Thieme Chemistry Journals Awardees - Where Are They Now? Bis(2-pyridyl)amides as Readily Cleavable Amides under Catalytic, Neutral, and Room-Temperature Conditions

Article abstract of DOI:10.1055/s-0036-1590932

Mild solvolytic cleavage of bis(2-pyridyl)amide under neutral and room-temperature conditions is described. The inherently stable amide was readily activated by catalytic amounts of metal cations to react with alcohols. Based on X-ray crystallographic analysis, the primary driving force was considered to be amide distortion induced by the metal coordination of two pyridyl groups in a bidentate fashion without affecting the amide functionality. The compatibility of the acid/base-sensitive functionalities and the absence of racemization during solvolysis highlight the mildness of the present protocol.

Full text of DOI:10.1055/s-0036-1590932

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© Georg Thieme Verlag Stuttgart · New York
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S. Adachi et al.
Letter
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Thieme Chemistry Journals Awardees – Where Are They Now?
Bis(2-pyridyl)amides as Readily Cleavable Amides Under Catalytic,
Neutral, and Room-Temperature Conditions
Shinya Adachi
Naoya Kumagai*
Masakatsu Shibasaki*
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Institute of Microbial Chemistry (BIKAKEN), Tokyo,
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021,
Japan
nkumagai@bikaken.or.jp
mshibasa@bikaken.or.jp
Received: 21.08.2017
Accepted after revision: 13.09.2017
Published online: 11.10.2017
DOI: 10.1055/s-0036-1590932; Art ID: st-2017-u0634-l
Abstract Mild solvolytic cleavage of bis(2-pyridyl)amide under neutral
and room-temperature conditions is described. The inherently stable
amide was readily activated by catalytic amounts of metal cations to re-
act with alcohols. Based on X-ray crystallographic analysis, the primary
driving force was considered to be amide distortion induced by the
metal coordination of two pyridyl groups in a bidentate fashion without
affecting the amide functionality. The compatibility of the acid/base-
sensitive functionalities and the absence of racemization during sol-
volysis highlight the mildness of the present protocol.
Key words amide, deconjugation, amide distortion, amide twisting,
solvolysis, metal coordination, mild conditions
The amide group is a vital functionality that determines
the primary structure of proteins by interconnecting α-
amino acid units, and it is ubiquitously present in various
naturally occurring compounds and artificial chemical enti-
ties, e.g., therapeutic agents and functional polymers. The
amide functionality is characterized by a flat structure that
dictates its inherently stable nature due to nN–π*C=O conju-
gation, which renders the robust amide-bond linkage least
reactive in the class of carbonyl-type functionalities.1 Mod-
ulation of amide planarity to elicit hidden reactivity of the
amide functionality has been a sustained topic in organic
chemistry2 since the first appearance of a postulated twist-
ed amide in 1938.3 Distortion of the flat structure of an am-
ide by twisting (τ) as well as N-pyramidalization (χN)4 was
established to significantly increase the susceptibility of
amide-bond linkages via deconjugation, best represented
by highly distorted examples 1–3 with rigid bicyclic archi-
tectures (Scheme 1, a).5,6 Recently, N-acylglutarimide 4 was
disclosed to exhibit a considerable twist angle comparable
to bridged derivatives 1–3 despite its noncyclic structure;2e–g,7
Naoya Kumagai was born in 1978 and raised in Ibaraki, Japan. After re-
ceiving his PhD in Pharmaceutical Sciences at the University of Tokyo in
2005, under the supervision of Prof. Masakatsu Shibasaki, he pursued
postdoctoral studies in the laboratory of Prof. Stuart L. Schreiber at
Harvard University in 2005–2006. He moved to Prof. Shibasaki’s group
at the University of Tokyo as an assistant professor in 2006. He is cur-
rently a chief researcher at the Institute of Microbial Chemistry, Tokyo.
He is a recipient of the Pharmaceutical Society of Japan Award for
Young Scientists (2010), Banyu Chemist Award (2012), and Mitsui
Chemicals Catalysis Science Award of Encouragement (2014). His re-
search interests include the development of new methodologies in ca-
talysis and their application to bioinspired dynamic processes.
this substantial distortion is general for other N-acylimides
and was elegantly exploited in a series of catalytic coupling
reactions involving facile oxidative addition of the C–N
bond.7a,8,9
The innate reactivity of other decorated amides, e.g.,
electron-deficient N-sulfonyl and N-Boc amides10 as well as
N-acylsaccharins,10c,11 N-pyrazolylamides,12 azetidine am-
ides,13 and anilides14 were also revealed as competent amides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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S. Adachi et al.
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tions (Scheme 1, d). X-ray crystallographic analysis suggest-
ed that amide distortion was the driving force behind the
solvolysis.
(a) Innate distorted amides
—highly distorted amides
—N-acylimides—
in a rigid bicyclic architecture—
O
O
O
N
We began our study with methanolysis of cinnamyl am-
ide 6a installed with two 2-pyridyl groups on the amide ni-
trogen (Table 1). Screening of readily available first-row
transition-metal salts as an azophilic chelator in CD3OD
quickly identified Zn(OTf)2 and Cu(OTf)2 as promising pro-
moters with catalyst loading of 5 mol%, affording nearly
quantitative yield of ester 7a-d3 at room temperature (Table
1, entries 1–4). Amide 6a was sufficiently stable in the ab-
sence of metal salts (Table 1, entry 5). While Zn(NTf2)2 ex-
hibited similar catalytic activity as Zn(OTf)2, ZnCl2 had a
slower catalytic profile, presumably due to intimate ion
pairing with chlorides retarding the coordination/dissocia-
tion kinetics (Table 1, entries 6 and 7). Because amide 6a
was sufficiently stable in acidic conditions and ester 7a-d3
was not detected after treatment with 1 equiv of TfOH,
metal cations were responsible for the catalysis, and the in-
volvement of any acidic impurities was ruled out (Table 1,
entry 8).17 On the other hand, amide 6a′ bearing isomeric
4-pyridyl groups did not exhibit any reactivity in the pres-
ence of 5 mol% or stoichiometric amounts of Zn(OTf)2,
which also supports the involvement of chelating activation
through two 2-pyridyl groups (Table 1, entries 9 and 10). To
shed light on the mechanistic aspect of this room-tempera-
2: n = 1
3: n = 0
n
Ph
N
N+
1
R
H
R
O
4
O
–
R
BF4
τ = 90–90.6°
τ = 90–90.9°
τ : amide twist angle
(b) Temporal distortion/activation via amide-N/metal coordination
τ = 91.4°
O
O
R2
R2
Mn+
Mn+
R1
R1
N
N
Mn+: metal cation
R3
R3
(c) Temporal distortion/activation via peripheral steric bias
R2
O
R2
O
R1
Mn+
N
R1
N
N
N
N
Mn+: metal cation
Mn+
Ph
N
Ph
Ph
5/Mn+
Ph
5
(d) This work: steric-driven activation with structurally simple
bis(2-pyridyl)amides
neutral & room temperature
solvolysis
H
cat.
O
O
Mn+
N
HOR2
O
R1
R1
N
N
N
OR2
R1
H
N
Mn+
N
including
acid or base
sensitive
Table 1 Methanolysis (CD3OD) of Bis(pyridyl)amide Derivatives 6 in
• activation by amide distortion
• amide functionality untouched
functionalities
6
the Presence of a Catalytic Amount of Metal Saltsa
Scheme 1 (a)–(c) Prior art to access distorted amides and (d) this work
on the solvolytic cleavage of amides under neutral and room-tempera-
ture conditions
Y
O
O
X
additive x mol%
CD3OD, rt, 12 h
Ph
N
Ph
OCD3
X
in reaction manifolds involving oxidative addition of the
amide C–N bond, where a low rotational barrier of the am-
ide C–N bond is proposed for high reactivity.7 In addition to
these inherently activated amides, in situ activation of un-
reactive amides by structural distortion is another highly
investigated topic, demonstrating that deformation indeed
occurs by direct metal coordination to the amide nitrogen
(Scheme 1, b).15 On the other hand, in situ distortion and
activation while maintaining the amide functionality un-
touched was recently manifested by our group, with pe-
ripheral steric bias induced by metal coordination having a
crucial role (Scheme 1, c).16 Although non-Lewis acidic am-
ide activation was supported by structural evidence (X-ray
and NMR) and solvolytic cleavage of the amide occurred at
room temperature, the rather uncommon structure of am-
ide 5 severely affected the utility of this sterically driven ac-
tivation mode. We reasoned that structural distortion for
temporary activation might take place even with structur-
ally simpler amides. Herein, we document mild solvolysis of
bis(2-pyridyl) amides 6 promoted by catalytic amounts of
metal salts under neutral and room-temperature condi-
7a
Y
6
Entry
Amide 6
Additive
x (mol%) Yield (%)b
X =
Y =
1
2
3
4
5c
6
7
8
9
N
N
N
N
N
N
N
N
H
H
H
H
H
H
H
H
H
H
N
N
6a
6a
6a
6a
6a
6a
6a
6a
6a′
6a′
Fe(OTf)2
Ni(OTf)2
Zn(OTf)2
Cu(OTf)2
–
5
5
69
20
>95
>95
0
5
5
–
Zn(NTf2)2
ZnCl2
5
>95
86
0
5
TfOH
100
5
Zn(OTf)2
Zn(OTf)2
0
10
a 5.6 mM.
100
0
b Determined by 1H NMR analysis of the crude mixture with dibenzyl as an
internal standard.
c Run for 48 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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ture solvolytic protocol and dissect the activation mode op-
erative for 6a in the presence of metal salts, single crystals
were grown from a mixture of 6a and Zn(OTf)2 at a 1:1 ratio
in anhydrous acetone/iPr2O (Scheme 2). X-ray crystallo-
graphic analysis of the crystals revealed a homoleptic
(6a)2/Zn2+ complex, in which two pyridyl groups coordinat-
ed to two Zn2+ in an octahedral coordination mode. Of note,
the amide functionality was free from the Zn2+ coordination
sphere and the involvement of Lewis acidic activation was
unlikely.
served as a complimentary amide cleavable by Zn(OTf)2 in a
catalytic manner, as shown in the competitive reaction out-
lined in Scheme 3.19 Whereas Cu2+ (Cu(OTf)2) was also com-
petent to effect the solvolysis of 6a (Table 1), the crystal
structure of 6a/Cu2+ indicated that distortion-driven activa-
tion mode was operative for 6a,20 and there was no direct
contact of the amide nitrogen to Cu2+ (Scheme 2).21
O
O
O
N
O
R
N
Zn(OTf)2
5 mol%
R
+
N
R
N
N
N
+
R
OCD3
N
N
N
CD3OD, rt
12 h
6a
8
7a
8
>95%
1 : 1 stoichiometry
remained
unchanged
R = (E)-PhCH=CH
Scheme 3 Chemoselective catalytic methanolysis (CD3OD) of 6a in
the presence of structurally similar amide 8
O
O
N
Zn(OTf)2 5 mol%
R1
N
OR2
R1
R2OH, rt
N
7
6
O
O
O
OMe
OMe
Ph
R2 = Me:7a,
R
R
OR2
BocHN
R3O
R2 = Me
R2 = Me
24 h, 92%a
2 = Et: 7ab, 24 h, 95%a
2 = iPr: 7ac, 72 h, 71%b
R3 = MOM: 7c, 24 h, 91%c
7b, 48 h, 82%
R
3 = TBS: 7d, 48 h, 96%
O
Scheme 2 Crystallographic analysis of 6a/Zn2+ and 6a/Cu2+ and re-
ported activation mode of structurally similar amide 8. For X-ray struc-
tures, hydrogen atoms, one molecule of triflate anion (for 6a/Zn2+), and
two triflate anions (for 6a/Cu2+) are omitted for clarity. Color code;
grey: carbon, blue: nitrogen, red: oxygen, light green: fluorine, yellow:
sulfur, dark green: cupper, purple: zinc.
O
O
OMe
O
FmocHN
tBuO
Ph
OMe
OMe
OMe
O
O
N
R2 = Me
7e, 24 h, 91%
R2 = Me
R2 = Me
R2 = Me
7f, 24 h, 97%
7g, 24 h, 95%
7h, 24 h, 89%, er 98:2
amide substrate
er 98:2
Instead, increasing peripheral steric bias induced by two
rigidified Zn2+-coordinated pyridyl groups deformed the
amide planarity (τ = 13.8°, χN = 14.9°; τ = 3.6°, χN = 6.2°), en-
hancing the susceptibility of the amide carbonyl to nucleo-
philic attack by methanol for solvolysis. As expected by the
catalytic solvolysis, coordination and dissociation of 6a to
Zn2+ was rapid and largely averaged spectra were observed
in NMR analysis.18 This activation mode was likely dictated
by the peripheral steric bias and distinct from that ob-
served for structurally similar amide 8; a methylene group
was embedded between the amide nitrogen and 2-pyridyl
group (Scheme 2). Reported crystallographic analysis of
complex 8/CuCl2 and 8/Cu(OTf)2 clearly revealed direct co-
ordination of the amide nitrogen to Cu2+, which was re-
sponsible for amide pyramidalization and the following sol-
volysis.15a,15c–e,15g–j Moreover, 8 recovered unchanged under
the solvolytic conditions with Zn(OTf)2 in CD3OD and 6a
Scheme 4 Catalytic solvolysis of bis(2-pyridyl)amides 6 promoted by
Zn(OTf)2 at room temperature. Reactions were run on 0.2 mmol scale,
and isolated yields are presented. Reactions were run on 0.1 M except
for the synthesis of 7ac (0.02 M); er: enantiomeric ratio. a 2 mol% of
Zn(OTf)2 were used. b 10 mol% of Cu(OTf)2 were used instead of
Zn(OTf)2. c 5 mol% of Cu(OTf)2 were used instead of Zn(OTf)2.
The present mild Zn-catalyzed solvolytic protocol was
validated with substrates having a variety of substituents
(Scheme 4).22 While smooth solvolysis was observed for
cinnamyl amide 6a in MeOH and EtOH with as little as 2
mol% of Zn(OTf)2 to give methyl and ethyl esters 7a, 7ab,
formation of corresponding isopropyl ester 7ac proceeded
sluggishly, and Cu(OTf)2 instead of Zn(OTf)2 exhibited bet-
ter catalytic activity. Bis(2-pyridyl)amides prepared from
benzoic acid derivatives were then examined. This mild
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protocol was also applicable to benzamides and acid-labile
N-Boc, O-MOM, and O-TBS groups were tolerated (7b–d). A
tBu ester group remained unchanged (7e). A substrate bear-
ing a pyridyl group, which can potentially impair the che-
lating activation by Zn(OTf)2, afforded desired methyl ester
7f in high yield. Amides derived from sp3-aliphatic carbox-
ylic acid exhibited high reactivity and a γ-keto group had
no detrimental effects (7g,h). The absence of racemization
in the catalytic solvolysis of the amide α-amino acid deriva-
tive underscored the mild solvolytic protocol,23 delivering
Fmoc-Ala-OMe (7h) in high yield without undesired depro-
tection of base-sensitive Fmoc group.
In conclusion, we demonstrated that bis(2-pyridyl)am-
ides are amenable to solvolytic cleavage to give the corre-
sponding esters under mild catalytic conditions using Zn2+
or Cu2+ salts. The neutral and room-temperature protocol
accommodates a variety of base- and acid-labile functional
groups. The observed coordination mode in X-ray crystallo-
graphic analysis indicated that the amide functional group
was not affected by metal cations, and the amide distortion
driven by peripheral steric bias was crucially involved in
engaging the amide in solvolysis.
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Funding Information
This work was financially supported by KAKENHI (17H03025 and
JP16H01043 in Precisely Designed Catalysts with Customized Scaf-
folding) from JSPS.
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Acknowledgment
(9) For examples of acid anhydride formation and Friedel–Crafts
reactions using N-acylimides, see: (a) Liu, Y.; Meng, G.; Liu, R.;
Szostak, M. Chem. Commun. 2016, 52, 6841. (b) Liu, Y.; Liu, R.;
Szostak, M. Org. Biomol. Chem. 2017, 15, 1780.
Dr. Tomoyuki Kimura is gratefully acknowledged for the X-ray crystal-
lographic analysis.
(10) (a) Li, X.; Zou, G. Chem. Commun. 2015, 51, 5089. (b) Baker, E. L.;
Yamano, M. M.; Zhou, Y.; Anthony, S. M.; Garg, N. K. Nat.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590932.
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ortioInfgrmoaitn
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(22) General Procedure: Catalytic Solvolysis of Amide 6
A flame-dried 5 mL round-bottomed flask equipped with a
magnetic stirring bar and a septum cap was charged with
amide 6 (0.20 mmol) and Zn(OTf)2 (0.01 mmol, 5 mol% or 0.004
mmol, 2 mol%; 0.02 mmol, 10 mol% or 0.01 mmol, 5 mol% of
Cu(OTf)2 were used for the synthesis of 7ac or 7c, respectively)
in a glove box under Ar atmosphere. After adding anhydrous
MeOH (2.0 mL; 2 mL of EtOH or iPrOH was used for the synthe-
sis of 7ab or 7ac) at rt, the resulting clear solution was stirred
for designated period of reaction time at the same temperature.
The reaction mixture was concentrated under reduced pressure,
and the resulting residue was purified by flash column chroma-
tography to give esters 7.
Methyl cinnamate (7a): white solid; yield 29.7 mg (92%).
Ethyl cinnamate (7ab): colorless oil; yield 33.5 mg (95%).
Isopropyl Cinnamate (7ac): colorless oil; yield 26.9 mg (71%).
Methyl 4-[(tert-butoxycarbonyl)amino]benzoate (7b): white
solid; yield 41.4 mg (82%).
(16) Adachi, S.; Kumagai, N.; Shibasaki, M. Chem. Sci. 2017, 8, 85.
(17) Although cation-driven solvolysis was much faster, partial sol-
volysis of amide 6a proceeded under basic conditions: 1 equiv
NaOH: 15%, 1 equiv DBU: 25% (identical conditions to Table 1: in
CD3OD, rt, 12 h). Compound 6a was sufficiently stable under
mild conditions and remained unchanged in the presence 1
equiv of Et3N.
(18) See Supporting Information.
(19) Other designed amide cleavable by stoichiometric amount of
Zn(OTf)2 was developed. See ref. 15j.
Methyl 4-(methoxymethoxy)benzoate (7c): clorless oil; yield
35.9 mg (91%).
Methyl 4-[(tert-butyldimethylsilyl)oxy]benzoate (7d): colorless
oil; yield 51.2 mg (96%).
tert-Butyl methyl terephthalate (7e): white solid; yield 42.8 mg
(91%).
Methyl picolinate (7f): colorless oil; yield 26.7 mg (97%).
Methyl 4-oxo-4-phenylbutanoate (7g): colorless oil; yield 36.4
mg (95%).
(S)-Methyl
2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)
(20) A part of the crsytal structure was disordered. See Supporting
Information.
propanoate (7h): white solid; yield 57.6 mg (89%).
(23) Determined by HPLC analysis.
(21) For transesterification and transamidation of innate reactive
amides, see: (a) Hutchby, M.; Houlden, C. E.; Haddow, M. F.;
Tyler, S. N.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E