Structure and Reactivity of Highly Twisted N-Acylimidazoles

Article abstract of DOI:10.1021/acs.orglett.9b00624

A modular and efficient synthesis of highly twisted N-acylimidazoles is reported. These twist amides were characterized via X-ray crystallography, NMR spectroscopy, IR spectroscopy, and DFT calculations. Modification of the substituent proximal to the amide revealed a maximum torsional angle of 88.6° in the solid state, which may be the most twisted amide reported for a nonbicyclic system to date. Reactivity and stability studies indicate that these twisted N-acylimidazoles may be valuable, namely as acyl transfer reagents.

Full text of DOI:10.1021/acs.orglett.9b00624

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Structure and Reactivity of Highly Twisted N‑Acylimidazoles
Elizabeth A. Stone, Brandon Q. Mercado, and Scott J. Miller*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: A modular and efficient synthesis of highly
twisted N-acylimidazoles is reported. These twist amides were
characterized via X-ray crystallography, NMR spectroscopy, IR
spectroscopy, and DFT calculations. Modification of the
substituent proximal to the amide revealed a maximum
torsional angle of 88.6° in the solid state, which may be the
most twisted amide reported for a nonbicyclic system to date.
Reactivity and stability studies indicate that these twisted N-
acylimidazoles may be valuable, namely as acyl transfer
reagents.
midazoles are a prevalent and critical scaffold in a variety of
Ibiological molecules, such as histidine and histamine;
modified biomolecules, including peptidomimetics; as well as
natural and synthetic products.1 Many of these imidazole-
containing compounds exhibit a vast array of bioactivities,
treating inflammation, pain, diabetes, infections, viruses, and
cancer (Figure 1). For example, L-779,450 has been identified as
a potent and selective B-Raf kinase inhibitor with Kd = 2.4 nM for
the treatment of strokes.2 Imidazoles are also valuable in
synthetic chemistry, serving as acyl transfer reagents,3 ionic
liquids,4 organocatalysts,5 precursors to N-heterocyclic car-
benes,6 and photochromic materials.7
Figure 2. Characteristics of amides. (a) Amide bond resonance,
inducing a planar structure. (b) Winkler−Dunitz distortion parame-
ters14 for describing twist amides, with (c) select examples.15
N−C(O) bond, (ii) lower rotational barrier for cis−trans
isomerization, (iii) higher CO infrared (IR) stretching
frequency, (iv) more downfield CO shift by 13C NMR
Figure 1. Examples of imidazole-containing compounds.2,7b,8
spectroscopy, and (v) increased reactivity in nucleophilic
addition and hydrolysis.16 To quantify the degree of distortion
in the amide bond, Winkler and Dunitz developed several
additional parameters (Figure 2b): twist angle (τ), pyramidaliza-
In the context of acyl transfer, N-acylation of imidazoles has
been shown to generate reactive heterocyclic amides or
tion at nitrogen (χN), and pyramidalization at carbon (χC).14 For
fully planar bonds, τ = χN = χC = 0°. Accordingly, a fully
orthogonal amide bond would correspond to a twist angle of 90°,
and χN = χC = 60° for fully pyramidalized amide bonds. However,
χC values are typically close to 0° regardless of the degree of
distortion due to the contribution of the amino ketone resonance
structures (Figure 2a, A and B). The Szostak group has also
identified the additive Winkler−Dunitz distortion parameter
(Στ + χN) for better predicting structural and energetic
properties of twist amides.17 In addition to the Winkler−Dunitz
azolides.9 Unlike typical amides, N-acylimidazoles are far more
reactive toward nucleophilic attack (e.g., hydrolysis). This
intriguing reactivity has spurred several studies of the stability
and conformational features of N-acylimidazoles.9,10 While this
class of imidazoles has been shown to exhibit conformational
equilibria, significantly twisted N-acylimidazoles have not been
synthesized.
Although the majority of amides are planar due to the strong,
stabilizing resonance between nN and π*CO (Figure 2a);11
deviations from this planarity have been observed in peptides12
and small molecules.13 Disruption of the amide bond
resonances, a fundamental characteristic of a twist amide,
induces several changes in the properties of the amide: (i) longer
Received: February 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
parameters, distortion of the amide bond can be quantified
according to θ, the sum of the bond angles at nitrogen, which is
328.4° for sp3-hybridized atoms and 360° for sp2 atoms.18
and efficiency of this route should facilitate synthesis of
numerous analogues of 8.
̌
The study of twist amides began with the proposal of Lukes in
1938 in which the incorporation of an amide bond nitrogen atom
at the bridgehead position in bi- or polycyclic molecules would
result in amide bond distortion.19 Since then, several
quintessential examples of twist amides have been synthesized
and characterized (Figure 2c). Notably, twist angles of 89.5° and
89.2° have been achieved by Kirby (1)15d and Stoltz (2),15e
respectively, in bridged lactams. Disrupting amide resonance in
nonbicyclic systems has been more challenging. Yet, this feat has
also been accomplished, with one early example of a twisted
mercaptothiazoline reported by Yamada in 1993 (3, τ =
74.3°).15b Remarkably, Szostak has very recently reported a
seminal case of an acyclic twist amide with nearly ideal
orthogonality of substituents using N,N-disubstituted benza-
mide 4.15c
Although the degree of twisting in N-acylimidazoles has been
examined,10e the highest degree of torsional distortion
previously reported crystallographically, to our knowledge, was
the case of 5 (τ = 47.0°) for a tetrasubstituted N-acylimidazole
prepared by Hashmi.15a While exploring the synthesis of highly
substituted imidazoles in pursuit of compounds with multiple
potential axes of chirality,20 we made the serendipitous discovery
of several new, highly twisted N-acylimidazoles, including one
that exhibits nearly ideal orthogonality. Thus, we report herein
the synthesis, crystal structures, and reactivity of these
compounds, including what may be the most twisted amide in
a nonbicyclic system reported to date (8a, τ = 88.6°).
Figure 3. An overlay of the crystal structure (maroon) and geometry
optimized structure (navy) of 7a (top) and 8a (bottom) is shown on the
left (B3LYP/6-311++G(d,p)). Select crystal packing motif of 7a (top)
and 8a (bottom) with intermolecular interactions highlighted in
turquoise and distances in Å indicated, 50% ellipsoids. A symmetry
equivalent Br-π interaction in 7a is omitted for clarity.
a
b
Table 1. Select Geometric Parameters, Spectroscopic Data,
c
and Computed N−C(O) Rotational Barriers of 7a and 8a
Scheme 1. Synthesis of Highly Twisted N-Benzoylimidazoles
entry
parameter
value for 7a
value for 8a
1
2
3
4
5
6
7
8
N−C
1.4520(18)
1.2026(18)
1.484(2)
1.3143(19)
1.3998(18)
−48.8(2)
120.59(15)
134.54(15)
−56.1(2)
52.5
10.6
3.3
63.1
359.35
1714
168.6
9.8
1.469(2)
1.201(2)
1.473(3)
1.376(2)
1.399(2)
−77.7(2)
80.4(2)
102.5(2)
−99.4(2)
88.6
21.6
0.2
110.5
357.06
1713
C−O
C−C1
N−C2
N−C3
C1−C−N−C2
C1−C−N−C3
O−C−N−C2
9
O−C−N−C3
10
11
12
13
14
15
16
17
τ
χN
χC
τ + χN
θ
ν(
̃
CO)
The synthesis of these highly twisted N-benzoylimidazoles
follows a strategy similar to that employed by Merck for the
generation of potent tetrasubstituted imidazole inhibitors of p38
mitogen-activated protein (MAP) kinase (Scheme 1).21 The
imidazole core was readily constructed via condensation of 2-
bromoacetophenone with benzamidine in DMF at 45 °C.
Installation of the benzoyl group was accomplished by
deprotonation of 6a with sodium hydride followed by addition
of benzoyl chloride. The crude product was carried forward
without further purification; bromination with N-bromosucci-
nimide thus afforded 7a in 74% yield over two steps. Lastly,
Suzuki−Miyaura cross coupling was performed with subsequent
TBS deprotection to produce 8a (54% over two steps). To
increase the solubility of the imidazole-containing compounds,
this procedure was repeated starting with 2-bromo-4′-
(trifluoromethyl)acetophenone to afford 6b−8b. The brevity
δ(13CO)
169.6
9.7
ΔG⧧ N−C(O)
a
Bond lengths and angles are reported in Å and degrees, respectively.
b
IR (neat) frequencies reported in cm−1; 13C NMR (151 MHz,
c
DMSO-d6) resonances reported in ppm. Calculated ΔG⧧ (B3LYP/6-
311++G(d,p)) values reported in kcal/mol.
Initially, crystallography was employed to confirm the
regioisomer obtained following benzoylation. Strikingly, we
observed a high degree of amide twisting in 7a, which was even
more pronounced in 8a (Figure 3). Table 1 summarizes key
geometric parameters of the crystal structures of 7a and 8a,
including bond lengths (entries 1−5), dihedral angles (entries
6−9), Winkler−Dunitz distortion parameters (entries 10−13),
and θ (entry 14); carbonyl IR stretching frequencies (entry 15)
B
DOI: 10.1021/acs.orglett.9b00624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Amide Reactivity of N-Acylimidazoles 7b and 8b
a
Suzuki−Miyaura cross coupling and deprotection conditions are shown in Scheme 1. Crystal structure of N- to O-benzoyl migration product (9)
shown on right with hydrogens omitted for clarity, 50% ellipsoids.
and 13C NMR shifts (entry 16); as well as calculated N−C(O)
rotational barriers (B3LYP/6-311++G(d,p); entry 17). While
the bond lengths for 7a and 8a are similar, the dihedral angles are
significantly different, revealing a greatly increased twist angle (τ
= 52.5° vs 88.6° for 7a and 8a, respectively; entry 10). Further
analysis of the Winkler−Dunitz distortion parameters reveals
that while the pyramidalization at nitrogen in 8a is greater than
that of 7a, there is also less pyramidalization at the carbonyl
carbon (entries 11 and 12, respectively). The nature of the amide
nitrogen is further described using the parameter θ, indicating
that this nitrogen has less s-character in 8a than in 7a (entry 14).
Lastly, the relative degrees of twisting are also described by their
significantly different values for the additive Winkler−Dunitz
distortion parameter (63.1° for 7a, 110.5° for 8a; entry 13).
In addition to examining the crystal structures of 7a and 8a,
these compounds were characterized spectroscopically. While
typical CO stretching frequencies for amides are 1690−1630
cm−1, 7a and 8a show resonances at 1714 and 1713 cm−1,
respectively, which are in the range of typical aliphatic ketones.
These resonances also allude to the highly electrophilic nature of
these amide carbonyls (entry 15).17 The twists intrinsic to these
amide bonds are also conveyed in the downfield shifts of the
carbonyl carbons in 13C NMR, with a greater shift seen for 8a
(168.6 ppm for 7a vs 169.6 ppm for 8a; entry 16).
Moreover, the N−C(O) rotational barriers were calculated
(B3LYP/6-311++G(d,p)). Relative to typical amides, with
rotational barrier for cis−trans isomerization between 15−20
kcal/mol, these twist amides exhibit low rotational barriers (9.8
and 9.7 kcal/mol for 7a and 8a, respectively; entry 17),
consistent with their elongated N−C bond (entry 1). In
determining this rotational barrier, we noted an intriguing
disparity in the degree of torsion between the crystal and
calculated structures (Figure 3). While the optimized ground
state of 7a displayed an increased τ (60.5° vs 52.5°, respectively)
relative to the solid state, this trend was reversed and amplified
for 8a (66.5° vs 88.6°, respectively). A better understanding of
these conformational discrepancies was realized by examining
the crystal packing. In the crystal lattice of 7a, relatively weak
Br−π and CH−π intermolecular interactions appear to spur the
slight deviation seen from the optimized ground-state structure
(Figure 3, top). Substitution of bromine for phenol, however,
induced a more significant conformational change, as the aryl
rings rotate to enable favorable CH−π, π−π, and H-bond
interactions within the crystal lattice. The crystal packing can
also be used to rationalize why 7a and 8a display significantly
enhanced twist angles relative to a similar tetrasubstituted N-
acetylimidazole (5) synthesized by Hashmi (τ = 47.0°, Figure 2)
that is incapable of engaging in π-interactions with the C-
substituent of the amide.15a While there are very few examples of
highly distorted amides with twist angles near 90°with most as
bicyclic systemsthe crystallographic and spectroscopic data
for 8a all reflect the nearly maximal twisting of the N-
acylimidazole moiety (τ = 88.6°) in the solid state.
With twist amides 7 and 8 in hand, their relative N−C(O)
stability and reactivity were examined experimentally (Scheme
2). Specifically, 7b and 8b were studied, as these compounds
were more soluble in various solvents. A crystal structure of 7b
was also obtained, affording a twist angle of 59.6° in the solid
state, similar to that of 7a (see Supporting Information). We also
anticipate the twist angleof 8b tobe comparable tothatexhibited
in 8a. Although twisted bridged lactams, such as aza-2-
adamantanones and 2-quinuclidones (Figure 1), are prone to
hydrolysis,15d,e both 7b and 8b were found to be stable when
stirred rapidly in aqueous acetonitrile (1:1 v/v) for 15 h (Scheme
2, condition A). Moreover, 8 is synthesized via Suzuki−Miyaura
cross coupling, involving prolonged exposure (16 h) to aqueous
toluene (10:1 v/v) at an elevated temperature (110 °C),
followed by TBS deprotection with TBAF (1 M in THF), further
indicating that 8a and 8b are lessproneto hydrolysis than twisted
bridged lactams. Interestingly, when this deprotection reaction
was quenched withcitric acid(10% w/v), N-toO-acyl transfer of
8b was observed, isolating 9 in 8% yield over three steps, an
outcome that was confirmed crystallographically (Scheme 2,
condition B). However, when twist amide 7b was exposed to a
biphasic citric acid solution, it proved stable (Scheme 2,
condition B′).
C
DOI: 10.1021/acs.orglett.9b00624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Given the enhanced reactivity of both twist amides15c,13b,16a,22
and N-acylimidazoles3,9 toward acyl transfer, we sought to
examine the efficacy of 7b and 8b as acylation reagents (Scheme
2, conditions C). Under mild conditions, complete benzoyl
transfer from 7b to N-benzylamine, furnishing 10 (full
conversion, 80% isolated yield) and N-benzylbenzamide, was
accomplished in 15 h. Of note, the use of 8b, presumably
possessing a larger degree of amide twisting, led to a more
sluggish reaction, affording 11 in 67% isolated yield (84%
conversion) within the same time frame. Although 8b should be
significantly more twisted than 7b, it may be that the increased
steric bulk surrounding the benzoyl group in 8b may impede the
reaction, perhaps due to increased steric demand in the
formation and breakdown of tetrahedral intermediates. Indeed,
it has been shown that sterically hindered N-acylimidazoles are
more stable against nucleophiles than those that are unhinder-
ed.9,10c Accordingly, our results reinforce the notion that
variation of the C3-amide moiety can tune the reactivity of
these twisted N-acyl imidazoles.
In conclusion, we report an efficient, modular synthesis and
full structural characterization of several new, twist amide N-
acylimidazoles. Crystallographic analysis of these twist amides
revealed a maximum torsional angle of 88.6° in the solid state,
which may be the most extreme case reported to date, slightly
closer to ideal than the recently reported and seminal example of
Szostak. IR spectroscopy, 13C NMR, and computational data all
support the presence of highly twisted amides. Preliminary
reactivity and stability studies indicate that 7b and 8b may be
used as mild acylating reagents with tunable reactivity depending
on the C3-amide substituent, which can be easily modified using
the synthetic route utilized herein. Furthermore, these twist
amides withstand hydrolysis; therefore, twisted N-acyl imida-
zoles could be explored as potential pharmaceuticals given the
diverse array of bioactivities exhibited by imidazole-containing
compounds.
ACKNOWLEDGMENTS
■
This research was supported by the National Institutes of Health
(NIGMS R37 068649). E.A.S. acknowledges the support of the
National Science Foundation Graduate Research Fellowship
(DGE-112249) and the NIH Molecular Biophysics Predoctoral
Training Grant (T32 GM008283).
REFERENCES
■
(1) (a) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bos, M.; Cook, C. M.;
Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E. Concepts and progress in
the development of peptide mimetics. J. Med. Chem. 1993, 36, 3039.
(b) Moore, G. J. Designing peptide mimetics. Trends Pharmacol. Sci.
́
1994, 15, 124. (c) Beltran, M.; Pedroso, E.; Grandas, A. Acomparison of
histidine protecting groups in the synthesis of peptide-oligonucleotide
conjugates. Tetrahedron Lett. 1998, 39, 4115. (d) De Luca, L. Naturally
Occurring and Synthetic Imidazoles: Their Chemistry and Their
Biological Activities. Curr. Med. Chem. 2006, 13, 1. (e) Gupta, R. R.;
Kumar, M.; Gupta, V. Heterocyclic Chemistry; Springer, 1999; Vol. II;.
(f) Bellina, F.; Cauteruccio, S.; Rossi, R. Synthesis and biological activity
of vicinal diaryl-substituted 1H-imidazoles. Tetrahedron 2007, 63, 4571.
(g) Jin, Z. Muscarine, imidazole, oxazole and thiazole alkaloids. Nat.
Prod. Rep. 2009, 26, 382. (h) Gupta, G.; Kumar, V.; Kaur, K. Imidazole
Containing Natural Products as Antimicrobial Agents: A Review. Nat.
Prod. J. 2014, 4, 73.
(2) Takle, A. K.; Bamford, M. J.; Davies, S.; Davis, R. P.; Dean, D. K.;
Gaiba, A.; Irving, E. A.; King, F. D.; Naylor, A.; Parr, C. A.; Ray, A. M.;
Reith, A. D.; Smith, B. B.; Staton, P. C.; Steadman, J. G. A.; Stean, T. O.;
Wilson, D. M. The identification of potent, selective and CNS penetrant
furan-based inhibitors of B-Raf kinase. Bioorg. Med. Chem. Lett. 2008,
18, 4373.
(3) (a) Copeland, G. T.; Jarvo, E. R.; Miller, S. J. Minimal Acylase-Like
Peptides. Conformational Control of Absolute Stereospecificity. J. Org.
Chem. 1998, 63, 6784. (b) Jarvo, E. R.; Copeland, G. T.; Papaioannou,
N.; Bonitatebus, P. J.; Miller, S. J. A Biomimetic Approach to
Asymmetric Acyl Transfer Catalysis. J. Am. Chem. Soc. 1999, 121,
11638. (c) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. Nonenzymatic
peptide-based catalytic asymmetric phosphorylation of inositol
derivatives. Chem. Commun. 2003, 15, 1781. (d) Lewis, C. A.;
Sculimbrene, B. R.; Xu, Y.; Miller, S. J. Desymmetrization of Glycerol
Derivatives with Peptide-Based Acylation Catalysts. Org. Lett. 2005, 7,
3021. (e) Heller, S. T.; Sarpong, R. Chemoselective Esterification and
Amidation of Carboxylic Acids with Imidazole Carbamates and Ureas.
Org. Lett. 2010, 12, 4572. (f) Heller, S. T.; Schultz, E. E.; Sarpong, R.
Chemoselective N-Acylation of Indoles and Oxazolidinones with
Carbonylazoles. Angew. Chem., Int. Ed. 2012, 51, 8304. (g) Lu, Y.; Wei,
P.; Pei, Y.; Xu, H.; Xin, X.; Pei, Z. Regioselective acetylation of
carbohydrates and diols catalyzed by tetramethyl-ammonium hydroxide
in water. Green Chem. 2014, 16, 4510.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00624.
Experimental details, characterization data, crystallo-
graphic details, and DFT computational details for N-
acylimidazoles (PDF)
(4) (a) Green, M. D.; Long, T. E. Designing Imidazole-Based Ionic
Liquids and Ionic Liquid Monomers for Emerging Technologies AU -
Green, Matthew D. Polym. Rev. 2009, 49, 291. (b) Troshenkova, S. V.;
Sashina, E. S.; Novoselov, N. P.; Arndt, K.-F.; Jankowsky, S. Structure of
ionic liquids on the basis of imidazole and their mixtures with water.
Russ. J. Gen. Chem. 2010, 80, 106. (c) Tao, Y.; Dong, R.; Pavlidis, I. V.;
Chen, B.; Tan, T. Using imidazolium-based ionic liquids as dual solvent-
catalysts for sustainable synthesis of vitamin esters: inspiration from bio-
and organo-catalysis. Green Chem. 2016, 18, 1240. (d) Mu, X.; Jiang, N.;
Liu, C.; Zhang, D. New Insight into the Formation Mechanism of
Imidazolium-Based Ionic Liquids from N-Alkyl Imidazoles and
Halogenated Hydrocarbons: A Polar Microenvironment Induced and
Autopromoted Process. J. Phys. Chem. A 2017, 121, 1133. (e) Dreier, T.
A.; Ringstrand, B. S.; Seifert, S.; Firestone, M. A. Synthesis and
application of a metal ion coordinating ionic liquid monomer: Towards
size and dispersity control of nanoparticles formed within a structured
polyelectrolyte. Eur. Polym. J. 2018, 107, 275.
Accession Codes
CCDC 1895220−1895222 and 1897303 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: scott.miller@yale.edu.
ORCID
Scott J. Miller: 0000-0001-7817-1318
Notes
(5) (a) Connors, K. A.; Pandit, N. K. N-Methylimidazole as a catalyst
for analytical acetylations of hydroxy compounds. Anal. Chem. 1978, 50,
1542. (b) Hojabri, L.; Hartikka, A.; Moghaddam, F. M.; Arvidsson, P. I.
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b00624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A New Imidazole-Containing Imidazolidinone Catalyst for Organo-
catalyzed Asymmetric Conjugate Addition of Nitroalkanes to
Aldehydes. Adv. Synth. Catal. 2007, 349, 740. (c) Zhang, Z.; Xie, F.;
Jia, J.; Zhang, W. Chiral Bicycle Imidazole Nucleophilic Catalysts:
Rational Design, Facile Synthesis, and Successful Application in
Asymmetric Steglich Rearrangement. J. Am. Chem. Soc. 2010, 132,
15939. (d) Li, Y.; Giulionatti, M.; Houghten, R. A. Macrolactonization
of Peptide Thioesters Catalyzed by Imidazole and Its Application in the
Synthesis of Kahalalide B and Analogues. Org. Lett. 2010, 12, 2250.
(e) Khan, M. N.; Pal, S.; Karamthulla, S.; Choudhury, L. H. Imidazole as
organocatalyst for multicomponent reactions: diversity oriented
synthesis of functionalized hetero- and carbocycles using in situ-
generated benzylidenemalononitrile derivatives. RSC Adv. 2014, 4,
3750.
promoted amide hydrolysis. Acc. Chem. Res. 1992, 25, 481. (b) Skorey,
K. I.; Somayaji, V.; Brown, R. S. The influence of a carboxylate group on
the rate of O-acylation of 2-hydroxymethylimidazoles by a strained
amide. J. Am. Chem. Soc. 1988, 110, 5205. (c) Somayaji, V.; Keillor, J.;
Brown, R. S. Model for the aspartate proteinases. Hydrolysis of a
distorted amidecatalyzed by dicarboxylic acids capable of forming cyclic
anhydrides. J. Am. Chem. Soc. 1988, 110, 2625. (d) Mujika, J. I.;
Mercero, J. M.; Lopez, X. Water-Promoted Hydrolysis of a Highly
Twisted Amide: Rate Acceleration Caused by the Twist of the Amide
Bond. J. Am. Chem. Soc. 2005, 127, 4445. (e) Wang, B.; Cao, Z. Acid-
Catalyzed Reactions of Twisted Amides in Water Solution: Competi-
tion between Hydration and Hydrolysis. Chem. - Eur. J. 2011, 17, 11919.
(f) Roy, O.; Caumes, C.; Esvan, Y.; Didierjean, C.; Faure, S.;
Taillefumier, C. The tert-Butyl Side Chain: A Powerful Means to
Lock Peptoid Amide Bonds in the Cis Conformation. Org. Lett. 2013,
15, 2246. (g) Elashal, H. E.; Raj, M. Site-selective chemical cleavage of
peptide bonds. Chem. Commun. 2016, 52, 6304. (h) Elashal, H. E.;
Cohen, R. D.; Elashal, H. E.; Raj, M. Oxazolidinone-Mediated Sequence
Determination of One-Bead One-Compound Cyclic Peptide Libraries.
Org. Lett. 2018, 20, 2374.
(6) (a) Janssen-Muller, D.; Schlepphorst, C.; Glorius, F. Privileged
̈
chiral N-heterocyclic carbene ligands for asymmetric transition-metal
catalysis. Chem. Soc. Rev. 2017, 46, 4845. (b) Peris, E. Smart N-
Heterocyclic Carbene Ligands in Catalysis. Chem. Rev. 2018, 118, 9988.
(7) (a) Bu, X. R.; Li, H.; Van Derveer, D.; Mintz, E. A. A novel
approach to synthesis of tricyanovinylthiophene for heterocyclic
imidazole nonlinear optical chromophores. Tetrahedron Lett. 1996,
37, 7331. (b) Sakuragi, R.; Ishige, O.; Fukusaka, K. EP 1684115 A1 Jul
26, 2006. (c) Fridman, N.; Kaftory, M.; Eichen, Y.; Speiser, S.
Spectroscopy, photophysical and photochemical properties of
bisimidazole derivatives. J. Photochem. Photobiol., A 2007, 188, 25.
(8) (a) Ohta, S.; Tsuno, N.; Nakamura, S. Total syntheses of naamine
A and naamidine A, marine imidazole alkaloids. Heterocycles 2000, 53,
(14) Winkler, F. K.; Dunitz, J. D. The non-planar amide group. J. Mol.
Biol. 1971, 59, 169.
(15) (a) Zeng, Z.; Jin, H.; Xie, J.; Tian, B.; Rudolph, M.; Rominger, F.;
Hashmi, A. S. K. α-Imino Gold Carbenes from 1,2,4-Oxadiazoles:
Atom-Economical Access to Fully Substituted 4-Aminoimidazoles. Org.
Lett. 2017, 19, 1020. (b) Yamada, S. Structure and Reactivity of a Highly
Twisted Amide. Angew. Chem., Int. Ed. Engl. 1993, 32, 1083. (c) Liu, C.;
Shi, S.; Liu, Y.; Liu, R.; Lalancette, R.; Szostak, R.; Szostak, M. The Most
Twisted Acyclic Amides: Structures and Reactivity. Org. Lett. 2018, 20,
7771. (d) Kirby, A. J.; Komarov, I. V.; Wothers, P. D.; Feeder, N. The
Most Twisted Amide: Structure and Reactions. Angew. Chem., Int. Ed.
1998, 37, 785. (e) Tani, K.; Stoltz, B. M. Synthesis and structural
analysis of 2-quinuclidonium tetrafluoroborate. Nature 2006, 441, 731.
̈ ̇
̆
1939. (b) Ucu̧ cu, U.; Karaburun, N. G.; Isi̧ kdag, I. Synthesis and
analgesic activity of some 1-benzyl-2-substituted-4,5-diphenyl-1H-
imidazole derivatives. Farmaco 2001, 56, 285.
(9) Staab, H. A. New Methods of Preparative Organic Chmistry IV.
Syntheses Using Heterocyclic Amides (Azolides). Angew. Chem., Int. Ed.
Engl. 1962, 1, 351.
(10) (a) Fife, T. H. Steric Effects in the Hydrolysis of N-
Acylimidazoles and Esters of p-Nitrophenol. J. Am. Chem. Soc. 1965,
87, 4597. (b) Fee, J. A.; Fife, T. H. Steric and Electronic Effects in the
Hydrolysis of N-Acylimidazoles and N-Acylimidazolium Ions. J. Org.
́
(16) (a) Szostak, M.; Aube, J. Chemistry of Bridged Lactams and
Related Heterocycles. Chem. Rev. 2013, 113, 5701. (b) Szostak, R.;
Szostak, M. Chemistry of Bridged Lactams: Recent Developments.
Molecules 2019, 24, 274.
̈
́
Chem. 1966, 31, 2343. (c) Zaramella, S.; Stromberg, R.; Yeheskiely, E.
(17) Szostak, R.; Aube, J.; Szostak, M. Determination of Structures and
Stability Studies of N-Acylimidazoles. Eur. J. Org. Chem. 2002, 2002,
2633. (d) Takahashi, Y.; Ikeda, H.; Kanase, Y.; Makino, K.; Tabata, H.;
Oshitari, T.; Inagaki, S.; Otani, Y.; Natsugari, H.; Takahashi, H.;
Ohwada, T. Elucidation of the E-Amide Preference of N-Acyl Azoles. J.
Org. Chem. 2017, 82, 11370. (e) Kong, X.; Tang, A.; Wang, R.; Ye, E.;
Terskikh, V.; Wu, G. Are the amide bonds in N-acyl imidazoles twisted?
A combined solid-state 17O NMR, crystallographic, and computational
study. Can. J. Chem. 2015, 93, 451. (f) Takahashi, Y.; Wakamatsu, S.;
Tabata, H.; Oshitari, T.; Natsugari, H.; Takahashi, H. Isolation of
Atropisomers of N-Benzoylated Pyrroles and Imidazoles. Synthesis
2015, 47, 2125.
Energetics of Small- and Medium-Sized One-Carbon-Bridged Twisted
Amides using ab Initio Molecular Orbital Methods: Implications for
Amidic Resonance along the C−N Rotational Pathway. J. Org. Chem.
2015, 80, 7905.
(18) Otani, Y.; Nagae, O.; Naruse, Y.; Inagaki, S.; Ohno, M.;
Yamaguchi, K.; Yamamoto, G.; Uchiyama, M.; Ohwada, T. An
Evaluation of Amide Group Planarity in 7-Azabicyclo[2.2.1]heptane
Amides. Low Amide Bond Rotation Barrier in Solution. J. Am. Chem.
Soc. 2003, 125, 15191.
̌
(19) Lukes, R. Collect. Czech. Chem. Commun. 1938, 10, 148.
(20) Barrett, K. T.; Metrano, A. J.; Rablen, P. R.; Miller, S. J.
Spontaneous transfer of chirality in an atropisomerically enriched two-
axis system. Nature 2014, 509, 71.
(11) Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide
Linkage: Structural Significance in Chemistry, Biology, and Materials
Science; Wiley, 2000.
(21) Liverton, N. J.; Butcher, J. W.; Claiborne, C. F.; Claremon, D. A.;
Libby, B. E.; Nguyen, K. T.; Pitzenberger, S. M.; Selnick, H. G.; Smith,
G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agarwal, L.; Dancheck, K.;
Forsyth, A. J.; Fletcher, D. S.; Frantz, B.; Hanlon, W. A.; Harper, C. F.;
Hofsess, S. J.; Kostura, M.; Lin, J.; Luell, S.; O’Neill, E. A.; Orevillo, C. J.;
Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Visco, D. M.; O’Keefe, S. J.
Design and Synthesis of Potent, Selective, and Orally Bioavailable
Tetrasubstituted Imidazole Inhibitors of p38 Mitogen-Activated
Protein Kinase. J. Med. Chem. 1999, 42, 2180.
(22) (a) Yamada, S.; Sugaki, T.; Matsuzaki, K. Twisted Amides as
Selective Acylating Agents for Hydroxyl Groups under Neutral
Conditions: Models for Activated Peptides during Enzymatic Acyl
Transfer Reaction. J. Org. Chem. 1996, 61, 5932. (b) Meng, G.; Shi, S.;
Lalancette, R.; Szostak, R.; Szostak, M. Reversible Twisting of Primary
Amides via Ground State N−C(O) Destabilization: Highly Twisted
Rotationally Inverted Acyclic Amides. J. Am. Chem. Soc. 2018, 140, 727.
(c) Szostak, R.; Szostak, M. N-Acyl-glutarimides: Resonance and
Proton Affinities of Rotationally-Inverted Twisted Amides Relevant to
(12) (a) Poland, B. W.; Xu, M.-Q.; Quiocho, F. A. Structural Insights
into theProtein Splicing Mechanism of PI-SceI. J. Biol. Chem. 2000, 275,
16408. (b) Romanelli, A.; Shekhtman, A.; Cowburn, D.; Muir, T. W.
Semisynthesis of a segmental isotopically labeled protein splicing
precursor: NMR evidence for an unusual peptide bond at the N-extein−
intein junction. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 6397.
(c) Shemella, P.; Pereira, B.; Zhang, Y.; Van Roey, P.; Belfort, G.; Garde,
S.; Nayak, S. K. Mechanism for intein C-terminal cleavage: a proposal
from quantum mechanical calculations. Biophys. J. 2007, 92, 847.
(d) Lizak, C.; Gerber, S.; Numao, S.; Aebi, M.; Locher, K. P. X-ray
structure of a bacterial oligosaccharyltransferase. Nature 2011, 474, 350.
(e) Lizak, C.; Gerber, S.; Michaud, G.; Schubert, M.; Fan, Y.-Y.; Bucher,
M.; Darbre, T.; Aebi, M.; Reymond, J.-L.; Locher, K. P. Unexpected
reactivity and mechanism of carboxamide activation in bacterial N-
linked protein glycosylation. Nat. Commun. 2013, 4, 2627.
(13) (a) Brown, R. S.; Bennet, A. J.; Slebocka-Tilk, H. Recent
perspectives concerning the mechanism of H3O+- and hydroxide-
E
DOI: 10.1021/acs.orglett.9b00624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
N−C(O) Cross-Coupling. Org. Lett. 2018, 20, 1342. (d) Szostak, R.;
̈
Szostak, M. Troger’s Base Twisted Amides: High Amide Bond Twist
and N-/O-Protonation Aptitude. J. Org. Chem. 2019, 84, 1510.
F
DOI: 10.1021/acs.orglett.9b00624
Org. Lett. XXXX, XXX, XXX−XXX