DBU-mediated transformation of arylmethylenecyclopropenes to alkylidenecyclopropanes

Article abstract of DOI:10.1016/j.tetlet.2013.04.076

An interesting DBU-mediated intramolecular isomerization of arylmethylenecyclopropenes 1 to alkylidenecyclopropanes (ACPs) has been described in this context. A variety of ACPs were obtained through a base-assisted manner in moderate to good yields under mild conditions with good stereoselectivities in most cases.

Full text of DOI:10.1016/j.tetlet.2013.04.076

Tetrahedron Letters 54 (2013) 3591–3594
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DBU-mediated transformation of arylmethylenecyclopropenes
to alkylidenecyclopropanes
⇑
Rui Sang, Hai-Bin Yang, Min Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An interesting DBU-mediated intramolecular isomerization of arylmethylenecyclopropenes 1 to alkylid-
enecyclopropanes (ACPs) has been described in this context. A variety of ACPs were obtained through a
base-assisted manner in moderate to good yields under mild conditions with good stereoselectivities in
most cases.
Received 18 March 2013
Revised 15 April 2013
Accepted 16 April 2013
Available online 24 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
DBU
Alkylidenecyclopropanes (ACPs)
Cyclopropanation
Cyclopropenes
Proton migration
Methylenecyclopropanes or alkylidenecyclopropanes (MCPs or
ACPs) are highly strained but readily accessible molecules that
have served as useful building blocks in organic synthesis.1 MCPs
(ACPs) can undergo a variety of ring-opening reactions because
the release of the cyclopropyl ring strain (40 kcal/mol)2 can
Ph3P
Br
Br
+
Ph3P
Br
xylene,
reflux, 16 h,
90%
Br
O
R2
R1
R1
R2
provide a thermodynamic driving force and the
p-character of
NaH, THF, reflux,
10 h, 50-90%
the ring bonds of the cyclopropane can afford the kinetic opportu-
nity to initiate the unleashing of the strain.3 Since the 1970s, the
chemistry of MCPs (ACPs) has been widely explored in the pres-
ence of transition metal catalysts4 and the developments in this
field have been comprehensively reviewed by Binger and Buech,5
Donaldson,6 Lautens et al.,7 Yamamoto and co-workers,8 Shi
et al.,9 Rubin et al.,10 Scheme 1 shows one of the most popular
methods for the synthesis of MCPs (ACPs), in which a two-step
process is involved including the formation of 3-bromo-triphenyl-
phosphonium bromide from the reaction of 1,3-dibromopropane
with triphenylphosphine and a subsequent Wittig reaction with
ketones and aldehydes.11
Another useful preparation method is the Rh(I)-catalyzed [2+1]
cyclopropanation of allenes with dizaocompounds (Scheme 2).12 In
this Letter, we wish to report an alternative method for the prepa-
ration of ACPs in moderate to good yields with good stereoselectiv-
ities in most cases under mild conditions from a DBU-mediated
isomerization of arylmethylenecyclopropenes (Scheme 2).
Initially, we started to prepare various cyclopropenes 1 by
means of Rh-catalyzed cyclopropanation of alkynes with diazo
Scheme 1. One of the most popular methods for the synthesis of MCPs (ACPs).
previous work:
EWG
N2
Rh2(OAc)4
solvent
EWG
R
+
R
H
this work:
EWG
EWG
DBU
solvent
R
R
Scheme 2. Alternative methods for the preparation of alkylidenecyclopropanes
(ACPs).
compounds 2. During the optimization of the reaction conditions
(see Supplementary data), we found that Rh2esp2 (bis[rhodium
(a,a, ,
a0 a0-tetramethyl-1,3-benzenedipropionic acid)]) is the best
catalyst for this transformation, affording the corresponding
cycloadducts 3 in good yields in toluene at room temperature
(Table 1).
⇑
Corresponding author. Tel.: +86 21 54925137; fax: +86 21 64166128.
E-mail address: Mshi@mail.sioc.ac.cn (M. Shi).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.076

3592
R. Sang et al. / Tetrahedron Letters 54 (2013) 3591–3594
Table 1
Table 2
Preparation of various cyclopropenes 3
Optimization of the reaction conditions for base-promoted isomerization of 3a
R1
R2
N2
CO2Et
CF3
CO2Et
CF3
Rh2esp2 (0.5 mol %)
toluene, r.t.
base
+
Ar
Ar
R1
R2
solvent, temp
2
1
3a
Base
4a
Entrya
1
2
Yieldb (%)
3
Entrya
3a:base
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
HMPA
HMPA
HMPA
HMPA
LDA
Et3N
DMAP
DBU
NaOH
Na2CO3
K2CO3
DBU
DBU
DBU
1:1
1:2
1:3
1:4
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
Toluene
DMF
DCE
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
72
80
85
85
60
41
56
92
14
—
N2
CO2Et
CF3
F3C
CO2Et
N2
1
2
2a
1a
3a
, 97
CO2Me
CO2Me
1a
1a
MeO2C
N2
CO2Me
2b
3b
, 90
CO2Et
—
3
4
H
CO2Et
88
76
80
87
92
2c
3c, 55
3d, 95
CO2Et
CF3
2a
2a
DBU
DBU
1b
CO2Et
CF3
a
The reactions were carried out with cycloprene 3a (0.2 mmol, 1 equiv) and base
(ꢀ equiv) in 2 mL solvent at room temperature within 5 h under argon.
5
6
7
b
Isolated yields.
1c
1d
3e, 70
CO2Et
CF3
the desired ACPs 4b and 4c in 89% and 65% yields under the stan-
dard conditions, respectively (Table 3, entries 2 and 3). However,
using 3d as the substrate, no reaction occurred, suggesting that
an arylmethylene group is required for this base promoted isomer-
ization (Table 3, entry 4). Moreover, regardless of whether Ar is a
naphthyl group or Ar bearing an electron-rich or -poor group, the
reactions proceeded smoothly to give the corresponding products
4e–4i in good yields, indicating that the electronic property of
the Ar group did not have significant impact on the reaction out-
comes (Table 3, entries 5–9). Other substrates, such as 3j and 3l
in which R1 = R2 = F or R1 = H, R2 = CF3, respectively, also afforded
the desired products 4j and 4l in good yields under the standard
conditions (Table 3, entries 10 and 12). Using arylmethylenecyc-
lopropenone 3k as the substrate, no desired product was formed
and complex product mixtures were obtained (Table 3, entry 11).
It should be also noted that in most cases, the desired ACPs were
formed as only E-configuration or E:Z ratio = 98:2 (entry 3). Only
in the case of 3j, the corresponding ACP 4j was formed in a E:Z ra-
tio = 1:0.9, perhaps due to the electronic property of fluorine atom
(Table 3, entry 10).
2a
2a
3f
, 87
Br
CO2Et
CF3
Br
1e
3g, 93
3h, 75
CO2Et
CF3
8
9
2a
2a
1f
Cl
CO2Et
CF3
Cl
1g
3i, 91
a
Standard reaction conditions: 2 (1.5 mmol, 3.0 equiv) in a degassed toluene
(15 mL) was added to a 5 mL toluene solution of 1 (0.5 mmol, 1.0 equiv) and
Rh2esp2 (0.5 mol %) by a micro-injection pump within 10 h at room temperature
under argon, and then, the reaction mixtures were stirred at room temperature for
4 h under argon.
b
Isolated samples.
The further transformations of 4a have been indicated in
Schemes 3 and 4, respectively. The hydroxylation of the ester
group in 4a produced 5a in 91% yield, which could be used to react
with p-bromobenzylamine in the presence of EDCI and HOBt to
give the corresponding amide product 6a in 45% yield (Scheme 3).
The structure of 5a has been assigned by X-ray diffraction. The
ORTEP drawing is shown in Figure 1 and the CIF data are presented
in the Supplementary data.13
With these cyclopropenes in hand, the base-promoted isomeri-
zation has been examined using 3a as a model substrate with a
variety of bases including inorganic bases and the results are
shown in Table 2. Using HMPA (hexamethylphosphoramide)
(1.0 equiv) as a base promoter afforded ACP 4a in 72% yield in
THF within 5 h (Table 2, entry 1). Increasing the employed
amounts of HMPA to 2.0, 3.0, or 4.0 equiv provided 4a in 80% or
85% yields, respectively (Table 2, entries 2–4). Using a strong base
such as LDA afforded 4a in 60% yield (Table 2, entry 5). The
examination of other organic bases (3.0 equiv) such as Et3N, DMAP
(4-N,N-dimethylaminopyridine) and DBU (1,8-diazabicyclo[5.4.0]
undec-7-ene) revealed that DBU is the most efficient base
promoter in this reaction, affording 4a in 92% yield in THF (Table 2,
entries 6–8). Inorganic bases are not effective promoters in this
reaction (Table 2, entries 9–11). We also examined the solvent
effects in this reaction and found that THF is the solvent of choice,
giving 4a in higher yield (Table 2, entries 12–16).
Upon treating ACP 4a with N-iodosuccinimide (NIS) in CH3CN:
H2O, a highly stereoselective iodolactonization took place to give
5b in 64% yield (Scheme 4).12a
To verify the reaction pathway, the isotope labeling experiment
has been performed upon treating 3a–d (see Supplementary data)
under the standard conditions and the desired product 4a–d was
obtained in 92% yield with one deuterium (100% D) incorporated
at the cyclopropyl ring, supporting the hydrogen transferred from
benzylic position to the cyclopropyl ring in product 4 (Scheme 5).
Based on the above investigations, we proposed a plausible
reaction mechanism for this DBU-promoted isomerization in
Scheme 6. Deprotonation of 3 with DBU gives intermediate A,
which undergoes an allylic migration to give intermediate B.
Under the optimized conditions, we next investigated the sub-
strate tolerance of this DBU promoted isomerization of strained
small ring and the results are summarized in Table 3. As can be
seen from Table 3, arylmethylenecyclopropenes 3b and 3c afforded

R. Sang et al. / Tetrahedron Letters 54 (2013) 3591–3594
3593
Table 3
The substrate scope of base-promoted isomerization of cyclopropenes
COOH
CF3
CO2Et
CF3
HCl (4.0 eq)
r.t., 20 min
NaOH (3.0 eq)
THF, r.t., 12 h
R1
R2
R1
R2
DBU
Ar
5a, 91% yield
Ar
4a
THF, r.t.
4
3
Br
Br
Entrya
Yieldb (%)
4
3
NH2
EDCI (2.0 eq)
HDBt (3.0 eq)
(1.5 eq)
CO2Et
CF3
CO2Et
CF3
HN
DMF, 0 °C, 15
min - r.t., 12 h
O
CF3
(E only)
1
2
4a, 92
3a
CO2Me
CO2Me
CO2Me
CO2Me
6a, 45% yield
(E only)
Scheme 3. The further transformation of 4a by hydroxylation.
4b
4c
, 89
3b
3c
CO2Et
CO2Et
(E:Z = 98:2)
O
3
4
CF3
, 65
CO2Et
CF3
O
NIS (1.2 eq)
CO2Et
CF3
I
CH3CN:H2O = 2:1
50 °C, 2 h
n.r.
4a
3d
3e
3f
CO2Et
CF3
CO2Et
CF3
5b, 64% yield
Scheme 4. The further transformation of 4a by the reaction with NIS.
5
6
7
(E only)
4e, 89
4f, 89
4g, 90
CO2Et
CF3
CO2Et
CF3
(E only)
CO2Et
CF3
CO2Et
CF3
(E only)
(E only)
Br
Br
3g
CO2Et
CF3
CO2Et
CF3
8
4h
, 94
3h
3i
CO2Et
CF3
CO2Et
CF3
(E only)
9
Cl
Cl
4i
, 96
F
F
F
F
(E:Z = 1:0.9)
10
4j
, 83
3j
3k
3l
Figure 1. ORTEP drawing of 5a.
O
11
12
n.p.
(100% D)
D D
(100% D)
D
(100% D)
CF3
CF3
D
D
(E only)
CF3
CO2Et
CO2Et
DBU
THF
2a, Rh2esp2
CF3
4l, 96
toluene
H
D (100% D)
a
Standard reaction conditions:
3 equiv) were stirred in 2 mL THF at room temperature within 5 h under argon.
3 (0.2 mmol, 1 equiv) and DBU (0.6 mmol,
1a
-d
3a-d, 97% yield
4a-d, 92% yield
b
Isolated yields. n.r. = no reaction, n.p. = no desired product.
Scheme 5. Deuterium labeling experiments
Reprotonation of intermediate B with DBU-H+ affords the desired
product 4.
+ DBU-H+
EWG
EWG
EWG
EWG
- H+
-
3
4
Ar
Ar
DBU
In conclusion, we have developed an interesting organic base-
promoted isomerization of a variety of arylmethylenecycloprop-
enes to alkylidenecyclopropane under mild conditions, affording
the desired ACPs in good yields with good stereoselectivities in
most cases. As for other type of cyclopropenes, Vidal reported a
similar double-bond migration process to prepare alkylidenecyclo-
propanes under harsh conditions and the desired products were
obtained in low E/Z selectivity (typical case, E: Z = 7:3).14 Further
-
A
B
Scheme 6. A plausible reaction mechanism.
investigation on the mechanistic insights and the extension of this
procedure to the synthesis of other types of ACPs in high stereose-
lectivity is under way in our laboratory.

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R. Sang et al. / Tetrahedron Letters 54 (2013) 3591–3594
3. Small Ring Compounds in Organic Synthesis III; de Meijere, A., Ed.; Springer:
Acknowledgments
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We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), National Basic Research Program of
China (973)-2009CB825300, the Fundamental Research Funds for
the Central Universities and the National Natural Science Founda-
tion of China for financial support (21072206, 20472096,
21102166, 20872162, 20672127, 21121062 and 20732008) and
Mr. Jie Sun for performing X-ray diffraction.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.076.
13. The crystal data of 5a have been deposited in CCDC with number 918658.
Empirical formula: C12H9F3O2; Formula Weight: 242.19; crystal color, habit:
colorless; crystal system: orthorhombic; crystal size: 0.212 ꢀ 0.145 ꢀ 0.089;
lattice parameters: a = 10.2447(19)Å, b = 9.1208(17)Å, c = 23.675(5)Å,
a = 90°,
References and notes
b = 90°,
c
= 90°, V = 2212.2(7)Å3; Space group: Pbca; Z = 8; Dcalc = 1.454 g/cm3;
F000 = 992; Final R indices [I > 2sigma(I)]: R1 = 0.0496; wR2 = 0.1167.
14. Vincens, M.; Dumont, C.; Vidal, M. Tetrahedron 1981, 37, 2683–2693. .
1. For the synthesis of MCPs, please see: (a) Brandi, A.; Goti, A. Chem. Rev. 1998,
98, 589–636; (b) Audran, G.; Pellissier, H. Adv. Synth. Catal. 2010, 352, 575–608.
2. Isaacs, N. S. Phys. Org. Chem.; John Wiley: New York, 1987. p. 283.