Development and Utilization of a Palladium-Catalyzed Dehydration of Primary Amides to Form Nitriles

Article abstract of DOI:10.1021/acs.orglett.8b02422

A palladium(II) catalyst, in the presence of Selectfluor, enables the efficient and chemoselective transformation of primary amides into nitriles. The amides can be attached to aromatic rings, heteroaromatic rings, or aliphatic side chains, and the reactions tolerate steric bulk and electronic modification. Dehydration of a peptaibol containing three glutamine groups afforded structure-activity relationships for each glutamine residue. Thus, this dehydration can act similarly to an alanine scan for glutamines via synthetic mutation.

Full text of DOI:10.1021/acs.orglett.8b02422

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Development and Utilization of a Palladium-Catalyzed Dehydration
of Primary Amides To Form Nitriles
†
‡
†
†
́
́
́
Mohammed H. Al-Huniti, Jose Rivera-Chavez, Katsuya L. Colon, Jarrod L. Stanley,
Joanna E. Burdette,§ Cedric J. Pearce,∥ Nicholas H. Oberlies,† and Mitchell P. Croatt*,†
†Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, 435 Sullivan Science Building,
Greensboro, North Carolina 27402, United States
‡
́
́
́
Institute of Chemistry, Universidad Nacional Autonoma de Mexico, Circuito Exterior s/n, Coyacan, Mexico City 04510, Mexico
§Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 A. Ashland Avenue, Chicago,
Illinois 60607, United States
∥Mycosynthetix, Inc., Suite 103, 505 Meadowlands Drive, Hillsborough, North Carolina 27278, United States
S
* Supporting Information
ABSTRACT: A palladium(II) catalyst, in the presence of Selectfluor, enables the efficient and chemoselective transformation
of primary amides into nitriles. The amides can be attached to aromatic rings, heteroaromatic rings, or aliphatic side chains, and
the reactions tolerate steric bulk and electronic modification. Dehydration of a peptaibol containing three glutamine groups
afforded structure−activity relationships for each glutamine residue. Thus, this dehydration can act similarly to an alanine scan
for glutamines via synthetic mutation.
Scheme 1. Metal-Catalyzed Methods To Convert Primary
Amides into Nitriles
n the area of new reaction design and development, the
Ichemoselective interconversion of functional groups is
highly sought after.1 Two noteworthy examples include (1)
the selective methylation of the carboxylic acid of amphotericin
B in the presence of seven alkenes, nine secondary alcohols, a
hemiacetal, and a primary amine2 and (2) the C−H
oxygenation of a bryostatin analogue with DMDO in the
presence of 11 similar C−H bonds, an alkene, an acetal, and
three carboxyl groups.3 The first case represents the conversion
of a carboxylic acid to an ester, a relatively simple
transformation that modifies reactivity, but the conversion in
amphotericin B is complicated by the other functional groups
surrounding it. For example, typical Fisher esterification using
a strong acid is not compatible with this molecule. Similarly,
the dehydration of a primary amide to form a nitrile, which has
been previously explored,4 is often complicated by the
presence of other functional groups.5 Transition metal
catalyzed dehydration reactions typically utilize acetonitrile4a,b
or N-methyl-N-(trimethylsilyl)trifluoroacetamide
(MSTFA)4c−e as a dehydrating agent (Scheme 1). These
reactions generate acetamide as a byproduct from acetonitrile
or N-methyltrifluoroacetamide and hexamethyldisiloxane from
MSTFA. For reactions involving MSTFA, high reaction
temperatures and excess amounts of MSTFA are required.
Nonaqueous acetonitrile reactions require excess amounts of
lithium and silver salts.4b On the other hand, reactions
involving water as cosolvent can proceed at room temper-
ature,4a but are limited to substrates that are stable and soluble
under aqueous conditions (Scheme 1a).
During our studies to semisynthetically improve the activity
of natural products, typically by incorporating fluorine into the
molecule,6 we attempted to fluorinate alamethicin F50, a 20-
mer peptaibol containing an acetylated N-terminus, a C-
Received: July 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02422
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Organic Letters
Letter
terminal phenylalaninol, and three glutamine (Gln) residues
reaction appears faster than that with Pd(OAc)2, the
purification was complicated by the dba (dibenzylidene-
acetone) ligand. Thus, catalyst loading and Selectfluor
stoichiometry were examined using the Pd(OAc)2 catalyst.
Using 5 mol % of catalyst, the reaction yielded 71% of the
desired nitrile after 16 h (Table 1, entry 6). Increasing the
amount of Selectfluor to 40% gave nitrile 10a, in addition to
the fluorinated nitrile derivative (Table 1, entry 8). Reactions
performed in the absence of Selectfluor or in the presence of
DABCO instead of Selectfluor yielded no nitrile product.
Although Selectfluor is a nonhygroscopic reagent, we examined
the requirement for water using Pd(OAc)2 in the absence of
Selectfluor (Table 1, entries 11−13). Increasing the amount of
water in the reaction improved the reaction yield (68% was
observed with 2.0 equiv of water). For comparison, the
addition of water to the reaction conditions with Selectfluor
was not beneficial. A previous report by Maffioli4a found that
the palladium-catalyzed dehydration requires water. We
verified their results in the absence of Selectfluor, which
indicates that Selectfluor is modifying the catalytic cycle,4b
such that water is no longer required. After screening a variety
of conditions, it was determined that 10 mol % Pd(OAc)2 and
20 mol % Selectfluor in acetonitrile (entry 1) was optimal.
With the optimal conditions in hand, a series of primary
amides were synthesized from their respective carboxylic acids
and screened in the dehydration conditions (Scheme 3). The
substrate scope is broad, with high yields for both aliphatic and
aryl amides to generate aliphatic and aryl nitriles. High yields
were observed from reactions involving non-, mono-, and
disubstituted benzamides (10a−c and 10e−g; 80−96%
yields). The lower yield for compound 10d (4-trifluoromethyl-
(Gln7, Gln18−19; Scheme 2).7 Although our fluorination
Scheme 2. Identification of a Chemoselective Dehydration
attempts were unsuccessful,8 it was determined that all three
glutamine residues were dehydrated in the presence of
Pd(OAc)2 and Selectfluor. This led to the formation of
tricyano product 2, along with semidehydrated analogues (3−
8; vide infra). This transformation was efficient and completely
chemoselective without modifying the primary alcohol or any
of the secondary or tertiary amides. Herein, we describe the
further optimization and exploration of this dehydration
reaction and utilize the dehydration of alamethicin F50 to
illustrate the benefits of this reaction as a quick method to
functionalize and determine the biological effects of the
glutamine residues in the peptaibol.
To examine the optimal conditions of the dehydration of
primary amides, 4-methoxybenzamide was used as a model
substrate in the presence of catalytic amounts of various metal
salts and Selectfluor. The reaction gave excellent yields of the
nitrile product in the presence of Pd(II) or Pd(0); contrasting
results were observed with Zn(II) or Cu(II) catalyzed
reactions (Table 1, entries 1−5). Although the Pd2(dba)3
Scheme 3. Various Substrates for Primary Amide
Dehydration
Table 1. Optimization of Palladium-Catalyzed Dehydration
with Selectfluor
a
entry
cat. (mol %)
additive (mol %)
time (h)
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
PdCl2 (10)
Pd2(dba)3 (5)
ZnBr2 (10)
Cu(OTf)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Selectfluor (20)
Selectfluor (20)
Selectfluor (20)
Selectfluor (20)
Selectfluor (20)
Selectfluor (20)
−
Selectfluor (40)
Selectfluor (5)
DABCO (20)
H2O (50)
16
16
13
24
24
16
24
16
24
24
16
16
16
96
82
91
trace
26
71
trace
93
88
b
9
c
10
11
12
13
NR
31
42
68
H2O (100)
H2O (200)
a
b
Isolated yield. 7% Fluorinated 4-methoxybenzonitrile was observed.
c
No reaction.
B
DOI: 10.1021/acs.orglett.8b02422
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benzamide, 42% yield) was likely due to electronic factors.
However, the effect was negligible on cinnamide derivatives
(10h−10j). Several aliphatic amides were also converted to
their corresponding primary, secondary, and tertiary nitriles in
good yields. Importantly, the cyclopropyl moiety in amides
(9t−9v) has been preserved under the reaction conditions to
generate cyclopropyl nitriles (10t−10v) in excellent yields
(86−93%). In total, 22 substrates were screened, and it was
determined that this reaction tolerates the presence of alkenes,
aromatic rings, heteroaromatic rings, nitro groups, cyclo-
propanes, and halides. To further test the chemoselectivity of
the reaction, we ran the dehydration of 9a in the presence of
either salicylaldehyde or 4-phenylbutyric acid. These reactions
gave desired product 10a (93% and 95% yield, respectively)
with quantitative recovery of salicylaldehyde and 4-phenyl-
butyric acid, illustrating that phenols, aldehydes, and carboxylic
acids are also tolerated.
Scheme 5. Synthesis of Mono-, Di-, and Tricyano
Alamethicin F50 Analogues
Based on our results and the similarity of conditions to prior
reports,4a the reaction mechanism (Scheme 4) might involve
for 12 h gave the tricyano peptaibol derivative (2; 47% yield
after purification), along with the dicyano product (3) where
the glutamines at positions 18 and 19 were dehydrated (13%
yield after purification). The structures of compounds 2 and 3
were confirmed by 1H and 13C NMR spectroscopy and
HRESIMS/MS data (SI).
Scheme 4. Postulated Mechanism for Dehydration
Subsequently, an analysis was carried out to examine the
reaction mixture for other variations of dehydration. In order
to perform the dehydration of up to three amides of
alamethicin F50 (1) in a timely manner, peptaibol 1 was
reacted with Pd(OAc)2 (5 mol %) using a full equivalent of
SelectFluor in MeCN (0.1 M). The reaction was monitored
using UPLC-UV-HRESIMS at intervals of 15−20 min for 5 h
(see SI for time course of the reaction in three different solvent
mixtures). Gratifyingly, UPLC analysis allowed for resolution
of all seven products and the starting material (Figure 1).
Scaling up of the reaction with SelectFluor in acetonitrile
permitted the isolation, structural characterization, and bio-
logical evaluation of dehydrated analogues 2−8. The structures
of these analogues were established through analyses of their
HRESIMS/MS spectra (SI). Importantly, these seven
the formation of a mixed imidic anhydride (B) that undergoes
proton transfer and coordination of acetate (C) followed by an
elimination to yield the desired nitrile and acetamide (D), as
has been proposed previously.4b The role of Selectfluor
remains uncertain, but one potential option is that it
accelerates the catalytic cycle by formation of a Pd(IV)
catalyst, as has been reported by others.8,9 Additional evidence
in support of a Pd(IV) mechanism is the observation of a
signal at −181 ppm in the 19F NMR when Pd(OAc)2 is added
to Selectfluor (19F NMR signals for SelectFluor are 48 (N−F)
and −151 (BF4) ppm, Supporting Information (SI)). A more
resolved mechanism for this reaction is still being examined
and will be published in due course.
To further establish the utility of the dehydration,
alamethicin F50 was re-examined as a starting material (1;
Scheme 5), with an approach focused on the exploration of the
structure−activity relationship of the different primary amides.
The reaction of compound 1 with SelectFluor (1.0 equiv) and
Pd(OAc)2 (5 mol %) in MeCN (0.1 M) at room temperature
Figure 1. HRESIMS spectra of the reaction of 1 (10 mg, 5.9 μmol)
with SelectFluor (2.1 mg, 5.9 μmol) and Pd(OAc)2 (0.011 mg, 0.05
μmol) in MeCN (0.1M) at 25 °C after 90 min. In black is the base
peak chromatogram, in maroon the extracted ion chromatogram for
the staring material (1) at m/z 1963.0, in green the extracted ion
chromatogram at m/z 1945.0 for the monocyano products (6−8), in
navy the extracted ion chromatogram at m/z 1927.0 for the dicyano
products (3−5), and in yellow the extracted ion chromatogram at m/
z 1909.0 for the tricyano product (2).
C
DOI: 10.1021/acs.orglett.8b02422
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Letter
analogues were all accessed by a single reaction using 1 as the
starting material instead of designing and developing seven
different approaches or through the use of protecting groups.10
Furthermore, in contrast to the more typically used alanine
scan,11 this method has a minimal change in the overall sterics
of the side chain since there is no deletion of carbon over the
course of the reaction.
Alamethicin F50 (1) is known to be antibacterial, antifungal,
anthelmintic, and cytotoxic.7,12 Based on our groups’ attempts
to generate anticancer leads,6a,c,13 we decided to determine the
impact of the glutamine residues on the bioactivity in a panel
of cancer cell lines (Table 2). The cytotoxicity data indicated
Figure 2. Far UV/CD spectra for alamethicin F50 (1) and its
dehydrated analogues (2−8). See SI for full spectra (Figure S19).
Table 2. Cytotoxicity of Alamethicin F50 and Dehydrated
a
Analogues
(Figure 2 and SI). Surprisingly, the helical nature of the
different peptaibol analogues did not have a strong correlation
with the cytotoxicity data (compare Figure 2 and Table 2). In
Figure 2, the UV/CD spectrum of alamethicin F50 (1) is most
similar to those of monocyano analogues 6−8, but analogue 8
is inactive. Likewise, there is a grouping in the spectra of
dicyano analogues 3−5, but analogue 3 is active, whereas
analogue 5 is inactive and compound 4 has decreased activity.
These data indicate that the cytotoxicity of alamethicin F50 is
dependent on the presence of a glutamine residue at position
seven, and that the activity is not simply a stabilization of the
α-helix conformation of the peptaibol.
compound
MDA-MB-435
MDA-MB-231
OVCAR3
1
4.4
3.7
7.8
2; R,R′,R′′ = CN
3; R′,R′′ = CN
4; R,R′′ = CN
5; R,R′ = CN
6; R′′ = CN
7; R′ = CN
8; R = CN
>25
2.6
3.1
>25
2.2
2.8
>25.0
1.2
8.7
22.3
1.3
2.0
>25
3.0
13.4
>25
4.6
3.9
>25
0.002
>25
0.0005
>25
0.009
Taxol
a
IC50 values in μM in the indicated cell lines were determined as the
In summary, a Selectfluor-modified palladium catalyst was
shown to enable the chemoselective dehydration of primary
amides to generate nitriles. The reaction tolerates the presence
of primary alcohols, primary amides, secondary amides,
aldehydes, carboxylic acids, nitro groups, alkenes, heteroar-
omatic rings, halides, and cyclopropanes and is efficient with
aromatic and aliphatic amides, with little impact by the
electronics or sterics of the system. The application of the
dehydration method facilitated the synthesis of the seven
possible dehydrated analogues of alamethicin F50 (1).
Importantly, all the peptaibol derivatives were generated in a
single reaction in sufficient amounts for purification, character-
ization, and biological evaluation. The application of this
methodology allowed us to generate data that highlight the
importance of each individual glutamine residue on the
bioactivity and conformation of 1. We hypothesize that this
primary amide dehydration methodology may be used as an
alternative to alanine scanning to assess the implications of
glutamine and possibly asparagine residues on the activity and
3D structure of peptides.
concentration required to reduce cellular proliferation by 50% relative
to the untreated controls following 72 h of continuous exposure.
that the glutamine at position seven was crucial for maintaining
the cytotoxic properties of the molecule. This was determined
since the analogue dehydrated exclusively at position seven (8)
was inactive, whereas monocyano 6 and 7 were active.
Similarly, dicyano 5 and 4, both of which had position seven
dehydrated, were inactive or much less active, respectively.
Dehydration of glutamine 18 and/or 19 led to analogues that
had similar activities. These results give unique insight into the
impact of each glutamine residue on the cytotoxic properties of
1 and show that position seven is crucial to the observed
cytotoxicity.
Several techniques, including X-ray diffraction,14
NMR,7,12f,15 CD,16 Raman, and molecular dynamics,7,17 have
been used to characterize the α-helical conformation of
alamethicin F50 (1) in both solution and solid states.7 In an
attempt to gain information about the conformational changes
induced by the dehydration of the glutamine residues in 1, the
CD spectrum for each analogue was recorded in MeCN
(Figure 2). The far UV/CD spectra, 260−180 nm, with
absorbances attributed to the peptide bond, is the most
extensively used spectroscopic readout to determine the
secondary structures of peptides in solution (α-helix, β-pleated
sheet, and random coil).18 The right handed α-helix is reported
to give two negative Cotton effects at 222 and 208 nm, while
the β-pleated sheet shows one negative and one positive
Cotton effect at 217 and 198 nm, respectively.18 Analysis of the
experimental CD data obtained for alamethicin F50 (1) and its
analogues (2−8) indicated that the mono- and dicyano
compounds (3−8) predominantly retained the α-helical
conformation, with a minor population of 310-helix, as
previously reported by Peggion et al.19 However, the CD
spectrum for tricyano 2 indicated that the conformation was
modified, increasing the population of the 310-helix conformer
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02422.
Experimental information and spectral data for all
compounds and cytotoxicity data for compounds 1−8
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mpcroatt@uncg.edu.
ORCID
Mitchell P. Croatt: 0000-0002-5643-7215
D
DOI: 10.1021/acs.orglett.8b02422
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported in part by P01 CA125066 from
the National Cancer Institute/NIH, Bethesda, MD, USA. The
authors thank Drs. Franklin J. Moy and Daniel A. Todd (both
from UNCG) for assistance with NMR and high-resolution
mass spectrometry data, respectively.
(13) Sy-Cordero, A. A.; Figueroa, M.; Raja, H. A.; Meza Avina, M.
̃
E.; Croatt, M. P.; Adcock, A. F.; Kroll, D. J.; Wani, M. C.; Pearce, C.
J.; Oberlies, N. H. Tetrahedron 2015, 71, 8899.
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