Tandem Condensation/Rearrangement Reaction of 2-Aminohetarene N-Oxides for the Synthesis of Hetaryl Carbamates

Article abstract of DOI:10.1002/adsc.201800407

A new approach to hetaryl carbamates through a tandem condensation/rearrangement reaction of 2-aminohetarene N-oxides was developed. The developed reaction is suitable for both five- and six-membered heterocycles and proceeds through the condensation of 2

Full text of DOI:10.1002/adsc.201800407

Title: Tandem Condensation/Rearrangement Reaction of 2-
Aminohetarene N-Oxides for the Synthesis of Hetaryl
Carbamates
Authors: Dmitry Bystrov, Egor Zhilin, Leonid Fershtat, Anna
Romanova, Ivan Ananyev, and Nina Makhova
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10.1002/adsc.201800407
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Tandem Condensation/Rearrangement Reaction of 2-
Aminohetarene N-Oxides for the Synthesis of Hetaryl
Carbamates
Dmitry M. Bystrov,a,b Egor S. Zhilin,a,b Leonid L. Fershtat,a Anna A. Romanova,c,d Ivan
V. Ananyev,c and Nina N. Makhovaa,*
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation,
Fax: +7 499 135 5328. E-mail: mnn@ioc.ac.ru
Department of Chemistry, Moscow State University, 119991 Moscow, Leninskie Gory 1-3, Russian Federation
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova str., 119991
b
c
Moscow, Russian Federation.
D. Mendeleev University of Chemical Technology of Russia, Higher Chemical College, Miusskaya sq. 9, 125047
d
Moscow, Russian Federation
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A new approach to hetaryl carbamates through a intramolecular rearrangement is catalyzed by a cyanide
tandem condensation/rearrangement reaction of 2- anion, while for six-membered hetarene N-oxides (azines),
aminohetarene N-oxides was developed. The developed Lewis acid catalysis is sufficient. The developed protocol is
reaction is suitable for both five- and six-membered characterized by operational simplicity and high efficiency,
heterocycles and proceeds through the condensation of 2- resulting in carbamoyl derivatives in good and high yields.
aminohetarene N-oxide with trimethyl orthoformate
followed by intramolecular N-oxide oxygen transfer. For
five-membered hetarene N-oxides (furoxans), the
Keywords: heterocycles; furoxan; pyridine; rearrangement;
N-oxide oxygen transfer
addition, an example of an asymmetric Boekelheide
reaction has been reported.[11] However, in most cases
Boekelheide rearrangements suffer from a poor
substrate scope since it can be applied mainly to
azines.
Introduction
Hetarene N-oxides make up a versatile class of
organic compounds that are of great interest in a wide
range of applications including medicine, agriculture,
and materials science.[1] In addition, 5- and 6-
membered heterocyclic N-oxides are of special
interest as useful precursors in the target-oriented
synthesis of complex molecular systems.[2] Pyridines
and their N-oxides arguably belong to the most
explored heteroarenes in modern synthetic
chemistry.[3] However, chemo- and regioselective
functionalization of this heterocyclic motif remains
challenging. In 1954,[4] Boekelheide reported an
approach to 2-hydroxymethylpyridine derivatives
from 2-methylpyridine N-oxide. The Boekelheide
reaction is the result of a formal N-oxide oxygen
transfer onto an alkyl group in the α-position of a
pyridine ring;[5] however, this transfer may not be
strictly intramolecular.[5j] Moreover, in most cases,
this approach requires the pyridine N-oxide to be
activated with a strong electrophile such as Ac2O,[4,6]
TFAA[7] or TsCl[8] (Scheme 1A). Recently, a
Boekelheide rearrangement was used as a key step in
the synthesis of cycloalkylaminopyridines[9] and in
the benzylic acyloxylation of 2-alkylazines.[10] In
In contrast with azine N-oxides, intramolecular N-
oxide oxygen transfers in azole N-oxides with
retention of the heterocyclic core are far less explored.
The limited number of such reactions is attributable
to the laborious synthesis of the corresponding N-
oxides, which usually involves ring formation
through a substrate-specific cyclization.[12] In addition,
the nucleophilicity of the N-oxide oxygen in 5-
membered hetarenes is significantly lower than those
in 6-membered rings; therefore, methods for the
rearrangement of azine N-oxides via N-oxide
activation are not directly applicable to azole N-
oxides.
Our ongoing scientific interests are concerned with
the synthesis and utilization of 1,2,5-oxadiazole 2-
oxides (furoxans).[13] Recently, we developed
efficient methods for the preparation of a variety of
hetarylfuroxans in which the furoxan ring is linked to
various pharmacophoric heterocycles via a C-C
bond.[14] However, to the best of our knowledge, there
are no examples of intramolecular N-oxide oxygen
1
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10.1002/adsc.201800407
Advanced Synthesis & Catalysis
transfers to a carbon atom of the substituent in a
furoxan system.
TMSCN in the presence of different fluorides (NH4F,
KF, CsF, TBAF) as additives (entries 10-13), and
NH4F was found to be the most effective (entry 10).
The reaction was also found to be catalyzed by KCN
as a cyanide anion source (entry 14), and the best
yield of carbamate 3a was attained with 50 mol % of
KCN (entry 15). Utilization of phase transfer
catalysts (entries 16 and 17) as well as different
solvents (entries 17-20) were less effective, while an
increase in the loading of KCN decreased the yield
(entries 21 and 22).
Here,
we
report
a
new,
tandem
condensation/rearrangement reaction of 5- and 6-
membered 2-aminohetarene N-oxides into hetaryl
carbamates via an intramolecular N-oxide oxygen
transfer (Scheme 1B). The preliminary synthesis of
furoxanyl α-imino ethers was necessary to perform
the rearrangement, while 2-aminoazine N-oxides
underwent the tandem reaction in a one-pot manner
to form hetaryl carbamates. Carbamates play
important roles as protecting groups for amines and
alcohols[15] and as intermediates in organic
synthesis.[16] In addition, carbamates are present as
subunits of biologically active compounds in
pharmaceuticals and agrochemicals.[17]
Table 1. Optimization of the reaction conditions.[a]
Entry cat.
additive
T
Solv.
yield 3a
(mol %)
(mol %) (°C)
(%)[b]
.
1
2
3
4
5
6
7
BF3 Et2O
(20)
BF3 Et2O
(20)
BF3 Et2O
(20)
BF3 Et2O
(100)
Sc(OTf)3
(5)
Y(OTf)3
(5)
Yb(OTf)3
(5)
[c]
-
-
-
-
-
-
20
20
40
40
20
20
CHCl3
MeCN
MeCN
MeCN
MeCN
MeCN
-
.
[c]
-
.
[c]
-
.
[d]
-
[c]
-
[c]
-
[d]
-
-
-
20
20
20
MeCN
MeCN
MeCN
-
Scheme 1. Methods for an intramolecular N-oxide oxygen
transfer.
[c]
8
9
GaCl3 (5)
NH4Cl
(100)
-
[c]
-
10
11
12
13
TMSCN
(100)
TMSCN
(100)
TMSCN
(100)
TMSCN
(100)
NH4F
(100)
KF
(100)
CsF
(100)
TBAF
(100)
-
Results and Discussion
20
20
20
20
MeCN 42
MeCN 36
MeCN 21
MeCN 23
To study the possibility of an intramolecular N-oxide
oxygen transfer in furoxan systems, 3-amino-4-
phenylfuroxan (1a) was converted into the
corresponding imino ether (2a) through a Lewis acid-
catalyzed condensation with trimethyl orthoformate.
Compound 2a was used for further investigations to
explore the optimal conditions for this rearrangement.
A number of Lewis acids, either in catalytic or
stoichiometric amounts, in different solvents at 20-
40 °C were found to be ineffective (Table 1, entries
1-9). This fact can be attributed to the very low
nucleophilicity of the N-oxide oxygen because of the
strong electron-withdrawing effect of the furoxan
ring. Therefore, we assumed that the addition of a
nucleophile that could exert an electron-withdrawing
effect on the C=N bond of the imino ether
functionality might facilitate the intramolecular N-
oxide oxygen transfer. It is known that cyanide anion
is a reactive nucleophile that adds to imine motifs in
o-aminophenolic Schiff bases, facilitating an
intramolecular cyclization.[18] Taking this into
account, we managed to perform the transformation
of furoxanyl imino ether 2a into furazanyl carbamate
3a under the action of an equimolar amount of
14
15
16
KCN (20)
KCN (50)
20
20
MeCN 33
MeCN 70
-
18-
KCN (20) crown-6 20
MeCN 35
(5)
TEBAC
(20)
-
17
18
EtOAc
-H2O
[c]
KCN (50)
KCN (50)
20
20
-
MeCN
-IL[e]
(1:1)
DMF
13
21
19
20
21
KCN (50)
KCN (50)
KCN
(100)
KCN
-
-
20
20
DMSO 15
-
-
20
20
MeCN 55
22
MeCN 57
(150)
[a]
Reaction conditions: 1a (1 mmol), catalyst, additive,
solvent (2 mL), 12 h. Isolated yields. [c] No reaction.
[b]
[d]
2
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10.1002/adsc.201800407
Advanced Synthesis & Catalysis
[e]
Partial decomposition of 1a was observed.
IL was
[bmim]BF4.
To investigate the substrate scope for the synthesis
of furazanyl carbamates 3, we synthesized a series of
initial 3-aminofuroxans 1b-j (for detailed synthetic
procedures, see the SI), which were transformed into
corresponding imino ethers 2b-j in high yields under
the conditions used for the synthesis of imino ether
2a (Scheme 2).
Scheme 3. Substrate scope for the synthesis of furazanyl
carbamates 3a-j. Reaction conditions: imino ether 2 (1.0
mmol), KCN (0.5 mmol), MeCN (3 mL), 10-14 h, 20 °C.
Isolated yields.
To extend the developed rearrangement to 6-
membered heterocyclic N-oxides, a series of 2-
aminopyridine N-oxides 4 were synthesized by the
Scheme 2. Substrate scope for the synthesis of furoxanyl
imino ethers 2b-j. Reaction conditions: aminofuroxan 1
(2.0 mmol), trimethyl orthoformate (5 mL), Sc(OTf)3 (0.1
mmol), 12 h, 20 °C. Isolated yields.
oxidation
of
commercially
available
2-
aminopyridines under the action of mCPBA.[20a]
Attempts to prepare corresponding imino ether 5a
through the condensation of N-oxide 4a with
.
trimethyl orthoformate in the presence of BF3 Et2O or
With the optimized conditions and the wide variety
of imino ethers 2b-j in hand, we investigated the
substrate scope for the synthesis of furazanyl
carbamates 3. It was found that all target furazans 3a-
j[19] were formed in good to high yields under very
mild conditions at 20 °C using 50 mol % of KCN.
Imino ethers 2b-d, bearing an electron-withdrawing
NO2 group on their aromatic ring, rearranged faster
(in 10 h) than other imino ethers (in 14 h).
Interestingly, the reaction also occurred with 6-
nitropiperonyl-substituted imino ether 2i, which
contains both electron-donating (1,3-dioxolane ring)
and electron-withdrawing (NO2) groups. In addition,
the reaction was accomplished with imino ether 2j,
which contains a hetaryl substituent (Scheme 3).
Sc(OTf)3 at 20 °C failed. Sc(OTf)3 was also
ineffective at elevated temperatures (40-100 °C) since
significant decomposition of starting material was
observed. However, refluxing N-oxide 4a with
.
trimethyl orthoformate in the presence of BF3 Et2O
directly afforded pyridyl carbamate 6a in a good
yield. Other 2-aminopyridine N-oxides, including
halogen-substituted pyridines 4b and 4c and isomeric
picolines 4d-f,[21] successfully underwent the tandem
condensation/rearrangement
protocol.
Polyfunctionalized 2-aminopyridine N-oxides 4g-i
were also transformed into the corresponding
carbamates in good yields (Scheme 4). In addition,
we performed the regioselective oxidation of 4-
amino-6-chloropyrimidine to corresponding 2-
aminopyrimidine N-oxide 4j (for detailed synthetic
procedure, see the SI).[22] Substrate 4j was also used
in the tandem condensation/rearrangement protocol to
afford target carbamate 6j; however, a low yield was
obtained.
3
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10.1002/adsc.201800407
Advanced Synthesis & Catalysis
derivatives constitute a prospective family of STAT3
inhibitors active against various cancer cell lines.[23,25]
In this furazan series, ureidofurazan 7 has been
proven to be one of the most effective compounds
with 36% STAT3 inhibitory activity.[23] To our
delight, we successfully prepared inhibitor 7 in high
yield directly from furazanyl carbamate 3a (Scheme
6).
Scheme 6. Application in the synthesis of STAT3 inhibitor
7.
To elucidate the reaction mechanism, several
control experiments were performed (Scheme 7). No
reaction occurred with furoxanyl-4-imino ether 2a’
under the standard conditions (Scheme 7a). 3-
Carbamoylpyridine was not generated from the 3-
aminopyridine N-oxide under the action of trimethyl
.
Scheme 4. Substrate scope for the synthesis of azine
carbamates 6a-j. Reaction conditions: 2-aminoazine N-
oxide (1.0 mmol), trimethyl orthoformate (5 mL), BF3 Et2O
orthoformate in the presence of BF3 Et2O (Scheme
7b). We also performed a competition crossover
.
(0.2 mmol), 4 h, reflux. Isolated yields.
To show the potential applications of our method,
we performed the reactions with furoxanyl imino
ether 2a and with multisubstituted aminopyridine N-
oxide 4i on a gram scale under the standard reaction
conditions. To our delight, the reactions proceeded
smoothly in both cases to afford furazan 3a and
pyridine 6i in good yields (Scheme 5).
Scheme 5. Larger scale synthesis.
Moreover, we demonstrated the synthetic utility of
our novel method for the synthesis of signal
transducer and activator of transcription 3 (STAT3)
inhibitor 7.[23] STAT3 activation is involved in many
types of carcinogenesis, making this protein a leading
target for cancer therapy.[24] Ureidofurazan
Scheme 7. Control experiments.
4
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10.1002/adsc.201800407
Advanced Synthesis & Catalysis
experiment between furoxans 2a and 2d, which
provided two major insights. First, substrate 2d,
bearing an electron-withdrawing NO2-group on the
benzene ring, rearranged faster than 2a under the
standard conditions. Second, possible intermolecular
reaction products, carbamoylfuroxans 3a’ and 3d’,
were not formed under these conditions (Scheme 7c).
In addition, we performed a reaction of furoxanyl
imino ether 2b with KCN in presence of 1 equiv. of
oxides are ambident nucleophiles, which are prone to
prototropic tautomerism between the amino group
and N-oxide functionality with tautomer 4’ being
favored.[29] In general, the condensation of the
substrate may occur either at the amino group (path
a) or the tautomeric N-hydroxy motif (path b).
However, path a seems unlikely since it involves the
formation of unstable imino ether 5 with its
subsequent 5-endo-trig cyclization, which is
disfavored according to Baldwin’s rules.[28a] In
contrast, path b includes the condensation of N-
hydroxy tautomer 4’ with trimethyl orthoformate
followed by the Lewis acid-catalyzed 5-exo-tet
cyclization of intermediate 10 to form bicyclic
structure 11. The thermal cleavage of the 1,2,4-
oxadiazoline ring in intermediate 12 furnishes final
pyridyl carbamate 6 (Scheme 8b). The thermal
degradation of the annulated 2,5-dihydro-1,2,4-
oxadiazole ring also has literature precedent.[27a,c] It
should be noted that the mechanisms for both 5- and
6-membered hetarene N-oxides involve the
intermediate formation of an annulated 2,5-dihydro-
1,2,4-oxadiazole framework; thus, unifying the
developed method of intramolecular N-oxide oxygen
transfer for azoles and azines.
18
H2 O (Scheme 7d). However, no 18O-labeled
furazanyl carbamate was detected according to the
mass spectral data (see the SI). These results strongly
suggested that the carbonyl oxygen in the final
carbamate is from the N-oxide oxygen transfer
(internal source), and the reaction was an
intramolecular rearrangement process. Since 2-
aminoazine N-oxides 4 underwent the tandem
condensation/rearrangement protocol in a one-pot
manner, we tried to isolate intermediate pyridine N-
oxide α–imino ether 5a; however, attempts to oxidize
the pyridine nitrogen of imino ether 5’a[26] with
different oxidants (mCPBA, 50% H2O2 or DMDO)
did not provide expected product 5a even under very
mild conditions and only resulted in the
decomposition of initial compound 5’a (Scheme 7e).
Based on the existing literature[18,27] and relying on
the reaction scope and control experiments, we
proposed a plausible mechanism for this hetarene N-
oxide rearrangement. In the case of furoxans, the first
step includes the nucleophilic addition of the cyanide
anion to the C(sp2) atom of the imino ether
functionality. After protonation, intermediate 8’
undergoes an intramolecular cyclization into bicyclic
structure 9 with elimination of the cyanide anion.
This cyclization is consistent with Baldwin’s rules (5-
exo-tet) for this type of reaction.[28] The subsequent
base-promoted 1,2,4-oxadiazoline ring cleavage
affords target furazanyl carbamate 3 (Scheme 8a).
The degradation of annulated 2,5-dihydro-1,2,4-
oxadiazole ring under the action of bases is a known
process, which proceeds under mild conditions.[27a,b]
In the case of 2-aminoazines, the reaction
mechanism is slightly different. 2-Aminoazine N-
Conclusion
In conclusion, we report
condensation/rearrangement
a
new tandem
protocol for the
synthesis of various hetaryl carbamates via
intramolecular N-oxide oxygen transfer. For five-
membered hetarene N-oxides (furoxans), this
rearrangement is catalyzed by cyanide anion, while
for six-membered hetarene N-oxides (azines), Lewis
acid catalysis is sufficient. The rearrangement of
furoxanyl derivatives requires the preliminary
synthesis of α-imino ethers, whereas 2-aminoazine N-
oxides undergo the condensation/rearrangement
sequence in a one-pot manner. In both cases, the
reaction is gram-scalable, proceeds under mild
Scheme 8. Plausible reaction mechanism.
5
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10.1002/adsc.201800407
Advanced Synthesis & Catalysis
conditions, and provides the target carbamates in
good to high yields. The synthetic utility of this
method was demonstrated by the synthesis of a
representative STAT3 inhibitor. The protocol
described in this work provides direct and effective
access to hetaryl carbamates, potentially enabling a
wider application of these derivatives in medicine and
related fields.
Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K.
Taylor), Elsevier, Oxford, 2008; pp. 41-99.
[4] V. Boekelheide, W. J. Linn, J. Am. Chem. Soc. 1954,
76, 1286-1291.
[5] a) G. Kobayashi, S. Furukawa, Pharm. Bull. 1953, 1,
347-349; b) S. Okuda, Pharm. Bull. 1955, 3, 316-318;
c) S. Furukawa, Yakugaku Zasshi 1959, 79, 492-499; d)
V. J. Traynelis, P. Pacini, J. Am. Chem. Soc. 1958, 80,
6590-6593; e) V. J. Traynelis, A. M. Gallagher IHM, R.
F. Martello, J. Org. Chem. 1961, 26, 4365-4368; f) V. J.
Traynelis, P. Pacini, J. Am. Chem. Soc. 1964, 86, 4917-
4922; g) S. Tamagaki, S. Kozuka, S. Oae, Tetrahedron
Lett. 1968, 9, 4765-4768; h) R. Bodalski, A. R.
Katritzky, J. Chem. Soc. B 1968, 831-838; i) R.
Bodalski, A. R. Katritzky, Tetrahedron Lett. 1968, 9,
257-260; j) S. Oae, T. Kitao, Y. Kitaoka, J. Am. Chem.
Soc. 1962, 84, 3359-3362.
Experimental Section
General Procedure for the Synthesis of Furazanyl
Carbamates 3a-j.
KCN (33 mg, 0.5 mmol) was added to a solution of a
furoxanyl imino ether 2 (1.0 mmol) in MeCN (3 mL). The
reaction mixture was stirred for 10-14 h at room
temperature (TLC monitoring, eluent – CHCl3) and then
diluted with water (15 mL). Carbamates 3a-d were isolated
by filtration, washed with water and dried in air.
Carbamates 3e-j were extracted with EtOAc (3x20 mL),
and the combined organic layers were washed with water
and dried over MgSO4. Removal of the drying agent by
filtration and evaporation of the solvent afforded the crude
carbamates, which were then purified by flash or column
chromatography on SiO2 (eluent CHCl3-EtOAc, 15:1).
[6] V. Boekelheide, W. L. Lehn, J. Org. Chem. 1961, 26,
428-430.
[7] C. Fontenas, E. Bejan, H. A. Haddou, G. G. A.
Balavoine, Synth. Commun. 1995, 25, 629-633.
[8] A. W. Sledeski, M. K. O’Brien, L. K. Truesdale,
Tetrahedron Lett. 1997, 38, 1129-1132.
General Procedure for the Synthesis of Pyridyl
Carbamates 6a-j.
[9] A. Massaro, A. Mordini, A. Mingardi, J. Klein, D.
Andreotti, Eur. J. Org. Chem. 2011, 271-279.
A mixture of corresponding 2-aminoazine N-oxide 4a-j
(1.0 mmol), trimethyl orthoformate (5 mL) and a catalytic
[10] C.-S. Wang, T. Roisnel, P. H. Dixneuf, J.-F. Soulé,
.
amount of BF3 Et2O (0.2 mmol, 25 μL) was refluxed for 4
Org. Lett. 2017, 19, 6720-6723.
h. Then, the reaction mixture was cooled to room
temperature and diluted with water (40 mL). The formed
solid was isolated by filtration, washed with water and cold
Et2O (10 mL) and dried in air.
[11] D. Andreotti, E. Miserazzi, A. Nalin, A. Pozzan, R.
Profeta, S. Spada, Tetrahedron Lett. 2010, 51, 6526-
6530.
[12] M. Begtrup, Adv. Heterocycl. Chem. 2012, 106, 1-
Acknowledgements
109.
This work was supported by the Russian Science Foundation
(Project No 14-50-00126).
[13] a) L. L. Fershtat, N. N. Makhova, Russ. Chem. Rev.
2016, 85, 1097-1145; b) I. V. Kuchurov, M. N.
Zharkov, L. L. Fershtat, N. N. Makhova, S. G. Zlotin,
ChemSusChem 2017, 10, 3914-3946; c) S. G. Zlotin, A.
M. Churakov, I. L. Dalinger, O. A. Luk’yanov, N. N.
Makhova, A. Yu. Sukhorukov, V. A. Tartakovsky,
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Advanced Synthesis & Catalysis
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7
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Advanced Synthesis & Catalysis
FULL PAPER
Tandem Condensation/Rearrangement Reaction of
2-Aminohetarene N-Oxides for the Synthesis of
Hetaryl Carbamates
Adv. Synth. Catal. Year, Volume, Page – Page
Dmitry M. Bystrov,a,b Egor S. Zhilin,a,b Leonid L.
Fershtat,a Anna A. Romanova,c,d Ivan V. Ananyev,c
and Nina N. Makhovaa,*
8
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