N-Ethynylation of Anilides Decreases the Double-Bond Character of Amide Bond while Retaining trans-Conformation and Planarity

Article abstract of DOI:10.1002/chem.201901451

Activated amide bonds have been attracting intense attention; however, most of the studied moieties have twisted amide character. To add a new strategy to activate amide bonds while maintaining its planarity, we envisioned the introduction of an alkynyl group on the amide nitrogen to disrupt amide resonance by nN→C_sp conjugation. In this context, the conformations and properties of N-ethynyl-substituted aromatic amides were investigated by DFT calculations, crystallography, and NMR spectroscopic analysis. In contrast to the cis conformational preference of N-ethyl- and vinyl-substituted acetanilides, N-ethynyl-substituted acetanilide favors the trans conformation in the crystal and in solution. It also has a decreased double bond character of the C(O)?N bond, without twisting of the amide. N-Ethynyl-substituted acetanilides undergo selective C(O)?N bond or N?C(sp) bond cleavage reactions and have potential applications as activated amides for coupling reactions or easily cleavable tethers.

Full text of DOI:10.1002/chem.201901451

A Journal of
Accepted Article
Title: N-Ethynylation of Anilides Decreases Double-Bond Character of
Amide Bond while Retaining Trans Conformation and Planarity
Authors: Ryu Yamasaki, Kento Morita, Hiromi Iizumi, Ai Ito, Kazuo
Fukuda, and Iwao Okamoto
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N-Ethynylation of Anilides Decreases Double-Bond Character of
Amide Bond while Retaining Trans Conformation and Planarity
Ryu Yamasaki*[a], Kento Morita[a], Hiromi Iizumi[a], Ai Ito[a], Kazuo Fukuda[a] and Iwao Okamoto*[a]
Abstract: In recent, activated amide bonds had been attracted
intense attention, however, most of them had twisted amide
character. To add a new strategy to activate amide bonds with
maintaining its planarity, we envisioned to introduce alkynyl group on
amide nitrogen to disrupt amide resonance by nN → Csp conjugation.
In this context, the conformations and properties of N-ethynyl-
substituted aromatic amides were investigated by DFT calculation,
crystallography and NMR. In contrast to the cis conformational
preference of N-ethyl- and vinyl-substituted acetanilides, N-ethynyl-
substituted acetanilide favors trans conformation in the crystal and in
solution. It also has a decreased double bond character of the C(O)–
In this context, we hypothesized that substitution of an
alkynyl group with an sp carbon in place of sp3 carbon of alkyl
groups would be a useful strategy to activate the amide bond;
introduction of an unsaturated bond would extend the resonance
structure, and weaken the amide bond without disruption of
planarity. To our knowledge, there has been no study so far on
acyclic N-ethynyl anilide, although structural studies of N-vinyl
anilides have been reported.[9] Considering the unique synthetic
utility of N-ethynyl amides (also known as ynamides),[10] we
anticipated that the decreased double bond character of N-
ethynyl amide might prove useful for further amide bond
transformations.[11] Here, we report the structural properties of N-
ethyl (3), vinyl (4), and ethynyl (5)-substituted acetanilides and
related aromatic amide derivatives in solution and in the crystal
state (Figure 1). We also describe selective hydrolysis and
cleavage reactions of these compounds.
N
bond, without twisting of the amide. N-Ethynyl-substituted
acetanilides undergo selective C(O)–N bond or N–C(sp) bond
cleavage reactions and may have potential applications as activated
amides for coupling reactions or easily cleavable tethers.
(1) Acetanilide (1)
(2) N-Methyl acetanilide (2)
Introduction
O
O
O
O
H
CH3
H3C
N
H3C
N
Amide bonds are ubiquitous in proteins and peptides, and are
also found in many biologically relevant small molecules. Their
key features, such as planarity, stability to nucleophiles, short
C–N bond length, and high rotational barrier, are a consequence
of their resonance structure.[1] On the other hand, the challenge
of breaking the amide bond under mild conditions has also
attracted intense interest, and many studies have demonstrated
the increased lability of twisted amides.[2] However, in many
cases, the necessary modifications, such as the introduction of
bridging structure or a sulfonyl group, are quite major.
H3C
N
H
H3C
N
CH3
trans
trans
cis
cis
(3) N-Ethyl (3), vinyl (4), and ethynyl acetanilide (5) (This study)
sp2
O
O
sp3
O
Structure
(cis-trans)
H3C
N
H3C
N
H3C
N
Resonance
(C(O)–N bond)
sp
Reactivity
3
4
5
From a structural perspective, the partial double bond
character of the amide bond permits the existence of two distinct
conformations, cis and trans,[3] and a secondary amide bond,
such as that in acetanilide (1), is normally more stable in trans
form (Figure 1). However, the introduction of an N-alkyl group on
the nitrogen atom of aromatic amide, as in 2, causes a
conformational alteration from trans to cis,[4] and this may cause
loss of biological activity.[5,6] A key factor in the cis preference is
considered to be the occurrence of steric and electronic
repulsion between the carbonyl group and the phenyl moiety in
the trans conformer.[7] The effect of such electrostatic repulsion
has been verified and applied to molecular conformational
Figure 1. N-Substituted anilide derivatives and definitions of conformers.
Results and Discussion
We commenced our project by performing density
functional theory (DFT) calculations (B97D/6-311G(d,p))
provided in Table 1 and in the SI. The calculated stable amide
conformer of 5 was trans, while those of 3 and 4 were cis (Table
1). The dihedral angles between the amide plane and phenyl
plane in all conformers of 3–5 were 40–90º, implying that all
substituent groups, including unsaturated hydrocarbon groups (4
and 5) on the amide nitrogen atom induce distortion of the
phenyl group from the amide plane (Table S1). In contrast, no
significant twisting of the amide plane itself was observed in the
stable conformers of compounds 3–5 (Table S1, χN and τ). N-
Vinyl acetanilide derivative (4) was more stable in s-trans form in
terms of the N–C(sp2) bond (see SI).
[a]
Dr. Ryu Yamasaki, Kento Morita, Hiromi Iizumi, Dr. Ai Ito, Dr. Kazuo
Fukuda, Prof. Dr. Iwao Okamoto
Showa Pharmaceutical University
3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, Japan 194-
8543
E-mail: yamaryu@ac.shoyaku.ac.jp, iokamoto@ac.shoyaku.ac.jp
Supporting information for this article is given via a link at the end of
the document.
switching systems.[8]
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10.1002/chem.201901451
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benzoyl derivatives (Table 2) was shown, including N-
methylbenzanilide reported previously as a reference.[16] As a
whole, amide nitrogen atoms of 3–7 kept relatively planar (Table
Table 1: Structural characters of compounds 3–5.
3
4
5
1 and S4, χN, τ and ∑( χN)),[17] and acetanilide derivatives, 3–5,
τ+
Calcd stable
str.[a]
cis
cis
trans
had more planar amide nitrogen character and smaller ∑(
χN)
τ+
values than those of benzoyl derivatives, 6,
7 and N-
DG (kcal/mol) [b]
3.6
cis
2.5
cis
1.5
methylbenzanilide. In addition, phenyl group were also tilted
from amide plane in the crystal state, in accordance with the
calculations (Figure 2 and Table S4).
Crystal Str.
trans
C(O)–N (Å)
1.355,
1.33,
1.391
1.364[c]
1.420[d]
EtI
NaOH、K2CO3
NBu4NI
O
O
H3C
N
C=O (Å)
1.238,
1.29,
1.215
1.364
1.454
H3C
N
1.229[c]
1.176[d]
H
Toluene
70 ºC
1
N–C(spx) (Å)
N–C(Ph) (Å)
1.476,
1.35,
3
83%
1.475[c]
1.43[d]
O
O
CuI, K3PO4
Vinyl bromide
1.436,
1.417,
H3C
N
R
N
H
1.440[c]
1.460[d]
THF
80 ºC
cN[e] (º)
t[f] (º)
10.0, 7.3[c]
8.4, 2.6 [c]
18.4, 9.9[c]
0, 0[d]
0, 0[d]
0, 0[d]
5.1
3.5
8.6
4 (R = CH3) 87%
6 (R = C6H5) 89%
Br
Si(iPr)3
CuSO4-5H2O
Phenanthroline
K3PO4
∑
(τ+χN) (º)
O
O
O
TBAF
R
THF
R
N
NMR stable str.
cis
cis
trans
0.9
N
R
N
H
Toluene
110 ºC
–40 ºC
DG213 K
(kcal/mol)
1.4
1.5
Si(iPr)3
5 (R = CH3) 77%
7 (R = C10H7) 70%
8 (R = C6H5) 68%
5’ (R = CH3) 77%
7’ (R = C10H7) 79%
8’ (R = C6H5) 75%
DGTc‡ (kcal/mol)
14.1
13.0
12.1
IR C=O (cm-1)
1655
1680
1689
Scheme 1. Synthesis of N-substituted anilides.
[a] Calculated at the B97D/6-311G(d,p) level. [b] At 213 K. [c] Two molecules
exist in an unsymmetric unit. [d] The structure shows disorder, which
generated two kinds of molecules. [e] Pyramidalization angle around the
nitrogen atom. [f] Twist angle of the nitrogen atom.
Next, compounds 3–5 were synthesized by means of N-
alkylation with EtI for
3 and Cu-catalyzed N–C coupling
reactions for 4[13] and 5[14] (Scheme 1). It is noteworthy that TIPS
protected N-alkynyl compounds (5’, 7’ and 8’) were relatively
stable and could be stored for several months, however terminal
alkyne compounds (5, 7 and 8) decomposed within an hour in
CD2Cl2 solution at 40 ºC and should be stored in refrigerator.
4
5
3
O
O
N
The structures of those compounds were determined by X-
ray single crystallography (Figure 2).[15] All compounds existed in
the conformer calculated to be more stable, i.e., 3 and 4 took cis
conformation in terms of the C–N bond, and 5 took trans
conformation. The vinyl double bond of 4 showed disorder that
made precise structural analysis difficult. Therefore, N-vinyl
benzanilide derivative 6 was prepared similarly and analyzed
crystallographically. It was found to be in cis form without any
disorder. In the crystal state, the vinyl moiety of 4 and 6 existed
in s-trans conformation as regards the N–C(sp2) bond. In
addition, naphthalene N-ethynyl derivative 7 existed as the trans
conformer in the crystal state. Structural analysis based on the
crystal structures of acetanilide derivatives (Table 1) and
N
7
6
Figure 2. Crystal structures of 3–7.
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Table 2: Structural analysis of compounds 6, 7, and N-methylbenzanilide.
6
7
N-
methylbenzanilide[a]
Crystal Str.
C(O)–N (Å)
C=O (Å)
cis
1.382
1.228
1.416]
1.445
9.9
trans
1.394
1.224
1.367
1.449
12.6
cis
1.355
1.232
1.469
1.437
18.1
N–C(spx) (Å)
N–C(Ph) (Å)
cN[b] (º)
[c] (º)
8.7
9.7
6.6
Figure 3. 1H-NMR spectra (400 MHz, 213 K, in CD2Cl2 for 3 and 5, in CDCl3
for 4) of 3–5.
t
∑
(τ+χN) (º)
18.6
22.3
24.7
[a] Adopted from CCDC 1183593. [b] Pyramidalization angle around the
nitrogen atom. [c] Twist angle of the nitrogen atom.
To obtain insight into the dominant conformation in solution,
we performed variable-temperature 1H-NMR (VT-NMR). The
preferred conformations of 3–5 were determined based on NOE,
and the cis/trans ratios were measured by integration of the
acetyl CH3 peak at 213 K in CD2Cl2 or CDCl3 (Figure 3 and SI).
The major conformer of 3–5 in solution was the same as that
identified by crystallography. The free energy differences (ΔG213
K) between cis and trans were also calculated from the cis/trans
ratios and the tendency was in good accord with the calculated
trend; 3 and 4 were predominantly in cis form (1.4 and 1.5
kcal/mol, respectively), and 5 showed moderate preference for
the trans conformer (0.9 kcal/mol) (Table 1). It is noteworthy that
the chemical shift of the major ortho proton peak of the phenyl
group of 5 was remarkably different from that of 3 or 4, probably
due to an anisotropic effect of the carbonyl group (Figure 3).
C=O-alkene
repulsion
No C=O-alkene
repulsion
C=O-Ar
repulsion
O
O
O
H3C
N
H3C
N
H3C
N
trans
O
4 cis (s-trans)
cis (s-cis)
C=O-Ar
repulsion
C=O-Ar
repulsion
C=O-alkyne
repulsion
O
O
H3C
N
H3C
N
N
Ar-alkyne
repulsion
8
5 trans
trans
cis
Since N-ethynyl-substituted acetanilide derivative (5)
favoured trans conformation, we next probed the generality of
this phenomenon. The solution structures of benzanilide
derivatives bearing an N-ethynyl group (8) and 7 were examined
by 1H-NMR. In both cases, trans conformation was more
favorable by 0.5 and 0.4 kcal/mol, respectively, in CD2Cl2 at 178
Figure 4. Possible explanations of conformational preference of 4 and 5.
K
(see SI). Thus, trans conformational preference of N-
ethynylated anilides seemed to be a quite general phenomenon.
At this stage, we believed that electronic repulsion between
the triple bond and carbonyl group encountered in the cis
conformer of 5 would be the major origin of the trans conformer
preference (Figure 4).[18] In the case of N-vinyl derivative (4), the
vinyl moiety can avoid this repulsion in the s-trans conformer,
which is not possible in 5. In 7 and 8, repulsion between Ar and
alkyne moieties could make the trans conformation less stable
than 5.
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Next, the effects of the N-ethynyl group on the C(O)–N
double bond character and rotational barrier were investigated.
N-Vinyl acetanilides are reported to have a lower rotation barrier
of the C–N bond compared to corresponding secondary
amides,[19] albeit few N-ethynyl acetanilides have been
examined. Taking the C(O)–N bond lengths in the crystal
structure as a measure of the double bond character, we found
non-nucleophilic TMSOTf activated the triple bond of N-alkynyl
anilide derivatives, probably through the coordination to carbonyl
group, furnished anilides with N–C(sp) bond cleaved after a
treatment with methanol. When 5 or 5’ was reacted with
TMSOTf followed by dry methanol, 1 was obtained in high yield.
Benzanilide derivative 8’ similarly afforded benzanilide in good
yield. This result confirmed that the reaction proceeded via N–
C(sp) bond cleavage.
that the C(O)–N bond was lengthened (5
> 3, 7>6>N-
methylbenzanilide) in the opposite order to the C=O bond length
(3 > 5, N-methylbenzanilide > 6 > 7) (Table 1 and 2). A similar
trend was also observed in the results of DFT calculation (Table
S1). This reflects the reduced amide bond resonance of 5,
probably due to the nN → Csp conjugation, which disrupts amide
resonance.[20] In fact, the N–C (spx) bond lengths were 1.476 (or
1.475) Å for 3, 1.416 Å for 6(4) and 1.364 Å for 5 in the crystal
state, which implies that the nitrogen lone-pair strongly
delocalized to the N–C(sp) bond (Table 1). The reduced C(O)–N
bond character was also reflected in the rotational barriers
calculated based on the results of VT-NMR (Table 1 and S5).[21]
The rotational barriers were estimated by the coalescence
method,[22] and the results are shown in Table 1 and SI. The
rotational barrier of 3 was roughly estimated to be 14.1 kcal/mol,
which is close to that of N-methyl acetanilide (2),[8a] while those
of 4 and 5 were decreased to 13.0 and 12.1 kcal/mol,
respectively. It is noteworthy that the rotational barrier of 5 was
(a) C(O)–N bond cleavage (hydrolysis)
O
NaOH
O
H3C
N
H3C
N
HN
THF-H2O
80 ºC, 5 h
H
1
59%
5
not isolated
HN
O
O
NaOH
R
N
(iPr)3Si
N
H
THF-H2O
80 ºC, 12 h
9
Si(iPr)3
not isolated
Si(iPr)3
5' or 8'
from 5' (R = CH3
from 8' (R = C6H5) 60%
)
99%
O
NaOH
H3C
N
98%
3
THF-H2O
80 ºC, 24 h
comparable to that of N-acyl pyrroles[20b] and showed
a
possibility of N-alkynyl substituted anilides as a new type of
ground-state-destabilized amides.[23] In addition, the peak
position of C=O stretching vibration in the IR spectra (KBr)
indicated decreased amide resonance of 4 and 5; the peak of 3
was at 1655 cm-1, while those of 4 and 5 were at 1680 and 1689
cm-1, respectively. This shift of wavenumber is consistent with
disfavored amide resonance in 4 and 5.[24]
3
O
NaOH
H3C
N
4 37%
THF-H2O
80 ºC, 24 h
4
(b) N–C(sp) bond cleavage
1) TMSOTf
(1.5 equiv)
The remarkably decreased amide resonance of N-ethynyl
anilides could promote C(O)–N bond scission reactions
(Scheme 2(a)). To test this idea, N-ethynyl acetanilide 5 was
subjected to basic hydrolysis at 80 ºC, to afford acetanilide (1)
by cleavage of amide bond followed by hydration of the resultant
ynamine by water.[25] The yield of the hydrolysis was improved
by using TIPS-protected derivatives, 5’, and the TIPS terminated
amide compound 9 was obtained as sole product in excellent
yield.[26] The structure of 9, the formal transacylation product,
was unambiguously confirmed by X-ray crystallography (see SI).
O
O
CH2Cl2, -78 ºC
H3C
N
R
H3C
N
H
2) CH3OH (20 equiv)
rt
1
from 5 (R = H)
from 5' (R = Si(iPr)3)
83%
82%
1) TMSOTf
(1.5 equiv)
O
O
N
CH2Cl2, -78 ºC
N
H
[27]
2) CH3OH (22 equiv)
rt
This hydrolysis of the amide bond was also applicable to
Si(iPr)3
8'
10
89%
benzanilide derivatives 8’ and the corresponding 9 was obtained
in 60% yield. These results support the reaction proceeded
through the hydrolysis of C(O)–N bond and successive hydration
of resultant ynamine, since the imide produced by hydration of
alkyne of ynamide would leads to a mixture of two products, 9
and 1 (or 10). To check the reactivity of amides, we exposed 3
and 4 to the same condition (at 80 ºC); this resulted in the
recovery of most of the reactants in the case of 3, and partial
recovery in the case of 4. Notably, selective cleavage of the N–
C(sp) bond was also possible (Scheme 2(b)). Iwasawa and
coworkers reported that TMSBr reacted with tosyl ynamide to
afford b-bromo alkene compounds,[28] and observed
dealkynylation by using methanol as a nucleophile. Similarly,
Scheme 2. Selective C(O)–N and N–C(sp) bond cleavage reactions.
Conclusions
In conclusion, we have found that aromatic tertiary amides
bearing an N-ethynyl group favor trans conformation, while N-
ethyl and vinyl aromatic amides take cis conformation. The
C(O)–N bond of N-ethynyl substituted amides has decreased
double-bond character and is more easily hydrolyzed than N-
ethyl-substituted amides, affording formally transacylated
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5106; b) G. Evano, N. Blanchard, G. Compain, A. Coste, C. S. Demmer,
W. Gati, C. Guissart, J. Heimburger, N. Henry, K. Jouvin, G.
Karthikeyan, A. Laouiti, M. Lecomte, A. Martin-Mingot, B. Métayer, B.
Michelet, A. Nitelet, C. Theunissen, S. Thibaudeau, J. Wang, M. Zarca,
C. Zhang, Chem. Lett. 2016, 45, 574–585.
secondary amides by hydrolysis of the ynamine. Interestingly,
these substituted anilides, including N-ethynyl-substituted
compounds, do not have a pyramidalized nitrogen atom, even
though they are susceptible to hydrolysis. In addition, the N–
C(sp) bond can be selectively cleaved by TMSOTf and MeOH.
Given the decreased double bond character of N-ethynyl-
substituted amides, these compounds might be useful as
activated amide substrates for coupling reactions. The results
presented here should also be useful in the design and
structure-activity relationship studies of conformationally
controlled biologically active compounds, as well as cleavable
tether groups for drug-delivery systems.
[11] For recent reviews of activation of amides, see; a) M. Szostak, G. Meng,
S. Shi, Synlett 2016, 27, 2530–2540; b) J. E. Dander, N. K. Garg, ACS
Catal. 2017, 7, 1413–1423; c) C. Meng, M. Szostak, Eur. J. Org. Chem.
2018, 2352–2365; d) S. Shi, S. P. Nolan, M. Szostak, Acc. Chem. Res.
2018, 51, 2589–2599; e) M. B. Chaudhari, B. Gnanaprakasam, Chem.
Asian J. 2019, 14, 76–93.
[12] M. J. Frisch, et al. Gaussian 09, Revision Ds.01; Gaussian, Inc.:
Wallingford, CT, 2013. (See SI for full citation.)
[13] L. Jiang, G. E. Job, A. Klapars, S. L. Buchwald, Org. Lett. 2003, 5,
3667–3669.
[14] a) M. O. Frederick, J. A. Mulder, M. R. Tracey, R. P. Hsung, J. Huang,
K. C. M. Kurtz, L. Shen, C. J. Douglas, J. Am. Chem. Soc. 2003, 125,
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Stahl, J. Am. Chem. Soc. 2008, 130, 833–835.
Acknowledgements
R. Y. is grateful to the The Japan Science Society for partial
support for this research. We are also grateful to Dr. Masatoshi
Kawahata for helpful discussions and advises concerning crystal
structual analysis.
[15] The data of crystals (CCDC 1895329 for 3, CCDC 1895328 for 4,
CCDC 1895326 for 5, CCDC 1895327 for 6 and CCDC 1895330 for
7) can be obtained free of charge
Crystallographic Data
http://www.ccdc.cam.ac.uk/data_request/cif.
from
The
Cambridge
via
Center
Keywords: Amides • Alkynes • Conformation analysis •
Ynamides • Transacylation
[16] A. Itai, Y. Toriumi, N. Tomioka, H. Kagechika, I. Azumaya, K. Shudo, T
Tetrahedron Lett. 1989, 30, 6177–6180.
[1]
[2]
A. Greenberg, C. M. Breneman, J. F. Liebman, The amide linkage:
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[18] An example of a similar situation, which repulsion of carbonyl oxygen
and alkyne determines the preferred conformation, see; M. Pilkington,
S. Tayyip, J. D. Wallis, J. Chem. Soc. Perkin Trans. 2 1994, 2481–2484.
[19] a) D. G. Gehring, W. A. Mosher, G. S. Reddy, J. Org. Chem. 1966, 31,
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[3]
[4]
In this paper, cis and trans, defined as shown in Figure 1, are used
instead of E and Z nomenclature to avoid confusion, since the priority of
the phenyl group would be different between 3 and 5.
[20] For a example of nN → πAr conjugation for amide activation, see; a) G.
Meng, R. Lalancette, R. Szostak, M. Szostak, Org. Lett. 2017, 19,
4656–4659; b) G. Meng, R. Szostak, M. Szostak, Org. Lett. 2017, 19,
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10.1002/chem.201901451
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Dr. Ryu Yamasaki*, Kento Morita,
Hiromi Iizumi, Dr. Ai Ito, Dr. Kazuo
Fukuda and Prof. Dr. Iwao Okamoto*
Page No. – Page No.
N-Ethynylation of Anilides Decreases
Double-Bond Character of Amide Bond
while Retaining Trans Conformation and
Planarity
N-Ethynylation of anilides keep trans conformation of secondary amide, while N-
alkylation and vinylation do not. In addition, N-ethnylated anilide has weakened
C(O)–N bond character without twisting of amide nitrogen, and easily hydrolyzed to
afford transacylated amide.
This article is protected by copyright. All rights reserved.