Thermally-Induced Intramolecular [4+2] Cycloaddition of Allylamino- or Allyloxy-Tethered Alkylidenecyclopropanes

Article abstract of DOI:10.1002/asia.202100635

A thermally-induced intramolecular [4+2] cycloaddition reaction of allylamino- or allyloxy-tethered alkylidenecyclopropanes has been reported in this paper, giving a new protocol for the rapid construction of polycyclic skeleton molecules in moderate to e

Full text of DOI:10.1002/asia.202100635

doi.org/10.1002/asia.202100635
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Thermally-Induced Intramolecular [4+2] Cycloaddition of
Allylamino- or Allyloxy-Tethered Alkylidenecyclopropanes
Leyi Tao, Yin Wei,* and Min Shi*[a]
Abstract: A thermally-induced intramolecular [4+2] cyclo-
addition reaction of allylamino- or allyloxy-tethered alkylide-
necyclopropanes has been reported in this paper, giving a
new protocol for the rapid construction of polycyclic skeleton
molecules in moderate to excellent yields with a broad
substrate scope. On the basis of control experiments and DFT
calculations, we disclosed that the reaction proceeded
through a [4+2] cycloaddition and trace of water assisted
1,3-H shift process to give the target product.
Alkylidenecyclopropanes (ACPs) are high-tension molecules
with high activity and diverse reactivity. Nevertheless, they
could be manipulated as stable compounds under ambient
conditions. On the basis of these properties, transformation of
ACPs has been a hot research topic in synthetic chemistry for a
long time, and they have been extensively used in the rapid
construction of various types of polycyclic skeleton molecules
under mild conditions.[1] Due to the potent thermodynamic
driving force of releasing the ring strain, a variety of cyclization
reactions of ACPs were reported upon heating,[2] Lewis or
Brønsted acid catalysis,[3] free radical initiated addition[4] and
transition metal catalysis.[5] In particular, thermally-induced
cyclization reactions of ACPs are mainly dominated by inter- or
intramolecular cycloaddition reactions involving with their
connected exocyclic double bond owing to that the electron
cloud density of ACP’s carbon-carbon double bond is higher
than that of general olefin’s one as a result of the conjugated
electron-donating effect of cyclopropyl ring.[6] Therefore, ACPs
can be used as a good carrier of the three-membered ring to
use their connected exocyclic double bonds undergoing the
cyclization reaction with dienes, dipoles and olefins via [4+2],[7]
[3+2],[8] [2+2][9] and the other cycloaddition reactions. With
regard to this aspect, in 1971–1972, Baldwin, Pasto and Noyori
groups reported the intermolecular [4+2] cycloaddition reac-
tion between diarylmethylenecyclopropanes and tetracyano-
ethylene (TCNE) successively.[7a,8a,9a] This cycloaddition reaction
generated the relatively unstable cycloaddition product, afford-
ing the naphthalene derivatives through the process of losing
one molecule of HCN and the ring-opening rearrangement of
three-membered ring (Scheme 1, eq 1).
introducing functional groups into ACPs, can significantly
expand the reaction modes of intra- or intermolecular
cyclizations.[1m] For the thermally-induced cycloaddition reaction
of ACPs, we found that ACPs tethered with functional groups
such as allene and alkene, could be applied to synthesize
complex polycyclic compounds effectively. In 2012, our group
reported a thermally-induced intramolecular [2+2] cycloaddi-
tion of allene-tethered ACPs to synthesize a series of bicyclo
[4.2.0] nitrogen atom containing heterocycles, bearing impor-
tant spiro[2.3]hexane structural motifs in organic and medicinal
chemistry (Scheme 1, eq 2).[10] In 2018, our group also reported
the thermally-induced intramolecular [2+2] cycloaddition of
acrylamide-tethered ACPs, affording the regio- and diastereose-
lective synthetic method of cyclobutane-containing spiro[2.3]
hexane fused with six-membered heterocycles (Scheme 1,
eq 3).[11]
Inspired by these interesting findings, we envisaged that
allyl-tethered ACPs could also afford polycyclic compounds
In recent years, we and others have found that functional-
ized alkylidenecyclopropanes (FACPs), which are produced by
[a] L. Tao, Dr. Y. Wei, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Center for Excellence Molecular Synthesis
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
University of Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai 200032 (P. R. China)
E-mail: weiyin@sioc.ac.cn
mshi@mail.sioc.ac.cn
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100635
Scheme 1. Previous work and this work.
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°
through an intramolecular cycloaddition pathway. Herein, we
wish to report a thermally-induced intramolecular [4+2] cyclo-
addition of tosylated, mesylated and the other sulfonated
allylamine- or allyloxy-tethered alkylidenecyclopropanes to
furnish a series of polycyclic skeleton molecules. This interesting
cyclization reaction features a [4+2] Diels-Alder cycloaddition
and H2O assisted 1,3-H shift process.
lowering the reaction temperature to 110 C or raising the
°
reaction temperature to 130 C did not improve the yield of
product 2a, suggesting that the appropriate temperature for
°
this reaction was 120 C (entries 8 and 9). In addition, shortening
or lengthening the reaction time did not give the desired
product 2a in better yields (entries 10 and 11). Finally, the
reaction could give product 2a with the same NMR yield (84%
yield) using 1 mL of toluene, and increasing the volume of
toluene to 4 mL did not improve the yield of 2a (entries 12 and
13). To summarize, this cycloaddition reaction should be carried
We first utilized substrate 1a as a model substrate for the
°
initial examination at 120 C in toluene under argon atmos-
phere, and found that the desired polycyclic product 2a was
given in 84% NMR yield within 12 h along with 80% isolated
yield (Table 1, entry 1). The structure of product 2a has been
unambiguously determined by X-ray diffraction (Figure 1), and
its crystal data are presented in the Supporting Information (SI).
Then, we further optimized the reaction conditions, and the
results are summarized in Table 1. Firstly, we screened other
organic solvents such as PhCl, 1,4-dioxane, DMF, DMSO, H2O
and DCE and identified that toluene was the best solvent for
this cycloaddition reaction (entries 2–7). Then, we found that
°
out in toluene (2.0 mL or 1.0 mL) at 120 C within 12 h.
With the optimal conditions in hand, we next investigated
the generality of this intramolecular cycloaddition reaction
using various tosylated and mesylated allylamine- or allyloxy-
tethered alkylidenecyclopropanes 1b–1aj as substrates and the
results are elucidated in Table 2. When R1 group is a halogen
atom at the para-position such as substrates 1b–1e, the
reaction proceeded smoothly, giving the desired products 2b–
2e in good to excellent yields ranging from 72%–92%.
Substrates 1f–1j, having an electron-rich aromatic ring, fur-
nished the corresponding products in the yields depending on
the position of substituent at the aromatic ring. When -CH3,
-OCH3 and -tBu groups were present at the para-position of
benzene ring, the corresponding products 2f, 2g and 2h were
obtained in 83%, 81% and 91% yields, respectively. However,
when -CH3 group was introduced at the ortho-position of
benzene ring, none of the corresponding product 2i was
afforded presumably due to the steric hindrance. However,
when -CH3 group was present at the meta-position of benzene
ring, products 2j and 2j’ were obtained in 52% and 40% yields
respectively as a regioisomeric mixture. These results indicate
that the electronic effect of substituent did not have significant
impact on product’s yield, however the substituted position
had an important influence on the reaction outcome due to the
steric effect. Then, we examined the substituent effect at
tosylated allylamine-tethered aryl moiety and found that the
substituents could be halogen atoms, methyl or methoxy group
and had little influence on the reaction outcomes of this
cycloaddition reaction, affording the desired products 2k–2o in
76%–92% yields. Next, substrates 1p and 1q having substitu-
ents on both aromatic rings were also examined, and the
corresponding product 2p was given in 76% yield, but the
desired product 2q could not be obtained due to the ortho-
substituent of chlorine atom for the same reason of steric
hindrance. In addition, substrate 1r bearing a 2-naphthyl
moiety and substrate 1s having a thiophene group were also
tolerated, furnishing products 2r and 2s in 93% and 70% yields,
respectively. It is worth mentioning that 13% of [2+2] cyclo-
adduct 2 s’ was also obtained in the reaction of 1s, perhaps
due to that the electron-rich thiophene group affected
electronic property of the connected olefinic unit as compared
with phenyl group.
Table 1. Optimization of the reaction conditions.[a]
entry
solvent
temp [ C]
time [h]
yield [%][b]
°
1
2
3
4
5
6
7
8
toluene (2 mL)
PhCl (2 mL)
1,4-dioxane (2 mL)
DMF (2 mL)
DMSO (2 mL)
H2O (2 mL)
120
120
120
120
120
120
80
110
130
120
120
120
120
12
12
12
12
12
12
12
12
12
8
84 (80)
82
32
34
52
56
-
52
84
73
84
84
81
DCE (2 mL)
toluene (2 mL)
toluene (2 mL)
toluene (2 mL)
toluene (2 mL)
toluene (1 mL)
toluene (4 mL)
9
10
11
12
13
16
12
12
[a] Unless otherwise specified, all reactions were carried out using 1a
(0.2 mmol) in solvent. [b] Yields were determined by 1H NMR spectroscopy
using 1,3,5-trimethoxybenzene as an internal standard and isolated yield
in parentheses.
When R1 group is a phenyl group, we also examined
substituent effect of R3 group and R4 group in the allyl moiety
and found that these substituents also had a significant effect
on the reaction outcome. For substrate 1t, in which R4 is a
methyl group, the desired product 2t was formed in 73% yield.
Figure 1. X-ray crystal structures of 2a and 2y.
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Table 2. Substrate scope of 1 for the cycloaddition reaction.[a,b]
However, [2+2] cycloaddition took place to give cycloadduct
2u in 41% yield and the recovered starting material (rsm) ratio
was 37% when R3 was a methyl group due to the steric effect as
well as electron-donating effect, and its relative configuration
was determined by 1H-1H NOESY spectra (for more detailed
information, see pages S116–117 in the Supporting Informa-
tion). When R4 group was a gem-dimethyl group, none of the
desired product 2v was formed because of the serious steric
effect. In the case of substrate 1w, the corresponding product
2w was furnished in 43% yield and trace amount of [2+2]
cycloaddition byproduct was also observed. Furthermore, we
also explored the tolerance of linker X in this cycloaddition and
found that the reaction proceeded quite well when X is a NMs,
NBs, and NSO2Ph, giving the corresponding products 2x, 2z,
and 2ab in 92%, 89% and 84% yields, respectively. As for
substrate 1y, in which X is a NMs and R4 is a phenyl group, the
reaction furnished the [4+2] cycloadduct 2y and the [2+2]
cycloadduct 2y’ in 26% and 51% yields, respectively also due to
the steric effect. Herein, we speculated that the reason for the
different experimental results of substrates 1u, 1w and 1y was
mainly due to the steric hindrance of substituents R3 and -Ts/-
Ms because intramolecular reaction is quite sensitive to the
steric effect. The structure of 2y has been unequivocally
determined by X-ray diffraction, and its ORTEP drawing is
indicated in Figure 1 and the related structural data are shown
in the SI. Moreover, the relative configuration of product 2y’
1
was also determined by H-1H NOESY spectra (see pages S117–
120 in the Supporting Information for more details). More
interestingly, when the linker X is a NNs group, the reaction
produced the desired product 2aa in 33% along with a benzylic
oxidative product 2aa’ in 24% yield presumably due to the
strong oxidizing property of -NO2 group.
When the linker X was an oxygen atom, we examined the
substituent effect at allyloxy-tethered aryl moiety and found
that the desired products 2ac–2af could be furnished in 76%–
89% yields when R2 is a hydrogen atom, a chlorine atom, a
methyl or a methoxy substituent. Finally, it should be also
emphasized here that substrates 1ag–1aj did not afford the
°
corresponding products even at 140 C, implying the impor-
tance of cyclopropane moiety and allyl unit in this thermally-
induced [4+2] cycloaddition reaction.[6] The electron-donating
effect of cyclopropyl group and the release of ring strain from
41 kcal/mol of methylenecyclopropane to 27.5 kcal/mol of
cyclopropane both are beneficial for the smooth proceeding of
this particular Diels-Alder reaction.
°
We attempted to change the temperature from 110 C to
°
140 C. However, the product distribution of substrates 1j, 1s,
1u, 1y and 1aa remained basically unchanged. In addition, the
°
substrates 1i and 1ag–1aj still did not react even at 140 C.
Meanwhile, it should be also mentioned here is that all the
products shown in Table 2 were obtained as a single diaster-
eomer.
Next, we focused on investigating the mechanism of this
[a] Unless otherwise specified, all reactions were carried out using 1
°
(0.2 mmol) in 2.0 mL toluene at 120 C within 12 h under Ar atmosphere.
cycloaddition
reaction.
According
to
the
previous
[b] Isolated yield.
reports,[7a,8a,9a,10,11] an initially proposed reaction mechanism for
this cycloaddition reaction is shown in Scheme 2. Firstly,
substrate 1 proceeds through a [4+2] Diels-Alder reaction
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upon treating product 2a under the same conditions
(Scheme 3, eqs 4 and 5). Finally, when the substrate 1a’ without
the tethered allyl group was employed to undergo the same
reaction in the presence of D2O in a sealed tube, no reaction
occurred and the recovered starting material (rsm) ratio of 1a’
was more than 99% (Scheme 3, eq 6). These results indicated
that ambient H2O in the reaction system is likely to participate
in this particular cycloaddition reaction process.
Scheme 2. The initially proposed reaction mechanism of this reaction.
On the basis of these mechanistic studies and the previous
DFT calculations, another plausible mechanism is outlined in
Scheme 4. The reaction firstly proceeds through a [4+2] Diels-
Alder reaction pathway to afford cyclohexadiene intermediate
A with an exocyclic carbon-carbon double bond. Then, the
exogenous water in the reaction system adds to the exocyclic
carbon-carbon double bond of intermediate A at high temper-
ature to furnish intermediate B, which undergoes a dehydration
process with another adjacent hydrogen atom to deliver the
target polycyclic skeleton product 2 along with the regener-
ation of water molecule. Thus, the formal 1,3-H shift process is
assisted by the trace of water existed in the reaction system. It
is worth noting that another addition intermediate B’ may also
be formed, however, it could be reconverted to intermediate A
through releasing of water molecule (Scheme 4). We also tried
to capture intermediate A or B upon adding external electron
deficient olefin such as methyl cinnamate into the reaction
system of substrate 1a. However, this trapping experiment was
not successful, and the corresponding product 2a was still
obtained along with the recovery of methyl cinnamate (for the
detailed information, see Scheme S8 and Figure S2 at page S11
in the Supporting Information).
The proposed reaction mechanism shown in Scheme 4 was
also investigated by DFT calculations using the same program
mentioned above. The solvation Gibbs free energy profile in
toluene for the suggested reaction pathway is shown in
Figure 2 (the ΔG298 (kcal/mol), see Supporting Information for
the details). In order to directly reflect the change of solvation
Gibbs free energy in the reaction process, the calculated
solvation Gibbs free energy values of 1a, TS1, A and 2a were
added the value of H2O’s calculated solvation Gibbs free energy.
We investigated the reaction pathway starting from intermedi-
ate 1a+H2O shown in Figure 1. Firstly, substrate 1a proceeds
through the Diels-Alder process to form intermediate A via TS1
with an energy barrier of 34.5 kcal/mol. Subsequently, the
addition of water molecule to the exocyclic carbon-carbon
process to afford intermediate A upon heating at high temper-
ature. Then, intermediate A delivers the target product 2 via a
1,3-H shift process.
Then, we embarked DFT studies on the proposed reaction
mechanism for this work. The mechanism was investigated by
DFT calculations using the SMD/M06/6-311+G(d,p)//B3LYP/6-
31G(d) level of theory with Gaussian 09 program. To simplify
the calculation process, we investigated the reaction pathway
starting from substrate 1a. However, the suggested transition
state from intermediate A to product 2a could not be located
after several attempts by the DFT calculations, prompting us to
consider whether the proposed mechanism is reasonable.
On the basis of Yu’s work,[12] a trace amount of water can
play a critical role in assisting the process of 1,2- or 1,4-H shift.
Therefore, to verify the reaction mechanism, several control
experiments were conducted, and the results are shown in
Scheme 3. Firstly, using butylated hydroxytoluene (BHT) and
2,2,6,6-tetramethylpiperidinooxy (TEMPO) as radical inhibitors,
the yields of the desired product 2a were obtained in 77% and
75% respectively under the standard conditions, suggesting a
non-radical reaction pathway (Scheme 3, eqs 1 and 2). Then, it
is surprising that adding 4 Å molecular sieves (100 mg) to get
rid of trace amount of water in the reaction system could
decrease the yield of 2a to 27% (Scheme 3, eq 3). Next, two
deuterium labeling experiments were performed by adding D2O
as deuterium source under the standard conditions. We found
that the corresponding product 2a was formed in 80% yield
along with 61% D content incorporation at the benzylic carbon
atom. Furthermore, no deuterium incorporation was observed
Scheme 3. Control experiments of this reaction.
Scheme 4. The proposed reaction mechanism of this reaction.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: Alkylidenecyclopropanes · [4+2] cycloaddition ·
DFT calculations · Water assistance · 1,3-H shift
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energy values in toluene solution are given in kcal/mol).
double bond of intermediate A generates intermediate B
through TS2 with an energy barrier of 39.0 kcal-mol, which is
the rate-determining step in the reaction. Finally, the hydroxyl
group of intermediate B is dehydrated away with another
adjacent hydrogen atom, delivering the target product 2a
through the transition state TS3 peaked at 38.3 kcal/mol. This
calculation result is in line with the experimental conditions in
which the high temperature is required for this reaction.
~
Moreover, the total G298,rxn in toluene of this reaction is –
40.5 kcal/mol overall, accounting for
favourable process.
a thermodynamically
In conclusion, we have discovered a novel thermally-
induced intramolecular [4+2] cycloaddition reaction of sulfo-
nated allylamine- or allyloxy-tethered alkylidenecyclopropanes,
giving a series of polycyclic skeleton molecules in moderate to
excellent yields with a broad substrate scope. On the basis of
control experiments and DFT calculations, a plausible reaction
mechanism has been proposed. In general, the reaction
proceeded through an intramolecular [4+2] cycloaddition and
trace of water assisted 1,3-H shift processes to afford the
desired polycyclic skeleton product. Further investigations on
expanding the applications of this synthetic method are
ongoing in our laboratory.
Acknowledgements
We are grateful for the financial support from the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant No.
XDB20000000), the National Natural Science Foundation of China
(21372250, 21121062, 21302203, 20732008, 21772037, 21772226,
21861132014 and 91956115).
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Manuscript received: June 12, 2021
Revised manuscript received: July 6, 2021
Accepted manuscript online: July 7, 2021
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Full Paper
FULL PAPER
L. Tao, Dr. Y. Wei*, Prof. Dr. M. Shi*
1 – 7
Thermally-Induced Intramolecular
[4+2] Cycloaddition of Allylami-
no- or Allyloxy-Tethered Alkylide-
necyclopropanes
A novel thermally-induced intramo-
lecular [4+2] cycloaddition of allyla-
mino- or allyloxy-tethered alkylidene-
cyclopropanes for the rapid
construction of polycyclic skeleton
molecules.