Mild Synthesis of Substituted 1,2,5-Oxadiazoles Using 1,1′-Carbonyldiimidazole as a Dehydrating Agent

Article abstract of DOI:10.1021/acs.orglett.8b00568

1,1′-Carbonyldiimidazole was found to induce the formation of a variety of 3,4-disubstituted 1,2,5-oxadiazoles (furazans) from the corresponding bisoximes at ambient temperature. This method enables these inherently energetic compounds to be prepared at t

Full text of DOI:10.1021/acs.orglett.8b00568

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mild Synthesis of Substituted 1,2,5-Oxadiazoles Using
1,1′-Carbonyldiimidazole as a Dehydrating Agent
Andrew J. Neel* and Ralph Zhao
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: 1,1′-Carbonyldiimidazole was found to induce the formation of a variety of 3,4-disubstituted 1,2,5-oxadiazoles
(furazans) from the corresponding bisoximes at ambient temperature. This method enables these inherently energetic com-
pounds to be prepared at temperatures well below their decomposition points and with improved functional group com-
patibility relative to prior methods. Conditions were developed that allowed for the first high-yielding synthesis of chlorofurazans
from their amino counterparts, enabling the mild synthetic manipulation of these heterocycles.
urazans (1,2,5-oxadiazoles, B, Figure 1) constitute an
important class of heterocycles that have found a myriad of
elsewhere in the molecule. Perhaps more importantly, the pres-
ence of two nitrogen−oxygen bonds contained within a cyclic
array confers considerable energetic properties to furazans, such
that they are being actively investigated as next-generation
explosives. Furthermore, the bisoxime precursors, which also
contain multiple nitrogen−oxygen bonds, are expected to be sim-
ilarly energetic (vide infra). These features represent significant
drawbacks to the preparation of furazan-containing molecules
on both laboratory and production scales with respect to manu-
facturing, handling, and shipping.
F
For these reasons, we sought to develop a method for the
synthesis of furazans from the corresponding bisoximes that
would proceed under mild conditions, minimizing the afore-
mentioned safety and functional group compatibility concerns.
Specifically, we hypothesized that a systematic survey might
identify a dehydrating reagent capable of significantly lowering
the barrier to cyclization upon adduct formation with a bisoxime
(C, Figure 1). Table 1 shows the results of a series of experi-
ments, in which bisoxime 1a was subjected to various potential
dehydrating reagents at 25 °C for 2 h. Although 1a was con-
sumed to some extent in all cases, the corresponding yields of
furazan 2a were typically poor, presumably due to stalling at the
stage of adduct formation. Strikingly, however, 1,1′-carbon-
yldiimidazole (CDI) was found to effect the desired transfor-
mation in nearly quantitative yield (Table 1, entry 6). Subse-
quent experimentation demonstrated that this reactivity was
general across a range of non-nucleophilic (and thus unreactive
Figure 1. Cyclodehydration approach to furazan synthesis.
applications in organic chemistry,1 in areas as disparate as the pro-
duction of biologically active molecules2 and energetic materials.3
Although numerous methods for the preparation of furazans
have been disclosed, the most straightforward approach involves
the dehydrative cyclization of vicinal bisoximes (A, Figure 1).
To this end, a typical reaction entails refluxing the precursor in
a high-boiling solvent (100−150 °C) in the presence of a
strong base, such as NaOH or KOH, followed by direct precip-
itation of the product or extractive workup. Various activating
reagents, including Ac2O,4 SOCl2,5 succinic anhydride,2j,5f,6 and
others,2c,7 have been reported to facilitate this cyclization, but
temperatures greater than 100 °C are typically required.
Although this method has been the standard in furazan syn-
thesis for over a century,1 it possesses inherent liabilities. The
harsh conditions required preclude the presence of sensitive
functional groups, such as esters or base-sensitive stereocenters,
Received: February 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00568
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Letter
Table 1. Survey of Potential Dehydrating Reagents
a
b
b
entry
reagent
Ac2O
conversion (%)
yield (%)
1
100
36
74
71
65
100
18
94
60
64
18
0
2
2
SOCl2
POCl3
BzCl
3
34
12
38
93
0
4
5
TFAA
CDI
6
7
Tf2O
8
KOH
3
9
HATU
T3P
17
47
13
>99
10
11
Burgess reagent
CDI
c
12
100
b
a
Reactions conducted using 0.1 mmol 1a. Determined via UPLC
using area percent vs concentration calibration curves. Reaction
conducted in THF (0.25 M) with a 2 min reaction time.
c
with CDI) solvents, and that the reaction was complete instan-
taneously upon mixing of 1a and CDI (Table 1, entry 12).
Furthermore, it was found that furazan 2a could be formed
without any loss in yield from bisoxime 1a generated in situ by
the addition of hydroxylamine to cyano-oxime 3a, precluding
the requirement for isolation of this potentially hazardous inter-
mediate (vide infra). Notably, a reaction conducted on prepara-
tive scale (Scheme 1) was accompanied by a 19.7 °C increase in
Figure 2. Scope of tandem hydroxylamine addition/CDI-induced
cyclodehydration. aIsolated yields for reactions conducted on
b
1.0−1.5 mmol scale. Hydroxylamine addition conducted in MeOH.
substituents could be formed from the analogous cyano-oxime
precursors.
To highlight the functional group compatibility of this tech-
nique, cyano-oxime 3o containing both a benzyl ester and a labile
stereogenic center (>99% ee) underwent hydroxylamine addi-
tion and subsequent CDI-induced cyclization in 84% yield
without any detectable loss in enantiopurity (eq 1). Further-
more, methyl-ester-containing furazan 3p was formed in 72%
yield (eq 2). Neither of these results would be expected under
the standard furazan-forming conditions requiring hydroxide at
Scheme 1. Synthesis of Furazan 2a without Isolation of
Intermediate Bisoxime
temperature that was concomitant with evolution of CO2. This
latter feature is believed to provide the driving force for the
otherwise recalcitrant cyclization.
Figure 2 depicts a collection of additional substrates that
underwent CDI-induced furazan formation. To avoid isolation
of the intermediate bisoximes (1), we elected to generate them
in situ from the corresponding cyano-oximes 3, resulting in a
series of substituted aminofurazans (2). Substrates containing
both tertiary (3b−d) and secondary (3e−i) amides bearing
both alkyl (3i) and electronically diverse aryl (3a,e−h) substit-
uents underwent smooth cyclization via the action of CDI at
room temperature. In all cases, the reactions were judged to be
complete as quickly as they could be assayed. A ketone-bearing
cyano-oxime (3n) underwent the desired reaction, albeit with a
diminished yield (55%) due to the competitive condensation
with hydroxylamine prior to the addition of CDI. Additionally,
furazans containing both aryl (2j−l) and heteroaryl (2m)
increased temperature. Finally, bisaryl furazan 2q was formed in
56% yield upon heating with CDI in DMF at 80 °C (eq 3). Pre-
vious syntheses of related compounds have required heating of
the bisoxime precursor in neat succinic anhydride at 180 °C.2j
To demonstrate the advantage of this method over the alter-
native thermal cyclodehydration from a safety perspective, the
energetic content of selected cyano-oximes (3a,j), bisoximes
B
DOI: 10.1021/acs.orglett.8b00568
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(1a,q), and furazans (2a,j,q) was characterized via differential
scanning calorimetry (DSC). As shown in Table 2, six of the
acidic solution of the corresponding aminofurazans (2) with
sodium nitrite in the presence of lithium chloride, with minimal
formation of the ring-opened byproducts (Figure 3c). Key to
the success of this reaction was minimization of water present
during diazotization. Notably, previous reports detailing amino-
furazan chlorination proceeded in less than 25% yield.2b,10
With these chlorofurazans (4) in hand, we demonstrated
their utility as substrates for nucleophilic aromatic substitution.
To this end, chlorofurazan 4a underwent smooth reaction with
both n-butanol (eq 4) and dodecanethiol (eq 5), affording good
yields of the corresponding furazans (5a and 6a) under mild
conditions. Although hydroxide itself was not a competent nucle-
ophile, it was found that hydroxide surrogate N-acetylhydroxamic
acid (7)11 afforded hydroxyfurazan 8a in good yield (eq 6).
This chlorination-displacement sequence represents the mildest
functionalization of aminofurazans reported to date.
Table 2. DSC Data for Selected Compounds
a
compound
type
exotherm (J/g)
tinit (°C)
3a
3j
cyano-oxime
cyano-oxime
bisoxime
bisoxime
furazan
1470
1448
1596
1414
1624
1679
705
166
151
129
209
248
234
243
1a
1q
2a
2j
furazan
2q
furazan
a
Standard run parameters for DSC: 5 °C/min up to 350 °C.
seven compounds tested displayed exothermic events of greater
than 1000 J/g, including the cyano-oxime precursors and
bisoxime intermediates. Merck internal process safety guidelines8
indicate that any compound displaying an exotherm greater
than 400 J/g upon DSC testing should be considered poten-
tially hazardous, not only from the standpoint of processing
(e.g., isolation, drying and handling) but also for transportation.
As all compounds listed in Table 2 fit this criterion, the ability
to conduct all manipulations more than 100 °C below their
decomposition points offers a clear advantage.
Finally, we demonstrated that the aminofurazans produced
by this method could be conveniently functionalized. The most
common approach involves oxidation of the amine to the corre-
sponding nitro group, followed by nucleophilic displacement
(Figure 3a).3i,9 Given the inherent safety concerns associated
In conclusion, it has been demonstrated that CDI enables the
cyclodehydration of bisoximes to the corresponding furazans at
temperatures more than 100 °C lower than typically required.
Based on this observation, a two-step protocol was developed
involving (1) hydroxylamine addition to readily prepared
cyano-oximes to afford the corresponding bisoximes in situ and
(2) CDI- induced cyclodehydration to form furazans. This
method was shown to be both more functional-group-tolerant
and safer than its thermal alternatives. Conditions were devel-
oped that allowed the aminofurazan products to be further
functionalized via a high-yielding chlorination-displacement
sequence. Given the aforementioned advantages, we believe
that this methodology will be rapidly adopted by the synthetic
community for the synthesis of furazan-containing molecules.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00568.
■
Figure 3. Aminofurazan derivatization: (a) derivatization via nitro
intermediate; (b) competitive cyano-oxime formation upon attempted
halogenation; (c) selected examples of aminofurazan chlorination.
aIsolated yields for reactions conducted on 1.0 mmol scale.
S
Full experimental details, characterization, and NMR
spectra for all new compounds (PDF)
with conversion of an energetic material to its nitro-containing
analogue, we sought to develop an alternative. Although nucle-
ophilic aromatic substitution on the corresponding halofurazan
would be preferable, this strategy has found limited use, prin-
cipally owing to the difficulty of forming the requisite halofurazans
due to competitive ring opening to the parent cyano-oximes
(Figure 3b).1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andrew.neel@merck.com.
ORCID
After considerable experimentation, we discovered that chloro-
furazans (4) could be obtained in good yields by treatment of an
Andrew J. Neel: 0000-0003-2872-5292
C
DOI: 10.1021/acs.orglett.8b00568
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Letter
T. T.; Satoh, J. Y.; Saitoh, K. J. Chem. Soc., Perkin Trans. 1 1990, 8,
2277.
(6) (a) Olofson, R. A.; Michelman, J. S. J. Am. Chem. Soc. 1964, 86,
1863. (b) Britsun, V. N.; Borisevich, A. N.; Samoilenko, L. S.;
Lozinskii, M. O. Russ. J. Org. Chem. 2005, 41, 745.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(7) (a) Ponzio, G. Gazz. Chim. Ital. 1932, 62, 860. (b) Nash, B. W.;
Newberry, R. A.; Pickles, R.; Warburton, W. K. J. Chem. Soc. C 1969, 0,
2794. (c) Ackrell, J.; Altaf-ur-Rahman, M.; Boulton, A. J.; Brown, R. C.
J. Chem. Soc., Perkin Trans. 1 1972, 12, 1587. (d) Nicolaides, D. N.;
Gallos, J. K. Synthesis 1981, 1981, 638. (e) Kamitori, Y. Heterocycles
1999, 51, 627. (f) Fylaktakidou, K. C.; Litinas, K. E.; Saragliadis, A.;
Adamopoulos, S. G.; Nicolaides, D. N. J. Heterocycl. Chem. 2006, 43,
579. (g) Winterwerber, M.; Geiger, R.; Otto, H.-H. Monatsh. Chem.
2006, 137, 1321. (h) Epishina, M. A.; Kulikov, A. S.; Makhova, N. N.
Russ. Chem. Bull. 2008, 57, 644. (i) Telvekar, V. N.; Takale, B. S. Synth.
Commun. 2013, 43, 221.
(8) Bassan, E.; Ruck, R. T.; Dienemann, E.; Emerson, K. M.;
Humphrey, G. R.; Raheem, I. T.; Tschaen, D. M.; Vickery, T. P.;
Wood, H. B.; Yasuda, N. Org. Process Res. Dev. 2013, 17, 1611.
(9) Stepanov, A. I.; Sannikov, V. S.; Dashko, D. V.; Roslyakov, A. G.;
Astrat’ev, A. A.; Stepanova, E. V. Chem. Heterocycl. Compd. 2015, 51,
350.
The authors gratefully acknowledge Greg Hughes, Tamas
Benkovics, and Ben Sherry (Merck) for assistance in manu-
script preparation, Joshua Bade (Merck) for assistance with
DSC measurements, and Patrick Fier (Merck) for donation of
reagent 7.
REFERENCES
■
(1) For comprehensive reviews, see: (a) Sheremetev, A. B.; Makhova,
N. N.; Friedrichsen, W. Adv. Heterocycl. Chem. 2001, 78, 65.
(b) Romeo, G.; Chiacchio, U. Modern Heterocyclic Chemistry 2011,
2, 1047. (c) Fershtat, L.; Makhova, N. Russ. Chem. Rev. 2016, 85, 1097.
(2) For selected examples, see: (a) Takabatake, T.; Hasegawa, M.;
Nagano, T.; Hirobe, M. Chem. Pharm. Bull. 1992, 40, 1644.
(b) Sauerberg, P.; Olesen, P. H.; Nielsen, S.; Treppendahl, S.;
Sheardown, M. J.; Honore, T.; Mitch, C. H.; Ward, J. S.; Pike, A. J. J.
Med. Chem. 1992, 35, 2274. (c) Tron, G. C.; Pagliai, F.; Del Grosso,
E.; Genazzani, A. A.; Sorba, G. J. Med. Chem. 2005, 48, 3260. (d) Lolli,
M. L.; Hansen, S. L.; Rolando, B.; Nielsen, B.; Wellendorph, P.;
Madsen, K.; Larsen, O. M.; Kristiansen, U.; Fruttero, R.; Gasco, A.;
Johansen, T. N. J. Med. Chem. 2006, 49, 4442. (e) Stavenger, R. A.;
Cui, H.; Dowdell, S. E.; Franz, R. G.; Gaitanopoulos, D. E.; Goodman,
K. B.; Hilfiker, M. A.; Ivy, R. L.; Leber, J. D.; Marino, J. P.; Oh, H.-J.;
Viet, A. Q.; Xu, W.; Ye, G.; Zhang, D.; Zhao, Y.; Jolivette, L. J.; Head,
M. S.; Semus, S. F.; Elkins, P. A.; Kirkpatrick, R. B.; Dul, E.;
Khandekar, S. S.; Yi, T.; Jung, D. K.; Wright, L. L.; Smith, G. K.; Behm,
D. J.; Doe, C. P.; Bentley, R.; Chen, Z.-X.; Hu, E.; Lee, D. J. Med.
Chem. 2007, 50, 2. (f) Guo, S.; Song, Y.; Huang, Q.; Yuan, H.; Wan,
B.; Wang, Y.; He, R.; Beconi, M. G.; Franzblau, S. G.; Kozikowski, A.
P. J. Med. Chem. 2010, 53, 649. (g) Giorgis, M.; Lolli, M. L.; Rolando,
B.; Rao, A.; Tosco, P.; Chaurasia, S.; Marabello, D.; Fruttero, R.;
Gasco, A. Eur. J. Med. Chem. 2011, 46, 383. (h) Huang, X.; Gillies, R.
J.; Tian, H. J. Labelled Compd. Radiopharm. 2015, 58, 156. (i) Stepanov,
A. I.; Astrat’ev, A. A.; Sheremetev, A. B.; Lagutina, N. K.; Palysaeva, N.
V.; Tyurin, A. Y.; Aleksandrova, N. S.; Sadchikova, N. P.; Suponitsky,
K. Y.; Atamanenko, O. P.; Konyushkin, L. D.; Semenov, R. V.; Firgang,
S. I.; Kiselyov, A. S.; Semenova, M. N.; Semenov, V. V. Eur. J. Med.
Chem. 2015, 94, 237. (j) Pal, P.; Gandhi, H. P.; Kanhed, A. M.; Patel,
N. R.; Mankadia, N. N.; Baldha, S. N.; Barmade, M. A.; Murumkar, P.
R.; Yadav, M. R. Eur. J. Med. Chem. 2017, 130, 107.
(10) Conole, D.; Beck, T. M.; Jay-Smith, M.; Tingle, M. D.; Eason, C.
T.; Brimble, M. A.; Rennison, D. Bioorg. Med. Chem. 2014, 22, 2220.
(11) Fier, P. S.; Maloney, K. M. Org. Lett. 2016, 18, 2244.
(3) For selected examples, see: (a) Zelenin, A. K.; Trudell, M. L.;
Gilardi, R. D. J. Heterocycl. Chem. 1998, 35, 151. (b) Veauthier, J. M.;
Chavez, D. E.; Tappan, B. C.; Parrish, D. A. J. Energ. Mater. 2010, 28,
229. (c) Martinez, H.; Zheng, Z.; Dolbier, W. R. J. Fluorine Chem.
2012, 143, 112. (d) Zhang, J.; Shreeve, J. M. J. Am. Chem. Soc. 2014,
136, 4437. (e) Wei, H.; He, C.; Zhang, J.; Shreeve, J. M. Angew. Chem.,
Int. Ed. 2015, 54, 9367. (f) Zhang, J.; Mitchell, L. A.; Parrish, D. A.;
Shreeve, J. M. J. Am. Chem. Soc. 2015, 137, 10532. (g) Zhai, L.; Wang,
B.; Xu, K.; Huo, H.; Liu, N.; Li, Y.; Li, H.; Lian, P.; Fan, X. J. Energ.
Mater. 2016, 34, 92. (h) Lempert, D. B.; Sheremetev, A. B. Chem.
Heterocycl. Compd. 2016, 52, 1070. (i) Pagoria, P. F.; Zhang, M.-X.;
Zuckerman, N. B.; DeHope, A. J.; Parrish, D. A. Chem. Heterocycl.
Compd. 2017, 53, 760.
(4) (a) Shaposhnikov, S. D.; Pirogov, S. V.; Mel’nikova, S. F.;
Tselinsky, I. V.; Nather, C.; Graening, T.; Traulsen, T.; Friedrichsen,
̈
W. Tetrahedron 2003, 59, 1059. (b) Samsonov, V. A.; Sal’nikov, G. E.;
Genayev, A. M. Russ. Chem. Bull. 2009, 58, 2369.
(5) (a) Tokura, N.; Tada, R.; Yokoyama, K. Bull. Chem. Soc. Jpn.
1961, 34, 270. (b) Tokura, N.; Shirai, I.; Sugahara, T. Bull. Chem. Soc.
Jpn. 1962, 35, 722. (c) Ohta, G.; Takegoshi, T.; Ueno, K.; Shimizu, M.
Chem. Pharm. Bull. 1965, 13, 1445. (d) Boulton, A. J.; Mathur, S. S. J.
Org. Chem. 1973, 38, 1054. (e) Pollet, P.; Gelin, S. Synthesis 1979,
1979, 977. (f) Zelenov, M. P.; Frolova, G. M.; Mel’nikova, S. F.;
Tselinskii, I. V. Chem. Heterocycl. Compd. 1982, 18, 21. (g) Takahashi,
D
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