Thermal induced intramolecular [2 + 2] cycloaddition of allene-ACPs

Article abstract of DOI:10.1039/c3ob40911b

A facile synthetic method for preparation of bicyclo[4.2.0] nitrogen heterocycles has been developed via a thermal induced intramolecular [2 + 2] cycloaddition reaction of allene-ACPs. The DFT calculations indicate that this intramolecular cycloaddition proceeds in a concerted manner and a strained small ring is essential. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40911b

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Thermal induced intramolecular [2 + 2] cycloaddition
of allene-ACPs†
Cite this: Org. Biomol. Chem., 2013, 11,
3949
Kai Chen,a Run Sun,a Qin Xu,*a Yin Weib and Min Shi*a,b
Received 2nd May 2013,
Accepted 4th May 2013
DOI: 10.1039/c3ob40911b
www.rsc.org/obc
A facile synthetic method for preparation of bicyclo[4.2.0] nitro- processes can trigger various reactions of MCPs with other
gen heterocycles has been developed via a thermal induced intra- substrates, giving efficient access to enhanced molecular com-
molecular [2 + 2] cycloaddition reaction of allene-ACPs. The DFT plexity in organic syntheses.10 However, only a few examples of
calculations indicate that this intramolecular cycloaddition pro- [2 + 2] cycloaddition of methylene- and alkylidenecyclo-
ceeds in a concerted manner and a strained small ring is essential.
propanes have been developed so far. In 2006, Nakamura,
Yamamoto and co-workers first reported silver salt-catalyzed or
thermal induced [2 + 2] cycloaddition of imines to (alkoxy-
methylene)cyclopropanes, giving the desired cycloadducts in
moderate to good yields.11 They also disclosed the [2 + 2] cyclo-
addition reaction of (benzyloxymethylene)cyclopropane with
alkylidenemalononitriles at ambient pressure upon heating,
affording the corresponding cyclobutane derivatives in high
yields.12 Since Yamamoto and co-workers first reported the Pd-
catalyzed chemical transformation of aniline-tethered alkylide-
necyclopropanes,13 recently we found a convenient synthetic
method of functionalized pyrrolo[1,2-a]indoles via a thermal
induced [3 + 2] cyclization reaction of aniline-tethered alkylide-
necyclopropanes with aldehydes.14 These interesting findings
have encouraged us to further explore more useful transform-
ations with these special MCPs or their derivatives such as
N-(buta-2,3-dienyl)-2-(cyclopropylidenemethyl)anilines 1, which
could be easily prepared according to the previous literature
(see the ESI†).15
During the past few decades, allene chemistry has been
revealed as an established member of the weaponry utilized in
modern synthetic chemistry.1 Cycloaddition reactions that
occur without the use of additional reagents or catalysts and
without creating any waste have attracted much attention in
recent years as an ideal process in terms of atom economy.2
The allene moiety represents an excellent partner for [2 + 2]
cycloaddition with alkenes and alkynes, affording the corres-
ponding cyclobutane and cyclobutene skeletons in a single
step. The importance of the cyclobutane or cyclobutene con-
taining compounds both as target molecules and as useful
building blocks for the construction of more complex mole-
cular structures has been widely demonstrated.3 Thus far, the
[2 + 2] cycloaddition of allenes has been studied upon photo-
irradiation4,5 or under thermal-induced conditions.6 More
recently, transition metal catalyzed [2 + 2] cycloaddition of
allenes has been also disclosed along with applications in
natural product synthesis.7
We found that upon heating 1 at 110 °C in toluene, the
bicyclo[4.2.0] nitrogen heterocycles 2 could be obtained in
good yields via an intramolecular [2 + 2] cycloaddition process,
affording a novel synthetic approach to the useful bicyclo
[4.2.0] nitrogen heterocycles. In this paper, we wish to report
the details of this interesting transformation.
Methylenecyclopropanes (MCPs), as highly strained but
readily accessible molecules, can undergo a variety of ring-
opening reactions in the presence of transition metals or
Lewis acids because the relief of ring strain can provide a
potent thermodynamic driving force.8,9 These ring-opening
We initially investigated the thermal induced [2 + 2] cyclo-
addition reaction of aniline-tethered alkylidenecyclopropane 1a
in different solvents at different temperatures and the results
are summarized in Table 1. The reaction of 1a in THF at 60 °C
did not give any new product (Table 1, entry 1). Using toluene
as the solvent and raising the reaction temperature to 80 °C, no
reaction occurred (Table 1, entry 2). Raising the reaction temp-
erature to 110 °C produced the corresponding [2 + 2] cyclo-
addition product 2a in 80% yield (Table 1, entry 3). Its structure
has been unambiguously determined by X-ray diffraction. Its
aKey Laboratory for Advanced Materials and Institute of Fine Chemicals, East China
University of Science and Technology, 130 MeiLong Road, Shanghai 200237,
P. R. China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
P. R. China. E-mail: mshi@mail.sioc.ac.cn
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data of new compounds. CCDC 885057 and 895654.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40911b
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Under the optimized reaction conditions (0.1 mmol 1 in
1.0 mL ortho-xylene at 140 °C), we next examined the substrate
scope of this reaction and the results are shown in Table 2. As
for substrates 1b–1d, in which R1 = 4-MeC6H4, 4-ClC6H4,
4-FC6H4, the reactions proceeded smoothly to furnish the
desired products 2b–2d in 62–77% yields, regardless of
whether they have electron-rich or electron-poor aromatic
rings (Table 2, entries 1–3). When aromatic R2 has a 5-Cl or a
4-MeO substituent, the reactions still proceeded efficiently to
afford the desired products 2e and 2f in 67–81% yields
(Table 2, entries 4 and 5). Changing X to NSO2(o-NO2C6H4),
NNs, NBs, NSO2Ph, NAc and NBz, the reactions also proceeded
smoothly, furnishing the desired products 2g–2l in 65–82%
yields (Table 2, entries 6–11). When R1 is a methyl group, the
reaction took place very well to afford the desired product 2m
in 76% yield at 170 °C in 1,2-dichlorobenzene (Table 2, entry
12). However, 1n could not be transformed to 2n presumably
due to the steric effect of the ortho-substituent in the aromatic
R1 group (Table 2, entry 13). Changing the R1 group to a hydro-
gen atom or changing X to an oxygen atom, no reactions
occurred (Table 2, entries 14 and 15). We also attempted to use
Au(PPh3)Cl, AgOTf, Au(PPh3)Cl/AgOTf or Pd(PPh3)4 as a cata-
lyst in this [2 + 2] cycloaddition reaction at lower temperature
(about 80 °C), but no reaction occurred.
Table 1 Optimization of the reaction conditions of thermal induced intramole-
cular [2 + 2] cycloaddition of 1a
Entry
Solvent
T/°C
Time/h
Yielda (%)
1
2
3
4
5
THF
Toluene
Toluene
ortho-Xylene
ortho-Xylene
60
80
110
130
140
18
12
36
12
8
0
0
80
89
91
a Isolated yield.
To gain more mechanistic insights into this intramolecular
[2 + 2] cycloaddition reaction, several control experiments were
performed as shown in Scheme 1. These control experiments
confirmed that this cyclization reaction under the optimized
Fig. 1 ORTEP drawing of 2a.
ORTEP drawing is presented in Fig. 1 and the corresponding conditions was unaffected by the addition of the radical
CIF data have been presented in the ESI.†16 Upon heating 1a at inhibitors such as TEMPO (2.0 equiv.) and 2,6-di-tert-butyl-
130 °C in ortho-xylene within 12 h, 2a was obtained in 89% 4-methylphenol (BHT) (2.0 equiv.), rendering unlikely the inter-
yield (Table 1, entry 4) and carrying out the reaction at 140 °C vention of a radical pathway. However, considering that the
led to the formation of 2a in 91% yield (Table 1, entry 5).
short-life biradical intermediate in a solvent cage may not be
Table 2 Substrate scope of intramolecular [2 + 2] cycloaddition of N-(buta-2,3-dienyl)-2-(cyclopropylidenemethyl)anilines 1a
Entry
Substrate
R1
R2
X
Product 2
Yieldb (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
4-MeC6H4
4-ClC6H4
4-FC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Me
2-ClC6H4
H
C6H5
H
H
H
5-Cl
4-MeO
H
H
H
H
H
H
H
5-Cl
H
4-MeO
NTs
NTs
NTs
NTs
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
77
70
62
67
81
78
78
65
73
82
82
76c
—
—
—
NTs
NSO2(o-NO2C6H4)
NNs
NBs
NSO2Ph
NAc
NBz
NTs
NTs
NTs
O
9
10
11
12
13
14
15
a Reaction conditions: 1 (0.1 mmol), ortho-xylene (1.0 mL), 140 °C, 8 h. b Isolated yield. c 1,2-Dicholorobenzene (1.0 mL), 170 °C, 8 h.
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Scheme 1 Control experiments of 1a in the presence of TEMPO or 2,6-di-tert-
butyl-4-methylphenol.
Scheme 4 A theoretical investigation of the formation of products 2a and 2a’.
cyclization reaction of 1a is a concerted cycloaddition rather
than a two-step reaction11,12 with an energy barrier of 69.2 kcal
mol−1, which accounts for the fact that the reaction requires
high temperature. For comparison, we also calculated the reac-
tion pathways of 1q and 1r, respectively. The calculation
results show that the reactions of 1q and 1r have higher energy
Scheme 2 Control experiments of 1q and 1r under the standard conditions.
barriers than that of 1a by 8.7 kcal mol−1 and 5.3 kcal mol−1
,
respectively, indicating that the reactions of 1q and 1r require
higher temperature or harsh reaction conditions. In addition,
the corresponding products 2q and 2r are thermodynamically
less stable than product 2a by 13.9 kcal mol−1 and 9.1 kcal mol−1
,
respectively. These results may explain why we did not
obtain the corresponding products 2q and 2r in the
above experiments under the standard reaction conditions.
Subsequently, we theoretically investigated the reaction
pathway for the formation of anti-product 2a′. The calculation
results showed that the energy barrier (69.7 kcal mol−1) is
slightly higher than that for the formation of syn-product 2a
(69.2 kcal mol−1) (Scheme 4). However, the syn-product 2a is
more stable than the anti-product 2a′ by 18.4 kcal mol−1
,
which may account for the fact that the syn-product 2a is
exclusively obtained in our experiments.
The cyclobutane group of the obtained bicyclo[4.2.0] nitro-
gen heterocycles can be converted into the cyclobutene group
along with the ring opening of cyclopropane. For example,
product 2a can be easily transformed into product 3a in 78%
yield by treatment of BiCl3 (2.0 equiv.) in toluene at 80 °C for
10 h (Scheme 5). This is a new type of 2a,3,4,8b-tetrahydro-
cyclobuta[c]quinoline derivatives which have not been intensively
studied so far. Its structure has been unambiguously deter-
mined by X-ray diffraction. Its ORTEP drawing and the corres-
ponding CIF data have been presented in the ESI.†16
Scheme 3 A theoretical investigation of the reaction pathways.
captured by the radical inhibitors such as TEMPO and BHT, a
free radical pathway cannot be completely ruled out at the
present stage.
The other control experiments were also performed as
shown in Scheme 2. These substrates 1q and 1r, which have
no cyclopropane moiety, could not be converted into the
desired products under the standard conditions, indicating
that the strained small ring is essential in this intramolecular
[2 + 2] cycloaddition reaction.
In order to further elucidate the mechanism of this intra-
molecular [2 + 2] cycloaddition reaction, we have theoretically
investigated the reaction pathways as shown in Scheme 3 (for
the details, see the ESI†). All calculations have been performed
at the B3LYP/6-31G(d) level with the Gaussian 09 program.17
The DFT calculations indicate that this intramolecular [2 + 2]
Scheme 5 Transformation of compound 2a to 3a.
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In summary, a facile synthetic method for preparation of
functionalized bicyclo[4.2.0] nitrogen heterocycles has been
developed via a thermal induced intramolecular [2 + 2] cyclo-
addition reaction of N-(buta-2,3-dienyl)-2-(cyclopropylidene-
methyl)anilines and the DFT calculations indicate that this
intramolecular cycloaddition proceeds via a concerted manner
and a strained small ring is essential. The products 2 and the
transformed product 3a have important structure motifs in
organic and medicinal chemistry. The potential utilization and
extension of the scope of this synthetic methodology are cur-
rently under investigation.
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Acknowledgements
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), the National Basic Research
Program of China (973) (2009CB825300), and the National
Natural Science Foundation of China (21072206, 20472096,
20872162, 20672127, 21102166, 20732008 and 21121062) for
financial support.
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