Pathways of Pd-catalyzed cyclopropanation of tetrahydroindene with diazomethane

Article abstract of DOI:10.1016/j.mencom.2020.09.020

The Pd-catalyzed cyclopropanation of 3a,4,7,7a-tetrahydro-1H-indene with diazomethane unexpectedly affords monoand dicyclopropanation products in good yields, the cyclopentene double bond being approximately three times more reactive than the cyclohexene one. In contrast, similar independent competitive cyclopropanation of a cyclopentene–cyclohexene mixture has shown that cyclohexene exhibits an abnormally low reactivity differing by about two orders of magnitude.

Full text of DOI:10.1016/j.mencom.2020.09.020

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 612–614
Pathways of Pd-catalyzed cyclopropanation
of tetrahydroindene with diazomethane
Evgeny V. Shulishov, Olga A. Pantyukh, Leonid G. Menchikov and Yury V. Tomilov*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. E-mail: tom@ioc.ac.ru
DOI: 10.1016/j.mencom.2020.09.020
The Pd-catalyzed cyclopropanation of 3a,4,7,7a-tetrahydro-
CH2N2
1H-indene with diazomethane unexpectedly affords mono-
and dicyclopropanation products in good yields, the cyclo-
pentene double bond being approximately three times more
reactive than the cyclohexene one. In contrast, similar
independentcompetitivecyclopropanationofacyclopentene–
cyclohexene mixture has shown that cyclohexene exhibits an
abnormally low reactivity differing by about two orders of
magnitude.
+
Pd(acac)2
CH2Cl2
~3:1
CH2N2
Pd(acac)2
up to 95%
Keywords: 3a,4,7,7a-tetrahydro-1H-indene, diazomethane, N-methyl-N-nitrosourea, cyclopropanation, palladium catalysis.
Cyclopropane moiety is met in numerous natural and biologically
active compounds, including polycyclic ones.1–4 Cyclopropane
compounds are widely used as intermediates in organic
synthesis.5–7 One of the general methods for building the
cyclopropane moiety involves the catalytic cyclopropanation of
double bonds with diazomethane in rather a wide range of
unsaturated compounds. In this case, palladium compounds
being the most efficient catalysts8–12 generally depriving of side
processes and formation of by-products. This reaction proceeds
without formation of carbene intermediates. Its mechanism
includes the initial formation of a complex of low-valence
palladium with an olefin, which then would react with a diazo
compound leading through a palladacyclobutane intermediate to
dicyclopentadiene 1 (both endo and exo isomers) with
diazomethane in the presence of Pd(OAc)2 or (PhCN)2PdCl2
occurred exclusively at the norbornene double bond to give
a
monocyclopropanation product, viz., compound
2
(Scheme 1).10,18–21 The cyclopentene moiety was not affected
under these conditions. Based on these facts, it was believed
until now that cyclopentene moiety was nearly inactive in the
Pd-catalyzed cyclopropanation with diazomethane.
CH2N2
Pd-cat.
endo- or exo-1
endo- or exo-2
a
cyclopropane product.7,8 Hence, palladium compounds
effectively catalyze the cyclopropanation of only those olefins
which are well coordinated with palladium. For example,
terminal double bonds are cyclopropanated most easily in
alkenes, whereas alkyl substituents at a double bond abruptly
decrease its cyclopropanation capability or totally preclude this
reaction.8 In some cases, even partial cyclopropanation of a
trisubstituted double bond requires 10- or even 100-fold excess
of diazomethane.13–15
Similar regularities are observed in the cycloalkene series: on
transition from cyclooctene to cyclohexene, the reactivity
decreases significantly with decreasing ring size. In fact, the
reactions of cyclooctene, cycloheptene and cyclohexene with an
equimolar amount of diazomethane in the presence of various
palladium-based catalysts [Pd(OAc)2, (PhCN)2PdCl2, etc.]
result in bicyclo[n.1.0]alkanes in yields of 90–93% (n = 6),
80–82% (n = 5), and no higher than 15% (n = 4).8,16 The very
low reactivity of cyclohexene in comparison with other
unsaturated compounds was also confirmed by the method of
competitive reactions:17 approximately a thousand times lower
than that of norbornene and two hundred times lower than that of
styrene. The catalytic cyclopropanation of the next member of
the cycloalkene series, cyclopentene, with diazomethane was not
reported. It was known that the cyclopropanation of
Scheme 1
On the other hand, cycloalkenes annulated with other rings or
incorporated into a polycyclic system can possess different
reactivity and would not be unable to undergo catalytic
diazomethane cyclopropanation.8 Of such polycyclic hydro-
carbons, compounds of polyhydro cyclopropa[a]indene family 3
in which the cyclopentane ring is fused with the cyclohexane one
are of particular interest since they are not uncommon among
natural and other practically valuable compounds (terpenes,
steroids, etc.).
3
To create moiety 3, multistage schemes are usually employed
in the targeted syntheses of hydrocarbons, in particular, with
preliminary incorporation of activating substituents at the double
bond.5 Development of methods for the direct cyclopropanation
of bicyclo[4.3.0]nonene derivatives should allow one to simplify
the synthesis of such compounds.
To identify the effect of annulation of a cyclopentene moiety
with a six-membered ring, we studied the cyclopropanation of
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2020, 30, 612–614
3a,4,7,7a-tetrahydro-1H-indene 4 which, in contrast to cyclo-
bond. Thus, the catalytic cyclopropanation of tetrahydroindene
with diazomethane at the first stage occurs at both double bonds,
but mainly at the cyclopentene one. Unfortunately, we failed to
identify unambiguously whether the resulting cyclopropane
moiety had anti or syn orientation. However, based on the
regularities of cyclopropanation of 1,3-cyclopentadiene and
1,5-cyclooctadiene moieties, it can be expected that the less
sterically hindered anti-5 and anti-6 tricyclic hydrocarbons
should be the main isomers.
Product of double cyclopropanation 7, according to NMR
data, is a mixture of three isomers (of four possible) in
approximately 8:1:1 ratio. The assignment of these isomers
seems to be even more difficult due to overlapping of the majority
of signals. However, if we take into account the predominant
formation of anti-isomers in the case of monoadducts and the
effect of steric factors in their further cyclopropanation, then the
predominant formation of the anti,anti-isomer among diadducts
7 appears quite reasonable (see Online Supplementary Materials,
Scheme S1). Most probably, syn,syn-7 should be the missing
isomer.
pentadiene dimers, contains no bridging methylene moiety that
determines the specific properties of the norbornene double
bond. The catalytic cyclopropanation of tetrahydroindene was
carried out in the presence of Pd(acac)2 under conditions of
in situ diazomethane generation from N-methyl-N-nitrosourea
(MNU). To our delight, we accomplished cyclopropanation of
each double bond in the molecule and even both double bonds
depending on the amount of diazomethane generated. In this
way, both regioisomeric monocyclopropanation products 5, 6
and diadduct 7 were accessed (Scheme 2). Importantly, to
complete cyclopropanation of both double bonds, no more than
3 equiv. of CH2N2 were required, which corresponded to the
application of about 4 equiv. of technical grade MNU (see Online
Supplementary Materials).22
MeN(NO)CONH2
KOH
CH2N2
+
Pd(acac)2
H
H
CH2Cl2
4
5
6
H
H
CH2N2
anti,anti-7
syn,syn-7
Pd(acac)2
7
When (PhCN)2PdCl2 is used as the catalyst, the conversion of
the starting 4 with the same amount of diazomethane decreases
by 15–20% compared to the case of Pd(acac)2. However, the
reaction products and their ratio remain almost the same.
Scheme 2
Since each of the monocyclopropane adducts 5, 6 can be anti-
and syn-configured and diadduct 7 structure can be conceived as
four stereoisomers, it was necessary to find out their spatial
configuration. It should be noted that preparative separation of
monocyclopropanation adducts just like dicyclopropanation
ones was not possible. At the same time, the use of various
amounts of generated diazomethane allowed us to obtain a
mixture of monoadducts 5, 6 in one experiment and diadduct 7
(as stereoisomer mixture) in the separate synthesis (Table 1).
The conversion of tetrahydroindene 4 up to 70–75% gave
monoadducts 5, 6 as the main reaction products which were
separated from other components by fractional distillation.
GC/MS analysis revealed all the 4 isomers, of which only two in
a ratio of (3.1–3.4):1.0 predominated, whereas the amount of
other two was ca. 1–2%. Approximately the same ratio of the
main isomeric monoadducts was observed in the 1H and
13C NMR spectra. Analysis of the spectra showed that the signals
for the protons and C atoms at the double bond in the main
component nearly coincided and corresponded to two CH2
moieties. This was possible only if the cyclohexene moiety was
preserved and, accordingly, the cyclopropanation of the
cyclopentene double bond in the starting diene 4 took place.
In the minor monoadduct, the signals for the olefinic H and C
atoms diverge strongly and correlate with different fragments
(with CH on one side, and with CH2 on the other side), which
evidenced for the cyclopropanation of the cyclohexene double
Thus, the change in the geometric and, apparently, electronic
parameters of the double bonds in tetrahydroindene 4 in
comparison with dicyclopentadiene made it possible to efficiently
perform its cyclopropanation. In order to estimate the reactivity
of double bonds in cycloalkenes themselves, we studied the
competitive cyclopropanation of an equimolar mixture of
cyclopentene, cyclohexene, cycloheptene, cyclooctene and
3a,4,7,7a-tetrahydro-1H-indene 4 with diazomethane in the
presence of Pd(acac)2. The ratio of bicyclo[n.1.0]alkene
derivatives C6H10/C7H12/C8H14/C9H16/5/6 in the reaction with
0.8 equiv. CH2N2 was approximately 100:1:110:120:160:55.
The fact that cycloheptene or cyclooctene rather well underwent
cyclopropanation in the presence of (PhCN)2PdCl2 has been
known previously.17 However, the fact that cyclopentene is by
two orders of magnitude more reactive than cyclohexene
appears rather unexpected, especially in view of the comparison
of the reactivity of the double bonds in tetrahydroindene 4.
Annulation of the cyclopentene and cyclohexene moieties
leads to the activation of both double bonds, moreover, the
reactivity of the cyclopentene double bond increases by about
one and a half times, while the reactivity of the cyclohexene
double bond increases by more than 50 times. Thus, in a series
of simple cycloalkenes, the cyclopentene double bond has a
high reactivity, whereas the reactivity of cyclohexene is
abnormally low.
Taking the results obtained into account, we studied the
cyclopropanation of dicyclopentadiene 1 (both endo and exo
isomers) with excess diazomethane in the presence of Pd(OAc)2
and (PhCN)2PdCl2 more thoroughly. Cyclopropanation of the
endo-isomer with a threefold excess of diazomethane afforded
1–3% of the pentacyclic bis-adduct 8 along with the main
monoadduct endo-2 (Scheme 3). In this case, after the
cyclopropanation of the norbornene double bond in compound 1
is complete, the catalyst quickly decomposed to give a Pd-
containing precipitate and the catalyst activity decreased sharply.
In the case of Pd(acac)2, which obviously gives a more stable
Table 1 The composition of the reaction mixture at different ratios of
diene 4 and generated diazomethane.
Composition of the reaction mixture (%)
CH2N2
Entry
(equiv.)
4
5
6
7
1
2
3
4
0.8
1.6
2.3
2.9
57
26
9
29
48
23
3.4
9
5
15
7
11
61
95
0.5
1.1
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endo-2
exo-2
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CH2N2
Pd(acac)2
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Scheme 3
catalytic form, and with a threefold excess of diazomethane, the
yield of hydrocarbon 8 from endo-dicyclopentadiene 1 can be
increased to ~25%, whereas in the case of exo-isomer 2, the
analogous bis-adduct is practically not formed (see Scheme 3).
The results obtained in this study show that the catalytic
cyclopropanation of double bonds with diazomethane is very
subtly affected by the nature of these bonds and their ability for
coordination with the active form of the palladium catalyst. Even
in the case of same-type double bonds in unsaturated hydro-
carbons where no significant electronic effect of substituents is
observed, their reactivity can differ by orders of magnitude.
In this case, cyclopropanation of even low-activity double bonds
can be achieved if the activity of the Pd catalyst itself is preserved,
like, for example, in the case of Pd(acac)2, and with a large
excess of diazomethane, which in such cases mainly decomposes
to give ethylene and cyclopropane. The discovered possibility of
relatively facile cyclopropanation of tetrahydroindene 4, mainly
at the cyclopentene moiety, opens a way for the synthesis of a
number of practically important compounds, in particular,
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The authors are grateful to V. A. Korolev (N. D. Zelinsky
Institute of Organic Chemistry) for GC-MS analyses, and to
Yu. A. Strelenko (N. D. Zelinsky Institute of Organic Chemistry)
for assistance in performing NMR analyses.
This study did not receive any grant from funding agencies in
the public, commercial, or nonprofit sectors.
25 A.-R. Wang, H.-C. Song, H.-M. An, Q. Huang, X. Luo and J.-Y. Dong,
Online Supplementary Materials
Chem. Biodiversity, 2015, 12, 451.
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.09.020.
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Received: 23rd April 2020; Com. 20/6204
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