (entry 8). Amidation of 6a with prepared triazinone-based reagent 12 containing DMAP from
2
6
benzylamine (9b, entry 9) and diethylamine (9c, entry 10) chlorotriazinone 11 (Fig. 3a). Treatment of a mixture of 6a
afforded the product in 94–100% yield. Similarly, amide 10dd and 9a with 12 provided the corresponding amide 10aa in 5%
was obtained from 6d and cyclohexylamine (9d) in quantitative yield based on 6a, along with aminotriazinone 13 in 75% yield
yield (entry 11). The reaction of aniline (9e, 1 equiv.) was com- based on 12 after 3 h (Fig. 3b). This result suggests that the
pleted after 3 h (70% after 10 min, entry 12; 97% after 3 h, triazinone core of 12 reacts with amines faster than with car-
boxylates, whereas the more reactive triazinedione core of
ATD-DMAP reacts selectively with carboxylates in the presence
of amines (Table 3, entry 1). The reason for this selectivity
difference is unclear at present.
Tables 2 and 3 reveal that esterification and amidation
using ATD-DMAP were completed rapidly (within 10 min in
most cases), attributed to the formation of a highly reactive
N-acylpyridinium intermediate in the reaction mixture. Fig. 4
illustrates the plausible reaction mechanism of ATD-DMAP:
the triazinedione electrophilic carbon in ATD-DMAP is
attacked by carboxylate 14, which is formed by deprotonation
of carboxylic acid 6 with NMM (esterification) or amine 9 (ami-
dation), to afford activated ester 15. The DMAP liberated from
ATD-DMAP then reacts with 15 to form N-acylpyridinium inter-
mediate 16 paired with the cyanurate anion. Alcoholysis or
aminolysis of this intermediate with alcohol 7 or amine 9
affords the corresponding ester 8 or amide 10, respectively,
along with N,N′-diallylcyanuric acid (17) and DMAP. NMM or
amine 9 is regenerated from the corresponding conjugated
acid under acid–base equilibria with DMAP.
Fig. 3 (a) Preparation of triazinone-based reagent 12 containing DMAP
and (b) attempted amidation using 12.
Fig. 4 Plausible reaction mechanism for esterification and amidation using ATD-DMAP.
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DMAP did not efficiently catalyze the transfer reaction of
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ATD-DMAP proceeded slowly under the standard conditions.
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sing reagent, ATD-DMAP. The advantages of this reagent
include its easy handling, simple experimental operation, and
short reaction time. The DMAP contained in this reagent is
designed to work as both an in situ-formed nucleophilic cata-
lyst and a leaving group on the triazinedione core. ATD-DMAP
exhibited powerful reactivity both in the esterification and ami-
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reagent.
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and H. Fujita: data curation. J. Liu and D. Shimada:
investigation. H. Fujita and M. Kunishima: writing–review and
editing. M. Kitamura: methodology. M. Kunishima: conceptu-
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There are no conflicts to declare.
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This work was partially supported by the JSPS Grants-in-Aid
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