Ynoate-Initiated Selective C-N Esterification of Tertiary Amines under Transition-Metal and Oxidant-Free Conditions

Article abstract of DOI:10.1055/a-1326-6973

An efficient and selective method for metal-and oxidant-free deaminated esterification of tertiary amines is presented. In this protocol, ynoates play a key role to activate the Csp ³-N bond through a process of in situ generation of zwitterionic salts. The transformations show that Csp ³-N bond in the zwitterionic species has a lower dissociation energy than Csp ²-N bond, leading to break preferentially and be trapped by carboxylic acids to generate the corresponding products in moderate to good yield.

Full text of DOI:10.1055/a-1326-6973

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, 713–717
letter
713
en
F. Sun et al.
Letter
Synlett
Ynoate-Initiated Selective C–N Esterification of Tertiary Amines
under Transition-Metal and Oxidant-Free Conditions
Feixiang Suna
Huangdi Feng*a,c
Liliang Huanga
R2
N
O
R3 COOH
R
R2
R1
O
COOEt
R
R
N
R1
R3
O
SN2 esterification
OEt
Junhai Huang*a,b
Selective metal- and oxidant-free C–N bond activation
Tertiary amine as carbon donor
24 examples with up to 90% yield
a College of Chemistry and Chemical Engineering, Shanghai University of
Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China
hdfeng@sues.edu.cn
b State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai
Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical
Industry, Shanghai, 201203, P. R. of China
huang_junhai@163.com
c Shanghai Engineering Research Center of Textile Chemistry and Cleaner
Production, Shanghai University of Engineering Science, 333 Longteng
Road, Shanghai 201620, P. R. of China
Corresponding Authors
Received: 24.10.2020
Accepted after revision: 01.12.2020
Published online: 01.12.2020
been exploited,10 these synthetic approaches generally re-
quire transition metals or supplementary oxidants to facili-
tate the process of C–N bond cleavage.11 Therefore, a poten-
tial general metal- and oxidant-free strategy for the C–N
bond activation of tertiary amines is still highly desirable
and needs to be formulated.
DOI: 10.1055/a-1326-6973; Art ID: st-2020-l0561-l
Abstract An efficient and selective method for metal- and oxidant-
free deaminated esterification of tertiary amines is presented. In this
protocol, ynoates play a key role to activate the Csp3–N bond through a
process of in situ generation of zwitterionic salts. The transformations
show that Csp3–N bond in the zwitterionic species has a lower dissocia-
tion energy than Csp2–N bond, leading to break preferentially and be
trapped by carboxylic acids to generate the corresponding products in
moderate to good yield.
A. Tertiary amines as amino donor
R2
R1
aryl
E =
R1
N
allylic
N
E
+
E+
Ts
R2
R
......
B. Tertiary amines as carbon source
Nu–
Me
Me
Me
N
[M]
TfOMe
Key words C–N activation, esterification, chemoselectivity, ynoate,
amines
R
Nu
N
R
Me
reductive
R
Me
C–N bond activation
C. Oxidative C–N bond activation
N
Amines play an important role in diverse fields, ranging
from biochemistry and medicinal chemistry to organic syn-
thesis and material science.1 In addition, they also widely
exist in natural products and functional molecules.2 Among
the transformation of amines, C–N bond activations are
ubiquitous processes in living organisms3 and successfully
applied in the modification of organic molecules.4 For ex-
ample, tertiary amines are usually introduced as the amino
donors through a process of N-dealkylation or dealkylative
nucleophilic substitution (Scheme 1A).5 However, the use of
tertiary amines as carbon sources has yet to be broadly rec-
ognized,6 one traditional strategy involves the transition-
metal-catalyzed aryl and benzyl C–N functionalization via a
reductive coupling of produced ammonium salts (Scheme
1B).7 Very recently, Song and co-workers reported the Cu-
catalyzed cyclization of 2-aminopyridines with acrolein
which was in situ formed by oxidative C–N bond activation
employing ethyl-containing tertiary amines as carbon
sources (Scheme 1C).8 In 2018, Gooßen and co-workers de-
scribed the [Ru(p-cymene)Cl2]2-catalyzed ortho-C–H allyla-
tion of benzoic acids using allyl amines as an allyl group
(Scheme 1D).9 Although some innovative methods have
NH2
Et
N
CuI/O2
N
+
N
Et
Et
CHO
OH
D. RuII-catalyzed C–N bond activation
O
O
O
R1
Ru(II)
OH
+
N
R
R
R2
H
E. Redox C–N bond activation
R4 COOH
path a
O
R4
O
OR3
well-known
b a
R1
N
R
Csp2–N vs Csp3–N
ynoate
N
OR3
R1
R2
activation
R2
R
O
int-I
O
R
R4 COOH
R4
O
path b
this development
Scheme 1 C–N bond activations of tertiary amines
Notably, alkyne-induced C–N bond activation reactions
of cyclic amines have emerged as powerful protocols for the
rapid assembly of N-containing compounds.12 For example,
Oguri and co-workers reported a modular access to indole
alkaloids by a ynoate-initiated Hofmann elimination.13 In
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 713–717
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

714
F. Sun et al.
Letter
Synlett
recent years, this strategy has been extended to the C–O
bond activation of carboxylic acids through enol ester spe-
cies.14 In this area, we found that the -acyl enol esters
could be produced effortlessly by a procedure of the Csp2–N
bond cleavage through in situ generated zwitterionic salts
int-I (Scheme 1E, path a).15 Inspired by these results, we
herein hypothesize a novel redox-neutral Csp3–N esterifica-
tion instead of the Csp2–N activation under metal- and oxi-
dant-free conditions (Scheme 1E, path b). Undoubtedly, the
most challenging of this protocol is the selective Csp3–N
and Csp2–N cleavage as well as the site-selective activation
of the N–R, N–R1, and N–R2 bond when the relatively com-
plex tertiary amines are used. To our delight, the combined
process of pathway a and pathway b was observed when di-
carboxylic acids were used, leading to the unsymmetric di-
carbonyl compounds.16 In this work, we disclose an effi-
cient and selective alkyne-induced Csp3–N esterification in
which amines proved to be critical to the reactivity.
In line with the difunctionalization of the dicarboxylic
acid, we proposed that a suitable tertiary amine could en-
able this selective Csp3–N esterification. Owing to the p–
conjugation, the benzyl cation seems to be more stable.
Therefore, we initially investigated the reactions of different
substituted benzylamines 1 with pyridine-2,6-dicarboxylic
acid (2a) in the presence of ethyl propiolate (3a). As expect-
ed, N,N-dimethyl-1-phenylmethanamine (1a) afforded the
desired diester product (4aa, 69% yield) in dioxane at 80 °C
(Table 1, entry 1). Interestingly, the alkyl chains length and
steric hindrance of the N-substituted group on the benzyl-
amine are vitally important to the yield of the target prod-
uct, revealing that either longer chain or bulkier amines led
to a reduced yield (entries 2–6). It is to be noted that the
highly sterically hindered N,N-dicyclohexylbenzylamine
fails to afford the esterification product. The screening of
solvents revealed that others were no better than dioxane,
providing the desired products in 22–60% yield (entries 7–
11). Furthermore, the amount evaluation of amine 1a and
ethyl propiolate (3a) was carried out (entries 12–16). Using
3 equivalents of 1a could offer a satisfactory result, promot-
ing the yield to 72% (entry 13). By contrast, the use of 2
equivalents or 4 equivalents of 1a did not deliver better re-
sults (entries 12 and 14). By increasing the amounts of 3a to
3.2 equivalents provided the target product in a good yield
(81%, entry 16). In comparison with the metal-catalyzed
and aerobic conditions, our results revealed the advance of
a redox-neutral approach for the selective C–N bond cleav-
age.
Table 1 Reaction Optimizationa
O
O
OH
OH
R1
N
(3a)
CO2Et
Bn
N
Bn
N
+
O
O
O
O
solvent (3 mL)
80 °C, 12 h
Bn
R2
1
2a
4aa
Entry
Ratio of 1/2a/3a
R1
Me
R2
Solvent
Yield (%)b
1
2
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
0.8:0.5:1.1
1.0:0.5:1.1
1.5:0.5:1.1
2.0:0.5:1.1
1.5:0.5:1.4
1.5:0.5:1.6
Me
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
MeCN
EtOH
69
44
32
32
30
0
Me
n-Bu
n-Bu
3
n-Bu
4
n-Hex
–(CH2)4–
Cy
n-Hex
5
6
Cy
7
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
45
34
22
53
8
Me
9
Me
THF
10
11
12
13
14
15
16
Me
DCE
Me
chloroform 60
Me
dioxane
dioxane
dioxane
dioxane
dioxane
58
72
54
63
81
Me
Me
Me
Me
a Reaction conditions: to a stirred solution of 2a (0.5 mmol), 3a (1.6 mmol)
in solvent (2 mL) was added 1/solvent (1.5 mmol/1 mL) over 10 min, and
the mixture was stirred for 12 h at 80 °C under atmosphere.
b Isolated yield.
ther electron-donating or electron-withdrawing groups
such as methyl or nitro were well tolerated (4ad–ai).
Whereas there was no target product isolated when using
5-aminoisophthalic acid (4ae). The transformation pro-
ceeded smoothly with naphthol carboxylic acids, not only
dicarboxylic acids but also monocarboxylic acid, to afford
the corresponding esterification products 4aj–al) in 51–
63% yield. Moreover, various monocarboxylic acids includ-
ing 4-methoxylbenzoic acid, 2-iodobenzoic acid, benzoic
acid, and lauric acid were tested (4am–ap), but unfortu-
nately no target product was obtained when the substrate
was switched to benzoic acid or lauric acid.
In view of the organic halides are a versatile class of
building blocks in coupling reactions,15 2-iodobenzoic acid
was chosen as a nucleophile to evaluate the substrate scope
of tertiary amines (Scheme 3). The application of methyl
propiolate to active Csp3–N bond of N,N-dimethylbenzyl
amines was initially explored, giving the corresponding
products (4bn–fn,hn,in) in good to excellent yield with a
good functional-group tolerance. However, dichloro-substi-
tuted amine afforded the product only in 26% yield (4gn).
Further investigations showed that dibenzyl amine was un-
able to produce the desired product. These results indicate
a direct correlation between the reactivity and steric hin-
With the optimized reaction conditions in hand, the
substrate scope of carboxylic acids was studied using N,N-
dimethylbenzylamine as the benzyl source (Scheme 2). A
series of heterocyclic dicarboxylic acids were selected to
capture the benzyl group by ethyl propiolate induced Csp3–
N activation, all of them proceed well and provided the tar-
get esters in 57–86% yield (4aa–ac). Subsequently, a diverse
set of isophthalic acids and terephthalic acids bearing ei-
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 713–717

715
F. Sun et al.
Letter
Synlett
O
O
CO2Et
NMe2
O
+
Ar
O
Ar
Ph
OH
O
dioxane, 80 °C
1a
2
4
O
O
O
O
S
O
N
Ph
Ph
O
O
O
Ph
O
O
O
O
Ph
Ph
Ph
Ph
4aa, 81%
4ac, 57%
4ab, 86%
O
O
O
O
O
O
Ph
O
O
Ph Ph
O
O
O
Ph
Ph
Br
4ad, 69%
NH2
Me
4ae, n.d.
4af, 45%
O
O
O
Br
O
O
O
Ph
Ph
O
Ph
Ph
Ph
O
O
Ph
O
O
Br
NO2
4ai, 77%
O
O
O
O
4ag, 53%
4ah, 56%
O
O
O
O
Ph
O
Ph
Ph
O
O
4aj, 63%
4al, 63%
4ak, 51%
O
O
I
O
O
O
Ph
O
Ph
O
Ph
O
Ph
MeO
4am, 46%
4an, 73%
4ap, n.d.
4ao, n.d.
Scheme 2 Scope of carboxylic acids. Reagents and conditions: to a stirred solution of carboxylic acid (0.5 mmol) and ethyl propiolate (1.6 mmol) in
dioxane (2 mL) was added N,N-dimethylbenzylamine/dioxane (1.5 mmol/1 mL) over 10 min, and the mixture was stirred for 12 h at 80 °C under atmo-
sphere; isolated yields are given; n.d. = not determined.
drance in molecules. Furthermore, the trialkyl amines such
as triethylamine and tripropylamine yielded the corre-
sponding product 4jn and 4kn in 57% and 66% yield, respec-
tively. No target product 4ln was detected when N,N-di-
methyl-2-phenylethanamine was submitted to the stan-
dard conditions. To our delight, a good result was also
obtained using pyridine-2,6-dicarboxylic acid as a nucleop-
hile, and the corresponding symmetric diester 4ca was ob-
tained in 81% yield.
Acknowledgment
The authors wish to thank Prof. Dr. Weiping Liu for discussions.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1326-6973.
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
n
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
n
In summary, we have developed a selective esterifica-
tion of tertiary amines with aromatic acids that proceeds by
ynoate-initiated metal- and oxidant-free Csp3–N bond acti-
vation.17 In this reaction, both electron-poor and electron-
rich N,N-dimethylbenzyl amines except dichloro-substitut-
ed revealed good reactivity, as well as the trialkyl amines.
Broad substrate scope of carboxylic acids makes this meth-
od much more attractive. Further studies of other capture
reagents are currently ongoing in our laboratories.
References and Notes
(1) (a) Kalck, P.; Urrutigoity, M. Chem. Rev. 2018, 118, 3833.
(b) Ryder, A. S. H.; Cunningham, W. B.; Ballantyne, G.; Mules, T.;
Kinsella, A. G.; Turner-Dore, J. C.; Alder, M.; Edward, L. J.; McKay,
B. S. J.; Grayson, M. N.; Cresswell, A. J. Angew. Chem. Int. Ed.
2020, 59, 14986. (c) Wang, F.; Feng, H.; Li, H.; Miao, T.; Cao, T.;
Zhang, M. Chin. Chem. Lett. 2020, 31, 1558. (d) RoughleyS, D.;
Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(2) (a) Chen, Y.; Hu, J.; Guo, L.-D.; Zhong, W.; Ning, C.; Xu, J. Angew.
Chem. Int. Ed. 2019, 58, 7390. (b) Xu, X.; Van der Eycken, E.;
Feng, H. Chin. J. Chem. 2020, 38, 1780. (c) Chiba, H.; Oishi, S.;
Fujii, N.; Ohno, H. Angew. Chem. Int. Ed. 2012, 51, 9169.
(3) (a) Qiao, C.; Chen, A.; Gao, B.; Liu, Y.; Huang, H. Chin. J. Chem.
2018, 36, 929. (b) Liu, C.; Yang, F.; Wang, T. Chin. J. Chem. 2014,
32, 387.
Funding Information
We gratefully acknowledge the financial support from the National
Natural Science Foundation of China (22078192, 31702070), the Nat-
ural Science Foundation of Shanghai (19ZR1437900), and Shanghai
University of Engineering Science (E3-0903-19-01366).
N
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ti
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(2
2
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7
8
1
9
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ti
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n
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atura
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S
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nc
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F
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u
n
dati
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f
C
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1
7
0
2
0
7
0)N
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Sc
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h
a
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4
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ha
i
U
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© 2020. Thieme. All rights reserved. Synlett 2021, 32, 713–717

716
F. Sun et al.
Letter
Synlett
O
I
O
I
R
R1
CO2Me
dioxane, 80 °C
R
N
R2
1
OH
+
O
2n
4
Entry
1
Substrate 1
Product 4
Entry
8
Substrate 1
Product 4
O
O
NMe2
NMe2
NMe2
NMe2
O
O
CI
I
CI
I
82% (4bn)
64% (4in)
O
O
N
O
O
2
3
9
CI
Ph
I
I
X
CI
65% (4cn)
n.d., X = Cl or H
CI
O
O
N
N
O
10
11
12
O
CI
I
CI
F
I
83% (4dn)
57% (4jn)
O
O
NMe2
NMe2
O
O
4
5
6
F
I
I
78% (4en)
O
66% (4kn)
O
O
O
NMe2
Br
CI
I
Br
I
90% (4fn)
n.d. (4ln)
CI
O
CI
O
NMe2
O
O
N
I
CI
b
Cl
26% (4gn)
NMe2
13a
Cl
O
O
O
Cl
NMe2
O
7
I
67% (4hn)
81% (4ca)
Scheme 3 Substrate scope of the tertiary amines as carbon donor. Reagents and conditions: to a solution of 2-iodobenzoic acid (0.5 mmol) and methyl
propiolate (0.9 mmol) in dioxane (2 mL) was added a mixture of tertiary amines/dioxane (0.8 mmol/1 mL) over 10 min, and the reaction mixture was
stirred for 12 h at 80 °C under the atmosphere; isolated yields are given; n.d. = not determined. a Pyridine-2,6-dicarboxylic acid (0.5 mmol), methyl
propiolate (1.6 mmol), and tertiary amines (1.5 mmol) were used.
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benzylamine (1a, 202 mg, 1.5 mmol, 3 equiv) solved in 1 mL
1,4-dioxane was added to the tube slowly for 10 min. And the
tube was stirred again and refluxed at 80 °C for 12 h. After the
removal of the volatiles in vacuo, the crude residue was loaded
on a silica gel (100–200 mesh) column and flashed with 20%
ethyl acetate in petroleum ether to afford the desired product
4aa in 81% yield.
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(15) (a) Xu, X.; Feng, H.; Huang, L.; Liu, X. J. Org. Chem. 2018, 83,
7962. (b) Xu, X.; Feng, H.; Li, H.; Huang, L. Eur. J. Org. Chem.
2019, 3921. (c) Sun, F.; Feng, H.; Huang, L.; Liu, W. ChemistrySe-
lect 2020, 5, 8687.
Dibenzyl 2,6-Pyridine-dicarboxylate (4aa)
White solid; 140 mg, 81% yield; mp 111–113 ℃. 1H NMR (400
MHz, CDCl3):  = 8.27 (d, J = 7.8 Hz, 2 H), 7.97 (t, J = 7.8 Hz, 1 H),
7.48 (m, J = 7.7 Hz, 4 H), 7.42–7.31 (m, 6 H), 5.45 (s, 4 H). 13C
NMR (101 MHz, CDCl3):  = 163.90, 148.01, 137.79, 134.97,
128.27, 127.88, 127.58, 67.26.
Dibenzyl 2,6-Furan-dicarboxylate (4ab)
White solid; 144 mg, 86% yield; mp 73–75 ℃. 1H NMR (400
MHz, CDCl3):  = 7.45–7.33 (m, 10 H), 7.20 (d, J = 4.1 Hz, 2 H),
5.36 (s, 4 H). 13C NMR (101 MHz, CDCl3):  = 157.39, 146.36,
134.75, 128.30, 127.97, 118.22, 66.66.
(16) Xu, X.; Huang, L.; Yin, X.; Van der Eycken, E. V.; Feng, H. Org.
Chem. Front. 2018, 5, 2955.
(17) General Procedure for the Synthesis of Dibenzyl 2,6-Pyri-
dine-dicarboxylate (4aa)
Dibenzyl 2,6-Thiophene-dicarboxylate (4ac)
A mixture of pyridine-2,6-dicarboxylic acid (2a, 83.5 mg, 0.5
mmol, 1.0 equiv) and ethyl propiolate (3a, 157 mg, 1.6 mmol,
3.2 equiv) was added a 10 mL tube along with a magnetic stir
bar, and then 2 mL 1,4-dioxane was added. The tube was stirred
and refluxed in oil bath at 80 °C. Subsequently, N,N-dimethyl-
White solid; 101 mg, 57% yield; mp 56–58 ℃. 1H NMR (400
MHz, CDCl3):  = 7.76 (s, 2 H), 7.46–7.33 (m, 10 H), 5.35 (s, 4 H).
13C NMR (101 MHz, CDCl3):  = 161.38, 139.01, 135.35, 133.25,
128.60, 128.28, 67.30. HRMS (EI): m/z calcd for C20H16O4S [M]+:
352.0764; found: 352.0765.
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 713–717