Diels-Alder reactions between hexafluoro-2-butyne and bis-furyl dienes: Kinetic: versus thermodynamic control

Article abstract of DOI:10.1039/c7cc09466c

The tandem [4+2] cycloaddition between hexafluoro-2-butyne and bis-furyl dienes, like difurfuryl ester, at room temperature leads to the kinetically controlled pincer -adducts-annulated 4a,8a-bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes. On the other hand, if these reactions proceed at 140 °C, only the thermodynamically controlled domino -adducts-annulated 2,3-bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes-are formed. Therefore, a very rare and unexpected example of full kinetic and thermodynamic control in the Diels-Alder reaction is reported in this paper.

Full text of DOI:10.1039/c7cc09466c

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Diels–Alder reactions between hexafluoro-2-
butyne and bis-furyl dienes: kinetic versus
thermodynamic control†
Cite this:DOI: 10.1039/c7cc09466c
Received 9th December 2017,
Accepted 24th January 2018
a
a
b
a
Kseniya K. Borisova,
Victor N. Khrustalev,
Eugeniya V. Nikitina,
Pavel V. Dorovatovskii,
Vladimir P. Zaytsev,
Roman A. Novikov,
Yan V. Zubavichus,
Alexey V. Varlamov
a
c
c
d
a
DOI: 10.1039/c7cc09466c
Maxim L. Kuznetsov,
and
a
Fedor I. Zubkov
*
rsc.li/chemcomm
The tandem [4+2] cycloaddition between hexafluoro-2-butyne and carbon based electronic materials.2 The annulated 7-oxabicyclo-
bis-furyl dienes, like difurfuryl ester, at room temperature leads [2.2.1]heptane moiety acts as a framework for molecular tweezers,3
to the kinetically controlled ‘‘pincer’’-adducts – annulated 4a,8a- various supramolecular systems,4 donor–bridge–acceptor
bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes. On the molecules,5 a wide range of bioactive and natural compounds,6
other hand, if these reactions proceed at 140 8C, only the thermo- high-molecular weight materials,6e,7 etc.
dynamically controlled ‘‘domino’’-adducts – annulated 2,3-bis(tri-
Taking into account such widespread actual or potential
fluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes – are formed. applications of the IMDAF reaction products, design of new
Therefore, a very rare and unexpected example of full kinetic and efficient molecular systems for these processes and the under-
thermodynamic control in the Diels–Alder reaction is reported in standing of intimate mechanistic details and driving forces under-
this paper.
lying these reactions are of obvious general importance.
Various alkynes were used in the tandem intramolecular [4+2]
Domino and tandem intramolecular Diels–Alder reactions of cycloaddition, but only limited information concerning the
furans (IMDAF reaction) are widely used in organic synthesis reactivity of fluorinated acetylenes is available.8 In 1985, this
for different purposes due to their simplicity, reliability and journal published pioneering work by Visnick and Battiste,9
controlled stereochemistry.1 In particular, the products of the who reported an unprecedented example of the total kinetic
IMDAF reaction are often applied as starting materials for the and thermodynamic control in the course of the domino [4+2]
synthesis of functionally substituted naphthalenes, indoles, cycloaddition between hexafluorobut-2-yne and N,N0-dipyrrolyl-
isoindoles, quinolines and isoquinolines.1c
methane (1, Scheme 1). When the reaction was carried out
The products of the reaction between furans and alkynes under kinetically controlled conditions (room temperature),
have a 7-oxabicyclo[2.2.1]heptene scaffold. The structural motif only the pincer-type polycycle 3 was formed through the open
has great potential as a tool for the design and synthesis of a intermediate 2. Upon heating, however, the pincer adduct 3
broad diversity of substances with various practically useful underwent an intramolecular rearrangement into the domino-
properties. For example, recently these cycloadducts have been type adduct 4. Both reactions proceeded in quantitative yields,
used for the construction of polycyclic aromatic hydrocarbons – unlike other known cycloadditions of this type,10 which usually
fragments of graphene, which can serve as a model for new lead to a mixture of products of kinetic and thermodynamic
control, regardless of the reaction temperature. For a long time,
a Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University
of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow, 117198,
Russian Federation. E-mail: fzubkov@sci.pfu.edu.ru
b V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,
32 Vavilov St., Moscow, 119991, Russian Federation. E-mail: novikovfff@bk.ru
c National Research Center ‘‘Kurchatov Institute’’, 1 Acad. Kurchatov Sq.,
Moscow, 123182, Russia. E-mail: yzubav@gmail.com
d
´
´
Centro de Quımica Estrutural, Instituto Superior Tecnico, Universidade de Lisboa,
Av. Rovisco Pais, Lisbon 1049-001, Portugal. E-mail: max@mail.ist.utl.pt
† Electronic supplementary information (ESI) available: Single-crystal X-ray
descriptions for 7c, d, and g and 8c, d, and g; computational details and tables
with energies and atomic coordinates; detailed synthetic procedures and spectral
data for compounds 5, 7, and 8. CCDC 1570123–1570128. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c7cc09466c
Scheme 1 Example of the total temperature control in the tandem intra-
molecular Diels–Alder reaction.9a
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the transformation discussed in that paper had been attractive TS2k or resulting in the formation of the domino product 8 via
in synthetic11 and theoretical12 chemistry research, but it TS2t. The calculations showed that the first channel is more
remained unique due to the limited accessibility of the suitable kinetically favourable (by 5.7–5.9 kcal molꢀ1), which is in
starting bis-dienes.
agreement with the published experimental observations9,13 on
In 1997, the second example similar to system 1 appeared in the exclusive formation of the pincer products at room tempera-
a report by Lautens and Fillion who demonstrated that difuryl ture. Meanwhile, the domino products 8 are more thermo-
bis-dienes in a reaction with alkynes are able to give pincer- dynamically stable than 7 by 4.2–4.7 kcal molꢀ1, and this fact
cycloadducts analogous to 3 under kinetically controlled may cause the isomerization of 7 into 8 at elevated temperature.
conditions.13
Indeed, the calculated activation barriers for the 7 - 8 iso-
Having obtained a significant insight from previous reports merization via the retro-Diels–Alder reaction of 7 followed by the
about the importance of kinetic and thermodynamic control in intramolecular [4+2]-cycloaddition in the chain intermediate 6 to
intra/intermolecular [4+2]-cycloaddition reactions, our main goal give 8 are 34.0–34.4 kcal molꢀ1. These values are reasonable to
in this study was to expand the available classes of dienes and permit such a process at a sufficiently high temperature. Taking
dienophiles for the implementation of the tandem Diels–Alder into account these predictions, the following experiments were
reaction under kinetic or thermodynamic control conditions. In performed.
this work, we focused on bis-furyldienes 5 that can be easily
Under kinetically controlled conditions, the reaction of bis-
obtained in a two-step process,10a,13a and on hexafluorobutyne as dienes 5 with hexafluorobutyne was carried out in sealed glass
a dienophile. The latter, apparently, is the most active known ampules at ꢀ70 1C, with subsequent increase of temperature to
dienophile and usually ensures excellent yields of the cycloaddition B21–24 1C during 2–3 h. Toluene was chosen as a solvent due
products at low temperatures. However, the experimental treatment to its inertness, relatively low volatility and low melting point.
of this alkyne has some peculiarities due to its gaseous state under Under these conditions, the reaction can occur within five days,
normal conditions.
but in order to reach a true equilibrium, all reactions were run
Theoretical DFT calculations (IEFPCM-M06-2X/6-311++G**) for 10 days at r.t.
1
of the reaction between F3CCRCCF3 and three dienes (5a, 5c,
The H NMR data of the crude reaction mixtures obtained
and 5g) were carried out (for computational details, see the after gentle evaporation of the solvent are given in Table 1.
ESI†). The reaction starts with the cycloaddition of F3CCRCCF3 In most cases, the cycloaddition occurs chemospecifically leading
at one of the furan moieties which occurs in a concerted fashion to the kinetically controlled adducts 7a, d, g, and h only in quanti-
via TS1 (Fig. 1) and represents the rate-limiting step of the whole tative yields or proceeds with a high level of chemoselectivity; the
process with the activation barrier of 23.1–26.8 kcal molꢀ1 ratio of pincer/domino adducts is 7/8 4 95/5 (entries e, f, and i).
(in terms of DGa).
The ratio of diene/alkyne varied from 1/1 to 1/1.4, and in most
Further, the reaction could proceed via two competing cases did not significantly affect both the yield of the products and
channels, i.e. either leading to the pincer-type products 7 via the composition of the reaction mixtures.
Fig. 1 Gibbs free energy profile for the reaction between bis-dienes 5a, c, and g and F3CCRCCF3. The relative energies are given in kcal molꢀ1 for
X = CH2 (plain text), S (italic) and NC(O)CF3 (bold).
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Table 1 Conditions of kinetic and thermodynamic control and yields of
adducts 7 and 8
Molar ratio of 5/C4F6 Ratiob of 7/8 7c (%) 8c,d (%)
a
Entry
X
a
b
c
d
e
f
g
h
i
CH2
O
S
N-Bn
N-Ac
N-Bz
N-COCF3 1/1.4
N-COCCl3 1/1
N-CO2Me 1/1
1/1.1
1/1.1
1/1.1
1/1.4
1/1.1
1/1.1
100/0
69
60
76
71
62
70
56
62
79
62
67
76
66
68
76
77
74
71
e
—
—
e
100/0
495/5
496/4
100/0
100/0
495/5
a
All reactions were carried out in sealed ampules at r.t. for 10 days.
b
Ratio of 7/8 according to the 1H NMR analysis of the reaction mixtures
c
obtained after solvent evaporation. Isolated yields after recrystalliza-
tion. Domino-adducts 8 were obtained by heating of pincer-adducts 7
in o-xylene for 2 h. See Table 2.
d
e
Scheme 3 Compositions of the reaction mixtures in the case of the [4+2]
cycloaddition between F3CCRCCF3 and bis-furans 5b and c.
However, two examples in Table 1 (rows b: X = O and c: X = S)
drop out of the series and gave rise to a lower chemoselectivity
(Scheme 2).
Table 2 Compositions of the crude reaction mixtures obtained after
In these cases, in addition to the side domino-adducts 8b
and c, the products of the double cycloaddition 9b and c and
10b and c were formed as inseparable diastereomeric pairs with
a practically equal ratio of components (Scheme 3 and Table 2).
The formation of bis-adducts 9 and 10 suggests that in these
examples, the intermolecular Diels–Alder reaction involving a
subsequent interaction of the second molecule of hexafluoro-
butyne with intermediates 6b and c takes place. In other words,
the intermolecular [4+2] cycloaddition between C4F6 and inter-
mediate 6 starts to compete with the intramolecular Diels–Alder
reaction in the chain intermediate.
interaction of bis-dienes 5b and
c with F3CCRCCF3 according to
1H NMR analysis
Entry
X
Ratio of 5/C4F6
5 (%)
7a (%)
8 (%)
9 + 10b (%)
b
O
O
S
1/1
1/1.1
1/1
14.9
4.4
8.3
5.2
64.9
63.2
82.3
78.0
5.1
4.5
3.6
2.9
15.1
27.9
5.8
b0
c
c0
S
1/1.1
13.9
a
The isolated yield of pincer-adducts 7 after recrystallization is given in
b
Table 1, rows b and c. Ratio of 9/10 is B50/50.
Initially, the reactions of 5b and c were carried out with adducts 9 and 10, but at the same time, the ratio of 7/8 remains
1.0 mol equivalent of C4F6 under similar conditions: 10 days at virtually constant (it changes only from 96/4 to 93/7).
r.t. (rows b and c in Table 2). At the equimolar ratio of 5/C4F6,
The rearrangement of the pincer-adducts 7 to the domino-
the reaction mixtures contained 8–15% of unreacted starting products 8 is observed at temperatures higher than 110 1C
bis-furans 5b and c, therefore the molar ratio of 5/C4F6 was (1H NMR experiments with a temperature gradient were carried
changed by 1/1.1. Under these conditions (rows b0 and c0), the out) and proceeds rather quickly at 120 1C. According to NMR
percentage of the initial 5b and c in the crude reaction mixtures spectroscopic data in boiling o-xylene, the products of thermo-
was reduced to 4–5%. Simultaneously, a sharp increase (up to dynamic control 8 were formed in 100% yields at 1–2 h, but after
28%) in the content of the double-adducts 9 and 10 was recrystallization they were isolated in moderate yields (Table 1).
observed. Due to this, we did not perform further experiments
Since the last transformation 7 - 8 occurred in reasonable
with a larger excess of hexafluorobutyne. The data shown in time without any by-products, the half-life and rate constant
Table 2 allow us to conclude that the excess of alkyne exerts a have been calculated using dynamic 1H NMR spectroscopy
significant influence on the fraction of the double cycloaddition assuming first-order kinetics. The reaction involving the
Scheme 2 Synthesis of pincer and domino adducts 7 and 8.
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,
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In conclusion, a rare example of full kinetic and thermo-
dynamic reaction control in the process of the tandem IMDAF
reaction of bis-furyl dienes with hexafluoro-2-butyne has been
discovered. At room temperature, the reaction occurs chemo-
selectively leading to adducts of the pincer-[4+2] cycloaddition.
The exclusive formation of domino-adducts is observed at elevated
temperatures. This reaction could be useful for the construction of
natural product and supramolecular frameworks and can serve as
an outstanding example of reaction reversibility to be used in
physical chemistry courses.
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Funding for this research was provided by the Ministry
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Conflicts of interest
There are no conflicts to declare.
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