Lewis acid-catalyzed [3+4] annulation of 2-(heteroaryl)- cyclopropane-1,1-dicarboxylates with cyclopentadiene

Article abstract of DOI:10.1002/adsc.201000783

A novel Lewis acid-catalyzed [3+4] annulation of 2-(heteroaryl) cyclopropane-1,1-dicarboxylates with cyclopentadiene is reported. This reaction proceeds via an electrophilic attack of the Lewis acid-activated donor-acceptor cyclopropane onto cyclopentadiene followed by Friedel-Crafts intramolecular alkylation of the heteroarene substituent. This is the first general example of reactions of donor-acceptor cyclopropanes wherein the donor substituent serves as a nucleophile. The described annulation represents a convenient approach to bicyclo[3.2.1]octa-2,6-dienes with heteroarenes annulated to C(2)-C(3) bond. Its efficiency was demonstrated for a series of furyl, thienyl, pyrrolyl, benzofuryl, benzothienyl, and indolyl substituted cyclopropanes. Additionally, in the case of 2-(5-methyl-2-furyl)cyclopropane-1,1-diester we observed the predominant formation of product of the [3+4] annulation or the tetracyclic 5,8-methanocyclopenta[a]azulene derivative, depending on the reaction conditions. Copyright

Full text of DOI:10.1002/adsc.201000783

FULL PAPERS
DOI: 10.1002/adsc.201000783
Lewis Acid-Catalyzed [3+4]Annulation of 2-(Heteroaryl)-
cyclopropane-1,1-dicarboxylates with Cyclopentadiene
Olga A. Ivanova,a Ekaterina M. Budynina,a,b Alexey O. Chagarovskiy,a
Alexey E. Kaplun,a Igor V. Trushkov,a,b and Mikhail Ya. Melnikova,*
a
M.V. Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory 1/3, Moscow 119991, Russia
Fax : (+7)-495-939-1814; phone: (+7)-495-939-1316; e-mail: melnikov@excite.chem.msu.ru or melnikov46@mail.ru
Federal Research Center of Pediatric Hematology, Oncology and Immunology, Laboratory of Chemical Synthesis,
b
Leninskii av. 117, Moscow 117997, Russia
Received: October 16, 2010; Revised: January 18, 2011; Published online: May 3, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000783.
Abstract: A novel Lewis acid-catalyzed [3+4]annu- C(2)-C(3) bond. Its efficiency was demonstrated for
lation of 2-(heteroaryl)cyclopropane-1,1-dicarboxy- a series of furyl, thienyl, pyrrolyl, benzofuryl, benzo-
lates with cyclopentadiene is reported. This reaction thienyl, and indolyl substituted cyclopropanes. Addi-
proceeds via an electrophilic attack of the Lewis tionally, in the case of 2-(5-methyl-2-furyl)cyclopro-
acid-activated donor-acceptor cyclopropane onto cy- pane-1,1-diester we observed the predominant for-
clopentadiene followed by Friedel–Crafts intramolec- mation of product of the [3+4]annulation or the tet-
ular alkylation of the heteroarene substituent. This is racyclic 5,8-methanocyclopenta[a]azulene derivative,
the first general example of reactions of donor-ac- depending on the reaction conditions.
ceptor cyclopropanes wherein the donor substituent
serves as a nucleophile. The described annulation
ꢀ
represents
a
convenient approach to bicyclo- Keywords: annulation; C C activation; fused-ring
[3.2.1]octa-2,6-dienes with heteroarenes annulated to systems; heterocycles; small ring systems
Introduction
ACHTUNGTREN[NGNU 3+3]cycloadducts in reactions with some 1,3-dipoles
demonstrating dipolarophile-like properties.[5]
The interest in cyclopropane derivatives constantly
Recently we have found that 2-arylcyclopropane-
grows owing to the unique and specific reactivity of 1,1-dicarboxylates in reactions with 1,3-diphenyliso-
the cyclopropane framework.[1] Nowadays cyclopro- benzofuran and anthracene reveal dienophile-like
panes are considered to be valuable building blocks properties yielding products of [3+4] cycloaddition.[6]
for the construction of various ring systems containing This process is a promising route to seven-membered
small, common, medium and large cycles, as well as cycles and can be considered a homo-version of the
complex annulated, bridged, and spiro-condensed ar- Diels–Alder reaction.
chitectures, etc.[2] Cyclopropanes with electron-donat-
In almost all of the cycloaddition reactions the DA
ing and electron-withdrawing groups at the vicinal cyclopropanes react with unsaturated compounds as
carbon atoms are referred to as donor-acceptor (DA) the synthetic equivalent to 1,3-zwitterionic synthons
cyclopropanes.[3] The presence of both donor and ac- of type A (Figure 1). However, there are some rare
ceptor substituents defines the ambiphilicity of such examples of a different kind of the reactivity of DA
cyclopropanes and makes them ideal substrates not cyclopropanes, wherein a nucleophilic center at ortho-
only for reactions with nucleophiles and/or electro- position of the aromatic ring takes part in the process.
philes but also for cycloaddition processes. Thus, 2-ar- In this case the DA cyclopropane enters the annula-
ylcyclopropane-1,1-dicarboxylates are widely applied tion reaction as a synthetic equivalent to 1,3-zwitter-
for the synthesis of five-membered carbo- and hetero- ionic synthon of type B. Such a reactivity was ob-
cycles via Lewis acid-catalyzed [3+2]cycloadditions.[4] served for cyclopropanes with electron-enriched aro-
In these reactions DA cyclopropanes show 1,3-dipole- matic substituents.[6b,7,8]
like behavior. Moreover, DA cyclopropanes form
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Olga A. Ivanova et al.
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Figure 1. Two possibilities for the ambiphilic reactivity of 2-aryl/heteroaryl-substituted DA cyclopropanes.
Within the framework of our research on the Lewis our method represents the first general convenient
acid-catalyzed interaction of DA cyclopropanes with route to such compounds.
1,3-dienes we have studied the reactivity of cyclopro-
pane-1,1-dicarboxylates, substituted at the C(2) posi-
tion with electron-enriched five-membered heterocy- Results and Discussion
cles, towards cyclopentadiene (1). On the one hand,
this compound is known to be one of the most reac- Reaction of Cyclopentadiene (1) with 2-Heteroaryl-
tive 1,3-dienes. On the other hand, unlike 1,3-diphe- Substituted Cyclopropane-1,1-dicarboxylates 2a–j
nylisobenzofuran[6a] and anthracene,[6b] it is able to
react with the DA cyclopropanes via both 1,2- and We have chosen thienylcyclopropane 2a as a model
1,4-addition reactions resulting in the formation of substrate due to its previously reported high reactivity
new five- or seven-membered rings, respectively. In towards unsaturated compounds in [3+2], [3+3] and
the case of 1,2-addition, a pentalene system should be [3+4]cycloadditions.[6,11] Initially we screened a wide
formed, whereas 1,4-addition should afford the variety of common Lewis acids [TiCl4, SnCl4,
bicyclo
G
TMSOTf, SnACHTUNGTERNNU(G OTf)2, YbACHTNUGTREN(UNNG OTf)3, etc.] as catalysts in the
reaction of 1 with 2a. The use of highly activating
TiCl4, SnCl4, or TMSOTf causes the polymerization of
1, which proceeds much faster than its interaction
with 2a even at ꢀ408C. It is consistent with literature
data that the DA cyclopropanes can initiate a cationic
polymerization of activated alkenes via cyclopropane
ring opening into a zwitterionic intermediate followed
by an attack of its cationic site onto nucleophilic
alkene.[12]
The application of moderately activating Lewis
acids as catalysts allowed us to avoid the polymeri-
zation of the initial substrates in this reaction. Thus,
in the presence of the metal triflates, ZnCl2 and MgI2,
the diene 1 was found to react with 2a yielding prod-
uct 3a. The results of catalyst optimization are pre-
Scheme 1. 1,2- and 1,4-additions as two alternative routes in
the reaction of cyclopentadiene (1) with 2-aryl/heteroarylcy-
clopropanes.
The results presented in this article indicate that in sented in Table 1. The highest yields of 3a were ob-
reactions with cyclopentadiene (1) 2-(heteroaryl)cy- tained when the 1:2a molar ratio was 4:1 and the re-
clopropane-1,1-dicarboxylates 2 demonstrate the reac- action proceeded at room temperature in the pres-
tivity of a 1,3-zwitterionic synthon B yielding hetero- ence of Yb
arene-annulated bicyclo[3.2.1]octadienes. The bicyclo- (Table 1, entries 1 and 2). The less activating Lewis
[3.2.1]octane skeleton is not only a basic framework acids provided lower conversions of the reagents and
of numerous biologically active natural compounds yields of 3a (entries 3–7).
ACHTUTGNERNNUG(OTf)3 or SnACHTUNGTREN(NGUN OTf)2 (5 mol%) in CH2Cl2
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
but also a powerful building block in organic synthe-
Utilization of di-tert-butyl 2-(2-thienyl)cyclopro-
sis. Due to the significant interest in these compounds, pane-1,1-dicarboxylate instead of diethyl ester 1a was
multiple approaches to the construction of this scaf- unsuccessful due to predominant recyclization of the
fold, both saturated and with one or two double parent cyclopropane into a g-butyrolactone deriva-
bonds, have been proposed.[9] However, no general tive.[13]
approach to a preparative synthesis of bicyclo-
[3.2.1]octadienes with heteroarenes annulated to the investigated the reactivity of a series of heteroaryl-
C(2)-C(3) bond has been developed as yet.[10] Thus,
With the optimized reaction conditions in hand, we
ACHTUNGTRENNUNG
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Lewis Acid-Catalyzed [3+4]Annulation of 2-(Heteroaryl)-cyclopropane-1,1-dicarboxylates
Table 1. The screening of moderately activating Lewis acids as catalyst in the reaction of diene 1 with thienylcyclopropane
2a.[a]
Entry
LA (mol%)
Yb(OTf)3 (5)
Reaction time [h]
Solvent
Yield of 3a [%][b] (endo:exo)[c]
1
2
3
4
5
6
7
G
26
3.5
22
2.5
24
24
3
CH2Cl2
CH2Cl2
C2H4Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
76 (83:17)
74 (85:15)
58 (82:18)
47 (73:27)
31 (78:22)
65 (74:26)
25[d]
Sn(OTf)2 (5)
In(OTf)3 (5)
Sc(OTf)3 (5)
Sm(OTf)3 (15)
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ZnCl2 (120)
MgI2 (5)
[a]
A 0.1M solution of 2a in the specified solvent was used.
Isolated yield.
Determined by NMR spectroscopy.
NMR yield.
[b]
[c]
[d]
substituted cyclopropanes 2b–j towards diene
(Table 2).
1
responding [3+4]annulation products 3b, c in good
yields (entries 2 and 3).
The reactions between thiophene derivatives 2b, c
A notable decrease in yield was observed for a
and diene 1 proceeded efficiently resulting in the cor- furan derivative 2d (Entry 4). We presume that this
Table 2. The reaction of 2-(heteroaryl)cyclopropane-1,1-dicarboxylates 2a–j with cyclopentadiene (1) under optimized condi-
tions.[a]
Entry
1
2
R
Ar
LA (mol%)
Reaction time [h]
Product 3
Yield 3 [%][b]
(dr endo:exo)[c]
2a
Et
Yb
N
26
76 (83:17)
81 (85:15)
68 (80:20)
2
3
2b
2c
Me
Me
Yb
N
22
24
SnACTHNUTRGEN(NUG OTf)2 (5)
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Table 2. (Continued)
Entry
2
R
Ar
LA (mol%)
Reaction time [h]
Product 3
Yield 3 [%][b]
(dr endo:exo)[c]
4
2d
Et
Yb(OTf)3 (5)
23
33 (50:50)
5
2e
Me
Yb(OTf)3 (5)
3
53 (77:23)[d]
Yb
ACHTUNGTRENNUNG
6
7
2f
2g
Me
Me
24
2
traces[e]
Sn
ACHTUNGTRENNUNG
Sn
N
56 (>95:5)
8
9
2h
Me
Sn
Sn
G
14
72 (75:25)
2i
2j
Me
Me
24
72 (92:8)
10
Yb
2.5
67 (63:37)
[a]
A 0.1M solution of 2 in CH2Cl2 was stirred with the appropriate catalyst and a 4-fold excess of 1 at room temperature,
except for 2e; the reaction with 2e was performed at ꢀ60!08C.
Isolated yield.
Determined by NMR spectroscopy.
Compound 3e (53%) was formed together with 4 (18%) (see text).
Polymeric products are formed predominantly.
[b]
[c]
[d]
[e]
33% yield is caused by a low stability of monosubsti- uct 4 as a result of the interaction of 2e with two cy-
tuted furans in the presence of Brønsted and Lewis clopentadiene molecules (see below).
acids. 2,5-Disubstituted furans are generally more
The low stability of N-methylpyrrolyl-substituted
stable towards electrophiles. So, we examined the re- cyclopropane 2f prevents its transformation into the
action of (5-methylfuryl)cyclopropane 2e with 1 corresponding adduct 3f (entry 6). Fortunately, the
(entry 5). Indeed, the corresponding product 3e was more stable related cyclopropane 2g with N-tosylpyr-
obtained in 53% yield. In this case the reaction was role as the donor substituent was found to smoothly
accompanied by the formation of an unusual by-prod- afford product 3g in 56% yield (entry 7).
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Lewis Acid-Catalyzed [3+4]Annulation of 2-(Heteroaryl)-cyclopropane-1,1-dicarboxylates
Scheme 2. Proposed mechanism for the interaction between diene 1 and 2-(heteroaryl)cyclopropane-1,1-dicarboxylates 2.
Finally, [3+4]annulated products 3h–j were found the diene 1 affording intermediate C. This intermedi-
to be readily formed from the corresponding cyclo- ate has at least two nucleophilic sites, namely, malonyl
propanes 2h–j containing benzannulated heterocyclic anion and ortho-position of the heterocycle. However,
substituents (entries 8–10).
Reaction of 1 with 2b, d, e, j is efficiently catalyzed reaction, since the formation of [3+4]cycloadducts
with Yb(OTf)3. Conversely, for cyclopropanes 2c, g, h, was not observed in these cases at all. Therefore, an
i, the application of Yb(OTf)3 in this reaction results electrophilic attack of allylic cation in C-1,4 onto the
only the aromatic nucleophilic site takes part in the
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
in low (ca. 30%) conversion. A moderate heating and ortho-position of heterocycle accomplishes the pro-
use of higher catalyst/substrate ratio does not increase cess and gives rise to the formation of the bicyclo-
the yield of 3 but initiates the polymerization process.
The full conversion of reagents and good yields of 3c,
g, h, i were achieved only when cyclopropanes 2c, g,
ACHTUNGTRNE[NUNG 3.2.1]octadiene scaffold of 3.
h, i reacted in the presence of the more activating NMR Spectral Studies and Configurational
Sn(OTf)2. Assignments
The interaction of 1 with 2 proceeds chemoselec-
ACHTUNGTRENNUNG
tively via 1,4-addition of 1 to the DA cyclopropane as To elucidate the structure of products 3, the careful
synthon B and yields polycyclic compounds 3 as mix- analysis of 1H and 13C NMR spectra and their compar-
tures of two diastereomers (Table 2). Generally, the ison with the described spectral data of related sys-
diastereoselectivity of the reaction correlates well tems was carried out. Herein we present a summary
with the electron-donating ability of heteroaromatic of the structural characterization of 3.
1
substituent in the starting DA cyclopropanes 2, i.e.,
The H and 13C NMR spectra of 3 were assigned
the cyclopropanes with more electron-donating hetar- using 2D COSY, HETCORR, HMBC and NOESY
enes demonstrate lower stereoselectivity in this annu- NMR techniques. The NMR data revealed the forma-
ꢀ
lation. The possible mechanism for the formation of tion of a bridged framework, containing two CH
products 3 is shown in Scheme 2. The coordination of CH2 CH systems in 3 that unambiguously proves
ꢀ
the Lewis acid to the acceptor group(s) of 2 leads to that: a) the DA cyclopropanes 2 react as synthon B
polarization and lengthening of the C(1) C(2) bond. but not A (Figure 1) and b) the conjugated diene 1
ꢀ
The resulting electrophilic center at C(2) atom attacks reacts as a 4p-component (Scheme 1).
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3
tively, that correspond to the expected J7,8 values of
5.1 and 0.9 Hz.
In several cases the measuring of coupling con-
stants for major isomers of 3 was hindered by a nota-
ble overlapping of the resonances corresponding to
the H-7 and H-8 atoms. Fortunately, the signals of the
H-7 and H-8 atoms for major isomers of 3b, c, j are
3
clearly observed. The values of J7,8 for these com-
pounds were determined to be 4.7–5.3 Hz which is in
accordance with an exo-configuration of H-8 and an
endo-configuration of the side-chain. For minor iso-
mers in most cases the problem of overlapping does
Figure 2. Representative NOE responses for the endo-
isomer of 3b.
ꢀ
ꢀ
The bridged CH CH2 CH fragment was character- not emerge and signals and coupling constants can be
3
ized by the following patterns. The characteristic identified. For minor isomer of 3a J7,8 is not observa-
2
value of the J coupling constant for the protons of ble, i.e., ꢁ1 Hz. However, in the cases of 3b, e, h the
3
bridged CH2 group is ca. 10 Hz. The signal of H-9syn corresponding J7,8 values were measured and
(enumeration is given according to Figure 2) ap- amounted to 1.0–1.1 Hz. Therefore, the major diaste-
peared as a doublet with notable line broadening, i.e., reomers of 3 were assigned to endo-isomers, while the
3Jꢁ1 Hz, whereas for the H-9anti proton the values of minor diastereomers were assigned to exo-isomers.
3
3J9anti,4 and J9anti,7 are higher (4.3–4.9 Hz). Moreover,
Our conclusions were confirmed with the NOESY
intensive cross-peaks are observed for the correlations spectrum of 3b. The strong NOE between H-9syn and
between H-9anti and H-4, H-9anti and H-7 in the COSY H-8 in the major isomer is in accordance with the pre-
NMR spectra. The low-field aliphatic resonances at dominant formation of the endo-product. The repre-
dC =38–44 ppm were assigned to the carbon atom of sentative NOE responses for endo-3b are summarized
this bridged CH2 group. These results are in full ac- in Figure 2.
cordance with the literature data for the similar com-
pounds containing the bicyclo
ACHTUNGERTN[NUNG 3.2.1]octadiene scaf-
fold.[14]
The Origin of Chemo- and Stereoselectivity
ꢀ
ꢀ
The second CH CH2 CH fragment consists of a
C(8)H methine group and a side-chain attached to it. The high chemoselectivity and predominant endo-se-
1
The H NMR spectra reveal the full coupling patterns lectivity could be explained in terms of charge trans-
2
ꢀ
for the CH CH2 fragment protons, namely J of ca. fer precomplex formation. We believe the reaction is
3
14 Hz and J of ca. 5–7 and 8–11 Hz, which are typical initiated by a coordination of Lewis acid to the ac-
for an aliphatic chain.
ceptor group(s) of 2, as in the absence of catalyst the
Our assignment of structure 3 is also supported by reaction does not proceed at all. The coordination of
the fact that a new signal of a quaternary carbon Lewis acid causes a significant increase of the cyclo-
ꢀ
atom is observed in the aromatic region of the propane C(1) C(2) bond polarization that might
13C NMR spectra instead of the carbon atom reso- result in a configurationally stable intimate ion pair
nance of a methine group.
formation. The electron-enriched heterocyclic sub-
To determine the relative configuration of the stituent provides stabilization of an electrophilic site
major and minor isomers of 3, we estimated the vici- at C(2) that leads to delocalization of developing pos-
nal coupling constants for the protons of the bicyclo- itive charge to heterocycle, i.e., to its electron defi-
ACHTUNGTRENNUNG[3.2.1]octadiene fragment. The coupling patterns that ciency. Diene 1 approaches the electrophilic site at
are important for the stereochemical characterization C(2) in such a way as to be in parallel with the heter-
of diastereomers of 3 are 3J7,8exo and 3J7,8endo. According oarene ring as this orientation provides interaction of
to literature data for bicycloACTHNUTRGNE[NUG 3.2.1]octadienes, the di- the electron-enriched conjugated p-system of 1 with
hedral angle between protons H-7 and H-8exo approxi- the electron-depleted heterocyclic substituent result-
mately equals 408, whereas the dihedral angle be- ing in a p-p* donor-acceptor complex. Then the diene
tween protons H-7 and H-8endo is ca. 608. Thus, in ac- 1 as a nucleophile attacks the C(2) atom of 2 that
cordance with the Karplus rule, the larger coupling leads to the formation of new zwitterions D with in-
3
constant J7,8 of ca. 5.0–5.5 Hz was observed for the version at C(2) position.[4g,5b,d,11d,15] During this step
3
endo-orientation of substituent (exo-proton) and J7,8 two stereogenic centers are formed which determine
was 0–2 Hz for the exo-isomer (endo-proton).[14] We unambiguously the stereochemistry of the final prod-
have also performed ab initio geometry optimization uct 3. A Re-face nucleophilic attack leading to endo-3
of 3b using the MP2/6-311G method.[13] According to minimizes the steric interaction, while in the case of
ꢀ
ꢀ
ꢀ
our calculations, the H C(7) C(8) H dihedral angles an Si-face attack leading to exo-3 steric repulsions
for the endo- and exo-isomers are 458 and 788, respec- arise between the heteroaryl substituent and one of
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Lewis Acid-Catalyzed [3+4]Annulation of 2-(Heteroaryl)-cyclopropane-1,1-dicarboxylates
Scheme 4. Reaction of diene 1 with (5-methyl-2-furyl)cyclo-
propane 2e.
reaction conditions and 1:2e molar ratio. The best
yields of 3e were obtained when an equivalent of 2e
was added to four equivalents of 1 in CH2Cl2 at
ꢀ608C in the presence of 5 mol% of the catalyst fol-
lowed by slow warming of resulting solution up to
08C for 3 h. These conditions provide a 53% yield of
3e and an 18% yield of 4 (Table 2). Whereas, a five-
fold excess of 1 and rapid warming up to room tem-
perature for 1 h affords 4 in 63% yield (Scheme 4).
The addition order does not influence the yields of 3e
and 4.
The reaction of 2e with two molecules of 1 pro-
ceeds in high chemo-, regio- and stereoselective
manner and affords 4 as a single diastereomer con-
taining six stereogenic centers. The composition and
structure of 4 were unambiguously proved by an ele-
mental analysis and 1D and 2D NMR spectroscopy.
1H and 13C NMR data clearly revealed the presence
of the bicycloACHTUNTRGNEUNG[3.2.1]octadiene framework in 4, which
is similar to the analogous motif in 3e. A careful anal-
ysis of the aromatic region disclosed that upfield reso-
nances corresponding to the furan moiety are absent.
Instead, a low-field resonance at dC =210.2 ppm is ob-
served in the 13C NMR spectrum, which was assigned
to a carbon atom of the arising C=O group. NMR
data also indicate that the tetracyclic skeleton of 4 is
Scheme 3. A model for the observed chemo- and stereose-
lectivity in the formation of 3.
H-5 atoms of diene 1. The formation of the bicyclo- formed as a result of annulation of the second mole-
ꢀ
[3.2.1]octane skeleton is ruled by orbital interactions cule of 1 via the C(1) C(2) bond. Among these evi-
between the allylic cation system and the heteroarene dences are: 1) the absence of characteristic patterns
2
ring in intermediates D-I and D-II. Whereupon the for the second bridged motif; 2) the J3,3 value of
exceptional chemoselectivity can be explained by the 16.9 Hz that dramatically differs from J=ca. 10 Hz
2
close proximity of two reaction centers in D-I (or D- for H atoms of bridged CH2 group; 3) intensive cross-
II), i.e., allylic cation and nucleophilic ortho-position peaks for correlations between H atoms of C(1)H=
of heterocycle. Despite the higher nucleophilicity of C(2)H fragment and methylene C(3)H2 and methine
the malonyl anion,[16] its attack in this case is not com- C(9a)H groups in the COSY NMR spectrum. The ste-
petitive (Scheme 3).
reochemical assignment for 4 was made using 2D
NOESY 1H NMR spectroscopy. All representative
NOE responses are shown in Figure 3.
Reaction of Cyclopentadiene (1) with (5-Methyl-2-
furyl)cyclopropane (2e)
The indicated relative stereochemistry of 4 allowed
us to propose the following mechanism for its forma-
tion (Scheme 5). The interaction of cyclopropane 2e
We pointed out above that in the reaction between 2e with the first molecule of diene 1 leads to zwitterion
and 1 a tricyclic adduct 3e was obtained as major E with an endo-orientation of substituent. Such a ste-
product together with minor tetracycle 4, which was reochemical result is in accordance with the predomi-
formed via interaction of 2e with two equivalents of nant formation of endo-3e (Table 2), since E is a
1. The yields of 3e and 4 depend significantly on the direct precursor of 3e. The second molecule of 1 at-
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Conclusions
In summary, we have developed a powerful general
approach to heteroarene-fused bicyclo-
[3.2.1]octadienes via a novel Lewis acid-catalyzed
AHCTUNGTREG[NNNU 3+4]annulation of 2-(heteroaryl)cyclopropane-1,1-
AHCTUNGTRENNUNG
diesters to cyclopentadiene. In this process DA cyclo-
propanes can be viewed as the synthetic equivalent to
an unusual ambiphilic synthon containing an electro-
philic site at the C(2) atom of the small ring and a nu-
cleophilic site at the ortho-position of the heterocycle,
Figure 3. Representative NOE responses for adduct 4.
tacks the cationic center in E followed by a new cy- whereas cyclopentadiene reacts as a 4p-component.
clopentane ring closure and furan ring opening to In general, the reaction can be represented as a se-
afford 4. Similar recyclizations are quite typical for quence of electrophilic processes: an interaction of
2,5-disubstituted furans[17] whereas they are much less the cyclopropane electrophilic center with cyclopenta-
efficient for other heterocycles tested here. The rela- diene followed by an intramolecular Friedel–Crafts al-
tive configuration of stereogenic centers in the final kylation at the ortho-position of the heteroarene sub-
product 4 indicates that diene 1 approaches E from stituent. The high chemoselectivity and predominant
the exo-surface, probably, due to the lower steric re- endo-stereoselectivity of the reaction might be rea-
pulsion caused by the bridged CH2 group in compari- soned by the initial formation of a p-p* complex be-
son to those from the bulky CH2CHACHTNUTRGENNG(U CO2Me)2 sub- tween cyclopentadiene and the electron-depleted het-
stituent. Then attack of the cationic center in E onto eroarene moiety in the Lewis acid-activated DA cy-
the Re-face of 1 occurs, while the alternative Si-face clopropane.
approach is shielded by exo- and bridged H atoms in
The proposed procedure provides a more conven-
E. It is noteworthy that diene 1 reacts with E as a 2p- ient and efficient preparation of heteroarene-fused
but not as a 4p-component. The possible reason is a bicycloACHTUNTRGNEUNG[3.2.1]octadienes in comparison with the pho-
higher thermodynamic stability of 4 in comparison to tochemical approach to these systems.[10e] Additional-
the isomeric doubly bridged products. Indeed, our ab ly, the simple access to the numerous parent 2-(heter-
initio calculations show that 4 is 25–26 kJmolꢀ1 more oaryl)cyclopropane-1,1-diesters via standard Knoeve-
stable than the corresponding isomers formed via 1,4- nagel/Corey–Chaykovsky reactions allows for an easy
addition of the second cyclopentadiene molecule.[13]
extension of the diversity of the desired products.
Therefore, the formation of 4 is an unusual electro- These compounds can be applied as useful building
philic cascade resulting in the formation of four new blocks in various transformations due to the presence
ꢀ
C C bonds and three new cycles. This reaction pro- of an easily modified double bond, a heteroaromatic
ceeds with an exceptional stereoselectivity: despite fragment and a malonyl moiety. The cage structure of
the formation of six stereocenters during this transfor- these molecules provides high stereoselectivity for the
mation, compound 4 was obtained as a single diaste- further transformations. Thus, the proposed strategy
reomer.
for the construction of heteroarene-fused bicyclo-
Scheme 5. Proposed mechanism for the reaction of diene 1 with (5-methyl-2-furyl)cyclopropane 2e.
1132
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1125 – 1134

Lewis Acid-Catalyzed [3+4]Annulation of 2-(Heteroaryl)-cyclopropane-1,1-dicarboxylates
A
target-oriented synthesis.
We thank the Russian Foundation of Basic Research (Project
09-03-00244-a) for financial support of this work.
Experimental Section
Synthesis of Dimethyl [(7,10-Dihydro-6H-7,10-meth-
anobenzo[b]cyclohepta[d]furan-6-yl)methyl]-
malonate (3h); Typical Procedure
References
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The solution of cyclopropane 2h (356 mg, 1.3 mmol), cyclo-
pentadiene (1) (340 mg, 0.43 mL, 5.2 mmol), and SnACTHNUTRGNEUNG(OTf)2
(27 mg, 0.065 mmol) in CH2Cl2 (10 mL) was stirred under an
argon atmosphere in the presence of 4ꢁ molecular sieves
for 14 h. The reaction progress was monitored by TLC and
1H NMR. The solvent was evaporated under reduced pres-
sure. The residue was purified by column chromatography
(SiO2, hexane:CHCl3, 1:1, as eluent) to afford 3h as a yellow
oil; yield: 318 mg (72%); Rf =0.63 (ethyl acetate:petroleum
ether; 1:3); endo:exo 75:25. IR (nujol): n=2965, 2930, 2875,
1735, 1606, 1465, 1380, 1140, 1120, 980, 900, 845, 820,
730 cmꢀ1; The enumeration in NMR assignments does not
correspond to IUPAC name. It is given according to
Figure 2 for simple comparison with data for other adducts
1
3. H NMR (CDCl3, 600 MHz for endo-isomer): d=1.92 (d,
2
3
2J9,9 =9.9 Hz, 1 H, Hsyn-9), 2.10 (ddd, J1’,1’ =14.0 Hz, J1’a,2’
=
3
7.0 Hz, J1’a,8 =8.3 Hz, 1H, Ha-1’), 2.29–2.35 (m, 2H, Hb-1’,
3
Hanti-9), 3.16–3.21 (m, 2H, H-7, H-8), 3.56 (dd, J4,5 =2.9 Hz,
3J4,9anti =4.3 Hz, 1H, H-4), 3.79 (s, 3H, CH3O), 3.82 (s, 3H,
CH3O), 4.02 (dd, 3J2’,1’a =7.0 Hz, 3J2’,1’b =8.1 Hz, 1H, H-2’),
5.77 (dd, 3J6,7 =2.8 Hz, 3J6,5 =5.7 Hz, 1H, H-6), 6.60 (dd,
3J5,4 =2.9 Hz, 3J5,6 =5.7 Hz, 1H, H-5), 7.16–7.20 (m, 2H),
7.39–7.42 (m, 1H), 7.48–7.50 (m, 1H); 1H NMR (CDCl3,
600 MHz for exo-isomer): d=1.95 (d, 2J9,9 =10.1 Hz, 1H,
2
3
3
Hsyn-9), 2.06 (ddd, J9,9 =10.1 Hz, J9,4 =4.3 Hz, J9,7 =4.6 Hz,
1 H, Han3ti-9), 2.29–3.35 (m, 1H, Ha-1’), 2.50 (ddd, J1’,1’
=
2
3
14.0 Hz, J1’b,8 =6.4 Hz, J1’b,2’ =8.7 Hz, 1H, Hb-1’), 2.72 (ddd,
3J8,7 =1.1 Hz, 3J8,1’b =6.4 Hz, 3J8,1’a =8.0 Hz, 1H, H-8), 2.90
(ddd, 3J7,8 =1.1 Hz, 3J7,36 =3.1 Hz, 3J7,9anti =4.6 Hz, 1H, H-7),
3
3.62 (dd, J4,5 =2.8 Hz, J4,9anti =4.3 Hz, 1H, H-4), 3.76 (s, 3H,
3
3
CH3O), 3.83 (s, 3H, CH3O), 4.05 (dd, J2’,1’a =6.4 Hz, J2’,1’b
=
3
3
8.7 Hz, 1H, H-2’), 5.83 (dd, J6,7 =3.1 Hz, J6,5 =5.5 Hz, 1H,
3
3
H-6), 6.44 (dd, J5,4 =2.8 Hz, J5,6 =5.5 Hz, 1H, H-5), 7.16–
7.20 (m, 2H), 7.39–7.42 (m, 1H), 7.48–7.50 (m, 1H); 13C
NMR (CDCl3, 150 MHz for endo-isomer): d=28.82
[C(1’)H2], 35.83 [C(4)H], 37.81 [C(8)H], 43.50 [C(7)H],
44.38 [C(9)H2], 49.91 [C(2’)H], 52.68 (2ꢂCH3O), 111.18
(CH), 118.19 (CH), 120.34 (C), 122.31 (CH), 122.79 (CH),
126.60 (C), 128.45 [C(6)H=], 144.31 [C(5)H=], 152.98 (C),
153.27 (C), 168.69 (CO2Me), 169.93 (CO2Me); 13C NMR
(CDCl3, 150 MHz for exo-isomer): d=33.60 [C(1’)H2], 35.87
[C(4)H], 36.73 [C(8)H], 38.86 [C(9)H2], 44.35 [C(7)H],
50.04 [C(2’)H], 52.68 (2ꢂCH3O), 111.18 (CH), 118.28 (CH),
120.20 (C), 122.29 (CH), 122.92 (CH), 126.58 (C), 130.17
[C(6)H=], 141.78 [C(5)H=], 153.27 (C), 153.38 (C), 169.74
(CO2Me), 169.91 (CO2Me); GC-MS: m/z (%)=340 (5)
[M]+, 209 (14), 208 (100), 207 (39), 181 (11), 169 (7), 168
(16), 165 (10), 152 (9), 115 (5), 59 (17); anal. calcd. for
C20H20O5: C 70.57, H 5.92; found: C 70.82, H 5.93.
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Adv. Synth. Catal. 2011, 353, 1125 – 1134