Zn-Catalyzed tert-Butyl Nicotinate-Directed Amide Cleavage as a Biomimic of Metallo-Exopeptidase Activity

Article abstract of DOI:10.1021/acscatal.7b02599

A two-step catalytic amide-to-ester transformation of primary amides under mild reaction conditions has been developed. A tert-butyl nicotinate (tBu nic) directing group is easily introduced onto primary amides via Pd-catalyzed amidation with tert-butyl 2-chloronicotinate. A weak base (Cs₂CO₃ or K₂CO₃) at 40-50 °C can be used provided that 1,1′-bis(dicyclohexylphosphino)ferrocene is selected as ligand. The tBu nic activated amides subsequently allow Zn(OAc)₂-catalyzed nonsolvolytic alcoholysis in tBuOAc at 40-60 °C under neutral reaction conditions. The activation mechanism is biomimetic: the C3-ester substituent of the pyridine in the directing group populates the trans-conformer suitable for Zn-chelation, C=O_amide-Zn-N_{directing group}, and Zn-coordinated alcohol is additionally activated as a nucleophile by hydrogen bonding with the acetate ligand of the catalyst. Additionally, the acetate ligand assists in intramolecular O-to-N proton transfer. The chemoselectivity versus other functional groups and compatibility with challenging reaction partners, such as peptides, sugars, and sterols, illustrates the synthetic applicability of this two-step amide cleavage method. The tBu nic amides do not require purification before cleavage. Preliminary experiments also indicate that other weak nucleophiles can be used such as (hetero)arylamines (transamidation) as exemplified by 8-aminoquinoline.

Full text of DOI:10.1021/acscatal.7b02599

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Article
Zn-catalyzed tert-butyl nicotinate-directed amide
cleavage as a biomimic of metallo-exopeptidase activity.
Clarence Chloë Daniëlla Wybon, Carl Mensch, Karlijn Hollanders, Charlène
Gadais, Wouter A. Herrebout, Steven Ballet, and Bert U. W. Maes
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02599 • Publication Date (Web): 14 Nov 2017
Downloaded from http://pubs.acs.org on November 14, 2017
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Zn-catalyzed tert-butyl nicotinate-directed
amide cleavage as a biomimic of
metallo-exopeptidase activity
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†
‡
†,¶
†,¶
Clarence C. D. Wybon, Carl Mensch, Karlijn Hollanders, Charlène Gadais,
‡
¶
∗,†
Wouter A. Herrebout, Steven Ballet, and Bert U. W. Maes
†
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020
Antwerp, Belgium
‡
Molecular Spectroscopy, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171,
020 Antwerp, Belgium
2
¶
Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit
Brussel, Pleinlaan 2, 1050 Brussels, Belgium
E-mail: bert.maes@uantwerpen.be
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Abstract
A two-step catalytic amide-to-ester transformation of primary amides under mild re-
action conditions has been developed. A tert-butyl nicotinate (tBu nic) directing group
is easily introduced onto primary amides via Pd-catalyzed amidation with tert-butyl 2-
0
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◦
chloronicotinate. A weak base (Cs CO or K CO ) at 40–50 C can be used provided 1,1´-
2
3
2
3
bis(dicyclohexylphosphino)ferrocene is selected as ligand. The tBu nic activated amides sub-
◦
sequently allow Zn(OAc) -catalyzed non-solvolytic alcoholysis in tBuOAc at 40-60 C under
2
neutral reaction conditions. The activation mechanism is biomimetic: the C3-ester substituent
of the pyridine in the directing group populates the trans-conformer suitable for Zn-chelation,
C=Oamide-Zn-Ndirecting group, and Zn-coordinated alcohol is additionally activated as a nucle-
ophile by hydrogen bonding with the acetate ligand of the catalyst. Additionally, the acetate
ligand assists in intramolecular O-to-N proton transfer. The chemoselectivity versus other
functional groups and compatibility with challenging reaction partners, such as peptides, sug-
ars and sterols, illustrates the synthetic applicability of this two-step amide cleavage method.
The tBu nic amides do not require purification before cleavage. Preliminary experiments also
indicate that other weak nucleophiles can be used such as (hetero)arylamines (transamidation)
as exemplified by 8-aminoquinoline.
Keywords
Amide cleavage, alcoholysis, esters, non-solvolytic, directing group, biomimicry, Pd-catalysis, Zn-
catalysis
Introduction
Amide functionalities are ubiquitous in natural products, agrochemicals and pharmaceuticals.
They are crucial to sustain life, since these entities make up the peptide bonds in life-essential
proteins such as enzymes. Therefore, amides can be considered as one of the most important
functional groups in contemporary organic chemistry. In view of the prevalence of the amide
functional group, and considering that nature has developed proteases to eꢀciently cleave them
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under mild conditions, it is at first glance remarkable that the further synthetic transformation
of this omnipresent structural entity has remained a challenging synthetic problem for organic
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chemists. The reason for this can be found in the chemical inertness of the amide carbonyl
1
, 2
towards nucleophilic addition. A general transformation of amides into thermodynamically less
stable esters is not a broadly accessible reaction for synthetic organic chemistry: amide esterifi-
cation normally requires harsh conditions (strong (Lewis) acid or base and an elevated reaction
0
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, 4
temperature), with the alcohol standardly acting as both nucleophile and solvent. These proto-
cols often result in functional group compatibility problems and solvolytic nucleophile use limits
the alcohol scope to liquids. The attempted reaction of Boc-L-Pro-L-Phe-NH (1a) or Boc-D-Phe-
2
NH (1b) with a complex and solid alcohol (the sugar derivative diaceton-α-D-galactopyranose (2a)
2
or cholesterol (2b)) in a solvent using diꢁerent Lewis acids illustrates this is not a synthetically
viable strategy (Scheme 1).
x mol% Lewis acid
3 equiv
O
O
H
H
O
O
O
O
O
O
O
2a
O
O
O
O
O
NH2
N
H
H
H
O
N
OH
N
O
H
X
N
O
O
Heptane, 100 °C, 24 h
O
1a
3a
x mol% Lewis acid
3 equiv cholesterol
2b
H
X
H
N
H
O
N
2
-MeTHF, 100 °C, 24 h
O
O
H
H
O
NH2
O
O
O
1
b
3b
Scheme 1: Unsuccesful Lewis acid-catalyzed/mediated non-solvolytic cleavage of primary amides
a and 1b with complex alcohols 2a and 2b (x mol% Lewis acid = 5 mol% Sc(OTf) , 5 mol%
Zn(OTf) , 100 mol% BF .Et O).
1
2
2
3
2
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Table 1: Selected catalyst screening in the solvolytic metal-catalyzed pyridine-directed cleavage of
pyridin-2-ylbenzamide (8a) in iPrOH.
10 mol% Catalyst
26.0 equiv iPrOH (2c)
O
N
O
O
N
+
N
T, 24h
H N
2
H
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9a
10b
◦
T ( C)
a,b
a,b
Entry Catalyst
8a
48
60
76
51
44
0
9a
1
FeCl3
140
140
140
140
140
140
75
42
2
3
4
5
6
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8
9
Fe(OAc)2
MnCl2
31
15
Mn(OAc)3
CuCl2
38
50
quant.
10
Cu(OAc)2
Cu(OAc)2
CoCl2
84
0
140
140
75
80
96
10
Co(OAc)2
Co(OAc)2
ZnCl2
1
1
1
1
0
86
37
8
1
140
140
75
62
90
23
2
ZnBr2
13
ZnBr2
74
0
1
1
1
1
4
5
6
7
Zn(OAc)2
Zn(OAc)2
140
75
quant.
25
72
63
4
c
NiCl .DME
2
140
140
5
Ni(OAc)2
Ni(OAc)2
89
5
18
75
86
a
b
1
0 mol% catalyst, 26 equiv iPrOH, T, 24 h; GC-yield with 1,3,5-trimethoxybenzene as internal
c
standard; Unselective reaction.
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However, this challenging amide transformation under mild conditions has a very interesting
synthetic potential both in using amides as stable acyl precursors in multistep synthesis and in
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making new derivatives of readily available complex amides. While transamidation with amines
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has been intensively studied, strategies to allow direct amide-to-ester transformation with less
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nucleophilic alcohols are far less developed. Distorted tertiary amides featuring reduced amide
resonance have been reported to undergo cleavage with simple alcohols under low temperature
1
, 7, 8a
conditions.
Amide activation can also be achieved through metal chelation in the leaving
8
group. All these methods require specific amide substitution patterns and are typically based on
solvolysis. Although these procedures represent very important conceptual advantages to tackle
the alcoholysis problem, chemoselective amide alcoholysis featuring an easily introducible activat-
ing group applicable to a broad set of amides under mild reaction conditions with non-solvolytic
alcohol remained an important synthetic challenge. Use of non-solvolytic alcohol is crucial to al-
low the use of more complex alcohols which are more expensive and often non-liquid (vide supra).
9
a
In 2015 a Ni-catalyzed amide alcoholysis was reported, showing the first oxidative addition of
10
the C-N bond of a distorted amide (Scheme 2). Tertiary (hetero)arenecarboxamides featuring both
◦
a N-phenyl and N-alkyl group were suitable substrates for non-solvolytic alcoholysis at 80 C.
9a, 11
To extend the scope towards less reactive aliphatic amides, the Garg group recently disclosed that
both a more activating N-Boc and a N-alkyl substituent were required in the substrate to allow
◦ 9b
alcoholysis at 100 C (Scheme 2). These processes were subsequently extended to Ni-catalyzed
12a,b, 13
transamidations with aliphatic amines (Scheme 2).
More recently, more reactive Pd-catalyzed
12c
transamidations with challenging anilines were reported (Scheme 2). The nitrogen substituents
in the tertiary amide are crucial to allow rate-determining oxidative addition of the C-N bond.
Both types of amides, N-Ph-N-alkyl and N-Boc-N-alkyl, are activated for metal insertion via dis-
∗
10
tortion which weakens the n(N)-π (C-O) conjugation. Besides steric distortion, the phenyl or Boc
enhances the amide reactivity through their electron withdrawing character. While the latter are
non planar amides, the former are predominantly planar and activated by n(N)-π*(Ar) delocal-
1
1b
ization. The Garg methodology is therefore ideal for the cleavage of secondary amides using
a two-step protocol: Boc-group introduction followed by amide alcoholysis of the tertiary amide
(
Scheme 2). Likewise, it would be interesting to have access to a complementary methodology for
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the alcoholysis of omnipresent carboxamide termini. Such a chemical transformation under mild
non-solvolytic conditions is hitherto not available, but its development would extend the modern
mild synthetic amide cleavage toolbox. Note that N-tert-butoxycarbonylation of a primary amide 1
(
resulting in the formation of 4), as used to activate secondary amides, does not provide a solution,
as application of the Ni-catalysis cleavage methodology on the resulting N-Boc secondary amide
a and 4b does not result in ester product 3 and 5 formation (Scheme 3). The only reaction that
occurs is N-Boc reductive cleavage of substrate. N-Boc removal is the major side-reaction typi-
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13e
cally observed in transition metal-catalyzed amide activation. Clearly, the N-H moiety present
requires another concept than amide distortion to increase its reactivity for mild cleavage using
limited excess of alcohol 2. As Ni(0) is air-sensitive a method based on a transition metal in an
oxidation state compatible with air would be beneficial.
14
Inspired by metallo-exopeptidases in nature, we reasoned that an easily introducible directing
1
5
group (DG) on the nitrogen atom of the primary amide, allowing bidentate chelation with a
transition metal might allow cleavage of a secondary amide under neutral and mild conditions
16
(Scheme 2). This directing group could biomimic the His/Glu coordination with the metal
that activates the amide carbonyl in metalloproteases (C=Oamide-M-(N ) ). Hydrogen bonding
His n
activation of the nucleophile with the carboxylate side chain of Asp/Glu can be imitated by a ligand
of the metal catalyst, such as a carboxylate. A pyridin-2-yl (py) group was initially selected for this
purpose, as it should be easily introducible via transition metal-catalyzed amidation. However,
computational chemistry calculations on model substrate N-(pyridin-2-yl)benzamide (8a) showed
that less than 0.01% of 8a exists in its trans-conformer I, with the amide carbonyl and DG
suitably oriented for bidentate chelation (Figure 1). We thus reasoned that a C3-py-substituent
might populate this desired conformer I through intramolecular hydrogen bonding with the amide
proton (in the case of a hydrogen bond acceptor (HBA) C3-substituent) and/or steric eꢁects (size of
this C3-substituent). Interestingly, conformational analysis on a set of N-(C3-substituted pyridin-2-
yl)benzamides 8 revealed that several C3-groups allow population of the desired trans-conformer
I (Figure 1). C3-ester substituents were predicted to be superior for bidentate chelation with up
to 99% population of the desired trans-conformer I through intramolecular hydrogen bonding
with the amide proton (Scheme 2). Based on these conformer calculations we decided to study
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CLEAVAGE OF TERTIARY AMIDES
Previous work
activated for metal insertion via distortion
Ni(cod)2 (10-15 mol%)
SIPr (10-30 mol%)
1.2 equiv NuH
O
O
R'
Het(Ar)
N
(Het)Ar
Nu
toluene, 80 °C
Garg group
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Ph
amide activation
1
(R = (hetero)aryl, alkyl)
O
'
R1
(R = alkyl, aryl)
R'
M = Ni or Pd
M
N
O
Ln
Ph/Boc
R'
N
H
R1
(
IPr)Pd(cinnamyl)Cl (3 mol%)
amide activation
2
-3 equiv ArNH2
3-4.5 equiv K2CO3
O
Szostak group
DME, 110 °C
R1
NHAr
O
(
R' = Ph)
R'
N
R1
Ni(cod)2 (5-15 mol%)
Ligand (5-20 mol%)
Boc
O
1
.2-2.5 equiv NuH
Garg group
R1
Nu
toluene, 35-100 °C
Ligand = terpyridine, SIPr
or Benz.ICy.HCl (cat. NaOtBu)
CLEAVAGE OF SECONDARY AMIDES
Our work
activated for bidentate chelation via directing group introduction
O
O
N
O
Zn-catalyst
NuH
amide activation
R1
NH2
R1
R1
N
Nu
H
solvent, 40-100 °C
COOR2
Nature
O
O
O
BIO-INSPIRATION
FOR AMIDE CLEAVAGE
His
H
His
His/Glu
Nu
Zn
O
Zn
N
O
H
H
O
O
O
O
O
R1
N
H
NH2
R1
Metallo-exopeptidase activity
OR2
-
-
-
Zn(II)-catalysis
Co(II) and Mn(II) also work
Zn-Npyridine coordination
- Zn(II)-catalysis most common
- Co(II) and Mn(II) also occur
- Zn-NHis coordination
- Zn-O=Cpeptide coordination
- HB-activated NuH
- Zn-O=Camide coordination
- HB-activated NuH
-
Nicotinate directed
Scheme 2: Ni- and Pd-catalyzed tertiary amide cleavage via secondary amide activation (top).
Bio-inspired Zn-catalyzed secondary amide cleavage via primary amide activation (bottom).
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substituted N-(pyridin-2-yl) groups as potentially suitable directing groups for mild metal-catalyzed
non-solvolytic cleavage of primary amides with alcohols.
O
O
Conditions a or b
Boc
R1
2
R1
OR2
N
H
+
R OH
+ H N Boc
2
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and 5
6a
4
a and 4b
1
2
R = phenyl, cyclohexyl
R = methyl, hexyl
2
Conditions a (R = methyl): 10 mol% Ni(cod) , 10 mol% SIPr, 1.2 equiv methanol (2d),
2
toluene, 80 °C, 12 h (closed vial)
2
Conditions b (R = hexyl): 10 mol% Ni(cod) , 10 mol% terpyridine, 1.25 equiv 1-hexanol (2e),
2
toluene, 100 °C, 12 h (closed vial)
Scheme 3: Attempted Ni-catalyzed cleavage of Boc-activated primary amides 4 with alcohols 2 (SI
S.5). SIPr = 1,3-Bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene, cod = 1,5-cyclooctadiene.
Results and discussion
Benzamide (1c) equipped with a py-DG (8a) was used as an initial test substrate for the op-
timization of the amide cleavage. In a first step, several metal salts (Fe, Cu, Zn, Co, Mn, Ni;
1
0.0 mol%) were screened as potential catalysts in alcohol, used as both nucleophile and solvent,
◦
at 140 and 75 C (Table 1, SI S.3.2). The more challenging secondary alcohol isopropanol (2c)
was selected over a primary alcohol for the method development phase. This screening under
solvolytic conditions resulted in the identification of Zn(OAc) as the optimal catalyst for further
2
development based on its low cost, non-toxicity and conversion. In order to further reduce the
required temperature for amide cleavage and increase in conversion, the eꢁect of substitution
onto the py-DG was subsequently studied with both electron-withdrawing (F, Cl, COOR, CN, CF3)
and -donating (Alkyl, Ph, OR) groups. Substitution at the C3- and C5-positions of the py-DG was
explored since the same group at both positions has a similar electronic, but diꢁerent electrostatic
eꢁect, which can be electrostatic repulsive (steric eꢁect) or attractive (intramolecular hydrogen
bond) (Figure 2, SI S.3.2.4-S.3.2.5). A C3-Cl, -OMe or -COOR-substituent gave the best results at 75
◦
C (Figure 2a). Of these, an ester at C3 of the py turned out to be the most eꢀcient substituent,
◦
as the required temperature for isopropanolysis with these DGs could be lowered to 40 C (Figure
2b). The suitability of the C3-Cl, -AO CMS eP oa rr a -g Co On OP Rl u ss u Eb ns tv i it ruo t ne md ep ny t-DG is in accordance with the
8

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2
predicted population of the trans-conformer(s) I of the corresponding N-(pyridin-2-yl)benzamide
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
and 13a (Figure 1, Table S35). The exceptional performance of the alkyl nicotinate DGs at 40
◦
C is in accordance with the complete locking of the N-DG amide in its conformer I. The reac-
tivity diꢁerence between an ether and ester at C3 of the DG is likely also due to the electron
withdrawing eꢁect of the ester causing a further reduction in amide resonance energy (N(n)-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
11
π*(Ar) delocalization). Resonance energy calculations support this (4.2 kcal/mol for tert-butyl
-benzamidonicotinate (13a) versus 8.2 kcal/mol for N-(3-methoxypyridin-2-yl)benzamide (8s)) (SI
2
S.9.2). tert-Butyl and isopropyl nicotinate (tBu/iPr nic) performed equally well as DGs, but the
◦
former was chosen for further studies to avoid potential transesterification with alcohol. At 40 C,
isopropanolysis of tert-butyl 2-benzamidonicotinate (13a) with 10 mol% of Zn(OAc) resulted in full
2
conversion to isopropyl benzoate (9a) (87% yield) and tert-butyl 2-aminonicotinate (10a) (96% yield)
in 48 h (standard conditions). The formed by-product 10a can be easily transformed in one-step
into tert-butyl 2-chloronicotinate (11a) via diazotization using aq. HCl and NaNO in the presence
2
of NaCl (Scheme 4, SI S.8), thus enabling recovery of the reactant required for DG-introduction
(Scheme 4).
1
.5 equiv NaNO2
H N
2
N
Cl
N
2
equiv NaCl
O
HCl (aq.), 0 °C to rt, 12 h
O
OtBu
0a
OtBu
1
11a (44%)
Scheme 4: Synthesis of tert-butyl 2-chloronicotinate (11a) reactant from tert-butyl 2-
aminonicotinate (10a) by-product produced in the directed amide cleavage with alcohols 2.
With the optimal DG in hand, a method to smoothly introduce tBu nic onto primary amides 1, at
an equally mild temperature as required for the cleavage, was needed (SI S.3.1). Evaluation of the
Pd-catalyzed amidation of tert-butyl 2-chloronicotinate (11a) with benzamide (1c) led to the identifi-
cation of the Buchwald Pd G3 precatalyst 12a of the ligand 1,1´-bis(dicyclohexylphosphino)ferrocene
17, 18
(dcpf) (7b) as the optimal precatalyst system (Table 2).
Both the use of Cs CO (1.2 equiv) as an
2
3
inorganic weak base and the renewable solvent 2-MeTHF proved to be indispensable to obtain full
◦
conversion at 40 C in 24 h with an isolated yield of 97% of tert-butyl 2-benzamidonicotinate (13a).
19
Both Cs CO and 2-MeTHF are recommended from a sustainability point of view. Interestingly,
2
3
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9
0
Conformational analysis of N-py amides via DFT-calculations at the SCRF/B3LYP/6-31G(d,p) level of theory
(
T = 298 K), using ’Gaussian 09’ software; see Supporting Information (SI 9.1.2). The self-consistent reaction
field (scrf) model was used to account for solvent-solute interactions with butyl acetate, as a model for the
eꢁect of tert-butyl acetate, the main solvent used for the experimental cleavage reactions. RE > 0: desired
reactive conformer I is the major conformer.
Figure 1: Rationalization of the directing group screening via computational conformational anal-
ysis of (C3- and C5-substituted) N-(pyridin-2-yl)benzamides 8 and 13a.
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R2
R2
x mol% Zn(OAc)2
6.0 equiv isopropanol (2c)
O
N
O
N
2
+
N
O
H N
2
T, t
H
R1
R1
8
, 13a
9
10
10
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12
13
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40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2: Directing group screening in the Zn-catalyzed directed cleavage of C3- and C5-substituted
N-(pyridin-2-yl)benzamides 8 and 13a.
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6
the optimal dcpf ligand 7b identified has not been described yet as a ligand for Pd-catalyzed
amidations. The applicability of the identified conditions to a variety of primary amides 1 was
explored (Table 2). Sometimes further fine-tuning of the DG-introduction conditions was required
(
SI S.3.1.3), involving the use of more Cs CO (1.2-7.5 equiv), K CO instead of Cs CO and DMF
3
2
3
2
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
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1
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
◦
as a co-solvent to allow full conversion at 40–50 C within 24 hours. The positive eꢁect of larger
amounts of insoluble weak carbonate base on the rate of Buchwald-Hartwig reactions (base-eꢁect)
20
has been previously reported and rationalized by our group (SI S.3.1.2). With these small mod-
ifications, the identified protocol proved to be applicable to all types of primary amides, both
(hetero)aromatic and (a)cyclic aliphatic ones. This also includes very challenging representatives
21
such as Boc-(AA) -NH derivatives (AA = amino acid, n = 1-3). Interestingly, primary amides
2
n
1 can be selectively N-arylated in the presence of secondary amides as exemplified by Boc-L-
17b,c
Pro-L-Phe-NH (1a) and Boc-L-Pro-L-Leu-Gly-NH (1p).
2
Chemoselectivity is also possible versus
2
other functionalities as illustrated by atenolol (1q), an API-carboxamide containing an unprotected
hydroxyl group and a secondary amine. Considering the weakly nucleophilic nature of amides
classical reaction with electrophiles via S AE, e.g. bocylation with Boc O, generally do not allow
N
2
22
such chemoselectivity and reaction will (additionally) occur at the more nucleophilic sites. In
all cases, full conversion and good to excellent yields of tert-butyl 2-amidonicotinates 13 were
obtained. Pd(OAc) in combination with Xantphos ligand in dioxane with K CO as base could
2
2
3
also be used to introduce the directing group, provided a higher reaction temperature is applied
17d
(
Table 2). These synthesized tert-butyl 2-amidonicotinates 13 allowed solvolytic cleavage with
primary and secondary (un)branched aliphatic alcohols 2 under the developed standard reaction
conditions (vide supra) (SI S.3.4).
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
Table 2: tert-Butyl nicotinate introduction on primary amides 1 via Pd-catalyzed amidation of
tert-butyl 2-chloronicotinate (11a). Reaction times were not minimized.
N
O
N
O
5 mol% precatalyst 12a
x equiv Cs CO3
2
+
Cl
R
N
R
NH2
H
2-MeTHF, 40 °C, 24 h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
OtBu
O
OtBu
1
.1 equiv
1
1a
1
13
H N
2
.THF
P
Pd
Fe
P
OMs
12a
1
Entry
1
RCONH2
O
1
x
Yield 13
13a, 97% (99%)
NH2
1c
1.2
2
92%
O
NH2
2
3
1d
1e
1.2
1.2
13b, 63% (92%)
F
O
NH2
13c, 78% (92%)
Cl
O
NH2
O
13d, 99% (quant.)
4
5
1f
7.5
1.2
2
78%
NO2
NH2
1g
13e, 92% (93%)
Me
O
6
7
1h
1i
1.2
1.2
13f, 75% (98%)
NH2
O
NH2
13g, 86% (quant.)
O
8
9
NH2
1j
5
13h, 83% (quant.)
13i, 59% (94%)
O
NH2
1k
1.2
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1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
3
3
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4
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5
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5
5
5
5
5
5
5
6
10
Boc-Gly-NH2
1l
1.2
1.2
13j, 83% (quant.)
2
13k, 80% (95%)
1
1
1
Boc-L-Pro-NH2
1m
2
1%
,3
9
2
3l, 98% (92%)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
Boc-L-Val-NH2
1n
2
3,4
9
4%
1
3
4
Boc-β-Ala-NH2
1o
1b
1aj
1a
2
13m, 99% (quant.)
5
1
Boc-D-Phe-NH2
Boc-L-Phe-NH2
7.5
7.5
2
13n, 92% (93%)
5
15
16
13ak, 93% (96%)
6
,7
Boc-L-Pro-L-Phe-NH2
13o, 93% (78%)
7,8
1
7
Boc-L-Pro-L-Leu-Gly-NH2 1p
Atenolol 1q
7.5
2.5
13p, 99% (quant.)
9
1
8
13q — (95%)
1
◦
mol% precatalyst 12a, x equiv. Cs CO , 2-MeTMF, 40 C, 24 h unless mentioned otherwise.
5
2
3
2
3
NMR-yield with TMB as internal standard between brackets; e.e. > 98%; 5 mol% Pd(OAc)2,
◦
0 mol% Xantphos, 4 equiv. K CO , dioxane, 90 C; e.e. 93%; dioxane, 7.5 equiv. K CO , 50 C,
4
5
◦
1
2
3
2
3
6
7
8
9
30 h; 2-MeTHF:DMF 1:1; d.e. > 99%; 10 mol% 12a; 10 mol% 12a, oven-dried Cs CO .
2
3
The formed by-product 10a can be easily transformed in one-step into tert-butyl 2-chloronicotinate
11a) via diazotization using aq. HCl and NaNO in the presence of NaCl (Scheme 4, SI S.8), thus
(
2
enabling recovery of the reactant required for DG-introduction (Scheme 4).
Next the suitability for non-solvolytic tBu nic-directed cleavage was studied. Online-IR reaction
monitoring experiments of the Zn-catalyzed directed cleavage of tert-butyl 2-benzamidonicotinate
13a with diꢁerent alcohols 2 (5.0 equiv) were subsequently performed in order to evaluate whether
alcoholysis under non-solvolytic conditions was also possible. tBuOAc was selected as the solvent
1
9
based on its green properties (Figure 3, SI S.7). Kinetic analysis showed that primary alcohols
give substantially faster reactions than secondary ones, but both are suited for non-solvolytic use
at low reaction temperatures. Full cleavage of 13a with the use of primary alcohols such as MeOH
◦
2d) (2.50 equiv in tBuOAc) takes only 30 minutes at 60 C (Figure 3). To establish the same
(
◦
result at 40 C, 10.0 equiv of Me OA HC S( 2P da )r aa gr oe nn Pe lcu e ss sEa nr vy ir (oF ni gmu er en t3). On the other hand, when
14

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53
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59
60
O
N
O
N
1
0 mol% Zn(OAc)2
x equiv MeOH (2d)
N
O
+
H N
2
H
tBuOAc, T
tBuO
O
tBuO
10a
O
[
amide 13a ]t=0 = 0.5M
13a
3c
Figure 3: Quantitative online-IR reaction monitoring of the Zn-catalyzed tert-butyl nicotinate
directed cleavage of tert-butyl 2-benzamidonicotinate (13a) with 2.50 and 10.0 equiv MeOH (2d)
◦
−1
at 40 and 60 C using the 1540-1470 cm amide band of 13a. Note that [MeOH (2d)]t=0 = 0.5 x
equiv MeOH (2d)).
(
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6
using 1.5 equiv of MeOH (2d) in tBuOAc, full cleavage of substrate 13a is also possible at room
temperature in one day. To the best of our knowledge, such performance is unprecedented in
current literature. The hitherto mildest known non-enzymatic cleavage of benzamide (1c) with the
use of a stoichiometric amount of MeOH (2d) under neutral conditions without first pre-activating
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
◦
benzamide (1c) to a non-carboxamide containing intermediate, requires 165 C for 22 h (CeO2-
4
catalysis, 1.0 equiv MeOH (2d) in mesitylene).
Based on our screening of non-solvolytic amide cleavage (SI S.3.6), 3.0 equiv of alcohol 2 and 10
mol% Zn(OAc) -catalyst were selected for the investigation of the non-solvolytic alcohol scope in
2
the Zn-catalyzed tert-butyl nicotinate directed amide cleavage of 13, using tBuOAc as a solvent
◦
(Table 3-5). Interestingly, alcohols that are solids, which cannot be used solvolytically at 40 C, and
more complex or expensive ones proved to be suitable nucleophiles for the non-solvolytic amide
cleavage reaction. The use of primary and secondary acyclic aliphatic alcohols for the cleavage
of (a)cyclic aliphatic and aromatic amides led to good to excellent isolated yields of the esters
3d-3o (Table 3). Structurally more complex alcohols were successfully applied, as exemplified by
the use of the sugars diaceton-α-D-galactopyranose (2a) and diaceton-α-D-glucose (2k) (esters 3p-
3
q), sterols such as cholesterol (2b) (esters 3r-3s) and dehydroepiandrosterone (2j) (ester 3t) and
naturally occurring alcohols such as L-menthol (2l) (esters 3u-3v) and cinnamyl alcohol (2n) (ester
x) (Table 4). Moreover, amino acid-derived alcohols such as aminoalcohol 2o derived from Boc-L-
3
Phe-OH (ester 3y) and Cbz-L-Ser-OMe (2p) (ester 3z) are also suitable nucleophiles (Table 5). Both
simple and more complex alcohols could also be combined with amino acid- and peptidic-derived
tBu nic amides 13 (esters 3w (Table 4), 3aa, 3ab, 3b, 3ac, 3ad, 3ae, 3af, 3a, 3ag, 3ah, 3ai (Table
5)). The eꢀcient synthesis of diꢁerent cholesteryl esters 3b, 3ac, 3ad, 3ae, 3af, glycopeptides 3a,
3
ag, 3ah and other chimeric dipeptides 3ai in a racemization- and epimerization-free manner
illustrates the power of the developed synthetic methodology. As indicated in the tables, depending
on the complexity of both amide and nucleophile slightly modified reaction conditions involving
◦
higher catalyst loading, (15 or 20 mol%), higher reaction temperature (40 to 60 C), longer reaction
time (24 to 72 h) or solvent change due to solubility problems (3r-3t, 3b, 3ac, 3ad, 3ae, 3af) were
sometimes required to achieve full conversion. Longer reaction times could easily be shortened
◦
if higher temperatures (80 C) were applied, as exemplified by the synthesis of 3d, 3h, 3x (Tables
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and 4). We always selected the lowest temperature possible to showcase the mildness of the
3
4
5
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
developed protocol. Sterically hindered amides, such as (aza)cycloalkanecarboxamides (R-CONH-
tBu nic; R = cyclohexyl (13i); Boc-L-Pro-NH-tBu nic (13k)) are more diꢀcult to cleave than other
aliphatic amide substrates (Tables 3 and 5, e.g. 3d, 3e, 3aa versus Table 3, 3f, 3g). The same
observation stands for the acyclic sterically hindered N-tBu nic pivalamide (13h) (3s) (Table 4).
Note that 3a and 3b which cannot be synthesized from the corresponding primary amide using
Lewis acid catalysis (Scheme 1), could be obtained under mild conditions and in good yield using
our two-step synthetic methodology.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3: Standard alcohol scope in the non-solvolytic Zn-catalyzed tert-butyl nicotinate directed
amide cleavage. Reaction times used for full conversion were not minimized and reactions were
screened every 12 h. Lowest possible temperature was selected.
N
O
N
O
1
0 mol% Zn(OAc)2
2
R1
1.5-3 equiv R OH 2
+
H2N
N
R1
OR2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
tBuOAc, 40-60 °C, 24-72 h
O
OtBu
O
OtBu
13
3
10a
a,b
Entry
1
Substrate 13
Ester 3
Yield (%)
O
6
6 (97)
O
13i
3d
3e
c,d
(89)
O
e,f
2
13i
66
60
O
O
O
g
3
4
13f
3f
O
O
O
g
13g
3g
46
O
h
O
quant.
O
c,i
5
13a
3h
(quant.)
NO2
h,j
(65)
O
O
O
O
h
6
7
13a
13a
3i
3j
63
O
O
h
70
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3
4
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Entry
Substrate 13
Ester 3
Yield (%)
O
O
O
O
8
13a
3k
3l
52
55
78
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
9
13a
13b
O
O
10
3m
O
F
O
1
1
13a
13a
3n
3o
56
65
O
Boc
N
O
1
2
O
a
2
◦
0 mol% Zn(OAc) , 3 equiv R OH 2, tBuOAc, 40 C, 48 h unless mentioned otherwise. Isolated
b
1
2
c
◦
yield. NMR-yield with 1,3,5-trimethoxybenzene as internal standard between brackets. 80 C.
d
e
◦
6 h. 60 C. 72 h. 1.5 equiv R OH 2. 24 h. 4 h. Reaction based on crude 13, yield over
f
g
2
h
i
j
3
two steps.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 4: Complex alcohol scope in the non-solvolytic Zn-catalyzed tert-butyl nicotinate directed
amide cleavage. Reaction times used for full conversion were not minimized and reactions were
screened every 12 h. Lowest possible temperature was selected.
N
O
N
O
1
0-20 mol% Zn(OAc)2
2
R1
3 equiv R OH 2
+
H2N
N
R1
OR2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
tBuOAc or 2-MeTHF, 50 °C, 24-72 h
O
OtBu
O
OtBu
13
3
10a
a,b
Entry
Substrate 13
Ester 3
Yield (%)
O
O
O
O
O
O
c
1
13e
13a
O
3p
74
O
O
H
O
H
O
O
c,d
2
3q
75
O
O
e,f
3
13b
H
3r
59
O
H
H
O
F
f,g,h
4
13h
3s
60
H
O
H
H
O
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4
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Entry
Substrate 13
Ester 3
Yield (%)
O
O
d,f
5
6
13b
3t
61
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F
O
O
c
13d
13e
3u
3v
86
NO2
O
c
7
quant.
O
O
Boc
Boc
N
O
N
e
8
13m
13c
3w
3x
86
H
O
c
8
6
O
9
i,j
(91)
Cl
a
2
0 mol% Zn(OAc) , 3 equiv R OH 2, tBuOAc, 50 C, 48 h unless mentioned otherwise. Isolated
◦
b
1
2
c
d
yield. NMR-yield with 1,3,5-trimethoxybenzene as internal standard. 20 mol% Zn(OAc)2. 72 h.
e
f
g
◦
h
i
◦
4 h. 2-MeTHF. 25 mol% Zn(OAc) , 60 C. 3 d. 87% NMR-based conversion. 80 C. 18 h.
j
2
2
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2
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 5: Amino acid and peptide derived amide and alcohol scope in the non-solvolytic Zn-
catalyzed tert-butyl nicotinate directed amide cleavage. Reaction times used for full conversion
were not minimized and reactions were screened every 12 h. Lowest possible temperature was
selected.
N
O
N
O
1
0-20 mol% Zn(OAc)2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
R1
N
3 equiv R OH 2
+
H2N
R1
OR2
H
tBuOAc or 2-MeTHF, 40-60 °C, 48-72 h
O
OtBu
O
OtBu
13
3
10a
a,b
Entry
1
Substrate 13
Ester 3
Yield (%)
quant.
O
H
N
O
Boc
13a
3y
O
H
N
O
O
c
2
3
4
13a
13k
13j
3z
18
O
O
O
O
Boc
N
O
d
3aa
3ab
85
O
H
N
H2N
O
O
e
85
O
O
O
H
f,g,h
5
13n
3b
93
O
H
N
H
H
O
O
O
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7
8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Entry
Substrate 13
Ester 3
Yield (%)
g,h
6
13l
H
3ac
59
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
H
N
H
H
Boc
O
g,h,i
7
13j
3ad
82
H
O
H
N
H
H
Boc
O
d,e,f,g,h
8
13k
3ae
52
H
O
H
H
O
NH
H
O
g,h,i
9
13o
3af
60
H
H
O
O
NH
Boc
N
O
O
O
O
O
g,i
1
0
13o
3a
82
O
NH
N
O
O
Boc
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a,b
Entry
Substrate 13
Ester 3
Yield (%)
O
O
H
O
O
H
O
O
d,f,g
11
13o
3ag
52
O
NH
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Boc
O
O
O
H
O
O
O
N
O
O
Boc
f,g
1
2
13p
13o
O
3ah
69
N
N
H
O
O
d,i,j
13
3ai
59
O
NH
N
Boc
a
2
0 mol% Zn(OAc) , 3 equiv R OH 2, tBuOAc, 40 C, 48 h unless mentioned otherwise. Isolated
◦
b
1
2
c
yield. NMR-yield with 1,3,5-trimethoxybenzene as internal standard between brackets. Low yield
d
e
f
due to diꢀcult isolation. 72 h. Boc-deprotection on silica gel during purification. 20 mol%
g
◦
h
i
j
◦
Zn(OAc) . 50 C. 2-MeTHF. 15 mol% Zn(OAc) . 60 C.
2
2
Next we investigated chemoselectivity with respect to competitive nucleophiles and other amides
in 13 (Scheme 5). For competitive nucleophilic centers we selected atenolol (1q). This API is a
challenging substrate as it features an unprotected secondary alcohol and a secondary acyclic
amine in its structure. Based on the limited quantities generally available for APIs, we preferred to
evaluate a strategy without intermediate purification after DG-introduction. On crude N-tBu nic
atenolol (13q), smooth cleavage was observed with methanol (2d) or 4-methoxybenzyl alcohol (2q)
as model alcohols (5a, 3aj). Interestingly, no products resulting from intermolecular reaction of the
alcohol or amine in the back bone were observed. Additionally, this strategy without purification
of the intermediate seems to be generally applicable, as exemplified by the scope example 3h
(
Table 3). To show chemoselectivity in amide type we selected peptidic substrate 13r (Scheme
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7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
secondary alcohol
OH
OH
H
20 mol% Zn(OAc)
H
2
O
N
2
5
equiv R OH (2)
O
O
N
N
O
O
ether
2
tBuOAc, 40 °C, 26 or 36 h
R O
N
secondary
aliphatic
amine
3aj and 5a
H
tBuO
tBu nic atenolol
not purified
13q
2
R = Me 52% (96%)*
6 h
3
2
R = 4-MeOC6H4CH2 99%
26 h
OH
1
q
H
N
O
*
NMR yield
O
Atenolol
selective β1-blocker
H2N
(a) Application of the cleavage methodology on the API atenolol (1q). See Table 2, Entry 18 for synthesis of
crude 13q.
10 mol% Zn(OAc)2
3
equiv
O
N
OtBu
tertiary
aromatic
amide
O
N
O
O
O
H
secondary
aliphatic
amide
2o
HN
O
OH
O
O
O
N
H
O
Me
NH
N
Me
H
N
tBuOAc, 80 °C, 24 h
NH
N
Ph
H
secondary
aliphatic
amide
O
N
Ph
O
O
secondary
aromatic
amide
13r
3ak
58%
O
O
NH2
O
NH2
primary
aliphatic
amide
(
b) Application of the cleavage methodology on oligoamide containing substrate 13r. For the synthesis of
3r, see SI S.6.9.
1
Scheme 5: Evaluation of amide chemoselectivity.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
). This structure features 5 electronically and sterically diꢁerent amides (primary, secondary and
tertiary amides, derived from aromatic and aliphatic carboxylic acids, both N-alkyl and N-aryl).
Applying our method on 13r with phenylalanol (2o) yielded the corresponding ester 3ak in 58%
yield. No other amides besides the tBu nic activated one cleaved under these reaction conditions,
exemplifying the potential applicability of our approach in organic synthesis. Important to note is
that also the tertiary N-methyl-N-phenylbenzamide, which is known to undergo alcoholysis under
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
a
Ni-catalysis, does not cleave. In fact, an aliphatic amide selectively cleaves in the presence
of aromatic amides. This is against expectations based on the electrophilicity of the carbonyl
moieties. The synthesis of 3ak is a good example of the use of N-tBu nic amides 13 in organic
synthesis as the substrate 13r is built up from Boc-L-Phe-NH-tBu (13ak) nic via classical amide
coupling reactions (Boc-deprotection: HCl in 1,4-dioxane; Amide formation: EDC.HCl, NEt , HOBt,
3
CH Cl ; SI S.6.9). This illustrates the stability of N-tBu nic amides 13 in the absence of zinc
2
2
catalyst and nucleophile.
To rationalize the parameters contributing to the lowering of the activation energy for directed
amide alcoholysis, some specific experiments with MeOH (2d) were performed (SI S.9.3). The
developed amide cleavage reaction is a catalytic reaction as in the absence of a metal catalyst,
neither benzamide 8a or 13a, featuring respectively a py- and tBu nic-DG, can be cleaved in
◦
the presence of an alcohol, even at 140 C. When comparing the results obtained with the C3-
and C5-substituted py-DGs on benzamide at the same reaction temperature (vide supra) and
considering a chemoselective cleavage of 13r (Scheme 5), the increased electrophilicity of the
amide carbonyl through resonance cannot solely explain the observed increased reactivity of 13a
under Zn-catalysis (Figure 2). When removing the intramolecular hydrogen bond capacity of 13a
◦
by N-methylation, no methanolysis was observed at 40 C (Table 6, Entry 3), proving its potential
role. N-methylation also results in trans to cis isomerization of the amide bond, likely also
contributing to switching oꢁ the reactivity of 14b (Supporting Table S35). Strong intramolecular
hydrogen bonding in all alkyl 2-benzamidonicotinates was confirmed via determination of the
1
ANMR-parameter ( H-NMR analysis) and charge density (ab initio calculations) (SI S.9.4). A
23
24
C3-ester substituent results in the strongest hydrogen bond, followed by a methoxy and chlorine
substituent, which form weaker hydrogen bonds with the amide proton. Only C3-fluorine does not
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2
◦
show the presence of a hydrogen bond, which is in line with its very poor reactivity at 75 C (Figure
a). The reactivity diꢁerence between diꢁerent substituents at C3 does not only involve a hydrogen
bonding strength element. Additionally, the electron withdrawing character of substituents will
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1
1
cause a further reduction in amide resonance energy (N(n)-π*(Ar)). The requirement of bidentate
chelation is clearly seen by using tert-butyl benzoate (Table 6, Entry 2) as DG, since tert-butyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-benzamidobenzoate (14a), lacking the azine nitrogen, does not undergo any alcoholysis at 40
◦
C. N-Phenylbenzamide (14d), missing both the nitrogen for bidentate coordination with Zn and
◦
a C3-HBA did not undergo alcoholysis, even at 140 C. The amide activating eꢁect of bidentate
chelation is also reflected when comparing with the state-of-the-art classical reaction conditions
for amide cleavage. After all, N-(hetero)arylamide cleavage normally requires an excess of a strong
2
5
acid or base to allow alcoholysis.
Table 6: Mechanistic experiments on model compounds to support the crucial factors in amide
activation in the Zn-catalyzed tert-butyl nicotinate directed amide alcoholysis.
O
X
O
X
1
1
0 mol% Zn(OAc)2
3 equiv MeOH (2d)
+
N
R
OMe
HN
R
COOtBu
tBuOAc, 40 °C, 24 h
COOtBu
13a, 14a and 14b
3c
1
0a, 14c and 15a
c
a
b
b
Entry
1
X
R
3c
Amide
13a, 0%
DG-NH2
10a, quant.
15a, 0%
N
H
quant.
0%
0%
2
3
CH
N
H
Me
14a, quant.
14b, 99%
14c, 0%
a
b
GC-yield with 1,3,5-trimethoxybenzene as internal standard;
trimethoxybenzene as internal standard.
NMR-yield with 1,3,5-
We used density functional theory (DFT) calculations to compute the catalytic cycle for Zn-
catalyzed cleavage of 13a with methanol (2d); Figure 4 shows the free energy profile. Bidentate
chelation of 13a in its most stable trans-conformer I with catalyst 17 results in a more stable
biomimetic precomplex 18a. Subsequently, the hydrogen-bonded MeOH (via acetate ligand of
Zn(OAc) ) can attack the amide carbonyl (‡19a), delivering intermediate 20a. Proton transfer
2
of the acetate proton to the exocyclic nitrogen (‡22a) allows elimination of 10a, yielding 3c.
The importance of the ligand of the metal catalyst was also experimentally found in the initial
metal catalyst screening. For example, ZnCl was found to give lower conversion than Zn(OAc) in
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2
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
◦
isopropanolysis at 140 C (Table 1). The rate-determining step in the catalytic cycle of the Zn(OAc)2-
catalyzed tBu nic-directed amide cleavage of 13a with MeOH (2d) is the elimination (‡22a). When
computing a py-DG instead of a tBu nic, the same mechanism and rate-determining step for the
postulated catalytic cycle is obtained. The major diꢁerence is that the precomplex 18b is 5.3 kcal
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
−
1
mol less stable than 18a. This is due to the involvement of the most stable trans-conformer
II of 8a, which needs to rotate to the less stable trans-conformer I before bidentate chelation
becomes possible. A major kinetic diꢁerence between both pathways is therefore expected since
the equilibrium concentration of trans-conformer I allowing bidentate chelation, is about 12,500
times (weight% trans-I 13a:8a = 99.517:0.008) lower for 8a than for 13a (Figure 1, Table S35). In
accordance with this, the cleavage of N-(pyridin-2-yl)benzamide (8a) under standard conditions
◦
(vide supra; 10 mol% of Zn(OAc) , 26.0 equiv isopropanol (2c), 40 C, 48 h) does not give any
2
reaction. Under non-catalytic conditions involving 2.5 equiv Zn(OAc) and 50 equiv of more
2
reactive MeOH (2d) (which equals solvolytic alcoholysis) at the same temperature, ester 3c was
formed, but the reaction required 10 days to achieve full conversion. The cleavage reactions with
1
3a and 8a are both exergonic.
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28

Page 29 of 101
ACS Catalysis
1
2
3
4
5
6
7
8
9
2
1.5
2
0.8
O
O
O
O
O
O
O
Zn
Zn
N
O
O
H
O
O
H
O
N
Zn
O
O
O
O
H
O
O
O
N
Zn
N
H
O
O
O
O
1
6
17.4
N
N
H
O
1
7.1
2
2a
O
6
.0
O
O
Zn
O
H
O
O
O
Elimination ‡
16
O
O
O
Zn
O
O
H
N
O
21a
1
7
H
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
O
O
d H
O
H
N
O
O
2
0
N
O
1
8a
H
O
O
Zn
O
N
O
H
O
-
2.3
O
Zn
O
O
O
N
O
-8.4
H
O
19a
Addition ‡
O
NH2
N
O
N
O
O
20a
O
3
c
10a
1
3a
tr !"#I
Complexation
Addition
Elimination
2
3.9
O
H
N
23.8
O
O
O
O
O
O
N
O
Zn
H
Zn
O
O
8
trans-II
a
H
N
O
O
O
O
H
O
O
22.4
22.4
N
N
Zn
N
O
O
O
H
O
Zn
O
Zn
O
O
H
H
H
N
O
O
16
N
N
22b
O
O
O
N
O
H
6
.0
1
8b
3.0
O
Zn
O
H
N
O
N
O
21b
Elimination ‡
16
O
17
O
H
O
H
O
O
O
Zn
O
O
Zn
O
O
d H
O
O
2
0
8
.5
-0.5
1
9b
20b
H
O
N
O
NH2
24
0
3.0
O
N
Addition ‡
N
N
O
N
O
H
1
7
18b
O
-
2.2
O
H
O
Zn
3c 10b
O
O
Zn
O
O
23
23
H
O
O
2
4
Complexation and rotation
Addition
Elimination
Figure 4: Computational study of the catalytic cycle of tBu nic- directed amide cleavage of 13a and py-directed amide cleavage of 8a with
MeOH (2d) via DFT-calculations (T = 298 K), using ’Gaussian 09’ software. The self-consistent reaction field (scrf) model was used to account for
solvent-solute interactions with butyl acetate, as a model for the eꢁect of tert-butyl acetate, the main solvent used for the experimental cleavage
reactions (figure is not on scale).
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