Aza-Wittig Reaction with Nitriles: How Carbonyl Function Switches from Reacting to Activating

Article abstract of DOI:10.1021/acs.orglett.8b04135

Transformations of α-EWG-substituted (electron-withdrawing group, EWG) γ-azidobutyronitriles proceeding via unusual aza-Wittig reactions between the phosphazene and nitrile functions and affording pyrrole-derived iminophosphazenes were developed. α-EWGs w

Full text of DOI:10.1021/acs.orglett.8b04135

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
aza-Wittig Reaction with Nitriles: How Carbonyl Function Switches
from Reacting to Activating
Hamidulla B. Tukhtaev,†,‡ Konstantin L. Ivanov,† Stanislav I. Bezzubov,§ Dmitry A. Cheshkov,∥
Mikhail Ya. Melnikov,† and Ekaterina M. Budynina*,†
†Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russia
‡Institute of Bioorganic Chemistry, Uzbek Academy of Sciences, Mirzo Ulugbek str. 83, Tashkent 100125, Uzbekistan
§Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskiy pr. 31, Moscow 119991, Russia
∥State Scientific Research Institute of Chemistry and Technology of Organoelement Compounds, Sh. Entuziastov 38, Moscow
105118, Russia
S
* Supporting Information
ABSTRACT: Transformations of α-EWG-substituted (electron-
withdrawing group, EWG) γ-azidobutyronitriles proceeding via
unusual aza-Wittig reactions between the phosphazene and nitrile
functions and affording pyrrole-derived iminophosphazenes were
developed. α-EWGs were found to control chemoselectivity and,
depending on their nature, act as CN group activators (e.g., ester,
amide, or nitrile) or competitors (e.g., ketone) in aza-Wittig
reactions. To demonstrate the synthetic utility of the obtained
iminophosphazenes as N,N-binucleophiles, their transformations
into pyrrole-fused systems, pyrrolo[1,2-a]imidazoles and pyrrolo-
[1,2-a][1,3]diazepines, were carried out.
Scheme 1. Strategy of This Work
he aza-Wittig reaction, a well-known rapid access to C
1
TN bond construction, provides numerous opportunities
for the synthesis of N-containing organic molecules. In this
context, the use of the aza-Wittig reaction for the synthesis of
N-heterocycles2 is of primary concern, owing to a broad
abundance of such structures in both natural and synthetic
bioactive compounds. Moreover, among U.S. FDA-approved
unique small-molecule pharmaceuticals, 59% of drugs contain
an N-heterocycle.3
Among various types of aza-Wittig reactions, the inter-
actions between aza-Wittig reagents, phosphazenes, and
compounds containing polar double bonds (primarily in the
carbonyl group) are the most explored. Oppositely, reactions
involving the triple CX bonds of acetylenes or nitriles are
described scarcely. This is apparently related to the lower
reactivities of CX units toward phosphazenes, which is due
to the insufficient electrophilicity of the carbon centers. In
particular, the very few scattered examples of the aza-Wittig
reaction with the CN bond are mostly limited to nitriles
activated with strong electron-withdrawing groups (EWGs)
(CHal3, CHal2R, CN) (Scheme 1A).4 Two additional similar
examples were reported to proceed in the Pt(II) coordination
sphere.5 The reactions between phosphazenes and nitriles are
cyclic systems with at least two nitrogen atoms. Meanwhile,
there are no examples of aza-Wittig reactions wherein the
distinct in that new aza-Wittig reagents are formed in their
process. Therefore, when the problem of low nitrile reactivity
is solved, this challenging type of aza-Wittig reaction could
allow for installing an additional nitrogen atom in the
assembled molecules and, thus, synthesizing various hetero-
Received: December 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04135
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
usually low-reactive nitrile can compete with an unchallenged
carbonyl group.
Scheme 2. Transformation of γ-Azidonitrile 1a into
Iminophosphazene 3a: Accumulation and Consumption of
Intermediate Phosphazene 2a
Here, we report an aza-Wittig reaction wherein the efficient
control of the competition between the CN and CO
groups provides for chemoselective assembly of N-hetero-
cycles. The strategy of our current work relies on new
precursors of aza-Wittig reagents, azides 1 (Scheme 1B).
Recently, we developed a convenient approach to similar
azides via nucleophilic ring opening of donor−acceptor (DA)
cyclopropanes6 with the azide ion.7 The strategic arrangement
of the functionalities in the obtained azides allows for their
successful transformations into N-heterocycles via various
pathways which incorporate the aza-Wittig reaction. Moreover,
in reactions with PPh3, these azides with ester or oxindole
groups as EWGs yield stable phosphazenes (Scheme 1C).7,8
Particularly, ester derivatives do not undergo spontaneous 1,5-
cyclization via intramolecular aza-Wittig reactions under
ambient conditions, whereas an increase in temperature
facilitates their cyclization into 2-alkoxypyrroline derivatives.
When keto groups act as an EWG, an intramolecular reaction
between the generated phosphazene and carbonyl units occurs
spontaneously.7 At the same time, the reactivity of similar CN-
substituted phosphazenes remained unexplored.
In this work, the reactions of azides 1 with triaryl/
trialkylphosphines were unexpectedly found to afford cyclic
iminophosphazenes 3 through the spontaneous trapping of a
phosphazene fragment in acyclic aza-Wittig intermediates 2 by
the CN group (Scheme 1B). Apparently, the advantageous 1,3-
relationship between the CN and N3 groups in 1 as well as the
presence of an α-activating EWG stimulate the nitrile unit to
participate in subsequent aza-Wittig reactions. Meanwhile, the
nature of the EWG was found to influence the reaction
chemoselectivity which can be switched from the phosphazene
attack on the nitrile moiety (EWG = ester, amide, or nitrile
groups) toward a typical attack on the EWG (EWG = keto
group).
Compounds 3 can be viewed as multifunctionalized
aminopyrrole building blocks. As N,N-binucleophiles, com-
pounds 3 provide ample opportunities for the construction of
pyrrole-derived N,N-heterocyclic systems in which the number
and the size of fused rings can be controlled by the nature of
the bielectrophilic counterpart used. Herein, we transformed
iminophosphazenes 3 into pyrrolo[1,2-a]imidazoles and
pyrrolo[1,2-a][1,3]diazepines, employing oxalyl, succinyl, or
ortho-phthaloyl chlorides as bielectrophiles.
NMR data. The presence of an external electrophile (e.g.,
benzaldehyde) did not induce an intermolecular aza-Wittig
reaction under these same conditions. The replacement of
triphenylphosphine by the more active tributylphosphine led
to the more labile iminophosphazene 3a′ which was isolated
upon column chromatography on SiO2 in a 21% yield only due
to considerable degradation. Consequently, the application of
the moderately active PPh3 in CH2Cl2 at ambient temperature
steers the reaction toward exclusive formation of iminophos-
phazene 3a.
Using identical conditions, we then explored the scope of 1-
into-3 transformation while varying the α-substituent R,
located at the geminal position to the N3 group in 1 (Scheme
3A). We found that this reaction was completely tolerant
toward aryl substituents with both electron-donating and
electron-withdrawing groups, as well as hetaryl and alkenyl
substituents. In most of the studied cases, iminophosphazenes
3 were isolated in very good yields (up to 93%). Some
decrease in the yield was only observed for phosphazene 3h
containing a bulky ortho-OMOM substituent in the aryl
fragment. Although the reaction does not directly involve
stereocenters at the C2 and C4 atoms of azides 1,
diastereomeric ratios (dr) of 3 can be regulated by the
keto−enol equilibrium. Therefore, their values differ from the
dr values for the initial azides 1. Notably, in the cases of 3l and
3o, dr values rose slightly (ca. 2:1) in comparison with those
for 1l,o (ca. 1:1). The obtained diastereomers cannot be
separated by the means of column chromatography apparently,
owing to the same keto−enol equilibrium. However, we
succeeded in growing crystals from the diastereomeric mixture
for the individual trans-isomer of 3p. Its structure was
unambiguously proved by single crystal X-ray analysis.
Initially, we examined the reaction of azide 1a, containing an
ester group at the α-position, toward the CN fragment, with
triphenylphosphine under ambient conditions, using CH2Cl2
1
as a solvent (Scheme 2). According to the results of H NMR
monitoring of this reaction mixture (25 °C, CDCl3), the
reaction was completed in 48 h after PPh3 had been added.
Surprisingly, cyclic iminophosphazene 3a was the predominant
product, apparently formed through the cyclization of
intermediate phosphazene 2a via the CN group. The
competitive product of phosphazene interacting with the C
O group, 4a, was formed in trace amounts under these
conditions, whereas the formation of its hydrolyzed successor
5a was not observed. However, increasing the reaction
temperature to 40 °C while allowing the reaction to complete
in 10 h facilitates a competitive process of 4a formation via an
aza-Wittig reaction with the ester group. When performed at
82 °C (CH3CN under reflux) for 4 h, the reaction yielded a
1
mixture of 3a and 4a in a 91:9 molar ratio, according to H
B
DOI: 10.1021/acs.orglett.8b04135
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Letter
Scheme 3. Scope of 1-into-3 Transformation under
Variation of γ- and α-Substituents
Scheme 4. Reductive 1,5-Cyclization of γ-Azidonitrile 1g
into Lactam 5b
We found that its replacement with the bulkier CO2But group
(1s) as well as amide (1t) or nitrile (1u) groups did not
influence the chemoselectivity of the reactions, affording the
corresponding iminophosphazenes 3s−u in high yields
(Scheme 3B). On the other hand, the reaction time can be
influenced. For 1s-to-3s transformation, the reaction time was
increased to 90 h, whereas 1u-to-3u transformation was
completed in 4 h. The reaction of 1w which contains an
additional CN group (X = CH2CN) chemoselectively led to a
similar five-membered iminophosphazene 3w via interaction of
the only α-EWG-activated CN substituent. Due to the
presence of the third α-substituent that successfully blocked
the interconversion of diastereomers, we succeeded in singling
out individual reaction times for transformations of (2RS,4SR)-
1x into trans-3x (8 h) and (2RS,4RS)-1x into cis-3x (35 h).
In the case of keto-derived γ-azidonitrile 1v, the CN group
was found to be noncompetitive in comparison with the more
active CO group in intermediate 2v (Scheme 5). As a result,
the reaction yielded 2-pyrroline 8 (apparently, via intermediate
1-pyrroline 7) rather than iminophosphazene 3v.
Scheme 5. Transformation of Keto-Derived γ-Azidonitrile
1s into 2-Pyrroline 8
a
b
Isolated yield. Diastereomeric ratios (dr) were determined by the
c
d
1H NMR analysis of crude products. dr 63:37 Reaction time was 90
h (3s), 4 h (3u), 8 h (trans-3x), and 35 h (cis-3x).
In all the cases, reactions of 1 with PPh3 proceeded with
exceptional chemoselectivity: only trace amounts of alkox-
ypyrrolines 4 or γ-lactams 5 can be detected. Meanwhile, the
reduction of the N3 group in γ-azidonitrile 1g as a model
substrate with the H2−Pd/C reductive system led to the
exclusive formation of γ-lactam 5b via spontaneous 1,5-
cyclization of intermediate γ-aminoester 6 under reaction
conditions (Scheme 4). Therefore, 1,5-cyclizations of
phosphazenes 2 and amines 6 can be considered comple-
mentary, allowing for chemoselectivity to switch between the
attacks on the CN and the CO groups and, thus,
providing divergent approaches to iminophosphazenes 3 and γ-
lactams 5, respectively.
In order to determine the extent of the influence that the
geminal EWG has on the CN reactivity, we carried out the
reaction of PPh3 with the EWG-free γ-azidonitrile 9a, obtained
from 1f via Krapcho demethoxycarbonylation (Scheme 6). The
reaction yielded stable phosphazene 10a which did not
undergo spontaneous aza-Wittig cyclization under the stand-
ard conditions. Additionally, the heating of 10a in toluene
under reflux also did not induce an intramolecular aza-Wittig
reaction, with a slow degradation of 10a into a complex
mixture of unidentified products taking place in its stead. The
more reactive PBu3 also gave acyclic phosphazene 10b which
was not prone to aza-Wittig cyclization (despite its higher
reactivity leading to considerable tarring and decrease in the
yield). The introduction of an alkyl substituent (9c: R′ = Et)
also did not facilitate an intramolecular aza-Wittig reaction.
To define the scope of the CN group reactivity toward the
phosphazene moiety as dependent on the geminal functional
group, we examined the reactions of PPh3 with γ-azidobutyr-
onitriles 1s−x containing EWGs other that the CO2Me group.
C
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Letter
Compounds 3 are quite stable ylides, owing to conjugation
of the phosphazene and imine fragments. This inhibits
reactions of 3 with the most common carbonyl compounds
such as benzaldehydes even at increased temperatures. At the
same time, 3 react with the more reactive aliphatic aldehydes
and acyl halides. However, in the case of acetic aldehyde or
acetyl chloride, the reactions resulted in a complex mixture of
products.15 Accounting for the presence of two N-nucleophilic
sites in the molecules of 3, we studied their reactions with
bielectrophilic reactants containing two halocarbonyl groups.
To our delight, phosphazenes 3 readily reacted with oxalyl,
succinyl, and ortho-phthaloyl chlorides, producing pyrrolo[1,2-
a]imidazoles 11 and pyrrolo[1,2-a][1,3]diazepines 12, respec-
tively (Scheme 7). The structures of 12a,c were supported by
single crystal X-ray analysis.
Scheme 6. Formation of Stable Phosphazenes 10 in Absence
of α-Activating EWG
a
b
1
Yield according to H NMR. Yield after column chromatography
(SiO2).
Scheme 7. Transformation of Iminophosphazenes 3 into
a
Pyrroloimidazoles 11 and Pyrrolodiazepines 12
Therefore, the interaction between 9c and PPh3 afforded
acyclic phosphazene 10c as the final product.
Next we performed DFT calculations at the B3LYP9/def2-
SVP10/RIJCOSX11 level of theory using ORCA 3.0.12 After
optimizing geometries for various stereoisomers of 2a, we
identified reacting conformers for both CN- and CO-mode
aza-Wittig reactions. Relying on the reported results of the
DFT study for the reaction between aldehydes and
phosphazenes,13 we easily localized stationary points and
then built analogous profiles for cyclization via CO in both
diastereomers of cyanoester 2a. The computation of
cyclization via CN proved to be a less trivial task. We
successfully optimized TS geometries for the [2 + 2]-
cycloaddition step in each reacting conformer, but the
calculated intermediates proved to be relatively unstable.
Although the TS of the cycloreversion step could be localized,
this is a virtually barrier-less process. The energy diagrams with
the lowest TS energy for the rate-determining step (RDS) for
both pathways are visualized using CYLview14 in Figure 1.
Since the entire reactions are irreversible, and the dr values for
2a, 3a, or 4a are determined by the keto−enol equilibrium, the
3a:4a ratio should correlate to the difference in the TS energies
of the corresponding RDS. The difference, amounting to 3.2
kcal/mol, is roughly consistent with the experimental ratio:
3a:4a > 95:5.
a
Conditions: (a) oxalyl, (b) succinyl, (c) ortho-phthaloyl chlorides
(1.1 equiv), CH2Cl2 (0.4 M), Δ, 30 min.
Pyrroloimidazoles 11 are structural analogues of dimirace-
tame and its derivatives which are nootropic agents of the
racetam family. A preliminary MTT assay of compounds 11
Figure 1. Energy diagrams for aza-Wittig reactions in isomers of 2a with the lowest TS energies for RDS (ΔG298, kcal/mol). Geometries of 3a and
4a correspond to the conformers with the lowest relative energy, not to the reacting conformers.
D
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assay of other biological properties of 11, including their
nootropic activity.
In conclusion, we have developed a new synthetic
transformation of γ-azidobutyronitriles into pyrrole-derived
iminophosphazenes proceeding via unusual aza-Wittig reac-
tions between the phosphazene and α-EWG-activated nitrile
units. The reactivity of this type was revealed for ester, amide,
or nitrile groups as activating α-EWGs. Alternatively, for α-
keto derivatives, the chemoselectivity was switched toward the
common aza-Wittig reaction between the phosphazene and
carbonyl groups. The obtained iminophosphazenes were found
to exhibit properties of typical N,N-binucleophiles, readily
reacting with such bielectrophiles as oxalyl, succinyl, or ortho-
phthaloyl chlorides to afford pyrrolo[1,2-a]imidazole and
pyrrolo[1,2-a][1,3]diazepine systems.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04135.
■
S
Experimental procedures, analytical data, details of DFT
calculations, and copies of H and 13C NMR spectra
1
(PDF)
Accession Codes
CCDC 1838688−1838689 (12b and trans-3p), 1852202 (8),
1852209 (12a), 1865323 (S2c), and 1873067 (cis-3w) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ekatbud@kinet.chem.msu.ru.
ORCID
Konstantin L. Ivanov: 0000-0002-1557-175X
Stanislav I. Bezzubov: 0000-0002-2017-517X
Ekaterina M. Budynina: 0000-0003-1193-7061
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Russian Foundation for
Basic Research, Grant Number 18-53-41009, and Ministry of
Innovation Development of the Republic of Uzbekistan, Grant
Number MRU-FA-74/2017. The NMR measurements were
carried out at the Center for Magnetic Tomography and
Spectroscopy, Faculty of Fundamental Medicine of Moscow
State University. X-ray diffraction studies were performed at
the Centre of Shared Equipment of IGIC RAS and at the
Durham X-ray Centre.
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DOI: 10.1021/acs.orglett.8b04135
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