(3+3)-Annulation of Donor–Acceptor Cyclopropanes with Diaziridines

Article abstract of DOI:10.1002/anie.201805258

The first example of (3+3)-annulation of two different three-membered rings is reported herein. Donor-acceptor cyclopropanes in reaction with diaziridines were found to afford perhydropyridazine derivatives in high yields and diastereoselectivity under mi

Full text of DOI:10.1002/anie.201805258

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Accepted Article
Title: (3+3)-Annulation of Donor-Acceptor Cyclopropanes with
Diaziridines
Authors: Igor V. Trushkov, Alexey O. Chagarovskiy, Vladimir S. Vasin,
Vladimir V. Kuznetsov, Olga A. Ivanova, Victor B. Rybakov,
Alexey N. Shumsky, and Nina N. Makhova
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805258
Angew. Chem. 10.1002/ange.201805258
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10.1002/anie.201805258
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(3+3)-Annulation of Donor-Acceptor Cyclopropanes with
Diaziridines
Alexey O. Chagarovskiy,[a] Vladimir S. Vasin,[a] Vladimir V. Kuznetsov,[b] Olga A. Ivanova,*[c] Victor B.
Rybakov,[c] Alexey N. Shumsky,[d] Nina N. Makhova,[b] and Igor V. Trushkov*[a,e]
Abstract: The first example of (3+3)-annulation of two different
three-membered rings is reported herein. Donor-acceptor
cyclopropanes in reaction with diaziridines were found to afford
perhydropyridazine derivatives in high yields and diastereoselectivity
under mild Lewis acid catalysis. The disclosed reaction is applicable
for the broad substrate scope and exhibits an excellent functional
group tolerance.
(azomethine ylides for aziridines,[8] carbonyl ylides for oxiranes,[9]
synthon II in Scheme 1a) producing cycloadducts in reactions
with the appropriate unsaturated compounds. This kind of
reactivity is predominant for most three-membered rings with
two heteroatoms. Thus, in reactions involving small ring opening
diaziridines act as synthetic equivalents of azomethine imines
(synthon II, X = Y = NR).[10]
Three-membered rings due to their dipolar nature are able to
undergo (3+3)-cyclodimerization affording the corresponding six-
membered rings (Scheme 1b).[11] However, (3+3)-annulation of
two different saturated three-membered rings has not been
reported thus far owing to the difficulties in the selective
activation of this reactivity mode.[12] The reported reactions of D–
A cyclopropanes with aziridines,[13] oxiranes,[14] oxaziridines[15]
led to various products different from (3+3)-cycloadducts. Herein,
we report the first successful (3+3)-annulation of two different
saturated three-membered rings exemplified by Lewis acid-
induced coupling of D–A cyclopropanes with diaziridines
(Scheme 1c).
One-step construction of cyclic molecules from simple building
blocks with a considerable increase in a structure complexity is
one of the most important challenges of contemporary organic
chemistry. The essential processes for this purpose are various
cycloadditions, annulations and domino reactions with diverse
unsaturated compounds being typical building blocks.[1,2] In
contrast to alkenes, imines, alkynes, etc., three-membered rings
remain significantly underexplored as starting compounds for the
synthesis of larger rings except for their involvement into (3+2)-
cycloadditions. Meanwhile, three-membered heterocycles have
a high potential for organic synthesis; the high strain energy and
facile cleavage of the polarized carbon-heteroatom bond ensure
their efficient use as synthetic equivalents of 1,3-zwitter-ionic
synthon I (Scheme 1a).[3]
Cyclopropanes were for a long time considered as rather
kinetically inert species due to the absence of highly polarized
bonds in the all-carbon ring. However, the intensive study of
donor-acceptor (D–A) cyclopropanes[4-6] during last decades has
disproved this belief. Donor and acceptor substituents at the
vicinal carbon atoms polarize C–C bond between, allowing D–A
cyclopropanes to react efficiently as equivalents of synthon I
(Scheme 1a).[7]
On the other hand, three-membered heterocycles can exhibit
a reactivity of synthetic equivalents of common 1,3-dipoles
[a]
[b]
[c]
Dr. A. O. Chagarovskiy, Dr. V. S. Vasin, Prof. Dr. I. V. Trushkov
Dmitry Rogachev National Research Center of Pediatric
Hematology, Oncology and Immunology
Samory Mashela, 1, Moscow, 117997 Russian Federation
Dr. V. V. Kuznetsov, Prof. Dr. N. N. Makhova
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences
Leninsky pr. 47, Moscow 119991 Russian Federation
Dr. O. A. Ivanova, Dr. V. B. Rybakov
Department of Chemistry, M. V. Lomonosov Moscow State
University
Leninskie Gory, 1-3, Moscow 119991 Russian Federation
E-mail: iv@kinet.chem.msu.ru
Dr. A. N. Shumsky
Emanuel Institute of Biochemical Physics, Russian Academy of
Sciences
Kosygina 4, Moscow 119334 Russian Federation
Prof. Dr. I. V. Trushkov
Scheme 1. General concept of this work.
We started our research by determining the optimal conditions
for the title annulation using 2-phenylcyclopropane-1,1-diester
1a and readily available bicyclic diaziridine 2a as model
compounds. The screening of Lewis acids, which were
previously reported as efficient initiators of D–A cyclopropane
reactions with diverse nitrogen nucleophiles,[16] the variation of
the reaction duration and temperature as well as ratio and
concentration of starting compounds (Table 1) revealed that the
best yields of the desired hexahydropyridazine 3a were
obtained under catalysis with Sс(OTf)3 (Table 1, entry 4) or
Ni(ClO4)2·6H2O (Table 1, entries 6, 7) in dichloromethane. It is
noteworthy that milder Lewis acids failed to initiate this
annulation, while more activating Lewis acids as well as heating
of the reaction mixture above 60 C promoted the
[d]
[e]
Faculty of Science, RUDN University
Miklukho-Maklaya 6, Moscow 117198 Russian Federation
E-mail: itrushkov@mail.ru
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201805258
Angewandte Chemie International Edition
COMMUNICATION
decomposition of diaziridine resulting in low conversion of D–A
cyclopropane.
hinders the nucleophilic attack of diaziridine on the cyclopropane
resulting in the higher proportion of decomposed diaziridine.
Table 1. Variation of reaction conditions for (3+3)-annulation of 1a and 2a.[a]
Entry
LA (mol%)
Solvent
T
[C]
t
[h]
Yield [%][b
(trans:cis)[c]
1
2
3
4
5
6
7
8
9
SnCl4 (110)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
CH3NO2
rt
1
4
4
4
4
4
4
4
2
-
Sn(OTf)2 (10)
rt
Traces
25[d]
Sn(OTf)2 (10)
40
40
40
40
40
83
80
Sc(OTf)3 (10)
78 (69:31)
10[d]
Ni(OTf)2 (20)
Ni(ClO4)2·6H2O (20)
Ni(ClO4)2·6H2O (20)
Ni(ClO4)2·6H2O (20)
Ni(ClO4)2·6H2O (20)
73 (89:11)[e]
79 (92:8)[f]
[g]
-
[g]
-
[a]
[b]
Reaction conditions: 0.05 M solution of 1a, 1.5 equiv. of 2a.
Isolated
[c]
yields. Diastereomeric ratio (dr) was determined by NMR analysis of crude
product. Low conversion of 1; dr was not determined. Addition of 2a in a
single portion. [f] Portionwise addition of 2a. [g] Decomposition of 2a prevailed.
[d]
[e]
With the optimized reaction conditions in hand, we investigated
the scope of the disclosed (3+3)-annulation by varying
substituents in both reactants (Scheme 2). The reaction was
found to proceed efficiently for a broad series of cyclopropanes
bearing electron-enriched (1b-g,i) and electroneutral (1a,f-h)
(hetero)aromatic group as
a
donor. Moreover, alkenyl-
substituted D–A cyclopropane 1j was found to be equipotent to
(het)aryl-substituted analogs. On the other hand, a large variety
of bicyclic diaziridines, both with aryl, alkyl, alkenyl, cyclopropyl
groups at the carbon atom of three-membered ring and
unsubstituted at this atom (2j) participated efficiently in the
annulation.
However, electron-withdrawing substituents in both aromatic
group of D–A cyclopropane 1 and diaziridine 2 significantly
decelerated the reported reaction. All attempts to involve 2-(2-
nitrophenyl)cyclopropane-1,1-dicarboxylate into this annulation
were unsuccessful. Similarly, 4-pyridyl analog of 2a was found to
be inert against cyclopropanes 1 under the used conditions.
Monocyclic triethyldiaziridine 2h demonstrated the intermediate
behavior. Its reaction with D–A cyclopropane 1d afforded (3+3)-
annulation product only in 36% yield due to the low conversion
(ca. 50%) of cyclopropane. In other words, yield based on the
consumed cyclopropane equals to ca. 72%. Presumably, trans-
arrangement of ethyl substituents at two nitrogen atoms[17]
Scheme 2. Scope of (3+3)-annulation of cyclopropanes 1 with diaziridines 2.
General reaction conditions: 0.05 M solution of 1, portionwise addition of 2
(1.25–3 equiv.), molecular sieves 4Å, CH2Cl2, reflux. Yields of isolated
products are given; dr was determined by NMR analysis of crude product.
In the presence of Lewis acids diaziridines can undergo (3+3)-
cyclodimerization; and the dimers, in reactions with unsaturated
compounds, were reported to demonstrate similar reactivity as
parent diaziridines affording the same products.[18] The possible
explanation is the intermediacy of the same 1,3-dipole in
reactions of both diaziridines and the corresponding cyclodimers
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10.1002/anie.201805258
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4. To check the validity of this hypothesis, we studied the
reaction of cyclopropanes 1 with compounds 4 and disclosed
that pyrazolo[1,2-a]pyridazine derivatives 3 were formed as well.
From the investigations presented in Scheme 4 it is possible to
conclude that: a) the studied annulation includes the
cyclopropane ring opening via SN2-like mechanism; b) the final
step of the adducts 3 formation is cyclization of 1,6-zwitter-ion X
(Scheme 5). Herewith, the reaction diastereoselectivity is
governed by: 1) the relative arrangement of the fragment of
former cyclopropane against the iminium moiety and 2) E-/Z-
configuration of this moiety. These features are similar for all X
formed from 1,5-diazabicyclo[3.1.0]hexanes (2a-g,i,k,l) but one
of two parameters is opposite in reactions of dimers 4 and 1,6-
diazabicyclo[3.1.0]hexanes 2o,p. The diastereoselectivity data
show also that X is transient species the cyclization of which is
faster than Z-/E-isomerization and sp3 nitrogen inversion
(otherwise compounds 2 and 4 should produce the same
reaction mixture).[22]
However,
a
surprising
reversal
of
the
reaction
diastereoselectivity was observed. When substrates 2 were
used as starting compounds, trans-3 were formed as major or
single products, while in reactions of dimers 4 the predominant
formation of cis-3 was noted (Scheme 3). Moreover, Sc(OTf)3
failed to promote the reaction of D–A cyclopropanes 1 with
dimers 4 in contrast to the reaction between 1 and 2.
Scheme 3. Reaction of D–A cyclopropanes 1 with diaziridine dimers 4.
Scheme 5. The intermediate X determining diastereoselectivity of 3 formation.
These results are in conflict with both the intermediacy of the
same species in two processes and the thermodynamic control
of this annulation. Indeed, according to DFT calculations at the
B3LYP/6-311G** level, cis-3ab is slightly (1.34 kJ mol-1) more
stable than trans-3ab,[19] however, any attempts to induce cis-
trans epimerization of both isomers of 3 were unsuccessful.[20]
To shed more light on the mechanism of reaction, we
studied its stereochemical features (Scheme 4). The reaction of
the optically pure cyclopropane (R)-1a with diaziridines 2c,p
proceeded with a full inversion at the reacting C(2) atom. On the
other hand, the reaction of diastereomerically pure D–A
cyclopropane 1k bearing two different acceptor groups with
diaziridine 2c resulted in an equimolar mixture of epimers at the
malonate carbon atom (Scheme 4).[21]
In turn, X is formed by the nucleophilic attack of a diaziridine on
D–A cyclopropane followed by a conrotatory ring opening of the
nitrogen heterocycle isoelectronic to a cyclopropane anion.[23]
Due to the steric restrictions induced by a small size of the linker
between two nitrogen atoms, this opening can proceed in one
direction only affording the intermediate X with Z-configuration of
the iminium moiety. Therefore, the reaction diastereoselectivity
is primarily determined by a relative arrangement of malonate
and iminium fragments in X that is resulted from the different
approaches of various diaziridines to D–A cyclopropanes in SN2
step.
As 1,5-diazabicyclo[3.1.0]hexanes has the pseudo-boat
conformation,[24] steric repulsions during its approach to 1 would
be minimal when the methine hydrogen at the cyclopropane
C(2) atom is directed to the C(6) atom of diaziridine. Oppositely,
this direction of the approach of two reactants is unfavorable due
to the boat conformation of the six-membered ring in diaziridines
2o,p.[19,24b] Therefore, these diaziridines approach to D–A
cyclopropane in a such way that the methine hydrogen at the
cyclopropane C(2) atom is directed to the C(3)–C(4) bond of
diaziridine. This is why intermediates A and A' are formed with
different diastereoselectivity. Further diaziridine ring opening and
cyclization of the produced intermediates B (B') proceed in a
stereoselective manner affording trans-3 and cis-3 respectively.
The results of this analysis are summarized in Scheme 6.
Nevertheless, further study of mechanism is desirable for the
better understanding factors influencing the reaction efficiency
and stereoselectivity.
Scheme 4. Stereochemical features of (3+3)-annulation between D–A
cyclopropanes 1 and diaziridines 2.
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10.1002/anie.201805258
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Scheme 6. Proposed mechanism of (3+3)-annulation.
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To conclude, we disclosed that the Lewis acid-catalyzed
reaction of donor-acceptor cyclopropanes with diaziridines
affords perhydropyridazine derivatives in high yield and
diastereoselectivity. This finding provides the way to a new
engaging valley of small rings reactivity: (3+3)-annulations of two
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Acknowledgements
We thank Russian Science Foundation (grant 17-73-10404) for
financial support of this work.
Keywords: annulation • small ring systems • donor-acceptor
cyclopropanes • diaziridines • nitrogen heterocycles
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789.
[18] a) Y. S. Syroeshkina, V. V. Kuznetsov, K. A. Lyssenko, N. N. Makhova,
Russ. Chem. Bull. 2009, 58, 366-379; b) Y. B. Koptelov, Russ. J. Org.
Chem. 2006, 42, 1510-1515.
[19] For details, see Supporting Information.
[20] For Lewis acid-induced opening of (3+n)-cycloadducts of D–A
cyclopropanes, see: a) Y. A. Volkova, E. M. Budynina, A. E. Kaplun, O.
A. Ivanova, A. O. Chagarovskiy, D. A. Skvortsov, V. B. Rybakov, I. V.
Trushkov, M. Y. Melnikov, Chem. Eur. J. 2013, 19, 6586-6590; b) A. O.
Chagarovskiy, O. A. Ivanova, E. M. Budynina, E. L. Kolychev, M. S.
Nechaev, I. V. Trushkov, M. Y. Melnikov, Russ. Chem. Bull. 2013, 62,
2407-2423.
[21] The structure of compound 3ac* as well as structures of compounds
3ca, 3hl, 3ao, 2p and 4b were unambiguously proved by X-ray data.
CCDC1582038 (2p), 1582039 (4dCHCl3), 1585886 ((5R,8S)-3ac*),
1581835 ((5RS,8SR)-3ca), 1581838 ((5RS,8SR)-3hl), and 1581841
((5RS,8RS)-3ao) contain the supplementary crystallographic data for
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10.1002/anie.201805258
Angewandte Chemie International Edition
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Beautiful dissymmetry: Reported
here is the first example of (3+3)-
annulation of two different saturated
A. O. Chagarovskiy, V. S. Vasin, V. V.
Kuznetsov, O. A. Ivanova,* V. B.
Rybakov, A. N. Shumsky, N. N.
Makhova, I. V. Trushkov*
three-membered
rings.
Namely,
coupling of diaziridines with donor-
acceptor cyclopropanes is shown to
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afford
hexahydropyridazine
(3+3)-Annulation of Donor-Acceptor
Cyclopropanes with Diaziridines
derivatives. This approach can be an
efficient tool for the synthesis of
diverse non-symmetric polysubstituted
six-membered rings.
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