Dehydration of Chiral α-Amides to Chiral α-Nitriles Under the Appel Reaction Conditions

Article abstract of DOI:10.1007/s10989-020-10101-y

An efficient synthesis of N^α-protected amino nitriles from N^α-protected amino acid amides employing Ph₃P, I₂ and NMM was described. Various amino acid amides, protected by Fmoc, Z and Boc were conveniently conve

Full text of DOI:10.1007/s10989-020-10101-y

International Journal of Peptide Research and Therapeutics
https://doi.org/10.1007/s10989-020-10101-y
Dehydration of Chiral α‑Amides to Chiral α‑Nitriles Under the Appel
Reaction Conditions
Shekharappa1 · L. Roopesh Kumar1 · C. Srinivasulu1 · Vommina V. Sureshbabu1
Accepted: 14 July 2020
© Springer Nature B.V. 2020
Abstract
An efcient synthesis of Nα-protected amino nitriles from Nα-protected amino acid amides employing Ph3P, I2 and NMM
was described. Various amino acid amides, protected by Fmoc, Z and Boc were conveniently converted to nitriles in high
yields. Side chain protected amino acid amides were well-tolerated and a good yield of products was obtained. The protocol
serves as one of the mild, among a few available, methods for the racemization-free conversion of Nα-protected amino acid
amides to corresponding nitriles with neither harsh condition nor catalyst.
Graphic Abstract
Nα-protected amino acid amides were efciently transformed to Nα-protected amino acid nitriles employing I2, PPh3, and
NMM under mild reaction conditions. Fmoc, Boc and Cbz-protected amino acid amides were converted into their corre-
sponding nitriles groups. Side chain protected amino acid amides also underwent facile conversion to their corresponding
nitriles with good yields.
Keywords α-Amide · α-Nitrile · N-Methylmorpholine · Molecular iodine · Triphenylphosphine
Introduction
Many attempts to synthesize nitriles are being made as
these are intermediates in the production of polyamides,
pharmaceuticals, dyes and numerous fne chemicals (Fati-
Electronic supplementary material The online version of this
adi et al. 1983; Miller and Marson 2001). And also, nitrile
article (https://doi.org/10.1007/s10989-020-10101-y) contains
group serves as an important intermediate in organic syn-
thesis for various functional group transformations (Cad-
dick et al. 2000; Munoz et al. 2011; Yamaguchi and Mizuno
2014; Wanga 2015) and has often been utilized as a versa-
tile precursor to synthesize various heterocyclic compounds
(Aureggi and Sedelmeier 2007; Bosch and Vilarrasa 2007;
supplementary material, which is available to authorized users.
* Vommina V. Sureshbabu
sureshbabuvommina@redifmail.com; hariccb@hotmail.com
1
Peptide Research Laboratory, Department of Studies
in Chemistry, Bangalore University, Jnana Bharathi,
Bangalore, Karnataka 560056, India
Vol.:(0123456789)
1 3

International Journal of Peptide Research and Therapeutics
Nishiwaki et al. 2011; Heller et al. 2002) (Fig. 1). Many
compounds having nitrile group possess a broad spectrum
of biological activities (Tarleton et al. 2012).
system (Kim et al. 1990), triphenylphosphine-N-chloro-
succinimide system (Iranpoor et al. 2002), cyanuric chlo-
ride (Maetz and Rodriguez 1997) have been employed for
this functional group transformation. There are reports for
the conversion of Nα-protected amino acid amides into
Nα-protected aminonitriles, which are often used inter-
mediates for the syntheses of various peptidomimetics
(Sureshbabu et al. 2007, 2009a, b ; Santhosh et al. 2017).
Till date, Burgess reagent (Claremon and Philips 1988),
(COCl)2–Et3N (Nakajima and Ubukata 1997), cyanuric
chloride (Maetz and Rodriguez 1997) and TFAA–pyri-
dine system (Sureshbabu et al. 2007, 2009a, b) are the
prominent ones exclusively employed for dehydration
of Nα-protected amino acid amides. However, not much
demonstration has come out of these reagents. Though
all the aforementioned protocols were able to transform
primary amide to nitriles, they are, by one or other, sufer
from drawbacks. Most of the methods require long dura-
tion with high refux temperatures and catalysts. Problems
involving storage, handling and waste generation and tedi-
ous work up warrants an improved protocol for the conver-
sion. Especially, most of these reagents are inconvenient to
use in amino acid chemistry, as they apply base-sensitive
or acid-sensitive protecting groups, like Fmoc and Boc,
respectively. Despite several protocols that are avail-
able, there is a continuous search for the mild protocols
as nitriles are of great practical importance. Besides, on
quick literature search, it was found that not many proto-
cols were reported to obtain Nα-protected aminonitriles
from corresponding amides. In an attempt to develop a
mild and simple protocol to achieve this conversion, we
found that combination of PPh3, I2 and a base could serve
as one. The combination was efciently used to convert
formamides to isonitriles at mild conditions and with the
minimum reaction duration (Wang et al. 2015). And also,
it is noteworthy that the combination of PPh3 and I2 (and
CBrCl3) along with base was efectively used for the syn-
thesis of nitriles from primary amides (Wang and Ganesan
2000; Jasema et al. 2014), however, exclusive application
of this combination is not yet demonstrated for the race-
mization free synthesis of Nα-protected amino nitrile from
the corresponding amides involving common, yet sensi-
tive functional groups. We envisaged exploiting this com-
bination for the conversion of amide functional groups
to nitrile. Reaction when carried out using Nα-protected
amino acid amides, the conversion of amide to correspond-
ing nitriles was completed in 3 h at room temperature. The
yields obtained were surprisingly better, up to 95%. With
our interest in developing a new, mild protocol for the
synthesis of Nα-protected amino nitrile, herein we report
a protocol to synthesize Nα-protected aminonitriles from
Nα-protected amino acid amides employing the combina-
tion of PPh3, I2 and NMM.
The most common way to synthesize nitriles is by dehy-
dration of primary amides. This involves the use of acidic
dehydrating reagents viz., P2O5 (Reisener and Horning
1963), POCl3 (Rickborn and Jensen 1962), SOCl2 (Krynit-
sky and Carhart 1963), and TiCl4 (Lehnert 1971). In an
attempt, sophisticated reagents, such as the combination of
ethyl dichlorophosphate and diazabicyclo[5.4.0]undec-7-
ene (DBU), were also used for the dehydration of amides
(Kuo et al. 2007). Amide dehydration catalyzed by iron
complexes (Zhou et al. 2009a, b), tetrabutylammonium
fuoride (Zhou et al. 2009a, b) and cyclopropenone (Rai
and Yadav 2013) can be found in literature. In addition,
iron complex bearing an N-heterocyclic carbene ligand
with hydrosilane at 100 °C has been used for this pur-
pose (Elangovan et al. 2015). Recently, primary amides
were converted to nitriles using visible light, with reac-
tion duration 16–30 h (Yadav et al. 2014). Aminoalane
reagent (Wojtkielewicz et al. 2015) and XtalFluor-E (Keita
et al. 2015) as dehydrating reagents have been employed to
access nitriles from amides. In addition, pivaloyl chloride-
pyridine system (Narasaiah and Nagaiah 2004), Burgess
(Claremon and Philips 1988) and similar type reagent
(Rappai et al. 2011), (benzotriazol-1-yloxy)trispyrroli-
dinolphosphoniumhexafuorophosphate (PyBOP) DIEA
system (Bose and Narasaiah 2001), trifuoroacetic anhy-
dride (TFAA)-pyridine system (Sureshbabu et al. 2007,
2009a, b), triphenylphosphine (PPh3)-carbon tetrachloride
Fig. 1 Selected examples of various functional group transformations
and heterocycles from nitrile
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International Journal of Peptide Research and Therapeutics
of examination, it was found that the absence or inade-
quate amount of any one of the reagent or with a reaction
time less than 3 h led to decrease in the yield (Table 1,
Entries 6–8). Reaction when carried out for 3 h, signif-
cant increase in yield was observed and further increase
in reaction duration did not improve the yield (Table 1,
Entry 9). Moreover, increasing molar ratios of PPh3 and
I2 had led to decrease in the yield (Table 1, Entry 10).
Reactions with DMF and EtOAc in two separate experi-
ments did not give noticeable conversion (Table 1, Entries
11 and 12).
Results and Discussions
In order to ascertain the feasibility of our envisaged prepa-
ration of nitriles using PPh3 and I2, Z-Phg-NH2 (1a) was
chosen as a model substrate. We began our investigation
based on the work by Wang et al., and Narasaiah group
(Wang et al. 2015; Narasaiah et al. 2006). In the latter,
nitriles were obtained from aldoximes with PPh3 and
I2 without a base. Initially, solvent THF was chosen as
Nα-protected amino acid amides were neatly soluble in it.
We began our screening with with PPh3 (1.0 equiv.) and
I2 (1.0 equiv.) in the absence of base and the conversion
did not take place, indicated by thin layer chromatography
(TLC) (Table 1, Entry 1). Speculating that adding base
could yield the conversion was also failed undeservedly as
only meagre conversion was observed (Table 1, Entries
2 and 3). On changing to DCM, it was still the same; no
nitrile was formed without a base (Table 1, Entry 4). On
addition of 1.0 equiv. of base, to our delight, nitrile was
formed, proving base was an indispensable factor for the
conversion (Table 1, Entry 5). Once the reagents neces-
sary for the preparation of nitriles were found, we further
investigated on the stoichiometric amount of reactants
that are required for the conversion. After a small series
Chiral RP-HPLC analysis of compounds Z-(L)Phg-CN
(2a) and Z-(D)Phg-CN (2a*) gave single peak in the chro-
matogram i.e., at tR1 =20.133 and tR2 =17.797 respectively
(see supporting information), confrming the products are
racemization free (for chiral RP-HPLC chromatograms of
the compounds 2d and 2g see supporting information).
Eventually, we arrived at the optimized conditions-PPh3
(1.5 equiv.), I2 (1.5 equiv.) and NMM (3.0 equiv.) with the
reaction time of 3 h having dry DCM as a solvent (Table 1,
Entry 13). Generality and scope of the protocol were dem-
onstrated, during which, it was found that Cbz-protected
amino acid amides showed maximum compatibility by giv-
ing maximum yields up to 95% (Scheme 1, Entries 2a–c)
Nevertheless, Boc and Fmoc-protected amino acid amides
gave a satisfactory yield, up to 90% and 76% respectively
(Scheme 1, Entries 2d–m). As an extension and to demon-
strate the tolerance, the protocol was applied to side chain
protected Nα-protected amino acid amides and they also
underwent facile conversion to nitriles and good yield of
products were isolated (Scheme 1, Entries 2f, 2l and 2m).
All the compounds were well characterized by mass,
1H and 13C NMR analysis and were correspondent with
the structures of the compounds. Infrared spectroscopy
showed medium-weak peaks at around 2239–2250 cm−1,
confrming nitrile functional group. RP-HPLC analysis of
the compounds using chiral column resulted in single peaks,
which confrmed the racemization- free synthesis of the title
compounds.
Table 1 Optimization of reaction conditions
Entrya Solvent Base (equiv.) PPh3:I2
(equiv.)
Time (h) Yieldb (%)
1
THF
THF
THF
DCM
–
1:1
12
12
12
6
–
2
Et3N (2.0)
Et3N (2.0)
–
1:1
Tracec
Tracec
–
Recent literature reports suggest that PPh3-I2 system
proved to be a versatile combination as it has been continu-
ously exploited in various organic syntheses viz., amidation
(Wangngae et al. 2015); N-alkylation of purine, pyrimidine
and azole derivatives (Rad and Soleimani 2016); allylic
amines (Chavan et al. 2014), substituted guanidines and
2-iminoimidazolin-4-ones (Wangngae et al. 2017); and
2,3-disubstituted-3H-quinazolin-4-ones (Phakhodee et al.
2017). Based on these literature precedents, reaction mech-
anism of the present work was proposed (Scheme 2). The
familiar reaction proceeds by the formation of Appel’s salt
A, to which nucleophilic addition of oxygen of the carbonyl
group of the amide forms the intermediate B, which subse-
quently yields nitrile on reacting with the base.
3
1.5:1.5
1:1
4
5
DCM Et3N (1.0)
DCM Et3N (2.0)
DCM Et3N (2.0)
DCM Et3N (3.0)
DCM Et3N (3.0)
DCM Et3N (3.0)
1:1
6d
6d
3d
3
36
6
1:1
55
7
1.5:1.5
1.5:1.5
1.5:1.5
2.0:2.0
1.5:1.5
1.5:1.5
74
8
75
9
3d
3
75
10
11
12
13
80
DMF
Et3N (3.0)
3
Tracec
Tracec
95
EtOAc Et3N (3.0)
3
DCM NMM (3.0) 1.5:1.5
3
aReactions were carried out under nitrogen atmosphere
bIsolated yield after aqueous workup and column chromatography
cIndicated by the TLC
dYield remained same for 12 h of reaction time
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International Journal of Peptide Research and Therapeutics
Scheme 1 Synthesis of Nα-protected amino nitriles from Nα-protected amino acid amides
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International Journal of Peptide Research and Therapeutics
layer was washed with saturated Na2S2O5 solution, water,
brine solution and dried over anhydrous MgSO4. The solvent
was removed under reduced pressure and resulting crude
compound was purifed by column chromatography (80:20
hexane:EtOAc).
Acknowledgements Shekharappa is thankful to University Grants
Commission for NFSC. Roopesh Kumar L are thankful to DST Nano-
mission, Government of India, for fnancial assistance.
Compliance with Ethical Standards
Scheme 2 Plausible reaction mechanism
Conflict of interest The authors declare that this article content has no
conficts of interest.
Conclusion
Research Involving Human and Animal Participants This article does
not contain any studies with human participants or animals performed
by any of the authors.
Amino acid nitriles, important intermediates in build-
ing various peptidomimetics, were accessed from simple,
straight forward protocol employing Ph3P, I2 and NMM was
reported. Various Boc, Z, and Fmoc protected amino acid
amides underwent racemization-free conversion to nitriles.
Side chain protected amino acid amides were also converted
to the products in good yields, which refected the widened
application and compatibility of the combination of the
reagents.
Informed Consent The article does not contain any studies in patients
by any of the authors.
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