Ring Opening of Donor-Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N-Heterocycles

Article abstract of DOI:10.1002/chem.201405551

A general method for ring opening of various donor-acceptor cyclopropanes with the azide ion through an S_N2-like reaction has been developed. This highly regioselective and stereospecific process proceeds through nucleophilic attack on the more-substituted C2 atom of a cyclopropane with complete inversion of configuration at this center. Results of DFT calculations support the S_N2 mechanism and demonstrate good qualitative correlation between the relative experimental reactivity of cyclopropanes and the calculated energy barriers. The reaction provides a straightforward approach to a variety of polyfunctional azides in up to 91% yield. The high synthetic utility of these azides and the possibilities of their involvement in diversity-oriented synthesis were demonstrated by the developed multipath strategy of their transformations into five-, six-, and seven-membered N-heterocycles, as well as complex annulated compounds, including natural products and medicines such as (-)-nicotine and atorvastatin. A new world of opportunities: Stereospecific ring opening of donor-acceptor cyclopropanes with the azide ion gives rise to densely functionalized building blocks that are valuable for the assembly of a diverse range of N-heterocycles (see scheme; EDG=electron donating group; EWG=electron withdrawing group). These synthetic opportunities are provided by the simultaneous presence of the N₃ group, which reacts as a latent amine or 1,3-dipole, easily modifiable donor and acceptor substituents, as well as the activated CH fragment.

Full text of DOI:10.1002/chem.201405551

DOI: 10.1002/chem.201405551
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Nitrogen Heterocycles |Hot Paper|
Ring Opening of Donor–Acceptor Cyclopropanes with the Azide
Ion: A Tool for Construction of N-Heterocycles
Konstantin L. Ivanov,[a] Elena V. Villemson,[a] Ekaterina M. Budynina,*[a, b] Olga A. Ivanova,[a]
Igor V. Trushkov,*[a, b] and Mikhail Ya. Melnikov[a]
Abstract: A general method for ring opening of various
donor–acceptor cyclopropanes with the azide ion through
an SN2-like reaction has been developed. This highly
regioselective and stereospecific process proceeds through
nucleophilic attack on the more-substituted C2 atom of a
cyclopropane with complete inversion of configuration at
this center. Results of DFT calculations support the SN2
mechanism and demonstrate good qualitative correlation
between the relative experimental reactivity of cyclopro-
panes and the calculated energy barriers. The reaction pro-
vides a straightforward approach to a variety of polyfunc-
tional azides in up to 91% yield. The high synthetic utility of
these azides and the possibilities of their involvement in
diversity-oriented synthesis were demonstrated by the
developed multipath strategy of their transformations into
five-, six-, and seven-membered N-heterocycles, as well as
complex annulated compounds, including natural products
and medicines such as (ꢀ)-nicotine and atorvastatin.
Introduction
through SN2-like ring opening of donor–acceptor (D–A)
cyclopropanes[5,6] 1 with the azide ion (Scheme 1a). The D–A
cyclopropanes that can be involved in this reaction include
aryl-, heteroaryl, and alkenyl-substituted cyclopropane-1,1-
diesters, keto- and nitroesters, diketones, and dinitriles.
The great synthetic opportunities that the azide function
provides to various organic molecules allow for the synthesis
of
a plethora of nitrogen-containing acyclic and cyclic
compounds, including physiologically active compounds.[1] The
main transformations of the azido-group that are accompanied
by the elimination of an N2 molecule (such as Staudinger, Cur-
tius, Schmidt, and Boyer reactions) can be used for the efficient
formation of synthetically and biologically important
compounds such as amines, imines, amides as well as various
azaheterocycles.[2] Among the reactions of azides that take
place without the loss of N2, the dominant reaction is [3+2]
cycloaddition of azides as dipoles to unsaturated compounds,
affording triazole and tetrazole derivatives.[3] These and many
other synthetic applications of alkyl, aryl, and alkenyl azides
have stimulated the development of numerous methods for
the preparation of these useful compounds.[4]
Curiously, SN2-like ring opening of D–A cyclopropanes with
the azide ion has not, to our knowledge, previously been stud-
ied.[7] Synthesis of g-azidoesters by a reaction of cyclopropane
hemimalonates with the azide ion has recently been reported
by Kerr and co-workers.[8] However, this reaction proceeds
through the initial formation of acyl azides followed by a [3,3]-
sigmatropic rearrangement with intermediate ketene genera-
tion. Chandrasekaran and co-workers reported an electrophilic
ring opening of 2-alkoxycyclopropanecarboxylates with the
NIS/NaN3 system, yielding g-iodoazides.[9] Nevertheless, both
methods[8,9] have significant limitations because other types of
D–A cyclopropanes, including the extensively studied 2-substi-
tuted cyclopropane-1,1-diesters, were found to be unable to
yield the desired azides under the conditions examined.
In contrast, our synthetic strategy, based on the stereo
specific SN2-like ring opening, allows for an impressive range
of readily available starting D–A cyclopropanes to be involved
in this transformation. This provides powerful access to libra-
ries of polyfunctional azides either in racemic or in optically
active forms, equipped with (hetero)aryl or alkenyl substituents
at the geminal position as well as electron-withdrawing
groups, such as ester, keto, nitro, and cyano groups at the g-
position.
Herein we primarily describe a simple and efficient regio-
and stereoselective synthesis of highly functionalized azides 2
[a] K. L. Ivanov, Dr. E. V. Villemson, Dr. E. M. Budynina, Dr. O. A. Ivanova,
Dr. I. V. Trushkov, Prof. M. Ya. Melnikov
Department of Chemistry, M. V. Lomonosov Moscow State University
Leninskie Gory 1-3, Moscow, 119991 (Russia)
Fax: (+7)4959391814
E-mail: ekatbud@kinet.chem.msu.ru
trush@phys.chem.msu.ru
[b] Dr. E. M. Budynina, Dr. I. V. Trushkov
Laboratory of Chemical Synthesis
Federal Research Center of Pediatric Hematology, Oncology, and Immunolo-
gy named after Dmitrii Rogachev
The high synthetic utility of azides 2 can be demonstrated
by their use as essential building blocks for the assembly of
a broad range of skeletal diversity of N-heterocyclic systems,
including natural compounds and medicines. Due to pre-
installed multiple functional groups (FG) that exhibit excellent
Samory Mashela 1, Moscow 117997 (Russia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405551.
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present methodology was also exploited in the synthesis of
natural products and synthetic drugs, such as (ꢀ)-nicotine and
atorvastatin (commercially available as a calcium salt under the
name Lipitor, which is a cholesterol-lowering medication that
is the all-time best-selling drug around the world).
Results and Discussion
Donor–acceptor cyclopropane ring opening with the azide
ion
During the search for appropriate conditions for the ring
opening of D–A cyclopropanes 1 with the azide ion, we relied
on critical aspects that influence efficiency in the reactions of
D–A cyclopropanes as well as reactions between electrophilic
cyclopropanes and nucleophiles. On the one hand, in most
reactions of D–A cyclopropanes, a Lewis acid (LA) activation is
required.[5,11] On the other hand, nucleophilic ring opening of
activated cyclopropanes is mainly considered to be an SN2-like
process wherein the leaving group is a carbanion that is stabi-
lized by electron-withdrawing substituent(s). In this regard, we
carried out initial experiments with the model cyclopropane
1a in the presence of a LA as an activator as well as under
conditions typical for SN2 reactions (Table 1).
Table 1. Optimization of the reaction conditions for 1a transformation
into azide 2a.[a]
Scheme 1. General strategy used in this work.
Entry XN3 (equiv) Additive (equiv) Solv
T [8C] t [h] Yield [%][b]
1
2
3
4
5
6
7
8
9
TMSN3 (1)
–
PhCl
PhCl
PhCl
PhCl
DMF
DMF
DMF
DMF
131
131
131
131
100
50
8
8
10
10
4
4
4
9
4
–
40
60
66
15
–
94
90
92
86
compatibility, azides 2 are densely functionalized templates,
offering promise in the design and development of novel
pathways for diversity-oriented synthesis.[10]
TMSN3 (3) TMSOTf (1.2)
TMSN3 (3) TMSOTf (3)
TMSN3 (3) TMSOTf (3.5)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (1)
NaN3 (2)
NaN3 (2)
–
To demonstrate these possibilities, we elaborated
a
Et3N·HCl (2)
Et3N·HCl (2)
Et3N·HCl (1)
Et3N·HCl (2)
NH4Cl (2)
branching synthetic strategy for the transformation of azides 2
based on the initial introduction of a suitable FG at one or
more sites of molecules 2 (electron-donating group (EDG),
electron-withdrawing group (EWG), activated CH, or azide) fol-
lowed by intramolecular functional group-pairing reactions
(Scheme 1b). In this work, EDG functionalization (A, through
formylation), N3-group modification (B, through reduction to
amine or iminophosphorane generation), or activated CH func-
tionalization (D, including alkylation, acylation, arylation) opens
100
100
DMSO 100
DMF 100
10
4
[a] 0.5m solution of 1a. [b] Yield determined by 1H NMR spectroscopic
analysis .
We started our research by using trimethylsilyl azide
multiple modes for further ring formation, for example, (TMSN3), which can serve as both an activating LA and
through Staudinger/aza-Wittig reactions (azide/carbonyl a source of the azide ion. However, no conversion of 1a into
groups pairing), alkylation/[3+2] cycloaddition (azide/alkyne azide 2a was observed even under prolonged heating in PhCl
or azide/nitrile pairing), and azide reduction/lactamization (Table 1, entry 1). This result can be attributed to the low LA
(azide/ester pairing). These sequences, involving an optional activity of TMSN3. Indeed, the addition of TMSOTf as an activa-
set of possible modifications of azides 2, provide straightfor- tor directs this reaction to azide 2a formation (Table 1,
ward access to structures that are highly valuable in drug de- entries 2–4). A brief screening of the ratio of 1a to TMSN3 to
velopment, such as pyrroles, pyrrolines, pyrrolidines, pyridines, TMSOTf revealed that 66% is the highest yield of 2a that can
piperidines, triazoles, and tetrazoles, as well as to complex an- be achieved under these conditions (Table 1, entry 4), whereas
nulated and spiro-fused heterocyclic skeletons. Moreover, the further increase in the amount of azide source and activator
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loadings as well as reaction time did not lead to an increase in
the yield of 2a.
Table 2. Variation of the donor substituents.[a]
When NaN3 in N,N-dimethylformamide (DMF), a typical
system for SN2 reaction, was used, we observed only 15%
conversion of 1a into the desired azide 2a (Table 1, entry 5)
and the ratio of 2a to 1a did not vary with time or with an in-
crease in the amount of NaN3. This result indicates the reversi-
bility of 1a ring opening with the azide ion, which serves as
a nucleophile in the forward reaction and as a leaving group
in the reverse nucleophilic substitution leading to closure of
the three-membered ring. Whereas the high nucleophilicity of
the azide ion is common knowledge, its ability to act as a leav-
ing group in SN2 reactions is a quite untypical phenomenon in
organic synthesis.[12] To verify this reversibility, we treated 2a
with NaH in DMF at 1008C (Scheme 2). After quenching, the
resulting mixture was found to contain cyclopropane 1a and
azide 2a in 85:15 ratio, which is identical to that obtained in
the reaction of 1a with NaN3.
1,2
EDG
T [8C]
t [h]
Yield [%][b]
R
a: H
b: Me
100
100
4
5
88
81
Hal
c: 4-F
d: 4-Br
e: 2-Br
100
100
100
8
7
10
73
78
71
(RO)n
f: 4-MeO
100
100
100
100
100
100
4
4
10
5
5.5
4
77
85
72
79
86
75
g: 2,3-(MeO)2
h: 2-BnO-3-MeO
i: 3,4-(MeO)2
j: 3,5-(MeO)2
k: 3,4,5-(MeO)3
l
100
2
80
EWG
m: NO2
n: CO2Me
o: CN
85
85
100
24
24
4
58
61
53
Scheme 2. Check of the reversibility of 1a ring opening with the azide ion.
To overcome the problem of reversibility, we carried out the
reaction of 1a with NaN3 in the presence of Et3N·HCl (Table 1,
entries 6–9), which should provide protonation of the incipient
malonate anion and preclude the reverse reaction. A brief
examination of variations in the loading of the nucleophile or
the proton source, reaction temperature, and duration
revealed that the optimal reaction conditions are heating of
a mixture of 1a, NaN3, and Et3N·HCl in 1:2:2 ratio in DMF at
1008C for 4 h (Table 1, entry 7). Replacement of DMF by
dimethyl sulfoxide (DMSO) did not lead to noticeable changes
in the reaction efficiency, whereas the employment of NH4Cl
instead of Et3N·HCl (Table 1, entry 10) resulted in a 10%
decrease in the yield of 2a.
p: 1-Me-pyrrol-2-yl
q:[c] 2-Fu
r: 2-Th
s: 2-benzofuryl
t: 2-benzothienyl
70
100
100
100
100
3
4
5
14
6
71
75
79
71
81
u: 1-Me-4-Ind
v: 1-Bn-3-Ind
w: 1-Bn-5-Cl-3-Ind
x: 1-Bn-2-Me-3-Ind
100
50
50
3
3
3
4
78
91
86
88
50
X
y: N
z: N!O
100
100
4
2
83
61
[a] Reaction conditions: 0.5m solution of
1
in DMF, NaN3 (2 equiv),
With the optimized conditions in hand, we studied the
scope of this reaction by using a broad range of cyclopropane-
1,1-diesters 1a–z with a wide variety of donor groups, includ-
ing aryls with different electronic and steric effects, heteroaryl
and alkenyl groups (Table 2). Cyclopropanes 1a–k bearing
alkyl, halogen, and alkoxy group(s) at various positions of the
aromatic ring as well as heteroarene-derived cyclopropanes
1p–x with furyl, thienyl, pyrrolyl, benzofuryl, benzothienyl, and
indolyl substituents afforded the corresponding azides 2a–k
and 2p–x in high isolated yields. It is noteworthy that pyrrolyl-
and 3-indolyl-substituted cyclopropanes 1p and 1v–x require
lower temperature for efficient conversion into azides 2. Mean-
while, introduction of electron-withdrawing substituents onto
the phenyl group, as in 1m–o, led to some decrease in the
yield of azides 2. The same trend, namely a decrease in yield
by approximately 20%, was observed for the reaction of 3-
pyridyl-substituted cyclopropane 2y and its more electron-de-
Et3N·HCl (2 equiv). [b] Yield of isolated product. [c] The corresponding
diethyl derivative 2q’ was obtained after 10 h (1008C) in 79% yield.
Fu=furyl; Th=thienyl; Ind=indolyl.
pleted N-oxide derivative 2z. The use of the ethyl ester instead
of its methyl analogue, as in the case of 2-furylcyclopropane-
1,1-diesters 1q and 1q’, did not influence the reaction yield
but decelerated the process.
For all substrates, the reaction proceeds with exceptional
regioselectivity through nucleophilic attack on the more-sub-
stituted C2 atom rather than the C3 atom. Nucleophilic ring
opening of 2-alkenyl-derivative 1l can proceed through attack
on either the C2 atom of the three-membered ring (SN2-like
reaction) or the b-atom of the C=C bond (SN2’-like reaction).
We found that 1l chemoselectively undergoes an SN2-like reac-
tion that furnishes azide 2l exclusively.
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The developed synthetic procedure is easily scalable without
any loss of efficiency. This was demonstrated by isolation of 2a
in 85% yield when 3.35 g (14 mmol) of 1a was used under the
developed conditions.
Table 4. One-pot transformation of cyclopropane-1,1-diesters 1 into 4-
azido-4-(hetero)arylbutyrates 3.[a]
To demonstrate the general character of the process and
significantly extend the collection of densely functionalized
azides, we then involved other subclasses of D–A cyclopro-
panes in this reaction (Table 3). Nitroester 1aa, dinitrile 1ab,
3
EDG
t [h]
Yield [%][b]
R
a: H
b: Me
15
20
85
80
Table 3. Variation of the acceptor substituents.[a]
(RO)n
c: 2,3-(MeO)2
d: 3,5-(MeO)2
e: 3,4-(MeO)2
f: 3,4,5-(MeO)3
28
23
20
24
76
81
71
65
2
Azide 2
T [8C]
t [h]
Yield [%][b]
76
aa
55
2
g
24
12
68
28
ab[c]
25
3
43
R
h[c]
ac: Me
ad: Et
90
90
4
3
80
79
[a] Reaction conditions: 1) 0.5m solution of 1 in DMF, NaN3 (2 equiv),
Et3N·HCl (2 equiv); 2) H2O (6 equiv), 1408C. [b] Yield of isolated product.
[c] Reaction conditions: 2) H2O (6 equiv), LiCl (2 equiv), 1258C.
ae
af
90
25
1
6
90
85
4-azido-4-(hetero)arylbutyrates 3 through cyclopropane ring
opening/Krapcho dealkoxycarbonylation[17] (Table 4). The first
step, a cyclopropane 1 ring opening, was carried out under
the previously optimized conditions (Table 2). Next, six equiva-
lents of water were added to the reaction mixture, which was
then heated at 1408C (Table 4). Variation of the aromatic sub-
stituents in cyclopropanes 1 had no significant influence on
the reaction efficiency, except for 3-pyridyl-substituted cyclo-
propane 1y. In the latter case, a complex mixture of products
of dealkoxycarbonylation and N-alkylation was obtained. To
prevent the side-process of N-alkylation, pyridine-N-oxide de-
rivative 1z was used, which undergoes dealkoxycarbonylation
furnishing 3h in reasonable yield.
This one-pot process provides a simple approach to 4-azido-
butyrates 3[18] and is a shortcut alternative to the two-step
procedure reported by Kerr.[8] Compounds 3 are immediate
precursors of 4-aminobutyrates, which are derivatives of g-ami-
nobutyric acid (GABA).[19] 4-Aminobutyrates can accentuate or
attenuate neuromediatory effects of GABA and are promising
compounds for the treatment of CNS-related diseases.[20] Addi-
tionally, derivatives of 4-amino-4-(hetero)arylbutyric acid are
known to inhibit Src SH2[21] and aggrecanases-1 and -2,[22] as
well as to exhibit other types of bioactivities.
[a] Reaction conditions: 0.5m solution of
Et3N·HCl (2 equiv). [b] Yield of isolated product. [c] Ratio of 1ab/NaN3/
Et3N·HCl=1:1:1.
1 in DMF, NaN3 (2 equiv),
ketoesters 1ac–ae, and diketone 1af were found to undergo
efficient ring opening with the azide ion under similar reaction
conditions. In all cases, higher reactivity was observed in com-
parison with diester 1a. Ketoesters 1ac–ae underwent full con-
version into 2ac–ae under heating at 908C in 1–4 h, whereas
for nitroester 1aa the reaction was complete after 2 h at 558C.
Dicyanocyclopropane 1ab and indan-1,3-dione-derived cyclo-
propane 1af, which underwent easy conversion into azides
2ab and 2af even at room temperature, proved to be the
most reactive substrates. Despite mild reaction conditions, 2ab
was isolated in only 43% yield because of formation of a
complex mixture of unidentified products.
The ring opening of D–A cyclopropanes with the azide ion
thus provides a straightforward general approach to various
types of previously difficult to access acyclic polyfunctional
compounds 2 with the strategic 1,3-relationship between N3
and other diverse functions, such as CO2R, COR, NO2, and
CN.[13–16] This supplies azides 2 with versatile reactivity and
makes them valuable intermediates for the construction of a
diverse range of molecular skeletons.
The elaborated methodology can be used for the nucleo-
philic ring opening of D–A cyclopropanes with not only tertiary
but also quaternary donor sites. Given that one carbon
substituent serves as a leaving group, SN2-like reactions of
such cyclopropanes can be compared with nucleophilic
substitutions in tertiary halides, which are considered to be
Relying on the reaction of cyclopropane diesters 1 with
NaN3, we developed a one-pot method for the preparation of
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poor substrates in SN2 processes.[23–25] Nevertheless, we suc-
ceeded in carrying out a chemoselective ring opening of cyclo-
propane 1ag (Scheme 3) through azide ion attack on the qua-
ternary cyclopropane C2 atom. The harsher conditions that
principal characteristics of a typical SN2 reaction. It is not-
able that Kerr and co-workers found total retention of absolute
configuration in the reaction of NaN3 with the cyclopropane
hemimalonate. This was explained by a notably different
mechanism involving an intermediate acyl azide formation and
its [3,3]-sigmatropic rearrangement.[8] Therefore, in terms of
stereochemistry, our method is complementary to Kerr’s ring
opening because the same enantiomer of a cyclopropane un-
dergoes enantioselective ring opening by azide ion with either
inversion or retention of its absolute configuration.
Scheme 3. Domino transformation of 2,2-diphenylcyclopropane-1,1-diester
1ag into azidobutyrate 3i.
DFT study of the reaction mechanism and the relative
reactivity of donor–acceptor cyclopropanes
were necessary for this transformation meant that ring open-
ing was accompanied by dealkoxycarbonylation leading to the
formation of azidobutyrate 3i. Unfortunately, the generation of
nitrene and its subsequent rearrangements compete with the
main reaction, ensuring formation of benzophenone as a side-
product and isolation of 3i in only moderate yield.
To gain a better understanding of the general reaction pattern,
we carried out density functional theory (DFT) calculations of
energy barriers for D–A cyclopropane ring opening with the
azide ion using the B3LYP hybrid functional and the standard
SVP basis set[28] implemented in the ORCA 2.9 program
package.[29] The solvent effects were estimated by using the
COSMO solvation model[30] with DMF as a solvent.
For all studied cyclopropanes 1 we localized transition states
(TS) of their SN2-like ring opening through azide ion attack
onto the C2 atom. These TS are of the type found in common
SN2 reactions but they are characterized by smaller values of
angle for the attack of a nucleophile (Nu). Whereas for typical
SN2 reactions the Nu-C-LG (leaving group) angle approaches
1808, for SN2-like ring opening of D–A cyclopropanes 1a–af
the angle varies from 1428 to 1488. A schematic representation
of the energy profile and the calculated energy barriers are
given in Table 5.
Ring opening of optically active cyclopropane (S)-1a with
the azide ion: Walden inversion as a support of SN2-like
mechanism
The development of a rapid synthetic access to enantiopure
azides of type 2 is critically important in the context of their
further employment as chiral reagents in the synthesis of bio-
logically active compounds such as GABA-based ring struc-
tures, as well as in diversity-oriented synthesis. The D–A cyclo-
propane ring opening with the azide ion should provide such
access because complete retention of stereo information in
the reaction involving optically active cyclopropanes is expect-
ed. Moreover, the stereochemical result of this reaction allows
for some insight into the mechanism of the transformation of
1 into 2.
In this regard, we carried out an experiment with enantio-
pure cyclopropane (S)-1a[26] furnishing azide 2a as an individu-
al enantiomer. To determine the absolute configuration of 2a,
it was converted into pyrrolidone 4a (Scheme 4), the optical
rotation of which, [a]TD, was previously reported for the individ-
ual enantiomers.[27] Comparison of the reported data with our
results allowed us to assign 4a and, thus, 2a to R-enantiomers.
Therefore, the transformation of 1 into 2 proceeds with full
inversion of configuration at the reacting C2 atom—one of the
The trend of variation in the calculated DG° (Table 5) quali-
tatively coincides with the changes in reaction conditions
(temperature, duration), which primarily characterize the reac-
tivities of the D–A cyclopropanes 1 towards the azide ion.
Meanwhile, both in vitro and in silico data indicate that the re-
activity of 1 depends significantly on the nature of the accept-
or substituents in their molecules. In particular, cyclopropane
1ah, which contains a single ester group as an acceptor
(Table 5, entry 1), has a very high transition state energy for
ring opening with the azide ion (DH° =28.4, DG° =38.6 kcal
molꢀ1). The presence of a second ester group (diester 1a)
lowers the energy barrier significantly (Table 5, entry 7; DH° =
17.6, DG° =24.4 kcalmolꢀ1), whereas an even greater decrease
in the energy barrier height is observed for the cyclopropanes
containing the more electron-withdrawing keto or nitro
groups (Table 5, entries 8 and 10; ketoester 1ad, DH° =14.4,
DG° =23.1 kcalmolꢀ1
,
nitroester 1aa, DH° =11.4, DG° =
21.0 kcalmolꢀ1). These results correspond well with the experi-
mental data. Namely, compound 1ah did not undergo ring
opening even under prolonged heating to reflux in DMF
(1538C). Diester 1a was converted into azide 2a at 1008C,
whereas the transformation of ketoester 1ad into the
corresponding azide 2ad required lower temperature (908C)
and nitroester 1aa reacted efficiently at 558C.
These changes in the reactivity of D–A cyclopropanes can
be qualitatively explained on the basis of the well-known
Scheme 4. Inversion of configuration in the nucleophilic ring opening of
cyclopropane (S)-1a.
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dependence of DG° on DrG as exemplified, for example by the
Marcus equation, DG° =(l+DrG)2/4l, where l is the total
reorganization energy.[31] Thus, the reaction of the azide ion
with diester 1a can be characterized by a slightly positive DrG
value, as exemplified by the results described above. In con-
trast, the DrG value for ring opening of 1aa is negative be-
cause the anion of the a-nitroester is more stable than that of
2a (pKa values for methyl nitroacetate and dimethyl malonate
in DMSO are 9.1 and 15.9[32]). Moreover, according to DFT
calculations, DrG for 1aa and 1a are ꢀ5.1 and +5.4 kcalmolꢀ1,
respectively.
Table 5. Energy profile and energy barriers for cyclopropane 1 ring
opening with the azide ion.
The lowest energy barriers were calculated for nucleophilic
ring opening of cyclopropanes 1af and 1ab (Table 5, entries 12
and 13; DG° =20.8 and 17.7 kcalmolꢀ1, respectively). This
result complies with the very high reactivities of 1ab and 1af,
which react with the azide ion at room temperature. These
low energy barriers cannot be explained only by the aforemen-
tioned dependence on the reaction energy, because the
anions of 2ab and 2af are more stable than that of 2a but
less stable than that of 2aa. Indeed, the pKa value for malono-
dinitrile in DMSO is 11.0[33] and the calculated DrG value is
ꢀ3.0 kcalmolꢀ1. The obtained results are in line with the
higher reactivity of benzylidene derivatives of malonodinitrile
and 1,3-indandione towards nucleophiles in comparison with
b-nitrostyrene or benzylideneacetylacetone.[34a] This reactivity
for Michael acceptors was explained in the terms of “the princi-
ple of nonperfect synchronization”[34] according to which the
stabilization of the formed carbanion (e.g., through negative
charge delocalization or solvent reorganization) is delayed with
respect to the progress of the reaction. Another explanation
can be given using “total reorganization energy” as defined in
the Marcus equation. The stabilization of the nitronate anion is
achieved by significant changes in substrate geometry or sol-
vation, for example. However, it means that significant reor-
ganization is also required for the TS in the reaction of 1aa. As
a result, energy of stabilization of the incipient carbanion in
this TS is lower than the reorganization energy required to pro-
vide this stabilization; that is, the l value for the reaction of
1aa is sufficiently large. In contrast, the rod-like shape of nitrile
groups and the rigid framework of the indanedione moiety
provide relatively small values of reorganization energy in the
TS for 1ab and 1af, ensuring their high reactivities.
Entry Cyclopropane 1
DH°/DG° [kcalmolꢀ1
]
Experimental
data
T [8C] t [h]
[a]
[a]
1
2
3
1ah 28.4/38.6
–
–
1ag 19.5/31.2
1ai 18.9/28.8
1m 15.2/26.7
135
100[b]
85
12
24[b]
24
4
5
1u 16.4/26.3
100
3
6
1 f 15.2/25.4
1a 17.6/24.4
1ad 14.4/23.1
1p 12.0/21.4
1aa 11.4/21.0
1aj 10.2/21.9
100
100
90
4
7
4
8
3
9
70
3
10
11
55
2
The variation of donor substituents also affects the reaction
barrier. In general, cyclopropane-1,1-diesters with more
electron-abundant aromatic substituents demonstrate higher
reactivity. For example, 3-indolyl- and 2-pyrrolyl-substituted
cyclopropanes 1v and 1p have lower DG° values than 1a (by
2.5–3.0 kcalmolꢀ1) and undergo ring opening with the azide
ion at lower temperatures (50 and 708C, respectively, vs.
1008C for 1a). At the same time, introduction of various
substituents into the phenyl group of 1a has a relatively small
effect on the reactivity of D–A cyclopropanes.
50[c]
3[c]
12
13
1af 12.0/20.8
1ab 9.1/17.7
25
25
6
3
[a] No conversion under prolonged heating at reflux (1538C) in DMF.
[b] Experimental data are for the corresponding diethyl ester.[7c] [c] Experi-
mental data are for N-benzyl analogue 1v.
It is noteworthy that 2-unsubstituted cyclopropane-1,1-
diester 1ai is less reactive than 2-phenyl derivative 1a. The
introduction of the phenyl group (1a vs. 1ai) leads to an in-
crease in cyclopropane reactivity against nucleophilic agents.
The same effect is well-known for SN2 reactions of alicyclic
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compounds (e.g., manifesting itself in higher reactivities of
benzyl halides in comparison with the corresponding methyl
halides).[23] This was ascribed to conjugation in the TS between
the three-atom four-electron HOMO, formed by the nucleo-
phile, the central carbon atom and the leaving group, and the
p* orbital of the aryl group. In the studied SN2-like reactions,
the phenyl group is located in a similar position, stabilizing the
TS for azide ion attack on the C2 atom of 1a (Figure 1a).
the C3 atom of 1a in comparison with the energy barriers for
azide attack onto the C2 atom (by 6.6 kcalmolꢀ1) as well as the
reaction of azide with 1ai (by 2.2 kcalmolꢀ1). In the corre-
sponding TS, the phenyl group does not demonstrate any sta-
bilizing effect but provides steric hindrance, which decelerates
nucleophilic ring opening (Figure 1b). To conclude, our DFT
calculations clearly support the proposed SN2 mechanism for
D–A cyclopropane ring opening by the azide ion under the
studied conditions. Moreover, we demonstrate that such calcu-
lations have the potential to predict the temperatures required
to perform ring opening with other D–A cyclopropanes and/or
nucleophiles.
Transformations of azides 2
The synthesized azides 2 possess multiple FGs with specific
sets of reactivity and, thus, can be easily involved in reactions
with both external and internal partners. We demonstrated
here that azides 2 can serve as templates for the rapid assem-
bly of complex and diverse nitrogen-containing skeletons
often employed in drug design. Modification of azides 2 with
suitable agents bearing additional FGs significantly extends the
scope of their transformations into a diverse array of five-, six-,
and seven-membered N-heterocycles through FG pairing,
which includes well-known processes such as aza-Wittig
reaction[35] and click [3+2] cycloaddition,[36] as well as original
domino reactions.
Figure 1. LUMO isosurfaces of SN2-like transition states for 1a ring opening
with the azide ion: a) C2-attack; b) C3-attack (contour value=0.04).
A similar effect can also be expected for 2,2-diphenylcyclo-
propane-1,1-diester 1ag. However, the optimization of TS for
the SN2-like ring opening of 1ag with the azide ion showed
that the DG° value is 31.2 kcalmolꢀ1; that is, 6.8 kcalmolꢀ1
higher than the DG° value for the reaction of 1a, and 2.4 kcal
molꢀ1 higher than that for the reaction of 2-unsubstituted
cyclopropane-1,1-diester 1ai. Evidently, this result can be ex-
plained by steric effects in the reaction of 1ag; the repulsion
between two phenyl groups prevents the efficient conjugation
discussed above. Moreover, the steric bulk obstructs the
approach of the nucleophile, which clearly manifests itself in
a change in the angle (N3-C2-C1). This angle amounts to 142–
1488 in the TS for almost all studied D–A cyclopropanes but
changes to 1318 in the TS for the reaction of 1ag. Neverthe-
less, the calculated energy barrier is much lower than that for
the reaction of 1ah, which was found to not react with the
azide ion experimentally. Based on the above qualitative agree-
ment between the calculated energy barriers and experimental
reactivity (exemplified here as reaction temperature), we
proposed that the reaction between 1ag and the azide ion
can be performed at higher temperatures. Indeed, we found
that heating of the reaction mixture at 1358C provided full
conversion of 1ag.
Synthesis of five-membered N-heterocycles through
Staudinger and aza-Wittig reactions
Azide 2 cyclization based on a combination of the azide group
as a latent amine function with a g-placed carbonyl group
opens an efficient route to five-membered N-heterocycles,
especially various GABA-based skeletons. In this part of the
current work, we used synthetic pathways involving Staud-
inger/aza-Wittig reactions that led to pyrrolidone and pyrroline
derivatives, which can be further transformed into poly-
functionalized pyrroles (Scheme 5).
Scheme 5. Use of azides 2 as a latent amine in the synthesis of five-
membered N-heterocycles.
The comparison of energy barriers for 1ag and 1ai allowed
us to suppose that nucleophilic attack on the C3 atom of 1ag
could compete with attack on the C2 atom. However, our cal-
culations showed that the DG° value for the regioisomeric
attack is much higher (38.1 kcalmolꢀ1). This is consistent with
the experimental data because tertiary azide 3i was obtained
in this reaction. In other words, the aryl group in position 2 of
the cyclopropane ring significantly deactivates the vicinal posi-
tion to attacks by nucleophiles. This conclusion was supported
by a higher DG° value (31.0 kcalmolꢀ1) for azide attack onto
Thus, the reduction of azides 2a and 2y through Staudinger
reaction/iminophosphorane hydrolysis produces aminomalo-
nates, which undergo spontaneous 1,5-cyclization furnishing
g-lactams 5a and 5b in high yields (Scheme 6).
The present methodology provides an easy and efficient
access to natural products, for example the tobacco alkaloid
family. On the basis of this reductive cyclization, we developed
a total synthesis of (S)-nicotine starting from optically active 3-
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Scheme 6. Synthesis of g-lactams through reductive cyclization of 2.
Scheme 9. Formal total synthesis of atorvastatin.
genation, yielding trisubstituted pyrrole 8b. The bromination
of 8b and further Suzuki cross-coupling afforded tetrasubsti-
tuted pyrrole 9, the transformation of which into atorvastatin
was reported earlier.[40]
Scheme 7. Total synthesis of (ꢀ)-nicotine.
pyridyl-derived cyclopropane (R)-1y (Scheme 7). It is notewor-
thy that Krapcho dealkoxycarbonylation of (S)-2y was carried
out in pyridine as a solvent to prevent the alkylation of the
3-pyridyl moiety in product 3j with CH3Cl evolving during de-
alkoxycarbonylation. Treatment of (S)-3j with Ph3P produced
lactam (S)-4b. Its reduction with LiAlH4 followed by reductive
methylation of the resulting pyrrolidine (S)-6 finalized the
synthesis of (ꢀ)-nicotine. This synthesis provides a rapid enan-
tioselective access not only to nicotine (which attracts much
attention due to its effects on the central nervous system as
well as its use as an insecticide) but also to its metabolites,
which exhibit various types of bioactivity.[37]
Synthesis of N-heterocycles through functionalization of
activated CH group as the key step
The presence of an activated methine group in 2 allows for
branching and additional functionalization of their alkyl chain
through nucleophilic substitution or addition reactions. These
simple operations furnish wide opportunities to synthesize
a great variety of highly functionalized acyclic and N-heterocy-
clic compounds. In the present work, we extended the syn-
thetic utility of azides 2 considerably through their alkylation
(SN2 or Michael addition), acylation and arylation (SNAr) allow-
ing for further intramolecular construction of heterocyclic
systems with various ring sizes (Scheme 10).
The introduction of ketoazides into a reaction with phos-
phane provides rapid access to densely substituted pyrrolines
and pyrroles. Thus, the treatment of ketoazides 2ad and 2ae
with Ph3P induced a domino process consisting of Staudinger
and aza-Wittig reactions as well as oxidation by air[38] leading
to 3-hydroxy-4,5-dihydro-3H-pyrroles 7a and 7b (Scheme 8).
The structure of 7a was unambiguously proved by single-crys-
tal X-ray analysis.[39] The aromatization of 7a afforded pyrrole
derivative 8a.
The synthesis of pyrroline 11 a can exemplify the employ-
ment of CꢀH functionalization in 2 through nucleophilic
substitution for the purpose of five-membered ring assembly
(Scheme 11). We acylated azide 2a with benzoyl chloride and
then treated the product 10a with Ph3P to initiate a sequence
To display the utility of this novel route to pyrroles, we ap-
plied it in the synthesis of the pyrrole subunit 9 of atorvastatin
(Scheme 9), the calcium salt of which is known as cholesterol-
lowering medication Lipitor. Synthesis of 9 was initiated by
a Staudinger/aza-Wittig reaction of 2ae followed by dehydro-
Scheme 10. Different modes of azide 2 cyclization after activated CH
Scheme 8. Synthesis of pyrrolines 7 and pyrrole 8 from 2.
functionalization.
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toxicity against selected cancer cells.[44] Moreover, the ability of
the pyrrolidone moiety to undergo selective reduction[45] as
well as the tendency of the NH2 group to undergo easy substi-
tution by H or various functional groups through diazonium
salt formation enables compound 13 to be transformed into
more complex structures of biological relevance.[46]
Nucleophilic addition of the Michael type was also found to
be suitable for the alkylation of azides 2 and, thus, for the syn-
thesis of branched polyfunctional compounds 10 with a 1,5-re-
lationship between the azide and carbonyl functions (n=2)
(Scheme 10). Thus, ketoazide 10c was synthesized by Michael
addition of 2a to methyl vinyl ketone (Scheme 13). For
Scheme 11. Synthesis of 1-pyrrolines and 1-piperideines from azides 2
through an SN/Staudinger/aza-Wittig reaction sequence.
of Staudinger/aza-Wittig reactions leading to 11 a in a high
yield.
The introduction of a two-carbon linker through alkylation
of azides 2 with a-haloketones opens a simple way to con-
struct six-membered rings. Thus, starting from azide 2a, we
obtained tetrahydropyridine 11 b by the alkylation of 2a with
4-bromophenacyl bromide followed by Staudinger/aza-Wittig
reactions (Scheme 11).
Functionalization of azides 2 through arylation provides
opportunities for the synthesis of benzannulated systems.
Thus, we developed an extremely simple approach to spiroox-
indole-3,3’-pyrrolidine 13 (Scheme 12A), the scaffold of which
Scheme 13. Azide 2 functionalization through Michael addition and further
Staudinger/aza-Wittig reaction.
compounds of type 10, and 10c in particular, Staudinger/
intramolecular aza-Wittig reactions can proceed through two
alternative pathways: namely, through nucleophilic attack of
intermediate iminophosphoranes on the electrophilic site of
keto- or ester groups, which, in the case of 10c, lead to seven-
or five-membered rings, respectively. We found that, despite
higher electrophilicity of the keto-group, chemoselective 1,5-
cyclization through the ester group takes place for 10c under
Staudinger/aza-Wittig reaction conditions (Scheme 13). As
a result, pyrroline 14 was obtained in good yield. To our knowl-
edge, this process is the first example of ester function priority
over a keto-group in reactions with aza-nucleophiles, when
cyclizations with both ester and keto group could produce
normal rings having no steric repulsions.
Scheme 12. Synthesis of spirooxindole-3,3’-pyrrolidine 13 from azide 2b
through SNAr/reduction/g-lactamization (A) and selected examples of
spirooxindole alkaloids (B).
Synthesis of triazolo- and tetrazolopyridines through a
sequence of activated CH-group functionalization and [3+2]
cycloaddition
is present in numerous spirooxindole alkaloids, such as spiro-
tryprostatins A and B, pteropodine, elacomine, and horsfiline
(Scheme 12B).[41] Our approach consists of preliminary arylation
of azide 2b with chloro-2,4-dinitrobenzene through an SNAr
reaction giving 12 followed by the transformation of 12 into
13. The latter reaction can be viewed as a tandem of double
domino sequences involving simultaneous N3 and NO2 reduc-
tion[42] that initiates double g-lactamization leading to spiroox-
indole 13. This unique process, in which three functional
groups of the parent azides 2 are involved at once, differs
from many other approaches to spirooxindole-3,3’-pyrrolidine
by affording simultaneous construction of indole and pyrroli-
dine cores. In terms of bioactivities, spirooxindole-3,3’-pyrroli-
din-2-one derivatives were shown to be efficient antagonists of
the CRTH2 (DP2) receptor, with the corresponding Ki values at
the nanomolar level.[43] They also demonstrate moderate cyto-
[3+2] Cycloadditions to double or triple bonds are the
principal transformations of azides among those that proceed
without N2 elimination. In this group of transformations, azide–
alkyne cycloaddition is of special importance. We elaborated
a simple access to triazolo- and tetrazolopyridines and -aze-
pines through intramolecular [3+2] cycloaddition of the N3
moiety to the CꢁC and CꢁN bonds, which were preinstalled by
means of CꢀH functionalization of azides 2 (Scheme 10).
Surprisingly, introduction of the propargyl moiety to azides
2 through their alkylation with propargyl bromide initiates
spontaneous Huisgen azide–alkyne [3+2] cycloaddition lead-
ing to triazolopyridines 16 in good yields (Table 6). A slight
decrease in yield was observed in reactions of azides 2u and
2y, which can be prone to side-processes due to the presence
of reactive heteroaryl substituents.
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Table 6. Synthesis of triazoles 16 through domino propargylation of
azides 2 and [3+2] cycloaddition.[a]
Table 7. Synthesis of tetrazolopyridines 20.[a]
2
Ar
t
19,
Yield of 19
[%][b]
t
Yield of 20
[h] [%][b]
2
Ar
15,16
t [h]
Yield of 16 [%][b]
[h] 20
a
h
Ph
2-BnO-3-
MeOC6H3
12
15
a
b
85
67
25 92
20 83
a
b
f
k
o
y
u
Ph
a
b
c
d
e
f
1.5
1.5
1.5
1.5
2
78
69
71
68
72
53
52
4-MeC6H4
4-MeOC6H4
3,4,5-(MeO)3C6H2
4-NCC6H4
3-Py
k
3,4,5-(MeO)3C6H2 14
c
d
e
f
69
77
75
79
84
22 71
30 74
23 72
34 68
40 68
q’[c] 2-Fu
15
15
19
26
r
t
u
2-Th
2-benzothienyl
4-(1-Me)Ind
1.5
1.5
4-(1-Me)Ind
g
g
[a] Reaction conditions: 0.5m solution of 2 in DMF/toluene (1:1), NaH
(1.2 equiv), propargyl bromide (1.5 equiv). [b] Yield of isolated product.
[a] Reaction conditions: 0.5m solution of 2 in DMF, NaH (1.1 equiv),
2-bromoacetonitrile (1.2 equiv). [b] Yield of isolated product. [c] Diethyl
ester 2q’ was used as a starting material.
The unique character of this domino process reveals itself in
the extreme ease of the intramolecular azide–alkyne cyclo-
additions (AAC), which proceed spontaneously under very
mild, catalyst-free conditions. Presumably, this is caused by the
proximity of reacting fragments[47] in intermediates 15 and
the formation of a stable bicyclo[4.3.0]nonane system in the
resulting structures 16.
Our preliminary experiments in vitro on HEK293T, MCF7, and
SiHa cell lines did not reveal any cytotoxicity of synthesized tri-
azoles 16 and tetrazoles 20 up to concentrations of 1 mm.
These results open opportunities to use these compounds in
screening for other types of bioactivity.
In contrast, reaction of azide 2a with homopropargyl bro-
mide produces 17 as a stable product of alkylation, which
does not undergo spontaneous azide–alkyne cycloaddition
under ambient conditions (Scheme 14). The transformation of
Synthesis of N-heterocycles through EDG functionalization
The presence of (hetero)aryl or alkenyl substituents in azides 2
and 3 opens up a broad range of possibilities for their further
functionalization through SEAr, cross-coupling, oxidation, and
other reactions. As an example of such functionalization, we
transformed indole-derived azide 3g into dipyrrolo[2,1-
a:4’,3’,2’-de]isoquinoline 22 through formylation of the indole
ring, producing azidoaldehyde 21, followed by the Staudinger/
aza-Wittig/reductive cyclization sequence (Scheme 15).
Scheme 14. Synthesis of triazoloazepine 18.
17 into triazoloazepine 18 through intramolecular azide–
alkyne [3+2] cycloaddition proceeds only under prolonged
heating at 1108C in a microwave reactor. In contrast to aza-
Wittig reaction-derived cyclization, which fails to give a seven-
membered ring (Scheme 13), azide–alkyne [3+2] cycloaddition
proved to be less sensitive to the ring-size effect and produces
challenging seven-membered rings albeit at higher tempera-
ture.
Scheme 15. Synthesis of tetracycle 22 from azide 21 through EDG
functionalization.
Analogously, alkylation of azides 2 with bromoacetonitrile af-
fords stable acyclic products 19, which undergo azide-nitrile
[3+2] cycloaddition to furnish tetrazolopyridines 20 only
under prolonged heating at 110–1208C (Table 7).
In general, this methodology including D–A cyclopropane
ring opening with azide ion, alkylation of product with a triple
bond containing halide compound followed by [3+2] cyclo-
addition provides a simple efficient route to aryl-substituted
triazolo[1,5-a]pyridines and -azepines as well as tetrazolo-
[1,5-a]pyridines, which are very attractive as potent pharmaco-
logical agents[48] that are difficult to access by other methods.
This is the first preparative approach to the dipyrrolo[2,1-
a:4’,3’,2’-de]isoquinoline scaffold.[49] Such a scaffold should be
of interest for medicinal chemistry because pyrrolo[4,3,2-de]iso-
quinolines, the closest polycyclic systems, have demonstrated
a broad range of bioactivities.[50]
Conclusion
We have developed a valuable new method that involves ring
opening of D–A cyclopropanes with the azide ion, providing
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straightforward access to libraries of polyfunctional azides of
broad structural diversity. Exceptional regioselectivity and ste-
reospecificity of the ring opening is furnished by the SN2-like
mechanism of this reaction. This conclusion was supported by
DFT calculations, which show that the optimized transition
states correspond to the SN2-like reaction, whereas nucleophilic
attack on the unsubstituted C3 atom has a significantly higher
energy barrier than that for the donor-substituted C2 atom.
The obtained azides were shown to be essential building
blocks for the assembly of a broad skeletal array of five-, six-,
and seven-membered N-heterocyclic systems of biological rele-
vance. Simple synthetic sequences based on the elaboration of
azides into more complex structures involve their modification
or additional functionalization followed by a variety of ring-
forming processes. We have described modular synthetic path-
ways incorporating aza-Wittig, lactamization, and 1,3-dipolar
cycloaddition reactions as ring-forming processes and yielding
multisubstituted pyrrolidones, pyrrolines, pyrroles, 1-piperi-
deines, spirooxindole-3,3’-pyrrolidines, triazolo[1,5-a]pyridines
and -azepines, tetrazolo[1,5-a]pyridines, and dipyrrolo[2,1-
a:4’,3’,2’-de]isoquinolines. The present methodology was also
exploited in the synthesis of natural products and synthetic
drugs, namely (ꢀ)-nicotine and atorvastatin (Lipitor). The
impressive synthetic potential of synthesized azides is not
restricted to this set of transformations and reaches beyond
the present work, allowing for the employment of manifold
functionalities of these compounds and for further design of
synthetic sequences for combinatorial, diversity- or biology-
oriented synthesis in drug discovery efforts.
Keywords: azides · donor–acceptor systems · heterocycles ·
nitrogen heterocycles · nucleophilic substitution
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Acknowledgements
We thank the Russian Scientific Foundation (project 14–13–
01178) for providing general support of this work and the Rus-
sian Foundation for Basic Research (project 12-03-00717-a) for
supporting the part of this work devoted to indole-derived
compounds. The NMR measurements were carried out in the
Laboratory of Magnetic Tomography and Spectroscopy, Faculty
of Fundamental Medicine of Moscow State University. X-Ray
study was performed using a STOE STADI VARI PILATUS-100K
diffractometer purchased through the MSU Development Pro-
gram.
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Received: October 7, 2014
Published online on && &&, 0000
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FULL PAPER
A new world of opportunities: Stereo-
specific ring opening of donor–acceptor
cyclopropanes with the azide ion gives
rise to densely functionalized building
blocks that are valuable for the assem-
bly of a diverse range of N-heterocycles
(see scheme). These synthetic opportu-
nities are provided by the simultaneous
presence of the N3 group, which reacts
as a latent amine or 1,3-dipole, easily
modifiable donor and acceptor
&
Nitrogen Heterocycles
K. L. Ivanov, E. V. Villemson,
E. M. Budynina,* O. A. Ivanova,
I. V. Trushkov,* M. Ya. Melnikov
&& – &&
Ring Opening of Donor–Acceptor
Cyclopropanes with the Azide Ion: A
Tool for Construction of N-
Heterocycles
substituents, as well as the activated CH
fragment.
A kaleidoscope of synthetic
opportunities…
…is provided by a new family of
densely functionalized organic
building blocks produced by means
of one simple operation;
regioselective and stereospecific
ring opening of donor–acceptor
cyclopropanes with the azide ion.
The tolerance of functionalities
versus their strategic placement
combined with ability to undergo
selective modification allow these
building blocks to easily yield
a great diversity of N-heterocycles
of synthetic and biological
relevance. For more details, see the
Full Paper by E. M. Budynina, I. V.
Trushkov et al. on page && ff.
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ÝÝ These are not the final page numbers!