1

Twisted N-Acyl-Hydantoins: Rotationally-Inverted

Urea-Imides of Relevance in N–C(O) Cross-Coupling

Roman Szostak,‡ Chengwei Liu,† Roger Lalancette,† and Michal Szostak*,†

‡Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland

†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United

States

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required

according to the journal that you are submitting your paper to)

Corresponding author

michal.szostak@rutgers.edu

2

Abstract

We report a combined structural and computational study on the properties of twisted acyclic

hydantoins. These compounds feature cyclic urea-imide moiety that is widely found in bioactive

compounds and is structurally-related to the classic bridged hydantoins proposed by Smissman more

than 50 years ago. We demonstrate that C to N-substitution of the imide moiety in the succinimide ring

to give hydantoin results in one of the most distorted acyclic amide bonds reported to date. The

energetic properties of twisted acyclic hydantoins with respect to structures, resonance energies, barriers

to rotation and proton affinities are discussed. The energetic and structural properties of twisted acyclic

hydantoins described provide a benchmark to facilitate the development of twisted amides based on the

biorelevant cyclic urea-imide scaffold.

3

1. Introduction

Hydantoin is an important heterocycle that is widely found in medicinal agents and biologically-active

compounds (Figure 1).1,2 In this context, hydantoins have attracted significant attention for developing

new pharmaceuticals for the treatment of cancer, inflammation, bacterial infections, hypertension and

perhaps most importantly seizure disorders.3 Especially, the unique structure of a cyclic urea-imide

moiety capable of hydrogen bonding has made hydantoins privileged ring systems in drug discovery

research.4

Hydantoin ring is planar; however, aryl substituents at the C5 position or at either of the nitrogen

atoms are twisted with respect to the planarity of the ring.5 Inspired by the unique properties of

hydantoins, in 1964, Smissman proposed the synthesis of bridged non-planar hydantoins as potential

anticonvulsants with improved bioactive properties (Figure 2).6 More than 20 years later, Brouillette

achieved the first synthesis of bridged hydantoins.7 In the ensuing years, the research on bridged lactams

has resulted in an array of strategies for the synthesis and manipulation of non-planar amides.8–10 In

2017, as part of their studies on the synthesis of unnatural amino acids by oxidative allyl scission, the

Stoltz group reported the synthesis and full structural characterization of a 1,7-

diazabicyclo[4.2.1]nonane-8,9-dione derivative.11 Intriguingly, this bridged hydantoin contains a

significantly distorted amide bond ( = 36.4°, N = 50.2°, C = 8.8°, N–C(O) = 1.404 Å; C=O = 1.210

Å, Winkler-Dunitz distortion parameters), which can be compared with the analogous bridged lactam in

a [4.2.1] scaffold ( = 36.9°, N = 47.7°).12 The use of another set of cyclic imides, such as non-planar

azolidones, e.g. 1,3-thazolidine-2-thiones, has been pioneered by Yamada and co-workers who showed

that the nature of the heteroatom has a significant effect on the distortion of the amide bond.13 In 2015,

our laboratory introduced a new manifold for transition-metal-catalyzed N–C(O) amide bond activation

enabled by steric and electronic destabilization of the amide bond using cyclic imides as model

substrates.14 At present, the activation of amides by transition metals represents a powerful activation

platform that facilitates a broad range of previously elusive transformations of amides.15,16

4

Herein, we report a combined structural and computational study17–19 on the properties of twisted

acyclic hydantoins. We demonstrate that C to N-substitution of the imide moiety in the succinimide ring

to give hydantoin results in an increase of steric distortion of the N-acyl amide bond. The energetic

properties of twisted acyclic hydantoins with respect to structures, resonance energies, barriers to

rotation and proton affinities are reported. Our data demonstrate that amidic resonance in N-acyl-

hydantoins is practically non-existent, and as such these systems should be considered as electronically-

disconnected amide bonds. We show that N-acyl-hydantoins favor protonation at the amide oxygen

atom despite twisted structures. Determination of rotational barriers shows that N-acyl- hydantoins

feature rotationally-inverted amide bonds. The energetic and structural properties of twisted acyclic

hydantoins described provide a benchmark to facilitate the development of twisted amides based on the

biorelevant cyclic urea-imide scaffold.

Figure 1. Selected examples of medicinally-relevant hydantoins.

5

Figure 2. Twisted hydantoins: steric restriction (“smissmanones”) and steric repulsion (acyclic twisted

hydantoins).

2. Results and Discussion

Twisted hydantoins selected for the study are shown in Figure 3. N-acyl-hydantoins with varying

substitution at the alpha carbon in a simple hydantoin ring (1a-e) were selected for the study because of

the ease of synthesis of the parent hydantoin from glycine1a and the importance of unsubstituted

hydantoins in medicinal chemistry research.3,4 A representative N-benzoyl-hydantoin substituted with

methyl groups at the C5 position (1f) was also selected for the study because of the availability of 5,5-

dialkylhydantoins by the classic Bucherer-Bergs reaction1a and to determine the effect on C5

substitution on the structural and energetic properties of medicinally-relevant twisted hydantoins.

Our study started by obtaining X-ray structures of the model N-benzoyl-hydantoins in the series (1d

and 1f, Figure 4). Selected parameters relevant to the twisted amide bond geometry in 1d and 1f along

with structural parameters in representative non-planar and planar amides are presented in Table 1.

We found that acyclic hydantoin 1d contains one of the most distorted acyclic amide bonds reported

to date ( = 52.0°, N = 17.6°, N–C(O) = 1.440 Å; C=O = 1.207 Å, amide bond N1–C1–O1) with the

additive Winkler-Dunitz distortion parameter (+N) of approx. 70°, which is close to half maximum of

theoretical full amide bond distortion, and much higher than in the related N-acyl-succinimide (Table

6

1).12 The very substantial distortion in N-acyl-hydantoins in the solid state is confirmed by the X-ray

structure of 1f ( = 49.5°, N = 13.3°, N–C(O) = 1.447 Å; C=O = 1.196 Å, amide bond N1–C1–O1)

with the additive Winkler-Dunitz distortion parameter (+N) of 62.9°. Comparison of the distortion

with the literature data for N-benzoyl-succinimide ( = 46.1°, N = 9.5°, N–C(O) = 1.439 Å; C=O =

1.209 Å)14b demonstrates that the major contributor to the increased destabilization of the amide bond in

N-acyl-hydantoins is pyramidalization of the amide bond. Apparently, nN → *C=O delocalization of the

N1 nitrogen of the urea moiety (N2–C2–O1, Figure 4A and 4B vs. imide bond O2–C2–N1–C3–O3,

Figure 4A and O3–C2–N1–C3–O2, Figure 4B) affects the pyramidalization of the exocyclic N-acyl

bond. Interestingly, the acyclic hydantoin 1d crystallized as a syn conformation with respect to the urea

bond, while the twisted hydantoin 1f crystallized as an anti conformation.

Figure 3. Structures of twisted hydantoins employed in the present study.

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Figure 4. Crystal structure of acyclic twisted hydantoins: (a) 1d. (b) 1f. Insets show Newman

projections along N–C(O) bonds. 50% ellipsoids. Selected bond lengths (Å) and angles (deg) in 1d: N1–

C1, 1.440(1); C1–O1, 1.207(1); C1–C5, 1.477(1); N1–C3, 1.397(1); N1–C2, 1.420(1); N2–C2,

1.335(1); C2–O2, 1.223(1); C3–O3, 1.205(1); C5–C1–N1–C2, –136.3(1); O1–C1–N1–C3, –119.7(1);

O1–C1–N1–C2, 42.7(2); C5–C1–N1–C3, 61.3(1); O2–C2–N1–C3, 179.4(1); O3–C3–N1–C2, –

174.1(1). In 1f: N1–C1, 1.447(3); C1–O1, 1.196(3); C1–C7, 1.486(3); N1–C3, 1.403(3); N1–C2,

1.413(3); N2–C2, 1.344(3); C2–O3, 1.228(3); C3–O2, 1.209(3); C7–C1–N1–C3, –135.7(2); O1–C1–

N1–C2, –125.2(2); O1–C1–N1–C3, 41.4(3); C7–C1–N1–C2, 57.6(3); O2–C3–N1–C2, –176.4(2); O3–

C2–N1–C3, 177.3(2). CCDC numbers have been deposited with the Cambridge Structural Data Center:

1d: 1860546; 1f: 1860547).

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Table 1. Selected Crystallographic Parameters of Acyclic Twisted Hydantoins 1d, 1f and

Representative Amidesa

entry amide N–C(O)

[Å]

C=O

[Å]

[deg]

N

[deg]

+N

[deg]

1a 1d 1.440 1.207 52.0 17.6 69.6

2a 1f 1.447 1.196 49.5 13.3 62.9

3b N-succinimide 1.439 1.209 46.1 9.5 55.6

4b N-glutarimide 1.475 1.200 87.5 5.6 93.1

5c Yamada’s

amide 1.448 1.196 74.3 29.5 103.8

6d formamide 1.349 1.193 0.0 0.0 0.0

aThis study. X-ray structures. bRef. 14b. cRef. 13.dCalculated values. Ref. 17.

Structural parameters of twisted acyclic hydantoins computed at the B3LYP/6-311++G(d,p) level are

listed in Table SI-1A (syn conformations) and Table SI-1B (anti conformations). B3LYP/6-

311++G(d,p) was selected to conduct geometry optimization as a result of good reproducibility of

literature data18,19c and method practicality. The structural data demonstrate close relationship between

all relevant structural parameters for the syn and anti conformation. A plot of the twist angle for the syn

conformation vs. twist angle for the anti conformation gives an excellent correlation (R2 = 0.99, Figure

5). This indicates that amide bond distortion is relatively independent of the syn/anti isomerism in N-

acyl-hydantoins.

Calculations predict the following order of conformer stability: anti > syn for all compounds in the

series (1a-f). This is in agreement with the more electron-deficient N–C(O)C endocyclic imide bond (cf.

N–C(O)N urea). However, the energy difference between the conformers is negligible at best and ranges

from 0.12 kcal/mol (1e, R = t-Bu) to 0.48 kcal/mol (1a, R = Me). The following values are obtained for

9

the remaining compounds in the series: 1b, R = Et, 0.36 kcal/mol; 1c, R = Cy, 0.38 kcal/mol; 1d, R =

Ph, 0.24 kcal/mol; 1f, R = Ph, 0.37 kcal/mol).

Calculations permit to gain valuable insight into the structural and energetic properties of the acyclic

twisted amide bond in the series (Figure 6).17–19 Interestingly, a good correlation is obtained between

pyramidalization at nitrogen and Charton steric parameter (Figure 6A, R2 = 0.97) as well as between

twist angle and Charton steric parameter (R2 = 0.81), indicating that amidic distortion is predominantly

steric in origin in the series.

Moreover, excellent linear correlations between twist angle and pyramidalization at nitrogen (Figure

6B, R2 = 0.96) and between twist angle and the N–C(O) amide bond length (Figure 6C, R2 = 0.93) are

observed. The data indicate that rotation around the N–C(O) amide bond is followed by changes in

nitrogen pyramidalization and an increase in N–C(O) bond length in agreement with classical resonance

model.17a

Even more interesting is the insight gained from examination of changes within the hydantoin ring

system. The presence of unsymmetrical urea-imide moiety introduces two possible syn and anti

conformations of the acyclic twisted amide bond. An excellent correlation between N–C(O) twist angle

and endocyclic N–C(O)N urea bond length in the syn conformation is observed (Figure 6D, R2 = 0.99).

The data indicate that an increase in distortion of the twisted amide bond is accompanied by shortening

of the N–C(O) bond syn to the twisted amide bond in both cases due to reinforced nN → *C=O

conjugation within the hydantoin ring system.

Likewise, an excellent correlation between the twist angle of the acyclic amide bond and the N–

C(O)C imide bond in the anti conformation is found (Figure 6E, R2 = 0.99). The N–C bond that is anti

to the twisted amide bond also shortens; however, a more scattered correlation is observed in both cases.

In contrast, other bonds, including the N–C(O) urea bond, remain relatively unchanged during the

rotation.

10

25 30 35 40 45 50 55 60

30

35

40

45

50

55

60

(s

yn)

[]

(anti) []

y = 0.886x + 7.242, R2 = 0.999

Plot of Twist Angle (syn) vs. Twist Angle (anti)

Figure 5. Correlation of twist angle () for the syn conformation with twist angle () for the anti

conformation in 1a-e.

The COSNAR method was used to calculate resonance energies of twisted hydantoins selected for the

study (Table 2).17a The data in Table 2 indicate that amidic resonance in N-acyl-hydantoins is practically

non-existent. The values range from 2.1 kcal/mol (R = Me) to -0.1 kcal/mol (R = Ph) and -2.0 kcal/mol

(R = t-Bu). Note that these values can be compared with N,N-dimethylacetamide, RE of 18.3 kcal/mol.

While all amides in the series lack any substantial nN → *C=O delocalization, the negative resonance

energies for twisted hydantoins 1d-e (R = Ph, t-Bu) indicate that these amides are the most reactive in

the series in terms of electrophilic properties of the amide bond.18d A closer analysis reveals an inverse

linear correlation between resonance energy and the N–C(O) amide bond length (Figure 6F, R2 = 0.98),

further indicating loss of amidic resonance upon N–C(O) rotation.

The amide bonds in acyclic twisted hydantoins feature an inverted rotational profile (Figure 7).13,14b

Rotational profile of N,N-dimethylacetamide is shown in Figure 7 for comparison. As shown, the

rotational barrier in 1d features energy minimum at ca. 50° (anti conformation), while the energy

reaches maximum at 180° (syn conformation) and 0° (anti conformation). The rotational barrier was

determined to be 6.07 kcal/mol. The high rotational barrier indicates the preference of twisted acyclic

hydantoins to remain in non-planar ground-state geometry in contrast to typical planar amides.

11

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

2

4

6

8

10

12

14

N [

]

(Charton)

y = 10.04x - 2.175, R2 = 0.965

Plot of Pyramidalization at N vs. Charton Steric Parameter

0 5 10 15 20 2520

30

40

50

60

70

80

90

[

]

N []

y = 3.082x + 19.17, R2 = 0.963

Plot of Twist Angle vs. Pyramidalization at Nitrogen

1.445 1.450 1.455 1.460 1.465 1.470 1.475 1.480 1.485 1.49020

30

40

50

60

70

80

90

[

]

N−C(O) [Å]

y = 1600x + 2289, R2 = 0.926

Plot of Twist Angle vs. N−C(O) Bond Length

1.436 1.438 1.440 1.442 1.444 1.446 1.448

30

35

40

45

50

55

60

[

]

N−C(O)N [Å]

y = -2387x + 3486, R2 = 0.999

Plot of Twist Angle vs. N−C(O)N Bond Length

1.398 1.400 1.402 1.404 1.406 1.408 1.410 1.412 1.414 1.416

25

30

35

40

45

50

55

60

[

]

N−C(O)C [Å]

y = -2222x + 3169, R2 = 0.999

Plot of Twist Angle vs. N−C(O)C Bond Length

1.445 1.450 1.455 1.460 1.465 1.470

-2

-1

0

1

2

ER [kcal/m

ol]

N−C(O) [Å]

y = -196.2x + 286.0, R2 = 0.978

Plot of Resonance Energy vs. N−C(O) Bond Length

Figure 6. Correlations for amides 1a-e. (a) Correlation of pyramidalization at nitrogen (N) to steric

Charton parameter. (b) Correlation of twist angle () to pyramidalization at nitrogen (N). (c)

Correlation of twist angle () to N–C(O) bond length. (d) Correlation of twist angle () to N–C(O)N

bond length [Å]. (e) Correlation of twist angle () to N–C(O)C bond length [Å]. (f) Correlation of

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resonance energy to N–C(O) bond length [Å]. Correlations for anti conformations (a-c and e-f) and syn

conformations (d) are shown. Plots b and c include perpendicular conformation of 1e (R = t-Bu).

Table 2. Resonance Energies Calculated using COSNAR Method (B3LYP/6-311++G(d,p))

entry amide 1 ER

[kcal/mol]

1

1a 2.1

2

1b 1.1

3

1c 0.3

4

1d -0.1

5

1e -2.0

6

1f 0.0

13

Table 3. Proton Affinities (PA) and Differences in Proton Affinities (PA) in 1d (B3LYP/6-

311++G(d,p))a

entry 1d NPA

[kcal/mol]

OPA

[kcal/mol]

PA

[kcal/mol]

1 N+ amide 194.4 - 25.6

2 N+ urea 198.7 - 21.3

3 O+ amide - 220.0 -

4 O+ urea - 218.5 1.5

5 O+ imide - 213.2 6.8

aRepresentative data on bridged lactams: ref. 17,18a.

-150 -100 -50 0 50 100 150-2

0

2

4

6

8

10

12

14

16

18

20

22 1d DMAc

E

[kcal/m

ol]

O−C−N−C []

Plot of Energy vs. O−C−N−C Dihedral Angle

Figure 7. Plot of E [kcal/mol] to O–C–N–C [°] in 1d. Plot of E [kcal/mol] to O–C–N–C [°] in DMAc

is shown for comparison.

Twisted acyclic hydantoins feature five possible protonation sites. Typical planar amides vastly favor

protonation at the oxygen atom; however, twisted amides, depending on steric and electronic properties,

may tend toward selective N-protonation. Since the N/O-selectivity of amide bond protonation is a

fundamental process that has been used to impact synthetic and biological properties,20 we were

interested in determining the protonation sites in twisted hydantoins. Proton affinities (PA) and

14

differences between N- and O-protonation affinities (PA, vs. the lowest PA) in a representative amide

1d (R = Ph) are shown in Table 3. Interestingly, we found that the twisted hydantoin 1d favors

protonation at oxygen atoms vs. amide and urea nitrogens (PA >20 kcal/mol). This can be compared

with PA of 12.6 kcal/mol favoring O-protonation for planar N,N-dimethylacetamide and PA of 24.1

kcal/mol favoring N-protonation for a fully twisted 2-quinuclidone.17,18

The amide nitrogen atom is the least preferred site of protonation. The data further indicate that out of

the three possible O-protonation sites the process is favored at the exocyclic amide and urea oxygens

(Table 3, entries 3-4 cf. endocyclic imide, Table 3, entry 5). O-protonation of the exocyclic amide bond

is expected to increase barrier to rotation, deactivating the twisted amide bond, while O-protonation of

the urea moiety disrupts the nN → *C=O delocalization, activating the amide bond towards selective N–

C(O) scission.14a,20a Thus, the data verifies that selective O-protonation may increase the reactivity of

twisted acyclic hydantoins.

3. Conclusions

In summary, we have presented extensive insights into the structures and energetics of twisted acyclic

hydantoins. These compounds feature unusual cyclic urea-imide moiety that is widely found in

bioactive compounds and can be traced back to the classic bridged hydantoins proposed by Smissman

more than 50 years ago. The X-ray structure of the parent compound in the series demonstrated one of

the most distorted acyclic amide bonds reported to date. The substantial distortion (approx. half

maximum) results from a combination of twist and nitrogen pyramidalization of the twisted amide bond.

We expect that this study will serve as a platform to facilitate the development of twisted amides based

on the biorelevant cyclic urea-imide scaffold. Ongoing studies are focused on expanding the

destabilization concept of amide bonds in organic synthesis. Future studies will address amide bond

distortion in fully acyclic analogues and experimental investigation of protonation sites in acyclic

15

twisted amides. Studies on the cross-coupling chemistry of N-acyl-hydantoins are ongoing and will be

reported in due course.

Acknowledgements. We gratefully acknowledge Rutgers University and the NSF (CAREER CHE-

1650766) for support. The 500 MHz spectrometer was supported by the NSF-MRI grant (CHE-

1229030). We thank the Wroclaw Center for Networking and Supercomputing (grant number

WCSS159).

Supporting Information. Cartesian coordinates and energies. Detailed description of computational

methods used. CIF files for amides 1d, 1f. This material is available free of charge via the Internet at

http://pubs.acs.org.

Author Information. Corresponding author: michal.szostak@rutgers.edu

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using Nickel Catalysis. ACS Catal. 2017, 7, 1413-1423.

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(16) For recent elegant examples of amide distortion by peripheral metal coordination, see: (a)

Adachi, S.; Kumagai, N.; Shibasaki, M. Pyramidalization/twisting of the amide functional group via

remote steric congestion triggered by metal coordination. Chem. Sci. 2017, 8, 85-90. (b) Adachi, S.;

Kumagai, N.; Shibasaki, M. Bis(2-pyridyl)amides as Readily Cleavable Amides Under Catalytic,

Neutral, and Room-Temperature Conditions. Synlett 2017, 29, 301-305.

(17) For classic computational studies on bridged lactams, see: (a) Greenberg, A.; Venanzi, C. A.

Structures and energetics of two bridgehead lactams and their N- and O-protonated forms: an ab initio

molecular orbital study. J. Am. Chem. Soc. 1993, 115, 6951-6957. (b) Greenberg, A.; Moore, D. T.;

DuBois, T. D. Small and Medium-Sized Bridgehead Bicyclic Lactams: A Systematic ab Initio

Molecular Orbital Study. J. Am. Chem. Soc. 1996, 118, 8658-8668. See, also: (c) Morgan, J.;

Greenberg, A. Novel bridgehead bicyclic lactams: (a) Molecules predicted to have O-protonated and N-

protonated tautomers of comparable stability; (b) hyperstable lactams and their O-protonated tautomers.

J. Chem. Thermodynamics 2014, 73, 206-212.

(18) For representative studies relevant to N–C activation, see: (a) Szostak, R.; Aube, J.; Szostak, M.

Determination of Structures and 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, 7905-7927. (b) Szostak, R.; Shi, S.; Meng, G.; Lalancette,

R.; Szostak, M. Ground-State Distortion in N-Acyl-tert-butyl-carbamates (Boc) and N-Acyl-tosylamides

(Ts): Twisted Amides of Relevance to Amide N−C Cross-Coupling. J. Org. Chem. 2016, 81, 8091-

8094. (c) 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, 727-734. (d) Szostak, R.; Szostak, M. N‐Acyl-Glutarimides:

Resonance and Proton Affinities of Rotationally-Inverted Twisted Amides Relevant to N−C(O) Cross-

Coupling. Org. Lett. 2018, 20, 1342-1345.

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(19) For selected theoretical studies on amide bonds, see: (a) Kemnitz, C. R.; Loewen, M. J. “Amide

Resonance” Correlates with a Breadth of C−N Rotation Barriers. J. Am. Chem. Soc. 2007, 129, 2521-

2528. (b) 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-

4453. (c) Glover, S. A.; Rosser, A. A. Reliable Determination of Amidicity in Acyclic Amides and

Lactams. J. Org. Chem. 2012, 77, 5492-5502. (d) Morgan, J.; Greenberg, A.; Liebman, J. F. Paradigms

and Paradoxes: O- and N-Protonated Amides, Stabilization Energy and Resonance Energy. Struct.

Chem. 2012, 23, 197-199. (e) Morgan, J. P.; Weaver-Guevara, H. M.; Fitzgerald, R. W.; Dunlap-Smith,

A.; Greenberg, A. Ab initio computational study of 1-methyl-4-silatranone and attempts at its

conventional synthesis. Struct. Chem. 2017, 28, 327-331.

(20) (a) Wiberg, K. B. The Interaction of Carbonyl Groups with Substituents. Acc. Chem. Res. 1999,

32, 922-929. (b) Cox, C.; Lectka, T. Synthetic Catalysis of Amide Isomerization. Acc. Chem. Res. 2000,

33, 849-858.