Synthesis of Oxadiazol-5-imines via the Cyclizative Capture of in Situ Generated Cyanamide Ions and Nitrile Oxides

Article abstract of DOI:10.1021/acs.orglett.6b00203

An unprecedented intermolecular cyclizative capture of the cyanamide anion and several nitrile oxides enables the synthesis of oxadiazol-5-imines.

Full text of DOI:10.1021/acs.orglett.6b00203

Letter
pubs.acs.org/OrgLett
Synthesis of Oxadiazol-5-imines via the Cyclizative Capture of in Situ
Generated Cyanamide Ions and Nitrile Oxides
Shreesha V Bhat, David Robinson, John E Moses,* and Pallavi Sharma*
†
‡
,‡
,†
†School of Chemistry, Joseph Banks Laboratories, University of Lincoln, Lincoln, LN6 7DL, U.K.
‡School of Chemistry, University Park, University of Nottingham, Nottingham, NG7 2RD, U.K.
*
S Supporting Information
ABSTRACT: An unprecedented intermolecular cyclizative capture of the
cyanamide anion and several nitrile oxides enables the synthesis of oxadiazol-5-imines.
itrogen heterocycles are important building blocks in
1
N
chemistry and biology. They are the key constituents of
DNA, RNA, and the protein-synthesizing ribosomes, as well as
being predominant functional groups in many coenzymes that
1
mediate primary metabolic transformations. Therefore, it is no
coincidence that nitrogen heterocycles are important functional
1
motifs in medicinal chemistry and drug synthesis.
Recent studies indicate that approximately 59% of all unique
small-molecule drugs approved by the U.S. FDA contain some
2
sort of nitrogen heterocycle, most commonly, piperidine,
pyridine, pyrrolidine, thiazole, imidazole, indole, and tetrazole.
Like any important functional class of compounds, developments
that facilitate their production are significant for process chemists
in the pharmaceutical industry. Hence, the symmetry between
the availability of gateway synthetic methodology and the
prevalence of nitrogen heterocycles in approved pharmaceuticals
2
is notable.
Figure 1. Representative examples of clinically important pharmace-
However, there are examples of “rare” nitrogen heterocycles
that might offer potential in lead discovery but are either too
synthetically demanding or have simply been overlooked. For
example, the five-membered ring 1,2,4-oxadiazol-5(4H)-imine
uticals.
enable access to 1,2,4-oxadiazol-5(4H)-one (4) and amidine (5)
derivatives, respectively (Figure 1 and Scheme 1A).
We report here an unprecedented formal 1,3-dipolar cyclo-
addition reaction of substituted cyanamides with nitrile oxides.
Harnessing the intrinsic electro- and nucleophilic duality of
cyanamides, in contrast to previous reports, the present method
incorporates the cyanamide N -nitrogen directly into the core
of the ring with the nitrile (−CN ) forming the exocyclic imine
(Scheme 1B vs 1C).
In formulating the reaction conditions, we envisaged that
the in situ generation and trapping of the reactive nitrile oxide
coupling partner 3 with cyanamide ion 7 was the key factor
3
motif features in only one pharmaceutical drug, the coronary
vasodilator, imolamine (Figure 1). The first reported synthesis of
the 1,2,4-oxadiazol-5(4H)-imine core appeared in the patent
3
8
literature in the 1960s. The stepwise route involved a 1,3-dipolar
1
cycloaddition of cyanamide with nitrile oxide to the 1,2,4-
oxadiazole-5-amine, followed by isomerization and an alkylation
to yield the target imine product (Scheme 1B). Not only step
intensive, this method is also restricted to the synthesis of alkyl
substituents at position 4 (product 1).
2
While the importance of 1,2,4-oxadiazol-5(4H)-imines wa4s
highlighted in a number of subsequent pharmacological studies,
only a limited number of synthetic reports have appeared in the
9
(Scheme 1C).
We elected to generate the nitrile oxide via either a fluoride
1
0
11
5
ion or base mediated dehydrochlorination of the
literature, and none since the late 1970s.
N-hydroximoyl chloride (6). The concomitant generation of
the cyanamide anion (7) could be achieved via detosylation of
Seeking a new approach to 1,2,4-oxadiazol-5(4H)-imines (1),
12
we envisaged a convergent approach involving the union of a
6
substituted cyanamide (2) with a nitrile oxide (3) via either
7
a stepwise or pericyclic pathway (Scheme 1). Subsequent
Received: January 21, 2016
hydrolysis and reduction of the imine product would further
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Reaction of Cyanamide with Nitrile Oxide: (A)
Retrosynthetic Analysis; (B) Previous Work; (C) Present Work
Scheme 2. Substrate Scope for the TBAF-Mediated
a b
,
Cyclizative Capture Reaction
13
the corresponding N-sulfonyl cyanamide (1). A reagent screen
was performed to find the optimal conditions for the reaction
between 2 and 6 (Table 1).
−
Table 1. Preliminary Screening of Base/F Reagents
a
,
b
c
entry
base
equiv of base time (h) yield (1a) (%)
d
1
2
3
4
5
6
7
8
9
K CO3
2
24
24
24
4
−
−
−
−
2
d
d
d
Et N
3
2
NH4F
CsF
2
2.4
3.4
3.4
6
CsF
>24
4
15
27
57
61
79
a
1
equiv of 6 and 1.25 equiv of 2 were dissolved in 0.5 mL of THF.
CsF:18C6 (1:1)
CsF
e
To this stirring solution at 0 °C, TBAF (1 M THF) (3 equiv) was added
4
b
via syringe pump over 1 h. Isolated yields.
TBAF
TBAF
3.4
3
10 min
f
1
a
b
increase in yield was recorded (Table 1, entry 6). Alternatively,
when chlorooxime 6a was added slowly over a period of 1.5 h in
the presence of a large excess of CsF (6 equiv), 1a was isolated in
Reactions were performed on 0.64 mmol scale. 0.5 M THF.
c
d
Isolated yield. 1a not detected; 2a remained unreacted with 9
e
detected by TLC only. Chloroxime 6a was added slowly over a period
of 1.5 h using a syringe pump. TBAF was added dropwise over 1 h
using a syringe pump at 0 °C with 1.25 equiv of 2a.
f
5
7% yield (Table 1, entry 7).
The addition of tetrabutylammonium fluoride (TBAF,
.4 equiv) in THF at room temperature resulted in full consump-
3
Unfortunately, K CO , Et N, NH F, and CsF returned only
dimeric diphenyl furoxan (9) (Table 1, entries 1−4). However,
when the concentration of CsF was increased from 2.4 to
tion of both 2a and 6a within 10 min (TLC). The target
cycloadduct 1a was isolated in 61% yield (Table 1, entry 8) with
some dimeric 9 also detected ( H NMR, TLC). Using TBAF
2
3
3
4
1
4
1
3
.4 mol equiv, the target cycloadduct 1a was formed in 15% yield
as the preferred fluoride ion source, a systematic optimization
study was next performed by screening a range of solvents and
temperatures. Additionally, the effect of the relative ratios of the
substrates, molar equivalents of TBAF, and its rate of addition
were studied (see Supporting Information (SI), Table S1−S2).
(
Table 1, entry 5), although only in a modest yield. This
unprecedented transformation validated the cyclizative capture
pathway as a viable route to 1,2,4-oxadiazole-5-imines. When a
10b
1
:1 ratio of CsF:18-Crown-6 (3.4 equiv) was used, a marginal
B
DOI: 10.1021/acs.orglett.6b00203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Under optimal conditions [2a:6a (1.25:1)/THF/0 °C/dropwise
addition of TBAF (3 equiv) over 1 h] the product 1a was isolated
in 79% yield.
Scheme 4. Reductive Decarboxylation of 1,2,4-Oxadiazol-
5(4H)-one to Amidine
1
5
Both electron-rich and electron-poor N-hydroximoyl
chloride participated in the reaction to provide the cyclo-
adducts. The electron-rich 6c delivered 1c in 84% isolated
yield, whereas the electronically poor substrates 6d−6f gave
16
moderate-to-low yields (Scheme 2, 1d−f). The heterocyclic
substrate 6h yielded the cycloaddition product 1h in 54% yield
(
Scheme 2).
Computational studies were performed to determine the
reaction mechanism and understand the nature of the bonding
within the cyanamide ion (7). We employed density functional
Modification of the electronic properties of the cyanamide
substrate had a more dramatic effect on the reaction outcome;
an 89% yield was registered when the electron-deficient
N-(4-fluorophenyl)-N-(4-tolylsulfonyl)-cyanamide (2c) was
reacted with the N-hydroximoyl chloride 6a under optimized
conditions. Further, a combination of electron-poor cyanamide
22
theory calculations using the ωB97X functional, 6-31+G*
2
3
24
(
geometries), and 6-311++G** (energies) basis sets. The
structure and key bond lengths are shown in the Supporting
Information (see SI, Figures S1−S2). The cyanamide ion retains
2
2
c with electron-rich N-hydroximoyl chloride 6c offered the 1l
in an impressive 96% isolated yield (Scheme 2). A moderate yield
35%, 1m) was recorded for an aliphatic cyanamide (2d) under
the triple bond to the terminal nitrogen (−CN ), while fitting
partial atomic charges to the electrostatic potential reveals that
1
(
the negative charge is localized on this nitrogen atom (N ).
the optimized conditions.
The reaction was found to proceed via the stepwise cyclization
pathway, while no transition state could be located for the
concerted mechanism (Scheme 1C). The reaction profile is
shown in Scheme 5, and the structures are displayed in Figure S3
The conversion of 1 into 1,2,4-oxadiazol-5-one (4) was next
17
investigated. These structures are important pharmacophores,
as demonstrated by the angiotensin II receptor antagonist
azilsartan medoxomil (Figure 1). Common approaches to
18
oxadiazolones like 4 are tedious and unreliable and often include
1
9
Scheme 5. Reaction Energy Profile Calculated Using
DFT with an Implicit Solvent (ωB97X/6-311++G**
with PCM)
multiple steps. Gratifyingly, treatment of the imine product 1a
with concd. HCl furnished the hydrolysis product 4a in an
20
excellent 95% yield (Scheme 3). The procedure was tolerant of
Scheme 3. Hydrolysis of 1,2,4-Oxadiazol-5(4H)-imines to
a
1,2,4-Oxadiazol-5-(4H)-one
(
see SI). The cyclization step reveals a low barrier from the
intermediate (8) to the product. Interestingly, the product shows
a large degree of solvent stabilization relative to the free molecule
in vacuo (cf. Figure S1, SI).
a
Isolated yields.
a number of differently substituted imine analogues, as illustrated
in Scheme 3. The atom connectivity of 4a and, in turn, that of 1a
were corroborated through single crystal X-ray crystallography
The new methodology described offers a unique and
convergent entry to 1,2,4-oxadiazol-5(4H)-imines, which we
hope will revitalize interest in this overlooked functional group.
Furthermore, the conversion of the 1,2,4-oxadiazol-5(4H)-imines
into the pharmacologically significant 1,2,4-oxadiazol-5-ones
and amidines can be readily achieved, thereby offering further
opportunity for lead discovery.
(
Scheme 3).
The reduction of the oxadiazolone 4a over Pd−C/H further
2
gave the amidine product 5a in an excellent yield, with no further
21
purification required (Scheme 4).
C
DOI: 10.1021/acs.orglett.6b00203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Blacklock, T. J. Tetrahedron Lett. 2006, 47, 6425−6427. For the fluoride
ion, see: Yasuhara, A.; Kameda, M.; Sakamoto, T. Chem. Pharm. Bull.
ASSOCIATED CONTENT
Supporting Information
■
*
S
1
999, 47, 809−812.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00203.
(13) N-Sulfonyl cyanamides are solid, shelf stable compounds.
Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2011,
5
(
(
0, 519−522.
14) (a) Gasco, A.; Boulton, A. J. Adv. Heterocycl. Chem. 1981, 29, 251.
b) Chiang, Y. H. J. Org. Chem. 1971, 36, 2146−2155. (c) Wiley, R. H.;
Wakefield, B. J. J. Org. Chem. 1960, 25, 546−551.
15) The corresponding N-phenyl cyanamide (PhNHCN) also
Experimental details including characterization data,
spectra for all newly synthesized compounds (PDF)
X-ray data for compound 4a (CIF)
(
AUTHOR INFORMATION
Corresponding Authors
participated in the cyclization reaction with nitrile oxide in the presence
of a fluoride ion, albeit in lower yield and with a longer reaction time (see
Supporting Information).
■
*
*
E-mail: psharma@lincoln.ac.uk.
E-mail: john.moses@nottingham.ac.uk.
Notes
(16) Electron-withdrawing groups are known to stabilize nitrile oxides
thus making them more reluctant to cyclize; see: Wakefield, B. J.;
Wright, D. J. J. Chem. Soc. C 1970, 1165−1168.
(
17) (a) Stefanie, K.; Wolfgang, W.; Maike, G.; Jochen, G.; Karen, C.;
Daniel, M.; Jean, M.; Patrick, B.; Baptiste, R.; Corinne, T. EP1586573
A1), 2005. (b) Rehse, K.; Brehme, F. Arch. Pharm. 1998, 331, 375−
379.
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
(
18) (a) Perry, C. M. Clin. Drug Invest. 2012, 32, 621−639. (b) Zaiken,
The authors would like to thank Dr. Alexandra Gower,
University of Nottingham for X-ray crystallography. P.S. would
like to thank the School of Life Sciences and School of
Chemistry, University of Lincoln for financial support and award
of a studentship to S.B. D.R. thanks the University of
Nottingham for provision of time on the Minerva High
Performance Computing cluster. The authors would also like
to thank Prof. K. Barry Sharpless and Dr. Hua-Li Qin, The
Scripps Research Institute, California for constructive feedback
on the manuscript.
K.; Cheng, J. W. M. Clin. Ther. 2011, 33, 1577−1589. (c) Baker, W. L.;
White, W. B. Ann. Pharmacother. 2011, 45, 1506−1515.
(
19) (a) Kara, Y. S. Spectrochim. Acta, Part A 2015, 149, 920−927.
(
b) Gerfaud, T.; Wei, H.-L.; Neuville, L.; Zhu, J. Org. Lett. 2011, 13,
6
172−6175. (c) Grundmann, C.; Frommeld, H.-D.; Flory, K.; Datta, S.
K. J. Org. Chem. 1968, 33, 1464−1466.
(20) Huisgen, R.; Wulff, J. Chem. Ber. 1969, 102, 1848−1858.
(21) Bolton, R. E.; Coote, S. J.; Finch, H.; Lowdon, A.; Pegg, N.;
Vinader, M. V. Tetrahedron Lett. 1995, 36, 4471−4474.
(
(
22) Chai, J.-D.; Head-Gordon, M. J. Chem. Phys. 2008, 128, 084106.
23) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta. 1973, 28, 213−
2
22.
REFERENCES
■
(24) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys.
(
1) (a) Walsh, C. Tetrahedron Lett. 2015, 56, 3075−3081.
b) Gomtsyan, A. Chem. Heterocycl. Compd. 2012, 48, 7−10. (c) Li, J.
1
980, 72, 650−654.
(
J. Heterocyclic Chemistry in Drug Discovery; John Wiley & Sons, Inc.:
013; pp 1−647. (d) Jordan, A. M.; Roughley, S. D. Drug Discovery
Today 2009, 14, 731−744.
2) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
0257−10274.
3) Marcel, J.; Anon-Samuel, D.; Sterne, J.-J. 1965, Patent No.
GB1010231A.
4) (a) Tremoli, E.; Maderna, P.; Cocuzza, E.; Mantero, O. Pharmacol.
2
(
1
(
(
Res. Commun. 1979, 11, 31−38. (b) Junien, J.; Lakatos, C. Arch. Int.
Pharmacodyn. Ther. 1975, 217, 140−151.
(
5) (a) Garapon, J.; Sillion, B. Bulletin de la Societe Chimique de France
1
1
1
975, 2671−2676. (b) Grundmann, C.; Richter, R. Tetrahedron Lett.
968, 9, 963−966. (c) Partridge, M. W.; Turner, H. A. J. Chem. Soc.
958, 2086−2091.
(
6) The chemistry of cyanamides has a rich history, being employed
widely in the chemical and pharmaceutical industries: (a) Larraufie, M.-
H.; Maestri, G.; Malacria, M.; Ollivier, C.; Fensterbank, L.; Lacote, E.
Synthesis 2012, 44, 1279−1292. (b) Nekrasov, D. D. Russ. J. Org. Chem.
004, 40, 1387−1402.
7) A similar cycloadduct of nitrile oxide with potassium thiocyanate
̂
2
(
has been previously demonstrated; see: Hussein, A. Q.; El-Abadelah, M.
M.; Sabri, W. S. J. Heterocycl. Chem. 1983, 20, 301−304.
(
(
8) Rao, B.; Zeng, X. Org. Lett. 2014, 16, 314−317.
9) (a) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339−
5342. (b) Grundmann, C.; Datta, S. K. J. Org. Chem. 1969, 34, 2016−
2018.
(
10) (a) Spiteri, C.; Sharma, P.; Zhang, F.; Macdonald, S. J. F.; Keeling,
S.; Moses, J. E. Chem. Commun. 2010, 46, 1272−1274. (b) Spiteri, C.;
Keeling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368−3371.
(
11) Spiteri, C.; Mason, C.; Zhang, F.; Ritson, D. J.; Sharma, P.;
Keeling, S.; Moses, J. E. Org. Biomol. Chem. 2010, 8, 2537−2542.
12) This was supported by reports on the detosylation of related N-
sulfonyl amines, which had been accomplished with a base or fluoride
ion. For the base, see: Bajwa, J. S.; Chen, G.-P.; Prasad, K.; Repic, O.;
(
̌
D
DOI: 10.1021/acs.orglett.6b00203
Org. Lett. XXXX, XXX, XXX−XXX